ENCEPHALITIS

Definition of Encephalitis:

 Encephalitis is characterized by inflammation of the brain, often caused by viral

infections or primary autoimmune processes.
 This discussion will primarily focus on the infectious causes of encephalitis. In some
cases, patients with encephalitis may also exhibit signs of associated meningitis
(meningoencephalitis) and, less commonly, spinal cord or nerve root involvement
(encephalomyelitis or encephalomyeloradiculitis).

Clinical Manifestations:

 Encephalitis typically presents as an acute febrile illness.

 Common clinical signs and symptoms include an altered level of consciousness, which
may manifest as confusion, behavioral abnormalities, mild lethargy, or even coma.
 Neurologic signs and symptoms are prevalent, with patients displaying focal or diffuse
abnormalities.
 Behavioral disorders, hallucinations, agitation, and even psychotic states can occur in
encephalitis cases.
 Focal or generalized seizures are common.
 Various focal neurologic disturbances may be present, such as aphasia, ataxia, motor
neuron weakness (upper or lower), involuntary movements (e.g., myoclonic jerks,
tremors), and cranial nerve deficits.
 Involvement of the hypothalamic-pituitary axis may result in temperature dysregulation,
diabetes insipidus, or the syndrome of inappropriate secretion of antidiuretic hormone
(SIADH).

Etiology:

 Encephalitis is a relatively common condition in the United States, with an estimated

~20,000 cases annually, although the true number may be higher.
 Several viruses are capable of causing encephalitis, but a specific cause is often
unidentified in acute encephalitis cases.
 Herpesviruses (e.g., herpes simplex virus, varicella-zoster virus, Epstein-Barr virus) are
commonly identified as causes of sporadic encephalitis in immunocompetent adults.
 Epidemics of encephalitis are often triggered by arboviruses (arthropod-borne viruses).
These include alphaviruses (e.g., eastern equine encephalitis virus), flaviviruses (e.g.,
West Nile virus), and bunyaviruses (e.g., California encephalitis virus serogroup).
 Since 2002, West Nile virus (WNV) has been a major contributor to arbovirus
encephalitis in the United States.
 Emerging viruses like Nipah virus, Toscana virus, Zika virus, and chikungunya virus have
also been associated with encephalitic conditions in various parts of the world.

Laboratory Diagnosis -
 CSF Examination:

 Cerebrospinal fluid (CSF) examination is essential in diagnosing encephalitis, except

when contraindicated by severely increased intracranial pressure.
 An optimal initial CSF sample should be collected, with a portion stored frozen for
further studies, including virus-specific polymerase chain reaction (PCR) or
metagenomic next-generation sequencing.
 The typical CSF profile is similar to viral meningitis, consisting of a lymphocytic
pleocytosis, mildly elevated protein concentration, and normal glucose concentration.
 A pleocytosis (more than 5 cells/μL) is present in over 95% of immunocompetent
encephalitis patients.
 In severely immunocompromised individuals, the CSF inflammatory response may be
absent.
 Polymorphonuclear pleocytosis (increased neutrophils) occurs in some patients with
encephalitis, particularly those with West Nile virus.
 Elevated red blood cells in the CSF can be present but are non-specific and may occur
with other focal encephalitides.
 Reduced CSF glucose concentration is uncommon in viral encephalitis and suggests non-
viral causes, such as bacterial or fungal infections or other inflammatory processes.

 CSF Polymerase Chain Reaction (PCR):

