Herpes Simplex Encephalitis

Etiology

HSV-1 and HSV-2 are members of the human herpesvirus family, which also includes varicella-zoster virus (ie, HHV-3), Epstein-Barr virus (HHV4), cytomegalovirus (HHV-5), HHV-6, HHV-7, and HHV-8 (Kaposi sarcoma-associated herpesvirus). All human herpes viruses except HHV-8 are known to cause encephalitides, though HSV-1 (about 90% of cases) and HSAV-2 (about 10% of cases) cause the vast majority of cases. 

HSV-1 and HSV-2 comprise large double-stranded DNA sequences protected by an icosahedral capsid and covered with an envelope containing viral glycoproteins. Herpesvirus entry mediator (HVEM) and the nectin proteins are herpesvirus binding sites on the host cell surface. Nectin-1 is especially important for viral entry of HSV into the nervous system.[12] 

In adults, viral factors and host immune responses determine virulence and invasiveness. Initial infection occurs when the herpesvirus infects epithelial cells of the mucosa or skin. The virus is then endocytosed by peripheral neuron axon terminals and conveyed in a retrograde manner to the cell bodies, where it takes up latent residency.[4] The complex mechanisms known to maintain the latency include suppression of viral lytic-phase genes through histone deposition by pattern recognition proteins, cytokine production activating the intrinsic immune system, and other mechanisms. The intrinsic immune system is activated first, followed closely by the innate immune system. In immunocompetent hosts, systemic infection does not occur.[5]

Epidemiology

HSV-1 is the most common cause of life-threatening sporadic encephalitis across the globe and does not exhibit any seasonal variation. About 60% to 90% of older adults worldwide are seropositive for HSV-1. In populations with higher sexual transmission of HSV-2, the prevalence is typically higher in women than men and is also age-related.[6] A survey conducted in the US from 2005 to 2010 among persons between 14 and 49 years found seropositivity for HSV-1 and HSV-2 at approximately 54% and 16%, respectively.

The annual incidence of herpes simplex encephalitis is about 2 to 4 per million population worldwide. Up to 70% of patients die without treatment, and mortality is 20% to 30% even with appropriate treatment.[7] About 20% to 50% of encephalitis cases result from viral infection, and HSVs are responsible for 50% to 75% of these viral encephalitis cases.[8]

 A multicenter population-based study identified herpes simplex as the UK's most common cause of infectious encephalitis.[9] HSV is again the most common pathogen identified in hospitalized encephalitis patients in Australia.[10] The incidence of HSV-1 encephalitis appears to be almost similar in Sweden and the United States.[7][11]

Though all age groups are affected, the incidence is most common and severe in children and older adults. Almost one-third of the cases occurred in children and adolescents, and half of the patients were older than 50 years.[12] Both sexes are equally affected.[9]

Pathophysiology

Transmission of HSV-1 and HSV-2 requires close contact between individuals. Initial primary infection of the skin or mucosa and subsequent intraepithelial viral replication causes inflammation and tissue damage, resulting in the characteristic herpes blisters.

HSV-1 commonly causes an initial infection manifested by oral lesions (fever blisters), which might follow a remitting and relapsing course with decreasing frequency, severity, and duration. HSV-2 infection usually causes genital lesions, which are noted to occur about one or two weeks after primary infection. The severity of relapses wanes over time as the host immunity slowly improves.[29]

About 30% of herpes simplex encephalitis is due to primary infection, while the remainder is attributed to reactivation of or reinfection with HSV-1. There are presumably three routes by which the HSV-1 is thought to enter the brain from the initial peripheral site of infection. The first path is from the site of primary oropharyngeal infection to the brain via the trigeminal or olfactory nerves. The second mechanism involves the same neuronal pathways from the reactivation of an initial peripheral infection. The last mechanism is due to the reactivation of the latent in-situ HSV-1 in the brain.[13] Neuronal cell destruction results from both direct injury caused by the virus and cell injury due to an overactivated immune system.

