Encephalitis and Encephalopathy Etiology

• Encephalitis is the inflammation of brain parenchyma with neurologic dysfunction.
• Encephalopathy is an altered consciousness plus inflammation.
• Pathologic examination and testing of brain tissue is the gold standard for diagnosis
• Diagnosis is usually based on clinical, laboratory, and imaging findings.
• Encephalopathy usually involves metabolic or toxic conditions.

Epidemiology

• There are approximately 5 cases of encephalitis per 100,000 population annually in the US from 1990-2017.
• There are more than 1 million cases annually worldwide.
• Rabies, measles, and Japanese encephalitis virus contribute to these cases.

Etiology

• The California Encephalitis Project (CEP) reviewed 1,570 cases over a 7-year period.
• Confirmed or probable etiology in 16% of cases were:
  • 69% viral
  • 20% bacterial
  • 7% prion
  • 3% parasitic
  • 1% fungal
• Possible etiology accounts for 13% of cases.

Reasons Etiology Not Identified

• Undiscovered pathogens
• Uncommon presentation by common pathogens
• Common presentation by uncommon pathogens
• Wrong test
• Wrong sample
• Wrong timing
• Cases can be a result of something other than an underlying infection

Pathogenesis

• Direct invasion, or neurotropism is a possible mechanism.
• Indirect invasion by an immune inflammatory process is also possible.
• Hematogenous spread is the most common mechanism,
• Portal of entry matters:
  • Respiratory portal includes: Measles, VZV, Influenza, Mumps
  • GIT portal includes: Poliovirus, Coxsackie, Echovirus
  • Skin portal includes: arthropod-borne viruses, Rickettsia rickettsia, trypanosomes

Rabies

• Rabies is transmitted by the bite of an infected animal
• Dogs are the principal vector, accounting for 98% of cases worldwide
• Rabies may be transmitted after unrecognized bites by bats
• Rabies is rare and sporadic in the US, with 125 cases from 1960-2018,
• Of the US cases, 36 or 28% were attributed to dog bites during international travel
• 89 cases were acquired in the US; 62 cases or 70% were attributed to bats
• Rabies is worldwide in distribution and results in 50,000-100,000 annual deaths.
• The incubation period for rabies is 20-90 days

Geographical vectors

• Skunks are common vectors in California, Texas, Kansas, Nebraska, North & South Dakota, Montana
• Foxes are common vectors in Arizona, New Mexico, and Alaska
• Raccoons are common vectors in Florida
• Mongoose are common vectors in Puerto Rico

Travelers

• Rabies is a risk wherever dogs are allowed to run free.
• Methods for Diagnosing Rabies:
  • Culture and PCR of saliva
  • CSF ab and RT-PCR
  • Biopsy nape of neck
  • Brain Biopsy (negri bodies)
  • Corneal smear
• Negri bodies are eosinophilic intranuclear inclusions found in brain biopsy.

Viral causes of encephalitis

• Viral causes include Family Togaviridae in the genus alphavirus.
  • Eastern Equine virus
  • Western Equine virus
  • Venezuelan Equine virus
  • Horses are the reservoir and are transmitted to humans via mosquito bite

Flaviviridae

• Flaviviridae consists of about 70 members, half of them associated with human disease
• these are Enveloped, spherical virions that are 40-50 nm in size.
• Virions have Two envelope proteins: E and M (pr M)
• Have a icosahedral capsid, with a diameter of 25-30nm
• Viruses contain an ss RNA genome, linear, positive polarity, with a size of 1.1 kb

Flaviviridae Encephalitis

• St. Louis encephalitis (SLE) is common in USA

• Japanese encephalitis (JE) is common in Asia

• Murray Valley encephalitis is common in Australia, New Guinea

• West Nile Virus encephalitis (WNV) is common in Africa, Mideast, USA

• Tick-borne Complex is common worldwide

• Geographical Distribution of the Japanese Encephalitis Serocomplex of the Family Flaviridae

• St. Louis encephalitis is common in the USA

• Rocio and St. Louis (Brazil) is common in South America

• Japanese encephalitis is common in East Asia and India.