 CSF PCR is a crucial diagnostic test for identifying central nervous system (CNS)
infections caused by specific viruses, including HSV (herpes simplex virus), CMV
(cytomegalovirus), EBV (Epstein-Barr virus), HHV-6 (human herpesvirus 6), and
enteroviruses.
 In the case of VZV (varicella-zoster virus) CNS infections, both CSF PCR and the detection
of virus-specific IgM or intrathecal antibody synthesis contribute to the diagnosis.
 Sensitivity and specificity of CSF PCRs vary depending on the virus being tested.
 HSV CSF PCR demonstrates high sensitivity (~96%) and specificity (~99%), often
surpassing those of brain biopsy.
 Interpretation of HSV CSF PCR results should consider the patient's disease likelihood,
test timing concerning symptom onset, and prior antiviral therapy. A negative HSV CSF
PCR can significantly reduce the likelihood of HSV encephalitis but does not exclude it.
For instance, in a patient with a 35% pretest probability of HSV encephalitis, a negative
test decreases the posttest probability to around 2%, while for a patient with a 60%
pretest probability, it reduces the posttest probability to roughly 6%. A positive test
makes the diagnosis almost certain (98-99%).
 There have been reports of initially negative HSV CSF PCR tests when performed within
72 hours of symptom onset, becoming positive when repeated 1-3 days later. Positive
HSV CSF PCR results become less frequent as the illness duration increases, with only
about 20% remaining positive after 14 days.
 The sensitivity and specificity of CSF PCR for viruses other than HSV are not firmly
established. Enteroviral (EV) CSF PCR has high sensitivity and specificity (>95%), except
for EV-A71, where sensitivity may be considerably lower (around 30% in some reports).
 Parechoviruses are not detected by standard EV reverse transcriptase (RT)-PCRs.
 The specificity of EBV (Epstein-Barr virus) CSF PCR remains uncertain, as positive results
may occur in conjunction with other pathogen findings, possibly reflecting EBV
reactivation due to unrelated infections or inflammatory processes.
 In VZV CNS infection cases, CSF antibody and PCR studies should be considered
complementary, as patients may show intrathecal synthesis of VZV-specific antibodies
despite negative CSF PCRs.
 In West Nile virus (WNV) infection, CSF PCR is less sensitive than the detection of WNV-
specific CSF IgM; however, PCR remains valuable in immunocompromised patients who
might not mount an effective anti-WNV antibody response.
 The SARS-CoV-2 (COVID-19) pandemic has been linked to cases of encephalopathy and
true encephalitis, with positive CSF RT-PCR for SARS-CoV-2 detected in cases of the
latter.
 Brain tissue RT-PCR and electron microscopy have confirmed neuroinvasion by SARS-
CoV-2, with viral particles observed in neurons and endothelial cells.
 Advanced metagenomic sequencing techniques can rapidly diagnose obscure
encephalitis cases and other brain infections by identifying infectious genomes in CSF,
brain, and other tissues.

 CSF Culture:

 CSF culture is generally of limited use for the diagnosis of acute viral encephalitis, often
being insensitive and slow to impact immediate therapy.
 More than 95% of HSV encephalitis cases have negative CSF cultures, as do virtually all
patients with EBV-associated CNS disease.

 Serologic Studies and Antigen Detection:

 For many arboviruses, such as WNV, serologic studies are crucial diagnostic tools.
 Serum antibody determination is less useful for viruses with high seroprevalence in the
general population, like HSV, VZV, CMV, and EBV.
 For viruses with low seroprevalence, acute viral infection can be diagnosed by
documenting seroconversion between acute-phase and convalescent sera or by
demonstrating the presence of virus-specific IgM antibodies.
 In patients with HSV encephalitis, antibodies to HSV glycoproteins and antigens can be
detected in the CSF, typically after the first week of illness.
 Demonstration of WNV IgM antibodies in CSF is diagnostic of WNV encephalitis, as they
do not cross the blood-brain barrier, indicating intrathecal synthesis.
 Timing of antibody collection may be critical, with the rate of CSF WNV IgM
seropositivity increasing during the first week after illness onset.
 While serum and CSF IgM antibodies generally persist for a few months after acute
infection, exceptions exist, and WNV serum IgM has been found to persist for over a
year in some cases following acute infection.

