1. VIRAL ENCEPHALITIS
James M. Mitchell, M.D.

2. VIRAL ENCEPHALITIS OBJECTIVES DEFINE VIRAL ENCEPHALITIS
UNDERSTAND ETIOLOGY AND EPIDEMIOLOGY
UNDERSTAND THE CLINICAL PRESENTATION
DIFFERENTIAL DIAGNOSIS
DIAGNOSTIC WORKUP
TREATMENT OPTIONS
PREVENTIVE MEASURES

5. VIRAL ENCEPHALITIS DEFINITIONS VIRAL (ASEPTIC) MENINGITIS ENCEPHALITIS
MENINGOENCEPHALITIS
MYELITIS
CEREBRITIS
ENCEPHALOMYELITIS

6. VIRAL ENCEPHALITIS VIRAL MENINGITIS
“ …usually a self-limited illness characterized by signs of meningeal irritation, such as headache, photophobia, and neck stiffness.”1

7. VIRAL ENCEPHALITIS ENCEPHALITIS
“ …entails involvement of parenchymal brain tissue as indicated by convulsive seizures, alterations in the state of consciousness, and focal neurological abnormalities.”1

8. VIRAL ENCEPHALITIS MENINGOENCEPHALITIS
“…both meningeal and encephalitic findings are present.”1

9. VIRAL ENCEPHALITIS MYELITIS
“infection of parenchyma of the spinal cord …may occur from infection of spinal motor neurons (paralytic disease, poliomyelitis), sensory neurons, autonomic neurons (bladder paralysis), or demyelination of white matter (transverse myelitis).”1

10. VIRAL ENCEPHALITIS CEREBRITIS
“…an acute inflammatory reaction and regional edema…describes the stage preceding abscess formation and implies a highly destructive bacterial infection of brain tissue.” 2,3

11. VIRAL ENCEPHALITIS INTRODUCTION TWO FORMS
Primary encephalitis- occurs when the virus directly invades the brain: herpes simplex, varicella-zoster, arboviruses, Epstein-Barr
Secondary (post-infectious) encephalitis- are immune-mediated processes which result in multifocal demyelination of perivenous white matter: rubeola, mumps, rubella, CMV

12. VIRAL ENCEPHALITIS INTRODUCTION Acute Chronic
Herpes simplex encephalitis
Varicella-zoster encephalitis
Epstein-Barr
Arboviral encephalitides
Chronic
Subacute sclerosing panencephalitis
Progressive rubella panencephalitis
HIV
HTLV-1
Progressive multifocal leukoencephalopathy
Prion diseases- Kuru, Creutzfeldt-Jakob

13. VIRAL ENCEPHALITIS ETIOLOGY Primary encephalitis- acute DNA viruses
RNA viruses

14. VIRAL ENCEPHALITIS DNA VIRUSES Herpes simplex (HSV)
Varicella-zoster (VZV)
Cytomegalovirus (CMV)
Epstein-Barr (EBV)
Papovavirus (PML)
Adenovirus

15. VIRAL ENCEPHALITIS RNA VIRUSES Arboviruses
Alphaviruses: Equine Encephalitis (Eastern, Western, Venezuelan)
Flaviviruses: St. Louis Encephalitis, Japanese Encephalitis, West Nile Encephalitis, Tick-borne Encephalitis
Bunyavirus: La Crosse Encephalitis
Orbivirus: Colorado Tick Fever

16. VIRAL ENCEPHALITIS RNA VIRUSES Paramyxoviruses: mumps, measles
Enteroviriuses: poliovirus, coxsackie, enterovirus 70/71
Togavirus- rubella
Rhabdovirus: rabies
Retroviruses: HIV, HTLV
Orthomyxovirus: Influenza
Arenavirus: Lymphocytic Choriomeningitis

17. VIRAL ENCEPHALITIS EPIDEMIOLOGY HSV- Varicella-zoster- Measles-
Most common cause of sporadic encephalitis in western countries, incidence 0.2/100,000 (neonatal HSV infection occurs in 2-3/10,000)
Varicella-zoster-
Tends to be mild, incidence of 1/2000 infected persons
Measles-
Two forms
Postinfectious , incidence 1/1000
Subacute sclerosing panencephalitis, incidence 1/100,000

