Encephalitis
S. Sears, MD
Herpes simplex virus type 1
Most common cause of fatal sporadic
encephalitis
HSV infection of the CNS
• Immediate CNS invasion
– From the trigeminal nerve or olfactory tract
– Follows an episode of primary HSV-1 of the oropharynx
• CNS invasion after recurrent HSV-1 infection
– Represents viral reactivation with subsequent spread
• CNS infection without primary or recurrent HSV-1 infection
– Represents reactivation of latent HSV in situ within the CNS
Pathogenesis
Necrosis occurs in the temporal lobe
• Direct viral-mediated inflammation
– Extent of viral load may be directly related to severity of
disease
• Indirect immune-mediated CNS damage
– Not more common in immunocompromised patients
Clinical features
Focal neurologic findings are acute (< 1 week)
•
•
•
•
•
•
•
Altered mentation - level of consciousness
Focal cranial nerve deficits
Hemiparesis
Dysphasia
Aphasia
Ataxia
Focal seizures
Fever
Later in the clinical course
•
•
•
•
Diminished comprehension
Paraphasic (word substitution) spontaneous speech
Impaired memory
Loss of emotional control
Behavioral syndromes
Hypomania
•
•
•
•
•
•
Inflammation of the temporal - limbic system
Elevated mood
Excessive animation
Decreased need for sleep
Inflated self-esteem
Hypersexuality
Kluver-Bucy syndrome
• Psychic blindness
• Loss of normal anger and fear responses
• Inappropriately oral and sexual
States of amnesia
Recurrent brainstem encephalitis
Upward gaze
Facial numbness
Signs of involvement
• Corticospinal tract
• Spinothalamic tract
• Cerebrellar pathways
Investigations
Laboratory
• CSF
–
–
–
–
–
Lymphocytic pleocytosis
Increased RBC
Elevated protein
Normal glucose
PCR-diagnostic confirmation
Electroencephalogram (EEG)
• Nonspecific
• Continuous periodic lateralizing epileptiform discharges
Investigations
Imaging
• CT
– Predominantly unilateral temporal lobe lesions
– May be associated with mass effect
• MRI
– More specific than CT
– Brain perfusion studies demonstrate hyperperfusion early in
disease
HSV encephalitis
Differential diagnosis
Arthropod viruses
Other herpesviruses (CMV,EBV,VZV)
Viral Meningitis
Brain abscess
Post-infectious Reye syndrome
Acute disseminated encephalomyelitis
Vasculitis
Neurosyphilis
Primary or secondary malignancy
Toxic encephalopathy
Diagnosis
Gold standard
•
•
•
•
PCR
Detects HSV DNA in the CSF
Positive early in the course of the disease
Detectable 2-4 weeks after the onset of illness
If PCR negative
• Patient clinically deteriorates on therapy
• Brain biopsy
• Still the only accurate way for certain diagnosis
CSF antigen and antibody determinations not
helpful
Viral culture rarely positive
Treatment
Acyclovir 10mg/kg IV q8hrs for 21 days
•
Infuse slowly and with fluid to prevent crystalluria and renal failure
Shorter courses have been associated with relapse
Treat early
•
•
•
Before loss of consciousness
Within 24 hours onset symptoms
Glasgow Coma Scale 9-15
Discontinue therapy
•
•
•
Low probability of encephalitis
Normal imaging, CSF, mental status
Negative CSF PCR
Continue therapy
•
•
•
High risk patient
Abnormal imaging, CSF, mental status,seizures, abnormal EEG
Look for alternative why PCR negative
–
Early testing, antiviral therapy, PCR inhibitors (bloody CSF)
Prognosis
Fatality
• 70 percent
Survivors
• Serious neurologic deficits
• Significant neuropsychiatric difficulties
• Significant neurobehavioral issues
Rabies
Neurotropic RNA viruses
•
Belong to the family Rhabdoviridae
Human infections
