Medical Grand Round

Dr. Lucy Strens Consultant Neurologist UHCW

Nov 24th 2009

Viral encephalitis
Causes Typical presentation Investigations Treatment Prognosis

Terminology
Encephalopathy
Clinical syndrome of reduced consciousness Many causes, incl. viral encephalitis

Encephalitis
Acute, diffuse, inflammatory process affecting brain parenchyma Most commonly viral

Meningitis: meningeal inflammation Myelitis: spinal cord inflammation Radiculitis: nerve root inflammation

Causes of encephalopathy
Hypoxic/ischaemic Metabolic (liver and renal failure, diabetes) Toxic (alcohol, drugs) Vascular (vasculitis, SLE, SAH, SDH, stroke, Behcets) Epileptic (non-convulsive status) Nutritional deficiency Systemic infections (malaria) Traumatic brain injury Malignant hypertension Mitochondrial cytopathy (Reyes and MELAS syndromes) Hashimotos encephalopathy

Causes of acute viral encephalitis Sporadic causes (not geographically restricted)

Herpes viruses HSV-1, HSV-2, VZV, CMV, EBV, HHV6, HHV7 Enteroviruses Coxsackie, echoviruses, enteroviruses 70/71, parechovirus, poliovirus Paramyxoviruses Measles, mumps Others (rarer causes) Influenza viruses, Adenovirus, parvovirus, lymphocytic choriomeningitis virus, rubella virus, rabies

Geographically restricted causes

Arboviruses Japanese B, St Louis, West Nile, Eastern equine, Western equine, Venezuelan equine, tick borne encephalitis viruses Bunyaviruses La Crosse strain of California virus

Non-viral causes of infectious encephalopathy

Bacterial Mycobacterium tuberculosis Mycoplasma pneumoniae Listeria monocytogenes Borrelia burgdorferi Leptospirosis Brucellosis Legionella Tropheryma whippeli (Whipples disease) Nocardia actinomyces Treponema pallidum

Rickettsial

Rickettsia rickettsia (Rocky Mountain spotted fever) Rickettsia typhi (endemic typhus) Rickettsia prowazeki (epidemic typhus) Coxiella burnetti (Q fever) Ehrlichiosis (Ehrlichia chaffeensis human monocytic ehrlichiosis)

Fungal

Cryptococcus Aspergillosis Candidiasis Coccidiomycosis Histoplasmosis North American blastomycosis

Parasitic

Human African trypanosomiasis (sleeping sickness) Cerebral malaria

Pathogenesis of viral encephalitis

Depends on the virus
direct viral destruction of cells Para or post-infectious inflammatory or immune-mediated response

Most viruses primarily infect brain parenchyma and neuronal cells Some cause a vasculitis Demyelination may follow infection

Herpes simplex encephalitis

HSV encephalitis (HSE) most common cause of viral encephalitis in industrialised nations Annual incidence 1 in 250,000-500,000 90% HSV-1 HSV-2 more common in immunocompromised, neonates

HSV-1
Primary infection occurs in oral mucosa
30% people get clinically apparent cold sores 90% healthy people have been infected with HSV1

Virus then travels along trigeminal nerve to ganglion in most (if not all) those infected 70% cases of HSV-1 encephalitis already have antibody present suggesting reactivation of virus most common mechanism Why HSV-1 reactivates not known

HSV-2
Transmitted via genital mucosa
Genital herpes in adults USA, 20% of adults sero-positive for HSV2

HSV-2 may cause

Meningitis (esp. recurrent meningitis) Encephalitis (esp in neonates) Lumbosacral radiculitis

Neonates can be infected during delivery: neonatal herpes (disseminated infection often with

Case example
57 yr old female 4 days N&V, severe headache, loss of appetite Confused, unable to find right word O/E
Temp 39oC, dysphasic, no focal neuro signs (upgoing plantars) WCC 11.7, CRP 4

