Herpetic infections have been well documented even in ancient Greek literature. Herpes viruses are large double-stranded DNA viruses. There are eight different types of herpes viruses affecting humans (human herpes virus (HHV)).
Herpes simplex encephalitis is an acute or subacute illness associated with focal or global cerebral dysfunction caused by herpes simplex viruses belonging to either type 1(HSV-1) or type 2(HSV-2). The vast majority of herpes simplex encephalitis is caused by HSV-1, with HSV-2 constituting only less than 10%. Almost all of the herpes encephalitis beyond the neonatal period is caused by herpes simplex type 1(HSV-1), which is identified as the most common cause for fatal encephalitis, occurring in a sporadic and non-seasonal pattern across the globe. Herpes encephalitis in neonates could be either due to HSV-1 or HSV-2 though the latter is more common. HSV-2 can also cause encephalitis in immunocompromised patients.
Herpes simplex 1 encephalitis (HSV-1) in adults is associated with significant morbidity and death despite treatment with antiviral therapy. Herpes simplex encephalitis is again a devastating disease in infants and children irrespective of treatment. Neonatal encephalitis caused by HSV-2 involves the brain more globally, and it results in more neurologic sequelae.
HSV-1 and HSV-2 are members of the human herpesvirus family which also includes varicella-zoster virus (VZV; HHV-3), Epstein-Barr Virus (HHV4), cytomegalovirus (HHV-5), HHV-6, HHV-7, and HHV-8 (Kaposi's sarcoma-associated herpesvirus). All human herpes viruses except HHV-8 are known to cause encephalitides, though the vast majority of herpes encephalitis is caused herpes simplex viruses, especially HSV-1.
In adults, viral factors along with host immune responses determine virulence and invasiveness. After initial infection, the virus establishes latent life long infection in the host and remains dormant until reactivated. The complex mechanisms known to maintain the latency include suppression of viral lytic-phase genes along with abolition or evasion of host cellular defense mechanisms by alteration of innate as well as adaptive immune responses. 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. Here again, the severity of relapses wanes over some time as the host immunity slowly improves.
The brain gets affected via local spread from a peripheral site or possible viremia. There are presumably 3 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 oro-pharyngeal infection to the brain via trigeminal or olfactory nerves. The second mechanism involves the same neuronal pathways from the reactivation of an initial infection at the periphery. The last mechanism is purely due to the reactivation of the latent in-situ HSV -1 in the brain. Viremia is well documented in neonates and immunocompromised patients. Primary infection causes encephalitis in most children. Neonatal encephalitis could be either due to primary infection or secondary infection due to viremia and multisystem involvement. In neonates, primary infection is almost always acquired due to perinatal exposure during labor or post-delivery.
Increased susceptibility to herpes infections is seen with defective molecular signaling in Toll-Like Receptors-3 (TLR-3) pathways, alteration in MHC class 1 allotype, and the high-affinity receptor/ligand pair KIR2DL2/HLA-C1 and the CD16A-158V/F dimorphism. People taking certain immunosuppressive drugs( eg natalizumab) or anti-inflammatory agents (eg TNF alpha inhibitors) are also found to have increased susceptibility to HSV-1 encephalitis.
HSV-1 is the most common cause for life-threatening sporadic encephalitis across the globe and does not exhibit any seasonal variation. About 60% - 90% of older adults across the world are seropositive for HSV-1. A survey conducted in the US from 2005 to 2010 among persons between 14 to 49 years found seropositivity for HSV-1 and HSV-2 as approximately 54% and 16%, respectively. The annual incidence of herpes simplex encephalitis is approximately 2 to 4 per 1000,000 population worldwide. HSV-1 encephalitis constitutes 10% to 20% of the 20,000 annual viral encephalitis patients in the USA. A multicenter population-based study identified herpes simplex as the most common cause of infectious encephalitis in the UK.HSV is again the most common pathogen identified in hospitalized encephalitis patients in Australia. The incidence of HSV-1 encephalitis appears to be almost similar in Sweden and the United States of America, as shown by studies in these countries.
Though all age groups are affected, the incidence is most common and severe in children and the elderly. Almost one-third of the cases occurred in children and adolescents, with half of the patients being over 50 years of age. Both sexes are equally affected.
