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Varicella-Zoster Virus: A Re-Emerging Infection

      Varicella-zoster virus (VZV) causes chickenpox (varicella), becomes latent in cranial nerve and dorsal root ganglia, and can reactivate many years later to produce shingles (zoster) and postherpetic neuralgia (PHN). Elderly and immunocompromised individuals are also at risk for complications of VZV reactivation involving the central nervous system (CNS), including myelitis, large-vessel encephalitis/granulomatous arteritis, small-vessel encephalitis, meningoencephalitis, and ventriculitis. Peripheral nervous system (PNS) complications range from zoster and postherpetic neuralgia to postinfectious polyneuritis (Guillain–Barre syndrome, GBS). These complications can occur with or without cutaneous manifestations. An increase in elderly and immunocompromised individuals will likely result in a higher prevalence of these conditions; therefore, VZV can be seen as a “re-emerging” infection of the early twenty-first century. In this review, we summarize our experience and the existing literature on CNS and PNS complications of VZV reactivation. Special attention is paid to reports of complications without rash, as these entities are more difficult to diagnose.

      Keywords

      Varicella-zoster virus (VZV) is a human alphaherpesvirus that causes chickenpox (varicella), becomes latent in cranial nerve and dorsal root ganglia, and can reactivate many years later to produce shingles (zoster) and postherpetic neuralgia (PHN). Elderly and immunocompromised individuals are also at risk for complications of VZV reactivation involving both the central nervous system (CNS) and the peripheral nervous system (PNS), and which can occur with or without skin lesions. As the number of elderly population in our society increases, as well as the number of immunocompromised patients due to human immunodeficiency virus (HIV) infection/acquired immune deficiency syndrome (AIDS), and the use of immunosuppressive medications (e.g., post-transplant), or the complications of drug therapy (e.g., antineoplastic agents) also increases, a larger population becomes susceptible to the rarer, and more serious complications of VZV reactivation. Therefore, VZV can be seen as a “re-emerging” infection of the early twenty-first century.

      Primary infection: varicella (chickenpox)

