Clinical relevance of serum antibodies to extracellular<i>N</i>-methyl-d-aspartate receptor epitopes

Zandi, Michael S; Paterson, Ross W.; Ellul, Mark; Jacobson, Leslie; Al-Diwani, Adam; Jones, Joanne L.; Cox, Amanda; Lennox, Belinda; Stamelou, María; Bhatia, Kailash P.; Schott, Jonathan M.; Coles, Alasdair; Kullmann, Dimitri M.; Vincent, Angela

doi:10.1136/jnnp-2014-308736

Cited by 99 publications

(58 citation statements)

References 24 publications

(48 reference statements)

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“…Indeed, low‐titer antibodies to VGKC complex or NMDARs have been found in some patients without autoimmune neurologic diseases,21, 25 and the fact that NMDARs were found in some children with generalized absence epilepsy makes them unlikely to be pathogenic in these cases. However, the binding to the surface of live hippocampal neurons, present in 8 of 17 sera, suggested that the antibodies could be pathogenic if they reach the brain parenchyma.…”

Section: Discussionmentioning

confidence: 99%

Neuronal antibodies in pediatric epilepsy: Clinical features and long‐term outcomes of a historical cohort not treated with immunotherapy

et al. 2016

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SummaryObjectiveIn autoimmune encephalitis the etiologic role of neuronal cell‐surface antibodies is clear; patients diagnosed and treated early have better outcomes. Neuronal antibodies have also been described in patients with pediatric epilepsy without encephalitis. The aim was to assess whether antibody presence had any effect on long‐term outcomes in these patients.MethodsPatients (n = 178) were recruited between 1988 and 1992 as part of the prospective Dutch Study of Epilepsy in Childhood; none received immunotherapy. Healthy age‐matched bone‐marrow donors served as controls (n = 112). All sera were tested for serum N‐methyl‐d‐aspartate receptor (NMDAR), alpha amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor, leucine rich glioma inactivated 1, contactin associated protein like 2 (CASPR2), contactin‐2, glutamic acid decarboxylase, and voltage gated potassium channel (VGKC)‐complex antibodies by standard techniques. No cerebrospinal fluid (CSF) samples were available. Results were correlated with clinical data collected over 15 years.ResultsSeventeen patients (9.5%) were positive for VGKC complex (n = 3), NMDAR (n = 7), CASPR2 (n = 4), and contactin‐2 (n = 3), compared to three (3/112; 2.6%) healthy controls (VGKC complex [n = 1], NMDAR [n = 2]; p = 0.03; Fisher's exact test). Titers were relatively low (≤1:100 for cell‐surface antibodies), but 8 (47%) of the 17 positive samples bound to the surface of live hippocampal neurons consistent with a potential pathogenic antibody. Preexisting cognitive impairment was more frequent in antibody‐positive patients (9/17 vs. 33/161; p = 0.01). Fourteen antibody‐positive patients were treated with standard antiepileptic drugs (AEDs); three (17%) became intractable but this was not different from the 16 (10%) of 161 antibody‐negative patients. In 96 patients with available follow‐up samples at 6 and/or 12 months, 6 of 7 positive antibodies had disappeared and, conversely, antibodies had appeared for the first time in a further 7 patients.SignificanceNeuronal antibodies were found at low levels in 9.5% of patients with new‐onset pediatric epilepsy but did not necessarily persist over time, and the development of antibodies de novo in later samples suggests they could be due to a secondary response to neuronal damage or inflammation. Moreover, as the response to standard AEDs and the long‐term outcome did not differ from those of antibody‐negative pediatric patients, these findings suggest that routine neuronal antibody testing is unlikely to be helpful in pediatric epilepsy. However, the higher incidence of preexisting cognitive problems in the antibody‐positive group, the CASPR2 and contactin‐2 antibodies in 7 of 17 patients, and the binding of 8 of 17 of serum samples to live hippocampal neurons suggest that neuronal antibodies, even if secondary, could contribute to the comorbidities of pediatric epilepsy.

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Section: Discussionmentioning

confidence: 99%

Neuronal antibodies in pediatric epilepsy: Clinical features and long‐term outcomes of a historical cohort not treated with immunotherapy

et al. 2016

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“…The specific NMDAR subunit targeted was not determined (GluN1 vs GluN2) and other control groups or additional confirmatory tests were not included. Indeed, using the same assay, these authors recently reported serum NMDAR antibodies in 23% of patients who had disorders considered unlikely to be immune mediated (e.g., posterior fossa glioma, atypical motor neuron disease, leukodystrophy, maple syrup urine disease, or idiopathic pure cerebellar syndrome) (Zandi et al, 2014). Given these findings, Zandi et al, have modified the interpretation of their assay scoring system, so that at least one of the three schizophrenia patients initially reported to harbor pathogenic auto-antibodies would currently be considered unlikely to have an immune associated disorder.…”

