Encephalitis is an inflammation of the brain parenchyma with clinical evidence of neurologic dysfunction and associated cerebrospinal fluid (CSF) and electroencephalography (EEG) findings. Encephalopathy refers to global brain disease and dysfunction manifested by an altered mental state regardless of its etiology. Leukoencephalopathy is a group of diseases affecting the brain white matter. Both are manifested by an inflammatory process in the brain.1
Noninfectious causes such as autoimmune diseases, connective tissue diseases and paraneoplastic syndromes are not within the scope of this article.
Encephalitis can occur due to direct infection of the brain. Finding the causative agent in infectious encephalitis is a daunting task; despite extensive diagnostic workup only 1/3 to 2/3 of the cases have a known etiology by the time of admission to rehabilitation.1,2 Etiological agents differ between immunocompetent and immunocompromised patients. Among the patients who may be immunocompetent predominantly from medical treatments, the predominant causes of encephalopathy are viral 40%, bacterial 30%, Lyme disease 7%, fungi 7%, syphilis 5%, Mycobacterium 5%, and prion diseases 3% in that order. As a comparison, in HIV patients, viruses are 46%, fungi in over 30%, and toxoplasmosis 10%.3,4 Immunocompromised patients due to organ transplantation or cancer are also associated with certain infectious encephalitis. 1 For example, Human Herpesvirus 6 (HHV-6) encephalitis is almost only found in immunocompromised patients such as after bone marrow transplantation,5 whereas Cytomegalovirus (CMV) encephalitis infection can be seen in both HIV and transplant recipients. 1
In addition to direct infection, post-infectious encephalitis can occur as an immune reaction to infection anywhere in the body. Acute disseminated encephalomyelitis (ADEM), which can be considered a multiple sclerosis variant, does not represent a novel infection but rather an autoimmune demyelination secondary to an immunological response to an infectious agent or immunization. 1 It occurs mostly after viral infections but is also seen after bacterial or parasitic infections and as a very rare complication after vaccination.
Some of the more common post bacterial autoimmune encephalopathies include:
- Varicella-zoster with neuromyelitis optica (antiaquaporin-4)
- Campylobacter associated with GBS (anti-GM1 antibodies)
- Group A Streptococcus with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS; ASO, ASK antibodies)
- Herpes-6 associated with limbic encephalitis (anti-GAD)
- More recently measles, as it has recurred due to vaccination rates going down.
Epidemiology including risk factors and primary prevention
There are an estimated 20,000 new cases of infectious encephalitis in the United States annually, with incidence of 3 to 7 in every 100,000. Infants and elderly patients are the most severely involved. Homeless patients and those with HIV have highest rates of infections; a higher exposure to mosquitoes in the case of the homeless, and a higher prevalence of opportunistic infections in the immunocompromised population may be contributing factors.3-5 Arboviruses are a family of viruses that are spread through arthropod vectors and are a common cause of encephalitis. Arboviral encephalitis epidemiology has geographic variations.6 California encephalitis is most common in the Midwest. 6 Eastern equine encephalitis is commonest on the East Coast. St. Louis encephalitis is common in both the Midwest and East Coast. West Nile virus (WNV) fever and western equine encephalitis are found throughout the country. 1, 6
ADEM is an uncommon illness, seen more in children than adults. Its incidence in children was 0.2/100,000 – 0.4/100,000.1,7
Dengue is encroaching into the southern United States and is likely to increase. It is transmitted by mosquitoes as the climate is now warmer.8 Zika virus9 and along with WNV6,10 have become an issue in North America and in U.S. territories.
Zika virus originated in Africa, spread through Asia, French Polynesia and then to central and South America. 8-10 It is generally transmitted by Aedes aegypti mosquito although there are cases felt to be due to sexual transmission. 8-10 Cases in the continental United States are not vector born but associated with travel to endemic areas.8 ,9 There have been cases in tropical U.S. territories.8 ,9 Zika has been associated with microcephaly as well as with cases of Guillain Barre syndrome (GBS). The virus may also be transmitted from mother to child, possibly through breastfeeding.10
In about 20% of cases, HIV patients may present with neurocognitive impairment prior to the initiation of treatment. After treatment with combination antiretroviral therapy (cART ) only about 2% of patients develop dementia. However, 50% of HIV-positive persons on medication and with undetectable viral load will still have either a mild neurologic disorder or neurocognitive impairment compared to matched controls.12
The various pathophysiologic causes of encephalitis makes this a difficult topic to briefly review. Some of the most important clinical issues and/or manifestations of the most commonly caused encephalopathies are the following:
- Varicella-Zoster virus (VZV) can lead to vasculitis with subsequent hemorrhagic stroke.
