The Anti-NMDA Receptor Encephalitis Foundation Newsletter

A podcast answering your questions about Covid-19 (Coronavirus) and encephalitis. Filmed on March 20.

 




Section 1 A 47-year-old man, with a medical history of vitiligo, presented to Peking Union Medical College Hospital for evaluation of progressive gait instability over a period of 10 months. He was initially noticed to walk with drunken gait and have difficulty performing accurate movements during goal-directed tasks. The patient also complained of difficulty in speaking and reported that objects appeared to move back and forth across his field of vision. The symptoms worsened, and he could not walk without assistance in the recent 2 months. There was no preceding infection or known family history of ataxia. The patient denied alcoholism. General clinical examination showed extensive vitiligo (figure, A). On neurologic examination, mental status was normal. The patient had slow, slurred, and irregular speech. Figure Vitiligo distribution and brain MRI (A) The patient’s hands with vitiligo. (B, C) Axial T2-wighted MRI sequence shows cerebellar atrophy. Cranial nerve examination was significant for broken smooth pursuits and rotatory nystagmus with leftward fast component. Strength and tendon reflexes were normal throughout, with flexor plantar responses. The examinations of coordinate movements revealed bilateral dysmetria on finger-to-nose and heel-to-shin testing, intention tremor, and dysdiadochokinesia with rapid alternating movements. Sensory examinations were normal. Gait imbalance was prominent, and the patient tended to fall when standing with his feet together whether his eyes were opened or closed. Questions for consideration: What is the localization for the patient’s presentation? What are the differential diagnoses and what further tests can be performed for evaluation? GO TO SECTION 2 Section 2 Based on the clinical presentations and physical signs of truncal and limb ataxia, accompanied by gaze-evoked nystagmus, and dysarthria due to oral motor ataxia, cerebellar hemispheres and midline cerebellar structures were involved. When approaching a patient with cerebellar ataxia, the first major point in the clinical decision tree is the onset and duration of the symptom. Although no formal definition exists, subacute cerebellar ataxia is generally defined as ataxia that occurs in days to weeks, with progression occurring over weeks to months rather than years, while chronic ataxia usually develops in months to years. Etiologies of subacute ataxia include (1) atypical infections, including progressive multifocal leukoencephalopathy; (2) metabolic factors, including systemic metabolic disorders, chronic exposure to toxins or medications, alcohol abuse, and vitamin deficiencies; (3) autoimmune etiologies, including CNS demyelinating disease, systemic immune disorders, autoantibody mediated ataxia, and paraneoplastic cerebellar degeneration; and (4) neoplasms, including primary or metastatic tumors involving the cerebellum. An initial workup usually includes basic laboratory data and extensive laboratory testing to identify infectious and inflammatory etiologies. Malignancy screening is necessary in patients with subacute progression combined with weight loss and cachexia. Brain MRI is recommended for the evaluation of space-occupying and demyelinating lesions. In this case, routine blood tests including complete blood count, erythrocyte sedimentation rate, fasting glucose, liver function, renal profile, HIV, and syphilis serologies were unremarkable. Common metabolic causes of ataxia were ruled out as the levels of vitamin B12, folate, vitamin E, copper, and thyroid-stimulating hormone were normal. Lack of antinuclear antibodies and antineutrophil cytoplasmic antibodies lowered the likelihood of systemic autoimmune diseases. CNS demyelinating diseases and neoplasms were excluded as the brain MRI showed mild cerebellar atrophy with no other abnormalities (figure, B and C). The CSF analysis revealed no evidence of infectious etiologies, with normal white cell count and protein and glucose levels and negative cultures. Owing to the rapidly progressive course, autoimmune ataxia was highly suspected. Serum and CSF samples were tested for autoantibodies including anti-glutamate decarboxylase 65 (GAD65) antibody, anti-Yo (Purkinje cell antibody 1) antibody, and anti-Tr (delta/notch-like epidermal growth factor-related receptor [DNER]) antibodies by using a commercial cell-based assay (FA 112d-1003-1; EUROIMMUN AG, Lübeck, Germany). Anti-Tr antibodies were positive in the serum and CSF, and their titers were both 1:32. An extensive workup for malignancy was negative, including thoracic, abdominal, and pelvic contrasted CT and whole body PET CT scan. Question for consideration: What is the final diagnosis and what treatments can be performed? GO TO SECTION 3 Section 3 Based on the patient’s history of progressive cerebellar ataxia and positive anti-Tr antibody status, autoimmune cerebellar ataxia (ACA) was diagnosed. The patient was started on IV immunoglobulin (IVIg) 2 g/kg divided over 5 days followed by oral prednisone (60 mg/day). Following initial treatment, the patient’s gait instability and dysmetria were improved. He was started on mycophenolate mofetil 750 mg twice daily and prednisone was tapered gradually. At 3 months follow-up, he was able to walk slowly without assistance, with a drop of 1 point in modified Rankin Scale score (from 4 to 3). He continues to have mild gait ataxia. Repetition of cancer screening was recommended for the patient 6 months after the initial evaluation. The clinical and radiologic long-term outcomes will be followed up closely. Question for consideration: What is the diagnostic value of vitiligo in this case? GO TO SECTION 4 Section 4 The medical history and physical sign of vitiligo were noted in this patient. Vitiligo was thought to be an acquired organ-specific autoimmune disorder that targets melanocytes, characterized by progressive skin depigmentation, with absence of melanocytes microscopically. Most evidence supports immune-mediated melanocyte damage as the main etiologic pathway in the pathogenesis. Vitiligo could coexist with other autoimmune disorders, which reflects a systemic process that has important implications beyond the skin.1 An innovative concept based on a functional cross-link between the nervous and immune system in the pathogenesis of vitiligo is emerging. Vitiligo has been reported to be present in patients with neuroimmune disorders, involving both peripheral nervous system and CNS. A cross-sectional study of 1,098 patients with vitiligo reported several comorbid autoimmune neurologic diseases, including 3 Guillain-Barré syndrome (0.2%), 2 myasthenia gravis (0.2%), and 2 multiple sclerosis (0.2%).1 A Mayo Clinic cohort study showed that in a series of 62 patients with GAD65 antibody–positive ACA, 10 (16%) had vitiligo.2 Guan3 reported 3 patients with autoimmune encephalitis accompanied by vitiligo. Among them, 2 had anti-leucine-rich glioma-inactivated 1 encephalitis and 1 had anti-IgLON5 encephalopathy; both antigens were plasma membrane proteins (PMPs). Although the nature of the association between neuroimmune disease and vitiligo is not completely understood, underlying mechanisms have been proposed. Both the skin and the nervous system are derived from the external germ layer, which provide the theoretical basis for the hypothesis that the autoantibodies induced by the exposure antigen triggered by vitiligo are more likely to attack the mimic extracellular epitopes of neuronal cell surface. The link between anti-Tr ACA and vitiligo has not been reported previously. Our case extends the spectrum of autoimmune association between vitiligo and neuroimmune disorders. Coexistence of vitiligo might be a diagnostic clue to an autoimmune cause for cerebellar ataxia. This hypothesis should be demonstrated further by investigating the exposure antigens expressed by both melanocytes and neural cells. Discussion ACA represents an important differential diagnosis in patients presenting with rapidly progressive cerebellar disease.4 ACAs are more frequently recognized due to advances in detecting autoantibodies. The anti-Tr antibody was first described in 1976 by Trotter et al.5 in a female patient with subacute paraneoplastic cerebellar degeneration and Hodgkin disease. DNER, the target antigen of anti-Tr, is a single-pass type I transmembrane protein highly expressed in Purkinje cell bodies and dendrites, as well as in various types of CNS neurons.6 ACA with anti-Tr antibody is rare and associated neurologic manifestations include subacute and severe cerebellar ataxia, encephalopathy, and sensory neuropathy. A large cohort study conducted at Mayo Clinic showed that anti-Tr antibody was detected in only 1 of the 118 neuronal autoantibody–seropositive patients with ataxia.4 Anti-Tr/DNER antibodies are almost exclusively found in patients with Hodgkin disease. Only a few patients have been reported in whom no Hodgkin disease (or any other tumor) was known at the time of testing.7 We present a patient with tumor-negative progressive cerebellar ataxia, which is a rare condition in anti-Tr antibody–positive ACA. We speculate that vitiligo may be a diagnostic clue to an autoimmune etiology for this case. Although autoimmune ataxia is usually severe, responsiveness to immunotherapy can be gratifying, particularly in patients with nonparaneoplastic disorders and in those with autoantibodies directed against neural PMPs. In the Mayo Clinic series of 118 patients with ACA, nearly half had neurologic improvement with immunotherapy, which was robust in 18.6%.4 Clinical recognition of autoimmune etiology and timely immunotherapy are critical for favorable functional outcome. For these patients, initiating high-dose corticosteroids or IVIg (or both sequentially) is indicated, and maintenance immunosuppressive therapy is required for sustained responses. Although the duration of therapy is uncertain, general recommendations are available.8 Evaluation for and treatment of any underlying cancer is another component for those patients with a paraneoplastic cause. Study funding No targeted funding reported. Disclosure The authors report no relevant disclosures. Go to Neurology.org/N for full disclosures. Appendix Authors Footnotes Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. © 2020 American Academy of Neurology References 1.↵Gill L, Zarbo A, Isedeh P, et al. Comorbid autoimmune diseases in patients with vitiligo: a cross-sectional study. J Am Acad Dermatol 2016;74:295–302.OpenUrl 2.↵Pittock SJ, Yoshikawa H, Ahlskog JE, et al. Glutamic acid decarboxylase autoimmunity with brainstem, extrapyramidal, and spinal cord dysfunction. Mayo Clin Proc 2006;81:1207–1214.OpenUrlCrossRefPubMed 3.↵Haitao R, Huiqin L, Tao Q, et al. Autoimmune encephalitis associated with vitiligo? J Neuroimmunol 2017;310:14–16.OpenUrl 4.↵Jones AL, Flanagan EP, Pittock SJ, et al. Responses to and outcomes of treatment of autoimmune cerebellar ataxia in adults. JAMA Neurol 2015;72:1304–1312.OpenUrl 5.↵Trotter JL, Hendin BA, Osterland CK. Cerebellar degeneration with Hodgkin disease: an immunological study. Arch Neurol 1976;33:660–661.OpenUrlCrossRefPubMed 6.↵de Graaff E, Maat P, Hulsenboom E, et al. Identification of delta/notch-like epidermal growth factor-related receptor as the Tr antigen in paraneoplastic cerebellar degeneration. Ann Neurol 2012;71:815–824.OpenUrlCrossRefPubMed 7.↵Bernal F, Shams’ili S, Rojas I, et al. Anti-Tr antibodies as markers of paraneoplastic cerebellar degeneration and Hodgkin’s disease. Neurology 2003;60:230–234. 8.↵McKeon A. Immunotherapeutics for autoimmune encephalopathies and dementias. Curr Treat Options Neurol 2013;15:723–737.OpenUrlCrossRefPubMed

