CLINICAL IMPLICATIONS OF BASIC NEUROSCIENCE RESEARCH

SECTION EDITOR: HASSAN M. FATHALLAH-SHAYKH, MD Neurological Complications of Virus Type 2

Joseph R. Berger, MD; Sidney Houff, MD, PhD

erpes simplex virus type 2 (HSV-2) infection is responsible for significant neurologi- cal morbidity, perhaps more than any other virus. Seroprevalence studies suggest that as many as 45 million people in the United States have been infected with HSV-2, and the estimated incidence of new infection is 1 million annually. Substantial num- bersH of these persons will manifest neurological symptoms that are generally, although not always, mild and self-limited. Despite a 50% genetic homology between HSV-1 and HSV-2, there are sig- nificant differences in the clinical manifestations of these 2 viruses. We herein review the neuro- logical complications of HSV-2 infection. Arch Neurol. 2008;65(5):596-600

The herpes viruses are responsible for sig- ready been infected by HSV-1. Primary nificant neurological morbidity. Three of HSV-2 infection in immunocompetent ado- the 8 human herpes virus types—herpes lescents and adults is usually asymptom- simplex virus type 1 (HSV-1), HSV-2, and atic, with most patients being unaware of —establish latency in their HSV-2 exposure. the peripheral sensory ganglia and per- sist in the host for a lifetime. Primary in- LATENCY AND REACTIVATION fection occurs at a mucocutaneous sur- face with retrograde transportation of the Neurons in the sacral ganglia tradition- virus to the peripheral sensory ganglia, ally have been considered to be the site of maintenance of the viral genome within HSV-2 latency. Examination of HSV-2 la- the peripheral sensory ganglia, and peri- tency using polymerase chain reaction odic reactivation with antegrade transmis- (PCR) techniques have demonstrated sion to the nerve endings and mucocuta- HSV-2 latency in ganglia throughout the neous surface. central nervous system (CNS) axis, al- beit at significantly lower frequencies than PRIMARY INFECTION in the sacral ganglia. Latency of HSV-2 has also been demonstrated to occur in tri- type 2–associated neu- geminal ganglia. The widespread latency rological may result from primary of HSV-2 suggests that the virus may reach infection or reactivation of latent HSV-2. ganglia far removed from the site of pri- Neurological disease after primary HSV-2 mary infection. The molecular mecha- infection is seen most often in neonates. Af- nisms underlying HSV latency are incom- ter the neonatal period, HSV-2 infection is pletely understood. principally, but not exclusively, acquired Although reactivation of latent HSV pri- through sexual activity. Primary HSV-2 in- marily has been studied in HSV-1– fection is delayed in most individuals until infected cells, it is likely that similar mecha- adolescence and early adulthood with the nisms underlie reactivation of HSV-2. advent of sexual activity. By the time of Latent HSV infection is reactivated by lo- HSV-2 infection, most individuals have al- cal and systemic stimuli. Current evi- dence suggests that the most plausible Author Affiliations: Department of Neurology, University of Kentucky College of mechanism for HSV reactivation is stimu- Medicine, Lexington. lation of latently infected cells through

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 pathways yet to be determined. The fected neonates are born to moth- tions due to HSV-1 and HSV-2. Dur- fate of neurons supporting replica- ers without symptoms or signs of ing the prodrome of tion of reactivated HSV remains un- genital herpes. Recent studies sug- and concomitant with the herpetic decided. Many patients with HSV-2 gest that as much as 30% of neona- eruption, affected patients experi- infection shed low levels of virus tal HSE is due to HSV-1. The risk of ence headache, neck stiffness, and continuously without demon- acquisition during a primary infec- low-grade fever. Back, buttock, peri- strated reactivation. tion with HSV-1 or HSV-2 is 50%. neal, and lower extremity pain may The risk of development of neona- be associated with urinary reten- EPIDEMIOLOGY tal HSE is reduced if a mother with tion and constipation. Analysis