Cerebral Cortical Encephalitis in Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease.

Cerebral cortical encephalitis (CCE) is a recently described myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) phenotype. In this observational retrospective study, we characterized 19 CCE patients (6.7% of our MOGAD cohort). Headache (n = 15, 79%), seizures (n = 13, 68%), and encephalopathy (n = 12, 63%) were frequent. Magnetic resonance imaging revealed unilateral (n = 12, 63%) or bilateral (n = 7, 37%) cortical T2 hyperintensity and leptomeningeal enhancement (n = 17, 89%). N-Methyl-D-aspartate receptor autoantibodies coexisted in 2 of 15 tested (13%). CCE pathology (n = 2) showed extensive subpial cortical demyelination (n = 2), microglial reactivity (n = 2), and inflammatory infiltrates (perivascular, n = 1; meningeal, n = 1). Most received high-dose steroids (n = 17, 89%), and all improved, but 3 had CCE relapses. This study highlights the CCE spectrum and provides insight into its pathogenesis. ANN NEUROL 2023;93:297-302.

Positive predictive value of myositis antibody line blot testing in patients with suspected idiopathic inflammatory myopathy.

INTRODUCTION/AIMS: Line blot (LB) is in widespread use for myositis antibody detection. Yet, studies of its positive predictive value (PPV) in patients with suspected idiopathic inflammatory myopathy (IIM), which would be of particular relevance to neuromuscular clinicians, are lacking. We aimed to determine the PPV of myositis antibody LB testing in patients with suspected IIM, and examine whether PPV was significantly impacted by intensity of antibody positivity. METHODS: This was a retrospective study of patients who underwent myositis antibody LB testing for suspected IIM between March 2019 and August 2022. RESULTS: Of 70 patients who underwent testing for suspected IIM and had positive myositis antibody LB results, 43 (61%) were female and the median age was 61 years (range: 10-83 years). Forty-four were classified as true-positives, yielding a PPV of 63%. The PPV of patients with weak-positive myositis antibody results (14/30, 47%) was significantly lower than the PPV of patients with moderate-positive or strong-positive myositis antibody results (30/40, 75%) (p = .02). DISCUSSION: Our study found that myositis antibody LB testing in patients with suspected IIM had a modest PPV, underscoring the need for antibody interpretation in the context of all available clinical and ancillary test data to avoid misdiagnosis. The significantly lower PPV in patients with weak-positive results emphasizes the particular importance of clinical correlation in such patients. Further study into the diagnostic performance of various LBs for myositis antibody detection is needed to inform their interpretation in clinical practice.

Canadian Consensus Guidelines for the Diagnosis and Treatment of Autoimmune Encephalitis in Adults.

Autoimmune encephalitis is increasingly recognized as a neurologic cause of acute mental status changes with similar prevalence to infectious encephalitis. Despite rising awareness, approaches to diagnosis remain inconsistent and evidence for optimal treatment is limited. The following Canadian guidelines represent a consensus and evidence (where available) based approach to both the diagnosis and treatment of adult patients with autoimmune encephalitis. The guidelines were developed using a modified RAND process and included input from specialists in autoimmune neurology, neuropsychiatry and infectious diseases. These guidelines are targeted at front line clinicians and were created to provide a pragmatic and practical approach to managing such patients in the acute setting.

Septin-5 and -7-IgGs: Neurologic, Serologic, and Pathophysiologic Characteristics.