 




Objective. To determine if an electroencephalographic (EEG) characteristic, beta:delta power ratio (BDPR), is significantly higher for N-methyl-d-aspartate receptor encephalitis (NMDARE) patients t…

 




Abstract Objective: To describe the sleep disorders in anti-NMDA receptor encephalitis (anti-NMDARe) Background: Patients with anti-NMDARe often have sleep problems. The severity and complexity of the accompanying neuropsychiatric symptoms, mask these sleep disorders, complicate their assessment, and explain the lack of prior studies Design/Methods: Patients recovering from anti-NMDARe were invited to participate in a prospective observational single center study including comprehensive clinical, video-polysomnography (V-PSG) sleep assessment and neuropsychological evaluation. Age and sex-matched healthy participants served as controls Results: Eighteen patients (89% female, median age 26 years, IQR 21–29) and 21 controls (81% female, median age 23 years, IQR 18–26) were included. In the acute stage, 16 (89%) patients reported insomnia and 2 hypersomnia (1 rapidly changed to insomnia). After the acute stage, 14 (78%) had hypersomnia. At study-admission (median 183 days after disease-onset, IQR 110–242) 8 patients still had hypersomnia, 1 insomnia, and 9 normal sleep duration. Patients had more daytime sleepiness than controls (higher Barcelona Sleepiness Index, p=0.02, and Epworth Sleepiness Score, p=0.04), but a similar perception of sleep quality. On V-PSG, sleep efficiency was similar in both groups although patients had more frequently multiple and longer confusional arousals in NREM sleep (p=0.03). Additionally, 13 (72%) patients had cognitive deficits, 12 (67%) psychological, social, or occupational disability, and 33% depression or mania. Between disease-onset and the last follow-up, 14 (78%) patients developed hyperphagia, and 6 (33%) hypersexuality (2 requiring hospitalization), all associated with sleep dysfunction. At study-admission, patients had a higher body mass index compared with controls (median, IQR: 23.5, 22.3–30.2 vs. 20.5, 19.1–21.1; p=0.007) Conclusions: Sleep disturbances are frequent in anti-NMDARe. They show a temporal pattern (predominantly insomnia at onset; hypersomnia during recovery), associate with behavioral and cognitive changes, and can occur with confusional arousals during NREM sleep. Disclosure: Dr. Ariño has nothing to disclose. Dr. Munoz-Lopetegi has nothing to disclose. Dr. Martinez-Hernandez has nothing to disclose. Dr. Armangue has received research support from Mutua Madrilena Foundation. Dr. Santamaria has nothing to disclose. Dr. Dalmau has received personal compensation in an editorial capacity for Editor: Neurology, Neuroimmunology, Neuroinflammation; and UpToDate. Dr. Dalmau has received royalty, license fees, or contractual rights payments from Euroimmune. Dr. Dalmau has received research support from Sage therapeutics.