of primary HSV-2 genital herpetic in- CSF reveals a lymphocytic pleocy- Humans are the only known reser- fection is seropositive for HSV-1. tosis. Viral cultures of CSF may yield voir of HSV-2. The frequency of Risk factors for neonatal HSV dis- diagnostic findings, but PCR for HSV-2 seropositivity varies by popu- ease include first-episode maternal HSV-2 is recommended.6 For lation. An estimated 45 million per- infection in the third trimester, in- samples obtained after the acute in- sons in the United States have geni- vasive monitoring, delivery before a fection, measurement of intrathe- tal herpes infection,1 with new gestational age of 38 weeks, and ma- cal antibody levels for HSV-2 may be occurring at an estimated ternal age of less than 21 years.3 De- diagnostically valuable.7 rate of approximately 1 million per livery by cesarean section signifi- year. Approximately 85% to 90% of cantly reduces the risk of HSV RECURRENT ASEPTIC infections are unrecognized and acquisition.3 In mothers who are se- MENINGITIS therefore remain undiagnosed. Sero- ropositive for HSV-2 only, the risk positivity for HSV-2 correlates with to the neonate is less than 1%. Disease Description the number of sexual partners, the Dissemination to the CNS occurs age of sexual debut, increasing age, in 70% of all infected neonates and is Recurrent aseptic meningitis due to black or Hispanic race, female sex, most commonly heralded by the ap- HSV-2 may occur with or without and the presence of other sexually pearance of focal or generalized sei- symptomatic herpetic mucocutane- transmitted , including hu- zures. Skin lesions are observed in ous disorder. The manifestations of man immunodeficiency virus (HIV) 66%. Laboratory test results often this disorder are identical to that ob- infection.2 Despite the widespread show abnormal liver function and dis- served with primary genital herpes.8 adoption of safer sex methods with seminated intravascular coagula- In 1 series, recurrent meningitis has the advent of the AIDS pandemic, se- tion. The cranial magnetic reso- been observed in 19%8 to 42%9 of pa- roprevalence studies in the United nance images (MRIs) and computed tients who experience meningitis with States suggest that the frequency of tomograms initially show diffuse their first episode of genital herpes. HSV-2 infection is increasing.1 Sero- edema and later cerebral atrophy, cal- Headaches occur in as many as 15% prevalence rates for HSV-2 in the de- cifications, and cystic encephaloma- of patients with recurrent genital her- veloped world are not very different lacia. Electroencephalography shows pes.8 Anecdotal experience suggests than those of the United States. slow background and paroxysmal dis- that suppressive prophylactic therapy charges. Results of cerebrospinal fluid with acyclovir sodium, famciclovir, NEUROLOGICAL (CSF) analysis are remarkable for a and valacyclovir hydrochloride pre- COMPLICATIONS lymphocytic pleocytosis, increased vents these recurrences. protein levels, and PCR findings that Many of these cases were previ- Although HSV-1 has a predilection are positive for HSV-2. Neonates with ously diagnosed as Mollaret menin- for the development of encephali- HSE due to HSV-1 have a better prog- gitis, before the recognition that tis after intracerebral injection in the nosis than those with infection due HSV-2 may be causative.10 Confu- mouse model, HSV-2 generally to HSV-2.4 The latter group has a sion, focal neurological manifesta- causes meningitis. However, the me- higher frequency of , greater tions, and cranial neuropathies may ninges are not the only component CSF pleocytosis and protein concen- be observed. Analysis of CSF often of the CNS involved in HSV-2 in- tration, and more CNS structural dis- reveals a large mononuclear cell with fection. Virtually any part of the ease on radiographic images.4 an indistinct cytoplasm referred to neuraxis may be affected by this vi- as the Mollaret cell. Herpes sim- rus, including the retina, brain, ACUTE ASEPTIC MENINGITIS plex virus type 2 is not the only vi- brainstem, cranial nerves, spinal IN ADULTS rus responsible for Mollaret menin- cord, and nerve roots. gitis, and