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Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and... - PubMed - NCBI

Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and... - PubMed - NCBI | AntiNMDA | Scoop.it
Lancet Neurol. 2018 Sep;17(9):760-772. doi: 10.1016/S1474-4422(18)30244-8. Epub 2018 Jul 23. Multicenter Study; Observational Study; Research Support, N.I.H., Extramural; Research Support, Non-U.S.Gov't...
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AE Day of Strength, 27 July 2019, Texas Children’s Hospital

AE Day of Strength, 27 July 2019, Texas Children’s Hospital | AntiNMDA | Scoop.it
The Foundation is honoured to have been invited by The Texas Children’s Hospital to participate in their AE Day of Strength, for survivors and caregivers on Saturday, 27 July 2019, in Houston, Texas. Building on the success of last year’s event, titled AE Day of Hope, the theme this year will be Strength.This special event will bring together patients and their families affected by autoimmune encephalitis to connect with other affected families, to exchange stories of shared hardship and ways of coping, as well as learning about the latest updates in the field of neuro-immunology. No one should have to face the hardships of autoimmune encephalitis alone and what better way than to dedicate a day and shine a stark bright light on a group of diseases that few had heard of, until their loved-one was stricken. The global AE family is growing and strengthened thanks to the contribution, leadership and solidarity with patients and their families of The Texas Children’s Hospital. The Foundation’s founding president, Ms. Nesrin Shaheen is looking forward to making the keynote presentation and to meeting patients and their families. If you are in the Houston area or can travel, we would love to see you there.
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Frontiers | Autism Associated With Anti-NMDAR Encephalitis: Glutamate-Related Therapy | Psychiatry

The purpose of this review is to correlate autism with autoimmune dysfunction in the absence of an explanation for the etiology of autism spectrum disorder. Anti-N-methyl-D-aspartate receptor (anti-NMDAR) autoantibody is a typical synaptic protein that can bind to synaptic NMDA glutamate...
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Anti-NMDA receptor encephalitis in a toddler: A diagnostic challenge

Anti-NMDA receptor encephalitis in a toddler: A diagnostic challenge | AntiNMDA | Scoop.it
Anti N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder and is considered to be one of the most common causes of encephalitis in children. Despite the fact that around half of all reported cases are of children, the number of ...
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Trial to Evaluate Efficacy and Safety of Bortezomib in Patients With...

Autoimmune Encephalitis is a disorder of the central nervous system caused by bodily substances, called antibodies. Antibodies normally help the body to...
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N2 Impact Factor Announced! | American Academy of Neurology Journals

We are excited to announce that Neurology® Neuroimmunology & Neuroinflammation (N2) has received our Impact Factor (7.353). We recognize that publishing in a journal with an impact factor is important to many authors, and we are excited to have the ability to receive and publish your contributions! We publish rigorously peer-reviewed open access reports of original research and in-depth reviews of topics in neuroimmunology & neuroinflammation. Clinical trials, instructive case reports, and small case series are also featured. Below are some highlights of what we have published over the past five years. We look forward to seeing your future work! Sincerely, Josep O. Dalmau, MD,PhD Editor, Neurology® Neuroimmunology & Neuroinflammation Highlights of Neurology® Neuroimmunology & Neuroinflammation from the past 5 years Zamvil SS, Slavin, AJ. Does MOG Ig-positive AQP4-seronegative opticospinal inflammatory disease justify a diagnosis of NMO spectrum disorder? Neurol Neuroimmunol Neuroinflamm 2015;1:262 https://nn.neurology.org/content/2/1/e62   Flanagan EP, Kotsenas AL, Britton JW et al. Basal ganglia T1 hyperintensity in LGI1-autoantibody faciobrachial dystonic seizures. Neurol Neuroimmunol Neuroinflamm 2015;2:e161 https://nn.neurology.org/content/2/6/e161   Ogawa R, Nakashima I, Takahashi T et al. MOG antibody-positive, benign, unilateral, cerebral cortical encephalitis with epilepsy. Neurol Neuroimmunol Neuroinflamm 2017;4:e322 https://nn.neurology.org/content/4/2/e322   Linnoila JJ, Binnicker MJ, Majed M, Klein CJ, McKeon A. CSF herpes virus and autoantibody profiles in the evaluation of encephalitis. Neurol Neuroimmunol Neuroinflamm 2016;3:e325 https://nn.neurology.org/content/3/4/e245   Baharnoori M, Lyons J, Dastagir A, Koralnik I, Stankiewicz JM.  onfatal PML in a patient with multiple sclerosis treated with dimethyl fumarate. Neurol Neuroimmunol Neuroinflamm 2016;3:e274 https://nn.neurology.org/content/3/5/e274   Gilden D, White T, Khmeleva N, Boyer PJ, Nagel MA. VZV in biopsy-positive and -negative giant cell arteritis: Analysis of 100+ temporal arteries. Neurol Neuroimmunol Neuroinflamm 2016;3:e216   Waters P, Woodhall M, O’Connor KC et al. MOG cell-based assay detects non-MS patients with inflammatory neurologic disease. Neurol Neuroimmunol Neuroinflamm 2015;2:e89 https://nn.neurology.org/content/2/3/e89   Spencer CM, Crabtree-Hartman EC, Lehmann-Horn K, Cree BAC, Zamvil SS. Reduction of CD8+ T lymphocytes in multiple sclerosis patients treated with dimethyl fumarate. Neurol Neuroimmunol Neuroinflamm 2015;2:e76 https://nn.neurology.org/content/2/3/e76   Azevedo CJ, Overton E, Khadka S et al. Early CNS neurodegeneration in radiologically isolated syndrome. Neurol Neuroimmunol Neuroinflamm 2015;2:e102 https://nn.neurology.org/content/2/3/e102   Zekeridou A, Lennon VA. Aquaporin-4 autoimmunity. Neurol Neuroimmunol Neuroinflamm 2015;2:e110 https://nn.neurology.org/content/2/4/e110   Galetta SL, Villoslada P, Levin N et al. Acute optic neuritis Unmet clinical needs and model for new therapies. Neurol Neuroimmunol Neuroinflamm 2015;2:e135 https://nn.neurology.org/content/2/4/e135   Bennett JL, O’Connor KC, Bar-Or A et al. B lymphocytes in neuromyelitis optica. Neurol Neuroimmunol  Neuroinflamm 2015;2:e104 https://nn.neurology.org/content/2/3/e104   Hacohen Y, Absoud M, Deiva K et al. Myelin oligodendrocyte glycoprotein antibodies are associated with a non-MS course in children. Neurol Neuroimmunol Neuroinflamm 2015;2:e81 https://nn.neurology.org/content/2/2/e81   Querol L, Rojas-Garcia R, Diaz-Manera J et al. Rituximab in treatment-resistant CIDP with antibodies against paranodal proteins. Neurol Neuroimmunol Neuroinflamm 2015;2:e149 https://nn.neurology.org/content/2/5/e149   Lejuste F, Thomas L, Picard G et al. Neuroleptic intolerance in patients with anti-NMDAR encephalitis. Neurol Neuroimmunol Neuroinflamm 2016;3:e280 https://nn.neurology.org/content/3/5/e280
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Higher CSF Levels of NLRP3 Inflammasome Is Associated With Poor Prognosis of Anti-N-methyl-D-Aspartate Receptor Encephalitis. - PubMed - NCBI

Front Immunol. 2019 May 31;10:905. doi: 10.3389/fimmu.2019.00905. eCollection 2019.
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The organizing principle of GABAB receptor complexes: Physiological and pharmacological implications - Fritzius - - Basic & Clinical Pharmacology & Toxicology - Wiley Online Library

