Segunda Opinion Neurológica

treatment of Multiple System Atrophy Using Intravenous Immunoglobulin

2013-03-26T16:10:00.001-07:00

treatment of Multiple System Atrophy Using Intravenous Immunoglobulin

Peter Novak, Arlene Williams, Paula Ravin, Omar Zurkiya, Amir Abduljalil, Vera Novak

BMC Neurol. 2012;12(131)

Abstract and Introduction

Abstract

Background Multiple system atrophy (MSA) is a progressive neurodegenerative disorder of unknown etiology, manifesting as combination of parkinsonism, cerebellar syndrome and dysautonomia. Disease-modifying therapies are unavailable. Activation of microglia and production of toxic cytokines suggest a role of neuroinflammation in MSA pathogenesis. This pilot clinical trial evaluated safety and tolerability of intravenous immunoglobulin (IVIG) in MSA.

Methods This was a single-arm interventional, single-center, open-label pilot study. Interventions included monthly infusions of the IVIG preparation Privigen®, dose 0.4 gram/kg, for 6 months. Primary outcome measures evaluated safety and secondary outcome measures evaluated preliminary efficacy of IVIG. Unified MSA Rating Scale (UMSARS) was measured monthly. Quantitative brain imaging using 3T MRI was performed before and after treatment.

Conclusions Treatment with IVIG appears to be safe, feasible and well tolerated and may improve functionality in MSA. A larger, placebo-controlled study is needed.Results Nine subjects were enrolled, and seven (2 women and 5 men, age range 55–64 years) completed the protocol. There were no serious adverse events. Systolic blood pressure increased during IVIG infusions (p<0 .05="" 19.0="" 1="" 23.3="" 23.9="" 26.1="" 5="" 6.0="" a="" activities="" all="" and="" because="" comparing="" daily="" different="" dropped="" from="" functions="" imaging="" improved="" in="" living="" motor="" mr="" non-threatening="" not="" of="" out="" p="" participants="" post-treatment.="" post-treatment="" pre-="" pre-treatment="" rash.="" results="" significantly="" skin="" study="" subjects="" the="" to="" two="" umsars-i="" umsars-ii="" unchanged="" usmars-ii="" vs.="" was="" were="" worsened="">

Beyond Amyloid Beta: A New Alzheimer Disease Biomarker?

2013-03-26T16:08:00.000-07:00

Medscape Medical News from the:

American Academy of Neurology (AAN) 65th Annual Meeting

Beyond Amyloid Beta: A New Alzheimer Disease Biomarker?

An AAN Poster Brief

Bret Stetka, MD, Jacques Hugon, MD, PhD

DisclosuresMar 25, 2013

Editor's Note:

This year's American Academy of Neurology Annual Meeting featured an Integrative Neuroscience Session looking at advances in, and the potential role of, biomarkers in Alzheimer disease (AD). Following the session, Medscape spoke with Jacques Hugon, MD, PhD, Professor of Neurology at Saint-Louis Lariboisière Fernand-Widal Hospital in Paris, France, about a biomarker with the potential to aid in AD diagnosis. It's not amyloid beta or tau.

Medscape: Dr. Hugon, what can you tell us about PKR?

Dr. Hugon: PKR is a kinase that has been shown to play a role in recognizing and signaling viral infection, but its activity has also been shown to be altered in several neurologic disorders in which it negatively modulates memory.^[1] Once overactivated, PKR becomes a toxic kinase. As we have shown in our study,^[2] PKR accumulates in the brain of patients with AD and can induce the death of neurons. We have seen that the PKR level in the cerebrospinal fluid (CSF) and the activity of PKR in the brain are highly elevated in patients with AD compared with non-AD patients. Our study showed that the mean level of PKR and phosphorylated PKR in the CSF was 300% higher in patients with AD. Sensitivity was 91.1% and the specificity was 94.3%.

In addition, patients with mild cognitive impairment already have high levels of total CSF PKR and phosphorylated PKR. So, the final story is that the level of PKR in those with high levels of the kinase can predict the degree of cognitive decline. Patients with high levels of PKR in the CSF have been followed for more than 2 years in our department, and we found a clear correlation between the levels of phosphorylated PKR and cognitive decline based on repeated mini-mental state exams. The patients with high CSF levels of PKR have had a more rapid cognitive decline.

Medscape: From your data it looks like PKR levels correlate with tau levels, What are the implications of this finding?

Dr. Hugon: Yes, they do correlate with tau levels. PKR can indirectly induce the phosphorylation of tau, so the two may be linked. PKR can also control the production of amyloid beta.

Dr. Hugon: Yes. This could definitely end up being a new biomarker. We performed CSF evaluations in my department rather frequently and now we have collected several hundreds of biomarker samples -- including PKR -- in patients with mild cognitive impairment and AD.Medscape: Amyloid beta, tau, and phosphorylated tau increasingly are being tested as biomarkers of AD, particularly in research and academic settings. Could PKR ultimately be added to the list?

This procedure is a major part of our practice, especially in young patients. In addition, we are testing potential PKR antagonists in preclinical settings. We have shown earlier that blocking PKR can attenuate amyloid-beta-induced neuronal death in cell cultures. PKR is a possible new target to alter the course of the disease and to possibly restore memory deficits in affected patients.

Coronary Calcium Predicts Stroke Risk

2013-03-01T18:55:00.000-08:00

Coronary Calcium Predicts Stroke Risk

Sue Hughes

Mar 01, 2013

Coronary artery calcium (CAC) is an independent predictor of future stroke events in the general population, results of a new study show.

In the trial, published online February 28 in Stroke, CAC predicted stroke in both men and women and was more predictive in persons younger than 65 years than in older individuals. It was also independent of the presence of atrial fibrillation and Framingham risk factors.

It was most effective in discriminating stroke risk specifically in persons in low (<10 20="" and="" categories="" framingham="" intermediate="" investigators="" p="" report.="" risk="" to="">

"When a patient stands in front of us we can find out about their risk factors such as diabetes, blood pressure et cetera, but we don't know much about their extent of vascular disease," lead investigator, Dirk M. Hermann, MD (University Hospital Essen, Germany), commented to Medscape Medical News. "We know that CAC is a good predictor of MI [myocardial infarction], but we wanted to know if it is a good predictor of stroke as well, and we found that it was. This study shows that the risks go together. If a patient is at risk of MI, they are also at risk for stroke. We now have a test that can tell us if a patient is at risk of 2 very common conditions."

"That CAC, as we now have shown, is able to predict stroke events independent of established risk factors, making this marker promising for risk stratification not only in the hands of cardiologists but also in the hands of neurologists," the authors conclude.

"This study suggests that broad CAC screening of the population may be the way forward," Dr. Hermann said. Still, he added, "We have to think carefully about whether this is feasible. We don't recommend this at the moment because of the radiation risk." However, he points out that imaging techniques are rapidly evolving and the ability to see disease processes in the body is improving "dramatically."

"New multislice CT [computed tomography] is associated with much lower radiation, so perhaps in the future broad screening programs will be possible. Then it will be public health question as to whether it is cost-effective," he said. "Even cardiologists are not routinely doing CAC screening at the moment, but it is starting to happen in certain centers practicing preventative medicine. This is modern medicine."

Heinz Nixdorf Recall Study

For the current study, 4180 persons aged 45 to 75 years from the population-based Heinz Nixdorf Recall study without previous stroke, coronary heart disease, or myocardial infarction, were evaluated for stroke events over an average 94 months.

Cox proportional hazards regressions were used to examine CAC as a stroke predictor in addition to established vascular risk factors (age, sex, systolic blood pressure, low-density lipoprotein, high-density lipoprotein, diabetes mellitus, smoking, and atrial fibrillation).

During the follow-up period 92 incident strokes occurred (82 ischemic and 10 hemorrhagic). Patients who sustained a stroke had significantly higher CAC values at baseline (median, 104.8) than those without stroke (11.2). In a multivariable Cox regression, log10(CAC+1) was an independent stroke predictor, with a hazard ratio of 1.52.

CAC was most predictive in patients at relatively low cardiovascular risk and in younger rather than older patients.

"That's probably because higher-risk and older patients have many more risk factors so the CAC result will become less relevant," Dr. Hermann speculated. "Whereas in younger and lower risk patients, there's nothing else to tell you that this person is at risk so it is more useful."

In the paper, the authors write, "These observations indicate that among cohorts without apparent risk, subjects exist that nonetheless exhibit a high stroke incidence. On the basis of our data, CAC is suitable to identify those subjects."

Dr. Hermann has disclosed no relevant financial relationships.

Stroke. Published online February 28, 2013. Abstract

Eye Tests May Predict Alzheimer's Risk

2013-03-01T18:50:00.003-08:00

Eye Tests May Predict Alzheimer's Risk

Deborah Brauser

Mar 01, 2013

Abnormalities in retinal vascular parameters (RVPs) may indicate increased amyloid plaque in the brain and can serve as biomarkers for preclinical Alzheimer's disease (AD), new research suggests.

Findings from the Australian Imaging, Biomarkers, and Lifestyle (AIBL) Flagship Study of Ageing showed that participants with AD had several significantly different RVPs, including narrower veins and a significantly higher arteriole-to-venule ratio (AVR), than their peers without AD.

In additional analysis of just the participants without an AD diagnosis, Pittsburgh compound B positron emission tomography (PiB-PET) imaging showed that participants who had high neocortical plaque burden also had some of these RVP changes, possibly representing preclinical AD.

"This is the first study to investigate retinal blood vessel changes with respect to amyloid plaque burden in the brain," write the investigative team, led by Shaun Frost, a PhD candidate at the Commonwealth Scientific and Industrial Research Organization in Perth, Australia.

"Models combining RVPs perform well at distinguishing diagnosed AD patients from healthy controls," they add.

The researchers note that because PET and magnetic resonance imaging scans can be expensive to administer and are not widely available, these eye tests may represent a simpler, noninvasive option — although not as a stand-alone measure.

"Retinal photographic analysis shows potential as an adjunct for early detection of AD or monitoring of AD-progression or response to treatments," they write.

The study was published online February 26 in Translational Psychiatry.

Difficult Diagnosis

"The primary neuropathological hallmark of [AD] is the presence of cerebral amyloid deposits (plaques)," write the investigators.

"Although post-mortem examination of the brain is required for confirmation of AD, a diagnosis of 'probable AD' can be made in patients, fulfilling the criteria set down by the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association," they add.

However, a conclusive diagnosis of probable AD only comes after neurologic damage has already occurred in these patients. Therefore, there is a great need for ways to detect the condition before irreversible damage occurs.

Because the retina "is a developmental outgrowth of the brain," the investigators sought to assess whether pathologic retinal vascular changes could be used as a potential screening measure for AD.

For this analysis, the investigators evaluated a cohort of the AIBL study participants, consisting of 25 with probable AD (52% women; mean age, 72.4 years) and 123 of their healthy peers (55% women; mean age, 71.6 years).

Digital retinal color photographs for these individuals were taken, and semiautomatic software was used to evaluate for 19 RVPs, such as width and branching of retina vessels. In addition, AVR was calculated for each participant on the basis of central retinal arterial to venular equivalent thickness.

Additional analysis of RVPs in relation to neocortical plaque burden, as shown with PiB-PET scans, was conducted for 45 of the healthy peers.

Significant Abnormalities

Results showed significant between-group differences in 13 of the RVPs measured.

These included lower central retinal arteriolar and venular equivalent calibers (P = .01 and P < .001, respectively), fractal dimension of both the arteriolar and venular networks (P = .008 and P < .001, respectively), venular curvature tortuosity (P = .02), and number of first branching arterioles and venules (P = .007 and .006, respectively) for those with probable AD vs those without.

In addition, the participants with probable AD had significantly elevated zone B arteriolar and venular standard deviations (P = .001 and .002, respectively), venular branching coefficient (P = .02), arteriolar and venular branching asymmetry factor (P = .02 and .03, respectively), and arteriolar length-to-diameter ratio (P = .03).

In the imaging data analysis, the subgroup of healthy volunteers with high levels of amyloid plaque (as shown by PET-PiB-measured standardized uptake value ratio greater than 1.5) had higher venular branching asymmetry factor (P = .01) and arteriolar length-to-diameter ratio (P = .02) compared with those who had lower levels of amyloid plaque.

These 2 parameters were also larger in patients with AD compared with those with high levels of amyloid plaque, "hence these results are consistent with the hypothesis that RVP changes may precede AD diagnosis," write the study authors.

There were also significantly more APOE ε4 carriers in the AD group vs the non-AD group (P = .02) and in those with high levels of amyloid plaque vs those with lower levels (P = .04).

An Even Better Biomarker?

"I think this is a good study, but I wish they had looked at another subgroup of patients," Gilbert T. Feke, PhD, senior research associate in the Department of Ophthalmology at Massachusetts Eye and Ear Infirmary in Boston, told Medscape Medical News.

"They looked at control subjects and those with Alzheimer's, but they didn't have an in-between group."

Dr. Feke, who was not involved with this research, presented preliminary findings from a similar study in a poster presentation at the 2011 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO).

His investigative team examined 7 elderly participants with probable AD, 10 with mild cognitive impairment (MCI), and 17 with normal cognition.

Results showed that the AD group had significantly narrower retinal veins than the other 2 groups, as well as decreased retinal blood flow. In addition, the MCI group had significantly lower blood flow and blood speed than those with normal cognition.

"This interim report suggests that hemodynamic abnormalities may precede neural loss in the retina in cognitively impaired subjects," said the researchers in the presentation.

"We found that decrease in vessel diameter doesn't happen until people actually have [AD]. Those with MCI didn't show it. Instead, they showed the reduction in blood speed and flow. So that puts a bit of a damper on relying on vessel diameter measurements to be the sole biomarker," added Dr. Feke.

He noted that diameters in his study and in the current study were measured when the retinal blood vessels were rather large. However, the AD process "starts in the tiniest vessels. And when things happen in those vessels, that slows down blood speed."

"There aren't a whole lot of people pursuing the idea of examining the retina in this way. But the idea itself is excellent because the retina is part of the brain," he concluded.

The AIBL study was funded by a grant from the National Institute for Mental Health, and portions were presented at the 2011 Alzheimer's Association International Conference in Paris, France. Dr. Zeke's research, abstract 2132/poster A102 , was presented at ARVO in Fort Lauderdale, Florida, May 2, 2011. The study authors and Dr. Feke have reported no relevant financial relationships.

Tansl Psychiatry. Published online February 26, 2013. Full article

No Greater Risk for Aneurysm Rupture in Pregnancy, Delivery

2013-02-26T16:55:00.000-08:00

No Greater Risk for Aneurysm Rupture in Pregnancy, Delivery

Pauline Anderson

Feb 26, 2013

A new study has found no increased risk for aneurysm rupture during pregnancy and delivery, suggesting that the relatively high rate of cesarean deliveries among women with an unruptured aneurysm that was also uncovered by the study may be unnecessary.

Further, the researchers found that when an aneurysm does rupture, prompt obliteration using surgical clipping or endovascular coiling may decrease poor outcomes.

"No one knows what the risk of rupture of a cerebral aneurysm is in a pregnant woman, or what the risk is with vaginal delivery," said study senior author, Brian Hoh, MD, the William Merz Associate Professor of Neurosurgery at the University of Florida, Gainesville. "We attempted to answer these questions using a large national hospital database."

The study appeared in the February issue of the journalNeurosurgery.

Clipping, Coiling

The researchers gathered hospital discharge data involving pregnancies or deliveries from the Nationwide Inpatient Sample (NIS) for 1988 to 2009. During that time, 2,715,161 hospitalizations were related to pregnancies; of these, 193 involved unruptured aneurysms and 714, ruptured aneurysms.

The investigators estimated the prevalence of unruptured aneurysms in the general population of women to be 3.95%, about half of that previously reported in the general population, and further estimated the rate to be 1.8% among women of child-bearing age, 45.3% as high as that among all women.

Assuming that rate of 1.8%, the researchers estimated that 48,873 of the hospitalized women had unruptured aneurysms. The estimated risk for aneurysm rupture during pregnancy was therefore 1.4% (714 of 48,873; 95% confidence interval [CI], 1.35% - 1.57%).

There were 17,340,466 hospitalizations involving deliveries, of which 218 involved unruptured and 172 ruptured aneurysms. Again, assuming a rate of 1.8%, 312,128 of these women had undetected unruptured aneurysms. This led to an estimated risk for an aneurysm rupture during delivery of 0.05% (172 of 312,128; 95% CI, 0.0468% - 0.0634%).

The study showed that the probability of a woman with an aneurysm during pregnancy receiving clipping is significantly higher than that of her receiving coiling. Of the 714 hospitalized pregnant women with a ruptured aneurysm, 2.9% received coiling, 10.5% received clipping, and 86.6% received neither. Of the 172 hospitalizations involving ruptured aneurysms with delivery, 4.7% received coiling, 12.8% received clipping, and 82.5% received neither.

The authors noted that for pregnancy, the mortality rate among patients who received no treatment was almost double that among those who received clipping or coiling (10.2% vs 5.2%).

Cesarean Deliveries

The researchers estimated a national cesarean delivery rate of 25.52% (95% CI, 25.50% - 25.54%). But among patients with unruptured aneurysm, the estimated rate was 70.18% (95% CI, 64.06% - 76.30%; P< .001).

The authors noted that there are no evidence-based recommendations for obstetric management in patients with unruptured intracranial aneurysm and no evidence to suggest that maternal or fetal outcome is improved by cesarean delivery compared with closely supervised vaginal delivery.

"Because the finding of an unruptured cerebral aneurysm in a pregnant woman is so rare, there is little evidence to guide obstetricians and neurosurgeons in the care of these patients," said Dr. Hoh.

The method of delivery for women with intracranial unruptured aneurysm should be based on obstetric considerations, he said. "Cesarean delivery would be indicated in several circumstances, such as when the clinical state of the mother is severe," for example, coma or brainstem damage, or when the aneurysm is diagnosed at labor.

The study was relatively small, which diminished its statistical power and limited the ability to incorporate covariates into the analysis, the authors note. Another limitation was that the diagnostic codes that were used may be incomplete.

Numbers Questioned

In an accompanying comment, R. Loch Macdonald, professor, surgery/neurosurgery, University of Toronto, division head, neurosurgery, St. Michael's Hospital, Toronto, Ontario, Canada, noted that the NIS is not population-based database because it includes selected patients admitted to a subset of hospitals, and that only 13% to 20% of the patients in the study who were coded as having subarachnoid hemorrhage were treated.

"There is something wrong with this number," he writes, adding that the figure is markedly lower than the percentage treated at hospitals such as his institution, St. Michael's, where the only cases not treated are those with nonaneurysmal subarachnoid hemorrhage and patients in very poor condition who are not expected to survive.

He also questioned the authors' estimates of pregnant women with unruptured and ruptured aneurysms. Patients with these aneurysms do tend to be female, but they're older and cigarette smokers, he said.

"The authors try to adjust for this and derive a 1.8% incidence of unruptured aneurysms among women 16 to 44 years of age," but this could still be an overestimation.

"Overall, this report adds to the literature, suggesting that, although intracranial hemorrhage is an important cause of obstetrical morbidity and mortality, aneurysmal cases are rare, and, if they are more likely to occur during pregnancy and the puerperium, then this increased risk is likely to be small."

The authors have disclosed no relevant financial relationships.

Neurosurgery. 2013;72:143-150. Abstract

Dural Venous Sinus Angioplasty and Stenting for the Treatment of Idiopathic Intracranial Hypertension

2013-02-26T15:04:00.000-08:00

Dural Venous Sinus Angioplasty and Stenting for the Treatment of Idiopathic Intracranial Hypertension

Jeremy D Fields, Parisa P Javedani, Julie Falardeau, Gary M Nesbit, Aclan Dogan, Erek K Helseth, Kenneth C Liu, Stanley L Barnwell, Bryan D Petersen

Disclosures

J NeuroIntervent Surg. 2013;5(1):62-68.

Abstract and Introduction

Abstract

Background Lumboperitoneal shunt (LPS), ventriculoperitoneal shunt (VPS) and optic nerve sheath fenestration (ONSF) are accepted surgical therapies for medically refractory idiopathic intracranial hypertension (IIH). In the subset of patients with IIH and venous sinus stenosis, dural venous sinus stenting has emerged as an alternative surgical approach.

Methods All cases of dural stents for IIH at our institution were retrospectively reviewed. Eligibility criteria included medically refractory IIH with documented papilledema and dural venous sinus stenosis of the dominant venous outflow system (gradient ≥10 mm Hg).

Results Fifteen cases (all women) of mean age 34 years were identified. All had failed medical therapy and six had failed surgical intervention. Technical success was achieved in all patients without major periprocedural complications. The mean preprocedural gradient across the venous stenosis was reduced from 24 mm Hg before the procedure to 4 mm Hg after the procedure. Headache resolved or improved in 10 patients. Papilledema resolved in all patients and visual acuity stabilized or improved in 14 patients. There were no instances of restenosis among the 14 patients with follow-up imaging.

Conclusion In this small case series, dural sinus stenting for IIH was performed safely with a high degree of technical success and with excellent clinical outcomes. These results suggest that angioplasty and stenting for the treatment of medically refractory IIH in patients with dural sinus stenosis warrants further investigation as an alternative to LPS, VPS and ONSF.

Introduction

Idiopathic intracranial hypertension (IIH), also known as pseudotumor cerebri and benign intracranial hypertension, is a rare disorder characterized by increased intracranial pressure (ICP) without an intracranial mass. The overall prevalence in North America is approximately 0.9–1.07/100 000 but rises to 15–19/100 000 among women aged 20–44 years who are overweight (≥20% above their ideal bodyweight).^[1] The most widely accepted criteria for diagnosis require: (1) symptoms and (2) signs referable only to elevated intracranial pressure; (3) cerebrospinal fluid (CSF) opening pressure >25 cm H₂O measured in the lateral decubitus position; (4) normal CSF composition; and (5) no evidence for an underlying structural cause (using MRI or contrast-enhanced CT for typical patients and MRI and MR venography for all others).^[2] The most common symptoms are headache, visual disturbance and tinnitus. Papilledema is present in at least 95%. Although headache may be severe, visual loss due to prolonged papilledema and secondary optic atrophy remains the most feared complication and may progress without recognition by the patients themselves.^[3,4]

Medical treatment generally consists of a combination of carbonic anhydrase inhibitors such as acetazolamide or topiramate (to decrease CSF production) and symptomatic treatment for headache. For medically refractory patients, two surgical strategies have most commonly been employed—CSF diversion with ventriculoperitoneal or lumboperitoneal shunts (VPS or LPS) and optic nerve sheath fenestration (ONSF). While progression of visual loss may be prevented by these surgical approaches, both have significant limitations. Both VPS and LPS have variable clinical response rates and significant shunt failure rates requiring subsequent surgical revision.^[5] Moreover, LPS may lead to a number of adverse events including acquired Chiari syndromes, low pressure headaches and archnoiditis of the lumbosacral nerve roots.^[6] Although ONSF often temporarily arrests visual loss associated with IIH, recurrence of visual symptoms is common and the procedure does not address headache, tinnitus or other symptoms associated with elevated intracranial pressure.

The underlying pathophysiology of IIH has yet to be fully defined, but a number of recent investigations have implicated stenosis of the dural venous sinuses as a potential contributor to the syndrome of IIH in a subset of patients. Transverse sinus stenosis was demonstrated by MRI in 90% of patients with IIH,^[7]although the degree to which venous sinus stenosis on MRI corresponds to trans-stenosis pressure gradients is not known. Furthermore, elevation of pressures within the dural sinuses proximal to the stenosis is common and significant pressure gradients across the venous stenoses have been demonstrated by direct manometry in patients with IIH.^[8,9] Although considerable controversy exists regarding whether dural venous stenosis is a cause of IIH or an effect of elevated intracranial pressure, the results of several case series suggest that stenting of the stenotic dural venous sinus may represent a therapeutic option for medically refractory IIH.^[3,10,11] In this paper we present our single-center experience with dural venous sinus stenting for IIH

Methods

We retrospectively reviewed all cases of patients treated with dural stents for IIH with papilledema at our institution. The study protocol was approved by our institutional review board.

Patient Selection and Characteristics

Patients were considered eligible for stenting based on the following criteria: (1) medically refractory IIH; (2) papilledema confirmed by an ophthalmologist; and (3) dural venous sinus stenosis of the dominant venous outflow system with a gradient of ≥10 mm Hg. This cut–off pressure was selected because a gradient of 5–6 mm Hg from the superior sagittal sinus to the internal jugular bulb is present in normal controls.^[9]

Demographic features (age, gender, body mass index (BMI)), prior treatments (medical and surgical), CSF opening pressures, neuro-ophthalmologic evaluation, procedural details and clinical outcomes were obtained by retrospective chart review. Headache intensity and the presence of tinnitus at last follow-up were assessed by a combination of chart review and telephone interview. Headache was evaluated by structured interview and was categorized as: (1) resolved (no further headache); (2) improved (residual symptoms not requiring continued intervention); (3) no change (no change in symptoms compared with before stenting procedure); (4) worsened (worse than before stenting procedure); and (5) different (change of symptoms compared with prior to the stenting procedure not otherwise meeting the criteria for categories 1–4).

Procedure

Prior to intervention, diagnostic angiography and venous pressure measurements were performed under moderate sedation. A full evaluation of the dural sinuses was performed by study of both internal carotid arteries and the posterior circulation. A 6F shuttle sheath (Cook Medical, Bloomington, Indiana, USA) was then placed in the dominant internal jugular vein. A 0.027 inch Renegade microcatheter (Stryker, Kalamazoo, Michigan, USA) was placed coaxially within the 6F shuttle and navigated over a 0.014 inch guidewire into the torcula. The microcatheter was then pulled back from the torcula to the internal jugular vein and simultaneous pressure measurements were obtained from the 6F sheath and microcatheter tip. These pressures were recorded to obtain pressure gradients from the torcula, transverse sinus and sigmoid sinus with respect to the internal jugular vein. After identifying a venous sinus stenosis, dural sinus venography was performed through the 0.027 inch microcatheter to define the anatomy of the stenosis and the size of the native dural sinus.

Patients with a dural venous sinus stenosis of the dominant venous outflow system with a gradient of ≥10 mm Hg were referred for stent placement.

All patients were pretreated with aspirin 325 mg and clopidogrel 75 mg for 5 days or loaded with aspirin 325 mg and clopidogrel 600 mg at least 4 h prior to the procedure. Intravenous heparin was given during the stent procedure to raise the activated clotting time to >250 s. Dual antiplatelet therapy was continued for 6 months and aspirin indefinitely thereafter.

All dural sinus stent procedures were performed with the patients under general anesthesia.

First, venous access was achieved in the jugular vein ipsilateral to the intended treatment site via the transfemoral approach. The choice of venous access sheath systems evolved as we gained experience with the procedure in order to provide adequate support for stent placement. The final venous access sheath system was a triaxial construct consisting of 12F, 9F and 7F 80–90 cm length sheaths. This system provided sufficient support for the delivery of the stent to the stenotic region of the transverse sinus.

After placement of the venous sheaths, diagnostic angiography was performed from the ipsilateral internal carotid artery and the venous phase of this study was used as a road map for traversal and stenting of the dural sinuses. Introduced through the venous sheaths, an 0.027 inch Renegade microcatheter was again navigated across the area of stenosis and placed with the distal tip at the level of the torcula. Dual venous pressure measurements were then repeated to confirm the presence of a persistent trans-stenosis gradient. Through this microcatheter, a stiff 0.018 inch guidewire (Platinum Plus; Stryker) exchange length guidewire was placed with the distal tip into the superior sagittal sinus or contralateral transverse sinus. Over this guidewire, a Sterling 6 mm×40 mm over-the-wire balloon angioplasty catheter (Stryker) was positioned across the stenosis and then inflated fully at 8–10 atmospheres for 10 s for two inflations. Following balloon angioplasty, in most cases a Zilver 518 10 mm diameter self-expanding stent (Cook Medical) was positioned across the residual area of narrowing and deployed. The self-expanding stents ranged from 40 to 80 mm in length and were chosen to completely cover the stenosis with at least 10 mm of coverage of the adjacent non-stenotic portion of the vein on each side. A single stent was used to treat the stenotic portion of the vessel in all but one case (for which two stents were used due to inadequate coverage of the stenosis). After initial experience suggested that bilateral stenting was not necessary, unilateral stenting procedures were performed.

Following stent placement, the 0.027 inch lumen microcatheter was then advanced through the stent to the level of the torcula and simultaneous pressure measurements were obtained to verify efficacy of the stenting procedure and elimination of the trans-stenosis pressure gradient. The arteriotomy was then closed with a StarClose device (Abbott, Chicago, Illinois, USA) and the venotomy was closed with manual pressure.

Angiographic Follow-up and Outcome Assessment

Papilledema and visual assessment by an ophthalmologist was undertaken in all patients before stent placement with initial follow-up examination generally 6 weeks after intervention. Evaluations included visual acuity testing, color vision, automated perimetry (Humphrey or Octopus) and funduscopic evaluation. Angiography to evaluate stent patency and restenosis was performed at 6 months after intervention in most patients, although non-invasive imaging was used in some cases. Clinical assessment took place at the time of follow-up angiography as well on an ad hoc basis if additional concerns arose.

Results

A total of 15 patients (all women) of mean age 34 years (range 20–56) and mean BMI 39 kg/m² pre-procedure and 39 kg/m²post-procedure (range 30–73 kg/m² pre-procedure and 30–49 kg/m² post-procedure) were treated ( Table 1 ). Only one patient had a reduction in BMI of >5% during the follow-up period (from 73 kg/m² to 47 kg/m²). Papilledema (diagnosed by an ophthalmologist) and intractable headache were present in all patients prior to the intervention. Pulsatile tinnitus was present in 14 of the 15 patients (93%).

All had failed medical treatment with acetazolamide; in addition, topiramate and amitriptyline for the treatment of headache were each administered to three patients (20%) and furosemide to two (13%). Surgical interventions prior to stenting had been performed in six of the patients (40%): CSF diversion (VPS, LPS or both) in four patients (27%) and ONSF in six (40%).

Technical success was achieved in all patients with no major complications. One minor complication (7%), a femoral pseudoaneurysm, was successfully treated with ultrasound-guided compression. The procedural details are shown in Table 2 and an illustrative case is depicted in figure 1. The gradient across the stenotic dural sinus was reduced from a mean of Hg (range 1–7). 1–7). A 6 mm × 40 mm balloon was used for pre–stent angioplasty in all patients. In most cases, a 10 mm × 60 mm self–expanding stent was placed. Stenting was unilateral in 13 of the 15 patients (87%) and bilateral in two (13%).

(Enlarge Image)

Figure 1.

Illustrative case of a 26-year-old woman with idiopathic intracranial hypertension (IIH). (A, B) Left internal carotid artery injection, venous phase, anteroposterior and lateral views. The left transverse sinus system is dominant and a venous stenosis at the transverse–sigmoid sinus junction is demonstrated. (C, D) Microcatheter injection at the torcula, anteroposterior and lateral views, again demonstrating the venous stenosis at the transverse–sigmoid sinus junction. (E, F) Roadmap images, anteroposterior and lateral views, demonstrating pre-stent angioplasty with a 6×40 mm over-the-wire balloon. The stiff 0.18 inch wire is positioned in the superior sagittal sinus. (G, H) Microcatheter injection at the torcula, anteroposterior and lateral views, immediately after angioplasty followed by deployment of a 10×60 mm self-expanding stent extending from the lateral aspect of the left transverse sinus to the left sigmoid sinus across the region of stenosis. The left transverse sinus system is now widely patent with evidence of residual stenosis. (I, J) Follow-up angiography 8 months after stent placement. The right internal carotid artery injection, anteroposterior and lateral views, shows no evidence of restenosis.

Clinical follow-up was available in all patients at a mean of 14 months (median 9 months) after stenting. Angiographic follow-up was performed in all patients (catheter angiography in 13 and MRV in 2) at a mean of 9 months (median 6 months) after stenting; the remaining patient has yet to undergo her 6-month angiogram. Stents were patent without evidence of restenosis. All patients were preloaded with aspirin and clopidogrel and these medications were continued as directed (clopidogrel for 6 months and aspirin indefinitely) in 14 patients; one patient discontinued both antiplatelet agents at 4 months without any untoward clinical effect.

Papilledema resolved in all 15 patients (see figure 2 for representative funduscopic images). Headache resolved or improved in 67% and tinnitus was eliminated in 79% of patients reporting tinnitus prior to the intervention. Visual acuity was assessed formally by an ophthalmologist in 14 of the 15 patients. Of the 14 patients with formal visual acuity testing, 13 (93%) stabilized or improved and one (7%) worsened. The patient who worsened progressed from 20/200 vision in the left eye to ability to detect hand motion only; because papilledema had resolved, the presumed mechanism was progression of optic atrophy due to injury sustained prior to stenting. Due to persistent refractory headache, two patients (13%) underwent VPS following the stenting procedure.

(Enlarge Image)

Figure 2.

Funduscopic examination (A) prior to stenting showing optic disc edema with obscuration of the optic disc margins, elevation of the optic disc and tortuosity of retinal veins and (B) 3 weeks after stenting showing resolution of optic disc edema and improved vascular tortuosity.

Discussion

For medically refractory patients with IIH, particularly those with visual loss and intractable headache, surgical options may be considered but, unfortunately, the available surgical interventions for IIH (ie, VPS, LPS and ONSF) have significant limitations. Response rates to CSF diversion vary considerably depending on the series. Stabilization or improvement in vision has been reported to occur in as few as 62% of patients undergoing VPS or LPS and headaches to improve or resolve in as few as 45%, with frequent recurrences over time. Shunt revisions are necessary in 38–63% of patients. Furthermore, although rare, serious complications (including a 0.5% risk of in-hospital death) have been reported.^[12] Similarly, ONSF is associated with substantial treatment failure rates (worsening in vision after a period of stabilization in 34% of patients at 1 year and 45% at 3 years) and failure to improve headache in one-third to one-half.^[12]

Given the problems inherent in the traditional surgical treatments for IIH, our results suggest that venous sinus stenting may be a reasonable alternative treatment in the subset of patients with venous sinus stenosis associated with a significant pressure gradient and, indeed, may treat the underlying etiology of the disease. Of the 15 patients treated, six had previously failed treatment with LPS, VPS or ONSF, including two patients who had undergone all three treatments. Visual acuity stabilized or improved in 93% of patients and papilledema resolved in all patients treated. Headaches improved or resolved in 67%. On follow-up imaging, all stents remained patent with no instances of in-stent thrombosis or restenosis.

Our results are consistent with those reported in previous case series. A systematic review of all published case series was recently performed, encompassing a total of 40 patients (37 undergoing unilateral stents and three bilateral). Among the 40 patients described in these studies, headache resolved or improved in 33 (83%), papilledema resolved or improved in 30 (75%) and optic atrophy occurred in eight (20%).^[11] Since the publication of this review, two relatively large single-center case series have been reported. In one series of 18 patients (with clinical follow-up in 15), 80% of patients had improvement or resolution of headache after stenting.^[13] The results of ophthalmologic examination were not reported in this study. Most recently, in a series of 52 patients, papilledema was eliminated in all patients and headache in 44. Among the eight patients without resolution of headache, six were found to have restenosis adjacent to the stent, resulting in an overall rate of restenosis of 12%.^[14]

Several technical considerations contribute to successful stenting and to symptom resolution. Venous sinuses require relatively large stents; we used 10 mm self-expanding stents in most cases and did not observe any instances of in-stent stenosis or restenosis of the adjacent dural sinus. The use of stents 10 mm in diameter may account for the absence of restenosis or stenosis of the adjacent dura observed in our study compared with the 12% rate of restenosis seen in the aforementioned case series. Due to the tortuosity inherent in the sigmoid sinus/transverse sinus system and the stiffness of the stent, a robust support system is required for adequate access. After evaluating several different configurations, we found a triaxial 12F/9F/7F shuttle system placed within the internal jugular vein provided adequate support to ensure stent delivery. Moderate oversizing of the stent diameter with respect to the dural sinus assures adequate apposition of the stent to the venous wall, theoretically decreasing clot formation and increasing patency. In addition, short-term restenosis may result from inadequate coverage or progression of the lesion and therefore relatively long stents were employed.^[15]

The pathophysiologic relationship between IIH and venous sinus stenosis remains controversial. Undoubtedly, dural venous sinus stenosis is much more common in patients with IIH than controls.^[7,16]Nonetheless, it remains unclear whether elevations in intracranial pressure are responsible for transverse sinus stenosis or transverse sinus stenosis causes elevations in intracranial pressure.^[16]Regardless, the high response rates to transverse sinus stenting seen in our patients as well as those from previous investigations strongly suggests that preserving the patency of the stenotic transverse sinus frequently ameliorates the pathophysiologic mechanism that ultimately leads to IIH, either by addressing the underlying venous stenosis or by preventing venous sinus collapse in the face of elevated intracranial pressure.

This study has a number of limitations. Invasive procedures are frequently associated with a high placebo response rate and the clinical course of IIH inherently fluctuates. Therefore, in the absence of a control group, the overall improvement in subjective symptoms such as headache and tinnitus could result from a placebo effect or the natural history of the disease rather than from the stenting procedure per se. On the other hand, papilledema was evaluated by ophthalmologists and was found to have resolved in all patients—an objective finding unlikely to result from either placebo or natural history.

Conclusions

We retrospectively reviewed the results of venous sinus stenting for IIH in 15 consecutive patients treated at a single institution. Patients were selected if they had IIH, with papilledema and a venous sinus stenosis with a gradient ≥10 mm Hg across the stenosis. Technical success and resolution of papilledema was achieved in all patients without any significant procedural complications. Headache improved or completely resolved in 67%. These results provide additional support for venous stenting as a surgical alternative in a properly selected subset of patients with IIH. Moreover, the high rate of clinical improvement following stenting provides additional evidence for the hypothesis that dural venous sinus stenosis contributes to the underlying etiology of IIH in a subset of patients.

New Criteria for Alzheimer Disease and Mild Cognitive Impairment

2013-02-19T16:41:00.000-08:00

New Criteria for Alzheimer Disease and Mild Cognitive Impairment

Implications for the Practicing Clinician

Andrew E. Budson, MD, Paul R. Solomon, PhD

Disclosures

Neurologist. 2012;18(6):356-363.

Abstract

Background: In most research studies and clinical trials, Alzheimer disease (AD) has been diagnosed using the criteria developed by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association work group in 1984. Developments over the last 27 years have lead to the need for new diagnostic criteria.

Review Summary: Four articles in the journal Alzheimer's & Dementia in 2011 describe new criteria for AD dementia and mild cognitive impairment (MCI) due to the AD pathophysiological process (MCI due to AD) and the underlying rationale for them. These new criteria emphasize that the AD pathophysiological process starts years and perhaps decades before clinical symptoms, and that biomarkers can be used to detect amyloid β deposition and the effects of neurodegeneration in the brain.

Conclusions: These new criteria are immediately helpful to the practicing clinician, providing more accurate and specific guidelines for the diagnosis of AD dementia and MCI due to AD. As new diagnostic tools and new treatments for AD become available, diagnosis using these criteria will enable patients with this disorder to receive the best possible care

Rationale for New Criteria

Updating the prior criteria developed by the National Institute of Neurological and Communicative Disorders and Stroke and theAlzheimer's Disease and Related Disorders Association work group in 1984, new clinical criteria have recently been published for Alzheimer disease (AD) and mild cognitive impairment (MCI) due to the AD pathophysiological process (MCI due to AD). Four articles in the journal Alzheimer's & Dementia in 2011 describe these criteria and the underlying rationale for them. The first is an introduction that provides the background of why new criteria are needed.^[1] The second details the hypothesis that the AD pathophysiological process starts years and perhaps decades before the onset of clinical symptoms and dementia. It also discusses the concept of "preclinical" AD.^[2] The third considers both clinical and research criteria for MCI due to AD.^[3] Finally, the fourth describes new clinical and research criteria for AD.^[4] We will focus on new clinical criteria, the area that will be of greatest use to practicing clinicians, and briefly touch on the research criteria and theoretical issues.

As discussed in these articles, the new criteria were developed because of the recognition of a number of important factors that have changed since 1984:

It is now believed that the AD pathophysiological process starts years before detectable cognitive changes and perhaps decades prior the onset of clinical dementia (Fig. 1). The concept of the "AD pathophysiological process" is thus separated from "AD dementia."
There are many patients whose cognition is not normal for age but also do not meet criteria for dementia.
Other causes of dementia such as frontotemporal dementia, vascular dementia, and dementia with Lewy bodies are now understood to be more likely mistaken for AD than are thyroid disorders and vitamin B₁₂ deficiency.
The genetics of AD are now better understood.
Putative biomarkers of AD are now available in some centers.
New criteria are needed for clinical trials and other research.
New treatments are being developed that are specific for the AD pathophysiological process, making it more important that patients truly have that process before the initiation of this type of specific treatment.

