The Effect of Dual Tasking and Deep Brain Stimulation Frequency Parameters on Gait in Advanced Parkinson's Disease.

OBJECTIVE: To study the effect of dual tasking and deep brain stimulation frequency parameters on gait in advanced Parkinson's disease. MATERIALS AND METHODS: This is an open label interventional study evaluating 40 post STN-DBS patients with gait disturbances. All patients were diagnosed as PD by a movement disorder specialist using the United Kingdom Parkinson's Disease Society Brain Bank (UKPDSBB) criteria. Patients underwent bilateral subthalamic deep brain stimulation by a qualified neurosurgeon. Patients were managed on a combination of dopamine replacement therapy as well as deep brain stimulation. Patients were assessed by stand walk sit (SWS) test for a 5 meter distance and FOG scoring during medication 'ON' state and device "ON" state, at four frequencies 180, 130, 90, 60 HZ and device "OFF" state. RESULTS: Out of 40 patients, 38 patients showed a significant improvement in gait at a single frequency (best response frequency) which is different for each patient. The mean FOG score showed significant improvement at all stimulation frequencies when compared to OFF stimulation (P < 0.05). The mean number of steps was 18.9 at best response frequency and 21.48 at 130 Hz (P < 0.0001). Number of freezing episodes also were significantly less with best frequency when compared to 130 Hz stimulation (0.28 and 0.65 respectively, (P < 0.0001). The mean FOG score was 6.45 at best frequency and 9.48 at 130 Hz (P < 0.0001). Mean Dual tasking score was 3.53 at best frequency and 5.15 at 130 Hz (P < 0.0002). CONCLUSION: Optimization of frequency setting for each patient can improve gait and that each patient may have a different optimal frequency.

Molecular and Histopathological Characterization of Patients Presenting with the Duchenne Muscular Dystrophy Phenotype in a Tertiary Care Center in Southern India.

OBJECTIVE: To study the histopathological characteristics and mutation spectrum of patients presenting with the Duchenne muscular dystrophy (DMD) phenotype. METHODS: This was a descriptive study conducted over a period of 8 years. Multiplex ligation-dependent probe amplification (MLPA) was done in patients presenting with the DMD phenotype. If MLPA was negative, patients were offered muscle biopsy for histopathological studies and/or next generation sequencing (NGS) based multigene panel testing for muscular dystrophies. RESULTS: Of the 510 patients included, mutation in the DMD gene was detected by MLPA in 372 (72.9%), of whom 342 (67.1%) had exonic deletions and 30 (5.9%) had exonic duplications. Exons 45-55 were most commonly involved in large deletions and exons 1-10 were the commonest exons involved in duplications. In the MLPA-negative cohort, 27 proceeded for muscle biopsy. NGS was done in 14 patients, 10 of whom had pathogenic mutations in the DMD gene, 3 were non dystrophinopathies and no pathogenic variant could be identified in one patient. CONCLUSIONS: For patients presenting with the DMD phenotype, MLPA of the DMD gene has a high diagnostic rate of about 73%, and non-dystrophinopathies may constitute a small but significant proportion.

Vasculitic Neuropathy: A Retrospective Analysis of Nerve Biopsies and Clinical Features from a Single Tertiary Care Center.

OBJECTIVE: Vasculitic neuropathy can be either restricted to the peripheral nerves or associated with systemic involvement of other organs. The objective of this study was to analyze the nerve biopsies reported as "vasculitic neuropathy" with clinical features. MATERIALS AND METHODS: All cases diagnosed with vasculitic neuropathy were retrospectively analyzed and categorized as systemic vasculitis and nonsystemic vasculitic neuropathy based on the clinical features. The histological features were further evaluated and classified according to the Peripheral Nerve Society Guidelines. RESULTS: Of the 126 cases, there were 65 nonsystemic vasculitis, 45 secondary systemic vasculitis, and 16 primary systemic vasculitis. Definite vasculitis was more common in the systemic vasculitis group. The epineurial vessels were predominantly involved with chronic axonal changes. CONCLUSION: The sensitivity of definite vasculitis on nerve biopsy was 54.76%. The sensitivity increases when the diagnostic criteria of definite and probable vasculitis were applied taking into account perivascular inflammation accompanied by vascular changes and axonopathy.

