Best Dx/Best Rx: Acute Viral Central Nervous System Diseases

Acute Viral Central Nervous System Diseases

Donald H. Gilden, M.D.
University of Colorado Health Sciences Center

Definition/Key Clinical Features
Differential Diagnosis
Best Tests
Best Therapy
Best References

Definition/Key Clinical Features

Viral Aseptic Meningitis

Headache

Fever

Stiff neck

Irritability/alterations in consciousness (occasional)

Viral Encephalitis

Insomnia
Lethargy
Mental status changes
Seizures
Aphasia
Hemiplegia
Focal deficits

Differential Diagnosis

Enteroviruses

Picornaviridae; ~ 70 distinct serotypes
Most common cause of viral aseptic meningitis
Most cases in children
Occurs primarily in summer
Fecal-oral transmission; respiratory transmission also possible
Fever often biphasic
- Constitutional, gastrointestinal symptoms in first phase
- Symptoms and signs of nervous system disease in second phase
CSF: mononuclear pleocytosis, elevated protein common; glucose usually normal

Herpes Simplex Virus Type 1

Focal encephalitis
- Medial temporal lobe
  - Aphasia, focal motor or sensory deficits when dominant temporal lobe affected
- Orbital surface of frontal lobe
May occur in any season
Fever, headache, irritability, confusion typical
Seizures in 40% of patients

CSF

Opening pressure often elevated
Pleocytosis in 90% of cases
Mononuclear cells predominant
RBCs frequent (xanthochromia may be present)
Protein elevated

Imaging

CT
- Hypodense lesion, usually in medial temporal region
- Sharp transition from lesion to normal basal ganglia
- Contrast enhancement in 50%
- Edema, mass effect in 80%
MRI
- Decrease in T₁ signal, increase in T₂ signal
- Larger area of involvement than in CT

EEG

Initially, background disorganization with generalized or focal slowing
After first few days, widespread, periodic, stereotyped sharp-wave and slow-wave complexes at 2–3 sec intervals

Herpes Simplex Virus Type 2

Third most common cause of aseptic meningitis in U.S. (5% of all cases)
May occur in any season
Headache, fever, stiff neck typical
May be associated with genital or pelvic pain
Self-limited

Varicella-Zoster Virus

May present in any season (varicella mostly in spring)

Localized Herpes Zoster (HZ)

Pain, vesicular rash on erythematous base in one to three dermatomes
8–10 times more common in persons > 60 yr
Pain usually lasts 4–6 wk
Cranial neuropathies may develop weeks to months after trigeminal dermatomal involvement

Postherpetic Neuralgia

Increased incidence in patients ≥ 60 yr

Vasculopathy

More appropriate designation than encephalitis
Small or large vessels (or both) may be affected
Symptoms may wax and wane
Multifocal
- Most common form of VZV CNS involvement
- Immunosuppressed patients (e.g., cancer, organ transplant recipients, AIDS)
- Subacute; death common
- Headache, fever, vomiting, mental changes, seizures, focal deficits from small-vessel vasculopathy common
- CSF
  - Mild to moderate pleocytosis (mostly mononuclear)
  - Normal or mildly elevated protein
  - Normal glucose
- Imaging
  - Large and small ischemic or hemorrhagic infarcts in cortex, subcortical gray and white matter
  - Deep-seated ischemic or demyelinative white-matter lesions
- Unifocal
  - Acute focal deficit
  - Typically in immunocompetent patients
  - Develops weeks to months after contralateral trigeminal HZ
  - May lead to stroke from vasculopathy, primarily in large cerebral arteries
  - Transient ischemic attacks, mental symptoms common
  - Mortality ~ 25%
  - CSF
    
    Pleocytosis, usually < 100 cells/mm³ (predominantly mononuclear)
    Oligoclonal bands
    Increased IgG

Arthropod-Borne Encephalitis Viruses

RNA viruses
Infection occurs primarily in summer and fall
Transmission from infected horses, birds, or rodents via bites from mosquitoes or ticks
Headache, photophobia, myalgia, fever, lethargy, confusion, seizures
Tremor, focal deficit may develop

St. Louis Encephalitis

Aseptic meningitis in 15%
Usually self-limited; mortality 3%–4%

Western Equine Encephalitis

Mortality ~ 10%
More severe in infants and children
May produce transient parkinsonism

Eastern Equine Encephalitis

Mortality > 50%
Mental, visual, auditory, speech, motor deficits in 80% of survivors

