"Cock-walk" gait and "horseshoe moustache" sign on MRI in inherited hypermanganesemia.

Exogenous manganese (Mn) intoxication leads only to neurotoxicity, whereas inherited hypermanganesemia additionally can cause cirrhosis and polycythemia. We report two affected siblings in a family from South India with severe dysarthria, without dysphagia, generalized dystonia, and characteristic "cock-walk" gait which are clinical clues. Genetic study showed homozygous mutation in the first exon of solute carrier family 30 member 10 (SLC30A10) gene (c.134T>C) confirming the diagnosis of inherited hypermanganesaemia with dystonia 1 (HMNDYT1). Characteristic brain MRI finding is involvement of pontine tegmentum on T1 axial images (due to affliction of central tegmental tract [CTT]) with sparing of ventral pons giving rise to "horseshoe moustache" sign. Symmetric hyperintensities in dentate nucleus, globus pallidus, and putamen while relatively sparing caudate nucleus on T1 without signal intensity abnormalities on T2 images are highly suggestive of hypermanganesaemia. Axial diffusion tensor imaging confirmed the "horseshoe moustache" sign to be constituted by the affected CTT. Hypermanganesaemia-induced CTT involvement in T1 needs to be differentiated from the other more common pediatric causes of CTT affliction which are evident on T2 or diffusion weighted images. Identification is crucial as it is a treatable disorder of metal deposition amenable to chelation.

Electrochemical impedimetric immunosensor based on stabilized lipid bilayer-tethered WS2@MWCNT for the sensitive detection of carcinoembryonic antigen.

An innovative and ultrasensitive electrochemical impedimetric immunosensor was developed for the quantitative detection towards carcinoembryonic antigen (CEA). CEA is a widely utilized tumour biomarker that is generated in a wide variety of cancers and it is a frequently used biomarker for clinical research and early detection of cancer. Novelty of the present work is the utilization of biomimetic membrane comprising gold nanoparticle-stabilized lipid bilayer (SLB) containing DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine) and DOTAP (N-[1-(2,3-Dioleoyloxy)propyl]-N,N,N-trimethyl ammonium Propane) for easy protein insertion, bio-affinity, and bio-functionalization towards the detection of CEA. The SLB is tethered on stable tungsten disulfide decorated MWCNT (WS2@MWCNT) surface for the sensitive and selective detection of CEA. The WS2@MWCNT surface has been chosen to tether SLB due to its numerous unique characteristics such as greater surface area, high conductivity, and excellent electronic conductivity, which in turn leads to the improvement of the superior electrochemical sensing ability towards CEA. The lone SLB when used for protein insertion lacks space and impedes the functional incorporation of transmembrane proteins with hydrophilic domains on both sides and biosensing applications. The SLB-tethered WS2@MWCNT surface (SLB-WS2@MWCNT) was examined by studying the electrochemical changes in the existence of redox probe K3/K4 [Fe(CN)6] through cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). The combined excellent properties of WS2@MWCNT and SLB have shown to amplify the sensitive detection of CEA with a LOD value of 0.2 pg mL-1. The developed sensor provides higher stability, sensitivity, and excellent reproducibility towards the detection of CEA with relative standard deviation (RSD) of < 5%. The encouraging results demonstrate that the CEA impedimetric immunosensor has potential in practical analysis and lays a solid platform for additional biomarker detection in early clinical diagnosis.

Deep brain stimulation for movement disorders.

Deep Brain Stimulation (DBS) was introduced into clinical practice nearly four decades ago and is currently the standard of care for patients with Parkinson's disease experiencing motor complications. Apart from this, it has several other established and emerging applications in movement disorders. The exact mechanisms by which DBS provides relief in movement disorders are still unclear; disruption of pathological neuronal synchrony and abnormal information flow through the neuronal circuits involved, are the most likely underlying mechanisms. DBS has been established to be a relatively safe procedure if patients are carefully selected and followed up by experienced multidisciplinary teams. Alternatives to the traditional stereotactic frame based techniques of lead implantation are emerging, and these, along with the other recent technological advances, are likely to extend the availability of this therapy to an increasing number of patients in the future.