 




SHARE March 31, 2020RESIDENT & FELLOW SECTION Mystery Case: Anti-NMDAR encephalitis with overlapping demyelinating syndrome View ORCID ProfileHyun Woo Kim, Christopher Lamb, Sheheryar Jamali, Alfonso Sebastian Lopez Chiriboga First published March 31, 2020, DOI: https://doi.org/10.1212/WNL.0000000000009320 FULL PDF CITATION PERMISSIONS MAKE COMMENT SEE COMMENTS Downloads12 Anti-NMDA receptor encephalitis can coexist with an overlapping demyelinating syndrome. © 2020 American Academy of Neurology YOU MAY ALSO BE INTERESTED IN RELATED ARTICLES No related articles found. TOPICS DISCUSSED ALERT ME

 




Objective Assess occurrence of the dendritic spine scaffolding protein drebrin as a pathophysiologically relevant autoantibody target in patients with recurrent seizures and suspected encephalitis …

 




Abstract Objective Autoimmune steroid-responsive meningoencephalomyelitis with linear perivascular gadolinium enhancement in brain MRI is regarded as glial fibrillary acidic protein (GFAP) astrocytopathy characterized by anti-GFAP antibodies (ABs). We questioned whether anti-GFAP ABs are necessarily associated with this syndrome. Methods Two patients with a strikingly similar disease course suggestive of autoimmune GFAP astrocytopathy are reported. Clinical examination, MRI, laboratory, and CSF analysis were performed. Neuropathologic examination of brain tissue was obtained from one patient. Serum and CSF were additionally tested using mouse brain slices, microglia-astrocyte cocultures, and a GFAP-specific cell-based assay. Results Both patients presented with subacute influenza-like symptoms and developed severe neurocognitive and neurologic deficits and impaired consciousness. MRIs of both patients revealed radial perivascular gadolinium enhancement extending from the lateral ventricles to the white matter suggestive of autoimmune GFAP astrocytopathy. Both patients responded well to high doses of methylprednisolone. Only one patient had anti-GFAP ABs with a typical staining pattern of astrocytes, whereas serum and CSF of the other patient were negative and showed neither reactivity to brain tissue nor to vital or permeabilized astrocytes. Neuropathologic examination of the anti-GFAP AB-negative patient revealed infiltration of macrophages and T cells around blood vessels and activation of microglia without obvious features of clasmatodendrosis. Conclusions The GFAP-AB negative patient had both a striking (para)clinical similarity and an immediate response to immunotherapy. This supports the hypothesis that the clinical spectrum of steroid-responsive meningoencephalomyelitis suggestive of autoimmune GFAP astrocytopathy may be broader and may comprise also seronegative cases. Glossary AB=antibody; GFAP=glial fibrillary acidic protein; IgG=Immunglobulin G First described in 2016, autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy has been characterized as a rare CNS disorder, typically manifesting as a steroid-responsive encephalitis, meningitis, myelitis, or meningoencephalomyelitis. Neurologic symptoms such as (sub)acute encephalopathy, blurred vision, postural tremor, and seizures often occur following an initial prodromal phase with influenza-like symptoms.1,2 A characteristic feature in brain MRIs is a linear perivascular gadolinium enhancement in the white matter extending radially outward from the ventricles. In addition, extensive lesions of the spinal gray matter may be detected.1 No definite diagnostic criteria have been established yet.3 For diagnosis of autoimmune GFAP astrocytopathy, detection of GFAP antibodies (ABs) in the patient’s CSF or serum is required.1 CSF cell count and CSF protein level are usually abnormal. Disease onset has been reported after influenza-like symptoms, a preceding herpes simplex encephalitis, and varicella zoster encephalitis, respectively.1,4 Other ABs, e.g., NMDA receptor IgG and aquaporin-4 IgG may also be detected in autoimmune GFAP astrocytopathy. Furthermore, the disease can be related to an underlying malignancy, with ovarian teratoma being the most common.1 The majority of patients improve after treatment with immunotherapy, especially corticosteroids.2 Yet, the pathophysiology of autoimmune GFAP astrocytopathy is unknown. Here, we compare clinical, radiologic, and serologic findings of two patients with a very similar disease course suggestive of GFAP astrocytopathy. Despite intriguing similarity, only one patient harbored anti-GFAP ABs in serum and CSF. We here discuss that the characteristic clinical syndrome of autoimmune meningoencephalomyelitis with linear perivascular gadolinium enhancement may not necessarily be associated with anti-GFAP ABs. Case report 1 During winter season, a 53-year-old Caucasian man was admitted to hospital due to influenza A infection. In the following weeks, the patient developed cognitive impairment, ataxia, tremor, and a left gaze–evoked nystagmus (for details, see table 1). Cranial MRI revealed areas with diffuse periventricular T2 hyperintensities and linear perivascular gadolinium enhancement in the supratentorial white matter extending radially outward from the ventricles (figure, A). CSF diagnostics revealed 86 cells/μL and 1,075 mg/L protein. High titers of anti-GFAP IgG ABs (titer 1:320) were found in CSF and serum. A typical staining pattern restricted to astrocytes could be detected after incubation of mouse brain slices and astrocyte and microglia cocultures with the patient’s CSF. A confirmatory cell-based assay with the GFAPα isoform (Euroimmun, Lübeck, Germany) was positive when incubated with the patient’s CSF (figure, B). After other differential diagnoses were ruled out (table 2), autoimmune GFAP astrocytopathy was diagnosed. The patient was treated with methylprednisolone 1000 mg/d for 5 consecutive days. A rapid clinical improvement and a reduction of anti-GFAP IgG AB titers (CSF 1:100, serum 1:100) could be observed. MRI follow-up revealed regressive gadolinium enhancement and decreased periventricular T2 hyperintensities. In addition, EEG follow-up showed improvement with basal alpha activity. When the daily oral prednisolone dose was reduced to less than 20 mg during the following months, the patient’s condition deteriorated again as he developed tremor. We therefore initiated 6 cycles of immunoadsorption and subsequently started rituximab treatment. This led to a clinical improvement with almost complete remission of clinical symptoms within 2 weeks. View inline View popup Table 1 Clinical characteristics of case reports 1 and 2 Figure Patients’ MRIs, immunofluorescence, and histologic findings Patient 1: (A.a) T2-weighted images demonstrate diffuse periventricular hyperintense lesions (thick arrows, A.a). Axial (A.b) and sagittal (A.c) T1-weighted images with gadolinium show linear perivascular enhancement extending radially through the periventricular white matter (thin arrows). (B) Characteristic staining pattern of GFAP-positive astrocytes in mouse brain slices incubated with CSF of patient 1 (B.a: hippocampus, coronal; magnification ×100; (B.b): Cerebellum, sagittal; magnification ×200). Incubation of astrocyte-microglial cocultures with CSF of patient 1 showed characteristic staining of astrocytes in fixed cells after permeabilization (B.c; magnification ×400), but not in vital cells (B.d; magnification ×200). Incubation of a cell-based assay transfected with the GFAPα isoform with the patient’s CSF revealed a positive staining pattern (B.e; magnification ×200). Scale bars: 50 μm each. Patient 2: (C) brain MRI shows similar features as shown in A with periventricular T2 lesions (thick arrows, C.a) and linear perivascular gadolinium enhancement (thin arrows, C.b, C.c). (D) Immunofluorescence stains with CSF of patient 2 revealed no specific staining in brain tissue (D.a: Hippocampus, coronal; magnification ×100; D.b: cerebellum, sagittal; magnification ×200) nor in permeabilized (D.c; magnification ×400) and vital cells (D.d; magnification ×200) in astrocyte-microglial coculture. Incubation of a cell-based assay transfected with the GFAPα isoform with the patient’s CSF did not show binding (D.e; magnification ×200). Scale bars: 50 μm each. (E) Histological analysis of patient 2 brain biopsy showed blood vessel–associated infiltration by hematopoietic cells (E.a; hematoxylin and eosin stain; magnification ×200; E.d; CD5-positive T lymphocytes; magnification ×200). Only scattered infiltration by single cytotoxic T cells was observed (E.b; CD8; magnification ×200). The majority of infiltrating cells were identified as macrophages (E.c; CD68; magnification ×200). Brain tissue showed microglial activation (E.e; CD68; magnification ×200) and astrogliosis (E.f; GFAP; magnification ×200), but no obvious signs of clasmatodendrosis. Scale bars: 50 μm each. GFAP = glial fibrillary acidic protein. View inline View popup Table 2 Diagnostics of case reports 1 and 2 before treatment Case report 2 In the same month, a 63-year-old Caucasian man presented with influenza-like