 MRI, CT, and EEG in Encephalitis:

 Patients with suspected encephalitis routinely undergo neuroimaging studies like MRI
(magnetic resonance imaging), CT (computed tomography), and often EEG
(electroencephalogram). These tests help in identifying or ruling out alternative
diagnoses and assist in distinguishing between focal and diffuse encephalitis.
 The presence of focal findings in a patient with encephalitis raises the suspicion of HSV
(herpes simplex virus) encephalitis. Examples of focal findings include increased signal
intensity areas in the frontotemporal, cingulate, or insular regions of the brain on T2-
weighted, fluid-attenuated inversion recovery (FLAIR), or diffusion-weighted MRI. Focal
areas of low absorption, mass effect, and contrast enhancement on CT scans, and
periodic focal temporal lobe spikes on EEG are also indicative.
 HSV encephalitis typically involves the temporal lobes in around 80% of cases.
Additional extratemporal areas may be affected as well. MRI sensitivity improves when
using FLAIR and diffusion-weighted images.
 In children with HSV encephalitis, MRI may show atypical patterns of lesions, involving
brain regions outside the frontotemporal areas.
 CT is less sensitive than MRI and may appear normal in up to 20-35% of encephalitis
cases.
 EEG abnormalities occur in over 75% of PCR-documented cases of HSV encephalitis.
These EEG abnormalities frequently involve the temporal lobes but are often non-
specific. In some cases, patients with HSV encephalitis exhibit a unique EEG pattern
characterized by periodic, stereotyped, sharp-and-slow complexes originating in one or
both temporal lobes.
 Patients with WNV (West Nile virus) encephalitis typically display generalized slowing in
their EEG, which may be more anteriorly prominent rather than the temporally
predominant pattern seen in HSV encephalitis.
 VZV (varicella-zoster virus) encephalitis can result in multifocal areas of hemorrhagic
and ischemic infarction due to the virus's tendency to induce a CNS vasculopathy.

 Indications of brain biopsy?

 CSF PCR studies fail to lead to specific diagnosis

 Focal abnormalities on MRI
 No serologic evidence of autoimmune disease
 Progressive clinical deterioraton despite t/t with acyclovir and supportive therapy
Differential Diagnosis

 Several other organisms and conditions can mimic viral encephalitis, necessitating
differentiation. In patients with biopsy-proven HSV encephalitis, common infectious
mimics of focal viral encephalitis include mycobacteria, fungi, rickettsiae, Listeria,
Mycoplasma, and other bacteria. Neurosyphilis can also mimic viral encephalitis.
 Autoimmune encephalitis, associated with various antibodies (NMDA receptor,
VGKC/LGI-I, AMPA, GABA receptors, GAD 65), can resemble viral infection. Diagnosis
usually involves detecting specific autoantibodies in serum and/or CSF.
 Paraneoplastic autoimmune encephalitis can be associated with certain cancers and
onconeuronal antibodies.
 Subacute or chronic forms of encephalitis may be linked to autoimmune reactions
against thyroglobulin and thyroperoxidase (Hashimoto's encephalopathy) and prion
diseases.
 Amebic encephalitis, caused by Naegleria fowleri (primary amebic meningoencephalitis),
Acanthamoeba, and Balamuthia, can mimic viral encephalitis. The CSF profile in primary
amebic meningoencephalitis may resemble bacterial meningitis, with neutrophilic
pleocytosis and hypoglycorrhachia.
 Baylisascaris procyonis, the raccoon pinworm, can cause encephalitis. A history of
raccoon exposure, particularly exposure to potentially contaminated dirt, may provide
clues for diagnosis.
 Rabies can present with various clinical forms, including the classic furious rabies with
hydrophobia and aerophobia, or paralytic (dumb) rabies with acute ascending paralysis.
A typical feature of rabies due to a bat bite is the absence of hydrophobia and
aerophobia, with a presentation of focal neurologic deficits, myoclonus, seizures, and
hallucinations.
 Flaviviruses, including WNV, may cause encephalitis with rapid progression, brainstem
involvement, or prominent movement disorders like tremor and myoclonus. Deep gray
matter structures' involvement suggests possible flavivirus infection. Poliomyelitis-like
acute flaccid paralysis may occur in some cases.
 Epidemiologic factors, such as the season, geographic location, travel history, and
animal exposures, provide important clues for diagnosing encephalitis. In the United
States, bat exposure is the most common risk factor for rabies, which can have a varied
clinical presentation depending on the type of exposure (bat vs. dog or wolf).

Treatment of Viral Encephalitis:

 Specific antiviral therapy is crucial and should be initiated when appropriate.

