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Clinical and Magnetic Resonance Imaging Outcome Predictors in Pediatric Anti-N-Methyl-D-Aspartate Receptor Encephalitis

Clinical and Magnetic Resonance Imaging Outcome Predictors in Pediatric Anti-N-Methyl-D-Aspartate Receptor Encephalitis | AntiNMDA | Scoop.it
Children with NMDARE exhibit significant brain volume loss and failure of age-expected brain growth. Abnormal MRI findings, a clinical presentation with sensorimotor deficits, and a treatment delay > 4 weeks are associated with worse clinical outcome.
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Frontal encephalopathy related to hyperinflammation in COVID-19

Frontal encephalopathy related to hyperinflammation in COVID-19 | AntiNMDA | Scoop.it
Dear Sirs, Since coronavirus disease 2019 (COVID-19) outbreak, neurologic manifestations have been increasingly reported including encephalopathy; however, the underlying pathophysiology remains mostly unclear [1]. Neurotropism of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been suspected [2], though neuropathological studies did not show specific brain changes [3]. Besides the SARS-CoV-2 infection, a dysregulated immune response resulting in a massive release of proinflammatory cytokines is involved in pathogenesis of severe COVID-19 manifestations and multi-organ failure [4]. This systemic hyperinflammatory state may be involved in neurologic impairment, as well. We report a case of COVID-19-related encephalopathy, questioning temporal relations between infection, cytokine storm, and neurologic involvement. A 77-year-old female, with no history of neurological disease, presented with impaired consciousness after 18-days history of SARS-CoV-2 infection and acute respiratory distress requiring invasive mechanical ventilation (Fig. 1). Patient was placed on hydroxychloroquine, levofloxacin, and piperacillin/tazobactam. Despite a remarkable respiratory improvement, at time of first neurologic evaluation, patient presented awake but mutacic, without any goal-directed behavior. No meningeal irritations or focal signs were found. Stimulus-induced myoclonus and positive primitive reflexes (blinking, left grasp) were observed. Electroencephalogram (EEG) recording showed a generalized slowing activity, prevalent in frontal regions. A magnetic resonance imaging (MRI) displayed diffuse white-matter lesions consistent with chronic small vessel disease without contrast enhancement (Fig. 2). Cerebrospinal fluid (CSF) analysis detected normal white blood cell counts and mild increase of the blood–brain barrier permeability (CSF protein = 56 mg/dl, reference range < 50; CSF/serum albumin ratio = 15,6, reference range < 7,4). CSF reverse transcription-PCR (RT-PCR) for SARS-CoV-2 was negative. Additional CSF studies, including oligoclonal bands, neurotropic virus, bacterial cultures, and autoimmune encephalitis antibody panel, were all negative. Cytokines levels were tested both in CSF and blood documenting a significant increase of interleukin-6 (IL-6) (55.1 and 9.1 pg/ml respectively, reference range < 5,9) and interleukin-8 (IL-8) (106 and 2721 pg/ml, respectively, reference range < 70) (Fig. 1). 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET/CT) scan showed a spread frontal lobe hypometabolism (Fig. 2). She was treated with intravenous methylprednisolone 60 mg for 10 days. Over time, patient slowly but progressively improved until complete recovery of speech and environment interaction. Serial EEGs showed gradual reduction of previous slow activity. The second lumbar puncture detected a mild increase of blood–brain barrier permeability (CSF protein = 66 mg/dl, reference range < 50; CSF/serum albumin ratio = 13,7, reference range < 7,4), but a significant reduction of cytokines levels. CSF RT-PCR for SARS-CoV-2 was still negative. Neurologic syndrome was characterized by a status of akinetic mutism in keeping with the frontal slowing and hypometabolism shown at EEG and 18F-FDG-PET/CT, respectively. Structural lesions were excluded by brain MRI as well as autoimmune underlying causes by CSF and serum findings. Repeated negative CSF RT-PCR make SARS-Cov-2 neuroinvasion unlikely, although the presence of SARS-CoV-2 in CSF may be transient or untraceable. Indeed, CSF analysis documented a downward trend of cytokines levels over time, from elevated IL-6 and IL-8 levels to normalization, which closely reflected the clinical improvement, suggesting a possible underlying cytokine-mediated inflammatory process. In particular, cytokine-mediated endothelial activation and increased brain–blood permeability are related to neurotoxicity [5, 6]. It is still not clearly understood in SARS-CoV-2 infection whether CSF neuroinflammation and subsequent neurotoxicity are induced by increased serum concentration of cytokines or directly driven by viral endothelial activation and blood–brain barrier disruption. However, high CSF/serum IL-6 ratio detected in our patient at time of first lumbar puncture suggests that after a primary hit, cell–cytokine relationships may exponentially amplify resulting in intrathecal synthesis of neuroinflammatory mediators and glutamate hyper-excitatory neurotoxicity. Predominant frontal symptoms with anterior slowing EEG findings and bilateral frontotemporal hypoperfusion have been similarly described in other cases of COVID-19-related encephalopathy [1, 7]. In our case, 18F-FDG-PET study confirmed the prevalent frontal involvement, showing spread frontal lobe hypometabolism. Frontal syndrome may thus be considered the predominant feature of acute encephalopathy COVID-19-related. Moreover, cross-checked serum and CSF cytokines levels may represent a useful biomarker of early detection and progression of the neurologic involvement, as well as a ground for therapeutic recommendations and prognosis predictions. Indeed, as the number of patients with COVID-19 increases worldwide, clinicians should be aware of predominant frontal lobe presentation and cytokine-mediated hyperinflammatory process. Further investigation is needed to evaluate efficacy of immunomodulatory therapies and interleukin/interleukin-receptor antagonist in COVID-19-related encephalopathy.
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Clinical characteristics of GAD 65‐associated autoimmune encephalitis - Zhu - 2020 - Acta Neurologica Scandinavica

Clinical characteristics of GAD 65‐associated autoimmune encephalitis - Zhu - 2020 - Acta Neurologica Scandinavica | AntiNMDA | Scoop.it
Objectives To examine the clinical characteristics of autoimmune encephalitis associated with the glutamate decarboxylase 65 (GAD 65) antibody. Materials and methods Medical records of all patients...
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Comment on “Anti-NMDA receptor encephalitis presenting as new onset refractory status epilepticus in COVID-19”

Monti and colleagues [1] described a patient who developed psychiatric symptoms followed
by refractory status epilepticus caused by anti N-methyl-D-aspartate receptor (NMDAr)
encephalitis. Despite the lack of lung involvement, the patient resulted positive
for SARS-CoV-2 infection.
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About Encephalitis Conference 2020

About Encephalitis Conference 2020 | AntiNMDA | Scoop.it
The Encephalitis Conference 2020 features 15 oral presentations and 24 posters covering all aspects of encephalitis from infectious to autoimmune, Covid-19 and neurology and an exciting book reading and interview with Brian Deer.
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Stop testing for autoantibodies to the VGKC-complex: only request LGI1 and CASPR2 | Practical Neurology

