Encephalitis

Epidemiology

Viral encephalitis has an estimated incidence of 7 per 100,000 per year. Many viruses ( Table 383-1 ) are implicated, and testing by nucleic acid identification (by polymerase chain reaction [PCR]) or by serology is required to identify the specific virus. The epidemiology of each virus responsible for central nervous system infection (see Table 383-1 ) is distinct in terms of the populations at highest risk, geographic distribution, and seasonal occurrence, especially the arboviruses ( Chapter 352 ) and enteroviruses ( Chapter 349 ), which are covered in separate chapters.

In the United States, the most common cause of nonepidemic encephalitis is herpes simplex encephalitis, which is caused by herpes simplex virus type 1 ( Chapter 345 ). The most common epidemic virus in the United States is now West Nile virus ( Chapter 352 ), which is a mosquito-transmitted Flavivirus related to St. Louis encephalitis virus and to its Asian counterpart, Japanese encephalitis virus, all of which share serologic cross reactivity ( Chapter 352 ). Emerging infections that can cause encephalitis in the United States are Chikungunya and Zika ( Chapter 352 ). ^, In Eastern Europe and Asia, tick-borne encephalitis ( Chapter 352 ) can occur. A zoonotic borna disease virus encephalitis has been associated with fatal human encephalitis in Germany, ^, and Nipah virus is a zoonosis in India with a case fatality rate of about 80%.

Pathobiology

In general, gross pathologic inspection of an encephalitic brain does not reveal purulence visible to the naked eye. If focal purulence is present, cerebritis is the more correct term. If frank necrosis and purulence are present, the correct pathologic term is brain abscess ( Chapter 382 ). Encephalitis, however, can be associated with substantial necrosis pathologically, and patients with severe acute viral encephalitis frequently have microscopic evidence of necrosis. Certain viral encephalitides, such as herpes simplex encephalitis, can be both focal and hemorrhagic.

Viruses that cause acute encephalitis often also may cause meningitis ( Chapter 381 ). Indeed, patients with encephalitis virtually always have some microscopic inflammatory changes in the leptomeninges. Conversely, patients with viral meningitis will inevitably have some component of microscopic encephalitis. The degree of inflammatory change present in the brain is determined by the individual viral pathogen and by host immune factors, which are responsible for the reaction to the invading virus.

Clinical Manifestations

The clinical findings in patients with acute viral encephalitis start with a subacute prodrome of fever, headache, malaise, myalgia, and nonspecific symptoms. Nausea, vomiting, diarrhea, cough, sore throat, and rash can precede the neurologic symptoms as part of the systemic initial manifestations of the infection. Invasion of the nervous system is typically accompanied by headache, photophobia, and altered consciousness, with symptoms progressing over a period of a few days. Seizures are a common heralding symptom. Signs of meningeal irritation may be present but are an unreliable finding in encephalitis.

Focal brain dysfunction is seen with some viruses. For example, West Nile virus ( Chapter 352 ) can cause a brain stem encephalitis with an early onset of coma. Herpes simplex virus ( Chapter 345 ) tends to cause focal cortical neurologic deficits, including hemiparesis, aphasia, and seizures. Limbic parts of the brain commonly involved by herpes simplex encephalitis, human herpesvirus-6 or rabies can lead to prominent behavioral changes at the beginning of the illness before the patient’s level of consciousness is depressed. Focal or generalized seizures are particularly common when encephalitis affects the cerebral cortex, especially the hippocampus and limbic system. Rabies is typically associated with brain stem–mediated laryngospasm, hydrophobia, and depressed consciousness. Because of spinal cord anterior horn cell involvement, West Nile virus, St. Louis encephalitis virus, Japanese encephalitis virus, poliovirus ( Chapter 349 ), and rabies virus infections can cause focal or asymmetrical weakness with areflexia.

Diagnosis

In patients with coma or focal deficits, computed tomography (CT) of the head usually should be performed before spinal fluid analysis to exclude substantial mass effect and to avoid the risk of herniation with lumbar puncture. In patients without focal findings, however, lumbar puncture should be performed immediately to establish the diagnosis; distinguish viral from bacterial, fungal, and parasitic causes; and guide early empirical treatment. Opening pressures should be measured because increased intracranial pressure can occur with all forms of viral encephalitis and may need additional treatment.

Spinal fluid analysis typically reveals an elevated protein level, which usually is less than 2 g/dL. The cerebrospinal fluid (CSF) glucose level is typically normal and greater than 40% of the coincident serum value, but rare patients may have a low CSF glucose level similar to what is seen in patients with bacterial infection ( Chapter 381 ). The CSF white blood cell count is typically elevated, usually in the range of 10 to 500 cells/µL, and often with a lymphocytic predominance. However, a polymorphonuclear predominance is seen in some cases, especially in some patients with West Nile encephalitis ( Chapter 352 ) or cytomegalovirus ventriculitis ( Chapter 347 ).

