Case Report
A 50‐year‐old man presented with fever, arthromyalgias, headache, fatigue, and inappetence followed by insomnia. His previous medical history was unremarkable apart from tobacco habit and recently increased bowel openings with slight weight loss. The patient received a brief course of antibiotics with prompt resolution of fever, despite the persistence of general malaise. During the following days, insomnia worsened, proving resistant to benzodiazepines, and he appeared increasingly anxious. Severe hypertension (up to 190/120 mmHg) was unexpectedly documented. Soon afterward, the patient developed psychomotor agitation, hypochondria, and delusions. After he was found disoriented, wandering in his courtyard, he was admitted to our hospital, where first he underwent several psychiatric consultations. Fluctuations of responsiveness were then observed, and his verbal output progressively decreased. His clinical condition rapidly worsened: within 10 days he became mute, almost motionless, with inconstant posturing, waxy flexibility, and paratonia. Viral encephalitis was initially suspected: in fact, brain magnetic resonance imaging was unremarkable, and cerebrospinal fluid (CSF) analysis showed moderate pleocytosis (83 mononucleates/mm3) and a slight protein increase (48 mg/dL), but no microbial agent was detected. Treatment with intravenous acyclovir and steroids was unsuccessfully attempted. During this catatonic phase, rhythmic, low frequency, small amplitude jerks, mainly involving the perioral muscles, were observed and interpreted as facial myorhythmias. Episodes of paroxysmal autonomic instability (hypertensive crisis with sinus tachycardia), rarely associated with foot dystonia, also occurred. During the following weeks, while the patient was still in a stupor, violent, self‐injuring stereotypies of the head (eg, tongue thrusting, biting, head shaking) and the upper limbs (eg, hand rubbing, self‐scratching) became prominent (Video S1) and were inconstantly terminated by benzodiazepines administration.
Serial magnetic resonance imaging scans never revealed abnormalities, whereas periodic CSF analysis documented a progressive normalization. Daily prolonged electroencephalogram recordings showed variable widespread, sometimes rhythmic, slow‐wave activities (Figure S1), which never clearly correlated with clinical manifestations. Several antiepileptic medications were administered, leading to transient electroencephalogram changes, without matching clinical improvement.
Considering the coexistence of psychiatric disturbances, dysautonomia, and protean movement disorders, N‐methyl‐D‐aspartate receptor (NMDAR) encephalitis was hypothesized: in fact, the search for NMDAR autoantibodies via commercial fixed cell‐based assays (CBA) was repeatedly negative (twice). Other viral (eg, Morbillivirus, Toscana virus, West Nile virus) and autoimmune encephalitides (anti‐LGI1, CASPR2, AMPAR, GAD65, GABAA/BR, GlyR, DPPX, Hu, Yo, Ri, CV2, PNMA2, Amphiphysin) were thoroughly investigated. Despite the lack of typical magnetic resonance imaging and electroencephalogram abnormalities, Creutzfeldt‐Jakob disease was also considered given the relentless clinical deterioration up to akinetic mutism; however, the 14‐3‐3 test was negative. Although our patient's facial myorhythmias differed from oculo‐masticatory myorhythmia, a polymerase chain reaction test for Tropheryma Whipplei was performed on the CSF and excluded Whipple's disease.
Eventually, because of the persistent strong clinical suspicion, NMDAR autoantibodies were searched via live CBA performed in a research laboratory, which proved positive on both CSF and serum. The patient received intravenous immunoglobulin therapy (started long before NMDAR autoantibody detection), and a steady, though very slow, clinical improvement was observed after the fourth intravenous immunoglobulin cycle. He was discharged to rehabilitation after 4 months on azathioprine. For more than 2 years, he has made remarkable progress, although he is still apathetic and neglectful.
