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June 14, 2021

Abnormal Movements in Bickerstaff Brainstem Encephalitis Mimicking Anti–N-Methyl-d-Aspartate Receptor Encephalitis

Author Affiliations
  • 1Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan
JAMA Neurol. 2021;78(9):1149. doi:10.1001/jamaneurol.2021.1698

A 20-year-old previously healthy woman presented with consciousness disturbance, rapidly progressing throughout 2 days. She had a low-grade fever with a temperature of 37.4 °C, and neurologic examination revealed lethargy (Glasgow Coma Scale score, E2V2M6), bilateral ptosis, and bilateral severe ophthalmoplegia. Motor weakness was not observed, while the right bicep reflex was brisk. Her consciousness level hindered examination for ataxia. Additionally, frequent facial grimacing and sniffing motion were observed, resembling orofacial dyskinesia observed in anti–N-methyl-d-aspartate receptor encephalitis (NMDARE) (Video, segment 1). The abnormal movements gradually spread to the extremities: rapid neck twists followed by slow and restless movements in her limbs (Video, segment 2). Test results for serum antinuclear, anticardiolipin, and anti–glutamic acid decarboxylase antibodies were all negative. Cerebrospinal fluid analysis showed leukocytosis (9/μL) and normal protein levels (0.023 g/dL; to convert to grams per liter, multiply by 10). Cerebrospinal fluid polymerase chain reaction results for herpes simplex viruses and bacterial cultures were negative. Nerve conduction study and brain magnetic resonance imaging results showed no abnormalities. A whole-body computed tomographic scan revealed no malignancy, including an ovarian teratoma. Intravenous immunoglobulin (0.4 g/kg/d for 5 days) and methylprednisolone (500 mg/d for 3 days) were started. Following the treatment, her consciousness and abnormal movements started to improve; the abnormal movements disappeared on the 13th day after admission, and she became alert and ambulatory on the 17th day after admission. She had no neurological deficits 2 months after the onset of symptoms. IgG anti-GQ1b antibodies were detected with enzyme-linked immunosorbent assay in her pretreatment serum (optical density value, 0.37 [reference value, <0.1]), and stool culture was positive for Campylobacter jejuni. The serum and cerebrospinal fluid anti-NMDAR antibodies were negative. Therefore, she was diagnosed with Bickerstaff brainstem encephalitis (BBE).

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    1 Comment for this article
    Anti-NMDA receptor encephalitis in COVID-19
    Calixto Machado, MD, PhD, FAAN | Institute of Neurology and Neurosurgery, Havana, Cuba
    Authors: Calixto Machado, Brandon Brock, Arthur Shiff
    Curiously, Kimura et al. did not mention the possibility of SARS-CoV-2 infection to discuss the conceivable etiology of their patient’s encephalitis, considering the worldwide spread of the pandemic.1 Several authors have found an association between anti-NMDA receptors and COVID-19 encephalitis.2
    Confirming the clinical diagnosis of anti-NMDA receptor encephalitis requires a positive serum or CSF sample screening for antibodies to the NMDA receptor subunit.2 Nonetheless, these authors found that the serum and CSF anti-NMDAR antibodies were negative.1
    Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an immune-mediated disorder that associates with IgG antibodies against
    the GluN1 subunit of the NMDAR. The symptoms range from psychiatric symptoms, movement disorders, cognitive impairment, and autonomic dysfunction. Epidemiological studies suggest that NMDAR encephalitis may be the most common cause of autoimmune encephalitis after acute demyelinating encephalitis. It is considered the most frequent autoimmune encephalitis in children. Previous studies reported that the autoimmune process could be triggered by an infection (herpes simplex virus, Epstein–Barr virus, toxoplasma gondii), vaccination, or occult neoplasm.2,3
    Monti et al. described a COVID-19 patient who presented a refractory status epilepticus. The patient showed increased levels of cytokines IL6 and IL8 on CSF; IL6 was raised in serum too.2
    The role of an unrestrained cytokine production, known as cytokine storm (CS), has been extensively discussed as the main cause for aggravating symptoms after Sars-CoV-2 infection. CS is characterized by an exaggerated pro-inflammatory response and ineffective control by the anti-inflammatory system, leading to tissue damage, multi-organ failure, acute respiratory distress syndrome, and death.4
    Pathological activation of NMDA receptors, either by direct or indirect mechanisms, results in excessive Ca2+ influx into the cytoplasm, leading to cell death. Mitochondria serve to buffer cytoplasmic Ca2+ resulting from activation of plasma membrane NMDA receptors.2,3 The CS hyper-inflammatory state of immune cells in Covid-19 might cause a dramatic change in metabolism, inducing cells to abandon mitochondrial oxidative phosphorylation for ATP production in favor of cytosolic aerobic glycolysis, which is inefficient to generate ATP. Hence, CS might be a triggering etiological factor in NMDAR encephalitis. 4
    COVID autoimmune encephalitis has been reported in several cases. 2 4 Therefore, it is necessary to consider the possibility of a SARS-CoV-1 infection in the presence of NMDAR encephalitis.
    1. Kimura M, H Y, N K. Abnormal Movements in Bickerstaff Brainstem Encephalitis Mimicking Anti–N-Methyl-d-Aspartate Receptor Encephalitis. JAMA Neurol 2021;78(9):1149.
    2. Monti G, Giovannini G, Marudi A, et al. Anti-NMDA receptor encephalitis presenting as new onset refractory status epilepticus in COVID-19. Seizure. 2020;81:18-20.
    3. 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(2):167-177.
    4. Machado C. Reader response: Encephalopathy and bilateral thalamic lesions in a child with MIS-C associated with COVID-19. Neurology. 2020;25(160). https://n.neurology.org/content/reader-response-encephalopathy-and-bilateral-thalamic-lesions-child-mis-c-associated-covid.