Predictors of Intracerebral Hemorrhage in Acute Stroke Patients Receiving Intravenous Recombinant Tissue Plasminogen Activator.

BACKGROUND: Symptomatic Intracerebral hemorrhage (sICH) is a serious complication of recombinant tissue-plasminogen activator (rt-PA) therapy for acute ischemic stroke (AIS). OBJECTIVE: To estimate the prevalence and predictors of sICH in patients after receiving IV rt-PA for AIS. MATERIAL AND METHODS: Consecutive patients of AIS thrombolysed between January 2010 and June 2016 in a University hospital in Hyderabad (India) were studied prospectively for sICH and it's various variables compared with the control group without sICH to determine any sigificantant difference. RESULTS: Out of 113 patients , sICH was detected in 12 (10.61%) whose mean age(58±12.0 years) and gender ratio ( 2:1 ) was not statistically significant from controls. In s ICH group mean NIHSS score was 16.53± 5.81 vs 10.19± 5.06 in controls (p<0.001), gap between stroke onset and thrombolysis was 227.50±46.15 min vs 178.50± 69.20 min in controls(p=0.018). At presentation mean blood sugar was 208.75±90.97 mg/dl in sICH group vs 146.83±70.21 mg/dl in controls (p=0.002). Prior diabetes was in 7(53.30%) vs 23 (22.8%) in controls (p= 0.014)and hypertension in 11 (91.7%) vs (56(55.4%) in controls (p= 0.026) The mortality in sICH was 7 (58.30%)vs 4 (4.94%) in controls (p<.0.001). At 3 months mean mRS ofsICH patients was 5.57± 0.54 vs 2.17± 1.69 in controls (p<.05). CONCLUSION: High NIHSS score, increased stroke onset to thrombolysis time , high blood sugar at presentation ,prior diabetes and hypertension increase the chances of sICH. None of these contraindicate thrombolysing strokes but should caution the physician.

Necrotizing Autoimmune Myopathy: Clinicopathologic Study from a Single Tertiary Care Centre.

BACKGROUND: Idiopathic inflammatory myopathies (IIMs) are a group of chronic, autoimmune disorders which include a new entity, necrotizing autoimmune myopathy (NAM). NAM lacks inflammation and presents with markedly elevated creatinine phosphokinase (CPK) levels. It is associated with connective tissue diseases (CTDs), statin use, malignancies, and most cases are idiopathic. OBJECTIVES: The objectives of this study are to describe the clinicopathologic features in muscle biopsy-proven cases of NAM. To emphasize the role of laboratory parameters such as CPK levels and myositis profile in the diagnosis of NAM. MATERIALS AND METHODS: This is a retrospective study including 15 patients of NAM diagnosed on muscle biopsy over a period of 2 years. The slides of the biopsies were reviewed, and clinical data, electromyography findings, and CPK levels were obtained. Myositis profile was done. RESULTS: Necrotizing myopathy accounted for 13.63% (15 cases) of total inflammatory myopathies (110 cases) in the study. These were grouped into CTD-associated NAM, statin-associated NAM, paraneoplastic NAM and idiopathic NAM which was the common type. All cases presented with progressive proximal muscle weakness and had markedly elevated CPK levels. Anti-3-hydroxy-3-methyl-glutaryl-coenzyme A reductase and antisignal recognition particle antibodies were seen to be positive in six patients. Muscle biopsies showed predominant fiber necrosis with significant fiber degeneration and regeneration in the absence of inflammation. All patients received immunotherapy with significant improvement was seen in six patients with two mortalities. CONCLUSION: Necrotizing myopathy is a new addition to the spectrum of IIM. Clinicopathologic correlation is important for appropriate diagnosis. It is found to be refractory to corticosteroids monotherapy. The course of illness is not uniform, and in some patients, there can be rapid worsening with mortality.