The virulence and invasiveness depend on viral as well as host immune factors. The exact mechanism of neuronal destruction is unknown. It could be either due to direct injury caused by the virus or an immune-mediated cell injury. HSV-1 can induce apoptosis of the involved cells affecting programmed cell death. A retrospective study on imaging found temporal lobe involvement in 60% of patients, with pure temporal lobe involvement in 20%, pure extra-temporal involvement in 15%, and normal imaging in 25% of the patients. Studies in the pre-acyclovir era have documented a rapidly evolving viral infection within the limbic system spreading to both sides of the brain with resultant inflammation and necrosis of the involved areas within three weeks. Lytic and hemorrhagic areas are often noted in the medial part of the temporal lobes and inferior part of the frontal lobes. The pathognomonic feature on brain biopsy is hemorrhagic encephalitis in orbitofrontal or limbic specimens. Cowdry A inclusion bodies are seen as well. A report of focal vasocentric corticosteroid-responsive granulomatous pathology has also been documented.
There is no evidence of increased incidence of herpes simplex encephalitis (HSE) in immunocompromised hosts though the mortality and morbidity are significantly higher. More diffuse involvement with the predominance of extratemporal lobe areas is often noted in such patients. Histopathology has revealed a non-inflammatory "pseudo ischemic" pattern in autopsies.
History and Physical
The clinical presentation of herpes encephalitis could be acute or subacute. A prodromal phase of fever, malaise, headache, and nausea often precedes more severe neurologic symptoms. The common clinical features of HSV -1 encephalitis include altered mentation lasting for more than 24 hours 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-Busy syndrome, and varying degrees of amnesia. Behavioral or personality changes could often be misdiagnosed as a psychiatric disorder. HSV-1 encephalitis can rarely manifest as recurrent brain stem encephalitis. Autoimmune encephalitis with antibodies directed against N- methyl-d-aspartate receptor for glutamate has to be considered in children and young adults who present with neurologic symptoms after a recent recovery from herpes simplex encephalitis. Rare presentations include selective language aphasia and intracerebral hemorrhage in an HIV positive patient. Presentation with extrapyramidal symptoms due to basal ganglia involvement in a child has been reported.
The most common physical findings include fever and altered mentation. Meningeal signs may be detected, although meningismus is uncommon. Neurologic deficits are usually acute onset with the duration often less than a week, and usually include focal cranial nerve palsies, hemiparesis, dysphasia, aphasia, ataxia, visual field defects, and papilledema. The anterior opercular syndrome has been described as an initial presentation or in association with encephalitis.
The childhood herpes simplex encephalitis (HSE) presents with clinical features including fever, lethargy, altered behavior, or sleepiness, with focal seizures or neurological abnormalities. Herpes simplex encephalitis in the neonate usually manifests between 1-3 weeks of life, and features include irritability, lethargy, 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 without any prodromal symptoms in immunocompromised patients(for example, HIV positive individual or corticosteroid therapy); hence the diagnosis could often be missed.
None of the clinical features are pathognomonic of herpes simplex encephalitis (HSE). Therefore, workup has to be expedited without delaying the treatment. A high index of suspicion needs to be there, especially in immunocompromised presenting with febrile encephalopathy. Cognitive or behavioral or personality changes could be easily misdiagnosed as a psychiatric illness. Routine blood tests might show evidence of infection or detect renal impairment where the drug dosages may have to be modified. Focal neurologic deficits, computed tomography (CT) or magnetic resonance imaging (MRI) findings, and CSF picture might also take time to manifest. A definite diagnosis can be achieved only by the HSV polymerase chain reaction (PCR) test, or rarely via a brain biopsy.
MRI will be almost 80%-90% sensitive in detecting abnormalities in HSE. MRI with diffusion-weighted images and flair sequences is most sensitive. The classic abnormality is the involvement of temporal lobe (sometimes associated with bleed), with associated early white matter changes. Inferomedial temporal lobe changes are most commonly observed with occasional abnormalities in the cingulate gyrus. Basal ganglia are typically spared.
CT is less sensitive than MRI and will be able to detect the abnormalities only in half to two-thirds of the patients. It may take 3-4 days to manifest the changes in temporal or frontal lobes. Hypodensities, hemorrhage, and edema are often noted, while contrast enhancement may take almost a week.
Single-photon emission computed tomography (SPECT) and dynamic technetium 99 ethyl cysteinate dimer single-photon emission computed tomography (T-99-m ECD SPECT) were found to be helpful in small studies.