Herpes simplex encephalitis usually affects the temporal lobes and the adjacent limbic systems. Meningeal congestion is frequently observed. Brain involvement is more diffuse in newborns. Immunocompromised patients may have atypical and more extensive tissue involvement, with lesions in the brainstem, cerebellum, and cerebral cortex.[29]

People taking certain immunosuppressive drugs (eg, natalizumab, OKT-3, alemtuzumab) or anti-inflammatory agents (eg, TNF-α inhibitors) are also found to have increased susceptibility to HSV-1 encephalitis. Cases of herpes simplex encephalitisafter whole-brain radiation therapy have also been reported.[14] 

Histopathology

On gross specimen, lytic and hemorrhagic areas are often noted in the medial part of the temporal lobes and the inferior part of the frontal lobes. The pathognomonic feature seen on brain biopsy is hemorrhagic encephalitis in orbitofrontal or limbic specimens.[15]

In the early stages of herpes simplex encephalitis, infected neuronal cells show decreased cytoplasm, suggesting acute ischemia associated with capillary dilation and hemorrhage. Cowdry type A inclusions, consisting of large, eosinophilic intranuclear inclusions, are found with HSV and varicella zoster infection. Viral antigens are detected mainly in the medial and inferior temporal lobes, amygdaloid nuclei, hippocampus, insula, cingulate gyrus, and olfactory cortex (which may serve as a port of entry). Neutrophil infiltration of infected brain areas occurs 2 to 3 days after onset of the disease, whereas macrophages and lymphocytes predominate after 10 to 15 days. After 3 weeks, the cellular necrosis progresses to frank necrosis, with inflammation and gliosis. Detection of viral antigens is decreased at this stage.[8]

In immunocompromised patients, lesions can be atypical, showing noninflammatory lesions, less hemorrhage and necrosis of brain tissue, and ongoing viral antigen detection longer than 3 weeks after infection.[8]

History and Physical

The clinical presentation of herpes encephalitis can be acute or subacute. A prodromal phase of fever, malaise, headache, and nausea often precedes more severe neurologic symptoms. The typical clinical features of HSV-1 encephalitis include altered mentation lasting more than 24 hours and associated with other features of brain inflammation, including fever, headache, seizures, and focal neurologic deficits. Cognitive, behavioral, and personality changes have also been described. Other associated features include urinary and fecal incontinence, aseptic meningitis, rashes with dermatomal distribution, and Guillain-Barré syndrome. Benign recurrent meningitis is an atypical manifestation. The behavioral syndromes mentioned above include hypomania, Klüver-Bucy syndrome, and varying degrees of amnesia. Behavioral or personality changes are often misdiagnosed as psychiatric disorders.

The most common physical findings include fever and altered mentation. Meningeal signs may be detected, but meningismus is present less than half the time. Neurologic deficits are usually acute, with a duration often less than a week, and usually include focal cranial nerve palsies, hemiparesis, dysphasia, aphasia, ataxia, visual field defects, or papilledema. The anterior opercular syndrome has been described as an initial presentation associated with encephalitis.[16] 

One large study found a prevalence of the following symptoms in herpes simplex encephalitis: fever (80%), confusion (72%), abnormal behavior (59%), headache (58%), decreased mental status (58%), seizures (54%), focal neurological disabilities (41%), nausea and vomiting (40%), aphasia or altered speech (40%), coma (33%), and meningismus (28%).[8] 

Childhood herpes simplex encephalitis presents with clinical features, including fever, lethargy, altered behavior, sleepiness, and focal seizures or neurological abnormalities. Herpes simplex encephalitis in neonates usually manifests between 1 to 3 weeks of life. Features include irritability, lethargy, and poor feeding associated with tremors or fits. Herpetic skin lesions are common in neonatal encephalitis. Altered liver function tests and thrombocytopenia are common when encephalitis occurs as part of multi-organ involvement. HSV-2 may rarely manifest with associated myelitis.

The presentation could be atypical or subtle in immunocompromised patients, who can have fewer prodromal symptoms and focal neurologic deficits than the immunocompetent, making the diagnosis more complicated.[8] As noted above, certain medications, especially those affecting T-cells, can predispose patients to herpes simplex encephalitis. 

Evaluation

No clinical features are pathognomonic of herpes simplex encephalitis. Therefore, the workup should be expedited without delaying the treatment. A high index of suspicion is needed, especially in immunocompromised patients presenting with febrile encephalopathy. Previously, the gold standard for herpes simplex encephalitis was brain biopsy, which is rarely performed now. Currently, the gold standard is cerebrospinal fluid (CSF) analysis from lumbar puncture performed as early as possible. Lumbar puncture is contraindicated in the presence of brain shift, herniation, or any other signs of increased intracranial pressure.[8]

CSF findings often include an elevated opening pressure, elevated protein level, normal glucose level, and pleocytosis with lymphocyte predominance. Elevated CSF WBC has a 95% sensitivity but may be absent early in the infectious process, in children, or the immunocompromised. Elevated RBC may be present as temporal hemorrhage is common. Amplified polymerase chain reaction (PCR) should be performed for HSV-1 and HSV-2 and has a sensitivity and specificity of 96% and 99%, respectively.[8] Usually, PCR will be positive for HSV during the first week of treatment with acyclovir and will become negative for HSV after 10 to 14 days of treatment.

False-negative tests may result from lower viral load in the initial 72 hours or due to the presence of blood in the CSF, as hemoglobin can interfere with the PCR. A false negative PCR could also be caused by acyclovir therapy ongoing for longer than 48 hours. A negative PCR obtained in a patient with a high pretest probability obtained within 3 days of the onset of symptoms should be repeated to rule out herpes simplex encephalitis. In the case of high pretest probability with an initially negative HSV PCR, the 2008 Infectious Diseases Society of America (IDSA) guidelines recommend continuing acyclovir therapy and repeating CSF PCR within 3-7 days. HSV PCR positivity in the blood has been reported in neonates and immunocompromised with herpes simplex encephalitis. This may help in indirect diagnosis in patients where lumbar puncture may have to be temporarily deferred due to various issues.

Identifying intrathecal synthesis of HSV-specific IgM antibodies can be valuable for diagnosing HSV encephalitis, especially when the CSF samples are unavailable or only available more than 1 week after treatment initiation.[17] Relying solely on serum serology is ineffective in diagnosing HSV encephalitis due to the high prevalence of HSV antibodies (IgG) in the general population. CSF antibodies to purified HSV glycoprotein B have a sensitivity of 97% and a specificity of 100%. Though a four-fold rise in viral antibody titers is expected to occur during the course of the illness, the initial detection is possible only after 10 to 14 days of illness, thereby helping only in late diagnosis.

Routine blood tests include CBC, coagulation studies, and basic metabolic panel. These may show an elevated WBC with lymphocytosis or be within normal limits.

A computerized tomography (CT) scan is often the first test performed to evaluate for midline shift, bleeding, or increased intracranial pressure. It is less sensitive than MRI and often shows no abnormalities in early infection. It may take 3 to 4 days to manifest the changes in the temporal or frontal lobes. Hypodensities, hemorrhage, and edema are often noted, while contrast enhancement may take almost a week.

Magnetic Resonance Imaging (MRI) is considered a more definitive test and is more than 90% sensitive in detecting abnormalities with herpes simplex encephalitis. T1, T2, diffusion-weighted images, and FLAIR sequences are usually performed. Lesions are usually hypodense on T1 and hyperintense on T2 and FLAIR images. The classic abnormality involves the temporal lobes (either unilaterally or bilaterally) showing early white matter changes, sometimes associated with hemorrhage, that progress along the limbic system to the inferior frontal lobes and insular cortex. High-resolution FLAIR sequences can detect thalamic abnormalities not seen on DWI sequences. The basal ganglia are typically spared. Children may have atypical patterns of MRI lesions and often show involvement outside the frontotemporal regions. Immunocompromised patients often have broader brain involvement and can include the brainstem and cerebellum.

Electroencephalogram (EEG) is frequently abnormal, and the medial temporal and hippocampal regions affected by herpes simplex encephalitis are highly epileptogenic. The typical EEG pattern shows recurrent, uniform, sharp-and-slow complexes originating in either one or both temporal lobes, repeating at consistent intervals of 2 to 3 seconds. These periodic complexes tend to manifest within a 2- to 15-day window after the onset of the illness and are observed in approximately two-thirds of confirmed HSV encephalitis cases. Periodic waveforms or paroxysmal lateralizing epileptiform discharges (PLED) are highly consistent with herpes simplex encephalitis in the appropriate clinical settings, though their absence does not rule out herpes simplex encephalitis. EEGs may also display prominent intermittent high-amplitude slow waves over the affected temporal areas. Diffuse slowing patterns are also described.[18]

Treatment / Management

Emergency management strategies include assessing the airway, breathing, and circulation and taking appropriate measures accordingly. A lumbar puncture should be followed unless contraindicated. Intravenous (IV) acyclovir should be started in all adults with suspected or confirmed cases of herpes simplex encephalitis at 10 mg/kg body weight every 8 hours. Children up to 11 years and neonates are treated with higher doses (15-20 mg/kg body weight). Ideal body weight is used for dose calculation in obese patients. It is worth noting that acyclovir penetrates the cerebrospinal fluid effectively, with drug levels approximately 50% of serum levels. Its mechanism is by acting as a guanosine analog phosphorylated by thymidine kinase, inhibiting the viral DNA polymerase.[19]

A large retrospective study showed a delay in initiating acyclovir for more than 48 hours as one of the factors associated with poor outcomes, leading to death in 13 patients (15%) and severe disability in 17 (20%) of 93 adult patients.[20] Viral and host cellular enzymes affect the conversion of acyclovir into acyclovir triphosphate, a strong inhibitor of HSV DNA polymerase, thereby inhibiting viral replication.(B2)

Acyclovir resistance can arise due to viral deoxypyrimidine kinase or DNA polymerase alterations. So far, acyclovir-resistant strains have not been a significant concern in immunocompetent individuals. Resistance to acyclovir is significantly higher in immunocompromised patients when compared with immunocompetent persons. Acyclovir resistance is usually managed with IV foscarnet or cidofovir. One study found after an initial standard course with IV acyclovir, routine administration of oral valacyclovir for three months did not provide any additional neuropsychological benefits in herpes simplex encephalitis patients when measured at 12 months.[21] 

The efficacy of acyclovir has been studied in several landmark randomized control trials.[22][23] Acyclovir is a relatively safe drug with a few major side effects, including thrombophlebitis related to extravasation and crystal-induced nephropathy. The risk factors for the latter include IV infusion, rapid administration, dehydration, concurrent use of nephrotoxic drugs, higher doses, and underlying renal impairment. Adequate hydration must be ensured while on acyclovir therapy. Possible complications of acyclovir therapy include the following: elevated blood urea nitrogen and creatinine levels (5%); thrombocytopenia (6%); gastrointestinal issues such as nausea, vomiting, and diarrhea (7%); and neurotoxicity, which may manifest as lethargy, obtundation, disorientation, agitation, hallucinations, confusion, tremors, or seizures (1%). Patients who present with HIV along with HSV encephalitis should be started on acyclovir first to avoid immune reconstitution syndrome. Acyclovir can be used in pregnant patients whenever the potential benefits of treatment outweigh the potential risks. A prospective registry on acyclovir use for 15 years showed no increased incidence of fetal malformations in the 756 women with first-trimester exposure, and no pattern of congenital disabilities was apparent.[24](A1)

The dose of acyclovir is 10 mg per kg body weight every 8 hours and is usually given for 14 to 21 days in immunocompetent adults. Neonates and older children are treated with a higher dose of IV acyclovir for 21 days. Immunocompromised persons may require a higher dose with a longer duration. In rare instances of IV acyclovir non-availability, IV ganciclovir could be used. 

Patients often require ICU admission for frequent neurologic checks, airway monitoring, hemodynamic instability, and blood pressure titration. Seizures, increased intracranial pressure, and other complications should be treated per institution protocol.