• From rabid animals through a bite
• In developing countries
– Dogs account for 90 percent of reported cases
• In the United States
– Four major animal reservoirs
•
•
•
•
Bats
Raccoons
Skunks
Foxes
• Unusual transmission
– Organ donor died of encephalitis-unknown cause
– All recipients were diagnosed with rabies
Pathogenesis
Viruses deposit in peripheral wounds
• Exposed skin vs bite through clothing
• Face and head vs peripheral site (distance
from CNS)
• Amount of virus in the saliva
• Degree of innervation at the site of bite
• Host immunity
Pathogenesis
Retrograde passage of virus
•
•
•
Peripheral nerve
Dorsal root ganglia
To brain
Viral replication in CNS
• Localizes
–
–
–
–
Brainstem
Thalamus
Basal ganglia
Spinal cord
Spread from CNS
• Heart
• Skin
• Salivary glands
Clinical manifestations
Classic forms
• Encephalitic
–
–
–
–
Hydrophobia
Aerophobia
Pharyngeal spasms
Hyperactivity
• Paralytic
– Quadriparesis
– Mimics Guillain-Barre
– Cerebral involvement is late in the course
Clinical manifestation
Non-classic form
• Bat-associated rabies
• Neuropathic pain
• Sensory/motor deficits
• Choreiform movements of the bitten limb
• Cranial nerve palsies
• Myoclonus
• Seizures
Clinical manifestation
Five general stages
•
•
•
•
•
Incubation period
Prodrome
Acute neurologic syndrome
Coma
Death
General stages of disease
Incubation period
•
•
One to three months
Can be days to one year
Prodrome
•
•
Lasts days-not more than a week
Flu-like symptoms
–
–
–
–
–
–
–
–
•
Malaise
Anorexia
Irritability
Low grade fever
Sore throat
Headache
Nausea
Vomiting
Viral site of entry
–
–
–
–
Paresthesias
Pain
Pruritus
Percussion myoedema
General stages of the disease
Acute neurologic syndrome
• Lasts two to seven days after prodrome
• Encephalitic rabies
• Paralytic rabies
• Atypical rabies
Coma
• Generalized flaccid paralysis
• Respiratory failure
• Vascular collapse
Death
• Two weeks after the onset of coma
Diagnosis
Clinical presentation
Investigations
•
Samples
– Saliva
• Reverse transcriptase PCR
• Viral culture
– Neck biopsy
• Full thickness
• At the hairline
• Cutaneous nerve
• Follicle
• RT/PCR
• Immunofluorescence staining for viral antigen
– Serum and CSF
• Antibody titers
– Brain biopsy
• RT/PCR
• Immunofluorescence staining for viral antigen
Rabies-negri body in neuron
Rabies-under electron microscope
Treatment
Rabies vaccine
•
•
Multiple site intradermal injections
To accelerate the immune response
Human rabies immune globulin
•
•
•
•
Total dose 20 IU/kg
Intramuscular
Infiltrated around the wound
To promote clearance of the infection
Ribavirin
•
Intravenous and intraventricular
IFN-alfa
•
Intravenous and intraventricular
Ketamine
•
•
Intravenous infusion
Inhibits rabies virus replication
Vaccine
•
For patients not previously vaccinated
Prevention
Rabies vaccine
• Preexposure
–
–
–
–
–
•
Rabies research lab workers
Rabies biologics manufacturing workers
Veterinarians
Animal control workers
Wildlife workers
Postexposure
–
Any patient not previously vaccinated
West nile virus encephalitis
West nile virus
Most widely distributed of all the arboviruses
•
From the group of flavivirus
Distribution
•
•
•
•
•
•
•
•
Now North America
Was from
Africa
Middle East
Europe
Russia
South Asia
Australia
Carried by wild birds
Transmitted
•
•
•
By the mosquito bite from the Culex species
Transfused blood
Transplanted organs
Culex pipiens pipiens-northern house mosquito
Clinical manifestation
Incubation ranges from 2-14 days