      Primary VZV infection produces varicella (chickenpox), a typically mild contagious disease of childhood. By adult life, nearly everyone in North America is seropositive. Approximately 4 million cases occur annually in the U.S.A., with 90% of cases in individuals 1–14 y of age (
      • Preblud S.R.
      Varicella complications and costs.
      ). In northern regions, only 2% of varicella occurs after age 20, whereas in tropical climates a higher incidence of varicella is seen in adults (
      • Nassar N.T.
      • Touma H.C.
      Susceptibility of Filipino nurses to the varicella-zoster virus.
      ;
      • Longfield J.N.
      • Winn R.E.
      • Gibson R.L.
      • Juchau S.V.
      • Hoffman P.V.
      Varicella outbreaks in army recruits from Puerto Rico.
      ).
      In temperate climates, chickenpox peaks in the spring, with another smaller peak in winter (
      • Preblud S.R.
      • D'Angelo L.J.
      From the Center for Disease Control. Chickenpox in the United States.
      ;
      • Preblud S.R.
      • Orenstein W.A.
      • Bart K.J.
      Varicella: Clinical manifestations, epidemiology and health impact in children.
      ). It is thought that the disease is transmitted by direct contact or by aerosols containing virus (
      • Leclair J.M.
      • Zaia J.A.
      • Levin M.J.
      • Congdon R.G.
      • Goldmann D.A.
      Airborne transmission of chickenpox in a hospital.
      ;
      • Gustafson T.L.
      • Lavely G.B.
      • Brawner Jr., E.R.
      • Hutcheson Jr., R.H.
      • Wright P.F.
      • Schaffner W.
      An outbreak of airborne nosocomial varicella.
      ;
      • Josephson A.
      • Gombert M.E.
      Airborne transmission of nosocomial varicella from localized zoster.
      ). Infection is probably initially in the respiratory tract, followed by viral replication, most likely in the pharynx and regional lymph nodes (
      • Tomlinson T.H.
      Giant cell formation in the tonsils in the prodromal stage of chickenpox.
      ;
      • Fenner F.
      The pathogenesis of the acute exanthems: An interpretation based on experimental investigations with mousepox (infectious ectromelia of mice).
      ;
      • Grose C.
      Variation on a theme by Fenner. The pathogenesis of chickenpox.
      ). The incubation period in healthy children is 9–21 d (
      • Fenner F.
      The pathogenesis of the acute exanthems: An interpretation based on experimental investigations with mousepox (infectious ectromelia of mice).
      ;
      • Grose C.
      Variation on a theme by Fenner. The pathogenesis of chickenpox.
      ;
      • Preblud S.R.
      • Orenstein W.A.
      • Bart K.J.
      Varicella: Clinical manifestations, epidemiology and health impact in children.
      ). Viremia in immunocompetent varicella patients has been demonstrated 1–11 d before rash (
      • Asano Y.
      • Itakura N.
      • Hiroishi Y.
      • et al.
      Viremia is present in incubation period in nonimmunocompromised children with varicella.
      ;
      • Kallander C.F.
      • Gronowitz J.S.
      • Olding-Stenkvist E.
      Varicella zoster virus deoxythymidine kinase is present in serum before the onset of varicella.
      ), predominantly in lymphocytes (
      • Ozaki T.
      • Ichikawa T.
      • Matsui Y.
      • et al.
      Lymphocyte-associated viremia in varicella.
      ;
      • Vonsover A.
      • Leventon-Kriss S.
      • Langer A.
      • et al.
      Detection of varicella-zoster virus in lymphocytes by DNA hybridization.
      ;
      • Koropchak C.M.
      • Solem S.D.
      • Diaz P.S.
      • Arvin A.M.
      Investigation of varicella-zoster virus infection of lymphocytes by in situ hybridization.
      ). Immunologic evidence indicates that subclinical reinfection with VZV is fairly common (
      • Baba K.
      • Yabuuchi H.
      • Takahaski M.
      Increased incidence of herpes zoster in normal children infected with varicella zoster virus during infancy: Community-based follow-up study.
      ;
      • Wharton M.
      The epidemiology of varicella-zoster virus infections.
      ). Fever, myalgia, and arthralgias precede or coincide with rash. The exanthem of chickenpox consists of macules and papules that develop into vesicles surrounded by an erythematous halo. Vesicles, which reflect degenerative changes of the corium and dermis, develop quickly and are characterized by multinucleated giant cells and intranuclear Cowdry type A inclusions (
      • Tyzzer E.E.
      The histology of the skin lesions in varicella.
      ), a hallmark of herpesvirus family infection. Vesicles contain abundant infectious virus that can be isolated in cell culture (
      • Weller T.H.
      • Witton H.M.
      • Bell E.J.
      The etiologic agents of varicella and herpes zoster. Isolation, propagation, and cultural characteristics in vitro.
      ). Rash usually begins on the trunk, then spreads to the face, limbs, and often to the buccal and pharyngeal mucosa. Skin areas that are sunburned or subject to irritation (e.g., from diapers) often exhibit a denser rash. New vesicles form within the first 4 d after outbreak, while crusting starts after 2–3 d; thus, both crusting and fresh vesicles may be seen at the same time. Patients are considered infectious from 2 d before rash until all vesicles have crusted, typically 6 d after the onset of rash. Immunization of children 12–18 mo old with a live attenuated varicella vaccine (Oka strain) may eventually shift the average age of infection to older susceptible individuals (
      • Halloran M.E.
      Epidemiologic effects of varicella vacinnation.
      ).

      Reactivation: zoster (shingles, ganglionitis) and postherpetic neuralgia (phn)