BACKGROUND AND OBJECTIVES: We sought to determine clinical significance of neuronal septin autoimmunity and evaluate for potential IgG effects. METHODS: Septin-IgGs were detected by indirect immunofluorescence assays (IFAs; mouse tissue and cell based) or Western blot. IgG binding to (and internalization of) extracellular septin epitopes were evaluated for by live rat hippocampal neuron assay. The impact of purified patient IgGs on murine cortical neuron function was determined by recording extracellular field potentials in a multielectrode array platform. RESULTS: Septin-IgGs were identified in 23 patients. All 8 patients with septin-5-IgG detected had cerebellar ataxia, and 7 had prominent eye movement disorders. One of 2 patients with co-existing septin-7-IgG had additional psychiatric phenotype (apathy, emotional blunting, and poor insight). Fifteen patients had septin-7 autoimmunity, without septin-5-IgG detected. Disorders included encephalopathy (11; 2 patients with accompanying myelopathy, and 2 were relapsing), myelopathy (3), and episodic ataxia (1). Psychiatric symptoms (≥1 of agitation, apathy, catatonia, disorganized thinking, and paranoia) were prominent in 6 of 11 patients with encephalopathic symptoms. Eight of 10 patients with data available (from 23 total) improved after immunotherapy, and a further 2 patients improved spontaneously. Staining of plasma membranes of live hippocampal neurons produced by patient IgGs (subclasses 1 and 2) colocalized with pre- and post-synaptic markers. Decreased spiking and bursting behavior in mixed cultures of murine glutamatergic and GABAergic cortical neurons produced by patient IgGs were attributable to neither antigenic crosslinking and internalization nor complement activation. INTERPRETATION: Septin-IgGs are predictive of distinct treatment-responsive autoimmune central nervous system (CNS) disorders. Live neuron binding and induced electrophysiologic effects by patient IgGs may support septin-specific pathophysiology. ANN NEUROL 2022;92:1090-1101.

Non-demyelinating disorders mimicking and misdiagnosed as NMOSD: a literature review.

BACKGROUND: Differentiating neuromyelitis optica spectrum disorder (NMOSD) from its mimics is crucial to avoid misdiagnosis, especially in the absence of aquaporin-4-IgG. While multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein-IgG associated disease (MOGAD) represent major and well-defined differential diagnoses, non-demyelinating NMOSD mimics remain poorly characterized. METHODS: We conducted a systematic review on PubMed/MEDLINE to identify reports of patients with non-demyelinating disorders that mimicked or were misdiagnosed as NMOSD. Three novel cases seen at the authors' institutions were also included. The characteristics of NMOSD mimics were analyzed and red flags associated with misdiagnosis identified. RESULTS: A total of 68 patients were included; 35 (52%) were female. Median age at symptoms onset was 44 (range, 1-78) years. Fifty-six (82%) patients did not fulfil the 2015 NMOSD diagnostic criteria. The clinical syndromes misinterpreted for NMOSD were myelopathy (41%), myelopathy + optic neuropathy (41%), optic neuropathy (6%), or other (12%). Alternative etiologies included genetic/metabolic disorders, neoplasms, infections, vascular disorders, spondylosis, and other immune-mediated disorders. Common red flags associated with misdiagnosis were lack of cerebrospinal fluid (CSF) pleocytosis (57%), lack of response to immunotherapy (55%), progressive disease course (54%), and lack of magnetic resonance imaging gadolinium enhancement (31%). Aquaporin-4-IgG positivity was detected in five patients by enzyme-linked immunosorbent assay (n = 2), cell-based assay (n = 2: serum, 1; CSF, 1), and non-specified assay (n = 1). CONCLUSIONS: The spectrum of NMOSD mimics is broad. Misdiagnosis frequently results from incorrect application of diagnostic criteria, in patients with multiple identifiable red flags. False aquaporin-4-IgG positivity, generally from nonspecific testing assays, may rarely contribute to misdiagnosis.

Positive Predictive Value of Anti-GAD65 ELISA Cut-Offs for Neurological Autoimmunity.

High anti-GAD65 levels associate with core manifestations of GAD65 neurological autoimmunity. ELISA cut-offs for high anti-GAD65 levels (>10,000 IU/ml in serum, >100 IU/ml in CSF) have been proposed that merit further evaluation. We reviewed patients who underwent anti-GAD65 ELISA for suspected autoimmune encephalitis and found values above these cut-offs to have a positive predictive value (PPV) for neurological autoimmunity of 88%. Anti-GAD65 values above proposed ELISA cut-offs have a reasonably high PPV for neurological autoimmunity in patients with suspected autoimmune encephalitis. Consideration of alternative diagnoses and corroboration with CSF can help flag potentially clinically irrelevant results and avoid patient misdiagnosis.