symptoms. He later developed cognitive impairment, aggressive behavior, ataxia, and apraxia (for details, see table 1). MRI revealed pronounced T2 hyperintensities and gadolinium enhancement extending radially along the vessels within the supratentorial white matter (figure, C). CSF analysis revealed 53 cells/μL and 2,130 mg/L protein. Repetitive testing for antineuronal, anti-myelin oligodendrocyte glycoprotein, and anti-GFAP ABs was negative including incubation of both the patient’s serum and CSF in mouse and monkey brain slices, vital respectively fixed glia cocultures after permeabilization, and a GFAP cell-based assay (figure, D). As most differential diagnoses were ruled out (table 2), the patient underwent frontal brain biopsy. Biopsy featured parenchymal blood vessel associated infiltration of macrophages and T cells. Brain tissue itself showed activation of microglia, infiltration of macrophages, and astrogliosis (figure, E). Although not specific, histopathologic findings are compatible with the few available histology reports of proven cases of autoimmune GFAP astrocytopathy in the literature.5 We did not observe direct signs of clasmatodendrosis or loss of aquaporin-4 (not shown), which is typically seen in anti–aquaporin-4 AB-positive neuromyelitis optica spectrum disorder. Following treatment with IV immunoglobulins, the patient’s condition deteriorated as he developed brainstem symptoms including dysarthria, dysphagia, and impaired consciousness. Artificial ventilation was required. Following methylprednisolone pulse therapy of 1000 mg/d for 5 consecutive days, a rapid clinical improvement was observed, and the patient could be extubated and was able to eat and walk again. Brain MRI confirmed a significant regression of T2 lesions and decreased radial perivascular gadolinium enhancement. Thus, oral prednisolone treatment was continued and tapered over the next months. EEG follow-up showed a significant improvement with basic alpha but still intermittent bifrontal delta activity. CSF measurement 3 months after first hospital admission revealed lower but still increased cell count (33 cells/μL) and protein levels (1,100 mg/L protein). Thereafter, 5 cycles of immunoadsorption were initiated with subsequent clinical improvement. However, after tapering prednisolone to less than 10 mg daily symptoms reoccurred, MRI demonstrated radial perivascular gadolinium enhancement, and CSF showed a persistent pleocytosis of 31 cells/μL. Additional treatment with azathioprine was initiated, and prednisolone was increased to 80 mg again and tapered over the following months. Discussion Detection of anti-GFAP ABs and typical MRI findings are regarded as essential features in the diagnosis of autoimmune GFAP astrocytopathy. We here compare two patients with a similar disease course suggestive of autoimmune GFAP astrocytopathy. Yet, only in one patient, anti-GFAP ABs were detected. Recent reports questioned the relevance of anti-GFAP ABs in this clinical syndrome.3,6 In line with these reports, we here support the hypothesis that autoimmune meningoencephalomyelitis with characteristic MRI findings and steroid responsiveness may present with diverse immunologic findings, and the presence of anti-GFAP ABs is not obligatory. So far, it is not clear whether the presence of anti-GFAP-ABs in some patients with this disorder is just an immunologic accompaniment or whether these patients with anti-GFAP-ABs represent a particular subgroup with a specific pathophysiology targeting the astrocyte. Because anti-GFAP ABs bind to astrocytic cytosolic intermediate filaments and ABs are not internalized, a direct pathophysiologic relevance of these ABs is unlikely. As known from autoimmune encephalitis and neuromyelitis optica spectrum disorders, pathophysiologically relevant ABs usually target membrane surface proteins.7 In contrast, in paraneoplastic disorders, specific onconeuronal ABs to intracellular antigens are not pathogenic but excellent biomarkers.7 In autoimmune GFAP astrocytopathy, a role of autoreactive T cells triggering a GFAP-specific autoimmune response has been suggested.3 In a rat model, CD3+ T cells have been shown in close proximity to GFAP-positive astrocytes, thereby inducing an immune response with production of IgG ABs to GFAP.8 This might be a first direct link of how the humoral response is initiated. Of note, in our patients and also in others, an observational link exists between viral infections, e.g., influenza A, herpes simplex, and varicella zoster and subsequent GFAP autoimmunity.1 The association of viral CNS infections and other forms of autoimmune encephalitis is well established. Here, antigen presentation due to neuronal damage caused by viral inflammation or virus-induced costimulation of immune cells is favored to be a pathophysiologic mechanism involved in promoting encephalitis.9 Although influenza A infection does not necessarily lead to neuronal damage in the CNS, it may be a predisposing factor to develop GFAP autoimmunity. The specificity of anti-GFAP ABs for meningoencephalomyelitis needs to be clarified in further studies, as serum anti-GFAP ABs can also be found in other diseases, e.g., traumatic brain injury, vascular dementia, and astrocytoma, or even in healthy controls.10 Study funding This study was funded by the Schilling Foundation (to C. Geis); Center for Sepsis Control and Care (CSCC; to C. Geis and J. Wickel); and Interdisciplinary Center for Clinical Research Jena University Hospital (IZKF; to H-Y. Chung and J. Wickel). Disclosure In the preparation of this manuscript, the funding sources played no role. J. Wickel, H.-Y. Chung, K. Kirchhof, and D. Boeckler report no disclosures. S. Merkelbach received travel funding, speaker, and/or advisory board honoraria from Bayer, Biogen, Daiichi Sankyo, Genzyme, and Merck Serono. P. Kuzman and W. C. Mueller report no disclosures. C. Geis received advisory board honoraria and speaker honoraria from Roche and Alexion and received research support from the Schilling Foundation, the German Research Council, and the German Ministry of Education. A. Günther received travel funding, speaker, and/or advisory board honoraria from Merz, Ipsen, Boehringer Ingelheim, Pfizer, Daiichi Sankyo, and Bayer. Go to Neurology.org/NN for full disclosures. Acknowledgment The authors thank the patients for their participation in this study and Claudia Sommer for excellent technical assistance. Furthermore, they thank Euroimmun (Lübeck, Germany) for their support in antibody diagnostics and Prof. Dr. Christine Stadelmann-Nessler and Dr. Jonas Franz (Institute of Neuropathology, University Medical Center Göttingen, Germany) for providing histological staining of aquaporin 1 and 4. Appendix Authors Footnotes Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article. ↵* These authors contributed equally to the manuscript. ↵† Shared seniority. The Article Processing Charge was funded by the authors. Received September 4, 2019. Accepted in final form November 26, 2019. Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. References 1.↵Flanagan EP, Hinson SR, Lennon VA, et al. Glial fibrillary acidic protein immunoglobulin G as biomarker of autoimmune astrocytopathy: analysis of 102 patients. Ann Neurol 2017;81:298–309.OpenUrl 2.↵Iorio R, Damato V, Evoli A, et al. Clinical and immunological characteristics of the spectrum of GFAP autoimmunity: a case series of 22 patients. J Neurol Neurosurg Psychiatry 2018;89:138–146. 3.↵Shan F, Long Y, Qiu W. Autoimmune glial fibrillary acidic protein astrocytopathy: a review of the literature. Front Immunol 2018;9:2802.OpenUrl 4.↵Fang B, McKeon A, Hinson SR, et al. Autoimmune glial fibrillary acidic protein astrocytopathy: a novel meningoencephalomyelitis. JAMA Neurol 2016;73:1297–1307.OpenUrl 5.↵Shu Y, Long Y, Chang Y, et al. Brain immunohistopathology in a patient with autoimmune glial fibrillary acidic protein astrocytopathy. Neuroimmunomodulation 2018;25:1–6.OpenUrl 6.↵Xie L, Liu T, Yao H, et al. Autoimmune inflammatory meningoencephalitis in a patient negative for glial fibrillary acidic protein-specific immunoglobulin G. Mult Scler Relat Disord 2019;28:167–171.OpenUrl 7.↵Dalmau J, Geis C, Graus F. Autoantibodies to synaptic receptors and neuronal cell surface proteins in autoimmune diseases of the central nervous system. Physiol Rev 2017;97:839–887.OpenUrlCrossRefPubMed 8.↵Park ES, Uchida K, Nakayama H. Establishment of a rat model for canine necrotizing meningoencephalitis (NME). Vet Pathol 2014;51:1151–1164.OpenUrlCrossRefPubMed 9.↵Armangue T, Leypoldt F, Málaga I, et al. Herpes simplex virus encephalitis is a trigger of brain autoimmunity. Ann Neurol 2014;75:317–323.OpenUrlCrossRefPubMed 10.↵Wang KK, Yang Z, Yue JK, et al. Plasma anti-glial fibrillary acidic protein autoantibody levels during the acute and chronic phases of traumatic brain injury: a transforming research and clinical knowledge in traumatic brain injury pilot study. J Neurotrauma 2016;33:1270–1277.OpenUrlCrossRef