Stop testing for autoantibodies to the VGKC-complex: only request LGI1 and CASPR2 | Practical Neurology | AntiNMDA | Scoop.it
VGKC ANTIBODIES: ORIGINS OF A DIAGNOSTIC TEST The initial clinical insights describing an autoimmune basis for acquired neuromyotonia (Isaacs’ syndrome), a form of peripheral nerve hyperexcitability, emerged in Oxford around 30 years ago. A patient with severe disease, refractory to sodium channel blocking medications, showed almost complete symptom resolution after plasma exchange.1 Moreover, this patient’s purified IgG induced muscle hyperexcitability in phrenic nerve–diaphragm preparations. These findings suggested an underlying autoantibody-driven mechanism for neuromyotonia, with voltage-gated potassium channels (VGKCs) considered a likely antigenic target. This prediction was directly tested with alpha-dendrotoxin (α-DTX), a neurotoxin derived from green mamba snake venom. α-DTX labels Kv1.1, 1.2 and 1.6 potassium channels and was radioiodinated to label soluble mammalian brain extracts upon establishment of the VGKC antibody radioimmunoassay. This radioimmunoassay detected serum or cerebrospinal fluid autoantibodies that precipitated iodinated α-DTX. Hence, these autoantibodies were originally thought to bind VGKCs,2 3 and some reports even showed IgG from patients binding directly to oocyte or HEK293T-cell-expressed VGKCs.2–4 During this series of molecular observations, VGKC antibodies were also identified in patients with Morvan’s syndrome (neuromyotonia with characteristic central nervous system manifestations)4 and limbic encephalitis.5–7 Importantly, patients with these syndromes improved markedly following immunotherapy. Overall, these serological discoveries helped to describe and classify a potentially reversible set of autoimmune neurological conditions. Subsequently, these findings were rapidly disseminated through the neurology community. To avoid missing a potentially immunotherapy-responsive condition, VGKC antibodies were requested in patients with a wider spectrum of clinical features. This led to a large number of positive VGKC antibody results, in broad-ranging phenotypes. Many of these syndromes were not immunotherapy-responsive or intuitively immune-mediated. This non-distinctive set of syndromes led us to question how antibodies to a single protein family could cause such a variety of diseases (Figure 1). Figure 1 LGI1 and CASPR2—but not double-negative VGKC—autoantibodies predict characteristic, immunotherapy-responsive syndromes. Pathogenic antibodies (shown in purple) bind to the surface-exposed domains of LGI1 and CASPR2. Also, some autoantibodies against LGI1 bind to the domain which docks with its receptors, a disintegrin and metalloproteases (especially ADAM22/23). Autoantibodies that bind extracellular protein domains are pathogenic, manifesting with characteristic clinical syndromes including faciobrachial dystonic seizures, limbic encephalitis and neuromyotonia. Both LGI1- and CASPR2-antibody mediated syndromes classically affect elderly men in their sixth decade, who improve markedly with immunotherapies. HLA-DRB1*07:01 is strongly linked to patients with LGI1 antibodies, and HLA-DRB1*11:01 to patients with CASPR2 antibodies. The non-pathogenic antibodies (shown in red) have been shown to bind the intracellular domain of VGKCs, and some bind the I125-α-dendrotoxin (α-DTX) used in the original VGKC radioimmunoassays. The targets of other double-negative antibodies are unknown, but likely to be other intracellular epitopes. Double-negative VGKC antibodies are found in a wide array of clinical syndromes, including epilepsies, dementias and primary psychiatric conditions, which span wide age ranges and lack either a clear immunotherapy response or a specific HLA association. CASPR2, contactin-associated protein like-2; HLA, human leukocyte antigen; LGI1, leucine-rich glioma-inactivated 1; VGKC, voltage-gated potassium channel. SPLITTING THE COMPLEX: IDENTIFICATION OF LGI1 AND CASPR2, AND CLINICAL ASSOCIATIONS Biochemical interrogation of proteins complexed to VGKCs identified that leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein like-2 (CASPR2) were the actual targets of patient autoantibodies in the immunotherapy-responsive syndromes: limbic encephalitis, Morvan’s syndrome and neuromyotonia.8 9 Also, a few patients had contactin-2 antibodies.8 Crucially, the extracellular-exposed domains of these proteins were the direct antigenic epitopes. Table 1 describes the characteristics of these molecules, plus the LGI1 receptors ADAM22 and 23. VIEW INLINE VIEW POPUP Table 1 Molecular characteristics of LGI1, CASPR2, and associated proteins LGI1 is a secreted neuronal protein, known to link pre- and post-synaptic terminals, akin to a molecular scaffold.19 Patients with LGI1 antibodies are typically aged over 60, with a 2:1 male to female predominance. LGI1 antibodies are prominent in patients with limbic encephalitis, found in many with Morvan’s syndrome, and in a few with neuromyotonia.8 9 23 In addition, around 50% of patients with LGI1-antibodies show a highly specific seizure semiology—termed faciobrachial dystonic seizures.24 Faciobrachial dystonic seizures typically begin before the onset of the cognitive impairment that characterises limbic encephalitis and are largely resistant to antiseizure medications but respond well to immunotherapies, often within a few days. They provide an excellent example of a distinctive phenotype with a robust response to immunotherapies whose characteristics translate to the other frequent focal seizure semiologies in patients with LGI1-antibodies.24 25 CASPR2 is a neurexin family protein with a large extracellular domain. Patients with CASPR2 autoantibodies are very often elderly males (Table 2). CASPR2 antibody–positive patients often have neuromyotonia or Morvan’s syndrome, and some have forms of limbic encephalitis as well as neuropathic pain syndromes. All typically respond to immunotherapy. Also, in patients with neuromyotonia and, especially, Morvan’s syndrome there is an association with tumours, typically thymomas.8 9 23 Importantly, LGI1 or CASPR2 specificities are rare outside of these syndromes. Taken together, LGI1 and CASPR2 antibodies have strong and specific clinical associations, and unequivocal clinical value in accurately detecting treatable syndromes. FEATURES ASSOCIATED WITH DOUBLE-NEGATIVE VGKC ANTIBODIES More recently, data from several groups have clarified the clinical relevance of double-negative VGKC antibodies, that is, VGKC antibodies without LGI1 or CASPR2 reactivities.26–28 Frequency and highly heterogeneous clinical features In the largest such series, testing of ~100 000 samples yielded 3910 (~4%) samples with VGKC antibodies. Only 256 of these 3910 (6.5%) showed concomitant LGI1 or CASPR2 reactivities.29 Other studies report comparable rates of LGI1/CASPR2 antibodies amongst VGKC-antibody positive results: ~20% in adults30 and, in children, <5%:31 both observations are consistent with our unpublished experience. Hence, double-negative VGKC antibodies appear to account for ~85% of routine VGKC antibody requests. Is there any clinical utility in detecting these common antibodies? The data suggest not. First, double-negative VGKC-complex autoantibodies occur in ~5% of healthy controls, complicating their interpretation especially with widespread testing.2 6 26 28 Second, and in marked contrast to the well-defined clinical phenotypes associated with LGI1 and CASPR2 autoantibodies (Figure 1, Table 2), double-negative VGKC antibodies associate with a constellation of syndromes without age or gender predilection. These range from epilepsies, non-neuropathic pain, Alzheimer’s disease, peripheral neuropathy and headache, to primary psychiatric syndromes and leptomeningeal metastasis.26–28 32 Hence, it appears that double-negative VGKC antibodies have limited clinical specificity. Third, the VGKC antibody titre is not a clinically reliable measure: double-negative VGKC antibodies can occur at very high titres (eg 400–3000 pM). Therefore, the titre itself does not help in identifying LGI1 or CASPR2 specificity.26 27 29 30 33 Indeed, in clinical practice the concept of a ‘clinically relevant’ VGKC antibody titre has created many misdiagnoses, often where finding the antibody has overruled the clinical diagnosis.33–36 VIEW INLINE VIEW POPUP Table 2 Comparisons of autoantibodies against LGI1, CASPR2, and the double-negative VGKC antibodies Immunotherapy response Patients with LGI1 and CASPR2 autoantibodies respond strikingly to immunotherapy, with improvements in 96%–100% of patients with LGI1 antibodies and 86%–100% with CASPR2 antibodies.24–26 29 Hence, detecting LGI1 and CASPR2 antibodies has clear therapeutic importance. In marked contrast, patients with double-negative VGKC antibodies respond poorly to immunotherapy, with response rates equal to those of placebo studies, or to rates observed from patients with negative VGKC test results.26 28 44 Serological observations: intracellular binding and non-pathogenicity As our clinical suspicions increasingly indicated that double-negative antibodies had little clinical relevance, we predicted that studying their antigenic targets would offer clinically-relevant insights.28 First, we observed that the double-negative serum IgGs did not bind to any surface determinants expressed on live hippocampal neurons. Second, no double-negative IgGs bound to the extracellular domain of HEK293T cell surface expressed VGKCs. However, in this preparation, around one-third bound to intracellular aspects of the Kv1.1/1.2/1.6 subunits.8 28 Finally, a small proportion of the double-negative VGKC antibody sera directly bound the non-mammalian α-DTX employed in the radioimmunoassay. Taken together, these findings established that double-negative VGKC antibodies often bind targets that, in vivo in humans, are inaccessible or unavailable, thus mitigating their pathogenic potential. By contrast, LGI1 or CASPR2 antibodies typically show robust cell-surface reactivity to the native, mammalian target (Figure 2) and strong data support their in vitro and in vivo functionality. For example, LGI1 antibodies can disrupt interactions between LGI1 and its receptors ADAM22/23, internalise the LGI1–ADAM complex and trigger neuronal hyperexcitability and memory deficits in vivo passive transfer models.20 21 25 42 There is also clear evidence supporting the pathogenicity of CASPR2 antibodies with rodent passive transfer reproducing human pain manifestations, and evidence that the antibodies can disrupt CASPR2 interactions with contactin-2.22 43 Figure 2 Cell surface-reactive autoantibodies measured by live cell-based assays or live hippocampal neuron binding. A. LGI1 antibody live cell-based assay. Serum from a patient with LGI1 antibodies binds to the surface of live LGI1-expressing cells (top row) but healthy control sera (bottom row) do not bind these cells. LGI1 tagged to enhanced green fluorescent protein (LGI1-EGFP, green) is expressed on the surface of live HEK293T cells; detected with anti-human IgG secondary autoantibodies (red); DAPI nuclear staining (blue). Images taken at ×40 magnification. B. Live hippocampal neuron assay. Human IgG autoantibodies (green) from a CASPR2 autoantibody-positive patient stain the surface of live hippocampal neurons (red, stained with an antibody against MAP2, microtubule-associated protein 2). Punctate green staining is observed along the dendrites and neuronal cell body. There is no neuronal reactivity when live hippocampal neurons are stained with healthy control serum (right). DAPI nuclear staining (blue). Images taken at ×63 magnification. In cases with seronegative syndromes, where the clinical picture is characteristic but the patient has negative results for the standard panel of known autoantibodies (LGI1, CASPR2, NMDA-R, GABAA/B-R, etc), live neuronal testing is an available diagnostic test which can be requested at our specialist laboratory. In this assay, any neuronal reactivity demonstrated by the serum/CSF, as above, strongly suggests the presence of a novel neuronal surface antibody and allows identification of novel antigenic targets. CASPR2, contactin-associated protein like-2; CSF, cerebrospinal fluid; DAPI, 4′,6-diamidino-2-phenylindole; GABAA/BR, gamma-amino butyric acid A/B receptor; LGI1, leucine-rich glioma-inactivated 1; NMDA-R, N-methyl-D-aspartate receptor. Genetic associations Recently, a very strong immunogenetic basis was established for the diseases associated with LGI1 and CASPR2 antibodies.32 40 41 45 HLA-DRB1*07:01 and HLA-DRB1*11:01 were found to be over-represented in patients with LGI1 autoantibodies (~95% vs ~25% in healthy controls) and in those with CASPR2 autoantibodies (~50% vs ~10% in healthy controls), respectively. Extended haplotype associations were also observed.32 Moreover, the few patients with both LGI1 and CASPR2 antibodies carried yet another set of distinct HLA alleles.32 By contrast, there were no distinct HLA associations in patients with intracellular VGKC antibodies.32 Our recent clinical observations suggest the HLA analyses may form a useful adjunct to complement clinico-serological diagnoses (Irani and Waters, unpublished, 2020). THE TEST MATTERS: LIVE CELL-BASED ASSAYS AND THE LIMITED SENSITIVITY OF VGKC ANTIBODY TESTING Our understanding of test systems for detecting pathogenic antibodies has evolved. As only antibodies that can ‘see’ their targets in vivo have clear pathogenic potential, we prefer to use ‘live’ cell-based assays that present only extracellular domains of antibody targets. These avoid the detection of non-pathogenic species and the potential for contamination by fixative, which can alter target epitopes and permeabilise cells.46 Many diagnostic centres use fixed cell-based assays, largely for convenience. However, live testing remains biologically intuitive; it has a higher sensitivity and specificity, and can resolve samples that routine commercial kit testing assess as indeterminate.46–49 Such target-specific cell-based assays, where individual proteins are selectively expressed on the surface of live cells without detergent or fixative, are possible across the range of surface-directed autoantibodies, including LGI1 and CASPR2⇓ (Figure 2A).8 These live cell-based assays have identified up to 15% of samples from patients with immunotherapy-responsive illnesses that have detectable LGI1 or CASPR2 antibodies but no VGKC-complex antibodies.50 51 Hence, direct LGI1 and CASPR2 antibody testing should be performed as first-line testing, not as a second-line reflexive test after a positive VGKC antibody result. SO, IS THERE ANY VALUE IN VGKC ANTIBODY TESTING? The above evidence strongly argues against VGKC antibody testing in routine clinical practice. Yet, these antibodies may have some limited value in the research setting. First, cohorts with positive VGKC antibodies may have high rates of malignancy (12%–47%), suggesting VGKC antibody as an onconeural