Seizures in anti-Hu-associated extra-limbic encephalitis: Characterization of a unique disease manifestation.

Anti-Hu-associated neurologic autoimmunity most often occurs in the context of small cell lung cancer and typically presents with peripheral neuropathy, cerebellar ataxia, and/or limbic encephalitis. Extra-limbic encephalitis causing seizures is a rare disease manifestation, with only sparse reports in the literature. Herein we present a patient with seizures in anti-Hu-associated extra-limbic encephalitis, and review the literature for other cases to more fully characterize this entity. Among 27 patients we identified, the median age was 46 years (range: 2-69 years) and 18 of 27 (67%) were female. Focal motor seizures were most common, followed by ictal expressive speech difficulty. Seizure semiologies along with neuroimaging findings most frequently suggested the involvement of the peri-Rolandic cortex, more anterior frontal operculum, and insula, although other cortical regions were rarely affected as well. In contrast to other classical paraneoplastic neurologic syndromes, good response to treatment with attainment of seizure-free survival was often reported, although over one-third still died. A propensity for chronic seizures among children indicated the potential to develop autoimmune-associated epilepsy. The predilection for certain extra-limbic regions, as well as the possibility of good response to treatment, may reflect unique disease mechanisms that would benefit from further study.

"Obvious" indications for Neural antibody testing in Epilepsy or Seizures: The ONES checklist.

OBJECTIVE: Numerous predictive scores have been developed to help determine which patients with epilepsy or seizures of unknown etiology should undergo neural antibody testing. However, their diagnostic advantage compared to only performing testing in patients with "obvious" indications (e.g., broader features of autoimmune encephalitis, characteristic seizure semiologies) requires further study. We aimed to develop a checklist that identifies patients who have "obvious" indications for neural antibody testing and to compare its diagnostic performance to predictive scores. METHODS: We developed the "Obvious" indications for Neural antibody testing in Epilepsy or Seizures (ONES) checklist through literature review. We then retrospectively reviewed patients who underwent neural antibody testing for epilepsy or seizures at our center between March 2019 and January 2021, to determine and compare the sensitivity and specificity of the ONES checklist to the recently proposed Antibody Prevalence in Epilepsy and Encephalopathy (APE2)/Antibodies Contributing to Focal Epilepsy Signs and Symptoms (ACES) reflex score. RESULTS: One-hundred seventy patients who underwent neural antibody testing for epilepsy or seizures were identified. Seventy-four of 170 (43.5%) with a known etiology were excluded from sensitivity/specificity analyses; none had a true-positive neural antibody. Of the 96 patients with an unknown etiology, 14 (15%) had a true-positive neural antibody. The proportion of false-positives was significantly higher among patients with a known etiology (3/3, 100%) compared to an unknown etiology (2/16, 13%; p = .01). There was no significant difference of the APE2/ACES reflex score compared to the ONES checklist with regard to sensitivity (93% for both, p > .99) or specificity (71% vs. 78%, p = .18) for true-positive neural antibodies. SIGNIFICANCE: Compared to only performing neural antibody testing in patients with epilepsy or seizures of unknown etiology who have "obvious" indications, predictive scores confer no clear diagnostic advantage. Prespecified definitions of what constitutes a true-positive neural antibody is required in future studies to avoid false-positives that can confound results.

Clinical spectrum of high-titre GAD65 antibodies.

