Challenges in the diagnosis of anti-NMDAR disease in a young male patient: a case report

Informed written consents were taken from the patient’s parents for publication of identifying information/images in an online open-access publication. The patient is a 15-year-old right-handed Egyptian male. He is a preparatory student with good scholastic achievement and he also worked in an aluminum factory. He is an occasional smoker. There is no consanguinity between his parents, and he has a negative perinatal history. His sister, however, is a known epileptic patient; after a hypoxic injury during prolonged labor. He has a history of recurrent attacks of tonsillitis.

At the age of 8 years, the patient had an attack of tonsillitis and ear pain associated with fever after which he developed recurrent convulsions. The convulsions were in the form of right focal to bilateral tonic clonic convulsions. They were associated with impaired consciousness, tongue biting and frothy secretions from the mouth, followed with post ictal fatigue and sleepiness. Each attack lasted for 2–3 min and occurred over 3 days during the same week.

The patient was then prescribed valproate 300 mg daily. He continued on this dose for 4 years till the age of 12. When he sought medical advice at our outpatient clinic, his attacks were diagnosed as acute symptomatic seizures and the decision was made to start withdrawing the medication. The patient remained seizure-free till the age of 15 years, after complete withdrawal of the medication.

At the age of 15 years, the patient presented to the epilepsy clinic at Kasr Al Ainy Cairo University hospitals in May, 2021 with 1 week history of acute altered mental status associated with behavior and personality changes in the form of disinhibition, socially inappropriate behavior, impulsiveness, diminished social interest and perseverative and compulsive behaviors. He suffered from severe anxiety, insomnia, hallucinations, agitation, slurred speech and cognitive impairment. He sought psychiatric advice and was prescribed risperidone and biperiden with no improvement in his condition.

Three days later, the patient started developing prodromal symptoms with fever and ear pain. The condition was followed by clustering of acute right tonic clonic evolving to bilateral tonic clonic seizures associated with impaired consciousness and urine incontinence. It was preceded by sense of fear, vomiting and salivation and followed by post ictal sleepiness. The patient has undergone monitoring in the Epilepsy Monitoring Unit (EMU) to confirm the organic pathology. Nihon Kohden Neurofax EEG apparatus (Tokyo, Japan) was used. Electrode placement was done according to the international 10–20 system. The electroencephalography (EEG) recorded both true seizures and non-epileptic movement disorders (Fig. 1).

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The patient was then admitted to the intensive care unit (ICU) and received intravenous acyclovir; as central nervous system (CNS) infection was suspected, loading dose levetiracetam, olanzapine and rispiredone. The seizures thereupon improved, however, the behavioral changes persisted. The patient also started developing dyskinesias together with fluctuation in both of his respiratory and heart rates. The toxicology screening was positive for barbiturates. Antistreptolysin O titre was negative. Thyroid profile and collagen vascular profile were normal.

Cerebrospinal fluid (CSF) analysis showed 17 cells mainly lymphocytes and positive oligoclonal bands (Type II, 4 bands). CSF anti-NMDA were positive. Magnetic Resonance Imagining (MRI) Brain was performed on a 1.5 T General Electric (GE) Signa clinical scanner (Milwaukee, WI, USA). It showed an increased T2/FLAIR signal of left hippocampus and amygdala relative to right side (Fig. 2a).

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The diagnosis of anti-NMDA encephalitis was made. The patient received pulse steroids for 5 days, and the mother reported minimal improvement in the behavioral changes. Pan computed tomography (CT) was done as part of paraneoplastic work-up and it was normal except for a benign epidydimal cyst. The plan was then to perform plasma exchange sessions. The patient underwent three sessions, then developed fever and more deterioration of his conscious level. The central line was removed and antibiotics were started empirically. After the infection subsided, the patient was started on 5 days of intravenous immunoglobulin (IVIG) together with 250mg IV steroids. During the second day, the patient developed 2 attacks of generalized tonic clonic convulsions and received a loading dose of phenytoin. A new CT scan was done showing positive Delta sign. Accordingly, sinus thrombosis was suspected and the patient was started on enoxaparin 60 twice daily. New MRI brain and magnetic resonance venography (MRV) were done and showed complete diffuse thrombosis of the superior sagittal and right transverse sinuses with congested superficial cortical veins on both sides. A venous infarction was also seen in the right frontal lobe, left inferior parietal gyrus and genu of the corpus callosum associated with thin bilateral subdural collection overlying both cerebral hemispheres (Subdural hygroma formation) (Fig. 2b, c and d).

Antiphospholipid work-up was done, to exclude antiphospholipid associated with anti-NMDA encephalitis, and the results were negative.

After finishing the IVIG, the patient showed marked improvement in the behavioral and psychiatric symptoms. He was then started on oral prednisolone 60 mg daily together with levetiracetam 1000mg twice daily, phenytoin 300 mg daily, oxcarbazepine 150 mg and warfarin 5 mg daily and was discharged after improvement.

After 1 month from stabilizing the patient’s condition, follow-up brain MRI and MRV were done showing partial recanalization of the superior sagittal and right transverse sinuses with complete resolution of the congested cortical veins and partial regression of the subdural hygroma (Fig. 2e, f).

Accordingly, anticoagulation was stopped together with gradual withdrawal of his anti-seizure medications. The patient then received rituximab and returned completely to his normal condition.