Discussion
The case we report is a typical example of NMDAR encephalitis, apart from the patient's age (50 years) and gender (male). Along with early psychiatric symptoms, autonomic manifestations, and seizures, a complex combination of different movement disorders represents a key clinical feature of this peculiar disease.1 The video shows the evolution of our patient's movement disorders over several months and documents the typical progression from the hypokinetic phase (characterized by rigidity, posturing, waxy flexibility, and paratonia) to the hyperkinetic phase. In the latter, facial myorhythmias and multifocal stereotypies, mainly involving the head and upper limbs, appeared predominant, although chorea and dystonic phenomena are often described, especially in children.2 The distinctive combination of polymorphic movement disorders, psychiatric symptoms, and cognitive disturbances points to the widespread derangement of complex cortico‐striatal networks, which include motor, limbic, and associative circuits.3 Some authors have hypothesized that antibody‐mediated cortico‐striatal “silencing” may lead to brainstem disinhibition and consequent central pattern generator release.4
Despite highly suggestive clinical features, in our case the diagnosis was hampered by the (repeatedly) negative results of NMDAR‐autoantibody testing performed via fixed CBA, which were eventually overturned thanks to live CBA. Such a circumstance, apart from reaffirming, once again, the unique role of clinical observation in the diagnostic process, highlights some thorny methodological issues. Indeed, fixed CBA are thought to be more sensitive than live assays,5 which might appear contrary to our own experience. However, in‐house assays might actually be more reliable than commercially available tests, especially if performed in specialized research laboratories. Therefore, in highly suspected cases, CSF samples should be sent to highly qualified testing services. Nevertheless, diagnostic struggles should not delay immunotherapy, whose timing is crucial for a disabling, still potentially reversible condition such as NMDAR encephalitis.
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 of the first draft, B. Review and Critique
C.D.B.: 1A, 1B, 1C, 3B
A.M.: 1B, 1C, 3A
L.M.B.: 1B, 1C
M.F.: 1B, 1C
A.T.G.: 1A, 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. The authors confirm that the approval of an institutional review board was not required for this work. The patient gave written informed consent for publication.
Funding Sources and Conflicts of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.
Financial Disclosures for the Previous 12 Months: The authors declare that there are no additional disclosures to report.
Supporting information
Video S1. The video shows a wide range of movement disorders developed by the patient over several months, including generalized rigidity with upper limb posturing (segment 1); perioral rhythmic slow muscle twitches, interpreted as myorhythmias (segment 2); facial myorhythmias with synchronous involvement of the abdominal wall (segment 3) or associated with facial stereotypies, mainly characterized by protrusion and lateral movements of the tongue (segment 4); violent stereotypies involving both upper limbs with different movement patterns (segments 5 and 6); copulatory and “pill rolling‐like” stereotypies (segments 7 and 8); a burst of uncontrollable laughter while still unresponsive to external stimuli (segment 9).
Figure S1. Electroencephalogram recording (10–20 International system, 21‐channel digital recording, bipolar longitudinal montage, 20 seconds/page, sensitivity of 10 μV/mm) showing widespread delta activity (2.5–3 Hz), more evident on fronto‐temporal regions of both hemispheres.
Relevant disclosures and conflicts of interest are listed at the end of this article.
References
- 1. Dalmau J, Lancaster E, Martinez‐Hernandez E, et al. Clinical experience and laboratory investigations in patients with anti‐NMDAR encephalitis. Lancet Neurol 2011;10 63–74. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Varley JA, Webb AJS, Balint B, et al. The movement disorder associated with NMDAR antibody‐encephalitis is complex and characteristic: an expert video‐rating study. J Neurol Neurosurg Psychiatry 2019;90(6):724–726. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Rodriguez‐Oroz MC, Jahanshahi M, Krack P, et al. Initial clinical manifestations of Parkinson's disease: features and pathophysiological mechanisms. Lancet Neurol 2009;8:1128–1139. [DOI] [PubMed] [Google Scholar]
- 4. Kleinig TJ, Thompson PD, Matar W, et al. The distinctive movement disorder of ovarian teratoma‐associated encephalitis. Mov Disord 2008;23:1256–1261. [DOI] [PubMed] [Google Scholar]
- 5. Gresa‐Arribas N, Titulaer MJ, Torrents A, et al. Antibody titres at diagnosis and during follow‐up of anti‐NMDA receptor encephalitis: a retrospective study. Lancet Neurol 2014;13:167–177. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Video S1. The video shows a wide range of movement disorders developed by the patient over several months, including generalized rigidity with upper limb posturing (segment 1); perioral rhythmic slow muscle twitches, interpreted as myorhythmias (segment 2); facial myorhythmias with synchronous involvement of the abdominal wall (segment 3) or associated with facial stereotypies, mainly characterized by protrusion and lateral movements of the tongue (segment 4); violent stereotypies involving both upper limbs with different movement patterns (segments 5 and 6); copulatory and “pill rolling‐like” stereotypies (segments 7 and 8); a burst of uncontrollable laughter while still unresponsive to external stimuli (segment 9).
Figure S1. Electroencephalogram recording (10–20 International system, 21‐channel digital recording, bipolar longitudinal montage, 20 seconds/page, sensitivity of 10 μV/mm) showing widespread delta activity (2.5–3 Hz), more evident on fronto‐temporal regions of both hemispheres.