Acute Viral Encephalitis/ Meningitis

Dr. Shatdal Chaudhary, M.D.Associate ProfessorUniversal College of Medical Sciences,Bhairahawa, NepalEmail: shatdalchaudhary@yahoo.com

Introduction• Encephalitis is an acute inflammatory process affecting the brain

parenchyma

• Meningoencephalitis• Encephalomyelitis• Encephalomyeloradiculitis

• Viral infection is the most common and important cause, with over 100 viruses implicated worldwide

• Incidence of 3.5-7.4 per 100,000 persons per year• ~20,000 cases reported anually in USA

Causes of Viral Encephalitis• Herpes viruses – HSV-1, HSV-2, varicella zoster virus, cytomegalovirus, Epstein-

Barr virus, human herpes virus 6 • Adenoviruses• Influenza A• Enteroviruses, poliovirus• Measles, mumps, and rubella viruses• Rabies• Arboviruses – examples: Japanese encephalitis; St. Louis encephalitis virus;

West Nile encephalitis virus; Eastern, Western and Venzuelan equine encephalitis virus; tick borne encephalitis virus

• Bunyaviruses – examples: La Crosse strain of California virus• Reoviruses – example: Colorado tick fever virus• Arenaviruses – example: lymphocytic choriomeningitis virus

What Is An Arbovirus?• Arboviruses = arthropod-borne viruses • Arboviruses are maintained in nature through biological

transmission between susceptible vertebrate hosts by blood-feeding arthropods

• Vertebrate infection occurs when the infected arthropod takes a blood meal

Major Arboviruses That Cause Encephalitis• Flaviviridae• Japanese encephalitis• St. Louis encephalitis• West Nile

• Togaviridae• Eastern equine encephalitis• Western equine encephalitis

• Bunyaviridae• La Crosse encephalitis

http://www.cdc.gov/ncidod/dvbid/arbor/worldist.pdf

Japanese Encephalitis

Japanese Encephalitis• Flavivirus related to St. Louis

encephalitis• Most important cause of

arboviral encephalitis worldwide, with over 45,000 cases reported annually

• Transmitted by culex mosquito, which breeds in rice fields• Mosquitoes become infected by

feeding on domestic pigs and wild birds infected with Japanese encephalitis virus. Infected mosquitoes transmit virus to humans and animals during the feeding process.

History of Japanese Encephalitis• 1800s – recognized in Japan

• 1924 – Japan epidemic. 6125 cases, 3797 deaths

• 1935 – virus isolated in brain of Japanese patient who died of encephalitis

• 1938 – virus isolated from Culex mosquitoes in Japan

• Today – extremely prevalent in South East Asia. 30,000-50,000 cases reported each year.

Distribution of Japanese Encephalitis in Asia, 1970-1998

West Nile Virus

West Nile Virus• Flavivirus• Primary host – wild

birds• Principal arthropod

vector – mosquitoes• Geographic distribution

- Africa, Middle East, Western Asia, Europe, Australia, North America, Central America

http://www.walgreens.com/images/library/healthtips/july02/westnilea.jpg

St. Louis Encephalitis

St. Louis Encephalitis

• Flavivirus• Most common

mosquito-transmitted human pathogen in the US• Leading cause of

epidemic flaviviral encephalitis

Eastern Equine Encephalitis• Togavirus• Caused by a virus transmitted to

humans and horses by the bite of an infected mosquito.

• 200 confirmed cases in the US 1964-present

• Human cases occur relatively infrequently, largely because the primary transmission cycle takes place in swamp areas where populations tend to be limited.