      Herpes zoster is a common disorder, with estimates of 300 000–850 000 cases occurring annually in the U.S.A. Except in immunocompromised individuals (especially AIDS patients), zoster is a disease of the elderly. The incidence among people over age 50 is double that of people under 50 (
      • Harnisch J.P.
      Zoster in the elderly: Clinical, immunologic and therapeutic considerations.
      ), which ultimately translates into an 8–10-fold increased frequency in people over age 60 compared with those under 60. As the aging population increases, the incidence of zoster-associated morbidity and mortality is also expected to increase. Varicella in infancy may predispose to zoster earlier in life (
      • Guess H.A.
      • Broughton D.D.
      • Melton L.J.
      • Kurland L.T.
      Epidemiology of herpes zoster in children and adolescents. A population-based study.
      ). The incidence of recurrent zoster is less than 5% (
      • Hope-Simpson R.E.
      The nature of herpes zoster: a long-term study and a new hypothesis.
      ). Although varicella outbreaks occur most often in the spring, zoster may develop at any time of the year. The risk of zoster in vaccinated individuals compared with those who developed naturally occurring chickenpox will not be known for decades. Some investigators have predicted an increased incidence of zoster with widespread use of the live attenuated varicella vaccine (
      • Garnett G.P.
      • Grenfell B.T.
      The epidemiology of varicella-zoster virus infections: The influence of varicella on the prevalence of herpes zoster.
      ;
      • Wharton M.
      The epidemiology of varicella-zoster virus infections.
      ). Other evidence indicates that, in children with leukemia who had been vaccinated, the incidence of zoster is less than in leukemic children who had naturally occurring chickenpox (
      • Brunell P.A.
      • Taylor-Wiedeman J.
      • Geiser C.F.
      • Frierson L.
      • Lydick E.
      Risk of herpes zoster in children with leukemia. Varicella vaccine compared with history of chickenpox.
      ;
      • Hardy I.
      • Gershon A.A.
      • Steinberg S.P.
      • LaRussa P.
      • the Varicella Vaccine Collaborative Study Group
      The incidence of zoster after immunization with live attenuated varicella vaccine.
      ).
      Herpes zoster is characterized by pain and a vesicular eruption on an erythematous base in 1–3 dermatomes. All levels of the neuraxis may be involved in zoster, with thoracic zoster being the most common, followed by lesions on the face, most often in the ophthalmic division of the trigeminal nerve. The latter is frequently accompanied by zoster keratitis, a potential cause of blindness if not recognized and treated promptly. Thus, if visual symptoms are present in a patient with trigeminal distribution zoster, they should have an immediate slitlamp examination by an ophthalmologist. Maxillary and mandibular trigeminal distribution zoster with osteonecrosis and spontaneous tooth exfoliation has also been described in adults (
      • Manz H.J.
      • Canter H.G.
      • Melton J.
      Trigeminal herpes zoster causing mandibular osteonecrosis and spontaneous tooth exfoliation.
      ) and children (
      • Garty B.Z.
      • Dinari G.
      • Sarnat H.
      • Cohen S.
      • Nitzan M.
      Tooth exfoliation and osteonecrosis of the maxilla after trigeminal herpes zoster.
      ). The seventh cranial nerve is also commonly involved. Weakness of all facial muscles of one side develops in conjunction with rash in the ear (zoster oticus) or on the ipsilateral anterior two-thirds of the tongue or hard palate. Unless searched for in patients with facial weakness, vesicles in either site are easily overlooked. The combination of zoster oticus and peripheral facial weakness constitutes the Ramsay Hunt syndrome, and the prognosis for recovery from facial weakness or paralysis is not as favorable as in idiopathic Bell's palsy. Zoster may be accompanied by ophthalmoplegia, most commonly affecting the third cranial nerve (
      • Thomas E.J.
      • Howard F.M.
      Segmental zoster paresis – a disease profile.
      ), optic neuritis (
      • Miller D.H.
      • Kay R.
      • Schon F.
      • McDonald W.I.
      • Haas L.F.
      • Hughes R.A.
      Optic neuritis following chickenpox in adults.
      ), or both (
      • Carroll W.M.
      • Mastaglia F.L.
      Optic neuropathy and ophthalmoplegia in herpes zoster oticus.
      ), and less often lower cranial nerve palsies (
      • Crabtree J.A.
      Herpes zoster oticus.
      ;
      • Steffen R.
      • Selby G.
      “Atypical” Ramsay Hunt syndrome.
      ). Zoster-associated cranial neuropathy often occurs weeks after acute VZV infection. One explanation for late-onset zoster cranial neuropathy is that virus spreads slowly along trigeminal and other ganglionic afferent fibers to small vessels supplying cranial nerves.
      Most neurologic complications of zoster manifest as postherpetic neuralgia (PHN), defined as pain persisting more than 4–6 wk after rash. Age is the most important factor in predicting the development of PHN (
      • Brown G.R.
      Herpes zoster: correlation of age, sex, distribution, neuralgia and associated disorders.
      ;
      • Ragozzino M.W.
      • Melton III, L.J.
      • Kurland L.T.
      • Chu C.P.
      • Perry H.O.
      Population-based study of herpes zoster and its sequelae.
      ). The risk of PHN in zoster patients over age 50 ranges from 43% to 47.5%. The incidence of PHN also appears to be slightly greater in women (
      • Hope-Simpson R.E.
      Postherpetic neuralgia.
      ) and after trigeminal distribution zoster (
      • DeMoragas J.M.
      • Kierland R.R.
      The outcome of patients with herpes zoster.
      ;
      • Rogers R.S.
      • Tindall J.P.
      Geriatric herpes zoster.
      ;
      • Hope-Simpson R.E.
      Postherpetic neuralgia.
      ).
      The mechanism of PHN is unknown. The detection of VZV-specific proteins in mononuclear cells (MNC) of patients with PHN (
      • Vafai A.
      • Murray R.S.
      • Wellish M.
      • Devlin M.
      • Gilden D.H.
      Expression of varicella-zoster virus and herpes simplex virus in normal human trigeminal ganglia.
      ) suggested that persistence of VZV may result in PHN. Later, VZV DNA was shown to persist in blood MNC of PHN patients (
      • Mahalingam R.
      • Wellish M.
      • Brucklier J.
      • Gilden D.H.
      Persistence of varicella-zoster virus DNA in elderly patients with postherpetic neuralgia.
      ) compared with zoster patients without PHN. It is possible that MNC trafficking through such ganglia encounter and engulf virus whose DNA can then be amplified by polymerase chain reaction. Ganglia need to be analyzed at autopsy from individuals who suffered from PHN at the time of death. If a greater virus burden could be demonstrated in these ganglia than has been found during latency (
      • Mahalingam R.
      • Wellish M.
      • Lederer D.
      • Forghani B.
      • Cohrs R.
      • Gilden D.
      Quantitation of latent varicella-zoster virus DNA in human trigeminal ganglia by polymerase chain reaction.
      ), this would provide a rationale for aggressive treatment of PHN patients with antivirals. Meanwhile, the existence of ganglionitis without rash is further supported by the presence of radicular pain up to 100 d preceding zoster (
      • Gilden D.H.
      • Dueland A.N.
      • Cohrs R.
      • Martin J.R.
      • Kleinschmidt-DeMasters B.K.
      • Mahalingam R.
      Preherpetic neuralgia.
      ), so-called preherpetic neuralgia. Furthermore, a recent report described four patients with acute trigeminal distribution zoster who, after years free from pain, developed severe trigeminal “PHN” (
      • Schott G.D.
      Triggering of delayed-onset postherpetic neuralgia.
      ).