18. VIRAL ENCEPHALITIS EPIDEMIOLOGY Arboviruses-
The most common causes of episodic encephalitis, incidence similar to that of HSV
All require an insect vector: mosquito, ticks
In the USA generally present between June and October
Two most common are St. Louis encephalitis and La Crosse encephalitis
Japanese encephalitis most common outside the USA, transmitted during summer and autumn in temperate regions of China, Japan, Korea, and eastern areas of Russia
Venezuelan equine encephalitis most common in Central and South America

21. VIRAL ENCEPHALITIS EPIDEMIOLOGY Enteroviruses Enteroviruses 70 and 71
Poliomyelitis
Relatively acid- and heat-resistant resulting in fecal-oral transmission during the summer months
Paralytic poliomyelitis: 13,000 cases reported to the WHO in 1991

22. CASE STUDY4
HPI
A 38-year-old woman was admitted to the hospital in early August 2002 because of fever and confusion. She had been well until 4 days earlier when a headache gradually developed and increased in intensity, accompanied by mild photophobia and stiffness of the neck. Two days prior to admission she believed that she was mildly febrile. The day before the admission she was examined at another facility and told that she had a “viral illness”. She was given IV fluid s and discharged. On the morning of admission she awoke with shaking chills and a temp of 40C. During the day she was aware of a rapid heart beat, lightheadedness and lethargy. Her husband observed that she was confused and brought her to the hospital where she was admitted

23. CASE STUDY4
PMHx: Hodgkin’s disease at age 21, treated with radiation and chemotherapy, without splenectomy, remained healthy thereafter
PSHx: none
SHx: married, lives in Boston, 2 children, no tobacco, alcohol, nor drugs; two weeks prior to admission traveled to St. Louis area for eight days, took walks in a wooded area and visited the zoo; visited the north shore area of Massachusetts 5 days prior to admission, was bitten by mosquitos, returned home two days prior to admission because of symptoms

24. CASE STUDY4
ROS: no history of exposure to animals, no contact with ill persons, photophobia, visual problems, seizures, focal neurological deficits, dyspnea, cough, vomiting, diarrhea, arthralgia, or rash

25. CASE STUDY4 Vital signs at admission Physical Exam
T 36.4, HR 100, RR 20, 90/60, Pox 99 on RA
Physical Exam
Slightly ill appearing, alert/oriented x3 but spoke in phrases of two to four words rather than complete sentences
No rash, petechiae, or LAD
Mouth and oropharynx normal
Neck was rigid and Kernigs sign was present
Lungs, heart, abdomen, and arms and legs were normal
Neurological exam was normal

26. CASE STUDY4 Laboratory WBC 9,200, Hct 36.8, HgB 12.9, Plt 215,000
Diff: PNM 78%, Lymph 17%, Monos 5%
Urine was normal
CMP was normal
Hcg negative
PT/PTT normal

27. CASE STUDY4 Lumbar Puncture CT without contrast was normal
Clear, no xanthochromia, RBC 139, WBC 107
Diff: Neutrophils 75, Lymph 22, Mono 3
Staining: abundant leukocytes, no AFB, GS negative
VDRL negative, cryptococcal Ag negative, PCR for HSV 1 and 2 negative
CT without contrast was normal

28. CASE STUDY4
Blood cultures were obtained. Vancomycin, Ceftriaxone, Doxycycline, and acyclovir were started.

29. CASE STUDY4 Hospital course
Shortly after the patients arrival the temperature rose to 39.8C accompanied by frank rigors and somnolence
Hospital day two the temp rose to 39.5C, when questioned she knew the name of the month but not the date or year or names of her children; later on the second day she became more lethargic and responded to questions only with “yes”
An MRI of the brain was performed before and after contrast material, showed a subtle hyperintensity on the T2 images in both the hippocampalregions and slight meningeal enhancement

30. CASE STUDY4 Hospital course:
On the third hospital day the temp max was 39.2; she was more responsive to commands than she had been on the previous day but could not distinguish the right hand from the left; she reported improvement in her headache and recognized her location; an EEG was done which revealed generalized low-amplitude slowing and continuous focal slowing over the entire left hemisphere; no epileptiform activity or organized electrographic seizure were seen

