Encephalitis and Encephalopathy

Encephalitis

• Encephalitis is inflammation of the brain parenchyma accompanied by neurologic dysfunction.
• Diagnosis uses clinical data, lab results, and imaging, but the gold standard is pathologic examination and testing of brain tissue.

Encephalopathy

• Encephalopathy involves altered consciousness (confusion, disorientation, behavioral changes, cognitive impairment) plus inflammation.
• Encephalopathy is typically due to metabolic or toxic conditions.

Epidemiology

• The annual incidence of encephalitis in the US is approximately 5 cases per 100,000 people between 1990 and 2017.
• There are greater than 1 million cases annually world wide.
• Encephalitic disease is frequently associated with rabies, measles, and Japanese encephalitis virus.

Etiology

• The California Encephalitis Project (CEP) reviewed 1,570 cases over a 7-year period.
• In 16% of the cases there was a confirmed or probable etiology.
• Confirmed or probable causes are 69% viral, 20% bacterial, 7% prion, 3% parasitic and 1% fungal.
• A possible etiology was identified in 13% of cases.

Reasons for Unidentified Etiology

• Some pathogenic etiologies remain undiscovered.
• Etiology could not be determined because of uncommon presentation by common pathogens.
• Testing, samples, and timing could have been performed incorrectly.
• The patient may not have been suffering from an infection at all.

Pathogenesis

• Direct invasion (neurotropism) or hematogenous spread (most common).
• Indirect invasion occurs through an immune inflammatory process.
• Respiratory portals of entry include measles, varicella-zoster, influenza, mumps.
• The gastrointestinal tract is a portal of entry for poliovirus, coxsackie, and echovirus.
• Skin is a portal of entry for arthropod-borne viruses, Rickettsia rickettsia, and trypanosomes.

Rabies

• An infected animal's bite transmits rabies.
• Dogs are the principal vector in 98% of cases worldwide.
• It can be transmitted by unrecognized bat bites.
• Rabies is rare and sporadic in the U.S.; there were 125 cases from 1960-2018.
• 36 (28%) of those cases were attributed to dog bites during international travel.
• 89 of the cases were acquired in the US; 62 (70%) were attributed to bats.
• Rabies is worldwide in distribution, causing 50,000-100,000 annual deaths.
• Rabies's incubation period is 20-90 days.
• Rabies poses a risk in areas where dogs roam freely.
• Rabies can be diagnosed via the culture and PCR of saliva, a CSF antibody and RT-PCR, a biopsy of the nape of the neck, a brain biopsy (to find negri bodies), or corneal smear.

Viral Causes - Togaviridae Family

• This family includes genus alphaviruses.
• These include Eastern Equine virus, Western Equine virus, and Venezuelan Equine virus.
• Horses are the reservoir, and transmission to human beings occurs via mosquito bites.

Flaviviridae

• About 70 members, half of which are linked to human illnesses.
• They are enveloped, spherical virions, 40-50 nm in size.
• They have two envelope proteins, E and M (pr M).
• The icosahedral capsid is 25-30nm.
• Flaviviridae have single-stranded RNA genome, linear, positive polarity, 1.1 kb, infectious.
• The St. Louis encephalitis (SLE) type is in the USA.
• The Japanese encephalitis (JE) type is in Asia.
• The Murray Valley encephalitis type is in Australia and New Guinea.
• The West Nile Virus encephalitis (WNV) type is in Africa, the Mideast, and the USA.
• Tick-borne Complex is worldwide.

Bunyaviridae

• California/La Crosse encephalitis (CE) and Rift Valley virus encephalitis are caused by viruses of this classification.

St. Louis Encephalitis (SLE)

• SLE has been reported in the USA, Canada, and the Caribbean.
• SLE is urban (eastern USA) and rural (western USA).
• SLE occurs during June, July, and August.
• Mosquitoes are SLE vectors.
• Birds are SLE animal hosts.
• Diagnosis involves finding antibodies in acute or convalescent sera.
• SLE is common in adults over 50; female to male ratio is greatesr.
• A clinical feature is dysuria.
• Mortality is 2-20%.
• Sequelae occur in 25% of cases.

Western Equine Encephalitis (WEE)

• WEE is in the West and Midwest.
• Infants and adults older than 50 are more susceptible.
• There is 5-15% mortality.
• Sequelae are moderate in infants, but low in others.
• Symptoms include headache, altered consciousness, and seizures.