some authorities have Aseptic meningitis occurs in 36% of suggested that the term be re- NEONATAL HERPES women with primary HSV-2 geni- stricted to recurrent aseptic menin- SIMPLEX tal infection and 13% of men5;itre- gitis without an identifiable cause.7 sults in hospitalization for 6.4% of When HSV-2 infection is men- infected women and 1.6% of in- Report of a Case tioned, neonatal herpes simplex en- fected men.5 Aseptic meningitis is a cephalitis (HSE), a devastating dis- rare manifestation of primary HSV-1 A woman aged 33 years presented order, is the disease most commonly genital infection and a rare compli- with a 4-day history of intractable considered. Seventy percent of af- cation of recurrent genital infec- headache, photophobia, nausea, and

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 neck and back discomfort. She had 3 dicular, with associated limb numb- her second child 10 years earlier. She previous hospital admissions for a ness, paresthesias, and weakness. had her initial outbreak of genital similar disorder, the first and most se- Herpetic skin lesions may accom- herpes at that time. Results of the ex- vere of which occurred concomi- pany the neurological manifesta- amination showed minimal weak- tantly with her initial outbreak of tions.14 An MRI of the spine typi- ness of the extensor hallucis lon- genital herpes. Results of her exami- cally shows enlargement of the gus, normal reflexes, and decreased nation were remarkable for a low- lower cord or conus medullaris pinprick sensation in an L5 distri- grade fever and stiff neck. A contrast- with an increased signal on T2- bution. Titers of IgG HSV-2 anti- enhanced MRI of the brain yielded weighted images and contrast en- body were elevated in the blood. normal findings. Results of CSF analy- hancement of adjacent nerve roots. Lumbosacral spine MRI with and sis showed a white blood cell count without contrast showed normal of 56/µL (90% lymphocytes), a pro- HSV-2 RADICULOPATHY findings. Analysis of CSF showed 12 tein level of 66 mg/dL, and a glucose white blood cells (84% lympho- level of 54 mg/dL. Results of PCR Disease Description cytes) and a protein level of 54 mg/ were positive for HSV-2. Her symp- dL. Results of CSF PCR for HSV-2 toms resolved shortly after treat- In autopsy studies, 40% of sacral dor- were positive. Therapy consisting of ment with intravenous acyclovir, and sal root ganglia contain dormant acyclovir sodium, 800 mg 3 times no further episodes were observed HSV-2. Only 5% of these individu- daily, was initiated, with prompt during a suppressive regimen of daily als had recognized genital herpes in- resolution of her symptoms. While acyclovir in the ensuing 3 years. fection during life. This disorder is al- receiving daily acyclovir suppres- most always misdiagnosed unless it sive therapy, she had no further re- ADULT HSV-2 ENCEPHALITIS occurs concomitantly with the ini- currences. AND MENINGOENCEPHALITIS tial outbreak of genital herpes. Ob- taining a history of recurrent genital CRANIAL NEUROPATHY Herpes simplex virus type 2 ac- herpes outbreaks occurring contem- counts for 1.6% to and 6.5% of all HSE poraneously with the radicular symp- Although it has been argued that the in adults.11 It is typically observed in toms is very helpful diagnostically. presence of detectable viral DNA in immunosuppressed individuals. Un- Unfortunately, the patient may be un- the geniculate ganglia of most hu- like HSV-1, HSV-2 affects mesial aware of the infection and the phy- mans cannot explain the annual in- temporal or orbitofrontal lobes less of- sician may be reluctant to inquire cidence of Bell palsy of 20 to 30 per ten and may demonstrate a predilec- about sexually transmitted disease. 