Dheeraj Khurana

NEUROPHYSIOLOGICAL MONITORING OF PHARMACOLOGICAL MANIPULATION IN ACUTE ORGANOPHOSPHATE (OP) POISONING. THE EFFECTS OF PRALIDOXIME, MAGNESIUM SULPHATE AND PANCURONIUM

OBJECTIVES The neuromuscular transmission failure in acute organophosphate (OP) poisoning occurs because of the irreversible inactivation of the enzyme acetylcholinesterase located in the neuromuscular junction, and is distinguished neuroelectrophysiologically by single electrical stimulus-induced repetitive responses and either a decremental or a decrement-increment response upon high-rate repetitive nerve stimulation (RNS). Understandably, the administration of pharmacological agents with actions at different sites in the neuromuscular junction would alter the neuroelectrophysiological findings in acute OP poisoning. METHODS The effect of several pharmacological agents including pralidoxime (10 patients), magnesium sulphate (4 patients) and pancuronium (7 patients) on the neuroelectrophysiological abnormalities was studied in 21 patients with acute OP poisoning. RESULTS Pralidoxime administration produced neurophysiological amelioration in 11 out of 15 occasions. In those cases where it produced a beneficial effect, pralidoxime administration was continued and its neuroelectrophysiological effects were studied daily. The efficacy of pralidoxime administration was demonstrated by neuroelectrophysiological testing for a maximum of 6 days after poisoning. Three types of neuroelectrophysiological responses to pralidoxime were noted: (i) lack of neuroelectrophysiological improvement (two patients); (ii) initial improvement with subsequent lack of improvement (two patients); and (iii) initial improvement with subsequent normalisation of neuromuscular transmission (5 patients). Normalisation of the electrodiagnostic tests and the failure of pralidoxime to ameliorate the neuromuscular transmission abnormalities were neuroelectrophysiological indications for the discontinuation of pralidoxime treatment. The administration of magnesium sulphate (MgSO4.7H2O, 4 g intravenous) resulted in a decrease in the CMAP amplitude, loss of the repetitive response and conversion of the decrement-increment response at high-rate RNS to an incremental response. Repetitive responses and the decremental response at high-rate RNS also disappeared after the administration of pancuronium (0.5 mg intravenous) to 6 patients. However, in one case where pancuronium administration was preceded by pralidoxime, there occurred a dramatic worsening of the neuromuscular transmission defect. CONCLUSIONS While the administration of all 3 agents-- pralidoxime, magnesium sulphate and pancuronium-- resulted in the reversion of the neuroelectrophysiological defects, only pralidoxime is contended to be therapeutically useful. The therapeutic benefit due to its administration is limited by a short duration of action, and hence it is recommended that it should be administered for a longer period of time under neuroelectrophysiolgical guidance.

Sodium Valproate, Hyperandrogenism and Altered Ovarian Function in Indian Women with Epilepsy: A Prospective Study

Summary:  Purpose: To assess the association of long‐term sodium valproate therapy with reproductive endocrine disorders in Indian women with generalized epilepsy.

Neurology of acute organophosphate poisoning

Acute organophosphate (OP) poisoning is one of the most common poisonings in emergency medicine and toxicological practice in some of the less-developed nations in South Asia. Traditionally, OP poisoning comes under the domain of emergency physicians, internists, intensivists, and toxicologists. However, some of the complications following OP poisoning are neurological and involve neurologists. The pathophysiological basis for the clinical manifestations of OP poisoning is inactivation of the enzyme, acetylcholinesterase at the peripheral nicotinic and muscarinic and central nervous system (CNS) nerve terminals and junctions. Nicotinic manifestations occur in severe cases and late in the course; these comprise of fasciculations and neuromuscular paralysis. There is a good correlation between the electrophysiological abnormalities and the severity of the clinical manifestations. Neurophysiological abnormalities characteristic of nicotinic junctions (mainly neuromuscular junction) dysfunction include: (1) single, supramaximal electrical-stimulus-induced repetitive response/s, (2) decrement-increment response to high frequency (30 Hz) repetitive nerve stimulation (RNS), and (3) decremental response to high frequency (30 Hz) RNS. Atropine ameliorates muscarinic manifestations. Therapeutic agents that can ameliorate nicotinic manifestations, mainly neuromuscular, are oximes. However, the evidence for this effect is inconclusive. This may be due to the fact that there are several factors that determine the therapeutic effect of oximes. These factors include: The OP compound responsible for poisoning, duration of poisoning, severity of poisoning, and route of exposure. There is also a need to study the effect of oximes on the neurophysiological abnormalities.

