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Neurological Complications of Herpes Simplex Virus Type 2 Infection

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Neurological Complications of Herpes Simplex Virus Type 2 Infection CLINICAL IMPLICATIONS OF BASIC NEUROSCIENCE RESEARCH SECTION EDITOR: HASSAN M. FATHALLAH-SHAYKH, MD Neurological Complications of Herpes Simplex Virus Type 2 Infection 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- Hbers 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 varicella zoster virus—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- Herpes simplex virus type 2–associated neu- geminal ganglia. The widespread latency rological disease 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 (REPRINTED) ARCH NEUROL / VOL 65 (NO. 5), MAY 2008 WWW.ARCHNEUROL.COM 596 ©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 genital herpes 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 infections 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 diseases, 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 seizures, 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 ENCEPHALITIS 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 (REPRINTED) ARCH NEUROL / VOL 65 (NO. 5), MAY 2008 WWW.ARCHNEUROL.COM 597 ©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.
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