Neonatal herpes simplex virus encephalitis (HSVE) often results in long-lasting neuro-disability in affected children. In addition to primary HSVE and HSVE relapses, children with herpes simplex virus are at increased risk of developing anti–N-methyl-d-aspartate receptor encephalitis (NMDARe), an autoimmune encephalitis. In this study, we describe a patient with neonatal disseminated herpes infection, who developed HSVE after discontinuation of 2 years of acyclovir suppressive therapy. After resolution of HSVE, the patient rapidly deteriorated with significant behavioral and neurologic changes including emotional outbursts, fearfulness, involuntary movements, and focal seizures. The patient was diagnosed with anti-NMDARe and was later found to have low toll-like receptor-3 function. In this study, we review published pediatric cases of anti-NMDARe after HSVE as well as previous literature and primary data examining the presentation, predisposing risk factors, predictive outcomes, future directions, and the role of immunodeficiency in HSVE-mediated anti-NMDARe. The neonatal immune system and developing brain are disproportionately vulnerable to early viral exposure; therefore, it is important to recognize the value of early immunodeficiency screening in patients with neonatal herpes simplex virus. By understanding the immune landscape within this patient population, we can mitigate long-term neurologic disability and improve the quality of life of affected children.

In this study, we discuss the clinical course of a patient with anti–N-methyl-d-aspartate receptor (NMDAR) encephalitis following herpes simplex virus encephalitis (HSVE) after 2 years of suppressive acyclovir treatment following diagnosis of disseminated herpes simplex virus (HSV) as a neonate. Although the diagnosis of HSVE and anti–N-methyl-d-aspartate receptor encephalitis (NMDARe) is uncommon, pediatric hospitalists are often the first service consulted for encephalopathic children, especially in the setting of suspected viral infection. Thus far, a comprehensive literature review examining HSVE-mediated anti-NMDARe in children does not exist. This article serves as comprehensive guide for hospitalists, infectious diseases specialists, as well as neurologists, seeking to understand the virology and neuroimmunology of clinical care in children with HSVE-mediated anti-NMDARe.

A 7-day-old boy born presented to an outside hospital with white circular and raised erythematous scalp lesions and oral pustules. There had been no fever, lethargy, or irritability. After transfer to Pennsylvania State University Hershey Children’s Hospital, physical examination revealed pustules on scalp, oral mucosa, chest, and axilla. Subsequent blood, skin, eye, and mouth polymerase chain reaction (PCR) for herpes simplex virus-1 (HSV-1) was completed and found to be positive. Skin, eye, and mouth viral cultures were also positive for HSV-1. Cerebrospinal fluid (CSF) PCR result was negative. Positive blood PCR led to a 21-day intravenous (IV) 50 mg every 8 hours (20 mg/kg per dose) acyclovir treatment of disseminated HSV. For prophylaxis, the patient was discharged on high-dose suppressive oral acyclovir therapy 320 mg twice daily, increased to 600 mg twice daily (1500 mg/m2 body surface area per dose) at 7 months of age for 2 years. He had a labial sore at 23 months that resolved with an increased dose of oral acyclovir treatment of 1 week. Acyclovir treatment was discontinued after the patient’s second birthday. At this point in time, there were no concerns regarding the patient’s development.

Seventeen days after discontinuing acyclovir suppression, the patient presented with fever, altered mental status, and seizures. At PICU admission, CSF contained 118 nucleated cells and 103 red blood cells with 69 mg/dL protein and 72 mg/dL glucose. HSV-1 PCR result of the CSF was positive. Brain MRI revealed hyperintensities within bilateral temporal lobes, posterior inferior frontal lobes, left insula, left hippocampus, and left thalamus with concurrent mild leptomeningeal enhancement (Fig 1). The patient was diagnosed with hemorrhagic HSVE and treated inpatient with 3 weeks IV acyclovir at 80 mg/kg per day and 20 mg/kg per day levetiracetam to prevent recurrent seizures. Repeat CSF HSV PCR at day 18 of treatment was negative. After treatment, the patient was discharged on twice daily oral doses of 720 mg (1500 mg/m2 body surface area per dose) oral acyclovir and a levetiracetam maintenance dose. At discharge, he had improved, and the family noted that the child was happy, playful, and interactive.