 




Abstract Objective To explore practice differences in the diagnosis and management of autoimmune encephalitis (AE), which is complicated by issues with sensitivity/specificity of antibody testing, nonspecific MRI/EEG/CSF findings, and competing differential diagnoses. Methods We used a worldwide electronic survey with practice-related demographic questions and clinical questions about 2 cases: (1) a 20-year-old woman with a neuropsychiatric presentation strongly suspicious of AE and (2) a 40-year-old man with new temporal lobe seizures and cognitive impairment. Responses among different groups were compared using multivariable logistic regression. Results We received 1,333 responses from 94 countries; 12.0% identified as neuroimmunologists. Case 1: those treating >5 AE cases per year were more likely to send antibodies in both serum and CSF (adjusted odds ratio [aOR] vs 0 per year: 3.29, 95% CI 1.31–8.28, p = 0.011), pursue empiric immunotherapy (aOR: 2.42, 95% CI 1.33–4.40, p = 0.004), and continue immunotherapy despite no response and negative antibodies at 2 weeks (aOR: 1.65, 95% CI 1.02–2.69, p = 0.043). Case 2: neuroimmunologists were more likely to send antibodies in both serum and CSF (aOR: 1.80, 95% CI 1.12–2.90, p = 0.015). Those seeing >5 AE cases per year (aOR: 1.86, 95% CI 1.22–2.86, p = 0.004) were more likely to start immunotherapy without waiting for antibody results. Conclusions Our results highlight the heterogeneous management of AE. Neuroimmunologists and those treating more AE cases generally take a more proactive approach to testing and immunotherapy than peers. Results highlight the need for higher-quality cohorts and trials to guide empiric immunotherapy, and evidence-based guidelines aimed at both experts and nonexperts. Because the average AE patient is unlikely to be first seen by a neuroimmunologist, ensuring greater uniformity in our approach to suspected cases is essential to ensure that patients are appropriately managed. Autoimmune encephalitis (AE) is a type of noninfectious neuroinflammation that is an increasingly recognized cause of acute or subacute progressive alteration in mental status with various presentations. Some cases are associated with specific autoantibodies to cell surface molecules and intracellular targets.1 However, antibody testing is not always available at many institutions, and results are of variable sensitivity and specificity, depending in part on the type of assay performed and on whether antibody testing is performed in both the serum and CSF or only in one or the other.2 The diagnostic process is complicated by new antibodies being identified at a rapid pace3,4 and known antibodies being identified in less characteristic cases, such as a first presentation of isolated psychosis.5 As antibody testing can often be negative, clinicians often must make a diagnosis using a combination of clinical phenotypes, neuroimaging, electroencephalography (EEG), and CSF results. To complicate matters, antibody-mediated syndromes might not be associated with any evidence of inflammation in MRI and CSF studies in some patients, and EEG findings are often nonspecific.6 There are also several differential diagnoses to consider with AE-like presentations.2 Although some cases of suspected AE might respond positively to immunotherapy, this outcome is neither consistent nor specific to the diagnosis of AE—improvement with steroids, for example, often seen with lymphoma.7 There remains a paucity of high-quality diagnostic and treatment studies. Given these uncertainties regarding the diagnosis and management of AE, we recently interviewed experts from 3 different continents regarding the challenges of AE diagnosis and the role of antibody testing.8 Despite their different practice settings, all of them agreed that the diagnosis of AE should be driven primarily by the patient’s clinical presentation and exclusion of key differential diagnoses, particularly infectious etiologies, and that workup should involve a thorough search for associated malignancies. They emphasized the importance of treating suspected AE cases with at least steroids while awaiting results of antibody testing. They agreed that antibody testing should be performed on both CSF and serum samples but cautioned against overreliance on these results. In particular, negative results for available antibodies would not dissuade them from treating patients with convincing presentations. This was in agreement with a recent position paper proposing a clinically grounded guideline for the diagnosis of AE.2 However, consensus among experts does not always reflect the “ground reality” of how neurologists approach these cases. Understanding how clinicians differ in their approach to complex diseases like AE can help inform not only further research but also educational initiatives and guideline development by highlighting enduring areas of uncertainty or clinical equipoise. Therefore, we explored practice differences in AE diagnosis and management using a worldwide electronic survey. Methods Survey The survey was launched by the Practice Current section of Neurology: Clinical Practice (neurology.org/collection/practice_current). We used an electronic survey that included 7 clinical and 8 demographic questions (appendix e-1, links.lww.com/CPJ/A113). The clinical questions pertained to 2 cases. Case 1 was deemed by 3 interviewed experts to be clinically convincing for autoimmune limbic encephalitis and consisted of a 20-year-old woman presenting with a neuropsychiatric syndrome, supportive brain MRI findings, and CSF lymphocytic pleocytosis.1 Respondents were asked whether they would send an autoantibody panel, and if so, in serum only or both serum and CSF. They were also asked whether they would start empiric treatment for AE with the autoantibody panel pending. Upon then being told that the panel has returned negative and the patient has still not improved with 2 weeks of first-line immunotherapy, respondents were asked whether they would continue immunotherapy (1st- and/or 2nd-line agents) or stop. Case 2 was more ambiguous and consisted of a 40-year-old man with new seizures, mild short-term memory impairment, right temporal lobe seizures, T2 hyperintensity in the right hippocampus, and negative infectious workup. However, the interviewed experts also deemed this case as suspicious enough for AE to warrant antibody testing and empiric immunotherapy.8 Respondents were asked whether they would send autoantibodies in the serum and/or CSF and whether they would start first-line immunotherapy. Those who did not start immunotherapy were asked if they would change their management, should the autoantibody panel return positive (low titer) for anti-NMDA receptor (NMDAR) antibodies in the serum and CSF in 2 weeks, with the patient experiencing focal seizures despite 2 adequately dosed antiepileptic drugs (AEDs). Demographic questions included whether respondents identified as neuroimmunologists, the number of cases of AE they would treat per year, the population treated (adults/children/both), years in practice, primary work setting, level of training, whether their practice was located in the United States or abroad, and in what US state or country. The survey was available online and was anonymous. Participation did not require membership in the American Academy of Neurology (AAN) or subscription to AAN journals. No compensation was offered. A link to the questionnaire was available in the Neurology® journals’ webpages, in online ads and the print version of the journals, and in the Practice Current dedicated webpage. The survey was also advertised by the AAN and Neurology journals via social media. Individual internet protocol address was collected to ensure authenticity of responses. We opened the survey from November 28, 2017, to May 28, 2018, and all responses collected were included in the analysis. Statistical analysis The frequency of responses for each question/scenario was calculated for different demographic groups, focusing on (1) subspecialty status (neuroimmunologist vs not), (2) cases of AE treated over the past 12 months, (3) years in practice (trainee, <10-year experience, and >10-year experience), (4) practice population (children/adults/both), and (5) practice location (United States vs abroad). For case 1, we examined the proportion of respondents in each group who chose to (a) send an antibody panel, (b) send the panel in both serum and CSF (vs serum alone), (c) provide empiric immunotherapy without waiting for antibody results, and (d) continue immunotherapy despite no meaningful response to immunotherapy at 2 weeks and negative antibody testing. For case 2, we examined the proportion of respondents in each group who chose to (a) send an antibody panel in both serum and CSF, (b) provide empiric immunotherapy without waiting for antibody results, and (c) start immunotherapy (if initially not doing so) on being informed that the panel had returned with low-titer positive anti-NMDAR antibodies in the serum and CSF. For univariable analyses, we used the Fisher exact test. After identifying significant differences between the groups on univariable analysis, multivariable logistic regression was performed to adjust for all confounding variables, namely subspecialty status (neuroimmunologist vs not), AE