N-Methyl-D-Aspartate Encephalitis our Experience with Diagnostic Dilemmas, Clinical Features, and Outcome.

INTRODUCTION: A neuropsychiatric syndrome characterized by a wide spectrum of clinical manifestations. It is seen in patients with antibodies against NR1-NR2 heteromers of the NMDA receptor. As the spectrum is mainly psychiatric most patients are treated as psychiatric disease resulting in huge diagnostic delay. PATIENT AND METHODS: Here we describe 29 patients with NMDA encephalitis seen by the authors in the last five years. Percentage of Transfected cells showing granular cytoplasmic florescence was considered for positivity and severity both in CSF and serum. Their presenting diagnosis, clinical features and the dilemmas, alarming gaps, laboratory data, response to treatment and relapses are discussed. OBSERVATIONS: All patients presented with a spectrum of psychiatric symptoms varying from panic to severe aggression, seizures, chorea, hemiplegia, catatonia, mitgehen, mutism, delirium, mania and memory problems. EEG is invariably abnormal as against imaging.
CONCLUSION: NMDA receptor mediated encephalitis should be suspected in all children and females of adolescent age with refractory neuropsychiatric syndrome. Both CSF and serum should be tested and regular follow up for relapses and neoplasms is mandatory.

INTRODUCTION

Immune-mediated encephalopathies are a group of disorders where immune dysregulation plays the major role in patients’ symptoms. The symptoms form a wide spectrum causing diagnostic delay unless a high degree of suspicion is exercised at every probable case. The clue to diagnosis is often subacute onset of memory complaint with at least one of the following: focal neurological deficits, unexplained seizures, mild cerebrospinal fluid (CSF) pleocytosis, magnetic resonance imaging (MRI) suggestive of encephalitis, and exclusion of other causes.[1] The common antibodies involved are N-methyl-d-aspartate receptor (NMDAR), glutamic acid decarboxylase (GAD), voltage-gated potassium channel, leucine-rich glioma inactivated 1, gamma-aminobutyric acid receptor–B, and contactin-associated protein-like 2. Immune-mediated encephalopathies can be categorized in to[2] those associated with antibodies to intracellular antigens such as anti-Hu observed with malignancy, extracellular epitopes of ion channels, receptors and associated proteins such as NMDA, intracellular synaptic proteins such as GAD65, syndromes with less clearly established antigens such as SLE, and other rheumatologic disorders.

In this article, we wish to discuss the NMDA-associated encephalopathies observed by the authors in the last 5 years, diagnostic problems, and course.

ANTI-NMDAR ANTIBODY SYNDROME

NMDA is an extracellular and synaptic substance involved in excitatory glutaminergic synaptic transmission and plasticity. Anti-NMDAR antibody encephalitis is one of the most common autoimmune encephalitis caused by the immunoglobulin G (IgG) antibodies against the GluN1 subunit of the NMDAR and described in 2007.[3] It is common in children and young adults. Relapse rate is 12% per year reported in untreated and partially treated patients. Relapses are more when treatment delay is more than 40 days from the onset of symptoms and are treated with second-line therapy for longer time, though exact duration is not defined. Patients with herpes simplex virus encephalitis might later develop NMDA encephalitis. Common situations that raise suspicion are as follows: rapidly progressive abnormal behavior or cognitive dysfunction in a previously well-preserved child, speech and language impairment, altered sensorium, seizures, perioral or generalized dyskinesia, autonomic dysfunction, hypoventilation with abnormality in one of the following: electroencephalography (EEG), IgG anti-GluN1 antibodies, systemic teratoma where antibody to NR1 and NR2 subunits of the NMDAR is observed, which is also expressed by the associated tumors, CSF pleocytosis, OligoClonalBand, and exclusion of other causes.[4567] Mechanism is believed to be due to binding of (Ig)G1and(Ig)G3 to NR1 subunit of NMDAR in the cortex and later subcortical structures.[8] EEG is unique in the sense that epileptic discharges are very rarely seen but shows diffuse or focal slowing, fast activity, and delta brush, which is diffusely seen and not altered by the state of arousal, and this pattern carries some prognostic relevance as those who had this pattern had a slightly longer course of illness.[910] Treatment options are plasmapheresis, steroids, IVIGs, second-line immunomodulators when first line fails, and tumor removal whenever detected.[1112] The antibodies could be present or absent in the serum, CSF, or both, and therefore both need to be examined at least at the first instance.[131415]

COURSE

Patient and methods

Patients admitted to our team with definite NMDA encephalitis (antibody-positive cases) from April 2013 to April 2018 were evaluated clinically. CSF examination for cell count, glucose level, protein level, viral and bacterial infections, and autoimmune encephalitis workup, 16 channel EEG, MRI of brain, X-ray of chest, ultrasonography of abdomen and pelvis for testis and ovaries, apart from routine blood and urine examination were carried out in all cases. Computed tomography scan of abdomen was carried out when indicated. Complete neuropsychology assessment was attempted in all cases. During follow-up, residual symptoms, clinical relapses, and serum NMDAR antibodies were checked.