 Continuous monitoring and support of vital functions such as respiration and blood
pressure are essential.
 In the initial stages, many patients with encephalitis may require care in an intensive
care unit.
 Basic management and supportive therapy should include the following:
 Careful monitoring of intracranial pressure (ICP).
 Fluid restriction.
 Avoidance of hypotonic intravenous solutions.
 Fever suppression.
 Treatment of seizures with standard anticonvulsant regimens.
 Prophylactic anticonvulsant therapy is considered due to the high frequency of seizures
in severe encephalitis cases.
 Patients immobilized with altered levels of consciousness are at risk of various
complications, including:
 Aspiration pneumonia.
 Stasis ulcers and decubiti (pressure sores).
 Contractures.
 Deep venous thrombosis and related complications.
 Infections of indwelling lines and catheters.
 Acyclovir is effective in treating HSV (herpes simplex virus) and should be started
empirically in patients with suspected viral encephalitis, especially if focal features are
present, while awaiting viral diagnostic studies.
 Treatment should be discontinued if the patient is found not to have HSV encephalitis,
with some exceptions for severe encephalitis cases due to VZV (varicella-zoster virus) or
EBV (Epstein-Barr virus).
 Acyclovir, famciclovir, and valacyclovir are antiviral drugs effective against HSV, VZV,
and EBV. However, their use in the primary treatment of encephalitis has not been
evaluated.
 Adjunctive intravenous glucocorticoids' role in treating HSV and VZV infection is
uncertain. While experimental models and case reports suggest their efficacy, no data
from randomized controlled human trials are available.
 Ganciclovir and foscarnet, either alone or in combination, are often used in the
treatment of CMV (cytomegalovirus)-related CNS infections, although their efficacy
remains unproven.
 Cidofovir may provide an alternative for patients who do not respond to ganciclovir and
foscarnet, although data on its use in CMV CNS infections are extremely limited.
 Valganciclovir is an orally bioavailable prodrug that can generate high serum levels of
ganciclovir. However, its efficacy in treating CMV CNS infections is not well-established.
 Foscarnet is another antiviral drug used for serious CMV-related neurologic illnesses.
Renal impairment is a common complication, but it is reversible following
discontinuation of the drug in most cases.
 Cidofovir is a nucleotide analogue effective in treating CMV retinitis and experimental
models of murine CMV encephalitis. However, data on its efficacy in human CMV CNS
disease are limited.
 Intravenous ribavirin has been reported to be beneficial in isolated cases of severe
encephalitis caused by certain viruses like California encephalitis (La Crosse) virus,
adenovirus, rotavirus, LCMV, and other arenaviruses. However, clinical trials are lacking.
 No specific antiviral therapy of proven efficacy is available for the treatment of WNV
(West Nile virus) encephalitis. Various drugs and therapies have been tested, but none
have shown significant benefit.
 For COVID-19, remdesivir, glucocorticoids, and other treatments have been studied,
with modest beneficial effects reported in some cases. Some treatments like
ritonavir/lopinavir and chloroquine/hydroxychloroquine have not shown significant
benefits despite anecdotal reports.
 Trials of convalescent plasma and inhibitors of proinflammatory cytokines are ongoing
in the treatment of severe COVID-19.

Sequelae of Viral Encephalitis:

 The incidence and severity of sequelae in patients surviving viral encephalitis vary
significantly.
 For EEE virus infection, approximately 80% of survivors experience severe neurologic
sequelae.
 Infections caused by EBV, California encephalitis virus, and Venezuelan equine
encephalitis virus typically result in fewer severe sequelae.
 For example, La Crosse virus infection leads to 5-15% of children having a residual
seizure disorder, and 1% having persistent hemiparesis.
 The NIAID-Collaborative Antiviral Study Group (CASG) trials provide detailed
information about sequelae in patients with HSV encephalitis treated with acyclovir. Of
32 acyclovir-treated patients, 26 survived, with varying sequelae:
 12 (46%) had no or only minor sequelae.
 3 (12%) were moderately impaired (gainfully employed but not functioning at their
previous level).
 11 (42%) were severely impaired (requiring continuous supportive care).
 The incidence and severity of sequelae were linked to the age of the patient and their
level of consciousness at the initiation of therapy.
 Patients with severe neurologic impairment at the start of therapy either died or
survived with severe sequelae.
 Young patients (less than 30 years old) had a better prognosis with 64% survival, of
which 57% had no or mild sequelae.
 Many patients with WNV infection have sequelae, including cognitive impairment,
weakness, and hyper- or hypokinetic movement disorders such as tremors, myoclonus,
and parkinsonism.
 The time to achieve recovery in WNV patients varies, with the mean time being 112-455
days depending on the specific aspect of recovery.

