Role of vascular endothelial growth factor in tuberculous meningitis: A prospective study from a tertiary care center in North India.

INTRODUCTION: The status of vascular endothelial-derived growth factor (VEGF) in the pathogenesis of tuberculous meningitis (TBM) remains far from clear. We prospectively evaluated the role of serum and cerebrospinal fluid (CSF) VEGF in TBM. PATIENTS AND METHODS: This prospective study was conducted at a tertiary care center in North India from January 2018 to June 2019. Consecutive drug-naive patients (n = 82) of TBM diagnosed on the basis of modified Ahuja's criteria were included in the study. The results were compared with 49 control subjects (n = 49). Serum and CSF VEGF were done in all the cases and controls. Follow-up serum VEGF levels were done in 34 patients after 3 months of completion of antitubercular therapy. The VEGF levels were estimated using the human VEGF enzyme-linked immunosorbent assay kit. RESULTS: The mean age was 29.9 ± 13.1 years. The study group consisted of 33 (40.2%) men and 49 (59.8%) women. BACTEC MGIT960 was positive in 15 (18%) patients while multiplex tuberculosis polymerase chain reaction was positive in 73 (89%) patients. Levels of VEGF in serum and CSF of TBM patients were not elevated when compared to controls. There was no association between final outcome in TBM and decrease in serum levels of VEGF at follow-up. CONCLUSION: VEGF may not be playing a significant role in the pathogenesis of TBM. Future studies with larger sample size may clarify the status of VEGF further in TBM.

Effectiveness of therapeutic plasma exchange in case of rare neurological disorder Isaacs syndrome.

Isaacs syndrome is a disease characterized by nerve hyperexcitability and pseudomyotonia and treated with immunomodulatory and symptomatic therapy approaches. Here, we report a case of anti-(leucine-rich glioma-inactivated 1) antibody-positive patient diagnosed as Isaacs syndrome and accomplished a nearly complete response to only four sessions of therapeutic plasma exchange (TPE). Our experience suggests that TPE along with other immunomodulatory agents may be beneficial and well-tolerated approach in patient with Isaacs syndrome.

Exposure to Toxocara Canis is not Associated with New-Onset Epilepsy.

Purpose: The association between exposure to Toxocara canis and epilepsy is at the best contentious. Most of previous studies were retrospective, community-based, and contradictory to one another. As the impact of a positive association on the magnitude of epilepsy will be huge especially in developing countries where toxocariasis is common owing to poor hygienic practices, this study was carried out to determine whether exposure to T. canis predisposes to development of epilepsy. Patients and Methods: This case-controlled observational study was carried out a tertiary healthcare center in North India on 120 patients with newly diagnosed epilepsy who presented within 3 months of diagnosis. A total of 120 age- and sex-matched individuals from the same community were chosen as controls. Epilepsy was defined according to ILAE 1993 definition. Serological testing for T. canis was carried out using commercially available ELISA kits. All the positive samples were subjected to Western blot testing for confirmation. Results: The prevalence of antibodies to T. canis was similar in cases (16/120; 13.3%) and controls (16/120; 13.3%). Among the various risk factors, history of pica was significantly associated with T. canis seropositivity, while lack of hand washing was significantly associated with higher risk of epilepsy. Conclusion: Our study could not find any association between exposure to T. canis and epilepsy.

Assessment of Blood-Brain Barrier Integrity in Tuberculous Meningitis Using Dynamic Contrast-Enhanced MR Perfusion.

Objective Tuberculous meningitis (TBM) is the most common form of central nervous system tuberculosis. The aim of the study was to quantitatively evaluate blood-brain barrier (BBB) perfusion changes in TBM patients using dynamic contrast-enhanced (DCE) MR perfusion. Methods and Material Thirty untreated patients of TBM and 10 healthy controls were prospectively evaluated by conventional imaging and DCE MR perfusion. Mean permeability indices- K trans and Ve-were calculated from multiple regions of interest (ROIs) placed in basal cisterns and comparison was done between the patients and controls. Results The permeability indices were significantly higher (where p < 0.001) in cisterns of TBM patients who showed basal meningeal enhancement when compared with healthy controls. Significant differences in permeability were observed between "enhancing" cases and controls as well as in "enhancing" cases when compared with the "non-enhancing" cases. However, no significant difference was observed in the mean cisternal value between "non-enhancing" cases and the controls. K trans with a cutoff value of > 0.0838 had 81.6% sensitivity and 78.6% specificity in differentiating cases and controls while V e mean value with a cutoff value of 0.0703 showed 86.8% sensitivity and 91.4% specificity in predicting the permeability difference between the cases and controls. Conclusion DCE MR perfusion is useful in the quantitative measurement of disruption of BBB and perfusion alterations in patients of TBM.