FIGURE 1

Axial MRI T2 weighted fluid-attenuated inversion recovery revealing hyperintensity in bilateral temporal lobes, left more extensive than right, within our patient during acute HSV encephalitis. Findings were consistent with HSV meningoencephalitis.

FIGURE 1

Axial MRI T2 weighted fluid-attenuated inversion recovery revealing hyperintensity in bilateral temporal lobes, left more extensive than right, within our patient during acute HSV encephalitis. Findings were consistent with HSV meningoencephalitis.

Close modal

Four days after discharge, his family observed that the patient was having significant behavioral and neurologic changes including emotional outbursts, focal seizures, and milestone regression including speech loss and reversion to crawling. The patient was readmitted to the PICU. During hospitalization, the patient developed nonpurposeful rhythmic movements, orofacial dyskinesia, and autonomic dysfunction manifesting as variable blood pressures, intermittent fevers, and tachycardia. Brain MRI revealed encephalomalacia and gliosis in the left mesial temporal lobe and left insular cortex. CSF revealed 35 nucleated cells (91% lymphocytes), 1 red blood cell, 53 mg/dL glucose, and 78 mg/dL protein. CSF and blood HSV PCR results were negative. Because his clinical presentation at this point was most consistent with autoimmune encephalitis (AE), CSF AE panel testing was completed. Results were remarkable for anti-NMDAR antibodies consistent with anti-NMDARe. Over his hospital course, the patient received 5 days of 300 mg IV methylprednisolone, 4-day course of 5 g intravenous immunoglobulin (IVIG), and 5 rounds of plasma exchange (PLEX). Despite treatment, the patient had significant choreiform movements, orofacial dyskinesias, and autonomic dysfunction. As a result, second-line rituximab therapy was initiated. He received 4 doses of 190 mg rituximab over a 4-week period. The patient was discharged to rehabilitation on suppressive oral acyclovir treatment, IVIG infusions every 3 weeks, and rituximab infusions at 6-month intervals (Fig 2). After treatment, the patient had elevated anti-NMDAR antibodies and neurologic deficits including a limited ability to talk with an ∼30-word vocabulary, irregular sleep, staring spells, and behavioral outbursts. At 6 years old, he is still receiving daily acyclovir and monthly IVIG. He did not develop other recurrent or unusual infections during this period. His most recent neuropsychological evaluation revealed an improvement in cognitive, gross, and fine motor skills. His vocabulary is expanding and he is able to vocalize his needs with 2- to 3-word sentences. He enjoys simple puzzles and playing with his grandmother.

FIGURE 2

Time line of patient clinical course during the first 3 years of life, including time of diagnosis and respective treatment course.

FIGURE 2

Time line of patient clinical course during the first 3 years of life, including time of diagnosis and respective treatment course.

Close modal

Because HSV encephalitis is uncommon outside of the neonatal period, the patient was tested for primary immunodeficiencies associated with poor control of herpes viruses at the University of Pennsylvania. With whole-blood analysis at a commercial laboratory, functional testing of toll-like receptor-3 (TLR-3) revealed a significantly decreased response to Poly I:C (polyinosinic:polycytidylic acid) compared with control sample suggesting possible low-functioning TLR-3. Functional tests on natural killer cell function were also completed, which were normal. Whole-exome sequencing and chromosomal microarray for gene variants in TLR-3, UNC93B, TRAF3, RBK1, and NEMO were completed. No clinically validated variants were found.

The incidence of HSVE in infants is 1 in 64 000 and, in children >1 year old, is 1 in 230 000 per year.1  Transmission of HSV to the neonate occurs most frequently through transvaginal infection but can also occur in utero and postnatally.2  Without antiviral treatment, 50% of neonates with central nervous system (CNS) and 85% with disseminated HSV succumb to disease by 1 year old.3  Although acyclovir has reduced mortality, it cannot deplete viral reservoirs and therefore cannot prevent viral reactivation once suppressive therapy is stopped.4,5  HSVE relapses result in significant neuronal damage, cognitive deficits, and behavioral changes.6  In other cases, for unknown reasons and in the absence of peripheral and central viremia, patients develop secondary long-term sequelae including AE.

