AntiNMDA

'The government, public health and some people don't want people to be scared and to panic, but I think people need to because that's all we've been doing as a family,'...

Background Limbic encephalitis (LE), a variant of autoimmune encephalitis, is inflammation of the limbic system of the brain. The disorder presents with subacute impairment of short-term memory, psychiatric manifestations, confusion and seizures.

We aimed to investigate the role of free triiodothyronine (FT3) in patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis. 137 consecutive inpatients (2016-2019) were registered prospectively and followed up for 12 months.

Multiple sclerosis Original research Brainstem and cerebellar involvement in MOG-IgG-associated disorder versus aquaporin-4-IgG and MS Samantha A Banks1, Padraig P Morris2, John J Chen1,3, http://orcid.org/0000-0002-6140-5584Sean J Pittock1,4, http://orcid.org/0000-0003-4698-663XElia Sechi1,5, http://orcid.org/0000-0002-8387-6491Amy Kunchok1,6, Jan-Mendelt Tillema1, James P Fryer4, Brian G Weinshenker1, Karl N Krecke2, A Sebastian Lopez-Chiriboga7, Adam Nguyen4, Tammy M Greenwood4, Claudia F Lucchinetti1, Nicholas L Zalewski8, Steven A Messina2, http://orcid.org/0000-0002-6661-2910Eoin P Flanagan1,4 Neurology, Mayo Clinic, Rochester, Minnesota, USA Radiology (Division of Neuroradiology), Mayo Clinic, Rochester, Minnesota, USA Ophthalmology, Mayo Clinic Rochester, Rochester, Minnesota, USA Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA Department of Clinical and Experimental Medicine, Sassari University Hospital, Sassari, Sardegna, Italy Neurology, Cleveland Clinic, Cleveland, Ohio, USA Neurology, Mayo Clinic, Jacksonville, Florida, USA Neurology, Mayo Clinic, Scottsdale, Arizona, USA Correspondence to Dr Eoin P Flanagan, Neurology, Mayo Clinic, Rochester, MN 55905-0002, USA; flanagan.eoin{at}mayo.edu Abstract Objective To determine the frequency and characteristics of brainstem or cerebellar involvement in myelin-oligodendrocyte-glycoprotein-antibody-associated-disorder (MOGAD) versus aquaporin-4-IgG-seropositive-neuromyelitis optica spectrum disorder (AQP4-IgG-NMOSD) and multiple sclerosis (MS). Methods In this observational study, we retrospectively identified 185 Mayo Clinic MOGAD patients with: (1) characteristic MOGAD phenotype, (2) MOG-IgG seropositivity by live cell-based assay and (3) MRI lesion(s) of brainstem, cerebellum or both. We compared the symptomatic attacks to AQP4-IgG-NMOSD (n=30) and MS (n=30). Results Brainstem or cerebellar involvement occurred in 62/185 (34%) MOGAD patients of which 39/62 (63%) were symptomatic. Ataxia (45%) and diplopia (26%) were common manifestations. The median age in years (range) in MOGAD of 24 (2–65) was younger than MS at 36 (16–65; p=0.046) and AQP4-IgG-NMOSD at 45 (6–72; p=0.006). Isolated attacks involving the brainstem, cerebellum or both were less frequent in MOGAD (9/39 (23%)) than MS (22/30 (73%); p<0.001) but not significantly different from AQP4-IgG-NMOSD (14/30 (47%); p=0.07). Diffuse middle cerebellar peduncle MRI-lesions favoured MOGAD (17/37 (46%)) over MS (3/30 (10%); p=0.001) and AQP4-IgG-NMOSD (3/30 (10%); p=0.001). Diffuse medulla, pons or midbrain MRI lesions occasionally occurred in MOGAD and AQP4-IgG-NMOSD but never in MS. Cerebrospinal fluid (CSF) oligoclonal bands were rare in MOGAD (5/30 (17%)) and AQP4-IgG-NMOSD (2/22 (9%); p=0.68) but common in MS (18/22 (82%); p<0.001). Disability at nadir or recovery did not differ between the groups. Conclusion Involvement of the brainstem, cerebellum or both is common in MOGAD but usually occurs as a component of a multifocal central nervous system attack rather than in isolation. We identified clinical, CSF and MRI attributes that can help discriminate MOGAD from AQP4-IgG-NMOSD and MS. Statistics from Altmetric.com View Full Text Footnotes Twitter @akunchok Contributors SAB: data acquisition, analysed and interpreted the data, drafting of manuscript PPM: radiographic data review, analysed and interpreted the data, critical revision of manuscript JJC: analysed and interpreted the data, critical revision of manuscript SJP: analysed and interpreted the data, critical revision of manuscript. ES: analysed and interpreted the data, critical revision of manuscript. AK: analysed and interpreted the data, critical revision of manuscript J-MT: analysed and interpreted the data, critical revision of manuscript. JPF: analysed and interpreted the data, critical revision of manuscript. BGW: analysed and interpreted the data, critical revision of manuscript KNK: analysed and interpreted the data, critical revision of manuscript. ASL-C: analysed and interpreted the data, critical revision of manuscript. AN: analysed and interpreted the data, critical revision of manuscript. TMG: analysed and interpreted the data, critical revision of manuscript. CL: analysed and interpreted the data, critical revision of manuscript. NLZ: analysed and interpreted the data, critical revision of manuscript. SAM: analysed and interpreted the data, critical revision of manuscript EPF: study concept and design, analysis and interpretation of data, critical revision of manuscript and study supervision. Funding This study was made possible using funding from the NIH (R01NS113828). Competing interests SAB: Reports no disclosures PPM: Reports no disclosures. JJC: Reports no disclosures. SJP: Reports grants, personal fees and non-financial support from Alexion Pharmaceuticals; grants from Grifols, Autoimmune Encephalitis Alliance; grants, personal fees, non-financial support and other from MedImmune; SJP has a patent # 9,891,219 (Application#12-573942) 'Methods for Treating Neuromyelitis Optica (NMO) by Administration of Eculizumab to an individual that is Aquaporin-4 (AQP4)-IgG Autoantibody positive'. SJP also has patents pending for the following IgGs as biomarkers of autoimmune neurological disorders (septin-5, Kelch-like protein 11, GFAP, PDE10A and MAP1B ES: Reports no disclosures. AK: Reports no disclosures J-MT: Reports no disclosures. JPF: Reports no disclosures. BGW: Receives royalties from RSR, Oxford University, Hospices Civil de Lyon, and MVZ Labor PD Dr Volkmann und Kollegen GbR for a patent of NMO-IgG as a diagnostic test for neuromyelitis optica spectrum disorders, served on adjudication committee for clinical trials in neuromyelitis optica spectrum disorders being conducted by MedImmune/VielaBio and Alexion, and consulted for Chugai/Roche/Genentech and Mitsubishi-Tanabe regarding clinical trials for neuromyelitis optica spectrum disorders. KNK: Reports no disclosures ASL-C: Reports no disclosures. AN: Reports no disclosures TMG: Reports no disclosures. CL: Reports no disclosures SAM: Reports no disclosures. EPF: EPF is a site principal investigator in a randomiSed placebo-controlled clinical trial of Inebilizumab (A CD19 inhibitor) in neuromyelitis optica spectrum disorders funded by MedImmune/Viela Bio. Patient consent for publication Not required. Ethics approval This study was approved by the institutional review board of Mayo Clinic, Rochester, Minnesota, USA. Provenance and peer review Not commissioned; externally peer reviewed. Data availability statement Data are available on reasonable request. Anonymised data used for this study are available from the corresponding authors on reasonable request. Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. Request Permissions If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways. Copyright information: © Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ. Linked Articles Editorial commentary Akiyuki Uzawa Masahiro Mori Satoshi Kuwabara Journal of Neurology, Neurosurgery & Psychiatry 2021; 92 348-348 Published Online First: 08 Feb 2021. doi: 10.1136/jnnp-2020-325503 Read the full text or download the PDF: Subscribe Log in

Diagnosis of rapidly progressive dementia (RPD) is very challenging.There are many conditions that fall into category of RPD ranging from autoimmune …...

This systematic review evaluates the presentation of immune checkpoint inhibitor–induced encephalitis to identify features helpful in assessing outcomes.

Throughout life, mechanisms such as damage and inflammation can alter the permeability of the blood-brain barrier(BBB). According to some studies, increasing the permeability of the blood-brain barrier can occur in a time-dependent manner following restraint stress.

ChiCTR2000029115 (Chinese clinical trial registry site, http://www.chictr.org).

To treat intractable cases of autoimmune encephalitis, the need for novel immunotherapy that penetrates the blood-brain barrier (BBB) is increasing. Tofacitinib is a Janus kinase (JAK) inhibitor used to treat refractory immune-mediated diseases that effectively penetrates the BBB.

Abstract Objectives: Whether PANS (pediatric acute-onset neuropsychiatric syndrome) and PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection) represent tr...

Exosomes expressing specific miRNAs in antibody positive AE may participate as a feedback regulation in cancer development.

