Cognitive Outcome in a Case of Herpes Simplex Virus Encephalitis-induced Anti-N-methyl-D-aspartate Receptor Encephalitis

To the Editor, Herpes simplex encephalitis (HSE) is one of the most common viral encephalitis with an annual incidence of 2–4 cases per million people worldwide, accounting for almost 20% of all encephalitis cases.[1] The frequency of postherpetic autoimmune encephalitis varies from 7% to 25% of all HSE cases. In most cases, antibodies to neuronal cell surface and synaptic antibodies, mainly anti-N-methyl-D-aspartate receptor (NMDAR), are detected in cerebrospinal fluid (CSF) and/or serum samples of postherpetic encephalitis.[2,3] Around 80% of NMDAR encephalitis patients live independently 2 years after diagnosis, and most cases have complete recovery after therapy with the best results in those with earlier treatment and earlier escalation to second-line drugs.[4-6] On the contrary, patients with postherpetic encephalitis are at increased risk of poor neurological outcomes and increased requirements for symptomatic treatment such as antiepileptic drugs.[2,3] The modified Rankin scale (mRS) and clinical assessment scale in autoimmune encephalitis (CASE) scores are mostly used for acute assessment of anti-NMDAR encephalitis. Although the mRS score has been introduced for acute stroke patients, it has also been used as a predictor of NMDAR encephalitis prognosis. The scale mainly focuses on motor function and thus is insufficient to evaluate autoimmune encephalitis patients since they do not only have motor disability. A study on validation of the CASE scores suggested that the CASE score can efficiently predict the probability of poor functional status at 1 year after discharge in Chinese patients with autoimmune encephalitis, higher CASE scores are associated with longer hospital and intensive care unit (ICU) stay, and CASE scores are positively correlated with the mRS score.[7] The anti-NMDAR encephalitis 1-year functional status (NEOS) is a new scale, which aims to predict 1-year functional status in patients with NMDAR encephalitis.[8] As a notable drawback of postherpetic NMDAR encephalitis, even cases with good functional outcomes may show persistent cognitive deficits of memory loss and executive dysfunction.[2,3,5] Importantly, early awareness of cognitive dysfunction is crucial in NMDAR encephalitis since cognitive symptoms and brain atrophy are potentially reversible by early escalation to second-line treatment and rehabilitation.[6,9] Thus, the aim of this case study was to provide a detailed account of the cognitive impairment in postherpetic NMDAR encephalitis following remission of clinical symptoms and assess the utility of currently available clinical assessment scales in the prediction of cognitive outcome. A 29-year-old male with no chronic disease was diagnosed with HSV1 encephalitis with positive polymerase chain reaction (PCR) in CSF after admission with encephalopathy and seizures. Fifteen days after receiving acyclovir treatment, he was discharged from the hospital with normal mini-mental state examination test (MMSE) score (27) and mRS score (0) [Table 1]. His cranial magnetic resonance imaging (MRI) before discharge was compatible with residual HSE findings characterized with lesions on the right temporal lobe [Figure 1a-f]. A month later, he applied to the emergency room again due to a 5-day history of anterograde amnesia, visual hallucinations, and confusion. Neurological examination showed dysarthria and agitation, and cranial MRI showed the same residual findings. His electroencephalogram (EEG) findings were consistent with widespread slow activity in the right temporal area.Table 1: Clinical findings and clinical assessment scores with timelineFigure 1: Brain magnetic resonance imaging findings of patients at first discharge (a-f) and second admission (g-l). On the first discharge of the patient; fluid attenuated inversion recovery (FLAIR) (a, c, and e)-T2 (b, d, and f) hyperintensities were observed in the right temporal lobe. New lesions were detected on the contralateral temporal lobe and at the right frontal lobe in the FLAIR (g, i, and k)-T2 (h, j, and l) sequences on the second admissionTwo days later, the patient developed coma and respiratory failure and was transferred to ICU. CSF analysis showed normal white blood cell count and increased protein level (720 mg/dl). While PCR screening for HSV was negative, NMDAR