A hospital-based registry of Creutzfeldt-Jakob disease: Can neuroimaging serve as a surrogate biomarker?

AIM: This study addresses the role of neuroimaging in addition to the available clinical criteria for Creutzfeldt-Jakob disease (CJD) and its impact on its diagnosis in the absence of cerebrospinal fluid (CSF) biomarkers and tissue-based approaches. METHODS: From a tertiary referral center in the city of Trivandrum, Kerala, South India, patients with rapidly progressive dementia (RPD) who fulfilled the World Health Organization (WHO) 1998 diagnostic criteria for CJD were included in this study. Their electrophysiological-clinical-radiological data were retrospectively studied and the results were analyzed. The other biomarkers of CJD were not assessed in the study. RESULTS: Of the 96 patients with RPD, 41 patients were diagnosed as having a 'probable' and 'possible' CJD using the WHO 1998 diagnostic criteria between 2000 and 2013. While 92% patients satisfied the University of California, San Francisco (UCSF) 2007 and European magnetic resonance imaging (MRI)-CJD consortium criteria (2009), only 73% satisfied the MRI components of these criteria in addition to the more stringent, proposed UCSF MRI criteria (2011). The latter required the presence of diffusion weighted imaging abnormalities more than fluid attenuation inversion recovery abnormalities in the cortical and subcortical regions for the establishment of diagnosis on MRI of 'definite' (53.7%) and 'probable' CJD (19.5%). CONCLUSIONS: Significant heterogeneity exists in the presentation of CJD with only 48.8% patients simultaneously satisfying the MRI and electrophysiological criteria, suggesting that the diagnosis is impacted by these components in any of the currently prevalent criteria. With 27% of the cohort not meeting the radiological criteria, CSF and molecular biomarker assays may be reserved for MRI negative patients with suspected CJD and in atypical presentations.

Familial adult myoclonus epilepsy: a pragmatic approach.

Familial Adult Myoclonus Epilepsy (FAME), with a prevalence of < 1/35 000, is known under different acronyms. The disease is transmitted in an autosomal dominant manner and is characterized by the occurrence of cortical myoclonic tremor, overt myoclonus, and rare bilateral tonic-clonic seizures. FAME is considered neurodegenerative, although it is relatively slow in progression. Diagnosis is based on specific neurophysiological testing, namely jerk-locked back-averaging, somatosensory evoked potentials, long latency reflex, and motor evoked potentials, among others. Imaging data, including functional magnetic resonance imaging, indicate a cortical origin of the cortical myoclonic tremor and decreased cerebellar activation. Cerebellar changes in Purkinje cells have been noted, from few neuropathology reports, in patients from isolated pedigrees. The differential diagnosis includes essential tremor, some forms of genetic generalized epilepsy, and progressive myoclonus epilepsies. Treatment is mainly symptomatic.

Widening the clinical, radiological and genetic spectrum of autosomal recessive ataxia of Charlevoix-Saguenay in Indian patients.

