Notes

Urea and electrolytes in venous blood

Blood loss

The most common explanation in men and post-menopausal women is gastrointestinal blood loss. This may result from occult gastric or colorectal malignancy, gastritis, peptic ulceration, inflammatory bowel disease, diverticulitis, polyps and angiodysplastic lesions. On a world-wide basis, hookworm and schistosomiasis are the most prevalent causes of gut blood loss. Gastrointestinal blood loss may be exacerbated by the chronic use of aspirin or NSAIDs, which cause intestinal erosions and impair platelet function. In women of child-bearing age, menstrual blood loss, pregnancy and breastfeeding contribute to iron deficiency by depleting iron stores; in developed countries one-third of women in this age bracket have low iron stores but only 3% display iron-deficient haematopoiesis. Rarely, chronic haemoptysis or haematuria may cause iron deficiency.

Malabsorption

A dietary assessment should be made in all patients to ascertain their iron intake. Gastric acid is required to release iron from food and helps to keep iron in the soluble ferrous state. Hypochlorhydria in the elderly or that due to drugs such as proton pump inhibitors may contribute to the lack of iron availability from the diet, as may previous gastric surgery. Iron is absorbed actively in the upper small intestine and hence can be affected by coeliac disease. Anyone with features of malabsorption or recurrent deficiency in the absence of other explanations, young men with normal diet or young women with normal menstruation and diet in association with iron deficiency, should be screened for coeliac disease.

Iron absorption, uptake and distribution in the body.

Physiological demands

At times of rapid growth such as infancy and puberty, iron demands increase and may outstrip absorption. This may be exacerbated by prematurity and breastfeeding in infants or menstruation in girls. In pregnancy, iron is diverted to the fetus, the placenta and the increased maternal red cell mass, and is lost with bleeding at parturition. There is no consensus about the routine use of iron supplementation in pregnancy but if women with a poor dietary history or previous heavy menstrual losses become pregnant and the side-effects are acceptable, it is a justifiable practice.

Investigations

Confirmation of iron deficiency

Plasma ferritin is a measure of iron stores and the best single test to confirm iron deficiency. It is a very specific test; a subnormal level is due to iron deficiency, hypothyroidism or vitamin C deficiency. Levels can be raised by liver disease and in an acute phase response; in these conditions a ferritin level of up to 100 μg/l may still be associated with absent bone marrow iron stores. Plasma iron and total iron binding capacity (TIBC) are measures of iron availability, hence are affected by many factors besides iron stores. Plasma iron has a marked diurnal and day-to-day variation and becomes very low during an acute phase response but is raised in liver disease and haemolysis. Transferrin levels are lowered by malnutrition, liver disease, an acute phase response and nephrotic syndrome but raised by pregnancy or the oral contraceptive pill. A transferrin saturation of less than 16% is consistent with iron deficiency but is less specific than a ferritin measurement.

All proliferating cells express membrane transferrin receptors to acquire iron; a small amount of this receptor is shed into blood and found in a free soluble form there. At times of poor iron stores, cells up-regulate transferrin receptor expression; hence the levels of soluble plasma transferrin receptor increase. This can now be measured by immunoassay and used to distinguish storage iron depletion in the presence of an acute phase response or liver disease where a raised level indicates iron deficiency. In difficult cases it may still be necessary to examine a bone marrow aspirate for iron stores.

Investigation of the cause

This will depend upon the age and sex of the patient as well as the history and clinical findings. In men over the age of 40 years and in post-menopausal women with a normal diet, the upper and lower gastrointestinal tract should be investigated by endoscopy or barium studies. If coeliac disease is suspected, serum antigliadin and anti-endomysium antibodies and duodenal biopsy are indicated. In the tropics stool and urine should be examined for parasites.

Management

Unless the patient has angina, heart failure or evidence of cerebral hypoxia, transfusion is not necessary and oral iron supplementation is appropriate. Ferrous sulphate 200 mg 8-hourly (120 mg of elemental iron per day) is more than adequate and should be continued for 3-6 months to replete iron stores. The occasional patient is intolerant of ferrous sulphate, with dyspepsia and altered bowel habit. In this case a reduction in dose to 200 mg 12-hourly or a switch to ferrous gluconate 300 mg 12-hourly (70 mg of elemental iron per day) should be made. Delayed-release preparations are not useful since they release iron beyond the upper small intestine where it cannot be absorbed.