(Enlarge Image)

Figure 1.

Postulated temporal lag between the deposition of amyloid β in amyloid plaques from an autopsy series and the development of clinical Alzheimer disease (AD) dementia based upon 3 epidemiological studies (from Sperling et al²).

The overall purpose of these changes to the criteria are to help the clinician identify and treat the disease as early as possible—ultimately before the onset of decline with the goal of enabling individuals to live long and productive lives free of the dementia caused by AD. Recent data from an Alzheimer's Association report suggest that a delay in the onset of symptoms of AD dementia by 5 years would result in a 45% reduction in the number of people with the disorder by the year 2050 and reduce projected Medicare costs of disease from 627 to 344 billion dollars.^[5]

In general, the new criteria differ from the original criteria along 2 important dimensions that have both immediate and future implications for the practicing clinician. One is the recognition of 3 stages of AD progression, with the first (preclinical AD) occurring before changes in cognition and everyday activities are detected, the second (MCI due to AD) occurring when cognitive symptoms emerge but function is still relatively unimpaired, and the third (AD dementia) diagnosed when day-to-day function is impaired. By contrast, the original guidelines only diagnosed AD dementia. Another is the incorporation of biomarkers into the diagnosis, whereas the original criteria were based primarily on clinical judgment.

The 3 stages of AD discussed are:

Preclinical AD: Preceding any clinical changes, this stage is defined by measureable changes in biomarkers and poor performance on challenging cognitive tests. The biomarkers may be detectable by brain imaging or by molecular changes in cerebrospinal fluid (CSF). There are currently no clinical criteria to make the diagnosis of preclinical AD. The primary purpose of the designation of preclinical AD is to provide a framework for researchers to better define this stage of AD.
MCI due to AD: This stage is characterized by the first clinical changes. Mild changes in memory and other cognitive abilities that are noticeable to patients and families and can be detected through careful evaluation, but are not sufficient to interfere with day-to-day activities.
Dementia due to AD: This stage is characterized by changes in 2 or more aspects of cognition and behavior that interfere with the ability to function in everyday life.

Preclinical AD and Biomarkers

As described by Sperling et al,^[2] one commonly used model of AD is that many factors including age, genetics, the environment, and others combine to lead to the accumulation of amyloid β (Aβ) in the brain, which in turn produces synaptic dysfunction, neurofibrillary tangle formation, and neuronal death, all of which ultimately lead to cognitive decline (Fig. 2). Given that the events in this pathologic cascade sequence likely take years or decades from the accumulation of Aβ to the development of dementia or even MCI, there must be a prior "preclinical" stage of AD (Fig. 3).

(Enlarge Image)

Figure 2.

Hypothetical model of Alzheimer disease (AD) pathophysiological cascade sequence (from Sperling et al²).

(Enlarge Image)

Figure 3.

Model of the clinical course of Alzheimer disease (from Sperling et al²). MCI indicates mild cognitive impairment.

The concept of a preclinical phase of a disease should not be new to practicing clinicians, nor should the concept of diagnosing a disease in the absence of symptoms. Cancer is routinely detected at the stage of "carcinoma in situ" and atherosclerosis may cause detectable narrowing of the arteries before myocardial infarct. Similarly, many diseases including Type II diabetes, osteoporosis, and hypertension are routinely detected and treated before symptoms emerge. The goal is to move AD to a similar status.

These guidelines are primarily aimed at helping researchers determine which signature biological changes (ie, biomarkers) occur years before the onset of clinical symptoms. Currently AD biomarkers have minimal impact on clinical practice, although it is likely that these biomarkers will be important to the clinician in the near future.

Table 1 presents several biomarkers of Aβ deposition or neurodegeneration that are currently in use. Markers of Aβ deposition include low CSF Aβ₄₂ and positive PET amyloid imaging. Markers of neurodegeneration include elevated CSF tau [both total and hyperphosphorylated tau (p-tau)], decreased metabolism in temporal and parietal cortex on ¹⁸flurodeoxyglucose (FDG) PET, and atrophy on magnetic resonance imaging (MRI) in temporal (medial, basal, and lateral) and medial parietal cortex. Although it makes the most sense scientifically to divide the biomarkers into those measuring either Aβ deposition or neurodegeneration, in clinical practice one tends to divide the biomarkers by how they are obtained: structural MRI, PET, and CSF studies.

Structural MRI, when analyzed using a quantitative protocol, can provide whole brain volume and volume in anatomically distinct areas of the brain. Patients in whom the AD pathophysiological process has caused neurodegeneration should have less brain tissue in temporal (medial, basal, and lateral) and medial parietal cortex—and they should lose tissue faster—than healthy individuals.^[6] Volumetric MRI is currently being used in a number of ongoing clinical trials to evaluate the efficacy of disease-modifying drugs in AD. In addition, the Alzheimer's Disease Neuroimaging Initiative also includes serial volumetric MRIs in AD and MCI patients and healthy controls.^[7] The Alzheimer's Disease Neuroimaging Initiative data should ultimately provide a normative database that would be an important step in allowing volumetric MRI to be used clinically. Volumetric MRI analyses are not routinely available, although we encourage all clinicians to look for qualitative patterns of atrophy in temporal (medial, basal, and lateral) and medial parietal cortex, and progressive atrophy when serial scans are available.

There are 2 types of PET biomarkers: those that show amyloid deposition, and those that show neurodegeneration. Brain neurodegeneration can be identified by measuring glucose metabolism in the brain with FDG PET. These scans show which areas of the brain are and are not functioning well. Decreased metabolism is observed in temporal and parietal cortex when the AD pathophysiological process has caused neurodegeneration.^[8] FDG PET scans are available to the clinician now, and are covered by Medicare. We do not, however, recommend using these scans routinely when the history, physical examination, cognitive testing, and structural imaging are all consistent with AD—it simply is not necessary.^[8] In situations, however, in which one suspects an atypical neurodegenerative disease, an FDG PET scan can help distinguish AD from another disorder (such as dementia with Lewy bodies or frontotemporal dementia). Another reason to obtain an FDG PET scan is if one is suspecting AD in a patient younger than 66 years of age. At such a young age the prevalence of AD is similar to that of many other etiologies (such as frontotemporal dementia),^[9] making it more critical to be sure that the diagnosis is AD before treatment is initiated.

Several compounds that can identify AB deposition using PET are currently being used for research and/or are under commercial development. The 2 most widely used are the Pittsburgh compound B and florbetapir. Both have been shown to bind to brain AB.^[10,11] Because amyloid accumulation is thought to be present years before the onset of clinical symptoms, PET identification of AB raises the possibility of identifying and treating patients with AD years before symptoms emerge—once a drug has been proven to be disease modifying. Amyloid PET imaging is currently being used in several clinical trials both to help identify individuals with preclinical AD and to measure the effects of antiamyloid treatments. Moreover, florbetapir has recently been submitted to the FDA for approval in clinical practice. Detection of β-amyloid by PET could be available to clinicians soon.

Standard CSF biomarkers for AD are Aβ₄₂, total tau, and p-tau. Studies have shown that when all 3 markers are combined, the accuracy of the diagnosis is highest, with sensitivity and specificity of 85% to 90%.^[12] Although CSF analysis is already commercially available (www.athenadiagnostics.com) and used by some clinicians to aid in diagnosis, we view this test as highly promising but not yet ready for routine clinical practice.^[8]

Based upon the current scientific model regarding when different events occur in the AD pathophysiological process (Fig. 4), Sperling et al^[2] discussed 3 stages of preclinical AD to be considered for research, based upon biomarkers and cognitive change. Stage 1 is asymptomatic cerebral amyloidosis, which could be determined by the presence of a biomarker sensitive to Aβ, in the absence of any marker of neurodegeneration or evidence of subtle cognitive change. Stage 2 is asymptomatic cerebral amyloidosis plus neurodegeneration in the absence of subtle cognitive change. Finally, stage 3 is amyloidosis plus neurodegeneration plus subtle cognitive or behavioral decline. Guided by these theoretical underpinnings, the new clinical and research criteria are next presented for MCI due to AD and AD dementia.

(Enlarge Image)

Figure 4.

Model of how the different stages of Alzheimer disease may be detected by changes in various biological, cognitive, and clinical markers (from Sperling et al²). CSF indicates cerebrospinal fluid; FDG, 18flurodeoxyglucose; MCI, mild cognitive impairment; MRI, magnetic resonance imaging.

Criteria for Mild Cognitive Impairment Due to the AD Pathophysiological Process

Based upon guidelines currently in use at memory centers and in research studies, Albert et al^[3] presented the criteria for MCI due to AD. These criteria, aimed both at clinicians and researchers, refer to the symptomatic phase of the AD pathophysiological process but before the individual develops the functional impairment that defines dementia. Clinicians are increasingly making a diagnosis of MCI and the new diagnostic guidelines will formalize this process. The guidelines recognize that everyone who eventually develops AD will go through a transitional period of mild but detectable cognitive impairment. Importantly, however, not everyone who is diagnosed with MCI will go on to develop AD. MCI can be due to a variety of disorders including, vascular dementia, frontotemporal dementia, dementia with Lewy bodies, and others. Both core clinical criteria for the diagnosis of MCI due to AD and clinical research criteria are presented. As the authors start their discussion on the core clinical criteria they point out that, in addition to these criteria, clinical judgment must be used to distinguish between normal cognition and MCI, and between MCI and dementia.

The new guidelines specify the criteria for making a diagnosis of MCI due to AD. The criteria include:

Excluding patients who have other causes of MCI including extensive vascular disease, frontotemporal dementia, and dementia with Lewy bodies. These exclusions will likely be accomplished through a combination of the clinical evaluation and imaging studies.
Including patients who show increasing cognitive decline over time. This decline could be detected historically or via serial evaluations over time.
Including patients who have the very rare mutations associated with early-onset familial AD (amyloid precursor protein, presenilin 1, or presenilin 2). These mutations can be identified via commercially available genotyping (http://www.athenadiagnostics.com).

Because patients with MCI due to AD may actually be considered very early AD patients, it will be important for practicing clinicians to identify this condition. There may be at least as many patients with MCI due to AD as there are with dementia due to AD.^[13,14] Although there is not substantial evidence that current treatments with FDA approved medications improve patients with MCI due to AD (there is ongoing research aimed at answering this question), patients with this condition may benefit from referrals to centers conducting studies with potential disease modifying treatments such as vaccines that are aimed at slowing the loss of neurons and thus the progression of the disease. It is becoming increasingly clear that disease-modifying drugs will be most beneficial in the earliest stages of the disease. There are now several ongoing studies with hypothesized disease modifying agents (eg, vaccines) for patients with MCI due to AD, and other studies are being planned.

The clinical criteria are divided into 2 parts (Table 2). First, criteria are presented for the clinical and cognitive syndrome of MCI, and second, criteria are presented regarding the etiology of the MCI syndrome being consistent with AD.

Research criteria for MCI due to AD incorporating biomarkers are next presented. The biomarkers discussed include those in Table 1. Two valuable reasons to add biomarkers is that they may help determine (1) the underlying etiology of the MCI and (2) the likelihood and time course of an individual with MCI becoming more impaired or demented. An important point discussed is that biomarkers that detect Aβ protein deposition are most useful in determining underlying etiology, whereas biomarkers that detect neuronal degeneration and injury are most useful in determining prognosis and progression. Adding each of these categories of biomarkers to the core clinical diagnosis of MCI due to AD leads to the following probabilities: If 1 of these 2 biomarker categories is positive, the "biomarker probability of AD etiology" rises to "intermediate," and both categories must be positive for the "highest" probability. The "lowest" probability is present if both categories are negative.

Criteria for All-cause Dementia and AD

The new criteria for AD clarify existing guidelines and are appropriate for use today by practicing physicians. The new guidelines propose 4 possible classifications of dementia caused by AD: (1) probable AD dementia, (2) probable AD dementia with increased level of certainty, (3) possible AD dementia, and (4) probable or possible AD dementia with evidence of AD pathophysiological process. The last criteria propose a system for providing additional diagnostic evidence through the use of biomarkers, and are currently intended for research purposes only, although it is likely that it will be increasingly used in future clinical practice. The hope is that the use of these new clinical criteria coupled with the judicious addition of biomarkers will eventually improve diagnostic accuracy and help make accurate diagnoses earlier in the disease process when intervention can be most beneficial. The new guidelines do not suggest any additional diagnostic procedures for patients already diagnosed with AD.

The new criteria suggest a 4-step approach to diagnosis of dementia due to AD (Table 3). Step 1 determines that dementia is present, step 2 determines that the dementia is due to AD, step 3 provides an increased level of certainty to the diagnosis, and step 4 evaluates the biomarker probability of AD etiology.

The next idea that is introduced is that of research criteria for "probable AD dementia with evidence of the AD pathophysiological process." These research criteria increase the certainty that the patient's clinical dementia is due to the AD pathophysiological process by adding biomarker evidence to the probable AD dementia criteria. The biomarkers fall into 2 categories, markers of Aβ protein deposition in the brain and markers of downstream neurodegeneration, (Table 1).

If 1 of these 2 biomarker categories is positive, the "biomarker probability of AD etiology" rises to "intermediate," and if both categories are positive the probability becomes "high." The authors are specific that they do not advocate obtaining AD biomarkers for routine clinical purposes at the present time, although they do note that they may be used when they are available and deemed appropriate by the clinician.

The clinical criteria for possible AD dementia can be found in Table 4. The term "possible" is used instead of "probable" in 2 scenarios. One is if the cognitive deficits look like AD but there is an atypical course of the disease: either sudden onset or no definite decline. The second is if there is evidence for a mixed etiology of the dementia, such that the patient meets criteria for probable AD dementia but there is also evidence of significant vascular disease, features of dementia with Lewy bodies, or other disease or condition that could be contributing to the patient's dementia.

Pathophysiologically proven AD is next discussed, consisting simply of the unchanged criteria of patients meeting both the clinical and neuropathologic criteria for AD. Finally the criteria for dementia unlikely to be due to AD is discussed (Table 5).

Implications for the Practicing Clinician

These new guidelines do not suggest a fundamental difference in the way clinicians will diagnose AD dementia or MCI due to AD. For now, diagnosis of these disorders will continue to be primarily clinical. The new guidelines also do not recommend any specific treatment strategies. Implicitly or explicitly, however, they do encourage clinicians to:

Recognize that AD is the end of a long process, spanning years or perhaps decades, leading to death of brain cells, cognitive loss, and ultimately dementia.
Diagnose (and perhaps treat) AD at the earliest possible stage. At present this would be the MCI due to AD stage, but eventually will include preclinical AD.
Begin to consider using biomarkers in the diagnosis of all stages of AD. For now, most biomarkers will only be used in research studies (both for diagnostic purposes and to evaluate the efficacy of disease modifying treatments), but some either are available to clinicians now (eg, FDG PET scans, CSF Aβ₄₂, and tau) or will be in the near future (eg, quantitative MRI, amyloid PET scans).
Evaluate patients with dementia to determine the cause of the dementia with special attention paid to amnestic and nonamnestic presentations of AD.
Remember that they will soon see a significant increase in patients in their practices with AD. There are currently 5.4 million patients in the United States with AD dementia and perhaps an equal amount with MCI. Because of the aging population, these numbers could triple in the next 50 years.

Conclusions

Today, these new criteria allow the practicing clinician to diagnose AD dementia and MCI due to AD with more clarity, providing greater certainty of the diagnosis for patients and families. In the future, these criteria will provide practitioners with the tools they need to know which patients are appropriate for the disease-modifying medications which are being developed to slow or even stop the AD pathophysiological process.

Current and Future Treatments for Alzheimer's Disease

2013-02-19T16:34:00.002-08:00

Current and Future Treatments for Alzheimer's Disease

Konstantina G. Yiannopoulou, MD, Sokratis G. Papageorgiou, PhD, MD

Disclosures

Ther Adv Neurol Disorders. 2013;6(1):19-33.

Abstract and Introduction

Abstract

Alzheimer's dementia (AD) is increasingly being recognized as one of the most important medical and social problems in older people in industrialized and nonindustrialized nations. To date, only symptomatic treatments exist for this disease, all trying to counterbalance the neurotransmitter disturbance. Three cholinesterase inhibitors (CIs) are currently available and have been approved for the treatment of mild to moderate AD. A further therapeutic option available for moderate to severe AD is memantine, an N-methyl- D-aspartate receptor noncompetitive antagonist. Treatments capable of stopping or at least effectively modifying the course of AD, referred to as 'disease-modifying' drugs, are still under extensive research. To block the progression of the disease they have to interfere with the pathogenic steps responsible for the clinical symptoms, including the deposition of extracellular amyloid β plaques and intracellular neurofibrillary tangle formation, inflammation, oxidative damage, iron deregulation and cholesterol metabolism. In this review we discuss current symptomatic treatments and new potential disease-modifying therapies for AD that are currently being studied in phase I–III trials.

Introduction

Dementia is increasingly being recognized as one of the most important medical problems in older people with a prevalence rising from 1% at the age of 60 to at least 35% at the age of 90 [Ferri et al.2005]. Within the spectrum of dementias, Alzheimer's disease (AD) is the most prevalent subtype, accounting for about 60% of all dementias. It is characterized clinically by progressive memory and orientation loss and other cognitive deficits, including impaired judgment and decision making, apraxia and language disturbances. These are typically accompanied by various neuropsychiatric symptoms (i.e. depression, apathy, anxiety, agitation, delusions, hallucinations). The continuing expansion of life expectancy, leading to a fast growing number of patients with dementia, particularly AD, has led to an enormous increase in research focused on the discovery of drugs for primary, secondary or tertiary prevention of the disease. Despite all scientific efforts, at the moment there are no effective pharmacotherapeutic options for prevention and treatment of AD.

To date, established treatments are only symptomatic in nature, trying to counterbalance the neurotransmitter disturbance of the disease. Three cholinesterase inhibitors (CIs) are approved for the treatment of mild to moderate AD [Birks, 2006]. A further therapeutic option available for moderate to severe AD is memantine [McShane et al. 2006]. At the same time antipsychotic and antidepressant treatments are used for the behavioral symptoms of the disease [Ballard and Corbett, 2010].

Treatments under research include compounds that act on the pathological substrate of the disease: extracellular amyloid β (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). In this review, current symptomatic treatments and new potential disease-modifying therapies for AD that are currently being studied in phase I–III trials are discussed.

Current Symptomatic Approaches to Alzheimer's Disease

Cholinesterase Inhibitors

The cholinergic hypothesis of AD concludes that cholinergic systems in the basal forebrain are affected early in the disease process, including loss of acetylcholine neurons, loss of enzymatic function for acetylcholine synthesis and degradation, resulting in memory loss and deterioration of other cognitive and noncognitive functions such as neuropsychiatric symptoms [Bartus et al. 1982; Cummings and Back, 1998]. A strategy to enhance the cholinergic transmission by using CIs to delay the degradation of acetylcholine between the synaptic cleft has been proposed. To date, three CIs are approved for the treatment of mild to moderate AD: donepezil (Pfizer, New York, NY, USA), rivastigmine (Novartis, Basel, Switzerland) and galantamine (Janssen, Beerse, Belgium) [Farlow, 2002]. These drugs have been regarded as the standard and first-line treatment for AD. Systemic reviews including many double- blind, randomized, placebo-controlled trials (RCTs) of these three CIs all showed benefit on cognitive functions, activities of daily living (ADL), and global function for patients with mild to moderate AD; there was no significant difference of efficacy between individual CIs [Farlow, 2002; Birks, 2006]. In addition, donepezil is now also approved for the treatment of severe AD in the USA [Cummings et al. 2010]. Although tacrine (First Horizon Pharmaceuticals, Alpharetta, Georgia, USA) was the first CI drug approved for AD in 1993, it is no longer used due to hepatotoxicity [Alfirevic et al. 2007]. Related systemic reviews showed that the incidence of gastrointestinal adverse effects, such as nausea, vomiting, diarrhea and abdominal cramp, was lower with donepezil than with rivastigmine and galantamine [Alva and Cummings, 2008]. The incidence of adverse effects was associated with higher therapeutic dose. However, it may be that galantamine and rivastigmine may be equal to donepezil in tolerability if a careful and gradual titration routine of more than 3 months is used. The dermal form of rivastigmine provides a lower dose with fewer adverse effects but comparable efficacy, and is was preferred by some caregivers [Blesa et al. 2007]. Use of CIs is also reported to be associated with increased rates of syncope, bradycardia and pacemaker insertion. The risk of these adverse events must be weighed carefully against the drugs' benefits [Gill et al. 2009].

Reviews and meta-analyses on CIs that have recently been published showed that they delay the decline in cognitive function as measured by the AD Assessment Scale – cognitive subscale (ADAS-cog), global clinical rating, behavior and ADL over 6–12-month periods. These benefits seem to be applicable to mild, moderate and severe AD [Birks, 2006; Hansen et al 2008; Qaseem et al. 2008]. Compared with those on placebo treatment, patients on CIs generally show an initial mild improvement in cognitive functions over the first 3 months. Thereafter, the mean decline in cognitive functions was also less rapid over the subsequent 3–9 months. At 6 months, the cognitive improvement (versusplacebo) was 2.7 points over the Mid range of ADAS-cog [Birks, 2006; Hansen et al. 2008]. Symptoms that were improved included attention, thinking, memory, praxis, language comprehension and communication [Qaseem et al. 2008].

Initiation of CI treatment in the early stages of AD is preferred. A 52-week study of the efficacy of rivastigmine in patients with mild to moderately severe AD reported that patients with AD who started the CI 6 months later achieved lower cognitive performance than those who started the drug immediately after the diagnosis [Farlow et al. 2000]. Preserved cognitive function was also observed after 12 months of treatment with rivastigmine in patients with mild AD in comparison to untreated patients who markedly worsened in cognition during the same period [Almkvist et al. 2004].

N-methyl-D-aspartate Antagonist

A further therapeutic option for moderate to severe AD is memantine (Lundbeck, Valby, Denmark). This drug is an uncompetitive, moderate- affinity N-methyl-D-aspartate (NMDA) antagonist believed to protect neurons from excitotoxicity. A systemic review of double-blind, parallel- group, RCT studies of memantine showed improvement in cognition, ADL and behaviors in people with moderate to severe AD after 6 months of use [McShane et al. 2006]. Another systemic review which included six RCT studies indicated that memantine may reduce behavioral and psychological symptoms of dementia [Maidment et al. 2008]. The most frequently reported adverse events in memantine trials were dizziness, headache and confusion. A small group of patients might develop agitation [Alva and Cummings, 2008].

Combination Therapy

RCT studies on parallel groups of patients with moderate to severe AD showed a significant benefit in cognitive function, language, ADL, behaviors and global state from combination use of memantine and donepezil over the placebo group (memantine and placebo) [Tariot et al. 2004; Feldman et al.2006; Howard et al. 2012]. However, such benefit was not demonstrated in patients with mild to moderate AD [Farlow et al. 2010].

Treatment of Behavioral and Psychological Symptoms of Dementia in Alzheimer's Disease

Noncognitive neuropsychiatric symptoms or behavioral and psychological symptoms of dementia (BPSD) are common in all clinical stages of AD and even in amnestic mild cognitive impairment (MCI) (the predementia stage of AD) with increasing prevalence when dementia progresses. They are the main determining factors for increased caregiver burden and institutionalization of patients. According to a large observational study, BPSD may be grouped into four major symptom clusters with high prevalence: psychosis (38% of the patients, e.g. delusions), affective symptoms (59%, anxiety and depression), hyperactivity (64%, e.g. aggression, disinhibition) and apathy (65%) [Zec and Burkett, 2008].

CIs and memantine may have an effect on behavioral symptoms [Farlow, 2002; Birks, 2006; Maidmentet al. 2008]. However, when BPSD become more severe, these antidementia drugs may not be as effective and other drugs also need to be given.

Serotonin reuptake inhibitors (SSRIs: fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine) are largely considered to be among the most efficient antidepressants to treat comorbid depression in AD dementia [Zec and Burkett, 2008]. Mirtazapine, venlafaxine and duloxetine, which are combined selective noradrenalin and serotonin inhibitors (SNRIs), and bupropion are other widely used antidepressants in this population.

A few RCTs with limited numbers of patients as well as meta-analyses support their efficacy to treat depression in AD dementia [Ballard and Corbett, 2010]. SSRIs may also be taken into consideration for the treatment of agitation and psychosis in AD dementia [Zec and Burkett, 2008]. However, a recent randomized, multicenter, double-blind, placebo-controlled trial of sertraline or mirtazapine for depression in dementia (HTA-SADD) showed absence of benefit compared with placebo and increased risk of adverse events. The trial concluded that the current practice of using these antidepressants, with usual care, for first-line treatment of depression in Alzheimer's disease should be reconsidered [Banerjee et al. 2011].

Psychotic symptoms and agitation/aggression are commonly treated with antipsychotics in patients with AD dementia. Atypical agents (olanzapine, risperidone, quetiapine, ziprasidone and aripiprazole) are preferred due to their milder parkinsonian effects [Ballard and Corbett, 2010]. The use of antipsychotics has been discussed controversially, as cerebrovascular morbidity and higher mortality have been found in patients with dementia taking antipsychotics. Furthermore, the use of antipsychotics may be associated with a higher risk of hip fracture and pneumonia, as well as worsening cognitive impairment. The increased mortality may be reduced if antipsychotics are only given over a short period, as stopping the antipsychotic medication may not be associated with a subsequent increase in BPSD [Zec and Burkett, 2008].

Benzodiazepines are used to reduce agitation and anxiety. However, they can also trigger further agitation in older people. An association of greater benzodiazepine use with more rapid cognitive and functional decline has been reported in AD and indeed in older people in general [Zec and Burkett, 2008].

Anticonvulsant drugs like carvamazepine can also reduce BPSD in AD to some degree [Ballard et al.2009].

It is obvious that drugs currently used for the treatment of AD have weak beneficial effects on cognitive function or offer some relief of BPSD. The discovery of new drugs that act during the early stages of AD could be considered a 'medical need' [Mancuso et al. 2011]. Early intervention is critical because a delay in treatment is associated with nonreversible symptom progression.

The Amyloid Hypothesis

The primary histopathologic lesions of Alzheimer's pathology are amyloid plaques, NFTs and neuronal loss. Mature plaques consist of a central amyloid core with surrounding degenerating neurons affected by the toxic effect of the Aβ. NFTs consist of hyperphosphorylated tau protein that has assumed a double helical filament conformation [Cummings, 2008b].

The Aβ derives from the amyloid precursor protein (APP) through sequential proteolysis by β secretase (BACE1) in the extracellular domain and γ secretase in the transmembrane region.

Full-length APP undergoes sequential proteolytic processing. It is first cleaved by α secretase (nonamyloidogenic pathway) or β secretase (amyloidogenic pathway) within the luminal domain, resulting in the shedding of nearly the entire ectodomain and the generation of α or β C-terminal fragments (CTFs). The major neuronal β secretase, named BACE1 (β-site APP cleaving enzyme), is a transmembrane aspartyl protease that cleaves APP within the ectodomain, generating the N-terminus of Aβ. The second proteolytic event in APP processing involves intramembranous cleavage of α and β CTFs by γ secretase. Major sites of γ-secretase cleavage correspond to positions 40 and 42 of Aβ. Amyloidogenic processing is the favored pathway of APP metabolism in neurons because of the greater abundance of BACE1, whereas the nonamyloidogenic pathway predominates in other cells [Vassar, 2004].

According to the 'amyloid hypothesis' Aβ production in the brain initiates a cascade of events leading to the clinical syndrome of Alzheimer's dementia [Golde, 2005]. Aβ is a protein consisting of two major forms, Aβ40 and Aβ42. Aβ42 is the most soluble form and has the tendency to aggregate into fibrils that form the major composite of amyloid plaques. It is the predominant form found in the brain parenchyma of patients with AD. Aβ40 is mostly found in the cerebral vasculature as part of 'cerebral amyloid angiopathy'. Aβ has a tendency to cluster into oligomers. Oligomers can form Aβ-fibrils and protofibrils that will eventually form amyloid plaques, which are believed to be nontoxic. It is the forming of amyloid oligomers to which neurotoxicity is attributed and initiates the amyloid cascade. The elements of the cascade include local inflammation, oxidation, excitoxicity (excessive glutamate) and tau hyperphosphorylation. As a result of this process, tau proteins fold into intraneuronic tangles, which results in cell death. Progressive neuronal destruction leads to shortage and imbalance between various neurotransmitters (e.g. acetylcholine, dopamine, serotonin) and to the cognitive deficiencies seen in AD [Cummings, 2008a; Golde, 2005].

On the basis of findings on AD pathogenesis, novel treatments under development aim to interfere with the pathogenic steps previously mentioned in an attempt to block the course of the disease in its early stages [Galimberti and Scarpini, 2011; Golde, 2005]. For this reason they have been termed 'disease-modifying' drugs. In this review, possible strategies for the development of novel disease-modifying therapies will be discussed.

Disease-modifying Approaches to Alzheimer's Disease

The production of Aβ, which is a crucial step in AD pathogenesis, is the result of cleavage of APP, which is overexpressed in AD [Griffin, 2006]. Aβ forms highly insoluble and proteolysis-resistant fibrils known as senile plaques (SPs). NFTs are composed of the tau protein. In healthy subjects, tau is a component of microtubules, which are the internal support structures for the transport of nutrients, vesicles, mitochondria and chromosomes within the cell. Microtubules also stabilize growing axons necessary for the development and growth of neurons [Griffin, 2006]. In AD, tau protein is abnormally hyperphosphorylated and forms insoluble fibrils, causing deposits within the cell.

Thus, both Aβ and tau are prime targets for disease- modifying therapies in AD. From this point of view, AD could be prevented or effectively treated by decreasing the production of Aβ and tau; preventing aggregation or misfolding of these proteins; neutralizing or removing the toxic aggregate or misfolded forms of these proteins; or a combination of these modalities.

A number of additional pathogenic mechanisms have been described, possibly overlapping with Aβ plaques and NFT formation, including inflammation [Griffin, 2006], oxidative damage [Reddy et al. 2009], iron deregulation [Adlard and Bush, 2006] and cholesterol metabolism [Stefani and Liguri, 2009].

Disease-modifying Treatments: Modulation of Amyloid Deposition Drugs Interfering with Amyloid β Deposition.

Anti-amyloid Aggregation Agents The hypothesis that aggregation of Aβ leads to toxic oligomeres has driven research into studying compounds that could prevent this aggregation ( Table 1 ) [Cummings, 2008b; Golde, 2005].

The only Aβ aggregation inhibitor reaching phase III is the synthetic glycosaminoglycan 3-amino- 1-propaneosulfonic acid (3APS, tramiprosate) [Gauthier et al. 2009]. It is designed to interfere with the binding of glycosaminoglycanes and Aβ. Disappointing results of the North American phase III trial in the year 2007 have led to discontinuation of the European phase III trial. Nevertheless, 3APS will now be commercialized as a branded nutraceutical. However, recent data suggest that tramiprosate promotes an abnormal aggregation of the tau protein in neuronal cells [Santa-Maria et al. 2007]. These results emphasize the importance of testing the potential drugs for the treatment of AD on both types of pathology (amyloid and tau).

Another molecule undergoing testing is colostrinin, a proline-rich polypeptide complex derived from sheep colostrum (O-CLN; ReGen Therapeutics, London, UK). Colostrinin inhibits Aβ aggregation and neurotoxicity in cellular assays and improves cognitive performance in animal models. Although a phase II trial demonstrated modest improvements in Mini Mental State Evaluation scores for patients with mild AD over a treatment period of 15 months, this beneficial effect was not sustained during an additional 15 months of continued treatment [Bilikiewicz and Gaus, 2004].

Another compound named scyllo-inositol is able to stabilize oligomeric aggregates of Aβ and inhibit Aβ toxicity in mouse hippocampus. An 18-month, randomized, double-blind, placebocontrolled, dose-ranging, safety and efficacy study of oral scyllo-inositol (ELND005) in participants with mild to moderate AD has been carried out by Transition Therapeutics (Toronto, ON, Canada)/Elan (Dublin, Ireland). A long-term follow-up class II study in subjects with AD provided insufficient evidence to support or refute a benefit of ELND005.

Primary clinical efficacy outcomes were not significant. The safety and cerebrospinal fluid (CSF) biomarker results will guide selection of the optimal dose for future studies, which will target earlier stages of AD [Salloway et al. 2011].

Drugs Interfering With Metals Zinc (Zn) and copper (Cu) are both involved in the aggregation of Aβ42. Several chelators of Zn/Cu have been shown to inhibit Aβ aggregation in vitro and in animal studies. PBT2 is a second-generation 8-OH quinoline metal-protein-attenuating compound that affects the Cu2⁺-mediated and Zn2⁺- mediated toxic oligomerization of Aβ. A recent phase IIa study concluded that the safety profile is favorable for the ongoing development of PBT2. The effect on putative biomarkers for AD in CSF but not in plasma suggests a central effect of the drug on Aβ metabolism. Cognitive efficacy was restricted to two measures of executive function. In the post hoc analysis, the cognitive, blood marker and CSF neurochemistry outcomes from the trial were subjected to further analysis. Ranking the responses to treatment after 12 weeks with placebo, PBT2 50 mg and PBT2 250 mg revealed that the proportions of patients showing improvement were significantly greater in the PBT2 250 mg group than in the placebo group. These findings further encourage larger-scale testing of PBT2 for AD [Faux et al. 2010].

Selective Aβ42-lowering Agents. Aβ is generated through proteolytic processing of the transmembrane peptide APP. APP can be cleaved by two competing proteases, α secretase and β secretase. Only cleavage by β secretase, followed by γ-secretase cleavage, which in AD is the dominant pathway, will lead to production of Aβ40 and Aβ42. By inhibiting β secretase and γ secretase or by increasing α-secretase cleavage, Aβ production may be reduced [Cummings, 2008a].

β-site AP-cleaving Enzyme Inhibition The β-secretase enzyme BACE1 is a promising therapeutic target, although the development of a BACE1 inhibitor therapy is problematic for two reasons. First, BACE1 has been found to have important physiological roles. Therefore, inhibition of the enzyme could have toxic consequences. Second, the active site of BACE1 is relatively large, and many of the bulky compounds that are needed to inhibit BACE1 activity are unlikely to cross the blood–brain barrier. Many of compounds able to inhibit BACE are still in the preclinical phase. Inhibitors based on the peptidomimetic strategy suffer from well known difficulties associated with polypeptides, such as blood–brain barrier crossing, poor oral bioavailability and susceptibility to P-glycoprotein transport. Efforts to overcome these problems led to the design of new nonpeptidomimetic β-secretase inhibitors that show high selectivity over BACE2 (BACE1/BACE2 selectivity >100) and other human proteases (cathD, pepsin and renin). Their weak or nonpeptidic character favors CNS penetration and oral bioavailability [Silvestri, 2009]. A ligand-based computational approach is currently used to identify the molecular chemical features required for the inhibition of BACE1 enzyme [John et al. 2011].

Only a few β-secretase inhibitors have entered clinical trials to date. The first publicly announced phase I clinical trial on a β-secretase inhibitor CTS-21166 was conducted by CoMentis (South San Francisco, USA) [Hey et al. 2008; Albert, 2008; Panza, 2009]. Phase I clinical trials on CTS-21166 have been carried out in healthy young men and evaluated for safety and preliminary Aβ responses. In these clinical trials, β-secretase inhibitor has been shown to reduce human plasma Aβ [Hey et al. 2008]. Clearly, the hope for the next step would be to develop inhibitors with better pharmaceutical properties and to carry out well designed efficacy trials to determine if they can rescue cognitive decline in patients with AD [Ghosh et al. 2012].

γ-Secretase Inhibition γ Secretase is a nucleoprotein complex with at least four different proteins from which preseniline PS-1 and PS-2 seem to be responsible for the enzymatic action on APP. Unfortunately, besides APP, γ secretase has many other substrates and cleaves several other transmembrane proteins, including the Notch receptor 1, which is necessary for growth and development. Notch-related side effects of γ-secretase inhibition (severe gastrointestinal and hemopoetic side effects) have been hampering the development of clinically useful γ-secretase inhibitors so far [Wong et al. 2004]. The most studied γ-secretase inhibitor, which is semagacestat (LY-450139), was shown to dosedependently decrease the generation of Aβ in the CSF of healthy people [Siemers et al. 2005]. Unfortunately, two large phase III clinical trials of semagacestat in patients with mild to moderate AD were prematurely interrupted because of the observation of detrimental effects on cognition and functionality in patients receiving the drug compared with those receiving placebo. These detrimental effects were mainly ascribed to the inhibition of Notch processing and to the accumulation of the neurotoxic precursor of Aβ (the C-terminal fragment of APP or CTFβ) resulting from the block of the γ-secretase cleavage activity on APP [Imbimbo and Giardina, 2011]. Two large phase III studies in patients with mild AD with tarenflurbil (or R-flurbiprofen), which is a putative γ-secretase modulator, were also completely negative. The failure of tarenflurbil was ascribed to low potency and brain penetration. New Notchsparing γ-secretase inhibitors and more potent and brain penetrant γ-secretase modulators are being developed with the hope of overcoming the previous setbacks [Imbimbo and Giardina, 2011].

A potent γ-secretase inhibitor, BMS-708163 (avagacestat; Bristol-Myers Squibb, New York, NY, USA), was tested in a phase I clinical trial. After 18 days, BMS-708163 caused a decrease in CSF Aβ40 and Aβ42 of 30% following a daily dose of 100mg as well as a decrease of 60% at a daily dose of 150mg. A phase II study is ongoing [Tong et al 2012].

α-Secretase Potentiation Etazolate (EHT 0202; ExonHit Therapeutics, Paris, France) stimulates the neurotrophic α-secretase (nonamyloidogenic) pathway and inhibits Aβ-induced neuronal death, providing symptomatic relief and modifying disease progression. The recent pilot, randomized, double-blind, placebo-controlled, parallel group, multicentre, phase IIA study was conducted in 159 randomized patients with mild to moderate AD. EHT0202 was shown to be safe and generally well tolerated. These first encouraging safe results support further development of EHT0202 to assess its clinical efficacy and to confirm its tolerability in a larger cohort of patients with AD and for a longer period of time [Vella et al.2011].

Immunotherapy. Immunotherapy is one of the strategies being studied by most pharmaceutical companies. The mechanism behind amyloid clearance by immunotherapy has not been fully elucidated. At least six mechanisms that are not mutually exclusive are considered to elicit a humoral response: First, by direct disassembly of plaques by conformation-selective antibodies; second, by antibody-induced activation of microglial cells and phagocytosis of pathological protein deposits; third, by noncomplement-mediated phagocytosis activation of microglial cells; fourth, by neutralization of toxic soluble oligomers; fifth, by a shift in equilibrium toward efflux of specific proteins from the brain, creating a peripheral sink by clearance of circulating Aβ cell-mediated immune responses; and finally, immunoglobulin M (IgM)-mediated hydrolysis. All these mechanisms may play roles depending on the specific immunotherapeutic scenario [Wisniewski and Konietzko, 2008] (Figure 2).

Both active immunization (vaccination) and passive immunization (monoclonal antibodies) are being studied. After promising preclinical results in animal studies, one of the first active vaccination trials was initiated using human Aβ1-42 (AN-1792) in conjunction with a T-helper adjuvant (QS-21). Unfortunately, in 2002, the phase II vaccination trial was discontinued because of the occurrence of meningoencephalitis (6%) [Gilman et al. 2005]. Additionally, only 19.7% of the AN-1792-treated patients developed the predetermined antibody response.

Double-blind assessment was maintained for 12 months, demonstrating no significant differences in cognition between antibody responders and the placebo group. In a small subset of patients, CSF tau levels were decreased in antibody responders but Aβ levels were unchanged [Gilman et al. 2005]. Long-term follow up of treated patients and further analysis of autopsy data modified and moderated the negative impact of the first results, encouraging additional clinical attempts. Subsequent observations of AN1792- vaccinated patients or transgenic models, and of brain tissue taken from mice and humans using a new tissue amyloid immunoreactive method suggested that antibodies against Aβ-related epitopes are capable of slowing down the progression of neuropathology in AD. In a recent 4-year study, Hock and Nitsch followed 30 patients who received a primary and booster immunization in the first year after vaccination, providing further support for continuation of the investigation of antibody treatment in AD [Hock and Nitsch, 2005].

