Isolated Nocturnal Occurrence of Orofacial Dyskinesias in N‐methyl‐D‐aspartate Receptor Encephalitis–A New Diagnostic Clue

Abstract

Background

The syndrome of anti‐N‐methyl‐D‐aspartate receptor encephalitis is classically associated with a combination of limbic dysfunction, dysautonomia, central hypoventilation and movement disorders. On clinical grounds, the diagnosis is often supported by the presence of generalized dyskinesias in a patient with encephalopathy and catatonic signs. Orofacial dyskinesias have been recognized as characteristic of the disorder but can be absent in some patients. Pure psychiatric syndromes without movement disorders have also been described.

Methods and Results

The authors describe 2 male patients who presented with prominent neuropsychiatric symptoms without movement disorders during wakefulness but isolated orofacial dyskinesias during sleep. In 1 patient, this observation supported the early introduction of immunotherapy; and, in both patients, the clinical outcome was excellent.

Conclusions

Careful history and nocturnal examination may reveal orofacial dyskinesias in patients with N‐methyl‐D‐aspartate receptor encephalitis who have apparent pure psychiatric manifestations.

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View Supplementary Video 2

The syndrome of anti‐N‐methyl‐D‐aspartate receptor (NMDAR) encephalitis is characterized by limbic dysfunction, autonomic instability, hypoventilation, and movement disorders.1 Recently, it has been recognized that the clinical spectrum encompasses isolated psychiatric presentations.2 Orofacial dyskinesia is a distinctive feature of NMDAR encephalitis, and its occurrence increases the likelihood of the diagnosis in the context of psychosis or encephalopathy; however, not all patients have this finding.1, 3 In a series of patients with NMDAR encephalitis, we have observed that some patients can present with prominent neuropsychiatric symptoms, and orofacial dyskinesias can occur almost exclusively during the night, indicating that this sign could be overlooked. Here, we describe 2 patients and provide video documentation of this observation.

Case 1

A 19‐year‐old male presented with subacute onset of abnormal behavior characterized by intermittent, complex auditory and visual hallucinations. He was fluctuating between periods of insomnia and somnolence, and he had 3 generalized seizures before admission. On examination, he was drowsy but was able to follow simple commands. Cranial and motor examination was unremarkable. He scored 5 points on the Bush‐Francis Catatonia Rating Scale (BFCRS), with the presence of immobility/stupor, stereotypies, staring, verbigeration, and dysautonomia. An electroencephalogram (EEG) revealed generalized slowing, and magnetic resonance imaging was normal. Cerebrospinal fluid (CSF) analysis revealed 18 monocytes and normal protein and glucose content. He was started with acyclovir to cover herpes simplex virus and methylprednisolone. Provisional videos were obtained before and during treatment. However, the mother reported that, during the night, he had involuntary facial movement, so she documented these events (Video S1). The movements were present intermittently but were frequent during the course of sleep throughout the night and early morning. After his hospital discharge, CSF and serum antibody tests were positive for NMDAR antibody. Antibodies for α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA), γ‐aminobutyric acid B (GABA B), metabotropic glutamate receptors 1 and 5 (mGluR1 and mGluR5, respectively), leucine‐rich glioma inactivated 1 (LGI1), and contactin‐associated protein like 2 (CASPR2) were negative in both CSF and serum samples. Three months after treatment, he scored 27 on the Montreal Cognitive Assessment and 0 on the modified Rankin scale. Further investigations searching for tumor were normal. Antibody titer was not available, and we did not conduct longitudinal tests for NMDAR antibodies.

Case 2

A 35‐year old man presented with a 3‐week history of generalized anxiety, auditory hallucinations, and insomnia. At examination, he was alert and able to follow commands; however, at times, he was also drowsy. He could repeat some sentences but with slurred speech. Cranial, motor strength, and sensory examinations were normal. Before treatment, his BFCRS score was 11, and he exhibited stupor, mutism, staring, stereotypy, negativism, mild rigidity, and cardiovascular dysautonomia. He was able to walk with partial assistance. The EEG revealed moderate, generalized slowing, and CSF and brain magnetic resonance imaging were unremarkable. Given our experience with the previous patient, we requested video documentation during the night time, which was provided by his brother during admission and showed the presence of orofacial dyskinesias (Video S2). After treatment with methylprednisolone and intravenous immunoglobulin, his BFCRS score was 3. Three months after hospital discharge, he scored 23 on the Montreal Cognitive Assessment and 1 on the modified Rankin scale. NMDAR antibodies were present in CSF and serum. Antibodies for AMPA, GABA B, mGluR1, mGluR5, LGI1, and CASPR2 were negative; and longitudinal testing was not performed.