Abstract GABAB receptors (GBRs), the G protein‐coupled receptors for the neurotransmitter γ‐aminobutyric acid (GABA), regulate synaptic transmission at most synapses in the brain. Proteomic approaches revealed that native GBR complexes assemble from an inventory of ~30 proteins that provide a molecular basis for the functional diversity observed with these receptors. Studies with reconstituted GBR complexes in heterologous cells and complementary knockout studies have allowed to identify cellular and physiological functions for obligate and several non‐obligate receptor components. It emerges that modular association of receptor components in space and time generates a variety of multiprotein receptor complexes with different localizations, kinetic properties and effector channels. This article summarizes current knowledge on the organizing principle of GBR complexes. We further discuss unanticipated receptor functions, links to disease and opportunities for drug discovery arising from the identification of novel receptor components. 1 GBR FUNCTIONS IN THE BRAIN GABAB receptors (GBRs) are G protein‐coupled receptors for the main inhibitory neurotransmitter in the central nervous system, γ‐aminobutyric acid (GABA).1-3 The GABA metabolite γ‐hydroxybutyrate (GHB), a psychoactive drug of abuse, is a second endogenous ligand of GBRs.4 Whether the concentrations of GHB in the brain are sufficiently high to activate GBRs is a matter of debate. However, GBRs clearly mediate most of the physiological effects observed with recreational use of GHB. GBRs activate heterotrimeric Gi/o‐type G proteins that inhibit adenylyl cyclase through the Gα subunit.1-3 The consequences of inhibiting cAMP production in neurons through GBRs include the inhibition of spontaneous neurotransmitter release and the disinhibition of two‐pore domain K+ channels.1 The best‐known neuronal GBR functions are the gating of voltage‐sensitive Ca2+ (Cav) channels and inwardly rectifying Kir3‐type K+ channels by the Gβγ subunits of the G protein.1, 2 GBRs inhibit N‐ and P/Q‐type Ca2+ channels, which dampens neurotransmitter release at many terminals, including GABAergic and glutamatergic terminals. Contrasting the dogma that GBRs inhibit Ca2+ channels and neurotransmitter release, recent reports suggest that GBRs activate R‐type Ca2+‐channels to trigger neurotransmitter release in habenular projections to the interpeduncular nucleus.5, 6 Since GBRs conventionally inhibit R‐type Ca2+ channels in heterologous cells, it remains to be elucidated how GBRs activate these channels in neurons. It is possible that activation of R‐type Ca2+ channels relates to receptor‐interacting proteins, intracellular signalling crosstalks and/or GBR effects on network activity. GBRs activate Kir3 channels in the dendrites of most neurons, which hyperpolarizes the membrane and shunts excitatory neurotransmission.1 Astrocytes in the brain also express GBRs. However, the physiological consequences of GBR signalling in astrocytes are largely unknown. Recent data support that parvalbumin‐ and somatostatin‐expressing interneurons induce GBR‐mediated Ca2+ elevations in astrocytes.7 These GBR‐induced Ca2+ responses decrease and increase upon repetitive stimulation of parvalbumin and somatostatin interneurons, respectively, revealing that GBR responses in astrocytes are plastic. The fact that Gi/o‐coupled GBRs induce Ca2+ responses in astrocytes is surprising and likely involves a signalling crosstalk with other receptors.1 2 MARKETED GBR DRUGS It is a widely accepted concept that disturbances in the excitation/inhibition balance underlie numerous neurological and neuropsychiatric disorders. Too little inhibition is linked to epilepsy, spasticity, anxiety, sleep disorders, depression, addiction and chronic pain while too much inhibition is associated with schizophrenia and cognitive deficits.8 GBRs modulate synaptic transmission and neuronal activity in most neurons of the brain. Reciprocally, GBR expression is down‐regulated in response to sustained neuronal excitation.1 It is therefore no wonder that dysregulated GBR signalling has long been associated with neurological and mental health disorders.1, 2, 9 Despite the well‐documented involvement of GBRs in disease, only two GBR drugs are currently on the market. The prototypical GBR agonist baclofen (Lioresal®) is prescribed to reduce muscle rigidity and spasms associated with multiple sclerosis.1 The small doses of intrathecal baclofen used to treat spasticity do not cause systemic side effects. GHB (also known as sodium oxybate, Xyrem®), the second marketed GBR drug, is prescribed to decrease daytime sleepiness and reduce sudden attacks of weak/paralysed muscles (cataplexy) in narcoleptic patients.4 The exact mechanism of action of Xyrem is unknown but it is generally assumed that Xyrem exerts its therapeutic effects by activating GBRs. Xyrem is administered orally during the night when potential side effects from systemic activation of GBRs, such as weakness and muscle relaxation, are less problematic. Differences in the dose, time and route of drug administration therefore allow using GHB and baclofen in different indications even though both activate GBRs. Baclofen is increasingly used off‐label to treat alcohol dependence.10 In France, baclofen is currently the most prescribed pharmacotherapy for alcohol use disorders. While clinical trials support the efficacy of high doses of baclofen for alcohol use disorders, they also note sedation as a major side effect.10 Recent trials support that GHB, like baclofen, may also be useful in the therapy of alcohol dependence.11 In fact, GHB (Alcover®) is already marketed in Italy to alleviate withdrawal symptoms and reduce the craving for alcohol. 3 FUNCTIONS OF OBLIGATE RECEPTOR COMPONENTS The molecular structure of GBRs remained for a long‐time elusive. In 1997, expression cloning using a high‐affinity radioligand antagonist allowed to identify the GB1 subunit, which by itself did not form a functional receptor.1 However, GB1 featured the typical seven‐transmembrane topology of G protein‐coupled receptors and exhibited homology to metabotropic glutamate receptors. Database searches and yeast‐two‐hybrid screens subsequently identified the sequence‐related GB2 subunit, which by itself again was non‐functional.1 Most neurons in the brain co‐expressed GB1 and GB2, which suggested that they act together in a complex. Electrophysiological and biochemical studies in transfected heterologous cells indeed revealed that co‐expression of GB1 with GB2 subunits was necessary to generate a functional receptor. This represented the first example of an obligate heterodimeric G protein‐coupled receptor. Confirmation that native GB1 and GB2 subunits form heterodimers was obtained in subsequent studies with knockout mice showing that lack of GB1 or GB2 subunits abrogated all electrophysiological and biochemical GBR responses.1 Analysis of knockout mice further revealed that the GB1/GB2 complex stabilizes its constituent proteins. The behavioural phenotypes of GB1 and GB2 knockout mice include epilepsy, cognitive impairments, hyperactivity, hyperalgesia, increased anxiety and a reduced threshold for fear responses.1 Recent studies addressed the functions of GBRs in identified neuronal populations. Genetic deletion of GBRs in principal neurons of the input layer of the auditory cortex produces deficits in auditory map remodelling, indicating that GBRs gate auditory critical period plasticity.12 Genetic deletion of GBRs in dopamine neurons of the ventral tegmental area (VTA) markedly increased cocaine‐induced locomotion without affecting general or morphine‐induced locomotor activity.13 It appears that long‐range GABAergic inputs from the nucleus accumbens to the VTA activate GBRs on dopamine neurons to regulate cocaine‐induced locomotion.13 Altogether, knockout studies confirmed that heterodimeric GB1/GB2 complexes represent the minimal functional unit required for receptor signalling and showed that neuronal GBRs regulate a wide array of physiological functions and behaviours. A large body of evidence supports that GB1 and GB2 assume distinct and non‐redundant functions in the heterodimeric receptor. Most notably, GB1 binds GABA while GB2 couples to the G protein and increases GABA affinity at GB1.1-3 Allosteric interactions between GB1 and GB2 are therefore necessary for activating the G protein at GB2 after binding of GABA to GB1.2, 3 X‐ray structures of the heterodimeric GB1/GB2 ectodomains in the resting and active states showed that the so‐called “venus fly‐trap domain” of GB1 closes upon GABA binding.2, 3 Conversely, antagonists stabilize the open inactive conformation of the GB1 venus fly‐trap domain. The GB2 venus fly‐trap domain remains constitutively open during the activation process.2, 3 The GB1/GB2 heterodimer exhibits high intrinsic conformational flexibility. In the absence of ligands, GB1 spontaneously oscillates between inactive and active states.2 Because of these frequent conformational changes, the receptor exhibits high basal activity in the absence of agonist.14 Heterodimerization of GB1 with GB2 occurs in the endoplasmic reticulum and regulates targeting to the plasma membrane.1 The endoplasmic reticulum‐resident prenylated Rab acceptor family 2 (PRAF2) protein binds to an endoplasmic reticulum retention signal in GB1.15 Assembly of GB1 with GB2 releases PRAF2, which allows the heterodimeric receptor to exit the endoplasmic reticulum and to traffic to the cell surface. GB1/GB2 heterodimers at the plasma membrane can form transient higher‐order complexes via interaction of their GB1 subunits.16 Higher‐order complexes assemble by random collision of heterodimers in an activity‐independent manner. Consequently, higher‐order complexes are more abundant at higher densities of heterodimers.2 Assembly into higher oligomers limits receptor signalling via G proteins because neighbouring G protein binding sites cannot be simultaneously occupied.16 Two main variants of the GB1 subunit exist, GB1a and GB1b, which differ by the presence of two sushi domains at the N‐terminus of GB1a.1-3 When expressed in heterologous cells, GB1a/GB2 and GB1b/GB2 receptors are functionally and pharmacologically alike.1 However, studies with GB1a and GB1b knockout mice showed that the lack of GB1a and GB1b subunits differentially influences synaptic plasticity processes,1 network oscillations1, 17 and behaviour.1 Biochemical and electrophysiological experiments further revealed that GB1a/GB2 receptors accumulate at axon terminals while GB1b/GB2 receptors accumulate in the somato‐dendritic compartment. Mechanistically, the sushi domains act as axonal trafficking signals1 and stabilize GB1a/GB2 receptors at the cell surface.18 Proteomic work identified the β‐amyloid precursor protein (APP), the adherence junction‐associated protein 1 (AJAP‐1) and the PILRα‐associated neural protein (PIANP) as interactors of the sushi domains of GB1a.19 APP, AJAP‐1 and PIANP may therefore play a role in axonal trafficking and localization of GB1a/GB2 receptors (see below). 