Heather Sheriff

The Frequency of Autoimmune N-Methyl-D-Aspartate Receptor Encephalitis Surpasses That of Individual Viral Etiologies in Young Individuals Enrolled in the California Encephalitis Project

BACKGROUND In 2007, the California Encephalitis Project (CEP), which was established to study the epidemiology of encephalitis, began identifying cases of anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis. Increasing numbers of anti-NMDAR encephalitis cases have been identified at the CEP, and this form rivals commonly known viral etiologies as a causal agent. We report here the relative frequency and differences among encephalitides caused by anti-NMDAR and viral etiologies within the CEP experience. METHODS Demographic, frequency, and clinical data from patients with anti-NMDAR encephalitis are compared with those with viral encephalitic agents: enterovirus, herpes simplex virus type 1 (HSV-1), varicella-zoster virus (VZV), and West Nile virus (WNV). All examined cases presented to the CEP between September 2007 and February 2011 and are limited to individuals aged ≤30 years because of the predominance of anti-NMDAR encephalitis in this group. The diagnostic costs incurred in a single case are also included. RESULTS Anti-NMDAR encephalitis was identified >4 times as frequently as HSV-1, WNV, or VZV and was the leading entity identified in our cohort. We found that 65% of anti-NMDAR encephalitis occurred in patients aged ≤18 years. This disorder demonstrated a predilection, which was not observed with viral etiologies, for females (P < .01). Seizures, language dysfunction, psychosis, and electroencephalographic abnormalities were significantly more frequent in patients with anti-NMDAR encephalitis (P < .05), and autonomic instability occurred exclusively in this group. DISCUSSION Anti-NMDAR encephalitis rivals viral etiologies as a cause of encephalitis within the CEP cohort. This entity deserves a prominent place on the encephalitic differential diagnosis to avoid unnecessary diagnostic and treatment costs, and to permit a more timely treatment.

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.

Herpes simplex virus encephalitis is a trigger of brain autoimmunity

In 5 prospectively diagnosed patients with relapsing post–herpes simplex encephalitis (HSE), N‐methyl‐D‐aspartate receptor (NMDAR) antibodies were identified. Antibody synthesis started 1 to 4 weeks after HSE, preceding the neurological relapse. Three of 5 patients improved postimmunotherapy, 1 spontaneously, and 1 has started to improve. Two additional patients with NMDAR antibodies, 9 with unknown neuronal surface antibodies, and 1 with NMDAR and unknown antibodies, were identified during retrospective assessment of 34 HSE patients; the frequency of autoantibodies increased over time (serum, p = 0.004; cerebrospinal fluid, p = 0.04). The 3 retrospectively identified NMDAR antibody–positive patients also had evidence of relapsing post‐HSE. Overall, these findings indicate that HSE triggers NMDAR antibodies and potentially other brain autoimmunity. Ann Neurol 2014;75:317–323

Use of Clinical and Neuroimaging Characteristics to Distinguish Temporal Lobe Herpes Simplex Encephalitis From Its Mimics

BACKGROUND We describe the spectrum of etiologies associated with temporal lobe (TL) encephalitis and identify clinical and radiologic features that distinguish herpes simplex encephalitis (HSE) from its mimics. METHODS We reviewed all adult cases of encephalitis with TL abnormalities on magnetic resonance imaging (MRI) from the California Encephalitis Project. We evaluated the association between specific clinical and MRI characteristics and HSE compared with other causes of TL encephalitis and used multivariate logistic modeling to identify radiologic predictors of HSE. RESULTS Of 251 cases of TL encephalitis, 43% had an infectious etiology compared with 16% with a noninfectious etiology. Of infectious etiologies, herpes simplex virus was the most commonly identified agent (n = 60), followed by tuberculosis (n = 8) and varicella zoster virus (n = 7). Of noninfectious etiologies, more than half (n = 21) were due to autoimmune disease. Patients with HSE were older (56.8 vs 50.2 years; P = .012), more likely to be white (53% vs 35%; P = .013), more likely to present acutely (88% vs 64%; P = .001) and with a fever (80% vs 49%; P < .001), and less likely to present with a rash (2% vs 15%; P = .010). In a multivariate model, bilateral TL involvement (odds ratio [OR], 0.38; 95% confidence interval [CI], .18-.79; P = .010) and lesions outside the TL, insula, or cingulate (OR, 0.37; 95% CI, .18-.74; P = .005) were associated with lower odds of HSE. CONCLUSIONS In addition to HSE, other infectious and noninfectious etiologies should be considered in the differential diagnosis for TL encephalitis, depending on the presentation. Specific clinical and imaging features may aid in distinguishing HSE from non-HSE causes of TL encephalitis.

