Clinical manifestations

Presentation and course

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 (237) and 13% of persons aged 14 to 49 years in 2016 (40).

Acute primary infection. Primary HSV-2 infections in adults, generally acquired through sexual contact, localizes initially to the genital regions of both men and women (51). 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, or 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 (81). 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 (48). The average time between the development of genital lesions and hospitalization for meningitis is 9.3 days (48). 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 has 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% (217; 21), and studies show approximately 4% of patients having genital outbreaks at the time of meningitis (171; 169; 148).

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 more likely reflect primary infection rather than reactivation (10), with host immunity playing a role in disease expression. 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 (18; 70). A number of cases of adult HSV-2 meningoencephalitis have been reported in patients with AIDS. They may have CSF pleocytosis and orbitofrontal and mesial temporal lobe involvement, which is typical of HSV-1 (18; 172). On the other hand, the presentation of herpes HSV-2 encephalitis in the immunosuppressed host may be atypical and may present as severe meningitis (152) with subacute but progressively worsening course (187), with behavior abnormalities, and without fever, headache, or CSF pleocytosis (90), or with normal or nonspecific MRI white matter lesions (18). Risk factors in cancer patients are recent craniotomy, radiotherapy to brain, chemotherapy, and corticosteroid use (87). However, brainstem encephalitis caused by primary HSV-2 infection can occur in immunocompetent adults (212). In one review, an estimated 21% of HSV brainstem encephalitis cases were caused by HSV-2 and 79% by HSV-1; the most common clinical features were neuro-ophthalmologic and cranial nerve abnormalities (136). Immunocompromise by HIV, bone marrow transplant, rheumatoid arthritis treatment, or TNF-alpha inhibitors, was noted in a minority of such patients. Traditionally, 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 (244) and HSV-2 herpes simplex encephalitis to TNF-alpha inhibitor (28) or low-dose methotrexate use in adults (141). The case of HSV-1 reactivation and encephalitis in a 67 year old with pneumococcal meningitis provides an example of CNS bacterial-herpes coinfection (69). The report raises the possibility that HSV-2 coinfections include more than cutaneous manifestations of coinfection, and CNS disease could be included in addition to herpes labialis described in adults with acute bacterial meningitis (227).

HSV-2 encephalitis has also been noted after craniotomy, with most cases involving surgeries in frontotemporal areas, pituitary gland in proximity to the trigeminal ganglion, or fifth cranial nerve decompression (17). Other risk factors are perioperative stress and steroids and factors contributing to immunosuppression.

As more patients with herpes simplex encephalitis are hospitalized early in their course, atypical presentations, such as HSV-2 vasculitis-induced thalamic hemorrhage in a 72-year-old man, have been noted (241). A 57-year-old woman with HSV-2 meningitis and vasculopathy producing hemorrhagic and ischemic stroke improved after treatment with acyclovir and steroids (202). Several cases of HSV-2 meningitis or encephalitis complicated by ischemic stroke have been reported (247; 242). In addition, stroke-like presentations of aphasic disorders without ischemic MRI changes have been reported with HSV-2 encephalitis (86).

Chronic meningoencephalitis. Chronic, active granulomatous HSV-2 encephalitis has been reported in an immunocompetent 8-year-old who was infected as a neonate (32) 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 (161).

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 (67), 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 (48). Signs referable to conus medullaris or lower thoracic cord may accompany infection. Diabetes, HIV infection, or malignancy increase risks of developing ascending myelitis (236).

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 rate of recurrence of HSV-2 infection is an average of 0.3 to 0.4 times per month (48), and several studies have reported frequency of recurrence as high as 60% (41; 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 (216).

The more severe the primary HSV-2 infection, the more likely and frequent the recurrent episodes of the disease (48; 126). 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 (21). 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 afterwards (217). 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 (109). Now, 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 reactivation of 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 appearance of genital vesicles by several hours or days, or pain radiating down into the buttocks and hips, known as “sacral dermatomal neuralgia” (48). Lumbosacral HSV-2 syndromes include an acute sensory neuropathy with delayed sensory nerve conduction velocities (198), stocking-glove distribution numbness and paresthesias, or unilateral sciatica (154). 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 (21). 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 (240).

In other circumstances, recurrent, difficult to treat, or chronic genital herpes indicate other types of immune dysregulation. For example, persistent genital herpes can signify underlying thymoma in a myasthenic patient years after transsternal thymectomy (186).

Over 40% of septic patients develop viremia with multiple viruses that include herpes family viruses released from latency (223). 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 (124). Conceivably, there may be a role for Herpesviridae reactivation 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 an epiphenomenon of the inflammatory disease process (166).

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 (57; 221; 203). 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; 204).

Cranial neuritis. Although 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 (196) and HSV-1 or 2 DNA can be found in the CSF of ON patients (170).

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 the treatment of Bell palsy (78; 95).

Genital herpes simplex virus type 1 in adults. Although most genital infections had been caused by HSV-2, a larger proportion is now occurring due to HSV-1 (103). 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 (197).

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 (174).

Dual strain infections. Investigations of multiple strain herpes simplex virus reinfection have shown dual strain HSV-2 genital infections with novel variants to be more frequent in HIV-positive patients and in people from Africa (130). Except for these groups, dual infection has been rare; therefore, naturally occurring immunity to HSV-2 may protect against a second strain in others (174).

Genital herpes zoster. Unilateral penile vesicular lesions due to varicella zoster virus were reported in an HIV-positive patient (137). Prior to 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 (26); and in a newer New York study, varicella zoster virus was detected in male and female genital specimens by multiplex PCR assay (88).

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 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 risk of vertical transmission is higher with HSV-1 than HSV-2 (81).

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 (55). Untreated with antivirals, 75% of babies with skin, eye, and mouth infection progress to CNS or disseminated disease (232; 112). 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, microphthalmia, and is recognized at the time of birth.

Acute retinal necrosis (ARN). Acute retinal necrosis caused by HSV-2 is now 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 (89). 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 (125). 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 (91). Early antiviral therapy limits extent of necrosis and decreases risk of retinal detachment and involvement of the opposite eye.

Prognosis and complications

Although an episode of HSV-2 meningitis is usually self-limited, almost half of 40 consecutive patients had verified or suspected neurologic recurrences during the first year after HSV-2 meningitis (11). Recurrent episodes of aseptic meningitis are also self-limited and resolve without long-term neurologic sequelae. In the series of patients followed after their initial episode of HSV-2 meningitis, symptoms of urinary retention, dysesthesias, paresthesias, headaches, and concentration difficulties, although common after the acute infection, had uniformly resolved within 6 months of the original illness (20). 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 (48; 83), although most cases encountered today receive antiviral treatment (238; 66; 240). 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 (236; 74; 160). 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 (164), UNC-93B deficiency, a gene encoding an ER transmembrane involved in toll signaling (38), TLR3 deficiency (244), and others, reviewed by Koelle and Corey (118)]. 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 (179).

In the elderly, HSV-1 infection in brain in combination with apoE4 genotype has been reported to increase risk of Alzheimer disease, and apoE4 genotype to increase risk of HSV-1 cold sores (99; 102). Conceivably, the different isoforms of APOE protein (types 2, 3, 4) might have differential effects on HSV-1 cell entry (100). HSV-1 as oral herpes and -2 as genital herpes can trigger amyloid-beta protein aggregation (101), and HSV-1 DNA is present in amyloid plaques (58).

Epidemiologic studies from Asia and Europe report that antiviral treatment for herpes simplex virus can reduce the risk for Alzheimer disease and other dementias. In one study, patients 50 years and older who were newly diagnosed with herpes simplex virus, as genital or labial infection, were found to have an almost 3-fold higher risk of any type of dementia (Alzheimer disease, vascular, and other) after 10 years, compared to a control group with no herpes simplex virus infection during the index year (218). Antiviral treatment reduced incidence of dementia at the 10-year follow up.

The current 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 (59). 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 (59). A small VALZ-pilot performed in Sweden (a phase 2 study of 4 weeks high-dose valacyclovir to persons greater than 65 years of 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 (228).

The role of viral polymorphisms in severity of herpes simplex virus CNS disease is not completely 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 diseases, may uncover neurovirulent phenotypes defined by strain-specific neuroinflammatory patterns, independent of host genetics (246).

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 (162). An adult with IgM antibodies to herpes simplex virus had opsoclonus-myoclonus (43). Possible pathogenic mechanisms include molecular mimicry (based on sequence or structural similarities), or super- or cryptic-antigen exposures by the virus.

Autoantibodies against neuronal surface, unclassified neural or nonneural IgG antibodies, and herpes virus DNA can coexist in encephalitic CSF (133; 77). Direct CNS viral infection and activation of immune-mediated disease may occur early in disease, with NMDA receptors detected on hospital admission (181). On the other hand, autoimmune encephalitis may be the cause of recurrent CNS encephalitic disease. The growing numbers 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 (82). 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; 82; 165; 168). 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; 204). 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 (61).

Besides anti-NMDA receptors, rare cases of anti-dopamine-2 receptor (D2R), anti-GABAb, anti-voltage-gated calcium channel, and LGI-1 antibodies have followed herpes simplex encephalitis (151; 29; 02; 177). One case of herpes simplex virus encephalitis had simultaneous Caspr2 antibodies in serum (16). Anti-NMDAR cases may be more frequent since 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 have the potential to reduce neurologic sequelae, persistent immune activation, and autoimmune encephalitis (179).

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 (225).

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%) (103). All babies, regardless of disease classification, should be considered at risk for CNS complications. Untreated, or receiving ineffective antivirals (idoxuridine or cytosine arabinoside), neonates with CNS disease 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 (231). 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-2 infection, as a genital ulcerative disease, may be associated with acquisition of both HIV-1 and human T-cell lymphotrophic virus type 1 (159; 97). In sub-Saharan Africa, HSV-2 has been the leading cause of genital ulceration, contributing to the HSV-2 and HIV syndemics. Infection with HSV-2 is associated with increased genital shedding of HIV-1 RNA and HIV-1 transmissibility (Wald and Link 2002; 53).

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 (76; 155). IRIS is suggested as a mechanism of HSV-2 reactivation, shedding, and genital ulcer disease recognized in Ugandan women initiating antiretroviral therapy (215). Like IRIS and more common among individuals with higher viral loads, HSV-2 shedding was most common among women with the highest HIV load prior to 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) (180). For herpes simplex, even latent viruses express proteins capable of driving chronic symptoms. Elevated cytokine expression is known to persist even when the virus is latent (nonreplicating) in peripheral nerve ganglia (42). 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 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 exam 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) (66). 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) (147) 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 (240). 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 continues on lifelong oral acyclovir given his immunocompromised state.

In the 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 management of genital herpes, particularly in patients with adequate HIV viral suppression and rising CD4 counts (175).

Biological basis

Etiology and pathogenesis

Clinical syndromes are caused by infection with HSV-2, a double-stranded DNA virus. 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 (144).

Genital route transmission is the usual way HSV-2 is acquired by adults. 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, after another round of viral replication in ganglia, latency is established.

All herpesviruses have the ability to become latent, persist in inactive state for variable time periods, and be reactivated by provocative stimuli. Latent virus has been recovered from trigeminal, sacral, and vagal ganglia of humans by explant co-cultivation (14; 13). The sacral ganglia are the main but not exclusive sites of HSV-2 latency. HSV-2 DNA at low copy number has been detected in ganglia throughout the neuraxis (18). Thus, HSV-2 viral DNA can be found in neuronal tissue in the absence of rash or cutaneous lesions (167). 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) (216).

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 (207), and animal studies (03).

The most acknowledged and studied route of entry for HSV into the CNS is neuronal. Intra-axonal spread into 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 (236). 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 cord, inflammation, intraparenchymal viral particles, and poor recovery is seen (236).

Transmission of HSV-2 infection through renal transplantation has been reported (64), so competent virus can disseminate by hematogenous spread as well.

Another potential mechanism of HSV CNS invasion is injury of brain microvascular endothelial cells. Recent in vitro experimental work shows infection of microvascular endothelial cells by either HSV-1 or -2 reducing cell-cell barrier resistance, with loss of viability of infected endothelial cells opening the blood-brain barrier (127).