• West Nile virus is common in African & Middle East

• Bunyaviridae: California/La Crosse encephalitis (CE), Rift valley virus encephalitis

St. Louis Encephalitis (SLE)

• Occurs in the USA, Canada, Caribbean
• Common in Urban Eastern USA, and Rural Western USA
• Common in June, July and August
• Vector is mosquitoes and animal host is birds
• Diagnosis via acute /convalescent sera looking for anitobodies in acute or covalescent phase
• Adults > 50, with Females > Males
• A common feature is dysuria
• Mortality is anywhere from 2-20% with sequelae presenting in 25%

Western Equine Encephalitis (WEE)

• Occurs in Western, and Midwestern USA
• Common in infants, however also effects other adults > 50
• Mortality percentages are anywhere from 5-15%
• Moderate sequelae in infants, with low sequelae in most others
• Includes Headache, altered consciousness, seizures

La Crosse Encephalitis (CE)

• Occurs in the US Midwest & NE, southern Canada
• Common in Woodlands in June-Sept
• Vector is Mosquitoes (Aedes) with animal hosts being Chipmunks, squirrels, small mammals
• Diagnosis via acute/ convalescent sera
• Common in Children <20 with males > females
• A common presentation is seizures
• Mortality is < 1% with very rare sequelae

Eastern Equine Encephalitis (EEE)

• Occurs in US Atlantic, Gulf coast, Caribbean, S. America, Coastal marshes in June,July,August
• Vector is Mosquitoes with animal hosts being birds and horses
• Diagnosis via acute/convalescent sera
• Commonly diagnosed in <10 & > 55yr olds
• Clinical features include CSF WBC > 1000/ul
• Presents with Mortality between 50-70% and Sequelae in 80% of patients esp.children children <10 yrs

Japanese Encephalitis (JE)

• Occurs: East & SEA, India in Rice Fields may to Sept.
• Vector: Mosquitoes (Culex tritaeniorhynchus) with Animal host : Wild birds
• Diagnosis : Acute/ convalescent sera
• GIT symptoms common
• Mortality: 7-50%
• Sequelae include 30-70% (young & elderly): 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
• Neurologic signs.
  • Includes hemiparesis or cranial nerve palsies
• Temporal lobe (HSV): bizarre behavior, hallucinations, aphasia: HSVE
• Local paresthesia at the site of a bite occurs in : Rabies
  • Parkinsonian-like Syndrome and Japanese encephalitis, WNV encephalitis

Laboratory findings of viral encephalitis

• Peripheral WBC : normal or leukopenia
  • CSF :
• Mononuclear pleocytosis (WBC <250/mm3)
  • Elevated protein (<150mg/dl)
  • Glucose : normal or slightly depressed*
• RBCs are absent except in cases of HSV-1
• Decreased Glucose in cases of HSV, mumps, some enteroviruses, and LCM.

Other diagnostic tools

• EEG, CT scan, MRI can be used. MRI is a lot more sensitive and specific than CT Scan

Presumptive Therapy

• HSV : ACV
• CMV : GCV, Foscarnet
• HIV : ZVD
• Supportive for Arboviruses
• Mannitol and hyperventilation are used to treat cerebral edema
• Vaccine: JE (Japanese Encephalitis)

West Nile Virus (WNV) Encephalitis

• First US cases reported in 1999 in New York City and main reservoirs are birds
• Is spread through a mosquito vector or: - Transplanted organs, Blood transfusions - Breast milk, Transplacental, Occupational settings

West Nile Virus Encephalitis Specifics

• Present in: USA (spreading), Israel, Mideast
  • Common Environment: Urban & rural in June to Oct
  • Vector: Mosquitoes and Animal host: birds
  • Acute/ convalescent sera in Adults > 50yrs, with Females>Males
  • Clinical features are: Flu-like syndrome followed by flaccid paralysis, seizures
  • Mortality 1-2% >60yrs, with Sequelae in 25% of patients

West Nile Virus Clinical Syndrome

• No clinical illness or symptoms in ~80% of patients or West Nile Fever in (~20%)
• Severe WNV Disease (1 in 150) with:
  • Meningitis (37%)
  • Encephalitis/Meningoencephalitis (53%)
  • Poliomyelitis-like flaccid paralysis (7%)

Diagnosis of WNV

• Diagnosis via a serum IgM antibody can be checked 8-14 days after the onset of the illness
  • CSF reveals lymphocytic pleocytosis and elevated protein; glucose is usually normal
  • CSF IgM is usually positive in >90% of cases
  • CSF PCR (<60% sensitivity)
  • Neuroimaging

WNV Encephalitis Therapy

• Supportive therapies are used
  • Ribavirin, interferon alpha, and IVIG don't work to treat

Anti-N-Methyl-D-Aspartate receptor (Anti-NMDAR) encephalitis

 - Is a neuronal antibody-associated encephalitis with a Female to male ratio of about 8:2
 - 37% of patients are younger than 18 years at presentation

• Presents with: Abnormal behavior aka psychiatric symptoms - Cognitive dysfunction or Seizures - Movement disorders (orofacial dyskinesias) - Decreased level of consciousness -Autonomic instability
  • May be associated with ovarian teratoma for ~50% of patients older than 18 years

Anti-NMDAR Encephalitis CSF Analysis

• Mild pleocytosis of (median WBC 23/mm3); 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