4 FUNCTIONS OF NON‐OBLIGATE RECEPTOR COMPONENTS Electrophysiology revealed that GBR‐mediated K+ currents in non‐neuronal cells exhibit a slower rise time than in neurons.20 Moreover, GBR‐induced K+ currents exhibit little desensitization in heterologous cells while they exhibit pronounced desensitization in some neurons.20 Differences between cloned and native GBR responses suggested early on the existence of receptor‐associated proteins that influence receptor kinetics. The search for GBR‐associated proteins sparked biochemical experiments showing that native GBRs form high‐molecular‐weight complexes of >500 kDa.1 Individual GB1/2 heterodimers of 220 kDa were not observed, corroborating that GB1/2 heterodimers execute their functions in combination with associated proteins. Quantitative proteomic approaches eventually identified approximately 30 proteins that stably or transiently associate with native GB1 or GB2 subunits19 (Figure 1). The protein inventory comprises sushi domain‐interacting proteins and signalling components, such as G protein subunits, ion channels and elements of the presynaptic release machinery. In addition, the protein inventory includes proteins of unknown functions. Most of the GBR‐associated proteins only show a partial spatial and temporal overlap with the expression patterns of GB1 and GB2 in the brain, indicating that they are non‐obligate receptor components. The anatomically and temporally restricted expression of most GBRs components suggests a highly diverse and modular receptor composition. Interestingly, many of the GBR‐associated proteins previously identified in yeast‐two‐hybrid screens were absent in the GBR proteome,2, 19 possibly because yeast‐two‐hybrid screens are better at detecting low‐affinity or transient pairings. However, it is also possible that yeast‐two‐hybrid screens erroneously detect protein interactions that do not occur in vivo, for example because the supposed partner proteins are expressed in different cellular or subcellular compartments. Below, we discuss progress made in dissecting the neuronal, cellular and behavioural functions of the GBR‐associated proteins identified using proteomic approaches and native tissue. The available data are compatible with a modular organization of GBR complexes, in which the GB1a/2 and GB1b/2 heterodimers can associate with a variable repertoire of proteins regulating trafficking, signalling and localization of the receptor complex (Figure 1). 4.1 KCTD proteins The cytosolic K+ channel tetramerization domain (KCTD) proteins KCTD8, KCTD12, KCTD12b and KCTD16 bind to the C‐terminal domain of GB21, 2 (Figure 1). Recent cryo‐electron microscopy and crystallization studies indicate that the T1 tetramerization domain of KCTD16 assembles into an open pentameric ring with an inner diameter of ~25 Å.21-23 Adjacent KCTD16 T1 subunits are arranged side‐by‐side with similar C‐ and N‐terminal orientation. The high‐resolution crystal structure of the T1 pentamer in complex with a C‐terminal peptide of GB2 shows that a single GB2 peptide binds to the inner surface of the open pentameric ring, with the interface having exceptionally high shape complementarity.22, 23 The GB2 peptide is located asymmetrically, off centre, away from the opening of the ring.23 The GB2 peptide loops around inside the ring structure of the pentamer with the N‐ and C‐termini of GB2 pointing to the KCTD16 N‐terminus.22 In addition to binding to GB2, KCTDs also interact with the Gβγ subunits of the G protein via their H1 homology domain.20, 22 Structural analysis revealed that a KCTD12 H1‐pentamer interacts with five copies of the Gβγ heterodimer in a near perfect C5 symmetry.22 Interactions between KCTD12 and Gβγ are confined to the Gβ subunit. The five Gβγ subunits each interact with two KCTD12 H1 domains. Lack of formation of partial KCTD12/Gβγ oligomers suggested that KCTD12 binding to Gβγ is highly cooperative.22 Importantly, combining the KCTDs with GB1 and GB2 subunits in heterologous cells confers the missing fast kinetics to recombinant GBRs.20, 24 Conversely, genetic ablation of the KCTDs in neurons leads to a slowing of GBR signalling.20, 24 In addition, the KCTDs shorten the delay between agonist application and onset of the receptor response.20 This acceleration of receptor signalling likely relates to the KCTD's ability to scaffold the G protein at the receptor, which renders diffusion of the G protein to the receptor during the activation process obsolete.20 On the other hand, scaffolding of the G protein may also prevent the receptor from activating multiple G proteins by random collision, which will reduce the signal amplification typically observed with G protein‐coupled receptors. KCTD12 and KCTD12b additionally induce a pronounced desensitization of the receptor response by activity‐dependent uncoupling of the Gβγ subunits from effector K+ channels.20, 22 Biochemical experiments and bimolecular bioluminescence resonance energy transfer (BRET) experiments revealed that not only KCTD homomers but also KCTD heteromers associate with the receptor (Figure 1).24 Of note, charged interactions at the pentameric interface of the KCTD16 T1 structure are conserved among all GABAB‐related KCTD proteins, which explains how pentameric heteromers can form. Moreover, conservation of amino acids in the GB2/KCTD interface is compatible with the observation that KCTDs can form heteromers that regulate GBR responses.23, 24 In fact, the formation of KCTD heteromers enables a fine‐tuning of receptor kinetics. KCTD12/16 heteromers, for example, increase the duration of slow inhibitory post‐synaptic currents (IPSCs) in hippocampal neurons.24 In addition to their kinetic effects on the receptor response, the KCTDs promote surface expression of the receptor complex and shift the EC50 value of GBR‐mediated K+ currents towards lower concentrations.1 The KCTDs exert per se little allosteric influence on the orthosteric GABA binding site,25 suggesting that the observed increase in GABA potency relates to KCTD effects on the G protein cycle. In addition to their kinetic effects, KCTD proteins scaffold effector channels and other proteins at the receptor. KCTD16, for example, recruits N‐type Ca2+ channels, hyperpolarization‐activated cyclic nucleotide‐gated 2 (HCN2) channels and 14‐3‐3 proteins to the receptor19 (Figure 1). The KCTD proteins are non‐obligatory GBR components. However, they stably associate with the receptor and co‐immunopurify with GB1 and GB2 under stringent solubilization conditions.19, 20 KCTDs should therefore be viewed as auxiliary receptor subunits that regulate surface expression and receptor kinetics. Of note, the GB2 C‐terminal domain of invertebrates lacks a KCTD binding site, indicating that auxiliary KCTD subunits represent a functional specialization of GBRs during vertebrate evolution. Likely, the KCTDs evolved to quickly initiate and terminate receptor signalling to effector channels. In addition, preassembly of the G protein at the receptor may increase constitutive activity and contribute to G protein/receptor specificity. 4.2 Sushi domain‐associated proteins APP, AJAP‐1 and PIANP are transmembrane proteins that co‐purify with native GB1a/2 receptors and bind in a mutually exclusive manner to the sushi domains of the presynaptic GB1a subunit19 (Figure 1). APP is the source of β‐amyloid (Aβ) peptides, a hallmark of Alzheimer's disease (Table 1). A recent report by Rice et al26 shows that binding of the soluble form of APP (sAPP) to the N‐terminal sushi domain of GB1a inhibits GBR‐mediated neurotransmitter release. A GBR antagonist disinhibits sAPP‐inhibited release, supporting that sAPP acts as GBR agonist or positive allosteric modulator. A related report shows that binding of full‐length APP to the N‐terminal sushi domain of GB1a is necessary for vesicular trafficking of GBRs to axon terminals.27 Consistent with vesicular GBR transport, kinesin‐1 adaptors of the c‐Jun N‐terminal kinase‐interacting protein (JIP) and calsyntenin (CSTN) protein families are shown to bind to APP and to link the APP/GBR complex to kinesin‐1 motors. In contrast to the report by Rice et al, no functional effects of sAPP at GBRs were observed. Functional effects of sAPP at GBRs therefore need to be independently confirmed. AJAP‐1 and PIANP share sequence similarity in their intracellular domains. The two proteins are expected to localize to adherens junctions that mediate adhesion between pre‐ and post‐synaptic membranes.28, 29 AJAP‐1 and PIANP do not play a role in vesicular axonal trafficking of GBRs.27 Possibly, these proteins anchor GB1a/2 receptors at synaptic sites by binding to the sushi domains in cis or in trans. Amyloid‐like protein 2 (APLP2), integral membrane protein 2B (ITM2B) and ITM2C are additional transmembrane proteins that selectively co‐purify with the GB1a subunit19 (Figure 1). Since these proteins associate with APP, they probably represent secondary interactors of GBRs (Figure 1). It therefore appears that GBRs can assemble with multiprotein APP complexes into supercomplexes (complexes of complexes). Receptor component Disease Molecular link Reference GB1 Encephalitis Autoantibodies 59, 61, 62 Alzheimer's disease Protein expression post‐mortem 63 GB2 Rett syndrome Mutations in TM3 and TM6 33, 34 Epileptic encephalopathy Exome sequencing 26 KCTD8 Type 2 diabetes GWAS 39 Brain size GWAS 35 KCTD12 Type 2 diabetes GWAS 40 Bipolar I disorder GWAS 38 Pain Proteomic 41 Major depressive disorder Gene expression post‐mortem 37 Gastrointestinal tumours Proteomic and gene mutation 42, 43 AJAP‐1 Migraine GWAS 46 Glioblastoma multiform Gene deletion, down‐regulated 47 Adolescent idiopathic scoliosis GWAS 45 PIANP Intellectual disability Exome sequencing 44 APP Alzheimer's disease Amyloid plaques 63 Nlgn‐3 Pain Proteomic 41 Syt‐11 Schizophrenia Patient sequencing 64 Parkinson's disease GWAS 65, 66 Cav subunit β2 Bipolar I disorder GWAS 38 Major depressive disorder Gene expression post‐mortem 37 HCN2 Generalized epilepsy Exome sequencing 67 TRPV1 Inflammatory pain Proteomic 30 Note Disease‐related alterations in receptor components, where known, are indicated. 