The occurrence of encephalitis led to the development of new vaccines, which lack the amino acid parts thought to be responsible for the T-cell response mediated encephalitis, but retain the residues (4–10) required for antibodies to bind to Aβ. Most of these vaccines are now being tested in phase I and II trials: the CAD-106 trial led by Novartis/Cytos (Basel, Switzerland) and the V950 trial initiated by Merck (Whitehouse Station, NJ, USA) [Brody and Holtzman, 2008]. Additional antibodies under testing include ACC- 001 (Wyeth, New Jersey, USA, two phase II studies ongoing in the USA and Japan), MABT5102A (Genentech, San Francisco, California, USA, phase I completed), PF-04360365 (Pfizer, phase I completed), R1450 (Hoffman-LaRoche, Basel, Switzerland, phase I completed), GSK933776A (GlaxoSmithKline, London, UK, phase I completed) [ClinicalTrials. gov; Galimberti and Scarpini, 2011].

Given the adverse reactions of the active immunization and the variable antibody response to vaccines in older individuals, passive immunization directed against various domains of Aβ emerged as an alternative immunotherapeutic strategy. A point of concern in these therapies is the occurrence of cerebral microhemorrhages. The underlying mechanism is probably related to vascular amyloid deposits (congophilic amyloid angiopathy), present in nearly all patients with AD. The need for vascular repair and regeneration during Aβ immunotherapy is another argument for early treatment and subtle clearance over a long period of time [Wilcock et al. 2007].

More advanced is the Elan/Wyeth trial of AAB- 001 monoclonal antibody (bapineuzumab), which entered phase III testing in 2007. This approach involves passive immunization with an Aβ N-terminal directed, humanized monoclonal antibody. The murine version of this antibody binds to both soluble and aggregated Aβ. The multiple-dose phase II trial including 240 participants did not attain statistical significance on the primary efficacy endpoints in the whole study population. Some patients in the treatment group had a vasogenic edema, which is a serious side effect. However, in the subgroup of participants who did not have the apolipoprotein E (ApeE) ε4 allele, clinically significant benefits were recorded in several scales and magnetic resonance imaging showed smaller loss of brain volume. Looking at the best result of different groupings, it seemed that a small subset of patients, the ApoE noncarriers who received the second lowest of the four doses six times, responded really well in 78 weeks. Therefore the phase III study was initiated in ApoE4 noncarriers with mild to moderate AD [Wisniewski and Konietzko, 2008].

The next most advanced trial to our knowledge is the Eli Lilly and Co. (Indianapolis, IN, USA) phase II trial of LY2062430 (solanezumab), which involves passive vaccination with an Aβ central domain directed, humanized monoclonal antibody. Systemic administration of the closely related central domain mouse monoclonal antibody m266 rapidly improved behavioral performance and decreased plaque formation in preclinical studies. However, this antibody did not worsen intracerebral hemorrhage or vascular pathology in older APP transgenic mice. The phase II results have been reported and no safety concerns were raised; a phase III study is being conducted [Brody and Holtzman, 2008].

Finally, natural antiamyloid antibodies have been found in human intravenous immunoglobulins (IVIgs) obtained from the pooled plasma of healthy blood donors. In light of these observations, a phase I trial has been carried out in the USA. Eight patients with AD were treated with IVIg (Gammagard S/D immune globulin intravenous human) donated by Baxter Healthcare Corporation (Deerfield, IL, USA). Seven patients completed the study. After 6 months, cognitive function stopped declining in all seven patients and improved in six. In 2009, a phase III clinical trial involving more than 360 patients with AD was initiated and may provide conclusive evidence for the effect of IVIg as a treatment option for AD [Dodelet al. 2010].

Passive vaccination requires repeated infusions, which have a high cost. Therefore active vaccination is always taken into consideration.

Data from preclinical studies regarding mice suggest that novel immunotherapeutic strategies like DNA epitope vaccine [Qu et al. 2010], antibodies against the β-secretase cleavage site of the APP [Rakoveret al. 2007] and mucosal vaccination [Hara et al. 2011] could be used as safe and effective methods for AD therapy. DNA epitope vaccines have received substantial interest because of the ease of selectively designing them to elicit specific immune responses. Mucosal vaccination is an alternative way to achieve humoral response. Its mechanism is based on the presence of lymphocytes in the mucosa of the nasal cavity and gastrointestinal tract. It produces primarily secretory IgA antibodies, but when the antigen is coadministered with adjuvants such as cholera toxin subunit B and heat labile Escherichia colienterotoxin, substantial serum IgM titers can be achieved. It has a more limited humoral response with little or no cell-mediated immunity. The last developed mucosal immunotherapy for AD by nasal administration used a recombinant Sendai virus vector carrying Aβ1-43 and mouse interleukin- 10 cDNA. It induced good antibody responses to Aβ. When APP transgenic mice (Tg2576) received this vaccine once nasally, the Aβ plaque burden was significantly decreased 8 weeks later, without inducing inflammation in the brain. Tg2576 mice showed significant improvement in cognitive functions when examined 3 months after the vaccination [Hara et al. 2011].

Disease-modifying Treatments: Modulation of Tau Deposition

Drugs Interfering With Tau Deposition Multiple compounds have been identified through cell culture or in vitro screens as tau aggregation inhibitors ( Table 2 ). A phenothiazine, methylene blue (MB) or methylthioninium chloride, has previously been used in humans and is currently being evaluated in AD trials. The problem with this drug is that urine is colored blue, resulting in a lack of blinding. However, promising results have emerged from a phase II clinical trial testing MB as a potential therapy for AD, as improvements in cognitive function of patients with AD after 6 months of MB administration have been reported [Gura, 2008].

Drugs Interfering With Tau Phosphorylation. The intriguing link between phosphorylation and tau pathology has provided the boost to examine the role of kinase inhibitors as potential therapeutics targeting tau. Kinases induce the hyperphosphorylation of tau [Yiannopoulou et al. 2009]. Despite the large number of tau phosphorylation sites and the ability of multiple kinases to phosporylate individual sites, glycogen synthase kinase 3 (GSK3β) has emerged as a potential therapeutic target. The most studied compound able to inhibit GSK3 is lithium, but several other compounds are under development, including pyrazolopyrazines, pyrazolopyridines, the aminothiazole AR-A014418, and sodium valproate [Martinez and Perez, 2008]. In recent studies, the effect of short-term treatment on cognitive and biological outcomes in people with amnestic MCI was shown and supports the notion that lithium has disease-modifying elements with potential clinical implications in the prevention of AD [Forlenza et al.2011].

Immunotherapy. Vaccination approaches targeting tau have been considered, but the development of a successful therapy is complicated because tau protein is intracellular [Galimberti and Scarpini, 2011].

Disease-modifying Treatments: Modulation of Inflammation and Oxidative Damage

Anti-inflammatory Drugs Epidemiological evidence suggests that long-term use of NSAIDs protects against the development of AD. Despite this premise, prospective studies showed lack of efficacy [Aisenet al. 2002, 2003] or treatmentlimiting gastrointestinal toxicity [Rogers et al. 1993].

Molecules Addressing Oxidative Damage. Potential antioxidants include mitoquinone, vitamin E, Ginkgo biloba, natural polyphenols such as green tea, wine, blueberries and curcumin, ω3 fatty acids, folate, vitamin B6 and vitamin B12 supplementation. A trial to determine whether the reduction of homocysteine levels with highdose folate, vitamin B6 and vitamin B12 supplementation can slow the rate of cognitive decline in subjects with AD had no beneficial effect on the primary cognitive measure, the rate of change in ADAS-cog score over 18 months, or on any secondary measures, although the vitamin supplement regimen was effective in reducing homocysteine levels [Aisen et al. 2006]. Clinical trials with vitamin E and ω3 fatty acids did not show beneficial effects in patients with AD [Barten and Albright, 2008].

More recent data have revealed that tumor necrosis factor (TNF), one of the few gliotransmitters, has strikingly acute effects on synaptic physiology. These complex influences on neural health suggest that manipulation of this cytokine might have important impacts on diseases characterized by glial activation, cytokine-mediated neuroinflammation and synaptic dysfunction. Toward such manipulation in AD, a 6-month study was conducted with 15 patients with probable AD who were treated weekly with perispinal injection of etanercept, an FDA-approved TNF inhibitor that is now widely used for the treatment of rheumatoid arthritis and other systemic diseases associated with inflammation. The results demonstrated that perispinal administration of etanercept could provide sustained improvement in cognitive function for patients with AD. Additionally, the authors were impressed by the striking rapidity with which these improvements occurred in the study patients. Nevertheless, etanercept merits further study in RCTs [Griffin, 2008].

Disease-modifying Treatments: Additional Approaches

Modulation ofCcholesterol and Vascular-related Risk Factors. A link between hypercholesterolemia, cardiovascular diseases and AD has also been suggested. Additional vascular-related risk factors for AD include hypertension, atrial fibrillation, hyperhomocysteinemia, atherosclerosis and stroke [Hooijmans and Kiliaan, 2008]. Epidemiological studies have indicated that patients treated for cardiovascular disease with cholesterol-lowering therapy (statins) showed a decreased prevalence of AD [Jick et al. 2000]. The Lipitor's Effect in Alzheimer's Dementia (LEADe) study tested the hypothesis that a statin (atorvastatin 80mg daily) is beneficial to patients with mild to moderate AD receiving background therapy of donepezil 10mg daily. Despite a promising premise, there were no significant differences in the coprimary or secondary endpoints, although atorvastatin was generally well tolerated [Feldman et al. 2010].

Simvastatin metabolites are high-affinity 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors, reducing the quantity of mevalonic acid, a precursor of cholesterol. Cholesterol Lowering Agent (simvastatin) to Slow Progression (CLASP) of Alzheimer's Disease Study is an ongoing randomized, double-blind, placebo-controlled, parallel-assignment phase III trial that investigates the safety and effectiveness of simvastatin in slowing down the progression of AD. It has not yet published its results [McGuinness et al. 2010]. However, a randomized, doubleblind, placebo-controlled recent trial of simvastatin was conducted in individuals with mild to moderate AD and normal lipid levels. Simvastatin had no benefit on the progression of symptoms in individuals with mild to moderate AD despite significant lowering of cholesterol [Sano et al. 2011].

Final Remarks

Currently available treatments for AD (donepezil, rivastigmine, galantamine and memantine) are symptomatic and do not decelerate or prevent the progression of the disease. However, these therapies demonstrate modest, but particularly consistent, benefit for cognition, global status and functional ability [Herrmann et al. 2011].

The search for disease-modifying interventions has focused largely on compounds targeting the Aβ pathway. To date, many treatments targeting this pathway, such as tarenflurbil, tramiprosate and semagacestat, have been unsuccessful in demonstrating efficacy in the final clinical stages of testing [Gauthier et al. 2009; Imbimbo and Giardina, 2011].

However, colostrinin, scyllo-inositol, PBT2, avagacestat, etazolate and active and passive immunization methods, treatments also targeting the Aβ pathway, are being tested in advanced clinical trials.

At the same time, other possible neuronal mechanisms that seem to play important roles in the pathophysiology of this multifactorial disorder, such as tau deposition and hyperphosphorylation, neuroinflammation and oxidative stress, are being researched as promising therapeutic targets. Clinical trials with drugs interfering with tau deposition or phosphorylation (lithium) are ongoing [Martinez and Perez, 2008]. Clinical trials of potential antioxidants such as vitamin E and ω3 fatty acids did not show beneficial effects in patients with AD [Barten and Albright, 2008].

Etanercept, a TNF inhibitor that is now widely used for the treatment of systemic diseases associated with inflammation, provided sustained improvement in cognitive function in patients with mild to severe AD after perispinal administration in a 6-month, open-label pilot study. However, etanercept merits further study in RCTs [Griffin, 2008].

Modulation of cholesterol and vascular-related risk factors is an additional possible disease-modifying approach. CLASP is an ongoing phase III trial investigating the effectiveness of simvastatin in slowing down the progression of AD [McGuinness et al. 2010].

The development of disease-modifying drugs for AD is recognized as a worldwide necessity. These must presumably be drugs that will modify, either by stabilizing or slowing, the molecular pathological steps leading to neurodegeneration and finally dementia.

The required design of clinical trials to test this concept raises many questions regarding the study populations, the duration of trials, the necessary primary and secondary endpoints, including biomarkers [Vellas et al. 2007]. It has been recognized that, to modify AD, which has recently been redefined to have presymptomatic and symptomatic phases, one must attempt to treat patients when neuronal dysfunction is far from full blown and largely irreversible [Dubois et al. 2010; Sperling et al. 2011].

The following considerations have emerged that should be taken into account when planning future clinical trials:

The mechanisms underlying the pathogenesis of AD need to be thoroughly investigated before focusing on the development of novel disease-modifying compounds. Despite promising premises related to different pathogenic mechanisms, large phase III trials with potentially disease-modifying properties have failed to demonstrate any effect on cognition. It is of crucial importance to better understand the relationship between tau, Aβ and other factors to develop successful disease-modifying drugs [Galimberti and Scarpini, 2011].
Treatments of AD appear effective only in certain phases of the disease. A few disease- modifying compounds have shown some benefits in mild but not moderate AD or even in MCI. Therapeutic trials should therefore be carried out as early as possible during the course of the disease, which requires the identification of more accurate tools for early diagnosis. New criteria for the diagnosis of AD have enlarged the window for the detection of the early stages of the disease and include biomarkers mechanistically related to AD pathology. Adoption of these early biomarkers in implementing design of future studies is highly desirable [Galimberti and Scarpini, 2011; Salomone et al. 2011].
AD is heterogeneous in clinical presentation, underlying neuropathology and mixed causes (especially in late-onset AD). This fact is one more reason to improve our tools for detecting patients with amnestic MCI at high risk of converting to AD before the different full-blown clinical features of the disease appear. A major challenge will also be to identify subgroups with homogeneous biomarkers. At present, the focus in AD drug development is shifting from treatment to prevention [Salomone et al. 2011; Vellas et al. 2011].
Indicators useful as surrogate outcome measures (surrogate biomarkers like magnetic resonance imaging, CSF tau and Aβ, and amyloid positron emission tomography) should be identified to have substitutes for clinical endpoints (i.e. neuropsychological testing), tools able to predict clinical benefit or the opposite, and to demonstrate whether the drug has disease- modifying properties [Galimberti and Scarpini, 2011].
Prolonged development times delay effective therapies from reaching patients in need. Several strategies are promising for answering the crucial question of, 'How much information is sufficient to proceed to phase III without excessive risk for failure?' Phase II proof of concept (POC) (IIa) and dose-finding (IIb) studies represent major challenges in drug development. Biomarkers, population enrichment with risk factors, clinical measures with greater sensitivity than standard trial instruments and adaptive dose–response designs might represent other strategies applicable to POC studies. All of these strategies are being considered as means of shortening phase IIb studies and creating a seamless interface with phase III. None of these strategies have been validated in a successful drug development program [Cummings, 2008b].

In conclusion, the new strategies seem to focus on examining the potential neuroprotective activity of disease-modifying drugs in the presymptomatic stages of AD, with the help of biomarkers that predict disease progression before development of overt dementia.

Neurostimulation Has Benefits in Early Parkinson's Disease

2013-02-15T16:42:00.003-08:00

Neurostimulation Has Benefits in Early Parkinson's Disease

Megan Brooks

Feb 15, 2013

Subthalamic nucleus deep brain stimulation (DBS) offers benefits earlier in the course of Parkinson's disease (PD), before the appearance of severe disabling motor complications, according to results of a randomized controlled trial.

In a group of patients with relatively mild early motor complications of PD, subthalamic stimulation plus medical therapy was superior to medical therapy alone on several key measures of quality of life and motor function.

Results of the Controlled Trial of Deep Brain Stimulation in Early Patients with Parkinson's Disease (EARLYSTIM) were published February 14 in the New England Journal of Medicine.

"The result of our study is that a new group of patients can do better with neurostimulation than with medication," study investigator Gunther Deuschl, MD, from Christian Albrechts University in Kiel, Germany, told Medscape Medical News.

A Second Honeymoon?

Levodopa remains the most effective current treatment for parkinsonian motor symptoms. But after an initial "honeymoon" period, which may last several years, the beneficial effects are hampered by levodopa-induced motor complications, which progressively compromise quality of life, the researchers note. For patients with advanced PD with medically intractable motor fluctuations and dyskinesia, neurostimulation of the subthalamic nucleus effectively reduces motor disability and improves quality of life and has become an established treatment option.

The EARLYSTIM study suggests that neurostimulation "may be a therapeutic option for patients at an earlier stage than current recommendations suggest," Dr. Deuschl and colleagues say.

In this 2-year trial, 251 patients with PD and early motor complications were randomly assigned to subthalamic nucleus stimulation plus medical therapy or medical therapy alone. The patients had a mean age of 52 years and had had PD for a mean of 7.5 years.

The intention-to-treat population included 124 patients assigned to neurostimulation (120 of whom underwent implantation and completed the study) and 128 assigned to medical therapy alone (125 underwent medical therapy and 123 completed the study).

In the intention-to-treat population, the primary outcome — Parkinson's Disease Questionnaire (PDQ-39) summary index score — was improved from baseline to 24 months by 7.8 points (26%) in the neurostimulation group but worsened by 0.2 point (1%) in the medical therapy group.

In this population, the between-group difference in the mean change from baseline was 8.0% (95% confidence interval, 4.2% - 11.9%; P = .002), which was similar to the between-group differences in the per-protocol population.

Neurostimulation was also superior to medical therapy with respect to the major secondary outcomes, with significant mean differences achieved in parkinsonian motor disability, activities of daily living, levodopa-induced motor complications (all P < .001), and time with good mobility and no dyskinesia (P = .01).

An expert panel confirmed that medical therapy was consistent with practice guidelines for 96.8% of patients in the neurostimulation group and 94.5% in the medical therapy group.

It appears from this study, therefore, that neurostimulation in combination with medical therapy can "improve motor symptoms better than medical therapy alone at this earlier stage," the authors say.

Monitor for Suicide

Serious adverse events occurred in 54.8% of patients in the neurostimulation group and in 44.1% of those in the medical therapy group. Serious adverse events related to surgical implantation or the neurostimulation device occurred in 17.7% of patients. A total of 26 serious adverse events were related directly to surgery or the implanted devices; 25 of them resolved completely, and 1 left a cutaneous scar.

The authors say serious adverse events in the medical therapy group were more often related to problems of mobility and adverse effects of medications, including hallucinations and behavioral problems, whereas major depression occurred more often among patients with neurostimulation, despite an overall improvement in mood at the end of the trial.

There were 3 suicides in study patients (2 in the neurostimulation group and 1 in the medical therapy group), as well as 4 suicide attempts (2 in the neurostimulation group and 2 in the medical therapy group). The frequency of suicidal behavior, including suicide, was high but did not differ between treatment groups, the authors note.

The study "did not suggest that neurostimulation is associated with a higher risk of suicide than medical therapy," they write. The authors hypothesize that the decision to eventually undergo neurostimulation may select a specific subgroup of patients with a higher risk for suicidal behavior than the general population. During the study, they established monitoring procedures for suicide, which they say may be useful in the future.

In a linked editorial, Caroline M. Tanner, MD, PhD, from the Parkinson's Institute, Sunnyvale, California, and Stanford University School of Medicine, Palo Alto, California, points out that suicide has "previously been associated with stimulation of the subthalamic nucleus but less so with other surgical targets."

Dr. Tanner says the EARLYSTIM study is one of the "most rigorously" conducted trials of neurostimulation, but she cautioned that patients in the trial do not match most patients with PD. All were 60 years of age or younger at the time of surgery, were in good general health, and had a good response to a levodopa challenge.

"Very few" patients with PD meet these criteria, she points out. Only 11% of cases of PD are diagnosed before age 60, and on average 30% of patients have dementia. "Whether these results would be obtained in older patients with PD or in less-experienced medical centers is not known," she writes.

Potential Candidates

Dr. Tanner also notes that little is known about the long-term efficacy of neurostimulation. But she notes that a study published in Archives of Neurology in 2011 and reported by Medscape Medical Newsshowed that motor improvement is sustained for as long as 10 years in a small number of selected patients. "This would argue in favor of using neurostimulation in carefully chosen, young patients with a recent onset of motor fluctuations," Dr. Tanner says.

Dr. Deuschl told Medscape Medical News that potential candidates for earlier neurostimulation include patients beyond the first years when medications do very well and the patients are close to normal (honeymoon period). "They are in a disease stage which we call 'intermediate period' (followed many years later or decades later by the 'late period')," he explained.

The mobility of these patients has been fluctuating for about 1.5 years on average and dyskinesias are developing over that time, although they are still able to participate in activities related to work, family, and sports, he said. "These patients have on average a disease duration of 7.5 years and do better with DBS. I think age should also play a role and younger patients have most likely a lower risk to have complications due to the surgery," Dr. Deuschl said.

The study was funded by the German Ministry of Research, the French Programme Hospitalier de Recherche Clinique National, and by Medtronic. Dr. Deuschl and several coauthors have disclosed financial relationships with Medtronic and other pharmaceutical companies. A complete list for study authors and Dr. Tanner can be found at www.NEJM.org.

N Engl J Med. 2013;368:610-622, 675-676. Abstract Editorial

Short Course of Aspirin, Clopidogrel Cuts Stroke Risk

2013-02-12T18:29:00.004-08:00

Short Course of Aspirin, Clopidogrel Cuts Stroke Risk

Pauline Anderson

Feb 11, 2013

Results of the Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events (CHANCE) trial were presented here at the International Stroke Conference (ISC) 2013.

The CHANCE trial, carried out exclusively in China, is a few steps ahead of a similar trial, the Platelet Oriented Inhibition in New TIA and stroke (POINT) trial, now enrolling mostly in the United States.

Although CHANCE was a "well done" trial and its results showed "a larger treatment effect," it's important to note that healthcare in China is different from that in the United States, said CHANCE co–principal investigator, S. Claiborne Johnston, MD, PhD, professor, neurology, and director, Stroke Service, University of California, San Francisco.

"Secondary prevention practices are not as robust there as they are in Europe and in North America, and that could have impacted the trial," he told Medscape Medical News. "Also, usually genetic differences don't matter, but in this case, they might because there are differences in polymorphisms that affect clopidogrel metabolism in Asian populations.

For these reasons, although American neurologists might see the CHANCE trial as a signal to go ahead and use combined therapy, "I think it's wise for us to wait for a confirmatory trial outside of China, said Dr. Johnston, who is also co–principal investigator of the POINT trial.

CHANCE co–principal investigator was Yongjun Wang, MD, professor of neurology and vice-president of Beijing TianTan Hospital, Capital Medical University, who presented the full results here.

High Risk for Hemorrhage

The study enrolled 5170 patients at least 40 years of age who had sustained a TIA or minor stroke. Within 24 hours of their symptom onset, they were randomly assigned to 1 of 2 groups: aspirin (1 day loading dose of 75 to 300 mg, followed by 75 mg/day) plus placebo, or the same aspirin regimen plus clopidogrel (loading dose of 300 mg followed by 75 mg/day).

Patients in the combination group were taken off aspirin at 21 days because of the concern that Chinese patients, as with other Asian populations, are at relatively high risk for hemorrhage. "Frankly, that belief comes from epidemiological studies, but the epidemiology may just reflect underlying risk factors and not a true propensity for it," said Dr. Johnston. He pointed out that the studies testing this have not been in the acute period.

The study showed that stroke occurred less frequently in those receiving both aspirin and clopidogrel. At 90 days, the hazard ratio (HR) for survival free of stroke — either ischemic or hemorrhagic — in the combination group was 0.68 (95% confidence interval [CI], 0.57 - 0.81; P < .001).

For the secondary outcome of combined events (stroke, myocardial infarction, vascular death), the HR was 0.69 (95% CI, 0.58 - 0.82; P < .001). The risk for hemorrhagic stroke was the same in the 2 groups (0.3%).

Notably, severe bleeding events occurred at a similar rate in the 2 groups (0.2% in each). Although mild bleeding occurred more often in the combination group (1.2% versus 0.7%), Dr. Johnston noted that these events included nose bleeds. "We did not see a signal that the combination was unsafe."

Both aspirin and clopidogrel affect platelets, but through different pathways. "Together, the 2 are much more powerful than either one alone," said Dr. Johnston.

CHANCE was the first trial to focus on the acute period in TIA and minor stroke, which Dr. Johnston emphasized is not being seen nearly enough in the emergency department. "People with TIA and minor stroke are not coming in acutely or they're calling the office and being seen in clinic," he said. "We need to remind people that this really is an emergency and it should be treated right away."

Asked whether the combination therapy would be an acceptable approach for more severe strokes, Dr. Johnston said it's impossible to know "where to draw the line." The researchers will do more subgroup analyses looking at stroke severity, but Dr. Johnston pointed out that "there was no difference between the TIA and stroke in terms of rates of hemorrhagic stroke or in the efficacy of the combination."

Compared with elsewhere in the world, the risk for stroke is very high in China. "There are a whole lot more strokes in China than there are in the US and even if you add Europe, you still have more strokes in China," said Dr. Johnston.

Healthcare Differences

Because the trial was so large and because standards for clinical research have improved dramatically in China, the CHANCE results are "incredibly important" and should have a major effect on public health around the world, said Dr. Johnston. However, there are important differences between healthcare in China and that in the United States.

For example, Dr. Johnston noted that about two thirds of the Chinese patients in the study had hypertension and less than half were receiving any drug for hypertension during follow-up. Undertreatment, he said, could "certainly" affect the absolute effect size that's seen in the trial.

It's probably wise to await what happens with the POINT trial before changing treatment approaches here in North America, said Dr. Johnston, who is that study's principal investigator. Interim POINT results will be available in May, he said. "That will provide an opportunity to say it's very important to continue POINT or it's not important to continue POINT."

The POINT trial, which is about a third of the way through recruitment, differs slightly from CHANCE, said Dr. Johnston. For example, it includes a higher loading dose of clopidogrel and requires enrollment within 12 hours instead of 24 hours. As well, patients in the combination group continue with aspirin for 90 days instead of stopping at 21 days as in the CHANCE study.

Dr. Johnston pointed out a graph showing times for survival free of stroke for the treatment groups. "Most of the separation in the 2 curves occurs just in the first couple of days, so certainly by 21 days, the curves are almost parallel."

POINT includes mainly centers in the United States, although some sites have been added internationally.

The idea of comparing aspirin plus clopidogrel in a North American trial dates back more than a decade, but the researchers ran into funding difficulties when the drug manufacturer pulled its backing. This, said Dr. Johnston, substantially delayed the start of the trial.

When asked about next steps for CHANCE, Dr. Johnston said the Chinese researchers will look at ancillary studies of biomarkers and subtyping based on vascular imaging. As well, they plan to provide outcomes at 1 year that will include results related to cognition.

Helpful Information

Invited to comment on the CHANCE trial results, Larry B. Goldstein, MD, professor, medicine, Division of Neurology, and director, Duke Stroke Center, Duke University, Durham, North Carolina, and a POINT investigator, said the information is "quite helpful" and could eventually alter the current treatment practice, which is to being aspirin alone. "This would suggest that aspirin with clopidogrel over a relatively short course may have some benefit."

He added that the "key" is the short course of the combination aspirin plus clopidogrel treatment. He pointed out that other trials, including SPS3 and MATCH (Management of ATherothrombosis with Clopidogrel in High-risk patients), found that long-term combinations are associated with an increased risk for major bleeding complications.

The lack of increased risk of bleeding, at least in the short term, "is quite encouraging," said Dr. Goldstein. He added that bleeding complications are more of a concern in Asia than in the United States, which has a much more ethnically diverse population and where the proportion of Asians is relatively low."Over the longer term, the addition of a more potent antiplatelet drug, or combinations in general, seem to carry a much higher risk of bleeding that attenuates any benefit they have in reducing ischemic stroke risk," said Dr. Goldstein. "In our current guidelines, there is actually a contraindication for the combination for long-term secondary stroke prevention."

Dr. Johnston has conflicts of interest. Other than being a POINT investigator, Dr. Goldstein has disclosed no relevant financial relationships.

International Stroke Conference (ISC) 2013. Abstract LB11. Presented February 8, 2013.

Clinical Features of Dopamine Agonist Withdrawal Syndrome in a Movement Disorders Clinic

2013-02-10T19:04:00.000-08:00

Clinical Features of Dopamine Agonist Withdrawal Syndrome in a Movement Disorders Clinic

Margarita Pondal, Connie Marras, Janis Miyasaki, Elena Moro, Melissa J Armstrong, Antonio P Strafella, Binit B Shah, Susan Fox, L K Prashanth, Nicolas Phielipp, Anthony E Lang

Disclosures

J Neurol Neurosurg Psychiatry. 2013;84(2):130-135.

Abstract and Introduction

Abstract

Background Recently, symptoms similar to addictive drug withdrawal have been reported in a structured longitudinal study of patients with idiopathic Parkinson's Disease (PD) withdrawing from dopamine agonists (DA): the dopamine agonist withdrawal syndrome (DAWS).

Objectives The objective of this study was to establish the frequency, predictors, and outcomes of DAWS in a movement disorders clinic.

Methods We conducted a retrospective chart review of a sample of patients with a clinical diagnosis of PD treated with DA in whom withdrawal or attempted withdrawal of DA was carried out because of adverse effects, or for any other reason. Out of 487 PD patient charts reviewed, 84 were withdrawn from the agonists and were evaluable.

Results Thirteen patients (15.5%) met criteria for DAWS (DAWS+) and 71 did not (DAWS−). DAWS developed upon withdrawal from pergolide, pramipexole and ropinirole, and did not respond to levodopa. DAWS outcomes included recovery in less than 6 months in 61%, in more than a year in 23%, and an inability to discontinue DA in 15% of patients. Development of impulse control disorders was the reason for DA withdrawal in all DAWS+, but only in 41% of DAWS− patients (p<0 .0001="" and="" daws="" did="" differ="" in="" not="" other="" p="" patients="" variables.="">

Conclusion DAWS is a disabling complication of DA use. Critical features of the syndrome are the strong link with impulse control disorders, possibly the independence of DA dosage and type, and the resistance to treatment, including levodopa. Further studies are required to characterise those at risk as well as to define an effective treatment.

Introduction

Dopamine is a critical neurotransmitter in mesocorticolimbic circuits involved in reward.^[1–3] Drugs that stimulate this circuit, such as amphetamines and cocaine, are a major societal cause of addiction.^[4–6]Dopamine replacement therapies (DRT) replenish the nigrostriatal pathway to control the motor symptoms of Parkinson's disease (PD), but also stimulate mesocorticolimbic circuits that are relatively intact,^[2–5] resulting in several addiction-related syndromes.^[4,7]

Among substance addiction syndromes reported in patients with PD on DRT, the dopamine dysregulation syndrome (DDS) is characterised by compulsive drug consumption accompanied by psychomotor agitation and euphoria, drug-related dyskinesias, resistance to dose reduction and withdrawal symptoms characterised by depression, anxiety and impairment in occupational and social functioning.^[3,8,9]

Impulse control disorders (ICD), commonly involving pathological gambling, hypersexuality, compulsive buying and compulsive eating, constitute a second type of DRT-related disinhibitory psychopathology considered a behavioural addition.^[4,10] ICD appear much more commonly in patients treated with dopamine agonists (DA), in whom they are reported in 14–17% of cases, while in patients with levodopa treatment the frequency ranges from 0.7% to 7%.^[4,6,10]

The clinical manifestations of dopamine agonist withdrawal syndrome (DAWS) resemble other psychostimulant withdrawal syndromes and the observed lack of response to levodopa, antidepressants and anxiolytics and the improvement with DA replacement are consistent with a drug-specific withdrawal syndrome.^[7] Rabinak and Nirenberg^[7] postulated that the patients with DAWS belong to a 'mesocorticolimbic variant' of PD, with disproportionate mesocorticolimbic versus nigrostriatal dopaminergic dysfunction, increased vulnerability to DAWS and ICD.

Most patients with ICD do not use DRT in a compulsive manner.^[11–14] On the other hand, the dose escalation in DDS patients can be accompanied by the development of ICD.^[4] Okai et al ^[15] reviewed the problems of diagnosing and assessing the severity of ICD and proposed an extension to the criteria for DDS diagnosis.

We aimed to determine the frequency of DAWS, the determinants for developing this syndrome, and the outcome of DAWS in a population of PD patients followed in a movement disorders clinic.The apathy that develops in PD patients following subthalamic nucleus stimulation has been linked to the drastic reduction in medication after surgery, and can be considered a DRT-related withdrawal syndrome.^[16] In contrast to this restricted postsurgical withdrawal syndrome, in a cohort of PD patients enrolled in a structured longitudinal study, Rabinak and Nirenberg^[7] reported symptoms similar to addictive drug withdrawal developing on withdrawal or attempted withdrawal of DA. They defined the DAWS as a severe stereotyped cluster of physical and psychological symptoms that correlate with DA withdrawal in a dose-dependent manner, cause clinically significant distress or social/occupational dysfunction, are refractory to levodopa and other PD medications, and cannot be attributed to other clinical factors.^[7]DAWS comprises psychiatric symptoms such as anxiety, panic attacks, depression, agitation, irritability, dysphoria, insomnia, fatigue, generalised pain, and drug cravings and autonomic signs and symptoms such as orthostatic hypotension, dizziness, nausea and diaphoresis.^[7]

Methods

We carried out a retrospective chart review of PD patients attending a large movement disorders clinic at the Toronto Western Hospital. The study project was approved by the Research Ethics Board of University Health Network, Toronto, Ontario, Canada.

Patient selection was carried out searching our database for a diagnosis of PD among patients with ongoing follow-up. All the information present in the chart was evaluated by a neurologist assessor. If clarification was required, and in all patients in whom DAWS was suspected, the case was discussed in detail with the attending neurologist. The inclusion criteria were a clinical diagnosis of PD using UK Parkinson's Disease Society brain bank criteria^[17] with a history of DA treatment for more than 3 months, in whom withdrawal of a DA had been carried out. Exclusion criteria were dementia as a clinical diagnosis stated in the chart, a history of functional neurosurgery for treatment of PD temporally close to withdrawal and insufficient information on DA treatment or withdrawal.

All data collection was completed before rendering a diagnosis of DAWS, which was retrospectively applied, upon reviewing the clinical information and the opinion of the patient's neurologist, using the criteria proposed by Rabinak and Nirenberg:^[7] a severe stereotyped cluster of physical and psychological symptoms that correlated with DA withdrawal in a dose-dependent manner, caused clinically significant distress or social/occupational dysfunction, were refractory to levodopa and other PD medications (apart from DA), and could not be attributed to other clinical factors. Psychiatric symptoms included anxiety, panic attacks, depression, agitation, irritability, dysphoria, insomnia, fatigue, generalised pain, and drug cravings and autonomic signs and symptoms included orthostatic hypotension, dizziness, nausea and diaphoresis.^[7] The symptoms did not improve with levodopa, even in the 'on' state, but did improve with DA repletion. Finally, the symptoms could not be explained by other clinical factors.^[7]

According to the chart description of functional impairment by the patients themselves, their family and caregivers, and patients' follow-up, the severity of DAWS was classified by the assessor as either mild–moderate if impairment was limited to demanding activities or if it had some impact on the patient's and family daily life, or severe if there was considerable disruption of the patient's and family daily life or inability to perform basic activities of daily life. The duration of DAWS symptoms was classified as remitting and lasting less than 6 months, 6 months to 1 year, or over a year, or not remitting and unable to withdraw from DA.

In addition to the gender and marital status, the following clinical variables were recorded: age at DA withdrawal, age at PD onset, PD duration at withdrawal time, history of smoking, and smoking at DA withdrawal time, ICD before PD, illicit drug use before PD. On the state unified Parkinson's disease rating scale (UPDRS) motor subscale scores were recorded during routine visits at DA withdrawal time. The levodopa equivalent daily dose (LEDD) was calculated as: regular levodopa plus 0.75 times the dose of continuous release levodopa plus 1.3 times the dose of levodopa/entacapone plus 100 times the dose of pramipexole dihydrocloride or pergolide mesylate plus 20 times the dose of ropinirole hydrochloride.^[7,18] Treatment variables recorded were: reason for DA withdrawal, specific DA withdrawn, dosage of levodopa (LD-LEDD), dosage of DA (DA-LEDD), total LEDD (DA-LEDD plus LD-LEDD) at withdrawal, cumulative dose exposure for DA (maintenance DA-LEDD times years of treatment), levodopa treatment duration and DA treatment duration in years.

Categorical variables were compared using the χ² test if the number expected in each cell was five or greater, and utilising Fisher's exact test otherwise. Continuous variables with a normal distribution as determined by the Kolmogorov–Smirnov test were compared by Student's t test, and otherwise by the non-parametric Mann–Whitney U test. No correction for multiple comparisons was applied. Statistical analysis was carried out using SPSS V.13.0 for Windows statistical software. Significance was set at p<0 .05.="" span="">The ICD diagnosis was clinical, rendered by the patient's neurologist, and registered in the chart when appropriate symptoms were reported by patients, their families and caregivers. In patients with ICD as the cause of withdrawal, the speed of DA withdrawal (DA-LEDD decrease per week), previous ICD with other DA, type of ICD, and duration of ICD before withdrawal were recorded. Patients with a diagnosis of DAWS (DAWS+) were compared with patients without (DAWS−); this was done for all patients, and a second comparison was restricted to patients withdrawn from DA due to ICD.

Results

Four hundred and eighty-seven active charts were reviewed; 297 patients (61%) had been treated with a DA, and in 98 (33%) of these DA were discontinued. Fourteen of these 98 patients were excluded from analysis, 10 because of insufficient data on treatment or withdrawal follow-up, two because they underwent PD surgery close to the time of DA withdrawal, and two because they had dementia at the time of DA withdrawal (figure 1).

(Enlarge Image)

Figure 1.

Patient flow chart. DA, dopamine agonist.

Five patients had a remote history of functional PD surgery before withdrawal; none of them was withdrawn from DA because of ICD. ICD were the most common reason for DA withdrawal, representing 50% of the withdrawals (n=42). Other causes were hypersomnia (thirteen), hallucinations (seven), worsening PD symptoms (five), nausea (five), cognitive impairment (five), hypotension (four), limb oedema (two) and isolated anxiety (one).

Out of 84 patients analysed, 13 (15.5%) fulfilled the diagnostic criteria for DAWS, and 71 patients did not develop DAWS on withdrawal from DA (figure 1).

ICD were the reason for DA withdrawal in all 13 DAWS+ patients (100%), compared to an ICD frequency of 41% in DAWS− patients (29 of 71), (p<0 .0001="" p="">

Each patient with DAWS had at least four (mean 4.9, median 5) of the 13 clinical manifestations suggestive of DAWS observed. These symptoms represented a change from their previous functioning level and were related in time to DA discontinuation. The most common of these were depressed mood in eleven patients (84%), fatigue in ten (77%), anxiety in nine (69%) and insomnia in eight (61%). Autonomic dysfunction was recorded in six patients (46%) including diaphoresis, dizziness, nausea and flushed face; four patients (31%) had panic attacks, four (31%) generalised pain, three (23%) irritability, three (23%) drug cravings and one loss of interest (8%). One patient voiced suicidal thoughts during the withdrawal period.

None of the clinical or treatment variables evaluated (see Methods section) significantly differed between DAWS+ and DAWS− patients ( Table 1 ).

DAWS was observed in subjects withdrawn from pergolide (one), pramipexole (five) and ropinirole (seven); there was no statistically significant difference in the frequency of DAWS between the specific DA. In the group of patients withdrawn from DA because of ICD there was a trend towards a more frequent use of ropinirole than other DA (Fisher's exact test 0.043).

The levodopa dose was increased in all patients at the time of withdrawal. Three of the DAWS+ patients increased levodopa dosages by 15–20% above the dose recommended by their physician in an attempt to treat DAWS symptoms after DA withdrawal: one of them had a history of DDS years before DA withdrawal and another developed DDS approximately 1 year after recovering from DAWS. Among the DAWS− patients who were withdrawn from DA because of ICD, just one had a history of DDS. DAWS symptoms were not abated in any patient by increasing the dose of levodopa. The degree of functional impairment was classified as mild–moderate in seven patients and severe in six ( Table 2 ).

Forty-two patients underwent DA withdrawal because of ICD, 13 DAWS+ and 29 DAWS−. Table 3 shows the frequencies of ICD in DAWS+ and DAWS− patients. There were no statistical differences in the type of ICD between the DAWS+ and DAWS− groups ( Table 3 ).There was no evident relationship between either the degree of functional impairment or the evolution of DAWS and the LD-LEDD, DA-LEDD, cumulative DA-LEDD or total LEDD at withdrawal. Regarding the evolution of DAWS, eight patients recovered in less than 6 months, no patient had a resolution of symptoms between 6 months and 12 months, recovery took over a year in three patients, and two patients were unable to remain off of DA due to disabling symptoms of DAWS. These patients had persistent, chronic ICD associated with an inability to wean the DA ( Table 2 ).

