Satish Jain

Molecular analysis of autosomal dominant hereditary ataxias in the Indian population: high frequency of SCA2 and evidence for a common founder mutation.

Abstract. Expansion of CTG/CAG trinucleotide repeats has been shown to cause a number of autosomal dominant cerebellar ataxias (ADCA) such as SCA1, SCA2, SCA3/MJD, SCA6, SCA7, SCA8 and DRPLA. There is a wide variation in the clinical phenotype and prevalence of these ataxias in different populations. An analysis of ataxias in 42 Indian families indicates that SCA2 is the most frequent amongst all the ADCAs we have studied. In the SCA2 families, together with an intergenerational increase in repeat size, a horizontal increase with the birth order of the offspring was also observed, indicating an important role for parental age in repeat instability. This was strengthened by the detection of a pair of dizygotic twins with expanded alleles showing the same repeat number. Haplotype analysis indicates the presence of a common founder chromosome for the expanded allele in the Indian population. Polymorphism of CAG repeats in 135 normal individuals at the SCA loci studied showed similarity to the Caucasian population but was significantly different from the Japanese population.

Molecular and clinical correlation in five Indian families with spinocerebellar ataxia 12

Spinocerebellar ataxia 12 (SCA12) is a recently identified form of autosomal dominant cerebellar ataxia associated with the expansion of an unstable CAG repeat in the 5′ untranslated region of the gene PPP2R2B. We analyzed 77 Indian families with autosomal dominant cerebellar ataxia phenotype and confirmed the diagnosis of SCA12 in 5 families, which included a total of 6 patients and 21 family members. The sizes of the expanded alleles ranged from 55 to 69 CAG repeats, and the sizes of the normal alleles ranged from 7 to 31 repeats. We believe our study is the first to demonstrate that SCA12 may not be as rare in some populations as previously thought.

Memory and intelligence outcome following surgery for intractable temporal lobe epilepsy: relationship to seizure outcome and evaluation using a customized neuropsychological battery

The main objectives of this prospective study were to (1) assess memory and intelligence outcome following surgery for intractable temporal lobe epilepsy, (2) correlate this with seizure outcome and side of surgery, and (3) perform (1) and (2) using an indigenously developed battery customized to the Indian population. Prior to use in our epilepsy surgery program, the test-retest and interexaminer variance reliability of this battery had been established in both normal and cognitively compromised populations. The memory scores were overall rather than material-specific. The battery was administered to right-handed adults undergoing surgery for intractable temporal lobe epilepsy without any evidence of opposite temporal lobe abnormality, both presurgery and postsurgery at a mean follow-up of 8 months. Twenty-five consecutive patients were included; 13 underwent right and 12 underwent left temporal surgery. Seizure outcome was assessed using Engels classification. Among 13 patients who underwent right temporal surgery, although 4 patients with poor seizure outcome had insignificant changes in scores, 7 of 9 patients with good seizure outcome exhibited considerable (> 20% over preoperative) improvement in their memory and intelligence scores. Statistical analysis using Students t test and the Mann-Whitney test revealed that the patients who underwent right temporal surgery with good seizure outcome had significant improvement in both memory (P = 0.007) and intelligence (P = 0.043) scores compared with those with poor seizure outcome. In contrast, patients who underwent left temporal surgery had no significant change in cognitive scores irrespective of seizure outcome. Cognitive improvement seems to occur in patients with good seizure outcome following nondominant temporal lobe surgery for intractable epilepsy with no evidence of pathology in the opposite temporal lobe. The same finding was not observed in patients undergoing left temporal surgery.

Surgical outcome of cortical dysplasias presenting with chronic intractable epilepsy: a 10-year experience.

BACKGROUND There has been sparse description of cortical dysplasias (CDs) causing intractable epilepsy from India. AIM Clinical retrospective study of CDs causing intractable epilepsy that underwent surgery. MATERIALS AND METHODS Fifty-seven cases of CDs reviewed (1995 till July 2006) are presented. All patients had intractable epilepsy, and underwent a complete epilepsy surgery workup (inter ictal electroencephalography (EEG), video EEG, MRI as per epilepsy protocol, SPECT {interictal, ictal with subtraction and co-registration when required}, and PET when necessary). Surgical treatment included a wide exposure of the pathology with a detailed electrocorticography under optimal anesthetic conditions. Mapping of the sensori-motor area was performed where indicated. Procedures included resection either alone or combined with multiple subpial transactions when extending into the eloquent areas. RESULTS Our study had 28 (49.12%) cases of isolated focal CDs, and 29 (50.67%) with dual pathology. Average age at the time of onset of seizures in our series was 7.04 years (three months to 24 years), and average age at the time of surgery was 10.97 years (eight months to 45 years). Among coexistent pathologies, one had associated MTS, 16 had coexistent gangliogliomas and 12 (dysembryonic neuroepithelial tumor) DNTs. At an average follow-up of 3.035 years (range 5-10 years), three patients were lost to follow-up. Fifty-one per cent (29/57) patients had a good outcome (Engel Grade I) and 26%(15/57) had a Grade II outcome. CONCLUSION Cortical dysplasias have a good outcome if evaluated and managed with concordant electrical and imaging modalities.