- Herpes Simplex (HSV) has a predilection for involving the fronto-temporal cortical areas due to its retrograde transmission through olfactory nerve and/or the trigeminal ganglion.1,5
- Japanese encephalitis and St. Louis encephalitis have a tendency to infect deep gray matter structures within the brain.13
- Epstein – Barr virus (EBV) central nervous system (CNS) involvement is widely variable, including meningitis, encephalitis affecting variable areas of the brain–mostly subcortical white matter and deep gray matter, spinal cord involvement with transverse mellitus, or it may present as Guillain-Barre syndrome (GBS).14
- In St. Louis encephalitis, the vast majority of the infected elderly develop actual encephalitis, while infection in those younger than 20 years old have presentations equally distributed between meningitis and encephalitis.15
- John Cunningham virus (JCV) is a polyoma virus that infects the oligodendrocytes causing sub-acute demyelinating disease.16 It rarely affects neurons and spares astrocytes.
- WNV fever can cause meningitis and encephalitis and may also affect the anterior horn cells, leading to flaccid paralysis, sometimes involving the diaphragm. It presents with a picture of axonal loss with no evidence of demyelination similar to polio.17,18 Other presentations can include spastic cervical myeloradiculopathy with severe clonus, pain, brainstem signs, and loss of VIII cranial nerve function. 19
- Natalizumab for the treatment of multiple sclerosis (MS) was associated with more than 30 cases of progressive multifocal leukoencephalopathy (PML) and was almost pulled from the market by the FDA.19 In one study there were 100 reported cases of non-Hodgkin’s lymphoma treated with rituximab that also also developed PML.20
- More recently measles has reemerged as a cause of encephalitis due to declining vaccination rates. 21
- With Dengue, rash can present with a low platelet count and low white blood cell count (WBC).8
- HHV-6 has a predilection for the medial temporal lobe and the limbic system of the brain leading to the clinical picture of short-term memory loss, seizures and sleep disturbance.6
- CMV infection has been reported to lead to a reversible encephalopathy and poly-radiculopathy. 1-4
- Only one out of 300 exposed to Japanese encephalitis or St. Louis encephalitis virus infections end up developing clinical manifestations. 1,8
- California encephalitis primarily affects children but results in a very low mortality and morbidity rates.1,8
- Prion encephalitis, when detected, is almost invariably fatal.3,4
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
The natural course of the disease is often very variable depending on the infecting agent, age, and immune status of the patient. A 2-week viral prodrome/incubation state is common in many etiologies due to infections. The diagnosis of the cause of the encephalitis is important as it impacts the prognosis, progression and rehabilitation potential as well as the long term course of recovery. Important acute treatment principles for patients without a definitive diagnosis include the following:
- In herpetic encephalitis the mortality without IV acyclovir treatment can be nearly 70%. Early treatment with IV acyclovir level (A-I) is the only parameter known to lower morbidity and mortality in herpetic encephalitis.22 Hence, treatment of all patients suspected of having encephalitis should be first started on acyclovir until the workup has progressed further.
- Post-infectious autoimmune encephalitis can cause significant damage beyond the infection itself. Aggressive management of this condition is needed once the infection is controlled. These treatments include: 23
- Steroids (usually intravenous methylprednisolone) are often the first-line therapy.
- Intravenous immunoglobulin (IVIG) is used but can cause aseptic meningitis as well.
- Plasma exchange has been useful in some case series.
- Rituximab and cyclophosphamide are also utilized in some cases. Both require long term surveillance over time for malignancy. 23
Specific secondary or associated conditions and complications encephalitis
Different infectious etiologies lead to different secondary conditions.