Acute Flaccid Myelitis of Unknown Etiology in California, 2012-2015.

IMPORTANCE There has been limited surveillance for acute flaccid paralysis in North America since the regional eradication of poliovirus. In 2012, the California Department of Public Health received several reports of acute flaccid paralysis cases of unknown etiology. OBJECTIVE To quantify disease incidence and identify potential etiologies of acute flaccid paralysis cases with evidence of spinal motor neuron injury. DESIGN, SETTING, AND PARTICIPANTS Case series of acute flaccid paralysis in patients with radiological or neurophysiological findings suggestive of spinal motor neuron involvement reported to the California Department of Public Health with symptom onset between June 2012 and July 2015. Patients meeting diagnostic criteria for other acute flaccid paralysis etiologies were excluded. Cerebrospinal fluid, serum samples, nasopharyngeal swab specimens, and stool specimens were submitted to the state laboratory for infectious agent testing. MAIN OUTCOMES AND MEASURES Case incidence and infectious agent association. RESULTS Fifty-nine cases were identified. Median age was 9 years (interquartile range [IQR], 4-14 years; 50 of the cases were younger than 21 years). Symptoms that preceded or were concurrent included respiratory or gastrointestinal illness (n = 54), fever (n = 47), and limb myalgia (n = 41). Fifty-six patients had T2 hyperintensity of spinal gray matter on magnetic resonance imaging and 43 patients had cerebrospinal fluid pleocytosis. During the course of the initial hospitalization, 42 patients received intravenous steroids; 43, intravenous immunoglobulin; and 13, plasma exchange; or a combination of these treatments. Among 45 patients with follow-up data, 38 had persistent weakness at a median follow-up of 9 months (IQR, 3-12 months). Two patients, both immunocompromised adults, died within 60 days of symptom onset. Enteroviruses were the most frequently detected pathogen in either nasopharynx swab specimens, stool specimens, serum samples (15 of 45 patients tested). No pathogens were isolated from the cerebrospinal fluid. The incidence of reported cases was significantly higher during a national enterovirus D68 outbreak occurring from August 2014 through January 2015 (0.16 cases per 100,000 person-years) compared with other monitoring periods (0.028 cases per 100,000 person-years; P <.001). CONCLUSIONS AND RELEVANCE In this series of patients identified in California from June 2012 through July 2015, clinical manifestations indicated a rare but distinct syndrome of acute flaccid paralysis with evidence of spinal motor neuron involvement. The etiology remains undetermined, most patients were children and young adults, and motor weakness was prolonged.

The Role of Continuous Electroencephalography in Childhood Encephalitis

BACKGROUND Seizures are a known complication of encephalitis. We sought to determine the incidence of seizures and the relative utility of routine and continuous electroencephalography in children with suspected encephalitis. METHODS Records from all 217 children (ages 0-20 years, enrolled 2004-2011) from our institution who had diagnostic samples sent to the California Encephalitis Project were reviewed. RESULTS One hundred children (46%) had at least one seizure observed clinically or recorded on electroencephalography. Diffuse abnormalities (e.g., generalized slowing) were more common than focal or epileptiform abnormalities (88.9% vs 63.2% and 57.3%, respectively; P < 0.0001), but focal and epileptiform abnormalities were more correlated with seizures (91.0% [P = 0.04] and 89.2% [P = 0.05], respectively vs 76.9%). Fifty-four patients (25%) had at least 1 day of continuous electroencephalography. When used, continuous electroencephalography recorded a seizure in more than half of patients. Six children had no recognized seizure (clinical or electrographic) before continuous electroencephalography was performed. Twenty-two children (10%) had a seizure recorded by continuous electroencephalography after routine electroencephalography did not record a seizure. Overall, continuous electroencephalography was more likely to capture a seizure, capture a subclinical seizure, or rule out a concerning event as a seizure than routine electroencephalography (all comparisons P < 0.0001). CONCLUSIONS Children with suspected encephalitis are at high risk for seizures. Continuous electroencephalography is better able than routine electroencephalography to determine whether seizures are present. Further, continuous electroencephalography can guide treatment by classifying a clinical event as seizure or seizure-mimic. Our findings support the expanded use of continuous electroencephalography in children with suspected encephalitis.

