Novel mutations in typical and atypical genetic loci through exome sequencing in autosomal recessive cerebellar ataxia families.

Nearly a thousand mutations mapping to 60 different loci have been identified in cerebellar ataxias. However, almost 50% of the cases remain genetically uncharacterized and there is a difference in prevalence as well as in the phenotypic spectrum of ataxia among various geographical regions. This poses a challenge for setting up a genetic panel for screening ataxia. In our ataxic cohort of 1014 families, 61% are genetically uncharacterized (UC). We investigated the potential of whole exome sequencing in conjunction with homozygosity mapping (HM) to delineate the genetic defects in three uncharacterized families with recessive inheritance each manifesting some unusual phenotype: (i) infantile onset ataxia with hearing loss (IOAH), (ii) Juvenile onset cerebellar ataxia with seizures (JCS) and (iii) Friedreich ataxia-like (FA-like). We identified a novel missense mutation in c10orf2 in the family with IOAH, compound heterozygous mutations in CLN6 in the family with JCS and a homozygous frame-shift mutation in SACS in the FA-like patient. Phenotypes observed in our families were concordant with reported phenotypes of known mutations in the same genes thus obviating the need for functional validation. Our study revealed novel variations in three genes, c10orf2, CLN6, and SACS, that have so far not been reported in India. This study also demonstrates the utility of whole exome screening in clinics for early diagnosis.

Need for a national epilepsy control program.

This article briefly outlines the proposed national epilepsy control program. The content of the article is based on four meetings held by invitation of the Ministry of Health. Invitees by ministry - Drs. D. C. Jain, M. Gourie Devi, V. Saxena, S. Jain, P. Satish. Chandra, M. Gupta, K. Bala, V. Puri, K. S. Anand, S. Gulati, S. Johri, P. S. Chandra, M. Behari, K. Radhakrishnan, D. Bachani. Presentations were made by Dr. M. Tripathi.The program will involve all neurologists across the country in teaching and training at state levels and a central monitoring committee.

Validity of the Berlin Questionnaire in identifying obstructive sleep apnea syndrome when administered to the informants of stroke patients.

Given the high prevalence of sleep-disordered breathing (SDB) in stroke and its importance as a vascular risk factor, a clinical instrument to assess its incidence would be useful. Acute stroke patients (n=121) were stratified into high- and low-risk groups for SDB using a modified Berlin Questionnaire (BQ) administered to the informants who were living with the patient. After a minimum of 4 weeks from stroke onset, patients who were fit underwent overnight polysomnography (PSG). On stratifying risk of obstructive sleep apnea (OSA) in these patients based on the BQ, 53% belonged to the high-risk group and 47% belonged to the low-risk group. There was poor correlation between the clinical questionnaire results and PSG findings, with sensitivity of 66.7%, specificity of 55.6%, a positive predictive value of 63.4%, and a negative predictive value of 58.8%.

Clinical spectrum of Hallervorden-Spatz syndrome in India.

Hallervorden-Spatz syndrome is a rare autosomal recessive disorder that involves progressive extrapyramidal manifestations. Classical and atypical clinical presentations are known. Clinical details of patients admitted to the neurology ward or attending the movement disorder clinic of the All India Institute of Medical Sciences between January 2001 and July 2007 were reviewed. Sixteen patients (9 males and 7 females) were included in the study (median age 14 years; range 6-25). The most common clinical presentation was limb or cranial onset progressive dystonia. The patients with early onset had more frequent truncal and axial dystonia, including retrocollis, oromandibular-facial dystonia and chorea, dysarthria, pyramidal signs, gait disturbance, cognitive impairment, delay in milestones, retinitis pigmentosa, optic atrophy, oculomotor abnormalities, positive family history and acanthocytosis. Although rare, cerebellar ataxia, behavioural abnormalities, parkinsonism and apraxia of eyelid opening were exclusively seen in late onset patients. The present study highlights the heterogeneity of this disease entity and also describes certain unusual clinical features.

Functional mapping in PD and PSP for sustained phonation and phoneme tasks.