La Crosse Encephalitis (CE)

• LAC is a California serogroup virus.
• LAC is found in the US Midwest & NE and southern Canada.
• LAC is found in woodlands.
• LAC occurs in June-September.
• Mosquitoes (Aedes) are the vector.
• Chipmunks, squirrels, and small mammals are animal hosts.
• Diagnosis involves acute/convalescent sera.
• LAC is more common in children younger than 20, M>F.
• LAC causes seizures.
• Mortality is less than 1%.
• Sequelae are rare (

Eastern Equine Encephalitis (EEE)

• EEE is found in the US Atlantic, Gulf coast, Caribbean, South America, and coastal marshes.
• EEE occurs in June, July, and August.
• Mosquitoes are the vector.
• Birds and horses are the animal hosts.
• Diagnosis involves acute/convalescent sera.
• EEE is diagnosed in patients 1000/ul.
• Mortality is 50-70%.
• Sequelae occur in 80% of cases especially children

Japanese Encephalitis (JE)

• JE is in East & SEA, and India.
• JE is found in rice fields.
• JE occurs May to September.
• JE is transmitted by Mosquitoes (Culex tritaeniorhynchus).
• Wild birds are the animal host.
• Diagnosis involves acute/convalescent sera.
• Symptoms commonly affect the GIT.
• Mortality is 7-50%.
• Sequelae occur in 30-70% of cases (young & elderly), resulting in Parkinson's-like syndrome.

Clinical Findings of Viral Encephalitis

• Acute-onset febrile illness and headache.
• Altered level of consciousness and disorientation.
• Behavioral and speech disturbances.
• Seizures are found.
• Neurologic signs such as hemiparesis or cranial nerve palsies.
• With Temporal lobe (HSV), patients can experience bizarre behavior, hallucinations, aphasia: HSVE.
• Patients can experience local paresthesia at the site of the bite with Rabies.
• Parkinsonian-like Syndrome is associated with Japanese encephalitis and WNV encephalitis.

Laboratory Findings of Viral Encephalitis

• Normal or leukopenic peripheral WBC count.
• CSF: Mononuclear pleocytosis (WBC 250/mm3)
• Elevated protein (150mg/dl)
• Glucose: normal or slightly depressed
• Red blood cells are typically absent except in cases of HSV-1.
• Decreased glucose in cases of HSV, mumps, some enteroviruses, and LCM.
• EEG, CT and especially MRI can be used to diagnose encephalitis.

Presumptive Therapy

• HSV: ACV
• CMV: GCV, Foscarnet
• HIV: ZVD
• Treat cerebral edema with Mannitol and hyperventilation.
• Vaccines are available for Japanese Encephalitis.

West Nile Virus (WNV) Encephalitis

• The first US cases were reported in 1999 in New York City.
• Birds are the main reservoirs.
• Mosquitoes are the main vector.
• WNV is also transmitted through transplanted organs, blood transfusions, breast milk, transplacentally, and occupationally.
• Positive IgM capture ELISA confirms it.
• WNV is found in the USA (spreading), Israel, and the Mideast.
• WNV is common in urban & rural areas.
• WNV occurs June to Oct.
• Mosquitoes are the vector.
• Birds are animal hosts.
• Diagnosis utilizes acute/convalescent sera.
• Adults older 50 are the most susceptible as well as women particularly.
• It presents as a flu-like syndrome followed by flaccid paralysis and seizures.
• Mortality is 1-2%, affecting those older than 60 mostly.
• Sequelae occur in 25% of cases.
• No clinical illness or symptoms occur in 80% of cases.
• Patients can experience West Nile Fever (20%)
• Some endure a severe WNV disease (1 in 150).

WNV Diagnosis

• Serum IgM antibody (8-14 days of illness onset).
• CSF reveals lymphocytic pleocytosis and elevated protein.
• A normal glucose level.
• CSF IgM is positive in >90% of cases.
• CSF PCR is less than 60% sensitive.
• Neuroimaging.
• Therapy is mostly supportive.
• Ribavirin, interferon alpha, and IVIG don't work.

Anti-N-Methyl-D-Aspartate Receptor (Anti-NMDAR) Encephalitis

• Neuronal antibody-associated encephalitis
• Female to male ratio of about 8:2
• 37% of patients are younger than 18 years at presentation
• Abnormal behavior (psychiatric symptoms)
• Cognitive dysfunction
• Seizures
• Movement disorders (orofacial dyskinesias)
• Decreased level of consciousness
• Autonomic instability
• May be associated with ovarian teratoma (in ~50% of patients older than 18 years)

Anti-NMDAR Encephalitis CSF Analysis

• Mild pleocytosis (median WBC 23/mm3) along with normal glucose and protein.
• Specific IgG antibodies to GluN1 subunit of the NMDAR in CSF and serum.
• Viral causes of encephalitis (e.g., HSV) are associated with the development of NMDAR antibodies.