West nile fever
•
•
•
•
•
Fever
Malaise
Back pain
Myalgias
Anorexia
Persists for 3-6 days
Most frequent symptom
•
•
Maculopapular rash
Involves
–
–
–
Chest
Back
arms
West nile fever - rash
Neuroinvasive disease
Increased risk
•
•
•
•
Older age
Alcohol abuse
Diabetes
Immunocompromised
Encephalitis
• Most common
• Presents with
–
–
–
–
Headache
Fever
Nausea
Vomiting
• Associated with muscle weakness and flaccid paralysis
Neurologic disease
Tremor
Myoclonus
Parkinsonian features
•
Rigidity
•
Postural instability
•
Bradykinesia
Cranial nerve palsies
•
Facial weakness
•
Vertigo
•
Dysarthria
•
Dysphagia
Acute flaccid paralysis syndrome
•
Anterior horn cell process (like polio)
Seizures
Cerebellar ataxia
Optic neuritis
Weakness
•
Brachial plexopathy
•
Radiculopathy
•
Demyelinating peripheral neuropathy
Other clinical features
Ocular manifestations
• Chorioretinitis
• Vitritis
• Uveitis
Rhabdomyolysis
Myocarditis
Hepatitis
Pancreatitis
Central diabetes insipidus
Palpable purpura
Diagnosis
Investigations
•
LP
–
CSF
•
•
•
•
Increased lymphocytes
Increased protein
Normal glucose
Imaging
–
CT
•
–
Usually normal
MRI
•
Hypertensity
–
Leptomeninges
–
Periventricular
–
Basal ganglia
–
Thalamus
–
Caudate nuclei
–
Brainstem
–
Spinal cord
Diagnosis
Serology
• IgM antibody capture enzyme-linked
immunosorbent assay
• Within first 8 days of illness
• Convelescent-phase serum as well
• Viral nucleic acid
CSF
• IgM antibody
West Nile fever
Treatment
• Supportive
Prognosis
• Increased risk
– Older age
– Immunosuppressed
Long-term sequelae
St. Louis encephalitis
Acute mosquito-borne illness
Virus is a single-stranded RNA flaviviridae
Vector -Culex mosquito
Second leading cause of encephalitis after West nile virus
Principally occurring
•
•
•
•
•
Ohio-Mississippi valley
Eastern Texas
Florida
Southeastern Canada
Northern Mexico
St. Louis encephalitis
Human infection
•
•
•
•
Inoculation of the virus into human host
Spread via lymphatics and blood
Reaches the choroid plexus
Results in lymphocytic encephalitis
Most severely affected regions
• Hypothalamus
• Cerebellum
• Cerebral cortex
• Basal ganglia
• Brainstem
• Cervical spinal cord
Incubation period
• 4-21 days
Clinical features
Prodromal symptoms
• Four to five days
• Fever
• Severe headache
• Photophobia
• Nausea
• Vomiting
• Malaise
• Myalgias
Clinical features
Neurologic signs
• Rapid onset
• Alerted sensorium
• Tremors
–
–
–
–
•
Eyelids
Tongue
Lips
Extremities
Cranial nerve dysfunction
– Unilateral facial motor weakness
– Oculomotor dysfunction
– Dysarthria
•
•
•
•
Myoclonus
Opsoclonus
Nystagmus
Ataxia
Investigations
Laboratory
• Increased ALT and CPK
• Hyponatremia
CSF
• Increased lymphocytes
• Increased protein
• Normal glucose
• Negative gram stain
Imaging
• No specific abnormalities
EEG
• Diffuse slowing
St. Louis encephalitis
Diagnosis
• Serum
• CSF
• IgM antibodies
• Acute and convalescence
Treatment
• No specific antiviral therapy
• Supportive
• Interferon alfa-2B
–
–
–
–
Reduced likelihood after first week in hospital
Quadriplegia
Quadriparesis
Respiratory insufficiency
Outcome
Death in the first two weeks
•
•
20 percent
From direct brain injury
Poor prognosis
• Sustained high fever
• Convulsions
• Advanced age
• Severely depressed state of consciousness
Convalescence
• Weeks to months
• Residual
• Headaches
• Irritability
• Memory deficits
• Persistent tremor
Prevention
No available vaccine
Mosquito control
Dengue virus infection
Dengue virus
• Member of the family flaviviridae