AIM: To elucidate the central basis of articulatory speech disorders in Parkinsonian syndromes using functional magnetic resonance imaging (fMRI). METHODS: Twenty-two patients with Parkinson's disease (PD) and 18 with progressive supranuclear palsy (PSP) were clinically evaluated for speech dysfunction. Functional magnetic resonance imaging (fMRI) was carried out in these patients using sustained phonation and phoneme tasks. Individual and group analysis using SPM2 was done for eight patients with PD, 7 with PSP and 6 healthy controls. SETTING: Tertiary Medical Teaching Institute. RESULTS: For sustained phonation paradigm, superior temporal gyrus area was activated in PD patients, and occipital cortex in PSP subjects in comparison to controls. For phoneme paradigm, the patients with PD recruit lingual gyrus obviating the need for more efforts for the task. Also wider areas as well as more clusters were activated in PD patients compared to controls. Lingual gyrus was found to be strongly activated in PSP patients. Reduced activation of the primary areas with recruitment of remote areas was another prominent finding in PSP. Due to excessive motion (>1.5 mm, >1 degrees ) in all the MSA patients, they could not be considered for analysis. CONCLUSION: The failure of the executive fronto-striatal network would lead to increased activation of other areas in PD, but in PSP, there is a widespread cortical dysfunction.

Clinical speech impairment in Parkinson's disease, progressive supranuclear palsy, and multiple system atrophy.

CONTEXT: Speech abnormalities are common to the three Parkinsonian syndromes, namely Parkinson's disease (PD), progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), the nature and severity of which is of clinical interest and diagnostic value. AIM: To evaluate the clinical pattern of speech impairment in patients with PD, PSP and MSA and to identify significant differences on quantitative speech parameters when compared to controls. DESIGN AND SETTING: Cross-sectional study conducted in a tertiary medical teaching institute. MATERIALS AND METHODS: Twenty-two patients with PD, 18 patients with PSP and 20 patients with MSA and 10 age-matched healthy controls were recruited over a period of 1.5 years. The patients were clinically evaluated for the presence and characteristics of dysarthria. This was followed by quantitative assessment of three parameters: maximum phonation time (MPT), semantic fluency and reading speed. The outcome measures were compared between the patient groups and with controls. RESULTS: Patients with PD had hypophonic monotonous speech with occasional rushes of speech while patients with MSA and PSP had mixed dysarthria with ataxic and spastic elements respectively. All quantitative parameters were affected when compared to controls (P values<0.001, 0.012 and 0.008 respectively). Maximum phonation time was significantly less in PSP when compared to MSA and PD (P=0.015). Reading speed also showed a similar trend which was not statistically significant. Semantic fluency was comparable in all three groups. CONCLUSION: Dysarthria in PD, PSP and MSA have many overlapping but certain distinctive features as well which could serve as a diagnostic clue. Patients with PSP had profound speech impairment probably indicative of the more severe frontostriatial pathology.

Hyperacute thrombolysis with IV rtPA of acute ischemic stroke: efficacy and safety profile of 54 patients at a tertiary referral center in a developing country.

BACKGROUND: Given the constraints of resources, thrombolysis for acute ischemic stroke (AIS) is under evaluation in developing countries. Prothrombin time (PT), platelet count and activated partial thromboplastin time (aPTT) may not be feasible within the time window. AIM: To evaluate the safety and efficacy of thrombolysis in selected patients without the coagulation profile. DESIGN: Open, nonrandomized, observational study. MATERIALS AND METHODS: Fifty-four stroke patients were classified using TOAST criteria (large artery atherosclerotic = 13; cardioembolic = 12; small vessel occlusion = 22; other determined etiology =three; undetermined etiology = four). The mean time to reach emergency was 2.4h (1.15-3.4), the mean door to CT, 24 min (10-47) and the door to recombinant tissue plasminogen activator (r-tPA) injection, 26.8 min (25-67). The NIHSS scores ranged from 11 to 22 (mean = 15.5 +/- 2.7). Patients with history of liver or renal disease or those on anticoagulants were excluded. The PT, aPTT and platelet count were not done. Recombinant tissue plasminogen activator was administered at a dosage of 0.9 mg/Kg. RESULTS: Thirty-five patients (65%) significantly improved on NIHSS at 48 h (> or =4 points) (mean change = 10; range= 4-17). At one month, 43 (79%) improved on Barthel Index (mean change = 45%). One each developed small frontal lobe hemorrhage and recurrent stroke; one died of aspiration; and eight showed no improvement. CONCLUSIONS: Hyperacute thrombolysis was found useful and safe in selected patients with AIS even without the coagulation studies.

Role of CSF serology in follow-up of subacute sclerosing panencephalitis patients on treatment.

Subacute sclerosing panencephalitis (SSPE) is a progressive inflammatory disease of the central nervous system with poor prognosis and high mortality. No effective treatment has a proven role; oral isoprinosine and intrathecal administration of alpha-interferon may prolong survival. We report an unusual case of adult onset SSPE patient on treatment with significant clinical improvement, even in the absence of conversion to seronegativity in either CSF or serum, on follow-up serological examination.