Detection of Dysferlin Gene Pathogenic Variants in the Indian Population in Patients Predicted to have a Dysferlinopathy Using a Blood-based Monocyte Assay and Clinical Algorithm: A Model for Accurate and Cost-effective Diagnosis.

BACKGROUND: Limb-girdle muscular dystrophy (LGMD) is the most common adult-onset class of muscular dystrophies in India, but a majority of suspected LGMDs in India remain unclassified to the genetic subtype level. The next-generation sequencing (NGS)-based approaches have allowed molecular characterization and subtype diagnosis in a majority of these patients in India. MATERIALS AND METHODS: (I) To select probable dysferlinopathy (LGMD2B) cases from other LGMD subtypes using two screening methods (i) to determine the status of dysferlin protein expression in blood (peripheral blood mononuclear cell) by monocyte assay (ii) using a predictive algorithm called automated LGMD diagnostic assistant (ALDA) to obtain possible LGMD subtypes based on clinical symptoms. (II) Identification of gene pathogenic variants by NGS for 34 genes associated with LGMD or LGMD like muscular dystrophies, in cases showing: absence of dysferlin protein by the monocyte assay and/or a typical dysferlinopathy phenotype, with medium to high predictive scores using the ALDA tool. RESULTS: Out of the 125 patients screened by NGS, 96 were confirmed with two dysferlin variants, of which 84 were homozygous. Single dysferlin pathogenic variants were seen in 4 patients, whereas 25 showed no variants in the dysferlin gene. CONCLUSION: In this study, 98.2% of patients with absence of the dysferlin protein showed one or more variants in the dysferlin gene and hence has a high predictive significance in diagnosing dysferlinopathies. However, collection of blood samples from all over India for protein analysis is expensive. Our analysis shows that the use of the "ALDA tool" could be a cost-effective alternative method. Identification of dysferlin pathogenic variants by NGS is the ultimate method for diagnosing dysferlinopathies though follow-up with the monocyte assay can be useful to understand the phenotype in relation to the dysferlin protein expression and also be a useful biomarker for future clinical trials.

Anticeramide antibody and butyrylcholinesterase in peripheral neuropathies.

Ceramide is a glycosphingolipid, a component of nerve and non neuronal cell membrane and plays a role in maintaining the integrity of neuronal tissue. Butyrylcholinesterase (BChE) is a multifunctional enzyme, its involvement in neurodegenerative diseases has been well established. Anticeramide antibody (Ab-Cer) and enzyme BChE have been implicated in peripheral neuropathies. The present study investigates whether there is an association between Ab-Cer and BChE activities and peripheral neuropathies. Patients included: human immunodeficiency virus associated peripheral neuropathy (HIV-PN, n=39), paucibacillary leprosy (PB-L, n=36), multibacillary leprosy (MB-L, n=52), diabetic neuropathy (DN, n=22), demyelinating sensory motor polyneuropathy (DSMN, n=13) and chronic inflammatory demyelinating polyneuropathy (CIDP, n=10). Plasma Ab-Cer was measured by indirect enzyme linked immune assay (ELISA) and BChE activity in plasma was measured by colorimetric method. Ab-Cer levels were significantly elevated in MB-L and DN as compared to healthy subjects (HS). BChE levels were significantly higher in MB-L and DN as well as in HIV and HIV-PN. There is no significant difference in either Ab-Cer or BChE levels in DSMN and CIDP. Elevated plasma Ab-Cer and BChE levels may be considered significant in the pathogenesis of neuropathies. The variation in concurrent involvement of both the molecules in the neuropathies of the study, suggest their unique involvement in neurodegenerative pathways.

A prospective study of diffusion weighted magnetic resonance imaging abnormalities in patients with cluster of seizures and status epilepticus.