West Nile Virus Encephalitis

Most human cases acquired by bites from infected mosquitoes
Infected blood products or transplanted organs may transmit infection
Wide range of possible presentations
- Meningoencephalitis
- Rhombencephalitis
- Opsoclonus-myoclonus cerebellar ataxia
- Unilateral brachial plexopathy with meningoencephalitis
- Guillain-Barré syndrome
MRI often shows deep-seated lesions in the basal ganglia and thalamus
Polymerase chain reaction (PCR) of CSF often reveals West Nile virus RNA

LaCrosse Virus Encephalitis (California Virus Encephalitis Subset)

Affects primarily school-age children
Disease usually mild
Seizures in 50%
Focal deficits, focal EEG abnormalities in 20%–40%
Hyponatremia common

Colorado Tick Fever

Transmitted in mountainous areas of western U.S. and Canada
Meningitis or encephalitis in 5%–10% of children

Cytomegalovirus

Congenital CMV

Most infections asymptomatic
Sensorineural hearing loss, intellectual deficits in some
Microcephaly, seizures, hypotonia, spasticity also seen

Adult Disease

Guillain-Barré syndrome most common neurologic complication in immunocompetent adults
Immunocompromised patients
- Transplant recipients
  - Encephalitis
- AIDS patients
  - Most common opportunistic infection in nervous system
  - Retinitis, encephalitis, progressive myelitis, polyradiculitis
  - Encephalitis
    - Subacute
    - Headache, seizures, progressive dementia, diffuse weakness
    - MRI: enhancement in ventricular ependyma (may also suggest ventriculitis)
    - CSF: neutrophilic or mononuclear pleocytosis; elevated protein; decreased glucose
    - Polyradiculitis
    - Cauda equina syndrome
      - Insidious onset
      - Asymmetrical paresthesias, distal weakness
      - Incontinence
      - Sacral-distribution sensory loss

HIV

Aseptic meningitis
- Affects 5%–10% of patients early in infection
- Headache, fever, altered mental status, focal or generalized seizures
Subacute encephalitis

Mumps

Meningitis
- Up to 23% of patients with mumps affected; encephalitis rare
- Fatality rare
- May be followed by aqueductal stenosis and hydrocephalus
- Associated with typical parotitis, pancreatitis, or oophoritis

Influenza

Encephalitis
- Seizures and mental status changes common

Best Tests

CSF

Glucose
Cells
Gram stain
PCR to detect viral RNA or DNA
Viral culture
Antigen or antibody testing
Serologic testing (e.g., enzyme immunoassay, Western blot)

Neuroimaging

Best Therapy

Nonspecific Therapy

Bed rest
Analgesia (headache)
Anticonvulsant therapy
Respiratory support
Nutritional support
Fluid restriction (encephalitis)
Monitoring for secondary infections
Physical therapy

Drug Therapy

Antiviral Agents

Acyclovir
- HSV-1 encephalitis
- HSV-2 encephalitis
- VZV multifocal and unifocal vasculopathy
- Dose: 15–30 mg/kg/day I.V. in three divided doses × ≥ 10 days
Famciclovir or valacyclovir
- Maintenance therapy after acyclovir in AIDS patients with HSV encephalitis or VZV vasculopathy
- Dose: famciclovir, 500 mg t.i.d., or valacyclovir, 1 g b.i.d.
Ganciclovir
- CMV encephalitis
- Dose: 5 mg/kg every 12 hr I.V. × 2 wk initially; 5 mg/kg I.V. q.d. maintenance (or 1,000 mg p.o., t.i.d., with food or 500 mg p.o., 6×/day with food)
- Cost/mo (oral maintenance): $1,478
- Discontinue if WBCs < 750/mm³)
Foscarnet
- CMV
- Dose: I.V. infusion, 90 mg/kg q. 12 hr or 60 mg/kg q. 8 hr over 2–3 wk
  - Adjust dose for renal impairment

Preventive Therapy for Arthropod-Borne Viral Encephalitis

Routine use of insect repellents
Protective clothing while outdoors

Best References

Gilden DH: J Neurol Sci 195:99, 2002 [PMID 11897238]

Nash D, et al: N Engl J Med 344:1807, 2001 [PMID 11407341]

Tedder DG, et al: Ann Intern Med 121:334, 1994 [PMID 8042822]

Wainwright MS, et al: Ann Neurol 50:612, 2001 [PMID 11706967]

The author has no commercial relationships with manufacturers of products or providers of services discussed in this module.

April 2006