Evaluation of 'Normal' Cognitive Functions and Correlation With MRI Volumetry: Towards a Definition of Vascular Cognitive Impairment.

Introduction It is important to establish criteria to define vascular cognitive impairment (VCI) in India as VCI is an image-based diagnosis and magnetic resonance imaging (MRI) changes resulting from age with prevalent vascular risk factors may confound MRI interpretation. The objective of this study was to establish normative community data for MRI volumetry including white matter hyperintensity volume (WMHV), correlated with age-stratified cognitive scores and vascular risk factors (VRFs), in adults aged 40 years and above.  Methods We screened 2651 individuals without known neurological morbidity, living in Mumbai and nearby rural areas, using validated Marathi translations of Kolkata Cognitive Battery (KCB) and geriatric depression score (GDS). We stratified 1961 persons with GDS ≤9 by age and cognitive score, and randomly selected 10% from each subgroup for MRI brain volumetry. Crude volumes were standardized to reflect percentage of intracranial volume.  Results MRI volumetry studies were done in 199 individuals (F/M = 90/109; 73 with body mass index (BMI) ≥25; 44 hypertensives; 29 diabetics; mean cognitive score 76.3). Both grey and white matter volumes decreased with increasing age. WMHV increased with age and hypertension. Grey matter volume (GMV) decreased with increasing WMHV. Positive predictors of cognition included standardized hippocampal volume (HCV), urban living, education, and BMI, while WMHV and age were negative predictors. Urban dwellers had higher cognitive scores than rural, and, paradoxically, smaller HCV.  Conclusion In this study of MRI volumetry correlated with age, cognitive scores and VRFs, increasing age and WMHV predicted lower cognitive scores, whereas urban living and hippocampal volume predicted higher scores. Age and WMHV also correlated with decreasing GMV. Further study is warranted into sociodemographic and biological factors that mutually influence cognition and brain volumes, including nutritional and endocrine factors, especially at lower cognitive score bands. In this study, at the lower KCB score bins, the lack of laboratory data pertaining to nutritional and endocrine deficiencies is a drawback that reflects the logistical limitations of screening large populations at the community level. Our volumetric data which is age and cognition stratified, and takes into account the vascular risk factors associated, nevertheless constitutes important baseline data for the Indian population. Our findings could possibly contribute to the formulation of baseline criteria for defining VCI in India and could help in early diagnosis and control of cognitive decline and its key risk factors.

COVID-19 Associated Stroke-A Single Centre Experience.

BACKGROUND AND PURPOSE: Various neurological complications have been reported in association with COVID-19. We report our experience of COVID-19 with stroke at a single center over a period of eight months spanning 1 March to 31 October 2020. METHODS: We recruited all patients admitted to Internal Medicine with an acute stroke, who also tested positive for COVID-19 on RTPCR. We included all stroke cases in our analysis for prediction of in-hospital mortality, and separately analyzed arterial infarcts for vascular territory of ischemic strokes. RESULTS: There were 62 stroke cases among 3923 COVID-19 admissions (incidence 1.6%). Data was available for 58 patients {mean age 52.6 years; age range 17-91; F/M=20/38; 24% (14/58) aged ≤40; 51% (30/58) hypertensive; 36% (21/58) diabetic; 41% (24/58) with O2 saturation <95% at admission; 32/58 (55.17 %) in-hospital mortality}. Among 58 strokes, there were 44 arterial infarcts, seven bleeds, three arterial infarcts with associated cerebral venous sinus thrombosis, two combined infarct and bleed, and two of indeterminate type. Among the total 49 infarcts, Carotid territory was the commonest affected (36/49; 73.5%), followed by vertebrobasilar (7/49; 14.3%) and both (6/49; 12.2%). Concordant arterial block was seen in 61% (19 of 31 infarcts with angiography done). 'Early stroke' (within 48 hours of respiratory symptoms) was seen in 82.7% (48/58) patients. Patients with poor saturation at admission were older (58 vs 49 years) and had more comorbidities and higher mortality (79% vs 38%). Mortality was similar in young strokes and older patients, although the latter required more intense respiratory support. Logistic regression analysis showed that low Glasgow coma score (GCS) and requirement for increasing intensity of respiratory support predicted in-hospital mortality. CONCLUSIONS: We had a 1.6% incidence of COVID-19 related stroke of which the majority were carotid territory infarcts. In-hospital mortality was 55.17%, predicted by low GCS at admission.