Interictal cerebral and systemic endothelial dysfunction in patients with migraine: a case–control study

Background Although systemic endothelial function is unimpaired in migraine, it is unknown whether cerebral endothelial function impairment exists in migraineurs. Materials and methods We conducted a prospective study to assess endothelial function in migraineurs (n=45) and healthy volunteers (n=44). Cerebral endothelial function was assessed by Breath Holding Index (BHI) on transcranial Doppler in bilateral middle cerebral artery (MCA at 30–60 mm), posterior cerebral artery (PCA at 60–80 mm) and basilar artery (BA at 80–120 mm) using bilateral monitoring probes fixed on headband. Brachial artery flow-mediated dilation (FMD) was used as measure of systemic endothelial function. Results There was no difference in baseline mean velocities of MCA, PCA, BA among migraineurs and controls. Mean BHI was significantly lower in PCA (p<0.001) and BA (p<0.001) in patients with migraine with no difference in MCA (p=0.909, 0.450). Cerebral endothelial dysfunction (BHI<1.15) was present in 62.2% of migraineurs in the right PCA (p<0.001), 57.8% in left PCA (p<0.001) and 77.8% in BA (BHI <0.83, p<0.001). There was no difference in BHI among migraineurs without and with aura (n=15). Cerebral and systemic endothelial function had no correlation in migraineurs. Increasing BMI was identified as a predictor of impaired BHI in the BA in migraineurs (p=0.020). Age, sex, presence of aura, lateralisation of headache, headache frequency, time to last attack and impaired FMD were not associated with impaired PCA and BA BHI in migraineurs. Conclusions Migraineurs may have isolated cerebral endothelial dysfunction restricted to the posterior circulation in the absence of systemic endothelial dysfunction.

Translation of Pre-Clinical Studies into Successful Clinical Trials for Alzheimer's Disease: What are the Roadblocks and How Can They Be Overcome?

Preclinical studies are essential for translation to disease treatments and effective use in clinical practice. An undue emphasis on single approaches to Alzheimers disease (AD) appears to have retarded the pace of translation in the field, and there is much frustration in the public about the lack of an effective treatment. We critically reviewed past literature (1990-2014), analyzed numerous data, and discussed key issues at a consensus conference on Brain Ageing and Dementia to identify and overcome roadblocks in studies intended for translation. We highlight various factors that influence the translation of preclinical research and highlight specific preclinical strategies that have failed to demonstrate efficacy in clinical trials. The field has been hindered by the domination of the amyloid hypothesis in AD pathogenesis while the causative pathways in disease pathology are widely considered to be multifactorial. Understanding the causative events and mechanisms in the pathogenesis are equally important for translation. Greater efforts are necessary to fill in the gaps and overcome a variety of confounds in the generation, study design, testing, and evaluation of animal models and the application to future novel anti-dementia drug trials. A greater variety of potential disease mechanisms must be entertained to enhance progress.

Association of metabolic syndrome with carotid atherosclerosis in the young North Indian population.

BACKGROUND Metabolic syndrome (MetS) and its components are associated with increased risk of stroke and cardiovascular disease. Relationship of MetS to carotid atherosclerosis has not been documented well in North Indian population. AIMS (1) To determine the incidence of metabolic syndrome in asymptomatic healthy young North Indian population; (2) to evaluate individuals with MetS patients for carotid atherosclerosis by carotid duplex ultrasound examination; (3) to determine the significance of each component of MetS in relation to carotid atherosclerosis in these patients. METHODS 440 individuals in the age group of 25-50 years, asymptomatic for cardiac or cerebrovascular disease were screened for metabolic syndrome. 162 patients from a hospital-based population fulfilled the criteria for MetS (as per NCEP ATP III criteria). Duplex ultrasound (DU) examination of extracranial carotid vessels was performed on all the subjects. 112 age- and sex-matched controls were screened, and they underwent DU examination for comparison. RESULTS Hypertriglyceridemia was the commonest component seen in 79.6% of the MetS subjects, followed by central obesity seen in 74.6% subjects. Carotid atherosclerotic disease was observed in 21.6% of patients with MetS. Mild atherosclerosis (intima media thickness (IMT) >0.09 cm) was observed in 82.8% and 17.3% had plaques with mild stenosis (<50%) in the extracranial carotid arteries. Among patients of MetS with carotid atherosclerotic disease 82.6% had hypertriglyceridemia and 71.5% had 4 or more components for MetS. Among controls, five subjects (4.46%) had evidence of mild carotid atherosclerosis (IMT >0.09 cm) on DU. MetS was significantly associated with carotid DU abnormalities (increased IMT >0.09 cm) compared to controls (Fischers exact test p<0.0001). Univariate analysis showed the relationship of hypertriglyceridemia to carotid atherosclerosis (p=0.03). On multivariate regression analysis none of the individual components of MetS contributed significantly to the presence of carotid atherosclerosis. CONCLUSIONS MetS is common in asymptomatic healthy North Indian population, with hypertriglyceridemia being the commonest component of MetS in this population, which may be predictive of carotid atherosclerotic disease. Serum triglyceride estimation can serve as a screen for asymptomatic healthy subjects to select the target population for cerebrovascular disease prevention.

Telestroke a viable option to improve stroke care in India.