The haemoglobin should rise by 10 g/l every 7-10 days and a reticulocyte response will be evident by 1 week. A failure to respond adequately may be due to non-compliance, continued blood loss, malabsorption or an incorrect diagnosis. The occasional patient with malabsorption or chronic gut disease may need parenteral iron with deep intramuscular injection of iron sorbitol (1.5 mg of iron per kg body weight). This will produce a haematological response and rapidly replete iron stores. Patients should be warned that a brown skin discoloration like a tattoo is likely to develop at the sites of administration.

Parkinson's disease. High power (× 400) of substantia nigra of a patient with Parkinson's disease to show classical Lewy body (haematoxylin and eosin).

Pathophysiology

A small number of cases are familial in nature and mutations in several genes have now been identified as an underlying cause. However, in the majority the cause is unknown, and no strong genetic factors have been identified. The discovery that methyl-phenyl-tetrahydropyridine (MPTP) caused severe parkinsonism in young drug users suggests that the idiopathic disease might be due to an environmental toxin; many candidate toxins have been studied, but there is no strong evidence in favour of any of them. There are several features, including depletion of the pigmented dopaminergic neurons in the substantia nigra, hyaline inclusions in nigral cells (Lewy bodies), atrophic changes in the substantia nigra and depletion of neurons in the locus coeruleus. Reduced dopaminergic output from the substantia nigra to the globus pallidus leads to reduced inhibitory effects on the subthalamic nucleus, neurons of which become more active than usual in inhibiting activation of the cortex. This in turn results in bradykinesia.

Clinical features

The classical syndrome of tremor, rigidity and bradykinesia may be absent initially, when non-specific symptoms of tiredness, aching limbs, mental slowness, depression and small handwriting (micrographia) may be noticed. The presentation is almost always unilateral, a resting tremor in an upper limb being a common presenting feature. The tremor may eventually affect the legs, mouth and tongue. It may remain the predominant symptom for some years. Bradykinesia may develop gradually. Most patients have difficulty with rapid fine movements, and this manifests itself as slowness of gait and difficulty with tasks such as fastening buttons, shaving or writing. Rigidity, or increased muscular tone, causes stiffness and a flexed posture. Postural righting reflexes are impaired early on in the disease, but falls tend not to occur until later. As the disease advances, speech becomes softer and indistinct. There are a number of abnormalities on neurological examination, and these are listed below.

Although the features are initially unilateral, gradual bilateral involvement is the rule. Muscle strength and reflexes remain normal, and plantar responses are flexor. There is a paucity of facial expression (hypomimia) and the blink reflex may be exaggerated and fail to habituate (glabellar tap sign). Eye movements are normal to standard clinical testing, provided allowance is made for the normal limitation of upward gaze with age. Sensation is normal and intellectual faculties are not affected initially. As the disease progresses, about one-third of patients develop cognitive impairment.

The diagnosis is made clinically, as there is no diagnostic test for Parkinson’s disease. Sometimes it is necessary to investigate patients to exclude other causes of parkinsonism if there are any unusual features. Patients presenting before the age of 50 are usually tested for Wilson’s disease, and imaging (CT or MRI) of the head may be needed if there are any features suggestive of pyramidal, cerebellar or autonomic involvement, or the diagnosis is otherwise in doubt.

Management

Drug therapy

Levodopa combined with a peripheral-acting dopa-decarboxylase inhibitor provides the mainstay of treatment in Parkinson’s disease but should only be started to help overcome significant disability. Other agents include anticholinergic drugs, dopamine receptor agonists, selegiline, COMT inhibitors and amantadine.