Discussion

The clinical presentation of NMDAR encephalitis can be varied and difficult to make on clinical grounds, especially early in the course of the illness or in patients who have pure psychiatric manifestations.2 For example, catatonia is frequent in adults with NMDAR encephalitis but also may be caused by primary psychiatric disorders, neuroleptic malignant syndrome, or systemic medical illness. Furthermore, psychosis can be observed in up to two‐thirds of pediatric patients as the initial presentation.4 Eventually, most patients develop orofacial dyskinesia and chorea. Early diagnosis is important, because timely treatment may result in better clinical outcomes.3 A definitive diagnosis usually relies on the identification of specific antibodies in CSF or serum, but the results may or may not be readily available, depending on the clinical setting.

Orofacial dyskinesias are reported in from 55% to 60% of adult NMDAR encephalitis series.1, 3 When the “classic” presentation with encephalopathy, seizure, hypoventilation, and a more generalized hyperkinetic movement disorder is present, the diagnosis is less challenging. However, in patients who are manifesting relatively pure psychiatric symptoms,2 the diagnosis currently relies on specific antibody testing or clues from nonspecific investigations, such as CSF cell counts or EEG. Our patients suggest that a careful history and nocturnal examination of patients, even those with apparent pure psychiatric manifestations, may reveal orofacial dyskinesias typical of those observed in NMDAR encephalitis: a novel diagnostic clue.

The precise nature of the orofacial dyskinesias observed in NMDAR encephalitis has been debated, but experimental evidence points toward decreased GABA function mediated by NMDAR antibody binding in inhibitory neurons.5 One hypothesis has been that the movement disorder of NMDAR encephalitis may represent status dissociatus, in which involuntary movements occur during severely disordered sleep.6 The appearance of the orofacial dyskinesias only during sleep in our patients supports this possibility, although formal sleep studies were not performed. Orofacial dyskinesias are not exclusively seen in NMDAR encephalitis but have also been reported in a recently described autoimmune encephalitis mediated by neurexin‐3α antibodies.7 It would be interesting to establish the behavior of orofacial dyskinesias during sleep in individuals with this disorder.

Author Roles

1. Research Project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing the First Draft, B. Review and Critique.

H.M.‐B.: 1A, 1B, 1C, 3A

V.S.C.F.: 1A, 1B, 1C, 3A, 3B

Disclosures

Ethical Compliance Statement: We confirm that we have read the journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest: The authors report no sources of funding and no conflicts of interest.

Financial disclosures for previous 12 months: Victor S.C. Fung receives a salary from NSW Health, has received research grants from the National Health and Medical Research Council of Australia, and is on advisory boards and/or has received travel grants from Abbott/AbbVie, Allergan, Boehringer‐Ingelheim, Hospira, Ipsen, Lundbeck, Novartis, Parkinson's KinetiGraph, Solvay, and UCB. Hugo Morales‐Briceño reports no sources of funding and no conflicts of interest.

Supporting information

Videos accompanying this article are available in the supporting information here.

Video S1: Segment 1. The video shows Patient 1 during sleep at night, with oromandibular choreic movements involving the lower face and tongue. There are no other hyperkinetic movements or dream enacting during sleep. Segment 2. The patient is shown awake but with drowsiness and attentional deficit, although he can perform some hand gestures when asked. Segment 3. Oromandibular dyskinesia is observed early in the morning while the patient is still sleeping.

Video S2: Segment 1. The video shows Patient 2 with oromandibular dyskinesia and tongue movements during sleep at night. Segment 2. The patient is shown awake without dyskinesias, but he has drowsiness and difficulty following verbal commands to smooth pursuit during examination. Segment 3. A similar pattern of night‐time oromandibular dyskinesias is observed during sleep.