OBJECTIVE: To study the frequency, imaging characteristics, and clinical predictors for development of periictal diffusion weighted MRI abnormalities. METHODS: We prospectively analyzed electro clinical and imaging characteristic of adult patients with cluster of seizures or status epilepticus between November 2013 and November 2015, in whom the diffusion weighted imaging was done within 24h after the end of last seizure (clinical or electrographic). RESULTS: There were thirty patients who fulfilled the inclusion and exclusion criteria. Twenty patients (66%) had periictal MRI abnormalities. Nine patients (34%) did not have any MRI abnormality. All the patients with PMA had abnormalities on diffusion weighted imaging (DWI). Hippocampal abnormalities were seen in nine (53%), perisylvian in two (11.7%), thalamic in five (30%), splenium involvement in two (11.7%) and cortical involvement (temporo-occipital, parieto-occipital, temporo-parietal, fronto-parietal and fronto-temporal) in sixteen (94.1%) patients. Complete reversal of DWI changes was noted in sixteen (80%) patients and four (20%) patients showed partial resolution of MRI abnormalities. Mean duration of seizures was significantly higher among patients with PMA (59.11+20.97h) compared to those without MRI changes (27.33+9.33h) (p<0.001). CONCLUSIONS: Diffusion abnormalities on MRI are common in patients with cluster of seizures and status epilepticus and were highly concordant with clinical semiology and EEG activity. Patients with longer duration of seizures/status were more likely to have PMA.

Association of tumor necrosis factor-alpha and interferon gamma gene polymorphisms and their plasma levels in leprosy, HIV and other peripheral neuropathies.

OBJECTIVE: Mycobacterium leprae and Human Immunodeficiency Virus (HIV) are causative agents known to be involved in nerve damage in leprosy and HIV-peripheral neuropathy (HIV-PN) respectively. Among other peripheral neuropathies the most common is diabetic neuropathy, which is metabolically induced. The proinflammatory cytokines TNF-α and IFN-γ have been implicated in the pathogenesis of peripheral neuropathy. The association between the plasma levels of these cytokines and their single nucleotide polymorphisms (SNPs) were investigated in leprosy neuropathy (LN), HIV-PN and other peripheral neuropathies (OPN). METHODS: Eighty-eight individuals with LN (PB=36; MB=52), 39 with HIV-PN, 52 patients with OPN, 101 HIV positive individuals without neuropathy (HIV) and 113 healthy subjects (HS) were included in the study. Plasma cytokine levels were measured by sandwich ELISA and one way ANOVA was carried out among the groups. SNPs of TNF-α- 308 G/A, -238 G/A and IFN-γ +874 T/A were investigated by amplification refractory mutation system polymerase chain reaction (ARMS-PCR). Their frequencies were compared between groups by Pearson's chi squared test. RESULTS: Plasma TNF-α and IFN-γ was significantly increased in LN (p<0.05), HIV-PN (p<0.05) and OPN (p<0.05) as compared to HS. A significant association was found between IFN-γ +874 A/A genotype in LN (p<0.05; OR=7.9), HIV-PN (p<0.05; OR=8.9) and OPN (p<0.05; OR=8.9) as compared to HS. CONCLUSION: Elevated levels of plasma TNF-α and IFN-γ and the association of IFN-γ +874 A/A genotype SNP in LN, HIV-PN and OPN suggests a common involvement of these cytokines in susceptibility/pathogenesis of peripheral neuropathy.

Pure neuritic leprosy: Resolving diagnostic issues in acid fast bacilli (AFB)-negative nerve biopsies: A single centre experience from South India.

