Neurovisual Manifestationsof Herpesviruses

Jonathan C. Horton, M.D., Ph.D.

Herpes simplex virus and varicella-zoster virus cause dermatitis, bleph-aroconjunctivitis, keratitis, uveitis, glaucoma, and retinitis. These condi-tions are encountered frequently by the ophthalmologist in clinical prac-tice. It should not be overlooked that herpesviruses can also produce anextraordinary variety of neuroophthalmological signs and symptoms.What follows is an overview of the most common and important neuro-ophthalmological manifestations of herpesvirus infection.

� Ophthalmoplegia

Palsy of an ocular motor nerve occurs occasionally after an attack ofherpes zoster (Fig 1). It is exceedingly rare after chickenpox or herpessimplex infection. Virtually all cases have been associated with herpeszoster ophthalmicus, although palsy has been claimed to occur withouteye involvement or skin lesions.1 In herpes zoster ophthalmicus, extra-ocular eye muscle palsy has been reported in 13,2 14,3 and 33%4 of pa-tients. In the author’s experience, these incidence rates are unusuallyhigh, probably because of referral bias.

In approximately 290 cases, Edgerton2 found the following distribu-tion of ocular nerve palsies: nerve III (47%), IV (10%), VI (23%), andmultiple nerves (20%). Sixteen cases of complete ophthalmoplegia havebeen recorded in the literature.5 The onset of ocular motor palsy occursusually 1 to 3 weeks after the eruption of the herpes zoster rash. When thethird nerve is involved, there is always ptosis. The pupil is often dilatedpartially. After recovery, aberrant regeneration of the third nerve is rarebut has been observed in some cases.

The mechanism of ocular motor nerve involvement is controversial.Edgerton2 proposed that herpes-induced inflammation spreads from thetrigeminal nerve to contiguous ocular motor nerves in the cavernoussinus. Another possibility is that herpesvirus induces an occlusive vasculitis

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that causes an ischemic neuropathy.6 The few cases studied at autopsyhave shown monocytic infiltration, demyelination, axonal degeneration,and vasculitis of vasa nervorum.7,8 Virus particles have not been demon-strated in postmortem specimens of ocular motor nerves.

The prognosis for eventual recovery from ocular motor nerve palsy isexcellent. Spontaneous resolution of diplopia usually occurs in 6 to 12months. There is no evidence that antiviral drugs or steroids hasten im-provement, although these agents are often employed.

� Herpesvirus Reactivation AfterSurgical Manipulation

Cushing9 observed reactivation of herpes simplex virus after nerveroot section for trigeminal neuralgia. In this phenomenon, vesicles appearin areas where sensory innervation remains intact but are absent in de-nervated skin.10 This observation implies that surgical manipulation of thesensory root triggers latent virus to replicate and travel distally along intactnerve fibers. After microsurgical decompression for trigeminal neuralgia,approximately 50% of patients develop herpesvirus reactivation. Virus canalso be cultured from oropharyngeal secretions in this setting.11

In addition, herpesvirus reactivation can occur from spinal surgery

Figure 1. (A) Acute herpes ophthalmicus in a 77-year-old woman. The picture was taken 3 daysafter the eruption of vesicles in a V1 and V2 distribution. She was treated with oral acyclovir,topical steroids, and tropicamide. (B) Ten days later, the patient returned with a completeoculomotor palsy and active uveitis. By this time, the skin lesions had nearly healed.

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and aneurysm clipping,12 indicating that direct trigeminal manipulation isnot required to reactivate latent herpesvirus. Indeed, herpes reactivationcan complicate any type of surgery, although it is most common in neu-rosurgery (Fig 2).

Many patients receive steroid medications routinely during and aftermajor neurosurgical procedures. Steroids may enhance the likelihood ofherpesvirus reactivation by producing immunosuppression. One mightpostulate that herpesvirus reactivation occurs because of steroid treatmentrather than from physiological stress or physical manipulation. However,surgical reactivation of herpesvirus was described long before the intro-duction of steroids in medicine, proving that steroids play a secondaryrole.

Herpetic outbreak after surgery is a distressing iatrogenic complica-tion. Patients should be treated with antiviral medications. Steroids shouldbe discontinued, when possible.