A locus for generalized tonic-clonic seizure susceptibility maps to chromosome 10q25-q26

Inheritance patterns in twins and multiplex families led us to hypothesize that two loci were segregating in subjects with juvenile myoclonic epilepsy (JME), one predisposing to generalized tonic‐clonic seizures (GTCS) and a second to myoclonic seizures. We tested this hypothesis by performing genome‐wide scan of a large family (Family 01) and used the results to guide analyses of additional families. A locus was identified in Family 01 that was linked to GTCS (10q25‐q26). Model‐based multipoint analysis of the 10q25‐q26 locus showed a logarithm of odds (LOD) score of 2.85; similar results were obtained with model‐free analyses (maximum nonparametric linkage [NPL] of 2.71; p = 0.0019). Analyses of the 10q25‐q26 locus in 10 additional families assuming heterogeneity revealed evidence for linkage in four families; model‐based and model‐free analyses showed a heterogeneity LOD (HLOD) of 2.01 (α = 0.41) and maximum NPL of 2.56 (p = 0.0027), respectively, when all subjects with GTCS were designated to be affected. Combined analyses of all 11 families showed an HLOD of 4.04 (α = 0.51) and maximum NPL score of 4.20 (p = 0.000065). Fine mapping of the locus defined an interval of 4.45Mb. These findings identify a novel locus for GTCS on 10q25‐q26 and support the idea that distinct loci underlie distinct seizure types within an epilepsy syndrome such as JME. Ann Neurol 2005;58:449–458

Serum prolactin levels for differentiation of nonepileptic versus true seizures: limited utility

Frequently occurring nonepileptic psychogenic seizures (PNES) are a cause of substantial morbidity. Differentiation of these from true seizures may sometimes be very difficult. Serum prolactin level estimation following the event has been described as a useful test for this purpose. We conducted this study to assess the role of this test in diagnosis of PNES. Serum prolactin was estimated from venous blood samples of 19 patients (13 females, 6 males) with PNES and 17 patients (5 females, 12 males) with true complex partial seizures with or without secondary generalization. The age range was 12-39 years in the PNES group and 9-42 years in the true seizure group. Five patients (all females) in the PNES group (26.3%) had raised prolactin levels, all of them having greater than twice normal levels. In the true seizure group, 10 of 17 (58.8%) patients had raised levels; only 3 (17.6%) of these had greater than twice normal levels. The difference in percentage of patients with abnormal prolactin levels between these groups was not found to be significant. We demonstrate that serum prolactin level estimation is not a useful method for differentiation of psychogenic nonepileptic from true epileptic seizures.

Neuropathological spectrum of Rasmussen encephalitis

BACKGROUND Rasmussen encephalitis (RE) is a chronic epileptic disorder of unknown etiology, and is clinically characterized by progressive neurological deterioration, focal seizures often progressing to intractable epilepsy, cognitive decline and hemispheric atrophy. AIMS We report the spectrum of neuropathological changes seen in RE, and discuss the evolutionary mechanisms of this disease. MATERIALS AND METHODS Surgically obtained specimens from RE patients diagnosed during 2002-2004 at this institute were evaluated for the presence and extent of different histopathological features of RE. The H&E and immunohistochemistry stained slides were also evaluated for the type and distribution pattern of inflammatory infiltrates, along with a semiquantitative evaluation for the severity of inflammation. RESULTS Four cases of RE were admitted during the study period, all of which presented with partial seizures with successive deterioration to intractable epilepsy. The age at onset varied between 5 and 10 years (mean 7.8 years), with three male and one female patients. Subsequently, all four patients underwent hemispherotomy. Histopathological features of perivascular lymphocytic infiltrate, neuronal loss, microglial nodules, and reactive astrocytosis, with or without evidence of neuronophagia confirmed a diagnosis of RE. These cases also had varying degrees of T-cell-rich (CD3-positive) inflammatory infiltrates and CD68-immunopositive microglial proliferation. It was observed that the severity of inflammation had a trend to inversely correlate with the duration of symptoms. CONCLUSION It is proposed that an accurate evaluation and histopathological grading of these lesions may possibly have a role in patient prognostication.

Development of a Validated Clinical Case Definition of Generalized Tonic–Clonic Seizures for Use by Community‐based Health Care Providers

Summary:  Purpose: To develop and test a clinical case definition for identification of generalized tonic–clonic seizures (GTCSs) by community‐based health care providers.

Post-zygotic de novo trinucleotide repeat expansion at spinocerebellar ataxia type 7 locus: evidence from an Indian family

AbstractSpinocerebellar ataxia type 7 (SCA7) is an autosomal dominant cerebellar ataxia caused by CAG repeat expansion. We found expansion at SCA7 locus in only two out of 235 Indian families clinically diagnosed for ataxia. In one of the families, a de novo mutation was observed wherein a paternal allele in intermediate range of 31 CAG repeats expanded to 59 in the offspring leading to the disease. No expanded alleles were observed in the sperm of the transmitting parent by small pool PCR. This suggests that de novo expansion by a pre-zygotic event is unlikely and could be post-zygotic. SCA7 expanded alleles from the two families were present on different genetic backgrounds, indicating multiple origins of the mutation.

Priority of epilepsy research in Asia

Summary:  Epilepsy is the most common serious disorder of the brain, characterized by recurrent unprovoked seizures. It is estimated that there are ∼50 million people with epilepsy worldwide, the majority of which today are living in the developing countries. Many countries in the Asian Oceanian regions have large populations and limited resources. Most such countries do have a vast health‐care network with few centres of excellence that are comparable to the best in the world. The peculiar sociocultural milieu of this region provides a large population with epilepsy that can be used as a unique tool to conduct research into the basic processes, clinical aspects and psychosocial consequences of epilepsy. The Asian Oceanian region offers tremendous opportunities for research despite its limited resources. The clinicians and scientists need to be aware of the basic realities of the region and take full advantage of the situation to work for the benefit of humanity.