BACKGROUND AND PURPOSE: Demonstration of lepra bacilli is essential for definite or unequivocal diagnosis of pure neuritic leprosy (PNL) on nerve biopsy. However, nerves always do not show bacilli owing to the changes of previous therapy or due to low bacillary load in tuberculoid forms. In absence of granuloma or lepra bacilli, other morphologic changes in endoneurium and perineurium can be of help in making a probable diagnosis of PNL and treating the patient with multidrug therapy. MATERIALS AND METHODS: Forty-six biopsies of PNL were retrospectively reviewed and histologic findings were compared with 25 biopsies of non leprosy neuropathies (NLN) including vasculitic neuropathy and chronic inflammatory demyelinating polyneuropathy (CIDP). The distribution of endoneurial infiltrate and fibrosis, perineurial thickening, and myelin abnormalities were compared between PNL and NLN biopsies and analyzed by Chi-square test. RESULTS: Out of 46 PNL casses, 24 (52.17 %) biopsies were negative for acid fast bacilli (AFB). In these cases, the features which favor a diagnosis of AFB-negative PNL were endoneurial infiltrate (51.1%), endoneurial fibrosis (54.2%), perineurial thickening (70.8%), and reduced number of myelinated nerve fibers (75%). INTERPRETATION AND CONCLUSION: Nerve biopsy is an efficient tool to diagnose PNL and differentiate it from other causes of NLN. In absence of AFB, the diagnosis of PNL is challenging. In this article, we have satisfactorily evaluated the various hisopthological features and found that endoneurial inflammation, dense fibrosis, and reduction in the number of myelinated nerve fibers are strong supportive indicators of PNL regardless of AFB positivity.

Guillain Barre syndrome as a manifestation of neurological melioidosis.

Neurological melioidosis is a very rare and very few cases have been reported from India. Presentation is an extremely varied and as this disease is associated with high mortality, high index of suspicion is needed to diagnose and treat. In this context, we report a patient presenting as Guillain Barre syndrome evaluated as melioidosis.

Spectrum of congenital myopathies: a single centre experience.

BACKGROUND: Congenital myopathies (CMs) are rare and they are clinically and genetically heterogeneous. Muscle biopsy is characterized by structural abnormality that is diagnostic. There are few studies from India. MATERIALS AND METHODS: This is a retrospective study of 12 years. The demographic data, clinical features and laboratory data of patients diagnosed as CMs on muscle biopsy were retrieved from medical records. The slides were reviewed for morphological and structural abnormalities using the following stains hematoxylin and eosin, modified Gomori trichrome, masson trichrome, periodic acid schiff, adenosine triphosphatase preincubated at pH 9.4, 4.6 and 4.3, nicotinamide adenine dinucleotide tetrazolium reductase, succinic dehydrogenase and cytochrome c oxidase. Immunohistochemistry was performed with dystrophin, sarcoglycans and desmin wherever necessary. RESULTS: There were 50 patients with CMs: Centronuclear myopathy (23), myotubular myopathy (3) and central core disease (CCD) (8), nemaline myopathy (5), congenital fiber type proportion (10) and desmin related myopathy with arrythmogenic right ventricular cardiomyopathy (ARVD) (1). Of the 50 patients, 30 (60%) presented in the first decade of life. Proximal muscle weakness and hypotonia were the common presenting features. Type 1 atrophy and predominance were seen in most cases on muscle biopsy. CCD had one patient with high creatine phosphokinase levels, biopsy in one patient showed both rods and cores, in the other limb girdle muscular dystrophy like picture and one biopsy showed uniform type 1 fibers. There was one desmin related myopathy with ARVD, who had cardiac transplantation and both skeletal and cardiac muscle showed characteristic rimmed vacuoles and inclusions positive for desmin. CONCLUSION: CMs are rare and the diagnosis can only be established on muscle biopsy. Defining the specific CMs helps the clinician in counseling the patient and family.

Cryptoccocal menigitis as a primary manifestation in a patient with intestinal lymphangictasia.