31. CASE STUDY4 Hospital course
On the fourth day the temp max was 38.0C, there was tremor in her right arm but she was fully oriented and able to converse and provide details of her life; blood and CSF specimens were negative and vanc and ceftriaxone were stopped

32. CASE STUDY4 Hospital course
On the fifth day the patient was alert and lucid; the tremor affected both arms, both legs, and the face with use but disappeared with rest; another LP was done
On the sixth hospital day an MRI was repeated; the patient was fully oriented and conversed normally
On the seventh day the patient was eating, walking, and no longer requested medication for headache; the action tremor persisted in the left arm and was improved in the right; the following day she was discharged home

33. CASE STUDY4 Second LP MRI Clear, no xanthochromia, RBC 300, WBC 32
Diff: PMN 4, lymph 94, monos 2
MRI
Subtle high-intensity signal on fluid recovery images in the posterior parietal lobe along the cortical surface or in the pia, considered nonspecific in meningoencephalitis

34. Acute meningoencephalitis
CASE STUDY4
Diagnosis
Acute meningoencephalitis

35. DIFFERENTIAL DIAGNOSIS
CASE STUDY4
DIFFERENTIAL DIAGNOSIS
HSV
Coxsackievirus
St. Louis encephalitis
Eastern equine encephalitis
Tick-borne encephalitis
West Nile encephalitis
Lyme disease
Leptospirosis
HIV

36. CLINICAL PRESENTATION
VIRAL ENCEPHALITIS
CLINICAL PRESENTATION
Clinical presentation and course can be markedly variable
May be severely ill within 24 hours after initial signs and symptoms or may take several days before neurological involvement is seen
Secondary encephalitis may not develop until seven to 30 days after the initial infectious process
The general viral prodrome is several days long and consists of sudden fever, severe headache, nausea and vomiting, lethargy, and myalgias
Specific prodrome in VZV, EBV, CMV, measles, and mumps include rash, lymphadenopathy, and parotid enlargement
Dysuria and pyuria has been reported with SLE
Extreme lethargy has been noted with WNE

37. CLINICAL PRESENTATION
VIRAL ENCEPHALITIS
CLINICAL PRESENTATION
Classic presentation is encephalopathy with diffuse or focal neurologic symptoms:
Behavioral and personality changes, decreased level of consciousness
Stiff neck, photophobia, and lethargy
Generalized or localized seizures (60% of children with LCE)
Acute confusion or amnestic states
Flaccid paralysis (10% with WNE)
Less common symptoms include headache and other complaints of meningismus

38. CLINICAL PRESENTATION
VIRAL ENCEPHALITIS
CLINICAL PRESENTATION
Neonatal HSV infection symptoms (1-45days)
Skin, eye, and mouth lesions (early presentation)
Encephalitis- change in level of alertness, irritability, seizures, poor feeding
Evidence of widespread, disseminated disease, such as rash or shock

39. CLINICAL PRESENTATION
VIRAL ENCEPHALITIS
CLINICAL PRESENTATION
Immunosuppression/HIV
Toxoplasma encephalopathy accounts for as many as 40% of patients who are HIV positive with neurologic disease who present with a subacute headache, encephalopathy, and a focal neurologic complaint; this may be the presenting symptom of HIV infection

41. VIRAL ENCEPHALITIS PHYSICAL EXAM
Signs may be diffuse or focal (80%of HSE patients present with focal findings
Altered mental status and/or personality
Hemiparesis, focal seizures, and autonomic dysfunction
Movement disorders
Ataxia
Cranial nerve defects
Dysphagia
Meningismus
Unilateral sensorimotor dysfunction

42. VIRAL ENCEPHALITIS PHYSICAL EXAM HSV infection in the neonate
Herpetic skin lesions
Keratoconjunctivitis
Oropharyngeal involvement, particularly the buccal mucosa and tongue
Seizures, irritability, change in level of attentiveness, bulging fontanels
Shock, jaundice, hepatomegaly

43. ACUTE MENINGOENCEPHALITIS
VIRAL ENCEPHALITIS
DIAGNOSIS
ACUTE MENINGOENCEPHALITIS
Herpes simplex virus
Varicella- -zoster
Arboviruses