Western Equine Encephalitis

• Togavirus• Mosquito-borne• 639 confirmed cases in

the US since 1964 • Important cause of

encephalitis in horses and humans in North America, mainly in the Western parts of the US and Canada

La Crosse Encephalitis• Bunyavirus• On average 75 cases per year

reported to the CDC• Most cases occur in children under 16

years old• Zoonotic pathogen that cycles

between the daytime biting treehole mosquito, and vertebrate amplifier hosts (chipmunk, tree squirrel) in deciduous forest habitats

• 1963 – isolated in La Crosse, WI from the brain of a child who died from encephalitis

Summary – Confirmed and Probable Human Cases in the USVirusVirus YearsYears Total casesTotal cases

Eastern Eastern EquineEquine

1964-20001964-2000 182182

Western Western EquineEquine

1964-20001964-2000 649649

La CrosseLa Crosse 1964-20001964-2000 2,7762,776

St. LouisSt. Louis 1964-20001964-2000 4,4824,482

West NileWest Nile 1999-present1999-present > 9,800> 9,800

Acute Viral Meningitis• Enterovirus(coxaschie viruses, echovirus,human

enterovirus68-71• HSV 2• HIV• Arbovirus• VZV• EBV

Clinical Manifestations

Symptoms

• Fever

• Headache, • Malaise, Anorexia, Nausea and Vomiting• Abdominal pain• Altered level of consciousness• Mild lethargy to Coma

• Behavioral changes, hallucinations, agitations, personality changes, frank psychosis

• Focal neurologic deficits: • Virtually every possible focal neurological disturbance

has been reported.

• Aphasia• Ataxia• Weakness: Hemiparesis with hyperactive tendon

reflexes• Cranial nerve deficits• Involantary movements- tremors, myoclonic jerks• Seizures >50% patients

• SIADH

Patient History• Detailed history critical to determine the likely cause of encephalitis. • Prodromal illness, recent vaccination, development of few days →

Acute Disseminated Encephalomyelitis (ADEM) .• Biphasic onset: systemic illness then CNS disease → Enterovirus

encephalitis. • Abrupt onset, rapid progression over few days → HSE.• Recent travel and the geographical context: • Africa → Cerebral malaria• Asia → Japanese encephalitis• High risk regions of Europe and USA → Lyme disease

• Recent animal bites → Tick borne encephalitis or Rabies.• Occupation• Forest worker, exposed to tick bites• Medical personnel, possible exposure to infectious diseases.

Lab Investigation

• CSF examination: Should be performed in all the patients until contraindicated

• Diagnosis is usually based on CSF • Mild increase in protein• Inrease cells with predominantly lymphocytes• Normal glucose• Absence of bacteria on culture. • Viruses occasionally isolated directly from CSF

• Less than half are identified

Laboratory Diagnosis• CSF PCR techniques• Detect specific viral DNA in CSF• Usually available for HSVCMV, EBV, HHV6, ENTEROVIRUS, VZV

• CSF CULTURE

MRI/ CT Scan

• Can exclude subdural bleeds, tumor, and sinus thrombosis • Help by• Focal or diffuse ence4phalitis process• In HSV encephalitis- 80% abnormalities in temporal lobe

MRI

MRI

EEG• In HSV: Periodic focal temporal lobe spikes on a background of

slow or low amplitude activity.

Brain Biopsy• Is generally reserved for patients in whom CSF PCR fail to lead

a specific diagnosis• Reserved for patients who are worsening, have an undiagnosed

lesion after scan, or a poor response to acyclovir.

D/D• Tuberculosis, Fungal, Rickettsia, Mycoplasma, Bacterial • Anoxic/Ischemic conditions• Metabolic disorders• Nutritional deficiency• Toxic (Accidental & Intentional)• Systemic infections• Critical illness• Malignant hypertension• Hashimoto’s encephalopathy• Traumatic brain injury• Epileptic (non-convulsive status)• CJD (Mad Cow)

Treatment• Suppportive• Vital monitoring• ABC• IVF• Treatment of raised ICP• Bed Care• Nutrition• DVT prophylaxis

Supportive Therapy• Fever, dehydration, electrolyte imbalances, and

convulsions require treatment.• For cerebral edema severe enough to produce

herniation, controlled hyperventilation, mannitol, and dexamethasone.• Patients with cerebral edema must not be overhydrated.• If these measures are used, monitoring ICP should be considered.