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is an autoimmune disorder mediated by antibodies against the NR1 subunits of the NMDA receptors in the brain [1]. It is predominantly described in young females in association with ovarian teratoma. Ovarian teratomas account for 94% of all neoplasms; however, neuroblastoma, lymphoma, lung, breast, thymic, testicular, and ovarian carcinoma have also been described [2, 3]. It is increasingly recognized as an important cause of autoimmune encephalitis. It is especially important to consider because most often, it is dismissed initially as a psychiatric symptom or viral encephalitis, and patients are initially referred for psychiatric evaluation [4]. This disorder is severe, yet potentially treatable. The best outcome depends on prompt immunotherapy and complete tumor removal if present. However, its diverse presentations and the low awareness among clinicians often cause delay in its diagnosis and treatment [5].

Such as with this patient, we need to suspect the possibility of Anti-NMDA Encephalitis, as the patients with anti-NMDAR encephalitis present clinically with several recognized stages. An initial prodromal phase occurs in almost 70% of patients consisting of headache, fever, nausea, vomiting or upper respiratory symptoms. Then, psychiatric symptoms develop, including; anxiety, insomnia, delusions, paranoia, mania, or social withdrawal [6]. The final stage presents with dyskinesia, extrapyramidal signs, motor automatisms and autonomic instability [2]. Complex seizures can develop early in the course of the disease. The frequency and intensity of seizures decrease with disease progression; however, they may recur at any time [2]. Our patient followed these stereotypical clinical stages.

The diagnosis of anti-NMDAR encephalitis is often difficult and requires exclusion of other similar conditions including; infectious, endocrine and other immune-mediated etiologies. The typical CSF analysis for anti-NMDAR encephalitis is lymphocytic pleocytosis with either normal or elevated protein. Demonstration of oligoclonal bands and anti-NMDAR autoantibodies in the CSF and the serum confirms the diagnosis [1, 7]. Our case showed all the previously described CSF findings.

EEG is abnormal in most cases, usually showing generalized slowing activities which do not correlate with the abnormal movements, as presented in our case [2]. In some cases, it may show extreme delta brushes.

Brain MRI is often inconclusive, although some patients may have T2/FLAIR hyperintensity in regions, especially the hippocampi. These findings, however, correlate poorly with the symptoms [1]. In our case, the patient’s MRI, during the acute stage of the disease, initially showed left hippocampal involvement.

Treatment strategies consist of tumor removal, corticosteroid and IVIG or plasmapheresis as first-line therapy, and rituximab and cyclophosphamide as second-line therapy [3]. Relapse of encephalitis occurs in 20–25% of patients within 3 months up to 9 years; often in those with undetectable or without tumor [8].

Cerebral venous sinus thrombosis (CVST) may present with variable symptoms. The onset can be acute, subacute, or chronic. It mostly presents with headache, and additional symptoms including focal neurological deficits, seizures, and encephalopathy [9].

Antiphospholipid syndrome (APS) is a primary or secondary autoimmune disease, whose patients become more prone to vascular thrombosis. It may develop in patients after exposure to infectious agents or with rheumatic diseases [10].

APS with cerebral venous thrombosis can be an associated comorbidity with anti-NMDAR encephalitis. Therefore, patients with anti-NMDAR encephalitis and a thrombotic event should be screened for APS.

There was a previous report of a similar case with APS associated with anti NMDA encephalitis [11]. Another study also found that high serum titers of NMDAR1-abs are related to unfavorable functional outcome after stroke and are associated with increased cardiovascular recurrent event [12].

Khan and his colleagues [13] also reported a case that was diagnosed as cerebral venous sinus thrombosis (CVST), and was started on anticoagulation then developed new movement abnormalities and was found to have anti-NMDA receptor antibody positive in cerebrospinal fluid. They explained that it may be a possibility that there is an inflammatory or autoimmune process that led to the formation of cerebral venous thrombosis along with anti-NMDA receptor antibodies.

Similarly Yang and Zhang [14] reported a boy who was initially diagnosed with Labbe vein thrombosis and later tested positive for both NMDA and GABA (B) receptors. Vasculitis and endothelial cell impairment caused by autoantibodies are the pathological mechanisms of thrombosis in some of systemic diseases as behcet and antiphospholipid syndrome. Therefore, they propose that the brain tissue damage caused by venous thrombosis triggered an immune response and produced the two different autoimmune antibodies.

In our patient, laboratory tests were negative for APS, so the possible explanations of these findings are that: (a) over activity of NMDA receptors can result in excitotoxicity and acute neuronal injury through excessive presynaptic glutamate release and reversal of calcium uptake by astrocytes [15, 16], (b) regional inflammation can trigger arterial or venous thrombosis [17], (c) studies indicate that NMDARs contribute to the functional mechanisms of the vasculature and to the blood flow characteristics [18, 19] and (d) NMDAR1-abs may critically impair vessel diameter adaptions to metabolic demand, by antagonizing NMDA-receptors in brain endothelial cells [18].

Anti-NMDAR disease should be suspected in any young individual who develops rapid encephalopathy associated with seizures, psychiatric symptoms and/or movement disorders. Identification of NMDAR antibodies confirms the diagnosis and should prompt early intervention with immunotherapy and neoplastic workup [8].