MR vessel wall imaging in tubercular meningitis.

PURPOSE: Tubercular meningitis (TBM) has the propensity to cause secondary vasculitis through various mechanisms leading to development of cerebrovascular complications. These vascular involvements can be detected by vessel wall imaging (VWI). In this study, we aimed to study detailed findings of vessel wall imaging in cases of tubercular meningitis. METHODS: All consecutive patients of suspected tubercular meningitis in whom diagnosis of TBM could be made according to diagnostic criteria given by Ahuja et al. were included in the study. High-resolution MR VWI and time of flight (TOF) magnetic resonance angiography (MRA) were done along with routine MRI sequences. Arteries up to second-order branches were studied, and statistical analyses were done with respect to stage of tubercular meningitis, infarctions and TOF MRA findings. RESULTS: Out of all 101 cases of TBM, infarctions were found in 49 cases (48.5%), and vessel wall enhancement was seen in 67 cases (66.3%). With increasing severity of disease, more severe vascular involvement was seen on VWI. There was significant association between enhancement of individual arteries and infarctions in their territories. VWI had better sensitivity than the MRA, while MRA had better specificity than VWI for detection of vascular complications. CONCLUSION: Tubercular vasculitis can be detected by VWI in the form of nodular or smooth segmental enhancement of vessel wall with or without stenosis. Incorporation of VWI in routine MR imaging can play a greater role in early detection and management of cerebrovascular complications which can help to improve prognosis of the disease.

Evaluation of Plasma Amyloid Peptides Aß1-40 and Aß1-42 as Diagnostic Biomarker of Alzheimer's Disease, its Association with Different Grades of Clinical Severity and 18F-Fluorodeoxyglucose Positron Emission Tomography Z score in the Indian Population: A Case-Control Study.

BACKGROUND: We estimated plasma amyloid-peptides levels (Aß1-42 and Aß1-40) as diagnostic biomarker of Alzheimer's disease (AD) and evaluated its association with clinical severity and 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) Z score of the different brain regions in the Indian population. PATIENTS AND METHODS: A case-control study was conducted. Diagnostic and statistical manual-IV, Dubois, and NIA-AA criteria were used for the diagnosis of AD. The plasma Aß1-42 and Aß1-40 concentration and 18F-FDG PET Z score were estimated for different brain regions. RESULTS: Forty-seven cognitive impairment patients (AD = 29, mild cognitive impairment = 18) and 33 age-matched controls were enrolled. Plasma Aß1-42 level was significantly higher in the AD group compared to controls (P = 0.046) and a cut-off >5.7 ng/mL has a specificity of 96.9%, sensitivity of 27.6%, positive predictive value 88.9%, and negative predictive value 60.4% for differentiating AD patients from controls. Significant correlation was seen between Aß1-40/Aß1-42 ratio and 18F-FDG PET Z score in the bilateral-parietal, temporal, frontal-association area, and posterior-cingulate areas. CONCLUSION: As a diagnostic biomarker of AD, plasma Aß1-42 level showed good specificity but low sensitivity in the Indian population.

Presence of allele CYP3A4*16 does not have any bearing on carbamazepine-induced adverse drug reactions in North Indian people with epilepsy.

OBJECTIVES: The objectives of this study were to determine the relationship between genetic polymorphisms in gene encodings for CYP3A4 and carbamazepine (CBZ)-induced dose-related side effects in North Indian people with epilepsy. PATIENTS AND METHODS: The current prospective study included 37 patients with CBZ-induced dose-related side effects and 102 patients who did not experience side effects while on CBZ. The genotyping for CYP3A4 allele (CYP3A4*16) was done using real-time polymerase chain reaction (RT-PCR) in Applied Biosystems 7500 RT-PCR System (USA). CBZ was administered in all patients at a dose varying from 15 to 20 mg/kg daily. RESULTS: Various demographic variables were comparable between the groups except that control of seizures was far better in controls. After testing, it was found that none of our patients had the presence of CYP3A4*16 allele. CONCLUSION: CYP3A4*16 allele is not represented significantly in North Indian people with CBZ-induced dose-related side effects.

Non-Arteritic Anterior Ischaemic Optic Neuropathy - Myths and Misconceptions: Experience from a Tertiary Care Centre in North India.