Introduction Autoimmune encephalitis (AE) comprises a group of non-infectious immune-mediated inflammatory disorders of the brain parenchyma often involving the cortical or deep grey matter with or without involvement of the white matter, meninges or the spinal cord.1–4 The original description of AE was based on paraneoplastic conditions related to antibodies against intracellular onconeuronal antigens such asANNA-1/anti-Hu.5 6 These ‘classical’ antibodies are non-pathogenic but represent markers of T-cell-mediated immunity against the neoplasm with secondary response against the nervous system. In recent years, an increasing number of antibodies targeting neuronal surface or synaptic antigens have been recognised such as N-MethylD-Aspartate Receptor (NMDAR)-antibody and Leucine-richglioma inactivated (LGI1)-antibody.1 Most of these surface antibodies have been shown to be likely pathogenic and are thought to mediate more immunotherapy-responsive forms of AE and have less association with tumours. Specific types of encephalitis can occur in the setting of antibodies against oligodendrocytes (eg, anti-myelin oligodendrocyte glycoprotein (MOG) brainstem encephalitis) or astrocytes (eg, anti-aquaporin-4 (AQP4) diencephalic encephalitis, anti-glial fibrillary acidic protein (GFAP) meningoencephalitis). In addition, some AE patients do not have any identifiable antibodies (seronegative) representing a disease category with novel, yet to be identified antibodies or T-cell mediated disease. Online supplemental appendix S1 contains a list of the commercially available neuronal autoantibodies (NAAs). Supplemental material Recent epidemiological studies suggest that AE is possibly as common as infectious encephalitis with an estimated prevalence rate of 13.7/100 000.7 The rapidly advancing knowledge of new antibodies and their associated syndromes has created a new and growing field of autoimmune neurology.8 However, advances from the laboratory bench have not been paralleled by advancement in clinical practice, leading to a large knowledge gap and many unanswered questions regarding the acute and long-term management of AE. The heterogeneity of AE presentation and findings on ancillary testing hinder large-scale clinical trials and limit the quality of evidence behind AE management. The objective of this paper is to evaluate available evidence for each step in AE management and provide expert opinion when evidence is lacking. Although the turnaround time of commercial NAAs panels may improve in the near future, currently these results are often unavailable at the time of early evaluation and management. Moreover, current commercial NAAs panels are inherently limited in their ability to diagnose AE, given the ever-growing numbers of antibodies identified and the likelihood of T-cell mediated pathogenesis in some cases. Consequently, clinicians have to approach AE initially as a clinical entity when deciding on investigations and treatment.1 Long-term management can then be modified according to the type of antibody identified, if any. Therefore, the aim of this paper is to emphasise the practical acute and long-term management of AE as a broad category rather than focusing on individual antibody syndromes. Another important goal is to represent the practice of experienced clinicians from different clinical and geographical backgrounds. Methods Core authors from the Autoimmune Encephalitis Alliance Clinicians Network (AEACN) developed the first draft of this paper (HA, JCP, SI, RCD, EPF, PG, AJ, YL, AR-G, IR, SJP and MJT). The AEACN is comprised of self-identified clinicians with interest and clinical expertise in AE management listed by the AE Alliance, a non-profit organisation founded by AE patients and families to establish a supportive community for patients and caregivers, enhance clinical collaboration, and facilitate AE scientific research. The AEACN includes a multidisciplinary international group of adult and paediatric neurologists, rheumatologists, psychiatrists, neuropsychologists and other specialists with real-life experience in AE management. The authors of the first draft reviewed available literature to compile existing evidence for every step in AE management. Where evidence was lacking or controversial, an electronic survey was distributed to all AEACN members to solicit individual responses. The survey questions were strategically planned to look at initial treatment, continued care and finally long-term management. After adding survey results to the manuscript, the updated version was circulated to all participating AEACN members for edits and further suggestions. Survey results The survey was distributed to 147 Clinical members. Sixty-eight (46%) members responded including the core authors. The most represented specialty/subspecialty of the respondents was neuroimmunology (66%), followed by general neurology (21%), paediatric neurology (16%), epilepsy (9%), behavioural/cognitive neurology (6%), hospital neurology-neurohospitalist (6%), neuromuscular neurology (6%), paediatric rheumatology (6%), neurocritical care (4%), psychiatry (4%), movement disorders (3%), general paediatrics (3%) and one specialist (1.5%) each of the following: autonomic disorders, adult rheumatology and paediatric critical care. Twenty-five members (37%) indicated more than one subspecialty. Clinicians from 17 countries participated including USA (69%), Brazil (4%), Canada (3%), China (3%), Spain (3%), Argentina, Australia, Indonesia, Israel, Italy, the Netherlands, the Philippines, Singapore, South Korea, Switzerland, Turkey and the UK (countries listed in a descending order based on the number of responders and alphabetically when the number of responders was equal). Of the total participating members, 88% practiced at academic tertiary referral centres and 76% were active in AE clinical research or scholarly publications. The participating members indicated personal clinical experience with an average of 7.3 AE subtypes (range 1–13 subtypes, median 8 subtypes). In total, 9% of the participating members were affiliated with reference neuroimmunology laboratories with NAAs testing capabilities. The results of individual survey questions are presented under the corresponding sections of AE management. The final draft was approved by all participating AEACN members after four rounds of revisions. The paper aimed to answer prespecified clinical questions as detailed below. Data availability statement The results of the survey are partially summarised in figure 1 and the detailed responses of all survey questions are published as online supplemental document 2. Supplemental material Figure 1 AEACN survey results for acute and bridging therapy. AE, autoimmune encephalitis; AEACN, Autoimmune Encephalitis Alliance Clinicians Network; IVMP, intravenous methylprednisolone; IVIg, intravenous Ig; PLEX, plasma exchange. Section 1: diagnosis of AE When to suspect AE clinically? A detailed history and examination is the first and most important step in AE diagnosis. The immune reaction in AE often results in acute or subacute presentation of a duration less than 3 months.1 Chronic presentations are only seen in some of these conditions, especially LGI1, Contactin-associatedprotein-like 2 (CASPR2), Dipeptidyl-peptidase-likeprotein 6 (DPPX) and Glutamicacid decarboxylase 65 (GAD65)-antibody encephalitis, and should otherwise raise suspicion of a neurodegenerative disease or other etiologies.9 Likewise, hyperacute presentations are also atypical and a vascular aetiology should be considered in those cases. A recurrent course may point towards an autoimmune aetiology but unlike the typical relapsing-remitting course of multiple sclerosis and systemic inflammatory disorders, AE relapses are rare and often result from insufficient treatment or rapid interruption of immunotherapy. A monophasic course is more common in idiopathic AE while a progressive course may be seen in some paraneoplastic syndromes especially paraneoplastic cerebellar degeneration, which tends to plateau after the cancer is treated. Patients with known cancer or those at increased cancer risk (smokers, the elderly, and patients with rapid unintentional weight loss) are prone to paraneoplastic AE, while patients with personal or family history of other autoimmune disorders are at increased risk of idiopathic AE.10 A preceding viral infection, fever or viral-like prodrome is common.11 AE may be triggered by herpes simplex virus (HSV) encephalitis or certain immune-modulating therapies such as TNFα inhibitors, and immune-checkpoint inhibitors (ICIs)—the latter can cause an accelerated form of paraneoplastic encephalitis in patients with advanced cancer.1 12 Table 1 shows practical classification concepts in AE. VIEW INLINE VIEW POPUP Table 1 Proposed classification concepts in autoimmune encephalitis The immune reaction in AE is usually diffuse, resulting in multifocal brain inflammation and occasionally additional involvement of the meninges, spinal cord and/or the peripheral nervous system.3 6 This diffuse inflammation may or may not be detectable on ancillary testing but it usually results in a polysyndromic presentation which is a clinical hallmark of AE. Although some antibodies have been linked to stereotypical symptoms (eg, oromandibular dyskinesia, cognitive/behavioural changes, and speech and autonomic dysfunction in NMDAR-antibody encephalitis, faciobrachial dystonic seizures in LGI1-antibody encephalitis, etc), there is significant symptom overlap between all antibodies and all forms of AE.1 11 Symptoms vary according to the anatomical localisation of inflammation and there are several clinical-anatomical syndrome categories in AE as summarised in table 2. VIEW INLINE VIEW POPUP Table 2 Anatomical-clinical syndromes of autoimmune encephalitis What investigations should be ordered when AE is suspected? After AE is suspected clinically, a detailed workup is needed to confirm the diagnosis and exclude competing possibilities like infective encephalitis or systemic/metabolic causes. In most cases, the workup starts with brain imaging and cerebrospinal fluid (CSF) analysis. The diagnostic algorithm follows the structure summarised in figure 2 and detailed below: Aim 1: confirming the presence of focal or multifocal brain abnormality suggestive of encephalitis Figure 2 Diagnostic algorithm for autoimmune encephalitis. *EEG can confirm focal or multifocal brain abnormality and rule out subclinical seizures. **In addition to neuronal autoantibodies, cerebrospinal fluid should be tested for infections, inflammatory markers (IgG index and oligoclonal bands), and in some cases cytology. ***In addition to neuronal autoantibodies, the differential diagnosis generated based on MRI results will guide what blood tests to send. ****In most cases, general neoplasm screening starts with CT then other screening modalities are added until a neoplasm is found or eventually ruled out. If the clinical picture is highly suggestive of a specific neoplasm, a targeted screening approach could be implemented (eg, starting with pelvic ultrasound if the clinical picture is suggestive of anti-NMDAR encephalitis). AE, autoimmune encephalitis; EEG, electroencephalogram; MRI WWO, MRI with or without contrast; PET, positron emission tomography. Brain MRI In addition to ruling out alternative diagnoses, standard Brain MRI with contrast can show changes consistent with one or more of the AE anatomical syndromes (table 1 and figure 3). According to the 2016 AE clinical criteria by Graus et al, the presence of bilateral limbic encephalitis is the only MRI finding sufficient to diagnose definite AE in the correct clinical setting (eg, negative CSF viral studies) even in absence of NAAs.1 All other MRI patterns (cortical/subcortical, striatal, diencephalic, brainstem, encephalomyelitis and meningoencephalitis) can support possible or probable AE unless the NAAs panel is positive for a clinically relevant antibody.1 2 Diffuse or patchy contrast enhancement suggestive of inflammation is seen in a few patients while intense enhancing lesions are unlikely in AE.3 9 Rare findings include focal or extensive demyelination, meningeal enhancement, and rarely cortical diffusion restriction (often related to secondary seizures). Brain MRI may also be normal. Patients with initially negative MRI may show changes suggestive of AE on repeat MRI a few days later. Gadolinium should be avoided during pregnancy. Table 3 shows the main differential diagnoses for each of the AE anatomical syndromes. VIEW INLINE VIEW POPUP Table 3 Differential diagnosis of autoimmune encephalitis anatomical syndromes and suggested additional testing Figure 3 Anatomical subtypes of autoimmune encephalitis. (A) Limbic encephalitis, (B) cortical/subcortical encephalitis, (C) striatal encephalitis, (D) diencephalic encephalitis, (E) brainstem encephalitis (arrow), (F) meningoencephalitis (arrow). Importantly, brain MRI can also help exclude alternative diagnoses such as acute stroke, neoplasm or Creutzfeldt-Jacob disease (CJD), although AE MRI changes can sometimes mimic some of these entities. Unilateral, and to a lesser extent bilateral, inflammation of the mesial and non-mesial temporal lobe as well as the orbitofrontal cortex on FLAIR or DWI sequences supports herpetic encephalitis over AE.13 Parenchymal haemorrhage on gradient echo sequence is more common in herpetic encephalitis than AE although this difference did not reach statistical significance in one underpowered study comparing the two types of encephalitis.14 In some related immune-mediated conditions, the diagnosis can be inferred from typical MRI patterns such as radial perivascular enhancement in autoimmune GFAP astrocytopathy and punctate brainstem/cerebellar enhancement in chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS).15 16 Electroencephalogram Electroencephalogram (EEG) is commonly performed in patients with suspected AE to exclude subclinical status epilepticus in encephalopathic patients or to monitor treatment response in patients with seizures. AE is a major cause of new onset refractory status epilepticus (NORSE), which can be convulsive or non-convulsive.17 EEG can also provide evidence of focal or multifocal brain abnormality when MRI is negative which would support encephalitis over metabolic encephalopathy.1 Findings suggestive of AE include focal slowing/seizures, lateralised