4.3 Effector channels GBRs gate Kir3‐type K+ channels and voltage‐sensitive Ca2+ channels in most neurons of the central nervous system.1, 5, 6 Kir3 channels do not appear to physically associate with GBRs while N‐type Ca2+ channels co‐purify with native GBRs by interacting with KCTD16 (Figure 1).19 Surprisingly, proteomic work indicates that transient receptor potential vanilloid 1 (TRPV1) and HCN2 channels also associate with GBRs (Figure 1).19, 30 Interestingly, activation of GB1 reverts the sensitized state of TRPV1 channels in a G protein‐dependent manner.30 Similarly, GBRs also inhibit transient receptor potential melastatin‐3 (TRPM3) channels.31, 32 However, no direct interaction of TRPM3 channels with GB1 has been reported. HCN2 channels, like N‐type Ca2+ channels, associate via KCTD16 with the receptor (Figure 1).19 Dopaminergic neurons of the VTA co‐express HCN2 channels, KCTD16 and GBRs and thus provided a cellular system to study the physiological consequences of the HCN2/GBR interaction. It was shown that GBRs activate HCN2 currents and shorten the duration of inhibitory post‐synaptic potentials19 (Figure 2). HCN2 channels are dissociated from GBRs in KCTD16 knockout mice, which prevents HCN2 activation and prolongs the duration of inhibitory post‐synaptic potentials. The mechanism(s) underlying GBR‐induced activation of HCN2 channels is still unknown. Possible mechanisms include (a) membrane hyperpolarization via Kir3 channels, (b) allosteric interactions between receptor and channel, and/or (c) dynamic interactions between the channel and G protein subunits or second messengers. 4.4 Other receptor components Additional proteins of the GBR interactome are neuroligin‐3 (Nlgn‐3), synaptotagmin‐11 (Syt‐11), calnexin, reticulocalbin‐2 and inactive dipetidylpeptidases 6/10 (DPP 6/10; Figure 1).19 It is unknown whether these proteins represent primary or secondary interactors of GB1 or GB2. Purification of native GBR complexes from knockout mice and reverse‐affinity purifications with antibodies against these proteins will reveal whether their presence in receptor complexes depends on other receptor components and hint at physiological functions. 5 NOVEL LINKS OF RECEPTOR COMPONENTS TO DISEASE As mentioned above, GBRs have long been associated with neurological and psychiatric conditions.1, 2 Genome‐wide association studies (GWAS), proteomic, exome sequencing and microarray studies have provided novel links of receptor components to disease (Table 1). Recently, mutations in the GB2 transmembrane domains 3 and 6 have been associated with Rett syndrome, epileptic encephalopathy and infantile epileptic spasms.33, 34 Some of these mutations increase constitutive receptor activity and therefore reduce the efficacy of GABA in stimulating the receptor. Auxiliary KCTD subunits have been associated with small brain size,35 schizophrenia,36 depression,37 bipolar I disorder,38 diabetes,39, 40 pain41 and cancer.42, 43 The sushi domain‐interacting proteins APP, AJAP‐1 and PIANP are linked to Alzheimer's disease, intellectual disability,44 adolescent idiopathic scoliosis,45 migraine46 and cancer.47 HCN2 mutations are associated with generalized epilepsy. Additional receptor components link to pain, schizophrenia, Parkinson's disease, bipolar I disorder and depression. For most genetic links, insights into pathophysiological mechanisms are lacking, which hinders the design of straightforward therapeutic concepts. It is also important to note that genetic links to disease in non‐obligate GBR components do not necessarily relate to dysfunctional GBR signalling. Nevertheless, it may be interesting to approach disease in terms of protein‐protein interactions in receptor complexes. Mutations in the same receptor component may lead to different disease phenotypes by disrupting different protein interactions and functions. Conversely, mutations in different proteins that disrupt the same interaction and receptor function may lead to the same disease. Knowledge about the organizing principle of GBRs may therefore pave the way for more specific therapeutic interference with disease (see below). 6 PHARMACOLOGICAL IMPLICATIONS Disturbances in the excitation/inhibition balance underlie numerous neurological and neuropsychiatric disorders.8 Many available therapies for these disorders work by restoring a normal excitation/inhibition balance in perturbed neuronal pathways. Since activation or inhibition of GBRs modulates the excitation/inhibition balance, GBRs have been the focus of many drug discovery programs targeting mental health disorders. Unfortunately, baclofen either lacked efficacy (Fragile X syndrome), had a short duration of action, produced tolerance (pain) or exhibited prohibitive side effects (mainly muscle relaxation, sedation and mental confusion) when tested in indications other than spasticity, its prime therapeutic use.2, 9, 48-50 It has been argued that positive allosteric modulators of GBRs should produce fewer side effects and less tolerance because they selectively enhance the activity of receptors activated by endogenous GABA. Positive allosteric modulators of GBRs showed promising effects in animal models of drug abuse, schizophrenia, visceral pain, epilepsy, anxiety and overactive bladder, while they tested negative for depression and neuropathic pain.48, 49 Preclinical studies further support that positive allosteric modulators indeed produce less adverse effects, such as sedation and muscle relaxation, than agonists.1, 2, 49 Thus far, however, no allosteric modulators for G protein‐coupled receptors have been approved for the treatment of psychiatric or neurological disorders, even though several allosteric modulators entered Phase II trials.51 There is some concern that allosteric modulators for G protein‐coupled receptors lack efficacy in human trials, even if preclinical data are positive.9 Despite this general reluctance in starting new trials, Addex Pharmaceuticals (Geneva, Switzerland) recently announced the first clinical study with a positive allosteric modulator of GBRs, ADX71441, for the treatment of cocaine addiction (https://www.addextherapeutics.com/en/partners-collaboration/). GBR antagonists showed promising nootropic, anti‐absence seizures and antidepressant effects in animal models.48, 52 They also showed statistically significant improvements of working memory and attention in a Phase II clinical trial with mild Alzheimer disease patients.53 However, seizure liability of antagonists remains a main concern. A general shortcoming of agonists, antagonists and positive allosteric modulators is that they do not discriminate GB1a/2 and GB1b/2 receptor subtypes and their effector systems. This is problematic because GBRs mediate pre‐ and post‐synaptic functions at excitatory and inhibitory synapses and thus may have opposite effects on the excitation/inhibition balance depending on the cellular context. Global activation, inhibition or allosteric modulation of GBRs therefore mitigates desired therapeutic effects and generates unwanted side effects.9 Influencing region/circuit specific GBR functions by targeting identified receptor complexes would improve drug selectivity and allow a more specific therapeutic interference with disease.54 It is possible that inclusion of receptor‐associated proteins into high‐throughput compound screens uncovers new pharmacological sites for regulating receptor activity, as has been shown for AMPA receptor antagonists blocking certain receptor/TARP combinations.8 Targeting disease‐relevant protein‐protein interactions with peptides constitutes another means to influence specific receptor functions without affecting others.54-56 A good example for this approach is NA‐1, a cell‐penetrating peptide reducing ischaemic brain damage by interfering with the NMDA receptor/PSD‐95 interaction.57 Interfering with KCTD12 binding to GBRs, for example, would allow increasing and prolonging post‐synaptic inhibition, which is expected to have anxiolytic effects. Similarly, preventing binding of APP to the N‐terminal sushi domain of GB1a may interfere with GBR‐mediated inhibition of glutamate release and enhance cognitive functions. Antibody‐based therapeutics that interfere with specific receptor components represent an additional means to regulate the activity of molecularly defined receptor complexes.58 Proof‐of‐principle that antibodies can regulate GBR activity is provided by activity‐blocking GB1 autoantibodies in the serum of patients with autoimmune encephalitis.59 7 FUTURE DIRECTIONS Given the fundamental roles that GBRs play in synaptic transmission, behaviour and disease, it is important to study the structural organization of these receptors. The past two decades have seen a constant remodelling of our concept of GBR structure—from the discovery of obligate heterodimers to the recognition that heterodimers can form structurally and functionally diverse multiprotein receptor complexes assembled with distinct repertoires of auxiliary KCTD subunits, ion channels, adhesion and signalling proteins. It emerges that mutual interactions between receptor components stabilize proteins that work together to convey and regulate a specific function (eg GB2, KCTDs and G protein subunits). The core receptor can assemble with itself (GB1/GB2 oligomerization) and with other multiprotein complexes (eg APP with ITM2B/C proteins) into supercomplexes. It will be important to address whether multiprotein GBR complexes are stable over time or whether they dynamically reorganize in response to neuronal activity or developmental cues. Moreover, a spatiotemporal map of GBR complexes at axonal and dendritic sites will be necessary for a detailed understanding of cellular GBR functions. A structural understanding of receptor complexes in different functional states and in association with interacting proteins will largely depend on the success of cryo‐electron microscopy and X‐ray crystallography efforts.60 Such studies will also provide information on the stoichiometry of receptor components and spark drug discovery efforts aiming at interfering with specific protein interactions and receptor functions. ACKNOWLEDGEMENTS We apologize to those whose work we were unable to cite owing to space constraints. We thank members of the Bettler laboratory for helpful discussions. This work was supported by grants of the Swiss Science Foundation (31003A‐172881) and the National Center for Competences in Research (NCCR) “Synapsy, Synaptic Basis of Mental Health Disease” (to B.B). CONFLICT OF INTEREST The authors declare no competing interests. REFERENCES
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AE Day of Strength, 27 July 2019, Texas Children’s Hospital