In India, stroke care services are not well developed. There is a need to explore alternative options to tackle the rising burden of stroke. Telemedicine has been used by the Indian Space Research Organization (ISRO) to meet the needs of remote hospitals in India. The telemedicine network implemented by ISRO in 2001 presently stretches to around 100 hospitals all over the country, with 78 remote/rural/district health centers connected to 22 specialty hospitals in major cities, thus providing treatment to more than 25 000 patients, which includes stroke patients. Telemedicine is currently used in India for diagnosing stroke patients, subtyping stroke as ischemic or hemorrhagic, and treating accordingly. However, a dedicated telestroke system for providing acute stroke care is needed. Keeping in mind Indias flourishing technology sector and leading communication networks, the hub-and-spoke model could work out really well in the upcoming years. Until then, simpler alternatives like smartphones, online data transfer, and new mobile applications like WhatsApp could be used. Telestroke facilities could increase the pool of patients eligible for thrombolysis. But this primary aim of telestroke can be achieved in India only if thrombolysis and imaging techniques are made available at all levels of health care.

Vitamin D status and risk of ischemic stroke in North Indian patients

Context: Accumulating evidence suggests that vitamin D deficiency is associated with increased risk of stroke. Contributing mechanisms have been linked to the association of vitamin D deficiency with the presence of hypertension, diabetes mellitus, and atherosclerosis, however, the evidence is conflicting. Aims: This study sought to determine the association of vitamin D deficiency with ischemic stroke and its risk factors. Settings and Design: Cross-sectional case control study. Subjects and Methods: We measured serum 25-hydroxyvitamin D [25(OH) D] and intact parathyroid hormone (iPTH) levels in 73 patients of ischemic stroke, presenting within 7 days of onset of stroke and compared with 70 age and gender matched controls. Statistical Analysis Used: The statistical analysis was carried out using Statistical Package for Social Sciences (SPSS Inc., Chicago, IL, version 17.0 for Windows). Results: The mean age of patients and controls was 59.9 ± 11.2 years and 57.9 ± 9.7 years, respectively (P = 0.26). Of 67.1% patients were men as compared to 65.7% controls (P = 0.86). There was no significant difference in the prevalence of vitamin D deficiency/insufficiency (P = 0.25), mean 25(OH) D levels (P = 0.75), and iPTH levels (P = 0.10) between cases and controls. No association of vitamin D deficiency/insufficiency was found with the prevalent risk factors in cases of ischemic stroke. Conclusions: Vitamin D deficiency does not bear an association with ischemic stroke or its risk factors.

Prognostic indices for cerebral venous thrombosis on CT perfusion: A prospective study

PURPOSE We determined the prognostic significance of CT perfusion characteristics of patients with cerebral venous sinus thrombosis (CVST) and assessed the change in perfusion parameters following anticoagulation therapy. MATERIALS AND METHODS 20 patients with CVST diagnosed on non-contrast computed tomography (NCCT), magnetic resonance imaging (MRI), and magnetic resonance venography (MRV) were included in this study. The initial CT perfusion study was performed at the time of admission. The following perfusion parameters: relative cerebral blood flow (rCBF), relative cerebral blood volume (rCBV), and relative mean transit time (rMTT) were calculated in the core and periphery of the affected area of the brain. Follow-up CT perfusion studies were performed at 1 month following anticoagulation therapy and the perfusion parameters thus obtained were compared with pre-treatment results. Receiver operating characteristic (ROC) curve analysis was performed to determine the prognostic significance of perfusion parameters. RESULTS All patients in this study showed areas of hypoperfusion on CT perfusion. To determine the favorable clinical outcome on basis of perfusion parameters, ROC curve analysis was performed which showed that the optimal threshold for rCBF>60.5%, rCBV>75.5%, and rMTT<148.5% correlated with better clinical outcomes. Post treatment perfusion parameters showed significant correlation in core of the lesion (p<0.05) than in the periphery. CONCLUSION CT perfusion studies in CVST are a good prognostic tool and yield valuable information regarding clinical outcome.

Teaching NeuroImages: Deep gray matter involvement in neurobrucellosis

A 27-year-old man, recent visitor to the Middle East, presented with 6-week history of fever (up to 102°F) followed by altered behavior and left hemiparesis. CSF was acellular with raised protein (138 mg/dL). CSF bacterial culture was sterile; adenosine deaminase normal (3 U/L); cryptococcal antigen, Venereal Disease Research Laboratory test, and Japanese B serology were negative. HIV serology and vasculitic workup were unremarkable. Serum Brucella agglutination titer was 320 IU (immunoglobulin M fraction 280 IU). Cranial MRI showed nonenhancing bilateral white matter and basal ganglia hyperintensities on T2-weighted images (figure, A–C). The patient was treated with IV ceftriaxone (1 month) along with oral doxycycline and rifampicin (4 months). At 3 months, Brucella agglutination titer was <20 IU and the patient became independent. Follow-up imaging showed a reduction in lesions (figure, D). Brucellosis frequently presents as chronic meningitis along with cranial neuropathies and spinal arachnoiditis.1 Demyelinating lesions are described in neurobrucellosis,1,2 involvement of the deep gray matter being unusual.