periodic discharges and/or extreme delta brush, which is occasionally seen in NMDAR-antibody encephalitis.18 Frequent subclinical seizures are commonly identified in LGI1-antibody encephalitis but patients may also have a normal EEG including those with classical faciobrachial dystonic seizures (FBDS).19 20 Although a normal EEG does not exclude AE, it can support primary psychiatric disorders when investigating patients with isolated new psychiatric symptoms. EEG can also help differentiate AE from CJD. Brain fluorodeoxyglucose positron emission tomography In the event of a negative brain MRI and clinical uncertainty despite high suspicion of AE, obtaining a brain fluorodeoxyglucose positron emission tomography (FDG-PET) can confirm focal or multifocal brain abnormality in the correct clinical setting.21 It can also substitute for MRI when MRI is contraindicated. In case series, brain FDG-PET was more sensitive than MRI and may reveal brain abnormalities at an earlier stage of the disease.22 Bilateral temporal hypermetabolism (in seropositive or seronegative limbic encephalitis) and bilateral occipitoparietal hypometabolism (in NMDAR-antibody encephalitis) are among the most common patterns seen and may prove useful biomarkers for specific syndromes. Importantly, further studies are needed to better differentiate AE metabolic patterns from neurodegenerative and neuroinfectious syndromes. In addition, immunosuppressants, anaesthetics and antiseizure therapies, commonly administered to AE patients, can also alter cortical metabolism. Seizures can also cause hypermetabolic changes on FDG-PET. The lack of specificity and the limited availability of FDG-PET are barriers against the wide utilisation of this technique in AE diagnosis. Aim 2: confirming an autoimmune inflammatory etiology and excluding other possibilities Following assessment for focal or multifocal brain abnormality by MRI or other studies, additional investigations are indicated to confirm AE and exclude other possibilities. Testing can be guided by the clinical-anatomical syndrome to narrow down the scope of investigations as shown in table 3. CSF analysis This is the most important test in AE evaluation and is usually the second step in the workup after brain MRI. Regardless of MRI findings, all patients with suspected encephalitis require a lumbar puncture (LP) unless there is a significant contraindication (eg, risk of herniation on brain imaging). In some cases, inflammatory CSF may be the only abnormality found on initial testing serving as the sole indication for empiric immunotherapy after infection is excluded. If timely brain MRI is not possible due to patient agitation or lack of access, clinicians should proceed with LP after a screening head CT so as not to delay immunotherapy. CSF analysis should include cell count and differential, protein, glucose, CSF/serum glucose ratio, albumin quotient, IgG index and synthesis rate, oligoclonal bands, broad viral studies including HSV1/2 PCR and varicella zoster virus (VZV) PCR and IgG/IgM, bacterial/fungal cultures when appropriate, cytology, flow cytometry, NAAs panel (eg, Autoimmune encephalopathy/encephalitis panel, etc), and in some cases, prion disorder panel (preferably RTQuIC when available). Common CSF findings in AE include mild to moderate lymphocytic pleocytosis (commonly 20–200 cells but can be as high as 900 cells with some antibodies), hyperproteinorrachia, and in some cases, elevated IgG index and/or IgG synthesis rate and positive intrathecal oligoclonal bands (unmatched in the serum).1 23 These findings in the setting of negative infectious and cytological studies support an immune-mediated aetiology but would not differentiate AE from other immune-mediated conditions (eg, neurosarcoidosis) so clinical correlation is always needed. In many patients, testing NAAs in both CSF and serum is needed because CSF detection is more sensitive for some antibodies (eg, NMDAR and GFAP antibodies) while serum is more sensitive for other antibodies (eg, onconeuronal, LGI1, and AQP4 antibodies).1 If the clinical picture is highly suggestive of an antibody with a higher serum sensitivity (eg, FBDS suggestive of LGI1-antibody encephalitis), then it might be reasonable to avoid CSF testing in clinical situations where CSF sampling is challenging. Although symptomatology can guide which neuronal antibodies (or antibody panels) to test for in some patients, it may be most practical to send the most comprehensive panel especially in patients with less defined presentations. This is because there is a significant syndromic overlap between most of these antibodies and because more than one antibody can coexist in the same patient.24 Notably, routine CSF studies may be normal in some AE patients and this does not exclude the diagnosis when other parameters are consistent with AE; therefore, testing NAAs panels is recommended in case of high clinical suspicion even if the CSF is normal.25 Blood tests In addition to testing NAAs in the serum, several blood tests are often needed to exclude other competing etiologies. Test selection can be guided by the MRI anatomical pattern as shown in table 3 but some tests may be useful in case of negative MRI such as antithyroid antibodies, toxicology screen, ammonia, vitamin B1/B12 levels, HIV, inflammatory markers, antinuclear antibodies, extractable nuclear antigen antibodies, antiphospholipid and lupus anticoagulant antibodies, immunoglobulins and metabolic and hormonal panels when appropriate.1 Monitoring sodium level is important since hyponatraemia is common with certain AE subtypes such as LGI-1 antibody encephalitis.19 Blood samples should be collected prior to treatment with intravenous immunoglobulins or plasmapheresis to avoid false positive or false negative results. Brain biopsy Most AE cases with normal brain MRI or typical MRI patterns (limbic, striatal, etc) do not require a brain biopsy. Rarely, a brain biopsy may be needed for atypical or mass-like lesions to exclude neoplastic or other possibilities especially when all other investigations point away from autoimmunity.1 Pathological findings in AE are nonspecific and include T-cell and/or B-cell perivascular and parenchymal infiltrates along with secondary gliosis.26 Aim 3: screening for an associated neoplasm It is nearly impossible to predict whether AE is paraneoplastic or non-paraneoplastic based on symptoms as both AE subtypes present similarly. Therefore, cancer screening should be considered in most adult AE patients at time of presentation.24 If the patient has a known history of cancer typically associated with paraneoplastic syndromes then a paraneoplastic aetiology is presumed, and repeat cancer screen is indicated to identify recurrence or progression. In patients with cancer history not typically associated with paraneoplastic neurologic syndromes (eg, basal cell skin cancer, prostate cancer), repeat cancer screen may unmask a new different tumour. The most common neoplasms associated with AE include small cell lung cancer, thymic neoplasm, breast cancer, ovarian teratoma or carcinoma, testicular teratoma or seminoma, neuroblastoma and lymphoma.24 In some patients, the suspicion of associated neoplasm may be high based on certain demographic factors (eg, smoking history or advanced age) or typical clinical picture (NMDAR-antibody encephalitis associated with ovarian teratoma). Although some antibodies have stronger cancer association than others (eg, antibodies against intracellular antigens), the implicated antibody is usually unknown at the time of first presentation. The following screening modalities are available: CT chest, abdomen and pelvis Initial screening with CT of the chest, abdomen and pelvis with contrast is a reasonable approach given its lower cost compared with FDG-PET and since it provides more structural details of the neoplasm (if present) to guide biopsy and further surgical intervention if indicated. A major limitation of CT-based screening is its low sensitivity for early breast and testicular cancers.24 In addition, CT is not preferred in children and pregnant women; and pelvic CT is not preferred for women in childbearing age in general. Moreover, CT contrast dye may be contraindicated due to renal impairment or dye allergy. In these situations, additional or alternative means (eg, MRI) of cancer screening are required. It is to be noted, however, that CT iodine-based dye is relatively safer in pregnant women compared with MRI gadolinium-based dye. Mammogram and breast MRI Breast cancer is a common source of paraneoplastic syndromes in females, and a mammogram should be performed if the initial CT screen is negative.24 Patients with a strong family history of breast cancer and those who are not up to date with their regular mammograms are a special concern. If mammogram is negative but the suspicion of breast cancer is high, then breast MRI may improve sensitivity of cancer detection. Pelvic or testicular ultrasound or MRI Young and middle age adults with a typical clinical picture of NMDAR-antibody encephalitis should be specifically screened for teratoma by a transvaginal or transabdominal pelvic ultrasound (or testicular ultrasound in males).24 In female patients with ataxic presentation (suggestive of PCA1/Yo antibody), pelvic ultrasound can screen for ovarian carcinoma. Likewise, in males with ataxia and other brainstem symptoms (suggestive of Ma and Kelch-like Protein-11 Antibodies), testicular ultrasound may reveal the associated neoplasm.27 Pelvic MRI may be useful if ultrasound is equivocal. Extraovarian and extratesticular germ cell tumours may be detected on CT-based or MRI-based general cancer screening. Whole body FDG-PET scan Whole body FDG-PET can be more sensitive for early neoplasms when initial CT screen is negative or inconclusive and the suspicion of cancer is high (eg, smoker elderly patient, classic paraneoplastic presentation).24 It can also be used as the initial screening tool when there is a contraindication to high resolution CT or iodine contrast. Insurance coverage can be an obstacle and insurers should consider fewer restrictions on FDG-PET in AE patients given the high likelihood of a coexisting cancer in those patients. Section 2: acute treatment Intensive care unit needs The main indications for intensive care unit (ICU) admission in AE include refractory status epilepticus, severe dysautonomia and respiratory compromise (eg, from brainstem involvement, associated neuromuscular syndrome or medication-induced hypoventilation).28 It is important for ICU clinicians to distinguish central non-infectious fevers caused by the primary disease from infectious processes. Careful monitoring and management of blood pressure and heart rate fluctuations is critical in patients with severe dysautonomia. A temporary pacemaker may be needed in patients with severe dysrhythmia until the dysautonomia improves. Patients with severe hyponatraemia may require controlled slow correction of sodium levels to avoid central pontine myelinolysis. In most cases, hyponatraemia is related to inappropriate antidiuretic hormone secretion and fluid restriction is sufficient. In rare occasions with massive inflammation and brain oedema, intracranial pressure monitoring and management may be indicated. AE patients are often subject to high doses of sedation, antiseizure medications, and other symptomatic therapies so monitoring for drug toxicity in the ICU is imperative. Empiric antimicrobial treatment In many encephalitis patients, differentiating infectious from autoimmune aetiologies may be difficult prior to CSF analysis and therefore starting empiric antimicrobials with CNS coverage is always recommended until infection is excluded. The common practice is to start CNS doses of intravenous acyclovir and standard coverage for bacterial meningitis. Antibiotics and acyclovir can later be discontinued if CSF bacterial and HSV/VZV studies return negative. Acute immunotherapy Several retrospective studies have shown that early and aggressive immunotherapy is associated with better outcomes in AE patients.1 29 The 2016 AE clinical criteria emphasise the importance of starting immunotherapy once AE is highly suspected and infectious etiologies are excluded based on CSF results (cell-count, glucose, viral PCR, gram stain). It is impractical and potentially hazardous to delay immunotherapy until AE is confirmed by a positive antibody. There are no robust clinical trials comparing the different modalities of acute immunotherapy; therefore, the choice of the initial therapy may be based on anecdotal evidence and factors related to the specific syndromic presentation and comorbidities as shown in figure 4 and detailed below: Figure 4 Therapeutic algorithm for autoimmune encephalitis. *Relative contraindications to steroids include uncontrolled hypertension, uncontrolled diabetes, acute peptic ulcer and severe behavioural symptoms that worsen with corticosteroid therapy. **Steroid-responsive conditions include faciobrachial dystonic seizures suggestive of LGI1-antibody encephalitis, autoimmune encephalitis in the setting of immune checkpoint inhibitors, central demyelination, autoimmune GFAP astrocytopathy, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids, and steroid-responsive encephalopathy associated with autoimmune thyroiditis. ***High thromboembolic risk includes patients with known or suspected cancer, smoking history, hypertension, diabetes, hyperlipidaemia and hypercoagulable states. Ab, antibody; AE, autoimmune encephalitis; Ag, antigen; IVMP, intravenous methylprednisolone; IVIg, intravenous Ig; IL-6: interleukin 6; NORSE, new-onset refractory status epilepticus; PLEX, plasma exchange. High-dose corticosteroids Empiric treatment with intravenous methylprednisolone at a dose of 1 g per day for 3–7 days is a common reasonable approach to achieve initial immunosuppressive and anti-inflammatory effect in AE patients.1 It is also the preferred approach in presentations known to be specifically corticosteroid-responsive namely demyelinating pattern on MRI (suggestive of AE overlap with demyelinating syndromes),30 or dotted or radial enhancement (suggestive of CLIPPERS or autoimmune GFAP astrocytopathy, respectively).15 16 Patients with FBDS suggestive of LGI1-antibody encephalitis may also show a dramatic response to corticosteroids.19 Patients with known or highly suspected paraneoplastic AE associated with classical onconeuronal antibodies are thought to have a primarily T-cell mediated inflammation making corticosteroids, theoretically, a preferred option for immunosuppression over intravenous IG or plasma exchange (PLEX). However, paraneoplastic conditions associated with classical onconeuronal antibodies are often resistant to immunosuppression and tend to respond best to cancer therapy. A notable exception are patients who develop accelerated paraneoplastic AE in the setting of ICI treatment. These patients may be particularly responsive to corticosteroids given their inhibitory effect on T-cell overactivity which is the pathogenic hallmark of ICI-associated immune adverse events; however, second-line therapies may also be needed in some cases.12 On our AEACN survey, 84% of responders chose corticosteroids alone (65%) or in combination with other agents (19%) for initial immunotherapy in patients with a general AE presentation. Likewise, 74% of responders chose corticosteroids for initial immunotherapy for patients presenting with FBDS suggestive of LGI1-antibody encephalitis, alone (58%) or in combination with other agents (16%). For NMDAR-antibody encephalitis, corticosteroids remained the most popular choice on the survey. However, the percentage was lower selected only by 63% of responders either alone (35%) or combined with other agents (28%) indicating a larger diversity among specialists when selecting first-line therapy in those patients. Similar diversity was present for treatment of known or highly suspected paraneoplastic AE; whereas corticosteroids remained the most popular choice, it was chosen by only 48.5% of responders, alone (29%) or combined with other agents (19%) (see online supplemental document S2). One theoretical disadvantage to corticosteroids in AE is their potential for causing initial worsening of behavioural/psychiatric symptoms hampering a timely evaluation of treatment response although in most cases, corticosteroids may actually improve these symptoms. The use of corticosteroids may also be difficult in patients with common comorbidities such as uncontrolled hypertension or diabetes. Some experts recommend avoiding corticosteroids in patients with known GAD65-antibody associated neurological syndromes for fear of inducing type-1 diabetes but this concern remains theoretical without confirmatory studies. In patients with atypical or mass-like lesions on brain MRI in whom primary CNS lymphoma is on the differential diagnosis, corticosteroids should be delayed so as not to interfere with pathology results if a biopsy is considered during hospitalisation. Similar precautions are advisable when systemic autoimmunity such as sarcoidosis is on the differential. Intravenous Ig Intravenous Ig (IVIg) at a dose of 2 g/kg over 2–5 days is a relatively easy-to-use and timely option for fast immunomodulation when corticosteroids are contraindicated or when the clinical picture is suggestive of or known to be related to antibody-mediated disease (eg, probable or definite NMDAR-antibody encephalitis).29 IVIg can be more readily available than PLEX in some centres and it does not require a central line. A recent randomised blinded study showed IVIg efficacy over placebo in controlling seizures in a small number of patients with LGI1-antibody and CASPR2-antibody AE.31 On our AEACN survey, IVIg was the most popular acute immunotherapy if corticosteroids are contraindicated chosen by 41% of responders. Also 40% of responders indicated choosing IVIg alone or in combination with corticosteroids and other immunotherapies for acute therapy if the clinical picture was suggestive of NMDAR-antibody encephalitis. A downside to IVIg is its association with increased thromboembolic risk. Therefore, IVIg should be used with caution in patients with known or suspected paraneoplastic AE or other risk factors for thrombosis (eg, heavy smokers and the elderly). In addition, the aetiology of paraneoplastic AE associated with antibodies against intracellular antigens is thought to be cell-mediated rather than antibody-mediated rendering the use of IVIg in this setting potentially ineffective. On our survey only 25% of responders indicated using IVIg in known or suspected paraneoplastic AE. The use of IVIg may also worsen coexisting hyponatraemia due to volume expansion, which may potentially predispose to brain oedema and worsening mental status.32 Plasma exchange PLEX (5–10 sessions every other day) is an effective option for acute immunomodulation when corticosteroids are contraindicated or ineffective. In a small retrospective study, patients with NMDAR-antibody encephalitis treated with both corticosteroids and PLEX had better improvement in the modified Rankin score than those treated with corticosteroids alone,33 which is similar to the results in other antibody-mediated conditions like NMOSD.34 PLEX may be particularly effective in AE cases with associated central demyelination or coexisting NMOSD. It provides a potentially faster immunomodulation in patients with severe or fulminant presentations. It has no known psychiatric side effects and does not increase the risk of thromboembolism except for line-related thrombosis. Major limitations include increased bleeding risk, volume shifts (which can be problematic in dysautonomic patients), and the need for central line placement (in some institutions) with its associated risks. In addition, it is less suitable for agitated patients. Combined first-line therapies If the initial clinical picture is severe (eg, NMDAR-antibody encephalitis, NORSE, severe dysautonomia), clinicians may consider using combined first-line therapies from the beginning despite the lack of high quality evidence to support this practice. On our AEACN survey, combination therapy was the second most popular choice after corticosteroids alone if the clinical picture was suggestive of NMDAR-antibody encephalitis chosen by 28% of responders, and for unspecified AE (19%). More commonly, combination therapy is done sequentially if there is no meaningful response to the initial agent (eg, adding IVIg and/or PLEX after completing corticosteroids). On the survey, 62% of responders chose adding a different first-line therapy if the initial agent was ineffective while 26% chose going directly to a second-line agent. Other options like adding a second round or prolonging the duration of the same first-line agent were less popular. Second line agents If there is no meaningful clinical or radiological response to optimised first-line therapy after 2–4 weeks, the addition of a second-line agent with both rapid and sustained immunosuppressive effects can improve the outcome.29 However, the exact definition and timing of treatment responsiveness is not well defined and some clinicians may anecdotally choose earlier initiation of second-line agents. Both rituximab and cyclophosphamide have been used as second-line agents for rescue therapy in AE with good results.29 Rituximab is less toxic than cyclophosphamide and therefore is preferentially considered by most clinicians although it may not be as effective for cell-mediated inflammation as in the case of antibodies against intracellular antigens. However, although rituximab acts mainly on B-cells, it indirectly suppresses T-cell activity by reducing B-cell drive to T-cells. In most newly diagnosed cases, it is hard to determine clinically whether AE is antibody or cell-mediated before the antibody results are available. Some clues may help the clinician come to a preliminary hypothesis regarding aetiology (eg, FBDS or typical NMDAR-antibody encephalitis presentation suggest antibody-mediated AE while patients with known or increased cancer risk are more likely to have cell-mediated AE). Based on these clues, clinicians may decide to use rituximab or cyclophosphamide as a second-line agent if antibody results are delayed or if there is no access to antibody testing. Common rituximab dosing regimens include 375 mg/m2 weekly for 4 weeks or two doses of 1000 mg 2 weeks apart. Common dosing regimen of cyclophosphamide include 600–1000 mg/m2. A few case series have shown response to proteasome inhibitors that block plasma-cell generation (bortezomib), interleukin (IL)-6 inhibition (tocilizumab), or low dose IL-2 in patients who did not respond quickly to conventional second-line agents.35–37 However, the evidence behind these non-conventional rescue therapies remains limited and more research is needed to confirm their effectiveness in refractory AE. A clinical trial of ocrelizumab (a humanised anti-CD20 monoclonal antibody with a similar mechanism of action to rituximab) is currently recruiting, and a clinical trial of bortezomib is underway (www.clinicaltrials.gov, accessed 13 April 2020). When a second-line agent is used in the acute setting, it also serves as a bridging therapy to prevent early relapses that might happen if immunosuppression is abruptly discontinued.38 Prognostication and clinical severity tools are being developed to help select patients who would benefit from conventional and non-conventional second-line agents such as the anti-NMDAR Encephalitis 1-year Functional Status score and the Clinical Assessment Scale in Autoimmune Encephalitis.39 40 On the AEACN survey, 50% of responders indicated they would consider adding a second-line agent in the acute setting only if there was no response to more than one first-line agent, 32% indicated adding a second-line agent if there was no response to one first-line agent, while only 15% indicated using a second-line agent in the acute setting on all patients regardless of the response to first-line therapy. As for the preferred second-line agent, 80% of responders chose rituximab while only 10% chose cyclophosphamide in a clinical scenario with unknown antibodies and no clinical clues for aetiology. Conclusion In this first part of the best practice recommendations, we covered the clinical presentation, diagnostic workup and acute management of AE guided by published studies and the results of the AEACN survey providing updated recommendations for management of patients with suspected AE. The second part will follow with a focus on bridging therapy, symptomatic treatment and maintenance immunotherapy. A discussion of the limitations will be presented at the end of the second part. A summary of the best practice recommendations for AE diagnosis and acute management is presented in box 1. Box 1 Best practice recommendations summary for acute management of autoimmune encephalitis (AE) Evaluate the likelihood of AE relative to the patient’s clinical picture. Perform brain MRI and/or EEG to look for focal or multifocal brain abnormality. Perform lumbar puncture to support inflammatory aetiology and rule out infective/neoplastic causes. Test oligoclonal bands, IgG index, IgG synthesis rate and neuronal autoantibodies in the cerebrospinal fluid (CSF). Send blood tests to rule out other potential causes guided by neuroanatomical and clinical data. Test neuronal autoantibodies in the serum. Consider brain FDG-PET when there is a high clinical suspicion of AE and other paraclinical studies are uninformative. Perform cancer screening with CT chest, abdomen, and pelvis with contrast in relevant cases (or MRI when CT is contraindicated or not preferred). If negative, consider further testing with mammogram/breast MRI, pelvic ultrasound, and/or whole body FDG-PET guided by the clinical presentation and each patient’s specific cancer risk factors. Once infection is ruled out based on basic CSF results (eg, number of cells) and if biopsy for primary CNS lymphoma or neurosarcoidosis is not a consideration, start acute immunotherapy with high dose corticosteroids (or IVIG or PLEX if steroids are not preferred or contraindicated). If there is no clinical, radiological or electrophysiological improvement by the end of the initial treatment cycle, add IVIG or PLEX. Consider IVIG first in agitated patients and in those with bleeding disorders. Consider PLEX first in patients with severe hyponatraemia, high thromboembolic (or cancer) risk, and if there is associated brain or spinal demyelination. Consider starting with a combination therapy of steroids/IVIG or steroids/PLEX from the beginning (as opposed to sequentially) in patients with severe initial presentation (eg, severe NMDAR-antibody presentation, new onset refractory status epilepticus, severe dysautonomia, etc). If there is no clinical or radiological improvement 2–4 weeks after completion of combined acute therapy, consider starting a second-line agent when the clinical suspicion is high and/or a clinically relevant antibody is present. Consider rituximab in known or highly suspected antibody-mediated autoimmunity (eg, NMDAR-antibody encephalitis) and consider cyclophosphamide in known or highly suspected cell-mediated autoimmunity (eg, classical paraneoplastic syndrome). If no clear objective or subjective evidence of improvement with conventional second-line therapies, consider novel approaches such as tocilizumab or bortezomib although there is only minimal evidence to support their use. Start bridging therapy with gradual oral prednisone taper or monthly intravenous Ig or intravenous methylprednisolone. Avoid steroid taper or implement a shorter taper in vague cases with poor response to initial immunosuppressive therapy or when immunosuppression may impose higher risks than benefits (eg, patients with cancer or active infection). Acknowledgments The authors would like to thank Kimberley de Haseth, Director of Programs at the Autoimmune Encephalitis Alliance for coordinating the communication between the AEACN members and for distributing the survey. References ↵Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016;15:391–404.doi:10.1016/S1474-4422(15)00401-9pmid:http://www.ncbi.nlm.nih.gov/pubmed/26906964OpenUrlCrossRefPubMed ↵Dalmau J, Graus F. Antibody-Mediated encephalitis. N Engl J Med 2018;378:840–51.doi:10.1056/NEJMra1708712pmid:http://www.ncbi.nlm.nih.gov/pubmed/29490181OpenUrlCrossRefPubMed ↵Heine J, Prüss H, Bartsch T, et al. 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This case describes a middle-aged man with anti-dipeptidyl-peptidase-like protein 6 (DPPX) encephalitis who exhibited the triad of memory loss, diarrhea, and tremor. The progression of his disease resembled neurodegenerative disease, and his first presentation ...