44. VIRAL ENCEPHALITIS ARBOVIRUSES Eastern Equine
Localized to the Atlantic and Gulf coasts and Great Lakes areas
The brain is markedly congested and there is widespread degenerative changes in the nerve cells; lesions are found in the gray and white matter and are most intensive in the cerebrum and brainstem
Rare human infection
Mainly affects infants, children, and adults over 50y; inapparent infection is common
Sudden onset of drowsiness, stupor, or coma with convulsive seizures, HA, vomiting, neck stiffness, high fever, cranial nerve palsies, hemiplegia, focal neurologic deficits
Mortality rate is 50%
Duration varies from less than one day in fulminating cases to 4 weeks
Sequelae are common: mental deficiency, cranial nerve palsies, hemiplegia, convulsions, aphasia
Diagnosis is made by serology; CSF or blood

45. VIRAL ENCEPHALITIS ARBOVIRUSES St. Louis
Two epidemiologic patterns: urban and rural
Rural epidemics tend to occur in the western US
Urban epidemics occur primarily in the Midwest, Mississippi river valley, and eastern US; outbreaks can be abrupt and extensive because humans are the intermediate host
Primarily affects the elderly; midsummer to early fall
Nuclear masses of the thalamus and midbrain are more affected than is the cortex
Usually results in inapparent infection
75% of patients with clinical manisfestations have encephalitis
Hyponatremia secondary to SIADH occurs in 25%
Acute course results in death or recovery in 2-3 weeks; mortality is 2-20%
Most common sequelae: headaches, insomnia, easy fatigability; 25% have permanent neurologic sequelae
Diagnosis is made by IgM assay

46. VIRAL ENCEPHALITIS ARBOVIRUSES Japanese encephalitis
Occurrence can be endemic (tropical) or epidemic (temperate)
Major medical problem throughout Asia; 20,000 cases annually
Involves the entire cerebral cortex, basal ganglia, cerebellum, and spinal cord
Disease is most common in children
Mortality rate of 60%
Severe neurologic residuals and mental defects are common
An inactivated vaccine is used routinely in Japan, China, Korea, and is available for travelers to the regions
Diagnosis is made by isolation of the virus in CSF, blood, or cerebral tissue and/or by serology IgM

47. VIRAL ENCEPHALITIS ARBOVIRUSES La Crosse
The most prevalent arboviral infection in children in North America
Often goes unrecognized
Typically cannot be isolated from CSF
Can masquerade as enteroviral meningitis when mild and as HSV encephalitis when severe
Occurs most frequently in midwestern states and along the eastern seaboard
Headache, N/V, changes in sensorium, meningeal irritation, and upper motor neuron signs
WBC is usually elevated
Mimics partially treated bacterial infections, WBC, CRP elevated
Sequelae include cognitive impairment and neurobehavioral effects (ADHD)
Diagnosis is made by serum IgG and/or IgM antibodies

48. VIRAL ENCEPHALITIS ARBOVIRUSES West Nile
Enzootic in Africa, Asia, and Europe
First outbreak recognized in Western Hemisphere in New York City in August 1999
Reservoirs include a variety of wild and domestic birds
Vectors are mosquitos; Culex
Most infections in humans are subclinical; overt disease occurs in approximately 1 out of 100 infections
Incubation period ranges from 3 to 15 days
Presents with fever, weakness, N/V, AMS,
Infections in older adults and immunocompromised patients are characterized by severe neurological disease; acute flacid paralysis, anterior horn involvement
In the NYC outbreak, a relation between WNE and DM showed increased fatal outcome
Diagnosis is made by IgM and IgG antibody-capture enzyme immunoassays and for confirmation, plaque-reduction neutralization assays in cell culture; test both serum and CSF

49. VIRAL ENCEPHALITIS ARBOVIRUSES West Nile
In 2002 there were more than 3500 cases and more than 200 deaths in the USA
It can be estimated that hundreds of thousands of Americans were infected during 2002
In 2002 WNV transmission occurred by blood transfusions, organ donations, and breast feeding
No effective therapies
Prevention is by reduced exposure to vectors, personal protection measures
Vaccine under development

51. DIFFERENTIAL DIAGNOSES
VIRAL ENCEPHALITIS
DIFFERENTIAL DIAGNOSES
Brain abscess
Leptospirosis
Subarachnoid hemorrhage
Systemic lupus erythematosus
Lyme disease
Rocky mountain spotted fever
Toxoplasmosis
Tuberculosis
CNS syphilis
CVA
Acute confusional states secondary to drugs, toxins, alcohol withdrawl, psychosis
Head trauma
Tumor
Amoeba (Naegleria, Acanthamoeba)