Since its discovery in 2007, anti-NMDARe has been identified as the leading cause of nonviral encephalitis worldwide.7,8  This AE results in autoantibodies against the GluN1 subunit of the NMDAR, leading to receptor malfunctioning and, as a result, persistent neurologic and neuropsychiatric symptoms.7,9  Although classic anti-NMDARe is associated with paraneoplastic processes, viral infections such as HSV, varicella zoster virus, and measles virus are increasingly associated with disease.10  As many as 27% of patients with HSVE develop AE after acyclovir treatment (published cases located in Tables 1 and 2; details in Supplemental Materials).11  The cause of AE after CNS viral infection is unknown. Several mechanisms have been postulated, including the possibility that during acute CNS viral infection, local destruction causes the release of neuronal antigen into draining lymphatics and subsequently autoantibody-producing B cells. However, this mechanism is contingent on failure of immune tolerance. Alternative hypotheses include molecular mimicry between HSV antigen and the NMDA receptor and in-born HLA antigen variation predisposing to autoimmunity.11,12 

TABLE 1

Disease Characteristics, Treatment Regimens, and Patient Outcomes in Children With Anti-NMDAR Encephalitis After HSV Encephalitis

CaseAgeSexDays Post-ACV with anti-NMDARe SymptomsSymptomsTreatmentOutcomePMID
2 mo Male During ACV treatment Choreoathetosis, irritability, and disordered sleep Acyclovir Deficits in visual tracking 2431840636  
6 mo Female Day 7 Choreoathetosis, dysphagia, dysphonia, seizure, irritability, insomnia, fever, diarrhea, hypoventilation, bradycardia, SIADH, and unresponsiveness IVMP, IVIg, Steroids, rituximab, cyclophosphamide, acyclovir Residual dysphagia, difficulty sitting, and hemiparesis 2431840636  
6 mo Female Day 7 Choreoathetosis, irritability, insomnia, restlessness, and dysautonomia with central hypoventilation IVIg, IV corticosteroids rituximab, cytoxan Global developmental delay 2566128837  
4a 6 mo Male During acyclovir treatment Seizure, diffuse choreoathetosis, orofacial dyskinesias, poor head control, right gaze preference, worsening attention, and long periods of unresponsiveness despite wakefulness IVIg, PLEX Regaining motor milestones and vocalizing 2328084038  
5b 8 mo Female On stopping acyclovir Encephalopathy and chorea Methylprednisolone, IVIg, acyclovir Dystonic quadriplegic cerebral palsy requiring a wheelchair for mobility, intellectual disability, and refractory epilepsy 2411533839  
8 mo Male Day 2 Choreoathetosis, seizure, irritability, insomnia, and unresponsiveness IVMP, IVIg, steroids, rituximab, cyclophosphamide, acyclovir Choreoathetosis and dysphagia 2431840636  
9 mo Female During acyclovir treatment Choreoatheototic and dystonic movement with seizure, suppressed level of consciousness, agitation, fever, apnea, and bradycardia IVIg, steroids, prednisolone, rituximab, acyclovir Neurodevelopmental delay with speech, cognitive and social deficit. Slow improvement in gross motor skill 2977405340  
10 mo Unknown Unknown Choreoathetotic movements, hypotonia, automatisms, irritability, and impaired feeding IVIg, methylprednisolone, acyclovir Gradual clinical and psychomotor improvement 2977405340  
11 mo Female During acyclovir treatment Poor head and truncal control with choreoathetosis, decrease motor control in right arm and hand, irritability, aggression, and sleep disturbance IVIg, prednisolone Hyperactive, delayed cognitive and speech development and with intractable epilepsy 2474291041  
10 1 y Female Unknown Encephalopathy, movement disorder, and seizure IVIg Cognitive and behavioral deficits with seizure 2534005842  
11 16 mo Female During acyclovir treatment Left hemiparesis, right-sided ballismus, orolingual/facial dyskinesia, dystonia, and developmental regression PLEX, acyclovir Some right-sided dyskinesia and dystonia, persistent left hemiparesis. Severe global developmental impairment 2618562143  
12 16 mo Female Unknown Encephalopathy and movement disorder PLEX Residual motor deficit 2534005842  
13 2 y Male Unknown Cognitive, behavioral, and motor regression IVIg Complete recovery 2534005842  
14 2.5 y Female During acyclovir treatment Generalized seizure, chorea, irritability, fever, and temperature instability IVMP, IVIg rituximab, cyclophosphamide Language regression 2850650344  
15c,d 26 mo Male During acyclovir treatment Emotional outbursts, fearfulness, focal seizures, regression of milestones, nonpurposeful rhythmic movements, orofacial dyskinesia, and autonomic dysfunction with variable blood pressures, intermittent fevers, and tachycardia IVIg, methylprednisolone, PLEX, rituximab, acyclovir Cognitive and behavioral deficits Current case 
16 28 mo Female Day 7 Choreoathetosis, orofacial dyskinesias, generalized tonic-clonic seizures, decreased consciousness, agitation, hyperexcitability and somnolence diarrhea, low grade fever, severe tachycardia, and transient hypoventilation Methylprednisolone, IVIg, steroids, rituximab, cyclophosphamide, acyclovir Residual opercular syndrome with inability to speak or swallow. Mild dystonic/ataxic gait with mild support. Intact cognition, can follow commands and communicate by signs 2316431545  
17 3 y Female Day 10 Encephalopathy, choreoathetosis, orofacial dyskinesia, stereotyped nonpurposeful movements, seizures and behavioral changes Steroids PLEX, MMF, rituximab, acyclovir Hyperactivity and disinhibition 2401409646  
18 3 y Female During acyclovir treatment Choreoathetosis, dyskinesia, irritability, and fever IVIg, prednisolone Neurodevelopmental delay improving with special educational therapy 2618448547  
19 3 y Male During acyclovir treatment Dysphagia, involuntary limb and facial movements, irritability, lethargy and sleepiness, apnea, vomiting, tachycardia, and excessive salivation IVMP, IVIg, prednisolone, cyclophosphamide, acyclovir Complete recovery 2665837948  
20 c 6 y Female 1 y Aggressive and paranoid thoughts IV Steroids, IVIg, rituximab Unknown 3148862732  
21 7 y Male During acyclovir treatment Left hand tremor, chorea, intermittent dystonic posturing, emotional lability, irritability, visual hallucinations, and urinary incontinence IV Steroids, IVIg, cyclophosphamide, valacyclovir Developmental delay 2411533839  
22 13 y Male Day 21 Headache, aggression, and hypertension IVMP Partial improvement of behavioral deficits, withstanding motor and cognitive deficits 2649108449  
23 15 y Female Day 39 Severe headache, concentration difficulties, sleepiness, disinhibition, and intracranial hypertension Methylprednisolone, cyclophosphamide Residual behavioral problems 2401409646  
24 15 y Male Day 30 Cognitive deficits, agitation, and aggression IVMP, poMP, IVIg, acyclovir Complete recovery 2649108449  
CaseAgeSexDays Post-ACV with anti-NMDARe SymptomsSymptomsTreatmentOutcomePMID
2 mo Male During ACV treatment Choreoathetosis, irritability, and disordered sleep Acyclovir Deficits in visual tracking 2431840636  
6 mo Female Day 7 Choreoathetosis, dysphagia, dysphonia, seizure, irritability, insomnia, fever, diarrhea, hypoventilation, bradycardia, SIADH, and unresponsiveness IVMP, IVIg, Steroids, rituximab, cyclophosphamide, acyclovir Residual dysphagia, difficulty sitting, and hemiparesis 2431840636  
6 mo Female Day 7 Choreoathetosis, irritability, insomnia, restlessness, and dysautonomia with central hypoventilation IVIg, IV corticosteroids rituximab, cytoxan Global developmental delay 2566128837  
4a 6 mo Male During acyclovir treatment Seizure, diffuse choreoathetosis, orofacial dyskinesias, poor head control, right gaze preference, worsening attention, and long periods of unresponsiveness despite wakefulness IVIg, PLEX Regaining motor milestones and vocalizing 2328084038  
5b 8 mo Female On stopping acyclovir Encephalopathy and chorea Methylprednisolone, IVIg, acyclovir Dystonic quadriplegic cerebral palsy requiring a wheelchair for mobility, intellectual disability, and refractory epilepsy 2411533839  
8 mo Male Day 2 Choreoathetosis, seizure, irritability, insomnia, and unresponsiveness IVMP, IVIg, steroids, rituximab, cyclophosphamide, acyclovir Choreoathetosis and dysphagia 2431840636  
