Medical Grand Round

Dr. Lucy StrensConsultant 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, Behcet’s)• Epileptic (non-convulsive status)• Nutritional deficiency• Systemic infections (malaria)• Traumatic brain injury• Malignant hypertension• Mitochondrial cytopathy (Reye’s and MELAS syndromes)• Hashimoto’s encephalopathy• Paraneoplastic limbic encephalitis• Neuroleptic malignant syndrome…….. (and more!)

Causes of acute viral encephalitisSporadic 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• Reoviruses — Colorado tick fever virus

Non-viral causes of infectious

encephalopathy

Bacterial Mycobacterium tuberculosis

Mycoplasma pneumoniae

Listeria monocytogenes

Borrelia burgdorferi

Leptospirosis

Brucellosis

Legionella

Tropheryma whippeli (Whipple’s disease)

Nocardia actinomyces

Treponema pallidum

Salmonella typhi

All causes of pyogenic meningitis

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

Toxoplasma gondii

Echinococcus granulosus Schistosomiasis

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 immuno-compromised, neonates

HSV-1• Primary infection occurs in oral mucosa

– 30% people get clinically apparent cold sores– 90% healthy people have been infected with HSV-1

• 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

• In children, HSV-1 encephalitis occurs during primary infection

HSV-2• Transmitted via genital mucosa

– Genital herpes in adults– USA, 20% of adults sero-positive for HSV-2

• 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 CNS involvement)

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

Viral encephalitis – clinical presentation• Typical 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– 33% seizures

*Raschilas et al 2002 Clin Infect Dis

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 possible CNS infection

Encephalopathy vs encephalitis?Encephalopathy Encephalitis

Clinical features

Fever Uncommon Common

Headache Uncommon Common

Depressed mental status Steady deterioration May fluctuate

Focal neurological signs Uncommon Common

Type of seizure Generalised Generalised or focal

Laboratory findings

Blood Leucocytosis uncommon Leucocytosis common

CSF Pleocytosis uncommon Pleocytosis common

EEG Diffuse slowing Diffuse slowing and focal abnormalities

MRI Often normal 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)– EEG– ((brain biopsy))

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 >95%

Typical CSF findings in CNS infectionsViral Bacterial TB Fungal Normal

Opening pressure

Normal/high High High High/v. high 10-20 cm

Colour Clear Cloudy Cloudy/yellow Clear/cloudy Clear

Cells/mm3 Sl. increase5-1000

High/v. high100-50,000

Sl. increase25-500

Normal/high0-1000 < 5

Differential Lymphocytes Neutrophils Lymphocytes Lymphocytes Lymphocytes

CSF/plasma glc ratio

Normal Low Low/v. low (<30%)

Normal/low66%

Protein (g/l) Normal/high0.5-1

High>1

High/v. high1-5

Normal/high0.2-5 <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 swelling,

seizures)

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– 25% epilepsy

www.encephalitis.info