AE Day of Strength, 27 July 2019, Texas Children’s Hospital | AntiNMDA | Scoop.it
Register: https://www.texaschildrens.org/health-professionals/conferences/autoimmune-encephalitis-day-strength
The Foundation is honoured to have been invited by The Texas Children’s Hospital to participate in their AE Day ...
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The Anti-NMDA Receptor Encephalitis Foundation Newsletter - June 17, 2019

The Anti-NMDA Receptor Encephalitis Foundation Newsletter - June 17, 2019 | AntiNMDA | Scoop.it
Anti-NMDA receptor (anti-NMDAR) encephalitis is a treatment-responsive autoimmune encephalitis, first described in 2007.1 Ovarian teratomas are found in one-third of the patients.2 The clinical features of this disorder vary between patients and age groups and usually include abnormal (psychiatric) behavior or cognitive dysfunction, speech dysfunction (pressured speech, verbal reduction, and mutism), seizures, movement disorders, dyskinesias, or rigidity/abnormal postures, decreased level of consciousness, autonomic dysfunction, or central hypoventilation.2 Cerebellar ataxia has been described as a symptom during the first months of the disease, especially in young children, in combination with other symptoms.2,3 It is extremely rare as the initial symptom, especially in adults. We report a case of a female adult with anti-NMDAR encephalitis presenting with cerebellar ataxia associated with recurrent mature ovarian teratomas. Case report A 32-year-old woman, born in South Korea and adopted at age 4 months, presented with vertigo, nausea, and vomiting for 4 days. Her medical history consisted of bilateral cystectomy revealing mature teratomas, discovered by ultrasound examination after a missed abortion at age 26 years. During cesarean sections afterward (ages 29 and 31 years), no macroscopic abnormalities were seen. Furthermore, she had had depressive symptoms, treated with venlafaxine for years. Neurologic examination showed a horizontal gaze-evoked nystagmus to the right without other neurologic signs or symptoms. Laboratory investigations on admission were normal, and brain CT showed no abnormalities. Initially, she improved after treatment with antiemetic drugs, but after 3 days, she deteriorated quickly, also complaining of headache. Neurologic examination showed nystagmus in all directions and dysarthric speech (cerebellar) that further worsened to impaired speech restricted to one-word sentences. She showed bilateral dysmetria of the lower and especially the upper limbs, truncal ataxia, and inability to stand and walk. Psychiatric evaluation showed rapid progression of depressive symptoms with suicidal ideation and labile affect. Brain MRI and MRV were normal. CSF analysis and extensive laboratory investigations showed pleocytosis (table). Anti-NMDAR antibodies were negative in serum, but positive in CSF,4 confirming the diagnosis of definite anti-NMDAR encephalitis.3 View inline View popup Table Overview of investigations The patient was treated with IV methylprednisolone 1,000 mg (day 13, 5 days) and IV immunoglobulins 0.4 g/kg (day 16, 5 days). Thorax/abdomen CT and transvaginal ultrasound revealed 2 lesions in the pelvic area with fat tissue and calcifications, suspect for teratomas. Bilateral laparotomic ovariectomy was performed (day 19). Pathologic examination showed mature cystic teratomas, without immature components, containing nervous tissue. Hormone replacement therapy was started. Her neurologic condition improved within a week, but the depressive mood remained. Recovery was hampered by urosepsis, treated with cefuroxime/amoxicillin. She was treated with a second course of methylprednisolone 4 weeks after the initial treatment and immunoglobulins at 8 weeks for remaining speech impairments and severe depression. This resulted in further improvement of both. After 6 weeks, the patient was transferred to a rehabilitation unit. After 6 months, the patient returned home. She was able to perform activities of daily living independently, but needed walking aids outside due to residual ataxia and had not returned to work (yet). Discussion This case with cerebellar ataxia as an initial symptom highlights an unusual presentation of anti-NMDAR encephalitis. If cerebellar ataxia is present in patients with anti-NMDAR encephalitis, it is almost exclusively found in (young) children, and most frequently, it appears later in the disease in combination with other symptoms.2 Different brainstem-cerebellar symptoms have been described, such as opsoclonus-myoclonus syndrome, ocular movement abnormalities, and low cranial nerve involvement in patients with ovarian teratomas, but these symptoms have more frequently been described in whom no NMDAR antibodies could be identified.5 Although 2 simultaneously occurring paraneoplastic neurologic syndromes, due to an ovarian teratoma, cannot be fully excluded, this is considered unlikely. The development of multiple symptoms quickly into diseases compatible with anti-NMDAR encephalitis (psychiatric symptoms and mutism), the confirmation of NMDAR antibodies by different tests,4 and the identification of an ovarian teratoma are suitable with a diagnosis of “definite anti-NMDAR encephalitis.”3 Although it is known that anti-NMDAR IgG antibodies bind to granular cells in the cerebellum (but not to Purkinje cells),6 it is unknown why only approximately 5% of patients show cerebellar complaints. MRI abnormalities of the cerebellum have been described in 6% of patients.7 A small study showed progressive cerebellar atrophy by follow-up MRI in 2 of 15 patients with anti-NMDAR encephalitis.6 In conclusion, cerebellar ataxia is unusual in adult patients and an extremely rare presenting symptom of anti-NMDAR encephalitis. This case shows that anti-NMDAR encephalitis should be considered in the differential diagnosis of cerebellar ataxia, especially in patients with previous teratomas and those developing other symptoms shortly afterward. Study funding No targeted funding reported. Disclosure M.J. Titulaer has filed a patent for methods for typing neurological disorders and cancer, and devices for use therein, and has received research funds for serving on a scientific advisory board of MedImmune LLC, for consultation at Guidepoint Global LLC, for teaching courses by Novartis, and an unrestricted research grant from Euroimmun AG. M.J. Titulaer has received funding from the Netherlands Organization for Scientific Research (NWO, Veni incentive), from the Dutch Epilepsy Foundation (NEF, project 14-19), and from ZonMw (Memorabel program). The other authors report no conflicts of interest. Go to Neurology.org/NN for full disclosures. Acknowledgment The authors thank J.J. Oudejans, pathologist, Tergooi, Blaricum, The Netherlands, and C.E. de Boer, physiatrist, Tergooi, Blaricum, The Netherlands, for their advice on this case. Appendix Authors Footnotes Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article. Informed consent: The patient gave informed consent. The Article Processing Charge was funded by the authors. Received January 3, 2019. Accepted in final form April 21, 2019. Copyright © 2019 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, Tuzun 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.↵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 3.↵Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016;15:391–404.OpenUrlCrossRefPubMed 4.↵Gresa-Arribas N, Titulaer MJ, Torrents A, et al. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol 2014;13:167–177.OpenUrlCrossRefPubMed 5.↵Armangue T, Titulaer MJ, Sabater L, et al. A novel treatment-responsive encephalitis with frequent opsoclonus and teratoma. Ann Neurol 2014;75:435–441.OpenUrl 6.↵Iizuka T, Kaneko J, Tominaga N, et al. Association of progressive cerebellar atrophy with long-term outcome in patients with anti-N-Methyl-d-Aspartate receptor encephalitis. JAMA Neurol 2016;73:706–713.OpenUrl 7.↵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
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Reply to “Grading the severity of autoimmune encephalitis: Advances and pitfalls” | MyNeuroNews