PCR testing of spinal fluid ( Table 383-2 ) has the advantage of proving direct viral infection within the central nervous system, but serologic testing is more sensitive for some infections, such as West Nile virus encephalitis, which is best confirmed by an immunoglobulin M (IgM) antibody response in spinal fluid. Next-generation sequencing can detect viral pathogens for which PCR assays are insensitive, not established, or not readily available, ^, such as Cache Valley viral encephalitis.

Magnetic resonance imaging (MRI) of the brain is the most sensitive technique for defining structural abnormalities in patients with viral encephalitis. Herpes simplex encephalitis often has a characteristic pattern involving the mesiotemporal, inferofrontal, and insular cortices, usually unilateral or asymmetrically bilateral ( Fig. 383-1 ). However, no imaging characteristics reliably distinguish among the various causes, and frank viral encephalitis can occur with normal findings on MRI.

Differential Diagnosis

Among children and adults with acute encephalitis, about 50% have a confirmed viral cause, 25% have an autoimmune cause, and 25% have no identifiable cause. A systematic approach ( Fig. 383-2 ) can usually detect the identifiable causes.

Several nonviral pathogens can cause encephalitis that is clinically and pathologically indistinguishable from viral encephalitis. Examples include Rickettsia ( Chapter 302 ), Lyme disease ( Chapter 296 ), Borrelia ( Chapter 297 ), Whipple disease ( Chapter 305 ), Toxoplasma ( Chapter 320 ), Mycoplasma ( Chapter 293 ), and Acanthamoeba ( Chapter 323 ), tuberculosis ( Chapter 299 ), and listeria ( Chapter 272 ). Other forms of infectious nonviral causes mimicking viral encephalitis include meningovascular syphilis ( Chapter 295 ) and cerebral cysticercosis ( Chapter 326 ).

Purulent bacteria and fungal reactions in the brain are referred to as cerebritis, which is the first stage of infection of the brain before frank abscess develops with parenchymal necrosis and purulence, but can also mimic encephalitis. Additionally, opportunistic Epstein-Barr virus related lymphoma or lymphoproliferative disorder ( Chapter 348 ) can behave like an encephalitis.

Additionally, autoimmune encephalitides (see later) can mimic viral encephalitis. Examples include limbic paraneoplastic encephalitis, especially associated with antibodies against antigens associated with the voltage-gated potassium channel complex, Hashimoto encephalopathy associated with autoimmune thyroiditis ( Chapter 207 ), and encephalitis associated with anti– N -methyl- d -aspartate (NMDA) receptor antibodies.

In parainfectious encephalitis, a systemic viral infection is associated with a febrile encephalopathy, sometimes with inflammatory spinal fluid but without direct evidence of brain invasion by the virus. Examples of parainfectious encephalitis include infection and encephalopathy associated with influenza virus ( Chapter 332 ), varicella virus ( Chapter 346 ), and Epstein-Barr virus ( Chapter 348 ). Monkeypox ( Chapter 343 ) is the latest virus recognized to produce this syndrome. Furthermore, primary demyelinating disease ( Chapter 380 ), particularly in the form of acute disseminated encephalomyelitis, overlaps clinically with viral encephalitis. In children, a syndrome associated with streptococcal infection has been labeled pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS), which is thought to represent a postinfectious streptococcal autoimmunity directed against the brain.

Treatment

Prognosis

The prognosis of viral encephalitis is dependent on the cause, with an overall mortality rate of about 6 to 10% in the United States. Herpes simplex encephalitis, even with adequate treatment, has a 20% mortality, and the likelihood of major persistent morbidity with seizures or defects in memory and behavior is 35 to 40%. Each of the arboviruses ( Chapter 352 ) has a different mortality rate, with eastern equine encephalitis virus associated with the highest mortality. La Crosse encephalitis virus has the lowest mortality.

About 50% of survivors will have significant clinical sequelae. Some forms of viral encephalitis have specific sequelae, such as sensorineural deafness or hydrocephalus associated with mumps encephalitis. In one large observational study of acute viral encephalitis, factors that portended a worse prognosis included advanced age, immunocompromised state, coma, mechanical ventilation, and acute thrombocytopenia. Conversely, the specific viral cause of encephalitis, the development of seizures or a focal neurologic deficit, and MRI findings were not associated with clinical outcomes.

Herpes Simplex Encephalitis