Mechanisms of drug action in Parkinson's disease. (1) Decarboxylase inhibitors (carbidopa and benserazide) decrease side-effects by reducing peripheral conversion of levodopa to dopamine by aromatic amino acid decarboxylase (AAAD). (2) Active transport of levodopa into the brain may be inhibited by competition from dietary amino acids after a high-protein meal. (3) In the nigrostriatal neurons, levodopa is converted into dopamine. (4) Amantadine enhances the release of dopamine at the nerve terminal. (5) Dopamine agonists act directly on striatal receptors. (6) The monoamine oxidase type B (MAO-B) inhibitor selegiline increases the availability of neuronal dopamine by reducing its metabolism outside the neuron. (7) The catechol-O-methyl-transferase (COMT) inhibitor entacapone prolongs the availability of dopamine by inhibiting the metabolism of dopamine and levodopa outside the neuron.

Levodopa

Although the number of dopamine-releasing terminals in the striatum is diminished in Parkinson’s disease, remaining neurons can be driven to produce more dopamine by administering its precursor, levodopa. If levodopa is administered orally, more than 90% is decarboxylated to dopamine peripherally in the gastrointestinal tract and blood vessels, and only a small proportion reaches the brain. This peripheral conversion of levodopa is responsible for the high incidence of side-effects if it is used alone. The problem is largely overcome by giving a decarboxylase inhibitor that does not cross the blood-brain barrier along with the levodopa. Two peripheral decarboxylase inhibitors, carbidopa and benserazide, are available as combination preparations with levodopa (as Sinemet and Madopar, respectively).

The initiation of levodopa therapy should be delayed until there is significant disability, since there is concern that its use makes long-term side-effects more likely. With this in mind, some authorities suggest that it is advisable to initiate treatment with a dopamine agonist (see below) or a slow-release preparation of levodopa in order to minimise or delay the onset of long-term side-effects, but evidence for this is not strong. The important point is to treat with as little medication as possible consistent with the patient being able to perform the activities of daily living. Levodopa is particularly effective at improving bradykinesia and rigidity. Tremor is also helped but rather unpredictably. The initial dose is 50 mg 8- or 12-hourly, increased if necessary. The total levodopa dose may be increased to over 1000 mg/day if necessary. Side-effects include postural hypotension, nausea and vomiting, which may be offset by the use of a peripheral dopamine antagonist such as domperidone. Other dose-related side-effects are involuntary movements, particularly orofacial dyskinesias, limb and axial dystonias, and occasionally depression, hallucinations and delusions. Unusual but important side-effects include change in personality with increased (sometimes pathological) gambling, hypersexuality and drug (levodopa)-seeking behaviour.

Late deterioration despite levodopa therapy occurs after 3-5 years in one-third to one-half of patients. Usually this manifests as fluctuation in response. The simplest form of this is end-of-dose deterioration due to progression of the disease and loss of capacity to store dopamine. More complex fluctuations present as sudden, unpredictable changes in response, in which periods of severe parkinsonism alternate with dyskinesia and agitation (the ‘on-off’ phenomenon). End-of-dose deterioration can often be improved by dividing the levodopa into smaller but more frequent doses, or by converting to a slow-release preparation. The ‘on-off’ phenomenon is difficult to treat, but sometimes subcutaneous injections of apomorphine (a dopamine agonist) are helpful to ‘rescue’ the patient rapidly from an ‘off’ period.

Involuntary movements (dyskinesia) may occur as a peak-dose phenomenon, or as a biphasic phenomenon (occurring during both the build-up and wearing-off phases). Management is difficult, but involves modifying the way levodopa is administered to obtain constant levels in the brain, and the use of alternative drugs, including amantadine and dopamine agonists. Continuous infusion of apomorphine may be particularly helpful in this situation.

Anticholinergic agents

These have a useful effect on tremor and rigidity, but do not help bradykinesia. They can be prescribed early in the disease before bradykinesia is a problem, but should be avoided in elderly patients in whom they cause confusion and hallucinations. Other side-effects include dry mouth, blurred vision, difficulty with micturition and constipation. Many anticholinergics are available-for example, trihexyphenidyl (benzhexol; 1-4 mg 8-hourly) and orphenadrine (50-100 mg 8-hourly).

Dopamine receptor agonists

Several of these drugs are now available. They all have slightly different activity at the various dopamine receptors in the brain. Apomorphine given alone causes marked vomiting and has to be administered parenterally. The vomiting can be overcome by the concomitant use of domperidone, and parenteral administration achieved through continuous subcutaneous infusion from a portable pump, or by direct injection as needed. This requires considerable nursing support but, used correctly, can be very useful.

