Neurology in the developing world.

The social and economic impact of neurologic disorders is being increasingly recognized in the developing world. Demographic transition, especially in large Asian populations, has resulted in a significant increase in the elderly population, bringing to the fore neurologic illnesses such as strokes, Alzheimer's disease, and Parkinson's disease. CNS infections such as retroviral diseases, tuberculosis, and malaria still account for high mortality and morbidity. Traumatic brain injury due to traffic accidents takes a high toll of life. Epilepsy continues to be a major health concern with large segments of the developing world's population receiving no treatment. A significant mismatch between the provision of specialized neurologic services and the requirement for them exists, especially in rural areas. Also, health insurance is not available for the majority, with patients having bear the costs themselves, thus limiting the procurement of available healthcare facilities. Neurologic training centers are few and the availability of laboratory facilities and equipment is largely limited to the metropolitan areas. Cultural practices, superstitious beliefs, ignorance, and social stigma may also impede the delivery of neurologic care. Optimizing available human resources, integrating primary, secondary, and tertiary healthcare tiers and making medical treatment more affordable will improve the neurologic care in the developing world.

Efficacy and safety of mitoxantrone, as an initial therapy, in multiple sclerosis: experience in an Indian tertiary care setting.

BACKGROUND AND PURPOSE: Mitoxantrone is an approved disease modifying agent for treatment of multiple sclerosis (MS). The aim of the study was to assess its efficacy and safety in Indian MS patients. MATERIALS AND METHODS: A total of 23 patients with clinically definite MS (Poser criteria) were enrolled in an open label study. Of which, 21 satisfied the McDonald's criteria for MS and two satisfied the diagnostic criteria of neuromyelitis optica (NMO). The numbers of relapses and expanded disability status scale (EDSS) score were used as primary and secondary outcome measures. The patients were monitored for the adverse effects. RESULTS: In 17 (15 MS and two NMO) patients who completed one year of therapy, there was significant difference in the mean annual relapse rates [before 0.879+/-0.58; on mitoxantrone 0.091+/-0.17, (P=0.003)]. Of the 17 patients, ten (MS 9 and NMO 1) completed therapy for two years. Annual relapse rates [before (1.024+/-0.59), on therapy (0.155+/-0.21), (P=0.0054)] and EDSS score [before start of therapy 5.3, at the end of therapy 2.4, (P=0.001)] showed significant benefit in the ten patients who completed two years therapy. This benefit persisted during the mean follow-up period of two and a half years after completion of therapy. The adverse events noted in the entire cohort were leucopenia in four patients and asymptomatic reversible decrease in cardiac ejection fraction in one patient. Leucopenia was severe in two patients requiring discontinuation of the therapy and mitoxantrone was also discontinued in the patient with cardiotoxicity. CONCLUSIONS: Mitoxantrone, as an initial therapy, decreases clinical exacerbations and disability progression, and has a reasonable safety profile in Indian patients with MS and NMO.

Primary central nervous system lymphoma: a profile of 26 cases from Western India.

BACKGROUND: Primary central nervous system (CNS) lymphoma (PCNSL) is a rare malignant non-Hodgkin's lymphoma and it accounts for 1% of all intracranial tumors. Only a few PCNSL studies have been reported from India, and studies on prognostic factors determining outcome, or evaluation of the response to currently accepted treatment, are lacking. AIMS: This study attempts to further delineate the clinical, radiological and pathological profile of PCNSL in India, to evaluate response to treatment and to assess usefulness of the International Extranodal Lymphoma Study Group (IELSG) score. SETTINGS AND DESIGN: All patients with pathologically proven PCNSL admitted over three years at a large tertiary care institution were studied. MATERIALS AND METHODS: Clinical features, IELSG prognostic score, imaging and pathological features, and response to treatment were evaluated. Results were analyzed using chi 2 test. RESULTS: Of 26 patients found, all except two were immunocompetent. Median age at diagnosis was 59 years. Focal deficits (76.9%) and neuropsychiatric symptoms (57.6%) were the commonest presenting complaints. Except for one case, at least some contrast enhancement was seen in brain lesions of all patients. Pathological studies showed high grade diffuse large B-cell (DLBCL) histology in 96.2% of patients. Of 22 patients who received methotrexate (MTX) based chemotherapy with/without radiotherapy; six died, with a response rate of 72.7%. Median survival was 10 months. Median follow-up duration was 14.5 months. Four patients developed treatment-related cognitive decline. All six patients with IELSG score of 4/5 died, while all 16 patients with a score of 0-3 survived. CONCLUSIONS: PCNSL presents most commonly in the sixth decade with focal neurological deficit, behavioral symptoms and cognitive decline. High grade DLBCL is the commonest histological subtype. Steroids should ideally be withheld until biopsy as they may confound the diagnosis. Most immunocompetent patients respond well to high dose MTX-based chemotherapy with/without radiation. High IELSG scores correlate with worse prognosis in patients with PCNSL.