      Cns and pns complications of vzv reactivation

      In immunocompetent and especially in immunocompromised patients, CNS complications can occur after VZV reactivation when virus spreads to the spinal cord, brain, or arteries. Immunocompetent individuals may develop myelitis or large-vessel encephalitis/granulomatous arteritis, whereas immunocompromised patients develop small-vessel encephalitis, meningoencephalitis, or ventriculitis. Some patients develop both large- and small-vessel disease, although one form usually predominates (
      • Gilden D.H.
      • Kleinschmidt-DeMasters B.K.
      • Wellish M.
      • Hedley-Whyte E.T.
      • Rentier B.
      • Mahalingam R.
      Varicella zoster virus, a cause of waxing and waning vasculitis. NEJM case 5–1995 revisited.
      ). In addition, PNS complications can occur, including postinfectious polyneuritis (Guillain–Barre syndrome, GBS). These clinical entities are reviewed in
      • Gilden D.H.
      • Kleinschmidt-DeMasters B.K.
      • LaGuardia J.J.
      • Mahalingam R.
      • Cohrs R.
      Neurologic complications of the reactivation of varicella-zoster virus.
      .

      Complications of vzv reactivation without rash

      Because of the relatively distinct features of skin findings associated with VZV primary infection and zoster, diagnosis is fairly straightforward; however, many complications of VZV reactivation can occur without rash, and these pose a more difficult diagnosis for neurologists, dermatologists, and colleagues caring for the patient. These include zoster sine herpete, encephalitis, myelitis, polyneuritis cranialis, and “Bell's” palsy, all caused by VZV without rash, and are reviewed below. Table I lists the published cases of VZV complications, without rash, seen at the University of Colorado Health Sciences Center in the past decade.
      Table IVZV complications without rash
      DiagnosisNumber of casesReference
      VZV myelitis4
      • Gilden D.H.
      • Beinlich B.R.
      • Rubinstien E.M.
      • Stommel E.
      • Swenson R.
      • Rubinstein D.
      • Mahalingam R.
      VZV myelitis: An expanding spectrum.
      Zoster sine herpete2; 1
      • Gilden D.H.
      • Wright R.R.
      • Schneck S.A.
      • Gwaltney Jr., J.M.
      • Mahalingam R.
      Zoster sine herpete, a clinical variant.
      ;
      • Amlie-Lefond C.
      • Mackin G.A.
      • Ferguson M.
      • Wright R.R.
      • Mahalingam R.
      • Gilden D.H.
      Another case of virologically confirmed zoster sine herpete, with electrophysiologic correlation.
      VZV encephalitis5
      • Amlie-Lefond C.
      • Kleinschmidt-DeMasters B.K.
      • Mahalingam R.
      • Davis L.E.
      • Gilden D.H.
      The vasculopathy of varicella zoster virus encephalitis.
      VZV meningoradiculitis1
      • Dueland A.N.
      • Devlin M.
      • Martin J.R.
      • et al.
      Fatal varicella zoster virus meningoradiculitis without skin involvement.
      VZV encephalomyelitis1
      • Kleinschmidt-DeMasters B.K.
      • Mahalingam R.
      • Shimek C.
      • Marcoux H.L.
      • Wellish M.
      • Tyler K.L.
      • Gilden D.H.
      Profound cerebrospinal fluid pleocytosis and Froin's syndrome secondary to widespread necrotizing vasculitis in an HIV-positive patient with varicella zoster virus encephalomyelitis.
      VZV ventriculitis2
      • Kleinschmidt-DeMasters B.K.
      • Amlie-Lefond D.
      • Gilden D.H.
      The patterns of varicella zoster virus encephalitis.
      The first case of zoster sine herpete (shingles without rash) was reported nearly 100 y ago. A 38-y-old man developed acute thoracic-distribution pain and hyperesthesia, a dilated pupil, CSF pleocytosis (predominantly mononuclear), and a negative serologic test for syphilis (
      • Widal
      ). He was presumed to have zoster sine herpete even though serologic tests for VZV were not done. Similarly, two patients who experienced segmental pain, hyperesthesias, and focal weakness were presumed to have zoster sine herpete despite lack of serologic confirmation (
      • Weber F.P.