100 000, there has been increasing tion for the brainstem. Herpes sim- Radiculopathy caused by HSV-2 in- acceptance of HSV-1 and varicella plex encephalitis due to HSV-2 may fection typically affects the lumbar or zoster virus as the cause of Bell occur without meningitic features. sacral nerve roots and is often recur- palsy.18 Other infectious diseases Neurological manifestations may in- rent. In addition to radicular pain, have been implicated as well. Al- clude altered level of consciousness, paresthesias, urinary retention, con- though sites of viral latency differ be- cranial neuropathies, hemiparesis, stipation, anogenital discomfort, and tween HSV-1 and HSV-2, likely and hemisensory loss.12 In contrast to leg weakness may be observed. Al- owing to their latency activity tran- HSE due to HSV-1, which typically though there are few descriptions of scripts, HSV-2 can certainly be har- demonstrates progressive deteriora- HSV-2 radiculitis and radiculomy- bored by the trigeminal ganglia. In tion, a fluctuating course may be ob- elitis,15-17 nerve root or lower spinal a study of more than 1000 people, served.13 The MRI may show normal cord edema, enlargement, and hy- 3.2% shed HSV-2 in their saliva on findings,13 nonspecific white matter perintensity on T2-weighted MRI and at least 1 occasion.19 Bell palsy has lesions, or lesions of orbitofrontal and contrast enhancement are antici- been reported after the discontinu- mesial temporal lobes suggestive pated; however, the lumbosacral MRI ation of acyclovir therapy in a pa- of HSE due to HSV-1. These lesions may show normal findings.16 The dis- tient being treated for HSE due to are best seen on T2-weighted or order is typically self-limited, resolv- HSV-2.12 fluid-attenuated inversion recovery ing after days or weeks, but recov- images.12 ery appears to be hastened by the use ACUTE RETINAL NECROSIS of antiviral medications.15 HSV-2 ASCENDING Acute retinal necrosis is heralded by Report of a Case red eye, periorbital pain, and im- Thoracic or lumbosacral ascending paired visual acuity. Examination re- myelitis is also seen with HSV-2 in- A woman aged 43 years presented sults will show episcleritis or scleri- fection but almost exclusively in im- with a burning, shooting pain radi- tis, keratic precipitates, retinal munocompromised patients, particu- ating down the back of her left leg vasculitis, and necrosis with retinal larly those with HIV infection. The and a sense of weakness in the leg detachment. Typically, this sight- lesions may be necrotizing and, if so, of 2 months’ duration. Driving and threatening disorder has a bimodal have a poor prognosis. Recurrent dis- climbing stairs were difficult. She age distribution, with varicella zos- ease also has been described.14 The commented on a similar, self- ter virus and HSV-1 infections affect- clinical presentation is character- limited discomfort occurring with ing older patients and HSV-2 infec- ized by pain, often anogenital or ra- variable frequency since the birth of tion affecting patients with a median

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 age of 20 years. Acute retinal necro- says for HSV antibodies are still use- other HSV-2–related neurological dis- sis may occur in association with ful in several settings. A study of ease, which suggests that acyclovir so- HSV-2 meningoencephalitis. neonatal HSV showed 40% of CSF dium at a dosage of 5 to 10 mg/kg 3 cultures were positive.23 Viral cul- times daily is sufficient for the treat- HSV-2 IN THE SETTING tures may be of more limited value in ment of HSV-2 meningitis and that a OF HIV INFECTION HSV-2 recurrences. Serological as- dosage of 10 mg/kg 3 times daily is says have limited value in the diag- sufficient in myelitis and radiculitis. An association between HSV-2 and nosis of HSV-2–associated neurologi- In patients with HSV-2 myelitis, the HIV has been recognized since the cal diseases. Although several addition of high-dose intravenous glu- onset of the HIV/AIDS pandemic. serological assays will differentiate be- cocorticosteroid therapy to antiviral Recent studies have demonstrated tween HSV-2 and HSV-1, the delay in therapy has been suggested to de- synergism between HSV-2 and HIV. the development of intrathecal anti- crease the risk of the development of Infection with HSV-2 increases the bodies limits their usefulness. Type- an ascending myelitis. risk of HIV acquisition 2- to 4-fold specific serological testing can de- Acyclovir-resistant HSV strains compared with patients without tect prior infection in most HSV-2– have been isolated from immuno- HSV-2 infection,20 