Spontaneous intracranial hypotension: Two cases including one treated with epidural blood patch.

Spontaneous intracranial hypotension (SIH) is characterized by orthostatic headache (OH), low cerebrospinal fluid (CSF) pressure, and diffuse pachymeningeal gadolinium enhancement (DPME). We present here the case studies of two patients. One patient demonstrated a CSF leak in the mid-thoracic region, and recovered completely with conservative treatment. The other patient in whom leak could not be demonstrated, developed dementia, rapidly worsening encephalopathy, and became comatose, necessitating urgent epidural blood patch (EBP) with 25 cc of autologous blood, after which immediate and complete symptomatic relief was obtained. A second EBP was required a few days later and also provided complete and sustained clinical benefit, without subsequent recurrence. Both patients had OH and showed bilateral subdural fluid collections, DPME and "sagging" of brain on MRI. A high index of suspicion, recognizing the orthostatic nature of headache, and typical findings on contrast enhanced MRI should point to the diagnosis of SIH. EBP can be effective treatment in patients unresponsive to conservative measures.

Myasthenia gravis: a study from India.

BACKGROUND: We present the findings from the largest hospital-based studies on myasthenia gravis from India, using data collected over a period of 43 years from the Neurology Department in a tertiary referral center in India. OBJECTIVES: To study the clinical presentation, age at onset, gender distribution, serological status and thymic pathology in patients with myasthenia gravis. MATERIALS AND METHODS: A retrospective study was carried out using records of patients with myasthenia gravis from the years 1965 to 2008. RESULTS: Of 841 patients, 836 (611 males and 225 females) had acquired myasthenia (myasthenia gravis) and five congenital myasthenia. The median age at onset was 48 years (males 53 years and females 34 years). The peak age at onset for males was in the sixth and seventh decade and in females, in the third decade. Two hundred and twenty-two (26.31%) patients had ocular and 616 (73.68%) generalized myasthenia. Serological studies were done in 281 patients with myasthenia gravis for Acetylcholine receptor (AchR) antibodies of which 238 (84.70%) were seropositive. The most common histopathology was thymoma and the second most common was thymic hyperplasia. CONCLUSION: Myasthenia gravis in our study was more common in males (M:F of 2.70:1). There was a single peak of age at onset (males sixth to seventh decade; females third decade). The higher prevalence of thymomas in this series is in all probability related to selection bias as patients with thymic enlargement or more severe disease underwent thymectomy. Thymoma was more common in males; hyperplasia in females.

Magnetic resonance imaging of Asians with multiple sclerosis was similar to that of the West.

Magnetic resonance imaging (MRI) of the brain is the most important paraclinical diagnostic test in multiple sclerosis (MS). The appearance of MRI in Asians with MS is not well defined. We retrospectively surveyed the first brain and spinal cord MRI in patients diagnosed to have MS, according to Poser's criteria in seven regions throughout Asia to define the MRI changes among Asians with MS. There were 101 patients with first brain, and 86 with first spinal cord MRI, 66 of whom had both. The brain MRI showed a mean of 17 lesions per patient in T2 weighted images, mostly asymptomatic. Almost all the lesions were in the white matter, particularly in the juxtacortical, deep and periventricular white matter. A third of the lesions were greater than 5 mm, 14% enhanced with gadolinium. There were more supratentorial than infratentorial lesions at a ratio of 7.5: 1. Ninety five percent of the spinal cord lesions were in cervical and thoracic regions, 34% enhanced with gadolinium. The lesions extended over a mean of 3.6 +/- 3.3 vertebral bodies in length. Fifty (50%) of the brain and 54 (63%) of the spinal MRI patients had the optic-spinal form of MS. The MRI of the optic-spinal and classical groups of patients were similar in appearance and distribution, except that the optic-spinal MS patients have fewer brain but longer and more severe spinal cord lesions. In conclusion, the brain and spinal cord MRI of Asian patients with MS was similar to that of the West, although, in this study, Asian MS patients had larger spinal cord lesions.

