P. Satishchandra

NMDA Receptor Activation by HIV-Tat Protein Is Clade Dependent

In countries infected with HIV clade B, some patients develop a rapidly progressive dementia that if untreated results in death. In regions of the world infected with HIV clade C, only milder forms of cognitive impairment have been recognized. HIV-infected macrophages are the principal mediators of dementia. HIV clade C, however, efficiently infects macrophages and HIV-infected macrophages are found in the brains of clade C-infected patients. HIV-infected macrophages release Tat protein, which may act directly on neurons to cause toxicity. We found that Tat released from Tat-expressing cells was at least 1000-fold more toxic than recombinant Tat protein. We determined whether Tat could interact with NMDA receptors and whether these interactions are clade dependent. It is demonstrated that Tat binds directly to the NMDA receptor leading to excitotoxicity. The Cys 30-Cys 31 motif in Tat is critical for exciting the NMDA receptor and the Cys31Ser mutation found in clade C Tat has a significantly attenuated neurotoxic response. Through molecular modeling and site-directed mutagenesis, we predict that Cys 31 disrupts the disulfide bond between Cys 744 and Cys 798 on the NR1 subunit of the NMDA receptor by directly interacting with Cys 744 leading to a free thiol group on Cys 798 and subsequent persistent activation of the NMDA receptor.

Cryptococcal meningitis: Clinical, diagnostic and therapeutic overviews

Cryptococcal meningitis has emerged as a leading cause of infectious morbidity and mortality in patients with AIDS. Among the human immunodeficiency virus (HIV)-seropositive subjects, cryptococcal meningitis is the second most common cause of opportunistic neuro-infection. Current trends are changing due to the marked improvement of quality and length of life produced by highly active antiretroviral therapy (HAART). The introduction of generic HAART in India has resulted in an increase in the number of individuals getting treatment for HIV infection, as the cost of highly active antiretroviral therapy (HAART) has decreased 20- fold. Cryptococcal meningitis occurs in non-HIV patients who are immunodeficient due to diabetes, cancer, solid organ transplants, chemotherapeutic drugs, hematological malignancies etc and rarely in healthy individuals with no obvious predisposing factors. Diagnosis of cryptococcal meningitis is fairly straightforward once the diagnosis is considered in the differential diagnosis of chronic meningitis. Treatment of a patient with cryptococcal infection is a challenge for both the physician and the patient, but rewarding, as many would recover with timely and adequate antifungal therapy.

Modulation of cardiac autonomic balance with adjuvant yoga therapy in patients with refractory epilepsy

The practice of yoga regulates body physiology through control of posture, breathing, and meditation. Effects of yoga on autonomic functions of patients with refractory epilepsy, as quantified by standardized autonomic function tests (AFTs), were determined. The yoga group (n=18) received supervised training in yoga, and the exercise group (n=16) practiced simple routine exercises. AFTs were repeated after 10 weeks of daily sessions. Data were compared with those of healthy volunteers (n=142). The yoga group showed significant improvement in parasympathetic parameters and a decrease in seizure frequency scores. There was no improvement in blood pressure parameters in either group. Two patients in the yoga group achieved normal autonomic functions at the end of 10 weeks of therapy, whereas there were no changes in the exercise group. The data suggest that yoga may have a role as an adjuvant therapy in the management of autonomic dysfunction in patients with refractory epilepsy.

Eccentric Target Sign in Cerebral Toxoplasmosis – neuropathological correlate to the imaging feature

Cerebral toxoplasmosis remains one of the most common focal brain lesions in patients with acquired immune deficiency syndrome (AIDS). Diagnosis is a challenge because on cranial imaging it closely mimics central nervous system lymphoma, primary and metastatic central nervous system (CNS) tumors, or other intracranial infections like tuberculoma or abscesses. A magnetic resonance imaging (MRI) feature on postcontrast T1‐weighted sequences considered pathognomonic of toxoplasmosis is the “eccentric target sign.” The pathological correlate of this imaging sign has been speculative. Herein we correlate the underlying histopathology to the MR feature of eccentric target sign in a patient with autopsy‐proven HIV/AIDS‐related cerebral toxoplasmosis. The central enhancing core of the target seen on MRI was produced by a leash of inflamed vessels extending down the length of the sulcus that was surrounded by concentric zones of necrosis and a wall composed of histiocytes and proliferating blood vessels, with impaired permeability producing the peripheral enhancing rim. J. Magn. Reson. Imaging 2010;31:1469–1472.