To describe the clinical features and outcomes of anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis in infants and toddlers.This was a single-ce…...

Introduction Glutamic acid decarboxylase-65 (GAD65) is an enzyme required for synthesis of gamma-aminobutyric acid, a major central nervous system inhibitory neurotransmitter.1 Antibodies targeting GAD65 are a biomarker of type 1 diabetes mellitus (T1DM). Low titres in serum lack clinical specificity for autoimmune neurological disease, and may be detected in patients with alternative neurological diagnoses, isolated T1DM or even healthy controls.2 3 In contrast, high-titre GAD65 antibodies, defined in our laboratory as more than 20 nmol/L in serum (over 1000-fold higher than the upper limit of normal), reportedly confer high clinical specificity for GAD65 neurological autoimmunity.2 GAD65 antibodies appear unlikely to be pathogenic given the intracellular location of GAD65, and may instead be a surrogate marker of cytotoxic T-cell-mediated disease in patients with associated neurological syndromes.1 Stiff-person spectrum disorders (SPSD) were first characterised by Moersch and Woltman in 1956 and later determined to be a prototypical presentation of GAD65 neurological autoimmunity.4–6 Other manifestations of GAD65 neurological autoimmunity that have since been described include cerebellar ataxia, epilepsy, limbic encephalitis (LE), cognitive impairment, myelopathy and/or brainstem dysfunction. These reports, however, are limited by small sample sizes or restriction to individual phenotypes, precluding complete disease characterisation.2 3 6–19 We, herein, evaluate the clinical manifestations, immunotherapy responses and outcomes of a large patient cohort with high-titre GAD65 antibodies who were systematically determined to have GAD65 neurological autoimmunity. Methods Patients provided written consent to the use of their records for research. Identification of patients with GAD65 neurological autoimmunity We retrospectively identified 323 patients with high-titre GAD65 antibodies (defined as >20 nmol/L in serum based on previous work demonstrating high clinical specificity for GAD65 neurological autoimmunity at this cut-off) detected in the Mayo Clinic Neuroimmunology Laboratory out of 380 514 samples submitted for anti-GAD65 testing from January 2003 to May 2018, using radioimmunoassay (RIA) as previously described.2 Their electronic medical records (EMRs) were then reviewed by two neurologists with fellowship training in Neuroimmunology/Autoimmune Neurology (AB and NLZ). Patients with non-neurological presentations (eg, GAD65 antibody detected as part of T1DM evaluation), as well as those with neurological presentations but a more likely alternative diagnosis than GAD65 neurological autoimmunity, were classified as not having GAD65 neurological autoimmunity; these patients were excluded from study analysis and summarised separately. Patients with no more likely alternative diagnosis but an atypical presentation for GAD65 neurological autoimmunity were also excluded from study analysis but described separately, to ensure potentially novel disease phenotypes were not overlooked. Remaining patients were classified as having GAD65 neurological autoimmunity, and data relating to their clinical presentation, neuroimaging, electrophysiological testing, laboratory findings, immunotherapy responses, and outcomes as measured by modified Rankin score (mRS)20 were extracted from their EMRs for analysis. Diagnosis of disease manifestations Diagnosis of disease manifestations in GAD65 neurological autoimmunity was based on clinical assessment by a Mayo Clinic physician with expertise in the disorder of interest, alongside EMR review by AB and NLZ as outlined above to ensure no more likely alternative diagnosis was present. Electrophysiological data (ie, auditory startle reflexes, exteroceptive responses and/or electromyography for SPSD as described previously,7 electroencephalography for epilepsy) were frequently gathered, but an abnormal electrophysiological study was not required for diagnosis given imperfect test clinical specificity.21 22 Patients with SPSD were classified as classical SPSD (trunk and limb involvement), partial SPSD (trunk or limb involvement), or SPSD with prominent exaggerated startle. LE was defined as medial temporal lobe T2-hyperintensity with subacute disease onset of less than 3 months. Cognitive impairment was diagnosed by the treating physician based on the Kokmen short test of mental status23 and/or formal neuropsychometric testing. Outcome measures Response to immunotherapy (corticosteroids, intravenous IG, plasma exchange (PLEX), rituximab, cyclophosphamide and/or autologous stem cell transplantation) was classified as no response, partial response, near-complete response (ie, minimal residual clinical signs/symptoms), or complete response (ie, no residual clinical signs/symptoms), as well as sustained (defined as benefit persisting for greater than 3 months) or non-sustained, based on review of the treating Mayo Clinic physician’s documentation by AB and NLZ. A poor outcome was defined as mRS >2 at last clinical follow-up. Statistical analyses Statistical analyses were performed using JMP Pro V.14.1.0. Continuous and categorical variables were reported as median (range) and number (percentage), respectively. Differences across multiple groups were assessed by the Kruskal-Wallis, Pearson’s χ2 or Fisher’s exact test for multiple categories, as appropriate. Associations with a poor outcome at last clinical follow-up were explored by univariate logistic regression analysis, while the simultaneous effect of multiple significant variables was assessed by multivariate logistic regression. A two-sided p<0.05 was considered statistically significant. Adjustment for multiple comparisons was not performed.24 The relationships among manifestations of GAD65 neurological autoimmunity were depicted using circular visualisation in R.25 Results One in three patients with high-titre GAD65 antibodies were classified as not having GAD65 neurological autoimmunity Of 323 patients with high-titre GAD65 antibodies, 37 (11%) had non-neurological presentations (eg, GAD65 antibody detected as part of T1DM evaluation) and were excluded from study analysis. Seventy-one of 323 patients (22%) were determined to have a more likely alternative diagnosis than GAD65 neurological autoimmunity after review of their EMR; these patients were excluded from study analysis but are summarised separately (online supplemental table 1). Three of 323 patients (1%) without more likely alternative diagnoses but presentations atypical for GAD65 neurological autoimmunity (hyperkinetic movement disorders) were also excluded from study analysis but are described separately (table 2). The remaining 212 of 323 patients (66%) were classified as having GAD65 neurological autoimmunity for study analysis. The median serum anti-GAD65 titre among patients classified as having a more likely alternative diagnosis was significantly lower compared with patients classified as having GAD65 neurological autoimmunity (149 nmol/L vs 534 nmol/L, p<0.0001), and was not significantly different compared with patients with non-neurological presentations (149 nmol/L vs 164 nmol/L, p=0.71). The process of classifying patients as having GAD65 neurological autoimmunity is depicted via flow diagram (figure 1). Supplemental material Figure 1 Flow diagram depicting patient selection for study inclusion. GAD65, glutamic acid decarboxylase-65. VIEW INLINE VIEW POPUP Table 2 Patients with high-titre GAD65 antibodies and hyperkinetic movement disorders Defining the core and secondary manifestations of GAD65 neurological autoimmunity Through EMR review, we found that SPSD, cerebellar ataxia, epilepsy without LE (simply referred to hereafter as epilepsy unless otherwise specified) and LE could all occur in isolation. These were thus designated core manifestations of GAD65 neurological autoimmunity. Patients with two or more core disease manifestations were designated overlap syndromes, with the exception of LE and epilepsy (all patients with LE had seizures). No patient had cognitive impairment, myelopathy or brainstem dysfunction reported in isolation (ie, in the absence of SPSD, cerebellar ataxia, epilepsy or LE). These co-occurring phenomena were thus designated secondary manifestations of GAD65 neurological autoimmunity. Core manifestations of GAD65 neurological autoimmunity are SPSD, cerebellar ataxia, epilepsy and LE The clinical characteristics, immunological/cancer associations and laboratory results of all 212 patients with GAD65 neurological autoimmunity are presented in table 1. The median age of symptom onset was 46 years (range: 5–83 years) and 163/212 (77%) were female. Concurrent systemic autoimmunity was documented in 125/212 (59%) patients with GAD65 neurological autoimmunity and was most often thyroid disease (72/212, 34%), T1DM (63/212, 30%), and/or pernicious anaemia (40/212, 19%). A diagnosis of cancer within 5 years of symptom onset was reported in 9/212 (4%). Stratification of these findings by core manifestation is included in table 1, and discussed in relevant sections below. VIEW INLINE VIEW POPUP Table 1 Characteristics of 212 patients with GAD65 neurological autoimmunity* Stiff-person spectrum disorders SPSD was the most common core manifestation and was often classical in presentation The most common core manifestation was SPSD, which was reported in 107/212 (50%). The majority (73/107, 68%) had classical SPSD. Partial SPSD was documented in 30/107 (28%), and a small minority were classified as SPSD with prominent exaggerated startle response (4/107, 4%). Electrophysiological findings supportive of SPSD were reported in 52/70 (74%). Common findings documented on clinical assessment included spasms (93/107, 87%), gait dysfunction attributed to SPSD (85/107, 79%) and hyperlordosis (49/107, 46%). Cerebellar ataxia Cerebellar ataxia was the second most common core manifestation and often affected gait Cerebellar ataxia was reported in 91/212 (43%). Gait ataxia was most frequently documented (76/91, 84%), followed by limb ataxia (63/91, 69%) and ataxic dysarthria (47/91, 52%). On brain MRI, cerebellar atrophy was observed in 24/91 (26%); no patient had cerebellar T2-hyperintensity or gadolinium enhancement indicative of cerebellitis. Rare paraneoplastic cases associated with cerebellar ataxia While a diagnosis of cancer within 5 years of symptom onset was reported in only 9/212 (4%), this ranged from 0/71 (0%) in SPSD to 6/55 (11%) in cerebellar ataxia (p=0.01). Cancers diagnosed included thyroid cancer, breast cancer, lung cancer, and thymoma (table 1). Epilepsy Epilepsy was classically temporal lobe in origin and occasionally musicogenic Epilepsy with or without LE was reported in 62/212 (29%). Seizures were focal-onset in 56/62 (90%) and unknown-onset in 6/62 (10%). Seizures most often localised to the medial temporal lobe (35/56, 63%). Other seizure localisations were temporal lobe not otherwise specified (11/56, 20%), temporal lobe involving Heschl’s gyrus (4/56, 7%), frontal lobe (3/56, 5%), tempoparietal region (1/56, 2%), temporal and occipital lobes (1/56, 2%), and hemispheric onset (1/56, 2%). Involvement of Heschl’s gyrus was presumed if music provoked seizures (three patients) or if the patient heard music during the seizure (one patient). Patients evaluated for seizure management were often medically refractory Seizures were medically refractory in the majority (42/57, 74%). However, medically refractory epilepsy was significantly more frequent among patients with epilepsy in isolation who were evaluated for seizure management (34/39, 87%), compared with patients with epilepsy as part of an overlap syndrome who may have presented for management of SPSD or cerebellar ataxia rather than epilepsy (8/18, 44%) (p=0.0007). Epilepsy surgery uniformly revealed gliosis and did not usually result in seizure freedom The most common neuroimaging finding prompting consideration of epilepsy surgery was mesial temporal sclerosis, or MTS (9/62, 15%). Eight of 62 patients (13%) underwent epilepsy surgery (unilateral anterior temporal lobectomy, 7 patients; unilateral anterolateral temporal/frontal lobe resections, 1 patient). Neuropathological data was available for 5/8 patients, all of whom had gliosis reported. Two of 5 had pathological evidence of chronic inflammation noted (mild leptomeningeal, focal superficial cortical and perivascular chronic inflammation, 1 patient; ‘patchy chronic inflammation’ as per Mayo Clinic physician interpretation of outside neuropathology report, 1 patient). No more likely alternative aetiology for seizures (eg, malformation of cortical development) was reported in any patient. At last follow-up after surgery, only 2/8 (25%) obtained seizure freedom (one patient had focal seizures with preserved awareness up to 9 months after surgery that ceased with intravenous IG over two further years of follow-up, 1 patient had focal seizures with impaired awareness up to ten years after surgery that ceased with addition of clobazam over two further years of follow-up). The remaining six patients continued to have disabling seizures (ie, seizures limiting daily activities, requiring acute medical evaluation and/or leading to injury) after surgery. Epilepsy was typically young-onset and chronic in disease duration On stratification by core disease manifestation (table 1), median age at symptom onset ranged from 24 years (range: 5–56 years) in epilepsy to 59 years (range: 14–83 years) in cerebellar ataxia (p<0.0001). We examined the age at symptom onset of individual core disease manifestations in patients with overlap syndromes, and similarly found that the median age ranged from 33 years (range: 11–60 years) for epilepsy onset to 53 years for both cerebellar ataxia onset (range: 26–69 years) and SPSD onset (range: 19–70 years) (p<0.0001). The median total symptom duration recorded ranged from 42 months (range: 3–171 months) in cerebellar ataxia to 137 months (range: 3–552 months) in epilepsy (p<0.0001). Epilepsy showed a trend toward less cerebrospinal fluid inflammation On review of laboratory results (table 1), median serum and cerebrospinal fluid (CSF) anti-GAD65 titre did not differ significantly across core manifestations of GAD65 neurological autoimmunity. Patients with epilepsy had the lowest median CSF anti-GAD65 titre (2.5 nmol/L) and the lowest frequency of elevated CSF IgG index (0/22, 0%) among core disease manifestations, but these differences did not reach statistical significance (p=0.10 and p=0.17, respectively). Limbic encephalitis Patients with epilepsy uncommonly had neuroimaging evidence of LE On MRI, medial temporal lobe T2-hyperintensity compatible with LE was seen in 10/62 (16%). These patients were classified separately as having LE and all had subacute-onset seizures/cognitive impairment. Only 1/10 (10%) were assessed at the Mayo Clinic within 3 months of disease onset, and 3/10 (30%) were assessed greater than 1 year after disease onset for management of sequelae of LE (ie, persistent seizures, cognitive difficulties). Secondary manifestations of GAD65 neurological autoimmunity include cognitive impairment, myelopathy and brainstem dysfunction Of the secondary disease manifestations cognitive impairment was the most common, being reported in 38/212 (18%). The predominant cognitive sphere impacted was short-term memory in 29/38 (76%), followed by working memory/attention in 6/38 (16%), and verbal fluency/expressive language in 3/38 (8%). Myelopathy was reported in 23/212 (11%), and manifested as upper motor neuron (UMN) signs (brisk tendon reflexes, extensor plantar responses and/or spasticity) in 19/23 (83%), followed by pyramidal weakness in 14/23 (61%) and bowel/bladder dysfunction in 4/23 (17%). No