Executive Summary: State-of-the Art: Acute Encephalitis

Encephalitis is a potentially devastating neurologic disease associated with significant morbidity during the acute illness and often complicated by prolonged neurologic deficits. Historically, only about half of all cases of encephalitis had a cause identified. Recent advances in molecular testing and the identification of a rapidly expanding number of autoimmune conditions have significantly impacted the evaluation and treatment of encephalitis. Best practices for the evaluation and management of adult patients with encephalitis are provided in the Summary Figure. This algorithm is directed toward pathogens found in the US and may require modification in other settings. Universal testing is recommended for a core group of common or treatable etiologies, with ancillary testing guided by epidemiologic, clinical, or radiographic findings suggestive of less common pathogens. The most common infectious causes of encephalitis in adults include herpes simplex virus (HSV)-1, varicella zoster virus (VZV), enteroviruses (EV) and West Nile virus (WNV). HSV-1 and EV are also common in children; VZV encephalitis has become rare following universal pediatric vaccination. In children and young adults, autoimmune conditions such anti-N-methyl-D-aspartate receptor (NMDAR) antibody encephalitis account for approximately 20-30% of cases, although onset may occur at any age. Empiric therapy for treatable pathogens is necessary pending testing results. Delay in treatment of HSV-1 encephalitis (HSE) is associated with adverse outcomes. Acyclovir should be continued until this diagnosis has been definitively excluded with a 2nd negative PCR test on a sequential CSF sample when there is a high clinical suspicion for HSE. Acyclovir dose can be increased (10-15 mg/kg every 8 hours) if VZV encephalitis is confirmed. Supportive care is necessary for other viral etiologies such as EV or WNV for which no effective antiviral therapy is available. Autoimmune encephalitis comprises a heterogeneous group of conditions, including anti-NMDAR antibody encephalitis, the most common antibody-associated encephalitis. This was initially associated with ovarian teratomas, thought to be due to molecular mimicry. It is now well established that other conditions can trigger anti-NMDAR antibody encephalitis, including HSE. Autoimmune disease occurs weeks to months following infection and should be considered in patients who develop new or progressive symptoms despite acyclovir therapy. Immunotherapy is indicated when autoimmune encephalitis is confirmed or thought probable. Autoimmune encephalitides are best managed in conjunction with a neuroimmunologist. Patients in whom no cause for encephalitis is identified represent a particular challenge. Additional evaluation can include probing for missed exposures, repeat lumbar puncture and brain MRI, imaging for occult malignancy (associated with paraneoplastic syndromes), and empiric immunomodulary treatment for antibody-negative autoimmune conditions. Next-generation sequencing (NGS) of CSF to identify novel or unexpected pathogens should be considered. Finally, brain biopsy may be of utility in immunocompromised patients or when there is a focal lesion on MRI. The rapid pace of discovery regarding autoimmune encephalitis and the development of advanced molecular tests such as NGS have improved diagnosis and outcomes in patients with encephalitis. Lacking are effective treatment options for non-herpes group viral pathogens. Research priorities include development of novel therapeutics and post-hospitalization interventions to optimize neurologic recovery. Summary Figure Abbreviations: ACV, acyclovir; AI, autoimmune; CrAg, cryptococcal antigen; CSF, cerebrospinal fluid; EV, enteroviruses; HIV, human immunodeficiency virus; HSV, herpes simplex virus; ICU, intensive care unit; IVIg, intravenous immunoglobulin; NGS, next generation sequencing; NMDAR, N-methyl-D-aspartate receptor; PCR, polymerase chain reaction; PLEX, plasma exchange; RPR, rapid plasma reagin; VDRL, venereal disease research lab; VZV, varicella zoster virus; WNV, West Nile virus.