• Distribution in every continent
• Except Europe and Antarctica
Transmitted by
• Mosquito-Aedes aegypti
• Breed in or close to houses
Aedes aegypti mosquito
Clinical presentation
• Asymptomatic infection
• After incubation period 3-14 days
– Self-limited dengue fever
– Dengue hemorrhagic fever with shock
Asymptomatic infection
• Seen in children under the age of 15 in
endemic areas
Dengue fever-classic
Acute febrile illness
• Headache
• Retroorbital pain
• Marked muscle and joint pain
• Fever-lasts 5-7 days
• Biphasic
– Second febrile phase for 1-2 days
Rash- in 2-5 days after fever
Hemorrhagic manifestations
• Spontaneous bleeding
• Melena
• Purpura
Classic dengue
Physical exam
•
•
•
•
•
Conjunctival injection
Pharyngeal erythema
Lymphadenopathy
Hepatomegaly
Maculopapular rash
Laboratory
•
•
•
•
Leukopenia
Thrombocytopenia
Serum aspartate transaminase elevated
Virus often found in high concentration in the liver
Dengue hemorrhagic fever
Defined by the World Health Organization
Four cardinal features
• Fever lasting 2-7 days
• Marked thrombocytopenia (dec platelets)
• Increased vascular permeability
–
–
–
–
–
–
Plasma leak syndrome
Preceded by abdominal pain
hypothermia
Hemoconcentration
Pleural effusion
Ascites
• Hemorrhagic tendency
–
–
–
–
Positive tourniquet test (greater than 20 petechiae)
Hematemsis
Melena
epistaxis
Positive tourniquet test
Uncommon syndromes
Liver failure
Encephalopathy
Encephalitis
Seizures
Motor weakness
• Mononeuropathies
• Polyneuropathies
• Guillain-Barre syndrome
• Transverse myelitis
Myocarditis
Cholecystitis
Retinal vasculitis
Diagnosis
Provisional diagnosis can be made on clinical basis
Laboratory testing
• Acute phase serum plasma for IgM immunoassay
• If negative repeat in 6 days
• At least 10-14 days later convalescent serum
• Both specimens analyzed together
• By hemagglutination inhibition
Viral detection
• Direct culture
Detection of plasma leakage
• Ultrasound
Direct Dengue viral culture
Treatment
No specific therapy-mortality dependent on severity of
disease and is variable
Directed at
Fever
• Acetaminophen
Bleeding
• Transfusion
– Red blood cells
– Platelets
Reversal of hypovolemic shock
• IV fluids
• Prevention of end organ damage
Arthropod-borne encephalitides
Similarities
• All viruses
• Family
–
–
–
–
Togaviridae
Flaviviridae
Bunyaviridae
Reoviridae
• Transmitted to humans via a vector
– Mosquito-Culex
– Tick
• Incubation time after inoculation
– From 3 days to two weeks
Arthropod-borne encephalitides
Similarities
• Prodrome
– Flu-like illness
• Results in encephalitis
• Diagnosis
– CSF
•
•
•
•
•
•
Lymphocytosis
Increased protein
Normal glucose
Gram stain negative
– IgM antibody by capture immunoassay in CSF
– Demonstrate viral antigen or genome in tissue
Treatment
– Supportive
Prevention
– Arthropod
• Control
• Avoidance
Family-Togaviridae
• Eastern equine encephalitis virus
• Western equine encephalitis virus
• Venezuelan equine encephalitis virus
Eastern equine encephalitis virus
• Virus distributed North,Central,South America and
Caribbean
• Virus transmitted by mosquito found in swamp areas
• Peak incidence in August and September
• Outbreaks along the Atlantic and Gulf coasts
• Neurologic deterioration is rapid once symptoms begin
• Common
– Seizures
– Focal neurologic signs
• Sequelae
– Convulsions
– Paralysis
– Mental retardation
• Mortality is 30%
Western equine encephalitis virus
• Found in North and South America
• Flooding
