Varicella-zoster virus infections of the nervous system

Clinical manifestations
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By Catherine Amlie-Lefond MD and Burk Jubelt MD

The clinical manifestations of varicella-zoster virus infections can be divided into primary infection (chickenpox) and reactivated infection (dermatomal shingles or disseminated herpes zoster).

Varicella. Chickenpox is an exanthematous illness that occurs with primary varicella-zoster virus infection. The rash typically starts on the scalp and then spreads to the trunk. The distal extremities are usually involved to a lesser extent. Lesions of different ages are seen. Early lesions are rose-colored macules with clear vesicles in the center. Within hours, the vesicles become purulent and, later, dry and crusted. A prodromal syndrome of 1 day to 2 days of fever and malaise is more likely to be seen in adults. During the exanthem, fever (100°F to 102°F) usually lasts for 2 days to 3 days. Non-neurologic complications, such as varicella-zoster virus pneumonitis and secondary bacterial infections, are more common in adults (Weller 1989).

The main neurologic syndromes related to primary acute varicella infections are encephalitis, acute cerebellar ataxia, myelitis, and meningitis. Other syndromes, such as acute inflammatory demyelinating radiculoneuropathy and Reye syndrome, are seen less frequently. Neurologic complications occur in approximately 1 in 2000 cases of varicella among children (Rack et al 2010).

Encephalitis is often severe. Most cases occur in the week following the exanthem, but onset may vary from 18 days before to 3 weeks after the rash (Holliday 1950; Appelbaum et al 1953; Boughton 1966). The onset may be abrupt or more gradual over several days, with fever, headache, vomiting, lethargy, and meningismus (Gibel et al 1960). Seizures are reported to occur in about 30% to 50% of patients, and progression to coma is not uncommon (Miller et al 1956; Gibbs et al 1964; Johnson and Milbourn 1970; Mazur and Dolin 1978). Deep tendon reflexes and muscle tone may be increased or decreased. Babinski signs may be present. Other manifestations may include visual impairment, hemiplegia, sensory deficits, and urinary dysfunction (Miller et al 1956).

Acute cerebellar ataxia is the most common extracutaneous complication of chickenpox in healthy children. It can precede the exanthem (Dangond et al 1993) but usually occurs 5 to 10 days after the rash. It usually presents with truncal ataxia. It is believed to be a localized form of varicella-zoster virus encephalomyelitis. Rarely, varicella has been associated with myelitis (paraparesis, abnormal deep tendon reflexes, Babinski signs, and sphincter dysfunction), with a variable outcome (Johnson and Milbourne 1970).

Zoster. Herpes zoster can occur anywhere in the neuraxis, but it is most common in the thoracic region. The next most commonly involved area is the ophthalmic division of the trigeminal nerve; this can lead to ocular involvement and blindness. Herpes zoster oticus (Ramsay Hunt syndrome) is caused by herpes zoster infection of the geniculate ganglion. It consists of severe ear pain and ipsilateral facial nerve palsy associated with herpetic eruption of the external auditory meatus. Herpes zoster is not only more common in immunocompromised patients, but it is also more likely in these patients to become generalized, with diffuse cutaneous lesions and internal organ involvement.

Complications of herpes zoster include postherpetic neuralgia, stroke, arteritis (particularly in immunocompromised patients), encephalitis, myelitis, and cranial neuropathy, including optic neuritis. Postherpetic neuralgia is persistence of the pain of herpes zoster for more than 4 to 6 weeks after the rash disappears (Portenoy et al 1986). For patients who develop zoster after the age of 60, the risk of developing postherpetic neuralgia has been reported to be as high as 50% (de Moragas and Kierland 1957; Ragozzino et al 1982). It is also more common after trigeminal ophthalmic division involvement. Postherpetic neuralgia may represent a smoldering varicella-zoster virus infection of the dorsal root ganglia (Gilden 1994).

Herpes zoster can also cause arteritis and stroke. Varicella-zoster virus has been detected in the involved blood vessels (Schmidbauer et al 1992; Melanson et al 1996). The virus appears to spread to the vessels both hematogenously and through the sensory nerves (Schmidbauer et al 1992). Both ischemic and hemorrhagic infarctions are associated with varicella-zoster virus (Kuriowa and Furukawa 1981; Eible 1983). Arteritis appears to result from infection and inflammation of intracranial vessels and, particularly with herpes zoster ophthalmicus, has been documented to result in devastating stroke ("herpes zoster ophthalmicus and contralateral hemiplegia") (Bourdette et al 1983; Hilt et al 1983) or hemorrhage (Fukumoto et al 1986). A similar syndrome has less frequently occurred after chickenpox (Caekebeke et al 1990; Ichiyama et al 1990). Development of multiple cerebral aneurysms with varicella-zoster virus vasculopathy has recently been reported (Liberman et al 2014). Varicella-zoster virus antigen has also been found in the temporal arteries of some patients with signs and symptoms of giant cell arteritis, including patients found to be giant cell arteritis–biopsy positive as well as negative (Gilden 2014).

Varicella-zoster virus encephalitis (zoster encephalitis) in immunocompromised individuals usually develops concurrent with the rash or weeks to months after acute herpes zoster and is characterized by mental status changes and multifocal neurologic deficits (Jemsek et al 1983). The small vessel vasculopathy that leads to leukoencephalopathy was first described by Horten and colleagues and confirmed by Morgello and colleagues (Horten et al 1981; Morgello et al 1988). Both demyelination and necrosis can be seen in the small vessel disease of varicella-zoster virus encephalitis (Horten et al 1981; Morgello et al 1988; Gray et al 1994; Amlie-Lefond et al 1995). Varicella-zoster virus vasculopathy can involve the large and small vessels, and the term varicella-zoster virus vasculopathy, rather than encephalitis, best defines this syndrome (Gilden et al 2002).

Varicella-zoster virus myelitis (zoster myelitis) is less common than encephalitis and characteristically presents with motor deficits that are greatest ipsilateral to the rash (monoparesis, abnormal deep tendon reflexes, and Babinski sign). This complication may remain ipsilaterally localized as segmental paresis (Thomas and Howard 1972) or spread to the contralateral cord causing paraparesis. Sensory findings are also frequent (Devinsky et al 1991). Bladder dysfunction may be seen. Although myelitis has typically been described in immunocompromised patients, it has also occurred in immunocompetent patients (Gilden et al 1994a; 2008).

Cranial and peripheral nerve palsies are the most common neurologic sequelae of herpes zoster, occurring in approximately 5% of patients with zoster (Thomas and Howard 1972). Involvement of these nerves can result in debilitating weakness and pain. Varicella-zoster virus associated polyradiculoneuritis (Cortese et al 2009) and polyneuritis cranialis (Murata et al 2010) have been reported in the absence of rash. Optic neuritis has been reported both preceding and following the varicella exanthem (Lee et al 1997; Kertes et al 1998).

In This Article

Historical note and nomenclature
Clinical manifestations
Pathogenesis and pathophysiology
Differential diagnosis
Diagnostic workup
Prognosis and complications
References cited