Opportunistic infections usually occur in patients with an immunocompromised state, and can be severe. Cryptoccocal meningitis is a fatal condition if left untreated, and is usually found in such patients. We report the case of an adult patient with cryptoccocal meningitis secondary to intestinal lymphangiectasia. A 30 year old female was admitted to our hospital for meningitis. Biochemical and radiological investigations were performed. A cerebrospinal fluid latex agglutination test showed positive cryptoccocal antigen. In addition, there were features of humoral and cell mediated immunity deficiency (lymphopenia, hypoalbuminemia, hypogammaglobulinemia), with a negative human immunodeficiency virus (HIV) test by enzyme linked immunosorbent assay and polymerase chain reaction. An upper gastroduodenoscopy was performed, which showed multiple lymphangiectasias, and a biopsy confirmed the diagnosis of primary intestinal lymphangiectasia (PIL). The patient was treated with intravenous amphotericin B and oral flucytosine, and the meningitis resolved. PIL should be suspected in patients with cryptoccocal meningitis, combined with humoral and cell mediated immunity with a negative HIV test. The management issues, in addition to antifungal therapy, include nutritional supplements for the protein losing enteropathy.

Risk factors, clinical profile, and long-term outcome of 428 patients of cerebral sinus venous thrombosis: insights from Nizam's Institute Venous Stroke Registry, Hyderabad (India).

BACKGROUND: With the widespread use of neuroimaging and hematological workup, many of the previously held concepts about cerebral sinus venous thrombosis (CSVT) are changing. OBJECTIVE: The objective of this study was to investigate the risk factors, clinical profile, and outcome of the fully investigated cases of CSVT from a major university referral hospital in South India. MATERIALS AND METHODS: Consecutive patients of CSVT confirmed by definite neuroimaging criteria and fully investigated for prothrombotic states, between June 2002 and September 2010, were prospectively studied in the Venous Stroke Registry of Nizam's Institute of Medical Sciences, Hyderabad, South India. RESULTS: Of the 428 patients, 230 (53.7%) were men and the mean age was 31.3 years (range 8-65 years). Seizures were noted in 126 (29.4%) patients, stroke like presentation was found in 122 (28.5%) patients, and benign intracranial hypertension like presentation was found in 78 (18.2%) patients. Common risk factors were anemia in 79 (18.4%), hyperhomocysteinemia in 78 (18.2%), alcoholism in 67 (15.6%), oral contraceptive pill intake in 49 (11.4%), postpartum state in 42 (9.8%), anticardiolipin antibodies in 31 (7.2%), and protein S deficiency in 53 (12.3%) patients. Good outcome at 90 days (modified Rankin Scale £ 2) was observed in 273 (71.2%) of 383 patients available for follow-up. In-house mortality was noted in 33 (7.7%) and recurrence in 22 (5.1%) patients. CONCLUSIONS: Compared to the previous studies, prevalence of CSVT was higher in men. Anemia, hyperhomocysteinemia, alcoholism, oral contraceptive use, and postpartum state were the most common risk factors. Overall prognosis was good, but a small percentage of patients died or showed recurrence.

Serious cardiac adverse events after decompressive craniectomy for malignant cerebral infarction.

BACKGROUND: There is a significant association between cardiac dysfunction and ischemic stroke. The serious cardiac adverse events (SCAEs) after decompressive craniectomy for malignant cerebral infarction from ischemic stroke were studied retrospectively. METHODS: Retrospective data were collected for preexisting cardiac risk factors, baseline clinical measures, and perioperative SCAEs including life-threatening arrhythmias, myocardial ischemia, cardiac failure, and cardiac arrest. The association between perioperative SCAEs and mortality was assessed using the χ(2) test. RESULTS: Data from 42 patients were analyzed. Mortality occurred in 19 (45.2%) patients. Eleven (57.9% of deaths) suffered mortality because of neurological causes, 7 patients (36.8% of mortality) because of cardiac causes, and 1 because of other causes. Mortality in patients who developed SCAEs was significantly higher than in those without SCAEs [75% mortality with SCAEs vs. 18.2% without SCAEs (P<0.0001)]. The odds ratio for mortality with SCAEs was 13.5 (3.1 to 59.5). There was a significant correlation between the number of SCAEs and mortality (Spearmans ρ=0.738 (P<0.0001). CONCLUSION: Serious cardiac events are common in the acute period after stroke and decompressive craniectomy, and are important contributors to mortality.