� Herpetic Optic Neuropathy

Visual loss from herpetic optic neuropathy is rare; there are no reli-able data concerning the incidence. Bilateral cases have been reported,13

although they are exceptionally rare. Onset usually occurs weeks after thedevelopment of a herpetic rash or uveitis. Impairment of acuity is often

Figure 2. (A) An 82-year-old man with complete right ophthalmoplegia, facial numbness, andvesicles on the nose and upper lip caused by pituitary apoplexy. (B) Magnetic resonance imagingshows hemorrhagic pituitary adenoma. The patient was thought to have herpesvirus reactivationand ophthalmoplegia caused by abrupt compression of cranial nerves from an adenoma expandinginto the cavernous sinus.

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fairly severe. Vitritis, retinitis, and neuroretinitis are frequently present. Insome patients, swelling of the optic disc can occur in conjunction with anarcuate pattern of retinal edema, necrosis, and hemorrhage that followsthe nerve fiber layer (Fig 3).14 The fundus appearance can be normal inthe retrobulbar form of herpetic optic neuropathy.15

The mechanism of optic neuropathy in association with herpesvirus isuncertain. It may result from an immune-mediated inflammatory reactionin the optic nerve. In some cases, the herpesvirus may invade the opticnerve, as it does the retina.16 Some cases have shown evidence of granu-lomatous inflammation of the optic nerve,6,7,17 giving rise to the idea thatsome cases may represent a form of anterior ischemic optic neuropathy.

Ophthalmologists frequently worry about the possibility of herpesvirusinfection in patients who present with acute visual loss from an opticneuropathy of unknown cause. One does not want to overlook a treatableoptic neuropathy. As a general rule, optic neuropathy from herpesvirusnever occurs without retinal necrosis, uveitis, or a recent herpetic skinrash. The only exceptions occur in patients who are immunocompromised.

In patients with the acquired immunodeficiency syndrome or otherforms of immunocompromise, optic neuropathy from herpesvirus canoccur in the setting of acute retinal necrosis syndrome. It is even possiblefor the optic neuropathy to precede the development of acute retinalnecrosis.18,19 Such patients may present with retrobulbar visual loss. Thecause of visual loss should be investigated aggressively with magnetic reso-nance imaging and lumbar puncture. Empirical therapy with antiherpesvirus drugs should be instituted if the diagnosis is unclear.

� Ramsay Hunt Syndrome

In 1907, Hunt described the simultaneous occurrence of unilateralfacial nerve palsy and herpetic vesicles on the pinna. The skin of the

Figure 3. Right eye of a55-year-old nurse with herpes zosterin a V1 distribution. There isdiffuse optic disc edema andhemorrhage, with an arcuatepattern of retinal necrosis.

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external auditory canal and central pinna is supplied by a small sensorybranch of the facial nerve. The cell bodies of these fibers, located in thegeniculate ganglion, are believed to harbor latent herpesvirus. RamsayHunt syndrome, therefore, is a rare form of herpetic skin eruption ac-companied by facial paralysis. Corneal exposure is the major ocular com-plication of Ramsay Hunt syndrome.

In recent years, evidence has mounted that idiopathic Bell’s palsy(without herpetic vesicles) may represent a herpetic mononeuritis (vari-cella-zoster virus or herpes simplex virus) of the seventh nerve. There is agrowing literature to support the treatment of Bell’s palsy with antiviralagents.20–24 Typical regimens are acyclovir (4,000 mg/day for a week) orvalacyclovir (3,000 mg/day for a week) in combination with prednisone (1mg/kg).

� Cerebral Vasculitis

A delayed cerebral vasculitis can occur 1 to 2 months after herpeszoster. This complication was reported by Womack and Liesegang25 in 4of 86 patients with herpes zoster ophthalmicus. Patients may present withcontralateral hemiplegia, aphasia, or confusion. Neuroimaging demon-strates a fresh infarct. Angiography usually shows multiple areas of seg-mental narrowing of the middle cerebral artery, anterior cerebral artery,or their branches. The posterior circulation is affected less frequently, butoccipital infarct with homonymous hemianopia has been reported.26

Autopsy studies have shown that infarcts in herpetic cerebral vasculitisare caused by a focal necrotizing granulomatous angiitis. In one study,varicella-zoster virus particles were identified by electron microscopy insmooth muscle cells of the vessel wall.27