increases the risk infected individuals who are unaware competent and, more commonly, of transmitting HIV to partners, and of prior infection. Two serological immunocompromised patients. accelerates the progression of HIV methods have been validated for the Increasing the dose of acyclovir infection to AIDS. Reduction of diagnosis of HSE. The HSV-specific for the treatment of drug-resistant HSV-2 shedding with the use of sup- antibody index and HSV-specific im- HSV infections is rarely successful pressive therapy with valacyclovir re- munoblotting of oligoclonal IgG re- because mutations in the thymi- sults in a reduction in HIV-1 RNA quire comparison of HSV-specific an- dine kinase gene are responsible levels.21,22 Infection with HIV, in tibody reactivity in CSF and serum to for drug resistance. Successful turn, alters the natural history of ensure that serum HSV antibodies treatment with valacyclovir of re- HSV-2 infection. Neurological dis- have not reached the CSF by means sistant HSE due to HSV-2 has been eases associated with HSV-2 may ap- of a sink mechanism. reported.13 Acyclovir-resistant HSV pear early in the course of HIV/ responds to foscarnet sodium and, AIDS. Associated neurological TREATMENT possibly, cidofovir. diseases reported in HIV-infected pa- tients include HSV-2 lumbosacral ra- phosphate was the first Accepted for Publication: April 22, diculoneuropathy, transverse my- agent to demonstrate efficacy in HSE. 2007. elitis, and encephalitis. Two large subsequent studies dem- Correspondence: Joseph R. Berger, onstrated the superiority of acyclo- MD, Department of Neurology, Uni- DIAGNOSIS vir, and it has been widely adopted as versity of Kentucky College of Medi- standard therapy.24,25 The current rec- cine, Kentucky Clinic Room L-445, Polymerase chain reaction assays are ommendation for HSE in adults and 740 S Limestone St, Lexington, KY rapid, sensitive, and specific for children older than 3 months is in- 40536-0284 ([email protected]). HSV-2 and HSV-1 and constitute the travenous acyclovir sodium at a dos- Author Contributions: Study con- criterion standard for the diagnosis age of 10 mg/kg every 8 hours for 14 cept and design: Berger and Houff. of HSV infections of the nervous sys- to 21 days. A clinical trial of oral vala- Analysis and interpretation of data: tem. The development of real-time cyclovir after intravenous acyclovir for Berger. Drafting of the manuscript: PCR and methods for identifying 14 to 21 days is currently being con- Berger and Houff. Critical revision of HSV-1 and HSV-2 allow rapid iden- ducted to determine whether pro- the manuscript for important intellec- tification of HSV in CSF, serum, and longed antiviral therapy will im- tual content: Berger. Administrative, other tissues. prove the outcome and decrease the technical, and material support: Houff. The sensitivity and specificity of recurrence rate. Age, level of con- Study supervision: Berger. CSF PCR for HSE due to HSV-1 or sciousness at presentation, duration Financial Disclosure: None re- HSV-2 infection exceeds 90% in most of encephalitis, and HSV viral load all ported. studies for children and adults. Poly- affect the treatment of HSE. In neo- merase chain reaction analysis has nates with suspected or proved neo- REFERENCES been helpful in detecting HSV in per- natal HSE, acyclovir sodium is rec- haps 15% to 20% of patients with mild ommended, with a regimen of 20 1. 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The Archives launched a new ARCHIVES Express section in the September 2000 issue. This section will enable the editors to publish highly selected papers within approxi- mately 2 months of acceptance. We will consider only the most significant research, the top 1% of accepted pa- pers, on new important insights into the pathogenesis of disease, brain function, and therapy. We encourage authors to send their most exceptional clinical or basic research, designating in the cover letter a request for ex- pedited Archives Express review. We look forward to pub- lishing your important new research in this accelerated manner. Roger N. Rosenberg, MD

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