BACKGROUND: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), classically presenting as a triad of early-onset cerebellar ataxia, lower extremity spasticity and peripheral neuropathy, is caused by mutations in SACS gene which encodes the protein sacsin. OBJECTIVE: To provide new insight into the occurrence of SACS mutations in South India. METHODS: Patients with three cardinal features of ARSACS-peripheral neuropathy, cerebellar ataxia, and pyramidal tract signs were included. Nine patients were clinically identified and genetically evaluated. Mutation screening of SACS by targeted sequencing of 40 recessive ataxia genes panel by next-generation sequencing was conducted. Additional investigations included magnetic resonance imaging (MRI), fundoscopy, optical coherence tomography (OCT) and nerve conduction studies (NCS). Functional disability was assessed by the Spinocerebellar Degeneration Functional Score. RESULTS: Two hundred and fifteen cerebellar ataxia patients were screened, and 9 patients with cerebellar ataxia with spasticity, peripheral neuropathy and MRI brain characteristics, consistent with a clinical diagnosis of ARSACS were identified, of which 7 patients were identified to have mutation in the SACS gene and are detailed hereafter. Age of presentation ranged from 20 to 55 years (29.8 ± 11.9) with a mean disease duration of 12.7 years (SD-7.65, range 5-22 years). All except one had onset of symptoms in the form of an ataxic gait noticed before 20 years of age. Additional features were subnormal intelligence (4/7), slow and hypometric saccades (1/7), seizures (1/7), kyphoscoliosis (1/7) and dysmorphic facies (1/7). SDFS was 3 in 5/7 patients signifying moderate disability with independent ambulation. MRI showed cerebellar atrophy with predominant atrophy of the superior vermis (7/7), horizontal linear T2 hypointensities in the pons(7/7), hyperintensities where lateral pons merges with the middle cerebellar peduncle (MCP) (7/7) well seen in fluid-attenuated inversion recovery (FLAIR) images, thickening of MCP (3/7), symmetric lateral thalamic hyperintensities (6/7), posterior fossa arachnoid cyst (4/7),thinning of posterior mid-body of corpus callosum (7/7), marginal mineralisation of the basal ganglia (7/7), bilateral parietal atrophy (7/7) and thinning of corticospinal tract on diffusion tensor imaging (DTI) (7/7). We identified pathogenic homozygous frameshift mutations in the SACS gene in six patients (including two siblings), while one patient had a heterozygous pathogenic deletion. CONCLUSIONS: This is the largest series of genetically confirmed ARSACS patients from India highlighting the clinical, ophthalmological, imaging and genetic features of this cohort.

Quantifying abnormal writing kinematics in writer's cramp using a novel software platform.

BACKGROUND: Writer's cramp is a task-specific focal hand dystonia, which is diagnosed clinically. Quantification of defect in WC is done using clinical scales, while digitized platforms are lacking. OBJECTIVE: To design and test a platform that can differentiate and quantify the abnormal kinematics of writing using a software interface and to validate it in adult-onset isolated writer's cramp (WC). METHODS: A native platform was designed using Java and Wacom Intuos pro tablet and the data analyzed using a MATLAB-based platform called Large Data-Based Evaluation of Kinematics in Handwriting (LEKH). We standardized this new platform by comparing the handwriting between patients with WC and age, and gender and education-matched healthy controls, using standard tasks to assess the kinematics. RESULTS: Comparison of the writing of right-handed WC patients (N = 21) and 39 healthy controls (N = 39) showed that patients differed from controls in the frequency of strokes (P < 0.001), number of inversions of velocity (P < 0.001), number of breaks (P = 0.02), air time and paper time (P < 0.001). CONCLUSIONS: Using the LEKH platform, the kinematic profile of patients with WC could be differentiated from healthy controls. Studies in larger samples will be needed to derive statistical models that can differentiate the flexion and extension types of WC which can help in muscle selection and to quantify the effects of treatment.

SIRT6 in Regulation of Mitochondrial Damage and Associated Cardiac Dysfunctions: A Possible Therapeutic Target for CVDs.

Cardiovascular diseases (CVDs) can be described as a global health emergency imploring possible prevention strategies. Although the pathogenesis of CVDs has been extensively studied, the role of mitochondrial dysfunction in CVD development has yet to be investigated. Diabetic cardiomyopathy, ischemic-reperfusion injury, and heart failure are some of the CVDs resulting from mitochondrial dysfunction Recent evidence from the research states that any dysfunction of mitochondria has an impact on metabolic alteration, eventually causes the death of a healthy cell and therefore, progressively directing to the predisposition of disease. Cardiovascular research investigating the targets that both protect and treat mitochondrial damage will help reduce the risk and increase the quality of life of patients suffering from various CVDs. One such target, i.e., nuclear sirtuin SIRT6 is strongly associated with cardiac function. However, the link between mitochondrial dysfunction and SIRT6 concerning cardiovascular pathologies remains poorly understood. Although the Role of SIRT6 in skeletal muscles and cardiomyocytes through mitochondrial regulation has been well understood, its specific role in mitochondrial maintenance in cardiomyocytes is poorly determined. The review aims to explore the domain-specific function of SIRT6 in cardiomyocytes and is an effort to know how SIRT6, mitochondria, and CVDs are related.