marker.33–36 However, such findings probably reflect an inherent clinical referral bias. Indeed, other reports suggest comparable tumour rates among patients with double-negative VGKC antibodies and matched VGKC-negative controls.26 Second, swine abattoir workers frequently have detectable, typically double negative, VGKC antibodies.39 While this is only rarely a vocational issue, it suggests that inhaled aerosolised brain tissue may be a model to study human autoimmunisation, although with resultant non-pathogenic reactivities. Interestingly, this observation suggests an inherent liability to a loss of immune tolerance against VGKC-complexed proteins may account for the high rates of VGKC antibodies occurring as secondary effects of multiple disparate disease processes.28 52 53 Finally, some observations suggest double-negative VGKC antibodies may co-exist with cell-surface autoantibodies.23 30 54 In this clinical context, the surface-directed antibody is likely to be directly pathogenic. Indeed, the high reported rates of VGKC antibodies in some diseases, such as neuromyotonia, may provide a lead for identification of samples with co-existent pathogenic reactivities. CONCLUSIONS: A CALL TO CHANGE CLINICAL PRACTICE In summary, double-negative VGKC antibodies usually target intracellular epitopes and lack pathogenic potential. They form the majority of the results in routine VGKC antibody testing. Importantly, and in stark contrast to finding antibodies directed against LGI1 and CASPR2, they do not predict a response to immunotherapy. Their detection in heterogeneous, often non-immune, clinical disorders at similar rates to healthy controls casts doubt on their detection in classic autoimmune scenarios. For example, this background rate is likely to the explain the common query that “my patient with Guillain–Barré syndrome / limbic encephalitis / Lambert–Eaton myasthenic syndrome has a double-negative VGKC of 1312 pM”. Further, the VGKC antibody radioimmunoassay is not an effective screening test for the key pathogenic autoantibody species as it misses ~15% of LGI1 or CASPR2 antibodies. Taken together, the evidence from multiple international groups suggests there are no longer clinical reasons to test for VGKC antibodies. Stopping this test will reduce clinically irrelevant results, improve diagnostic accuracy and limit the use of unnecessary, potentially toxic, immunotherapies in patients. Most ‘non-immune’ syndromes referred to our specialist centre are associated with ‘double-negative’ VGKC antibody results. Yet, several laboratories continue to offer VGKC antibody testing, sometimes as a screening test to prompt LGI1 and CASPR2 antibody testing. Presenting local laboratories with the data and conclusions herein should encourage a change in testing regimens, towards patient benefit. While this may be one of the final articles regarding VGKC antibody testing, work on LGI1 and CASPR2 antibodies will probably continue for several years, as the underlying immunology, autoantibody biology, and the molecular effector pathways still require clarification. These outputs could all impact on patient care by offering opportunities towards highly focussed examples of precision medicine. Nevertheless, for now, the evidence presented above should offer a marked improvement to the routine care of many patients each year. Key points Patients with pathogenic LGI1 or CASPR2 autoantibodies show distinct clinical syndromes and excellent responses to immunotherapy. In contrast, those with non-pathogenic VGKC antibodies but with no LGI1 or CASPR2 reactivities have heterogeneous clinical syndromes and poor responses to therapy. Testing for VGKC antibodies is deleterious for patient care and should cease. By contrast, directly testing for LGI1 and CASPR2 antibodies can offer clear clinical benefit, with an accurate diagnosis and the chance of disease-modifying therapies. Acknowledgments SRI is supported by the Wellcome Trust (104079/Z/14/Z), The UCB–Oxford University Alliance, BMA Research Grants—Vera Down (2013) and Margaret Temple (2017), Epilepsy Research UK (P1201) and by the Fulbright UK–US commission (MS-Research Society Award). The research was funded/supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC; The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health). PW is supported by the UK NMO commissioning group. We thank Dr Antonio Berretta for his contribution to live neuronal staining images used within figure 2. REFERENCES ↵Sinha S, Newsom-Davis J, Mills K, et al. Autoimmune aetiology for acquired neuromyotonia (Isaac’s syndrome). Lancet 1991;13:75–7. doi: 10.1016/0140-6736(91)90073-XOpenUrl ↵Shillito P, Molenaar PC, Vincent A, et al. Acquired neuromyotonia: evidence for autoantibodies directed against K+ channels of peripheral nerves. Ann Neurol 1995;38:714–22. ↵Hart IK, Waters C, Vincent A, et al. Autoantibodies detected to expressed K+ channels are implicated in neuromyotonia. Ann Neurol 1997;41:238–46. doi: 10.1002/ana.410410215 ↵Liguori R, Vincent A, Clover P. Morvan’s syndrome: peripheral and central nervous system and cardiac involvement with antibodies to voltage-gated potassium channels. Brain 2001;124:2417–26. doi: 10.1093/brain/124.12.2417 ↵Pozo-Rosich P, Clover L, Saiz A. Voltage-gated potassium channel antibodies in limbic encephalitis. Ann Neurol 2003;54:530–5. doi: 10.1002/ana.10713 ↵Vincent A, Buckley C, Schott JM, et al. Potassium channel antibody‐associated encephalopathy: a potentially immunotherapy‐responsive form of limbic encephalitis. Brain 2004;127:701–12. doi: 10.1093/brain/awh077 ↵Thieben MJ, Lennon VA, Boeve BF, et al. Potentially reversible autoimmune limbic encephalitis with neuronal potassium channel antibody. Neurology 2004;62:1177–82. doi: 10.1212/01.WNL.0000122648.19196.02OpenUrlCrossRefPubMed ↵Irani SR, Alexander S, Waters P, et al. Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan’s syndrome and acquired neuromyotonia. Brain 2010;133:2734–48. doi: 10.1093/brain/awq213 ↵Lai M, Huijbers MG, Lancaster E, et al. Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series. Lancet Neurol 2010;9:776–85. doi: 10.1016/S1474-4422(10)70137-X Kalachikov S, Evgrafov O, Ross B, et al. Mutations in LGI1 cause autosomal-dominant partial epilepsy with auditory features. Nat Genet 2002;30:335–41. doi: 10.1038/ng832 Rodenas-Cuadrado P, Pietrafusa N, Francavilla T, et al. Characterisation of CASPR2 deficiency disorder - a syndrome involving autism, epilepsy and language impairment. BMC medical genetics. BMC Med Genet 2016;1:1–7.OpenUrl Muona M, Fukata Y, Anttonen A-K, et al. Dysfunctional ADAM22 implicated in progressive encephalopathy with cortical atrophy and epilepsy. Neurol Genet 2016;2:e46. doi: 10.1212/NXG.0000000000000046 Stogmann E, Reinthaler E, ElTawil S, et al. Autosomal recessive cortical myoclonic tremor and epilepsy: association with a mutation in the potassium channel associated gene CNTN2. Brain 2013;136:1155–60. doi: 10.1093/brain/awt068 Sagane K, Ohya Y, Hasegawa Y, et al. Metalloproteinase-like, disintegrin-like, cysteine-rich proteins MDC2 and MDC3: novel human cellular disintegrins highly expressed in the brain. Biochem J 1998;334:93–8. doi: 10.1042/bj3340093 Savvaki M, Panagiotaropoulos T, Stamatakis A, et al. Impairment of learning and memory in TAG-1 deficient mice associated with shorter CNS internodes and disrupted juxtaparanodes. Mol Cell Neurosci 2008;39:478–90. doi: 10.1016/j.mcn.2008.07.025 Poliak S, Salomon D, Elhanany H, et al. Juxtaparanodal clustering of shaker-like K+ channels in myelinated axons depends on caspr2 and TAG-1. J Cell Biol 2003;162:1149–60. doi: 10.1083/jcb.200305018 Fukata Y, Lovero KL, Iwanaga T, et al. Disruption of LGI1-linked synaptic complex causes abnormal synaptic transmission and epilepsy. Proc Natl Acad Sci USA 2010;107:3799–804. doi: 10.1073/pnas.0914537107 Sagane K, Ishihama Y, Sugimoto H. LGI1 and LGI4 bind to ADAM22, ADAM23 and ADAM11. Int J Biol Sci 2008;4:387–96. doi: 10.7150/ijbs.4.387 ↵Schulte U, Thumfart J-O, Klöcker N, et al. The epilepsy-linked Lgi1 protein assembles into presynaptic Kv1 channels and inhibits inactivation by Kvβ1. Neuron 2006;49:697–706. doi: 10.1016/j.neuron.2006.01.033 ↵Petit-Pedrol M, Sell J, Planagumà J, et al. LGI1 antibodies alter Kv1.1 and AMPA receptors changing synaptic excitability, plasticity and memory. Brain 2018; Nov 1. 141: 3144–59.OpenUrl ↵Ramberger M, Berretta A, MM TJ, et al. Distinctive binding properties of patient-derived monoclonal LGI1-autoantibodies determine pathogenicity. Brain 2020; doi: 10.1093/brain/awaa104 ↵Saint-Martin M, Joubert B, Pellier-Monnin V, et al., Contactin-associated protein-like 2, a protein of the neurexin family involved in several human diseases. Eur J Neurosci 2018;48:1906–23. doi: 10.1111/ejn.14081doi: 10.1111/ejn.14081OpenUrlCrossRefPubMed ↵Irani SR, Pettingill P, Kleopa KA, et al. Morvan syndrome: clinical and serological observations in 29 cases. Ann Neurol 2012;72:241–55. doi: 10.1002/ana.23577OpenUrlCrossRefPubMed ↵Irani SR, Michell AW, Lang B, et al. Faciobrachial dystonic seizures precede LGI1 antibody limbic encephalitis. Ann Neurol 2011;69:892–900. doi: 10.1002/ana.22307 ↵Thompson J, Bi M, Murchison AG, et al. The importance of early immunotherapy in patients with faciobrachial dystonic seizures. Brain 2017;141:348–56. doi: 10.1093/brain/awx323OpenUrl ↵van Sonderen A, Schreurs MWJ, de Bruijn MAAM, et al. The relevance of VGKC positivity in the absence of LGI1 and Caspr2 antibodies. Neurology 2016;86:1692–9.OpenUrlCrossRefPubMed ↵Olberg H, Haugen M, Storstein A, et al. Neurological manifestations related to level of voltage-gated potassium channel antibodies. J Neurol Neurosurg Psychiatry 2013;84:941–3. doi: 10.1136/jnnp-2013-305252OpenUrlFREE Full Text ↵Lang B, Makuch M, Moloney T, et al. Intracellular and non-neuronal targets of voltage-gated potassium channel complex antibodies. J Neurol Neurosurg Psychiatry2017;88:353–61. doi: 10.1136/jnnp-2016-314758 ↵Gadoth A, Pittock SJ, Dubey D, et al. Expanded phenotypes and outcomes among 256 LGI1/CASPR2-IgG-positive patients. Ann Neurol2017;82:79–92. doi: 10.1002/ana.24979OpenUrlCrossRefPubMed ↵Klein CJ, Lennon VA, Aston PA, et al. Insights from LGI1 and CASPR2 potassium channel complex autoantibody subtyping. JAMA Neurol 2013;70:229–34. doi: 10.1001/jamaneurol.2013.592OpenUrl ↵Chiriboga ASL, Klein C, Zekeridou A, et al. LGI1 and CASPR2 neurological autoimmunity in children. Ann Neurol 2018;84:473–80.OpenUrl ↵Binks S, Varley J, Lee W, et al. Distinct HLA associations of LGI1 and CASPR2-antibody diseases. Brain 2018;141:2263–71. doi: 10.1093/brain/awy109OpenUrlPubMed ↵Paterson R, Zandi M, Armstrong R, et al. Clinical relevance of positive voltage-gated potassium channel (VGKC)-complex antibodies: experience from a tertiary referral centre. J Neurol Neurosurg Psychiatry 2014;85:625–30. doi: 10.1136/jnnp-2013-305218 ↵Huda S, Wong SH, Pettingill P, et al. An 11-year retrospective experience of antibodies against the voltage-gated potassium channel (VGKC) complex from a tertiary neurological centre. J Neurol 2014;262:418–24. doi: 10.1007/s00415-014-7588-0OpenUrl ↵Jammoul A, Shayya L, Mente K, et al. Clinical utility of seropositive voltage-gated potassium channel: complex antibody. Neurol Clin Pract Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 2016;6:409–18. ↵Tan KM, Lennon VA, Klein CJ, et al. Clinical spectrum of voltage-gated potassium channel autoimmunity. Neurology 2008;70:1883–90.OpenUrlCrossRefPubMed Lancaster E, Huijbers MGM, Bar V, et al. Investigations of caspr2, an autoantigen of encephalitis and neuromyotonia. Ann Neurol 2011;69:303–11. doi: 10.1002/ana.22297 Dahm L, Ott C, Steiner J, et al. Seroprevalence of autoantibodies against brain antigens in health and disease. Ann Neurol 2014;76:82–94. doi: 10.1002/ana.24189OpenUrlCrossRefPubMed ↵Meeusen JW, Klein CJ, Pirko I, et al. Potassium channel complex autoimmunity induced by inhaled brain tissue aerosol. Ann Neurol 2012;71:417–26. doi: 10.1002/ana.22674OpenUrlPubMed ↵Kim T-J, Lee S-T, Moon J, et al. Anti-LGI1 encephalitis is associated with unique HLA subtypes. Ann Neurol 2017;81:183–92.OpenUrl ↵Mueller SH, Färber A, Prüss H, et al. Genetic predisposition in anti-LGI1 and anti-NMDA receptor encephalitis. Ann Neurol 2018;83:863–9. doi: 10.1002/ana.25216OpenUrl ↵Ohkawa T, Fukata Y, Yamasaki M, et al. Autoantibodies to epilepsy-related LGI1 in limbic encephalitis neutralize LGI1-ADAM22 interaction and reduce synaptic AMPA receptors. J Neurosci 2013;33:18161–74. doi: 10.1523/JNEUROSCI.3506-13.2013 ↵Dawes JM, Weir GA, Middleton SJ, et al. Immune or genetic-mediated disruption of CASPR2 causes pain hypersensitivity due to enhanced primary afferent excitability. Neuron 2018;97:806–22. doi: 10.1016/j.neuron.2018.01.033OpenUrlCrossRefPubMed ↵Bittar C, Nascimento OJM, Placebo and nocebo effects in the neurological practice. Arq Neuro-Psiquiatr 2015;73:58–63. doi: 10.1590/0004-282X20140180OpenUrl ↵van Sonderen A, Roelen DL, Stoop JA, et al. Anti-LGI1 encephalitis is strongly associated with HLA-DR7 and HLA-DRB4. Ann Neurol 2017;81:193–8.OpenUrlPubMed ↵Tea F, Lopez JA, Ramanathan S, et al. Characterization of the human myelin oligodendrocyte glycoprotein antibody response in demyelination. Acta Neuropathol Commun 2019;7:1451–22.OpenUrl ↵McCracken L, Zhang J, Greene M, et al. Improving the antibody-based evaluation of autoimmune encephalitis. Neurol Neuroimmunol Neuroinflamm 2017;4:e404–7. doi: 10.1212/NXI.0000000000000404 ↵Waters PJ, Komorowski L, Woodhall M, et al. A multicenter comparison of MOG-IgG cell-based assays. Neurology 2019;92:e1250–5.OpenUrl ↵Waters P, Reindl M, Saiz A, et al. Multicentre comparison of a diagnostic assay: aquaporin-4 antibodies in neuromyelitis optica. J Neurol Neurosurg Psychiatry 2016;87:1005–15. doi: 10.1136/jnnp-2015-312601 ↵Irani SR, Stagg CJ, Schott JM, et al. Faciobrachial dystonic seizures: the influence of immunotherapy on seizure control and prevention of cognitive impairment in a broadening phenotype. Brain 2013;136:3151–62. doi: 10.1093/brain/awt212 ↵Becker EBE, Zuliani L, Pettingill R, et al. Contactin-associated protein-2 antibodies in non-paraneoplastic cerebellar ataxia. J Neurol Neurosurg Psychiatry 2012;83:437–40. doi: 10.1136/jnnp-2011-301506 ↵Jones M, Odunsi S, Plessis Du D, et al. Gerstmann-straüssler-scheinker disease: novel PRNP mutation and VGKC-complex antibodies. Neurology 2014;82:2107–11.OpenUrlCrossRefPubMed ↵Rossi M, Mead S, Collinge J, et al. Neuronal antibodies in patients with suspected or confirmed sporadic Creutzfeldt-Jakob disease. J Neurol Neurosurg Psychiatry 2015;86:692–4. doi: 10.1136/jnnp-2014-308695 ↵Pettingill P, Kramer HB, Coebergh JA, et al. Antibodies to GABAA receptor α1 and γ2 subunits: clinical and serologic characterization. Neurology 2015;84:1233–41.OpenUrlCrossRefPubMed
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Altered EEG markers of synaptic plasticity in a human model of NMDA receptor deficiency: anti-NMDA receptor encephalitis | medRxiv

medRxiv - The Preprint Server for Health Sciences...
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In search of lost time from "Demonic Possession" to anti-N-methyl-D-aspartate receptor encephalitis

In search of lost time from "Demonic Possession" to anti-N-methyl-D-aspartate receptor encephalitis | AntiNMDA | Scoop.it
In search of lost time from "Demonic Possession" to anti-N-methyl-D-aspartate receptor encephalitis...
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Anti-CASPR2 antibody associated encephalitis with anosmia and demyelinating pseudotumor: A case report

Anti-CASPR2 antibody associated encephalitis with anosmia and demyelinating pseudotumor: A case report | AntiNMDA | Scoop.it
A 20-year-old female presented with fine motor deficits and visual field defect was
admitted to our hospital. CSF tests for autoimmune encephalitis antibodies and onconeuronal
antibodies were unremarkable.
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What's happening in Neurology® Neuroimmunology & Neuroinflammation | Neurology

What's happening in Neurology® Neuroimmunology & Neuroinflammation | Neurology | AntiNMDA | Scoop.it
Articles appearing in the March 2020 issue Clinical approach to the diagnosis of autoimmune encephalitis in the pediatric patient Objective Autoimmune encephalitis (AE) is an important and treatable cause of acute encephalitis. Diagnosis of AE in a developing child is challenging because of overlap in clinical presentations with other diseases and complexity of normal behavior changes. Existing diagnostic criteria for adult AE require modification to be applied to children, who differ from adults in their clinical presentations, paraclinical findings, autoantibody profiles, treatment response, and long-term outcomes. Methods A subcommittee of the Autoimmune Encephalitis International Working Group collaborated through conference calls and email correspondence to consider the pediatric-specific approach to AE. The subcommittee reviewed the literature of relevant AE studies and sought additional input from other expert clinicians and researchers. Results Existing consensus criteria for adult AE were refined for use in children. Provisional pediatric AE classification criteria and an algorithm to facilitate early diagnosis are proposed. There is also discussion about how to distinguish pediatric AE from conditions within the differential diagnosis. Conclusions Diagnosing AE is based on the combination of a clinical history consistent with pediatric AE and supportive diagnostic testing, which includes but is not dependent on antibody testing. The proposed criteria and algorithm require validation in prospective pediatric cohorts. NPub.org/N2/9512a Intrathecal B-cell activation in LGI1 antibody encephalitis Objective To study intrathecal B-cell activity in leucine-rich, glioma-inactivated 1 (LGI1) antibody encephalitis. In patients with LGI1 antibodies, the lack of CSF lymphocytosis or oligoclonal bands and serum-predominant LGI1 antibodies suggests a peripherally initiated immune response. However, it is unknown whether B cells within the CNS contribute to the ongoing pathogenesis of LGI1 antibody encephalitis. Methods Paired CSF and peripheral blood (PB) mononuclear cells were collected from 6 patients with LGI1 antibody encephalitis and 2 patients with other neurologic diseases. Deep B-cell immune repertoire sequencing was performed on immunoglobulin heavy chain transcripts from CSF B cells and sorted PB B-cell subsets. In addition, LGI1 antibody levels were determined in CSF and PB. Results Serum LGI1 antibody titers were on average 127-fold higher than CSF LGI1 antibody titers. Yet, deep B-cell repertoire analysis demonstrated a restricted CSF repertoire with frequent extensive clusters of clonally related B cells connected to mature PB B cells. These clusters showed intensive mutational activity of CSF B cells, providing strong evidence for an independent CNS-based antigen-driven response in patients with LGI1 antibody encephalitis but not in controls. Conclusions Our results demonstrate that intrathecal immunoglobulin repertoire expansion is a feature of LGI1 antibody encephalitis and suggests a need for CNS-penetrant therapies. NPub.org/N2/9512b Most-Read Articles As of July 21, 2020 Aquaporin-4 autoimmunity Zekeridou and V.A. Lennon. 2015;2:e110. doi.org/10.1212/NXI.0000000000000110 MOG cell-based assay detects non-MS patients with inflammatory neurologic disease Patrick Waters, Mark Woodhall, Kevin C. O'Connor, et al. 2015;2:e89. doi.org/10.1212/NXI.0000000000000089 Increased frequency of anti-Ma2 encephalitis associated with immune checkpoint inhibitors Alberto Vogrig, Marine Fouret, Bastien Joubert, et al. 2019;6:e604. doi.org/10.1212/NXI.0000000000000604 Next-generation sequencing in neuropathologic diagnosis of infections of the nervous system Steven L. Salzberg, Florian P. Breitwieser, Anupama Kumar, et al. 2016;3:e251. doi.org/10.1212/NXI.0000000000000251 Does time equal vision in the acute treatment of a cohort of AQP4 and MOG optic neuritis? Hadas Stiebel-Kalish, Mark Andrew Hellmann, Michael Mimouni, et al. 2019;6:e572. doi.org/10.1212/NXI.0000000000000572 © 2020 American Academy of Neurology
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Anti-CASPR2 clinical phenotypes correlate with HLA and immunological features | Journal of Neurology, Neurosurgery & Psychiatry