9 mo Female During acyclovir treatment Choreoatheototic and dystonic movement with seizure, suppressed level of consciousness, agitation, fever, apnea, and bradycardia IVIg, steroids, prednisolone, rituximab, acyclovir Neurodevelopmental delay with speech, cognitive and social deficit. Slow improvement in gross motor skill 2977405340  
10 mo Unknown Unknown Choreoathetotic movements, hypotonia, automatisms, irritability, and impaired feeding IVIg, methylprednisolone, acyclovir Gradual clinical and psychomotor improvement 2977405340  
11 mo Female During acyclovir treatment Poor head and truncal control with choreoathetosis, decrease motor control in right arm and hand, irritability, aggression, and sleep disturbance IVIg, prednisolone Hyperactive, delayed cognitive and speech development and with intractable epilepsy 2474291041  
10 1 y Female Unknown Encephalopathy, movement disorder, and seizure IVIg Cognitive and behavioral deficits with seizure 2534005842  
11 16 mo Female During acyclovir treatment Left hemiparesis, right-sided ballismus, orolingual/facial dyskinesia, dystonia, and developmental regression PLEX, acyclovir Some right-sided dyskinesia and dystonia, persistent left hemiparesis. Severe global developmental impairment 2618562143  
12 16 mo Female Unknown Encephalopathy and movement disorder PLEX Residual motor deficit 2534005842  
13 2 y Male Unknown Cognitive, behavioral, and motor regression IVIg Complete recovery 2534005842  
14 2.5 y Female During acyclovir treatment Generalized seizure, chorea, irritability, fever, and temperature instability IVMP, IVIg rituximab, cyclophosphamide Language regression 2850650344  
15c,d 26 mo Male During acyclovir treatment Emotional outbursts, fearfulness, focal seizures, regression of milestones, nonpurposeful rhythmic movements, orofacial dyskinesia, and autonomic dysfunction with variable blood pressures, intermittent fevers, and tachycardia IVIg, methylprednisolone, PLEX, rituximab, acyclovir Cognitive and behavioral deficits Current case 
16 28 mo Female Day 7 Choreoathetosis, orofacial dyskinesias, generalized tonic-clonic seizures, decreased consciousness, agitation, hyperexcitability and somnolence diarrhea, low grade fever, severe tachycardia, and transient hypoventilation Methylprednisolone, IVIg, steroids, rituximab, cyclophosphamide, acyclovir Residual opercular syndrome with inability to speak or swallow. Mild dystonic/ataxic gait with mild support. Intact cognition, can follow commands and communicate by signs 2316431545  
17 3 y Female Day 10 Encephalopathy, choreoathetosis, orofacial dyskinesia, stereotyped nonpurposeful movements, seizures and behavioral changes Steroids PLEX, MMF, rituximab, acyclovir Hyperactivity and disinhibition 2401409646  
18 3 y Female During acyclovir treatment Choreoathetosis, dyskinesia, irritability, and fever IVIg, prednisolone Neurodevelopmental delay improving with special educational therapy 2618448547  
19 3 y Male During acyclovir treatment Dysphagia, involuntary limb and facial movements, irritability, lethargy and sleepiness, apnea, vomiting, tachycardia, and excessive salivation IVMP, IVIg, prednisolone, cyclophosphamide, acyclovir Complete recovery 2665837948  
20 c 6 y Female 1 y Aggressive and paranoid thoughts IV Steroids, IVIg, rituximab Unknown 3148862732  
21 7 y Male During acyclovir treatment Left hand tremor, chorea, intermittent dystonic posturing, emotional lability, irritability, visual hallucinations, and urinary incontinence IV Steroids, IVIg, cyclophosphamide, valacyclovir Developmental delay 2411533839  
22 13 y Male Day 21 Headache, aggression, and hypertension IVMP Partial improvement of behavioral deficits, withstanding motor and cognitive deficits 2649108449  
23 15 y Female Day 39 Severe headache, concentration difficulties, sleepiness, disinhibition, and intracranial hypertension Methylprednisolone, cyclophosphamide Residual behavioral problems 2401409646  
24 15 y Male Day 30 Cognitive deficits, agitation, and aggression IVMP, poMP, IVIg, acyclovir Complete recovery 2649108449  

