A Case of Lethargy Followed by New Abnormal Movements in an Infant With a History of HSV Encephalitis

Case Report

A 29-day-old former full-term baby girl presented with 3 days of poor feeding and decreased activity. Her mother reported that the patient had a decreased appetite associated with decreased urine output and stool, but without fever, rhinorrhea, vomiting, diarrhea, or rash. Several family members reportedly had cold symptoms the week prior to presentation. She was born to a 21-year-old mother via uncomplicated normal spontaneous vaginal delivery with no known pregnancy complications. Prenatal infectious labs were reportedly negative including rubella IgG positive, and negative for syphilis, hepatitis B surface antigen, HIV 1 and 2, and group B streptococcus. On presentation to the emergency department, the patient was ill appearing with a temperature of 35.4°C, a weak cry and suck, dry mucous membranes, delayed capillary refill, mottling, and poor respiratory effort. She received fluid resuscitation and supplemental oxygen for respiratory distress. Laboratory findings included a normal complete blood count and urine studies, but her comprehensive metabolic panel (CMP) was significant for elevated aspartate aminotransferase 200 U/L and alanine aminotransferase 102 U/L. A respiratory viral panel was positive for rhinovirus/enterovirus.

A lumbar puncture was performed, and she received ampicillin and ceftazidime to empirically treat bacterial meningitis. Cerebrospinal fluid (CSF) revealed a white blood cell count of 211 with large mononuclear cells, red blood cell count of 2, protein 356, glucose 25, and negative enterovirus. Xanthrochromia was present. HSV-2 polymerase chain reaction (PCR) was positive in both the CSF and blood. She was then admitted to the pediatric intensive care unit, and placed on continuous video electroencephalography (EEG), which demonstrated electrographic seizures arising from the bilateral posterior quadrants. She was started on phenobarbital with rapid control of her seizures. Magnetic resonance brain imaging (MRI) with and without contrast revealed diffuse leptomeningeal enhancement, communicating hydrocephalus, and a few hemorrhagic foci of the choroid plexus (see Figure 1A and B). She was treated with intravenous acyclovir (20 milligrams per kilogram per dose every 8 hours) until her CSF was negative for HSV-2. She completed a 58-day course due to multiple positive HSV CSF PCRs. She was noted to have gradual clinical improvement by day 52 of treatment. She was then transitioned to a suppressive dose for 6 months.

Figure 1.

Initial MRI brain T1 post contrast imaging demonstrates diffuse leptomeningeal enhancement (A). Leptomeningeal enhancement is also seen on T2 turbo inversion recovery magnitude (TIRM) post contrast along with increased T2 signal in the basal ganglia and thalamus (B). Follow-up imaging 1 month later demonstrates cystic encephalomalacia on T1 post contrast and T2 TIRM post contrast imaging (C,D).

On hospital day 44, she was noted to have new abnormal movements marked by rhythmic head deviation and jaw thrusting concerning for seizure activity, as well as increased irritability. Continuous video EEG revealed diffuse attenuation, and a suppressed discontinuous background without seizures. Repeat MRI brain with and without contrast showed extensive cystic encephalomalacia of the supratentorial brain without any new lesions (see Figure 1C and D). Repeat HSV PCR in the CSF was negative. Given her new abnormal movements and mental status change, serum antibodies to NMDA were sent, and found to be elevated 1:1280 (normal <1:10). CSF antibodies were not sent due to limited CSF availability. Other metabolic derangements were ruled out with CMP, and movements were not felt to be secondary to medication side effects.

Consent was obtained from the parent for this report.

Final Diagnosis

The final diagnosis is anti-NMDA receptor encephalitis (NMDARE), occurring after HSV-2 encephalitis.

Hospital Course

Following the diagnosis of NMDARE, the patient was treated with intravenous immunoglobulin (IVIG) 2 grams per kilogram divided over 5 days, and then continued on 1 gram per kilogram monthly for 1 year.