52. VIRAL ENCEPHALITIS DIAGNOSTIC WORKUP Laboratory Imaging
Electroencephalography
Procedures

53. VIRAL ENCEPHALITIS LABORATORY
Complete blood count with differential (usually within normal range)
Serum electrolytes (usually normal)
Liver function testing
PT/PTT
Urine/serum tox screen
Viral serology
HSV cultures of lesions, blood, CSF
CSF PCR for HSV
Heterophile antibody and cold agglutinins for EBV
Serologic tests for toxoplasmosis

54. VIRAL ENCEPHALITIS IMAGING
A head CT with and without contrast should be performed in virtually all patients prior to an LP to search for evidence of elevated ICP, obstructive hydrocephalus, or mass effect. An MRI is more likely to show abnormalities earlier in the disease course than the head CT.
An MRI may show several foci of increased T2 signal in the medial temporal lobes and inferior gray matter in HSE. A head Ct may show petechial hemorrhage in the same areas.
EEE and tick-borne encephalitis may show increased signals in the basal ganglia and thalami.
In Toxoplasmosis, a CT with contrast typically reveals several nodular or ring-enhancing lesions.

55. ELECTROENCEPHALOGRAHPY
VIRAL ENCEPHALITIS
ELECTROENCEPHALOGRAHPY
HSV-
Characteristic paroxysmal lateral epileptiform discharges (PLEDS) are often observed
Diffuse slowing of background rhythms is the most common EEG abnormality
Nonspecific and is present in patients with diffuse encephalopathies of various causes including toxic, metabolic, anoxic, and degenerative
Focal slowing suggests localized parenchymal dysfunction
Virtually diagnostic EEG changes are seen in subacute sclerosing panencephalitis
Stereotyped bursts of high-voltage Delta waves recurring at regular 4- to 10-second intervals

56. VIRAL ENCEPHALITIS LUMBAR PUNCTURE
CSF PCR: A PCR for DNA HSV is 100% specific and 75-98% sensitive within the first hours. Types 1 and 2 cross-react, but there is no cross-reactivity with other herpes viruses.

59. VIRAL ENCEPHALITIS BRAIN BIOPSY
Criterion standard because of its 96% sensitivity and 100% specificity

60. VIRAL ENCEPHALITIS TREATMENT General measures
Treat for shock or hypotension with crystalloid
Consider airway protection in patients with altered mental status
Consider seizure precautions
In suspected HSV, acyclovir should be initiated as soon as possible
Signs of hydrocephalus and ICP
General measures: manage fever and pain, control straining and coughing and avoid seizures and systemic hypotension
Early use of diuresis, steroids, hyperventilation

61. VIRAL ENCEPHALITIS TREATMENT
Empiric emergency treatment for HSV meningoencephalitis and VZV encephalitis is acyclovir 10mg/kg q8h for days; give acyclovir 10-15mg/kg IV q8h for neonatal HSV; in pediatrics give acyclovir 10mg/kg IV q8h
In HIV-positive patients, consider foscarnet, given increased incidence of acyclovir-resistant HSV and VZV

62. VIRAL ENCEPHALITIS PREVENTION Personal preventive measures
Avoid areas
Insect repellent: DEET
Proper clothing
Mosquito eradication
Vaccination: JE

64. VIRAL ENCEPHALITIS REFERENCES
Merritt’s Textbook of Neurology, Ninth Edition 1995
Pathology, Rubin and Farber; Second Edition 1994
Encephalitis, Lazoff, et al.; emedicine September 9, 2002
Encephalitis, Japanese; CDC Website Travelers Health
Hirsch M, Werner B. Case : A 38-year-old Woman with Fever, Headache, and Confusion; Case Records of the Massachusetts General Hospital. N ENG J MED 2003;348:
Nash D, Mostashari F, Fine A, et al. The Outbreak of West Nile Virus Infection in the New York City Area in 1999,. N ENG J MED 2001;344:
McJunkin J, De Los Reyes E, Irazuzta J, et al. La Crosse Encephalitis in Children. N ENG J MED 2001;344: