Genital herpes: neurologic complications …

Marylou V Solbrig MD

Infectious Disorders

Updated 11.15.2024
Released 06.27.1995
Expires For CME 11.15.2027

Genital herpes: neurologic complications

Author: Marylou V Solbrig MD

See Contributor Disclosures

Editor: John E Greenlee MD

Genital herpes: neurologic complications

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Introduction

Overview

Genital herpes viruses are important causes of CNS infection, regardless of immune status. In this article, the neurologic complications of genital herpes as herpes simplex virus type 1 and type 2 infections in adults and neonates are reviewed, including disease in patients with heritable, acquired, or treatment-acquired immunodeficiencies. The recommendations for acute and suppressive treatments from the International Herpes Management Forum are summarized, and illustrative cases of HSV-2 lumbosacral radiculomyelitis in an immunocompromised patient and HSV-2 meningoencephalitis in a child are presented.

This update reports on heritable risk factors for HSV infection susceptibility and severity, expands the list of target antigens for herpes simplex encephalitis-triggered autoimmune encephalitis, and examines the newest evidence linking herpes simplex virus infection and Alzheimer disease.

Key points

	• HSV-1 and HSV-2 are prevalent viruses that can establish lifelong infections and episodic reactivation. As with all herpesviruses, HSV-2 performs two distinct genetic programs, lytic replication and latency, to produce primary and recurrent infections.
	• In 2018, the Centers for Disease Control and Prevention estimated there were 572,000 new genital herpes infections and 18.6 million existing cases in the United States (126). Globally, there are approximately 500 million individuals living with genital herpes (247).
	• Estimates of 60% to 78% of new genital herpes cases in the United States are attributed to HSV-1 (13), whereas most cases of recurrent genital infection are due to HSV-2.
	• Estimates of HSV-2 seroprevalence (persons 14 to 49 years) in the United States is 13% (42).
	• The clinical presentation of HSV-2 infection of the CNS in adults is mainly meningitis but can be encephalitis, myelitis, and lumbosacral radiculitis.
	• When a pathogen is detected, HSV-2 is one of the leading causes of aseptic meningitis in adults.
	• Recurring lymphocytic meningitis is most often a reactivation of HSV-2.
	• In immunocompetent adults, HSV-2 is responsible for up to 10% of herpes simplex virus encephalitis cases (estimates range from 2% to 10%), with the rest due to HSV-1.
	• Ever-increasing HSV-1 genital disease contributes to the enduring HSV-1 disease burden in the United States.

Historical note and terminology

“Throughout nature, infection without disease is the rule rather than the exception” (65) is a statement appropriate to certain primary, latent, and recurrent herpetic syndromes. The term "herpes" was first used in ancient Greece for migratory (creeping or crawling) skin lesions. The ancient Greek historian Herodotus labeled mouth and lip ulcers during fever "herpes febrilis" (153; 246). Shakespeare referred to recurrent herpes simplex virus labial lesions in Romeo and Juliet (248). In the 1700s, the French royal court physician introduced genital herpes infections in the medical literature (09).

Transmissibility was established by the passage of material from human lip and genital lesions to the cornea or abraded skin of rabbits. CNS transmission was demonstrated when Goodpasture showed that material from herpes labialis lesions inoculated onto scarified rabbit cornea produced encephalitis (88). Herpes simplex virus was isolated from a case of encephalitis in 1941 (212), and two antigenic types of herpes simplex virus were recognized in 1968 (167). It is estimated that HSV-1 and HSV-2 diverged 6 to 8 million years ago (242). Viral typing distinguished HSV-1, which was mainly responsible for infections “above the belt,” from HSV-2, primarily responsible for infections “below the belt.” Later studies, however, have shown that either virus can infect the mouth, genital tract, or brain.

At present, eight herpesviruses are known causes of human disease. They are herpes simplex virus types 1 and 2, varicella-zoster virus, cytomegalovirus, human herpesvirus-6 and -7, Epstein-Barr virus, and Kaposi sarcoma virus (human herpesvirus-8). HSV-2 causes a lifelong genital viral infection characterized by high rates of clinical and subclinical reactivation in genital mucosa and risk of sexual transmission. Although HSV-2-associated syndromes such as meningitis may have been under-recognized in the past, now widespread use of polymerase chain reaction amplification of herpes simplex virus DNA has expanded the recognized spectrum of HSV-2-related infections of the CNS. Advances in laboratory detection, together with epidemiologic and pathogenesis studies, have enhanced the understanding of infection acquisition, natural history of disease, and strategies for prevention.

Over the last 20 years, while estimated seroprevalence of HSV-1 and HSV-2 has been declining in some groups, specific populations remain disproportionally affected by HSV infection. The 2015-2016 National Health and Nutrition Examination Survey of persons aged 14 to 49 years reported the highest seroprevalence of HSV-1 to be in Mexican American (72%) and non-Hispanic Black (59%) persons compared with the general United States population (48%) (150). Estimated seroprevalence of HSV-2 in US non-Hispanic Black adolescents and adults (35%) is nearly three times that in the general US population (12% to 13%). Estimated seroprevalence of HSV-2 in pregnant individuals is 22% (231).

Clinical manifestations

Presentation and course

	• Herpesviruses perform two distinct genetic programs, lytic replication and latency, to produce primary and recurrent infections.
	• Herpes simplex virus infections can be asymptomatic, mild, moderate, or life-threatening.
	• In adults, primary genital disease may be accompanied by meningitis, meningoencephalitis, myelitis, and lumbosacral radiculitis.
	• Thereafter, patients can have concurrent or separate episodes of mucocutaneous and neurologic symptoms, have only neurologic recurrences, or have only mucocutaneous recurrences.
	• In neonates, when genital herpes infection is transmitted during or after birth, infection of the infant may appear as skin, eye, and mouth disease only; as CNS disease with or without skin, eye, and mouth disease; or as disseminated disease.

Herpes simplex virus has biological properties - neurovirulence and latency - that affect human disease. The virus can cause disease by direct CNS invasion and replication. Alternatively, this virus can infect sensory ganglia, become latent, and provide a reservoir for reactivation with recurrent disease. A balanced household survey from 1999 to 2004 estimated that 17% of U.S. adults were infected with HSV-2 (252) and 13% of persons aged 14 to 49 years in 2016 (42).

Acute primary infection. Primary HSV-2 infections in adults, generally acquired through sexual contact, localize initially to the genital regions of both men and women (54). Infection is associated with pain, itching, dysuria, vaginal or urethral discharge, and tender inguinal adenopathy; vesicular, ulcerative, and then crusting lesions develop over the external genitalia. Symptoms including fever, headache, malaise, or signs of meningitis, encephalitis, or lumbosacral radiculitis can accompany infection. Among adolescent Americans, in whom the seroprevalence of HSV-1 has been declining over the last 30 years, the lack of protective HSV-1 antibodies when becoming sexually active has meant an increased frequency of HSV-1 genital herpes acquired from oral-genital sex practices. As a result, in some U.S. populations, HSV-1 has developed into a more common cause of genital herpes than HSV-2 (85). At present, primary HSV-1 accounts for the majority of cases of first episode of genital herpes in the U.S. and Northern Europe.

Meningitis. Symptoms of meningitis during primary genital herpes are reported in 36% of women and 11% of men (51). The average time between developing genital lesions and hospitalization for meningitis is 9.3 days (51). Although patients have fever, meningeal signs, and lymphocytic pleocytosis, the course of meningitis is usually benign. Exceptions are cases of meningoencephalitis, chronic meningitis, and recurrent aseptic meningitis.

The history and association of genital lesions and HSV-2 meningitis have varied across studies. Early studies showed a history of genital lesions in about 40% of patients with HSV-2 meningitis and concurrent outbreaks in up to 86% (228; 22), and studies show approximately 4% of patients having genital outbreaks at the time of meningitis (180; 178; 156).

Meningoencephalitis. In immunocompetent adults, about 10% of cases of herpes simplex encephalitis are caused by HSV-2, with the rest due to type 1 (10). Cases of HSV-2 encephalitis are more likely to reflect primary infection than reactivation (10), with host immunity playing a role in disease expression in some cases. Subsequent studies have revised downward percentages of HSV-2 encephalitis cases, with estimates of 2% to 6.5% of cases of herpes simplex encephalitis due to HSV-2 in Western countries (19; 73).

As more patients with herpes simplex encephalitis are hospitalized early in their course, there are increasing reports of atypical presentations, particularly vascular events. Examples include HSV-2 vasculitis-induced thalamic hemorrhage in a 72-year-old man (257) and HSV-2 meningitis and vasculopathy producing hemorrhagic and ischemic stroke in a 57-year-old woman, improving after treatment with acyclovir and steroids (213). HSV-2 meningitis or encephalitis complicated by ischemic stroke has been reported (263; 258), and stroke-like presentations of aphasic disorders without ischemic MRI changes have occurred with HSV-2 encephalitis (90).

Meningoencephalitis (immunocompromised or immunosuppressed hosts), HSV-2 meningoencephalitis with CSF pleocytosis, and orbitofrontal and mesial temporal lobe involvement, typical of HSV-1, are recognized in adult AIDS patients (19; 181). Numerous other atypical presentations of herpes HSV-2 encephalitis in the immunocompromised host include cases with behavior abnormalities without fever, headache, or CSF pleocytosis (94), with normal or nonspecific MRI white matter lesions (19), with subacute but progressively worsening course (198), or with severe meningitis (160). Risk factors in cancer patients are recent craniotomy, radiotherapy to the brain, chemotherapy, and corticosteroid use (91).

Patients immunocompromised by HIV, bone marrow transplant, rheumatoid arthritis treatment, or TNF-alpha inhibitors are among adult patients with brainstem encephalitis caused by primary HSV-2 infection, but most cases have been in immunocompetent adults (223). Overall, an estimated 21% of HSV brainstem encephalitis cases are HSV-2, and 79% are HSV-1, with the most common clinical features being neuro-ophthalmologic and cranial nerve abnormalities (142).

Generally, sporadic herpes simplex encephalitis as temporal lobe encephalitis has not been overly associated with immunodeficiency, but some pediatric herpes simplex encephalitis cases have been linked to interferon-signaling defects (260; refer to section 6, “Epidemiology-Host Genetics” for full discussion) and adult HSV-2 herpes simplex encephalitis to TNF-alpha inhibitor (30) or low-dose methotrexate use (148; refer to section 18, “Special considerations-Medication use” for complete list of immunomodulatory drugs).

For immunocompetent patients, perioperative stress and steroids, factors contributing to immunosuppression, have been noted as risk factors in HSV-2 encephalitis after craniotomy for particular types of surgeries. Most cases involve surgeries in frontotemporal areas, pituitary gland in proximity to the trigeminal ganglion, or fifth cranial nerve decompression (18).

CNS bacterial-herpes coinfection has been recorded in a 67-year-old as pneumococcal meningitis and HSV-1 reactivation and encephalitis (72). Several cases of HSV-1 or-2 encephalitis have occurred within weeks of COVID-19 diagnosis (96). Given that a septic patient can develop a local productive infection or viremia with a herpesvirus released from latency, acute bacterial meningitis or other severe infections in adults can trigger not only recognizable cutaneous herpes but also CNS HSV-2 infections (240).

Chronic meningoencephalitis. Chronic, active granulomatous HSV-2 encephalitis has been reported in an immunocompetent 8-year-old who was infected as a neonate (34) and in a 66-year-old immunocompetent man with 6 months of refractory posterior uveitis, 1 month of difficulties with memory and orientation, and right parietal lesions (170).