Neuro-inflammation Original research Anti-CASPR2 clinical phenotypes correlate with HLA and immunological features http://orcid.org/0000-0001-5958-3288Sergio Muñiz-Castrillo1,2, Bastien Joubert1,2, Mad-Hélénie Elsensohn3,4, Anne-Laurie Pinto1,2, Margaux Saint-Martin1,2, http://orcid.org/0000-0002-3652-7061Alberto Vogrig1,2, Géraldine Picard1,2, Véronique Rogemond1,2, Valérie Dubois5, Ryad Tamouza6,7, Delphine Maucort-Boulch3,4, Jérôme Honnorat1,2 French National Reference Center on Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hôpital Neurologique, Hospices Civils de Lyon, Bron, France SynatAc Team, Institut NeuroMyoGène, INSERM U1217/CNRS UMR 5310, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France Department of Biostatistics-bioinformatics, Hospices Civils de Lyon, Lyon, France Laboratory of Biometrics and Evolutionary Biology, Biostatistics Team, CNRS UMR5558, Université de Lyon, Université Claude Bernard Lyon 1, Villeurbanne, France HLA Laboratory, French Blood Service, EFS Auvergne-Rhône-Alpes, Lyon, France Mondor Institute for Biomedical Research, INSERM U955, Université de Paris-Est-Créteil, Créteil, France Department of Psychiatry, Hôpitaux Universitaires Henri Mondor, Créteil, France Correspondence to Professor Jérôme Honnorat, Centre de Référence pour les Syndromes Neurologiques Paranéoplasiques, Centre Hospitalier Universitaire de Lyon, Lyon, France; jerome.honnorat{at}chu-lyon.fr Abstract Objective Antibodies against contactin-associated protein-like 2 (CASPR2-Abs) have been described in acquired neuromyotonia, limbic encephalitis (LE) and Morvan syndrome (MoS). However, it is unknown whether these constitute one sole spectrum of diseases with the same immunopathogenesis or three distinct entities with different mechanisms. Methods A cluster analysis of neurological symptoms was performed in a retrospective cohort of 56 CASPR2-Abs patients. In parallel, immunological features and human leucocyte antigen (HLA) were studied. Results Cluster analysis distinguished patients with predominant limbic symptoms (n=29/56) from those with peripheral nerve hyperexcitability (PNH; n=27/56). In the limbic-prominent group, limbic features were either isolated (LE/−; 18/56, 32.1%), or combined with extralimbic symptoms (LE/+; 11/56, 19.6%). Those with PNH were separated in one group with severe PNH and extralimbic involvement (PNH/+; 16/56, 28.6%), resembling historical MoS descriptions; and one group with milder and usually isolated PNH (PNH/−; 11/56, 19.6%). LE/− and LE/+ patients shared immunogenetic characteristics demonstrating a homogeneous entity. HLA-DRB1*11:01 was carried more frequently than in healthy controls only by patients with LE (94.1% vs 18.3%; p=1.3×10−10). Patients with LE also had serum titres (median 1:40 960) and rates of cerebrospinal fluid positivity (93.1%) higher than the other groups (p<0.05). Conversely, DRB1*11:01 association was absent in PNH/+ patients, but only they had malignant thymoma (87.5%), serum antibodies against leucine-rich glioma-inactivated 1 protein (66.7%) and against netrin-1 receptor deleted in colorectal carcinoma (53.8%), and myasthenia gravis (50.0%). Interpretation Symptoms’ distribution supports specific clinical phenotypes without overlap between LE and MoS. The distinct immunogenetic characteristics shared by all patients with LE and the particular oncological and autoimmune associations of MoS suggest two very different aetiopathogenesis. View Full Text Statistics from Altmetric.com View Full Text Footnotes SM-C and BJ contributed equally. Contributors Conception and design of the study and drafting the manuscript and figures: SM-C, BJ and JH. Acquisition and analysis of data: all authors. Funding This study is supported by research grants from ANR (ANR-14-CE15-0001 MECANO) and Fondation pour la recherche medicale DQ20170336751. This work has been developed within the BETPSY project, which is supported by a public grant overseen by the French National Research Agency (ANR), as part of the second ‘Investissements d'Avenir’ program (reference ANR-18-RHUS-0012). SM-C is supported by a research a grant from Fundación Alfonso Martín Escudero (Spain). Competing interests None declared. Patient consent for publication Not required. Ethics approval The Institutional Review Board of Université Claude Bernard Lyon 1 and Hospices Civils of Lyon approved the study (ICARE NCT-04106596). Provenance and peer review Not commissioned; externally peer reviewed. Data availability statement Data reported in this manuscript are available within the article. More information regarding the data is available from the corresponding author on reasonable request. Individual data will not be shared to conform to the privacy statement signed by the patients. 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)) 2020. No commercial re-use. See rights and permissions. Published by BMJ. Linked Articles Editorial commentary Sophie Binks Sarosh R Irani Journal of Neurology, Neurosurgery & Psychiatry 2020; 91 1033-1034 Published Online First: 10 Jul 2020. doi: 10.1136/jnnp-2020-323457 Read the full text or download the PDF: Subscribe Log in
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Immune Checkpoint Inhibitor Associated Autoimmune Encephalitis - ScienceDirect

Immune Checkpoint Inhibitor Associated Autoimmune Encephalitis - ScienceDirect | AntiNMDA | Scoop.it
Immune checkpoint inhibitor (ICI) therapy offers an efficacious and novel way to treat many types of cancer.ICIs upregulate the immune system (specif…...
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Allosteric modulation of NMDA receptors prevents the antibody effects of patients with anti-NMDAR encephalitis | Brain | Oxford Academic

Allosteric modulation of NMDA receptors prevents the antibody effects of patients with anti-NMDAR encephalitis | Brain | Oxford Academic | AntiNMDA | Scoop.it
Abstract. 24(S)-hydroxycholesterol is a potent and selective positive allosteric modulator of NMDA receptors. Mannara et al.show that SGE-301, a synthetic ana...
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Glioblastoma: a mimic of NMDA receptor encephalitis | BMJ Case Reports

Description An Indian woman in her 40s without any medical or psychiatric history presented with a seizure. She had become uncharacteristically quiet before suddenly cackling and banging her hands and feet repeatedly. She developed facial and upper limb dystonic posturing including the extension of one arm. The acute onset, short duration, loss of responsiveness and unilateral dystonic posturing were compatible with a frontal lobe seizure. Several episodes occurred during transfer to the hospital, each lasting 3–30 min. CT head imaging was unremarkable (figure 1). Figure 1 CT head reported as normal. She was discharged and seen in ambulatory care 3 days later. Her lymphocytosis, neutrophilia (described as ‘reactive’) and elevated creatine kinase (10 006 IU/L) were attributed to recent motor seizure activity, despite the broad differential. An electroencephalogram, brain MRI and neurology appointment were arranged, in accordance with the Trust’s ‘first fit’ pathway, which mandates follow-up within 2 weeks, similar to the established National Institute for Health and Care Excellence guidelines.1 Five days later, she was brought back to hospital: she had become increasingly withdrawn, expressing a delusion that ‘someone’ was controlling her. She had stopped recognising her children. On examination, she stared unblinkingly and demonstrated echolalia, echopraxia and stereotyped, repetitive, slow rotation of both wrists. However, she had intervals of apparent lucidity when she was able to answer simple questions. Physical examination was limited by behavioural disturbance, but no other abnormal neurological signs were noted. This syndrome of frontal lobe seizures, acute psychiatric disturbance, unusual mixed hyperkinetic movement disorder and encephalopathy with normal CT brain imaging was suggestive of N-methyl D-aspartate (NMDA) receptor encephalitis. In particular, her movements did not fit more common disorders such as tremor, chorea, myoclonus, dystonia or tics and had a bizarre appearance that experts have found difficult to classify.2 However, an MRI brain revealed a 18×16×17 mm ring-enhancing intra-axial lesion at the frontal pole with extensive surrounding vasogenic oedema and mass effect (figure 2). Given the neutrophilia and lymphocytosis, an infective lesion (particularly a tuberculoma due to her ethnicity) was then considered the foremost differential. Figure 2 MRI head showing a frontal lobe ring-enhancing lesion (left), with extensive surrounding oedema (right). She was transferred to a tertiary neuroscience centre, where investigations interrogating an infectious process were negative, including lumbar puncture, QuantiFERON, cysticercal, HIV and fungal serology. A chest–abdomen–pelvis CT was normal. A brain biopsy revealed a grade IV glioblastoma. She has been treated with levetiracetam, radiotherapy and temozolomide. Her psychiatric and motor symptoms have resolved since treatment and she has been seizure-free for 6 months. We attribute her previous symptoms to ictal activity. Glioblastoma multiforme accounts for >60% of all adult brain tumours.3 Although presentation can vary depending on the location of the lesion, this case is unusual in that the initial presentation was a phenocopy of NMDA encephalitis and fits clinical criteria for diagnosis.4 However, recognised differentials of NMDA receptor encephalitis are varied, including infective, psychiatric, metabolic, neoplastic, paraneoplastic, cerebrovascular and other inflammatory disorders.4 The orbitofrontal location of this lesion explained all the clinical features. The refutation of the top two clinical differentials (NMDA encephalitis and tuberculoma) highlights the importance of having a wide differential diagnosis with unusual neurological presentations. Learning points Simplified pathways for common presentations like ‘first fits’ can streamline services, but without careful history-taking, complex presentations such as this may be inappropriately funnelled into a standardised pathway. A psychiatric presentation with movement disorder and seizure activity may represent a frontal space-occupying lesion, not necessarily NMDA receptor encephalitis.
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Cytokine release syndrome‐associated encephalopathy in patients with COVID‐19 - Perrin - - European Journal of Neurology

Cytokine release syndrome‐associated encephalopathy in patients with COVID‐19 - Perrin - - European Journal of Neurology | AntiNMDA | Scoop.it
Background and purpose Neurological manifestations in coronavirus disease (COVID)‐2019 may adversely affect clinical outcomes. Severe COVID‐19 and uremia are risk factors for neurological complicat...
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Pharmacological Treatment and Early Rehabilitation Outcomes in Pediatric Patients Diagnosed with Anti-NMDA Receptor Encephalitis

To describe the immunotherapy and pharmacological treatments administered to pediatric
patients with NMDARE during inpatient rehabilitation as well as to examine clinical
and demographic variables associated with early functional outcomes.
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Hashimoto's encephalopathy: Follow‐up data from neuropsychology, lumbar puncture, and FDG‐PET - Lagström - 2019 - Clinical Case Reports

Hashimoto's encephalopathy: Follow‐up data from neuropsychology, lumbar puncture, and FDG‐PET - Lagström - 2019 - Clinical Case Reports | AntiNMDA | Scoop.it
Abstract Hashimoto's encephalopathy is a rare disease with nonspecific symptoms, associated with elevated levels of anti‐TPO and/or anti‐TG. It can be potentially fatal. However, it is responsive t...
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Tardive syndromes | Practical Neurology