patient had spinal cord T2-hyperintensity or gadolinium enhancement indicative of myelitis. Concern for brainstem dysfunction was reported in 22/212 (10%) and was on the basis of oculomotor findings in all, including vertical misalignment (11/22, 50%), horizontal misalignment (7/22, 32%) and conjugate ophthalmoparesis (4/22, 18%). No patient had brainstem T2-hyperintensity or gadolinium enhancement indicative of brainstem encephalitis. Secondary manifestations of GAD65 neurological autoimmunity clustered with specific core manifestations Secondary disease manifestations clustered with specific core disease manifestations: cognitive impairment with epilepsy/LE (N=30/38, 79%), myelopathy with SPSD (N=18/23, 78%), and brainstem dysfunction with cerebellar ataxia (N=20/22, 91%). The relationships among core and secondary disease manifestations are depicted via chord diagram (figure 2). Figure 2 CHORD diagram depicting relationships among manifestations of GAD65 neurological autoimmunity in this chord diagram, Arcs representing the relationships among core manifestations (stiff-person spectrum disorder (SPSD), cerebellar ataxia, epilepsy and limbic encephalitis (LE)) and secondary manifestations (myelopathy, brainstem dysfunction and cognitive impairment) of GAD65 neurological autoimmunity are shown. The size of the Arc is proportional to the significance of the relationship. Orientation of disease manifestations around the CHORD diagram has been chosen to highlight significant overlap of neighbouring categories: cognitive impairment and epilepsy/LE, myelopathy and SPSD, and brainstem dysfunction and cerebellar ataxia. GAD65, glutamic acid decarboxylase-65. An atypical presentation of GAD65 neurological autoimmunity: hyperkinetic movement disorders Three patients had high-titre GAD65 antibodies but atypical presentations for GAD65 neurological autoimmunity (table 2). All had unilateral hyperkinetic movement disorders (dystonia, 2 patients; chorea, 1 patient). In patients with dystonia the onset was insidious, while in the patient with chorea onset was subacute. One patient with right lower extremity dystonia received intravenous IG and reported 90% improvement that was confirmed by the treating physician; however, dystonia recurred seven to 8 weeks after intravenous IG was discontinued due to intolerability. Responses to immunotherapy and outcomes in GAD65 neurological autoimmunity Responses to immunotherapy were stratified by core disease manifestation and are presented in table 3. Immunotherapy usage (corticosteroids, intravenous IG, PLEX, rituximab and cyclophosphamide) was not significantly different except for corticosteroid usage (p<0.0001). This was driven by infrequent corticosteroid usage in SPSD (7/44, 16%), the majority of whom received intravenous IG (38/44, 86%). VIEW INLINE VIEW POPUP Table 3 Responses to immunotherapy among 142 patients with GAD65 neurological autoimmunity Patients with epilepsy received immunotherapy later and were least immunotherapy responsive The median time from symptom onset to first immunotherapy ranged from 5 months (range: 1–22 months) in LE to 50.5 months (range: 1–324 months) in epilepsy (p<0.0001). The number of patients with sustained response to immunotherapy ranged from 5/20 (25%) in epilepsy to 32/44 (73%) in SPSD (p=0.002). Complete response to immunotherapy was rare Among all patients treated with immunotherapy, a complete response was reported in only 2/142 (1%); one patient had mild ataxic dysarthria that resolved after corticosteroids, and one patient had new-onset seizures with cortical-subcortical lesions on MRI that resolved after corticosteroids, intravenous IG and PLEX. In retrospect this patient’s clinicoradiographic presentation was concerning for co-existing for gamma-aminobutyric acid type A receptor encephalitis,26 but confirmatory testing for this antibody was not performed. Presence of cerebellar ataxia and serum GAD65 antibody titre >500 nmol/L predicted poor outcome Among patients with GAD65 neurological autoimmunity the mRS at last follow-up was as follows: 0, 2/212 (1%); 1, 28/212 (13%); 2, 61/212 (29%); 3, 65/212 (31%); 4, 49/212 (23%); 5, 3/212 (1%); 6, 4/212 (2%). Logistic regression analysis revealed that mRS >2 at first Mayo Clinic evaluation, cerebellar ataxia and serum GAD65 antibody titre >500 nmol/L were independent predictors of poor outcome (mRS >2) at last clinical follow-up (table 4). VIEW INLINE VIEW POPUP Table 4 Logistic regression analysis assessing predictors of poor outcome (MRS >2) at last clinical follow-up in 212 patients with GAD65 neurological autoimmunity Discussion This study of patients with GAD65 neurological autoimmunity provides numerous important insights into the disease. Through systematic review of all Mayo Clinic patients with high-titre GAD65 antibodies identified in our Neuroimmunology Laboratory over a 15-year period, we found that SPSD, cerebellar ataxia, epilepsy, and LE were core disease manifestations. Phenotypically, SPSD was usually classical in presentation, in keeping with previous studies.7 Cerebellar ataxia most often impacted gait, although limb and speech ataxia were also commonly reported. Among those with epilepsy, seizures typically originated from the temporal lobe. Interestingly, three patients had musicogenic epilepsy, suggesting patients with this rare form of reflex epilepsy should be considered for GAD65 antibody testing.27 28 With regard to immunotherapy-responsiveness, this differed significantly across core disease manifestations; SPSD was the most likely to respond to immunotherapy, while epilepsy was least immunotherapy responsive. We also determined that serum GAD65 antibody titre >500 nmol/L as well as cerebellar ataxia independently predicted poor outcome. An mRS >2 at first Mayo Clinic evaluation also independently predicted poor outcome, although the external validity of this finding to other centres requires further study. Across core disease manifestations the age of symptom onset was youngest for epilepsy, indicating that a prior epilepsy diagnosis in a patient presenting with features of SPSD or cerebellar ataxia may be a clue to GAD65 neurological autoimmunity. Medically-refractory epilepsy was reported in the majority but was significantly more frequent among those with epilepsy in isolation who were evaluated for seizure management, compared with those with epilepsy as part of an overlap syndrome who may have been evaluated for management of SPSD or cerebellar ataxia. This suggests that referral bias may skew toward more severe epilepsy in publications, a finding that should be part of a balanced prognostic discussion in newly-diagnosed GAD65 epilepsy patients. LE was least-represented in our cohort, which likely reflects the rarity of this presentation as well as the primarily outpatient tertiary care setting of this study; patients with severe presentations of LE might have been less likely to travel to our facility. A cancer diagnosed within 5 years of symptom onset, which is the timeframe within which an associated neurological disorder is typically considered paraneoplastic,29 only occurred in 9/212 (4%). However, this differed significantly across core disease manifestations, with the highest rates of cancer in patients with cerebellar ataxia (6/55, 11%) and LE (1/7, 14%) as noted previously.30 Cognitive impairment, brainstem dysfunction and myelopathy were frequent accompaniments of GAD65 neurological autoimmunity but did not occur in isolation, hence their designation as secondary disease manifestations. This finding emphasises that patients with high-titre GAD65 antibodies who only have cognitive impairment, myelopathy or brainstem dysfunction should be thoroughly evaluated for alternative etiologies, because such presentations in isolation are not typical of GAD65 neurological autoimmunity. Secondary disease manifestations clustered intuitively with core disease manifestations: cognitive impairment with epilepsy/LE, myelopathy with SPSD, and brainstem dysfunction with cerebellar ataxia. Cognitive impairment was typically amnestic in keeping with medial temporal lobe dysfunction, as would be expected given the high rate of co-occurrence with temporal lobe epilepsy and LE.31 32 Myelopathic findings were most often reported in SPSD and usually manifested as UMN findings (brisk reflexes, extensor plantar responses, mild UMN pattern of weakness), in keeping with previous reports.7 The frequent coexistence of brainstem dysfunction with cerebellar ataxia on the basis of oculomotor findings could reflect more diffuse posterior fossa inflammation (‘rhombencephalitis’) in some patients, as well as the difficulties parsing out whether such findings are brainstem or cerebellar in clinical practice.33 34 Three patients had hyperkinetic movement disorders, suggesting this phenotype may be part of the spectrum of GAD65 neurological autoimmunity.35 However, given the paucity of cases, thorough evaluation for other causes of a hyperkinetic movement disorder in a patient with high-titre GAD65 antibodies is recommended. On review of immunotherapy usage across core disease manifestations, only corticosteroid usage differed significantly. This was driven by the low usage of corticosteroids in patients with SPSD who instead largely received intravenous IG, which is likely due to randomised-controlled trial evidence for intravenous IG in SPSD.36 When evaluating immunotherapy-responsiveness, due to the retrospective nature of this study we were not able to implement standardised measures of disease severity when monitoring responses to immunotherapy. We thus chose to classify patients as having no response, partial response, near-complete response, or complete response to immunotherapy, based on the Mayo Clinic treating physician’s documentation. There is an element of subjectivity to this approach, but it has immediate translatability to clinical practice (eg, sustained response to immunotherapy is least often seen in epilepsy, response to immunotherapy is rarely complete) and is thus of clear utility to practitioners.37 Rates of sustained response to immunotherapy ranged from 73% in SPSD to only 25% in epilepsy, highlighting the recalcitrance of this disease manifestation.12 While the poor response to immunotherapy in patients with epilepsy and high-titre GAD65 antibodies may lead one to question whether or not anti-GAD65 is directly relevant to epilepsy aetiology, the high prevalence of epilepsy among these patients along with previously published series support a true disease association. Median time from symptom onset to first immunotherapy was longest for epilepsy (50.5 months), which may contribute to lack of immunotherapy-responsiveness. This delay to immunotherapy likely reflects epilepsy chronicity in GAD65 neurological autoimmunity, which in combination with the younger age of onset would explain the long median symptom duration recorded for epilepsy (137 months). The indolence of GAD65 epilepsy is unique compared with other autoimmune epilepsies, which usually present more rapidly.38 Inflammation was reported neuropathologically in only 2/5 patients with GAD65 epilepsy who underwent epilepsy surgery, and there was also a trend toward lower median CSF anti-GAD65 titre and less frequent elevated CSF IgG index among these patients compared with other core disease manifestations. Taken together, these findings may reflect a lack of inflammation in patients with chronic GAD65 epilepsy at the time they undergo clinical evaluation; whether a more prominent inflammatory response is present early on that may be more amenable to immunotherapy remains undetermined. With regard to patient outcomes we found that serum GAD65 antibody titre >500 nmol/L and cerebellar ataxia were independent predictors of poor outcome (mRS >2). The mRS was chosen as a measure of disease outcome given its frequent usage in scoring neurological disability and relative ease of determination, but may skew towards poor outcomes among patients with disease manifestations that prominently affect gait (ie, cerebellar ataxia). Despite this limitation of the mRS, its broad applicability means that predictors of a poor outcome as defined by mRS >2 are helpful when discussing disease prognosis. There are several limitations to this retrospective study. Clinical reporting of GAD65 antibodies in the Mayo Clinic Neuroimmunology Laboratory is based only on RIA, and so confirmation of high-titre GAD65 antibodies by a second assay (eg, rodent brain tissue indirect immunofluorescence, or TIIF) was not required for study inclusion. However, reporting of anti-GAD65 by TIIF is not routinely done, and so our approach is representative of clinical practice. Additionally, even serum positivity for anti-GAD65 by TIIF may occur in patients without GAD65 neurological autoimmunity,19 highlighting the challenge in determining what test methodology or cut-off best defines a clinically relevant high-titre GAD65 antibody result. Implementation of other test methodologies such as ELISA, immunoblot or cell-based assay to detect high-titre GAD65 antibodies in some laboratories has created the need for assay comparison studies, which is an area of active investigation in our laboratory. Based on our findings and that of the previous literature, high-titre GAD65 antibodies in serum are best viewed as necessary, but not sufficient for a diagnosis of GAD65 neurological autoimmunity.39 The presence of anti-GAD65 in CSF supports an autoimmune aetiology in the appropriate clinical context,39 which in keeping with our finding of anti-GAD65 CSF positivity in all patients who were classified as having GAD65 neurological autoimmunity. Calculation of intrathecal anti-GAD65 synthesis has recently been suggested as the most definitive laboratory evidence of GAD65 neurological autoimmunity.39 This calculation (which requires paired serum and CSF as well as albumin measurement to determine synthesis rate) is not performed in our testing laboratory, and was not required for study inclusion. While its calculation may aid in the determination of GAD65 neurological autoimmunity, it is not yet in widespread use and so systematic evaluation of its diagnostic utility in clinical practice is required. Given the lack of a diagnostic gold standard for GAD65 neurological autoimmunity that is independent of GAD65 antibody testing,39 rigorous clinical evaluation to rule out alternative diagnoses in patients with atypical features remains prudent. Prior to study analysis, we excluded one-third of patients with high-titre GAD65 antibodies who were classified as not having GAD65 neurological autoimmunity due to non-neurological presentations (eg, isolated T1DM) or more likely alternative neurological diagnoses. This seemingly high number of excluded patients could in part reflect referral bias at our specialised tertiary care centre, which may be enriched with patients who have atypical presentations for GAD65 neurological autoimmunity and are ultimately determined to have more likely alternative diagnoses. Additionally, it is possible that some patients who were considered to have a more likely alternative diagnosis for their neurological presentation may have had contributory GAD65 neurological autoimmunity (eg, SPSD potentially contributing to stiffness/spasms in a patient with myotonia congenita, GAD65 cerebellar dysfunction potentially contributing to episodic vestibular symptoms in patients diagnosed as having more common vestibular disorders such as vestibular neuritis or migraine, or GAD65 epilepsy potentially contributing to seizure aetiology in a patient with febrile seizures who developed MTS). 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We are immensely proud to offer for the 3rd year in a row, The Anti-NMDA Receptor Encephalitis prize, in collaboration with the Canadian Neurological Society ...Read More...