Lumbosacral radiculitis. HSV-2 sacral radiculitis (Elsberg syndrome) is characterized by acute urinary retention and lumbosacral radicular dysfunction: constipation, erectile dysfunction, anogenital pain, paresthesias, loss of sensation, or flaccid paresis of leg muscles. HSV-2 has been so frequently implicated as causing a self-limited syndrome of acute urinary retention, root or cord dysfunction, and CSF pleocytosis that matches the descriptions of Elsberg more than 70 years ago (70) that now HSV-2 sacral radiculitis and Elsberg syndrome have become almost synonymous.

Lumbosacral radiculitis during primary genital herpes infection is reported in 2% of patients (51). Conus medullaris or lower thoracic cord signs may also accompany infection. Diabetes, HIV infection, or malignancy increase the risk of developing ascending myelitis (249).

Reactivation and recurrent disease. Recurrent HSV-2 infection due to latent genital infection with reactivation from sacral ganglia sites of HSV-2 latency can be either symptomatic or asymptomatic. The estimated recurrence rate of HSV-2 infection is an average of 0.3 to 0.4 times per month (51), and several studies have reported a frequency of recurrence as high as 60% (44; 01). Recurrence may be associated with a shorter duration of viral shedding and fewer lesions.

Patients can have concurrent or separate episodes of mucocutaneous and neurologic symptoms, have only neurologic recurrences, or have only mucocutaneous recurrences. Associated genital herpes is found in a majority of patients with primary meningitis yet absent in nearly all patients with secondary meningitis, perhaps leading to underdiagnoses. An estimated 60% of patients with polymerase chain reaction-confirmed recurrent aseptic herpes simplex virus meningitis had no previous history of genital herpes (227).

The more severe the primary HSV-2 infection, the more likely and frequent the recurrent episodes of the disease (51; 132). Neurologic syndromes that accompany reactivation of latent herpesvirus can be similar to those that developed during initial infection in that individual. An estimated 20% of patients with an initial episode of HSV-2 meningitis will have recurrences (22). Recurrences, such as meningitis or self-limited seizures, cranial nerve palsies, or pathological reflexes, tend to disappear after several episodes over a period of years, but recurrence has been documented up to 28 years afterward (228). Most (95%) cases of recurrent aseptic meningitis, previously designated Mollaret meningitis (episodes of fever, headache, and stiff neck lasting 2 to 5 days), are caused by HSV-2. PCR is most sensitive in detecting HSV-2 DNA from CSF if sampled 2 to 5 days after symptom onset (115). Diagnosis of Mollaret meningitis is used for cases of recurrent aseptic meningitis of unknown etiology.

Lumbosacral radicular dysfunction with acute or subacute urinary retention can develop not only with initial genital herpes but also due to the reactivation of a latent HSV-2 virus. Skin lesions need not be present for HSV-2-induced acute urinary retention.

Up to 50% of patients with recurrent genital herpes infections can have a prodrome consisting of local hyperesthesias and dysesthesias, which precedes the appearance of genital vesicles by several hours or days, or pain radiating down into the buttocks and hips, known as “sacral dermatomal neuralgia” (51). Lumbosacral HSV-2 syndromes include an acute sensory neuropathy with delayed sensory nerve conduction velocities (209), stocking-glove distribution numbness and paresthesias, or unilateral sciatica (162). Remission is mostly complete in milder cases after 1 to several weeks, and antiviral treatment may shorten the symptomatic period. Additionally, lumbosacral root involvement may complicate or follow recurrent HSV-2 meningitis (22). In HIV-1-positive patients, herpetic lumbosacral radiculitis can be seen fairly early after AIDS onset, can occur as an immune reconstitution syndrome, or can even lead to a new diagnosis of AIDS (255).

In others, recurrent, difficult-to-treat, or chronic genital herpes may indicate other types of immune dysregulation. For example, persistent genital herpes can signify underlying thymoma in a myasthenic patient years after transsternal thymectomy (197).

Over 40% of septic patients develop viremia with multiple viruses, including herpes family viruses released from latency (236). Investigation of herpesvirus DNA in CSF of patients with tick-borne encephalitis or enteroviral meningoencephalitis revealed two instances of HSV-2 with enterovirus meningitis, interpreted as bystander reactivation (130). COVID-19 infection causing HSV-1 reactivation resulted in encephalitis in two cases and encephalomyelitis in another (97) and was associated with eight cases HSV-1 or HSV-2 encephalitis during or within 6 weeks of infection (96). Conceivably, Herpesviridae reactivation may have a role in the symptoms of long-haul COVID-19. A switch to the active state due to SARS-CoV-2 persistence or aberrant immune function may link to long-term disease.

In one paraneoplastic “encephalitis,” in which CNS inflammation caused by anti-Ri (ANNA-2) antibodies was associated with small cell cancer of the lung, HSV-2 DNA was found in CSF. In this case, HSV-2 was judged as reactivation and interpreted as an epiphenomenon of the inflammatory disease process (175).

Autoimmune encephalitis following HSV encephalitis. When herpes simplex virus encephalitis (causative agent HSV-1 in 90% of cases, HSV-2 in 10% of cases) fails to respond to antiviral treatment, or when there is recurrent disease despite early appropriate treatment, autoantibodies may be the cause (60; 234; 214). In an approximately 5-week time frame from treatment, 27% of patients with herpes simplex encephalitis develop an immune response to NMDA and other neuronal surface proteins, and another 30% of patients develop autoantibodies in serum or CSF without symptoms (08; 215).

Cranial neuritis. Although the varicella-zoster virus has been the herpesvirus best known for an association with optic neuritis, optic neuritis has been reported with symptomatic HSV-2 genital infection (207), and HSV-1 or 2 DNA can be found in the CSF of ON patients (179).

Bell palsy. Low- to moderate-quality evidence from Cochrane reviews shows a benefit from the combination of herpes antivirals with corticosteroids compared to corticosteroids alone for treating Bell palsy (81; 101).

Genital herpes simplex virus type 1 in adults. Although historically most herpetic genital infections had been caused by HSV-2, a larger proportion is now occurring due to HSV-1 (109). Genital HSV-1 infections tend to be less severe and less likely to recur. A single case of recurrent myelitis attributed to herpes simplex virus infection was found to be caused by type 1 (208).

HSV-1 and HSV-2 have approximately 70% genomic homology, with HSV-1 thought to be the older human pathogen with a more stable genome than HSV-2. Nevertheless, HSV-1 DNA segments have been found in genital HSV-2 strains, establishing the possibility that cellular coinfection with HSV-1 and HSV-2 yields viable interspecies recombinants (184).

Dual strain infections. Investigations of multiple strain herpes simplex virus re-infection have shown dual strain HSV-2 genital infections with novel variants to be more frequent in HIV-positive patients and in people from Africa (136). Except for these groups, dual infection has been rare; therefore, naturally occurring immunity to HSV-2 may protect against a second strain in others (184).

Genital herpes zoster. Unilateral penile vesicular lesions due to varicella zoster virus were reported in an HIV-positive patient (143). Before that case, varicella-zoster virus-positive genital specimens had been reported from two laboratories. Three percent of genital herpetic lesions tested in a lab in Australia were PCR-confirmed varicella-zoster virus in 2003 (27); and in a newer New York study, varicella zoster virus was detected in male and female genital specimens by multiplex PCR assay (92).

Neonatal disease. Neonatal herpes simplex virus infection most often occurs during delivery, although infection can also be acquired in utero or postpartum during the first 4 weeks of life. Acquisition of primary infection in late pregnancy, prolonged rupture of membranes (greater than 6 hours), or use of fetal scalp monitors increase the risk of transmission. HSV-2 infection in neonates infected during or after birth may have skin, eye, and mouth disease only; CNS disease with or without skin, eye, and mouth disease involvement; or disseminated disease. Acquisition of primary infection during late pregnancy is associated with a 30% to 50% risk of transmission, and the risk of vertical transmission is higher with HSV-1 than with HSV-2 (85).

HSV-2 disease occurs as skin, eye, and mouth disease (vesicles and keratoconjunctivitis), tremors, poor feeding, temperature instability, bulging fontanelle, and pyramidal signs. Two weeks of age is the most likely time for neonatal HSV encephalitis, with frequency declining by the second month of life (58). Untreated with antivirals, 75% of babies with skin, eye, and mouth infections progress to CNS or disseminated disease (245; 118). Cutaneous vesicles are absent at presentation in about 40% of CNS cases. A history of genital lesions in the mother or her sexual partner is important in implicating HSV-2 as a cause of encephalitis in the newborn.

Congenital disease. Five percent of neonatal herpes infections are congenital herpes simplex infections acquired in utero by transplacental spread. The congenital form of disease is characterized by encephalomalacia, ventricular enlargement, calcifications, microcephaly, and microphthalmia and is recognized at the time of birth.

Acute retinal necrosis (ARN). Acute retinal necrosis caused by HSV-2 is recognized as the most common cause of acute retinal necrosis in children and adolescents. It may accompany neonatal HSV-2 encephalitis, meningitis, or otherwise asymptomatic neonatal infection. Cases of HSV-2 acute retinal necrosis can also occur many years after either symptomatic or subclinical neonatal infections (93). The eye is red, vision is blurred, and confluent white patches in the peripheral retina are seen on funduscopic exam. The opposite eye is affected in about one third of patients, but disease in the second eye may lag by months to several years (131). Specific diagnostic criteria include one or more foci of retinal necrosis, rapid progression, circumferential spread, occlusive vasculopathy, and inflammation in the vitreous and anterior chamber (95). Early antiviral therapy limits the extent of necrosis and decreases the risk of retinal detachment and involvement of the opposite eye.

Prognosis and complications

An episode of HSV-2 meningitis is usually self-limited. In a series of patients followed after their initial episode of HSV-2 meningitis, symptoms of dysesthesias, paresthesias, headaches, concentration difficulties, and urinary retention (although common after the acute infection) had uniformly resolved within 6 months of the original illness (21).

Similarly, most episodes of recurrent aseptic meningitis are self-limited and resolve without long-term neurologic sequelae; however, one study found almost half of 40 consecutive patients with meningitis or myleoradiculitis would have suspected neurologic recurrences (meningitis, myelitis, radiculitis, headache, or diffuse neurologic complaints) during the first year (11).

The natural history of lumbosacral sensory and autonomic symptoms that may accompany genital and anorectal HSV-2 infections is also resolution over a period of several days to several weeks (51; 87), although most cases encountered today receive antiviral treatment (253; 69; 255). Ascending myelitis has a variable course and prognosis. Typically, patients have longer periods of disability, and although a few have recovered, others have been fatal (249; 77; 169). The factors responsible for variation in HSV-2 severity in apparently immunocompetent persons are incompletely understood. Host polymorphisms in innate immune pathways have been associated with severe or fatal HSV-1 encephalitis, eg, NEMO NFKappaB essential modulator deficiency (173), UNC-93B deficiency, a gene encoding an ER transmembrane involved in toll signaling (40), TLR3 deficiency (260), and others (124). These host genetic results raise the possibility of a role for manipulations of innate immunity in infection control. For example, children with a heritable defect in IFN-a production or IFN-a response and herpes simplex encephalitis could benefit from a combination of acyclovir and IFN-a2b (189).

Like host genetics, the role of viral polymorphisms in the severity of herpes simplex virus CNS disease is incompletely understood. Mechanisms leading to latency and reactivation, which viral and host factors control these effects, and which viral genes confer neurotropism are research topics. Further investigations, derived from new knowledge and understanding of CNS disease as inflammatory disease, may uncover neurovirulent phenotypes defined by strain-specific neuroinflammatory patterns independent of host genetics (262).

HSV and Alzheimer disease. In the elderly, HSV-1 infection in the brain in combination with the apoE4 genotype has been reported to increase the risk of Alzheimer disease, and apoE4 genotype has been reported to increase risk of HSV-1 cold sores (105; 108). The different isoforms of APOE protein (types 2, 3, 4) might have differential effects on HSV-1 cell entry (106). HSV-1 as oral herpes and -2 as genital herpes can trigger amyloid-beta protein aggregation (107), and HSV-1 DNA is present in amyloid plaques (61).

