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.

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.

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.

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.

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.

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.

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).

Albendazole in single CT ring lesions in epilepsy.

Single, small, enhancing lesions that often resolve spontaneously are frequent findings on CTs of Indian patients with seizures. Based on ELISA and biopsy data, the majority of these lesions are probably cysticercosis. To determine if these patients should be treated with albendazole, we performed a double-blind, randomized, placebo-controlled study involving 75 patients with seizures and the appropriate CT abnormality without neurologic abnormality on examination. Patients were randomized to albendazole (15 mg/kg/d) and placebo for 1 week, and we obtained serial CTs at the end of 1 week, 1 month, and 3 months. All patients completed a 3-month follow-up and none had systemic evidence of tuberculosis or cysticercosis. The lesions varied in size from 3 mm to 2.1 cm, with an average size of 1.18 cm. Serum ELISA for cysticercosis was positive in 30 and CSF ELISA was positive in 20 of 45 patients. Forty patients received albendazole and 35 received placebo. At the end of 3 months, a total of 68 patients showed resolution. Thirty-five of 40 patients who received albendazole showed resolution, as opposed to 33 of 35 patients on placebo. We conclude that albendazole therapy was not beneficial.

Comparison between multiple sclerosis in India and the United States: a case-control study.

The prevalence of MS in India is low, and it is unclear whether the manifestations of the disease in India are similar to the United States. We carried out a case-control study to compare the disease in the two populations and used clinical, evoked potential, and MRI criteria to assess similarities and differences. Our results indicate that the rate of disease progression and frequency of involvement of the cerebral hemispheres, cerebellum, spinal cord, and brainstem were similar in the two populations. The visual system was more frequently involved in Indian patients. No Indian patient had a family history of MS; this suggests an environmental disease-triggering agent.

Excessive daytime sleepiness in Parkinson's disease as assessed by Epworth Sleepiness Scale (ESS).

OBJECTIVE: To assess daytime sleepiness in patients with Parkinson's disease (PD) using the Epworth Sleepiness Scale (ESS). MATERIAL AND METHODS: One hundred and forty-nine patients with PD (126 men, 23 women) and 115 age matched controls recruited from relatives of medical staff or spouses and other family members accompanying patients to the Movement Disorder Clinic of the All India Institute of Medical Sciences in New Delhi were included in the study. An ESS score of > or =8 was considered abnormal. Data obtained were analyzed using Chi square test for categorical variables and Student's t-test for continuous variables. RESULTS: The mean age of patients with PD was 58.37 (S.D.=10.45) years, and that of controls 56.50 (S.D.=11.45) years, with a mean duration of disease of 5.68 (S.D.=3.85) years. The mean ESS score was 4.9 (S.D.=3.63) and 2.17 (S.D.=2.54) in PD patients and controls, respectively (P<0.05). Thirty-two patients with PD (21%) had an ESS score of >8 whereas only 3% of controls scored > or =8 on the ESS (P<0.05). Higher ESS scores were associated with a higher Hoehn and Yahr (H&Y) stage of disease and higher Unified Parkinson's Disease Rating Scale (UPDRS) (part I, III and total) scores (P<0.019, P<0.013 and P<0.011, respectively). CONCLUSION: Excessive daytime sleepiness was more common in PD patients as compared to controls. Higher ESS scores correlated significantly with higher H&Y stage and higher UPDRS (part I, III and total) scores.

Eating epilepsy.

The term "reflex epilepsy" denotes epilepsies characterized by a specific mode of seizure precipitation. Seventeen patients in whom the act of eating precipitated seizures are described. Interictal EEG showed generalized seizure discharges in three and focal discharges in five patients. In four patients EEG was recorded during eating. In one of these, the frequency of seizure discharge increased, but none had a clinical seizure during the recording. Eating epilepsy is predominantly a disorder of young adults, and the triggering mechanisms are extremely complex and elaborate. The role of the limbic system and amygdala in the precipitation of eating-induced seizures is discussed.

Pregnancy and epilepsy.

In a prospective study, 30 pregnant epileptic patients were followed through their pregnancy to determine the effect of seizures on pregnancy and its outcome and the effect of pregnancy on seizures. An attempt was made to correlate the serum hormone and anticonvulsant drug levels with seizure frequency, complications of pregnancy, occurrence of status epilepticus and teratogenicity. In 14 patients seizure frequency increased, in 15 it remained unchanged and in 1 patient it decreased. There were 2 spontaneous abortions, 2 patients had status epilepticus and 1 offspring of a patient had a ventricular septal defect. This patient was receiving carbamazepine and diphenylhydantoin. Patients with increased seizures frequency had significantly higher oestrogen levels, lower level of progesterone and lower level of anticonvulsant drugs as compared with those with no change in seizures. Patients who had abortions and those who developed status epilepticus had high serum oestrogen levels.

The heart in polymyositis-dermatomyositis.