Review Rhomboencephalitis http://orcid.org/0000-0002-9657-5815Jonathan Cleaver1,2, Richard James3, http://orcid.org/0000-0002-9851-4426Claire M Rice2,4 Department of Neurology, Royal United Hospitals Bath NHS Foundation Trust, Bath, UK Department of Neurology, North Bristol NHS Trust, Bristol, UK Department of Neuroradiology, Royal United Hospitals Bath NHS Foundation Trust, Bath, UK Clinical Neuroscience, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK Correspondence to Dr Claire M Rice, Clinical Neuroscience, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK; C.M.Rice{at}bristol.ac.uk Abstract Rhomboencephalitis—inflammation of the brainstem and cerebellum—has myriad clinical presentations including encephalopathy, cranial neuropathies, long tract signs and cerebellar dysfunction and is associated with significant morbidity and mortality. There are a variety of potential underlying causes that respond variably to treatment, including infections, parainfective syndromes, inflammatory disorders including autoimmune encephalitis and paraneoplastic syndromes. Here, we review its clinical presentation and outline a practical approach to its investigation, aiming to facilitate prompt diagnosis and confirmation of the underlying cause, to start appropriate management early and optimise the clinical outcome. Statistics from Altmetric.com View Full Text Footnotes Contributors The manuscript was designed by JC and CMR. All authors contributed to drafting and revision of the manuscript for intellectual content. Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. Competing interests None declared. Patient consent for publication Not required. Provenance and peer review Commissioned. Externally peer reviewed by Emma Tallantyre, Cardiff, UK. Request Permissions If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways. Copyright information: © Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ. Linked Articles Editors’ commentary Phil E M Smith Geraint N Fuller Practical Neurology 2021; 21 91-91 Published Online First: 16 Mar 2021. doi: 10.1136/practneurol-2021-002990 Read the full text or download the PDF: Subscribe Log in Other content recommended for you Nationwide survey of patients in Japan with Bickerstaff brainstem encephalitis: epidemiological and clinical characteristics Michiaki Koga et al., Journal of Neurology, Neurosurgery & Psychiatry, 2012 Infectious encephalitis: mimics and chameleons Michel Toledano et al., Practical Neurology, 2019 Bickerstaff ’s brainstem encephalitis associated with anti-GM1 and anti-GD1a antibodies Jonathan Cleaver et al., BMJ Case Reports, 2020 Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) in limited cutaneous sclerosis: a rare disease combination Sucharita Anand et al., BMJ Case Reports, 2019 Clinical and neuroradiological differences of paediatric acute disseminating encephalomyelitis with and without antibodies to the myelin oligodendrocyte glycoprotein M Baumann et al., Journal of Neurology, Neurosurgery & Psychiatry, 2014 The corpus callosum in the diagnosis of multiple sclerosis and other CNS demyelinating and inflammatory diseases Nidhi Garg et al., Journal of Neurology, Neurosurgery & Psychiatry, 2015 Autoantibody biomarkers in childhood - acquired demyelinating syndromes: results from a national surveillance cohort Yael Hacohen et al., Journal of Neurology, Neurosurgery & Psychiatry, 2013 Back on the scent: the olfactory system in CNS demyelinating diseases Albert Joseph et al., Journal of Neurology, Neurosurgery & Psychiatry, 2016 An MRI review of acquired corpus callosum lesions Dimitri Renard et al., Journal of Neurology, Neurosurgery & Psychiatry, 2014 Bickerstaff 's brainstem encephalitis associated with ulcerative colitis Miyuki Yamamoto et al., BMJ Case Reports, 2012