Epilepsia Partialis Continua over last 14 years: experience from a tertiary care center from south India.

Epilepsia Partialis Continua (EPC), a subtype of status epilepticus has varied etiology and the outcome depends on the cause. The aim of this study was to analyze the demographic, semiology, etiology, radiological findings, therapeutic response and outcome of EPC. This is a retrospective analysis of 76 patients (M:F: 46:30; mean age: 30.2+/-23.4 years; median age: 26 years) evaluated at our center over last 14 years. Twenty-three subjects (30.3%) had epilepsy for a mean of 25.8+/-52.3 months (range: 1-81 years; median: 14) before developing EPC and in half of them, seizures were controlled with anti-epileptic drugs (AEDs). Rest 53 (69.3%) manifested as de novo. The mean duration of EPC was 47.02+/-188.2 days (range: 1h to 48 months; median: 3 days). One patient of generalized convulsive SE (GCSE) evolved into EPC while five patients of EPC evolved into GCSE. CT scan of brain (n-76) was abnormal in 53 (69.7%) while all the 11 MRI scans which were available were abnormal. EEG (n-21) was abnormal in all but one, however it was non-specific in 7. The diagnoses were-idiopathic: 17, ischemic stroke: 15, meningo-encephalitis: 8, Rasmussens encephalitis (RE): 7, granuloma: 6, diabetic-non-ketotic-hyperosmolar-coma (DNKHC): 6, CNS malignancies (primary/secondary): 4, birth injury: 4, cerebral venous thrombosis: 3, CNS tuberculosis: 2, and cerebritis, HIV-related, toxemia of pregnancy, and MERRF one each. Patients of >40 years (n=21) had stroke (10), idiopathic (6), DNKHC (4) and metastasis (1) as common causes. Only 12 of them received single AED, while others required 2 or more AEDs to control the seizures. The outcome (n=72) was-controlled: 43 (59.7%); uncontrolled: 26 (36.1%) (RE: 7, idiopathic: 5, birth injury: 4, encephalitis: 3, malignancy: 2, granuloma and MERRF: 1 each) and three patients succumbed (encephalitis: 2, idiopathic: 1). Causes of EPC are varied and it depends on age. Underlying cause determined the outcome and could be refractory in RE, idiopathic, and when associated with birth injury, malignancy and encephalitis. Treatment of underlying cause is essential in addition to AEDs.

Seizures in HIV-seropositive individuals : NIMHANS experience and review

Seizures are not uncommon in patients with human immunodeficiency virus (HIV) infection, and with the upsurge in HIV infection this may be an important cause for acute symptomatic seizures. Seizures may rarely be the presenting manifestation of HIV infection. Opportunistic infections such as toxoplasmosis, tuberculosis, progressive multifocal leucoencephalopathy (PML), cryptococcal meningitis and polymicrobial infections, metabolic and electrolyte disturbances, and drugs are common causes of new‐onset seizures in HIV‐seropositive individuals. In the absence of any cause, primary HIV infection may be considered responsible for seizures. Because seizures tend to recur in and because they are a poor prognostic indicator in HIV infection, treatment with antiepileptic drugs (AEDs) is the norm. The treatment of HIV‐infected individuals with seizures comprises of the administration of AEDs, specific treatment of the underlying conditions, and antiretroviral drugs. Clinicians must consider both therapy‐compromising drug–drug and drug–disease interactions while choosing appropriate AEDs. The ideal AED in this setting is one that does not affect viral replication, have limited protein binding, and have no effects on the hepatic cytochrome P450 enzyme system. The risks for AED‐induced allergic skin rash appears to be high in HIV‐seropositive individuals.