Epidemiologic studies from Asia, Europe, and North America report that antiviral treatment for herpes simplex virus can reduce the risk for Alzheimer disease and other dementias.

Using a national health database from Taiwan, investigators evaluated the risk of developing dementia in individuals with a history of symptomatic HSV infection and assessed whether antiviral medications could reduce the risk. The investigators retrospectively identified patients 50 years and older who were newly diagnosed with herpes simplex virus infection in 2000 as having genital or non-genital infection (therefore, both HSV-1 and -2) and compared the HSV-infected group to a control group with no herpes simplex virus infection during the index year. The HSV group had an almost three-fold higher risk of any type of dementia (Alzheimer disease, vascular, and other) after 10 years, but antiherpetic medications could reduce the risk of developing dementia by nearly 90.8%. Longer therapy, greater than 30 days, had better outcomes. Average treatment times in days in the longer-treated groups were: acyclovir 193.93 + 273.71, famciclovir 165.56 + 220.76, ganciclovir 186.87 + 249.95, valaciclovir 149.38 + 223.29, valganciclovir 154.82 + 208.97 (229).

A cohort study of symptomatic HSV-1 or -2 infection and risk of dementia in United States veterans did not find HSV infection to be associated with increased risk of dementia, but, like the Taiwan study, did find that antiherpetic antiviral medication was associated with a protective effect against dementia. Similarly, longer durations of coverage were associated with greater reductions in risk. Any antiherpetic treatment was associated with a 25% reduced risk of dementia, and greater than 1 year of coverage had a 43% risk of dementia (256).

The VALAD trial (valacyclovir treatment of Alzheimer disease) repurposes valacyclovir as an anti-Alzheimer disease drug for treatment of patients with mild Alzheimer disease who have serum antibodies for HSV-1 or -2 (62). In a 78-week trial, patients receive valacyclovir dose-titrated from 2 g to a target dose of 4 g orally daily, to slow cognitive decline. Cognitive, functional testing, neuroimaging, and ApoE genotype are recorded (62). A small VALZ-pilot performed in Sweden (a phase 2 study of 4 weeks looking at high-dose valacyclovir in persons older than 65 years with early-stage Alzheimer disease, anti-HSV IgG, and apoE4 genotype for effects on MMSE and CSF biomarkers) showed a short valacyclovir regimen to be feasible, tolerable, and safe (241).

HSV and autoimmunity. There are increasing reports of herpes infections associated with para- and postviral autoantibody syndromes, along with greater attention toward their pathogenesis and treatment. A 41-year-old man with genital herpes developed bilateral optic neuritis, along with thoraco-lumbar allodynia, urinary retention, and abnormal meningeal and dorsal root ganglia enhancement on MRI, due to myelin oligodendrocyte glycoprotein antibodies (171). An adult with IgM antibodies to herpes simplex virus had opsoclonus-myoclonus (46). Possible pathogenic mechanisms include molecular mimicry (based on sequence or structural similarities), or super- or cryptic-antigen exposures by the virus.

Autoantibodies againstthe neuronal surface, unclassified neural or nonneural IgG antibodies, and herpes virus DNA can coexist in encephalitic CSF (139; 80). Direct CNS viral infection and activation of immune-mediated disease may occur early in disease, with NMDA receptors detected on hospital admission (191). On the other hand, autoimmune encephalitis may be the cause of recurrent CNS encephalitic disease. The growing number of cases of N-methyl-D-aspartate receptor (NMDAR) antibody encephalitis diagnosed following herpes simplex encephalitis support the idea that relapsing herpes simplex encephalitis, especially in children, is more frequently anti-NMDAR encephalitis than recurrence of herpes simplex virus (86). Patients with symptomatic autoimmune post-herpes simplex encephalitis typically have new areas of contrast enhancement on brain MRI. Anti-NMDAR IgG antibodies can be found in blood or CSF of 7% to 30% of patients as early as 1 to 4 weeks after herpes simplex encephalitis, and the presence of anti-NMDAR antibodies in herpes simplex encephalitis survivors is associated with poorer cognitive recovery (07; 86; 174; 177). Overall, in an approximately 5-week time frame from treatment, 27% of patients with herpes simplex encephalitis develop an immune response to NMDA and other neuronal surface proteins, and another 30% of patients develop autoantibodies in serum or CSF without symptoms (08; 215). Two cases of abrupt onset neuropsychiatric symptoms in older patients, 7 and 12 months after HSV-1 encephalitis, have been reported as late-onset anti-NMDAR encephalitis (64).

Besides anti-NMDA receptors, rare cases of the anti-dopamine-2 receptor (D2R), anti-GABAb, anti-voltage-gated calcium channel, and LGI-1 antibodies have followed herpes simplex encephalitis (159; 31; 02; 187). One case of herpes simplex virus encephalitis had simultaneous Caspr2 antibodies in serum (17). Anti-NMDAR cases may be more frequent because NMDA receptors are more abundant in the CNS than many other receptors and channels. With NMDAR antigen potentially released at higher levels following tissue destruction by herpes simplex virus, post-herpes simplex encephalitis anti-synaptic antibodies could develop from self-immunization to antigens released from injured brain tissue (02).

To be effective, immunomodulatory drugs should be given at an optimal time window, such as one defined by biomarkers of inflammation. Post-herpes simplex virus NMDAR encephalitis responds to IVIG, steroids, or rituximab. Well-timed adjunctive immunomodulatory drugs to reduce inflammatory responses can potentially reduce neurologic sequelae, persistent immune activation, and autoimmune encephalitis (189).

There is one published case of autoimmune encephalopathy successfully treated with antiviral therapy alone. The authors reported improvement in headache, sleep, movement, and behavior disorder of IgLON5 encephalopathy with 19 days of intravenous acyclovir and not immunotherapy. Surprisingly, the patient had tested negative for herpesviruses (238).

Maternal genital herpes. Maternal genital herpes infection may transmit disease to the baby. Neonatal herpes encephalitis may be acquired in utero (5%), during delivery (85%), or during the first 4 weeks of life (10%) (109). All babies, regardless of disease classification, should be considered at risk for CNS complications. In neonates with CNS disease, those who are untreated or receiving ineffective antivirals (idoxuridine or cytosine arabinoside) have a mortality rate of 50%, with disseminated disease a mortality of 80%. With treatment, mortality for skin, encephalitis, and disseminated disease is 0%, 5%, and 30% 24 months after treatment, and long-term neurodevelopment outcomes after CNS disease remain poor (244). Prematurity is associated with higher mortality from CNS disease. Relapse may occur in a small percentage of cases.

Recurrent disease may be associated with interferon pathway genetic defects and require lifelong suppressive therapy.

HSV and co-infections. HSV-2 infection, as a genital ulcerative disease, has been associated with the acquisition of both HIV-1 and human T-cell lymphotrophic virus type 1 (168; 103). In sub-Saharan Africa, where HSV-2 has been the leading cause of genital ulceration, infection with HSV-2 is associated with increased genital shedding of HIV-1 RNA and HIV-1 transmissibility, contributing to the HSV-2 and HIV syndemics (Wald and Link 2002; 56).

IRIS, immune reconstitution inflammatory syndrome, has been documented with several other herpes family viruses: varicella-zoster virus, Kaposi sarcoma-associated herpes virus (HHV-8), and cytomegalovirus (79; 163). IRIS is suggested as a mechanism of HSV-2 reactivation, shedding, and genital ulcer disease recognized in Ugandan women initiating antiretroviral therapy (226). Like IRIS and more common among individuals with higher viral loads, HSV-2 shedding was more likely among women with the highest HIV load before antiretroviral therapy.

Herpesviruses are some of the persistent viruses humans accumulate over the course of a lifetime and could have a role in protracted or chronic disease states, such as chronic fatigue syndrome/myalgic encephalomyelitis and postacute sequelae of COVID-19 (PASC) (190). For herpes simplex, even latent viruses express proteins capable of driving chronic symptoms. Elevated cytokine expression persists even when the virus is latent (nonreplicating) in peripheral nerve ganglia (45). Why COVID has lingering effects or why new symptoms develop, in some cases, might relate to a herpes family member. Herpesvirus reactivated under conditions of immune dysregulation, such as during COVID-19 infection, could, in turn, infect new body sites or produce new symptoms that become chronic.

Clinical vignette

A 43-year-old man with HIV presented with low back pain radiating to the legs, accompanied by progressive bilateral leg weakness, for 2 weeks. He denied sensory loss and experienced two episodes of bowel incontinence. General examination revealed an emaciated man with generalized decreased muscle bulk, and a resolving herpes lesion was present near the anus. Motor exam and reflexes were normal in the arms. Tone was decreased in the legs with moderate proximal and mild distal weakness, areflexia, and flexor plantar responses. Rectal tone was decreased. Sensory examination was normal. He was unable to walk, even with assistance. MRI of the spine and MR neurogram of the lumbosacral roots with contrast were normal. EMG and nerve conduction study showed evidence for bilateral polyradiculopathy versus motor neuropathy. Laboratory investigations revealed mild anemia, normal creatine kinase, erythrocyte sedimentation rate of 37 mm per hour, cytomegalovirus antigen negative, rapid plasma reagin nonreactive, CD4 count 18 cells/mm3, and HIV viral load 62,000 copies/mL. CSF studies showed a mixed lymphocytic and monocytotic pleocytosis with elevated protein (white blood cell count 498 cells/mm3 with 54% lymphocytes, 37% monocytes, 3% neutrophils; red blood cell count 6 cells/mm3; protein 143 mg/dL; glucose 48 mg/dL). Ganciclovir was started for possible cytomegalovirus or herpes simplex virus radiculopathy. CSF cytology; cytomegalovirus, enterovirus, varicella-zoster virus, and herpes simplex virus-1 polymerase chain reaction tests; venereal disease research laboratory test; West Nile antibody; and fungal and bacterial cultures were negative or nonreactive. HSV-2 polymerase chain reaction of CSF was positive. The patient’s pain and weakness improved within days of intravenous ganciclovir treatment (5 mg/kg intravenously over 12 hours). Treatment was modified to a 3-week course of intravenous acyclovir (10 mg/kg intravenously over 8 hours) following results of CSF HSV-2 infection. Within 1 week, the patient walked with the assistance of a walker. At follow-up 1 month later, on continued oral acyclovir (400 mg by mouth, twice daily), he walked with a cane without pain and demonstrated marked improvement in leg strength.

Comment. This case demonstrates a pure motor lumbosacral polyradiculopathy associated with HSV-2 in a patient with advanced HIV and may represent a more extensive version of the Elsberg variant of herpes simplex virus (lumbosacral polyradiculopathy associated with genital herpes) (69). This clinical presentation illustrates overlap with cytomegalovirus polyradiculitis associated with HIV. The final diagnosis relies on viral polymerase chain reaction or culture. However, a CSF profile of lymphocytic (more common in herpes simplex virus) versus neutrophilic predominance (more common in cytomegalovirus) (155) may help to distinguish the viral infections but is not pathognomonic. Finally, it is critical to exclude other infections, such as tuberculosis, neurosyphilis, and lymphoma.

The optimal type and duration of intravenous antiviral treatment for herpes simplex virus-associated polyradiculopathy is not clearly established but depends on clinical response, possible antiviral resistance, severity of symptoms, and drug tolerance (255). Our patient was treated with 3 weeks of intravenous acyclovir based on persistent but slow recovery during this time and good tolerance to the drug. He continued on lifelong oral acyclovir, given his immunocompromised state.