- Seizure Disorder: Viruses that have predilection for cerebral cortex, especially those involving the frontal-temporal and parietal lobes like HSV and HHV-6, are more likely to cause seizures. Infections that involve white matter or deep brain structures such as WNV or PML are much less likely to cause seizures. 22, 24
- Movement Disorders: Parkinsonism, choreoathetosis, myoclonic jerks and dystonia are seen in infections of the basal ganglia and deep grey matter associated with St. Louis encephalitis and Japanese encephalitis. 25
- Cranial nerve involvement with facial weakness, paranesthesia, and/or ptosis is very common with WNV26 and Japanese encephalitis.
- Flaccid paralysis is usually due to axonal injury and anterior horn cell involvement in WNV10
- GBS has been reported in some cases of EBV and also with HIV encephalitis in cases that are predominately demyelinating.14,17,20
- Visual disturbance, such as alien hand phenomenon, has been noted in some cases of non-HIV PML which involves the subcortical occipital area of the brain. 27
- Communicating hydrocephalus, as noted by cognitive changes, ataxia and incontinence, can be a late occurrence in all causes of encephalitis.1
- Many of these patients will have problems with cognitive, behavioral and motor disorders, similar to patients with traumatic brain injury (TBI). Similar management is recommended for these problems.
- Depression and anxiety are very common in HHV-6 infection due to involvement of the limbic system. 28
- Acute Zika virus infection presents with pruritic rash, retro-orbital pain, diarrhea, nausea, malaise, joint problems, and headaches.9 More recently there have been increased reports of patients presenting with GBS, acute myelitis, viral meningoencephalitis and sensory neuropathy.9,11
- Congenital anomalies, especially microcephaly, have been frequently reported due to acute Zika virus infection of pregnant mothers.11
ESSENTIALS OF ASSESSMENT
A comprehensive history of patients with suspected encephalitis should include assessment of the premorbid functional, vocational, medical and social status, along with a detailed history of focal and generalized neurologic impairments, including seizures. Specific details pertaining to diagnosing potential treatable causes of infectious encephalitis include1:
- Exposure to mosquito or tick bites as seasonal risk factors.
- Impaired immune status of the affected individual such as HIV infection with documented CD4 count trends.
- Duration of time between symptom onset and treatment.
- Presence of documented increased intracranial pressure, seizures or hydrocephalus during the acute hospital stay.1,24
- Any recent travel history to high risk areas for some types of infectious agents.
The clinical presentation ranges from obtunded encephalopathy to more specific focal neurological deficits. A detailed neurological examination should include assessment of mental status and overall orientation. In severely obtunded patients, one should rule out subclinical seizures with the use of EEG. 1 Cranial nerve exam should be performed, including ophthalmologic exam evaluating for any signs of raised intracranial pressure. Manual muscle testing may reveal findings consistent with polyradiculopathy, axonal loss, or demyelinating lesions. Skin rash can raise suspicion for a bacterial cause of encephalitis/meningitis (Neisseria meningitis), which is important to diagnose early since it is acutely life-threatening requiring contact isolation and usually responds very well to intravenous (IV) third-generation cephalosporin.1
Assessment should include a detailed motor and sensory examination as well as a cognitive examination. Cognitively, at a minimum, a mini-mental status examination is required. If this is abnormal, a more detailed cognitive battery utilizing the measures commonly employed after brain injury medicine is useful.29-31 The supplemental assessment tools often mentioned in the literature for patients with impaired consciousness from encephalitis included the orientation log (which carries same clinical value as the Galveston Orientation and Amnesia Test),29 the cognition-log,30 as well as the Coma Recovery Scale-Revised. 31,32
The Functional independence measure (FIM), including all 18 components assessing cognitive and physical function, is often administered during inpatient rehabilitation for these patients.