CSF may show xanthochromia in the acute setting. A lymphocytic pleocytosis in the range of 10- 500 leukocytes/microliters could be seen, and red blood cells (RBCs) could be high as well (10-500/microliters) because of underlying hemorrhagic pathology. The glucose level will be normal or slightly low. The CSF profile could be initially normal in about 5%-10% of patients, especially in children. Normal CSF profile has also been described in immunocompetent adults in the early phase of the disease and in patients who are taking tumor necrosis factor (TNF) alpha inhibitors. The cell count and protein values were found to increases in serial evaluations. CSF pleocytosis may be absent in immunocompromised patients. CSF PCR has to be sent for both HSV-1 and HSV-2. The PCR test has a sensitivity of 94%-98%, with the specificity being 98%-100%. CSF PCR usually becomes positive within 24 hours of the onset of symptoms and will remain detectable 5-7 days even after initiation of acyclovir therapy. False-negative tests may result from lower viral load in the initial 72 hours, or due to the presence of blood in the CSF with hemoglobin interfering with the PCR. A false negative PCR could also be caused by acyclovir therapy of more than 48 hours. A negative PCR obtained in a patient with a high pretest probability obtained within 3 days of onset of symptoms should be repeated to rule out HSE. 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 HSE. This may help in indirect diagnosis in such patients where lumbar puncture (LP) may have to be deferred temporarily due to various issues.
CSF antibodies to purified HSV glycoprotein B has 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, its initial detection is possible only after 10-14 days of illness, thereby helps only in retrospective diagnosis.
Electroencephalogram (EEG) has good sensitivity to abnormal patterns but has low specificity. Focal abnormalities are seen in more than 80% of cases. Periodic waveforms or paroxysmal lateralizing epileptiform discharges (PLED) are highly consistent with HSE in the appropriate clinical settings, though their absence does not rule out HSE. EEGs may also display prominent intermittent high amplitude slow waves over the affected temporal areas. Diffuse slowing patterns are also described.
Brain biopsy is very rarely performed in modern days due to the availability of HSV PCR tests in CSF, which are highly sensitive as well as specific. Procedure-related complications have been reported in 3% of patients with a brain biopsy. Moreover, the currently available antiviral drugs have good safety profiles, and even empirical treatment with IV acyclovir could be initiated at least for a short duration in suspected cases until and unless the diagnosis is disproved. A rare case of corticosteroid-responsive vasocentric granulomatous inflammation in HSV-1 encephalitis in 2 adult patients detected only by brain biopsy has been reported. The patients had temporal lobe MRI changes, positive intrathecal IgG antibody in paired blood and CSF, but CSF PCR was negative. The current considerations for brain biopsy include undiagnosed encephalitis after extensive workups, where the patient is not improving or is further deteriorating.
Tzanck smears from vesicular lesions may sometimes show positive results in neonates.
Treatment / Management
Emergency management strategy includes an assessment of airway, breathing, and circulation, and taking appropriate measures accordingly. A lumbar puncture has to be followed in suspected cases if the brain imaging does not suggest evidence of intracranial hypertension or a space-occupying lesion. Intravenous (IV) acyclovir needs to be started in all adults with suspected or confirmed cases of HSE in the dose of 10 mg per Kg body weight every 8 hours. Children up to 11 years and neonates are treated with higher doses (15-20 mg per Kg body weight). Ideal Body Weight is used for dose calculation in obese patients.
A large retrospective study showed a delay in initiating acyclovir for more than 48 hours as one of the factors associated with poor outcomes. Viral and host cellular enzymes affect the conversion of acyclovir into acyclovir triphosphate, which is a strong inhibitor of HSV DNA polymerase, thereby inhibiting viral replication. Acyclovir is a relatively safe drug with few major side effects, including thrombophlebitis in case of extravasation, and rarely crystal-induced nephropathy. The risk factors for the latter include IV infusion, rapid administration, dehydration, concurrent use of nephrotoxic drugs, higher dose, and underlying renal impairment. Adequate hydration has to be ensured while on acyclovir therapy. Resistance to acyclovir has been found significantly high in immunocompromised patients when compared with immunocompetent persons. After an initial standard course with IV acyclovir, routine administration of oral valacyclovir for 3 months did not provide any additional neuropsychological benefits in HSE patients when measured at 12 months.
The dose of acyclovir is 10 mg per Kg bodyweight 8 hourly and is usually given for 14 to 21 days in immunocompetent adults. Neonates and older children are treated with a higher dose of IV aciclovir for 21 days. Immunocompromised persons may require a higher dose with a longer duration. Oral aciclovir prophylaxis has been shown to reduce relapse in children after the initial treatment with IV acyclovir. In rare instances of IV acyclovir non-availability, IV ganciclovir could be used. Acyclovir resistance is usually managed with IV foscarnet or cidofovir. Acyclovir could be used in pregnant patients whenever the potential benefits of treatment outweigh the potential risks. A prospective registry on acyclovir use for 15 years did not show any increased incidence of fetal malformations in the 756 women with first-trimester exposure.