In HIV-positive patients, recommended drug treatments for daily suppressive therapy are: acyclovir 400 mg orally two or three times per day or valacyclovir 500 mg orally twice a day. Resistance to acyclovir due to herpes simplex virus thymidine kinase mutations is a growing clinical worry in immunocompromised patients on long-term acyclovir. Intermittent cessation of suppressive antiviral therapy for genital herpes is recommended in the 2017 European guidelines for managing genital herpes, particularly in patients with adequate HIV viral suppression and rising CD4 counts (185).

Biological basis

Etiology and pathogenesis

	• The biological bases of HSV’s neurologic complications are the virus’ properties of neurovirulence and latency.
	• The most acknowledged and studied route of entry for HSV into the CNS is neuronal.
	• Host immune responses have a role in outcomes and disease severity.
	• Herpes simplex encephalitis can trigger autoimmune encephalitis.

Clinical syndromes are caused by infection with HSV-1 or HSV-2, double-stranded DNA viruses. Latent genital infection with reactivation is the largest reservoir for transmission of HSV-2, and most HSV-2 transmissions occur as a result of asymptomatic shedding (152).

Genital route transmission is the usual way adults acquire HSV-2. The virus replicates in the vaginal tract or on penile skin with seeding of the sacral ganglia via virion transport by retrograde axonal flow. In most cases, latency is established after another round of viral replication in ganglia.

All herpesviruses can become latent, persist in an inactive state for variable periods, and be reactivated by provocative stimuli. Latent virus has been recovered from trigeminal, sacral, and vagal ganglia of humans by explant co-cultivation (15; 14). The sacral ganglia are the main but not exclusive sites of HSV-2 latency. HSV-2 DNA at a low copy number has been detected in ganglia throughout the neuraxis (19). Thus, HSV-2 viral DNA can be found in neuronal tissue in the absence of rash or cutaneous lesions (176). Aseptic meningitis may complicate either primary or recurrent disease, and HSV-2 DNA can be identified in CSF of many patients with recurrent aseptic meningitis (Mollaret meningitis) (227).

Alternatively, replication during primary infection can produce CNS disease with cytolytic viral replication or systemic infection. The pathogenesis of meningitic, radicular, myelitic, and encephalitis syndromes, especially as it relates to neuronal or hematogenous mechanisms of the spread of virus, has been addressed in case reports, studies, reviews (218), and animal studies (03).

The most acknowledged and studied route of entry for HSV into the CNS is neuronal. Intra-axonal spread into the spinal cord through the dorsal roots, and segmental spread by direct neuronal extension, was suggested based on the absence of viral antigen or immunoreactivity in vessel walls of severe myelitis cases (249). Spinal cord disease may be limited to a few segments and followed by recovery or, in immunosuppressed patients, an ascending necrotizing myelopathy with coagulative necrosis of the cord, inflammation, intraparenchymal viral particles, and poor recovery is seen (249).

A potential mechanism of HSV CNS invasion is injury of brain microvascular endothelial cells. In vitro, HSV-1 or -2 can infect microvascular endothelial cells, reducing cell-cell barrier resistance and opening the blood-brain barrier through loss of viability of infected endothelial cells (133).

Transmission of HSV-2 infection through renal transplantation (67) and neonatal diseases indicates that competent virus also can disseminate by hematogenous spread.

Neonatal encephalitic disease has examples supporting viral spread by both neuronal and hematogenous routes. Neuronal transmission would explain the focal CNS encephalitic disease without distal organ infection seen in some neonates. On the other hand, the hematogenous spread of virus is consistent with finding systemic, disseminated disease and diffuse brain involvement. Any part of the brain may be affected, including the grey and white matter of the cerebrum, cerebellum, or brainstem. Necrotizing encephalitis is accompanied by lymphocytic and monocytic infiltrates of meninges and parenchyma. Nuclear inclusions, viral antigens, and DNA can be found during early infection in the first week.

A swollen, congested brain with or without parenchymal or ventricular hemorrhage is associated with acute encephalitis. Long-term survivors show changes in cystic encephalomalacia.

Herpes simplex virus type 2 encephalitis (coronal section)

The patient was a 5-and-a-half-year-old male with history of HSV-2 encephalitis at 10 months. The brain was reduced in volume, with extensive involvement of the temporal and frontal lobes. Coronal section shows extensive multilocu...

The variable natural history and infection outcomes in adults and children are consequences of not only cytolytic viral replication but also host immunity, with severe disease a consequence of either impaired or exaggerated immune responses. For example, the development of autoimmunity with HSV encephalitis shows the role of host immune response in disease expression. The important post-herpes simplex encephalitis postviral syndrome of autoimmune encephalitis may result from molecular mimicry, herpesvirus-specific properties triggering host autoimmunity, antigenic material released by neuronal injury becoming autoimmune foci, or heritable or baseline immunity risk factors (83; 215).

Epidemiology

	• The appearance of HSV-2 antibodies reflects the acquisition of infection and correlates with the onset of sexual activity. Latent genital infection with subsequent reactivation is the largest reservoir for transmission of HSV-2.
	• HSV-2 seroprevalence in persons 14 to 49 years is an estimated 13% in the United States (42). Among Americans over 30 years of age, one in four has had HSV-2.
	• In the United States, predictors of HSV-2 serologic status include female sex, African American background, and greater lifetime number of sexual partners (42).
	• Given the high prevalence of type 2 herpes, HSV-2 has been a dominant cause of aseptic meningitis in adults in Europe and North America.
	• Both HSV-1 and HSV-2 can cause primary genital infections, with HSV-1 undergoing a transitioning epidemiology from an oral to increasingly genital infection in the United States.
	• Estimates of 60% to 78% of new genital herpes cases in the United States are attributed to HSV-1 (13), whereas most cases of recurrent genital infection are due to HSV-2.
	• Neonates who acquire infection by birth canal delivery develop CNS infection in 50% of cases.

The appearance of HSV-2 antibodies reflects the acquisition of infection and correlates with the onset of sexual activity. Latent genital infection with subsequent reactivation is the largest reservoir for transmission of HSV-2. Reactivation of infection may appear as skin vesicles or mucosal ulcers. However, subclinical reactivation in genital mucosa is also associated with viral proliferation, shedding, and risk of sexual transmission.

Both HSV-1 and HSV-2 can cause primary genital infections, with HSV-1 undergoing a transitioning epidemiology from an oral to increasingly genital infection in the United States. Genital HSV-1 has a milder natural history than HSV-2, with a reduced frequency of viral shedding (199). Improvements in hygiene and living conditions have meant fewer childhood HSV-1 infections by oral-to-oral transmission. Adolescents reach sexual debut lacking protective HSV-1 antibodies against contracting HSV-1 through sexual activities (13). Estimates of 60% to 78% of new genital herpes cases in the United States are attributed to HSV-1 (13), whereas most cases of recurrent genital infection are due to HSV-2.

HSV-2 is common throughout the world. The WHO estimates 3.7 billion people younger than 50 years (67%) have HSV-1 infection as oral or genital infection, and about 491 million people aged 15 to 49 years (13%) have HSV-2 infection (251), up from the earlier estimated 417 million people aged 15 to 49 living with HSV-2 worldwide (11.3% global prevalence), and 19.2 million aged 15 to 49 years are newly infected (0.5% of all individuals globally) in a 2015 global study (146). An estimated 45 million people in the United States have genital herpes infection, and new infections occur at a rate of approximately 1 million per year. Roughly 85% to 90% of infections are unrecognized and, therefore, undiagnosed (134). Women, particularly those with multiple sex partners, have the highest rates of infection. The highest prevalence of antibodies to HSV-2 in the United States was identified in female prostitutes (75%) (168). Factors that influence the acquisition of HSV-2 include gender (greater for women than men), race (more frequent in African Americans than whites), marital status (more for divorced than single or married), and residence (more in cities than suburbs) (243). Meningitis is more common in women (36%) than men (13%) after primary genital HSV-2 infection (51), whereas lumbosacral involvement is more common in homosexual men with HSV-2 proctitis (87). Previous herpes simplex virus-1 infection does not reduce the rate of HSV-2 infection, but it does increase the likelihood of asymptomatic seroconversion, as compared to symptomatic seroconversion (132). Across several studies, no consistent relation between concurrent genital herpes infection and HSV-2 meningitis was found, with only about 4% of patients having genital outbreaks at the time of meningitis (156).

Given the high prevalence of type 2 herpes, HSV-2 has been a dominant cause of aseptic meningitis in adults in Europe and North America. HSV-2 was the leading cause of CSF pleocytosis in adult patients in a Colorado study (33), and HSV-2 proved to be the second leading cause of aseptic meningitis cases in adults in a study from Finland. HSV-2 infection accounted for 17% of cases, second after the enterovirus family (26% of cases) (128).

A second Finnish study has shown a high prevalence of HLA-DRB1*01 allele and low plasma immunoglobulin G1 concentration in patients with HSV-2-associated recurrent lymphocytic meningitis, suggesting these heritable factors may predispose to recurrent meningitis (114).

Host genetics. Susceptibility and severity of HSV-2 infection involve both innate and adaptive immune responses. Toll-like receptor 3 (TLR3) recognizes dsRNA and activates antiviral immune responses by producing inflammatory cytokines and type I interferons. Now, two single nucleotide polymorphism variations of TLR3 (enabling higher levels of TLR3 mRNA expression in response to HSV-2 stimulation) have been found to be associated with reduced incidence of HSV-2 infection (222). The same protective allele, rs3775291, is also thought to confer natural resistance to tick-borne encephalitis virus (121) and HIV-1 (211). Mutations in TLR3 and TLR3 pathway genes producing TLR3 deficiency (TLR3, TICAM1, TRIF, TRAF3, UNC93B1, TBK1, and IRF3) are risk factors for herpes encephalitis (211; 215) and predictive of herpes simplex encephalitis recurrence (135). For example, a missense mutation in the transcriptional factor IRF3, which controls multiple IFNa/b pathways, including that of TLR3, was associated with herpes simplex encephalitis in an adolescent (05). Given the various genetic associations with impaired TLR3-IFNa/b intrinsic immunity and herpes simplex encephalitis, investigators have considered using IFN-a treatment in select patients (259).

Increased susceptibility to symptomatic herpes infections or recurrent disease is also seen with alteration in MHC class 1 allotrope, the receptor/ligand pair Killer Cell immunoglobulin-like receptor KIR2DL2/HLA-C1, and the CD16A-158V/F dimorphism (161; 127).

Genetic analysis of two adult patients with recurrent HSV-2 lymphocytic Mollaret meningitis showed that, in these cases, IFN-independent antiviral mechanisms in CNS caused increased susceptibility to recurrent HSV-2 infection (102). Each patient carried a rare monoallelic variant in one of the autophagy proteins, ATG4A and LC3B2. When their primary fibroblasts were infected by HSV-2, impaired induction of autophagy, increased viral load, and increased cell death were observed (102).

Post-mitotic cells, such as neurons, may use autophagy rather than classical IFN antiviral mechanisms to avoid pathological IFN effects on the CNS. That autophagy has a functional role in human herpesvirus infection means that inborn errors in autophagy may represent a novel class of primary immunodeficiencies (102).

Genital HSV and HIV. Around the world, about 70% of persons with HIV are HSV-2 seropositive, and 95% are seropositive for either HSV-1 or HSV-2 (252). Clinical and epidemiological studies have shown the synergy between HSV-2 and HIV-1 (233). HSV-2 genital infection increases the risk of acquiring HIV two- to three-fold (144). In coinfected patients, HSV-2 reactivation increases HIV RNA levels in the blood and genital secretions (166).

Genital herpes in persons with HIV infection is associated with more severe and chronic lesions (221). One mechanism for the HIV and HSV-2 comorbidity is based on HSV-2-mediated inflammation. HSV-2 reactivation in an HIV-negative individual increases the numbers of CD4+ cells recruited to genital HSV-2 lesions to serve as targets for HIV (261), and HSV can stimulate HIV replication through cytokines released from HSV-infected cells (182). A second biological mechanism is based on virus interaction. HSV immediate-early gene products can increase HIV-1 transcription in vitro (138).