All patients should to be tested for syphilis and HIV as these are very treatable causes of encephalitis. Specific assessment tools for infectious encephalitis can include CSF and serum viral load in cases like HSV, and VZV, and following the CD4 counts in HIV patients.1
CSF analysis should be obtained in all patients with suspected encephalitis. A pleocytosis (10-2,000 cells/μL) with lymphocytic predominance, an elevated protein and normal to mildly low glucose level associated with a negative Gram stain and bacterial cultures suggests a viral encephalitis. Any time infectious encephalitis is suspected, polymerase chained reaction (PCR) studies of the CSF should include viral DNA studies for HSV, WNV, VZV, EBV, CMV, and HIV. These tests are highly specific when positive, but they are not very sensitive. Virus-specific CSF to serum IgG ratios should be obtained as a high ratio indicates an infection of CSF. For herpes viruses one should test for CSF immunoglobulin M (IgM) as IgM does not pass through the blood-brain barrier. Serums studies should include serology for WNV, EBV, mycoplasma, borrelia, rickettsia, coccidiosis and histoplasma infections.1
The common EEG picture with encephalitis is not very different from that of encephalopathy with generalized slowing, but in cases of HSV encephalitis focal abnormalities involving the temporal lobes are commonly found. EEG is valuable in evaluating an obtunded patient with encephalitis to rule out subclinical status epilepticus.1, 23, 24
Acute assessment should include a head computerized tomography (CT) to rule out any space-occupying lesions and contraindications to lumbar puncture with elevated intracranial pressure. Magnetic resonance imaging (MRI) is the diagnostic tool of choice in patients with encephalitis,1 with variable T2 lesions corresponding to different etiologies. For example, HSV commonly involves the frontal-temporal lobes and it’s almost never seen outside the frontal-temporal areas alone. WNV fever does not usually have any prominent MRI findings. Varicella zoster (VZV) vasculitis presents with multiple areas of hemorrhagic infarction while progressive multiple leukoencephalopathy (PML) causes primarily demyelinating lesions.27
Early predictions of outcomes
The most significant early predictor of better outcome is the early administration of IV acyclovir in the case of HSV encephalitis and for this reason all patients with suspected encephalitis should be started on acyclovir pending further studies.1, 22 The type of infectious agent can predict long-term complications and outcome. For example, clinically symptomatic encephalitis due to Japanese or St. Louis encephalitis have a low incidence of permanent neurologic deficit, they do have a higher prevalence of long-term neurological dysfunction than that seen with California encephalitis. 1, 8 Cognitive impairment in patients with PML and low CD4 counts associated with HIV infection is usually progressive, irreversible, and ends with dementia.27,33
Worse outcomes are expected with secondary complications such as intraparenchymal hemorrhage in cases of VSZ CNS vasculitis and in cases of severe intracranial edema with Herpes encephalitis.1,28
Zika is associated with congenital anomalies with an increased risk for microcephaly due to infection of the mother affecting the fetus. Other possible fetal problems from Zika infection can include cardiac disorders, hearing loss, blindness, spinal cord lesions, and birth defects, with infection in the first trimester conferring the highest risk.11
As with any patient with neurological impairment, accommodations have to be provided for patients, ranging from supervision to home care for those with cognitive impairments. The utilization of assistive devices and orthotics and physical assistance for those with primarily motor weakness should be obtained early on. For care-takers of these patients it should be stressed that the viral etiologies of encephalitis are not routinely contagious, so patients need not be under contact isolation. Care-takers need not worry about close physical contact with their dependent patients.
Social role and social support system
Etiologies like Japanese and California encephalitis mostly affect children, resulting in need for special accommodations at home/school and playground. Some of the tick-mediated infections can affect otherwise healthy functioning and employed adults causing issues pertaining to long-term loss of productivity and work. Patients and their families require education regarding how long it may take for recovery, if ever. Similar to patients with TBI, prognosis may be difficult to make in the first 6 months.
Rehabilitation Medicine Treatment Issues on Initial Evaluation
Given the high rate of misdiagnosis in the acute setting, which can be up to 2/3 of the initial cases, rehabilitation physicians need to be versed in evaluating the diagnosis. A delayed diagnosis carries significant implications related to the potential therapeutic windows of antivirals. The earlier treatments such as acyclovir in the case of HSV and VZV,1,33,34 or ganciclovir with foscarnet in CMVencephalitis1,28 are initiated the better the potential outcome. A proper diagnosis is also necessary for planning rehabilitation goals, family education and training as well as for discharge planning. In addition, risk stratification for patients with MS encephalitis, should be screened for PML particularly for anyone to be treated with natalizumab.14
REHABILITATION MANAGEMENT AND TREATMENTS
Available or current rehabilitation treatment guidelines
Given the relatively low incidence of encephalitis, rehabilitation studies are sparse, consisting mainly of case reports. Some medications used for other neurologic disorders have been tried for encephalitis. As an example, the utilization of dopamine agonists such as amantadine may improve alertness and arousal.35,36 There are reports of utilizing dopamine agonists to improve cognitive function in encephalitis when deep grey matter structures are involved, as in the case of St. Louis and Japanese encephalitis.37
The utilization of donepezil may be helpful for short-term memory loss and aphasia commonly seen in WNL, PML and HHV-6 similar to brain injury.36 Sertralinefor prevention of depression and potential improvement of motor recovery may be helpful, especially in those illnesses that involve the limbic system and deep white matter like HHV-6, PML and WNL.38 There is some evidence for benefits of cognitive rehabilitation for short-term memory and amnesia in post-viral encephalitis.39 More recently there have been reports of SSRI medications such as fluoxetine linked to improved motor recovery in brain injuries associated with stroke.40
Coordination of care
Close coordination of care with the infectious disease specialist, primary care physician, local infection control agencies (as some cases have to be reported to the CDC), and neurologist, along with the rest of the rehabilitation team, is of great importance. Coordination with community integration (schools, vocational, geriatric) resources and support groups should be maximized.