Leukodystrophies: Indian scenario.

The leukodystrophies are familial disorders with onset usually in infancy or childhood. The clinical features consist of motor dysfunction with varying degree of cognitive decline. Magnetic Resonance Imaging (MRI) has helped to identify and characterize these disorders. In some leukodystrophies, biochemical enzymatic and genetic defects have been identified. The commonest leukodystrophy seen in India is Megalencephalic Leukodystrophy with subcortical cysts. The essential features consist of large head, mild pyramidal and cerebellar dysfunction, and occasional seizures. MRI studies show extensive white matter changes with temporal cysts. It is common in the Agarwal community in India. An identical mutation in exon 2 of the MLC 1 gene has been identified in this community suggesting a founder effect.

Molecular analysis of GAA repeats and four linked bi-allelic markers in and around the frataxin gene in patients and normal populations from India.

Friedreich ataxia (FRDA), the most common type of ataxia worldwide, is an autosomal recessive disease. Homozygous expansion of GAA repeats in the first intron of the frataxin gene constitute the major type of mutation that causes the disease. The prevalence of FRDA in diverse ethnic populations of India has not been widely studied. We have studied the distribution of polymorphic GAA repeats in the frataxin gene among 6 clinically diagnosed patients and 160 ethnically matched normal individuals, to gather information on the prevalence of FRDA in the eastern part of India. Homozygous expansion in the range of 250-730 GAA repeats was detected among the patients. Among normal individuals, we observed a unimodal distribution of GAA repeats, consisting of 10 different alleles ranging from 7 to 16 GAA repeats, where the 9 repeat allele had maximal frequency. Only 5.9% of all chromosomes were found to harbour >12 GAA repeats. Haplotype analysis using closely linked four bi-allelic markers in and around the frataxin gene indicated that 66.7% of the expanded alleles harbour the ATCC haplotype that has been reported worldwide. This haplotype was present in 53.3% of the chromosomes with >12 GAA repeats, and accounted for only 3.8% of chromosomes with 7 to 12 GAA repeats. We found one novel haplotype, ACCT, among the expanded alleles as well as among normal individuals, though at low frequency; this haplotype may be characteristic of Indian populations.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL): a case report with review of literature.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is an inherited arterial disease, commonly overlooked or misdiagnosed. We report a case of CADASIL in a 51 years old woman who presented with progressive subcortical dementia, recurrent ischemic events and seizures in the absence of known vascular risk factors of five years' duration. Her mother had a history of similar illness. Magnetic resonance imaging (MRI) of brain revealed subcortical and deep white matter hyperintense lesions within the cerebral white matter on T2-weighted images. DNA mutation of Notch 3 gene confirmed the diagnosis of CADASIL.

Indian Agarwal megalencephalic leukodystrophy with cysts is caused by a common MLC1 mutation.

BACKGROUND: A distinct clinical syndrome characterized by megalencephaly, mild to moderate cognitive decline, slowly progressive spasticity, ataxia, occasional seizures, and extensive white matter changes with temporal cysts by imaging studies has been described in a particular ethnic group (Agarwals) in India. This disorder is very similar to megalencephalic leukoencephalopathy with subcortical cysts (MLC), a newly characterized leukodystrophy whose molecular basis was recently shown to be mutations in a gene (KIAA0027) that has been renamed MLC1. OBJECTIVE: To determine if this disorder among the Agarwals is due to mutations in MLC1 by a mutation screening study conducted on affected Agarwal patients. METHODS: Genomic DNA from these Indian leukodystrophy patients was screened for mutations in the entire coding region, including the exon-intron boundaries, of the MLC1 gene. RESULTS: Thirty-three affected individuals whose clinical and imaging presentations were consistent with MLC were screened. All were from northern India and included 31 known Agarwals, 1 non-Agarwal, and 1 adopted patient whose ethnicity is unknown. All 31 Agarwal patients tested positive for a homozygous insertion of a cytosine in exon 2. The adopted patient was homozygous for A157E. No mutation in the coding region was found in the non-Agarwal patient. CONCLUSIONS: Indian patients with megalencephaly and MRI changes that show extensive white matter changes with temporal cysts should raise suspicion for MLC. Members of the Agarwal ethnic group affected with the disorder present with a mildly progressive course and show a common mutation (320insC) in the MLC1 gene, suggesting a founder effect.