Providing anti-HSV treatment for 3 months to co-infected persons who are not on anti-retroviral therapy lowers the mean plasma HIV-1 RNA level by 0.53 log10, which could postpone the need for anti-retroviral therapy (165) and reduce HIV-1 disease progression, measured by a fall in CD4 counts below 350 cells/microL (137).

Additional randomized trials tested whether HSV-2 treatment could limit the spread of HIV. The results were mixed. Although treatment with acyclovir 400 mg twice daily does not reduce HIV incidence or transmission, suppressive acyclovir and valacyclovir reduce HIV levels in plasma, seminal fluids, and genital and rectal tracts (59; 41). Although the demonstration of direct inhibitory action of phosphorylated acyclovir on HIV-1 reverse transcriptase in a cell-free system offers new insights into the analysis of these results (141), future clinical trials will need to consider characteristics of acyclovir activity: (1) that the direct effect of acyclovir on HIV-1 depends on the ability of HSV-2 to produce sufficient phosphorylated acyclovir to suppress HIV reverse transcriptase, (2) host enzymes may differentially affect amounts of phosho-acyclovir, and (3) different doses of acyclovir would produce different amounts of phospho-drug (140).

The antiretroviral tenofovir is active against the herpes simplex virus DNA polymerase. Formulated as a vaginal microbicide gel, tenofovir reduces the risk of acquiring HIV and HSV-2. However, herpes simplex virus isolates that develop DNA polymerase mutations during acyclovir and/or foscarnet treatment are also resistant to tenofovir (06).

Neonatal herpes encephalitis. Neonatal herpes encephalitis is acquired in utero, during delivery, or during the first 4 weeks of life. The incidence, previously estimated as approximately one in 3500 to 5000 live births, with about three quarters of neonatal herpes simplex virus infections due to HSV-2, has dropped to an estimated one in 3200 live births in the U.S. (245; 244; 147). The per-delivery risk of neonatal infection is higher in maternal primary infections in which IgG antibody is lacking than in maternal chronic infections, in which a mature IgG response can cross the placenta. The difference implies protection by passively transferred antibody (35). Neonates who acquire infection by birth canal delivery develop CNS infection in 50% of cases (118).

The incidence of neonatal herpes infections worldwide is about 10 cases per 100,000 live births, approximately 14,000 cases annually (4000 for HSV-1; 10,000 for HSV-2). The most neonatal HSV-2 cases occurred in Africa, whereas HSV-1 contributed more cases in the Americas, Europe, and the Western Pacific (145).

The statistics reflect the changing epidemiology of genital herpes infections, with increased proportions of primary infections (up to 80% in some populations of young women) being HSV-1, which translates to more babies with HSV-1 infections (109; 244).

Other. Virus type is also linked to cardiovascular health in adults. Treatment of HSV-1 infections led to a normal neurologic outcome in about 70%, whereas treatment of HSV-2 brain infections led to normal development in only about 35% of infants (244). In Japan, there were three MRI patterns of neonatal herpes simplex encephalitis linked to neurodevelopmental outcome: (1) inferior frontal and temporal pole pattern; (2) watershed distribution pattern; and (3) corticospinal tract pattern (pre- and postcentral gyrus and corticospinal tracts, with or without lateral thalamus). Corticospinal tract injury is associated with motor impairment, and frontal and temporal involvement show a trend with West syndrome (117).

Virus type is also being considered as a determinant of cardiovascular health in adults. There is increasing experimental evidence that HSV-2, but not HSV-1, infection is linked to arteriosclerosis and coronary artery disease, relating to its recurrent inflammatory disease. Evidence of HSV-2 infection has been found in vessel biopsies of patients undergoing coronary artery bypass grafts, whereas positive HSV-2 IgG serology, and not HSV-1, has been associated with premature cardiovascular disease, essential hypertension, and elevated C-reactive protein levels (151).

CNS hemorrhage and CNS infarction, complications of HSV CNS infection, are linked to different virus types. Ischemic strokes have been associated with HSV-2 and large-vessel vasculitis, and intracerebral hemorrhage, mainly temporal lobe hemorrhage, has been associated with the CNS necrotic process of HSV-1. These differential CNS vascular findings further support the hypothesis that virus type is associated with different vascular pathology (100).

Type-specific syndromes could change, overlap, or merge because contemporary circulating genital HSV-2 strains from wide-ranging geographic areas now show evidence for recombination with HSV-1 (125). Humans are unique among primates in that humans are known to harbor two simplex viruses, both having homologous sets of about 74 open reading frames in single-segment linear double-strand DNA. The HSV-1 recombinant sequences identify within three different nucleotide metabolism genes, with implications for pathogenesis, viral evolution, drug therapy, vaccines, and viral vector safety (125).

Prevention

	• Prevent primary infection by preventing person-to-person spread with contact precautions for someone with active mucocutaneous herpetic lesions.
	• Offer suppressive valacyclovir therapy (500 mg by mouth once daily) to immunocompetent individuals concerned about transmitting genital herpes to a heterosexual partner.
	• Prevent neonatal HSV-2 infection by cesarean section delivery when the mother has genital lesions or prodromal symptoms.
	• In pregnant women with a history of genital herpes, use antiviral prophylaxis with acyclovir from 36 weeks gestation to delivery.
	• During pregnancy, use suppressive therapy in discordant relationship: in the seropositive partner of a seronegative gravid woman.

Preventing the neurologic complications of HSV-2 begins with preventing person-to-person virus transmission. A first clinical episode of genital herpes is treated with oral acyclovir 400 mg three times daily for 7 to 10 days, or oral famciclovir 250 mg three times daily for 7 to 10 days, or oral valacyclovir 1 gm twice daily for 7 to10 days (43).

Suppressive antiviral therapy reduces the frequency of HSV-2 genital herpes recurrences by 70% to 80% among patients who have frequent recurrences and is valuable in managing some complications of recurrent genital herpes. Recommended regimens are: oral acyclovir 400 mg twice daily, oral valacyclovir 500 mg once daily, oral valacyclovir 1 gm once daily, or oral famciclovir 250 mg twice daily. Recurrences are less frequent after HSV-1 genital herpes, and suppressive regimens are generally used in those with frequent recurrences (43).

The International Herpes Management Forum has recommended that physicians offer suppressive valacyclovir therapy (500 mg by mouth once daily) to immunocompetent individuals concerned about transmitting genital herpes to a heterosexual partner and advises safer sex behavior (52; 57).

Because peak HSV replication occurs rapidly after the reactivation of latent virus, there is a narrow window of opportunity to prevent replication using an antiviral agent. Episodic therapy for recurrent HSV-2 genital herpes is initiated within 1 day of lesion appearance or in the prodromal period. Recommended regimens are: oral acyclovir 800 mg twice daily for 5 days, oral acyclovir 800 mg three times daily for 2 days, oral famciclovir 1 gm twice daily for 1 day, famciclovir 500 mg once then 250 mg twice daily for 2 days, famciclovir 125 mg twice daily for 5 days, oral valacyclovir 500 mg twice daily for 3 days, oral valacyclovir 1 gm once daily for 5 days (53; 186; 43).

Acyclovir, valacyclovir, and famciclovir effectively suppress HSV-2 reactivation in persons co-infected with HIV-1 and HSV-2 (239; 221). The use of suppressive acyclovir to decrease HIV-1 transmission or improve the clinical course of HIV-1 infection has become an additional important reason for early diagnosis and treatment of HSV-2 infection in HIV-infected persons. To date, despite increasing use of suppressive acyclovir therapy, there has been little increase in the detection of acyclovir-resistant HSV-2 isolates (221).

The use of topical microbicides such as resiquimod, a toll-like receptor 7 and 8 agonist that induces interferon-alpha, is used for treating mucosal infection and preventing HSV-2 infection (149). Formulated as a vaginal microbicide gel, the antiretroviral tenofovir, active against the herpes simplex virus DNA polymerase, reduces the risk of acquiring HIV and HSV-2.

Strategies to prevent neonatal herpes infection depend on preventing the acquisition of genital herpes in late pregnancy and avoiding exposure of the neonate to herpetic lesions or viral shedding during delivery. Measures include cesarean section delivery and the use of suppressive therapy in the seropositive partner of a seronegative gravid woman.

For pregnant women with active genital herpes, a cesarean section performed within 4 hours of membrane rupture reduces the rate of neonatal herpes simplex virus infection from 7.2% to 1.5% in comparison to vaginal delivery (36). Recommendations for late-pregnancy use of acyclovir or valacyclovir in the obstetrics literature have shown that acyclovir administered from 36 weeks of gestation through delivery decreases the incidence of outbreaks of HSV-2, viral shedding at delivery, and the need for cesarean section (202; 205). Recommended regimens are oral acyclovir 400 mg three times daily or oral valacyclovir 500 mg twice daily starting at 36 weeks gestation--or administered intravenously to pregnant women with severe infection (43). American Academy of Pediatrics guidelines state that if the mother has a primary infection in the third trimester, 14-day prophylactic treatment is administered (04). If the mother has a history of genital herpes, surface cultures are performed within 24 hours of delivery. If positive, an infant with skin disease is treated for 14 days or for 21 days for organ involvement. A well neonate discovered postnatally to have been delivered via an HSV-lesioned or culture-positive birth canal is treated prophylactically with intravenous acyclovir (60 mg/kg/day in three divided doses) for 10 days (219).

In the United Kingdom, the Royal College of Obstetricians and Gynaecologists has recommended cesarean section for women with a first episode of genital herpes at the time of delivery, and not for women with a first episode of genital herpes in the first or second trimester. Elective cesarean is considered at term for women with a first episode of genital herpes within 6 weeks of the expected date or onset of preterm labor (195; 220). The most cautious approach is avoidance of vaginal delivery in all women with a history of genital herpes simplex virus infection and is justified by experimental evidence that asymptomatic herpes simplex virus shedding can be frequent in seropositive individuals (219).

Vaccination. Although oral bioavailable antiviral drugs can control HSV-2 infections, these agents do not cure the individual. Antiviral drugs treat actively replicating virus, limit subclinical shedding, and prevent 50% of transmissions of HSV-2 within couples. As such, antivirals do not affect latent virus and are not completely effective. Because HSV-2 can cause severe recurrent disease and establish lifelong infection, and because there may be linkage of HSV-2 and HIV-1 control (165), HSV-2 vaccines are public health priorities (111). To date, however, no vaccines have been licensed. Experimental products have had mixed and, at times, discouraging outcomes.

The objective of a prophylactic vaccine is to induce sterilizing immunity effective at all portals of HSV entry (genital mucosa, facial mucosa, eye). HSV in genital lesions and vaginal/cervical secretions exists as a cell-free virus, so vaccine induction of high levels of neutralizing antibody would be required. A difficulty is that a vaccine that provides effective immunity against HSV-2 must produce an immune response, such as a strong neutralizing antibody response, that exceeds the response produced by natural infection. One vaccine that has entered clinical trials is a recombinant glycoprotein vaccine, an alum and monophosphoryl lipid A-adjuvanted subunit glycoprotein D2 vaccine (gD-alum-MPL) containing truncated gD2 in a novel lipid adjuvant. Activity in the prevention of HSV-2 infection and disease in HSV-2-uninfected women was investigated in a phase III clinical trial (216; 123). Early results showed the glycoprotein D vaccine had efficacy against genital herpes in women who were seronegative for both HSV-1 and HSV-2 at baseline but not in those who were seropositive for HSV-1 and negative for HSV-2. The vaccine elicited antibody and CD4 T cell responses but had no efficacy in men, regardless of their HSV serostatus (217). A large follow-up study in a population representative of the general population of HSV-1 and HSV-2 seronegative women (Herpevac study) concluded that prophylactic vaccination failed to prevent HSV-2 infection and disease. The investigational vaccine effectively prevented HSV-1 genital disease and infection but not HSV-2 disease or infection (16). This was the most recent large trial of the HSV-2 gD2 vaccine.