More easily administered drugs include bromocriptine, lisuride, pergolide, cabergoline, ropinirole and pramipexole, which can all be taken orally, and rotigotine which can be administered as a transdermal patch. These drugs are less powerful than levodopa in controlling features of parkinsonism, but they are much less likely to cause dose fluctuations or dyskinesia, though they will certainly exacerbate the latter once these have developed. Side-effects include nausea, vomiting, confusion and hallucinations. The dose of bromocriptine is 1 mg initially, increased to 2.5 mg 8-hourly, and thereafter up to 30 mg/day. Pergolide dose starts at 50 μg, increased to 250 μg 8-hourly, and possibly to 3000 μg/day. Dopamine agonists derived from ergot (pergolide and cabergoline) have recently been associated with the development of fibrotic reactions and thickening of heart valves. For this reason, the use of these agents is not advised.

Amantadine

This has a mild, usually short-lived effect on bradykinesia, but may be used early in the disease before more potent treatment is needed. Amantadine can be particularly useful in controlling the dyskinesias produced by dopaminergic treatment later in the disease. The dose is 100 mg 8- or 12-hourly. Side-effects include livedo reticularis, peripheral oedema, confusion and seizures.

Selegiline

Selegiline has a mild therapeutic effect in its own right. An early suggestion that it slows the progression of the disease has been discredited, as has the suggestion that it might be associated with an increased risk of sudden death. The usual dose is 5-10 mg in the morning.

COMT (catechol-O-methyl-transferase) inhibitors

Entacapone (200 mg with each dose of levodopa) prolongs the effects of each dose and reduces motor fluctuations when used with levodopa. This allows the levodopa dose to be reduced and given less frequently.

Surgery

Stereotactic thalamotomy can be used to treat tremor, though this is needed relatively infrequently because of the medical treatments available. Other stereotactic lesions are currently undergoing evaluation, in particular the implantation of stimulating electrodes into the globus pallidus to help in the management of drug-induced dyskinesia. The implantation of fetal mid-brain cells into the basal ganglia to enhance dopaminergic activity remains experimental.

Physiotherapy and speech therapy

Patients at all stages of Parkinson’s disease benefit from physiotherapy, which helps reduce rigidity and corrects abnormal posture. Speech therapy may help in patients where dysarthria and dysphonia interfere with communication.

Recent Approaches for Parkinson’s Disease Therapy

The characteristic lesion of RF is the Aschoff nodule, which is a granulomatous lesion. It is composed of an area of central fibrinoid necrosis surrounded by multinucleated giant cells which have elongated nuclei with a distinct chromatin pattern, macrophages and T lymphocytes.

The diagnosis of acute rheumatic fever is based on revised Duckett Jones criteria plus evidence of preceding streptococcal infection. This includes a history of recent scarlet fever, an anti-streptolysin O titre (ASO titre) >250 Todd units in adults and >333 in children or a positive rapid streptococcal antigen test or throat culture. Other tests are anti-hyaluronidase, anti-DNase, anti-streptokinase and the Streptozyme test.

Clinical features

The clinical features of carditis include chest pain, pericardial rub and effusion, tachycardia out of proportion to fever, muffled heart sounds, a gallop rhythm, low cardiac output and, rarely, syncope. Cardiomegaly may occur.

Endocarditis is characterized by fever and changing murmurs.

The pansystolic murmur of mitral regurgitation is the most common while a mid-diastolic murmur at the apex (Carey Coombs murmur) due to acute rheumatic valvulitis and an early diastolic murmur of aortic regurgitation may also occur.

Congestive heart failure with hepatic congestion is a recognized feature. Cardiac failure is often due to valve dilatation and not myocarditis. ST and T wave changes, reduction in QRS voltages, first-degree atrioventricular block and other conduction defects may be seen in the electrocardiogram.

Subcutaneous nodules usually occur over bony prominences such as the olecranon, external occipital protuberance and vertebral bodies. They measure 0.5-2 cm in size, and are firm and painless. Their presence is strongly associated with carditis. Nodules may also occur over joints and tendons, and have a histological appearance resembling Aschoff nodules.