We prospectively evaluated 22 consecutive patients (24 eyes) suffering from non-arteritic anterior ischaemic optic neuropathy (NAION) at a tertiary care centre in Northern India. The mean age was 51.7 years. Visual loss on awakening was noticed only in three (12.5%) eyes. Six (27.3%) patients had headache while three (9.7%) patients had retro-orbital pain at the onset of visual loss. Peripapillary haemorrhages were seen in two (8.3%) eyes. At follow up, only one eye showed improvement in visual acuity. The results of our study suggest that NAION may not always present with the classic clinical picture. Accordingly, a high index of suspicion remains the key to correct diagnosis.

Pattern Recognition Approach to Brain MRI Findings in Patients with Dengue Fever with Neurological Complications.

BACKGROUND AND PURPOSE: Dengue can present with variable neurological complications including encephalitis, encephalopathy, acute disseminated encephalomyelitis (ADEM), and ischemic and hemorrhagic stroke. Our study describes a pattern-based approach to recognize different brain MRI findings in dengue-seropositive patients with neurological symptoms. MATERIALS AND METHODS: Thirty-six serologically proven dengue patients with neurological symptoms and undergoing brain MRI over a 6-month period were included in this study. The diagnosis of dengue encephalopathy or encephalitis was established by presence of signs/symptoms of acute encephalitic syndrome with the presence of Immunoglobin M (IgM) antibody against dengue antibody in the serum and/or presence of dengue antigen (NS1) in serum. The MRI brain along with diffusion weighted imaging and susceptibility weighted imaging sequences were evaluated by an experienced neuroradiologist. RESULTS: Eleven patients had normal MRI finding. In the rest 25 patients, 12 were found to have encephalitic pattern, 4 had encephalopathic (seizure related/metabolic) pattern, 3 had features of ADEM, and isolated micro- or macro-hemorrhages were found in 6 patients. In the encephalitis group, eight had concomitant involvement of brainstem, cerebellum, and ganglio-thalamic complexes with additional involvement of cortex and subcortical white matter (WM) found in three. Isolated brainstem and cerebellar involvement were seen in three in this group, whereas one had isolated cerebellar involvement. Interspersed hemorrhage was noted in the structures involved in eight patients in encephalitis group. CONCLUSION: Radiologists should be aware of various MRI brain findings in dengue and a pattern recognition approach often helps in reaching the correct diagnosis albeit after exclusion of other differentials based on laboratory studies.

Atypical neurological manifestations of dengue fever: a case series and mini review.

BACKGROUND: In this mini review, we discuss some of the atypical neurological manifestations of dengue virus and attempt to bring them to attention to highlight the neurotropic property of the dengue virus. METHODS: Cases were chosen from retrospective hospital and outpatient records of all patients seropositive for dengue who attended the neurology referral. Seven patients have been chosen as illustrative examples of dengue-associated neurological involvement. We discuss the various central and peripheral nervous system involvement of patients and discuss the relevant findings in them. CONCLUSION: Through this case series, we wish to highlight that the dengue virus can affect the nervous system at various targets, using multiple mechanisms of pathogenesis to generate a plethora of presentations. Hence, it is vital to be aware of its presentations to be able to diagnose dengue and treat it accordingly.

Identification of Taenia solium DNA by PCR in blood and urine samples from a tertiary care center in North India.

BACKGROUND: NCC is a neglected zoonotic disease with high endemicity and disease burden. Neurocysticercosis is a frequent cause of seizures in endemic countries. Early diagnosis and therapy helps in reducing morbidity and DALYs (daily adjusted life years) lost. Definite diagnosis still relies on neuroimaging identification of scolex or by histopathological examination. Molecular method such as PCR (Polymerase Chain Reaction) is an emerging modality to supplement or complement these Gold standard methods. AIM: To determine the utility of PCR in detecting Taenia Solium DNA in NCC patients. METHODS: A total of 100 blood samples of cases of NCC and 50 control blood samples, 58 urine samples of NCC cases and 24 control samples were collected. Repetitive element PTsol9 of the Taenia Solium was targeted. RESULTS: The sensitivity and specificity of PCR in blood samples was 57% and 94%, while sensitivity and specificity in urine samples was 64% and 87%. CONCLUSION: PCR assay can be used as an adjunct for the diagnosis of NCC especially in ambiguous cases, this is relatively rapid and non-invasive diagnostic modality.

Use of rituximab in muscle-specific tyrosine kinase antibody-positive myasthenia gravis: Preliminary observations from a tertiary care center in Northern India.