At the most recent follow-up at 20 months of age (18 months after her admission), her parents report some improvement in irritability and abnormal movements with no apparent seizures. She continues to have intermittent shaking of the arms and legs, but they are suppressible. Clonazepam and gabapentin are helpful at times for irritability, and she remains on levetiracetam. Developmentally, she is making gains but delayed for a 20-month-old. She is able to roll both ways and can hold onto toys. She is able to fix and track visually. She coos but has only a little babbling. She continues to have insomnia, despite melatonin, gabapentin, and clonazepam. She also continues to have dysphagia. On examination, she is awake and intermittently cries but is consolable. She is microcephalic. Her cardiac and pulmonary examination is unremarkable. On her neurologic exam, she can track faces, has rare square wave jerks, and central hypotonia with appendicular hypertonia. She is able to move all extremities antigravity and prefers to keep her hands fisted but is opening them more. She has 4+ symmetric deep tendon reflexes throughout, with 1-2 beats of clonus and upgoing toes bilaterally. She does not bear weight on legs even with assistance.

Currently, she receives IVIG monthly as well as physical, occupational, and speech-language therapy. She is followed by nephrology, endocrinology, physiatry, infectious disease, and gastroenterology.

Her most recent brain MRI (without contrast) showed overall unchanged extensive supratentorial cystic encephalomalacia with volume loss and ventriculomegaly along with unchanged evidence of scattered parenchymal calcifications.

Discussion

Anti-NMDA receptor encephalitis (NMDARE) is an autoimmune encephalitis that causes neuropsychiatric symptoms and is mediated by antibodies that target the NMDA receptor. A small subset of patients can develop NMDARE after herpes simplex virus encephalitis.¹ While rare, NMDARE is the second most common cause of encephalitis in children.² Here we discuss an infant who developed increased irritability and abnormal movements after HSV encephalitis (HSVE) found to have positive anti-NMDA receptor antibodies.

Prior case reports suggest that children tend to have choreoathetosis and reduced levels of consciousness in NMDARE following prior viral encephalitis,³ or that they present with a biphasic illness with predominant movement disorder.⁴ NMDARE has been reported in both children and in adults with a history of HSVE; in fact, 27% of HSVE develop neuronal antibodies, two-thirds of which are to the NMDA receptor.⁵ Post-HSVE NMDARE is hypothesized to occur secondary to HSV-mediated brain injury that consequently leads to exposure of NMDA receptors to the infected person’s immune system. This causes anti-NMDAR immunoreactivity and can lead to the development of NMDARE.¹ While anti-NMDA receptor antibodies are the most common post-HSV antibodies, other antineuronal antibodies are also observed.⁵

This case is unique in that to our knowledge our patient is the youngest to have anti-NMDAR antibodies after HSVE. Moreover, this case adds to the literature of symptoms of NMDARE in infants, as clinical presentation of NMDARE in infants is unknown due to being rare. In addition, most reports of HSVE associated with NMDARE occurred after HSV-1 encephalitis with only a few reports of post-HSV-2 NMDARE, rarely in infants.⁶ Our patient developed new abnormal movements and increased irritability, which triggered the search for anti-NMDAR antibodies; however, it remains unknown whether her symptoms were sequelae from HSVE or new anti-NMDARE. While she did not exhibit dramatic improvement initially from IVIG, on subsequent follow-up her abnormal movements have since subsided and her family reports that her irritability has improved after IVIG. Moreover, post viral NMDARE is potentially chronic, which would then require long-term immunotherapy treatment such as continued IVIG.³ Our patient also had hydrocephalus of which the cause is unclear; some putative mechanisms could be due to inflammation with ependymitis or viral particles bridging ependymal cells leading to mechanical obstruction and decreased absorption of CSF.⁷ The hydrocephalus did resolve after therapy but was likely also affected by the marked encephalomalacia.

Previous reports have indicated that NMDARE could be present if after the resolution of HSV infection, choreoathetotic movements persist.⁶ If these movement disorders persist, testing for anti-NMDA receptor antibodies is recommended.⁶ In addition to residual movement disorders, persistent encephalopathy, regression, or symptoms concerning for recurrent HSVE after an initial improvement are also indications to test for NMDARE. In addition, children have been found to have higher rates of neurological symptoms relapses with a significantly shorter latency between HSV and anti-NMDARE than in adults.³

Conclusion

Anti-NMDA receptor encephalitis should always be considered in patients after HSV encephalitis, especially if they develop new seizures, abnormal movements, changes in mental status, overall worsening after an initial improvement, or if concerns for recurrent HSV encephalitis arise.⁶