Widespread electromyographic abnormalities in patients with monomelic amyotrophy: a detailed EMG study.

OBJECTIVE: To evaluate subclinical electromyographic changes in unaffected muscles of the patients with monomelic amyotrophy (MMA). PATIENTS AND METHODS: 35 patients of MMA with single limb atrophy (30 patients with upper limb involvement and 5 patients with lower limb involvement) were studied at All India Institute of Medical Sciences, New Dellhi, from September 2000 to September 2002. All the patients were evaluated clinically, by detailed three limb electromyography (EMG) and by MRI scan of the spine to rule out other disorders. RESULTS: The mean age of 35 male patients was 24.17 (+/-6.8) years and the mean duration of illness was 3.64 (+/-2.7) years. Patients with upper limb involvement had segmental pattern of atrophy, predominantly distal or proximal. EMG revealed evidence of subclinical diffuse chronic reinnervative changes. All the patients (100%) had bilateral chronic reinnervative changes and 50% had chronic reinnervative changes in three limbs. CONCLUSIONS: Patients with clinically single limb MMA were found to have evidence of widespread chronic reinnervative changes on EMG.

Primary AL (kappa-light chain) amyloidosis manifesting as peripheral neuropathy in a young male without increase in serum and urine immunoglobulin load: a diagnostic challenge.

Primary systemic or AL amyloidosis is a multisystem disorder characterized by diffuse extracellular infiltration of a fibrillar protein of monoclonal light chain origin (AL). Majority of the patients have monoclonal immunoglobulin in serum and/or urine and some have clonal proliferation of plasma cells in their bone marrow. This disease has the widest spectrum of organ involvement, most commonly affecting the kidneys, heart and liver. Involvement of peripheral nervous system is not infrequent and may be the presenting feature of the disease process. Thus, recognition of peripheral neuropathy and affecting the kidney as an early symptom of AL amyloidosis may widen the scope for therapeutic intervention. We describe here a rare case of primary amyloidosis (AL) kappa-light chain presenting with clinical features of peripheral neuropathy and affecting the kidney and heart at an early age of 18 years, hitherto unreported in literature. The case was further interesting as it was not associated with increased serum/urine immunoglobulins or plasma cells in bone marrow. Diagnosis was confirmed using immuno-electron microscopy on sural nerve biopsy.

Quality of life in patients with Parkinson's disease.

We evaluated the quality of life (QoL) in 278 Indian patients with Parkinson's disease (PD) using PDQL questionnaire, with measures various aspects of health status in PD patients including parkinsonian symptoms, systemic symptoms, social and emotional functions. Apart from demographic and treatment details parkinsonian disability and stage was assessed by Hoehn and Yahr stage, Schwab and England scale and UPDRS scores. We conclude that female gender, presence of depression, low degree of independence, higher levodopa dose (>400 mg/day) and higher UPDRS activity of daily living score have the most detrimental impact on QoL in patients with Parkinson's disease. Depression was the most significant factor impairing the QoL and it needs to be treated.

Erythrocyte antioxidant enzymes in Parkinson's disease.

BACKGROUND & OBJECTIVES: Oxidative stress is incriminated to play a central role in the pathogenesis of Parkinson's disease (PD). Oxidative stress, to which neurons are highly susceptible, is also known to induce oxidative changes in human red blood cells (RBCs), in vivo and in vitro. Earlier studies on oxidative stress in RBCs in patients with PD have yielded controversial results claiming unaltered activity to reduced activity. Using RBC as a model, we have undertaken this study to ascertain the possibility of oxidative damage to the RBCs in PD by measuring the cytosolic antioxidant enzymes viz., superoxide dismutase (SOD), catalase (CAT) glutathione peroxidase (G-Px) and glucose-6-phosphate dehydrogenase (G6PD). METHODS: Activities of antioxidant enzymes were measured in erythrocytes of 115 PD patients and 37 normal age-matched healthy persons as controls. Enzymes activities were correlated with age of patients, age of onset of disease, duration of disease, United Parkinson's Disease Rating Scale (UPDRS) and Hoehn and Yahr stage. RESULTS: The SOD, CAT, G-Px and G6PD activities were significantly lower in patients with PD compared to the control. A significant (P<0.05) negative correlation of enzyme activities with Hoehn and Yahr stage of the disease and also with UPDRS score was found. INTERPRETATION & CONCLUSION: Results of the present study showed involvement of oxidative stress as one of the risk factors, which can initiate and/or promote neurodegeneration in PD and was correlated to the severity of the disease.