Oromandibular Dystonia - A Systematic Review.

Oromandibular dystonia (OMD) is a clinical problem which is commonly encountered in the practice of movement disorders. OMD results from a variety of genetic and acquired etiologies and can occur as an isolated manifestation, or as part of an isolated generalized or a combined dystonia syndrome. There are only very few systematic reviews on this condition which often causes significant disability. We review here the etiology, clinical features, diagnostic approach and management of OMD.

Cognitive outcome following bilateral subthalamic nucleus deep brain stimulation for Parkinson's disease-a comparative observational study in Indian patients.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves motor symptoms and motor complications of Parkinson's disease (PD). The intervention is expected to result in some cognitive changes, the nature of which is not uniform across the studies which have reported them. PD itself is associated with progressive cognitive decline and hence longitudinal follow-up studies with medically managed control group of patients are needed to explore the cognitive deficits attributable to DBS. METHODS: We conducted a prospective comparative observational study to assess the effects of bilateral STN DBS on cognition. Cognitive functions were assessed at baseline and after a minimum of two years after surgery, and compared with baseline and follow-up assessments in patients on medical management alone. RESULTS: Thirty-four patients with PD who underwent bilateral STN DBS and thirty-four medically managed patients participated in the study. At a mean follow-up of around 33 months, we found a significant decline in verbal fluency scores in the DBS group compared to those on medical management alone (1.15 ± 1.23 vs 0.59 ± 0.93, p = 0.034) and a trend for decline was noted in digit span test. There was no difference in the performance in tests addressing other cognitive domains, or tests of global cognitive function. No patient developed dementia. Motor functions and activities of daily living (ADL) were significantly better in the surgical group. CONCLUSION: STN DBS results in minor deficits in executive functions, particularly verbal fluency. These may be inconsequential, considering the marked improvement in motor functions and ADL.

Gender differences in progressive supranuclear palsy.

The gender differences in progressive supranuclear palsy (PSP) are not extensively studied. The objective of this study was to determine the gender differences in the phenotypic expression and progression in PSP. We did a retrospective review of medical records of patients diagnosed with PSP over a 21-year period. The interval between disease onset and attainment of the five clinical disability milestones namely wheel chair dependency, unintelligible speech, severe dysphagia, severe cognitive impairment and urinary catheterization was used to determine the progression. Data was analysed from the case records of 334 patients with PSP. 209 patients (62.2%) were male and 125 (37.4%) among the patients were women (male:female ratio = 1.6:1). Males had older age at onset with longer duration of illness at time of presentation. Tremors were more common, PSP-P phenotype was more frequent and time to attain wheelchair dependency was earlier in males. Falls within 1 year of disease onset, apathy and executive dysfunction were more frequent and time to attain unintelligible speech, severe dysphagia and cognitive impairment were earlier in females. This study in a large cohort of clinically diagnosed cases of PSP has showed that gender differences exist in PSP in terms of clinical characteristics, progression of the disease.

Calcific Miliary Brain Metastasis in Adenocarcinoma Lung Treated with Gefitinib.

Calcific miliary brain metastasis is an extremely rare form of brain secondaries. A 52-year-old man diagnosed with lung adenocarcinoma, on oncotherapy with gefitinib had a partial initial response to treatment. Later he was readmitted with seizures and cognitive dysfunction. His initial brain computed tomography (CT) and magnetic resonance imaging (MRI) were normal. However, his later CT images revealed multiple small calcified lesions over both hemispheres and contrast MRI revealed scattered tiny miliary nodules enhanced by gadolinium over bilateral cerebral, cerebellar hemispheres, thalami, and basal ganglia with foci of hypointensity in susceptibility-weighted images (SWI) and phase imaging suggesting calcification. A diagnosis of calcific miliary brain metastasis was made. Miliary calcification as an initial presentation of brain metastases in patients with lung cancer is uncommon. Use of oral tyrosine kinase inhibitor like gefitinib increases the likelihood development of calcific brain metastases due to the prolonged survival time contributed by its use.

Effect of Moringa oleifera leaf extract on exercise and dexamethasone-induced functional impairment in skeletal muscles.