Tardive syndromes | Practical Neurology | AntiNMDA | Scoop.it
INTRODUCTION Movement disorders developing as a direct consequence of the administration of dopamine receptor-blocking neuroleptic drugs were first reported in 1957, 5 years after their introduction into psychiatric practice. The year 1964 saw the first collective description of these movement disorders as a ‘tardive’ (from the latin tardus, meaning late) phenomenon,1 reflecting their delayed onset following medication administration, in contrast to ‘acute’ dystonic reactions, which also follow dopaminergic blockade. This term was rapidly adopted, and in the following decades, a flurry of publications were to expand the phenotypic spectrum of the disorder. Concurrently, theories aiming to explain disease pathogenesis began to emerge, and several therapeutic strategies were explored. This review provides physicians with a pragmatic, clinically based platform with which to approach tardive syndromes. In addition, we explore recent developments in our understanding of disease pathophysiology, discuss how to approach treatment of tardive syndromes and try to dispel some commonly held myths. The nosology of tardive syndromes is plagued by inconsistent use of descriptive language. The term ‘tardive dyskinesia’, when first introduced, was intended to subsume the range of diverse movements that can emerge in a delayed fashion following long-term neuroleptic administration. However, more recently, a less confusing approach which classifies tardive movements according to their clinical phenomenology has been promoted, and will be used in this review. Accordingly, we use ‘tardive syndrome’ as the umbrella term for any/all potential tardive movement disorders but reserve ‘tardive dyskinesia’ as a descriptor of a specific clinical entity, namely the characteristic oro-bucco-lingual choreiform movements (see The ‘typical’ tardive syndrome). The scale of the problem Tardive syndromes are a predictable, sometimes permanent, disabling consequence of medication administration. They occur predominantly in the psychiatric population, where they exacerbate the burden of social stigma and are linked to poorer quality of life and increased morbidity and mortality.2 3 Antipsychotic drugs are by far the most common offenders, though numerous others have also been implicated (table 1). VIEW INLINE VIEW POPUP Table 1 Examples of medications known to cause tardive syndromes4–11 Tardive syndromes affect 20%–50% of patients receiving neuroleptic drugs.12 Advancing age is the most robust risk factor, with incidence increasing from 5% per annum in those aged under 40 years to 12% or more per annum in older age groups.12–14 The risk increases cumulatively with duration of exposure and medication dose, with a cumulative incidence rate of 20%–25% after 5 years of exposure.15-17 Note however that the medication compliance rate in patients with schizophrenia is around 50%, so these figures may well be an underestimate.18 Numerous other factors may further increase the risk, including history of an affective disorder, previous organic brain damage, diabetes mellitus, female sex (oestrogen perhaps being protective premenopausally) and race.19 Indeed, disease prevalence is lower on average in Asians (roughly 20%) and higher on average in African–Americans compared with Caucasians.19–21 Disease pathophysiology The pathophysiological basis of tardive syndromes remains poorly understood, as reflected in the large number of theories purporting to explain the delayed development of these movement disorders. The earliest theory to gain popular acceptance was the so-called dopamine receptor hypersensitivity theory. This suggested that dopamine-blocking neuroleptics led to compensatory upregulation and/or hypersensitivity of postsynaptic dopamine (particularly D2) receptors.22 23 Hypersensitivity of these receptors, which are expressed on indirect pathway medium spiny neurones and are inhibitory, would have the net effect of pallidal and subthalamic nucleus disinhibition, producing abnormal hyperkinetic movements.22 This hypothesis was largely based on clinical observations, such as the greater likelihood of tardive syndromes in patients receiving potent D2 blockers and the apparent improvement in tardive dyskinesia with additional dopaminergic blockade, as well as on some animal studies.22 23 However, evidence in humans for such alterations is lacking. There is no correlation between in vivo striatal D2 receptor ligand binding assessed by positron emission tomography and the severity of tardive dyskinesia. Equally, postmortem examinations have not demonstrated significant differences in D2 receptor numbers in those with and without tardive syndromes.22 Moreover, this theory does not explain why many patients do not recover after they stop the offending medication; if the only problem were receptor upregulation/hypersensitivity, one would expect this to normalise following drug withdrawal. An alternative hypothesis is that tardive syndromes actually represent a neurodegenerative disorder of striatal interneurones induced by oxidative stress. This theory, which is supported by animal and human neuropathological studies,24 25 holds that dopaminergic receptor blockade causes increased dopamine turnover and oxygen free radical production by monoamine oxidase.22 These free radicals are thought to be toxic to striatal interneurones, causing gliosis within the basal ganglia, thus explaining why the symptoms persist after stopping the medication. However, the significant and sustained improvement that sometimes follows deep-brain stimulation for tardive syndromes might argue against this idea. A further theory implicates damaged or dysfunctional striatal gamma-aminobutyric acid (GABA)ergic neurones in the pathogenesis of tardive dyskinesia. These neurones synapse on the soma of medium spiny neurones, providing potent feedforward inhibition, balancing activity in the direct and indirect basal ganglia pathways, and providing surround inhibition.22 23 Selective lesioning of these neurones produces dyskinesia.26 Long-term D2 agonism, in theory, could potentially damage GABAergic interneurones via glutamate-mediated excitotoxicity and increased oxidative stress from dopamine turnover.27 Finally, altered N-methyl-D-aspartate (NMDA)-mediated synaptic plasticity may provide a unifying theory. Antipsychotics are known to influence NMDA receptor-mediated synaptic plasticity. In this setting, patterns of abnormal neurotransmission, for example, secondary to D2 receptor hypersensitisation could be abnormally potentiated, perpetuating a cycle of abnormal sensorimotor integration and abnormal tardive movements.22 Of course, not everyone who is exposed to neuroleptic drugs develops a tardive syndrome, implying that other, possibly genetic factors are at play, conferring increased vulnerability to tardive syndromes. Genome-wide association studies have identified some potential candidate genes, though their relevance to clinical practice remains unclear.28 Making the diagnosis: the devil is in the detail This section describes the typical (or perhaps simply better recognised) and less typical presentations of tardive syndromes. One must be mindful however that individual components of the syndrome rarely occur in isolation, but rather generally coexist to greater or lesser degrees (though one may be dominant). A confident diagnosis often depends on identifying multiple movement phenomena that are compatible with a tardive syndrome. Thus, an important part of the evaluation involves not only identifying a movement of potentially tardive aetiology, but actively searching for the presence of other compatible abnormalities. Failing to notice clues, such as a fidgety patient (akathisia) who sighs deeply (respiratory dyskinesia) and moves his legs back and forth during the consultation (stereotypies), can rapidly lead one down the wrong diagnostic path. Although diagnostic criteria for tardive syndromes have been developed (table 2), only three questions matter in clinical practice: Is there a history of taking a dopamine receptor-blocking or other tardive syndrome-causing drug, as prescription medication, over-the-counter/traditional remedies or poisoning? What is the temporal relationship of taking this drug intake to the onset of the movement disorder? Is the clinical phenomenology compatible with a tardive syndrome (see below)? VIEW INLINE VIEW POPUP Table 2 Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) definition of tardive syndromes The ‘typical’ tardive syndrome ‘Classic’ tardive dyskinesia involves stereotyped choreoathetoid movements predominantly involving the lips, tongue and perioral region. The movements often predominate in the lower face, with frontalis involvement being unusual. Patients often move the tongue in a writhing motion inside the mouth, are prone to frequent rapid tongue protrusion (‘flycatcher tongue’) and pushing of the tongue against the inside of the cheek, creating a bulge (‘bonbon sign’). Chewing and/or grimacing movements, lip smacking and puckering are typical. This may be accompanied by low amplitude choreiform movements of the distal limbs, the so-called ‘piano player dyskinesia’, resembling finger movements on piano keys.29 Patients are often unaware of these involuntary movements, though those involving the lips and tongue may cause problems with feeding. Tardive dyskinesia is usually accompanied by one or more of the following tardive phenomena: Tardive akathisia This is an uncomfortable sense of inner restlessness, requiring the affected individual to repeatedly move about in order to ease the unpleasant sensation. Movements can include rocking in one place when seated, marching when standing, repetitively scratching or rubbing, or just appearing generally ‘fidgety’ during the consultation. Tardive stereotypies These are patterned, purposeless, repetitive and somewhat ritualistic movements that may appear as truncal rocking, pelvic thrusting, to-and-fro leg movements, hand-wringing or crossing/uncrossing of the legs. They may outwardly resemble akathisia but are not accompanied by inner restlessness. Tardive dystonia As with most tardive syndromes, tardive dystonia adopts distinct phenomenological characteristics which are easily identified by the trained observer. The disorder frequently involves the craniocervical region, manifesting as retrocollis. Dystonia may extend to the trunk as opisthotonic posturing, while in the arms, abduction, internal rotation and wrist flexion is the classically adopted posture.29 Blepharospasm may also emerge. In contrast to other tardive syndromes, tardive dystonia is particularly common in young men aged around 40 years.24 Remission is also less likely than with tardive dyskinesia, particularly with drug exposure beyond 10 years.24 The following tardive disorders are less well defined, with only a handful of reported cases. Tardive tourettism This rare disorder manifests as multiple motor and verbal tics that emerge after exposure to dopamine receptor-blocking agents. The tics generally resemble those of primary tic disorders, exhibiting suppressibility, build-up of tension before the tic and release of tension afterwards.30 31 Tardive tremor This was first proposed as an entity in a 1992 report of five patients with a 3–5 Hz postural and action greater than rest tremor but without parkinsonism.32 Although similar to parkinsonian tremor, tardive tremor is distinguished by its postural and kinetic (rather than rest) predominance, its coarse disabling nature, its lack of levodopa responsiveness and its occasional improvement with further dopaminergic blockade or tetrabenazine.32 33 The syndrome generally persists despite withdrawal of dopamine receptor-blocking agents. Tardive myoclonus This describes brief, upper-limb predominant postural myoclonic movements that are said to result from long-term dopaminergic blockade.34 35 However, there is only very limited literature on this entity, which should therefore be interpreted with caution.34 35 Tardive gait This is a poorly characterised and non-uniform phenomenon, with gait disturbances having been described as ‘dancing’ (multiple short steps followed by a long step) or ‘duck-like’ (broad based with short stride length and some steppage features). Other abnormalities include walking with initial floor contact with toes rather than heels, spastic qualities and abnormal arm swing.36 Some ‘atypical’ presentations Patients with tardive syndromes not infrequently exhibit other less recognised, but nonetheless characteristic features that point towards the diagnosis. Among these, the most important are respiratory phenomena, tardive Pisa syndrome and withdrawal emergent dyskinesia. Respiratory dyskinesia First described in 1964, respiratory dyskinesia involves periodic disturbances of ventilatory rate, rhythm and amplitude, sometimes with ventilatory pauses or forced inspiration against a closed glottis.37 Patients may complain of dyspnoea or dysphonia, or may be seen to huff, grunt, gasp or take short, rapid breaths.38 These phenomena often accompany other more classic tardive motor features. Tardive Pisa syndrome This phenomenon, predominantly affecting older women, describes a drug-induced persistent truncal dystonia manifesting as tonic lateral flexion, occasionally with slight rotation.39 The ‘laterally leaning patient’ is an important clue to a tardive aetiology. Withdrawal emergent dyskinesia This syndrome is considered a variant of tardive dyskinesia, which generally develops after either abruptly stopping or significantly reducing the dose of neuroleptic medications.40 It predominantly affects children and usually manifests as generalised chorea (as opposed to the facial-predominant movements observed in classic tardive dyskinesia). It is usually self-limiting and resolves after days to weeks.40 Tardive oculogyric crises Oculogyric crises were originally described as being characteristic of encephalitis lethargica, although now they are more commonly associated with medication-related acute dystonic reactions (as well as dopamine synthesis pathway defects). However, oculogyric crises can also rarely develop as a tardive phenomenon in patients chronically exposed to antipsychotic medications.41 42 Tardive oculogyric crises often accompany other tardive motor phenomena and may go unrecognised. They are sometimes associated with transient recurrences of psychiatric symptoms, including anxiety, auditory hallucinations and bizarre behaviour.41 Tardive pain syndromes A variety of tardive pain syndromes have also been described, temporally associated with neuroleptic use and often responding to standard tardive syndrome treatments. Examples include tardive oral pain, which describes an uncomfortable, often burning sensation in the mouth and lips, and painful genital syndrome, with similar affliction of the genital region.43 Tardive bruxism Bruxism, of either the grinding or mixed grinding-clenching type, may develop as a side effect of long-term neuroleptic exposure. It probably represents a forme fruste of tardive oromandibular dystonia.44 A striking feature of the syndrome is noise production, sometimes sufficiently severe to annoy roommates. The movements disappear during sleep. Assessing the severity of tardive syndromes Before prescribing dopamine receptor-blocking drugs, clinicians should strive to document the presence or absence of abnormal involuntary movements. While both physician and nurse-led standardised assessment tools (such as the abnormal involuntary movement scale and ScanMove instrument, respectively) may not always be practical in the busy clinical setting,45 46 a focused examination is nevertheless important. It was recognised over 140 years ago that psychiatric patients may exhibit stereotypies, chorea or abnormal facial grimacing as a result of their disease—failure to document this before treatment may lead to these later being misattributed to a drug effect.47 48 It has also been suggested that some older people develop spontaneous movements of the face as part of normal ageing. Whether this is true or merely represents the emergence of facial or craniocervical dystonic syndromes with age is yet to be resolved. FACTS AND FALLACIES Myth number 1: Second-generation antipsychotics, with their lower D2 binding affinity, have reduced the incidence of tardive syndromes This has been a particularly contentious issue and it is difficult to make a definite statement in either direction. What can be said with certainty is that the introduction of second-generation antipsychotics has not done away with tardive syndromes. Rather, due to rapid uptake in their prescription, including off-label use for mood disorders and sleep, ironically they may have contributed further to the problem. While some studies suggest that the incidence of tardive syndromes with second-generation antipsychotics is not vastly dissimilar from that of their first-generation counterparts,10 49 the largest literature review to date, involving 34, 555 patients treated with antipsychotics across 56 studies, found an annualised incidence rate of 2.98% with second-generation antipsychotics versus 7.7% with first-generation antipsychotics, supporting the claim that second-generation antipsychotics may indeed carry a lower risk.50 A recent large meta-analysis of 57 studies on tardive syndromes also supported this.9 Myth number 2: Prolonged exposure to a causative drug is necessary to be at risk of tardive syndromes Although, as detailed above, the cumulative risk of tardive syndromes increases year-on-year and most patients develop the disorder after at least 1–2 years of drug exposure,23 24 there are reports of its occurrence after just a single dose of neuroleptic. Prolonged drug exposure is therefore not always necessary. Myth number 3: Some neuroleptics are safe The recognition that first-generation (‘typical’) antipsychotics were associated with a number of extrapyramidal side-effects prompted the development of newer compounds, termed ‘atypical’ antipsychotics, which were supposedly defined by the absence of extrapyramidal symptoms at therapeutic doses. Numerous mechanistic differences of these newer compounds, including effects on serotonergic signaling, more rapid dissociation from the D2 receptor, limbic selectivity and in the case of aripiprazole, partial dopaminergic agonism were posited as the reason behind their more favourable side effect profiles. While it is true that not every neuroleptic has the same propensity to cause tardive syndromes, none is devoid of risk. All classes of antipsychotics can produce tardive syndromes.20 51 Nevertheless, newer ‘atypical’ agents probably carry about half the risk of producing later tardive syndromes as compared with their ‘typical’ counterparts.9 Furthermore, it is important to remember that it is not just neuroleptics that are implicated in the development of tardive syndromes (table 1). Differential diagnoses not to miss, and how to spot them Differentiating spontaneous from drug-induced movement disorders in patients with psychiatric illness can be a challenging endeavour. Nonetheless, it is imperative to give adequate thought to excluding important differential diagnoses that can present with the combination of psychiatric disease and abnormal movements,29 and particularly the following conditions: Huntington’s disease As a trinucleotide repeat expansion disorder with the cardinal manifestations of chorea, psychiatric disease and cognitive decline, Huntington’s disease is one of the most important differential diagnoses of tardive dyskinesia. Psychiatric disease (often requiring neuroleptic treatment) can precede the development of hyperkinetic movements in this condition by several years. Inexperienced observers can therefore easily misdiagnose such hyperkinetic movements as tardive. In this setting, there are some particularly helpful clinical clues52 including Hyperkinetic movements: In tardive dyskinesia, these movements tend to be stereotyped and semi-purposeful, as opposed to the random, flowing movements of chorea that typify Huntington’s disease. Topographical distribution: In tardive syndromes, the movements are predominately lower facial and axial, manifesting as retrocollis and opisthotonus. In contrast, patients with Huntington’s disease often have significant limb chorea, which is unusual in tardive syndromes. Hyperkinetic movements of the frontalis muscle are also common in Huntington’s disease but uncommon in tardive syndromes. Eye movements: Eye movement disorders are often a prominent, early feature of Huntington’s disease. They can involve disorders of saccadic initiation, broken pursuits and gaze impersistence. However, in tardive dystonia, the eye movements are generally normal. Thus, a careful oculomotor examination is an important part of the evaluation of all tardive syndromes. Motor impersistence (of grip, tongue protrusion or gaze fixation): This is a classic feature of Huntington’s disease but is very uncommon in tardive dyskinesia, and therefore a valuable clinical sign. Other features: Akathisia and opisthotonus strongly suggest tardive syndromes. Conversely, a family history suggesting dominant inheritance and caudate atrophy on MR scan of brain would suggest Huntington’s disease. Anti-NMDA receptor encephalitis Several autoimmune movement disorders can have co-existent neurobehavioural features, which are extensively reviewed elsewhere.53 Anti-NMDA receptor encephalitis in particular however, could be confused with tardive dyskinesia, due to the prominent stereotyped perioral dyskinesia that typifies the disorder. The condition presents differently depending on age: children have more ‘neurological’ (seizures, movement disorders) phenotypes, while adults tend to present with neurobehavioural syndromes, which can be mistaken for psychosis.54 Sometimes, the neuropsychiatric features require neuroleptic treatment, creating an additional pitfall in the diagnostic pathway. A ‘full house’ of symptoms, including autonomic dysfunction, generally develops within 1 month.54 Clinical suspicion should prompt testing for the causative antibody in serum and cerebrospinal fluid. Wilson’s disease This condition should always be kept in the differential diagnosis of any movement disorder, especially in patients under the age of 40 years (though late presentations are reported). Psychiatric symptoms are common in Wilson’s disease, and perioral movements are also classic. However, they tend to assume a more dystonic quality, frequently producing risus sardonicus. Dysarthria and drooling are also common in Wilson’s disease, but unusual in tardive dyskinesia. Edentulous dyskinesia This hyperkinetic movement disorder affects 15% of the edentulous population,55 manifesting as stereotyped, choreiform perioral and lip movements which bear striking resemblance to tardive oro-bucco-lingual dyskinesia. It presents in people with partial or complete edentulism, and often resolves or significantly improves with the introduction of dentures to the mouth. Its pathogenesis is thought to relate to altered sensory feedback from oral structures as a result of malocclusion. Meige syndrome This primary dystonic disorder mostly affects women in their 50s and 60s, being characterised by the combination of blepharospasm and oromandibular dystonia. Differentiation from tardive conditions on purely clinical grounds can be particularly difficult; hence, a history of exposure to dopamine receptor-blocking agents is critical to explore thoroughly in the history. TREATMENT The management of tardive syndromes should incorporate three key aspects. First, prevention is always better than cure. As such, medications with documented potential for inducing tardive syndromes should be used at the lowest possible dose for the shortest period of time possible. This may of course not always be possible. Second comes the question of medication withdrawal. In actual fact, the evidence that withdrawing the offending drug significantly alters the natural history of tardive syndromes is not as strong as one might think.56 Nevertheless, this is an intuitive move in clinical medicine—remove the thing that is causing the problem. Most movement disorder physicians would therefore advocate stopping the offending dopamine receptor-blocking agent, or at least changing it to a drug with less potential for tardive phenomena, if possible. The alternative drug of choice in this setting is often clozapine, both due to its proven efficacy in the treatment of and its lower risk of inducing tardive syndromes.57–59 Close consultation with psychiatric services is necessary before embarking on such a course of action. It is also important to realise that tardive symptoms may initially worsen following neuroleptic drug withdrawal and that equally the symptoms may be suppressed by switching to a more potent dopamine receptor-blocking agent.60 Finally comes the question of symptomatic treatments for tardive syndromes. Numerous agents have been trialled in this regard, with varying evidence for their effectiveness. As mentioned earlier, tardive syndromes are often a complex medley of different movement disorders, and approaches that may work for one movement may worsen another. It is therefore important to adopt a tailored approach, focused on addressing the issue that primarily bothers the patient; generally, this will be either tardive dyskinesia or tardive dystonia. Concerning tardive dyskinesia, the mainstay of medical treatment resides around the administration of vesicular monoamine transporter-2 (VMAT-2) inhibitors (tetrabenazine, deutetrabenazine, valbenazine—the latter two being the only Food and Drug Administration-approved drugs for the treatment of tardive dystonia), which act through presynaptic dopamine depletion. The main side effects of these medications are the development of reversible parkinsonism, as well as dose-dependent mood changes, particularly in the elderly; the side effect profiles of deutetrabenazine and valbenazine appear significantly more favourable.61 Other compounds worth mentioning include amantadine, which has shown antidyskinetic properties in multiple controlled and uncontrolled studies, and is supported by American Academy of Neurology guidelines for short-term treatment of tardive dyskinesia. Propranolol has surprisingly good data to support its use, though this is likely due to its effect of increasing neuroleptic drug concentrations.47 Clonazepam also appears effective, though in the randomised controlled trial setting it appeared to lose its efficacy after 5–8 months and thus can only be tentatively recommended for short-term use. Several antioxidants have also been trialled but data on their efficacy are largely inconclusive.60 Other options such as additional dopaminergic blockade, for example, with haloperidol, have proven efficacy in reducing tardive dyskinesia, at least in the short term. However, this comes at the cost of an increase in akinetic rigid syndromes. Furthermore, there are insufficient data on the long-term effects of such approaches, and given that these agents have great propensity to cause tardive syndromes, additional potent dopaminergic blockade is not recommended as a treatment for these conditions.60 Botulinum toxin is an effective option for tardive dystonia.23 Trihexyphenidyl can also improve dystonic syndromes, though occasionally at the cost of worsening dyskinesia. Functional neurosurgery is gaining increasing recognition as a treatment for both tardive dyskinesia and dystonia. Indeed, pallidal deep-brain stimulation can be greatly beneficial, and early referral to a centre with experience in this procedure should be encouraged in refractory or debilitating cases.62 Physicians may be reluctant to recommend this procedure due to the risk of worsening underlying psychiatric comorbidity, though in practice, this is seldom an issue, especially with pallidal targets.62 Pallidotomy can also be considered in poor surgical candidates. Tardive akathisia can be equally bothersome, but there is little evidence regarding its optimal treatment. Clonidine, moclobemide and benzodiazepines as well as electroconvulsive therapy have been used in some instances, with varying degrees of success.63–66 Tardive pain syndromes often respond to VMAT-2 inhibitors, though other options such as electroconvulsive therapy have been used.43 Withdrawal emergent dyskinesia often settles spontaneously over a few weeks without treatment. Severe symptoms can however be managed by reintroduction of the offending drug, followed by a slower taper. PATIENT OUTCOMES In an ideal world, patients developing tardive syndromes would have their causative neuroleptic treatment stopped. Then, and only then, could the true reversibility of the syndrome be assessed. However, the nature of psychiatric disease means that ongoing treatment is often needed, making it difficult to assess the outcomes of tardive syndromes. Predictors of poor outcome appear similar to those of developing tardive syndromes in the first place and include advanced age, longer duration of antipsychotic treatment and greater cumulative dose.67 Once established, the severity of tardive syndromes often fluctuates over time, though in a significant proportion, the tardive syndrome fails to resolve.56 68 Key points Tardive syndromes can comprise many characteristic movement disorders; each needs to be carefully sought in suspected cases Clozapine is the drug of choice for patients with tardive syndromes who require ongoing neuroleptic treatment Vesicular monoamine transporter-2 (VMAT-2) inhibitors, such as tetrabenazine, deutetrabenazine and valbenazine, are the best medical treatment options for tardive dyskinesia Pallidal deep-brain stimulation is an effective treatment option in refractory or debilitating tardive syndromes REFERENCES ↵Faurbye A, Rasch P-J, Petersen PB, et al. 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Br J Psychiatry 2012;200:387–92. doi: 10.1192/bjp.bp.111.101485 ↵Correll CU, Schenk EM. Tardive dyskinesia and new antipsychotics. Curr Opin Psychiatry 2008;21:151–6. doi: 10.1097/YCO.0b013e3282f53132 ↵Ertugrul A, Demir B. Clozapine-induced tardive dyskinesia: a case report. Prog Neuro-Psychopharmacology Biol Psychiatry 2005;29:633–5. doi: 10.1016/j.pnpbp.2005.01.014OpenUrl ↵Kumar H, Jog M. Missing Huntington’s disease for tardive dyskinesia: a preventable error. Can J Neurol Sci/J Can Des Sci Neurol 2011;38:762–4. doi: 10.1017/S0317167100012294OpenUrl ↵Balint B, Vincent A, Meinck H-M, et al. Movement disorders with neuronal antibodies: syndromic approach, genetic parallels and pathophysiology. Brain 2018;141:13–36. doi: 10.1093/brain/awx189OpenUrlCrossRefPubMed ↵Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. 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Valbenazine and deutetrabenazine for tardive dyskinesia. Innov Clin Neurosci 2018;15:13–16.OpenUrl ↵Macerollo A, Deuschl G. Deep brain stimulation for tardive syndromes: systematic review and meta-analysis. J Neurol Sci 2018;389:55–60. doi: 10.1016/j.jns.2018.02.013OpenUrl ↵Peng L-Y, Lee Y, Lin P-Y. Electroconvulsive therapy for a patient with persistent tardive dyskinesia. J Ect 2013;29:e52–4. doi: 10.1097/YCT.0b013e31829e0aeaOpenUrl ↵Amann B, Erfurth A, Grunze H. Treatment of tardive akathisia with clonidine: a case report. Int J Neuropsychopharmacol 1999;2:S1461145799001376. doi: 10.1017/S1461145799001376 ↵Emmanuel T. Remission of treatment-resistant depression with tardive akathisia with electroconvulsive therapy. BMJ Case Rep 2019;12:e229714. doi: 10.1136/bcr-2019-229714 ↵Ebert D, Demling J. Successful treatment of tardive akathisia with moclobemide, a reversible and selective monoamine-oxidase-a inhibitor. Pharmacopsychiatry 1991;24:229–31. doi: 10.1055/s-2007-1014473OpenUrlPubMed ↵Cavallaro R, Regazzetti MG, Mundo E, et al. Tardive dyskinesia outcomes: clinical and pharmacologic correlates of remission and persistence. Neuropsychopharmacology 1993;8:233–9. doi: 10.1038/npp.1993.26 ↵Kane JM, Woerner M, Borenstein M, et al. Integrating incidence and prevalence of tardive dyskinesia. Psychopharmacol Bull 1986;22:254–8.
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Etiological associations and outcome predictors of acute electroencephalography in childhood encephalitis - ScienceDirect