Host immune responses have a role in outcomes and disease severity. The variable natural history and outcomes of infection are consistent with a role for both cytolytic viral replication and host immunity in pathogenesis. The important post-herpes simplex encephalitis postviral syndrome of autoimmune encephalitis may result from: molecular mimicry, herpesvirus-specific properties trigger host autoimmunity, antigenic material released by neuronal injury become autoimmune foci, or heritable or baseline immunity risk factors (79; 204).

Neonatal encephalitic disease yields 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, hematogenous spread of virus is consistent with finding systemic, disseminated disease and diffuse brain involvement. Any part of the brain may be affected, including grey and white matter of cerebrum, cerebellum, or brainstem. Necrotizing encephalitis is accompanied by lymphocytic and monocytic infiltrates of meninges and parenchyma. Nuclear inclusions, viral antigen, 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 of cystic encephalomalacia.

Epidemiology

The appearance of HSV-2 antibodies reflects acquisition of infection and correlates with 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 reduced frequency of viral shedding (188). 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 (12).

Still, infection with HSV-2 is common throughout the world. There are an 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) (139). 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 (128). 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%) (159). Factors that influence 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) (230). Meningitis is more common in women (36%) than men (13%) after primary genital HSV-2 infection (48), whereas lumbosacral involvement is more common in homosexual men with HSV-2 proctitis (83). 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 (126). Across several studies, no consistent relation between genital herpes and HSV-2 meningitis was found (148).

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 (31), 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) (122).

A second Finnish study has shown 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 (108).

The mechanisms of susceptibility and severity of HSV-2 infection are incompletely understood, but appear to 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 (211). The same protective allele rs3775291 is also thought to confer natural resistance to tick-borne encephalitis virus (115) and HIV-1 (200). Mutations in TLR3 and TLR3 pathway genes producing TLR3 deficiency (TLR3, TICAM1, TRIF, TRAF3, UNC93B1, TBK1, and IRF3) are risk factors for herpes encephalitis (200; 204) and predictive of herpes simplex encephalitis recurrence (129). 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 (243).

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 (153; 121).

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 (96). 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 (96).

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 (96).

A synergy between HSV-2 and HIV-1 has been shown in clinical and epidemiological studies (220). In HIV-1-infected persons, high rates of HSV-2 infection are also common, ranging from 50% to 90% in studies of HIV-infected populations around the world. Genital herpes in persons with HIV infection is associated with more severe and chronic lesions, as well as increased rates of genital shedding of virus (210). Biological mechanisms for the HIV/HSV-2 comorbidity or epidemiological synergy have mainly focused on HSV-2-mediated inflammation. HSV-2 reactivation in an HIV-negative individual increases numbers of CD4+ cells recruited to genital HSV-2 lesions to serve as targets for HIV (245), and HSV can stimulate HIV replication through cytokines released from HSV-infected cells (173). In addition, HSV immediate-early gene products can increase HIV-1 transcription in vitro (132). Providing anti-HSV treatment for 3 months to co-infected persons 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 (157), and reduces HIV-1 disease progression, as measured by a fall in CD4 counts below 350 cells/microL (131).

Several additional randomized trials are testing whether HSV-2 treatment can limit the spread of HIV. The results are mixed. Although treatment with acyclovir 400 mg twice daily does not reduce HIV incidence or transmission, suppressive acyclovir and valacyclovir reduces HIV levels in plasma, seminal fluids, and genital and rectal tracts (56; 39). Although the demonstration of direct inhibitory action of phosphorylated acyclovir on HIV-1 reverse transcriptase in a cell-free system offers new insights into analysis of these results (135), 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 (134).

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 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. (232; 231; 140). The per-delivery risk of neonatal infection is higher in maternal primary infection in which IgG antibody is lacking than in maternal chronic infection, in which a mature IgG response can cross the placenta. The difference implies protection by passively transferred antibody (33). Neonates who acquire infection by birth canal delivery develop CNS infection in 50% of cases (112).

The incidence of neonatal herpes infections worldwide is estimated at 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 Western Pacific (138).

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 (103; 231).

Virus type is an outcome determinant for babies with encephalitis. 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 (231). 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 (111).

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 (143).

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 (94).

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 (119). 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 (119).

Prevention

Preventing the neurologic complications of HSV-2 begins with preventing person-to-person transmission of the virus. Suppressive antiviral therapy is valuable in managing some complications of recurrent genital herpes. The International Herpes Management Forum (IHMF) now recommends 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 (49). The U.S. Food and Drug Administration has approved valacyclovir for prevention of HSV-2 transmission. However, the protective benefit of daily suppressive therapy is incomplete. Valacyclovir only halves the transmission rate of HSV-2 to an uninfected partner (54).

Because peak HSV replication occurs rapidly after reactivation of latent virus, there is a narrow window of opportunity to prevent replication using an antiviral agent. A single-day, high-dose, patient-initiated therapy regimen of famciclovir (1500 mg single dose or 750 mg twice daily, single day) is reportedly effective in the treatment of recurrent genital herpes in immunocompetent adults and now is licensed (176). Three-day treatments with valacyclovir, 2-day courses with acyclovir, and 1- or 2-day courses with famciclovir can all be used in treating recurrences of genital herpes (50).

Acyclovir, valacyclovir, and famciclovir effectively suppress HSV-2 reactivation in persons co-infected with HIV-1 and HSV-2 (226; 210). 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 (210).

Use of topical microbicides such as resiquimod, a toll-like receptor 7 and 8 agonist that induces interferon-alpha, is under investigation for treating mucosal infection and prevention of HSV-2 infection (142).

Strategies to prevent neonatal acquisition of HSV-2 infection include caesarean section delivery and use of suppressive therapy in the seropositive partner of a seronegative gravid woman. For pregnant women with active genital herpes, caesarian 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 (34). 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 need for caesarian section (191; 194). 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 (208).

In the United Kingdom, the Royal College of Obstetricians and Gynaecologists has recommended caesarian 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 caesarian 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 (185; 209). 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 (208).

Vaccination. Although HSV-2 infections can be controlled by the use of orally bioavailable antiviral drugs, 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 (157), HSV-2 vaccines are public health priorities (105). To date, however, no vaccines have been licensed.

The objective of a prophylactic vaccine will be 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 that 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 with 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 (205; 117). 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 sero-status (206). 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 vaccine failed to prevent HSV-2 infection and disease. The investigational vaccine was effective in preventing HSV-1 genital disease and infection but not in preventing HSV-2 disease or infection (15). 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. To accomplish this, the vaccine should enhance the host's specific immune responses. Probably the therapeutic vaccine will have to boost different immune responses than that of a prophylactic vaccine. The success of prophylactic vaccines has not been observed in therapeutic vaccine trials when the same prophylactic vaccines were used (183). The finding of substantial genetic conservation between primary and recurrent episodes of genital HSV-2 infection (150) 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 (139). 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 replicates in mucosal tissues but are ablated for neuroinvasion, and technologies that target virus-specific CD8 T-cell responses, are being developed and studied (117; 24; 22; 23). The preclinical pipeline includes subunit, whole virus, DNA and attenuated or mutated live virus platforms (188). Vaccines that elicit both effector/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 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 (118).

A therapeutic herpes simplex virus vaccine is more challenging than the live attenuated and subunit varicella zoster virus vaccines currently in use. Distinct from varicella zoster virus, herpes simplex virus reactivates frequently with a larger repertoire of genes that escape host immune response (47).

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 (234).

Importantly, herpes simplex virus vaccines could substantially impact 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 (75).

Developers of any herpes simplex virus vaccine will also be required to take into account the results of the STEP HIV vaccine trial (35). 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 (192). Therefore, any effective HSV vaccine should not induce a mucosal CD4+ T cell response that would increase the risk for HIV (188).

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 plasma of patients with primary herpes genitalis, deferral of blood donations from individuals with primary herpes infections is recommended (107). The current 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 include 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 (231). 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 (106). 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 (199). Therefore, polymerase chain reaction procedures capable of detecting 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 (213; 36). The tests are particularly useful in evaluating HIV-infected patients with neurologic disorders related to human herpesviruses (182).

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 (93) and as reversible progressive cognitive decline in a 78-year-old man with B cell chronic lymphocytic leukemia (219). 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 (63). 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 (73).

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, or sarcoidosis.

Evaluation of the septic-appearing newborn with CSF pleocytosis and elevated protein includes CSF examination for herpes simplex virus types 1 and 2, as well as 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 timing of the study with respect to disease course (163). Infants with perinatal/postnatal HSV-2 encephalitis may have diffuse bilateral disease or periventricular white matter lesions and meningeal enhancement on MRI (116), including extensive diffusion restriction of thalami, corpus callosum, frontal cortex, corticospinal tracts, and subcortical white matter (214). 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) (111). 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 (27).

Viral causes of acute retinal necrosis in childhood include varicella-zoster virus, cytomegalovirus, HSV-1, as well as 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 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 in the differential diagnosis (25).

Diagnostic workup

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 (20). Neuroimaging and EMG nerve conduction velocity studies are performed as needed. Spinal MRI may be normal in radiculomyelitis cases.

Herpes simplex virus polymerase chain reaction of genital lesions has been more sensitive than viral culture in determining etiology of genital ulcer disease. Currently, 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 (81). 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 (236).

Neonatal herpes may occur in the absence of skin lesions, so if the 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 for disseminated infection includes liver function tests, complete blood count, CSF, and chest x-ray (112). The genomes of HSV-1 and HSV-2 have approximately 70% homology. HSV type differentiation can be by type-specific glycoprotein antibody response, restriction endonuclease fingerprinting, and DNA sequencing (103).

Management

Management is symptomatic, along with empiric antiviral and antibiotic treatment, until a diagnosis is available. Adjunctive steroid therapy is used in select brainstem encephalitis cases (136) or in edema cases with risk of herniation or CSF block. CNS injury that occurs during herpes simplex encephalitis is caused by viral replication and excess inflammatory response. Currently, 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 (146). DexEnceph, sponsored by University of Liverpool and University of Grenoble, is the current multinational study of dexamethasone in adults with herpes simplex virus encephalitis, having made changes in GACHE admission criteria and endpoints (179). The study is a randomized control trial examining the clinical benefit of 4 days of 10 mg dexamethasone every 6 hours added to acyclovir, with a primary endpoint the impact on verbal memory score (60; 179). Expected to finish in 2021, study results are pending as of December 2022.

There is anecdotal evidence that acyclovir can be effective in the treatment of HSV-2 meningitis, whereas some reviews report lack of efficacy of suppressive antiviral treatment of Mollaret meningitis (231). 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 can shorten the symptomatic period, improving signs and symptoms of meningitis within 72 hours. Oral agents may also work in such cases (216). Meningitic doses are lower doses than recommended by the IHMF for herpes simplex encephalitis (acyclovir 10 mg/kg intravenously every 8 hours for 14 to 21 days) outside the newborn period. Differentiation of 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 elimination of replicating virus (216).

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 (66). 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 (210). 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 deletion of the HSV thymidine kinase (tk) gene. Less often, resistance is due to HSV-tk gene or viral DNA polymerase mutations (71). Infrequent case reports of resistance to acyclovir link resistance to very high viral loads (105 or greater) in CSF (231). HSV clinical isolates are quasispecies composed of acyclovir-sensitive and -resistant variants, with resistant variants presumably achieving critical numbers in these cases.

At present, 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 immunoprivileged sites such as cornea (149). 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 indicate a more important role for DNA polymerase mutations in acquisition of acyclovir resistance in HSV-2 isolates (149).

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 (189) or 90 mg/kg intravenously every 12 hours for 14 to 21 days (19). Resistance to nucleoside analogues previously estimated as rare (less than 5%), without significant increase since acyclovir was introduced more than 20 years ago (132), could ultimately be higher in immunocompromised patients receiving long-term prophylactic treatment with acyclovir (44). Cidofovir, another nucleoside analogue, phosphorylated to its active form by cellular enzymes, is another potential second-line drug (156). Tk-negative HSV-1 mutants, without neurovirulence in animal studies, have been thought to be less neurovirulent in humans (189).

The IHMF recommends that neonates with suspected herpes simplex virus encephalitic infection be treated with intravenous acyclovir (20 mg/kg) every 8 hours for 21 days. If the disease is localized to skin, eyes, and mouth, treatment is for 14 days, but neuroimaging is indicated even with mild (skin, eye, or mouth) presentations of disease (231). 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 (112). Thus, PCR provides a quantitative guide to treatment and is used to determine 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 (114). HSV-1 infections of the brain do not benefit from extended oral antiviral therapy, nor did 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. (80).

In suspected or proven herpes simplex virus disease in neonates, when acyclovir is not available, it is recommended that the patient be treated with intravenous ganciclovir (6 mg/kg) every 12 hours, and intravenous foscarnet (60 mg/kg) every 12 hours can be used as second-line therapy (224).

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 (179).

Prophylaxis and treatment strategies are also tailored to pediatric recipients of hematopoietic stem cell transplants because recipient serostatus is an identified risk factor for herpes simplex virus infections (65).

Shorter episodes or resolution of Mollaret meningitis with antiherpes treatment have been reported. However, therapy does not affect the viral reservoir in dorsal root ganglia.

Mostly, 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 developed 30 years ago. Thiazolylamide pritelivir (BAY 57-1293) is the first of a new class of antiherpes viral agents that inhibit viral replication by targeting the viral helicase-primase enzyme complex, and shows efficacy in suppressing viral shedding and lesion development in patients with genital herpes (222). In the case of genital infections, resistance may be suspected when lesions last for more than 1 week after initiating antiviral treatment, or new satellite lesions appear during treatment.

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 (45). The potential for combination therapy for those with life-threatening herpes simplex virus infections (beyond foscarnet and cidofovir) may now 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 (104). For example, HIV integrase inhibitors block replication of alpha, beta, and gamma herpesviruses in vitro (239). Because immunocompromised patients are at risk for multiple herpesvirus infections, a broad-spectrum agent, such as brincidofovir, would also be considered in prophylactic regimens (104) and is under investigation in herpes simplex encephalitis models (179). 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. Multiple determinants of outcome are speed of initiating treatment, high level nursing care, management of complications such as cerebral edema, age, and level of consciousness (184).

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) (52). 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 (231).

Special considerations

Pregnancy

Clinical manifestations of recurrent genital herpes infections are similar in pregnant and nonpregnant women (48). 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 (190; 191; 194). Based on combined data of acyclovir and valacyclovir, there does not appear to be any major risk to the fetus from acyclovir or valacyclovir (30). 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 (103). 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 (231).

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 (200; 82; 204). Monoallelic variant in one of the autophagy proteins, ATG4A and LC3B2, is linked to recurrent HSV-2 lymphocytic Mollaret meningitis of two adult patients (96).

Medication use

There is limited information on a role for commonly used medications in progression to 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 (85). PDE5 inhibitors increase blood brain barrier permeability.

The immunomodulatory drugs reported to increase risk of herpes simplex encephalitis, in general, do so by reducing T lymphocytes, the mechanism for maintaining herpes simplex virus latency (179). For example, second generation disease modifying therapies for multiple sclerosis have been associated with herpes simplex virus infections due to reactivation (68).

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 on public documents (195). 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 (72). These numbers include the multiple sclerosis patient who developed HSV-2 meningitis while on monthly natalizumab (195). Other cases had typical medial temporal and insular (193) lesions, bitemporal (123), or atypical parietal lesions (92).

Ocrelizumab (an anti-CD20 monoclonal antibody that depletes circulating immature and mature B cells and spares CD20-negative plasma cells) 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 (63).

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 (37).

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 (46). Additional cases of severe HSV-1 encephalitis (178) and disseminated HSV-2 infection triggering fatal hemophagocytic lymphohistiocytosis (98) 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 treatment of Crohn disease, ulcerative colitis, plaque psoriasis, and psoriatic arthritis (110).

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 (179).

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: