Lessons for clinical trials from natalizumab in multiple sclerosis.
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Biomedical subjects
Publications and source records attributed to Abhijit Chaudhuri.
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Multiple sclerosis (MS) is a demyelinating disease of the central nervous system that runs a chronic course and disables young people. The disease is more prevalent in the geographic areas that are farthest from the equator. No form of treatment is known to be effective in preventing MS or its disabling complications. A number of epidemiological studies have shown a protective effect of exposure to sunlight during early life and a recent longitudinal study confirmed that vitamin D supplementation reduced life-time prevalence of MS in women. Very little is known regarding the role of vitamin D on the developing brain but experimental data suggest that cerebral white matter is vitamin D responsive and oligodendrocytes in the brain and spinal cord and express vitamin D receptors. It is possible that differentiation and axonal adhesion of oligodendrocytes are influenced by vitamin D level during brain development and a relative lack of vitamin D may increase oligodendroglial apoptosis. The age effect of migration on susceptibility to develop MS could be explained by a role of vitamin D on brain development. In areas of high MS prevalence, dietary supplementation of vitamin D in early life may reduce the incidence of MS. In addition, like folic acid, vitamin D supplementation should also be routinely recommended in pregnancy. Prevention of MS by modifying an important environmental factor (sunlight exposure and vitamin D level) offers a practical and cost-effective way to reduce the burden of the disease in the future generations.
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Chronic fatigue is a typical symptom of neurological diseases, and is most disabling in multiple sclerosis, postpoliomyelitis, poststroke, and in chronic fatigue syndrome. Disorders of neuromuscular junction transmission and metabolic diseases cause muscle fatigability, which is characterised by failure to sustain the force of muscle contraction (peripheral fatigue). Fatigue is also seen in diseases that affect the central, peripheral, and autonomic nervous systems (central fatigue). Enhanced perception of effort and limited endurance of sustained physical and mental activities are the main characteristics of central fatigue. Metabolic and structural lesions that disrupt the usual process of activation in pathways interconnecting the basal ganglia, thalamus, limbic system, and higher cortical centre are implicated in the pathophysiological process of central fatigue. A state of pre-existing relative hypocortisolaemia might sensitise the hypothalamic-pituitary-adrenal axis to development of persistent central fatigue after stress. The contributions of physiological, cognitive, and affective changes underlying fatigue are variable, and treatment is largely symptomatic and rehabilitative.
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Post-exertional muscle pain is an important reason for disability in patients who are diagnosed to have Chronic Fatigue Syndrome (CFS). We compared changes in pain threshold in five CFS patients with five age and sex matched controls following graded exercise. Pain thresholds, measured in the skin web between thumb and index finger, increased in control subjects with exercise while it decreased in the CFS subjects. Increased perception of pain and/or fatigue after exercise may be indicative of a dysfunction of the central anti-nociceptive mechanism in CFS patients.
The initiation of antibiotic treatment on suspicion of bacterial meningitis is important, but it is not enough to improve the prognosis for patients, especially those with pneumococcal meningitis. The mortality and morbidity of pneumococcal meningitis are still devastating, and results of a recent randomised trial have shown evidence in favour of dexamethasone treatment given before or with the first antibiotic dose. Adjuvant dexamethasone is unequivocally recommended in children and adults with haemophilus meningitis or pneumococcal meningitis. The benefit of adjunctive dexamethasone is likely to be greatest in patients who are otherwise healthy and present early with acute bacterial meningitis. Dexamethasone is not currently recommended for the treatment of gram-negative bacillary meningitis and neonatal meningitis. Dexamethasone, before or with the first dose of antibiotic, is likely to be one of the most significant practice changes that will benefit many adults and children with common types of acute bacterial meningitis and has been of proven value in the developed world.
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Hashimoto's encephalopathy may present with a wide variety of different neurological symptoms and signs. These include recurrent severe migrainous headache, psychoses, seizures, ataxia, dementia, stupor and coma. We present a personal series of 18 adult patients with Hashimoto's encephalopathy and a review of the literature in this paper. The natural history, laboratory abnormalities and neuroimaging data in these cases favour an immunopathological basis for this syndrome similar to relapsing acute disseminated encephalomyelitis. We suggest that Hashimoto's encephalomyelitis should be considered in the differential diagnosis of seizures, coma, atypical migraine and reversible dementia. Serological screening for anti-thyroid antibody should form part of the initial investigations in all relapsing and reversible encephalopathies.