• If there is evidence of ventricular enlargement, intracranial pressure may be monitored in conjunction with CSF drainage.

Acyclovir• Acyclovir is a synthetic purine nucleoside analogue with

inhibitory activity against HSV-1 and HSV-2, varicella-zoster virus (VZV), Epstein-Barr virus (EBV) and cytomegalovirus (CMV)• In order of decreasing effectiveness• Acyclovir 10 mg/kg 8 hrly 14-21day

Acyclovir Action• Thymidine Kinase (TK) of uninfected cells does not use acyclovir as a

substrate.• TK encoded by HSV, VZV and EBV2 converts acyclovir into acyclovir

monophosphate. • The monophosphate is further converted into diphosphate by

cellular guanylate kinase and into triphosphate by a number of cellular enzymes.

• Acyclovir triphosphate interferes with Herpes simplex virus DNA polymerase and inhibits viral DNA replication.

• Acyclovir triphosphate incorporated into growing chains of DNA by viral DNA polymerase.

• When incorporation occurs, the DNA chain is terminated.• Acyclovir is preferentially taken up and selectively converted to the

active triphosphate form by HSV-infected cells. • Thus, acyclovir is much less toxic in vitro for normal uninfected cells

because: 1) less is taken up; 2) less is converted to the active form.

• Ganicyclovir/Foscarnet: For CMV related CNS infection• Ganicyclovir 5mg/kg (over 1 hr) 12 hrly during induction therapy

the od in maintenance therapy• Foscarnet: 60mg/kg 8hrly during induction then maintenance 60-

120 mg/kg

Dexamethasone• Synthetic adrenocortical steroid • Potent anti-inflammatory effects• Dexamethasone injection is generally administered initially via

IV then IM• Side effects: convulsions; increased ICP after treatment;

vertigo; headache; psychic disturbances

Prognosis• The mortality rate varies with etiology, and epidemics

due to the same virus vary in severity in different years. • Bad: Eastern equine encephalitis virus infection, nearly 80% of

survivors have severe neurological sequelae. • Not so Bad: EBV, California encephalitis virus, and Venezuelan

equine encephalitis virus, severe sequelae are unusual. • Approximately 5 to 15% of children infected with LaCrosse virus

have a residual seizure disorder, and 1% have persistent hemiparesis.

• Permanent cerebral sequelae are more likely to occur in infants, but young children improve for a longer time than adults with similar infections. • Intellectual impairment, learning disabilities, hearing loss, and

other lasting sequelae have been reported in some studies.

Prognosis w/ Treatment• Considerable variation in the incidence and severity of sequelae.• Hard to assess effects of treatment.

• NIAID-CASG trials: • The incidence and severity of sequelae were directly related to the age

of the patient and the level of consciousness at the time of initiation of therapy.

• Patients with severe neurological impairment (Glasgow coma score 6) at initiation of therapy either died or survived with severe sequelae.

• Young patients (<30 years) with good neurological function at initiation of therapy did substantially better (100% survival, 62% with no or mild sequelae) compared with their older counterparts (>30 years); (64% survival, 57% no or mild sequelae).

• Recent studies using quantitative CSF PCR tests for HSV indicate that clinical outcome following treatment also correlates with the amount of HSV DNA present in CSF at the time of presentation.

Vaccination

• None for most Encephalitides• JE• Appears to be 91% effective• There is no JE-specific therapy other than supportive

care • Live-attenuated vaccine developed and tested in China • Appears to be safe and effective• Chinese immunization programs involving millions of children

• Vero cell-derived inactivated vaccines have been developed in China• 2 millions doses are produced annually in China and Japan

• Several other JE vaccines under development