Capsular Warning Syndrome - A Case Series and Discussion on Management Dilemmas.

BACKGROUND: The term 'Capsular warning syndrome (CWS)' refers to recurrent, stereotypical transient ischemic attacks, either motor, sensory or both, without cortical symptoms or signs. Of these patients, 42-71% go on to develop infarcts. There are no defined treatment guidelines for this lesser known entity. METHODS: We studied 9 patients who presented over last 2 years to our hospital with recurrent and stereotypical transient ischemic attacks suggestive of capsular warning syndrome. Their clinical characteristics, neuroimaging findings, relevant etiological investigations, management and outcomes were studied. RESULTS: Seven out of 9 patients were under 40 years of age. The commonest presentation in our series was a pure motor syndrome. The duration of neurologic deficits ranged from 5 minutes to 20 minutes with complete recovery in between episodes. Three patients had concordant abnormalities on CT brain angiography. Five out of 9 patients received IV thrombolysis with t-PA. One patient worsened neurologically post thrombolysis, whilst the others improved clinically. DISCUSSION: Despite multiple hypotheses, the pathogenesis and management of CWS has not been established clearly. Due to fluctuating neurological symptoms with complete recovery in between the episodes, there is a dilemma concerning treatment of such patients with intravenous thrombolysis. However, intravenous thrombolysis appears to be safe in CWS as in acute ischemic stroke, followed by treatment with antiplatelet agents.

Tocilizumab improves survival in severe COVID-19 pneumonia with persistent hypoxia: a retrospective cohort study with follow-up from Mumbai, India.

BACKGROUND: Cytokine storm triggered by Severe Coronavirus Disease 2019 (COVID-19) is associated with high mortality. With high Interleukin -6 (IL-6) levels reported in COVID-19 related deaths in China, IL-6 is considered to be the key player in COVID-19 cytokine storm. Tocilizumab, a monoclonal antibody against IL-6 receptor, is used on compassionate grounds for treatment of COVID-19 cytokine storm. The aim of this study was to assess effect of tocilizumab on mortality due to COVID-19 cytokine storm. METHOD: This retrospective, observational study included patients of severe COVID-19 pneumonia with persistent hypoxia (defined as saturation 94% or less on supplemental Oxygen of 15 L per minute through non-rebreathing mask or PaO2/FiO2 ratio of less than 200) who were admitted to a tertiary care center in Mumbai, India, between 31st March to 5th July 2020. In addition to standard care, single Inj. Tocilizumab 400 mg was given intravenously to 151 consecutive COVID-19 patients with persistent hypoxia, from 13th May to 5th July 2020. These 151 patients were retrospectively analysed and compared with historic controls, ie consecutive COVID-19 patients with persistent hypoxia, defined as stated above (N = 118, from our first COVID-19 admission on 31st March to 12th May 2020 i.e., till tocilizumab was available in hospital). Univariate and multivariate Cox regression analysis was performed for identifying predictors of survival. Statistical analysis was performed using IBM SPSS version 26. RESULTS: Out of 269 (151 in tocilizumab group and 118 historic controls) patients studied from 31st March to 5th July 2020, median survival in the tocilizumab group was significantly longer than in the control group; 18 days (95% CI, 11.3 to 24.7) versus 9 days (95% CI, 5.7 to 12.3); log rank p 0.007. On multivariate Cox regression analysis, independent predictors of survival were use of tocilizumab (HR 0.621, 95% CI 0.427-0.903, P 0.013) and higher oxygen saturation. CONCLUSION: Tocilizumab may improve survival in severe COVID-19 pneumonia with persistent hypoxia. Randomised controlled trials on use of tocilizumab as rescue therapy in patients of severe COVID-19 pneumonia with hypoxia (PaO2/FiO2 less than 200) due to hyperinflammatory state, are warranted.