Complied data from published case reports, case series, and observational studies of children with anti-NMDARe after HSVE. All children within this study had positive CSF HSV PCR result during HSVE. Furthermore, all children were positive for anti-NMDAR antibodies. Patients with concurrent diagnosed immunodeficiency are noted. IVMP, intravenous methylprednisolone, MMF, mycophenolate mofetil; SIADH, syndrome of inappropriate secretion of antidiuretic hormone.

a

Neonatal skin, eye, mucus membrane disease treated with 21 d of IV ACV and 6 mo of suppressive oral ACV.

b

Patient also had antidopamine receptor antibodies.

c

Patient had TLR-3 mutation.

d

Neonatal skin and mucus membrane disease treated with 21 d of IV ACV and 2 y of suppressive oral ACV.

TABLE 2

Summary Statistics for Disease Characteristics, Treatment Regimens, and Patient Outcomes in Children with Anti-NMDAR Encephalitis After HSV Encephalitis

N = 24, n (%)
Symptoms at presentation  
 Chorea 58 
 Seizure 38 
 Irritability 42 
Treatment  
 Steroids 71 
 IVIG 75 
 PLEX 21 
 Rituximab 38 
 Cyclosporine 29 
 Mycophenolate 
 Acyclovir or valacyclovir 54 
Outcome  
 Full recovery 12 
 Abnormal behavior 29 
 Epilepsy 
 Developmental delay 46 
 Motor delay 42 
N = 24, n (%)
Symptoms at presentation  
 Chorea 58 
 Seizure 38 
 Irritability 42 
Treatment  
 Steroids 71 
 IVIG 75 
 PLEX 21 
 Rituximab 38 
 Cyclosporine 29 
 Mycophenolate 
 Acyclovir or valacyclovir 54 
Outcome  
 Full recovery 12 
 Abnormal behavior 29 
 Epilepsy 
 Developmental delay 46 
 Motor delay 42 

Table represents summary statistics for information represented in Table 1. Data summarized include symptoms at disease onset, treatment regimen, and patient outcome. Many children had overlapping clinical outcomes.

Because HSV and HSVE significantly predisposes children to anti-NMDARe, HSV suppressive therapy should be considered as a critical treatment component.11,13  A double-blind, placebo-controlled study of 74 neonates revealed that 6 months of suppressive acyclovir therapy improved neurodevelopmental outcomes after neonatal herpes infection. Children on suppressive therapy for 6 months had higher 23-month Bayley Scales of Infant Development mental-development scores than those who were on therapy for <6 months or placebo controls.14  Unfortunately, authors of this study did not examine the effects of suppressive therapy for longer than 6 months. However, a smaller, uncontrolled, open-label study revealed that only 6% of children developed severe mental delay and 21% developed severe motor impairment with 2 years of suppressive acyclovir therapy after neonatal HSV infection.15  Neither study reported sustained adverse drug reactions related to prolonged antiviral exposure.14,15  Although a randomized placebo-controlled trial is imperative in establishing efficacy of prolonged acyclovir suppression, the limited number of affected patients and obstacles with recruitment makes it unlikely that such a trial will be performed. However, given the risk of viral reactivation and subsequent AE on the developing brain, suppressive therapy for a duration longer than 6 months may improve outcomes, although treatment cannot deplete viral reservoirs.4,5 

Diagnosing AE after HSVE in pediatric populations can be difficult because of the limited ability of children to vocalize symptoms and overlapping clinical presentation with HSVE.16,17  Furthermore, symptoms of anti-NMDARe vary by age. Infants and toddlers present with choreoathetosis and seizures; conversely, teenagers present with behavioral and psychiatric manifestations and less commonly with motor manifestations (Table 2).11,18  Symptoms and imaging findings are often more severe in HSV-associated anti-NMDARe than with classic anti-NMDARe, as with our patient.11  This may be due to blood–brain barrier dysfunction induced by preceding viral infection resulting in peripheral immune access to the CNS parenchyma.11,19 

Although uniform treatment regimens have not been established for the treatment of anti-NMDARe, therapy commonly–used includes antiepileptic medications and immunosuppressive medication including IVIG, IV methylprednisolone, rituximab, and PLEX (Table 2).17,20,21  Despite treatment, children who develop anti-NMDARe have profound neuro-disability, with many children developing persistent cognitive deficits and fatigue resulting in decreased academic achievement and lower quality of life.18  Antiepileptic treatment reduces seizure threshold in the acute encephalitic phase; however, data suggest that immunotherapeutic initiation is what improves neurocognitive outcomes and seizure recurrence.22  Additionally, observational cohort studies suggest that treatment outcome and relapse prevention is dependent on the amount of time between symptom onset and immunotherapeutic treatment initiation. Patients treated earlier during the disease course have better outcomes.10,23,24  This is likely due to less damage to the CNS parenchyma with earlier therapeutic intervention. Furthermore, additional studies reveal that poor functional status 1 year after diagnosis is associated with a combination of markers of disease severity, including ICU admission, treatment delay, prolonged time to clinical improvement, abnormal MRI result, and CSF pleocytosis.25  These studies reveal that patients identified earlier in disease onset and treated with current treatment regimens have better outcomes, although to date, there is no definitive cure for this autoimmune disease.