Etiological associations and outcome predictors of acute electroencephalography in childhood encephalitis - ScienceDirect | AntiNMDA | Scoop.it
To examine EEG features in a retrospective 13-year cohort of children with encephalitis.354 EEGs from 119 patients during their admission were rated b…...
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Possible autoimmune encephalitis with claustrum sign in case of acute SARS-CoV-2 infection | Canadian Journal of Neurological Sciences

Possible autoimmune encephalitis with claustrum sign in case of acute SARS-CoV-2 infection...
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Paraneoplastic anti-NMDA receptor encephalitis in 1830? | Neurology Neuroimmunology & Neuroinflammation

Paraneoplastic anti-NMDA receptor encephalitis in 1830? | Neurology Neuroimmunology & Neuroinflammation | AntiNMDA | Scoop.it
Abstract Objective Our aim was to identify patients with probable anti-NMDA receptor encephalitis among historical medical cases. Method A case report published in leading Hungarian-, German- and Italian-language medical journals in the early 1840s was revisited. Results In 1830, an 18-year-old, healthy woman suffered epileptic seizures, followed by a 6-day-long state characterized by catalepsy, unresponsiveness, motionless, and light breathing. Her symptoms regularly returned in the following 1.5 years. Meanwhile, a progressively growing huge abdominal tumor appeared. One day, she suddenly started vomiting a large amount of foul-smelling pus mixed with blood, accompanied by bone fragments. Pus mixed blood with some membranous substance was also evacuated through the anus and vagina. After this event, she completely recovered; 1.5 years later, she married and later gave birth to 3 healthy children. The patient remained healthy during the 11-year follow-up. Conclusions We suggest that in the description of a paraneoplastic case, an anti-NMDA receptor encephalitis can be dated back as far as to the 19th century, with an especially rare type of resolution: the disappearance of the symptoms after the spontaneous elimination of an ovarian teratoma. Anti-NMDA receptor encephalitis was discovered by Dalmau et al.1,2 in 2005/2007, although cases were probably described already in 1997.3,4 Moreover, because of revisiting published cases dating back as far as the 19th century, more and more cases are suggested to be of anti-NMDA receptor encephalitis etiology. Merwick et al.5 pointed out that from the case series published by Bickerstaff—in which Bickerstaff encephalitis was described—in one patient, the symptoms were indicative of anti-NMDA receptor encephalitis. In the late 1800s, ovariotomy (Battey's operation) was introduced as a treatment of—among others—“histeroepilepsy.”6 In the course of the recent revisitation of these published cases, symptoms can also be attributed to anti-NMDA receptor encephalitis in more than one patient; this suggestion is also supported by the observation of Battey, namely that “cystic degeneration” was common in the resected ovaries.6 This is the most common autoimmune encephalitis, where 80% of patients are women with a median age of 21.7 Epileptic seizures occur in 76%,8 catatonia-like episodes in 70%,9 whereas hypoventilation in 66% of patients.8 In adult women patients, anti-NMDA receptor encephalitis is associated with ovarian teratoma in 58% of cases.7 Other tumors are rare: in paraneoplastic cases, 94% of the underlying tumor is ovarian teratoma.7 We found an interesting case report published in leading Hungarian-, German- and Italian-language medical journals referring to a presentation at the 3rd Meeting of the Italian Scientists in Florence held in 1841.10,–,12 We suggest that the description of an anti-NMDA receptor encephalitis can be dated back as far as to the 19th century. Case On September 17, 1841, the case was presented by Dr. Odoardo Linoli (figure).10,–,12 In 1830, an 18-year-old, hitherto healthy female patient suffered epileptic seizures, followed by a strange 6-day-long state characterized by a “catalepsy” pose and an unresponsive motionless state. The only sign of life was a very light breathing. Epileptic seizures and the catalepsy regularly returned in the following 1.5 years. Meanwhile, a progressively growing huge abdominal tumor appeared, which reached the level of the chest on the left side. One day, she suddenly started vomiting a large amount of coffee-colored liquid. Two weeks later, she vomited a foul-smelling pus mixed with blood. This was accompanied by more than 100 bone fragments. Some of these fragments were flat, others were long- or ball-shaped. Pus-mixed blood with some membranous substance was also evacuated through the anus and vagina. After this event, both epileptic seizures and “catalepsy” states disappeared, and she apparently became healthy again; 1.5 years later, she married and later gave birth to 3 healthy children. At the time of Dr. Linoli's presentation (11 years after the disease onset), she was in excellent health. During the discussion, Dr. Linoli argued that the abdominal tumor was probably a “fetal cyst” or “fetus in fetu.” Prof. Carlo Burci—the chairman of the section—suggested that the tumor could have been a “skin cyst,” whereas others speculated that it could have been an extrauterine pregnancy. Figure Case presentation The title page of the Österreichische Medizinische Wochenschrift from 1843 (A) and the case presentation in German (B). Available at the Bayerische Staatsbibliothek München, H.misc. 33 t-16, S. 244, urn:nbn:de:bvb:12-bsb10737557-2. Discussion The medical language in the first half of the 19th century was certainly different from today. The reliability of the description is enhanced by the fact that the case has been described in 3 different languages in the 1840s.10,–,12 The case was presented by Odoardo Linoli (1801–1886), a well-known surgeon from Pietrasanta,13 and discussed by Carlo Burci,14 who was the professor of surgery at the University of Pisa, indicating that the case was observed and discussed by the most prestigious professionals of that time. We tried to interpret this case report according to today's medical concepts. Although catatonia was not described as such until 1874, the described motionless and unresponsive state accompanied by catalepsy meet the criteria of a catatonia.15 Another issue is the type of the described huge abdominal tumor that contained bone fragments. According to Dr. Linoli's interpretation, it was a “fetus in fetu.” Fetus in fetu is extremely rare in adulthood16 and should contain vertebral axis or limbs, otherwise it should classify as teratoma.17 Dr. Burci suggested that the tumor was a “skin cyst.” According to today's nomenclature, dermoid cyst (i.e., skin-like cyst) is a synonym for teratoma. The presence of bone is not unusual in teratoma.18 Based on the presence of bone, a teratoma was diagnosed during a paleopathological examination of a female skeleton from the late Roman age.19 Ovarian teratomas without treatment can reach a huge size, some of them can be up to 30 cm in diameter.18 Not only the size, localization, and the presence of bone but also the strange elimination of the tumor through the gastrointestinal system and vagina may also support the concept of teratoma. Teratomas (dermoid cysts) can perforate into the adjacent organs including bowel and vagina.20,–,23 For example, Flood et al.22 reported a 23-year-old woman who discovered teeth-like structures in her underwear, which were the contents of an ovarian teratoma excreted in the vagina through a fistula. Mitui et al.23 reported a 72-year-old woman whose diarrhea, in which she found hair, was caused by an ovarian teratoma perforating into the bowels. Summarizing our interpretation, a young woman had newly onset seizures, followed by catatonia-like symptoms and hypoventilation. This was associated with an abdominal tumor, which was probably a teratoma. The symptoms disappeared after the spontaneous elimination of the tumor, and the patient remained healthy during the 11-year follow-up. According to a recent position study, new-onset seizures and altered mental status (unresponsive state) with subacute onset meet the criteria for “possible autoimmune encephalitis.”24 Epileptic seizures, altered mental status, abnormal posturing, and hypoventilation meet the symptoms criteria for “possible anti-NMDA receptor encephalitis.”24 The young age and female sex as well as the presence of ovarian teratoma also strengthen our assumption that Dr. Linoli's case study might be the first description of anti-NMDA receptor encephalitis. In paraneoplastic anti-NMDA receptor encephalitis, the symptoms usually resolve after tumor removal, may that be either ovarian or extraovarian.7,25 Regarding Dr. Linoli's patient, the symptoms were present when the tumor was present and disappeared after the tumor also disappeared. Thus, we state that the description of a paraneoplastic story can be dated back as far as to 1830, ahead of the description of Trousseau's syndrome in 1865.26 Study funding Study funded by the Hungarian Brain Research Program (2017-1.2.1-NKP-2017-00002), NKFIH EFOP-3.6.2-16-2017-00008 government-based funds. Our research was partly financed by the Higher Education Institutional Excellence Program of the Ministry of Human Capacities in Hungary, within the framework of the 5th thematic program of the University of Pécs, Hungary (20765/3/2018/FEKUSTRAT). The study was furthermore supported by the University of Pécs Medical School. Disclosure None of the authors report anything to disclose. Go to Neurology.org/NN for full disclosures. Appendix Authors Footnotes Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article. The Article Processing Charge was funded by University of Pécs. Received July 30, 2020. Accepted in final form August 12, 2020. Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. References 1.↵Dalmau J, Tüzün E, Wu HY, et al. Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol 2007;61:25–36.OpenUrlCrossRefPubMed 2.↵Vitaliani R, Mason W, Ances B, Zwerdling T, Jiang Z, Dalmau J. Paraneoplastic encephalitis, psychiatric symptoms, and hypoventilation in ovarian teratoma. Ann Neurol 2005;58:594–604.OpenUrlCrossRefPubMed 3.↵Nokura K, Yamamoto H, Okawara Y, Koga H, Osawa H, Sakai K. Reversible limbic encephalitis caused by ovarian teratoma. Acta Neurol Scand 1997;95:367–373.OpenUrlCrossRefPubMed 4.↵Okamura H, Oomori N, Uchitomi Y. An acutely confused 15-year-old girl. Lancet 1997;350:488.OpenUrlCrossRefPubMed 5.↵Merwick A, Dalmau J, Delanty N. Insights into antibody-associated encephalitis—Bickerstaff's 1950's papers revisited. J Neurol Sci 2013;334:167–168.OpenUrlPubMed 6.↵Komagamine T, Kokubun N, Hirata K. Battey's operation as a treatment for hysteria: a review of a series of cases in the nineteenth century. Hist Psychiatry 2020;31:55–66.OpenUrl 7.↵Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 2013;12:157–165.OpenUrlCrossRefPubMed 8.↵Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 2008;7:1091–1098.OpenUrlCrossRefPubMed 9.↵Espinola-Nadurille M, Flores-Rivera J, Rivas-Alonso V, et al. Catatonia in patients with anti-NMDA receptor encephalitis. Psychiatry Clin Neurosci 2019;73:574–580.OpenUrl 10.↵Linoli O. Fall von Epilepsie mint Katalepsie [A case of epilepsy with catalepsy, German]. Österreichische Medizinische Wochenschrift 1843;12:319. Available at (free access): opacplus.bsb-muenchen.de/Vta2/bsb10086743/bsb:5976959?page=325. Accessed June 23, 2020.OpenUrl 11.↵Third Meeting of Italian Scientists in Florence. Annali Universali di Medicina 1842;40:17–20. Available at (free access): archive.org/details/s12id13209690/page/17. Accessed June 23, 2020.OpenUrl 12.↵Bugát P, Flór F. Kivonatok idegen lapokbul és munkákbul. Kór- és gyógytudomány. Nehézkor dermengéssel. [Extracts from foreign works. Pathology and medicine. Epilepsy with catalepsy, Hungarian] Orvosi Tár 1843;17:295. Available at (free access): library.hungaricana.hu/hu/view/ORSZ_ORVO_OT_1843_04/. Accessed June 23, 2020.OpenUrl 13.↵Wikipedia article. Available at: treccani.it/enciclopedia/odoardo-linoli_(Dizionario-Biografico)/. Accessed June 12, 2020. 14.↵Wikipedia article. Available at: it.wikipedia.org/wiki/Carlo_Burci. Accessed June 12, 2020. 15.↵Tandon R, Heckers S, Bustillo J, et al. Catatonia in DSM-5. Schizophr Res 2013;150:26–30.OpenUrlCrossRefPubMed 16.↵Kumar A, Paswan SS, Kumar B, Kumar P. Fetus in fetu in an adult woman. BMJ Case Rep 2019;12:e230835.OpenUrl 17.↵Willis RA. The structure of teratoma. J Pathol Bacteriol 1935;40:1–36.OpenUrlCrossRef 18.↵Caruso PA, Marsh MR, Minkowitz S, Karten G. An intense clinicopathologic study of 305 teratomas of the ovary. Cancer 1971;27:343–348.OpenUrlCrossRefPubMed 19.↵Armentano N, Subirana M, Isidro A, Escala O, Malgosa A. An ovarian teratoma of late Roman age. Int J Paleopathol 2012;2:236–239.OpenUrl 20.↵von-Walter AR, Nelken RS. Benign cystic ovarian teratoma with a fistula into the small and large bowel. Obstet Gynecol 2012;119:434–436.OpenUrlPubMed 21.↵Zarain García F. Teratoma quístico del ovario con absceso y fístula a vagina (Cystic teratoma of the ovary with abscess and fistula in the vagina [in Spanish]). Ginecol Obstet Mex 1974;36:49–53.OpenUrlPubMed 22.↵Flood K, Breathnach F, Gleeson N. An unusual presentation of a dermoid cyst. J Obstet Gynaecol 2010;30:72–73.OpenUrlPubMed 23.↵Mitui AH, Fujita R, Sugata F, Kienebuchi M, Suzuki K, Sagawa F. A case of ovarian dermoid cyst with malignant transformation perforated into the rectosigmoid colon and small intestine. Endoscopy 1983;15:331–333.OpenUrlCrossRefPubMed 24.↵Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016;15:391–404.OpenUrlCrossRefPubMed 25.↵Kümpfel T, Gerdes LA, Heck C, Prüss H. Delayed diagnosis of extraovarian teratoma in relapsing anti-NMDA receptor encephalitis. Neurol Neuroimmunol Neuroinflamm 2016;3:e250. doi: 10.1212/NXI.0000000000000250. 26.↵Darnell RB, Posner JB. Paraneoplastic Syndromes. Oxford/New York: Oxford University Press; 2011.
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Glioblastoma: a mimic of NMDA receptor encephalitis | BMJ Case Reports

Description An Indian woman in her 40s without any medical or psychiatric history presented with a seizure. She had become uncharacteristically quiet before suddenly cackling and banging her hands and feet repeatedly. She developed facial and upper limb dystonic posturing including the extension of one arm. The acute onset, short duration, loss of responsiveness and unilateral dystonic posturing were compatible with a frontal lobe seizure. Several episodes occurred during transfer to the hospital, each lasting 3–30 min. CT head imaging was unremarkable (figure 1). Figure 1 CT head reported as normal. She was discharged and seen in ambulatory care 3 days later. Her lymphocytosis, neutrophilia (described as ‘reactive’) and elevated creatine kinase (10 006 IU/L) were attributed to recent motor seizure activity, despite the broad differential. An electroencephalogram, brain MRI and neurology appointment were arranged, in accordance with the Trust’s ‘first fit’ pathway, which mandates follow-up within 2 weeks, similar to the established National Institute for Health and Care Excellence guidelines.1 Five days later, she was brought back to hospital: she had become increasingly withdrawn, expressing a delusion that ‘someone’ was controlling her. She had stopped recognising her children. On examination, she stared unblinkingly and demonstrated echolalia, echopraxia and stereotyped, repetitive, slow rotation of both wrists. However, she had intervals of apparent lucidity when she was able to answer simple questions. Physical examination was limited by behavioural disturbance, but no other abnormal neurological signs were noted. This syndrome of frontal lobe seizures, acute psychiatric disturbance, unusual mixed hyperkinetic movement disorder and encephalopathy with normal CT brain imaging was suggestive of N-methyl D-aspartate (NMDA) receptor encephalitis. In particular, her movements did not fit more common disorders such as tremor, chorea, myoclonus, dystonia or tics and had a bizarre appearance that experts have found difficult to classify.2 However, an MRI brain revealed a 18×16×17 mm ring-enhancing intra-axial lesion at the frontal pole with extensive surrounding vasogenic oedema and mass effect (figure 2). Given the neutrophilia and lymphocytosis, an infective lesion (particularly a tuberculoma due to her ethnicity) was then considered the foremost differential. Figure 2 MRI head showing a frontal lobe ring-enhancing lesion (left), with extensive surrounding oedema (right). She was transferred to a tertiary neuroscience centre, where investigations interrogating an infectious process were negative, including lumbar puncture, QuantiFERON, cysticercal, HIV and fungal serology. A chest–abdomen–pelvis CT was normal. A brain biopsy revealed a grade IV glioblastoma. She has been treated with levetiracetam, radiotherapy and temozolomide. Her psychiatric and motor symptoms have resolved since treatment and she has been seizure-free for 6 months. We attribute her previous symptoms to ictal activity. Glioblastoma multiforme accounts for >60% of all adult brain tumours.3 Although presentation can vary depending on the location of the lesion, this case is unusual in that the initial presentation was a phenocopy of NMDA encephalitis and fits clinical criteria for diagnosis.4 However, recognised differentials of NMDA receptor encephalitis are varied, including infective, psychiatric, metabolic, neoplastic, paraneoplastic, cerebrovascular and other inflammatory disorders.4 The orbitofrontal location of this lesion explained all the clinical features. The refutation of the top two clinical differentials (NMDA encephalitis and tuberculoma) highlights the importance of having a wide differential diagnosis with unusual neurological presentations. Learning points Simplified pathways for common presentations like ‘first fits’ can streamline services, but without careful history-taking, complex presentations such as this may be inappropriately funnelled into a standardised pathway. A psychiatric presentation with movement disorder and seizure activity may represent a frontal space-occupying lesion, not necessarily NMDA receptor encephalitis.
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Standing on the shoulders of giants: 100 years of neurology and epidemic infections | Journal of Neurology, Neurosurgery & Psychiatry

