ISCHEMIC STROKE / CLASSIFICATION AND ETIOPATHOGENESIS
Varicella-zoster virus vasculopathy
David Goldemund M.D.
Updated on 21/02/2024, published on 20/02/2024
- varicella-zoster virus (VZV) is a neurotropic herpesvirus responsible for two distinct clinical conditions: varicella (primary infection) and herpes zoster (reactivation)
- while the cutaneous manifestation is a well-known aspect of VZV infection, the virus also harbors the potential for serious neurovascular complications (after either primary infection or viral reactivation)
- CNS complications of VZV infection:
- encephalitis
- aseptic meningitis
- myelitis
- acute cerebellar ataxia
- Reye’s syndrome
- Ramsay-Hunt syndrome
- stroke
- stroke due to VZV vasculitis is, however, rare
- VZV vasculitis involves inflammation of the blood vessels triggered by the virus, affecting both large and small vessels
- affected arterial walls show thickening, reduced elasticity, and arterial occlusion
- vasculopathy is more common in immunocompromised individuals
- stroke due to vasculitis may occur without apparent herpes zoster, leading to underdiagnosis
- VZV vasculopathy is also called VZV vasculitis, or post-varicella arteriopathy
Etiopathogenesis
- the exact mechanism of VZV-induced vasculitis is complex and involves direct viral invasion of the arterial wall, followed by an inflammatory response (Gilden, 1996)
- VZV targets endothelial cells, smooth muscle cells, and perivascular nerves, leading to vessel wall damage, thrombosis, and ischemia
- the immune response to the virus further exacerbates vascular injury through inflammatory mediators
- transient protein S deficiency and high APL antibody titers have also been described in association with varicella infection
- ⇒ segmental stenoses develop
- VZV vasculopathy has also been associated with granulomatous aortitis and giant cell arteritis (GCA) [Nagel, 2017]
Clinical presentation
- recent varicella or herpes zoster (most commonly in the ophthalmic region) in a younger stroke patient without traditional risk factors should raise suspicion of possible VZV-related vasculitis
- neurological deficits may develop within days to months after infection
- the risk of stroke is highest in the first 6 months [Langana, 2014]
- the risk seems lower in patients treated with antivirals [Langana, 2014]
- symptoms depend on the affected vessels and brain regions – focal deficit may be accompanied by headache, seizures, or altered mental status
- some patients may initially present with symptoms and signs of encephalitis followed by a focal deficit
- intracranial hemorrhage and SAH have also been described [Jain, 2003]
Diagnostic evaluation
Parenchymal and vascular imaging
- parenchymal imaging
- detects nonspecific ischemic lesion(s) (ideally FLAIR, DWI and GRE); rarely, the spinal cord is affected
- often multifocal and/or bilateral strokes
- contrast enhancement may be present (a sign of breakdown of the blood-brain barrier)
- vessel-wall imaging (T1C+ BB) may show enhancement in larger arteries
- vascular imaging (CTA/MRA, DSA)
- angiography may show features suggestive of vasculitis (typically segmental constrictions often followed by poststenotic dilatation)
- complications may lead to aneurysm formation or dissection
- MRA and CTA have low sensitivity if small vessels are affected
- angiography may show features suggestive of vasculitis (typically segmental constrictions often followed by poststenotic dilatation)
Antibodies detection
- elevated titers of VZV antibodies (IgM, IgG)
- confirmation of either intrathecal production of anti-VZV antibodies or the presence of VZV DNA in CSF is required
- IgM antibodies indicate recent or acute infection, positive IgG antibodies indicate past infection or immunity to VZV
- negative results of antibody testing and PCR in the CSF exclude the diagnosis of VZV vasculopathy
CSF analysis
- pleocytosis + elevated protein
- glucose concentration is normal
- PCR (gold standard)
- PCR detects VZV DNA in various samples, including blood, cerebrospinal fluid (CSF), and vesicular fluid
- PCR is generally the most sensitive and specific method for CNS infection, especially during the first two weeks and in immunocompromised hosts
- a negative finding does not rule out infection entirely (especially beyond 2 weeks)
- elevated titers of anti-VZV antibodies (IgM, IgG)
- intrathecal antibodies and a reduced serum/CSF ratio suggest the diagnosis
- detectable since the second week after infection
Management
- if VZV infection is suspected, start antiviral treatment (acyclovir IV 10 mg/kg every 8 hours) [Gilden, 2004]
- antivirals reduce the risk of stroke due to VZV vasculitis [Nagel, 2017]
- if anti-VZV IgG antibody or VZV DNA in CSF confirms the diagnosis, continue for 14-21 days
- the patient should be monitored clinically, perform repeated MRI or CSF analysis in case of poor response or worsening
- corticosteroids (DEXONA 8 mg every 8 hours or PREDNISONE 1mk/kg for 5 days) may be added to reduce inflammation, particularly in severe vasculitis
- start antiplatelet therapy (DAPT may be considered, but there is no hard data on risk-benefit)+ treat vascular risk factors
- prognosis depends on the timeliness of treatment and extent of vascular involvement; early therapeutic intervention can significantly improve outcomes