Insights into Pediatric Herpes Simplex Encephalitis From a Cohort of 21 Children From the California Encephalitis Project, 1998–2011:

Twenty-one children with confirmed herpes simplex encephalitis were identified in the California Encephalitis Project. Noteworthy features included 6 (29%) patients with an initial negative herpes simplex virus cerebrospinal fluid polymerase chain reaction test and 13 (59%) patients with extratemporal lobe involvement identified by neuroimaging. Eleven cases were <4 years of age, but all 4 fatal cases occurred in adolescents.

Encephalitis With Thalamic and Basal Ganglia Abnormalities: Etiologies, Neuroimaging, and Potential Role of Respiratory Viruses

BACKGROUND Encephalitis is a severe neurological syndrome with devastating consequences. Despite extensive testing, the etiology often remains unknown. Involvement of the thalamus or basal ganglia (T/BG) occurs in a subset of patients with encephalitis and may be an important etiological clue. In order to improve diagnosis of T/BG patients, we reviewed this subgroup within the California Encephalitis Project (CEP). METHODS Data from T/BG cases enrolled in CEP were retrospectively reviewed. Cases were stratified by age and grouped by etiological classification: infectious, postinfectious, and noninfectious. Neuroimaging reports were examined and compared between etiologies. RESULTS T/BG neuroimaging abnormalities were reported in 6% of 3236 CEP cases. An etiology was found in 76%: 37% infectious, 16% postinfectious, and 23% noninfectious. The most frequently identified infectious agents were respiratory viruses, accounting for 31%, predominantly in children. Other infections more common in the T/BG group included Creutzfeldt-Jakob disease, arbovirus, and Mycobacterium tuberculosis. Infectious and postinfectious cases had higher median cerebrospinal fluid white blood cell count than noninfectious etiologies. Notably, T/BG neuroimaging characteristics were associated with distinct etiologies. In particular, symmetric hemorrhagic abnormalities involving the thalamus were most frequently found within the respiratory virus group. CONCLUSIONS T/BG involvement in patients with suspected encephalitis was associated with specific etiologies. In addition to agents with established predilection for the T/BG such as M. tuberculosis and arboviruses, a surprisingly high number of cases were associated with respiratory viruses, especially in children. Neuroimaging abnormalities in such patients can aid clinicians in narrowing the etiological scope and in guiding testing.

A Case Series of Three US Adults With Japanese Encephalitis, 2010–2012

BACKGROUND Japanese encephalitis (JE) virus is the leading cause of vaccine-preventable encephalitis in Asia. Although the risk for acquiring JE for most travelers to Asia is low, it varies based on the destination, season, trip duration, and activities. METHODS We present case reports of three US adults who were infected with JE virus while traveling or residing in Asia. RESULTS Among the three JE patients, the first made a 10-day trip to mainland China and participated in outdoor activities in a rural area, the second had been resident in Taiwan for 4 months, and the third, fatal case was an expatriate living in South Korea. CONCLUSIONS JE should be considered in the differential diagnosis for any patient with an acute neurologic infection, who has recently been in a JE-endemic country. Health-care providers should assess the itineraries of travelers to JE-endemic countries, provide guidance on personal protective measures to prevent vector-borne diseases, and consider recommending JE vaccine for travelers at increased risk for JE virus infection.

The LGBTQI health forum: an innovative interprofessional initiative to support curriculum reform

ABSTRACT Lesbian, gay, bisexual, transgender, queer, and intersex (LGBTQI) individuals continue to face barriers to accessing appropriate and comprehensive healthcare. Compounding this problem, healthcare trainees report few training opportunities and low levels of preparedness to care for LGBTQI patients. In 2009, an interprofessional group of students and a faculty advisor at the University of California, San Francisco, developed a novel student-organized LGBTQI Health Forum for medical, dental, pharmacy, nursing, and physical therapy students to deliver LGBTQI health content that was otherwise absent from the formal curriculum. This elective course has evolved based upon participant feedback, emerging educational strategies, and the existing curricula infrastructure at our institution. After eight years of growth, this 10-contact hour weekend elective attracts over 250 participants each year. Plenary sessions deliver foundational terminology and skills to all attendees. Learners then select breakout sessions to attend, allowing for an individualized curriculum based upon specific interests and knowledge gaps. Breakout session topics prioritize traditionally underrepresented aspects of LGBTQI health in professional school curricula. This Forum serves as a model in which to supplement LGBTQI content into existing school curricula and offers an opportunity for interprofessional education. Next steps include conducting a formal evaluation of the curriculum, expanding our performance-based assessments, and potentially implementing a continuing education program for licensed practitioners. With a core group of interprofessional student organizers and a faculty champion, other institutions may view this course architecture as a potential way to offer learners not only LGBTQI content, but other underrepresented subjects into their own educational programs.