An effective therapeutic HSV vaccine is needed because current antiviral agents do not fully suppress shedding or recurrent ulcers. The objectives of a therapeutic vaccine will be to prevent recurrences or minimize their severity and duration. Virus reactivation in the ganglion should be prevented, or virus replication after leaving the nerve should be limited. The vaccine should enhance the host's specific immune responses to accomplish this. The therapeutic vaccine will probably have to boost different immune responses than a prophylactic vaccine. The success of prophylactic vaccines has not been observed in therapeutic vaccine trials when the same prophylactic vaccines were used (193). The finding of substantial genetic conservation between primary and recurrent episodes of genital HSV-2 infection (158) is consistent with strong selective pressure on the fidelity of the viral genome during reactivation and, thus, has implications for therapeutic vaccines.

Early results from ongoing trials of postexposure therapeutic vaccines against genital HSV-2 infection show less HSV-2 shedding in vaccine recipients compared to placebo (146). These are preliminary results for GEN-003 (Genocea), which is based on viral antigens ICP4 and gD2, and HerpV (Agenus), which contains recombinant HSP-70 and 32 HSV-2 antigens.

Other vaccine formats, including attenuated live or replication-incompetent HSV-2 strains, live-attenuated HSV-1 strains that replicate in mucosal tissues but are ablated for neuroinvasion, and technologies that target virus-specific CD8 T-cell responses, are being developed and studied (123; 25; 23; 24). The preclinical pipeline includes subunit, whole virus, DNA, attenuated or mutated live virus platforms, and trivalent mRNA-lipid nanoparticle (glycoprotein gD2, gC2, gE2) (199; 12). Vaccines that elicit both effector or protective antibodies and adaptive T-cell responses probably offer the best hope for developing effective immunogens. Some of the strategies for HIV-1 vaccines, such as the inclusion of fusion intermediates as targets for antibodies and the use of viral vectors to elicit CD8 T-cell responses, may be adapted for HSV vaccine development (124).

A therapeutic herpes simplex virus vaccine is more challenging than the live attenuated and subunit varicella-zoster virus vaccines in use. Distinct from the varicella-zoster virus, the herpes simplex virus reactivates frequently with a larger repertoire of genes that escape host immune response (50).

Optimistic estimates for an HSV-2 vaccine are in several years’ time. Because immunologic correlates of protection for prophylactic or therapeutic vaccines were not clear, very large clinical trials were thought to be needed for prophylactic vaccines. The future of herpes simplex virus vaccine development is in computational methods for preliminary data on targets and newer vaccine formulations, such as trivalent subunits, nucleoside-modified mRNA nanoparticles, adjuvants, and multivalent DNA vaccines (247).

The World Health Organization, National Institutes of Health, and global partners launched STI Watch, a portal with updates on vaccines where lists of current preventive and therapeutic HSV vaccines under development and in clinical trials are found (250).

Importantly, herpes simplex virus vaccines could substantially impact the incidence of HIV. Over 20 years in most model scenarios, fewer than 100 prophylactic vaccinations against HSV-2 would be required to avert one HIV infection (78).

Developers of any herpes simplex virus vaccine must take into account the results of the STEP HIV vaccine trial (37), in which an adenovirus vector HIV vaccine increased the incidence of HIV in the vaccine group in men with serologic evidence of past exposure to the adenovirus used in the vaccine (Ad5). One interpretation was that CD4+ T cell expansion to adenovirus vector linked to HIV-1 susceptibility and that the presence of both antibody and virus could lead to the activation of T cells and provide an environment favorable to HIV replication (203). Therefore, any effective HSV vaccine should not induce a mucosal CD4+ T cell response that would increase the risk for HIV (199).

Transfusion. Although HSV-2 transfer by transfusion has been considered very rare, HSV-2 is joining cytomegalovirus and HHV-8 as herpes viruses of concern in transfusion medicine. Due to the ability to detect herpes simplex virus DNA in the plasma of patients with primary herpes genitalis, deferral of blood donations from individuals with primary herpes infections is recommended (113). The consensus is that blood donors with recurrent herpes simplex virus infection are probably not at risk of transmitting herpes simplex virus.

Differential diagnosis

The differential diagnosis is of a meningitic, encephalitic, lumbosacral radicular, or myelitic syndrome and inflammatory CSF with a mild-to-moderate lymphocytic pleocytosis (10 to 500 WBC/µl), mildly elevated protein (less than 100 mg/dl), and normal or depressed glucose. CSF glucose may be depressed in patients with HSV-2, mumps, varicella-zoster virus, and lymphocytic choriomeningitis virus; CSF glucose levels below 25 mg/dl should prompt a search for bacteria, fungi, sarcoid, or carcinomatous meningitis.

The differential diagnosis of a localized viral exanthem and aseptic meningitis includes varicella-zoster virus and more generalized rashes with meningitis, including measles, rubella, enteroviruses (particularly Echo 9), B19 parvovirus, and dengue. Other agents producing rash and aseptic meningitis are syphilis, Lyme borreliosis, leptospirosis, and rickettsial diseases.

HSV-2 meningitis is distinguished from aseptic meningitis caused by other viruses or by spirochetes, Chlamydia, Rickettsia, Mycoplasma, Brucella, Ehrlichiae, partially treated bacterial meningitis, parameningeal infection, tuberculosis, fungal meningitis, endocarditis, postviral or vaccination meningeal reaction, drugs, leaking epidermoid cyst, posttraumatic skull defects, collagen vascular diseases, and subarachnoid hemorrhage based on CSF, serum, and neuroimaging studies.

Recurrent HSV-2 meningitis is distinguished from chronic meningeal processes with recurrent episodes of symptomatic meningitis (spirochetes, Brucella, fungi), idiopathic inflammatory conditions (sarcoid, Behçet disease, Vogt-Koyanagi-Harada syndrome), chemical meningitis, or drug reaction (nonsteroidal anti-inflammatories, trimethoprim-sulfamethoxazole) by history, CSF, serum, and neuroimaging studies.

Temporal lobe localization is characteristic of herpes encephalitis in anyone older than 3 months (244). The incidence of herpes simplex encephalitis due to HSV-1 and -2 is approximately one case per 100,000 per year in the United States, and, in nonepidemic years, herpes simplex encephalitis accounts for an estimated 10% of encephalitis hospital admissions (112). Acute encephalitis in adults due to herpes simplex virus type 1 and type 2 may have similar focal or multifocal clinical and imaging patterns, although comparison studies have described more varied MRI patterns with HSV-2 encephalitis, such as extensive temporal and frontal, focal thalamic, or bilateral limbic or inferior frontal signal abnormalities (210). Therefore, polymerase chain reaction procedures that can detect both herpes simplex virus types 1 and 2 in CSF are used. Instead of the single polymerase chain reaction tests, the multiplex or consensus-herpes polymerase chain reaction for simultaneous detection of a number of human herpesviruses has gained ground in diagnostics (224; 38). The tests are particularly useful in evaluating HIV-infected patients with neurologic disorders related to human herpesviruses (192).

Herpes simplex encephalitis caused by HSV-2 with normal MRI brain imaging is rare. Atypical HSV-2 encephalitis cases with normal MRIs have been reported as febrile encephalopathy in a 68-year-old man (99) and as reversible progressive cognitive decline in a 78-year-old man with B cell chronic lymphocytic leukemia (230). No acute MRI changes were associated with encephalitis as headache and seizures in a 61-year-old man with secondary progressive multiple sclerosis on ocrelizumab (66). Risk factors for atypical disease with normal imaging or only subtle imaging changes by CT or MRI are age, steroid use, AIDS, immunomodulatory drugs, or history of malignancy (76).

Besides HSV-2, viral causes of lumbosacral radiculomyelitis include herpes simplex virus-1, cytomegalovirus, Epstein-Barr virus, varicella-zoster virus, human T-cell lymphotropic virus type 1, West Nile virus, and tick-borne encephalitis viruses. Bacterial causes include syphilis and tuberculosis. Lumbosacral root hyperintensity on T2-weighted MRI images or contrast enhancement is not specific for viral radiculitis, as it also occurs with Guillain-Barré, lymphoma, and metastatic malignant disease. Myelitis without radiculitis is associated with CNS inflammatory conditions such as multiple sclerosis, neuromyelitis optica, anti-MOG antibody myelitis, sarcoidosis, and Lyme disease.

Evaluation of the septic-appearing newborn with CSF pleocytosis and elevated protein includes CSF examination for herpes simplex virus types 1 and 2 and other bacterial and viral infections. Intrauterine herpes simplex virus infection causes encephalomalacia, ventricular enlargement, calcifications, microcephaly, and microphthalmia. Perinatal/postnatal herpes simplex virus encephalitis has more varied imaging and depends on the timing of the study with respect to the disease course (172). Infants with perinatal/postnatal HSV-2 encephalitis may have diffuse bilateral disease or periventricular white matter lesions and meningeal enhancement on MRI (122), including extensive diffusion restriction of thalami, corpus callosum, frontal cortex, corticospinal tracts, and subcortical white matter (225). Three characteristic patterns of neonatal herpes simplex encephalitis MRI brain lesions have been reported in Japan, along with multiple punctate lesions on DWI (termed “stardust appearance”) in the affected cortex: (1) inferior frontal and temporal pole pattern; (2) watershed distribution pattern; and (3) corticospinal tract pattern (pre and postcentral gyrus and corticospinal tracts, with or without lateral thalamus) (117). A history of genital lesions in the mother or her sexual partner is helpful. Infants with neonatal herpes simplex virus meningoencephalitis typically present at 5 to 14 days of life.

Five percent of neonatal herpes infections arise from in-utero transmission, resulting in congenital disease seen at the time of birth. Children with congenital herpes simplex virus infection most closely resemble babies with congenital Zika infection based on their combinations of microcephaly, retinitis, microphthalmia, skin scarring, and limb abnormalities (29).

Viral causes of acute retinal necrosis in childhood include varicella-zoster virus, cytomegalovirus, HSV-1, and HSV-2. Many cases of acute retinal necrosis caused by HSV-2 have been reported in children, teenagers, and young adults as a result of the reactivation of congenital or neonatal infections, which may have been subclinical.

HSV-1 or -2 encephalitis in glioma patients may be suspected in patients with hyperthermia, rapid change in mental status to coma, or appearance of new epileptic foci not corresponding to the site of the primary tumor. Diffusion-weighted MRI and CSF HSV polymerase chain reaction will aid the differential diagnosis (26).

Diagnostic workup

	• The gold standard for documenting CNS HSV disease is the polymerase chain reaction: detection of viral DNA by molecular amplification.
	• PCR has a sensitivity of 95% to 100% and a specificity of 94% in herpes simplex encephalitis in children and adults (herpes simplex encephalitis after the neonatal period) (119).
	• PCR has a sensitivity of 75% to 100% and a specificity of 71% in neonatal HSV CNS disease (119).
	• If the physician strongly suspects herpes simplex encephalitis, empiric acyclovir therapy should be started immediately. Management should not be diverted or deferred based on a single negative HSV CSF PCR result.
	• The diagnostic method of establishing HSV disease outside the CNS is viral culture or PCR. Ninety-five percent of vesicular genital lesions will grow HSV, compared with 70% of ulcerative lesions and 30% of crusted lesions. Herpes simplex virus PCR of genital lesions can be more sensitive.