BACKGROUND: Chronic administration of steroids like dexamethasone produces symptoms including weight loss and skeletal muscle dysfunction. Similar events are reported in chronic or high-intensity exercises, that can lead to fatigue and muscle damage. OBJECTIVE: In the present study, the effect of Moringa oleifera leaf extract was evaluated against dexamethasone (Dex) and exercise (Exe)-induced muscle changes in rats. MATERIALS AND METHODS: Six groups each containing 6 rats, namely normal, Dex control, Exe Control, Dex + M. oleifera leaf extract (300mg/kgp.o.), Dex + Exe, Dex + Exe + M. oleifera leaf extract were assessed in the study. Dex was administered at 0.6 mg/kg i.p. daily for 7 days. Exercise was given for a total of 10 days after 30 minutes of dosing using treadmill equipment for 900 seconds at speed 18 m/min. Animals were assessed for variation in body weight, muscular endurance using treadmill, locomotor activity using actophotometer, motor coordination using rotarod on day zero, and day seven. Hemidiaphragm of rats were isolated and used for evaluation of the glucose uptake. Gastrocnemius muscle was isolated and subjected to hematoxylin and eosin staining. RESULTS: Dex and Exe control animals showed a significant decrease in skeletal muscle activity when compared to normal control animals in the actophotometer test. Improvement in endurance were seen in Dex + M. oleifera leaf extract, and Dex + exercise + M. oleifera leaf extract groups compared to Dex control group. Improvement in locomotor activity was seen in Dex group subjected to exercise and was significant when treated with M. oleifera leaf extract. Histology reports were in accordance with the functional parameters. CONCLUSION: M. oleifera leaf extract supplemented with exercise showed a reversal in the dexamethasone-induced functional impairment in skeletal muscles.

Spectrum of medication-induced complications in the abdomen: role of cross-sectional imaging.

OBJECTIVE: This article provides a comprehensive review of the role of MDCT and MRI in the diagnosis of drug-induced complications in the abdomen and pelvis in adults. A systematic organ-based review of these complications is presented, including but not limited to hepatic changes after chemotherapy, renal complications such as tumor lysis syndrome and lithium nephropathy, gastrointestinal manifestations, various opportunistic infections and secondary neoplasms, mycotic aortic aneurysm from intravesical bacille Calmette-Guérin, complications of anticoagulant therapy, and oral contraceptives. CONCLUSION: Advancements in imaging have led to recognition of radiologic features of previously unsuspected diseases. Occasionally, imaging may also identify effects of treatments instituted for these diseases. Consequently, imaging plays a critical role in the accurate diagnosis of a broad spectrum of drug-induced complications in the abdomen, both in emergent and nonemergent settings. Knowledge of the natural history, clinical manifestations, and salient imaging features of these entities is crucial to facilitate accurate clinical diagnosis in a timely fashion.

"Emanating from Mastaba".

Just when the caterpillar thought it has been wound up into a mastaba, it became a butterfly.

Dopa-responsive dystonia, DRD-plus and DRD look-alike: a pragmatic review.

Dopa-responsive dystonia (DRD) and DRD plus are diseases of the dopamine pathway with sizeable genetic diversity and myriad presentations. DRD has onset in childhood or adolescence with focal dystonia, commonly affecting lower limb, diurnal fluctuations with evening worsening of symptoms and a demonstrable sleep benefit. DRD "plus" has "atypical features" which include infantile onset, psychomotor delay, cognitive abnormalities, oculogyric crisis, seizures, irritability, spasticity, hypotonia, ptosis, hyperthermia and cerebellar dysfunction. Neurodegeneration, however, is not a feature of either DRD or DRD-plus disorders. Tetrahydrobiopterin (BH4), a key cofactor, deficiency leads to inadequate dopamine and serotonin synthesis. Norepinephrine deficiency may coexist, depending on the enzyme defect. Hyperphenylalaninemia (HPA) is a clue for BH4 paucity. However, HPA is conspicuously absent in autosomal-dominant guanosine triphosphate cyclohydrolase 1 deficiency and sepiapterin reductase deficiency. DRD look-alike is a group of neurodegenerative disorders involving the nigrostriatal dopaminergic system, which could present with dystonia responsive to dopaminergic drugs or neurodegenerative or non-neurodegenerative disorders without involving the nigrostriatal dopaminergic system yet responsive to levodopa. Although levodopa is the mainstay of therapy, response to this drug can be unsatisfactory in DRD plus and DRD look-alike and other drugs are tried. Simultaneous management of HPA leads to remarkable improvement in both motor and cognitive functions. The aim of this review is to help neurology practitioners in treating patients with DRD, DRD-plus and DRD look-alike as many of them have excellent outcome with appropriate therapy.