      Herpes zoster: its occasional association with a generalized eruption and its occasional connection with muscular paralysis; also an analysis of the literature of the subject.
      ). The notion of zoster sine herpete received further credence when
      • Lewis G.W.
      Zoster sine herpete.
      described numerous zoster patients who, days later, also developed pain without rash in a different dermatome distribution, often on the opposite side.
      The first serologic evidence of zoster sine herpete occurred in a physician who developed acute trigeminal distribution pain associated with a 4-fold rise in complement-fixing antibody to VZV, but not to HSV (
      • Easton H.G.
      Zoster sine herpete causing acute trigeminal neuralgia.
      ). Virologic confirmation of zoster sine herpete did not come until the analysis of two men with thoracic-distribution radicular pain that had lasted for months to years revealed amplifiable VZV DNA, but not HSV DNA, in their CSF and blood MNC (
      • Gilden D.H.
      • Wright R.R.
      • Schneck S.A.
      • Gwaltney Jr., J.M.
      • Mahalingam R.
      Zoster sine herpete, a clinical variant.
      ). After diagnosis, both men were treated successfully with intravenous acyclovir. A third virologically confirmed case of thoracic-distribution zoster sine herpete persisting for years included the demonstration of frequent fibrillation potentials restricted to chronically painful thoracic root segments (
      • Amlie-Lefond C.
      • Mackin G.A.
      • Ferguson M.
      • Wright R.R.
      • Mahalingam R.
      • Gilden D.H.
      Another case of virologically confirmed zoster sine herpete, with electrophysiologic correlation.
      ); however, the third patient did not improve after treatment with intravenous acyclovir and oral famciclovir.
      VZV encephalitis without rash may occur, with the typical clinical picture being an immunocompromised individual (usually suffering from AIDS) who develops CNS disease at the time of acute zoster, or who may have a history of zoster weeks to months earlier, or even recurrent zoster. CNS disease in such patients develops more often in the absence of acute zoster than at the time of acute zoster (
      • Amlie-Lefond C.
      • Kleinschmidt-DeMasters B.K.
      • Mahalingam R.
      • Davis L.E.
      • Gilden D.H.
      The vasculopathy of varicella zoster virus encephalitis.
      ). Encephalitis is usually of the “small vessel” type (
      • Gilden D.H.
      • Kleinschmidt-DeMasters B.K.
      • LaGuardia J.J.
      • Mahalingam R.
      • Cohrs R.
      Neurologic complications of the reactivation of varicella-zoster virus.
      ), and disease is usually protracted. Diagnosis may be difficult unless the clinician is alert to the history of recurrent zoster followed by the typical clinical features and multifocal lesions seen by brain MRI in “small vessel” encephalitis. Many patients die of chronic progressive VZV encephalitis without ever having developed rash (
      • Amlie-Lefond C.
      • Kleinschmidt-DeMasters B.K.
      • Mahalingam R.
      • Davis L.E.
      • Gilden D.H.
      The vasculopathy of varicella zoster virus encephalitis.
      ;
      • Gilden D.H.
      • Kleinschmidt-DeMasters B.K.
      • Wellish M.
      • Hedley-Whyte E.T.
      • Rentier B.
      • Mahalingam R.
      Varicella zoster virus, a cause of waxing and waning vasculitis. NEJM case 5–1995 revisited.
      ). The most extreme example of VZV infection of the nervous system we encountered was a 77-y-old man with T cell lymphoma who developed a fatal meningoradiculitis and died 3 wk after the onset of neurologic disease (
      • Dueland A.N.
      • Devlin M.
      • Martin J.R.
      • et al.
      Fatal varicella zoster virus meningoradiculitis without skin involvement.
      ). He did not develop zoster before or during neurologic disease. Postmortem examination revealed hemorrhagic, inflammatory lesions with Cowdry A inclusions in meninges and nerve roots extending from cranial nerve roots to the cauda equina. The brain contained similar lesions, although to a lesser extent. We found VZV antigen and nucleic acid, but not HSV or CMV antigen or nucleic acid, in infected tissue at all levels of the neuraxis. Thus, VZV should be included in the differential diagnosis of acute encephalomyeloradiculopathy, particularly since antiviral treatment is available.