Chronic Encephalitis

 Progressive Multifocal Leukoencephalopathy:

 PML is characterized by multifocal areas of demyelination found throughout the brain

but sparing the spinal cord and optic nerves.
 Pathologically, PML exhibits characteristic cytologic alterations in both astrocytes and
oligodendrocytes:
 Astrocytes are enlarged and contain hyperchromatic, deformed, and bizarre nuclei with
frequent mitotic figures.
 Oligodendrocytes have enlarged, densely staining nuclei containing viral inclusions
formed by crystalline arrays of JC virus (JCV) particles.
 Clinical features include visual deficits (45%), typically presenting as a homonymous
hemianopia, mental impairment (38%) with symptoms like dementia, confusion, and
personality changes, weakness, including hemi- or monoparesis, and ataxia.
 Seizures occur in about 20% of PML patients, primarily in those with lesions abutting the
cortex.
 Almost all PML patients have an underlying immunosuppressive disorder or are
receiving immunomodulatory therapy.
 Common associated conditions with PML include AIDS (80%), hematologic malignancies
(13%), transplant recipients (5%), and chronic inflammatory diseases (2%). Up to 5% of
AIDS patients may develop PML.
 Around 1000 cases of PML have been reported in patients treated for multiple sclerosis
and inflammatory bowel disease with natalizumab, a humanized monoclonal antibody
that inhibits lymphocyte trafficking into the central nervous system (CNS) and bowel
mucosa by binding to α4 integrins.
 The overall risk of PML in natalizumab-treated patients is estimated at around 4 cases
per 1000 treated patients, but the risk varies depending on factors such as anti-JCV
antibody serostatus, the magnitude of the JCV antibody response, prior
immunosuppressive therapy use, and duration of natalizumab therapy.
 Patients lacking detectable JCV antibodies have a risk of developing PML after 24
months of natalizumab therapy, with a risk of over 1.3 cases per 100 treated patients.
 Extended dosing interval regimens of natalizumab (5-6 week intervals) have been
suggested to reduce the risk of PML.
 Among JCV-seropositive individuals, those with higher JCV antibody index values are at
higher risk due to the "immunizing" effects of more frequent JCV reactivations.
 PML cases have also been reported in patients receiving other immunomodulatory
agents including rituximab, ocrelizumab, fingolimod, and dimethyl fumarate, but the
relative risks have not been clearly established.
 The basic clinical and diagnostic features are similar in HIV-associated PML and PML
associated with immunomodulatory drugs. Immunomodulatory cases are more likely to
exhibit MRI enhancement of PML lesions.
 In natalizumab-associated PML, patients typically experience clinical and radiographic
worsening of lesions after discontinuation of therapy, attributed to the development of
immune reconstitution inflammatory syndrome (IRIS).

Diagnostic Studies:

 MRI frequently suggests the diagnosis of PML. MRI reveals multifocal asymmetric white
matter lesions in various brain regions such as the periventricular area, centrum
semiovale, parietal-occipital region, and cerebellum. These lesions show increased
signal on T2 and FLAIR images and decreased signal on T1-weighted images.
 PML lesions do not typically cause edema or mass effect.
 CT scans, which are less sensitive than MRI, may show hypodense nonenhancing white
matter lesions.
 The cerebrospinal fluid (CSF) is usually normal, although mild elevations in protein
and/or IgG may be present. Pleocytosis occurs in less than 25% of cases, is mainly
mononuclear, and rarely exceeds 25 cells/μL.
 PCR amplification of JCV DNA from CSF is an important diagnostic tool. A positive CSF
PCR for JCV DNA in association with typical MRI lesions is diagnostic of PML, although
sensitivity may vary, and a negative CSF PCR does not rule out the diagnosis.
 Patients with PML may require brain biopsy for definitive diagnosis.