OBJECTIVES: Approximately 10%-15% of patients with myasthenia gravis (MG) are refractory to standard treatment. A sizable chunk of these patients is due to muscle-specific tyrosine kinase (MuSK) antibody-positive MG which often runs a severe course with frequent relapses and poor response to conventional treatment. We report six patients with refractory MuSK-positive MG who responded well to the treatment with rituximab. PATIENTS AND METHODS: In this prospective institute-based observational study, we report six MuSK antibody-positive MG patients, who did not achieve remission with standard treatment and were later started on rituximab infusion. RESULTS: There was a significant clinical improvement in all patients after starting rituximab. CONCLUSION: Rituximab is an effective immunomodulatory therapy in MuSK antibody-positive MG patients who are not responding to the standard treatment.

Clinical, Etiological and Imaging Profile of Posterior Reversible Encephalopathy Syndrome: A Prospective and Follow-Up Study.

BACKGROUND: Although first described more than two decades ago, posterior reversible encephalopathy syndrome (PRES) continues to be enigmatic. We prospectively followed consecutive patients of PRES both clinically and radiologically for a better understanding of natural history, symptomatology, and prognosis of this not so uncommon entity. PATIENTS AND METHODS: The current study included 22 consecutive patients of PRES who were followed both clinically as well as radiologically at a tertiary care institute in Northern India from December 2014 to June 2016. RESULTS: Mean age was 30.68 ± 12.68 years. The most common symptoms included altered sensorium (77.3%), headache (72.7%), seizures (63.6%), vomiting (36.4%), and visual disturbances (22.7%). About 94.5% of patients had parieto-occipital signal changes on neuroimaging. Magnetic resonance imaging (MRI) (n = 20) revealed involvement of sites considered atypical for PRES in 95% (frontal [55%], temporal [40%], cerebellum [40%], basal ganglia [15%], deep white matter [10%] and brainstem [10%]). Diffusion restriction, haemorrhage, and contrast enhancement were seen in 30%, 22.2%, and 25% of patients. At 3 months follow-up, modified Rankin scale was 0 in 19 patients and 1 in 1 patient. Two (9.1%) patients died. Eight (36.4%) patients had eclampsia, 5 (22.7%) each had chronic kidney disease and essential hypertension whereas 2 (9.1%) each had immune-mediated disorders and drug-induced PRES. None of the clinical or imaging features predicted outcome in PRES. CONCLUSION: Atypical MRI presentations of PRES are common, and there is a need to keep a strong index of suspicion for the diagnosis of PRES. The prognosis of PRES is good, and most cases show excellent recovery, particularly if underlying etiology can be treated satisfactorily.

Pre-clinical to Clinical Translational Failures and Current Status of Clinical Trials in Stroke Therapy: A Brief Review.

In stroke (cerebral ischemia), despite continuous efforts both at the experimental and clinical level, the only approved pharmacological treatment has been restricted to tissue plasminogen activator (tPA). Stroke is the leading cause of functional disability and mortality throughout worldwide. Its pathophysiology starts with energy pump failure, followed by complex signaling cascade that ultimately ends in neuronal cell death. Ischemic cascade involves excessive glutamate release followed by raised intracellular sodium and calcium influx along with free radicals' generation, activation of inflammatory cytokines, NO synthases, lipases, endonucleases and other apoptotic pathways leading to cell edema and death. At the pre-clinical stage, several agents have been tried and proven as an effective neuroprotectant in animal models of ischemia. However, these agents failed to show convincing results in terms of efficacy and safety when the trials were conducted in humans following stroke. This article highlights the various agents which have been tried in the past but failed to translate into stroke therapy along with key points that are responsible for the lagging of experimental success to translational failure in stroke treatment.

Sorting out difficulties in immunological diagnosis of neurocysticercosis: Development and assessment of real time loop mediated isothermal amplification of cysticercal DNA in blood.