Jung‐Ah Lim, Soon‐Tae Lee, Kon Chu, Sang Kun Lee June 15, 2019 Read More... See Also: Grading the severity of autoimmune encephalitis: Advances and pitfalls Read More...... Reply to “epidemiology of autoimmune versus infectious encephalitis” Annals of Neurology, Volume 83, Issue 5, Page 1038-1038, May 2018. Read More...... Autoimmune Encephalitis Epidemiology and a comparison to Infectious Encephalitis Abstract Objectives We evaluate incidence and prevalence of autoimmune encephalitis and compare the epidemiology of autoimmune and infectious encephalitis. Methods We performed a population-based comparative study of the incidence and prevalence of autoimmune and infectious encephalitis in Olmsted County, USA. Autoimmune encephalitis diagnosis and subgroups were defined by 2016 diagnostic... Biomarkers of Neurodegeneration in Autoimmune-Mediated Encephalitis Peter Körtvelyessy, Harald Prüss, Lorenz Thurner, Walter Maetzler, Deborah Vittore-Welliong, Jörg Schultze-Amberger, Hans-Jochen Heinze, Dirk Reinhold, Frank Leypoldt, Stephan Schreiber, Daniel Bittner Read More...Read More......
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Management of antibody-mediated autoimmune encephalitis in adults and children: literature review and consensus-based practical recommendations