Editorial commentary Autoimmune encephalitis: new hammers in the toolbox Jenny Linnoila Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA Correspondence to Dr Jenny Linnoila, Neurology, Massachusetts General Hospital, Boston, MA 02114, USA; Linnoila.Jenny{at}mgh.harvard.edu Statistics from Altmetric.com Updated guidelines for the diagnosis and acute treatment of autoimmune encephalitis Recently, the field of autoimmune neurology has been expanding and evolving at a brisk pace. There has been renewed interest in the field, especially with the discovery that many rapidly progressive dementias, cryptogenic refractory seizures and movement disorders are autoimmune in aetiology. Excitement has grown with the recognition that numerous novel neural autoantibodies identified over the past decade and a half are associated with highly treatable autoimmune encephalitides, where patients have demonstrated good outcomes, particularly if diagnosed and treated early. This provides great hope for patients, families and practitioners alike and is in stark contrast with many of the now ‘classic’ paraneoplastic neurological disorders associated with intracellularly targeted antibodies, such as anti-Hu/antineuronal nuclear antibody type 1 (ANNA-1) or anti-Yo/Purkinje cell cytoplasmic antibody type 1 (PCA-1), which are well known to be poorly responsive to treatment, often leaving patients with devastating neurological sequelae. Knowing … View Full Text Footnotes Contributors JL is the sole author of this invited piece. Competing interests None declared. Patient consent for publication Not required. Provenance and peer review Commissioned; internally peer reviewed. Request Permissions If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways. Copyright information: © Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ. Linked Articles Neuro-inflammation Hesham Abboud John C Probasco Sarosh Irani Beau Ances David R Benavides Michael Bradshaw Paulo Pereira Christo Russell C Dale Mireya Fernandez-Fournier Eoin P Flanagan Avi Gadoth Pravin George Elena Grebenciucova Adham Jammoul Soon-Tae Lee Yuebing Li Marcelo Matiello Anne Marie Morse Alexander Rae-Grant Galeno Rojas Ian Rossman Sarah Schmitt Arun Venkatesan Steven Vernino Sean J Pittock Maarten J Titulaer Autoimmune Encephalitis Alliance Clinicians Network Rawan Tarawneh Heather Van Mater Eyal Muscal Ilene Ruhoy Yaacov Anziska Erin Longbrake Susa Benseler Cynthia Wang Michelle Apperson Raffaele Iorio Mateus Mistieri Simabukuro Ning Zhong Stephan Rüegg Amanda Piquet Jonathan Kuo Bahadir Konuskan Elena Frid Joseph Deng Wendy Mitchell GenaLynne Mooneyham Riwanti Estiasari Yuhei Chiba Melanie Alarcio Velda Han Jon Williams Michael Sweeney Tania Cellucci Kyle Blackburn Marisa Klein-Gitelman Jonathan D Santoro Raymond Suarez Jose Irazuzta Staley Brod Ann Hyslop Katrina Manibog Domingo Escudero William Noland Stacey Clardy Soe Mar William Kilgo Journal of Neurology, Neurosurgery & Psychiatry 2021; - Published Online First: 01 Mar 2021. doi: 10.1136/jnnp-2020-325300 Read the full text or download the PDF: Subscribe Log in

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<span><b>Introduction:</b> Autoimmune encephalitis is a disorder associated with antibodies directed against central nervous system proteins with variable clinical features.This study aims to add to knowledge of the disease by reporting the details of a cohort of patients with autoimmune encephalitis...

Future analysis evaluating the optimal candidate for disease and duration of treatment for the use of tofacitinib in autoimmune encephalitis is needed, according to the study authors.

The assistant professor of neurology at Mayo Clinic detailed the areas of autoimmune encephalitis research that need more attention, as well as the diagnostic potential of autoantibody assays.

The current study provides a comprehensive view of characteristic multimodal network dysfunction in anti-NMDAR encephalitis, which is crucial to establish new diagnostic biomarkers and promising therapeutic targets for the disease.

Abstract Objective To investigate the nature of prodromal headache in anti‐NMDA receptor (NMDAR) encephalitis. Methods Retrospective review of the clinical information of 39 patients with anti‐NMDA...