Neurologic Complications of VaricellaZoster Virus Infection

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Neurologic Complications of Varicella-Zoster
Virus Infection

• John W. Gnann, Jr. MD
• University of Alabama at Birmingham
• Birmingham, AL USA
• IHMF Paris 2003

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• Varicella in an
• Immunocompetent
• Adult

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Varicella in the Immunocompetent Host

• Serious neurologic complications occur in cases
• Aseptic meningitis
• Cerebellar ataxia
• Transverse myelitis
• Encephalitis
• Guillain-Barré syndrome
• Arterial ischemic strokes
• Optic neuritis

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Varicella with Cerebellar Ataxia - 1

• Incidence - 1/4000 cases of varicella
• Presentation
• Ataxia usually simultaneous with rash (can
  precede the rash)
• Ataxia accompanied by HA, vomiting, lethargy
• 25 have fever, nuchal rigidity, nystagmus
• Seizures are rare
• Diagnosis
• Clinical diagnosis sufficient in typical cases
• CSF usually normal. Pleocytosis (25
• EEG - diffuse slow wave activity (20)
• MRI - rarely see focal cerebellar or brain stem
  lesions

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Varicella with Cerebellar Ataxia - 2

• Pathogenesis
• Direct viral involvement of cerebellum?
• Positive CSF VZV PCR and antibody
• Parainfectious immune-mediated process?
• Prognosis
• Self-limited disease, most patients improve in
  1-3 weeks
• Virtually all recover without sequelae
• Therapy
• Role of antiviral drugs has not been studied, but
  administration is probably appropriate

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Varicella Encephalitis - 1

• Incidence
• 1-2/10,000 cases of varicella
• Incidence highest in adults and infants
• Presentation
• Symptoms usually appear about one week after rash
  (though may be earlier or later). Acute or
  gradual onset.
• Fever, HA, vomiting, altered mental status
• Focal neurologic findings -- hyper/hypo-reflexia,
  hemiparesis, sensory changes
• Seizures 29-52 of cases

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Varicella Encephalitis - 2

• Diagnosis
• Lumbar puncture
• Increased opening pressure, pleocytosis (WBC), elevated protein, normal glucose
• EEG
• Slow wave activity consistent with diffuse
  encephalitis
• CT scan
• Cerebral edema, areas of low attenuation
  consistent with demyelination.
• MRI scan
• Limited data

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Varicella Encephalitis - 3

• Pathogenesis
• Role of active viral replication in CNS?
• Pathologic findings more consistent with
  post-infectious demyelinating process. Inclusion
  bodies rarely seen.
• Prognosis
• Mortality about 5-10 (higher mortality in older
  literature probably due to Reyes syndrome)
• 10-20 of survivors will have neurologic sequelae
• Therapy
• IV acyclovir recommended, but no prospective data

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Pediatric Arterial Ischemic Stroke Syndromes

• Immunocompetent children (median age 5 yr)
  present with acute hemiplegia
• Median interval between varicella and onset of
  neurologic deficits 2 months
• CT/MRI unilateral infarcts of deep structures
  (e.g., basal ganglia, internal capsule)
• Angiography vasculopathy of the branches of the
  middle cerebral artery
• Outcome frequently good (better than adults)
• Ref Moriuchi et al. Pediatr Infect Dis J
  19648, 2000

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Does Varicella Cause Pediatric Strokes?

• Incidence of childhood ischemic strokes
  3.3/100,000 children/yr
• In a prospective study, 31 (22/70) children with
  strokes had varicella within prior 12 mo,
  compared with 9 of controls
• Children with strokes and recent varicella had
  higher rates of basal ganglia infarction,
  abnormal CNS vascular imaging, and recurrent
  ischemic attacks.
• Conclusion Post-varicella angiopathy may
  account for 1/3 of all childhood strokes
• Ref Askalan et al Stroke 321257,2001 deVerber
  et al Sem Ped Neurol 7309, 2000

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Fatal VZV CNS vasculopathy in a 4 year old girl
occlusion of left MCA
Please see figure in Berger et al, Ped Infect Dis
J 19653, 2000
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Neurologic Complications of Herpes Zoster

• Postherpetic neuralgia pathology in the central
  and peripheral nervous system
• Cranial nerve syndromes (e.g., Ramsay-Hunt,
  Bells palsy)
• Motor neuropathies
• Retinal necrosis
• Large-vessel encephalitis (granulomatous
  arteritis)
• - Delayed contralateral hemiplegia
• Chronic small-vessel encephalitis
  (immuno-compromised host)
• - Multifocal leukoencephalopathy

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Ramsay-Hunt Syndrome Herpes Zoster of the 7th
Cranial Nerve
Please see figure in Kleinschmidt-DeMasters et
al, Arch Path Lab Med 125770, 2001
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HZO Followed by Contralateral Hemiparesis
Please see figure in Nogueira and Sheen, NEJM
3461127, 2002
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Herpes Zoster Ophthalmicus with Delayed
Contralateral Hemiparesis - 1

• Reported in normal and immunocompromised patients
• Usual onset 7 wk (up to 6 mo) after ophthalmic
  zoster
• Presents as a stroke -- HA, hemiplegia
  (contra-lateral to the zoster)
• Mortality 20-25 -- high probability of
  neurologic sequelae

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Herpes Zoster Ophthalmicus with Delayed
Contralateral Hemiparesis - 2

• Diagnosis
• CT or MRI shows infarction
• CSF shows mononuclear cell pleocytosis (WBC
• Angiography shows diagnostic narrowing of middle
  or anterior cerebral arteries
• Pathology -- giant cell arteritis, vessel
  thrombosis, brain infarction PCR positive for
  VZV
• Therapy -- IV acyclovir plus steroids, but
  benefit uncertain irreversible ischemic changes

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Hemiparesis Following Herpes Zoster

• Please see figure in Gilden et al, NEJM 342635,
  2000

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Zoster Sine Herpete

• Radicular neuropathic pain in a dermatomal
  distribution without cutaneous eruption
• Pathogenesis VZV reactivation in ganglion, but
  transaxonal spread of virus to skin halted by
  host immune response?
• Prevalence unknown
• Difficult to diagnose -- a few cases have been
  linked to VZV by 4-fold antibody rises or
  positive CSF PCR for VZV DNA
• Anecdotal reports of clinical response to
  antiviral therapy

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Myelitis Complicating Herpes Zoster

• Please see figure in Kleinschmidt-DeMasters et
  al, Arch Path Lab Med 125770, 2001

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Chronic VZV Encephalitis in AIDS

• Usually occurs months after herpes zoster
• 30 - 40 have no history of recent VZV skin
  disease
• Subacute onset of HA, hemiplegia, mental status
  changes, seizures
• MRI - infarcts of cortical and subcortical gray
  and white matter (multifocal leukoencephalopathy)
• Pathology - small vessel vasculitis. CSF PCR
  for VZV DNA
• Therapy - high dose IV acyclovir. Efficacy
  undefined
• Prognosis - Poor. Progressive neurologic
  disease, death

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Chronic VZV Encephalitis in AIDS

• Please see figure in Gilden et al, NEJM 342635,
  2000