Among the multiple demographic, clinical and treatment variables compared, the only differences within the group of patients withdrawn from DA because of ICD were that DAWS+ patients were taking higher doses of levodopa (expressed in LEDD) at the time of DA withdrawal (p<0 .02="" a="" and="" frequent="" had="" history="" href="" more="" nbsp="" p="" smoking="" style="color: #5757a6; text-decoration: initial;">Table 4

Discussion

Our retrospective chart review in a clinic practice setting confirms the concept of DAWS as identified by Rabinak and Nirenberg.^[7] Using the same diagnostic criteria, we found a very similar frequency of the syndrome among those patients in whom DA were withdrawn, 15.5% in our series versus 19% in theirs. A frequency of 7.8% of patients withdrawn from DA was reported in the only other study that we are aware of that examined DAWS.^[19] Unlike our study and that of Rabinak and Nirenberg,^[7] that series included subjects who had undergone deep brain stimulation (DBS) surgery while DA were discontinued, and thus some confusion with the postsurgical apathy-related features (see below) may have been possible.

Similarities in the results of our study and that of Rabinak and Nirenberg^[7] include the frequency of ICD as the cause of withdrawal from DA (50% vs 58%), the proportion of subjects who developed DAWS when ICD were the reason for DA withdrawal (approximately one third in both series), and the 100% association between DAWS and ICD, contrasting with the 34% reported by Limotai et al. ^[19]Previous ICD were significantly more common in DAWS+ than in DAWS− cases (p<0 .0001="" all="" at="" compared="" effect="" either="" magnitude="" marginal="" most="" of="" or="" other="" p="" significance.="" studied="" the="" this="" to="" variables="" were="" without="">

In our study the patients who attempted to improve their withdrawal symptoms by increasing their levodopa dose by 15–20% more than prescribed by their physician did not have other clinical manifestations suggestive of DDS at this time. DAWS symptoms did not disappear with equivalent or higher doses of dopaminergic medications other than DA, as previously reported.^[7] We cannot exclude the possibility that there may be a milder group of 'treatable DAWS' patients who had subtle DAWS symptoms and who responded to levodopa adjustment. Mild self-limited withdrawal symptoms not meeting the DAWS criteria of Rabinak and Nirenberg^[7] that we used in our study were included in a recent report of patients tapering DA.^[20] These patients would have been diagnosed as DAWS− in our study and it is not at all clear that the reported milder symptoms of low mood or apathy have the same pathogenic basis as the more complex psychostimulant drug withdrawal-like symptoms of DAWS. Self-medication with supratherapeutic doses of levodopa in an attempt to alleviate DAWS symptoms^[7] and the significant association reported in one series between DAWS and DDS^[19] suggest an overlapping vulnerability to DDS in the DAWS+ patients. This tendency of DAWS+ patients to escalate levodopa dosage is also consistent with 'negative reinforcement' models of addiction.^[2] Okai et al ^[15] considered that patients with DDS and even non-DDS patients often take extra medication to avoid the distress and dysphoria that appears during the off state, and propose that this pattern is similar to that of DAWS. In our opinion the two entities differ in that DAWS is related to a drug withdrawal situation, in contrast to the steady or escalating dose of levodopa in DDS patients, and the spectrum of symptoms of DAWS is broader and more typical of an addictive drug withdrawal. The symptoms of DAWS were extremely disruptive to the patients and their families: in almost 40% of patients, DAWS symptoms were either associated with a protracted course, taking over a year to withdraw the offending agent fully, or they were refractory to attempts to withdraw DA; these patients required ongoing treatment with the result that their ICD continued unabated.

The average age of PD onset in our series of patients is just over 50 years and below that expected in the general population.^[21] The presence of dementia as a clinical diagnosis stated in the chart as one of the exclusion criteria could have contributed to reducing the number of older patients included in our series. Our study was not designed to determine the frequency of ICD in PD patients treated with DA. Pathological gambling was the type of ICD most commonly observed, as reported by Voon et al. ^[13] The frequency of multiple ICD, observed in 28% of all our ICD patients, is similar to the one quarter^[6] and one third^[22] reported in other surveys. On the other hand, in patients with DAWS Rabinak and Nirenberg^[7] observed a much higher (80%) frequency of multiple ICD than our 30%. Among patients with ICD, there was no difference in the type or multiplicity of ICD between DAWS+ and DAWS− in our study, suggesting that the presence of DA-induced ICD, rather than the type or complexity, is the relevant predictor for the development of DAWS.

A significantly lower UPDRS motor score (suggesting a less severe form or earlier PD stage) in DAWS+ patients was reported previously,^[7] but we could not confirm this using on-state UPDRS scores obtained during routine clinic visits. Our failure to demonstrate a difference in motor symptomatology between DAWS+ and DAWS− patients does not exclude a role of the mesocorticolimbic system in the pathogenesis of DAWS. However, we did not find evidence to support a disproportionate sparing of the motor circuit in these patients.

In contrast to other studies, we did not find either a higher baseline dose of DA in DAWS patients^[7] or higher DA cumulative exposure,^[7,19] although a statistical trend towards higher cumulative DA-LEDD was observed (p=0.08). When we restricted the comparison to the group with ICD, DAWS patients had a higher LD-LEDD at DA withdrawal (p<0 .02="" associated="" be="" daws.="" development="" higher="" icd="" is="" ld-ledd="" of="" patients="" reported="" similarly="" style="font-size: 0.85em; line-height: 0;" sup="" than="" the="" to="" with="" without="">[6]

however, ICD can develop irrespective of DA dosage,^[6] and even with very low DA cumulative exposure in patients with restless legs syndrome.^[23–25]

All DAWS+ patients in the original report of Rabinak and Nirenberg^[7] were using pramipexole. We extend the concept of DAWS by describing this syndrome with other DA. We did not find statistically significant differences among the specific DA drugs in the frequency of development of DAWS in the total sample of 84 patients; however, the small numbers in each treatment group limit interpretation. Although in the group of patients withdrawn from DA because of ICD there was a trend towards a more frequent use of ropinirole than other DA (Fisher's exact test 0.043), we do not consider this result relevant because of the marginal significance. The RR of developing ICD with pramipexole compared to other DA has been disputed in the literature, but it is clear that several DA can induce the syndrome, and the general consensus is that this is a class effect.^[6,26–28] While reported cases of ICD in PD secondary to bromocriptine are scarce,^[29] the two patients withdrawn from bromocriptine in our series had ICD.

Among patients with ICD, a history of smoking (considered an addictive behaviour) was present more often in DAWS+ than in DAWS− patients (p<0 .03="" p="">

We did not correct for multiple comparisons. With this caveat it is interesting to note the trend we found in patients with ICD towards higher doses of dopamine replacement treatments and addictive behaviour in the DAWS+ group compared to the DAWS− group. Our study has two major limitations. First, it is a retrospective chart review with all the acknowledged problems inherent with this approach. Second, it is purely clinical, and thus contributes no insights into the pathophysiological mechanisms or the genetic risk factors for the development of DAWS.

Further prospective studies are required to determine the frequency and spectrum of severity of DAWS, and to define effective treatment for DAWS, given the potential for considerable disability and extended course experienced by many patients.In conclusion, DAWS is an important clinical problem with manifestations resembling those of other drug withdrawal syndromes and a relevant concept in the management of patients with PD. The individual tendency to develop ICD in response to exposure to any DA, rather than other treatment or demographic factors, may be the major determinant in the development of DAWS. The fact that a smoking history in the ICD group increases the likelihood of developing DAWS suggests a susceptibility to addiction in these patients. A higher dose of levodopa may also contribute to the development of DAWS in patients with ICD.

Alzheimer's Disease

2013-02-10T17:26:00.000-08:00

Alzheimer's Disease

Mimics and Chameleons

Jonathan M Schott, Jason D Warren

Pract Neurol. 2012;12(6):358-366.

Abstract and Introduction

Introduction

Alzheimer's disease (AD), the commonest cause of dementia, is estimated to affect over 400 000 people in the UK,^[1] with numbers around the world set to rise dramatically as the population ages. Distinguishing AD from other causes of cognitive impairment is important for numerous reasons, including provision of appropriate care and access to medications. As and when disease-modifying therapies become available, the priority for earlier and more accurate diagnosis will increase still further.

An important starting point is the definition of AD. This is not as straightforward as it might seem: concepts of AD have evolved rapidly over recent years, with new criteria proposed as recently as 2011 continuing to provoke debate. Ultimately, a diagnosis of AD requires pathological confirmation. However, even a pathological diagnosis comes with a degree of uncertainty^[2] and the pathological phenotype of AD is itself heterogeneous.^[3]

Diagnosis in life has until relatively recently depended on very broad clinical criteria dating back to the 1980s, mandating that an individual be 'demented', that is, have progressive impairment of memory and at least one other cognitive domain sufficient to impact on activities of daily living.^[4] The new criteria for diagnosis of AD have built on a large body of work demonstrating that biomarkers of AD—including MRI, cerebrospinal fluid (CSF) and positron emission tomography (PET)—may improve diagnostic sensitivity and specificity. The criteria also reflect a growing move to try to achieve earlier diagnosis. The new criteria propose that AD can be diagnosed with different degrees of certainty based on the extent of the cognitive deficits and presence/absence of biomarker abnormalities. These criteria were reviewed recently in this journal.^[5]

For the purposes of this article and with the aim of providing a practical guide to the differential diagnosis of AD, we will first consider the 'typical' clinical presentation of late-onset, sporadic, amnestic AD, before reviewing other conditions that can mimic these symptoms. Turning then to the chameleons, we will discuss some atypical or unusual clinical presentations that can be associated with histologically proven AD.

Clinical Features of 'Typical' AD

commonest cause. The prevalence roughly doubles every 5 years, from ~1% in 65-year-olds to 69-year-olds to 30%+ in those aged 90 years or more.^[1] AD is typically sporadic, that is, the vast majority of patients do not have a family history consistent with autosomal-dominant inheritance. The cognitive deficits of AD are typically insidiousrather than rapid in onset, with early problems relating to subtle changes in confidence and the emergence of problems with episodic memory, for example, forgetting appointments and telephone conversations. As the disease progresses, patients develop problems in other cognitive domainsincluding anomia; problems with route finding and orientation; problems with arithmetic (eg, handling money) and spelling; and difficulties with multitasking and problem-solving. Whereas a degree of social withdrawal and depression are common, patients with mild–moderate AD typically have a preservedsocial façade, without major personality change. Early in the disease course the physical examination is typically normal, although later myoclonus is fairly common. The disease typically slowly and relentlessly progresses over several years, with concomitant impairments in activities of daily living requiring increasing assistance, until the patient eventually becomes dependent. Death occurs after a median of ~7 years,^[6] although with considerable variation between individuals. Currently, no investigations are required to reach a diagnosis of AD, although all patients should have blood testing and structural brain imaging as part of the diagnostic work-up.^[7] Brain imaging may be normal in the very early stages, but progressive atrophy, usually symmetrical and particularly involving medial temporal lobe structures, is typical. CSF examination is not routinely performed, but would be expected to be acellular and without oligoclonal bands. Where available, testing for CSF β-amyloid (Aβ)1–42 (low) and tau or phosphorylated tau (raised) supports a diagnosis of AD.^[8] Although not currently part of routine clinical practice, functional imaging using single photon emission computed tomography (SPECT) or glucose PET typically reveals temporo-parietal hypometabolism.^[9] Amyloid deposition can be imaged in vivo using PET combined with ¹¹C PIB (Pittsburgh Compound B) or a number of relatively new ¹⁸F amyloid tracers,^[10] one of which (Florbetapir, or Amyvid) was recently licensed for clinical use in the USA.

Mimics: What's not Typical AD, But Looks Like It?

In view of its remarkably high prevalence in the elderly, AD is often the 'default' dementia diagnosis. While many conditions superficially resemble AD, few are really true mimics (Table 1). Here we adopt a pragmatic position, and focus on conditions that might mislead an experienced general neurologist. As this group includes several potentially reversible entities, accurate diagnosis is especially important.

'Worried Well'

Often the most difficult diagnostic challenge arises when a patient presents with very mild cognitive complaints, which could potentially represent early AD, but might also reflect the effects of ageing or anxiety. The situation is further complicated by evidence suggesting that older individuals with concerns about memory but no objective impairment (so-called worried well) may have a higher incidence of subsequent conversion to AD.^[11] In our experience, cognitive symptoms more suggestive of anxiety than degeneration include concerns about normal phenomena (eg, not remembering why one has entered a room or going on 'automatic pilot' when driving) or reports of dramatic worsening with stressors despite normal function at other times. Obtaining a collateral history is paramount, and may be very revealing.^[12] Often, the anxious patient is more concerned than the informant, whereas the opposite is more typical in AD. There is some evidence to suggest that individuals asked to bring a collateral source to a consultation but who attend alone are less likely to have an organic cause for their symptoms.^[13] A further pointer to anxiety may be impaired performance on bedside cognitive testing despite demonstrably competent and unchanged performance in everyday life. On the contrary, deteriorating occupational or social confidence (particularly when corroborated by others) and early loss of topographical or visuospatial awareness are red flags for AD even in an otherwise competent individual. The extent to which it is appropriate to investigate the 'worried well' depends on the situation. Formal neuropsychometry is very helpful in determining whether there are objective focal impairments, which when present should prompt further investigation. In case of doubt, interval assessment and investigation may help to determine whether there has been objective evidence for decline, as would be expected in a neurodegenerative condition.

Depression and Other Psychiatric Disorders

The pattern of cognitive impairment associated with depression may overlap with that seen in the worried well, and is often qualitatively different from that seen in AD. Impaired concentration and attention is often prominent, leading to poor registration of information: where patients do attend to the task in hand, performance may improve dramatically. Direct questioning may reveal biological symptoms of depression, and it may be helpful to ask specifically about current and past stressors, and for the presence of ruminations and impaired concentration. Depression, however, may complicate existing AD, and there is a growing body of evidence to suggest that depression may either be a risk factor or an early manifestation of AD, consistent with the dysfunction of limbic structures predicted on neuroanatomical grounds. We are particularly cautious about attributing cognitive concerns to depression in older individuals particularly without obvious stressors or previous psychiatric illness. In such cases we investigate, treat the depression and have a low threshold for keeping the patient under review until the situation is clarified.

Metabolic

It is important to exclude metabolic conditions that may influence cognition, and we routinely check glucose, B12, folate and thyroid function in all patients. Although it is not uncommon to detect abnormalities in these variables, particularly in the elderly, it is rare in our practice for these conditions to be profound, or on careful questioning closely to mimic AD; there is ongoing debate as to whether certain vitamin deficiencies may be risk factors for AD. It is important to correct/treat any such abnormalities, and in selected cases this can give quite dramatic improvements.^[14] However, we would usually be cautious about attributing progressive episodic memory impairment or other focal deficits to metabolic derangements, particularly with imaging evidence for atrophy.

Infection

Although several acute infections—notably herpes simplex encephalitis—may lead to memory impairments that in the chronic state might resemble those of AD, infection is not usually a realistic mimic of AD, either on history or on cognitive examination. Primary HIV infection or syphilis can undoubtedly cause cognitive impairment, but we have not seen either truly mimicking AD clinically, and both can be excluded through appropriate investigations.

Tumours, Space-occupying Lesions and Hydrocephalus

Mass lesions involving the temporal lobes can cause progressive memory impairments conceivably resembling AD, but this is not common and is easily resolved through structural imaging. Normal pressure hydrocephalus (NPH) is a controversial entity, classically associated with the triad of cognitive impairment, urinary incontinence and gait disturbance. The frequency by which NPH is diagnosed varies very widely between centres, and, at least in our experience, rarely mimics classical AD. Although the role of Alzheimer pathology in NPH is debated, there is evidence that individuals with significant plaques and tangles have worse outcomes following shunting, suggesting that AD biomarkers may have role in selecting patients for surgery.^[15]

Autoimmune Cognitive Syndromes

The spectrum of autoimmune disorders affecting the central nervous system has expanded dramatically over the last decade. Several antibodies can cause paraneoplastic or non-paraneoplastic limbic encephalopathies (there have been recent reviews on both in this journal).^[16,17] These conditions are usually distinct from typical AD, being rapid and associated with acute encephalopathy, seizures and/or movement disorders, and often signal change on MRI. Patients who have recovered from limbic encephalitis—particularly voltage-gated potassium channel complex receptor antibody (LGi1 (leucine-rich glioma inactivated 1 gene)) type—may be left with a dense amnesia and focal hippocampal atrophy on MRI, which superficially may resemble AD. However, the type of amnesia in such patients is usually different from that seen in AD, taking the form of a dense and often temporally ungraded loss of memory for events for many years preceding the acute illness.^[18] However, the spectrum of recognised phenotypes associated with these disorders continues to expand, and there are at least anecdoctal reports of elderly patients with a syndrome of insidiously progressive amnesia and hippocampal atrophy closely resembling AD; and a recent study demonstrated synaptic autoimmunity in a proportion of patients with NMDA receptor antibodies and unexplained slowly progressive cognitive impairment.^[19]Pragmatically, where the differential diagnosis includes autoimmunity and AD, clinicians should consider testing for neuronal-specific antibodies and/or assessing the CSF for AD markers.

Vascular Cognitive Impairment

Vascular cognitive impairment (VCI) is very common and can—at least clinically—closely resemble AD. As with AD, VCI becomes more common with age and in contrast to previous dogma, is more usually associated with insidiously progressive than stepwise evolution.^[20] AD and VCI share many risk factors—notably hypertension, and commonly coexist. Clinical clues to a diagnosis of VCI include cognitive slowing, relatively preserved episodic memory, lack of mental flexibility and subtle personality change. The presence of a brisk jaw jerk, facial jerks and deep tendon reflexes—with or without asymmetry—often with flexor plantars is suggestive of VCI; the classical 'marche à petits pas' gait is useful when present, but in our experience—at least in a cognitive clinic—is not particularly common. The absence of conventional vascular risk factors, although not excluding the diagnosis, should prompt reappraisal. Imaging—particularly with T2/fluid attenuated inversion recovery MRI—has revolutionised the diagnosis of cerebrovascular disease, and is generally decisive; the diagnosis of VCI becomes untenable if the scan shows no significant vascular damage. It is important not to overcall the extent of vascular burden: a small vascular load is common in the elderly and the pattern and extent of vascular changes needs to be correlated with the clinical picture. It is also important not to be distracted by the vascular pathology and to ignore the presence of medial temporal lobe atrophy, which may point to coexistent or even dominant AD pathology. On the contrary, strategic vascular damage (eg, affecting the thalamus) may produce a disproportionate cognitive deficit even if the overall vascular burden is mild.^[21] Detailed history taking may reveal a history of acute decline in such patients. When performed, T2* or susceptibility-weighted imaging can usefully demonstrate the presence of iron, and thus cerebral microbleeds. Microbleeds in subcortical structures are typical of vascular disease, whereas lobar-specific microbleeds are thought to reflect amyloid angiopathy and thus may be markers of AD pathology, although they only occur in minority of cases.^[22]

Epilepsy

Epilepsy and AD are both very common and not infrequently coexist. However, seizures do not typically occur as a consequence of AD pathology until the disease is advanced. Medial temporal lobe seizures can lead to significant memory impairment—transient epileptiform amnesia (TEA)—in the absence of other seizure-related phenomena. Very frequent, subclinical seizure activity can produce a clinical syndrome reminiscent of AD. Clinical features that should raise suspicion of TEA include periods of dense amnesia for distinct events (eg holidays) with relative preservation at other times, amounting to 'gaps' in the memory record; worsening after sleep; and a history of olfactory hallucinations, staring episodes or automatisms suggestive of epileptic activity.^[23] Prolonged EEG may be required to determine epileptiform activity, and in addition to brain MRI, we have a low threshold for checking VGKC receptor complex and NMDA antibodies (although these are rarely positive) and examining the CSF in such patients.

Drugs and Alcohol

Drugs and alcohol can both cause significant cognitive decline, but neither in isolation produces a clinical syndrome likely to be mistaken for AD. One possible exception is Korsakoff's psychosis where patients have very severe episodic memory impairments, albeit usually without the typical loss of confidence and intellectual blunting that is typical for AD. As well as a history of Wernicke's encephalopathy (if elicited), another potentially useful clinical clue is confabulation, which is common and may be profound in Korsakoff's,^[24] but at least in our experience, is relatively rare in AD.

Sleep Apnoea

Obstructive sleep apnoea is not an uncommon cause of memory complaints and referral to memory clinics, and can occasionally mimic the clinical manifestations of AD surprisingly closely. As obstructive sleep apnoea is potentially treatable we routinely ask patients and their partners about sleep and snoring; where it is a possibility sleep studies should be performed.

Other Neurodegenerative Disorders

AD is most frequently and closely mimicked by other neurodegenerative diseases. Even in specialist centres, the in vivo diagnosis is not infrequently incorrect: in a recent study 88/526 (16.7%) patients diagnosed with clinically probable AD had alternate diagnoses at postmortem; the vast majority (78/88, 89%) of these had other neurodegenerative diseases.^[2]

Frontotemporal Lobar Degeneration

Frontotemporal lobar degeneration (FTLD) comprises a diverse group of disorders with non-AD proteinopathies including tau and TDP-43. FTLD can broadly be divided into behavioural variant frontotemporal dementia (bvFTD); and primary progressive aphasia.^[25] In keeping with all neurodegenerative diseases, at their most extreme these conditions are phenotypically very distinct from 'classical' AD. However, some patients with FTLD pathologies, particularly those with mutations in the tau gene,^[26] and some patients with TDP-43 pathology—including individuals who go on to develop FTD/motor neurone disease either on a sporadic basis or due to mutations in the recently identified C9orf72 gene^[27] —can present with an insidious onset of episodic memory impairment, sometimes with focal medial temporal lobe atrophy resembling AD. We have occasionally seen the progressive anomia of early semantic dementia mistaken for episodic memory impairment, and thus AD, though the semantic dementia syndrome (in particular, the early disintegration of verbal and semantic knowledge) is highly distinctive and not a feature of typical AD. In difficult cases, demonstration of amyloid deposition using CSF measures of Aβ1–42 (or in due course, amyloid PET) may help to distinguish AD from non-AD pathologies.

Dementia with Lewy bodies (DLB) is the second-most common neurodegenerative cause of later life dementia, and is typically associated with several clinical features that are uncommon in AD. These include significant cognitive fluctuations, motor parkinsonism, hallucinations, REM sleep behaviour disorder and autonomic dysfunction. Consensus clinical criteria, based on these and other features, have high sensitivity and specificity for DLB.^[28] However, some patients with postmortem-proven DLB have a clinical course dominated by progressive memory impairment without the emergence of any of these features (case vignette 1). MRI may be helpful in distinguishing AD from DLB on a group level with medial temporal lobe structures typically affected relatively selectively early on in AD but relatively preserved in DLB; this is, however, not always useful on an individual patient basis. DLB often shows evidence of nigrostriatal degeneration on dopamine transporter imaging. However, even with investigations, it may not be possible to distinguish AD and DLB during life: in the absence of motor parkinsonism patients may have negative dopamine transporter imaging. As DLB and AD commonly coexist at postmortem, even an AD-like CSF profile does not exclude concomitant DLB pathology.

Case Vignette 1 A 74-year-old woman was referred with a 2-year history of progressive problems with episodic memory. On examination, she scored 23/30 on the mini-mental state examination (MMSE), and there was evidence for episodic memory impairment and subtle loss of confidence. The neurological examination was normal. MRI showed mild volume loss involving medial temporal lobe structures. Neuropsychometric testing confirmed generalised intellectual underfunctioning and significant episodic memory impairment. A diagnosis of AD was made and she was started on an acetylcholinesterase inhibitor, which improved her attention and memory. Over the following years she began to get lost, and developed progressive cognitive impairments. Seven years into the course of the disease, the MMSE was 5/30. There were no Parkinsonian signs, significant fluctuations or hallucinations at any stage during the disease. She died 9 years after disease onset. At postmortem examination, the pathological diagnosis was of DLB without significant AD pathology. This case both demonstrates the difficulties of in vivo diagnosis based on clinical phenotype, but also the value of a trial of acetylcholinesterase inhibition—which may be particularly helpful in the context of Lewy body pathology—where AD is possible.

Other Neurodegenerative Conditions

Chameleons: Unusual and Atypical Presentations of ADOf the large range of other neurodegenerative pathologies, most do not usually produce a phenotype consistent with AD. Exceptions include argyrophilic grain disease or tangle-only dementia, which are currently not reliably diagnosable during life.^[29] Autosomal-dominant mutations in the prion gene can produce a slowly progressive amnestic syndrome indistinguishable from AD.^[30] These patients generally have a younger age at onset; the family history, while often informative, may be censored. Very occasionally patients with hippocampal sclerosis can develop a dementia that can be mistaken for AD: whether the hippocampal sclerosis in such cases is occurring on a degenerative, autoimmune, infective or other basis remains unclear.^[31] Patients with progressive supranuclear palsy often have significant cognitive and behavioural changes which, although usually very different from those seen in AD, are a conceivable mimic. Such cases, although rare, demonstrate the very real difficulties of determining a definitive diagnosis during life and support the use of well-validated, AD-specific biomarkers in unusual or atypical cases.

A small although significant proportion of patients with AD present in ways that diverge from the typical pattern outlined above.

Young Onset AD

Young-onset dementia is arbitrarily defined as disease onset below 65 years.^[32] Of the myriad causes of dementia in this group, AD is still the most common neurodegenerative aetiology. Although some patient with young-onset AD (YOAD) have a disease otherwise indistinguishable from typical, late onset AD, they are more likely to have a non-amnestic phenotype, or autosomal-dominant disease (see below). Patients with otherwise typical YOAD are more likely to have early and sometimes quite prominent myoclonus, which, combined with their young-onset disease, can cause diagnostic confusion.

Familial AD

Autosomal-dominantly inherited familial AD (FAD) due to mutations in the APP, Presenilin 1 or Presenilin 2 genes accounts for <1 50="" a="" ad.="" ad="" age="" all="" and="" as="" aside="" associated="" at="" be="" before="" by="" can="" cognitive="" contrast="" course="" decade.="" detail="" disease="" domains="" early="" episodic="" experience="" fad="" fairly="" feature="" fourth="" from="" have="" however="" impairment="" in="" involve="" is="" least="" may="" memory="" mutations="" of="" onset:="" other="" otherwise="" our="" over="" patients="" phenotypic="" present="" presenting="" progressing="" reviewed="" rossor="" ryan="" several="" specific="" sporadic="" striking="" style="font-size: 0.85em; line-height: 0;" sup="" the="" their="" these="" time.="" to="" typical="" typically="" uncommon.="" variants="" very="" with="" years="" young-onset="" young="">[33]

). These include patients with prominent language impairment; and those with behavioural and psychiatric changes sometimes sufficient to be mistaken for frontotemporal dementia. To date, FAD has not been associated with visual (posterior cortical atrophy) variant AD (see below). Neurological signs are more prominent in FAD than sporadic AD: myoclonus and seizures are common, with certain mutations being associated with spastic paraparesis, extrapyramidal signs or cerebellar ataxia. Patients with APP duplications have a very high frequency of seizures, white matter signal change on MRI and prominent amyloid angiopathy. Two important clinical points are that the absence of a family history does not preclude a diagnosis of FAD, particularly if the family history is censored; and that certain mutations can also be associated with late-onset FAD.^[34]

Posterior Cortical Atrophy

In posterior cortical atrophy (PCA), as the name suggests, the burden of the disease is at least initially focused on the parietal/occipital rather than temporal lobes: this syndrome has recently been reviewed in detail.^[35] Patients with PCA are typically young (50–65 years), but not exclusively so. Patients often have early anxiety, followed by the emergence of problems centred on combinations of visual processing, praxis, calculation and spelling, with relative preservation of memory, naming and executive function (case vignette 2). Imaging can be normal, but MRI often shows focal posterior atrophy (figure 1) and PET/SPECT hypometabolism. Patients are not infrequently initially dismissed as functional, and/or referred to opticians or ophthalmologists, before a diagnosis is made.

Case Vignette 2 A 55-year-old man presented with a 3-year history of progressive problems in several cognitive domains including calculation, spelling, dressing and performing complex tasks. There were no significant problems with memory, or of personality change. On examination, the MMSE was 28/30, and there was finger myoclonus. Bedside and formal neuropsychometric testing showed significant parietal lobe dysfunction with impaired spelling and calculation, and prominent dyspraxia. He could not identify fragment letters. There were mild word-finding difficulties, but episodic memory was relatively spared. The MRI scan showed mild generalised atrophy, with prominent parietal lobe volume loss (Figure 1). There was progressive cognitive impairment over the following years, although significant memory decline was not evident until 7 years after disease onset. He developed seizures 8 years into the course of the disease, and died 1 year later. Postmortem examination of the brain confirmed severe Alzheimer pathology.

(Enlarge Image)

Figure 1.

Coronal volumetric 1.5 T MRI scan from case vignette 2 shows marked parietal lobe atrophy. The hippocampal volumes were by contrast preserved.

AD Presenting With Language Disturbance

For some patients with AD, progressive language decline is the presenting feature.^[36] These cases include those with a fairly specific AD-related syndrome—logopenic aphasia (LPA)—and those with a syndrome overlapping with progressive non-fluent aphasia (PNFA) or, less commonly, semantic dementia (SD). In LPA, speech is typically hesitant, with long word-finding pauses, prominent anomia, reduced digit span, particular difficulty repeating phrases and sentences compared with single words, and the early emergence of associated dominant parietal deficits. Clinically, a minority of patients with a PNFA or SD syndrome have underlying AD pathology. Such cases can closely resemble language cases with the more typical non-AD pathologies. In contrast to typical AD, in language-led syndromes, the MRI scan is more likely to show asymmetrical atrophy; and in SD there is usually strikingly focal involvement of the anterior-dominant temporal lobe. CSF and/or amyloid PET may help to confirm or refute the presence of AD pathology.

Frontal or Dysexecutive AD

Early behavioural changes—either disinhibition or apathy—characterise the bvFTD syndrome: while most cases are due to non-AD pathologies, some of these patients have AD at postmortem.^[37]Prominent episodic memory impairment may be a feature in these cases but no clinical or structural neuroimaging features reliably differentiate AD from non-AD pathologies in the bvFTD spectrum, and this remains one of the most diagnostically challenging of the AD chameleons. CSF and amyloid PET biomarkers may prove decisive but their role is not yet established.

Corticobasal Syndrome Due to AD

Corticobasal syndrome is an asymmetric, akinetic-rigid, levodopa resistant syndrome, with additional features including apraxia, cortical sensory loss, focal myoclonus, dystonia and alien limb phenomena. It is increasingly recognised that cognitive decline is part of the protean corticobasal syndrome; this may take the form of language impairment, executive or behavioural dysfunction, or posterior cortical deficits overlapping the syndrome of PCA. This phenotypic variation is underpinned by wide histopathological heterogeneity; recent studies have demonstrated that 15–20% of cases are due to AD pathology.^[38]

Rapid AD

Case Vignette 3 A 59-year-old woman presented with a 14-month history of progressive memory decline accompanied by myoclonus and generalised tonic–clonic seizures. There was no relevant medical or family history. On examination, she showed severe widespread cognitive impairment, myoclonus and brisk tendon reflexes. Blood screens were normal. Brain MRI showed mild generalised atrophy with no signal abnormalities. An EEG showed multifocal epileptiform changes with a diffuse excess of slow activity. CSF examination showed normal basic constituents and negative oligoclonal bands. A right frontal lobe biopsy, performed to exclude cerebral vasculitis, revealed the features of AD, with no evidence of vascular or other superadded pathology.While AD is typically slowly progressive, it may be much more rapid, sufficiently so that brain biopsy has been performed in some cases, principally to exclude cerebral vasculitis (case vignette 3).^[39] Atypical features reported in rapid AD include myoclonus, gait ataxia, extensor plantar responses, hallucinations, aphasia and falls, sometimes sufficient to suggest prion disease.^[40] In such cases, imaging and CSF studies are particularly valuable. Although the mechanisms are not entirely clear, there is likely to be some overlap between AD, and rare cases of inflammatory cerebral amyloid angiopathy.

Conclusions

AD generally presents as a slowly progressive amnestic syndrome in later life, but there are several conditions that can mimic AD; conversely AD can mimic a range of other conditions. The high prior likelihood that an elderly individual with cognitive impairment has AD should not preclude consideration of other causes, and in particular it is always important to consider 'reversible' or treatable conditions, even if they are rare. Aside from endogenous variation in the AD phenotype, a further issue (particularly in older patients) is the real possibility of mixed pathology, eg, superadded vascular damage or Lewy body pathology, which may modify the AD phenotype. In many cases, careful history taking and bedside assessment can help to define atypical or unusual cases, but standard investigations—particularly MRI and neuropsychology—can be very useful in assessing the likelihood of AD versus other conditions. Pragmatically, while we advocate attempting to arrive at a diagnosis with reasonable certainty, we have a low threshold for empirical trials of treatment for AD in patients with an AD-like phenotype or one of the canonical chameleon syndromes (particularly PCA and LPA). This situation will, however, be transformed by the advent of targeted disease-modifying therapies with the potential both for substantial benefit but also side effects. This prospect lends impetus to the search for new and robust in vivo biomarkers of AD pathology: such biomarkers are already beginning to revolutionise differential diagnosis, and will continue to do so as they are more widely adopted

.

Impact of Perioperative Dexamethasone on Postoperative Analgesia and Side-effects

2013-02-10T17:22:00.003-08:00

Impact of Perioperative Dexamethasone on Postoperative Analgesia and Side-effects

Systematic Review and Meta-analysis

N. H. Waldron, C. A. Jones, T. J. Gan, T. K. Allen, A. S. Habib

Disclosures

Br J Anaesth. 2013;1(2):191-200.

Abstract and Introduction

Abstract

The analgesic efficacy and adverse effects of a single perioperative dose of dexamethasone are unclear. We performed a systematic review to evaluate the impact of a single i.v. dose of dexamethasone on postoperative pain and explore adverse events associated with this treatment.

Methods MEDLINE, EMBASE, CINAHL, and the Cochrane Register were searched for randomized, controlled studies that compared dexamethasone vs placebo or an antiemetic in adult patients undergoing general anaesthesia and reported pain outcomes.

Results Forty-five studies involving 5796 patients receiving dexamethasone 1.25–20 mg were included. Patients receiving dexamethasone had lower pain scores at 2 h {mean difference (MD) ™0.49 [95% confidence interval (CI): ™0.83, ™0.15]} and 24 h [MD ™0.48 (95% CI: ™0.62, ™0.35)] after surgery. Dexamethasone-treated patients used less opioids at 2 h [MD ™0.87 mg morphine equivalents (95% CI: ™1.40 to ™0.33)] and 24 h [MD ™2.33 mg morphine equivalents (95% CI: ™4.39, ™0.26)], required less rescue analgesia for intolerable pain [relative risk 0.80 (95% CI: 0.69, 0.93)], had longer time to first dose of analgesic [MD 12.06 min (95% CI: 0.80, 23.32)], and shorter stays in the post-anaesthesia care unit [MD ™5.32 min (95% CI: ™10.49 to ™0.15)]. There was no dose–response with regard to the opioid-sparing effect. There was no increase in infection or delayed wound healing with dexamethasone, but blood glucose levels were higher at 24 h [MD 0.39 mmol litre^™1 (95% CI: 0.04, 0.74)].

Conclusions A single i.v. perioperative dose of dexamethasone had small but statistically significant analgesic benefits.

Introduction

Glucocorticoids have been used to reduce inflammation and tissue damage in a variety of conditions, including inflammatory bowel disease, rheumatoid arthritis, and some malignancies. Glucocorticoids have potent immunomodulatory effects, and are used in the treatment of acute allograft rejection. They also have antiemetic properties and dexamethasone is commonly used for the prevention of postoperative nausea and vomiting (PONV).^[1–3]

Long-term treatment with glucocorticoids is associated with many side-effects.^[13] However, it is unclear if a single perioperative dose of dexamethasone increases the risk of these adverse effects. This is due to many of the published studies being underpowered to detect clinically relevant side-effects,^[2] and many studies also excluded patients at the highest risk of glucocorticoid-related adverse effects.^[1]The efficacy of glucocorticoids for reducing pain and inflammation after surgery has recently been explored. Early studies in patients undergoing dental procedures showed that glucocorticoids were effective in reducing postoperative pain and oedema.^[4–6] A number of recent studies have investigated the potential analgesic benefit of a single perioperative dose of dexamethasone but have inconsistent findings.^[7–12]

We therefore performed this systematic review to determine if a single perioperative dose of dexamethasone in adult surgical patients undergoing surgery under general anaesthesia has a useful analgesic effect in the postoperative period. We also investigated whether the use of dexamethasone increases the risk of postoperative adverse effects
.

Complications of intracerebral haemorrhage

2013-02-07T09:07:00.000-08:00

Complications of intracerebral haemorrhage

Joyce S Balami, MRCP^a
Alastair M Buchan, Prof, FMedSci

^a Acute Stroke Programme, Department of Medicine and Clinical Geratology, Oxford University Hospitals NHS Trust, Oxford, UK
^b Acute Vascular Imaging Centre, University of Oxford, Oxford University Hospitals NHS Trust, Oxford, UK

^* Correspondence to: Prof Alastair M Buchan, Biomedical Research Centre, University of Oxford, Oxford University Hospitals NHS Trust, John Radcliffe, Oxford, OX3 9DU, UK

E-mail address: alastair.buchan@medsci.ox.ac.uk

Introduction

Spontaneous or primary intracerebral haemorrhage (ICH) is a major cause of morbidity and mortality worldwide. It is the second most common form of stroke, accounting for 10–30% of first-ever strokes.^[1]^,^[2]^,^[3]The 30 day mortality for ICH has been reported to be 30–55%,^[1]^,^[2]^,^[3]^,^[4]^,^[5]^,^[6]with half the deaths occurring in the acute phase, especially in the first 48 h.^[1]^,^[2]^,^[5]The complications of ICH are among the major predictors of early mortality and poor outcome.

ICH complications include haematoma expansion (HE), perihaematomal oedema (PHE), intraventricular extension of haemorrhage (IVH) with hydrocephalus, seizures, venous thromboembolic events (VTE), hyperglycaemia, increased blood pressure (BP), fever, and infections. Complications such as HE,^[7]^,^[8]IVH with obstructive hydrocephalus,^[9]^,^[10]^,^[11]and hyperglycaemia^[4]^,^[12]^,^[13]are major predictors of increased early mortality and adverse outcome during the hyperacute phase of ICH. Similarly, HE, hydrocephalus, and PHE have been associated with early neurological deterioration (END) and poor outcome.^[14] A prospective observational study reported END in about 33% of patients with ICH within 48 h of onset, with an associated 30 day mortality of 47% in those with END.^[14]

The complications of ischaemic stroke (IS) and their management have been reviewed extensively,^[15]^,^[16]with little discussion of the complications of ICH. Despite its seriousness, the treatment options for ICH are restricted and few evidence-based data exist to guide the management of ICH complications. By contrast with IS, for which therapeutic advances have been made to improve clinical outcome, the management of ICH is generally supportive, but with poor prognosis because no specific treatments have been shown to improve outcome after ICH. For example, the management of HE is of unproven value because all measures aimed at restricting HE have so far not improved outcome in controlled trials. Similarly, PHE management is mainly supportive and measures aimed at decreasing intracranial pressure (ICP) are also of unproven value. Also, insufficient evidence exists with regard to the efficacy of surgical treatment for ICH, and whether or not surgical approaches are beneficial remains controversial.

Additional therapeutic dilemmas can arise over the safest and most effective approach to VTE prevention in patients with ICH because prophylaxis with anticoagulants can increase the risk of HE or further bleeding. Perhaps a more difficult therapeutic dilemma is how to manage patients with clinical thromboembolic complications after ICH, balancing the risk of subsequent life-threatening thromboembolism if untreated against the risk of recurrence of ICH. A related issue is whether or when to resume anticoagulation after ICH in patients with cardiac disease associated with high embolism risk, such as those who need mechanical valve prostheses or those with atrial fibrillation.

In this review, we focus on the early complications of ICH, discussing emerging therapies and relevant preventative and management strategies based on available evidence and guidelines. We draw attention to the scarcity of evidence to guide the management of many important and common complications of ICH.

Haematoma expansion

Clinical features

HE, defined as an increase in volume of 33–50% or an absolute change in haematoma volume of 12·5–20 mL (on repeat CT), is a common early and severe complication of ICH.^[8]^,^[17]^,^[18]^,^[19]^,^[20]Although HE is one of the main pathophysiological phases of ICH, it can also be a serious complication subsequent to the acute phase—up to 40% of the haematoma grows in the first few hours post ictus. Various terms such as haematoma extension, expansion, progression, growth, enlargement, and rebleeding have been used to describe this subsequent increase in haematoma volume after ICH.

The precise mechanism of early HE during the acute phase is poorly understood. It is proposed to be a heterogeneous process that includes dysregulation of haemostasis via inflammatory cascade activation and matrix metalloproteinase (MMP) overexpression, breakdown of the blood–brain barrier, a sudden increase in ICP leading to local tissue distortion and disruption, and vascular engorgement due to reduced venous outflow.^[8] Early HE can also result from an increased plasma concentration of cellular fibronectin (c-FN) and the inflammatory mediator interleukin-6 (IL-6).^[21] Pathological studies have shown multiple microscopic and macroscopic bleeding points around the border of haemorrhages, arising from ruptured arterioles or venules that result from the stretching of surrounding vessels after clot expansion.^[22]

Several studies indicate that early HE occurs in 18–38% of patients scanned within 3 h of ICH onset^[7]^,^[18]^,^[19]and more than 70% develop at least some extent of HE within 24 h of symptom onset,^[23] even in the absence of known coagulopathy, suggesting an active bleeding process in the hyperacute phase of ICH.^[22] In warfarin-associated ICH, 27–54% of patients develop early HE and a delayed expansion because of protracted bleeding,^[24]^,^[25]^,^[26]which is associated with up to 70% increase in mortality.^[24]^,^[27]

A prospective study showed 38% of patients had an increase in haematoma volume (>33% increase compared with admission CT) within 3 h of symptom onset. HE was evident even within 1 h of the baseline scan in two-thirds of those patients, whereas an additional 12% developed growth within the next 21 h, which suggests continued active bleeding.^[7] Subsequent prospective studies have confirmed this finding, noting that 23–32% of patients had an increase in haematoma volume (>33% from baseline or 12·5 mL) in the first 24 h.^[8]^,^[20]

CT angiographic studies that show contrast extravasation (the so-called spot sign) into the haematoma^[28]^,^[29]^,^[30]have provided additional evidence of progressive bleeding several hours after the onset of ICH. The spot sign is an important predictor of haematoma growth and might be useful in the prediction of HE with high specificity^[28]^,^[29]^,^[30]and as a predictor of mortality.^[28]^,^[30]^,^[31]In fact, the spot-sign score (figure 1), which is used to grade the number of spot signs and their maximum dimensions and attenuation, is the strongest predictor of HE and is an independent predictor of in-hospital mortality and poor outcome in people with ICH.^[31]

Other important predictors of HE include large haematoma volume on presentation,^[29]^,^[32]early presentation (especially within 3 h of onset),^[17]^,^[19]^,^[29]^,^[32]heterogeneity of haematoma density on admission CT,^[33] and prior use of warfarin.^[17]^,^[24]^,^[25]Blood biomarkers such as increased IL-6, MMP-9, c-FN, and tumour necrosis factor, reduced platelet activity,^[21] reduced fibrinogen concentrations,^[19] and increased serum creatinine,^[32] have been suggested to predict HE in patients with ICH. Conflicting results were seen for increased D-dimers as a predictor of HE.^[34]^,^[35]Some studies have shown an association between systolic BP (SBP) and HE,^[36]^,^[37]but others have not.^[7]^,^[19]^,^[32]^,^[38]Similarly, some studies show an association between prior use of antiplatelet drugs and HE,^[32]^,^[34]^,^[39]although others do not.^[40]^,^[41]Other risk factors include hyperglycaemia,^[4]^,^[12]^,^[36]previous cerebral infarction, liver disease,^[36] a decreased level of consciousness, and heavy alcohol intake.^[19]

HE is often associated with END and is an independent predictor of poor outcome and increased mortality.^[1]^,^[8]^,^[23]^,^[42]Findings from a meta-analysis of 218 patients with ICH who had CT scans within 3 h of onset and follow-up scans within 24 h^[23] showed that for every 10% increase in ICH growth there was a 5% increased risk of death, a 16% increased risk of worsening outcome as measured with the modified Rankin score (mRS), and an 18% increased likelihood of being dependent or of a poor outcome on the Barthel index.

Management

Interventions to restrict HE include haemostatic therapy, cautious lowering of high BP, quick reversal of prior anticoagulation, and surgical evacuation (table 1). Clinical trials^[8]^,^[43]targeting HE in ICH and a meta-analysis^[65]have shown that the use of recombinant factor VII (rFVIIa) limits the extent of HE in patients with non-coagulopathic ICH. However, there was an increase in thromboembolic risk with no clear clinical benefit in unselected patients. The SPOTLIGHT (Spot Sign Selection of Intracerebral Hemorrhage to Guide Hemostatic Therapy; ClinicalTrials.govidentifier NCT01359202) and STOP-IT (Spot Sign for Predicting and Treating ICH Growth Study; NCT00810888) trials that are underway use the CT angiography spot sign to stratify patients most at risk of HE who might benefit from therapy with rFVIIa. However, rFVIIa is not recommended at present for routine use to restrict HE.^[45]

Table 1 -- Management to restrict haematoma expansion

	Description	Level of evidence^[*]
Medical management
Haemostatic therapy with rFVIIa	In a phase 2 trial in patients with ICH, rFVIIa (NovoSeven; Novo Nordisk Health Care, Bagsvaerd, Denmark) led to a reduction in HE (p=0·01) and improvement in neurological outcomes and mortality,^[8] but the phase 3 study (FAST trial), despite showing a statistically significant (p=0·009) reduction in haematoma growth in rFVIIa-treated patients, did not show any functional or survival benefit;^[43] however, post-hoc analysis of the FAST data suggests a potential benefit of rFVIIa in younger patients (<70 2="" a="" as="" factors="" for="" given="" h="" haematoma="" href="http://www.mdconsult.com/das/article/body/402007529-5/jorg=journal&source=&sp=24859238&sid=0/N/944818/1.html?issn=1474-4422#r11702642044" if="" ivh="" known="" large="" ml="" name="xref_r11702642044" of="" onset="" or="" outcome="" poor="" style="color: #0560a6; margin: 0px; padding: 0px; text-decoration: initial;" substantial="" such="" symptoms="" the="" volume="" within="" without="" years="">^[44]

AHA/ASA guidelines do not recommend rFVIIa for routine use in restricting HE in patients with ICH^[45]Level 3A Blood pressure controlIn the INTERACT trial, the mean HE was 22·6% less at 24 h in the group that received intensive blood pressure control than it was in the guideline-based blood pressure control group (36·3%; p=0·04), but no statistically significant difference was recorded in functional outcome at 3 months between the two groups (median mRS score was 2 in both groups; p=0·66);^[20] a further subanalysis showed a beneficial effect of early blood pressure reduction on HE, extending over 72 h^[46]Level 1B In the ATACH phase 1 trial, in which patients were divided into tiers on the basis of blood pressure control (tier 1 being the highest level), HE was seen in 33% of patients in tier 1, 15% of patients in tier 2, and 22% of patients in tier 3^[47]Level 1B Surgery CraniotomyA meta-analysis of ten trials of surgery for supratentorial ICH showed a benefit of surgery in primary supratentorial ICH on reduction of odds of an unfavourable outcome at follow-up; however, the authors noted that more trials were needed to make a definitive conclusion^[48]Level 1A The STICH trial, which randomised 1033 ICH patients, showed no overall benefit of early surgery compared with initial conservative treatment for patients (26% vs 24% favourable outcome; p=0·41); however, a subgroup analysis showed that patients with haematoma within 1 cm of the cortical surface benefited from early surgery, although this did not reach statistical significance (p=0·007)^[49]Level 1B The AHA/ASA guidelines state the following: (1) that evacuation of supratentorial ICH with standard craniotomy might be considered for patients presenting with lobar clots >30 mL and within 1 cm of the surface;^[45] andLevel 2b B (2) that surgical evacuation of infratentorial ICH is recommended as soon as possible for patients with cerebellar haemorrhage who are deteriorating neurologically or who have brainstem compression and/or hydrocephalus from ventricular obstruction^[2]^,^[45]Level 1B Decompressive craniectomyEvidence for the beneficial effect of decompressive surgery comes from small case series: in one series of 12 consecutive patients with a hypertensive ICH volume of >60 mL treated with decompressive craniectomy, 11 patients survived at discharge, of whom six had a good functional outcome (mRS 0–3)^[50]Level 2b B In another case series of 23 patients with putaminal haematoma who underwent decompressive craniectomy, 13 patients had a good outcome and 10 had a poor outcome (including three deaths) at 90 days,^[51] suggesting that decompressive craniectomy might also have a role in the management of patientsLevel 2b B Minimally invasive surgery with stereotactic aspiration and thrombolysis AlteplaseThe combination of frameless stereotactic aspiration and thrombolysis (FAST) in a phase 2 study of 28 patients with deep subcortical ICH showed the procedure to be safe and associated with reduction in ICH volume and early improvement on the NIHSS, with the potential to improve outcome^[52]Level 3B In another study of 15 patients who underwent frameless stereotactic aspiration and thrombolysis (FAST) of the clot, demonstrable ICH reduction without perihaematoma enlargement was detected^[53].. UrokinaseEvidence for the potential beneficial effect of stereotactic infusion of urokinase on survival but not necessarily rebleeding has been provided by randomised trials^[54]^,^[55]^,^[56]^,^[57]^,^[58]Level 2b B In a randomised controlled trial that compared 64 patients treated with MISPTT and 58 treated with conventional craniotomy, the MISPTT group had fewer complications and a trend towards improved short-term and long-term outcomes^[58]Level 1B Image-guided stereotactic endoscopic aspirationSmall randomised^[59]^,^[60]and non-randomised studies^[61]^,^[62]^,^[63]have shown the image-guided stereotactic endoscopic aspiration procedure to be effective for immediate haematoma evacuation, with improved functional outcome and reduced mortality compared with best medical management^[61]^,^[62]^,^[63]Level 2b B In view of the uncertainty of the effectiveness of MIS for haematoma evacuation and the need for further research, the application of MIS with either stereotactic or endoscopic aspiration with or without thrombolysis is not recommended for routine use^[2]^,^[45]Level 2b B

AHA/ASA=American Heart Association/American Stroke Association. ATACH=Antihypertensive Treatment of Acute Cerebral Hemorrhage. FAST trial=Factor Seven for Acute Haemorrhagic Stroke trial. HE=haematoma expansion. ICH=intracerebral haemorrhage. INTERACT=Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial. IVH=intraventricular extension of haemorrhage. MIS=minimally invasive surgery. MISPTT=minimally invasive stereotactic puncture and thrombolysis therapy for acute intracerebral haemorrhage. mRS=modified Rankin score. NIHSS=National Institutes of Health Stroke Scale. rFVIIa=recombinant factor VIIa. STICH=Surgical Trial in Intracerebral Haemorrhage.

*	The level of evidence is according to the Oxford Centre for Evidence-based Medicine (Level 1A being the highest level of evidence).^[64]

Evidence from the INTERACT (Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial) and ATACH (Antihypertensive Treatment of Acute Cerebral Hemorrhage) trials show that SBP reduction might restrict HE in the hyperacute phase of ICH.^[20]^,^[46]^,^[47]Both INTERACT 2 (NCT00716079) and ATACH 2 (NCT01176565) are phase 2 trials underway to further investigate the benefit of early BP reduction on HE and clinical outcome in patients with ICH.

The role of surgical treatment for ICH is controversial. Surgical procedures with varying amounts of supportive evidence include conventional craniotomy,^[48]^,^[49]minimally invasive surgery (MIS),^[52]^,^[53]^,^[54]^,^[55]^,^[56]^,^[57]^,^[58]^,^[59]^,^[60]^,^[61]^,^[62]^,^[63]^,^[66]and decompressive craniectomy.^[50]^,^[51]Results from the STICH (Surgical Trial in Intracerebral Haemorrhage) trial^[49] showed no overall benefit of early surgical clot evacuation compared with initial conservative treatment in patients with ICH. However, a subgroup analysis showed a potential benefit for surgery in lobar ICH within 1 cm of the cortical surface.^[49] Pending the results of the STICH phase 2 trial (NCT00716079), craniotomy is currently recommended in selected patients with lobar clots of more than 30 mL and within 1 cm of the surface.^[2]^,^[45]

MIS is a promising option with many advantages over conventional craniotomy, such as shorter surgery time, reduced tissue damage, and the fact that the procedure can be done with local anaesthesia. The several methods of MIS include stereotactic guidance with aspiration and thrombolysis with alteplase^[52]^,^[53]^,^[66]or urokinase,^[54]^,^[55]^,^[56]^,^[57]^,^[58]and image-guided stereotactic endoscopic aspiration.^[59]^,^[60]^,^[61]^,^[62]^,^[63]The preliminary analysis of MISTIE (Minimally Invasive Surgery Plus rtPA for Intracerebral Hemorrhage Evacuation;NCT00224770), an ongoing evacuation trial combining stereotactic clot aspiration with different doses of alteplase, suggests that MIS plus alteplase shows greater clot resolution than does conventional medical management.^[66]

Although decompressive hemicraniectomy is a life-saving procedure for malignant middle cerebral artery infarction, no randomised controlled trial has been done in patients with ICH. The evidence for the potential beneficial effect of decompressive craniectomy comes from small case series.^[50]^,^[51]In the absence of further data, both MIS and decompressive craniectomy are not recommended for routine use in patients with ICH.^[2]^,^[45]

In anticoagulant-associated ICH (AAICH) the goal of treatment is to rapidly normalise the international normalised ratio (INR) and correct clotting factors immediately (table 2). AAICH should be reversed immediately with vitamin K and fresh frozen plasma or prothrombin complex concentrate.^[45] The INCH (INR Normalization in Coumadin Associated Intracerebral Haemorrhage; NCT00928915) trial comparing the use of fresh frozen plasma with prothrombin complex concentrate in patients with AAICH is underway. Further studies are needed to confirm the efficacy of platelet replacement or other interventions aimed at preventing or treating antiplatelet-related ICH because the usefulness of platelet transfusion in this group of patients is unclear.^[45] The decision as to whether or when to restart anticoagulation therapy after ICH will depend on the risk of subsequent arterial or venous thromboembolism, the risk of recurrent ICH, and the clinical state of the patient.

Table 2 -- Management of anticoagulant-associated intracerebral haemorrhage

	Description	Level of evidence^[*]
Reversal of anticoagulation	The AHA/ASA recommend immediate reversal of anticoagulation;^[2]^,^[45]recommendations for reversal of anticoagulation in patients with ICH are as follows:	..
	Patients with a severe coagulation factor deficiency or severe thrombocytopenia should receive appropriate factor replacement therapy or platelets, respectively^[45]	Level 1C
	Patients with ICH whose INR is increased because of oral anticoagulants should have their warfarin treatment discontinued and receive therapy to replace vitamin K-dependent factors and to correct their INR^[45]	Level 1C
	Vitamin K (5–10 mg intravenously) remains an adjunct to initial therapy for OAC-associated haemorrhage because normalisation of INR can take up to 24 h^[45]	Level 1C
	FFP (10–50 U/kg) is commonly used as an adjunct to vitamin K; it acts within a few h, but is associated with greater volume expansion, which might precipitate heart failure, and requires much longer infusion times^[2]	Level 2b B
	Prothrombin complex concentrates (10–50 U/kg), which act within a few min and have not shown improved outcome compared with FFP, might lead to fewer complications than FFP and can be considered as an alternative to FFP^[45]	Level 2a B
	rFVIIa (40–80 μg/kg), which acts within a few min, does not replace all clotting factors, and although the INR might be lowered, clotting might not be restored in vivo; rFVIIa is therefore not routinely recommended as a sole agent for OAC reversal in ICH^[45]	Level 3C
	The usefulness of platelet transfusions in ICH patients with a history of antiplatelet use is unclear and is considered investigational^[45]	Level 2b B
Resumption of anticoagulation therapy after ICH	The decision as to whether to resume anticoagulation depends on analysis of the risk of recurrent haemorrhage balanced against the risk of thromboembolism because either complication can be associated with poor outcome and high mortality	..
	The decision as to whether to resume anticoagulation should be based on underlying risk factors for recurrence: lobar location of the initial ICH, older age (>65 years), ongoing anticoagulation, presence of the apolipoprotein ɛ2 or ɛ4 alleles, and greater number of microbleeds on MRI^[45]	Level 2a B
	For nonvalvular AF, long-term anticoagulation should be avoided after spontaneous lobar ICH because of the high risk of recurrence, but antiplatelet agents might be considered; antiplatelet treatment is probably safer than anticoagulation because it carries a substantially lower risk of bleeding^[2]^,^[40]	Level 2a B
	Anticoagulation after non-lobar ICH might be considered depending on the indication^[2]	Level 2a B
When to resume anticoagulation	The optimum timing of the resumption of anticoagulation is a crucial issue with conflicting evidence:
	A large retrospective study of 2869 patients with AF, mechanical heart valves, and additional risk factors for stroke with warfarin-related ICH suggests resumption of warfarin after about 10–30 weeks^[67]	Level 2B
	By contrast with reference 67, another systematic review of 492 patients concluded that anticoagulation might be resumed after 72 h^[68]	Level 2A
	A systematic review of six retrospective studies of 120 patients with mechanical heart valves and ICH concluded that resumption of warfarin within 2 weeks is safe^[69]	Level 2A
	However, the AHA/ASA suggest that in patients with a very high risk of thromboembolism for whom restarting warfarin is considered, warfarin can be restarted 7–10 days after ICH onset;^[2] the European Stroke Initiative recommends that warfarin can be restarted after 10–14 days^[70]	Level 2b B
Alternatives to warfarin	Factor Xa and direct thrombin inhibitors are alternatives to warfarin, both of which might reduce the risk of thromboembolism with fewer bleeding complications^[71]	..
	The direct thrombin inhibitor dabigatran (Pradaxa) has been shown to prevent ischaemic stroke to a similar extent as does warfarin, with reduced bleeding complications^[72]	Level 1C

AF=atrial fibrillation. AHA/ASA=American Heart Association/American Stroke Association. ATACH=Antihypertensive Treatment of Acute Cerebral Hemorrhage. FFP=fresh frozen plasma. ICH=intracerebral haemorrhage. INCH=International Normalized Ratio (INR) Normalization in Coumadin Associated Intracerebral Haemorrhage. OAC=oral anticoagulant. rFVIIa=recombinant factor VIIa.

*	The level of evidence is according to the Oxford Centre for Evidence-based Medicine (Level 1A being the highest level of evidence).^[64]

Although guidelines from the American Heart Association and American Stroke Association (AHA/ASA)^[2] suggest restarting warfarin 7–10 days after ICH onset in patients with a very high risk of thromboembolism, the European Stroke Initiative (EUSI) recommends starting warfarin after 10–14 days.^[70]

Perihaematomal oedema

Clinical features

PHE, which is present in most patients with ICH, can be associated with increased mass effect and END^[14]^,^[73]and is a predictor of poor functional outcome and mortality.^[1]^,^[73]^,^[74]^,^[75]PHE develops early in the hyperacute phase (increasing in volume by 75% in the first 24 h),^[75] evolves over many days, and increases strongly during the first week ^[74] before it reaches its maximum during the second week after bleeding.^[1]^,^[14]^,^[76]

Although the mechanisms of oedema formation after ICH are not fully understood, several potential mechanisms have been postulated for the different stages of PHE formation after ICH. Whereas early PHE is caused by the vasogenic effect of pro-osmotic substances (protein, electrolytes) from the clot, starting immediately after bleeding and peaking at 4–5 days,^[76] delayed PHE arises from a combination of vasogenic and cytotoxic effects and lasts for 2–4 weeks.^[77] Within the hyperacute first phase (a few hours post ictus) the development of hydrostatic pressure during haematoma formation and clot retraction leads to leakage of serum proteins from the clot into the surrounding tissue, resulting in vasogenic oedema.^[78] A second phase (which begins a few days post ictus) results from activation of the coagulation cascade and thrombin production.^[79] The third, delayed phase (which begins days to weeks post ictus) is related to erythrocyte lysis and haemoglobin-mediated toxic effects caused by the iron-catalysed production of reactive oxygen species.^[80]^,^[81]

Thrombin-induced activation of the inflammatory cascade and overexpression of MMPs is another potential mechanism that leads to blood–brain barrier breakdown and PHE formation after ICH.^[79]^,^[82]MMPs probably act by enhancing extracellular matrix proteolysis, damaging the basal lamina, and degrading c-Fn, a glycoprotein that is essential for haemostasis.^[83]

Radiological evidence of PHE formation after ICH has been provided by various studies.^[73]^,^[74]^,^[75]^,^[84]^,^[85]^,^[86]In the INTERACT study of patients with CT-confirmed ICH who were assessed within 6 h of onset, PHE volume increased within 72 h of the initial CT.^[84] In an MRI study, PHE volume increased most rapidly in the first 2 days after symptom onset and peaked towards the end of the second week.^[86]

Other factors that have been proposed to affect PHE volume include hyperglycaemia, coagulation factors, and use of statins.^[86]^,^[87]Likewise, increased serum concentrations of MMP-9^[88]^,^[89]and persistently increased SBP^[90] are associated with an increased PHE volume.

Although the possible presence of an ischaemic penumbra around the area of the ICH—leading to secondary neuronal injury and cytotoxic oedema—was previously a concern, evidence against a perihaemorrhagic penumbra has since been provided by MRI and perfusion CT studies, which have linked perihaematoma hypoperfusion to reduced metabolic demand rather than tissue ischaemia.^[91]^,^[92]

The oedema volume can exceed that of the original haematoma, leading to substantial additional mass effect with tissue shifts, and might contribute to further neuronal injury and poor outcome after ICH.^[14]^,^[73]^,^[74]^,^[80]Also, rapidly developing PHE could lead to increased ICP or obstructive hydrocephalus and subsequent herniation.^[80] The increased ICP resulting from surrounding PHE can contribute to brain injury and END, and to reduced cerebral perfusion pressure.^[45]

Evidence for an effect of PHE on clinical outcome and mortality after ICH is unclear: although some observational studies have recorded an association between PHE and poor outcome,^[73]^,^[74]^,^[80]another study detected no clear association.^[75] Also, in another study, absolute oedema volume growth was correlated with a decrease in neurological status at 48 h after ICH, but not with 3 month functional outcome.^[86]

In the INTERACT trial, both absolute and relative growth in PHE volume were associated with mortality or dependency at 90 days after adjustment for age, sex, and randomised treatment, but not when further adjusted for baseline haematoma volume.^[84]

Management

The goal of therapy for PHE that occurs as a complication of ICH is to prevent secondary brain insults, reduce ICP, maintain blood supply and oxygen delivery, and optimise cerebral metabolism. The treatment options for PHE and increased ICP complicating ICH are mostly supportive (table 3). Elevation of the head to 20–30° and avoidance of pain and fever could minimise any rise in ICP. Medical measures such as hyperventilation and the use of analgesia, sedatives, and osmotic diuretics are designed to lower ICP before placement of an ICP monitor or any definitive neurosurgical intervention such as craniotomy or ventriculostomy.^[2] Placement of an ICP monitor is recommended, especially in patients with a Glasgow Coma Scale (GCS) score of less than 8 and those with transtentorial herniation.^[45]

Table 3 -- Management of perihaematomal oedema and increased intracranial pressure after intracerebral haemorrhage

		Description	Level of evidence^[*]
General considerations		Little evidence exists for the management of ICP in patients with ICH; data on the management principles for increased ICP in patients with ICH are based on guidelines for traumatic brain injury, which recommend maintenance of CPP at 50–70 mm Hg^[93]	..
		Reduction of increased ICP and maintenance at <20 50="" as="" at="" become="" cerebral="" cpp="" font="" have="" hg="" hypoperfusion="" life-threatening="" maintenance="" mm="" of="" potentially="" prevent="" size="-1" style="margin: 0px; padding: 0px;" targets="" therapeutic="" to="" well="">^[45]

^,^[93].. Medical Simple measuresSimple non-interventional therapeutic manoeuvres for reduction of raised ICP include elevating the patient's head to 30° and use of analgesia and sedation^[2]^,^[45]Level 2a B Suggested drugs for analgesia and antitussive effect are morphine or alfentanil; propofol, etomidate, or midazolam are the suggested drugs for sedation.. Advanced measuresMore aggressive therapies for reducing ICP include osmotic diuretics (mannitol and hypertonic saline solution), drainage of CSF through a ventricular catheter, neuromuscular blockade hyperventilation (with agents such as vecuronium or pancuronium), and hypothermia^[2]^,^[45]Level 2a B Despite the beneficial effect of corticosteroids on vasogenic oedema (stabilisation of the capillary endothelial junction and reduction of cerebrovascular permeability), corticosteroids are contraindicated because randomised controlled trials showed no efficacy in the treatment of oedema after ICH for lowering ICP and improving neurological deficit^[2]Level 3B Concomitant monitoring of ICP and blood pressure to maintain CPP at >70 mm Hg is recommended when aggressive measures are being used^[2]Level 2a B AHA/ASA guidelines recommend the consideration of ICP monitoring and treatment for patients with a Glasgow Coma Scale score of 8 or less, those with clinical evidence of transtentorial herniation, or those with substantial IVH or hydrocephalus to maintain CPP at 50–70 mm Hg, depending on the status of cerebral autoregulation^[45]Level 2b C HypothermiaA small pilot study of 12 patients with large ICH with mild endovascular hypothermia (35°C) for 10 days showed the following: hypothermia is safe and feasible in this patient group; hypothermia prevented the increase of PHE as compared with the matched historical controls, in whom PHE volume doubled within 2 weeks; no rebound effect was recorded after rewarming, and all patients survived during the 90 day follow-up period, unlike the historical control group, in which about 25% died because of an increase in oedema and herniation within the first week of treatment;^[94] complications such as pneumonia, shivering, and bradycardia did not seriously affect clinical course during the studyLevel 3C NeurosurgeryDefinitive neurosurgical interventions include craniotomy or ventriculostomy^[2]Level 2a B

AHA/ASA=American Heart Association/American Stroke Association. CPP=cerebral perfusion pressure. ICH=intracerebral haemorrhage. ICP=intracranial pressure. IVH=intraventricular extension of haemorrhage. PHE=perihaematomal oedema.

*	The level of evidence is according to the Oxford Centre for Evidence-based Medicine (Level 1A being the highest level of evidence).^[64]

Intraventricular extension of haemorrhage and hydrocephalus

Clinical features of IVH

IVH is common after ICH, occurring in 30–50% of patients, and is a major additional predictor of poor prognosis (figure 2).^[9]^,^[10]^,^[11]^,^[95]^,^[96]^,^[97]A relation exists between the location and volume of ICH and the presence of IVH.^[11]^,^[95]A subanalysis of the activated rFVIIa phase 2 trial showed a relation between thalamic ICH and increased frequency of IVH.^[11] This was attributable to the anatomical closeness of the thalamus to the third ventricle and the predisposition for blood to spread medially.^[11]^,^[95]

Hallevi and colleagues^[95] calculated a decompression range for each location of ICH, the range of ICH volume within which IVH is more likely to occur during the acute phase of ICH as the haematoma enlarges and below which ICH is unlikely to be complicated by IVH. They noted a narrow decompression range for thalamic and pontine haemorrhages, a wide range for lobar ICH, and a non-measurable decompression range for caudate haemorrhage.^[95]

Several studies have shown that IVH in patients with ICH is an independent predictor of poor functional outcome and higher mortality,^[9]^,^[10]^,^[11]^,^[43]^,^[49]^,^[75]^,^[95]^,^[98]with a reported overall mortality rate of 50–75%.^[75]^,^[99]^,^[100]^,^[101]The 30 day mortality rate was shown to be 43% in ICH patients with IVH compared with 9% in those without.^[9] In the rFVIIa trial, although 38% of 375 patients with ICH had IVH at baseline, 45% had developed IVH by 24 h after presentation. A good functional outcome (mRS 0–3) was achieved by 43% of the patients without IVH at presentation compared with only 20% of those with IVH at baseline. Similarly, out of the group that had IVH growth in the first 24 h, only 7% had a good functional outcome (mRS 0–3) at 90 days.^[11] A mean arterial pressure (MAP) of greater than 120 mm Hg at baseline, a large baseline ICH volume, and the presence of IVH at presentation were identified as risk factors for IVH growth.^[11] Both the presence of IVH at any time and IVH growth increased the likelihood of death or severe disability at 90 days.^[11]

In the subanalysis of the STICH trial, only 15% of the 377 patients with IVH had good (normal, good, or moderate recovery) Glasgow Outcome Scale functional outcomes, compared with 31% of the 375 ICH patients without IVH.^[10]

Proposed mechanisms for the deleterious effects of IVH on mortality and morbidity include damage to periventricular brain structures, especially the brainstem, complications of acute obstructive hydrocephalus, and IVH-induced inflammatory response, possibly due to blood and its breakdown products.^[10]^,^[102]^,^[103]

The volume of IVH affects morbidity and mortality at 30 days.^[11]^,^[98]^,^[104]A review of 47 patients with ICH by Young and colleagues^[98] identified a lethal volume of 20 mL, above which patients had a poor outcome. Similarly, early expansion of IVH worsens clinical outcome and increases mortality to 50–75%.^[9]

Although IVH volume in itself is associated with poor outcome, an even stronger association exists between the total (ICH plus IVH) volume and adverse outcomes.^[1]^,^[10]^,^[95]^,^[98]^,^[104]Another study identified a 40 mL total volume as a cutoff value, above which patients were 41 times more likely to have a poor prognosis, and 50 mL as a poor outcome threshold, above which 100% of patients would have an unfavourable outcome.^[104]

Clinical features of hydrocephalus

Extension of haemorrhage into the ventricles can impede normal CSF flow and, with direct mass effects of ventricular blood, lead to acute obstructive hydrocephalus (AOH). AOH can be a life-threatening disorder, especially if the third and fourth ventricles are affected.^[9]^,^[10]^,^[11]Up to 50% of patients with IVH secondary to ICH can develop hydrocephalus caused by obstruction of the third and fourth ventricles by ventricular clots.^[105]

Many studies have shown involvement of the third and fourth ventricles in patients with IVH after ICH to be predictive of adverse outcome and high mortality.^[9]^,^[10]^,^[11]^,^[105]In a subanalysis of CT images from the STICH trial, the presence of hydrocephalus reduced the likelihood of positive outcome from 15·1% to 11·5%.^[10]

Acute hydrocephalus is more common in patients with high IVH volume (Graeb score ≥6) than it is in patients with low to moderate IVH volume (Graeb score ≤6).^[101] Hydrocephalus occurs more with thalamic than with putaminal haemorrhages and is almost absent in the case of lobar haemorrhages, probably because small thalamic haemorrhages can easily compress the cerebral aqueduct leading to obstruction to normal CSF flow and subsequent hydrocephalus, whereas small ganglionic haemorrhages rarely have any effect on ventricular size.^[98]^,^[105]Communicating hydrocephalus can develop with impairment of the Pacchioni granulations by ventricular haemorrhage.^[97]^,^[106]^,^[107]Increased ICP can result from large volume ICH, especially in the presence of IVH with hydrocephalus, leading to further clinical deterioration and poor outcome.^[9]^,^[10]^,^[11]

Management

The aim of treatment in ICH patients with IVH and hydrocephalus is to evacuate the intraventricular haematoma, thus relieving the obstruction to CSF flow, reversing ventricular dilatation, and restoring normal intracerebral pressure (table 4). Insertion of external ventricular drainage (EVD) can be a life-saving procedure, relieving acute hydrocephalus and subsequent herniation in ICH patients with severe IVH and AOH.^[97]^,^[100]^,^[108]EVD is recommended for the treatment of hydrocephalus in patients with decreased consciousness.^[45]

Table 4 -- Management of ventricular extension of haemorrhage and hydrocephalus

	Description	Level of evidence^[*]
External ventricular drainage	EVD insertion has been suggested as a life-saving procedure in patients with ICH with severe IVH and AOH through reduction of ICP and subsequent herniation;^[97]^,^[100]^,^[108]however, the complications of EVD include occlusion by blood clots leading to inadequate CSF drainage,^[97]^,^[100]infections leading to frequent EVD exchange,^[96]^,^[107]^,^[109]and CH caused by impairment of the Pacchioni granulations by IVH^[107]	Level 2b C
	AHA/ASA guidelines recommend that:
	Patients with a GCS score of 8, those with clinical evidence of transtentorial herniation, or those with substantial IVH or hydrocephalus should be considered for ICP monitoring and treatment; treatment should aim to maintain a CPP of 50–70 mm Hg, depending on the status of cerebral autoregulation^[45]	Level 2b C
	Ventricular drainage as treatment for hydrocephalus should be considered in patients with a decreased level of consciousness^[45]	Level 2a B
Intraventricular fibrinolysis	Compared with ventriculostomy alone, IVF with either urokinase^[106]^,^[109]or alteplase^[110]^,^[111]^,^[112]has been shown to promote early and effective clearance of blood in the ventricles, maintain EVD functionality, and reduce the need for permanent shunts as well as improve clinical outcome and reduce mortality; the benefits of IVF might be offset by complications such as secondary haemorrhage and EVD infection^[111]^,^[113]^,^[114]	Level 2b B
	IVF can reduce the mortality rate from a range of 60–90% to only 5%;^[112] two systematic reviews of clinical studies recorded a 30–50% reduction in mortality after IVF^[115]^,^[116]	Level 2a B
	Improved short-term outcome in patients with EVD and IVF can improve 30 day^[106] and 90 day outcome,^[111] but not long-term outcome after 12 months^[110]	Level 2B
	In the CLEAR IVH phase 2 trial, designed to assess the safety of open-label doses of intraventricular alteplase in 52 patients with IVH, one dose of 1 mg alteplase and a dosing interval of 8 h was shown to be the most appropriate dosing for IVH,^[117] suggesting that low-dose alteplase can be safely given to treat stable intraventricular clots and can increase the lysis rates; symptomatic bleeding occurred in 4% and bacterial ventriculitis in 2% of patients with a 30 day mortality rate of 17%^[117]	Level 3B
	AHA/ASA guidelines do not recommended the routine use of IVF in clinical practice^[45]	Level 2bB
Endoscopic surgical evacuation	Evidence for the potential beneficial effect of neuroendoscopic surgical removal of IVH comes from observational studies:^[118]^,^[119]^,^[120]^,^[121]in one study, 24 of 25 patients who had ESE of IVH and obstructive hydrocephalus had resolution of hydrocephalus;^[120] similarly, in another study of 17 patients with IVH and hydrocephalus treated with ESE, all patients had successful resolution of hydrocephalus with good outcomes;^[121] and in a non-randomised comparison study, patients treated with ESE of IVH had a higher rate of good recovery at 2 months than did those treated with EVD^[119]	Level 3B
Lumbar drainage	LD is an alternative option for extracorporeal CSF drainage in patients with CH and has been shown to be a simple, safe, and less invasive procedure; it avoids the need for EVD exchange and can substantially reduce the incidence of permanent hydrocephalus and the need for shunt surgery; it also has a lower complication profile than does EVD^[97]^,^[107]^,^[122]	..
	In a prospective case series of three patients, the combination of IVF and LD was shown to be a simple and promising alternative for the treatment of CH after ICH and IVH^[122]	Level 1C
	In a retrospective analysis of 16 patients with persisting CH after secondary IVH who received an EVD and concurrent LD compared with 39 historical patients treated with EVD alone, LD replaced the need for repeated EVD exchanges, extending the duration of extracorporeal CSF drainage (16 days EVD vs 21 days EVD plus LD) and eventually reducing the need for a permanent ventriculoperitoneal shunt (18·75% vs 33%; p<0 a="" href="http://www.mdconsult.com/das/article/body/402007529-5/jorg=journal&source=&sp=24859238&sid=0/N/944818/1.html?issn=1474-4422#r11702642107" in="" ld-treated="" name="xref_r11702642107" patients="" style="color: #0560a6; margin: 0px; padding: 0px; text-decoration: initial;">^[107]

Level 2b C In a prospective study, 32 patients with ICH and severe IVH with AOH received an EVD (n=32), and of the 28 patients who developed CH, early LD replaced the need for EVD, with one patient requiring a shunt; the additional treatment with either IVF or LD reduced the incidence of EVD exchange (to 32% and 40%, respectively) and shunt surgery (to 18%)^[97]Level 1C

AHA/ASA=American Heart Association/American Stroke Association. AOH=acute obstructive hydrocephalus. CH=communicating hydrocephalus. CLEAR IVH=Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage. CPP=cerebral perfusion pressure. ESE=endoscopic surgical evacuation. EVD=external ventricular drainage. GCS=Glasgow Coma Scale. ICH=intracerebral haemorrhage. ICP=intracranial pressure. IVF=intraventricular fibrinolysis. IVH=intraventricular extension of haemorrhage. LD=lumbar drainage.

*	The level of evidence is according to the Oxford Centre for Evidence-based Medicine (Level 1A being the highest level of evidence).^[64]

Because EVD is often occluded by blood clots, leading to inadequate CSF drainage, thrombolytics can be instilled into the ventricles to maintain EVD functionality and promote fast clearance of the ventricles.^[106]^,^[109]^,^[110]^,^[111]^,^[112]^,^[113]^,^[114]^,^[115]^,^[116]^,^[117]Findings from the CLEAR IVH (Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage) phase 2 trial^[117] suggest that low-dose alteplase can be safe and might increase the lysis rate. However, pending the results of the ongoing CLEAR phase 3 trial (NCT00784134), routine clinical use of intraventricular fibrinolysis is not recommended.^[45] Other treatment options include endoscopic surgical evacuation of the haemorrhage^[118]^,^[119]^,^[120]and the less-invasive lumbar drainage.^[97]^,^[107]^,^[122]

Seizures and epilepsy

Clinical features

Seizures are a frequent complication of ICH and can even be the presenting symptom.^[123] Seizures most commonly occur at the onset of ICH, but can be delayed. About 50–70% of seizures occur within the first 24 h, and 90% in the first 3 days,^[124]^,^[125]^,^[126]^,^[127]with an overall 30 day risk of seizures of about 8%.^[123]

Early seizures are defined as those occurring within 2 weeks of initial ictus, late seizures occurring thereafter.^[124]^,^[125]Whereas early seizures are thought to be caused by structural disruption and cellular biochemical dysfunction, late seizures are attributed to gliosis and the development of meningocerebral cicatrices.^[124]^,^[125]Early seizures can be predictive of epilepsy development.^[128]

The incidence of seizures after ICH varies widely depending on study design, diagnostic criteria, duration of follow-up, and the population studied. Similarly, the true incidence of seizures might be underestimated, because subclinical seizures can be detected with use of continuous EEG (cEEG) monitoring only. Overall incidence after ICH is 4·2–20%^[123]^,^[124]^,^[127]^,^[129]^,^[130]for clinical seizures and 29–31% for subclinical seizures.^[125]^,^[126]^,^[131]In a series of 63 patients with ICH in an intensive care unit (ICU) who had cEEG monitoring within 72 h of admission, non-convulsive seizures were detected in 28%, four times the incidence of observable seizures. The presence of seizures was independently associated with increased midline brain shift on 48–72 h follow-up head CT scans, with neurological deterioration.^[126]

In a retrospective review^[125] of 102 patients with ICH with cEEG monitoring, 19% had convulsive seizures, 13% had electrographic seizures, and 5% had both, with 94% of the seizures detected in the first 72 h. Subclinical seizures were associated with expanding haemorrhages, especially if they expanded by more than 30% in the first 24 h or if they reached the cortex, and were also associated with a poor outcome. Electrographic seizures were twice as common (31% vs 14%) in patients with expanding haemorrhages.^[125]

The reported frequency of status epilepticus is 0·3–21·4%.^[130]^,^[132]^,^[133]In an earlier study of 1402 patients with ICH, status epilepticus occurred in 11 of 65 patients with seizures and was the initial presentation of ICH in six of these 65 patients.^[130] Epilepsy (recurrent seizures) has been reported to develop in 2·5–4% of patients,^[124]^,^[130]but Passero and colleagues^[123] reported the risk of late seizures or epilepsy in survivors of ICH to be 5–27%. Recurrent seizures occurred in four of 14 patients in one study, despite the provision of antiepileptic treatment.^[133]

Although the cause of seizures in patients with ICH is unclear, the combination of sudden development of a space-occupying lesion with mass effect, focal ischaemia, and blood breakdown products has been postulated to account for seizures early in ICH.^[124] Early-onset seizures are thought to be directly related to the insult of ICH to the brain.^[127]

Identified predisposing factors include haemorrhagic size, the presence of hydrocephalus, intracranial midline shift, low GCS, and severe neurological deficit.^[124] Lobar location is an independent predictor of early seizures.^[123] Non-occipital lobar haemorrhages,^[125]^,^[126]^,^[127]^,^[133]as well as subcortical haemorrhages,^[126] are commonly associated with seizures.