– Increases breeding of Culex mosquito
• Summer outbreaks
• Large outbreaks
– Horses and humans
– Western United States
• Decreasing incidence
– Declining horse population
– Equine vaccine
– Improved vector control
• Neurologic sequelae
– Common in infants
• Mortality is 3-7%
Venezuelan equine encephalitis virus
• Distributed from Florida to South America
• Six subtypes
• Epizootic subtype
–
–
–
–
IAB and IC
Produces outbreaks of illness in animals
Cause equine and severe human illness
Transmitted by several mosquitoes
• Enzootic subtype
–
–
–
–
ID-F, II, III, IV, V, VI
Infects animals sporadic illness
Causes illness in humans
Transmitted by Culex mosquito
• Long-term sequelae and fatalities uncommon
Family-Flaviviridae
•
•
•
•
Japanese encephalitis virus
Murray Valley encephalitis virus
Powassan virus
Tick-borne encephalitis virus
Japanese encephalitis virus
•
Widespread throughout Asia
–
–
•
•
Seizures are common
Extrapyramidal features
–
–
–
•
Thalamus
Basal ganglia
Midbrain
Pons
Medulla
Diagnosis
–
•
•
Expressionless facies
Hypertonia
Cogwheel rigidity
MRI abnormalities
–
–
–
–
–
•
Occurs in late summer in temperate regions
Transmitted by Culex mosquito in rice fields
Viral antigen or DNA in tissue
Mortality is 30%
Severe neurologic sequelae
–
–
–
Motor weakness
Cerebellar signs
Extrapyramidal signs
Murray Valley Encephalitis virus
•
•
•
•
Occurs Australia, New Guinea, eastern part of Indonesia
Transmitted by Culex mosquito
Seizures are common in children
Severe cases
–
–
–
–
Hyperactive reflexes
Spastic paresis
Coma
Death
• CT
– Mild hydrocephalus
– Cerebral edema
– Decrease in thalamus to brainstem
• Mortality is 30%
• Neurologic sequelae is 50%
Powassan virus
•
•
•
Found in eastern Canada and northeastern United States
Occurs from June to September
Transmitted by ticks
– Species
• Ixodes
• Dermacentor
•
•
Incubation period 8-34 days
Presents with
– GI complaints
– Seizures
– Confusion
•
•
Mortality 5-10%
Neurologic sequelae
–
–
–
–
Hemiplegia
Headaches
Memory impairment
Ophthalmoplegia
Tick-borne encephalitis virus
•
•
Subtypes
– Far eastern
– Western Europe
– Siberian
Transmitted by
– Ticks
• Species
• Ixodes
•
•
•
– Ingestion of raw milk (cows,sheep,goats)
Occurs in spring and summer
Gastrointestinal complaints common
Forms
– Meningeal
– Poliomyelitic
– Polyradiculoneuritic
– Chronic
• Over months to years
• Parkinson-like,progressive muscle atrophy, mental deterioration
•
•
Mortality is 1-8%
Vaccines are available in Europe and Canada
Family-Bunyaviridae
La Crosse (California) encephalitis virus
• Found in central and eastern United States
• Occurs July to September
• Transmitted by Aedes mosquito
• Common in school-aged children
• Common features
– Seizures
– Focal neurologic signs
• CT
– Generalized cerebral edema
• Mortality is low
• Neurologic sequelae 10%
– Focal neurologic
– Cognitive deficit
– Behavioral deficit
Family-Reoviridae
Colorado tick fever virus
• Found in western United States and Canada
• Transmitted by the wood tick
• Occurs from March to September
• Peaks April to June
• Clinical features
– Petechial rash
– Increasing fatigue
• Virus infects bone marrow
– Leukopenia common
• Prognosis is favorable
Chandipura virus
•
•
•
•
Found in India
Transmitted by the sandfly
Occurs mostly in children
Identified
– Electron microscopy
– Complement fixation
– Neutralizing tests
• Rapid onset
– Vomiting
– Altered mental status
– Seizures
• Progressive encephalitis
• Mortality rate 50%