The use of adjuvant corticosteroids in herpes simplex encephalitis continues to be controversial. The potential benefit of corticosteroids in suppressing immune-mediated damage is questioned by their equal potential to cause enhanced viral replication due to the same immune suppression. Many authors reserve corticosteroids only for patients with significant edema with a mass effect. One nonrandomized trial of 45 patients with herpes simplex encephalitis treated with acyclovir showed outcome benefits in the corticosteroid group at three months.[25] Some experts suggest initiating corticosteroids several days after the administration of acyclovir when the inflammatory process is most prevalent.[8]

Viral and Autoimmune Relapses

After a first herpes simplex encephalitis episode, the incidence of relapse is estimated at 5% to 27%. Most cases involve children treated with a full antiviral course who develop symptoms within 3 months, but adults can also be affected. The presentation usually follows 2 courses: 1) CSF is positive for HSV DNA, suggesting persistent infection or viral reactivation. New necrotic and hemorrhagic lesions often accompany this presentation. The severity is usually less than the initial infection. 2) A secondary autoimmune process can cause the presence of autoantibodies, with CSF negative for HSV PCR, and new MRI lesions are absent. A suggested mechanism is that HSV causes neuronal lysis, thereby exposing neural antigens to already activated B-cells and resulting in autoimmunity. This is called herpes simplex encephalitis–induced autoimmune encephalitis. Presentation includes choreoathetosis, altered mental status, and refractory seizures in children younger than 4 years. Older children and adults often show cognitive deficits and psychiatric symptoms.[8] 

Autoimmune encephalitis is thought to occur in up to 27% of cases within 3 months after HSV encephalitis. The most commonly found autoantibody is the anti-N-methyl-D-aspartate receptor (NMDAR), comprising about 74% of cases, and about 26% are associated with unknown antigens. Risk factors were younger age (≤4 years) and a shorter interval between herpes simplex encephalitis and detection of autoimmune encephalitis antibodies.[26] (B3)

Case reports also describe MRI-proven new transient or chronic white matter lesions after herpes simplex encephalitis. It is thought that these lesions may be sequella of herpes simplex encephalitis, causing a chronic inflammatory process.[8] 

Differential Diagnosis

Differential diagnoses should enlist conditions that could mimic encephalopathy or encephalitis. These include the following: 

• Other viral causes of encephalitis can have similar presentations. Some of these include other herpes viruses (EBV, CMV, VZV, HHV 6 and 7); arboviral infections like West Nile and St. Louis encephalitis; Eastern and Western equine encephalitis; California and Japanese encephalitis; Rubulavirus (mumps); enterovirus; adenovirus; and dengue virus.
• Bacteria, including mycobacteria/atypical organisms, prions, fungi, or parasites, can cause primary or secondary CNS infections.
• Hypoxemic or septic encephalopathies can present with similar mental status and focal neurologic symptoms. 
• Noninfectious causes of encephalitis can also present similarly, including autoimmune or paraneoplastic encephalitis.
• Metabolic causes include hepatic or uremic encephalopathies, Wernicke encephalopathy, mitochondrial encephalopathies, hypoglycemia, hyponatremia, hypernatremia, hypocalcemia, and hypercalcemia.
• Other neurovascular causes include primary or secondary brain tumors, seizure disorders, vasculitis, neurosyphilis, and trauma.
• Systemic diseases like systemic lupus erythematosus (SLE) and Behçet disease can have neurologic involvement.
• Progressive multifocal leukoencephalopathy caused by JC virus is a rare cause of neurologic disorders.
• Although rare with widespread vaccination, measles infection can cause subacute sclerosing panencephalitis. In this disease, children with a history of measles develop progressive neurologic symptoms after 6 to 8 years of latency.

Pertinent Studies and Ongoing Trials

A prospective multinational, randomized, placebo-controlled trial was conducted among 87 patients with herpes simplex encephalitis to evaluate the potential benefit of adjuvant oral valacyclovir 6 g per day in reducing neuro-psychological sequelae assessed at 12 months. Valacyclovir was administered for three months in continuation with standard IV acyclovir therapy for all patients in the treatment arm. The benefit of additional valganciclovir for 3 months was null in this study.[21]