In the treatment of other pediatric neuroinfectious diseases, adjunctive corticosteroid treatment either improves or has no effect on patient outcome.2628  It remains unknown whether immunosuppressive agents provided in conjunction with acyclovir during the inciting HSVE episode improves outcomes within the pediatric population. However, a nonrandomized retrospective HSVE study in adults revealed that the addition of corticosteroids to acyclovir was a significant predictor of improved neurocognitive outcome.29  Although larger randomized studies are needed, recruitment of sufficient numbers of affected patients is difficult, as depicted by the discontinued German trial on acyclovir and Corticosteroids in HSVE; this study was closed after slow recruitment over a 5-year period.30  A new trial studying neurocognitive outcome after dexamethasone treatment with acyclovir in HSVE patients is ongoing and may reveal whether immune suppression during encephalitis treatment results in a lower likelihood of developing AE (NCT03084783).

Within our case report, we describe the first case of anti-NDMARe 2 years after neonatal HSV infection. Our patient was ultimately found to have a possible primary immunodeficiency in TLR-3 function. Toll-like receptors and their pathways are imperative in pattern recognition, viral sensing, and the initiation of the antiviral host immune response.19  As a result, TLR-3 deficiency leads to poor HSV control and increased likelihood of HSVE relapse.31,32  HSVE, in turn, leads to an increased risk of anti-NMDARe development, although the exact mechanism has yet to be determined.32  As depicted by this case and previously published literature, it is possible that children who develop anti-NMDARe after HSVE may have undiagnosed primary immunodeficiencies or disorders that lead to the development of CNS-specific autoimmune antibodies.32,33  However, as depicted in Tables 1 and 2, the use of immunomodulators such as PLEX, IVIG, and rituximab in the setting of anti-NMDARe is successful in controlling this encephalitis. It remains unknown whether TLR-3 deficiency in the absence of infection predisposes to NMDAR encephalitis.34  Because the neonatal immune system and developing brain are disproportionately vulnerable to early viral exposure, it is important to understand the value of early immunodeficiency screening in patients with neonatal HSV.

Thus far, the mechanism of anti-NMDAR antibody development after HSVE remains unknown. Understanding this mechanism may allow us to create treatments to prevent AE and prolonged neurodevelopmental disability. Furthermore, we lack understanding of the relationship between the Herpesviridae family and the development of neuro-disability as a whole. Herpes viruses, including Epstein-Barr virus, cytomegalovirus, and varicella zoster virus, are associated with the development of multiple sclerosis, sensorineural hearing loss, and peripheral neuropathy, respectively.19,35  However, the intersection of viral latency, host immunity, and neuronal architecture has yet to be fully elucidated within all of these diseases. Although the incidence of HSVE and anti-NMDARe is low, it is critically important to recognize these encephalitides and provide therapeutic intervention as early as possible to prevent long-term neurologic dysfunction and improve the quality of life of affected children.

Monica Manglani collected data, conducted the initial analyses, drafted the manuscript, completed all subsequent revisions, and provided final approval of the version to be published; Marian Poley contributed to conception, assisted in the first draft of this manuscript, and provided final approval of the version to be published; Ashutosh Kumar and George McSherry provided substantial contributions to conception and design, critically reviewed and revised the manuscript, and provided final approval of the version to be published; Jessica Ericson conceptualized, coordinated and supervised data collection, critically reviewed and revised the manuscript, assisted in completion of all subsequent revisions and provided final approval of the version to be published; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: No external funding.

AE

autoimmune encephalitis

CNS

central nervous system

CSF

Cerebrospinal fluid

HSV

herpes simplex virus

HSV-1

herpes simplex virus-1

HSVE

herpes simplex virus encephalitis

IV

intravenous

IVIG

intravenous immunoglobulin

NMDAR

N-methyl-d-aspartate receptor

NMDARe

N-methyl-d-aspartate receptor encephalitis

PCR

polymerase chain reaction

PLEX

plasma exchange

TLR-3

toll-like receptor-3

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

Supplementary data