OBJECTIVE: To determine clinical manifestations, immunotherapy responsiveness and outcomes of glutamic acid decarboxylase-65 (GAD65) neurological autoimmunity. METHODS: We identified 323 Mayo Clinic patients with high-titre (>20 nmol/L in serum) GAD65 antibodies out of 380 514 submitted anti-GAD65 samples (2003-2018). Patients classified as having GAD65 neurological autoimmunity after chart review were analysed to determine disease manifestations, immunotherapy responsiveness and predictors of poor outcome (modified Rankin score >2). RESULTS: On review, 108 patients were classified as not having GAD65 neurological autoimmunity and 3 patients had no more likely alternative diagnoses but atypical presentations (hyperkinetic movement disorders). Of remaining 212 patients with GAD65 neurological autoimmunity, median age at symptom onset was 46 years (range: 5-83 years); 163/212 (77%) were female. Stiff-person spectrum disorders (SPSD) (N=71), cerebellar ataxia (N=55), epilepsy (N=35) and limbic encephalitis (N=7) could occur either in isolation or as part of an overlap syndrome (N=44), and were designated core manifestations. Cognitive impairment (N=38), myelopathy (N=23) and brainstem dysfunction (N=22) were only reported as co-occurring phenomena, and were designated secondary manifestations. Sustained response to immunotherapy ranged from 5/20 (25%) in epilepsy to 32/44 (73%) in SPSD (p=0.002). Complete immunotherapy response occurred in 2/142 (1%). Cerebellar ataxia and serum GAD65 antibody titre >500 nmol/L predicted poor outcome. INTERPRETATION: High-titre GAD65 antibodies were suggestive of, but not pathognomonic for GAD65 neurological autoimmunity, which has discrete core and secondary manifestations. SPSD was most likely to respond to immunotherapy, while epilepsy was least immunotherapy responsive. Complete immunotherapy response was rare. Serum GAD65 antibody titre >500 nmol/L and cerebellar ataxia predicted poor outcome.

Musicogenic epilepsy: Expanding the spectrum of glutamic acid decarboxylase 65 neurological autoimmunity.

The objective of this study was to describe serological association of musicogenic epilepsy and to evaluate clinical features and outcomes of seropositive cases. Through retrospective chart review, musicogenic epilepsy patients were identified. Among 16 musicogenic epilepsy patients, nine underwent autoantibody evaluations and all had high-titer glutamic acid decarboxylase 65-immunoglobulin G (GAD65-IgG; >20 nmol·L-1 , serum, normal ≤ .02 nmol·L-1 , eight women). Median GAD65-IgG serum titer was 294 nmol·L-1 (20.3-3005 nmol·L-1 ), and median cerebrospinal fluid titer (n = 4) was 14.7 nmol·L-1 . All patients had temporal lobe epilepsy, and bitemporal epileptiform abnormalities were common. Right temporal lobe seizures were most frequently captured when seizures were induced by music on electroencephalogram (3/4; 75%). Intravenous (IV) methylprednisolone and/or IV Ig (IVIG) was utilized in four patients, with one having greater than 50% reduction. Rituximab (n = 2) and mycophenolate (n = 1) were ineffective. Two patients underwent right temporal lobe resections but continued to have seizures. Vagus nerve stimulation was effective at reducing seizures in one patient by 50%, and an additional patient was seizure-free by avoiding provoking music. Right temporal lobe epilepsy was more common among patients with musicogenic epilepsy when compared to nonmusicogenic GAD65 epilepsies (n = 71, 89% vs. 47%, p = .03). GAD65-IgG should be tested in patients with musicogenic epilepsy, given implications for management and screening for comorbid autoimmune conditions.

Neural Antibody Testing for Autoimmune Encephalitis: A Canadian Single-Centre Experience.