      Acute VZV myelopathy may also occur in the absence of rash. The initial description was of a 31-y-old immunocompetent man who developed transverse myelitis with partial recovery (
      • Heller H.M.
      • Carnevale N.T.
      • Steigbigel R.T.
      Varicella zoster virus transverse myelitis without cutaneous rash.
      ). Disease was attributed to VZV based on the development of antibody in CSF. Later,
      • Gilden D.H.
      • Wright R.R.
      • Schneck S.A.
      • Gwaltney Jr., J.M.
      • Mahalingam R.
      Zoster sine herpete, a clinical variant.
      encountered two patients with VZV myelopathy in the absence of rash. The first patient developed zoster followed by myelopathy 5 mo later, at which time amplifiable VZV DNA was detected in CSF. A second patient developed myelopathy at the time of acute zoster. The myelopathy resolved, but recurred 6 mo later. Five months after the recurrence of myelopathy, the patient's CSF contained both amplifiable VZV DNA as well as antibody to VZV. Overall, the spectrum of VZV myelopathy can be broad, ranging from acute to chronic and rarely recurrent myelopathy.
      Further VZV involvement of the CNS without rash was verified by the intrathecal synthesis of antibodies to VZV in two patients with aseptic meningitis (
      • Martinez-Martin P.
      • Garcia-Saiz A.
      • Rapun J.L.
      • Echevarria J.M.
      Intrathecal synthesis of IgG antibodies to varicella-zoster virus in two cases of acute aseptic meningitis syndrome with no cutaneous lesions.
      ), later in four additional patients with aseptic meningitis (
      • Echevarria J.M.
      • Martinez-Martin P.
      • Tellez A.
      • et al.
      Aseptic meningitis due to varicella-zoster virus: Antibody levels and local synthesis of specific IgG, IgM and IgA.
      ), and in one patient with acute meningoencephalitis (
      • Vartdal F.
      • Vandvik B.
      • Norby E.
      Intrathecal synthesis of virus-specific oligoclonal IgG, IgA and IgM antibodies in a case of varicella-zoster meningoencephalitis.
      ). We encountered an adult man who was taking low-dose methotrexate for rheumatoid arthritis and who developed acute encephalitis (fever, aphasia, and a profound CSF mononuclear pleocytosis). His CSF contained amplifiable VZV and Epstein–Barr virus DNA. Zosteriform rash never developed, and he recovered completely after treatment with intravenous acyclovir.
      There have been two instances of polyneuritis cranialis produced by VZV. The first occurred in a 70-y-old man who seroconverted to VZV during acute disease (
      • Mayo D.R.
      • Booss J.
      Varicella zoster-associated neurologic disease without skin lesions.
      ). Another report described a 43-y-old man with acute polyneuritis cranialis who developed antibody in CSF to VZV, but not to other human herpesviruses, or to multiple ubiquitous paramyxoviruses or togaviruses (
      • Osaki Y.
      • Matsubayashi K.
      • Okumiya K.
      • Wada T.
      • Doi Y.
      Polyneuritis cranialis due to varicella-zoster virus in the absence of rash.
      ). Both men were apparently immunocompetent. Finally, cases of acute unilateral facial (Bell's) palsy that developed in the absence of zosteriform rash have been attributed to VZV infection (so-called geniculate zoster sine herpete) based on “a positive serum complement fixation test” (
      • Aitken R.S.
      • Brain R.T.
      Facial palsy and infection with zoster virus.
      ). A recent study revealed that VZV was the likely causative agent of acute peripheral facial palsy in 29% of patients clinically diagnosed with Bell's palsy due to a lack of vesicles in the external ear or on the palate (
      • Furuta Y.
      • Ohtani F.
      • Kawabata H.
      • Fukuda S.
      • Bergstrom T.
      High prevalence of varicella-zoster virus reactivation in herpes simplex virus-seronegative patients with acute peripheral facial palsy.
      ).