Patients with issues regarding airway, breathing, and hemodynamics need to be shifted to the intensive care unit (ICU) for further monitoring and management. Those with significantly impaired neurology need ICU admission for intubation to facilitate airway protection. Other indications for ICU admissions are persistent seizures or features of increased intracranial pressure (ICP) for which intubation and ventilation may be required. Seizures are initially treated with benzodiazepines, with longer-acting agents (for example, levetiracetam, carbamazepine, or fosphenytoin) added subsequently. Increased ICP is usually treated with head-end elevation and mannitol, frusemide, or hypertonic saline as per institutional protocol.
The use of adjuvant corticosteroids in HSE continues to be controversial. The potential benefit of corticosteroids in suppressing immune-mediated damage is questioned by its 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 showed outcome benefits in the corticosteroid group at 3 months. A randomized control trial by German, Austrian and Dutch investigators (GACHE) assessing the clinical benefit of adjuvant corticosteroids in the treatment of HSV encephalitis had to be prematurely stopped due to poor recruitment. Dex-Enceph trial is an ongoing multinational randomized study assessing the clinical benefit of the addition of dexamethasone to acyclovir with its potential effect on a verbal memory score.
Differential diagnoses should enlist conditions that could mimic encephalopathy or encephalitis. These include:
Primary or secondary CNS infections caused by bacteria, including mycobacteria/atypical organisms/virus/prion/ fungus or parasites.
Hypoxemic & septic encephalopathies
Non-infectious causes for encephalitis (for example, autoimmune or paraneoplastic encephalitis, acute disseminated encephalomyelitis)
Metabolic causes, including hepatic /uremic encephalopathies, Wernicke's encephalopathy, and mitochondrial encephalopathies, hypoglycemia, hyponatremia or hypernatremia, hypocalcemia or hypercalcemia.
Drugs/toxins including alcohol & heavy metals, cerebrovascular accident, primary or secondary brain tumor, seizure disorders, vasculitis, neurosyphilis, systemic lupus erythematosus (SLE), Behcet's disease & trauma.
The differential diagnoses of viral encephalitis must include arboviral infections, including West Nile, and St Louis encephalitides, Eastern & Western equine encephalitides, as well as California and Japanese encephalitides. Other etiologies include herpes viruses (EBV, CMV, VZV, HHV 6 & 7), and also miscellaneous causes like mumps, enterovirus, dengue, adenovirus, lymphocytic choriomeningitis, subacute sclerosing panencephalitis due to hypermutated measles virus & progressive multifocal leukoencephalopathy caused by JC virus.
Pertinent Studies and Ongoing Trials
A prospective multinational, randomized placebo-controlled trial was conducted among 87 HSE patients to evaluate the potential benefit of adjuvant oral valacyclovir 6 grams per day in the reduction of neuro-psychological sequelae assessed at 12 months. Valacyclovir was administered for 3 months in continuation with standard IV acyclovir therapy for all patients in the treatment arm. The clinical benefit of additional valganciclovir for 3 months was negated by the lack of clinical benefits observed in this study.
The clinical benefits of adjuvant corticosteroid in HSE treatment continue to be controversial. A non-randomized retrospective study on 45 HSE patients where adjuvant corticosteroids were added to acyclovir did a stepwise logistic regression analysis and concluded that the predictors of poor outcome were advanced age, GCS at the time of acyclovir initiation and non-initiation of adjuvant corticosteroid. GACHE trial was a multicentre multinational, randomized double-blind trial where the treatment arm received 40mg dexamethasone for 4 days in addition to 2 weeks of therapy with acyclovir. 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 6 hourly in addition to acyclovir treatment, with the primary endpoint being the impact on a verbal memory score.
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. One large retrospective study found an APACHE Score of more than 27, and more than 48 hours delay in starting acyclovir after hospital admission as key factors in predicting poor outcomes. Severe disability was seen by about 20% of patients in this study. Morbidity and mortality are significant in neonates and children, whether treated or untreated.
Significant long term morbidity, including cognitive and behavioral abnormalities, anterograde amnesia, and features of Klüver Busy Syndrome, have been well documented. Even though the standard mental status examination is within normal limits, many suffer from dysnomia and difficulty for 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. Autoimmune encephalitis with antibodies against the N-methyl-D-aspartate receptor for glutamate has been reported in children and young adults. Recurrent neurologic symptoms occurring in a patient with a recent history of HSE should prompt a CSF evaluation for HSV DNA and anti-NMDAR antibodies.
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 (for example, aphasia, ataxia, dysphasia, amnesia), cognitive, behavioral, physical, and neuropsychiatric abnormalities. Autoimmune encephalitis with antibodies directed against the N-methyl-D-aspartate receptor needs to be considered in any patient with recent history HSE presenting with recurrent neuro symptoms.