Patient & family education
Patient and family should be educated about the prognosis and potential long-term complications and need for long-term assistance for the affected individual. The potential progressive nature of some diseases such as PML27 or prion disease41 should be well discussed with families and care-givers.
Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills
Risk stratification for patients with MS, including serologic testing for JC virus41 has been implemented for anyone to be treated with natalizumab, due to documented cases of PML (see pathophysiology section above). Those with positive JC serology are not good candidates for natalizumab.41
CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE
Cutting edge concepts and practice
Nakayama vaccine was developed for Japanese encephalitis (the world’s most common infectious encephalitis, affecting 50.000 annually) with > 95% immunity rate,despite Japanese encephalitis virus being very hybrid and with different lineages.42 Work is ongoing for vaccines in susceptible groups such as against JC virus in HIV patients as well as for arthropod viruses for campers and hikers.
GAPS IN THE EVIDENCE-BASED KNOWLEDGE
Gaps in the evidence-based knowledge
Most of the evidence related to outcomes are either case reports or retrospectivestudies. Considering the diversity of the causes and presentations and low numbers it has been difficult to even assemble large numbers of patients for retrospective reviews. Larger multicenter trials as well as clinical pathophysiologic correlates need to be retrospectively reviewed and larger prospective studies developed to advance management for each of the varied causes of encephalitis
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- Johnson TP, Larman HB, Lee MH, Whitehead SS, Kowalak J, Toro C, Lau CC, Kim J, Johnson KR, Reoma LB, Faustin A, Pardo C, Kottapalli S, Howard J, Monaco D, Weisfeld-Adams J, Blackstone C, Galetta S, Snuderl M, Gahl WA, Kister I, Nath A. Chronic dengue virus encephalitis in a patient with progressive dementia with extrapyramidal features. Ann Neurol 2019 Aug 28. doi: 10.1002/ana.25588. [Epub ahead of print]
- White MK, Wollebo HS, David Beckham J, Tyler KL, Khalili K. Zika virus: an emergent neuropathological agent. Annal Neurol 2016;80:479-489.
- Arnold C. West Nile virus bites back. Lancet Neurol 2012;11:1023-4.
- Honein, Margaret A., et al. “Birth defects among fetuses and infants of US women with evidence of possible Zika virus infection during pregnancy.” JAMA 2017;317: 59-68.
- Lamers, Susanna L., et al. “HIV DNA is frequently present within pathologic tissues evaluated at autopsy from combined antiretroviral therapy-treated patients with undetectable viral loads.” J Virology 2016;90:8968-8983.
- Solomon T, Dung NM, Kneen R, Gainsborough M, Vaughn DW, Khanh VT. Japanese encephalitis. J Neurol Neurosurg Psych 2000;68(4):405-415.
- Doja A, Bitnun A, Jones EL, Richardson S, Tellier R, Petric M, Heurter H, Macgregor D. Pediatric Epstein-Barr Virus – associated encephalitis: 10-year review. Child’s Neurology 2006; 21(5): 384-391.
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Original Version of the Topic
Jay M. Meythaler, MD, JD andAyman Tarabishy, MD. Infectious encephalopathies and leukoencephalopathies. 9/20/2014
Jay M. Meythaler, MD, JD
Nothing to Disclose
Ayman Tarabishy, MD
Nothing to Disclose