� Meningitis and Encephalitis

Primary skin infection by herpes simplex virus is accompanied byaseptic meningitis in approximately 10% of patients. The term Mollaret’smeningitis refers to a phenomenon of recurrent episodes of headache andstiff neck caused by aseptic meningitis from herpesvirus. Cerebrospinalfluid analysis shows a lymphocytic pleocytosis and herpes simplex virustype 2 DNA on polymerase chain reaction.28

Rarely, herpes simplex causes encephalitis. Any region of the braincan be affected, but there is a predilection for temporal lobe involvement.Pathological specimens show a hemorrhagic, necrotizing encephalitiswith Cowdry type A inclusion bodies in neurons. These are intranuclearbodies containing viral particles.

The diagnosis of herpetic encephalitis is difficult, because cutaneous

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evidence of viral infection is usually absent. The virus is difficult to culturefrom the cerebrospinal fluid. The enzyme-linked immunosorbent assaymethod may show rising titers of IgG and IgM antibodies. Moleculartechniques (e.g., polymerase chain reaction amplification of viral DNAfollowed by restriction enzyme analysis) can provide the diagnosis.29,30

The diagnosis can also be made by brain biopsy. Because of the obviousdisadvantages of brain biopsy, many neurologists recommend empiricaltreatment with acyclovir in all cases of unexplained encephalitis.31

Chickenpox is complicated by central nervous system involvement in1 of 1,000 patients. It can produce acute cerebellar ataxia, optic neuritis,32

meningitis, myelitis, delayed cerebral vasculitis, or encephalitis (Fig 4).Similar neurological sequellae can occur after attacks of herpes zoster.

� Postherpetic Neuralgia

Herpes zoster is usually heralded by the onset of pain. When thetrigeminal nerve is affected, a physician may suspect temporal arteritis,until telltale vesicles appear on the skin. Pain may persist after the skinlesions have healed, especially in older patients. This pain, defined aspostherpetic neuralgia, is described variously as burning, itching, aching, orlancinating. Although skin sensation is reduced, trivial stimulation pro-vokes a painful response (dysesthesia). The mechanism of postherpeticneuralgia is not understood.33 It is believed that damaged peripheralC-fiber afferents may be abnormally sensitized or that deafferented cen-tral neurons may signal pain through increased spontaneous activity.

It is uncertain whether postherpetic neuralgia can be prevented.Nucleoside analogs such as acyclovir appear to mitigate attacks of herpeszoster and reduce acute pain. However, it is unclear whether these agentsreduce the incidence of postherpetic neuralgia.34 Corticosteroids do notreduce the likelihood of developing postherpetic neuralgia.35

Patients with postherpetic neuralgia can be incapacitated by pain.Treatment with tricyclic antidepressants (amitriptyline) is beneficial inmost patients. Capsaicin cream is also helpful, although it produces in-tolerable burning on application in many patients. Stabbing pain mayrespond to anticonvulsants (carbamazepine).

� Monkey Herpes B Virus

Cercopithecine herpes B virus is widespread in Old World monkeycolonies. The disease can be communicated to humans. More than adozen fatalities have been reported in the medical literature. The diseaseshould be suspected in any patient with evidence of herpes infections anda history of occupational exposure to monkeys (e.g., zookeepers, labora-tory researchers).

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The most recent death from this virus occurred in 1997.36 A 22-year-old scientist felt a drop splash into her right eye while transferring a rhesusmonkey in a cage. Ten days later, the eye became injected. She consultedan ophthalmologist, who observed no dendritic corneal lesions. Twoweeks after exposure, she developed nausea, photophobia, and worseningright retroorbital pain. A vesicular rash erupted in the right V1 and V2

distribution. Despite treatment with ganciclovir, the patient developedparalysis and respiratory failure resulting in death 6 weeks after exposure.The diagnosis of cercopithecine herpes B virus infection was confirmed byWestern blot analysis of serum.

Figure 4. (A) A 20-year-old college student with blindness, urinary retention, weakness, andconfusion 2 weeks after an attack of chickenpox. (B) A T2-weighted magnetic resonance imagingscan shows lesions scattered throughout the white matter. (C, D) Bilateral optic disc edema. Visualacuity was hand motions OD, no light perception OS. The patient was treated with intravenousacyclovir and hospitalized for supportive care. After 3 months, he made a complete recovery.

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