A neurology consult is a must for expert evaluation and management. Infectious disease consult is ideal if no cause for the encephalitis could be established after initial workup, and especially if the patient is not adequately improving or is deteriorating. Neurosurgeons may need to be involved if significant brain involvement with midline shift occurs or a brain biopsy is planned (rarely indicated or performed currently). Rehabilitation consult has to be given for short term as well as long term neurorehabilitation. Psychologist/psychiatrist referral may be required for patients and family members to cope with the long term neuropsychiatric issues.
Similarly, in children, apart from neonatology or pediatrician involvement for patients belonging to this age group, pediatric infectious disease and neurology experts may have to be involved.
Deterrence and Patient Education
Herpes simplex encephalitides have significant morbidity and mortality despite prompt detection and antiviral treatment. Varying degree of neurologic sequelae and/or neuropsychiatric disorders are common among survivors in children and adults. Significant neurologic sequelae occur in neonates due to HSV-2 infection even with treatment. No available strategies currently prevent HSE in older children or adults. Person to person spread has not been described. Prophylactic treatment of close contacts and isolation precautions are not indicated. Neonatal transmission could be mitigated by conducting a cesarian delivery of the baby in women who are having active herpes labialis during pregnancy and/or avoiding contact with persons with an active infection in the neonatal period.
Pearls and Other Issues
Herpes simplex encephalitis (HSE) could be caused by either HSV-1 or HSV-2. Among herpes simplex encephalitis, the vast majority of the encephalitis is caused by HSV-1, with HSV-2 being the etiology in less than 10% of the cases. HSV-1 causes encephalitis in adults and children beyond the neonatal period. It is the most common cause of life-threatening sporadic encephalitis across the globe. HSV-2 causes encephalitis is predominant in neonates and immunocompromised patients. Herpes simplex encephalitis (HSE) has significant morbidity and mortality, even with early diagnosis and treatment.
Immunocompromised patients or patients in extremes of age might present with subtle or atypical symptoms or signs. Behavioral, cognitive, or personality changes could easily be misdiagnosed as a psychiatric disorder. Radiology, CSF profile, and HSV PCR of CSF could be normal in the initial phase of the disease. Immunocompromised patients and immunocompetent adults in the early part of illness may not show evidence of CSF pleocytosis. CSF needs to be repeated for HSV PCR if the initial PCR test is negative in a patient with a high index of suspicion, especially if it was done within 72 hours after the onset of symptoms.
HSE is a neurologic emergency. A high index of suspicion among attending physicians, rapid diagnostic workup, and early diagnosis will result in early initiation of IV acyclovir in all suspected or diagnosed cases, which could further decrease morbidity and mortality. All patients with suspected HSE based on radiology, CSF profile, or EEG features, as well as the confirmed cases, must be rapidly initiated on intravenous acyclovir.
Enhancing Healthcare Team Outcomes
HSV encephalitis management requires close coordination between the treating interprofessional team. Interprofessional discussions and coordination between various specialties are necessary to improve patient outcomes. Internists, emergency physicians, neurologists, neurosurgeons, infectious disease specialists, intensivists, pharmacists, physiatrists, psychologists, and psychiatrists are usually involved in the care.
Herpes simplex encephalitis is a neurologic emergency that requires a high degree of suspicion, rapid diagnostic workup, and treatment. Patients might need intubation either for airway protection (in case of a significant drop in consciousness) or persistent seizures. Lumbar puncture needs to done promptly after brain imaging rules out intracranial hypertension or space-occupying lesions, and CSF analysis should be reported as soon as possible. Intravenous acyclovir needs to be administered as soon as possible in all suspected or confirmed cases of HSV encephalitis. Intensive care unit admission is indicated once the patient is intubated or requires other organ supports. Continued neurology review is a must, and infectious disease consultation will be indicated if no other cause could be established despite initial evaluations, especially if the patient is not improving or is deteriorating.
HSE causes significant morbidity in the survivors. After the acute phase, there needs to be continued follow up by the rehabilitation and neurology team. A psychiatry or psychology consultation may be needed not only for patients but also for the family members to cope up with the stress of long term rehabilitation.
(Click Image to Enlarge)
Herpes Encephalitis MRI
29 yo female brought unconscious with a history of mild fever and heady for 3 days prior
MRI Brain diffusion and Axial FLAIR show insular and medial temporal faint abnormal T2 Hyper intensity with restricted diffusion on DW
Contributed by and with permission from Dr. Balaji Anvekar (http://www.neuroradiologycases.com)
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