A case series of three patients presenting with isoniazid induced toxicity and N-acetyl transferase 2 gene mutation: A management conundrum for programmatic therapy of tuberculosis in India.

Isoniazid is an essential drug in the management of tuberculosis but there is a high degree of variation in the Indian population's capacity to acetylate or inactivate isoniazid to the inactive metabolite acetyl isoniazid, and they can be distinctly characterized phenotypically as being either slow or rapid inactivators (the concentration of the enzyme being higher in rapid inactivators). Several mutations in the N-acetyl transference 2 (NAT2) gene account for majority of the slow acetylator genotypes in the human population (NAT2*5A, NAT2*5B, and NAT2*6A). Such individuals are at a greater risk of drug-induced adverse reactions due to reduced drug elimination, compared to those possessing the wild type allele. Here we discuss two cases of Isoniazid induced peripheral neuropathy and one case of Isoniazid induced hepatotoxicity confirmed as having heterozygous or homozygous NAT2 gene mutation. In all 3 cases, the presence of NAT2 gene mutation was associated with the adverse events and the adverse events subsided on stopping or reducing the dose of isoniazid. However, due to lack of guideline-based management of adverse events occurring due to isoniazid, the drug was either abruptly stopped or dosage lowered based only on clinical expertise, which could potentially lead to further resistance to Mycobacterium tuberculosis (as occurred in one of our cases). Further studies of the relationship between NAT2 genotypes, isoniazid concentrations and adverse drug events are required to make genotyping a helpful tool for optimizing isoniazid's therapeutic response and minimizing adverse drug reactions, particularly in countries with a high burden of tuberculosis.

Dysphagia in Parkinsonism: Prevalence, Predictors and Correlation with Severity of Illness Fasting).

INTRODUCTION: Dysphagia is frequently present in Parkinsonian syndromes and is associated with increased morbidity and mortality. Early identification of swallowing dysfunction is critical to minimize complications like aspiration pneumonia and malnutrition. Published prevalence rates for dysphagia in Parkinsonian syndromes vary widely with a very few studies from India. In this study we aimed to determine prevalence of dysphagia in Parkinson's disease and other Parkinson plus syndromes; to correlate it with severity of underlying illness and to determine the factors predicting dysphagia in patients of Parkinson's disease. METHODS: It was a prospective observational study performed over 18 months in the neurology clinic of tertiary care public teaching hospital in Mumbai. All patients of Parkinson's disease (PD) diagnosed by UKPDS criteria and all patients of Parkinson-plus syndromes diagnosed clinically were included in the study serially. Patients with cognitive dysfunction (MMSE<24) and those having other neurological or non-neurological causes of dysphagia were excluded from the study. Swallowing dysfunction was assessed by MASA scoring sheet. Disease severity of PD was assessed by modified Hoehn and Yahr scale. Peripheral oxygen desaturation after swallowing water was monitored by pulse-oxymetry; as a bedside test for micro-aspiration. The data was tabulated and analyzed. RESULTS: 70 patients were included in the study including 63 with PD, 5 with PSP and 2 with MSA. Dysphagia was present in 40 (57.4%). 27 had mild; 12 had moderate and 1 had severe dysphagia. In Parkinson's disease dysphagia was significantly associated with following predicting factors: age > 65 years, disease duration > 3 years, modified Hoehn and Yahr scale > 2 and MMSE < 27 (p < 0.001 for all). By multiple logistic regression analysis, the duration of disease and MMSE score were the independent predictors for dysphagia in Parkinson's disease. Severity of dysphagia directly correlated with severity of underlying disease demonstrated by decreasing MASA score with rising Hoehn and Yahr stage. CONCLUSIONS: Prevalence of dysphagia in Parkinsonian syndromes was overall 57.14%; being 55.16% in Parkinson's disease. Prevalence and severity of dysphagia showed direct correlation with severity of Parkinson's disease. Duration of disease and cognitive dysfunction are the independent predictors of dysphagia in Parkinson's disease.

Piper sarmentosum Promotes Endothelial Nitric Oxide Production by Reducing Asymmetric Dimethylarginine in Tumor Necrosis Factor-α-Induced Human Umbilical Vein Endothelial Cells.

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide synthase (eNOS). ADMA is degraded by dimethylarginine dimethylaminohydrolase (DDAH). Elevated levels of ADMA lead to reduction in nitric oxide (NO) production, which is linked to endothelial dysfunction and atherosclerosis. Piper sarmentosum is an herb that has shown stimulation on endothelial NO production by increasing both expression and activity of eNOS. Thus, this study determined whether the positive effect of P. sarmentosum on NO production is related to its modulation on the DDAH-ADMA pathway in cultured human umbilical vein endothelial cells (HUVEC) exposed to tumor necrosis factor-α (TNF-α). HUVEC were divided into four groups: control, treatment with 250 µg/ml of aqueous extract of P. sarmentosum leaves (AEPS), treatment with 30 ng/ml of TNF-α, and concomitant treatment with AEPS and TNF-α for 24 h. After treatments, HUVEC were collected to measure DDAH1 messenger RNA (mRNA) expression using quantitative real-time polymerase chain reaction. DDAH1 protein level was measured using enzyme-linked immunosorbent assay (ELISA), and DDAH enzyme activity was measured using colorimetric assay. ADMA concentration was measured using ELISA, and NO level was measured using Griess assay. Compared to control, TNF-α-treated HUVEC showed reduction in DDAH1 mRNA expression (P < 0.05), DDAH1 protein level (P < 0.01), and DDAH activity (P < 0.05). Treatment with AEPS successfully increased DDAH1 mRNA expression (P < 0.05), DDAH1 protein level (P < 0.01), and DDAH activity (P < 0.05) in TNF-α-treated HUVEC. Treatment with TNF-α caused an increase in ADMA level (P < 0.01) and a decrease in endothelial NO production (P < 0.001). Whereas treatment with AEPS was able to reduce ADMA level (P < 0.01) and restore NO (P < 0.001) in TNF-α-treated HUVEC. The results suggested that AEPS promotes endothelial NO production by stimulating DDAH activity and thus reducing ADMA level in TNF-α-treated HUVEC.

The Effect of Hypertension and Diabetes Mellitus on White Matter Changes in MRI Brain: A Comparative Study between Patients with Alzheimer's Disease and an Age-matched Control Group.

BACKGROUND: White matter hyperintensities (WMH) on MRI brain in the periventricular and deep white matter regions are commonly seen in older persons with normal cognition and in patients with AD. AIMS: To compare presence and severity of WMHs in patients with AD with that in a cognitively normal control group, and to evaluate effect of presence of Hypertension and Diabetes on WMHs in both groups. MATERIAL AND METHODS: Thirty four patients with AD were serially recruited from Neurology and Psychiatry OPDs. An age and gender matched cohort of 24 persons with MMSE over 27/30 from the community acted as controls. Vascular risk factors, MMSE and MRI brain were assessed in all. Fezeka's and Pasquier grading of WMH and atrophy were done. Periventricular WMHs (PVWMH) and Deep WMH (DWMH) were assessed separately. RESULTS AND CONCLUSIONS: Overall, Periventricular WMHs of grade 2 and over were seen in 19/34 patients, and in 7/24 controls (P value 0.044). Significantly higher grades of PVWMHs were seen in hypertensives as compared to nonhypertensives in the case group, and in women compared to men. In the control group, hypertension had no effect on severity of PVWMHs. Among both Diabetics and non-diabetics, no difference in PVWMHs was found between the case and control groups. DWMHs were, conversely, seen only in the control group. Overall, over a quarter of cognitively normal older persons had WM hyperintensities of grade 2 and over on MRI brain; 55% of AD patients had PVWMH of Gd 2 or over, and no DWMHs.

Unusual presentation of extramedullary haematopoiesis in a young boy.

Acute transverse myelopathy in a young person may be due to infection, postinfective or inflammatory demyelination, or vascular causes. Rarely, a completely reversible cause of acute transverse myelopathy may be seen, as described here in our case of transverse myelopathy due to extramedullary haematopoiesis (EMH). An 18-year-old man who had a history of a lone blood transfusion at age of 7 years presented with paraplegia. MRI showed multiple epidural space masses of EMH compressing the spinal cord. He was detected to have thalassaemia intermedia and was treated with blood transfusions, steroids and radiotherapy to the involved paraspinal areas. He recovered fully over 15 days and remained symptom free at 6 months.

Piper sarmentosum attenuates TNF-α-induced VCAM-1 and ICAM-1 expression in human umbilical vein endothelial cells.

OBJECTIVES: Inflammation plays a key role in the pathogenesis of atherosclerosis. Piper sarmentosum is an herb with antioxidant and anti-atherosclerotic activities. The aim of this study was to evaluate the anti-inflammatory properties of an aqueous extract of P. sarmentosum (AEPS) in human umbilical vein endothelial cells (HUVECs). METHODS: HUVECs were divided into six groups: control, treatment with 10 ng/ml TNF-α, and co-treatment of 10 ng/ml TNF-α with four different concentrations of AEPS (100, 150, 250, and 300 µg/ml) for 24 h. Subsequently, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) protein expression, U937 monocyte cells adhesion, and nuclear factor-kappaB (NF-κB) p65 expression in HUVECs were measured. RESULTS: Treatment of TNF-α-stimulated HUVECs with AEPS at different concentrations resulted in decreased VCAM-1 and ICAM-1 protein expression in a dose-dependent manner. Furthermore, AEPS also inhibited TNF-α-stimulated U937 monocyte cells adhesion to HUVECs. In addition, AEPS reduced TNF-α-induced NF-κB p65 expression in a dose-dependent manner. CONCLUSIONS: The results indicated that AEPS suppressed TNF-α-induced VCAM-1 and ICAM-1 expression NF-κB signaling.

Psychiatric Co-morbidities in Women with Epilepsy.

Background: The co-existence of psychiatric co-morbidities with Epilepsy in women is multifactorial and complex, being closely related to hormonal status, medication side effects, and psychosocial factors. Aims: We aimed to study associated Psychiatric co-morbidities in women with Epilepsy (WWE), and correlate the same with seizure subtype and medication , compliance with treatment and seizure control. Material and Methods: This was a prospective, interview based study in OPD over 18 months, evaluating WWE over 13 years of age with at least 1 seizure in the last 1 year. The primary outcome evaluated was the psychiatric diagnosis. Covariables assessed included sociodemographic data, details of seizures and treatment taken. Study population included 143 WWE. Thirty women with a chronic disease, viz., Diabetes and with no h/o seizures, and another group of 25 healthy women from the community with no seizures ever and no Diabetes, were evaluated as 2 sets of controls. Results and Conclusions: One hundred and forty three women with Epilepsy (WWE) were recruited into the study. Psychiatric co-morbidity prevalence was 28.6 % (41/143) in WWE, 13.7 % in women with Diabetes and 8.3 % in women with no Epilepsy or Diabetes (normal controls). Overall, Depression was the commonest psychiatric co-morbidity. Psychiatric co-morbidity was significantly more in WWE as compared to normal controls. Seizure duration over 2 years, complex partial seizures and Polypharmacy were significantly linked to Psychiatric co-morbidities.