Observation

We had a total of 29 cases that were observed by our team. Surprisingly, only three were male [Figure 1]. Their age group varied from 3–31 years and the mean age was 17 years. Age-wise distribution showed maximum incidence in 12–18 years group [Figure 2]. Referral diagnosis in the patients varied from viral encephalitis in five, catatonia in six, attention deficit disorder in two, autism spectrum disorder in three, rheumatic chorea in two, autoimmune encephalitis in five, psychiatric illness unspecified in five, rabies in one, and schizophrenia in one [Figure 3]. Of the 29 patients, 20 reported minor respiratory infection preceding the problem by 4–10 days. One patient had global developmental delay with congenital heart disease, one patient had hydronephrosis that was operated 4 years ago, and one patient was bitten by dog and received anti-rabies vaccine 30 days before symptom onset. All patients had psychiatric symptoms. Severe mania-like features were seen in one and schizophreniform symptom in one, severe panic in nine, unexplained anxiety in eleven, catatonia in six, mutism in one, biting self and others in one [Figure 4], and delusions and hallucinations in seven [Figure 5]. Neurological features observed in patients were hemiplegia and aphasia in one, mutism in one, seizures in twenty-one, cognitive decline in twenty-nine, and chorea in three. Two patients had benign ovarian teratoma [Figure 6]. EEG showed slowing of background in twenty-three patients, epileptiform discharges in nine, and extreme delta brush in eleven [Figure 7]. MRI was normal in seven cases. Though reported normal, signal changes in limbic structures were observed in five cases. All others showed clear-cut features of limbic encephalitis [Figure 8]. None had any other tumors. CSF test showed moderate antibody titers with less than 10% of transfected cells showing two to three plus granular cytoplasmic florescence, and serum test showed very high titers of up to 40%–60% in seven cases, reverse in twelve cases, and both were moderately positive in ten cases. During follow-up at 6 months, only two patients remained positive in serum test. CSF was not tested during follow-up. , , , , , , ,

Figure 1

Gender distribution in the patients

Figure 2

Age-wise distribution of the current cohort

Figure 3

Referal Diagnosis

Figure 4

(A) Bite mark in the shoulder of the patient’s brother. (B) Bite mark in self both inflicted by the patient

Figure 5

Distribution of neurological and Psychiatric symptoms

Figure 6

First part is axial view and second sagital view of CT abdomen with arrows pointing to the ovarian Terratoma

Figure 7

(A) EEG with very low frequency delta. (B) Delta slowing with delta brush

Figure 8

MRI showing fluid attenuated inversion recovery images hyperintensities in the cingulum, medial temporal regions. First Cut shows signal changes marked at medial temporal regions and the second one at cingulum and insular region

Treatment

All patients received intravenous methyl prednisolone in addition to symptomatic treatment. Good response was seen in 11 patients. They were continued on monthly pulses for 6 months. The patients with teratoma were operated. Of the 18 nonresponders, 4 patients received intravenous immunoglobulin (2g/kg), and all 3 had good response during follow-up at 3 months and was continued for 6 months. One patient showed poor response and shifted to rituximab (375mg/m2 of body surface) weekly for 4 weeks with moderate improvement. Other nonresponders that constituted 14 patients were treated with plasmapheresis five times a month for 6 months and all of them responded. Relapse occurred after 3 years in a patient after surgery for fracture of femur. He developed super refractory status epilepticus and passed away. Other two improved with the repetition of the previous regime. Only two patients who started with new-onset seizures were first treated by physicians. All others were treated by psychiatrists. Diagnostic delay varied from 4 weeks to 7 months.

Outcome

Follow-up period varied from 5 years to 6 months. Mortality was seen in one patient at 3 years. All others survived. Cognitive decline of varying degree was seen in 27 patients. Two patients returned to original level of functioning. However, irritability and aggressive behavior were reported by most patients. Excessive somnolence was seen in one. Symptomatic treatment was continued based on the symptoms. Only two patients were seropositive at 6 months in this group, though they have clinically improved.

DISCUSSION

This small series shows that this particular type of immune-mediated encephalitis is more common in women, children, and adolescents. Diagnosis was suspected only in 24% of patients, which is a huge suspicion gap. One patient came with a serious diagnosis of rabies as she was biting self and others. Diagnostic delay is huge, which is responsible for persistent neuropsychiatric sequelae. Clinical presentation involves a wide spectrum of neurological and psychiatric features. These symptoms are resistant to symptom modifying treatment options with out immunotherapy. Both CSF and serum need to be tested as the sensitivity in both is variable. Imaging may not be diagnostic in all cases. However, when the response to treatment with symptomatic measures is not satisfactory, EEG serves as a cheap screening instrument as it is abnormal even in those who do not have seizures. Early initiation of immunotherapy and shift to a second line of therapy in poor responders are mandatory. Even though exact duration of therapy is not clear, the authors followed a minimum of 6-month course except with rituximab. Frequent follow-up reassessment for neoplasms is mandatory in those who do not become antibody negative. None of the patients in this group had dysautonomia as against what is described in the literature. Those who responded to monotherapy were continued on the same and we did not find relapses in them in spite of being on monotherapy.

CONCLUSION

NMDA antibody-related encephalitis seems to be more commonly present with a rapid-onset neuropsychiatric syndrome in children and young girls. Autonomic involvement was not seen in this cohort as against the literature. Immunotherapy with a single responsive drug was sufficient in most of our patients. Majority of patients are left with cognitive behavioral sequelae and hence, high degree of suspicion is essential for early diagnosis and treatment. Some of the aggressive and panicky behavior of the patients can even mimic the potentially fatal diagnosis of rabies and needs caution. To the best of our knowledge, this review is the first to report self-mutilating behavior in NMDA encephalitis.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.