PURPOSE OF THE STUDY: Among various immunological tests available for diagnosis of neurocysticercosis (NCC), only EITB (Electroimmunotransfer blot for detection of anticysticercal antibodies) had gained widespread acceptance. However EITB is not available widely and is costly (Indian rupees 15,000/- approximately). We evaluated utility of Loop mediated isothermal amplification (LAMP) assay for detection of Taenia solium cox1 gene in blood of patients with NCC. PATIENTS AND METHODS: Current study included 100 consecutive patients of NCC at a tertiary teaching hospital in Northern India. All the patients underwent detailed history and examinations as well as gadolinium enhanced magnetic resonance imaging of brain. LAMP assay was performed in all the patients. The results were compared with 50 controls. RESULTS: LAMP detected Taenia Solium cox1 gene in 74% of all blood samples in patients of NCC.T he overall sensitivity of LAMP assay for detection of cox1 gene was 74% in all patients with NCC, 71.8% in patients with intraparenchymal brain cysts only and 86.7% of patients with extraparenchymal brain cysts with or without intraparenchymal brain cysts. The overall specificity of LAMP assay was 90% in all these three subgroups. The positive predictive value of real time LAMP assay was close to 93% for almost all forms of NCC- both solitary and multiple while negative predictive value ranged from 57 to 64%. CONCLUSION: Real time LAMP assay of blood for detection of Taenia solium cox1 gene appears to be a promising toll for diagnosis of NCC.

Tuberculous meningitis: Challenges in diagnosis and management: Lessons learnt from Prof. Dastur's article published in 1970.

It has been approximately five decades since Dastur et al., published their seminal work on pathology of tuberculous meningitis (TBM). Though most of their findings find relevance in today's era, there is an important difference; these findings can now be replicated during life using modern day technology. In this article, we review the seminal words of Professor Dastur and colleagues, analyse their findings, interpret how these revolutionized our understanding of TBM and highlight their relevance in today's era. We also discuss challenges in the management of TBM, which we continue to face today and the various options required to overcome these challenges.

Prevalence of Epilepsy and its Association with Exposure to Toxocara canis: A Community Based, Case-control Study from Rural Northern India.

OBJECTIVES: Many community-based and hospital-based studies across the world have yielded contradictory results regarding association of positive Toxocara canis serology and epilepsy. The present study was planned to analyze disease burden of epilepsy in rural community of North India and its association with exposure to T. canis in this part of the world. METHODS: A door-to-door screening survey was carried out in the rural community using a validated questionnaire for epilepsy by trained field workers, which was finally confirmed by trained neurologists. The risk factors for epilepsy and for predisposing infections were also enquired. The results were compared with an equal number of age- and sex-matched healthy controls enrolled from the same community. Serologic evaluation was carried out to detect antibodies against T. canis. RESULTS: A total of 41,973 persons from the rural community in 49 villages were enrolled in the study. Two hundred and eleven persons were confirmed to be suffering from active epilepsy, resulting in a crude prevalence of 5 per 1000 population. More than 50% of people with epilepsy were in the second or third decade of life. The prevalence of antibodies to T. canis was similar in people with epilepsy (13.7%; 29 of 211 individuals) and controls (9.95%; 21 of 211 individuals). Of the 151 persons with epilepsy, who underwent CT scan, 34 people (22.3%) had evidence of inflammatory granuloma, thereby confirming high incidence of this infestation in rural Northern India. SIGNIFICANCE: Our study does not support the association between epilepsy and exposure to T. canis in rural Northern Indian population.

Hypothalamic and pituitary dysfunction is common in tubercular meningitis: A prospective study from a tertiary care center in Northern India.

INTRODUCTION: Current literature is poor with respect to well conducted prospective studies of hypothalamic pituitary axis (HPA) dysfunction in tubercular meningitis (TBM). As hormonal deficiencies are associated with poor clinical outcome in various neurological and non-neurological disorders, we prospectively evaluated the hypothalamic pituitary axis (HPA) dysfunction in TBM. PATIENTS AND METHODS: Present study included newly diagnosed drug naive TBM patients (n = 63) at a tertiary care centre in Northern India. All patients underwent detailed clinical, radiological evaluation (Gadolinium enhanced magnetic resonance imaging of brain) and HPA hormonal profiles (electrochemiluminescence assay) both at initial presentation and at six month follow up. All the data was recorded on a predesigned proforma. RESULTS: 77.8% patients had definite and 22.2% had highly probable TBM. 84.2% of patients had pituitary hormonal abnormalities at presentation. These included hyperprolactinemia (49.2%), secondary adrenal deficiency (42.9%), secondary hypogonadism (38.1%) and central hypothyroidism (9.5%). At follow up, 42.1% patients had HPA abnormalities [hyperprolactinemia (13.2%), secondary hypogonadism (15.8%), secondary adrenal deficiency (10.5%) and central hypothyroidism (10.5%)]. On multivariate logistic regression analysis, secondary hypocortisolism (Odd ratio: 4.042; 95% CI = 1.074-15.22; P = .039) was associated with poor outcome in TBM. CONCLUSION: Abnormalities of HPA are common in TBM. Patients with TBM should be evaluated for dysfunction of HPA and treated accordingly.