For adult meningitis, encephalitis, myelitis, or radiculitis cases, diagnostic evaluation is directed toward confirmation of viral etiology by polymerase chain reaction analysis of CSF for HSV-1 or -2 DNA and exclusion of other causes of lymphocytic or monocytic CSF pleocytosis. Detection of polymerase chain reaction-amplified viral nucleic acid in the CSF is supported by virus isolation or serology (such a rise in serum HSV-1 or -2 immunoglobulin G or proof of intrathecal HSV-1 or -2 immunoglobulin G synthesis). HSV-2 can be isolated from the CSF of many patients with primary HSV-2-induced meningitis using standard virological techniques but rarely during recurrent meningitis (21). Neuroimaging and EMG nerve conduction velocity studies are performed as needed. Spinal MRI may be normal in radiculomyelitis cases.

Five percent to 10% of patients, especially children, may initially have normal CSF profiles. This can occur in immunocompetent adults early in the disease and in patients taking TNF alpha inhibitors (127).

Herpes simplex virus polymerase chain reaction of genital lesions has been more sensitive than viral culture in determining the etiology of genital ulcer disease. Type-specific serologic tests using HSV glycoprotein G antigens with low crossreactivity distinguish between type 1 and 2. Detection of HSV-2-specific IgG indicates genital herpes, even in patients without a clinical history of infection. HSV-1-specific IgG is consistent with genital or orolabial infection (85). For CNS tissue specimens, the absence of inclusions by light microscopy does not exclude HSV-2. HSV-2 myelitis and encephalitis have occurred without demonstrating inclusions in biopsy or postmortem material (249).

Neonatal herpes encephalitis may occur in the absence of skin lesions, so if an encephalitic infection is suspected, swabs of the oropharynx, conjunctiva, rectum, skin lesions, mucosal lesions, and urine should be taken and sent for virus culture. CSF should be sent for polymerase chain reaction detection of herpes simplex virus DNA. Evidence of disseminated infection, including hepatitis, pneumonitis, or disseminated intravascular coagulation, is found with liver function tests, complete blood count, CSF, and chest x-rays (118).

The genomes of HSV-1 and HSV-2 have approximately 70% homology. HSV type differentiation can be achieved through type-specific glycoprotein antibody response, restriction endonuclease fingerprinting, and DNA sequencing (109).

Management

	• Herpes simplex encephalitis treatment is acyclovir 10 mg/kg intravenously every 8 hours for 14 to 21 days.
	• If the physician strongly suspects HSV encephalitis, empiric acyclovir therapy should be started immediately. Management should not be diverted or deferred based on a single negative HSV CSF PCR result.
	• Acyclovir-resistant strains are treated with foscarnet, a pyrophosphate analogue/viral DNA polymerase inhibitor, 90 mg/kg intravenously every 12 hours for 14 to 21 days.
	• Intravenous acyclovir 10 mg/kg every 8 hours for 10 to 14 days has been the consensus treatment for patients with severe or progressive herpetic radiculomyelitis or for immunocompromised patients.
	• Meningitic acyclovir doses are lower than for herpes simplex encephalitis. Treatment of primary or recurrent meningitis in the presence of HSV-2 genital lesions with intravenous acyclovir (5 to 10 mg/kg intravenous three times daily) for 7 to 10 days can shorten the symptomatic period, improving signs and symptoms of meningitis within 72 hours.
	• Neonates with suspected herpes simplex virus encephalitic infection are treated with intravenous acyclovir (20 mg/kg) every 8 hours for 21 days. CSF is sampled toward the end of the 21 days. If PCR remains positive, treatment is extended with weekly CSF sampling, and acyclovir is stopped when negative. Following intravenous acyclovir, suppressive therapy with oral acyclovir (300 mg/m2 per dose three times per day) should continue for 6 months.

The management of encephalitis is symptomatic, along with empiric antibiotic and antiviral treatment (intravenous acyclovir 10 mg/kg every 8 hours for 14 to 21 days), until CSF test results are in and a diagnosis can be made. Adjunctive steroid therapy is used in select brainstem encephalitis cases (142) or in edema cases with a risk of herniation or CSF block. CNS injury that occurs during herpes simplex encephalitis is caused by viral replication and excess inflammatory response. Corticosteroids are recommended in herpes simplex encephalitis cases of brain edema, raised intracranial pressure, and brain shift. The first study of the routine use of adjuvant corticosteroid treatment in herpes simplex encephalitis, the German GACHE study, was terminated early due to low patient numbers (154). DexEnceph, sponsored by the University of Liverpool and the University of Grenoble, was the next multinational study of dexamethasone in adults with herpes simplex virus encephalitis, having made changes in GACHE admission criteria and endpoints (189). The now-completed study was a randomized control trial examining the clinical benefit of 4 days of 10 mg dexamethasone every 6 hours added to acyclovir (steroid doses comparable to doses used in bacterial or tuberculous meningitis), with a primary endpoint being the impact on verbal memory score (63; 189); the study included HSV-2 cases among the patients with herpes simplex encephalitis. Previewed results have shown no differences in auditory memory index, no differences in neuropsychological outcomes, no differences in edema between the steroid and nonsteroid groups, and no safety concerns. Although subgroup analysis may provide additional information, the study has not changed the recommendations for adjunctive use of corticosteroids in herpes simplex encephalitis.

Differentiating HSV-2 from type 1 in adult herpes simplex virus encephalitis may lead to prolonged acyclovir treatment, potentially followed by prophylaxis to prevent symptomatic relapse with HSV-2. At the close of encephalitis treatment, polymerase chain reaction assessment of CSF is recommended to verify response to treatment and eliminate replicating virus (227).

Clinical trials have not clearly defined the treatment of single or recurrent episodes of HSV-2 meningitis. There is anecdotal evidence that acyclovir can effectively treat HSV-2 meningitis and that oral agents may work in such cases.

Treatment of primary or recurrent meningitis in the presence of HSV-2 genital lesions with intravenous acyclovir 5 to 10 mg/kg three times daily for 7 to 10 days or intravenous acyclovir for 5 to 7 days and oral valacyclovir to complete a 14-day course can shorten the symptomatic period, improving signs and symptoms of meningitis within 72 hours (227). Doses for meningitis are lower than for herpes simplex encephalitis (intravenous acyclovir 10 mg/kg every 8 hours for 14 to 21 days) outside the newborn period.

Whether to treat patients during acute attacks of Mollaret meningitis continues as an open question. Shorter episodes or resolution of Mollaret meningitis with acyclovir (intravenous or oral) or valacyclovir (oral) have been reported, whereas others note a lack of efficacy of suppressive antiviral treatment of Mollaret meningitis (244). Therapy does not affect the viral reservoir in dorsal root ganglia.

Intravenous acyclovir 10 mg/kg every 8 hours for 10 to 14 days has been the consensus treatment for patients with severe or progressive herpetic radiculomyelitis or for immunocompromised patients (69). However, there has been no evidence of improvement from controlled clinical trials. If response to therapy is poor and the isolate is found to be resistant to acyclovir, intravenous foscarnet (a non-thymidine-kinase dependent agent) is indicated because all acyclovir-resistant strains are resistant to valacyclovir and most are also resistant to famciclovir (221). Valacyclovir is biotransformed to acyclovir and L-valine by first-pass intestinal or hepatic metabolism. Famciclovir, a synthetic acyclic guanine derivative, is the prodrug of the active antiviral penciclovir. Resistance to nucleoside analogues is most commonly due to the deletion of the HSV thymidine kinase (tk) gene. Less often, resistance is due to HSV-tk gene or viral DNA polymerase mutations (74). Infrequent case reports of resistance to acyclovir link resistance to very high viral loads (105 or greater) in CSF (244). HSV clinical isolates are quasispecies composed of acyclovir-sensitive and -resistant variants, with resistant variants presumably achieving critical numbers in these cases.

Acyclovir-resistant herpes simplex virus is estimated in less than 1% of immunocompetent patients but more often in immunocompromised individuals (4% to 30%) and in infected and immunoprivileged sites such as cornea (157). Some Tk-negative HSV-1 mutants have no neurovirulence in animal studies and, therefore, may be less neurovirulent in humans (200).

There is lower genetic variability of the thymidine kinase gene of HSV-2 compared to HSV-1. The higher genetic variability of the HSV-2 DNA polymerase gene compared to its thymidine kinase gene may signify a more important role for DNA polymerase mutations in the acquisition of acyclovir resistance in HSV-2 isolates (157).

Foscarnet, a structural mimic of the anion pyrophosphate that inhibits the pyrophosphate binding site of viral DNA polymerase, is not activated by HSV-tk. Foscarnet has been used as 40 mg/kg intravenous every 8 hours is added to acyclovir in encephalitis cases of suspected acyclovir resistance (200) or 90 mg/kg intravenously every 12 hours for 14 to 21 days (20). Resistance to nucleoside analogues previously estimated as rare (less than 5%), without a significant increase since acyclovir was introduced more than 20 years ago (138), could ultimately be higher in immunocompromised patients receiving long-term prophylactic treatment with acyclovir (47).

Cidofovir, a deoxymonophosphate analogue and a thymidine kinase-independent inhibitor of HSV infection, is an off-label alternative to foscarnet in patients with acyclovir-resistant HSV (164). Cidofovir is administered intravenously as 5 mg/kg body weight once weekly for 2 weeks, then 5 mg/kg body weight once every 2 weeks for three doses, with hydration and probenecid to prevent nephrotoxicity (183).

Based on International Herpes Management Forum recommendations, neonates with suspected herpes simplex virus encephalitic infection should be treated with intravenous acyclovir (20 mg/kg) every 8 hours for 21 days. If the disease is localized to the skin, eyes, and mouth, treatment is for 14 days, but CNS evaluation and neuroimaging are indicated even with mild (skin, eye, or mouth) disease presentations (244). The neutrophil count for children receiving intravenous acyclovir should be monitored, and decreasing the dose or administering granulocyte colony-stimulating factor should be considered for absolute neutrophil counts below 500/mm3. At the end of therapy in CNS and disseminated disease, polymerase chain reaction assessment of the CSF is recommended and treatment continued if the child remains polymerase chain reaction positive at this site (118). Thus, PCR provides a quantitative guide to treatment and is used to determine the duration of therapy in the newborn. Following intravenous acyclovir treatment of HSV-2 neonatal encephalitis, oral acyclovir treatment (300 mg/m2 orally every 8 hours) should be administered for at least 6 months, treating persistent low-level replication of HSV in the young brain (120). Young patients with HSV-1 brain infections do not benefit from extended oral antiviral therapy, nor do older patients. Patients over 12 years with PCR-confirmed herpes simplex virus encephalitis did not show added neuropsychological benefit from a 3-month course of oral valacyclovir after completing standard intravenous acyclovir treatment. (84).

In suspected or proven herpes simplex virus disease in neonates, when acyclovir is not available, intravenous ganciclovir (6 mg/kg) every 12 hours for 3 weeks is recommended as first-line therapy. Intravenous foscarnet (60 mg/kg) every 12 hours during acute illness is used as second-line therapy (237).

Children with inborn errors in innate immunity, particularly younger children, are at risk of developing herpes simplex virus encephalitis at the time of primary infection with HSV-1. They are followed closely until adolescence or until HSV-1 seroconversion occurs (189).

Prophylaxis and treatment strategies are also tailored to pediatric recipients of stem cell transplants. HSV reactivation is a common problem after allogeneic hematopoietic stem cell transplant, and recipient serostatus is an identified risk factor for herpes simplex virus infections (68).

Mostly, the treatment of herpes simplex infections has relied on nucleoside analogues with similar mechanisms of action that inhibit the HSV DNA polymerase after phosphorylation by viral thymidine kinase. These were introduced in the early 1980s.

Thiazolylamide pritelivir (BAY 57-1293, AIC316), the first of a new class of antiherpes viral agents that inhibit viral replication by targeting the viral helicase-primase enzyme complex, was developed to treat acyclovir-resistant and dual (acyclovir and foscarnet) resistant mucocutaneous genital herpes. Resistance is suspected when lesions persist more than 1 week after initiating antiviral treatment or new satellite lesions appear during treatment, and pritelivir shows efficacy in suppressing viral shedding and lesion development (235). A phase 3 trial is underway. Pritelivir received US FDA Breakthrough Therapy Designation on June 5, 2020 (28).

Preclinical studies also are showing synergistic activity of another helicase-primase inhibitor amenamevir (ASP2151) with nucleoside analogues against HSV-2, raising the possibility of combination therapy for treating severe disease and infections suspected to be caused by nucleoside analogue-resistant viral variants (48). The potential for combination therapy for those with life-threatening herpes simplex virus infections (beyond foscarnet and cidofovir) may be closer.

Although the potential for combination therapy for patients with life-threatening herpes simplex virus infections (beyond foscarnet and cidofovir) is approaching, combination therapy with agents with matched pharmacodynamics and different molecular targets also will require strategies to manage herpesvirus infections in immunosuppressed hosts requiring long-term treatments. Potential regimens consist of a DNA polymerase inhibitor supplemented with a helicase-primase inhibitor and potentially a third target inhibitor (110). For example, HIV integrase inhibitors block the replication of alpha, beta, and gamma herpesviruses in vitro (254). Because immunocompromised patients are at risk for multiple herpesvirus infections, a broad-spectrum agent, such as brincidofovir, would also be considered in prophylactic regimens (110) and is under investigation in herpes simplex encephalitis models (189). Brincidofovir is the orally bioavailable lipid conjugate of cidofovir (an acyclic nucleoside analogue) that has good blood-brain barrier penetrance.

Outcomes

Genital herpes. Suppressive therapy reduces but does not eliminate asymptomatic viral shedding in genital herpes.

Herpes simplex encephalitis. Before acyclovir, the risk of death from herpes simplex encephalitis was 70% to 80%. After the introduction of acyclovir, mortality was reduced to 10% to 20% but sequelae of memory loss, epilepsy, cognitive impairment, and neuropsychological changes have remained. Best prognoses correlate with early administration of antiviral treatment. Determinants of outcome are speed of initiating treatment, high-level nursing care, management of complications such as cerebral edema, age, and level of consciousness (194).

Neonatal herpes encephalitis. Before antiviral treatment was available, 50% of infants with central nervous system disease died within 1 year. Acyclovir has improved survival (from 50% to 6% with intravenous acyclovir therapy) (55). Now, prematurity is associated with mortality among infants with CNS disease and virus type is a determinant of outcome morbidities. Neonates with HSV-2 CNS infection have high rates of developmental problems at 1 year, including developmental delay, epilepsy, blindness, and cognitive disabilities. Treatment of HSV-1 infections leads to a normal neurologic outcome in about 70% whereas treatment of HSV-2 brain infections led to normal development in only about 35% of infants (244).

Special considerations

Pregnancy

Clinical mucocutaneous manifestations of recurrent genital herpes infections are similar in pregnant and nonpregnant women (51). Differences in the frequency of neurologic manifestations from HSV-2 infection during pregnancy are not known. Use of acyclovir suppression to prevent clinical recurrences and use of acyclovir or valacyclovir prophylaxis during late pregnancy (after 36 weeks of gestation) to prevent recurrent herpes at delivery are evaluated in several manuscripts (201; 202; 205). Based on combined data of acyclovir and valacyclovir, there does not appear to be any major risk to the fetus from acyclovir or valacyclovir (32). The manufacturer of famciclovir maintains a pregnancy registry to monitor maternal-fetal outcomes of women exposed to famciclovir during pregnancy. If the mother has a proven primary infection in the third trimester, prophylactic treatment is given for 14 days. Maternal genital infection may be asymptomatic or subtle, accounting for the nearly 80% of women who vertically transmit HSV to the newborn without a history of genital herpes lesions (109). If the mother has a history of genital herpes, surface cultures within 24 hours of delivery are recommended. If positive, treatment of the neonate is 14 days for skin-only disease and 21 days if there is organ involvement (244).

Genetically vulnerable groups

Several single gene errors in TLR3-interferon type I and type III pathways resulting in abnormal cellular interferon responses have been reported in children with increased susceptibility to herpes simplex encephalitis. Other mutations in TLR3, TICAM1, TRIF, TBK1, TRAF3, UNC93B1, STAT1, IRF3, and MAVS, involved in innate antiviral immune response pathways, have been implicated in increased susceptibility to herpes simplex encephalitis in children or adults (211; 86; 215). Monoallelic variant in one of the autophagy proteins, ATG4A and LC3B2, is linked to recurrent HSV-2 lymphocytic Mollaret meningitis in two adult patients (102).

Medication use

There is limited information on a role for commonly used medications in the progression of herpes simplex encephalitis. One paper raises concern about phosphodiesterase type 5 inhibitors, such as sildenafil (brand name Viagra), after a 62-year-old man developed herpes simplex encephalitis after primary genital infection and use of sildenafil (89). PDE5 inhibitors increase blood-brain barrier permeability.

The immunomodulatory drugs reported to increase the risk of herpes simplex encephalitis, in general, do so by reducing T lymphocytes, the mechanism for maintaining herpes simplex virus latency (189). For example, second-generation disease-modifying therapies for multiple sclerosis have been associated with herpes simplex virus infections due to reactivation (71).

Natalizumab (the monoclonal antibody against the a4 subunit of a4B1 integrin adhesion receptor on the surface of leukocytes, limiting migration of leukocytes across the blood-brain barrier) reduces CD4+/CD8+ T-cell ratio in CSF. Natalizumab labeling includes one fatal case of herpes encephalitis while receiving the medication and one herpes meningitis case who survived. The type of virus of the cases, whether HSV-1 or HSV-2, was not reported in public documents (206). Postmarketing data on natalizumab have yielded five HSV-1 encephalitis cases, five HSV-2 cases (two encephalitis, two meningitis, one meningoencephalitis), and six nontyped as to HSV-1 or HSV-2 (three encephalitis, three meningitis) cases in Europe and in the United States (75). These numbers include the patient with multiple sclerosis who developed HSV-2 meningitis while on monthly natalizumab (206). Other cases had typical medial temporal and insular (204) lesions, bitemporal (129), or atypical parietal lesions (98).

Ocrelizumab (an anti-CD20 monoclonal antibody that depletes circulating immature and mature B cells and spares CD20-negative plasma cells) has been shown to deplete CD3+CD20+ T Cells and indirectly decrease effector memory EM CD8+CCR5+ and EM CD4+CCR6− T Cells corresponded to activated and cytotoxic T cells (82). Ocrelizumab was associated with HSV-2 encephalitis in a 61-year-old man with secondary progressive multiple sclerosis who developed headache and seizures 4 weeks after a second application of ocrelizumab when his CD19 lymphocyte count (B cell marker covering early B cell genesis through maturation) was 5%. The patient, with a CSF monocytic pleocytosis (546 of 559 cells/microliter), positive PCR for HSV-2 in CSF, and MRI with no acute encephalitic lesions, recovered after 3 weeks of intravenous acyclovir (66).

Rituximab (an anti-CD20 monoclonal antibody) was associated with herpes encephalitis in a 30-year-old woman with longstanding multiple sclerosis whose other risk factors included prior exposure to cyclophosphamide, natalizumab, fingolimod, and dimethyl fumarate (232).

One case of (unspecified) viral meningitis and several cases of recurrent oral HSV-1 infections were reported in the study of Alemtuzumab (a monoclonal antibody that recognizes the CD52 receptor site present on mature lymphocytes and monocytes) versus interferon beta-1-a for early multiple sclerosis (39).

Fatal herpes simplex virus encephalitis occurred in one subject taking a 1.25 mg dose of fingolimod during the phase III study of fingolimod versus interferon beta-1-a (49). Additional cases of severe HSV-1 encephalitis (188) and disseminated HSV-2 infection triggering fatal hemophagocytic lymphohistiocytosis (104) have been associated with fingolimod.

A single case of meningococcal and HSV-2 meningitis was reported in a patient treated with ustekinumab for pityriasis rubra pilaris. Ustekinumab is an anti-IL12/23 IgG1 kappa monoclonal antibody approved for treating Crohn disease, ulcerative colitis, plaque psoriasis, and psoriatic arthritis (116).

Overall, long-term treatment with immunomodulatory drugs, and particularly, more than one drug or whole brain radiation used together, has been associated with herpes simplex encephalitis (189).

Recommendations for herpes simplex virus prophylaxis with acyclovir, dosed as 200 to 400 mg orally twice daily, assuming normal renal function, have been “Yes” or “Consider” in the following cases:

	• Alemtuzumab: Yes; From the start of alemtuzumab until CD4+ ≥200 cells/µL and until at least 2 months after alemtuzumab is administered.
	• Natalizumab: Consider on a case-by-case basis, for example, in patients with prior immunosuppression or with frequent oral or genital herpes simplex recurrences.
	• Fingolimod: Consider when coadministered with corticosteroids (except 3 to 5 days of high-dose corticosteroid treatment without tapering) or in patients with frequent oral or genital herpes simplex recurrences.
Adapted from (71).

In Germany, a risk-adapted approach (based on T-cell count) with (val)acyclovir antiviral prophylaxis against herpes simplex virus and varicella-zoster virus is recommended in patients with solid tumors and hematologic malignancies treated with alemtuzumab, bortezomib, or purine analogues (196). Recommended acyclovir doses are 400 mg three or four times daily, and valacyclovir doses are 500 mg two or three times daily.

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Marylou V Solbrig MD

Dr. Solbrig of the University of Manitoba has no relevant financial relationships to disclose.
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Editor

John E Greenlee MD

Dr. Greenlee of the University of Utah School of Medicine has no relevant financial relationships to disclose.
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Former Authors

David N Irani MD
Dena Dubal MD PhD
David D Brown MD

Patient Profile

Age range of presentation: 6 to 65+ years
Sex preponderance: female>male, >2:1
Heredity: none
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-10: Anogenital herpesviral infection, unspecified: A60.9

Herpesviral infection, unspecified: B00.9

Congenital herpesviral [herpes simplex] infection: P35.2
ICD-11: Herpes simplex infection of genitalia or urogenital tract: 1A94.0

Herpes simplex infection of perianal skin or rectum: 1A94.1

Anogenital herpes simplex infection without further specification: 1A94.Z

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Genital herpes: neurologic complications

Differential Diagnosis

mumps
varicella-zoster virus
lymphocytic choriomeningitis
meningitis
measles
- rubella
- enterovirus (Echo 9)
- B19 parvovirus
- dengue
- syphilis
- Lyme borreliosis
- leptospirosis
- rickettsial diseases
- idiopathic inflammatory conditions (sarcoid, Behçet disease, Vogt-Koyanagi-Harada syndrome)
- chemical meningitis
- drug reaction (nonsteroidal anti-inflammatories, trimethoprim-sulfamethoxazole)
- HSV-1
- cytomegalovirus
- Epstein-Barr virus
- human T-cell lymphotropic virus type 1
- West Nile virus
- tick-borne encephalitis viruses
- tuberculosis
- Guillain-Barré
- lymphoma
- metastatic malignant disease
- hyperthermia
- rapid change in mental status to coma
- appearance of new epileptic foci not corresponding to the site of the primary tumor
- temporal lobe localization
- congenital Zika infection

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Molecular diagnosis of CNS infections

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NIH: Meningitis

Genital herpes: neurologic complications

Introduction

Overview

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Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Genetically vulnerable groups

Medication use

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Malaria

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Gram-negative bacillary meningitis

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