Conflicting results on the association of seizures after ICH with clinical outcome and mortality have been reported. In one study,^[134] the in-hospital mortality rate was 37·9% in patients with both acute ICH and IS with seizures within 48 h of symptom onset compared with 14·4% for patients without seizures. Another study^[128] of ICH and IS showed an increased risk of mortality within 30 days if seizures developed within the first 24 h after stroke (32·1% vs 13·3%). Although mortality rates were higher in patients with seizures, seizures were not an independent predictor of mortality at 30 days or of poor outcome post stroke after adjusting for other factors, although the risk in patients with ICH was not independently determined.^[128]

Findings from one study^[126] showed that post-ICH seizures are associated with worsening neurological function as measured with the NIHSS (National Institutes of Health Stroke Scale), and recorded a trend towards increased poor outcome, with a mortality rate of 27·8% compared with 15% in those without seizures.^[126] However, other studies have recorded no substantial difference in mortality between patients with or without seizures after stroke,^[124] and, surprisingly, there was an association with better outcomes after stroke as measured with Scandinavian stroke scales.^[135]

Management

No randomised controlled trials (RCTs) have been done to guide decisions on seizure prophylaxis or treatment in patients with ICH. Similarly, no definitive evidence or clear guidelines exist for the choice of treatment or duration of treatment for patients with one or more seizures or status epilepticus (table 5). However, available guidelines recommend that patients with clinical seizures should be treated with antiepileptic drugs (AEDs).^[45] The choice of initial AED is dependent on the individual characteristics of each patient, including medical comorbidities, concurrent drugs, and contraindications. The benefit of seizure prophylaxis after ICH is controversial. Whereas previous studies have advocated the use of prophylaxis in most patients,^[123]^,^[136]two observational studies have since shown prophylactic therapy with AEDs to be associated with poor outcome.^[136]^,^[137]Whereas previous guidelines^[2]^,^[64]have recommended a 30 day course of prophylactic AED in patients with lobar haemorrhage or those who have had seizures, the most up-to-date guideline recommends against prophylactic use.^[45]

Table 5 -- Clinical management of seizures and epilepsy after intracerebral haemorrhage

	Description	Level of evidence^[*]
General considerations	No randomised controlled trials have been done to guide decisions on seizure prophylaxis or treatment in patients with ICH; however, AHA/ASA guidelines^[45] recommend the following:	..
	Patients with clinical seizures should be treated with AEDs	Level 1A
	Patients with a change in mental status who have electrographic seizures on EEG should be treated with AEDs	Level 1C
	EEG monitoring is indicated in ICH patients with depressed mental status that is out of proportion with the extent of brain injury	Level 2a B
Antiepileptic drugs	The choice of initial AED depends on individual circumstance and contraindications; the AEDs to be considered for the acute treatment of post-haemorrhagic stroke seizures include intravenous lorazepam (0·05–0·10 mg/kg) followed by a loading dose of phenytoin or fosphenytoin (15–20 mg/kg), valproic acid (15–45 mg/kg), levetiracetam (500–1500 mg), or phenobarbital (15–20 mg/kg)	..
Prophylaxis	The benefit of seizure prophylaxis after ICH is controversial: some investigators have advocated the use of prophylaxis in most patients^[126] and previous guidelines^[2]^,^[70]have recommended a 30 day course of prophylactic AEDs in patients with lobar haemorrhage or those who have had seizures, on the basis of risk reduction of seizures in patients with lobar haemorrhage reported in observational studies^[123]	..
	However, two observational studies have since shown prophylactic therapy with AEDs to be associated with poor outcome:^[136]^,^[137]in a prospective study of 98 patients with ICH, prophylactic phenytoin was associated with higher fever and worse outcome at 14 days or at discharge, and worse functional outcome at 14 day, 28 day, and 3 month follow-up;^[136]similarly, in another trial, an association was recorded between AED use and worse 3 month functional outcome^[137]	Level 3B
	In the absence of data for patients with ICH showing a benefit of seizure prophylaxis, the most up-to-date AHA/ASA guidelines recommend against prophylactic use of AEDs^[45]	Level 3B

AEDs=antiepileptic drugs. AHA/ASA=American Heart Association/American Stroke Association. ICH=intracerebral haemorrhage.

*	The level of evidence is according to the Oxford Centre for Evidence-based Medicine (Level 1A being the highest level of evidence).^[64]

Venous thromboembolic events

Clinical features

VTE are a common and potentially fatal complication in patients with ICH that can manifest as either deep-vein thrombosis (DVT) or pulmonary embolism (PE).^[138]^,^[139]The reported rate of clinically symptomatic VTE is 3–7%.^[138]^,^[140]^,^[141]Overall, studies have estimated the short-term post-ICH risk of PE to be 1–2% and of DVT to be 1–4%.^[138] Subclinical DVT is more common than is clinically apparent DVT, with asymptomatic DVT rates occurring in up to 17% of patients with ICH.^[142] In a small prospective study of 52 patients with acute ICH, DVT was detected in 40% of patients within 2 weeks, with one case of PE recorded.^[143] The high rate was attributed to the extent of paralysis due to severe stroke. In the rFVIIa trial,^[8] about 2% of patients in both the placebo and treatment groups developed DVT, and about 2% developed PE.^[8]

DVT is a risk factor for PE. PE generally arises from venous thrombi that develop in a paralysed lower leg or pelvis.^[144] However, about 30% of patients diagnosed with acute PE show no evidence of DVT in their lower legs, implying that a negative venous duplex ultrasound does not exclude the diagnosis of acute PE.^[145]

Independent risk factors associated with the development of VTE in patients with ICH include severe stroke, lengthy immobilisation, advanced age, and increased prothrombotic activity.^[143]^,^[146]Discontinuation of antithrombotic agents after ICH could also accelerate the formation of DVT.^[143]

Although a high D-dimer value is a useful predictor of DVT formation in patients with ICH, this value could also be increased because of the presence of infection or hyperfibrinolysis caused by the cessation of anticoagulation.^[143]

In a retrospective study of symptomatic VTE in patients with ICH, the most commonly identified risk factors were age (>40 years), immobility due to paresis or restrictions for mechanical ventilation, presumed infection, and the presence of an indwelling central venous catheter.^[141]

A systematic review detected racial disparity in the incidence of VTE after ICH, with a higher rate of DVT in black patients than in white patients after adjusting for differences in the risk factors for ICH.^[147] A sex difference also exists, with women being at greater risk of VTE.^[139]^,^[148]

VTE is associated with a 30 day mortality rate of 35–52%.^[2] In the Oxford Community Stroke Project, 5% of patients with ICH died of PE within the first 30 days.^[3] Both DVT and PE can slow down rehabilitation and recovery, and extend the duration of hospital stay.^[144]

Management

A clinical dilemma can arise as to the best possible approach to VTE prevention in patients with ICH, because anticoagulants can increase the risk of HE or rebleeding. Although this decision is often made on the basis of a risk–benefit analysis in the context of the individual patient, prophylaxis for VTE in patients with ICH has been addressed in some guidelines.^[2]^,^[149]Options for reducing the risk of VTE after ICH include intermittent pneumatic compression, low-dose subcutaneous low-molecular-weight heparin or unfractionated heparin (table 6).^[2]^,^[45]

Table 6 -- Prevention and clinical management of venous thromboembolic events after intracerebral haemorrhage

	Description	Level of evidence^[*]
Prevention
Non-pharmacological approaches	On the basis of findings from a randomised controlled trial that showed intermittent pneumatic compression combined with elastic stockings to be better than elastic stockings alone in the reduction of the rate of asymptomatic DVT after ICH (4·7% vs 15·9%)^[142] and the finding that graduated compression stockings alone are ineffective in preventing DVT,^[150] AHA/ASA guidelines recommend that patients with ICH should have intermittent pneumatic compression for prevention of venous thromboembolism in addition to elastic stockings^[2]^,^[45]	Level 1B Level 1B
Pharmacological approaches	Randomised trials,^[144]^,^[151]a non-randomised study,^[152] and a retrospective study^[140] have shown pharmacological prophylaxis with LMWH for DVT and PE prevention 24–48 h after ICH to be safe with no increased risk of haematoma expansion or further bleeding, although LMWH has not been shown to be better than elastic stockings	Level 2b B
	On the basis of these studies, AHA/ASA guidelines suggest that after cessation of bleeding, low-dose subcutaneous LMWH or unfractionated heparin can be considered for prevention of venous thromboembolism in patients who are immobile after 1–4 days from onset of ICH^[45]	Level 2b B
Treatment
IVC filters	Insertion of an IVC filter is an option for patients who cannot receive therapeutic anticoagulation or for those who have to wait for several weeks before starting anticoagulation;^[153]^,^[154]^,^[155]^,^[156]IVC filters prevent PE by trapping most of the large emboli originating from the deep veins of the pelvis and feet,^[157] but the benefits can by counterbalanced by complications such as venous thromboembolism and caval occlusion, with no difference in mortality^[153]^,^[154]^,^[155]^,^[156]	..
	A retrospective review of 371 mixed stroke patients (105 [28%] with ICH) who received an IVC filter recorded a 16% incidence of symptomatic post-filter DVT, a 0·8% incidence of post-filter fatal PE, and a 5·1% incidence of caval occlusion; other filter-related complications included fracture of filter, penetration of caval wall, and filter migration^[156]	Level 2b C
	No randomised controlled trial has compared vena cava filters with anticoagulation in patients with ICH or ischaemic stroke; nonetheless, in the PREPIC randomised controlled trial of 400 patients with documented proximal DVT or PE who received concurrent anticoagulation, IVC filters reduced the risk of PE, even after 8 years, although there was an associated long-term risk of recurrent DVT but no statistically significant reduction in mortality, probably because of the older study population, and most deaths were due to cancer or cardiovascular diseases^[158]	Level 1B
	Similarly, an earlier randomised study comparing the effectiveness of a combination of anticoagulation and IVC filters versus anticoagulation alone in patients with proximal DVT showed a statistically significant decrease in the incidence of PE in the filter group (1·1%vs 4·8%); there was, however, a subsequent excess of recurrent DVT, without any difference in mortality^[153]	Level 1B
	The AHA/ASA and international guidelines recommend that patients with ICH who develop an acute proximal DVT, particularly those with clinical or subclinical PE, should be considered for acute placement of a vena cava filter^[2]^,^[149]	Level 2b C
Anticoagulation	The AHA/ASA guidelines recommend that the decision to start antithrombotic therapy several weeks after the placement of a vena cava filter must be made on the basis of a risk–benefit analysis of the potential for recurrent bleeding (amyloid-related ICH has higher risk of recurrent ICH than does hypertension-related ICH), as well as associated disorders with increased arterial thrombotic risk (eg, atrial fibrillation), and the overall health and mobility of the patient^[2]	Level 2b B
Surgical embolectomy	The evidence for the benefit of surgical embolectomy as a life-saving procedure for PE as a complication of ICH comes from case series: in one series of three consecutive cases of pulmonary embolectomy in patients with ICH with massive PE, the interval between the onset of intracranial bleeding and emergency surgical embolectomy was 7–16 days, and all three patients survived without any neurological exacerbation;^[159] however, the problem associated with surgical embolectomy is the possible exacerbation of intracranial bleeding from systemic heparinisation	Level 3C

AHA/ASA=American Heart Association/American Stroke Association. DVT=deep-vein thrombosis. ICH=intracerebral haemorrhage. IVC=inferior vena cava. LMWH=low-molecular-weight heparin. PE=pulmonary embolism. PREPIC=Prévention du Risque d'Embolie Pulmonaire par Interruption Cave.

*	The level of evidence is according to the Oxford Centre for Evidence-based Medicine (Level 1A being the highest level of evidence).^[64]

An even greater clinical therapeutic dilemma is the management of patients with ICH who subsequently develop VTE. If untreated, the risk of recurrent fatal PE is increased and, if treated, patients are at increased risk of bleeding. Anticoagulation has been estimated to double the risk of recurrent ICH compared with the overall recurrence risk of ICH, and the mortality rate associated with recurrent ICH can be as high as 50%.^[160] The risk of recurrent ICH can depend on factors such as the patient's age and the location of ICH. Patients with lobar haemorrhages are at higher risk of rebleeding, probably due to suspected amyloid angiopathy.^[161]

Insertion of a vena cava filter is recommended in patients with ICH who develop an acute proximal venous thrombosis. The decision to start antithrombotic treatment several weeks after the vena cava filter should be made on the basis of a risk–benefit analysis of the potential for rebleeding as well as the patient's comorbidities and mobility.^[2]

Fever

Clinical features

Fever occurs in up to 40% of patients after ICH,^[162]^,^[163]and is independently associated with a poor outcome and increased mortality.^[163]^,^[164]^,^[165]^,^[166]^,^[167]The incidence of fever (temperature >38·3°C) is high in basal ganglionic and lobar ICH, especially in patients with IVH.^[45]^,^[162]^,^[163]The cause of high temperature after stroke is not always apparent, although increased body temperature might be a direct consequence of brain damage caused by stroke or accompanying infections.^[164]^,^[168]Increased body temperature could result from damage to the thermostatic centre after hypothalamic stroke^[164]—patients with IVH are thought to have more of a neurogenic or central fever.^[166]

A high body temperature after ICH is associated with HE, cerebral oedema, increased ICP, and END.^[45]^,^[169]Fever after ICH is associated with longer ICU and hospital stays, poor functional outcome, and increased mortality.^[167] A prospective study of 390 mixed ischaemic and intracerebral haemorrhagic stroke patients (9% with ICH) admitted within 6 h of stroke onset showed that the relative risk of poor outcome increased by 2·2 times and that mortality increased by a factor of 1·8 for each 1°C increase in baseline body temperature.^[166]

In a subanalysis of data from the PAIS (Paracetamol [Acetaminophen] In Stroke) trial^[168] of 1332 IS and ICH patients admitted within 12 h of stroke onset, 10% of 163 ICH patients had admission body temperatures of more than 37·5°C. An early rise in body temperature rather than high body temperature on admission was the greatest risk factor for adverse outcome.^[164]

In a study of 251 cases of ICH, initial body temperature was not an independent prognostic factor, but an increase in body temperature during the first 72 h, which occurred in 91% of patients, was associated with poor clinical outcome. Also, for those patients surviving the first 72 h after hospital admission, a longer duration of fever was associated with a worse outcome.^[163]

In a retrospective study of 330 patients with acute IS and ICH, of the 37·6% of 330 patients who had fever, 22·7% had a documented infection and 14·8% had fever without a documented infection.^[170] Reith and colleagues^[166]detected infection in a fifth of the 25% of mixed IS and ICH pyrexial patients (body temperature >37·5°C on admission within 6 h of stroke onset). Pulmonary and urinary infections are the main causes of infectious fever in patients with stroke.^[162]^,^[163]^,^[168]^,^[171]In the PAIS study, most infectious fevers were due to pneumonia and urinary tract infections (UTIs).^[168] In the review with only ICH patients, pulmonary infection was diagnosed within the first 72 h in 84 patients (43% of 196 patients) and UTI was diagnosed within the same time in 69 patients (35% of 196 patients).^[163]

Management

ICH patients with a high temperature should be physically examined and investigated to establish the cause of fever and possibly the source of infection. Generally, treatment with antipyretics and cooling blankets is used^[169] for patients with a sustained fever of more than 38·3°C (panel). Although new adhesive surface-cooling systems and endovascular heat-exchange catheters might prove more effective,^[171]^,^[173]they have not been systematically investigated in patients with ICH. No evidence is available from RCTs linking fever treatment with improved clinical outcome or reduced mortality. A Cochrane review showed no statistically significant effect of pharmacological or physical temperature-lowering therapy in reducing the risk of death or dependency.^[172] In the PAIS RCT,^[168] no difference was seen between the placebo group and the group treated with paracetamol in patients with IS and ICH within 12 h of symptom onset. However a post-hoc analysis of patients with a baseline body temperature of 37–39°C who were treated with paracetamol showed improved outcome. Sources of infectious fever should be treated with appropriate antibiotics, and antipyretics should be given to lower temperature in ICH patients with fever.^[2]

Panel

Clinical management of fever and infection after intracerebral haemorrhage

The goal should be to maintain normothermia and treat infections in patients with ICH. Patients with ICH and sustained fever in excess of 38·3°C should be treated with antipyretics and cooling blankets^[163]^,^[169](Level 1C). However, there is no evidence from randomised controlled trials to link fever treatment with improved clinical outcome or reduced mortality. A Cochrane review of five pharmacological temperature-lowering trials and three physical cooling trials with 423 participants recorded no statistically significant effect of pharmacological or physical temperature-lowering therapy in reducing the risk of dependency (odds ratio 0·9, 95% CI 0·6–1·4) or death (0·9, 0·5–1·5)^[172] (Level 1C). Equally, an updated meta-analysis of a Cochrane review with six pharmacological temperature-lowering therapies did not show any statistically significant difference between the treated and placebo groups in the proportion of patients who were alive and independent (modified Rankin score ≤2) at final follow-up (1·1, 0·9–1·3)^[168] (Level 1C). In PAIS, a randomised controlled trial, treatment with high-dose acetaminophen (6 g daily) in 1400 patients with ischaemic stroke and ICH within 12 h of symptom onset was associated with a 0·26°C (95% CI 0·18–0·31) reduction in mean body temperature measured 24 h after admission; the trial did not provide sufficient evidence to lend support to routine use of high-dose paracetamol in patients with acute stroke. However, in a post-hoc analysis of patients with a baseline body temperature of 37–39°C treated with paracetamol, a 9% absolute increase was recorded in the number of patients with improved outcome, with a number needed to treat of 11; serious adverse events occurred in 8% of the paracetamol group versus 10% of the placebo group (Level 1B). Although no evidence from randomised controlled trials is available to lend support to the routine use of physical or pharmacological strategies to reduce temperature in patients with acute stroke, the AHA/ASA guidelines recommend that the sources of fever should be treated with appropriate antibiotics and that antipyretic drugs should be given to lower temperature in febrile patients with ICH (Level 1C).^[2]

AHA/ASA=American Heart Association/American Stroke Association. ICH=intracerebral haemorrhage. PAIS=Paracetamol (Acetaminophen) In Stroke. The level of evidence is according to the Oxford Centre for Evidence-based Medicine (Level 1A being the highest level of evidence).^[64]

Hyperglycaemia

Clinical features

A high proportion of patients (about 60%) might develop hyperglycaemia even in the absence of a previous history of diabetes after ICH.^[174] Increased blood glucose in the acute setting of ICH is probably a response to stress and severity of ICH^[13] and can persist for up to 72 h after ICH.^[174]

Many studies have shown that increased serum glucose on admission is associated with larger haematoma size, HE, PHE, cell death, and increased risk of poor outcome,^[12]^,^[32]^,^[174]^,^[175]^,^[176]and that it is a potent predictor of 30 day mortality in both diabetic and non-diabetic patients with ICH^[13] as well as an independent predictor of early mortality and worse functional outcome in non-diabetic patients with ICH.^[175]^,^[176]

In the post-hoc analysis of the ATACH trial of 60 patients, the risk of poor outcome (mRS 4–6) in patients with persistent or increasing serum glucose concentrations was more than twice that of patients with a reduction in serum glucose concentrations (relative risk [RR]=2·64, 95% CI 1·03–6·75). Also, the RRs were 2·59 (1·27–5·30) for HE of more than 33%, and 1·25 (0·73–2·13) for a relative oedema expansion of more than 40%.^[177]

Management

Poor outcomes associated with hyperglycaemia could be avoided or minimised through monitoring glucose and maintaining normoglycaemia (table 7). Control of hyperglycaemia in the acute setting of ICH decreases the likelihood of HE, PHE, ICP, and seizures, and improve outcomes,^[12]^,^[177]although the optimum glucose target and duration of glucose control in patients with ICH are unclear. However, studies have suggested targeting a glucose concentration of 150 mg/dL in the acute setting of ICH,^[12]^,^[174]and the avoidance of hyperglycaemia during the first 72 h after symptom onset, possibly because admission hyperglycaemia can persist for at least 72 h post ictus.^[174]^,^[177]

Table 7 -- Clinical management of hyperglycaemia after intracerebral haemorrhage

	Description	Level of evidence^[*]
General considerations	Data from the post-hoc analysis of the ATACH trial has linked a decrease in serum glucose concentration to a reduction in haematoma expansion and improved clinical outcome^[177]	Level 1B
Optimum glucose target	The optimum glucose target is unclear and various glucose concentrations from 127 mg/dL to 180 mg/dL have been suggested; some prospective studies have suggested a target glucose concentration of 150 mg/dL in the acute setting of ICH^[12]^,^[174]	Level 1B
	In the Oxfordshire Community Stroke Project, in 645 patients (86%) with ischaemic stroke and 105 (14%) with haemorrhagic stroke, a plasma glucose concentration higher than 144 mg/dL (>8 mmol/L) was associated with increased mortality, particularly in the first month after stroke^[178]	Level 2B
	In the Acute Brain Bleeding Analysis, a prospective study of 1387 patients with ICH, an admission glucose concentration of >167 mg/dL was shown to be an independent risk factor for early mortality^[176]	Level 1B
Optimum duration of glucose control	The optimum duration of glucose control is unclear, although studies have suggested the avoidance of hyperglycaemia during the first 72 h of symptom onset, possibly because admission hyperglycaemia can persist for up to 72 h post ictus^[174]^,^[177]	..
	In a post-hoc analysis of the ATACH trial, patients who had serum glucose reduction during the first 72 h after ICH had a lower relative risk of death or disability at 3 months^[177]	Level 1B
	In a prospective observational study of 295 patients, individuals with a serum glucose concentration maintained within 60–150 mg/dL during the first 72 h after ICH did better than those with a persistently high serum glucose concentration^[174]	Level 1B
	In GIST-UK, which had a shorter duration than did ATACH, 24 h of intensive glucose control did not reduce mortality or improve functional outcome in the treatment group,^[179] although the trial had a small number of patients with ICH (114 of the total 933) randomly allocated to treatment within 24 h of stroke onset; no separate analysis for patients with ICH was reported	Level 2B
	AHA/ASA guidelines suggest that serum glucose concentrations of >140 mg/dL (>7·8 mmol/L) should be treated with insulin^[2]^,^[45]	Level 2a C

AHA/ASA=American Heart Association/American Stroke Association. ATACH=Antihypertensive Treatment of Acute Cerebral Hemorrhage. GIST-UK=UK Glucose Insulin in Stroke Trial. ICH=intracerebral haemorrhage.

*	The level of evidence is according to the Oxford Centre for Evidence-based Medicine (Level 1A being the highest level of evidence).^[64]

Although large RCTs are needed to define the optimum glucose target and duration of treatment that can improve clinical outcomes in patients with ICH, an increased serum glucose of more than 140 mg/dL (>7·8 mmol/L) should be treated with insulin.^[2]^,^[45]

Increased blood pressure

Clinical features

Increased BP (≥140/90 mm Hg) is common in the acute phase of ICH, occurring in more than 70% of patients on presentation.^[180]^,^[181]Increased BP in the acute setting of ICH occurs even in the absence of a previous history of hypertension and is independently associated with poor outcome.^[180]^,^[182]

The mechanism for the acute increase of BP after ICH is unknown. However, it is proposed to be a multifactorial process that includes activation of the neuroendocrine systems (sympathetic nervous system, glucocorticoid system, or the renin–angiotensin axis), increased cardiac output, and stress response to conditions such as increased ICP, headache, and urinary retention.^[45]^,^[180]^,^[182]

Many studies have shown an association between increased BP in the acute phase of ICH and HE, PHE, and rebleeding.^[19]^,^[36]^,^[37]^,^[90]Increased BP in the acute setting of ICH is associated with worse outcome and increased mortality.^[180]^,^[182]^,^[183]In a large study of 3930 mixed stroke patients (1760 with ICH), the in-hospital case-fatality rate was 5·9% for patients with ICH. Also, both SBP and diastolic BP were associated with odds of death or disability in such patients.^[183]

However, the effect of BP levels on mortality seems to conform to a U-shaped distribution after ICH, as poorer outcomes have also been seen at very low SBP (<120 and="" at="" hg="" high="" mm="" very="">220 mm Hg) SBP values.^[184]

Management

The poor outcome associated with increased BP after ICH could be minimised with BP monitoring and treatment aimed at maximisation of cerebral perfusion while minimising ongoing bleeding (table 8). The rationale for lowering BP after ICH is because SBP reduction can reduce the rate of HE and possibly improve clinical outcome.

Table 8 -- Clinical management of raised blood pressure after intracerebral haemorrhage

	Description	Level of evidence^[*]
Blood pressure control	The INTERACT pilot trial that compared intensive (target SBP 140 mm Hg) with guideline-based (target SBP 180 mm Hg) BP control showed the feasibility and safety of early intensive BP reduction within the first 6 h of onset of supratentorial ICH; however, no statistically significant difference was recorded in functional outcome at 3 months between the two groups (median mRS score was 2 in both groups; p=0·66)^[20]	Level 1B
	In the ATACH phase 1 trial, patients with a SBP of >170 mm Hg were treated with intravenous nicardipine within 6 h of onset of lobar supratentorial ICH to reduce BP in three escalating target BP tiers: tier 1 (170–200 mm Hg; n=18), tier 2 (140–170 mm Hg; n=20), and tier 3 (110–140 mm Hg; n=22); BP reduction was safe and feasible in all three tiers^[47]	Level 1B
	AHA/ASA guidelines recommend that in patients presenting with a SBP of 150–220 mm Hg, acute lowering of SBP to 140 mm Hg is probably safe^[45]	Level 2a B
Target blood pressure	The following target BP should be considered in various situations:^[2]^,^[45]
	If SBP is >200 mm Hg or MAP is >150 mm Hg, aggressive reduction of BP could be considered with continuous intravenous infusion, with frequent BP monitoring every 5 min	Level 2b C
	If SBP is >180 mm Hg or MAP is >130 mm Hg and there is the possibility of increased ICP, then consider monitoring ICP and reducing BP using intermittent or continuous intravenous drugs while maintaining a cerebral perfusion pressure of 60 mm Hg
	If SBP is >180 mm Hg or MAP is >130 mm Hg and there is no evidence of increased ICP, then consider a slight reduction of BP (eg, MAP of 110 mm Hg or target BP of 160/90 mm Hg), using intermittent or continuous intravenous drugs to control BP, and clinically re-examine the patient every 15 min
	If SBP exceeds 180 mm Hg or MAP exceeds 130 mm Hg, management should involve either bolus or continuous infusion of drugs to a target MAP of 110 mm Hg or less or a goal BP of 160/90 mm Hg	Level 2b C
Antihypertensive drugs recommended in AHA/ASA guidelines	Suitable antihypertensive drugs include labetalol, esmolol, or nicardipine (drugs with a cerebral vasodilation effect should be avoided)^[2] Labetalol: 5–20 mg (intermittent boluses) every 15 min or 2 mg/min in continuous infusion (drip) Esmolol: 250 mcg/kg (loading dose), then 25–300 mcg/kg per min (maintenance) Nicardipine: 5–15 mg/h Hydralazine: 5–20 mg (intermittent boluses) Nitroprusside: 0·1–10 mcg/kg per min	Level 2bC

AHA/ASA=American Heart Association/American Stroke Association. ATACH=Antihypertensive Treatment of Acute Cerebral Haemorrhage. BP=blood pressure. ICH=intracerebral haemorrhage. ICP=intracranial pressure. INTERACT=Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial. MAP=mean arterial pressure. mRS=modified Rankin score. SBP=systolic blood pressure.

*	The level of evidence is according to the Oxford Centre for Evidence-based Medicine (Level 1A being the highest level of evidence).^[64]

The INTERACT trial showed that a reduction of SBP to 140 mm Hg is safe and might reduce the risk of HE in patients treated within 6 h of onset of ICH, but had no effect on outcome.^[20]^,^[46]In ATACH, aggressive SBP reduction to 110–140 mm Hg in the first 24 h was well tolerated, with a low risk of HE, neurological deterioration, and in-hospital mortality.^[47]

The results of both INTERACT 2 and ATACH 2 are awaited, and might further answer the question of whether there are other benefits of early SBP reduction in patients with ICH, and provide clearer evidence for the target BP and the choice of drugs. Pending these results, the AHA/ASA guidelines recommend BP lowering if SBP is 150–220 mm Hg or MAP is higher than 150 mm Hg, and that acute lowering of SBP to 140 mm Hg is probably safe.^[45] Meanwhile, the EUSI recommends a target of 160/100 mm Hg or a MAP of 125 mm Hg in patients with a history of hypertension and 150/90 mm Hg or a MAP of 110 mm Hg in those without a history of hypertension.^[64]

Conclusions

Complications occurring during the acute phase of ICH add further detrimental effects to an already potentially fatal disorder and substantially affect the clinical outcome. In view of the small number of therapeutic options available for ICH, a need exists to provide the best evidence-based supportive care. Patients should be managed in a neuroscience ICU or a similar setting during the acute phase of ICH, with continuous monitoring of vital signs and frequent neurological assessment. Improved surveillance is needed for the early detection of complications, which should be managed on the basis of current recommendations and guidelines, especially when little evidence exists or when trials are still in progress. Once patients are stabilised, early rehabilitation is needed to prevent or reduce the risk of further complications. The implementation of appropriate preventative and therapeutic interventions could minimise the morbidity and mortality associated with this devastating type of stroke. A clear need exists for further research into the prevention and treatment of ICH complications to improve the level of evidence available, because most guidelines and recommendations are based on empirical data.

comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX)

2013-02-07T09:00:00.001-08:00

Articles
Comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX): a phase 3 randomised controlled trial

Giancarlo Comi, Prof, MD^a^,^*
Nicola De Stefano, Prof, MD^b
Mark S Freedman, Prof, MD^c
Frederik Barkhof, Prof, MD^d
Chris H Polman, Prof, MD^e
Bernard MJ Uitdehaag, Prof, MD^e
Florence Casset-Semanaz, MSc^f
Brian Hennessy, MSc^f
Margaretha Stam Moraga, MSc^f
Sanda Rocak, PhD^f
Bettina Stubinski, MD^f
Ludwig Kappos, Prof, MD^g

^a  Department of Neurology, Ospedale San Raffaele, Milan, Italy
^b  Department of Neurological and Behavioural Sciences, University of Siena, Siena, Italy
^c  Multiple Sclerosis Research Unit, Ottawa Hospital-General Campus, Ottawa, ON, Canada
^d  Diagnostic Radiology and Image Analysis Centre, VU Medical Center, Amsterdam, Netherlands
^e  Department of Neurology, VU Medical Center, Amsterdam, Netherlands
^f  Merck Serono SA, Geneva, Switzerland
^g  Neurology and Department of Biomedicine, University Hospital Basel, Basel, Switzerland

^* Correspondence to: Prof Giancarlo Comi, Department of Neurology, Ospedale San Raffaele, Via Olgettina, 60, 20132 Milan, Italy

E-mail address: g.comi@hsr.it

PII S1474-4422(11)70262-9

Summary

Background

In patients presenting with a first clinical demyelinating event that is suggestive of multiple sclerosis (MS), treatment with interferon beta can delay the occurrence of further attacks and the onset of MS. We investigated the effects of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event.
Methods

We undertook a multicentre phase 3 study (REbif FLEXible dosing in early MS [REFLEX]) that included patients (aged 18–50 years) with a single clinical event suggestive of MS, and at least two clinically silent T2 lesions on brain MRI. Participants were randomly assigned in a 1:1:1 ratio by use of a centralised interactive voice response system to receive the serum-free formulation of subcutaneous interferon beta-1a 44 μg three times a week or once a week (plus placebo twice a week for masking), or placebo three times a week for up to 24 months. Patients and physicians were masked to group allocation. The primary endpoint was time to a diagnosis of MS as defined by the 2005 McDonald criteria and the main secondary endpoint was time to clinically definite MS (CDMS) as defined by the Poser criteria. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, numberNCT00404352.
Findings

517 patients were randomly assigned (171 to subcutaneous interferon beta-1a three times a week, 175 to subcutaneous interferon beta-1a once a week, and 171 to placebo) and 515 were treated. The 2-year cumulative probability of McDonald MS was significantly lower in patients treated with subcutaneous interferon beta-1a (three times a week 62·5%, p<0 0="" 2-year="" 20="" 21="" 75="" a="" adverse="" beta-1a.="" beta-1a="" both="" cdms="" ci="" conversion="" dosing="" established="" events="" for="" hazard="" hr="" interferon="" lower="" of="" once="" p="" placebo="" profile="" rates="" ratio="" regimens="" subcutaneous="" than="" the="" three="" times="" to="" versus="" week="" were="" within="">Interpretation

Both regimens of subcutaneous interferon beta-1a delayed clinical relapses and subclinical disease activity. The potential differences between the regimens warrant longer-term study.
Funding

Merck Serono SA, Geneva, Switzerland.

Introduction

The first clinical manifestation of multiple sclerosis (MS) is often a single neurological event consistent with one or more white matter lesions in the CNS, such as optic neuritis.^[1] This event is usually followed by the recurrent attacks that characterise relapsing MS.^[2]^,^[3]The recurrence of attacks consistent with CNS demyelination has traditionally been used to make a definitive diagnosis of MS (clinically definite MS [CDMS]).^[4]^,^[5]The criteria introduced by Poser and colleagues^[5] in 1983 required two clinical attacks for a diagnosis of CDMS, although clinical, paraclinical, and laboratory evidence could be taken into account for a diagnosis of probable MS. More recently, advances in MRI techniques have led to the development of the McDonald criteria^[6]^,^[7]^,^[8]for an earlier diagnosis of MS (McDonald MS) if the first clinical event is accompanied by specific subclinical MRI features. For a diagnosis of McDonald MS, the MRI evidence of disease must show that CNS lesions are disseminated in time and space. These criteria, first introduced in 2001,^[6] were revised in 2005^[7] and 2010^[8] to improve their sensitivity for early MS diagnosis without compromising specificity.

Many patients are now treated as early as possible after a first clinical event, without the need to wait for a diagnosis of definite MS.^[9] In several studies, treatment with interferon beta or glatiramer acetate at the time of the first clinical event delayed the occurrence of further attacks and the onset of MS.^[10]^,^[11]^,^[12]^,^[13]^,^[14]Furthermore, early treatment with interferon beta can also affect long-term disease progression.^[11]^,^[15]In the Early Treatment of MS (ETOMS) study,^[16] subcutaneous interferon beta-1a at 22 μg once a week was effective in delaying MS. However, until now the effect of subcutaneous interferon beta-1a at 44 μg three times a week—the licensed dosing regimen for MS—has not been assessed in people with a clinically isolated event. In our 2-year, double-blind phase 3 study (REbif FLEXible dosing in early MS [REFLEX]), we compared the effects of two dosing frequencies of a serum-free formulation of subcutaneous interferon beta-1a 44 μg with placebo on time to development of MS, as defined in the 2005 version of the McDonald criteria.^[7]

Methods

Patients

Patients from 80 centres in 28 countries were recruited into the phase 3 REFLEX study. They were eligible for inclusion if they were aged 18–50 years and had the following: an expanded disability status scale (EDSS)^[17] score of 0–5·0; a single event suggestive of MS within 60 days before study entry; and at least two clinically silent lesions of 3 mm or more on T2-weighted brain MRI scan, at least one of which was ovoid, periventricular, or infratentorial. Exclusion criteria included diagnosis of MS as per the 2005 McDonald criteria and any other disease that could better account for the signs and symptoms. Previous use of any other immunomodulatory or immunosuppressive therapy was prohibited. Women of childbearing age were required to use contraception.

The study was undertaken in compliance with the Declaration of Helsinki and standards of Good Clinical Practiceaccording to the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Before initiation of the trial at each centre, the relevant institutional review board or independent ethics committee reviewed and approved the trial protocol, patient information leaflet, informed consent forms, and investigator brochure. All patients provided written informed consent at the screening visit.

Randomisation and masking

The study centre dialled a centralised interactive voice response system (provided by S-Clinica, Brussels, Belgium) to randomly assign patients in a 1:1:1 ratio to the serum-free formulation of subcutaneous interferon beta-1a 44 μg three times a week (the dosing regimen generally recommended for established relapsing MS), the same formulation and dose of interferon beta-1a once a week, or placebo. Patients assigned to the once a week regimen were given two additional subcutaneous injections of placebo per week for masking purposes, and patients assigned to placebo received three subcutaneous injections per week. Placebo was supplied as a transparent sterile solution for injection in prefilled syringes matching the interferon beta-1a prefilled syringes, each containing 0·5 mL. The double-blind period was defined as the time between randomisation and CDMS (defined as either a second event suggestive of MS or an increase of at least 1·5 points in the EDSS^[17] score that was sustained for at least 3 months), until study withdrawal, or 24 months, whichever occurred first.

Dynamic treatment allocation, by use of a minimisation algorithm with an element of chance, was applied to minimise imbalance between the treatment groups. Randomisation was stratified according to baseline factors: age (<30 i="" nbsp="" style="margin: 0px; padding: 0px;" years="">vs

≥30 years), steroid use for first event (yes vs no), classification of first event (monofocal vs multifocal), and at least one gadolinium-enhancing lesion (yes vs no).

A treatment kit number, corresponding to the randomisation group, was allocated centrally to each patient for use only by that individual. A two-physician (treating and assessing) model was used to assist with study masking. The treating physician was responsible for supervision of study drug administration and for recording adverse events and safety assessments. The assessing physician was not involved in the care of study participants and was exclusively responsible for all neurological assessments, beginning with the prestudy assessment. Injection sites were covered before a patient saw the assessing physician to maintain masking.

In the active treatment groups, patients received 20% of the full dose for 2 weeks, 50% for a further 2 weeks, and the full dose for the remainder of the study. On conversion to CDMS, patients were switched to open-label subcutaneous interferon beta-1a at 44 μg three times a week until the end of the 24 months, with titration to this dose for all patients to maintain masking to the original randomised treatment group. After conversion to CDMS, patients underwent MRI scans every 6 months.

Procedures

Patients' demographics, and medical history were obtained at the screening visit. Their visits were scheduled every 3 months from baseline to month 24 to gather EDSS, MRI, and other efficacy data, and to report safety. An additional safety visit was made at month 1 for all patients.

Patients were strongly recommended to take ibuprofen (400 mg) or paracetamol (1000 mg) prophylactically with each injection during the first 12 weeks of treatment. Short courses of corticosteroid treatment for MS relapses were permitted according to the trial protocol at the discretion of the treating physician. Any on-study MRI scan had to be done before administration of steroids or at least 7 days after the last steroid dose.

All centres were required to follow an MRI operations protocol to ensure standardised scanning, image acquisition, and data transfer. Each patient was scanned by the same machine throughout the trial whenever possible. When a machine had to be changed, every effort was made to keep the parameters consistent. The protocol specified a preference for 1·5 T scanners. T1-weighted scans without and with administration of a single dose of contrast medium (gadolinium-diethylene triamine pentaacetic acid, 0·2 mL/kg) and T2-weighted double-echo scans were done. Scans were obtained in the axial plane parallel to the line joining the genu and splenium of the corpus callosum and consisted of 46 contiguous images with a slice thickness of 3 mm.

Blood samples for the assessment of binding antibodies and neutralising antibodies to interferon beta were obtained from all patients on study day 1 and then every 6 months until month 24 or study termination. Samples were tested first for binding activity, and those that were positive were tested for neutralising activity using the cytopathic effect assay.^[18]

On completion of the trial, all patients were offered the opportunity to participate in a double-blind extension trial for another 3 years. Patients who had not converted to CDMS at 24 months and decided not to participate in the extension trial were offered an optional additional 1-year open-label treatment with subcutaneous interferon beta-1a at 44 μg three times a week. Patients who declined both these options had a 4-week safety follow-up.

An independent adjudication committee (which remained masked throughout the study and consisted of neurologists and a neuroradiologist with expertise in MS) was responsible for assessing eligibility in all patients, confirming or reclassifying each patient's first event as monofocal or multifocal, reviewing all relapses that contributed to conversion to CDMS, and thus confirming whether the diagnostic criteria for McDonald MS and CDMS were met. The reporting and assessment of relapses were continuous and independent of scheduled visits. A relapse was defined as a new or worsening neurological symptom, in the absence of fever, lasting for at least 24 h, accompanied by an objective change in the relevant (ie, symptomatic) functional system, and preceded by 30 days or more of clinical stability or improvement. MRI scans were assessed centrally at the VU Medical Center, Amsterdam, The Netherlands.