Lacunar Syndromes--Where is the Lesion?

OBJECTIVES: The study aimed to evaluate different imaging localizations of the classical Lacunar syndromes, including multiplicity of lacunes. MATERIALS AND METHODS: This prospective study was conducted in a tertiary care municipal hospital over 2 years. Patients with clinical Lacunar syndromes, confirmed on imaging, were evaluated for etiopathogenetic factors, lesion localization, and presence of multiple simItaneous lacunes. Angiographic data and cognitive evaluation was done in a subset of the cohort. RESULTS: 82 patients were studied, 12 undergoing DSA and 46 being evaluated cognitively. Commonest risk factors were Hypertension (97%) and tobacco usage (62%). Pure motor stroke (PMS-70.7%) was the commonest lacunar syndrome, Internal capsular lesions accounting for 53.4% of this syndrome. Among PMS, localisation to Carotid territory was seen in 84.4%, to vertebrobasilar territory in 10.3% and to both in 5.1% of patients. Sensorimotor lacunar syndrome was seen in 14.6% patients, half of them having a thalamic lesion. Overall, 17% patients had multiple simultaneous lacunes, over half of these being cortical, and multiplicity being seen in PMS most commonly. Of 46 patients tested for cognition, 69.5% showed significantly low scores on ACER, with a significant association with multiplicity of lacunes in this group. CONCLUSIONS: In our study, Pure motor stroke was the commonest lacunar syndrome, 84% of PMS being due to Anterior circulation stroke. Multiple lacunes of similar age were seen in 17% patients, the predominantly cortical localization of these raising a possibility of embolism. Postlacunar stroke executive dysfunction was seen in over two-thirds of our patients.

A Diagnosis Made by 'Facilitation'.

Lambert Eaton myasthenic syndrome is a presynaptic neuromuscular junction disorder, which has unique features on electrodiagnostic testing. Here we describe a middle aged lady with symmetric, progressive, areflexic weakness in lower limbs, who had the typical electrodiagnostic findings of diffuse attenuation of motor amplitudes, and increase in these amplitudes after brief exercise of the muscle sampled.

Acute disseminated encephalomyelitis--a prospective study of clinical profile and in-hospital outcome predictors.

INTRODUCTION: There is paucity of data on acute disseminated encephalomyelitis (ADEM) in adults in India. Recent reports indicate that demyelinating disorders in the eastern hemisphere are quite distinct from conventional western type multiple sclerosis. AIMS: This study aimed to study the clinical profile, laboratory and imaging parameters, in-hospital morbidity/ mortality and clinical and imaging predictors of in-hospital outcome in ADEM. RESULTS: A total of 29 patients were studied, gender ratio being not significantly different. Prior infection was present in 55.1% patients. Motor deficits (68.9%), bowel bladder abnormalities (65.5%) and sensory deficits (24.1%) were the commonest presenting features. Encephalopathy was seen in 24.1% patients. 10.3% patients had seizures and meningism. A polysymptomatic presentation was seen in 79.3% patients. Pure spinal cord affection (41.3%) was the commonest MRI pattern followed by subcortical (31%) and periventricular white matter involvement (24.1%). A normal MRI was seen in 17.2% of patients. 63% patients showed raised Cerebrospinal fluid (CSF) protein. The commonest in-hospital morbidity was urinary tract infection (18.5%). At admission; 81.4% patients had modified Rankin's score (MRS) between 4 and 6. At 6 weeks post admission, 90.4% patients had MRS score between 0-3, i.e, a favourable MRS. CONCLUSION: This short term, in-hospital study of ADEM showed preponderance of polysymptomatic onset with motor deficits, commonest MRI pattern being pure spinal cord involvement. A good prognosis for short-term recovery at 6 weeks was noted, despite moderate to severe disability at admission.