cases per year (coded categorically as 0, 1–5, or >5), practice population (children/adults/both), and practice location (United States vs abroad). Statistical significance was set at 2-sided p < 0.050, except for subsequent 2 × 2 tests for significant associations in 3 × 2 tables, in which case significance was set at 2-sided p < 0.017 (Bonferroni correction p = 0.050/3). All analyses were performed using STATA 13.1. Standard protocol approvals, registrations, and patient consents The study was certified as exempt from review by Children’s National Medical Center Institutional Review Board. Data availability Anonymized data will be shared by request from any qualified investigator. Results We received 1,333 responses from 94 countries, of which 1,084 (81.3%) were complete with all questions answered. The key respondent characteristics are shown in table 1. View inline View popup Table 1 Characteristics of the survey respondents (n = 1,128) Case 1 When presented case 1, 92.3% of respondents chose to send an autoimmune antibody panel. On univariable analysis, the population treated and years in practice were associated with the decision to send an antibody panel (table 2). On multivariable regression, those who reported treating more cases of AE in the past 12 months (adjusted odds ratio [aOR] for >5 cases per year vs 0: 3.29, 95% CI 1.31–8.28, p = 0.011) were more likely to send antibodies, whereas those working with both adults/children were less likely to do so than those working with adults alone (aOR: 0.46, 95% CI 0.25–0.84, p = 0.011, table e-1, links.lww.com/CPJ/A112). View inline View popup Table 2 Autoantibody panel sent for case 1 (1,128 respondents) Of those choosing to send an autoantibody panel, 91.6% chose to send the panel in both serum and CSF, whereas 8.4% chose to send it in the serum alone. On univariable analysis, respondents working with children were more likely to send antibodies in both serum and CSF rather than just serum compared with those working with both adults and children (table 3). However, on multivariable regression, no associations were found with this decision; respondents working with children alone were “dropped” because they all favored sending antibodies in both serum and CSF (table e-2, links.lww.com/CPJ/A112). View inline View popup Table 3 Autoantibody panel sent in both serum and CSF vs serum alone for case 1, among those choosing to send a panel (1,053 respondents) Of note, 85.1% of those choosing to send a panel said that they would treat the patient empirically for presumed AE, whereas 9.2% said that they would wait for the antibody panel to come back and treat only if it was positive at least in the serum, and 3.2% said that they would treat only if it was positive in both serum and CSF. Of note, 2.4% suggested alternative plans, including starting acyclovir (n = 12) or treating both with acyclovir and immunotherapy (n = 5). Although respondents were told that extended toxicology testing, CT of the chest/abdomen/pelvis, and extensive infectious workup were negative, a few wanted additional investigations before deciding on immunotherapy, such as obtaining EEG to look for supportive patterns like extreme delta brush (n = 2), further exclusion of infectious causes particularly herpes (n = 6), and a pelvic ultrasound to rule out ovarian teratoma (n = 2). A few others reported that their choice would depend on factors such as clinical disability (n = 2) or presence of additional signs like refractory seizures (n = 2). On univariable analysis, the number of AE cases managed annually (per respondent report) was associated with the decision to start empiric immunotherapy while awaiting antibody results (table 4). On multivariable regression, the number of AE cases per year remained associated with the decision to pursue empiric immunotherapy (aOR for 1–5 per year vs 0: 2.31, 95% 1.51–3.51, p < 0.001; >5 per year: aOR: 2.42, 95% CI 1.33–4.40, p = 0.004, table e-3, links.lww.com/CPJ/A112). View inline View popup Table 4 Empiric immunotherapy chosen in case 1 (1,147 respondents) If no meaningful improvement at 2 weeks with first-line immunotherapy and antibody panel negative in CSF and serum, 577/970 (59.5%) who favored empiric therapy said that they would continue immunotherapy (first- and second-line agents), whereas 367 (37.8%) said that they would stop immunotherapy and reassess for other causes. Of note, 2.7% proposed alternatives, including both continuing immunotherapy while reassessing for other causes (n = 12), repeating the lumbar puncture perhaps with extended antibody screening (n = 4), additional body cancer screening or consideration of brain biopsy (n = 2), long-term EEG monitoring (n = 1), waiting longer for delayed treatment effect before continuing (n = 1), or considering oophorectomy (n = 1). On univariable analysis, the number of AE cases per year was associated with the decision to continue immunotherapy despite no response at 2 weeks and negative antibody testing (table 5). On multivariable regression, respondents who reported seeing >5 AE cases per year were more likely to persist with immunotherapy (aOR: 1.65, 95% CI 1.02–2.69, p = 0.043, table e-4, links.lww.com/CPJ/A112). View inline View popup Table 5 Continued immunotherapy despite no meaningful response to immunotherapy at 2 weeks and negative antibody testing in case 1 (970 respondents) Case 2 For case 2, 846/1,237 (68.4%) chose to send antibodies in both serum and CSF, 117 (9.5%) in serum alone, whereas 264 (21.3%) chose not to send antibodies. Ten (0.8%) had independent responses including that they would only send antibodies if there was CSF leukocytosis (n = 3) or supportive features like contrast enhancement on MRI (n = 1), or refractory or exceptionally frequent seizures (n = 2). Three said that they would wait for herpes virus PCR to return negative. One respondent indicated that most of the time they could not afford antibody testing. On univariable analysis, respondents identifying as neuroimmunologists were more likely to send off antibodies in the serum and CSF (p = 0.003, table 6). On multivariable regression, identifying as a neuroimmunologist remained associated with sending antibodies in both serum and CSF (aOR: 1.80, 95% CI 1.12–2.90, p = 0.015, table e-5, links.lww.com/CPJ/A112). View inline View popup Table 6 Antibody panel sent in both serum and CSF in case 2 (1,237 respondents) When asked whether they would consider empiric immunotherapy, only 498 (40.3%) said that they would do so at this time, whereas 355 (28.7%) said that they would only do so if the antibody panel came back positive. Three hundred fifty-seven (28.9%) said that they would not treat. Twenty seven (2.2%) had independent responses including starting acyclovir (n = 4), starting both acyclovir and steroids (n = 1), ruling out infectious or CNS/body neoplastic processes (n = 4), only if refractory to antiepileptic drugs (n = 5), CSF suggestive of autoimmunity with oligoclonal bands, elevated protein, and/or pleocytosis (n = 6), or pending the development of new symptoms or signs (n = 1). On univariable analysis, respondents living outside the United States (p = 0.016) were more likely to choose immunotherapy without waiting for antibody results, and the number of AE cases per year was also associated with this decision (p = 0.040, table 7). On multivariable regression, seeing more AE cases per year and living outside the United States remained associated with choosing immunotherapy without waiting for antibody results (table e-6, links.lww.com/CPJ/A112). View inline View popup Table 7 Empiric immunotherapy chosen in case 2 without waiting for antibody results (1,237 respondents) On being informed that the antibody panel returned with low-titer positive anti-NMDAR antibodies in the serum and CSF while the patient was continuing to have focal seizures despite 2 appropriately dosed AEDs, 50/120 (41.7%) who initially said that they would not treat then said that they would treat with immunotherapy; 60 (50.0%) additionally said that they would make changes to the AEDs besides starting immunotherapy. Ten (8.3%) said that they would only change AEDs. On univariable analysis, living outside the United States was associated with choosing immunotherapy (p = 0.04); 100% of those who reported seeing >5 AE cases per year chose immunotherapy vs 76.2% of those reporting zero cases per year (p = 0.058, table e-7, links.lww.com/CPJ/A112). On multivariable regression, seeing more AE cases per year was associated with choosing immunotherapy with positive antibody results (aOR for 1–5 per year vs 0: aOR: 5.55, 95% CI 1.03–29.8, p = 0.046, table e-8, links.lww.com/CPJ/A112). Discussion In a large Practice Current worldwide survey of neurologists using representative cases, we identified considerable heterogeneity in the diagnosis and management of AE. In particular, neuroimmunologists and those treating more AE cases per year generally took a more proactive approach to testing and immunotherapy than peers. Our findings have implications for guideline development and educational initiatives, the design of future large-scale cohorts or trials of AE, and for estimates of AE prevalence. First, the considerable differences in approach between different groups of physicians, particularly between those identifying as neuroimmunologists