Rabies viral encephalitis: clinical determinants in diagnosis with special reference to paralytic form

Background Rabies is an important public health problem in developing countries such as India where an alarmingly high incidence of the infection is reported every year despite the availability of highly effective, potent and safe vaccines. In clinical practice, diagnosis of the furious (encephalitic) form of rabies poses little difficulty. In contrast, the paralytic form poses a diagnostic dilemma, to distinguish it from Guillain–Barré syndrome. The problem is further compounded in the absence of a history of dog bite, clinical features resembling a psychiatric syndrome. Method The present study analysed the spectrum of neurological manifestations in 47 cases of rabies encephalitis (34 paralytic, six encephalitic, and seven psychiatric manifestations) from two hospitals in south India, confirmed at post-mortem by demonstration of a viral antigen in the brain. A history of dog bite was elicited in 33 patients and fox bite in one. Twenty-two patients received postexposure prophylaxis. The incubation period ranged from 7 days to 4 years. Clinical features were analysed, looking for any clinical pointers that provide clues to a diagnosis of paralytic rabies. Results and discussion Fever, distal paresthaesias, fasciculation, alteration in sensorium, rapid progression of symptoms and pleocytosis in cerebrospinal fluid should alert the neurologist to consider rabies encephalomyelitis. Detection of the viral antigen in the corneal smear and a skin biopsy from the nape of the neck had limited usefulness in the ante-mortem diagnosis. Although a few clinical signs may help indicate rabies encephalomyelitis antemortem, confirmation requires neuropathological/neurovirological assistance. The preponderance of atypical/paralytic cases in this series suggests that neurologists and psychiatrists need to have a high index of clinical suspicion, particularly in the absence of a history of dog bite.

Management of generalised convulsive status epilepticus (SE): A prospective randomised controlled study of combined treatment with intravenous lorazepam with either phenytoin, sodium valproate or levetiracetam – Pilot study

OBJECTIVE This study was conducted to compare the efficacy of phenytoin, valproate and levetiracetam in patients with GCSE. METHODS This randomised controlled prospective study was conducted on 150 patients to compare the efficacy of phenytoin (n = 50), valproate (n = 50) and levetiracetam (n = 50) along with lorazepam in patients with GCSE. All recruited patients received i.v. lorazepam (0.1mg/kg) followed by one of the 3 AEDs viz. phenytoin (20 mg/kg), valproate (30 mg/kg), and levetiracetam (25 mg/kg). Those who remained uncontrolled with 1st AED, received the other two AEDs sequentially. Clinical, imaging, EEG, etiological factors were analysed. Predictors of poor seizure control and outcome at discharge and at one month follow-up were assessed. RESULTS In the phenytoin subgroup, the seizures could be controlled in 34 (68%) with lorazepam+phenytoin infusion. In the valproate subgroup (n = 50), seizures could be controlled in 34 (68%) with lorazepam+valproate infusion. In the levetiracetam subgroup (n = 50), seizures could be controlled in 39 (78%) with lorazepam+levetiracetam infusion. There was no statistically significant difference between the subgroups (p = 0.44). Overall, following lorazepam and 1st AED, 107/150 (71.3%) were controlled; with addition of 2nd AED, 130/150 (86.7%) and by adding 3rd AED, 138/150 (92%) were controlled. Fifteen out of 110 (13.6%) expired within 1 month of SE: phenytoin-6; valproate-4; and levetiracetam-5. Interestingly, 3 patients in the levetiracetam had post-ictal psychosis. SIGNIFICANCE Phenytoin, valproate, and levetiracetam are safe and equally efficacious following lorazepam in GCSE. The choice of AEDs could be individualised based on co-morbidities. SE could be controlled in 92% of patients with AEDs only and anaesthetics were not required in them.

Progressive myoclonic epilepsy: A clinical, electrophysiological and pathological study from South India

Progressive myoclonic epilepsy (PME) is a syndrome complex encompassing different diagnostic entities and often cause problems in diagnosis. We describe the clinical, electrophysiological and pathological features of 97 patients with the diagnosis of PME evaluated over 25 years. Case records of confirmed patients of Neuronal ceroid lipofuscinosis (NCL = 40), Lafora body disease (LBD = 38), Myoclonic epilepsy with ragged red fibers (MERRF = 10), and probable Unverricht-Lundberg disease (ULD = 9) were reviewed. The mean age at onset in patients with NCL (n = 40) was 5.9+/-9.1 years (M:F:: 28:12). Subtypes of NCL were: late infantile (n = 19), infantile (n = 8), juvenile (n = 11) and adult (n = 2) NCL. EEG (n = 37) showed varying degree of diffuse slowing of background activity in 94.6% and epileptiform discharges in 81.1% of patients. Slow frequency photic stimulation evoked photo-convulsive response in 5 patients only. Giant SSEP was demonstrated in 7 and VEP study revealed a prolonged P100 (2) and absent waveform (7). Electrophysiological features of neuropathy were present in 3 patients. Presence of PAS and Luxol Fast Blue (LFB) positive, auto fluorescent (AF) ceroid material in brain tissue (n = 12) and electron microscopy of brain (n = 5), skin (n = 28) and muscle (n = 1) samples showing curvilinear and lamellar bodies established the diagnosis. Patients of LBD (mean age of onset at 14.4+/-3.9 years, M:F:: 24:14) with triad of PME symptoms were evaluated. EEG (n = 37) showed variable slowing of background activity in 94.6% and epileptiform discharges in 97.4%. Photosensitivity with fast frequency was observed only in 5 patients. CT (n = 32) and MRI (n = 4) revealed diffuse cortical atrophy. Giant SSEP was demonstrated in 24 patients of LBD while VEP study revealed a prolonged P100 (4) and absent waveform (8). Electrophysiological features of neuropathy were present in one patient. Diagnosis was established by the presence of PAS positive diastase resistant, Lugols Iodine labeled inclusions in sweat glands of axillary skin (n = 35), brain (n = 2) and liver (n = 1). Ten patients with MERRF (mean age at onset: 14.6+/-5.8 years; M: F:: 3:2) had triad of PME symptoms. Muscle biopsy revealed oxidative reaction product and classical ragged red fibers. In nine patients of PME without cognitive decline, probable diagnosis of ULD (mean age at onset: 13.8+/-9.5 years) was considered after biopsy of skin and/or muscle excluded other forms of PMEs. Neuronal ceroid lipofuscinosis and Lafora body diseases were the common causes of PME in the series from south India. This is one of the largest series from the Indian subcontinent to the best of our knowledge. Photosensitivity is notably less common in LBD/NCL in this series distinctly different from those reported in the literature. Further exploration is required to determine whether different genotype is responsible. Morphological changes were helpful in diagnosis and could be confirmed by biopsy of peripheral tissues like skin and muscle in majority (60%). Electron microscopy was helpful in the diagnosis NCL and MERRF.

Neuronal ceroid lipofuscinosis: a clinicopathological study.

We report the clinical, electrophysiological, radiological and morphological features in a series of 12 patients of histopathologically confirmed cases (infantile, juvenile and adult onset) of neuronal ceroid lipofuscinosis (NCL) observed from 1979 to 1998 at National Institute of Mental Health & Neurosciences (NIMHANS), Bangalore (South India). The commonest type of NCL was juvenile (n = 8, 67%) while infantile and adult forms were two each (n = 2, 16.8%). The age at presentation ranged from 2 to 45 years (mean--12.6, 14.3 years; median--7 years; M:F ratio of 2:1). Four patients (33%) had positive family history and five patients had history of consanguineous parentage (41.6%). The commonest presenting symptoms were regression of milestones (83.3%) and/or seizures, myoclonus (83.8%) followed by involuntary choreiform movements (50%), visual loss (41.6%), ataxia (33.3%) and abnormal behaviour (16.6%). Neuro-ophthalmological abnormalities like optic atrophy (50%), macular degeneration (33.3%) and retinitis pigmentosa (8.3%) were seen in two thirds. Nerve conduction studies (n = 4) revealed abnormalities in two, suggestive of sensorimotor neuropathy. Scalp EEG (n = 9) showed slowing of background activity (BGA) of varying degrees with paroxysmal bursts of seizure discharges in majority. Cranial CT scan (n = 4) revealed varying degrees of diffuse atrophy. Diagnostic brain biopsy was carried out in 11 and brain was examined at autopsy in 1 case. Histological examination revealed characteristic PAS and Luxol Fast Blue (LFB) positive, autofluorescent (AF) intracellular ceroid material, both in neurons and astrocytes in the grey matter. Electron microscopy (n = 5) revealed curvilinear (n = 4), lamellar (n = 2) and electron dense (n = 2) inclusions in neurons, astrocytes and vascular endothelial cells. To conclude, this neurodegenerative disease had varied but characteristic clinical presentations and required histopathological confirmation of diagnosis.