Fourteen patients with polymyositis-dermatomyositis (PM-DM) underwent prospective cardiac assessment with non-invasive techniques. One patient had electrocardiographic evidence of Long-Ganong-Levine syndrome with multiple supraventricular premature beats. Echocardiographically one patient had late systolic prolapse of the posterior mitral leaflet and another had paradoxical movements of the interventricular septum. The study suggests that cardiac involvement is infrequent in PM-DM.

Electrophysiological studies in patients with blepharospasm before and after botulinum toxin A therapy.

Botulinum toxin (BTX) is the treatment of choice for blepharospasm. To investigate if the locally injected BTX influences the central nervous system and in particular the brain stem, amplitude and latency of compound muscle action potential (CMAP) of orbicularis oculi, blink reflex and brain stem auditory evoked potential were studied in 12 blepharospasm patients before BTX therapy, 9 patients after BTX therapy and 9 age and sex matched healthy controls. The mean amplitude of orbicularis oculi in patients was significantly lower before BTX therapy (p < 0.05) and after BTX therapy (p < 0.02). The amplitudes of R1, R2 and contralateral R2 (CR) was higher in patients than controls but did not reach statistical significance. Following BTX therapy there was a reduction in amplitude of R1, R2 and CR (p < 0.001) and prolongation of latency of R2 and CR (p < 0.05). The ratio of blink reflex amplitude/CMAP amplitude of orbicularis oculi showed a significant decline after BTX therapy (p < 0.01). This small study suggests the involvement of brain stem pathways following BTX therapy in patients with blepharospasm.

Motor fluctuations in Parkinson's disease.

OBJECTIVES: To assess patterns, prevalence, and risk factors of motor fluctuations in an unselected population of Parkinson's disease patients attending Movement Disorders Clinic of a tertiary hospital. MATERIAL AND METHODS: Eighty patients with Parkinson's disease were interviewed and data about their clinical characteristics, motor fluctuations, i.e. dyskinesia, dystonia, motor blocks and details of drug therapy, were collected. RESULTS: Forty patients had at least one type of motor fluctuation. Twenty three patients had motor blocks, 20 had dyskinesia and 11 had dystonia. Interval between onset of symptom and start of levodopa therapy and duration of levodopa therapy correlated with presence of motor fluctuations in general and to dyskinesia in particular. Patients with dyskinesia had younger age of onset of disease. Motor blocks showed a positive relationship to duration of disease. CONCLUSIONS: Fifty percent of unselected patients of Parkinson's disease had motor fluctuations after a mean duration of 5 years of illness. Early initiation and longer duration of levodopa therapy were identified as risk factors for motor fluctuations. Younger patients had more risk of developing dyskinesias. Motor blocks were more common in patients with a longer duration of illness.

Risk factors of Parkinson's disease in Indian patients.

Epidemiological data on risk factors of Parkinson's disease (PD) are not available from India. In a case control study, we investigated environmental and genetic risk factors in the etiology of idiopathic Parkinson's disease. Three hundred seventy-seven patients of Parkinson disease (301 men, 76 women, mean+/-SD age 56.78+/-11.08 years) and equal number of age matched (+/-3 years) neurological controls (271 men, 106 women, mean+/-SD age 56.62+/-11.17 years) were included in the study. Conditional logistic regression model was used to determine the risk factors of PD. We found that male gender, family history of Parkinson's disease, past history of depression of up to 10-year duration and well water drinking of more than 10-year duration were significantly associated with occurrence of Parkinson's disease, whereas tobacco smoking of up to 20-year duration and exposure to pets had protective effect. However, tobacco smoking of more than 20-year duration, well water drinking of up to 10-year duration, vegetarian dietary habit, occupation involving physical exertion, rural living, farming, exposure to insecticides, herbicides, rodenticides, alcohol intake and family history of neurodegenerative diseases had no significant correlation with occurrence of PD in the patient population studied. Results of our study support the hypothesis of multifactorial etiology of PD with environmental factors acting on a genetically susceptible host.

Peripheral silent periods in essential tremor.

BACKGROUND: Pathophysiology of essential tremor (ET) is controversial. In the present study, peripherally induced silent period (SP) in ET patients is studied. AIMS AND OBJECTIVES: To study if the peripherally induced SP was different in ET patients as compared to age matched healthy controls. MATERIAL AND METHODS: 24 patients of ET diagnosed according to diagnostic criteria of Louis et al. [Neurology 50 (1998) 1351] (mean age 45.37+/-14.86 years) and an equal number of healthy controls (mean age 36.21+/-15.72 years) were recruited for the study. Peripherally induced SP was recorded according to the methods already described. Student's t-test and Wilcoxon sign rank test were used for statistical analysis. RESULTS: The peripheral SP was 50.29+/-50.15 and 93.04+/-35.93 ms (p=0.0014) in ET patients and controls respectively. CONCLUSION: Our study shows that peripheral silent period is shorter in patients of ET as compared to normal individuals.