vs as non-neuroimmunologists and between those encountering AE more vs less often, highlight the importance of further educational initiatives and evidence-based guidelines aimed at both experts and nonexperts. Both cases in our survey were deemed by interviewed experts to be suspicious enough for AE to warrant antibody testing and empiric immunotherapy,8 but clearly this opinion was not unanimous among survey respondents. This lack of uniformity is worrisome, as observational data indicate that AE can leave 20% of patients dependent for daily activities and that early treatment is a key predictor of good outcome.9 Because the typical patient with AE is unlikely to be seen first by a neuroimmunologist, ensuring greater uniformity in our approach to suspected cases is essential to ensure that patients are appropriately managed and investigated for this potentially devastating disease. The absolute difference in responses between those identifying as neuroimmunologists vs non-neuroimmunologists was much smaller for the less ambiguous case 1—which was very much in keeping with NMDAR antibody encephalitis1—and may reflect greater awareness of one form of AE among neurologists, encouragingly indicating the potential effectiveness of education in this regard. Second, the areas of relative disagreement identified by our survey may help inform the design of future large-scale cohorts or trials in AE, which need to be based on an understanding of practice patterns and attitudes of physician stakeholders to successfully recruit patients and help resolve practical uncertainties. In particular, it is unclear what the threshold should be to send an autoimmune panel and use immunotherapy in patients with new-onset, imaging-negative temporal lobe epilepsy, as in case 2. Although neuroimmunologists were more likely to send testing, this is not necessarily the most pragmatic or cost-effective option. Future cohort studies should assess the yield of testing such undifferentiated cases and the risks/benefits of early treatment vs waiting for positive antibody results. There is also the challenge of identifying patients presenting with psychotic or other neuropsychiatric symptoms who may warrant further investigation for AE. For example, in NMDAR antibody encephalitis, central psychopathologic features of mood and psychotic disorders consistently coexist within individual patients, although well-controlled prospective studies are needed to further advance this approach.10 The definition of acceptable treatment delay and “red flag” symptoms also requires further evidence-based clarification. For example, a recent cohort study found that delays to treatment longer than 4 weeks and lack of improvement in that time frame were both independently associated with poor 1-year functional outcome, in addition to intensive care unit admission, abnormal MRI, and CSF white blood cell count >20 cells/μL.11 A smaller retrospective cohort study found that treatment delays shorter than 60 days and the absence of status epilepticus were associated with better cognitive performance over a year after symptom onset.12 It may very well turn out that antibody testing is best reserved for patients with additional concerning features like status epilepticus, unambiguous cognitive impairment, or psychiatric manifestations and that waiting 2 weeks for more evidence from antibody results does not dramatically change outcomes. Third, the apparent discrepancies in our approach to AE cases will contribute to inaccurate estimates of the incidence/prevalence of AE and response to treatment, particularly if such data are derived from physician diagnostic codes or other administrative data. For example, missed cases of AE can lead to underestimates of incidence/prevalence, whereas overzealous diagnoses can lead to additional erroneous labels of immunotherapy failure. This can in turn compromise decisions about resource allocation and the development of AE treatment protocols. These challenges further emphasize the need for high-quality cohort studies that ideally incorporate direct clinical evaluations or at least comprehensive review of patient records guided by diagnostic criteria.13 Although our analysis has several strengths, including a large worldwide sample and representation of neurologists across specialties and levels of experience, there are important shortcomings. First, we could not represent the full spectrum of AE presentations and diagnostic/treatment conundrums needed for more granular analyses of physician decision making. The cases presented may not be generalizable to all practice settings. However, we chose to limit this survey to 2 cases in the interest of maximizing brevity and survey completion. Second, our survey-based study is vulnerable to selection bias; for instance, respondents more interested in autoimmune neurology may have been overrepresented. Third, respondents may have been biased by us framing the survey as related to AE, which may have resulted in an overestimate of the proportion of respondents who would investigate and treat the cases as AE. Fourth, we cannot be confident whether respondents chose an option because they thought it was the best course of action or because it seemed most feasible within their practice. Fifth, because we did not contact respondents ourselves, we could not verify the veracity of respondents’ qualifications. However, by not limiting respondents to our network, we were able to capture a greater diversity of respondents. In conclusion, our results highlight the heterogeneous management of AE, the need for higher-quality cohorts and trials to guide empiric immunotherapy, and call for evidence-based guidelines aimed at both experts and nonexperts. Study funding No targeted funding reported. Disclosure A. Ganesh is a member of the editorial team of Neurology; has received speaker honoraria from The Meritas Seminar Series, Oxford; has served as a consultant for Adkins Research Group and Genome BC; has received research support from The Rhodes Trust and Wellcome Trust; and holds stock/stock options from SnapDx, TheRounds.ca, and Advanced Health Analytics (AHA Health Ltd). L. Bartolini is a Section Editor for Neurology Clinical Practice. Dr. Bartolini is an employee of the federal government. This manuscript was not a term of his employment, nor did he receive any compensation for the manuscript. S.F. Wesley has been a member of the editorial staff of the Resident and Fellow Section of Neurology. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp. Appendix Authors Footnotes Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp. Infographic: Npub.org/NCP/pc06-research Explore this topic: Npub.org/NCP/pc6 Interactive world map: NPub.org/NCP/map06 More Practice Current: NPub.org/NCP/practicecurrent Received March 7, 2019. Accepted May 16, 2019. © 2019 American Academy of Neurology References 1.↵Dalmau J, Geis C, Graus F. Autoantibodies to synaptic receptors and neuronal cell surface proteins in autoimmune diseases of the central nervous system. Physiol Rev 2017;97:839–887.OpenUrlCrossRefPubMed 2.↵Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016;15:391–404.OpenUrlCrossRefPubMed 3.↵Gresa-Arribas N, Planaguma J, Petit-Pedrol M, et al. Human neurexin-3alpha antibodies associate with encephalitis and alter synapse development. Neurology 2016;86:2235–2242.OpenUrl 4.↵Sabater L, Gaig C, Gelpi E, et al. A novel non-rapid-eye movement and rapid-eye-movement parasomnia with sleep breathing disorder associated with antibodies to IgLON5: a case series, characterisation of the antigen, and post-mortem study. Lancet Neurol 2014;13:575–586.OpenUrlCrossRefPubMed 5.↵Kayser MS, Titulaer MJ, Gresa-Arribas N, Dalmau J. Frequency and characteristics of isolated psychiatric episodes in anti-N-methyl-d-aspartate receptor encephalitis. JAMA Neurol 2013;70:1133–1139.OpenUrl 6.↵Escudero D, Guasp M, Arino H, et al. Antibody-associated CNS syndromes without signs of inflammation in the elderly. Neurology 2017;89:1471–1475.OpenUrl 7.↵Porter AB, Giannini C, Kaufmann T, et al. Primary central nervous system lymphoma can be histologically diagnosed after previous corticosteroid use: a pilot study to determine whether corticosteroids prevent the diagnosis of primary central nervous system lymphoma. Ann Neurol 2008;63:662–667.OpenUrlCrossRefPubMed 8.↵Ganesh A, Wesley SF. Practice Current: when do you suspect autoimmune encephalitis and what is the role of antibody testing? Neurol Clin Pract 2018;8:67–73. 9.↵Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 2013;12:157–165.OpenUrlCrossRefPubMed 10.↵Al-Diwani A, Handel A, Townsend L, et al. The psychopathology of NMDAR-antibody encephalitis in adults: a systematic review and phenotypic analysis of individual patient data. Lancet Psychiatry 2019;6:235–246.OpenUrl 11.↵Balu R, McCracken L, Lancaster E, Graus F, Dalmau J, Titulaer MJ. A score that predicts 1-year functional status in patients with anti-NMDA receptor encephalitis. Neurology 2019;92:e244–e252.OpenUrl 12.↵Hebert J, Day GS, Steriade C, Wennberg RA, Tang-Wai DF. Long-term cognitive outcomes in patients with autoimmune encephalitis. Can J Neurol Sci 2018;45:540–544.OpenUrl 13.↵Dubey D, Pittock SJ, Kelly CR, et al. Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis. Ann Neurol 2018;83:166–177.OpenUrlCrossRefPubMed

