Acute encephalitis in immunocompetent adults

Summary

Encephalitis is a condition of inflammation of the brain parenchyma, occurs as a result of infectious or autoimmune causes, and can lead to encephalopathy, seizures, focal neurological deficits, neurological disability, and death. Viral causes account for the largest proportion, but in the last decade there has been growing recognition of anti-neuronal antibody syndromes. This Seminar focuses on the diagnosis and management of acute encephalitis in adults. Although viral and autoimmune causes are highlighted because of their prominent roles in encephalitis, other infectious pathogens are also considered. The role of cerebrospinal fluid studies, MRI, and novel diagnostic modalities (eg, next-generation sequencing) are discussed. Management approaches, including treatment of acute neurological complications and the use of immune suppressive and modulatory drugs for cases of suspected or confirmed autoimmune cause, are covered. Additionally, we discuss the remaining challenges in the diagnosis, management, and prognosis of encephalitis.

Introduction

Encephalitis is inflammation of the brain parenchyma with associated neurological dysfunction and can be due to a wide variety of infectious and autoimmune causes. Encephalitis most often manifests as encephalopathy, although for autoimmune encephalitides short-term memory loss or new onset psychiatric changes alone can occur (panel 1).1, 2 Patients with suspected encephalitis must be evaluated for alternative conditions3, 4 because encephalopathy can arise from a broad range of pathological processes. Additionally, clinical consensus criteria incorporate the requirement of acute to subacute clinical progression on the order of days to weeks to better differentiate acute encephalitis from other neurodegenerative causes of rapidly progressive dementia.⁵ Other supportive elements for a diagnosis of encephalitis include fever, seizures not attributable to a pre-existing seizure disorder, new onset focal neurological findings, or investigative findings (eg, cerebrospinal fluid [CSF] pleocytosis and neuroimaging or electroencephalographic abnormalities). Confidence in the diagnosis of encephalitis rises with increasing numbers of supportive features.¹ Notably, the frequency of autoimmune encephalitis could be underestimated by the use of such definitions since the presence of supportive elements, in particular CSF pleocytosis and MRI abnormalities, might be less common than in infectious encephalitis. Autoimmune encephalitis can present with new onset seizures and status epilepticus in the absence of other cognitive or behavioural changes, and therefore accounts for a subset of patients with the clinical syndromes of new onset refractory status epilepticus or febrile infection-related epilepsy syndrome.6, 7 Although rare, autoimmune encephalitis can manifest with isolated psychiatric symptoms.⁸

Up to 12·6 per 100 000 individuals are affected by encephalitis annually, with the highest incidence in children.9, 10, 11, 12 The leading identified causes are viral, followed by the syndrome of acute disseminated encephalomyelitis (ADEM), which is typically a post-infectious or para-infectious condition. Of viral causes, Japanese encephalitis virus (JEV) is the most commonly identified epidemic cause and herpes simplex virus (HSV) the most commonly identified sporadic cause. In recent years the epidemiology has changed because of the emergence and spread of arthropod-borne viruses such as Zika and chikungunya, and the increasing use of vaccines (eg, against JEV and varicella zoster virus) in some countries. Overall, approximately 40–50% of all identified cases are caused by infectious agents.9, 13 Autoimmune conditions, increasingly recognised and tested for since the initial description of anti-N-methyl-D-aspartate (anti-NMDA) receptor encephalitis over a decade ago, account for approximately 20–30% of cases,13, 14, 15 and the remaining cases do not have a causal diagnosis despite extensive evaluation.

In this Seminar we chiefly focus on the diagnosis and management of acute encephalitis in immunocompetent adults.