Section: Anti-nmdar Antibodies and Psychosismentioning

confidence: 97%

Anti-NMDA Receptor Encephalitis, Autoimmunity, and Psychosis

Kayser

Dalmau

2016

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Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a recently-discovered synaptic autoimmune disorder in which auto-antibodies target NMDARs in the brain, leading to their removal from the synapse. Patients manifest with prominent psychiatric symptoms -and in particular psychosis -early in the disease course. This presentation converges with long-standing evidence on multiple fronts supporting the glutamatergic model of schizophrenia. We review mechanisms underlying disease in anti-NMDAR encephalitis, and discuss its role in furthering our understanding of neural circuit dysfunction in schizophrenia.

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“…6 In a cohort of patients with diverse symptoms tested for NMDAR antibodies using a live cellbased assay similar to that used initially in this patient, 23% of cases considered antibody-positive did not have anti-NMDAR encephalitis or autoimmune disorders (e.g., glioma and leukodystrophy, among others). 7 In our patient, more specific and comprehensive immunologic testing including CSF and serum demonstrated that she did not have NMDAR antibodies. 2 This case emphasizes the difficulties in recognizing narcolepsy-cataplexy in children, the importance of prioritizing the clinical assessment over a serologic test especially when the symptoms do not fit with the test result, and the need for including CSF and comprehensive immunologic studies for NMDAR antibody determination.…”

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When a serum test overrides the clinical assessment

2015

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The clinical features of narcolepsy-cataplexy are substantially different from anti-NMDA receptor (NMDAR) encephalitis. We report a patient whose diagnosis was established only after traditional clinical assessments prevailed over a presumably abnormal serum test result.Clinical case. A 10-year-old girl without a medical history of interest came for a second opinion regarding treatment of anti-NMDAR encephalitis. Her symptoms started 16 months earlier when she developed tiredness, irritability, episodes of falling asleep during the day, and lingual movements when doing enjoyable activities, such as playing. On 2 occasions, she had sudden falls without loss of consciousness. Blood chemistry, brain MRI, and EEG were normal. Six months after symptom onset, she was seen at a second institution, where a blood test using a live cell-based assay was reported as low positive for NMDAR antibodies. Routine CSF studies (antibodies not examined) were unremarkable. Based on this serum test, she was diagnosed with anti-NMDAR encephalitis, screened for an underlying tumor (abdominal ultrasound negative), and treated with steroids, IV immunoglobulin, and psychotherapy. Her symptoms did not improve, and she continued falling asleep at school and while playing. Nine months after symptom onset, she was seen at a third institution; repeat NMDAR antibody testing in the same laboratory was reported positive, and additional immunotherapy was recommended but not given. She continued with excessive daytime sleepiness, irritability, and mood-dependent lingual movements (video on the Neurology ® Web site at Neurology.org); however, she was maintaining her grades in school, although she required a 30-minute nap during the day and a 2-hour nap after school.At arrival to our center, 16 months after symptom onset, her family described, in addition to the above mentioned symptoms, episodes of floppy head without losing consciousness; nocturnal shouting, talking, and moving; and compulsive eating and a weight gain of 14 kg (over 97th percentile) that started before receiving steroids. At examination, the patient was attentive and collaborative but showed childish behavior inappropriate for her age, and rapid mood swings when asked about her symptoms. She did not exhibit memory, cognitive, or language dysfunction, and there was no evidence of myoclonus or dyskinesias during the visits.The polysomnogram revealed a total sleep time of 442 minutes, sleep efficiency 73%. Episodes of smile-like movements and bursts of EMG activity in the muscles of the face were noted during REM sleep. She had periodic leg movements during wakefulness and sleep, associated with arousals and vocalizations as if she was complaining (index of movements during sleep: 30). No sleep-disordered breathing was noted. A 5-nap multiple sleep latency test 1 showed 5 sleep-onset REM episodes, immediately after wakefulness (2 naps) or after a short stage N1 (3 naps), and a very short mean sleep latency (1 minute 24 seconds; normal .8 minutes). Human leukocyte antigen typing was DQ...

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Clinical relevance of serum antibodies to extracellularN-methyl-d-aspartate receptor epitopes

Cited by 99 publications

References 24 publications

Neuronal antibodies in pediatric epilepsy: Clinical features and long‐term outcomes of a historical cohort not treated with immunotherapy

Neuronal antibodies in pediatric epilepsy: Clinical features and long‐term outcomes of a historical cohort not treated with immunotherapy

Anti-NMDA Receptor Encephalitis, Autoimmunity, and Psychosis

When a serum test overrides the clinical assessment

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