Neurotuberculosis: an update.

Tuberculous (TB) meningitis (TBM), accounting for 70-80% of cases of neurotuberculosis, is one of the most severe forms of extrapulmonary tuberculosis. Two-thirds of new TB cases come from eight countries. Polymorphisms in toll-interleukin-1 receptor domain and in leukotriene A4 hydrolase (LTA4H) gene, affect the risk of inflammation in TBM. The common site of tuberculoma in children is cerebellum, and they may rarely develop tuberculous encephalopathy which has a high mortality. Young females with a high cerebrospinal fluid (CSF) protein have an increased predisposition to develop optochiasmatic arachnoiditis. Spinal TB meningitis may mimic transverse myelitis or Guillain-Barre syndrome. An extra-neural focus of TB should be sought clinically and radiologically as it may indicate safer and more accessible sites for diagnostic samplings. Cartridge-based nucleic acid amplification test (CBNAAT), also known as Genexpert test, is a polymerase chain reaction (PCR)-based method for detection of TB which also detects rifampicin resistance as it targets the rpob gene of mycobacteria. Line probe assays, based on PCR and reverse hybridization methods, identify mutations associated with drug resistance within a week. TBM being a paucibacillary disease, often evades a definite diagnosis and empirical treatment for a minimum of 9 months is warranted based on clinical judgement. All TBM patients should receive adjunctive corticosteroids, even those with HIV infection. Drug resistance is strongly associated with previous treatment and bedaquiline as well as delamanid have received approvals for multidrug resistant (MDR) TB. The key principle of managing MDR TB is never to add a single drug to a failing regimen. Correct combination and duration of most effective second line drugs in MDR TB require further modifications. Early shunting should be considered in those with hydrocephalus failing medical management. The single most important determinant of outcome is the stage of TBM at which treatment has been started.

Weekly methotrexate may reduce valproate levels causing relapse of genetic generalized epilepsy.

•Seizures have been observed in epilepsy patients receiving high dose intravenous or intrathecal Methotrexate (Mtx) therapy for the treatment of leukemias, due to reduction in valproic acid (VPA) levels.•Prolonged low dose weekly Mtx exposure can also produce reduction in VPA levels causing seizure relapse as reported in this case.•Mtx competes with VPA for binding to albumin as a result of which a larger proportion of VPA become unbound and is rapidly metabolized by the liver causing decline in VPA levels.•Awareness about pharmacological interactions of anti-epileptic drugs (AEDs) is essential in epilepsy management.

Myoclonus- A Review.

Myoclonus is a hyperkinetic movement disorder characterized by a sudden, brief, involuntary jerk. Positive myoclonus is caused by abrupt muscle contractions, while negative myoclonus by sudden cessation of ongoing muscular contractions. Myoclonus can be classified in various ways according to body distribution, relation to activity, neurophysiology, and etiology. The neurophysiological classification of myoclonus by means of electrophysiological tests is helpful in guiding the best therapeutic strategy. Given the diverse etiologies of myoclonus, a thorough history and detailed physical examination are key to the evaluation of myoclonus. These along with basic laboratory testing and neurophysiological studies help in narrowing down the clinical possibilities. Though symptomatic treatment is required in the majority of cases, treatment of the underlying etiology should be the primary aim whenever possible. Symptomatic treatment is often not satisfactory, and a combination of different drugs is often required to control the myoclonus. This review addresses the etiology, classification, clinical approach, and management of myoclonus.