Introduction One hundred years ago, neurologists were faced with a surge of cases of uncertain cause manifesting a protean array of symptoms. Through careful semiological description, pattern recognition and histopathological analysis, von Economo and others unified these seemingly disparate cases, defining the epidemic of encephalitis lethargica. Several landmark papers in the Journal of Neurology and Psychopathology (now JNNP) helped to illuminate clinical and pathological aspects of this new disease. In the subsequent hundred years, there have been other infectious epidemics affecting the nervous system, with causative agents including flaviviruses, influenza, enteroviruses (eg, poliomyelitis) and coronaviruses (CoV). Neurologists seeing patients in the age of COVID-19 have much to gain from the historical lessons of the epidemics of the last 100 years in responding to these new challenges. A case of encephalitis lethargica involving chiefly the cerebral cortex Authors: Watson GA Year Published: 1920 Epidemic encephalitis: Clinical papers by various authors Authors: Horder T Year Published: 1920 Encephalitis lethargica The first systematic descriptions of encephalitis lethargica were those of von Economo in 1916–1917, who coined the term (figure 1),1 which is also known as ‘von Economo’s disease’.2 However, there were probable cases in 1915 predating the ‘influenza epidemic’, and von Economo and others suggested that earlier epidemics throughout modern history may also have been related.3 Figure 1 Constantin Freiherr Economo von San Serff (von Economo (1876–1931)) Austrian neurologist, psychiatrist, pilot and originator of the diagnosis encephalitis lethargica (https://commons.wikimedia.org/wiki/Category:Constantin_von_Economo). Encephalitis lethargica appears to have spread from Eastern Europe to Germany, France and Britain between 1916 and 1918 and and then to have affected much of the rest of the world in the following few years.1 4 It probably affected more than a million people during the first half of the twentieth century, before apparently disappearing, although some clinicians have continued to apply the diagnosis, particularly in children.4 Three forms were recognised by von Economo: ‘somnolent-ophthalmoplegic form’ characterised by mild prodrome and somnolence with ophthalmoplegia; ‘hyperkinetic form’ in which the patients had sudden onset neck and back pain followed by mental and motor unrest; a ‘myostatic-akinetic form’ that had a milder acute phase of weakness and rigidity and was more likely to have chronic sequelae which could occur immediately after the acute phase or after months or years.1 4 Most patients had change in conscious level, and von Economo discriminated carefully between somnolence as a result of brain dysfunction versus that caused by systemic disease2—a distinction which clearly remains important for COVID-19. Histopathology of most cases in the acute phase showed reddish-grey discolouration of the brainstem grey matter with lymphocytic infiltrates surrounding vessels and diffuse inflammation with haemorrhage.1 In the chronic phase, persistent inflammation was evident with generalised brain atrophy and degeneration of the substantia nigra.1 The aetiology remains unproven, and it is not clear whether all the cases in the literature truly represent a single disease.5 The prevailing contemporary hypothesis was that proposed by von Economo himself—that the disease was owing to an infectious agent, although he observed that cases appeared to predate the emergence of the 1918 influenza pandemic.2 5 von Economo’s view that the disease was the result of direct viral infection of the central nervous system (CNS) has now been largely superseded by the proposition that the disease reflected a para/post-infectious inflammatory process.5 Although evidence for this is lacking, it fits neatly with the modern view of other neurological syndromes such as Guillain-Barré syndrome (GBS), acute disseminated encephalomyelitis (ADEM) and N-methyl-D-aspartate receptor (NMDA-R) antibody encephalitis, the latter of which may be triggered by herpes simplex virus in some.6 7 Indeed, NMDA-R antibodies were present in serum (and cerebrospinal fluid (CSF) when available for study) in around 50% of 20 children with dyskinetic ‘encephalitis lethargica’ (collected over many years),8 and antibodies to the dopamine receptor in a proportion of the remaining more akinetic cases. Many of the clinical features overlap, although encephalitis lethargica is more heterogeneous in both its acute symptoms and its natural history.2 A para/postinfectious pathogenesis, rather than direct viral infection, is in keeping with the observations that single members of families were often affected, which puzzled epidemiologists at the time; and that an infectious agent was not readily detected in CSF or brain tissue.2 It is possible that encephalitis lethargica represented a final common pathway of brain inflammation potentially triggered by several different infectious agents, although were this the case the reasons for the disease’s decline remain obscure. Clinical material from patients with encephalitis lethargica is no longer available in sufficient quantity to support or refute the myriad aetiological hypotheses proposed over the last 100 years.5 Encephalitis lethargica in JNNP The British epidemic began in earnest in 1918, and was a major burden on neurological, psychiatric and public health services for much of the first half of the twentieth century.9 Cases published in the Journal of Neurology and Psychopathology provide a glimpse of the struggles of neurologists trying to understand the emergence of this new enigma.10 11 In 1920, the journal published a case described by Watson, of the Rainhill asylum near Liverpool, then one of the largest asylums in Europe.10 While the condition was often thought to affect the brainstem, this case mainly affected the cerebral cortex. A young patient had been admitted in April 1918 with self-inflicted laceration across the neck, preceded by headache and sleeplessness for 2 weeks.10 Six months after the initial presentation, they developed neck and back pain with reduced mobility, 2 months later developing expressive aphasia with retained comprehension, and death occurred less than a month later.10 The postmortem results describe a widespread meningoencephalomyelitis with vascular proliferation, perivascular inflammation, thrombosis, haemorrhage and destruction of nervous tissue.10 A subsequent case series collated by Sir Thomas Horder, also published in 1920, comprises 25 cases described by several neurologists from Bristol, and is notable for detailed and varied descriptions of cases of encephalitis lethargica in patients of all ages.11 Their dilemmas trying to unify these disparate clinical presentations are clearly evident. While lethargy and/or psychiatric features are almost universal, movement disorders were variably present, as were corticospinal tract and cerebellar signs.11 The outcomes were varied with death in 10/25 (40%) and residual neurological or psychiatric symptoms in most survivors.11 Speculation on aetiology in this study is limited, but there is an assumption that an infectious agent is responsible. Horder states that “it therefore becomes a matter of prime importance that clinicians should marshal their experiences, and set down their observations, with as much care and exactness as possible, and this whilst questions of exact pathology await the results of laboratory research”.11 In subsequent years, papers in the journal analysed the phenomenology of sleep disorders in encephalitis lethargica,12 behavioural abnormalities in children13 and a case series of postencephalitic Parkinsonism14 among many others. Subsequently, fascinating reports emerged of the efforts to treat patients suffering with postencephalitic Parkinsonism with levodopa.15 Other respiratory epidemics affecting the nervous system Influenza Although 1918 influenza has been suggested as the causative agent of encephalitis lethargica, similar clinical phenotypes have not been seen in association with other pandemic strains of influenza.5 However, a wide range of other neurological manifestations are described. The 2009 H1N1 pandemic was associated with complications of the nervous system in up to 4% of those diagnosed with H1N1 influenza infection and most commonly included altered mental status, seizures, narcolepsy and encephalopathy, particularly in children.16–18 Several seemingly pathognomic encephalopathy syndromes have emerged, including acute necrotising encephalopathy with bilateral thalamic involvement.16–18 The virus is rarely identified by molecular tests of the CSF in these patients, and it has been suggested that the mechanism for the complications may be a parainfectious cytokine storm.18 Coronaviruses The severe CoV, severe acute respiratory syndrome (SARS) and MERS, have been associated with limited reports of both central and peripheral nervous system disease, including ADEM.19 Sporadic, seasonal CoV have also occasionally been implicated in neurological disease.20 COVID-19, caused by SARS-CoV-2, represents the most devastating respiratory pandemic since the influenza pandemics of 1918 (‘Spanish flu’; H1N1), 1957 (‘Asian flu’; H2N2) and 1968 (‘Hong Kong flu’; H3N2).21 Reports of neurological syndromes associated with SARS-CoV2 are frequent, initially reported where the virus began in Wuhan,22 and continued in case reports and series from across the world.21 23 24 A UK-wide surveillance study identified 153 cases with CNS disorders reflecting cerebrovascular events, altered mental status including 7 patients with encephalitis, and a surprising number of psychiatric syndromes, such as psychosis and catatonia.21 It is currently unclear how many cases are causally related to SARS-CoV-2 and in what proportion this is a coincidental infection.23 It is becoming apparent that dysfunction of the clotting cascade, together with possible endotheliopathy, is in some cases associated with cerebrovascular disease in COVID-19.21 23 24 The number of patients with encephalopathy is also striking, and in a few cases the virus has been detected in CSF.21 25 Many cases of GBS and its variants are also emerging.26 Conclusion The historical papers of von Economo, Horder and others are refreshing in their straightforward and detailed accounts of the symptoms, signs and clinical course of their patients, which risk being diminished in current studies if there is over-reliance on investigations alone. The reporting of cases should be systematic and collaborative, which is far easier now, in the age of online platforms, than it was 100 years ago; such as is currently being employed through the UK-wide CoroNerve study (www.CoroNerve.com) and international collaborations, such as the COVID-19 NeuroNetwork (https://braininfectionsglobal.tghn.org/covid-neuro-network/). In addition to analysis of clinical samples, these historic cases emphases the importance of histopathological descriptions, which may be more difficult to conduct now that postmortem material may be less frequently obtained. We are indebted to those who donate and their families, so that we, like von Economo and those before us, might better understand the impact of pandemic respiratory viruses on the CNS. Perhaps the greatest lesson from our predecessors is to maintain clinical curiosity and a healthy degree of scepticism, to drive logical enquiry and experiment. Nevertheless, we are left with the original questions posed throughout this history: to what extent are these manifestations due to direct viral CNS infection, the host inflammatory response to non-CNS infection, or the broader psychosocial effects of pandemic infection, and who is at risk? Despite the human and economic suffering of COVID-19, this pandemic represents the first time ever, for the neuroscience community to use the many tools at our disposal, including digital global collaboration and biobanking for next-generation and single-cell sequencing, ‘omics, immunophenotyping, and genome-wide association, to finally begin to answer these questions. Keep up to date with the latest developments in the neurological and psychiatric complications of COVID-19 via our JNNP blog: https://blogs.bmj.com/jnnp/2020/05/01/the-neurology-and-neuropsychiatry-of-covid-19/ References ↵Hoffman LA, Vilensky JA. Encephalitis lethargica: 100 years after the epidemic. Brain 2017;140:2246–51.doi:10.1093/brain/awx177OpenUrl ↵Turner MR, Kieran MCVincent A. Encephalitis Lethargica. In: Turner MR, Kieran MC, eds. Landmark papers in neurology. Oxford University Press, 2015: 478–83. ↵Crookshank FG. A note on the history of epidemic encephalomyelitis. Bost Med Surg J 1920;182:34–45.doi:10.1056/NEJM192001081820203OpenUrl ↵Reid AH, McCall S, Henry JM, et al. Experimenting on the past: the enigma of von Economo's encephalitis lethargica. J Neuropathol Exp Neurol 2001;60:663–70.doi:10.1093/jnen/60.7.663OpenUrlPubMed ↵Tappe D, Alquezar-Planas DE. Medical and molecular perspectives into a forgotten epidemic: encephalitis lethargica, viruses, and high-throughput sequencing. J Clin Virol 2014;61:189–95.doi:10.1016/j.jcv.2014.07.013OpenUrl ↵Kaida K. Pathogenic roles of antiganglioside antibodies in immune-mediated neuropathies. Clin Exp Neuroimmunol 2013;4:60–9.doi:10.1111/cen3.12007OpenUrl ↵Salovin A, Glanzman J, Roslin K, et al. Anti-Nmda receptor encephalitis and nonencephalitic HSV-1 infection. Neurol Neuroimmunol Neuroinflamm 2018;5:e458.doi:10.1212/NXI.0000000000000458 ↵Dale RC, Irani SR, Brilot F, et al. N-Methyl-D-Aspartate receptor antibodies in pediatric dyskinetic encephalitis lethargica. Ann Neurol 2009;66:704–9.doi:10.1002/ana.21807 ↵Bramwell E, Miller J. Encephalitis lethargica (epidemic encephalitis). The Lancet 1920;195:1152–8.doi:10.1016/S0140-6736(00)92412-7OpenUrl ↵Watson GA. A case of encephalitis lethargica involving chiefly the cerebral cortex. J Neurol Psychopathol 1920;1:34–44.doi:10.1136/jnnp.s1-1.1.34pmid:http://www.ncbi.nlm.nih.gov/pubmed/21611435OpenUrlPubMed ↵Horder T. Epidemic encephalitis: Clinical papers by various authors. J Neurol Neurosurg Psychiatry 1920;s1-1:221–35.doi:10.1136/jnnp.s1-1.3.221OpenUrl ↵Coburn M. Short notes and clinical cases: report of a case of insomnia following encephalitis lethargica. J Neurol Psychopathol 1921;2:249–53.doi:10.1136/jnnp.s1-2.7.249pmid:http://www.ncbi.nlm.nih.gov/pubmed/21611473OpenUrlPubMed ↵Parkes Weber F, Shrubsall F, Cameron H, et al. Section for the study of disease in children: cases: hypertelorism. Proc R Soc Med 1928;21. ↵Young AW. A clinical analysis of an extrapyramidal syndrome; paralysis agitans and postencephalitic parkinsonism. J Neurol Neurosurg Psychiatry 1927;S1-8:9–18.doi:10.1136/jnnp.s1-8.29.9OpenUrl ↵Duvoisin RC, Lobo-Antunes J, Yahr MD. Response of patients with postencephalitic parkinsonism to levodopa. J Neurol Neurosurg Psychiatry 1972;35:487–95.doi:10.1136/jnnp.35.4.487 ↵Surana P, Tang S, McDougall M, et al. Neurological complications of pandemic influenza A H1N1 2009 infection: European case series and review. Eur J Pediatr 2011;170:1007–15.doi:10.1007/s00431-010-1392-3OpenUrlCrossRefPubMed ↵Reed C, Chaves SS, Perez A, et al. Complications among adults hospitalized with influenza: a comparison of seasonal influenza and the 2009 H1N1 pandemic. Clin Infect Dis 2014;59:166–74.doi:10.1093/cid/ciu285OpenUrlCrossRefPubMed ↵Goenka A, Michael BD, Ledger E, et al. Neurological manifestations of influenza infection in children and adults: results of a national British surveillance study. J Neurol Neurosurg Psychiatry 2014;58:775–84.doi:10.1093/cid/cit922OpenUrl ↵Ng Kee Kwong KC, Mehta PR, Shukla G, et al. COVID-19, SARS and MERS: a neurological perspective. J Clin Neurosci 2020;77:13–16.doi:10.1016/j.jocn.2020.04.124OpenUrl ↵Morfopoulou S, Brown JR, Davies EG, et al. Human coronavirus OC43 associated with fatal encephalitis. N Engl J Med 2016;375:497–8.doi:10.1056/NEJMc1509458OpenUrlCrossRefPubMed ↵Varatharaj A, Thomas N, Ma E, et al. UK-wide surveillance of neurological and neuropsychiatric complications of COVID-19 : The first 153 patients. Lancet Psychiatry 2020. ↵Mao L, Jin H, Wang M, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol 2020;77:683–90.doi:10.1001/jamaneurol.2020.1127OpenUrl ↵Ellul M, Varatharaj A, Nicholson TR, et al. Defining causality in COVID-19 and neurological disorders. J Neurol Neurosurg Psychiatry 2020;6. doi:doi:10.1136/jnnp-2020-323667. [Epub ahead of print: 05 Jun 2020].pmid:http://www.ncbi.nlm.nih.gov/pubmed/32503883OpenUrlPubMed ↵Beyrouti R, Adams ME, Benjamin L, et al. Characteristics of ischaemic stroke associated with COVID-19. J Neurol Neurosurg Psychiatry 2020. doi:doi:10.1136/jnnp-2020-323586. [Epub ahead of print: 30 Apr 2020].pmid:http://www.ncbi.nlm.nih.gov/pubmed/32354768OpenUrlPubMed ↵Ellul M, Benjamin L, Singh B, et al. Neurological associations of COVID-19. SSRN Journal 2020.doi:10.2139/ssrn.3589350 ↵Toscano G, Palmerini F, Ravaglia S, et al. Guillain-Barré syndrome associated with SARS-CoV-2. N Engl J Med 2020;382:2574–6.doi:10.1056/NEJMc2009191pmid:http://www.ncbi.nlm.nih.gov/pubmed/32302082OpenUrlPubMed
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The Anti-NMDA Receptor Encephalitis Foundation Newsletter

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Cerebrospinal fluid, antineuronal autoantibody, EEG, and MRI findings from 992 patients with schizophreniform and affective psychosis From...
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Decreased inflammatory cytokine production of antigen-specific CD4+ T cells in NMDA receptor encephalitis | medRxiv

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