Evidence for novel DRB1*15 allele association among clinically definite multiple sclerosis patients from Mumbai, India.

Multiple sclerosis (MS) is a clinically heterogeneous demylinating disease and an important cause of acquired neurologic disability. MS has been reported from different regions of India and its infrequency has been attributed to have genetic implications. Further, a high incidence of MS and its human leukocyte antigen B12 (HLA-B12) associations have been reported among highly inbred Parsi population from Mumbai. However, consistent HLA associations have not been reported from India. We analyzed the HLA-B, -Cw, and -DRB1 allele associations among 23 clinically definite Western Indian non-Parsi MS patients and compared them with 146 ethnically matched clinically normal individuals. HLA serologic (A, B, and Cw) as well as molecular (DRB1) typing methodology was followed. The study revealed a significant increase of HLA-A11 (24% vs. 13%; OR = 2.6; EF = 0.14; 95%CI = 1.1-3.05), B16 (4.3% vs 0.3%; OR = 13.8; EF = 0.03; 95% CI = 1.19-134.44), Cw7 (15.2% vs 3.7%; OR = 5.46; EF = 0.12; 95% CI = 0.944-17.86), and DRB1*15 (21.7% vs 2.2%; OR = 16.15; EF = 0.19; 95% CI = 1.33-68.64). Further molecular subtyping of HLA-DRB1*15 among the patients revealed two novel alleles, DRB1*1506 (20%) and DRB1*1508 (30%), along with the commonly reported DRB1*1501 (50%) for the first time in MS patients that were hitherto unidentified from other parts of India and world as well. This study reveals that there is a complexity of the genetic susceptibility to MS in different populations studied and reported.

Substantia nigra lesions in viral encephalitis.

Post-encephalitic parkinsonism is a well-known entity, but involvement of the basal ganglia is rarely documented. We describe a 21-year-old man who developed parkinsonism following encephalitic illness presumed to be of viral origin with substantia nigra lesions evident on magnetic resonance imaging scan.

Intramedullary neurenteric cyst in mid thoracic spine in an adult: a case report.

Neurenteric cysts are very rare, particularly in adults. These are congenital intraspinal cysts of endodermal origin. A 67 years old man, presenting with backache and paraesthesiae of one and half years' duration, followed by subacute flaccid paraplegia, developing in a week is described. MRI revealed intramedullary cyst at T7. He underwent emergency thoracic laminectomy and complete excision of the cyst. Histopathology confirmed a neurenteric cyst. In view of their rarity, peculiarity in terms of age, location and presentation, we report this case.

Immunoglobulin G subclass distribution of autoantibodies to gangliosides in patients with Guillain-Barre syndrome.

IgG anti-ganglioside antibodies are present in a proportion of patients with the Guillain-Barré syndrome (GBS). To determine if antibodies to gangliosides are restricted in IgG subclass distribution, we evaluated IgG subclass antibody responses to gangliosides in sera of patients with GBS. Sera from GBS patients with IgG activity against gangliosides were analyzed for IgG subclass distribution using an enzyme-linked immunosorbent assay. The anti-LM1 antibodies in sera from GBS patients were predominantly of the IgG3 subclass while anti-GM1 and anti-GT1a antibodies were predominantly of the IgG1 and IgG3 subclasses. The results indicate a Th2-dependent antibody response.

MR imaging and proton MR spectroscopy in adult Krabbe disease.

We present the MR imaging findings in four patients (two pairs of siblings from two unrelated families) with adult Krabbe disease. In the first family, clinical presentation mimicked familial spastic paraplegia. Their MR images showed selective, increased signal intensity on T2-weighted sequences along the corticospinal tracts, most prominently in the proband and barely detectable in her brother. Proton MR spectroscopy showed increased choline and myo-inositol in the affected white matter. In the second family, the clinical presentation differed in that the signs of pyramidal tract involvement were asymmetrical, with concomitant asymmetry on MR images in one. In adults, Krabbe disease may present on MR imaging with selective pyramidal fiber involvement.