      Diagnosis

      To confirm the role of VZV in producing the many varied clinical syndromes of the central and peripheral nervous system, polymerase chain reaction and antibody testing of CSF should be performed, as effective antiviral therapy exists. In the appropriate clinical setting (i.e., acute or chronic spinal cord disease, acute or chronic progressive encephalitis, or chronic radicular pain without rash), the presence of VZV DNA or anti-VZV antibody, or both, in CSF is strong presumptive evidence of VZV infection. Even the detection of anti-VZV antibody in CSF without polymerase chain reaction-amplifiable VZV DNA supports the diagnosis of VZV infection of the nervous system (
      • Gilden D.H.
      • Bennett J.L.
      • Kleinschmidt-DeMasters B.K.
      • Song D.D.
      • Yee A.S.
      • Steiner I.
      The value of cerebrospinal fluid antiviral antibody in the diagnosis of neurologic disease produced by varicella zoster virus.
      ). Analysis of serum anti-VZV antibody is of no value in the work-up of these patients, because anti-VZV antibodies persist in nearly all adults throughout life, and the presence of antibodies in serum to different VZV glycoproteins and nonglycosylated proteins is variable (
      • Vafai A.
      • Mahalingam R.
      • Zerbe G.
      • Wellish M.
      • Gilden D.H.
      Detection of antibodies to varicella-zoster virus proteins in sera from the elderly.
      ).