Treatment:

 No definitive therapy for PML is available.

 Therapeutic interventions aimed at enhancing or restoring immunocompetence should
be considered since PML occurs almost invariably in immunocompromised individuals.
 In some cases, PD-1 inhibitor pembrolizumab has demonstrated clinical improvement
and stabilization.
 Infusions of BK or JC virus-specific cytotoxic T lymphocytes have shown positive results
in small case series.
 Restoring immune competence through the institution of highly active antiviral therapy
(HAART) has led to disease stabilization and, rarely, improvement in HIV-positive
patients with AIDS.
 Patients with AIDS and PML treated with HAART have a 1-year survival rate of about
50%, with up to 80% of survivors experiencing significant neurologic sequelae.
 In cases where immunomodulatory agents such as natalizumab are suspected to have
caused PML, therapy should be halted. Plasma exchange or immunoadsorption may be
utilized to remove drugs with long pharmacokinetic or biological half-lives.
 Patients should be closely monitored for the development of IRIS, which is generally
treated with intravenous glucocorticoids, although controlled clinical trials of efficacy
remain lacking.

 Subacute Sclerosing Panencephalitis (SSPE):

 SSPE is a rare, chronic, and progressive demyelinating disease of the central nervous
system (CNS) associated with a chronic nonpermissive infection of brain tissue with the
measles virus.
 Its frequency is estimated at 1 in 100,000 to 500,000 cases of measles, with around five
cases reported each year in the United States.
 The incidence of SSPE has significantly decreased since the introduction of the measles
vaccine.
 Most SSPE patients have a history of primary measles infection at an early age, followed
by a latent interval of 6-8 years before the development of a progressive neurologic
disorder.
 Approximately 85% of SSPE patients are between 5 and 15 years old at the time of
diagnosis.
 Initial symptoms include poor school performance, mood and personality changes, but
they don't manifest typical signs of a CNS viral infection like fever and headache.
 As the disease progresses, patients experience progressive intellectual deterioration,
focal and generalized seizures, myoclonus, ataxia, and visual disturbances.
 In the late stage, patients become unresponsive, quadriparetic, and spastic, exhibiting
hyperactive tendon reflexes and extensor plantar responses.
Diagnostic Studies for SSPE:

 MRI is often normal in the early stages but may later reveal areas of increased T2 signal
in the brain's white matter and brainstem.
 The EEG may initially show nonspecific slowing, but as the disease progresses, it exhibits
a characteristic periodic pattern.
 The CSF is acellular with a normal or mildly elevated protein concentration and a
markedly elevated gamma globulin level (>20% of total CSF protein).
 CSF antimeasles antibody levels are elevated, and oligoclonal antimeasles antibodies
are often present.
 Measles virus can be cultured from brain tissue using special cocultivation techniques.
Viral antigen and genome can be identified through immunocytochemistry, in situ
hybridization, or PCR amplification.

Treatment for SSPE:

 Unfortunately, no definitive therapy for SSPE exists.

 Treatment with isoprinosine (Inosiplex) alone or in combination with intrathecal or
intraventricular interferon-α has been reported to prolong survival and produce clinical
improvement in some patients but hasn't undergone controlled clinical trials.

 Progressive Rubella Panencephalitis:

 This is an extremely rare disorder that primarily affects males with congenital rubella
syndrome, although isolated cases have been reported following childhood rubella.
 After a latent period of 8-19 years, patients develop progressive neurologic
deterioration, with manifestations similar to SSPE.
 CSF shows a mild lymphocytic pleocytosis, slightly elevated protein concentration,
markedly increased gamma globulin, and rubella virus-specific oligoclonal bands.
 No therapy is available for progressive rubella panencephalitis.
Prevention:
 Universal prevention of both congenital and childhood rubella through the use of the
available live attenuated rubella vaccine would be expected to eliminate the disease.