Neural antibodies have emerged as useful biomarkers in suspected autoimmune encephalitis. We reviewed results of neural antibody testing (anti-N-methyl D-aspartate receptor (NMDAR), leucine-rich glioma-inactivated protein (LGI1), contactin-associated protein-like 2 (CASPR2), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), γ-aminobutyric acid type B receptor (GABA(B)R), dipeptidyl-peptidase-like protein-6 (DPPX), IgLON family member 5 (IgLON5) and glutamic acid decarboxylase-65 (GAD65)) using cell-based assays (CBAs) and tissue indirect immunofluorescence (TIIF) at our centre. Our findings suggest increased clinical sensitivity of CBA compared to TIIF. However, this may come at some expense to clinical specificity, as evidenced by possible false-positive results when weak serum positivity by CBA was observed for certain antibodies (i.e. anti-NMDAR, CASPR2). In such cases, correlation with serum TIIF, as well as CSF CBA and TIIF, aids in identifying true-positive results.

Neural Antibody Testing in Patients with Suspected Autoimmune Encephalitis.

BACKGROUND: Autoimmunity is an increasingly recognized cause of encephalitis with a similar prevalence to that of infectious etiologies. Over the past decade there has been a rapidly expanding list of antibody biomarker discoveries that have aided in the identification and characterization of autoimmune encephalitis. As the number of antibody biomarkers transitioning from the research setting into clinical laboratories has accelerated, so has the demand and complexity of panel-based testing. Clinical laboratories are increasingly involved in discussions related to test utilization and providing guidance on which testing methodologies provide the best clinical performance. CONTENT: To ensure optimal clinical sensitivity and specificity, comprehensive panel-based reflexive testing based on the predominant neurological phenotypic presentation (e.g., encephalopathy) is ideal in the workup of cases of suspected autoimmune neurological disease. Predictive scores based on the clinical workup can aid in deciding when to order a test. Testing of both CSF and serum is recommended with few exceptions. Appropriate test ordering and interpretation requires an understanding of both testing methodologies and performance of antibody testing in different specimen types. SUMMARY: This review discusses important considerations in the design and selection of neural antibody testing methodologies and panels. Increased collaboration between pathologists, laboratorians, and neurologists will lead to improved utilization of complex autoimmune neurology antibody testing panels.

The Predictive Value of Endpoint Quaking-Induced Conversion in Creutzfeldt-Jakob Disease.

Creutzfeldt-Jakob disease (CJD) is a fatal neurological illness for which accurate diagnosis is paramount. Real-time quaking-induced conversion (RT-QuIC) is a prion-specific assay with high sensitivity and specificity for CJD. The Canadian endpoint quaking-induced conversion (EP-QuIC) test is similar, but unlike RT-QuIC there is little data regarding its diagnostic utility in clinical practice. In this exploratory predictive value analysis of EP-QuIC in CJD, the negative predictive value (NPV) and positive predictive value (PPV) was 100% and 83%, respectively, with one false-positive result identified. Re-testing this sample with an optimized EP-QuIC protocol eliminated this false-positive result, leading to a PPV of 100%.

La valeur prédictive de la méthode diagnostique dite de conversion provoquée par tremblement au point final dans le cas de la maladie de Creutzfeldt-Jakob. La maladie de Creutzfeldt-Jakob (MCJ) est une maladie neurologique qui entraîne à terme un décès et pour laquelle l'établissement d'un diagnostic précis est primordial. La conversion provoquée par tremblement en temps réel (RT-QuIC en anglais) est une méthode diagnostique qui repose sur la détection de la protéine prion. Dans le cas de la MCJ, cette méthode est réputée posséder une sensibilité et une spécificité élevées. La méthode canadienne dite de conversion provoquée par tremblement au point final (EP-QuIC en anglais) se veut similaire mais, à la différence de la RT-QuIC, il existe peu de données en ce qui concerne son utilité diagnostique dans le cadre d'une pratique clinique. Dans cette analyse prédictive exploratoire de la EP-QuIC en lien avec la MCJ, la valeur prédictive négative (VPN) et la valeur prédictive positive (VPP) ont été respectivement de 100 % et de 83 %, un seul résultat faux-positif ayant été identifié. Le fait de soumettre notre échantillon à un nouveau test effectué à l'aide d'un protocole d'EP-QuIC optimisé a permis d'éliminer ce résultat faux-positif, ce qui a débouché sur une VPP de 100 %.