      Treatment

      The treatment for acute zoster generally includes analgesics such as extra-strength acetaminophen and/or codeine 30–60 mg every 6 h when necessary (
      • Portenoy R.K.
      • Duma C.
      • Foley K.M.
      Acute herpetic and postherpetic neuralgia: clinical review and current management.
      ;
      • Watson C.P.N.
      ;
      • Bowsher D.
      Post-herpetic neuralgia in older patients: incidence and optimal treatment.
      ;
      • Kost R.G.
      • Straus S.E.
      Postherpetic neuralgia B pathogenesis, treatment, and prevention.
      ;
      • Gilden D.H.
      • Kleinschmidt-DeMasters B.K.
      • LaGuardia J.J.
      • Mahalingam R.
      • Cohrs R.
      Neurologic complications of the reactivation of varicella-zoster virus.
      ). Oral acyclovir (800 mg five times daily) or famciclovir (500 mg three times daily) has been reported to decrease new lesion formation and reduce acute pain (
      • Tyring S.
      • Nahlik J.
      • Cunningham A.
      • the Collaborative Famciclovir Herpes Zoster Study Group
      Efficacy and safety of famciclovir in the treatment of patients with herpes zoster: results of the first placebo-controlled study.
      ;
      • Wood M.J.
      • Johnson R.W.
      • McKendrick M.W.
      • Taylor J.
      • Mandal B.K.
      • Crooks J.
      A randomized trial of acyclovir for 7 days or 21 days with and without prednisolone for treatment of acute herpes zoster.
      ). Although the value of antiviral therapy, especially in immunocompetent individuals under age 50, remains to be definitively proven, our practice is to prescribe oral acyclovir or famciclovir for 7 d if any new skin lesions have developed within the past week. In addition, all patients with ophthalmic distribution zoster should receive antivirals for at least 7 d.
      For the treatment of PHN, more than 40 pharmacologic, antiseptic, and surgical therapies, including aspirin, hormones, narcotics, vitamins, immunoglobulins, radiotherapy, and various nerve blocks or excision, have been tried with limited success (
      • Watson C.P.N.
      ). Tricyclic antidepressants, such as amitriptyline or nortriptyline (25–75 mg at night), and the anticonvulsants carbamazepine (400–1200 mg daily) and phenytoin (300–400 mg daily), relieve pain in some PHN patients (
      • Kost R.G.
      • Straus S.E.
      Postherpetic neuralgia B pathogenesis, treatment, and prevention.
      ). A recent report describes dramatic improvement of PHN with gabapentin (neurontin), 300 mg three times daily (
      • Segal A.Z.
      • Rordorf G.
      Gabapentin as a novel treatment for postherpetic neuralgia.
      ), and a randomized, placebo-controlled trial demonstrated the effectiveness of gabapentin in PHN (
      • Rowbotham M.
      • Harden N.
      • Stacey B.
      • Bernstein P.
      • Magnus-Miller L.
      Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial.
      ). A short course of steroids, e.g., prednisone (40–60 mg daily for 3–5 d and sometimes longer), may reduce inflammation contributing to pain. Subcutaneous infusion of ketamine reduced PHN (
      • Eide K.
      • Stubhaug A.
      • Oye I.
      • Breivik H.
      Continuous subcutaneous administration of the N-methyl-D-aspartic acid (NMDA) receptor antagonist ketamine in the treatment of post-herpetic neuralgia.
      ), but was associated with intolerable side-effects. Topical aspirin in chloroform has been shown to relieve zoster pain and PHN (
      • King R.B.
      Topical aspirin in chloroform and the relief of pain due to herpes zoster and postherpetic neuralgia.
      ). Recently, the Food and Drug Administration approved a topical lidocaine patch for the treatment of PHN (
      • Galer B.S.
      • Rowbotham M.C.
      • Perander J.
      • Friedman E.
      Topical lidocaine patch relieves postherpetic neuralgia more effectively than a vehicle topical patch: results of an enriched enrollment study.
      ).
      The more serious CNS and PNS complications of VZV reactivation, including myelitis, encephalitis/arteritis, and radiculitis, are treated with intravenous acyclovir as soon as the diagnosis is suspected. Treatment may then be withdrawn if negative results are obtained for both anti-VZV antibody and VZV DNA from the CSF. Otherwise, treatment should be continued for 10–14 d. The rationale for such treatment is that VZV virions, antigen, and DNA are present in arteries of patients with large and small vessel encephalitis (
      • Fukumoto S.
      • Kinjo M.
      • Hokamura K.
      • Tanaka K.
      Subarachnoid hemorrhage and granulomatous angiitis of the basilar artery: demonstration of the varicella-zoster virus in the basilar artery lesions.
      ;
      • Gilden D.H.
      • Kleinschmidt-DeMasters B.K.
      • Wellish M.
      • Hedley-Whyte E.T.
      • Rentier B.
      • Mahalingam R.
      Varicella zoster virus, a cause of waxing and waning vasculitis. NEJM case 5–1995 revisited.
      ).

      Summary

      VZV reactivation is typically manifested as a zosteriform rash, and may be associated with prolonged pain after resolution of rash (PHN); however, several other CNS and PNS complications may occur after VZV reactivation, many of which may not be accompanied by rash. Therefore, neurologists, dermatologists, and other specialists should be aware of these possible complications, especially when caring for elderly and/or immunocompromised patients.

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