antibody was detected in serum and CSF. The patient was negative for LGI1, CASPR2, GABAB receptor, AMPA receptor, DPPX, and GAD antibodies. NMDAR antibody was confirmed by an in-house live cell-based assay (end-point titer 1/640 for serum and 1/4 for CSF). He was in nonmedical coma and was having frequent focal motor and myoclonic seizures. EEG findings were transformed into periodic epileptic discharges lateralized to the right temporal area. His cranial MRI showed new left temporal and right frontal lobe lesions without contrast enhancement [Figure 1g-l]. The patient was clinically unresponsive to treatment despite receiving all first-line therapy options including intravenous pulse methylprednisolone, plasma exchange, and intravenous immunoglobulin. Rituximab was started as 1 g/week for 4 weeks. He began to respond after the first dose of therapy and was weaned off the ventilator after the second dose. Neurological examination showed moderate muscle weakness and cerebellar findings, and his MMSE score was 20 indicating impaired cognition. The patient’s clinical progression was assessed by mRS, CASE, and NEOS scores [Table 1]. His discharge mRS score was 1 due to minimal left hemiparesis and cerebellar ataxia. On the 1st-year (12-month) follow-up, cognitive tests were applied for assessment of quality of life, memory, executive functions, language, visual-spatial skills, praxis, and social cognition. Despite admirable progress in his somatic neurologic assessment, the patient showed mild-to-severe impairment in all neuropsychological tests and an MMSE score of 23 [Table 2].Table 2: Cognitive test resultsPatients with classical NMDAR encephalitis have been shown to recover to full health or with minor deficits in up to 75% of cases.[4-6] By contrast, the clinical outcome of postherpetic NMDAR encephalitis is notably worse than that described in patients of the same age with classical anti-NMDAR encephalitis. Furthermore, these patients often require second-line immunomodulating treatment and develop cognitive dysfunction.[2,3] Our case signifies the previously established fact that postherpetic NMDAR encephalitis often presents with a severe clinical course and requirement for mechanical ventilation. Despite early intervention with immunosuppressive medications and prompt escalation to second-line therapy, these patients often display severe and permanent impairment of cognitive functions. Previously, two patients have been shown to display permanent residual cognitive deficits in ≥12-month follow-up despite appropriate treatment and mild somatic neurologic impairment.[10,11] In another study, NMDAR antibody-positive HSE patients showed a trend toward less improvement than antibody-negative HSE patients in MMSE and Mattis Dementia Rating Scale scores from baseline to follow-up at 24 months.[12-14] In our study, we have applied a broad panel of cognitive tests for the first time to a case of postherpetic NMDAR encephalitis 12 months after discharge and identified moderate-to-severe impairment in all investigated cognitive domains. Seventy-five percent of patients with NMDAR encephalitis are left with permanent cognitive deficits of varying severity, predominantly in the domains of memory, attention, and executive control. Early immunotherapy is consistently associated with favorable cognitive outcomes.[13] Our case emphasizes once again that early escalation to second-line treatment may be particularly beneficial in the treatment of postherpetic NMDAR encephalitis. Despite previously established association between mRS/CASE scores and poor prognosis in autoimmune encephalitis,[7] our case showed a good recovery despite high mRS and CASE scores. In this context, NEOS has been demonstrated to be a better predictor of clinical outcome in NMDAR encephalitis.[8] As a matter of fact, our patient received a NEOS score of 2 due to ICU admission and abnormal neuroimaging features, which corresponds to around 70% good recovery (mRS 0 or 1) in 1-year follow-up.[8] To the best of our knowledge, the utility of NEOS in postherpetic encephalitis has been investigated for the first time in our case. In conclusion, it appears crucial to introduce comprehensive cognition evaluation tools to assess cognitive dysfunction in postherpetic NMDAR encephalitis since these patients may benefit from cognitive rehabilitation and social support.[15] Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.