To meet the McDonald criteria for diagnosis of MS, patients had to have evidence of spatial and temporal dissemination of MRI lesions or a second clinical attack. For patients without a second attack, MRI follow-up scans were assessed and lesions were classified qualitatively as persisting, new, or enlarging and the location recorded as infratentorial, juxtacortical, periventricular, or deep white matter. Dissemination in space on MRI was defined as three of the following: at least one gadolinium-enhancing lesion or at least nine T2 hyperintense lesions; at least one infratentorial lesion; at least one juxtacortical lesion; or at least three periventricular lesions. Alternatively, dissemination in space could be defined as at least two MRI lesions consistent with MS plus positive CSF. Dissemination in time was defined as a new gadolinium-enhancing lesion more than 3 months after onset of the first clinical demyelinating event (at a site different from the initial event) or a new T2 lesion at any time compared with a scan at least 30 days after the onset of the initial clinical event.

The safety and tolerability of subcutaneous interferon beta-1a were assessed by documentation of adverse events, laboratory tests, vital signs, electrocardiograms, physical examination, and neutralising antibodies to interferon beta. The following were not judged to be adverse events in the safety analysis: pregnancies, MS symptoms, relapses, and exacerbations or worsening MS, unless the event was judged to be related to the study drug. Adverse events were coded with the Medical Dictionary for Regulatory Activities (MedDRA) and analysed according to the preferred terms. The preferred terms pertaining to prespecified adverse events that were known to be related to interferon beta—flu-like syndrome (influenza-like illness), cytopenia, hepatic disorders, thyroid disorders, hypersensitivity reactions, skin rashes, depression and suicidal ideation, and injection-site reactions—were grouped and analysed together.

Statistical analysis

The primary endpoint was time to conversion to McDonald MS as defined according to the 2005 version of the criteria.^[7] The main secondary endpoint was time to conversion to CDMS and the main MRI secondary endpoint was the mean number of combined unique active lesions per patient per scan. A combined unique active lesion was defined as a new or persisting gadolinium-enhancing lesion on T1 MRI or a new or enlarging lesion on T2 MRI that was non-gadolinium-enhancing on T1 MRI. To control for type 1 error, a hierarchical hypothesis testing strategy was applied, based on the significance of the relevant confirmatory test in the following order: subcutaneous interferon beta-1a 44 μg three times a week versus placebo for time to McDonald MS, time to CDMS, and mean number of combined unique active lesions; then subcutaneous interferon beta-1a 44 μg once a week versus placebo for the same endpoints in the same order. The six confirmatory tests were two-sided and done at the 0·05 significance level in the prespecified sequence; confirmatory testing continued if the null hypothesis in the sequence was rejected. The order of the hierarchical testing was such that the regimen of subcutaneous interferon beta-1a currently recommended in patients with relapsing MS (44 μg three times a week) was tested against all or as many of the primary and secondary endpoints as possible before the once a week regimen. The predefined comparisons between the interferon beta-1a three times a week and once a week dosing regimens were not part of the hypothesis testing and type 1 error control, and were thus exploratory.

The primary analysis was a pair-wise comparison of the treatment groups undertaken for the primary and main secondary endpoints by use of a two-sided stratified log-rank test at the 0·05 significance level. The probability of patients remaining event-free over time (from randomisation) in each of the three treatment groups was shown in the form of survival curves estimated by use of the non-parametric Kaplan-Meier method for the primary and main secondary endpoints. The treatment effect was also assessed by use of hazard ratios with the Cox's proportional hazards model, adjusted by the randomisation stratification factors. For the main MRI endpoint, treatment groups were compared pair-wise at the 0·05 significance level by use of a non-parametric ANOVA on ranks model including treatment and randomisation stratification factors as covariates. The estimates of rate ratios for the main MRI endpoint were calculated by use of a negative binomial model with treatment and randomisation stratification factors as covariates and log number of scans as an offset variable.

150 patients per group were estimated to be needed to achieve 165 events (diagnosis of McDonald MS) for the comparison of subcutaneous interferon beta-1a three times a week versus placebo, and 238 events in total (96 in the placebo group, 73 in the once a week group, and 69 in the three times a week group) to give 90% power for the primary comparison with a two-sided 0·05 ɑ error for detection of a hazard ratio of 0·6 in the primary efficacy endpoint, assuming a 10% dropout rate. This hazard ratio corresponds to an expected proportion of 15% of patients free from McDonald MS at 24 months in the placebo group and 32% in the subcutaneous interferon beta-1a three times a week group, based on a previous study of subcutaneous interferon beta-1b in a similar population.^[19]Assuming a withdrawal rate of 10% over 24 months, the sample size was increased to 160 patients per group.

The intention-to-treat population consisted of all patients who were randomly assigned to treatment (treated or not), analysed according to their original allocation, and was used for the efficacy analyses. The double-blind safety population included all patients who were given at least one dose of treatment, analysed according to the treatment they had received during the double-blind period (up to month 24, study withdrawal, or CDMS, whichever occurred first). As patients were switched to open-label treatment with 44 μg three times a week when they were diagnosed as having converted to CDMS, the open-label safety population consisted of all patients from the double-blind safety population who were given at least one open-label study treatment injection after conversion to CDMS. This analysis also corrected for the variation in the duration of treatment between patients. We noted that no bias had been introduced by this feature, so the data are not reported. The primary endpoint was also analysed in subpopulations defined according to the randomisation stratification factors and predefined subgroups.

The study is registered with ClinicalTrials.gov, number NCT00404352.

Role of the funding source

The study was designed by members of the steering committee (LK, MSF, GC, NDS) and the study sponsor. The study sponsor collected the data, did the analysis, and was involved in the interpretation of the data. The data were available to all authors, and they contributed to the analysis and interpretation of the data. The steering committee was responsible for the final decision to submit this report for publication.

Results

The first patient's first visit was on Nov 16, 2006; the last patient's last visit was on Aug 13, 2010. 701 patients were screened and of these 517 were randomly assigned and included in the intention-to-treat population (subcutaneous interferon beta-1a three times a week, n=171; subcutaneous interferon beta-1a once a week, n=175; and placebo, n=171; figure 1). One patient in each group withdrew consent before treatment, resulting in a total of 514 patients from the intention-to-treat population who were allocated to the study drug or placebo (subcutaneous interferon beta-1a three times a week, n=170; subcutaneous interferon beta-1a once a week, n=174; and placebo, n=170). The groups demographic, clinical, and MRI characteristics at baseline are shown in table 1. One patient allocated to interferon beta-1a once a week was first given a three times a week treatment kit; this patient was included in the once a week group in the intention-to-treat population and the three times a week group for the safety population. Another patient was not randomly assigned because no treatment kit was available within 60 days of screening. Treatment was allocated in a double-blinded manner once a kit was available. To ensure the patient received consistent treatment after this initial kit was received, further treatment allocation was by use of the interactive voice response system so that double blinding was maintained. This patient was included in the safety population but not in the intention-to-treat population. After unblinding, it was revealed that this patient had been given placebo, resulting in a total of 515 patients who were given the study drug or placebo.

Table 1 -- Baseline demographic and disease characteristics of intention-to-treat population

		Interferon beta-1a three times a week (n=171)	Interferon beta-1a once a week (n=175)	Placebo (n=171)	Overall (n=517)
Age (years)		30·6 (8·5)	30·7 (8·1)	30·9 (7·9)	30·7 (8·2)
Women		114 (67%)	106 (61%)	112 (65%)	332 (64%)
EDSS score		1·50 (0–4·0)	1·50 (0–3·5)	1·50 (0–3·5)	1·50 (0–4·0)
Time since first demyelinating event (days)		57·6 (3·7)	57·7 (3·4)	57·6 (4·2)	57·6 (3·8)
Classification of first clinical demyelinating event as monofocal (according to the investigator)		99 (58%)	104 (59%)	97 (57%)	300 (58%)
Classification of first clinical demyelinating event as monofocal (according to the adjudication committee)		96 (56%)	90 (51%)	91 (53%)	277 (54%)
Steroid use at first clinical demyelinating event		121 (71%)	123 (70%)	121 (71%)	365 (71%)
Gadolinium-enhancing lesions
	Patients with at least one T1 gadolinium-enhancing lesion	68 (40%)	72 (41%)	73 (43%)	213 (41%)
	Number of gadolinium-enhancing lesions	1·3 (2·5)	1·5 (3·5)	1·2 (2·7)	1·3 (2·9)
	Gadolinium-enhancing lesion volume (mm³)	156·54 (427·33)	194·15 (593·66)	193·68 (588·50)	181·56 (541·68)
T2 hyperintense lesions
	Number of T2 lesions	22·0 (18·8)	23·6 (21·0)	21·3 (20·2)	22·3 (20·0)
	Patients with at least nine T2 lesions	129 (75%)	126 (72%)	122 (71%)	377 (73%)
	T2 lesion volume (mm³)	3110·53 (3410·74)	3853·12 (4716·71)	3334·92 (3990·41)	3436·11 (4083·90)

Data are number (%), mean (SD), or median (range). Interferon beta-1a was administered subcutaneously. EDSS=expanded disability status scale.

The safety population consisted of 515 patients who were given at least one masked injection, 514 from the intention-to-treat population plus the patient who was not randomly assigned but given placebo (subcutaneous interferon beta-1a three times a week, n=171; subcutaneous interferon beta-1a once a week, n=173; and placebo, n=171). Of these patients, 56 (11%) withdrew from the study treatment during the double-blind period (subcutaneous interferon beta-1a three times a week, 21 [12%]; subcutaneous interferon beta-1a once a week, 15 [9%]; and placebo, 20 [12%]). Reasons for withdrawal were adverse events (15 [27%]), disease progression (five [9%]), loss to follow-up (four [7%]), pregnancy (two [4%]), death (one [2%]), and other reasons (29 [52%]). Of the patients in the double-blind safety population who withdrew from treatment, five (24%) of 21 in the interferon beta-1a three times a week group, four (27%) of 15 in the interferon beta-1a once a week group, and six (30%) of 20 in the placebo group did so because of adverse events. Two deaths occurred, both in the placebo group. 402 (78%) of 517 randomly assigned patients entered the extension trial, 20 (4%) entered the 1-year open-label follow-up, and 26 (5%) did not choose either of these options and completed the 4-week safety follow-up. 130 patients were judged to have converted to CDMS (129 because of a second event that was suggestive of MS, 1 because of an increase in EDSS score of ≥1·5 for ≥3 months), of whom 120 switched to open-label treatment for the rest of the study; 12 of these patients subsequently withdrew from treatment. The mean scheduled dose administered in the double-blind period was 98·67% (SD 3·43) in the subcutaneous interferon beta-1a three times a week group, 98·66% (3·82) in the subcutaneous interferon beta-1a once a week group, and 98·78% (3·25) in the placebo group.

379 patients converted to McDonald MS over 2 years (subcutaneous interferon beta-1a three times a week, n=106; subcutaneous interferon beta-1a once a week, n=129; and placebo, n=144). The 2-year cumulative probability of McDonald MS was significantly lower in patients treated with subcutaneous interferon beta-1a versus that in those treated with placebo (figure 2; table 2). The risk of McDonald MS over 24 months was lower with subcutaneous interferon beta-1a three times a week versus subcutaneous interferon beta-1a once a week (table 2).

Table 2 -- Effect of treatment on conversion to McDonald multiple sclerosis

	Interferon beta-1a three times a week versus placebo	Interferon beta-1a once a week versus placebo	Interferon beta-1a three times a week versus interferon beta-1a once a week
Hazard ratio (95% CI)^[*]	0·49 (0·38–0·64)	0·69 (0·54–0·87)	0·71 (0·54–0·91)
Relative risk reduction	51%	31%	29%
Absolute risk reduction (95% CI)	23·3% (12·6–34·0)	10·3% (0·2–20·4)	13·0% (2·0–24·0)
Log-rank p-value^[‡]	<0 td="">	0·0080	0·0087

Interferon beta-1a was administered subcutaneously.

*	Adjusted Cox's proportional hazards model with treatment group and randomisation stratification factors as covariates.
‡	Two-sided log-rank test, stratified by randomisation stratification factors.

Table 3 -- Effect of treatment on conversion to clinically definite multiple sclerosis

	Interferon beta-1a three times a week versus placebo	Interferon beta-1a once a week versus placebo	Interferon beta-1a three times a week versus interferon beta-1a once a week
Hazard ratio (95% CI)^[*]	0·48 (0·31 to 0·73)	0·53 (0·35 to 0·79)	0·90 (0·56 to 1·43)
Relative risk reduction	52%	47%	10%
Absolute risk reduction (95% CI)	16·9% (5·8 to 28·0)	15·9% (4·7 to 27·1)	1·0% (-8·8 to 10·8)
Log-rank p value^[‡]	0·0004	0·0023	0·7737

Interferon beta-1a was administered subcutaneously.

*	Adjusted Cox's proportional hazards model with treatment group and randomisation stratification factors as covariates.
‡	Two-sided log-rank test, stratified by the randomisation stratification factors

The rate ratios for mean number of combined unique active lesions per patient per scan were 0·19 (95% CI 0·14–0·26) for subcutaneous interferon beta-1a three times a week group versus placebo group, 0·37 (0·27–0·50) for subcutaneous interferon beta-1a once a week group versus placebo group, and 0·52 (0·38–0·71) for subcutaneous interferon beta-1a three times a week group versus subcutaneous interferon beta-1a once a week. The mean number of combined unique active lesions per patient per scan was significantly lower with both interferon beta-1a dosing regimens (three times a week 0·60 [SD 1·15], p<0 1="" a="" active="" combined="" lesions="" lower="" mean="" number="" of="" once="" p="0·0015).</p" patient="" per="" placebo="" regimen="" scan="" than="" the="" three="" times="" unique="" was="" week="" with="">

The significance of the effect of interferon beta-1a three times a week regimen was maintained when time to McDonald MS was analysed by selected randomisation stratification factors and subgroups (table 4). This was also true for the once a week regimen, with the exceptions of the subgroups with monofocal presentation, and without gadolinium-enhancing lesions at screening. The treatment effect with the three times a week regimen was greater than that with the once a week regimen in the subgroups of patients with multifocal presentation, no gadolinium-enhancing lesions at screening, and at least nine T2 lesions at screening (table 4).

Table 4 -- 2-year cumulative probability of a diagnosis of McDonald multiple sclerosis by selected randomisation stratification factors and subgroups

	Interferon beta-1a three times a week (n=171)	Interferon beta-1a once a week (n=175)	Placebo (n=171)	Interferon beta-1a three times a week versus placebo		Interferon beta-1a once a week versus placebo		Interferon beta-1a three times a week versus interferon beta-1a once a week
				Hazard ratio (95% CI)	p value	Hazard ratio (95% CI)	p value	Hazard ratio (95% CI)	p value
Monofocal presentation	54%	61%	75%	0·58 (0·40–0·84)	0·0035	0·72 (0·50–1·03)	0·0735	0·83 (0·56–1·21)	0·3280
Multifocal presentation	73%	90%	97%	0·45 (0·31–0·64)	<0 td="">	0·64 (0·47–0·88)	0·0065	0·66 (0·46–0·93)	0·0187
No gadolinium-enhancing lesions at screening	54%	69%	79%	0·49 (0·35–0·70)	0·0001	0·74 (0·53–1·02)	0·0688	0·67 (0·47–0·96)	0·0272
At least one gadolinium-enhancing lesion at screening	75%	85%	94%	0·54 (0·38–0·79)	0·0012	0·66 (0·46–0·93)	0·0185	0·81 (0·56–1·18)	0·2708
Fewer than nine T2 lesions at screening	37%	40%	62%	0·42 (0·22–0·80)	0·0077	0·51 (0·29–0·91)	0·0222	0·84 (0·42–1·68)	0·6239
At least nine T2 lesions at screening	70%	89%	96%	0·46 (0·35–0·62)	<0 td="">	0·71 (0·55–0·93)	0·0119	0·63 (0·47–0·83)	0·0011

Interferon beta-1a was administered subcutaneously. Data are percentages, unless otherwise indicated. Hazard ratios and p values (two-sided Wald test) were obtained from Kaplan-Meier cumulative incidence analyses at 2 years and were calculated by use of a Cox's proportional regression model with treatment as a covariate.

No new or unexpected adverse drug reactions were encountered in either of the active treatment groups during this study. The most frequent treatment-emergent adverse events, grouped according to the MedDRA preferred terms and reported in more than 10% of patients in any treatment group, are shown in the webappendix. Table 5 shows the prespecified adverse events that occurred during the double-blind period. As expected, injection-site reactions, hepatic disorders (increases in liver enzyme levels), hypersensitivity reactions, and cytopenia were more frequent with subcutaneous interferon beta-1a three times a week than with subcutaneous interferon beta-1a once a week or with placebo. Influenza-like illness was less frequent in the interferon beta-1a three times a week group than in the once a week group, but more frequent in both active treatment groups than in the placebo group. Depression and suicidal ideation was reported at a similar incidence in all three groups; no MedDRA-preferred terms relating to suicide were reported for any patient. In all other categories of prespecified adverse events, there was no pattern to indicate an increased frequency in the active treatment groups compared with the placebo group.

Table 5 -- Incidence of prespecified treatment-emergent adverse events (preferred terms) during the double-blind period (safety population, n=515)

	Interferon beta-1a three times a week (n=171)	Interferon beta-1a once a week (n=173)	Placebo (n=171)
Patients with prespecified events	127 (74%)	137 (79%)	69 (40%)
Cytopenia	19 (11%)	9 (5%)	4 (2%)
Depression and suicidal ideation	14 (8%)	11 (6%)	14 (8%)
Influenza-like illness	93 (54%)	122 (71%)	34 (20%)
Hepatic disorders^[*]	19 (11%)	16 (9%)	8 (5%)
Hypersensitivity reactions	16 (9%)	10 (6%)	11 (6%)
Injection-site reactions	61 (36%)	42 (24%)	12 (7%)
Skin rashes	16 (9%)	8 (5%)	9 (5%)
Thyroid disorders	11 (6%)	5 (3%)	2 (1%)

Interferon beta-1a was administered subcutaneously.

All except four of the preferred terms in this category (hepatic pain [n=1] and increased blood bilirubin [n=1] in the interferon beta-1a once a week group, and hyperbilirubinaemia [n=1] and liver disorder [n=1] in the interferon beta-1a three times a week group) referred to shifts in liver enzyme levels.

Serious adverse events were reported in 26 patients during the double-blind period (interferon beta-1a three times a week, n=6; interferon beta-1a once a week, n=8; placebo, n=12). Serious adverse events that were judged to be possibly related to the study drug were varicella (interferon beta-1a once a week, n=1) and spontaneous abortion (placebo, n=1; interferon beta-1a once a week, n=1). All other serious adverse events were judged to be either unrelated or unlikely to be related to the study drug.

The number of patients who tested positive for neutralising antibodies (titre ≥20 neutralising units/mL) at month 24 or at their last test was 25 of 169 (14·8%, 95% CI 9·8–21·1) in the subcutaneous interferon beta-1a three times a week group and 28 of 168 (16·7%, 11·4–23·2) in the subcutaneous interferon beta-1a once a week group.

Discussion

The serum-free formulation of subcutaneous interferon beta-1a significantly delayed time to McDonald MS and CDMS compared with placebo in patients with a first demyelinating event that was suggestive of MS, thereby further supporting the early treatment model of MS. The effect was consistent across subgroups defined according to baseline characteristics. In this subgroup analysis, the risk reductions in the interferon beta-1a group were around 50%, which can be regarded as clinically relevant.

The present study is, to our knowledge, the first comparison of the efficacy of two dosing frequencies of subcutaneous interferon beta-1a. The three times a week and once a week regimens similarly delayed the occurrence of a clinical relapse, but the three times a week regimen had a more pronounced effect on McDonald MS than did the once a week regimen. This difference might be partly attributable to the inclusion of subclinical disease measures in the McDonald criteria, resulting in an increased power to detect an existing difference through a higher frequency of diagnoses. However, this result might also indicate a more pronounced effect of more frequent dosing on MRI outcomes that is not directly related to functional deficits. This explanation is supported by the difference between the treated groups in the number of combined unique active lesions per patient per scan.

Our study had limitations. How the short-term effects of early treatment translate to later effects on disease progression has not been established.^[20] This limitation also arises in other studies of disease-modifying drugs in similar patient populations (panel; table 6).^[11]^,^[12]^,^[14]Longer follow-up might be also needed to detect any differences in effects on clinical relapses between the three times and once a week regimens.

Panel

Interpretation

The design of the present study and the patient population included are broadly similar to those of the previous studies of disease-modifying drugs in patients with a first demyelinating event. REbif FLEXible dosing in early multiple sclerosis (REFLEX) is the first study in which the effect of two different dose frequencies of active treatment was assessed. Differences between studies were noted in the proportions of patients with monofocal presentation or steroid use for the first clinical demyelinating event, suggestive of minor differences in the populations of patients. All previous studies included clinically definite multiple sclerosis (CDMS) as the primary endpoint, but the definition of CDMS differed between studies. By contrast, the REFLEX study included CDMS as a secondary endpoint, with McDonald MS as the primary endpoint, consistent with increasing use of the McDonald criteria in clinical practice. Only one study^[10] (that of subcutaneous interferon beta-1b) included McDonald MS as a secondary endpoint, but this was the 2001 iteration of the guidelines rather than the 2005 version used here. Despite this difference, the probability of McDonald MS in placebo-treated patients was similar in the two studies and a similar effect of interferon beta treatment (risk reduction) was noted (subcutaneous interferon beta-1a three times a week vs placebo, 51%; subcutaneous interferon beta-1b vs placebo, 46%).^[10]The effect of active treatment versus placebo on CDMS in the previous studies was also similar to that in REFLEX. Due to differences in MRI procedures and reporting in the different trials, direct comparisons are not possible, but interferon beta and glatiramer acetate seem to improve MRI outcomes. Taken together, these results confirm that treatment with subcutaneous interferon beta-1a significantly delays the onset of MS as defined according to either McDonald criteria or CDMS, similar to results reported for other interferon beta preparations or glatiramer acetate, and support treatment initiation at the time of the first clinical demyelinating event.

Table 6 -- Comparison of the REFLEX study and other large trials of disease-modifying drugs in patients with a first clinical demyelinating event

	Active treatment	Study design	Conversion to CDMS versus placebo	Notes
Comi et al (REFLEX)	Subcutaneous interferon beta-1a (44 μg three times a week or once a week)	Primary endpoint, McDonald MS (2005 criteria); secondary endpoint, CDMS	Three times a week, adjusted HR 0·48 (95% CI 0·31–0·73; p<0 0="" a="" adjusted="" ci="" hr="" once="" p="0·0023)</td" week="">	Monofocal presentation, 54%; steroid treatment, 71%
Kappos et al (BENEFIT)^[10]	Subcutaneous interferon beta-1b (250 μg every other day)	Primary endpoint, CDMS; secondary endpoint, McDonald MS (2001 criteria)	Adjusted HR 0·50 (95% CI 0·36–0·70; p<0 td="">	Similar conversion to McDonald MS in placebo group; similar risk reduction for McDonald MS and CDMS; monofocal presentation, 53%; steroid treatment, 71%
Jacobs et al^[12] and O'Connor et al^[22](CHAMPS)	Intramuscular interferon beta-1a (30 μg once a week)	Primary endpoint, CDMS	Rate ratio 0·56 (95% CI 0·38–0·81; p=0·002); adjusted rate ratio 0·49 (95% CI 0·33–0·73; p<0 td="">	Monofocal presentation, 70%; steroid treatment, 100%
Comi et al (PRECISE)^[14]	Subcutaneous glatiramer acetate (20 mg per day)	Primary endpoint, CDMS	HR 0·55 (95% CI 0·40–0·77; p=0·0005)	Monofocal presentation, 100%; steroid treatment, 61%
Comi et al (ETOMS)^[16]	Subcutaneous interferon beta-1a (22 μg once a week)	Primary endpoint, CDMS	Odds ratio 0·61 (95% CI 0·37–0·99; p=0·045)	Monofocal presentation, 61%; steroid treatment, 64%

CDMS=clinically definite multiple sclerosis. REFLEX=REbif FLEXible dosing in early MS. HR=hazard ratio. MS=multiple sclerosis.

The safety data reported here are in accordance with the well established safety profile of subcutaneous interferon beta-1a. However, although the frequencies of most prespecified treatment-emergent adverse events (four are presented)—injection-site reactions, hepatic disorders, hypersensitivity reactions, and cytopenia—were greater with three times a week dosing than with once a week dosing, the proportions of patients who had the most common prespecified treatment-emergent adverse event—influenza-like illness—was lower with three times a week dosing than with once a week dosing. This difference could be due to tachyphylaxis, wherein tolerance of the drug with respect to this adverse event often increases with greater cumulative exposure, as has been noted previously.^[23]For example, in the EVIDENCE (Evidence of Interferon Dose–response: European–North American Comparative Efficacy) study,^[24] influenza-like illness was more common, severe, and persistent in patients treated with intramuscular interferon beta-1a at 30 μg once a week than in patients given subcutaneous interferon beta-1a at 44 μg three times a week.^[24]

The long-term differences between interferon beta-1a three times a week and interferon beta-1a once a week, in terms of the effect on MRI-related disease activity and adverse-event profile, warrants further study and is the focus of the ongoing preplanned, dose-frequency-blinded, 3-year extension of this study.

Neurostimulation Effective in Migraine Prevention

2013-02-06T18:31:00.001-08:00

Neurostimulation Effective in Migraine Prevention

Sue Hughes

Feb 06, 2013

The first randomized controlled with a device that stimulates the trigeminal nerve in the head has shown a moderate effect in the prevention of migraine.

The device (Cefaly, STX-Med, Herstal, Belgium) is worn like a headband and stimulates the nerve through the skin. In the study, using the device for 20 minutes each day was associated with a 25% reduction in migraine days from baseline and a 19% reduction in migraine attacks.

"As the first randomized trial of this device, this is the first real evidence that it works," lead investigator Jean Schoenen, MD, PhD, from Liège University, Belgium, commented to Medscape Medical News. "It is not a revolution but it is a worthwhile addition to the current armamentarium. It is an interesting treatment for some patients but not all. A major advantage is that, unlike most drug therapies, it does not have side effects."

The current study, known as the PREvention of MIgraine using the STS Cefaly (PREMICE) trial, is published online February 6 in Neurology.

Awaiting Approval

The Cefaly device is already available in Europe, as well as several South American and Middle Eastern countries and Canada. It is awaiting approval in the United States and China. It does need a prescription and can be bought directly by the patient at a cost of 295.

For the study, 67 patients with at least 2 migraine attacks per month underwent a 1-month run-in period and were then randomly assigned to the Cefaly device or sham stimulation (which produced a tingling sensation but did not effectively stimulate the trigeminal nerve) for 20 minutes each day for 3 months.

Patients in the active device group showed a reduction in the number of migraine days per month, migraine attacks, and intake of acute migraine drugs compared with the control group.

The 50% responder rate (the percentage of patients in whom migraine days were reduced by 50% or more) and the 25% responder rate (the percentage of patients in whom migraine days were reduced by 25% or more) were also higher in the active treatment group.

Table. PREMICE: Major Results

Endpoint	Active Treatment	Sham Control	PValue
Change in number of migraine days from run-in to month 3	-2.06	0.32	.054
50% responder rate (%)	38.2	12.12	.023
25% responder rate (%)	58.8	27.3	.14
Change in migraine attacks from run-in to month 3	-0.82	-0.15	.044
Change in acute migraine drugs needed from run-in to month 3	-4.2	0.04	.0072

No adverse effects were reported in either group.

Dr. Schoenen noted that many drug treatments for migraine prevention are available, which vary in effectiveness in different individuals.

"I would say they are effective about half the time," he said. "Clearly there is a need for more therapies. This is just one that might be useful especially for people who feel uncomfortable taking drugs every day." He added that it could also be combined with drugs with the possibility of added effectiveness.

In their discussion, the researchers compared the effectiveness of trigeminal nerve stimulation with that of topiramate, which they say is one of the more effective migraine prophylactic drugs.

Although this was not a head-to-head trial, they point out that topiramate has a 50% responder rate of about 45%, compared with 38% for Cefaly in the current study. Dr. Schoenen notes that around a quarter of patients stop taking topiramate because of adverse effects, whereas "this should not be such a problem with the device."

Adherence May Be an Issue

But adherence is still likely to be an issue with the device. In the current study, adherence was only around 60%, which is lower than that reported for migraine prophylactic drugs, probably because of the time taken to use the device.

"It is obviously more time-consuming than taking a pill," Dr. Schoenen commented. "But it is actually quite user friendly. It can be worn when the patient is getting on with other things like working at the computer or making dinner. It is best if people can build it into their routine and put it on for 20 minutes every day at the same time, for example when making breakfast or before they go to sleep at night."

. He said that using the device is not painful, "but the patient will feel the electrical stimulation, which grows in intensity gradually. It is possible to stop the increase in intensity by just pushing a button."

Dr. Schoenen added that the time of 20-minute use each day chosen was totally empirical. "We considered what may be effective and what would be considered convenient for adherence to treatment. More time might produce better results, but it might also result in lower compliance. Twenty minutes was a compromise."

He noted that the device has been quite popular in patients in his clinic. "We have a database of more than 2000 patients who have had the device. They can borrow it for 2 months from the company to try and if they like it they can then buy it. In our database, 46% of patients decided to go ahead and buy it. This is similar to our study results."

Mechanism?

It is not well understood exactly how the device works. Although peripheral nerve stimulation is an accepted treatment for chronic pain, it is poorly studied in headaches. It is believed that stimulation of peripheral nerves around the head may reduce headache.

The researchers note that migraine pain is mediated through the trigeminal nerve, and it is thought that stimulation of this nerve might change activity in supraspinal centers belonging to the pain matrix or the migraine matrix, increasing the migraine threshold.

Previous studies have also suggested that stimulation of the occipital nerve can reduce headaches, and Dr. Schoenen and colleagues are now testing a new device that stimulates both the occipital and trigeminal nerves.

They say that the evidence cannot be considered stronger than this because the effect size was small and that unblinding might have been an issue given that there would have been a large difference in perceived intensity between the active and sham treatments.In an accompanying editorial, Eishi Asano, MD, PhD, MS, and Peter J. Goadsby, MD, PhD, point out that the PREMICE study has provided class III evidence that neurostimulation with this device is effective and safe as a preventive therapy for migraine.

However, they conclude that, "New therapies are needed in migraine, and further studies of neurostimulation using innovative study designs are warranted to explore the optimum way to create an acceptable evidence base for widespread use of this potentially valuable treatment modality."

This was an investigator-initiated trial funded by the Walloon Region. STX-Med provided the devices. None of the investigators has any financial interest in STX-Med.

Neurology. 2013;80:697-704, 694-694. Published online February 6, 2013. Abstrac
t

Cannabis-Stroke Link: First Case-Control Study

2013-02-06T18:28:00.000-08:00

Cannabis-Stroke Link: First Case-Control Study

Sue Hughes

Feb 06, 2013

Honolulu, Hawaii — More evidence that smoking cannabis is associated with an increased risk for stroke has come from a New Zealand study.

The first case-control study to investigate this association, presented at the American Stroke Association's International Stroke Conference (ISC) 2013, found that patients with ischemic stroke/transient ischemic attack (TIA) were twice as likely to have recently used cannabis as age-, sex-, and ethnicity-matched controls.

"Cannabis is generally perceived as having few serious adverse effects, but this study suggests that this may not be the case," lead author Alan Barber, PhD, MD, from University of Auckland, New Zealand, concluded.

For the study, Dr. Barber and colleagues tested urine for cannabis within 72 hours of hospital admission in 160 patients with ischemic stroke/TIA aged 18 to 55 years and 160 controls (patients admitted with nonstroke diagnoses, matched for age, sex, and ethnicity).

The cannabis screen was positive in 25 (16%) of the stroke/TIA group vs 13 of 160 (8%) control participants. Logistic regression analysis found an odds ratio of 2.30 (95% confidence interval, 1.07 - 4.95).

Dr. Barber said the 16% rate of cannabis use in the stroke patients "took us by surprise." Cannabis users were more likely to be male, tobacco smokers, and Maori. No other illicit drugs were detected.

He explained that he and his colleagues conducted the study after a young woman presented to their emergency department with a stroke after smoking cannabis. "We looked in the literature and found several other case reports, and so decided to do a study."

Dr. Barber said a causal association between cannabis and stroke is plausible, given that cannabis use has been shown to increase sympathetic and decrease parasympathetic activity and to increase heart rate; it is also associated with supine hypertension and postural hypotension, as well as increased cardiac output. It also reduces the oxygen-carrying capacity of blood and may lead to accelerated atherosclerosis, along with cerebral vasoconstriction.

He noted that cannabis use has been associated with a 5-fold increased risk for myocardial infarction in the 60 minutes after use and with atrial fibrillation and sudden unexplained cardiovascular death.

Tobacco Confounding

A problem with the study, Dr. Barber said, was that tobacco use confounded the result; 24 of the 25 stroke patients who tested positive for cannabis were also smokers. "We couldn't tease apart the confounding effect of tobacco, but what we can say is that a lifestyle that includes cannabis use appears to double your risk of stroke."

Dr. Barber explained that the ethics committee of this study did not give permission for any more information other than age, sex, and ethnicity to be revealed about the control patents, given that cannabis was an illicit drug. "That made controlling for confounding factors impossible. We are going to ask them again if we can go through the control patients' notes for this additional information so we might be able to establish a causal effect."

Nevertheless, Dr. Barber believes cannabis has an effect on stroke over and above that of tobacco. He referred to a study conducted in 1974. That study randomly assigned patients with angina to placebo, nicotine, or cannabis cigarettes; time to angina on exercise was reduced by 8% with placebo, 23% with nicotine, and 50% with cannabis.

He concluded, "Future research should determine if the association we found is independent of tobacco." But he warned that even though this may prove difficult given ethical strictures and risk of bias with studying an illicit drug, "the high prevalence of cannabis use in this cohort, as well as moves to decriminalize cannabis makes this research imperative."

Surprising Finding

Asked for comment on these findings, Kyra Becker, MD, professor of neurology and neurological surgery at the University of Washington School of Medicine and co-director of the University of Washington Stroke Center at Harborview, Seattle, said that to her, the findings were not anticipated.

"To me it's actually quite surprising," she told Medscape Medical News. "It's something that I didn't anticipate, and certainly it's something that we don't screen for in our young stroke patients. I'm very intrigued and I'd like to see the follow up studies to actually prove the causation, and why cannabis would actually increase the risk of stroke."

She pointed out that, ironically, some data suggest cannabis is actually neuroprotective in the acute phase of stroke, the difference between the effect on the vessels and the effect on the neurons. "So at the time of stroke, if you get cannabis in your system it actually protects and limits the amount of brain injury," she said, similar to the observed effects with estrogen.

Larry Goldstein, MD, professor of neurology at Duke University Medical Center and director of the Duke Stroke Center, Durham, North Carolina, was cautious. "The thing to keep in mind is that there are very limited data on these patients," he said. "It was done retrospectively so there is undoubtedly residual confounding and factors that weren't measured that might be important."

The authors have disclosed no relevant financial relationships.
"It raises a signal that might need to be paid attention to, but I think more work needs to be done before we understand what that risk is, and whether it's real or not after you fully control for other factors," he concluded.In addition, a high relative risk doesn't mean a high absolute risk, and the absolute risk is not clear from this kind of observation.

International Stroke Conference 2013. Abstract 147. Presented February 6, 2013.

Smokers With Stroke May Benefit More From tPA

2013-02-06T18:24:00.002-08:00

Smokers With Stroke May Benefit More From tPA

Sue Hughes

Feb 06, 2013

New findings suggest that smokers may have a better response to tissue plasminogen activator (tPA) for the treatment of stroke than nonsmokers.

In the study, smokers had a 4-fold greater chance of reperfusion, a 6-fold greater chance of recanalization, and a trend toward better functional outcomes at 3 months compared with nonsmokers.

Similar findings have previously been reported in patients with myocardial infarction (MI) receiving thrombolysis, but this is thought to be the first time this result has been shown in stroke patients with imaging used to verify the results.

"Our results suggest that for smokers having a stroke the chances of recovery if tPA is given quickly are very good," lead researcher, Anna Kufner, MSc, from Charité–Universitätsmedizin Berlin, Germany, commented to Medscape Medical News. "This means it is even more important to seek help quickly if you are a smoker."

Their results were published online January 3 and appear in the February issue of Stroke.

Better Effect of Thrombolysis

Kufner explained that the study came about because she noticed that stroke patients in the clinic where she worked appeared to be having better outcomes, measured by using the Rankin score at 3 months.

"Everybody thought I was crazy at first, or that it was just due to the smokers being younger, but when we found the MI studies suggesting a better effect of thrombolysis in smokers we thought there may be something in it, and we started the current project to look at imaging data on stroke patients receiving tPA and compare smokers with nonsmokers," she said.

The study included 148 consecutive patients with acute ischemic stroke who had MRI before and 1 day after thrombolysis with tPA, which was given within 4.5 hours of stroke symptom onset. Smokers, who made up 21.6% of the population, were significantly younger, were more often male, and had significantly larger mean baseline perfusion deficits.

Results showed that smoking was associated with significantly reduced relative infarct growth and with large increases in the chance of recanalization of the affected vessel and reperfusion.

Table. Response to Thrombolysis Based on Smoking Status in Patients With Proven Vessel Occlusion

Endpoint	Nonsmokers	Smokers	P Value
Recanalization (%)	50	81.1	.02
Reperfusion (%)	30.6	75	.02
Median relative infarct growth (mL)	3.0	1.5	.007
Good outcome at 3 mo (%)	48.1	66.7	.27

After adjustment for confounding factors, including age, sex, hypertension, glucose, and perfusion deficit, smoking was associated with odds ratios of 5.6 for recanalization and 4.3 for reperfusion.

Although smokers had an increased chance of a favorable outcome, as measured by modified Rankin score 3 months after stroke, the researchers note that this was most likely because of their low clinical risk profiles.

"Nonetheless, a favorable functional outcome after stroke was positively associated with reperfusion, suggesting that increased tPA efficacy in smokers may partially contribute to the observed smoking-thrombolysis paradox phenomenon," they write.

A Logical Explanation

But although these findings may appear paradoxical at first, there is a possible scientific explanation. Kufner explained that smokers are believed to have a reduced amount of endogenous tPA released from endothelial cells, which causes them to have a higher risk of clotting. tPA breaks down fibrin, and a few studies have suggested higher fibrin levels in the blood of smokers vs nonsmokers, she noted.

Therefore, clots formed in smokers could well have a higher fibrin content than those in nonsmokers, which would make them more susceptible to be lysed by tPA when it is given as a treatment for stroke.

"This would mean that smokers would be more susceptible to having a stroke in the first place, but also that they have a greater chance of a good outcome after tPA treatment," she added. "And indeed this is what we appear to be seeing."

Kufner noted that a previous study has suggested a better outcome with tPA after stroke in smokers vs nonsmokers, but that study did not use imaging. "Our imaging study gives more information on the possible mechanism behind this effect," she said.

She commented, "We will now integrate these results into the clinic, and we will ask patents more detailed information about smoking behavior to see if we can establish a dose curve; if the amount of smoking correlates with the degree of recanalization and reperfusion."She cautioned that with only 140 patients, this study should be viewed as preliminary. But Kufner's group is now planning further research in this area.

Funding for this research was provided by the Federal Ministry of Education and Research via the Center for Stroke Research Berlin, the Volkswagen Foundation, the European Union, and the German Research Foundation. Kufner has disclosed no relevant financial relationships; she occasionally smokes.

Stroke. 2013;44:407-413. Abstract

What's Hot at International Stroke Conference 2013?

2013-02-05T19:10:00.001-08:00

What's Hot at International Stroke Conference 2013?

Susan Jeffrey

Feb 01, 2013

Honolulu is the backdrop this year for the International Stroke Conference 2013, and sessions will kick off with a Hawaiian ceremonial welcome at the opening plenary session on Wednesday.

Chairman of the Program Committee this year is Steven M. Greenberg, MD, PhD, professor of neurology at Harvard Medical School, John J. Conway Endowed Chair in Neurology and Director, Hemorrhagic Stroke Research at Massachusetts General Hospital Stroke Research Center in Boston, Massachusetts.

"The number of abstract submissions set the record for the International Stroke Conference, and I certainly give first level of credit to the setting in Honolulu," Dr. Greenberg laughs, "but I think it's also a tribute to what we still see, which is a growth in both the quality and quantity of stroke-related research."

Dr. Greenberg discussed some of the highlights of this year's program with Medscape Medical News.

Latest Research

Of primary interest, as always, is the top research, presented in hundreds of oral sessions and posters, symposia, and lectures. In particular, there are 2 major sessions of late-breaking science: 1 a concurrent session held Thursday afternoon and 1 a plenary session held Friday morning.