Management of antibody-mediated autoimmune encephalitis in adults and children: literature review and consensus-based practical recommendations | AntiNMDA | Scoop.it
Autoimmune encephalitis associated with antibodies against neuronal surface targets (NSAE) are rare but still underrecognized conditions that affect adult and pediatric patients. Clinical guidelines...
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The Anti-NMDA Receptor Encephalitis Foundation Newsletter - June 10, 2019

The Anti-NMDA Receptor Encephalitis Foundation Newsletter - June 10, 2019 | AntiNMDA | Scoop.it
Anti-NMDA receptor (anti-NMDAR) encephalitis is a treatment-responsive autoimmune encephalitis, first described in 2007.1 Ovarian teratomas are found in one-third of the patients.2 The clinical features of this disorder vary between patients and age groups and usually include abnormal (psychiatric) behavior or cognitive dysfunction, speech dysfunction (pressured speech, verbal reduction, and mutism), seizures, movement disorders, dyskinesias, or rigidity/abnormal postures, decreased level of consciousness, autonomic dysfunction, or central hypoventilation.2 Cerebellar ataxia has been described as a symptom during the first months of the disease, especially in young children, in combination with other symptoms.2,3 It is extremely rare as the initial symptom, especially in adults. We report a case of a female adult with anti-NMDAR encephalitis presenting with cerebellar ataxia associated with recurrent mature ovarian teratomas. Case report A 32-year-old woman, born in South Korea and adopted at age 4 months, presented with vertigo, nausea, and vomiting for 4 days. Her medical history consisted of bilateral cystectomy revealing mature teratomas, discovered by ultrasound examination after a missed abortion at age 26 years. During cesarean sections afterward (ages 29 and 31 years), no macroscopic abnormalities were seen. Furthermore, she had had depressive symptoms, treated with venlafaxine for years. Neurologic examination showed a horizontal gaze-evoked nystagmus to the right without other neurologic signs or symptoms. Laboratory investigations on admission were normal, and brain CT showed no abnormalities. Initially, she improved after treatment with antiemetic drugs, but after 3 days, she deteriorated quickly, also complaining of headache. Neurologic examination showed nystagmus in all directions and dysarthric speech (cerebellar) that further worsened to impaired speech restricted to one-word sentences. She showed bilateral dysmetria of the lower and especially the upper limbs, truncal ataxia, and inability to stand and walk. Psychiatric evaluation showed rapid progression of depressive symptoms with suicidal ideation and labile affect. Brain MRI and MRV were normal. CSF analysis and extensive laboratory investigations showed pleocytosis (table). Anti-NMDAR antibodies were negative in serum, but positive in CSF,4 confirming the diagnosis of definite anti-NMDAR encephalitis.3 View inline View popup Table Overview of investigations The patient was treated with IV methylprednisolone 1,000 mg (day 13, 5 days) and IV immunoglobulins 0.4 g/kg (day 16, 5 days). Thorax/abdomen CT and transvaginal ultrasound revealed 2 lesions in the pelvic area with fat tissue and calcifications, suspect for teratomas. Bilateral laparotomic ovariectomy was performed (day 19). Pathologic examination showed mature cystic teratomas, without immature components, containing nervous tissue. Hormone replacement therapy was started. Her neurologic condition improved within a week, but the depressive mood remained. Recovery was hampered by urosepsis, treated with cefuroxime/amoxicillin. She was treated with a second course of methylprednisolone 4 weeks after the initial treatment and immunoglobulins at 8 weeks for remaining speech impairments and severe depression. This resulted in further improvement of both. After 6 weeks, the patient was transferred to a rehabilitation unit. After 6 months, the patient returned home. She was able to perform activities of daily living independently, but needed walking aids outside due to residual ataxia and had not returned to work (yet). Discussion This case with cerebellar ataxia as an initial symptom highlights an unusual presentation of anti-NMDAR encephalitis. If cerebellar ataxia is present in patients with anti-NMDAR encephalitis, it is almost exclusively found in (young) children, and most frequently, it appears later in the disease in combination with other symptoms.2 Different brainstem-cerebellar symptoms have been described, such as opsoclonus-myoclonus syndrome, ocular movement abnormalities, and low cranial nerve involvement in patients with ovarian teratomas, but these symptoms have more frequently been described in whom no NMDAR antibodies could be identified.5 Although 2 simultaneously occurring paraneoplastic neurologic syndromes, due to an ovarian teratoma, cannot be fully excluded, this is considered unlikely. The development of multiple symptoms quickly into diseases compatible with anti-NMDAR encephalitis (psychiatric symptoms and mutism), the confirmation of NMDAR antibodies by different tests,4 and the identification of an ovarian teratoma are suitable with a diagnosis of “definite anti-NMDAR encephalitis.”3 Although it is known that anti-NMDAR IgG antibodies bind to granular cells in the cerebellum (but not to Purkinje cells),6 it is unknown why only approximately 5% of patients show cerebellar complaints. MRI abnormalities of the cerebellum have been described in 6% of patients.7 A small study showed progressive cerebellar atrophy by follow-up MRI in 2 of 15 patients with anti-NMDAR encephalitis.6 In conclusion, cerebellar ataxia is unusual in adult patients and an extremely rare presenting symptom of anti-NMDAR encephalitis. This case shows that anti-NMDAR encephalitis should be considered in the differential diagnosis of cerebellar ataxia, especially in patients with previous teratomas and those developing other symptoms shortly afterward. Study funding No targeted funding reported. Disclosure M.J. Titulaer has filed a patent for methods for typing neurological disorders and cancer, and devices for use therein, and has received research funds for serving on a scientific advisory board of MedImmune LLC, for consultation at Guidepoint Global LLC, for teaching courses by Novartis, and an unrestricted research grant from Euroimmun AG. M.J. Titulaer has received funding from the Netherlands Organization for Scientific Research (NWO, Veni incentive), from the Dutch Epilepsy Foundation (NEF, project 14-19), and from ZonMw (Memorabel program). The other authors report no conflicts of interest. Go to Neurology.org/NN for full disclosures. Acknowledgment The authors thank J.J. Oudejans, pathologist, Tergooi, Blaricum, The Netherlands, and C.E. de Boer, physiatrist, Tergooi, Blaricum, The Netherlands, for their advice on this case. Appendix Authors Footnotes Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article. Informed consent: The patient gave informed consent. The Article Processing Charge was funded by the authors. Received January 3, 2019. Accepted in final form April 21, 2019. Copyright © 2019 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, Tuzun 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.↵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 3.↵Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016;15:391–404.OpenUrlCrossRefPubMed 4.↵Gresa-Arribas N, Titulaer MJ, Torrents A, et al. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol 2014;13:167–177.OpenUrlCrossRefPubMed 5.↵Armangue T, Titulaer MJ, Sabater L, et al. A novel treatment-responsive encephalitis with frequent opsoclonus and teratoma. Ann Neurol 2014;75:435–441.OpenUrl 6.↵Iizuka T, Kaneko J, Tominaga N, et al. Association of progressive cerebellar atrophy with long-term outcome in patients with anti-N-Methyl-d-Aspartate receptor encephalitis. JAMA Neurol 2016;73:706–713.OpenUrl 7.↵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
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A Unique Shape of Brainstem Lesion that Caused Orthostatic Hypotension in Anti-NMDAR Encephalitis. - PubMed - NCBI