Quantitative thermal sensory testing in patients with monomelic amyotrophy.

BACKGROUND: Quantitative thermal sensory testing (QST) is a non-invasive method to assess somatic small fibre dysfunction, which is not evaluated with routine nerve conduction studies (NCS). Monomelic amyotrophy (MMA), is a pure motor disorder with no sensory abnormalities on routine NCS, and has not been evaluated using QST. AIMS AND OBJECTIVE: Present study aimed to evaluate somatic small fibre involvement in MMA patients. Forty patients with MMA with no sensory abnormalities or routine NCS were evaluated using QST for thresholds of cold sensation (CS), warm sensation (WS), cold pain (CP) and warm pain (WP), using method of limits. These were compared with 40 age-matched controls. RESULTS: No abnormalities in thresholds for CS, WS, CP and WP were found in MMA group as compared to controls. CONCLUSION: QST thus failed to demonstrate any abnormality. Hence we conclude that MMA is a pure motor disorder, with no involvement of somatic small sensory fibres (A delta and C).

Leigh's syndrome.

A 15-month-old female child presented with sudden onset cough and hyperventilation along with evidence of metabolic acidosis. She had past history of recurrent vomiting, episodes of abnormal posturing, difficulty in deglutition and regression of milestones since 12 months of age. CT scan of the brain revealed hypodense lesions in bilateral basal ganglia and on MRI there were T2 hyperintensities in bilateral lentiform nuclei, caudate nuclei, thalamus, red nuclei and dentate nuclei. Biochemical examination revealed persistently elevated serum lactate levels with high lactate/pyruvate ratio. Resuscitative measures were of no avail and the child succumbed to the illness on the second day of admission. Neuropathological examination at autopsy demonstrated marked spongiosis, focal necrosis, endothelial proliferation, reactive astrogliosis and extensive demyelination involving bilateral basal ganglia, midbrain and spinal cord which were typical of Leigh's sub acute necrotizing encephalomyelopathy.

Threshold intensity and central motor conduction time in patients with monomelic amyotrophy: a transcranial magnetic stimulation evaluation.

OBJECTIVE: To determine the Cortical threshold intensity (TI) and central motor conduction time (CMCT) in patients with monomelic amyotrophy (MMA). METHODS: TI and CMCT were evaluated by means of transcranial magnetic stimulation in 18 patients of MMA and 12 healthy controls at the clinical neurophysiology laboratory, department of neurology, All India Institute of Medical Sciences, New Delhi. RESULTS: The mean age of patients was 23.6 (SD 6. 7) years and of controls was 24.3 (SD 3.2) years (p > 0. 05). The mean TI in patients was 60.83% (SD 11.28) on ipsilateral and 60% (11.5%) on contralateral cortex stimulation. In controls, the mean TI was 66.67% (SD 11.5) on one side and 65% (11.87%) on contralateral cortex stimulation. There was no significant difference in the TI between these two groups (p > 0.05). The mean CMCT in patients was 8.3 (SD 1. 7) ms on ipsilateral and 9.4 (SD 1.6) ms on contralateral cortex stimulation (p > 0.05). In controls CMCT was 8.3 (SD 1.8) ms on one side and 8.6 (SD 1.4) ms on contralateral cortex stimulation. Upper limit of normal CMCT was 12.7 ms. CONCLUSIONS: As compared to controls there was no significant abnormality in TI and CMCT was normal in all except two patients where it was marginally prolonged. This could be because of excessive loss of anterior horn cells.

Increased depressant effect of phenytoin sodium as compared to carbamazepine on cortical excitability: a transcranial magnetic evaluation.

To evaluate the effect of monotherapy (phenytoin sodium (DPH) and carbamazepine (CBZ) on the threshold intensity (TI), cortical latency (CL), central conduction time (CCT), using transcranial magnetic stimulation (TMS). A single pulse transcranial magnetic stimulation was used for recording the motor-evoked potentials (MEP) from the thenar muscles of both hands, in 36 patients with well-controlled epilepsy on monotherapy, with normal EEG and imaging studies. The TI, CL, CCT and the MEP amplitude were recorded and compared with 20 healthy controls. The threshold intensity was significantly higher in patients on DPH, (P< 0.05) with a significant decrease in the MEP amplitude when compared with controls (P< 0.05). Anticonvulsants alter the excitability of human motor pathways in epileptic subjects. This effect differs among the drugs used; DPH had a greater depressant effect on the excitability than CBZ in the present study.