Another trial presented here for the first time is a second arm of the Secondary Prevention of Small Subcortical Strokes (SPS3) trial, which looks at aggressive blood pressure–lowering to prevent recurrence in patients with recent lacunar stroke. The first arm of the trial, presented last year at this meeting and reported by Medscape Medical News at that time, compared aspirin alone with aspirin plus clopidogrel in these patients and was stopped early because of increased bleeding with dual therapy.Among the most eagerly anticipated trials presented for the first time at this year's meeting is the Mechanical Embolectomy versus Standard Care for Acute Ischemic Stroke (MR RESCUE), he said. "This will be the first report of a large randomized trial that used neuroimaging, magnetic resonance imaging criteria, to select patients to be randomized either to mechanical embolectomy or regular medical care," he said. "In a field where there have been exciting technologic advances in how to remove a clot in an acute stroke but relatively few carefully controlled trials, these are results that people are very anxious to hear."

Another first presentation, the Randomized Evaluation of Carotid Occlusion and Neurocognition (RECON), looks at cognitive outcomes from extracranial-intracranial (EC-IC) bypass surgery among patients with symptomatic internal carotid occlusion in the Carotid Occlusion Surgery Study (COSS). Main COSS results, already reported, showed no benefit of the surgery for stroke prevention, but this analysis will look at whether the surgery may improve cognitive functioning.

Session IX: Concurrent G; Thursday, February 7, 12:30 pm; Kalakaua Ballroom B

LB1: Mistie Trial: 365-day Results
LB2: Intra-operative CT-Guided Endoscopic Surgery for ICH (ICES)
LB3: Qualifying and Outcome Strokes in the RESPECT PFO Trial: Additional Evidence of Treatment Effect
LB4: Combined Approach to Lysis Utilizing Eptifibatide and rt-PA in Acute Ischemic Stroke-Enhanced Regimen (CLEAR-ER) Stroke Trial
LB5: Prolonged Ambulatory Cardiac Monitoring Improves the Detection and Treatment of Atrial Fibrillation in Patients with Cryptogenic Stroke: Primary Results from the EMBRACE Multicenter Randomized Trial
LB6: Results of the Membrane-Activated Chelator Stroke Intervention (MAC SI) Randomized Trial of DP-b99 in Acute Ischemic Stroke
LB7: Final Results of the Solitaire FR Thrombectomy for Acute Revascularization (STAR) – Prospective, Multicenter, Controlled Clinical Trial in EU, Australia and Canada

Session XIII: Plenary Session III; Friday, February 8, 11:30 am; Hall III

LB8: The Secondary Prevention of Small Subcortical Strokes (SPS3) Trial: Results of the Blood Pressure Intervention
LB9: Time to Angiographic Reperfusion Is Highly Associated With Good Clinical Outcome in the Interventional Management of Stroke Phase III (IMS III) Trial
LB10: Randomized Evaluation of Carotid Occlusion and Neurocognition (RECON): Main Results
LB11: Clopidogrel and Aspirin Versus Aspirin Alone for the Treatment of High-risk Patients With Acute Non-disabling Cerebrovascular Event (CHANCE): A Randomized, Double-blind, Placebo-controlled, Multicenter Trial
LB12: Primary Results of a Randomized Trial of Neuroimaging Selection for Mechanical Embolectomy versus Standard Care for Acute Ischemic Stroke (MR RESCUE)

Session X: Concurrent Symposia C; Thursday, February 7, 2:30 pm; Kalakaua Ballroom B

Main results of the long-anticipated MS-III trial will be presented by principal investigator Joseph P. Broderick, MD, from the University of Cincinnati, Ohio, at a session dedicated just to this trial. "The bottom line for this trial is it was stopped early because it was clear that it would be unable to generate a positive result, but the most important information will be in the details," Dr. Greenberg notes.

IMS III was a phase 3, randomized, open-label trial that assessed whether a combined intravenous and intraarterial approach to stroke treatment was superior to intravenous tissue plasminogen activator alone. As reported previously by Medscape Medical News, the trial was halted in April 2012 when a preplanned interim analysis showed "a low likelihood of demonstrating the pre-specified clinically significant difference in benefit between treatment arms of the study," according to a statement from the National Institute of Neurological Disorders and Stroke at that time.

The Data and Safety Monitoring Board's decision was based on the primary outcome of the trial, the Modified Rankin score at 3 months, "meeting the threshold for futility," the statement adds. "While enrollment was stopped because of futility, no serious safety concerns were identified."

Investigators from the 50 sites involved would be disappointed with the decision, one of the investigators, Pooja Khatri, MD, associate professor of neurology at the University of Cincinnati, toldMedscape Medical News at that time. "We all expected this trial to show a significant advantage of this therapy in severe strokes."

At the meeting, Dr. Broderick will present the overall results and subgroup comparisons, and other speakers will look more closely at the data and at the current and future use of endovascular treatment in stroke care.

The "Next Big Thing" for Stroke

New this year is a forward-looking session examining the "next big thing" in stroke, but "at lightning speed," Dr. Greenberg said. "The idea will be to have 11 leaders in stroke ranging from high-level population epidemiology of stroke, both in the US and world-wide, down to the level of individual clinical trials in specific areas of stroke such as vascular cognitive impairment and neuroimaging, and focusing all the way down to t he molecular level on new approaches for stroke prevention and stroke recovery," he said.

The format is for speakers to present for exactly 5 minutes, no more, with a "hard cutoff, even if it's midsentence," he added. The result is "sort of speed-dating for stroke," he says wryly. The idea is "a realistic but forward-looking idea of where the stroke field might be going, and to do it in a fun and stimulating atmosphere, and also provide time for rapid-fire questions from the audience to what will be a very strong speaker panel."

"It will be either a glorious success or a noble failure," he added. "We'll see how people respond, but I'm really looking forward to it."

Wednesday, February 6, 2013; Session V: Concurrent Symposia B; The Next Big Thing in Stroke (at Lightning Speed); Kalakaua Ballroom B

Moderators: Steven M Greenberg, MD, PhD, Boston, Massachusetts, and Kyra Becker, MD, Seattle, Washington

2:30 Session Overview: Steven M. Greenberg, MD, PhD, Boston, Massachusetts
2:32 Race, Ethnic and Socioeconomic Disparities throughout the Globe: Lewis B Morgenstern, MD, Ann Arbor, Michigan
2:38 Biological Case Definition — The Science of Stroke Clinical Trials Comes of Age: Steven Warach, MD, PhD, Austin, Texas
2:44 Brain Ischemia Orchestrates Remote Organ Responses That Impact Outcome: Michael Moskowitz, MD, Charlestown, Massachusetts
2:50 Carotid Artery Disease Worldwide: Present and Future Trials: Thomas G Brott, MD, Jacksonville, Florida
2:56 The Emergence of Restorative Therapies: Drugs and Devices: Randolph J. Nudo, PhD, Kansas City, Kansas
3:02 Vascular Cognitive Impairment Exists: Now What?: Lenore Launer, PhD, Bethesda, Maryland
3:08 Worldwide Stroke Prevention: Setting the Priorities Right: Valery Feigin, MD, PhD, Auckland, New Zealand
3:14 Stroke Genetics: Moving to Personalized Stroke Prevention: Ralph L Sacco, MS, MD, Miami, Florida
3:20 Robotics in Stroke Recovery: Joel Stein, MD, New York, New York
3:26 Neuroprotection Within a Decade: Good News and Bad: Michael Tymianski, MD, PhD, Toronto, Ontario, Canada
3:32 Stroke Prevention and Treatment: The Need for a Life Course Perspective: Joanna Wardlaw, MD, Edinburgh, United Kingdom

In Memoriam: C. Miller Fisher

Of note as well this year at the meeting will be sessions remembering Charles Miller Fisher, MD, professor emeritus at Harvard Medical School, by all accounts a giant in the stroke field, who died April 14, 2012, at the age of 98.

"Many of us feel that Dr. Fisher towers over just about all of us, and there will be both an In Memoriam presentation at one of the plenary sessions and a symposium focusing on how Dr. Fisher's work continues to influence the stroke field," notes Dr. Greenberg, who will give the In Memoriam address.

Dr. Fisher's approach to understanding stroke, he said, "continues to be front and center in terms of how we think about the causes and treatments of stroke."

According to his obituary in the Harvard Crimson, Dr. Fisher was born in 1913 in Waterloo, Ontario, Canada, and graduated from the University of Toronto Medical School before serving as a surgical lieutenant in the British Royal and Canadian navies. "His ship, the HMS Voltaire, was sunk off the coast of Cape Verde in 1941, and Fisher was held in a Nazi prison camp for the next 3 and a half years," the obit notes. "After the war, Fisher returned to Canada and then to Boston and MGH [Massachusetts General Hospital], where he ultimately spent more than 50 years serving as both teacher and clinician."

"In a quiet and modest way, he was just a true visionary and the kind that doesn't come along every day," Dr. Greenberg says. "He was just a tremendously influential guy in the field."

Wednesday, February 6, 2013; Session III: Plenary Session I; Hall III

In Memoriam: C Miller Fisher: Steven M. Greenberg, MD, PhD, Boston, Massachusetts

Thursday, February 7, 2013; Session VII: Concurrent Symposia A; Kalakaua Ballroom C

C. Miller Fisher's Approach to Stroke: Past, Present and Future
7:40 Introduction: J. Philip Kistler, MD, Boston, Massachusetts
7:48 "No Man's Land": Large Vessel Brain Disease: J.P. Mohr, MS, MD, New York, New York
8:05 "Outnumbering All Other Lesions Combined": Lacunar Infarction: Geoffrey Donnan, MD, MBBS, Parkville Victoria, Australia
8:22 "Avalanche": Intracerebral Hemorrhage: Steven M. Greenberg, MD, PhD, Boston, Massachusetts
8:39 "Quite Different from a Gaping Patulous Hole": Subarachnoid Hemorrhage and Vasospasm: Robert Loch Macdonald, MD, Toronto, Ontario, Canada

Major Awards

Major awards this year again honor some great names in stroke research, Dr. Greenberg said.

The Thomas Willis Lecture, for achievement in basic science, is won this year by Eng H. Lo, PhD, a colleague of Dr. Greenberg's at Massachusetts General Hospital. "Eng has just been a tremendous inspiration to the field in his ability to open up new molecular and cellular pathways in both normal vessel function and abnormal function following stroke," he said.

The William M. Feinberg Award for Excellence in Clinical Stroke goes this year to Marc I. Chimowitz, MD, from the Medical University of South Carolina in Charleston, for major contributions in clinical research. "Dr. Chimowitz has led 2 of the most influential trials in our understanding of how to prevent stroke, he said, including the WASID trial, looking at the role of anticoagulation in patients with intracranial stenosis, and more recently, and the SAMMPRIS trial, which argued against use of stenting over best medical therapy to address intracranial lesions.

Finally, the David G. Sherman award is a lifetime achievement honor in basic or clinical research, won this year by Robert Adams, MD, by coincidence also from the Medical University of South Carolina. "Dr. Adams is really a pioneer and a leader in an otherwise poorly studied aspect of stroke, which is strokes related to sickle cell anemia. It's a devastating aspect of the disease, and he has really been the beacon setting the direction for how strokes related to sickle cell are studied and treated."

Medscape Medical News will be onsite, providing in-depth news coverage and feature interviews, beginning Tuesday, February 5. Follow us on Twitter (@MedscapeNeuro) and Facebook (http://www.facebook.com/#!/medscapeneurology). Follow ISC on Twitter @HeartNews, #ISC13.Thomas Willis Lecture: Friday, February 8, 11:05 am, Hall III: Causation and Collaboration for Stroke Research, Eng H. Lo, PhD
William M. Feinberg Award for Excellence in Clinical Stroke: Wednesday, February 6, 10:35 am, Hall III: Treatment of Intracranial Atherosclerosis: Learning From the Past and Planning for the Future, Marc I. Chimowitz, MD
David G. Sherman Lecture: Thursday, February 7, 10:40 am, Hall III: Towards a Stroke-Free Childhood in Sickle Cell Anemia, Robert Adams, MD

Next year's ISC is planned for February 2014 in San Diego, California.

Dr. Greenberg reports receiving research grants from the National Institutes of Health and participating as a Consultant/Advisory Board member for Hoffman-Laroche, MRI review committee.

International Stroke Conference (ISC) 2013: February 6-8, 2012. Hawaii Convention Center, Honolulu

Bbetter Midlife Fitness Linked to Lower Dementia Risk

2013-02-05T19:06:00.005-08:00

Better Midlife Fitness Linked to Lower Dementia Risk

Sue Hughes

Feb 04, 2013

Higher fitness levels in midlife are associated with a lower risk for dementia in later life, a new study suggests.

"We already know exercise has cardiovascular and many other benefits, but this may give people more incentive to get moving," lead author, Laura F. DeFina, MD, from The Cooper Institute, Dallas, Texas, commented to Medscape Medical News. "Dementia is the second most feared disease after cancer, and our research suggests you can lower your risk by keeping fit."

She noted that although there is a lot of literature on physical activity and dementia, a 2010 statement from the National Institutes of Health suggested that evidence was insufficient to promote lifestyle change for brain health because the studies conducted so far have been small, with short follow-up, and the definition of patients and of dementia has been inadequate.

"Our study overcomes many of these shortcomings, with a large homogeneous patient population, an objective measure of fitness, and a long follow-up. We therefore believe our data give a strong message to improve fitness, which we think may be more powerful than some previous attempts at changing behavior."

The study is published in the February 5 issue of the Annals of Internal Medicine.

The study included 19,458 individuals participating in the Cooper Clinic Longitudinal Study at the Cooper Institute, a preventive medicine clinic. All underwent standardized fitness testing in midlife (median age, 49.8 years) and were then followed for an average of 25 years. Cases of dementia were found from Medicare claims data.

There were 1659 cases of all-cause dementia reported. After multivariable adjustment, participants with the highest fitness level (quintile 5) at midlife had a 36% reduction in risk of developing dementia from any cause during follow-up than those in the lowest fitness category (quintile 1).

Table. Risk for Dementia With Increasing Fitness Level

Fitness Quintile	Hazard Ratio for Dementia (95% Confidence Interval)	P Value
1 (lowest fitness level)	1.00 (reference)	-
2	0.88 (0.76 - 1.02)	.089
3	0.79 (0.67 - 0.92)	.002
4	0.70 (0.60 - 0.83)	< .001
5 (highest fitness level)	0.64 (0.54 - 0.77)	< .001

"The long follow-up time in our study is essential as there is evidence that changes on the brain may begin up to 20 years before dementia starts to become evident," Dr. DeFina noted.

"Another strength of our study is that we objectively measured cardiorespiratory fitness in a uniform way (on a treadmill) in all participants," she added. "Normally studies looking at physical activity rely on self-reported exercise which is notoriously inaccurate."

Dr. DeFina also pointed out that the reduction in dementia was consistent in patients who had had a stroke and in those who hadn't, suggesting that the mechanism does not just involve vascular disease. "Exercise is known to reduce cardiovascular disease, which we would expect to be translated into benefit on stroke, but because we also saw a similar reduction in dementia with improved fitness in patients who hadn't had a stroke, this suggests that other mechanisms are also involved."

She added that animal studies have suggested that increased fitness and activity correlates with a reduction in brain atrophy and loss of cognition, and changes in amyloid have been seen with regular activity.

Although this was a study of fitness, rather than actual physical activity undertaken, Dr. DeFina said the results were consistent with US physical activity guidelines that recommend 150 minutes of moderate exercise or 75 minutes of vigorous activity per week for health benefits.

Never Too Late to Start

The researchers believe that although it is best to achieve fitness earlier in life and keep it up throughout life, benefits could still be seen in people starting later. Dr. DeFina noted: "It is never too late to improve fitness. If you're not 49, there are still functional benefits of being active in your later years."

Coauthor Benjamin L. Willis, MD, MPH, also from the Cooper Institute, added, "The best time to plant a tree is 20 years ago, but the second best time is today."

However, they agree that the fear of Alzheimer's disease "may provide both the context for physicians to introduce the topic of physical activity and the motivation for patients to heed advice to increase physical activity."In an accompanying editorial, Mary Sano, PhD, Mount Sinai School of Medicine, New York, and James J. Peters, Veterans Affairs Medical Center, New York, point out that adherence to exercise regimens is notoriously difficult, and less than 10% of the US population is estimated to achieve the 150-minutes-per-week guideline.

The study was supported by the Cooper Institute; the University of Texas Southwestern Medical Center; the National Heart, Lung, and Blood Institute; and the American Heart Association. Disclosures are available online with the article.

Cerebrolysin: Positive Cognitive Effect in Vascular Dementia

2013-02-05T18:54:00.002-08:00

Cerebrolysin: Positive Cognitive Effect in Vascular Dementia

Pauline Anderson

Feb 05, 2013

Cerebrolysin, a peptide preparation produced from purified pig brain proteins, may have positive effects on cognitive function in older patients with vascular dementia (VaD), according to a new meta-analysis.

The analysis also found that most adverse effects related to Cerebrolysin were mild to moderate in severity.

"However, due to the limited number of included trials, varying treatment durations, and short-term follow-up, there is insufficient evidence to recommend Cerebrolysin as a routine treatment for patients with VaD," write the authors, led by Ning Chen, Department of Neurology, West China Hospital, Sichuan University, Chengdu, China.

They added that the treatment is not widely used because it must be given by intravenous infusion and requires a long-term and demanding treatment schedule.

The study is published online January 30 in The Cochrane Database for Systematic Reviews.

Improved Cognition

Cerebrolysin is a mixture of 80% low-molecular-weight peptides and 20% free amino acids. Various studies have shown that the agent's multiple effects include promotion of neuroprotection, neuroplasticity, and neurogenesis. It is approved in many countries for treatment of Alzheimer's disease (AD), stroke, and/or traumatic brain injury, although not in the United States. A Cochrane review of Cerebrolysin for stroke published in 2010 concluded there was not enough evidence to evaluate its use in stroke, and a review of its use in AD is underway, the authors note.

After searching various literature sources, including ALOIS (the Cochrane Dementia and Cognitive Improvement Group's Specialized Register), as well as MEDLINE and EMBASE, researchers selected 6 randomized controlled clinical trials to include in the review. The analysis involved 507 male and female participants with mild to moderate VaD, which can include dementia caused by ischemic or hemorrhagic cerebrovascular disease or by ischemic hypoxic brain lesions of cardiovascular origin.

Two trials were conducted in multiple centers in Russia and China, and the others were carried out in single centers. Study sample sizes ranged from 29 to 242 patients. The mean age of participants ranged from 60.4 to 70.8 years, and the mean duration of dementia was 4.6 months to 4.3 years in 3 trials (the others did not include this information).

In all trials, Cerebrolysin was administered in an intravenous infusion. Four trials compared Cerebrolysin with placebo, and the others compared Cerebrolysin plus routine treatment with the same treatment only. The dose of the treatment ranged from 10 to 30 mL daily. The length of the treatment period varied between trials, and follow-up ranged from 15 days to 3 years.

The analysis showed significant improvements in cognitive function, as measured by the Mini-Mental State Examination (MMSE) (weighted mean difference [WMD], 1.10; 95% confidence interval [CI], 0.37 - 1.82) or by the Alzheimer's Disease Assessment Scale Cognitive Subpart, extended version (ADAS-cog) (WMD, –4.01; 95% CI, –5.36 to –2.66).

As for global function, the study found improvements in response rates (relative risk, 2.71; 95% CI, 1.83 - 4.00).

Subgroup analysis suggested a larger effect with long-term treatment than with short-term treatment.

No serious adverse events were attributable to the treatment, and nonserious adverse events were not significantly more common with the treatment drug (relative risk, 0.97; 95% CI, 0.49 - 1.94).

No data on quality of life or caregiver burden were available from any of the trials.

No Recommendations

Because of the variation in the trials, the analysis is not conducive to providing recommendations for the optimal treatment schedule, said the authors.

In the western world, VaD is the second most common form of dementia after AD. The prevalence of VaD doubles approximately every 5.3 years, compared with every 4.5 years for AD.

The most typical expression of VaD is executive dysfunction. The widely used MMSE may underestimate the cognitive decline in patients with VaD because it contains few items related to executive function, according to the study authors.

No definitive treatments are currently available for VaD.

The authors have disclosed no relevant financial relationships.

Cochrane Database Syst Rev. Published online January 30, 2013. Abstrac
t

Shared Genetic Link Found in Epilepsy, Migraine With Aura

2013-01-29T19:22:00.004-08:00

Shared Genetic Link Found in Epilepsy, Migraine With Aura

Pauline Anderson

Jan 28, 2013

For the first time, researchers have demonstrated a shared genetic susceptibility to epilepsy and migraine with aura in a large cohort of patients with generalized epilepsy (GE) or nonacquired focal epilepsy (NAFE).

In their new study, migraine with aura was more than twice as likely in patients with epilepsy who had 3 or more first-degree relatives with a seizure disorder.

The findings are "potentially transformational," said lead author Melodie R. Winawer, MD, MS, assistant professor of neurology, Columbia University, New York.

The study results represent "a major step in our understanding that epilepsy does not stand alone as a disorder," Dr. Winawer told Medscape Medical News. "We should start to consider intersecting combinations of disorders as clinical entities to be treated."

The study was published online January 7 in Epilepsia, a journal of the International League Against Epilepsy.

Assessing Migraine

The analysis included 730 participants aged 12 years or older from 501 families who were enrolled in an arm of the Epilepsy Phenome/Genome Project (EPGP) that included sibling pairs or parent-child pairs with well-characterized GE or NAFE. The EPGP is an ongoing study that includes detailed phenotyping and collection of DNA from participants with epilepsy at 27 clinical centers in the United States, Canada, Argentina, Australia, and New Zealand.

Researchers assessed migraine using a standardized and validated interview. Migraine with aura or migraine without aura was diagnosed according to criteria of the International Classification of Headache Disorders (2004). Data on history of seizure disorders in other family members were collected through a single interview question.To be classified with NAFE, neuroimaging findings had to be normal or demonstrate mesial temporal sclerosis or focal cortical dysplasia, and patients had to have focal electroencephalographic abnormalities or clinical semiology consistent with focal seizures. To be classified as having GE, participants had to have generalized-onset seizures, normal results on neuroimaging (if done), and an electroencephalogram showing generalized epileptiform activity with a normal posterior dominant rhythm for age.

The researchers found that the prevalence of any migraine and migraine with aura in enrolled participants increased when 2 or more first-degree relatives, in addition to the enrolled pair, were reported to have seizure disorders (adjusted odds ratio [OR] for any migraine, 2.0; 95% confidence interval [CI], 0.99 - 3.85; adjusted OR for migraine with aura, 2.5; 95% CI, 1.13 - 5.46).

The prevalence of migraine without aura did not increase with 2 or more additional relatives with seizure disorders (OR, 1.1; 95% CI, 0.50 - 2.38).

It has already been established that some genetic mutations — for example, in the CACNAIA and SCNIAgenes — occur in certain types of epilepsy and a specific rare form of migraine called familial hemiplegic migraine. However, a shared genetic effect on common forms of epilepsy and commonly occurring migraine has not been previously demonstrated.

This new research should have a huge influence on the conception of disease boundaries and therefore on understanding of the causes of disease, said Dr. Winawer. "It really changes prevention; it changes prediction; and it changes the way in which patients are viewed as being at risk."

Serotonin Role?

Asked to comment on this study, Andres Kanner, MD, director of the Comprehensive Epilepsy Center, University of Miami Miller School of Medicine, Florida, said the findings "proved a point."

Previous research had observed only "interesting associations" between migraine with aura and epilepsy. For example, a history of migraine with aura in those with epilepsy predicted a worse course of epilepsy, he told Medscape Medical News.

One of the more interesting findings to date came from a 2007 Icelandic study showing that the co-occurrence of migraine with aura with major depression or suicide attempt increased the risk of developing unprovoked seizures more than did these conditions alone, Dr. Kanner said (Epilepsy Res. 2007;75:220-223).

These kinds of findings have helped convince Dr. Kanner that the neurotransmitter serotonin may play a role not only in depression but also in epilepsy and migraine with aura.

"This study we're looking at [by Winawer et al] showed a common genetic mechanism. We now want to go a step further and ask what could these genes be doing at a neurochemical or neurophysiological level. This is speculation, but one possible common pathogenic mechanism is serotonin."

Dr. Winawer agrees that serotonin may represent a "tremendous advance" in therapy.An investigation in animal models of epilepsy has shown that selective serotonin reuptake inhibitors (SSRIs) improved seizure activity, and open trials had similar findings. Now, a study funded by the National Institutes of Health is examining whether a serotonin agonist that increases synaptic concentrations of serotonin improves seizures. Dr. Kanner's own research group is planning a study that will look into treating seizures with an SSRI.

"If we could understand the cause and pinpoint a very specific pathophysiology, then that would lead to the development of novel therapies that are directed at novel targets, and therefore we could open a whole new avenue of treatment," she said. "Serotonin may very well be one such avenue."

The study was supported by the National Institute of Neurological Disorders and Stroke. Dr. Winawer has disclosed no relevant financial relationships. Dr. Kanner is a member of the editorial advisory board for Medscape Neurology; he has disclosed no relevant financial relationships.

Epilepsia. Published online January 7, 2013. Abstract

Effectiveness of Intravenous Dexamethasone versus Propofol for Pain Relief in the Migraine Headache

2013-01-29T15:21:00.002-08:00

Effectiveness of Intravenous Dexamethasone versus Propofol for Pain Relief in the Migraine Headache

A Prospective Double Blind Randomized Clinical Trial

Hassan Soleimanpour, Rouzbeh R Ghafouri, Aliakbar Taheraghdam, Dawood Aghamohammadi, Sohrab Negargar, Samad EJ Golzari, Mohsen Abbasnezhad

Disclosures

BMC Neurol. 2012;12(114)

References

Topic Alert

Receive an email from Medscape whenever new articles on this topic are available.

Add Migraine to My Topic Alert

Abstract

Background There are many drugs recommended for pain relief in patients with migraine headache.

Methods In a prospective double blind randomized clinical trial, 90 patients (age ≥ 18) presenting to Emergency medicine Department with Migraine headache were enrolled in two equal groups. We used intravenous propofol (10 mg every 5–10 minutes to a maximum of 80 mg, slowly) and intravenous dexamethasone (0.15 mg/kg to a maximum of 16 mg, slowly), in group I and II, respectively. Pain explained by patients, based on VAS (Visual Analogue Scale) was recorded at the time of entrance to ED, and after injection. Data were analyzed by paired samples t test, using SPSS 16. P < 0.05 was considered to be statistically significant.

Results The mean of reported pain (VAS) was 8 ± 1.52 in propofol group and 8.11 ± 1.31 in dexamethasone group at presenting time (P > 0.05). The VAS in propofol group was obviously decreased to 3.08 ± 1.7, 1.87 ± 1.28 and 1.44 ± 1.63 after 10, 20 and 30 minutes of drug injection, respectively. The VAS in dexamethasone group was 5.13 ± 1.47, 3.73 ± 1.81 and 3.06 ± 2 after 10, 20 and 30 minutes of drug injection, respectively. The mean of reported VAS in propofol group was less than dexamethasone group at the above mentioned times (P < 0.05). The reduction of headache in propofol group, also, was very faster than dexamethasone group (P < 0.05). There were no adverse side effects due to administration of both drugs.

Conclusions Intravenous propofol is an efficacious and safe treatment for patients presenting with Migraine headache to the emergency department.

Trial registration Clinical Trials IRCT201008122496N4

Perampanel Reduces Refractory Partial-Onset Seizures

2013-01-29T15:17:00.002-08:00

Perampanel Reduces Refractory Partial-Onset SeizuresMay 03, 2012

R

NEW YORK (Reuters Health) May 01 - Adding the investigational agent perampanel to antiepilepsy therapy reduced seizure frequency in patients with refractory partial-onset seizures in a phase III trial.

"The data also support the hypothesis that direct targeting of glutamatergic neurotransmission using AMPA-receptor antagonism is a valid approach for treating seizures," Dr. Gregory L. Krauss at Johns Hopkins University in Baltimore, Maryland, and colleagues comment in their report in Neurology online April 18.

The multicenter team explains that AMPA receptor hypersensitivity and increased glutamate binding sites have been documented in brains of epileptics, and that AMPA receptors are primary modulators of seizure spread. Perampanel is a highly selective AMPA-type glutamate receptor antagonist.

The current study involved 706 patients with persistent partial-onset seizures despite treatment with up to three antiepileptic drugs. They were randomized to receive adjunctive placebo or perampanel at 2, 4 or 8 mg/day for 13 weeks.

The median change in seizure frequency from baseline in the four arms was -10.7%, -13.6%, -23.3%, and -30.8%, respectively, the investigators report. The differences between the placebo group and the groups receiving the two higher doses of perampanel were significant.

The tolerability profile was generally favorable, the authors report, and the most frequent treatment-emergent adverse event was dizziness.

While this study defined the minimum effective perampanel as 4 mg/day, two subsequent trials investigated 8 mg/day and 12 mg/day doses of perampanel, Dr. Krauss and colleagues note.

They conclude, "The utility of this novel, selective, noncompetitive AMPA-type glutamate receptor in the adjunctive treatment of uncontrolled partial-onset seizures is promising given the treatment-resistant nature of this study population."

The study was funded by Eisai Inc., which also employs four of the paper's 11 authors. Eisai resubmitted its New Drug Application for perampanel to the U.S. Food and Drug Administration early in March 2012.

SOURCE: http://bit.ly/JaVuod

Neurology 2012.

What are the needs of your relapsing MS patients?

2013-01-15T18:43:00.001-08:00

What are the needs

An effective start on therapy

Rebif^® (interferon beta-1a) delivered proven efficacy across all 3 key disease measures in the 2-year PRISMS^a study

Significant relapse reductions and MRI improvement seen at 2 years^1-3,b

The exact correlation between MRI findings and the current or future clinical status of patients, including disability progression, is unknown.

^aPrevention of Relapses and Disability by Interferon β-1a Subcutaneously in Multiple Sclerosis (PRISMS) was a randomized, double-blind, placebo-controlled, 2-year study. Patients received subcutaneous injections of Rebif 22 mcg tiw (n=189),Rebif 44 mcg tiw (n=184), or placebo (n=187).

^bBased on comparisons from a rank-based ANOVA.

Early reductions in relapses and MRI activity in the 2-year PRISMS study

In a post-hoc analysis of a subset of patients in the PRISMS study, significantly fewer combined active MRI scans^d per patient were seen at 2 months with Rebif 44 mcg tiw than with placebo (32% vs 55% mean combined active scans per patient; P=0.0008)^2,e
Over 9 months in a subset of patients in the PRISMS study, significantly fewer combined active MRI scans^d per patient were seen with Rebif 44 mcg tiw than with placebo (19% vs 50% mean combined active scans per patient; P<0 .0001=".0001" style="bottom: 0.4em; font-size: 11px; position: relative; vertical-align: baseline;" sup="sup">2,e

In a post-hoc analysis of the PRISMS study, significantly fewer patients taking Rebif 44 mcg tiw experienced a relapse at 3 months compared with those taking placebo (29% vs 40%;P=0.0381)^2,e

The exact correlation between MRI findings and the current or future clinical status of patients, including disability progression, is unknown.

^dProportion of scans per patient per treatment group with new activity including new, enlarging, recurrent PD/T2 lesions, or enhancing T1 lesions.

^eAnalysis of the subgroup of patients undergoing PD/T2 and T1-Gd MRI scans at pre-study screening, study day 1, and monthly for the first 9 months of treatment based on ANOVA on the ranks taking center and number of active lesions at baseline into account.

Demonstrated efficacy in a range of relapsing MS patients (Expanded Disability Status Scale [EDSS] 0 to 5.0)

Rebif^® (interferon beta-1a) delivered significant relapse reductions in a range of relapsing MS patients in the 2-year PRISMS study

Total patient cohort (EDSS 0 to 5.0): Significant reductions in mean number of relapses with 44 mcg at 2 years^1,2

High-EDSS cohort (EDSS >3.5 to 5.0): Significant reductions in mean number of relapses with 44 mcg at 2 years²

Rebif^® (interferon beta-1a) delivered a significant delay in disability progression in a range of relapsing MS patients in the 2-year PRISMS study

Total patient cohort (EDSS 0 to 5.0): Significantly longer time to disability progression with Rebif 44 mcg at 2 years versus placebo^1,2

High-EDSS cohort (EDSS >3.5 to 5.0): Significantly longer time to disability progression with Rebif 44 mcg at 2 years versus placebo¹

In time to confirmed progression, a statistically significant difference was seen between Rebif^®(interferon beta-1a) 22 mcg and placebo in the total patient cohort (0 to 5.0) but was not seen in the high-EDSS group (>3.5 to 5.0)¹

The rate of serious events (regardless of causality) was 20% versus 11.3% for the total patient cohort (EDSS 0 to 5.0).

Rebif^® (interferon beta-1a) allows you to adjust the dose to meet individual patient needs without changing therapy.

• Like Rebif 44 mcg, Rebif 22 mcg is proven in all 3 keydisease measures

Superior efficacy versus Avonex^® (interferon beta-1a)

Rebif^® (interferon beta-1a) is the only self-injected treatment with superior relapse reductions versus Avonex in a class I clinical trial

Rebif 44 mcg tiw delivered superior relapse outcomes versus Avonex 30 mcg qw in the EVIDENCE^f study^3,4

^fEVidence of Interferon Dose-response: European North American Comparative Efficacy (EVIDENCE)—a head-to-head, randomized, class I, evaluator-blinded comparison of Rebif 44 mcg tiw (n=339) with intramuscular injections of Avonex30 mcg qw (n=338) over an average of 64 weeks.

Patients who transitioned from Rebif to Avonex experienced significant relapse reduction

Relapse rates were reduced over an average of 8 months in patients taking Rebif 44 mcg compared with the last 6 months on Avonex (P<0 .001=".001" style="bottom: 0.4em; font-size: 11px; position: relative; vertical-align: baseline;" sup="sup">5

Change in relapse rate during EVIDENCE extension phase

Of the 605 patients receiving therapy at the end of the comparative phase of EVIDENCE, 495 patients enrolled in the extension phase of the study. In the comparative arm of the study, 73% (n=223) had been in the Avonex arm and 91% (n=272) had been in the Rebif arm. Clinical assessments were not blinded, but MRI evaluations were blinded. All assessments were within-treatment-group comparisons. Patients were followed for an average of 8 months posttransition. Annualized relapse rate is based on a time-adjusted analysis.

Important Safety Information

Compared with Avonex, adverse events were similar, despite higher, more frequent dosing with Rebif. Exceptions included injection-site disorders (85% vs 33%), hepatic function disorders (18% vs 10%), and white blood cell disorders (14% vs 5%), which were more frequent with Rebif. Flu-like symptoms were more frequent with Avonex (53% vs 45%).

Adverse events reported more frequently posttransition by patients who transitioned from Avonex to Rebif were (Rebif vs Avonex): injection-site disorders (51% vs 33%), hepatic function disorders (14% vs 10%), and white blood cell disorders (10% vs 5%).

Well-established safety profile

INDICATION

Rebif is indicated for the treatment of patients with relapsing forms of MS to decrease the frequency of clinical exacerbations and delay the accumulation of physical disability. The efficacy of Rebif in chronic progressive MS has not been established. Available in22 mcg and 44 mcg prefilled, preassembled syringes and a titration pack.

IMPORTANT SAFETY INFORMATION

Rebif is contraindicated in patients with a history of hypersensitivity to natural or recombinant interferon, human albumin, or any other component of the formulation.

Rebif should be used with caution in patients with depression, a condition that is common in people with multiple sclerosis. Depression, suicidal ideation, and suicide attempts have been reported to occur with increased frequency in patients receiving interferon compounds, including Rebif.

Severe liver injury, including some cases of hepatic failure requiring liver transplantation, has been reported rarely in patients taking Rebif. The potential for liver injury should be considered when used in combination with other products associated with liver injury.

Anaphylaxis and other allergic reactions (some severe) have been reported as a rare complication of Rebif.

Caution should be exercised when administering Rebif to patients with pre-existing seizure disorders. Seizures have been associated with the use of beta interferons including Rebif. Leukopenia and new or worsening thyroid abnormalities have developed in some patients treated with Rebif. Regular monitoring for these conditions is recommended.

Female patients should be warned about the potential risk of miscarriage; discontinuation should be considered if pregnancy occurs.

Potential serious side effects with Rebif include hepatic dysfunction, depression, suicidal ideation, suicide attempts, risk to pregnancy, allergic reactions, and injection-site reactions, which include redness, pain, and swelling. A few patients developed necrosis at the injection site, which resolved with conservative management.

The most common side effects with Rebif are injection-site reactions, flu-like symptoms, depression, abdominal pain, elevated liver enzymes, and blood abnormalities.

	Placebo	Rebif 44 mcg	Significance
Mean number of relapses	2.56	1.73	P<0 .0001=".0001" td="td">
Percentage of patients relapse-free	15%	32%	P<0 .0001=".0001" td="td">
Median number of T2 active lesions per patient per scan^1,b	2.25	0.5	P<0 .0001=".0001" td="td">

Segunda Opinion Neurológica

treatment of Multiple System Atrophy Using Intravenous Immunoglobulin

treatment of Multiple System Atrophy Using Intravenous Immunoglobulin

Abstract and Introduction

Abstract

Beyond Amyloid Beta: A New Alzheimer Disease Biomarker?

Medscape Medical News from the:

Beyond Amyloid Beta: A New Alzheimer Disease Biomarker?

An AAN Poster Brief

Coronary Calcium Predicts Stroke Risk

Coronary Calcium Predicts Stroke Risk

Eye Tests May Predict Alzheimer's Risk

Eye Tests May Predict Alzheimer's Risk

No Greater Risk for Aneurysm Rupture in Pregnancy, Delivery

No Greater Risk for Aneurysm Rupture in Pregnancy, Delivery

Dural Venous Sinus Angioplasty and Stenting for the Treatment of Idiopathic Intracranial Hypertension

Dural Venous Sinus Angioplasty and Stenting for the Treatment of Idiopathic Intracranial Hypertension

Abstract and Introduction

Abstract

Introduction

Methods

Patient Selection and Characteristics

Procedure

Angiographic Follow-up and Outcome Assessment

Results

Discussion

Conclusions

New Criteria for Alzheimer Disease and Mild Cognitive Impairment

New Criteria for Alzheimer Disease and Mild Cognitive Impairment

Implications for the Practicing Clinician

Abstract

Rationale for New Criteria

Preclinical AD and Biomarkers

Criteria for Mild Cognitive Impairment Due to the AD Pathophysiological Process

Criteria for All-cause Dementia and AD

Implications for the Practicing Clinician

Conclusions

Current and Future Treatments for Alzheimer's Disease

Current and Future Treatments for Alzheimer's Disease

Abstract and Introduction

Abstract

Introduction

Current Symptomatic Approaches to Alzheimer's Disease

Cholinesterase Inhibitors

N-methyl-D-aspartate Antagonist

Combination Therapy

Treatment of Behavioral and Psychological Symptoms of Dementia in Alzheimer's Disease

The Amyloid Hypothesis

Disease-modifying Approaches to Alzheimer's Disease

Disease-modifying Treatments: Modulation of Amyloid Deposition Drugs Interfering with Amyloid β Deposition.

Disease-modifying Treatments: Modulation of Tau Deposition

Disease-modifying Treatments: Modulation of Inflammation and Oxidative Damage

Disease-modifying Treatments: Additional Approaches

Final Remarks

Neurostimulation Has Benefits in Early Parkinson's Disease

Neurostimulation Has Benefits in Early Parkinson's Disease

Short Course of Aspirin, Clopidogrel Cuts Stroke Risk

Short Course of Aspirin, Clopidogrel Cuts Stroke Risk

Clinical Features of Dopamine Agonist Withdrawal Syndrome in a Movement Disorders Clinic

Clinical Features of Dopamine Agonist Withdrawal Syndrome in a Movement Disorders Clinic

Abstract and Introduction

Abstract

Introduction

Methods

Results

Discussion

Alzheimer's Disease

Alzheimer's Disease

Mimics and Chameleons

Introduction

Clinical Features of 'Typical' AD

Mimics: What's not Typical AD, But Looks Like It?

'Worried Well'

Depression and Other Psychiatric Disorders

Metabolic

Infection

Tumours, Space-occupying Lesions and Hydrocephalus

Autoimmune Cognitive Syndromes

Vascular Cognitive Impairment

Epilepsy

Rebif^® (interferon beta-1a) delivered proven efficacy across all 3 key disease measures in the 2-year PRISMS^a study

Rebif^® (interferon beta-1a) delivered significant relapse reductions in a range of relapsing MS patients in the 2-year PRISMS study

Rebif^® (interferon beta-1a) delivered a significant delay in disability progression in a range of relapsing MS patients in the 2-year PRISMS study

Superior efficacy versus Avonex^® (interferon beta-1a)

Rebif^® (interferon beta-1a) is the only self-injected treatment with superior relapse reductions versus Avonex in a class I clinical trial