 




Abstract Objective: To determine the frequency of anti-NMDAR encephalitis without detectable serum NMDAR antibodies (NMDAR-abs) and the potential changes in the syndrome presentation. Background: Some patients with anti-NMDAR encephalitis do not have detectable NMDAR-abs in serum. The clinical implications are unknown. Design/Methods: Retrospective assessment of patients with anti-NMDAR encephalitis and available paired serum/CSF samples examined at Hospital Clínic-IDIBAPS, Barcelona, between January 2007 and December 2017. NMDAR-abs were determined with (1) rat brain immunostaining, (2) in-house cell-based assay (CBA), and (3) a commercial CBA. Patients were considered seronegative if NMDAR-abs were undetectable in serum using the 3 indicated techniques (NMDAR-abs only present in CSF). Results: Among 578 patients with anti-NMDAR encephalitis, 75 (13%) were seronegative. Compared with seropositive patients, the seronegative were older (23.5 years [IQR: 17–43] vs 20.5 [IQR: 14–31]; p<0.0001), less frequently female (39 [52%] vs 313 [76%]; p<0.001), and less frequently had a tumor (6 [9%] vs 128 [32%]; p<0.001). Additionally, seronegative patients were less likely to have seizures (44 [60%] vs 294 [73%]; p= 0.028), movement disorders (52 [69%] vs 355 [86%]; p<0.001), hypoventilation (12 [16%] vs 132 [32%]; p=0.008), and intensive care admissions (27 [43%] vs 283 [69%]; p<0.001). Treatment with immunotherapy and outcome were similar in seronegative and seropositive patients (mRS>2 at one year follow-up, 8 [19%] vs 60 [27%]; p=0.265). In multivariate analysis, older age at diagnosis, absence of tumor and less need for ICU admission were independent variables associated with seronegativity. No differences were observed in time from symptom onset to diagnosis (median days 30 [21–60] vs 35 [21–63]; p=0.3792), or frequency of relapses (one or more in 9 [16%] vs 28 [11%]; p=0.307). Conclusions: 13% of patients with anti-NMDAR encephalitis are seronegative. These patients are more likely to be male, with milder forms of the disease, and without tumors. Disclosure: Dr. Guasp has nothing to disclose. Dr. Módena-Ouarzi has nothing to disclose. Dr. Armangue has received research support from Mutua Madrilena Foundation. Dr. Dalmau has received personal compensation in an editorial capacity for Editor: Neurology, Neuroimmunology, Neuroinflammation; and UpToDate. Dr. Dalmau has received royalty, license fees, or contractual rights payments from Euroimmune. Dr. Dalmau has received research support from Sage therapeutics. Dr. Graus has nothing to disclose.

 




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PubMed comprises more than 30 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

 




Taylor Larsen talks to writer Susannah Cahalan about her new book, “The Great Pretender: The Undercover Mission that Changed Our Understanding of Madness.”…

 




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