Case 2
CSF
WCC 36 (80% lymphocytes), RCC 2 Normal glucose, protein 0.91g/l HSV-1 PCR positive

 Typical presentation

Viral encephalitis clinical presentation

Acute flu-like prodrome High fever, severe headache, N&V Altered consciousness (lethargic, drowsy, confused, coma) (Seizures) (Focal neurological signs)

Recent study of HSV-1 encephalitis*

91% febrile on admission 76% disorientated 59% speech disturbances 41% behavioural change *Raschilas et al 2002 Clin Infect Dis 33% seizures

Clinical presentation
More subtle presentations now recognised
Low grade fever Speech disturbances (dysphasia, aphasia) Behavioural changes

Subacute and chronic presentations can be caused by CMV, VZV, HSV (immuno-compromised) Any adult with seizure + fever or seizure from which they do not recover must be investigated for

Encephalopathy vs encephalitis?
Encephalopathy Clinical features Fever Headache Uncommon Uncommon Common Common May fluctuate Common Generalised or focal Encephalitis

Depressed mental statusSteady deterioration Focal neurological signs Uncommon Type of seizure Laboratory findings Blood CSF EEG Generalised

Leucocytosis uncommon Leucocytosis common Pleocytosis uncommon Diffuse slowing Pleocytosis common Diffuse slowing and focal abnormalities

Clues in history
Recent rashes Vaccination history Travel history Recent animal/insect bites, contact with sick animals Immunosuppression (HIV, transplant) Drugs, alcohol

Clues on examination
Skin rashes, bites, injection sites Examine chest, abdo, ears, genitals, urine for infection Meningism, subtle motor seizures, focal neuro signs NB cold sores not diagnostic!

Investigations
General
Haematological and biochemical blood screen Serology, blood cultures, HIV Drug screen, urine analysis CXR

Neurological
CT head, MRI brain LP (if not contraindicated on cranial imaging)

MRI brain (T2W image): right temporal lobe high signal in a patient with herpes encephalitis

Axial DWI: restricted diffusion in the left medial temporal lobe consistent with herpes encephalitis.

CSF examination
Opening pressure Send samples for
Cell count and differential Protein, glucose (plasma glucose) Gram stain and culture Viral PCRs (HSV 1*, HSV2, VZV, EBV, CMV, enteroviruses) Other tests as appropriate (discuss with micro!)

*HSV-1 CSF PCR still positive in 80% pts after one week of treatment (may be negative in first few days) PCR tests for HSV have overall sensitivity and specificity

Typical CSF findings in CNS infections Viral Bacterial TB Fungal

Opening pressure Colour Normal/high High High High/v. high

Normal 10-20 cm

Clear

Cloudy

Cloudy/yellow Clear/cloudy

Clear

Cells/mm3

Sl. increase 5-1000

High/v. high 100-50,000

Sl. increase 25-500

Normal/high 0-1000

<5

Differential CSF/plasma glc ratio Protein (g/l)

Lymphocytes Neutrophils Normal Low

Lymphocytes Lymphocytes Lymphocytes Low/v. low (<30%) High/v. high 1-5 Normal/low

66%

Normal/high 0.5-1

High >1

Normal/high 0.2-5

<0.45

Bloody tap: subtract 1 WBC for every 700 RBCs subtract 0.1g/l protein for every 1000 RBCs

Management of viral encephalitis

O2, fluids, NG feed?, ITU? Aciclovir
Start as soon as suspect viral encephalitis iv aciclovir 10mg/kg tds 14-21 day course in confirmed HSE Monitor renal function Only stop if definite other diagnosis made

Antibiotics too if delay in getting CSF/imaging Management of complications (brain

Prognosis in HSE
Mortality > 70% if untreated (20% with Rx) Poor prognostic factors
Age > 60 yrs GCS < 7 Delay in starting aciclovir (esp > 2 days)

2/3 rds pts have neuropsychiatric sequelae

69% memory impairment 45% personality/behaviour change 41% dysphasia www.encephalitis.info