The clinical benefits of adjuvant corticosteroids in herpes simplex encephalitis treatment continue to be controversial. A non-randomized retrospective study on 45 patients with herpes simplex encephalitis where adjuvant corticosteroids were added to acyclovir did a stepwise logistic regression analysis. It concluded that the predictors of poor outcome were advanced age, GCS at the time of acyclovir initiation, and non-initiation of adjuvant corticosteroid.[25] GACHE trial was a multicentre multinational, randomized, double-blind trial where the treatment arm received 40 mg dexamethasone for four days and two weeks of therapy with acyclovir.[27] However, the trial had to be stopped prematurely due to poor recruitment, with inconclusive results. Dex-Enceph is an ongoing randomized control trial evaluating the clinical benefit of 4 days of 10 mg dexamethasone every six hours in addition to acyclovir treatment, with the primary endpoint being the impact on a verbal memory score.[28]

Treatment Planning

Acyclovir should be diluted to a concentration of less than 7 mg/mL for intravenous administration. For instance, a person weighing 70 kg would receive a 700 mg dose, which should be mixed in at least 100 mL of solution. The infusion should be given with a fluid bolus over at least one hour to prevent crystalluria kidney dysfunction. Special care must be taken to avoid extravasation or administering it intramuscularly or subcutaneously, as the alkaline nature of acyclovir can lead to local inflammation and phlebitis. Patients with impaired renal function would require dose adjustment as shown below:

Acyclovir Dosage Adjustment According to Creatinine Clearance (CrCl)

• Greater than 50 mL/min: No adjustment
• Usual dose every 12 hours for those with clearance of 25 to 50 mL/min
• Usual dose every 24 hours for those with clearance 10 to 25 mL/min
• Half of the usual dose every 24 hours for those with clearance 10 mL/min or below
• Intermittent hemodialysis (IHD): 5 mg/kg/dose every 24 hours, post-dialysis on dialysis days
• Peritoneal dialysis (PD): 5 mg/kg/dose every 24 hours, no supplemental dose
• Continuous renal replacement therapy (CRRT): 10 mg/kg/dose every 12 hours

Prognosis

Herpes simplex encephalitis in adults is associated with significant morbidity and mortality. The mortality is estimated to be between 20 to 30%, even with prompt diagnosis and treatment.[22][23] One large retrospective study found an APACHE score of more than 27 and more than 48 hours of delay in starting acyclovir after hospital admission as key factors in predicting poor outcomes.[20] Severe disability was seen by about 20% of patients in this study. Morbidity and mortality are significant in neonates and children, both if treated and untreated.[3] Morbidity and mortality are significantly higher in immunocompromised patients, with 36% mortality compared to 7% mortality in the immunocompetent.[28]

Significant long-term morbidity, including cognitive and behavioral abnormalities, anterograde amnesia, and features of Klüver Bucy Syndrome, have been well-documented. Even though the standard mental status examination is usually within normal limits, many suffer from dysnomia and difficulty with new learning, especially via visual and verbal media. A Swedish study showed rehospitalization in 87% of patients for various indications, including seizure episodes, neuropsychiatric symptoms, and thromboembolic events.[7] 

Complications

Short-term complications include cerebral edema, status epilepticus, increased intracranial pressure, aspiration pneumonitis, cerebral venous thrombosis, cerebral infarction, and diabetes insipidus. Long-term sequelae include neurological deficits with varying severity (ie, aphasia, ataxia, dysphasia, amnesia) and cognitive, behavioral, physical, and neuropsychiatric abnormalities. About 70% of patients report long-term behavioral and cognitive issues.[5]

Possible Link Between HSV and Alzheimer Disease

One proposed theory is that infection with HSV may predispose patients to developing Alzheimer disease (AD) later in life. The regions of the brain most affected by HSV—the temporal lobes and basal forebrain—are similarly affected in AD.[29] Patients who survive herpes simplex encephalitis often have significant anterograde and retrograde memory loss, also similar to AD. Another risk factor for AD is the apolipoprotein E (epsilon) 4 (APOE-E4) allele, but its presence alone does not definitively result in AD, and AD can occur without this gene. There is a significant correlation between the APO-E4 gene and HSV genome loads. Therefore, patients with HSV latency and the APO-E4 allele may be especially susceptible to AD.[29]