Arun Venkatesan

Case Definitions, Diagnostic Algorithms, and Priorities in Encephalitis: Consensus Statement of the International Encephalitis Consortium

BACKGROUND Encephalitis continues to result in substantial morbidity and mortality worldwide. Advances in diagnosis and management have been limited, in part, by a lack of consensus on case definitions, standardized diagnostic approaches, and priorities for research. METHODS In March 2012, the International Encephalitis Consortium, a committee begun in 2010 with members worldwide, held a meeting in Atlanta to discuss recent advances in encephalitis and to set priorities for future study. RESULTS We present a consensus document that proposes a standardized case definition and diagnostic guidelines for evaluation of adults and children with suspected encephalitis. In addition, areas of research priority, including host genetics and selected emerging infections, are discussed. CONCLUSIONS We anticipate that this document, representing a synthesis of our discussions and supported by literature, will serve as a practical aid to clinicians evaluating patients with suspected encephalitis and will identify key areas and approaches to advance our knowledge of encephalitis.

Evolution of HIV dementia with HIV infection

Dementia remains one of the most fearsome complications of HIV infection. It also poses a significant challenge for the clinician both in terms of diagnosis and treatment. The use of antiretroviral agents has led to a decrease in the incidence of HIV dementia but the prevalence of milder forms of neurocognitive impairment has increased. Occasionally, the immune reconstitution caused by these agents may target the brain leading to a syndrome characterized by a severe, progressive and often fatal dementia. The progression of HIV dementia may also be determined by host and viral genetic factors, and the existence of co-morbid factors such as drug abuse, hepatitis C infection and aging. Oxidative stress markers appear to be predictive of active dementia. However, currently there is no specific treatment available for HIV dementia.

Gut Microbiota in Multiple Sclerosis: Possible Influence of Immunomodulators

Objectives Differences in gut bacteria have been described in several autoimmune disorders. In this exploratory pilot study, we compared gut bacteria in patients with multiple sclerosis and healthy controls and evaluated the influence of glatiramer acetate and vitamin D treatment on the microbiota. Methods Subjects were otherwise healthy white women with or without relapsing-remitting multiple sclerosis who were vitamin D insufficient. Patients with multiple sclerosis were untreated or were receiving glatiramer acetate. Subjects collected stool at baseline and after 90 days of vitamin D3 (5000 IU/d) supplementation. The abundance of operational taxonomic units was evaluated by hybridization of 16S rRNA to a DNA microarray. Results While there was overlap of gut bacterial communities, the abundance of some operational taxonomic units, including Faecalibacterium, was lower in patients with multiple sclerosis. Glatiramer acetate–treated patients with multiple sclerosis showed differences in community composition compared with untreated subjects, including Bacteroidaceae, Faecalibacterium, Ruminococcus, Lactobacillaceae, Clostridium, and other Clostridiales. Compared with the other groups, untreated patients with multiple sclerosis had an increase in the Akkermansia, Faecalibacterium, and Coprococcus genera after vitamin D supplementation. Conclusions While overall bacterial communities were similar, specific operational taxonomic units differed between healthy controls and patients with multiple sclerosis. Glatiramer acetate and vitamin D supplementation were associated with differences or changes in the microbiota. This study was exploratory, and larger studies are needed to confirm these preliminary results.

Ketogenic diet for adults in super-refractory status epilepticus

Objective: To describe a case series of adult patients in the intensive care unit in super-refractory status epilepticus (SRSE; refractory status lasting 24 hours or more despite appropriate anesthetic treatment) who received treatment with the ketogenic diet (KD). Methods: We performed a retrospective case review at 4 medical centers of adult patients with SRSE treated with the KD. Data collected included demographic features, clinical presentation, diagnosis, EEG data, anticonvulsant treatment, and timing and duration of the KD. Primary outcome measures were resolution of status epilepticus (SE) after initiation of KD and ability to wean from anesthetic agents. Results: Ten adult patients at 4 medical centers were started on the KD for SRSE. The median age was 33 years (interquartile range [IQR] 21), 4 patients (40%) were male, and 7 (70%) had encephalitis. The median duration of SE before initiation of KD was 21.5 days (IQR 28) and the median number of antiepileptic medications used before initiation of KD was 7 (IQR 7). Ninety percent of patients achieved ketosis, and SE ceased in all patients achieving ketosis in a median of 3 days (IQR 8). Three patients had minor complications of the KD including transient acidosis and hypertriglyceridemia and 2 patients ultimately died of causes unrelated to the KD. Conclusion: We describe treatment of critically ill adult patients with SRSE with the KD, with 90% of patients achieving resolution of SE. Prospective trials are warranted to examine the efficacy of the KD in adults with refractory SE. Classification of evidence: This study provides Class IV evidence that for intensive care unit patients with refractory SE, a KD leads to resolution of the SE.

Atypical manifestations and poor outcome of herpes simplex encephalitis in the immunocompromised

ABSTRACT Objective: To characterize clinical features, neuroimaging, and outcomes of herpes simplex encephalitis (HSE) in immunocompromised individuals. Methods: We performed a retrospective case control review of patients diagnosed with HSE. Adult patients were dichotomized into immunocompromised (n = 14) and immunocompetent groups (n = 15). Results: Fewer immunocompromised patients presented with prodromal symptoms and focal deficits. While the majority of CSF profiles in the immunocompromised patients were mononuclear cells predominant, 3 had polymorphonuclear predominance and another 3 had normal profiles. MRI showed widespread cortical involvement, with brainstem or cerebellar involvement in some. Two immunocompromised patients had recurrent HSE. The immunosuppressed state was associated with a decrease in Karnofsky Performance Status Scale (KPSS) score of 23.1 (p = 0.018). Every 1-day delay in initiation of acyclovir was associated with a decrease in KPSS of 10.2 (p = 0.002), and every 10 cell/mm3 increase of CSF leukocytosis was associated with an increase in KPSS of 0.7 (p = 0.009). Mortality rate was 6 times higher in the immunocompromised patients. Conclusions: Immunocompromised states may predispose to HSE with atypical clinical and neuroradiologic features. Immunocompromised individuals with HSE have significantly worse outcomes and mortality. Early diagnosis and treatment is associated with improved outcome. The findings are particularly important in light of the increasing use of potent immunosuppressive and immunomodulatory therapies.

Toll/Interleukin-1 Receptor Domain-Containing Adapter Inducing Interferon-β Mediates Microglial Phagocytosis of Degenerating Axons

Following CNS injury, microglial phagocytosis of damaged endogenous tissue is thought to play an important role in recovery and regeneration. Previous work has focused on delineating mechanisms of clearance of neurons and myelin. Little, however, is known of the mechanisms underlying phagocytosis of axon debris. We have developed a novel microfluidic platform that enables coculture of microglia with bundles of CNS axons to investigate mechanisms of microglial phagocytosis of axons. Using this platform, we find that axon degeneration results in the induction of type-1 interferon genes within microglia. Pharmacologic and genetic disruption of Toll/interleukin-1 receptor domain-containing adapter inducing interferon-β (TRIF), a Toll-like receptor adapter protein, blocks induction of the interferon response and inhibits microglial phagocytosis of axon debris in vitro. In vivo, microglial phagocytosis of axons following dorsal root axotomy is impaired in mice in which TRIF has been genetically deleted. Furthermore, we identify the p38 mitogen-activated protein kinase (MAPK) cascade as a signaling pathway downstream of TRIF following axon degeneration and find that inhibition of p38 MAPK by SB203580 (4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole) also blocked clearance of axon debris. Finally, we find that TRIF-dependent microglial clearance of unmyelinated axon debris facilitates axon outgrowth. Overall, we provide evidence that TRIF-mediated signaling plays an unexpected role in axonal debris clearance by microglia, thereby facilitating a more permissive environment for axonal outgrowth. Our study has significant implications for the development of novel regenerative and restorative strategies for the many traumatic, neuroinflammatory, and neurodegenerative conditions characterized by CNS axon degeneration.

Encephalitis hospitalization rates and inpatient mortality in the United States, 2000-2010.

Background Encephalitis rates by etiology and acute-phase outcomes for encephalitis in the 21st century are largely unknown. We sought to evaluate cause-specific rates of encephalitis hospitalizations and predictors of inpatient mortality in the United States. Methods Using the Nationwide Inpatient Sample (NIS) from 2000 to 2010, a retrospective observational study of 238,567 patients (mean [SD] age, 44.8 [24.0] years) hospitalized within non-federal, acute care hospitals in the U.S. with a diagnosis of encephalitis was conducted. Hospitalization rates were calculated using population-level estimates of disease from the NIS and population estimates from the United States Census Bureau. Adjusted odds of mortality were calculated for patients included in the study. Results In the U.S. from 2000–2010, there were 7.3±0.2 encephalitis hospitalizations per 100,000 population (95% CI: 7.1–7.6). Encephalitis hospitalization rates were highest among females (7.6±0.2 per 100,000) and those <1 year and >65 years of age with rates of 13.5±0.9 and 14.1±0.4 per 100,000, respectively. Etiology was unknown for approximately 50% of cases. Among patients with identified etiology, viral causes were most common (48.2%), followed by Other Specified causes (32.5%), which included predominantly autoimmune conditions. The most common infectious agents were herpes simplex virus, toxoplasma, and West Nile virus. Comorbid HIV infection was present in 7.7% of hospitalizations. Average length of stay was 11.2 days with mortality of 5.6%. In regression analysis, patients with comorbid HIV/AIDS or cancer had increased odds of mortality (odds ratio [OR]  = 1.70; 95% CI: 1.30–2.22 and OR = 2.26; 95% CI: 1.88–2.71, respectively). Enteroviral, postinfectious, toxic, and Other Specified causes were associated with lower odds vs. herpes simplex encephalitis. Conclusions While encephalitis and encephalitis-related mortality impose a considerable burden in the U.S. in the 21st Century, the reported demographics of hospitalized encephalitis patients may be changing.

Adult hippocampal neurogenesis: regulation by HIV and drugs of abuse

Abstract.New dentate granule cells are continuously generated from neural progenitor cells and integrated into the existing hippocampal circuitry in the adult mammalian brain through an orchestrated process termed adult neurogenesis. While the exact function remains elusive, adult neurogenesis has been suggested to play important roles in specific cognitive functions. Adult hippocampal neurogenesis is regulated by a variety of physiological and pathological stimulations. Here we review emerging evidence showing that HIV infection and several drugs of abuse result in molecular changes that may affect different aspects of adult hippocampal neurogenesis. These new findings raise the possibility that cognitive dysfunction in the setting of HIV infection or drug abuse may, in part, be related to alterations in hippocampal neurogenesis. A better understanding of how HIV and drugs of abuse affect both molecular and cellular aspects of adult neurogenesis may lead to development of more effective therapeutic interventions for these interlinked epidemics.

Circular compartmentalized microfluidic platform: Study of axon-glia interactions.

We describe a compartmentalized circular microfluidic platform that enables directed cell placement within defined microenvironments for the study of axon-glia interactions. The multi-compartment platform consists of independent units of radial microchannel arrays that fluidically isolate somal from axonal compartments. Fluidic access ports punched near the microchannels allow for direct pipetting of cells into the device. Adjacent somal or axonal compartments can be readily merged so that independent groups of neurons or axons can be maintained in either separate or uniform microenvironments. We demonstrate three distinct modes of directed cell placement in this device, to suit varying experimental needs for the study of axon-glia interactions: (1) centrifugation of the circular platform can result in a two-fold increase in axonal throughput in microchannels and provides a new technique to establish axon-glia interactions; (2) microstencils can be utilized to directly place glial cells within areas of interest; and (3) intimate axon-glia co-culture can be attained via standard pipetting techniques. We take advantage of this microfluidic platform to demonstrate a two-fold preferential accumulation of microglia specifically near injured CNS axons, an event implicated in the maintenance and progression of a number of chronic neuroinflammatory and neurodegenerative diseases.

Impairment of adult hippocampal neural progenitor proliferation by methamphetamine: role for nitrotyrosination

Methamphetamine (METH) abuse has reached epidemic proportions, and it has become increasingly recognized that abusers suffer from a wide range of neurocognitive deficits. Much previous work has focused on the deleterious effects of METH on mature neurons, but little is known about the effects of METH on neural progenitor cells (NPCs). It is now well established that new neurons are continuously generated from NPCs in the adult hippocampus, and accumulating evidence suggests important roles for these neurons in hippocampal-dependent cognitive functions. In a rat hippocampal NPC culture system, we find that METH results in a dose-dependent reduction of NPC proliferation, and higher concentrations of METH impair NPC survival. NPC differentiation, however, is not affected by METH, suggesting cell-stage specificity of the effects of METH. We demonstrate that the effects of METH on NPCs are, in part, mediated through oxidative and nitrosative stress. Further, we identify seventeen NPC proteins that are post-translationally modified via 3-nitrotyrosination in response to METH, using mass spectrometric approaches. One such protein was pyruvate kinase isoform M2 (PKM2), an important mediator of cellular energetics and proliferation. We identify sites of PKM2 that undergo nitrotyrosination, and demonstrate that nitration of the protein impairs its activity. Thus, METH abuse may result in impaired adult hippocampal neurogenesis, and effects on NPCs may be mediated by protein nitration. Our study has implications for the development of novel therapeutic approaches for METH-abusing individuals with neurologic dysfunction and may be applicable to other neurodegenerative diseases in which hippocampal neurogenesis is impaired.