Arthritis seen in rheumatic fever is classically a polyarthritis that is migratory in nature. Large joints are predominantly affected, especially knees (75%) and ankles (50%). Deformities are not a feature of rheumatic arthritis, except in rare cases of the so-called ‘Jaccoud’s arthritis’ where periarticular fibrosis causes deformity of the metacarpo-phalangeal joints.

Erythema marginatum is very uncommon in South Asia although it is present in 10-20% of patients in the West. It is a transient, evanescent, non-itchy rash with elevated edges and a fading centre. The rash extends centrifugally to become circinate or leaf-like. The trunk is commonly affected and the face is characteristically spared.

Chorea (Sydenham’s or St. Vitus’ dance) is a late manifestation of rheumatic fever and occurs 3-6 months after its onset. The movements are described as rapid, jerky, irregular, non-repetitive, involuntary and semi-purposive, and disappear during sleep. Other features include emotional lability, hypotonia, pendular knee jerks, a ‘Jack in the box’ or darting tongue, speech disturbances and ‘milkmaid’s’ grip. Rheumatic chorea does not usually affect adult males. About 25% of patients with chorea eventually develop chronic valvular heart disease.

Pneumonia, pleural effusions, abdominal pain (due to mesenteric adenitis) and recurrent epistaxis have also been reported in association with rheumatic fever.

Treatment

Acute rheumatic fever is treated with bed rest and procaine penicillin 0.6 mega units intramuscularly daily or phenoxymethyl penicillin 500 mg orally four times daily, for 8 days.

A single dose of benzathine penicillin 1.2 mega units intramuscularly has also been advocated. Patients allergic to penicillin can be given erythromycin or tetracycline 500 mg four times daily for the same period.

Patients with arthritis should be treated with high dose salicylates (aspirin 100 mg/kg bodyweight/day up to 6-8 g/day, tapering the dose after 2 weeks to 60 mg/kg bodyweight/day for 6 weeks). Aspirin is sometimes given to the limit of tolerance determined by the development of tinnitus. The arthritis of rheumatic fever responds dramatically to salicylates, and failure to respond should make one suspect the accuracy of the diagnosis (‘salicylate test’).

Steroids in the form of prednisolone 1-2 mg/kg bodyweight/day are given when carditis is present, and slowly tapered off over 2-4 weeks. Steroids may be overlapped with aspirin during the tapering period. Intravenous steroids can be used in fulminant carditis.

Chorea is treated by nursing the patient in a quiet environment and with drugs such as haloperidol or other sedatives when required. Carbamazepine and valproic acid have been found to be very effective in the treatment of chorea.

Prophylaxis

All patients with rheumatic fever should be given long-term penicillin prophylaxis for prevention of recurrence of rheumatic fever. Prophylaxis is given in the form of benzathine penicillin 1.2 mega units by deep intramuscular injection into the gluteal region, once every 3 weeks. As an alternative, phenoxymethyl penicillin may be given at a dose of 250 mg orally twice a day. Patients allergic to penicillin should be given sulfadiazine 0.5-1 g orally once daily depending on their bodyweight. Erythromycin is reserved for patients who are allergic to both penicillin and sulfonamides. Prophylaxis is life-long if rheumatic carditis has occurred and in the presence of chronic rheumatic heart disease. In other cases, prophylaxis should be given until the patient reaches the age of 40 years or for 5 years after the last attack of rheumatic fever, whichever is the longer period. Prophylaxis for rheumatic fever does not exempt patients with chronic rheumatic valvular heart disease from requiring prophylaxis for infective endocarditis.

Prognosis

Fifty per cent of patients with acute rheumatic fever will eventually develop chronic rheumatic valvular heart disease after 10-20 years. This most commonly affects the mitral valve, followed by the aortic valve. The tricuspid valve is rarely affected, and the pulmonary valve is hardly ever affected. In the Indian subcontinent the development of valvular heart disease occurs at a much younger age. It may at times occur in children less than 10 years of age (juvenile mitral stenosis). However, only about 50% of persons with established rheumatic heart disease give a history of acute rheumatic fever. This may be due to the trivial or mild nature of rheumatic fever in some individuals.