A Unique Shape of Brainstem Lesion that Caused Orthostatic Hypotension in Anti-NMDAR Encephalitis. - PubMed - NCBI | AntiNMDA | Scoop.it
Intern Med. 2019 Jun 7. doi: 10.2169/internalmedicine.2805-19.[Epub ahead of print]...
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Frontiers | Immunological findings in psychotic syndromes: a tertiary care hospital's CSF sample of 180 patients | Frontiers in Human Neuroscience

Immunological mechanisms and therapy approaches in psychotic syndromes were recently supported by the discovery of autoantibody-associated limbic and non-limbic encephalitis. However, how clinical diagnostic procedures in psychiatry should be adapted to these new insights is still unclear.
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Anti-NMDA Receptor Antibody Positivity and Presentations Without Seizure, Involuntary Movement, Hypoventilation, or Tumor: A Systematic Review of t... - PubMed - NCBI

Anti-NMDA Receptor Antibody Positivity and Presentations Without Seizure, Involuntary Movement, Hypoventilation, or Tumor: A Systematic Review of t... - PubMed - NCBI | AntiNMDA | Scoop.it
J Neuropsychiatry Clin Neurosci. 2017 Summer;29(3):267-274. doi: 10.1176/appi.neuropsych.16050101. Epub 2017 Jan 25.Review; Systematic Review...
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How caring for a three-year-old led me to a research career

How caring for a three-year-old led me to a research career | AntiNMDA | Scoop.it
How caring for a three-year-old boy led Dr Anusha Yeshokumar to a career researching autoimmune neurology at Mount Sinai Hospital, New York.
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The Man’s Blood Pressure Dropped, and He Was Acting Strange. What Was Going On? - The New York Times

The Man’s Blood Pressure Dropped, and He Was Acting Strange. What Was Going On? - The New York Times | AntiNMDA | Scoop.it
The older man was unsteady on his feet and seemed to be talking nonstop. Then the seizures started, and his wife sounded the alarm.
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Distinct serum and cerebrospinal fluid cytokine and chemokine profiles in autoantibody-associated demyelinating diseases. - PubMed - NCBI

Mult Scler J Exp Transl Clin. 2019 May 15;5(2):2055217319848463. doi: 10.1177/2055217319848463. eCollection 2019 Apr-Jun.
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Neuroimmunology – the past, present and future - Nutma - - Clinical & Experimental Immunology - Wiley Online Library

Summary Neuroimmunology as a separate discipline has its roots in the fields of neurology, neuroscience and immunology. Early studies of the brain by Golgi and Cajal, the detailed clinical and neuropathology studies of Charcot and Thompson’s seminal paper on graft acceptance in the central nervous system, kindled a now rapidly expanding research area, with the aim of understanding pathological mechanisms of inflammatory components of neurological disorders. While neuroimmunologists originally focused on classical neuroinflammatory disorders, such as multiple sclerosis and infections, there is strong evidence to suggest that the immune response contributes to genetic white matter disorders, epilepsy, neurodegenerative diseases, neuropsychiatric disorders, peripheral nervous system and neuro‐oncological conditions, as well as ageing. Technological advances have greatly aided our knowledge of how the immune system influences the nervous system during development and ageing, and how such responses contribute to disease as well as regeneration and repair. Here, we highlight historical aspects and milestones in the field of neuroimmunology and discuss the paradigm shifts that have helped provide novel insights into disease mechanisms. We propose future perspectives including molecular biological studies and experimental models that may have the potential to push many areas of neuroimmunology. Such an understanding of neuroimmunology will open up new avenues for therapeutic approaches to manipulate neuroinflammation. Introduction Neuroimmunology encompasses fundamental and applied biology, immunology, chemistry, neurology, pathology, psychiatry and virology of the central nervous system (CNS). Scientists in the field study the interactions of the immune and nervous system during development, homeostasis and response to injuries with the major aim of developing approaches to treat or prevent neuroimmunological diseases. The immune system has been generally regarded as autonomous and the brain protected by the blood–brain barrier, (BBB) and in the words of Rudyard Kipling (Barrack‐room ballads, 1892), ‘never the twain shall meet’. In the past decades these dogmas have been strongly challenged and dispelled with the wealth of evidence showing that not only does the nervous system receive messages from the immune system, but that signals from the brain regulate immune functions that subsequently control inflammation in other tissues 1. Communication between the immune system and the CNS is exemplified by the finding that many molecules associated with the immune system are widely expressed and functional in the nervous system and vice versa. Cross‐talk between microglia and neurones is known to be essential for maintaining homeostasis, yet such cross‐talk also occurs between oligodendrocytes and microglia 2. Disturbance in this communication due to peripheral infections in mice are known to trigger microglia activation and augment neurodegeneration 3. Similarly, recent experimental studies show that maternal infections lead to long‐term changes in microglia and abnormal brain development in the offspring 4, 5. Despite this evidence, it is surprising that the term ‘neuroimmunology’ was only first used on PubMed in 1982, coinciding with the first Neuroimmunology Congress in Stresa, Italy (Fig. 1) and following the launch of the Journal of Neuroimmunology in 1981. Although neuroimmunology research has focused on multiple sclerosis (MS; using the search term ‘neuroimmunology’, 43% of papers on PubMed in 2018 were on MS), immune responses are also observed in Guillain–Barré syndrome (GBS), white matter diseases, psychiatric disorders, infections, trauma and neurodegenerative diseases traditionally considered to be ‘cell autonomous’ (Table 1). Disease Clinical characteristics Immune involvement Ref ADEM Lethargy, visual problems, paralysis associated with viral infection or vaccination Demyelination, inflammation, axonal loss, hypertrophic astrocytes, activated microglia 6 ALS motor neurone disease Fatal motor neurone disease affecting the motor neurones leading to weakness of voluntary muscles Systemic immune activation, microglia activation and hypertrophic astrocytes. Complement deposition 7-9 AD Progressive cognitive decline. Amyloid plaques, synaptic loss and neurofibrillary tangles. Anti‐inflammatory drugs associated with reduced risk Microglia, astrocytes, complement and cytokines in plaques. Aβ binds and activates microglia. Aβ reactive T cells in blood, immunoglobulin in CSF 10, 11 Autoimmune encephalitis Psychiatric symptoms may predominate Autoantibodies directed against neuronal surface proteins including adhesion molecules, ion channels and receptors used as biomarkers of disease 12, 13 CFS Chronic dysfunction including fatigue, headaches and cognitive impairment PET imaging shows microglia activation. Immune dysregulation in cytokine profiles and T and B cells, immunoglobulin and natural killer cell cytotoxicity 14 CNS vasculitis Fatigue, impaired cognition, speech problems, seizures, paralysis Inflammation of blood vessels in the CNS 15 Depression Anxiety, cognitive impairment, panic attacks. Changes in serotonergic or glutamatergic transmission Increased T cells and cytokines. Injection of inflammatory mediators, e.g. interleukin‐2 and interferon gamma induce symptoms of depression 16, 17 Epilepsy Seizures associated with cognitive and psychological sequelae Innate and adaptive immune responses. Antibodies deposits on BBB. Anti‐inflammatory agents control forms of epilepsy 18, 19 GBS Acute paralytic neuropathy. High cerebrospinal fluid protein levels Disease seen following Zika virus infection Pathogenic antibodies to gangliosides arise due to molecular mimicry in Campylobacter jejuni lipo‐oligosaccharide infection 20, 21 HD and other polyQ diseases Mutant huntingtin protein (or other polyQ) aggregates. Neostriatal atrophy and neuronal loss in putamen and caudate nucleus Microglia express mutant huntingtin (and other polyQ) protein are dysfunctional. Expression of complement components in associated with severe atrophy 22 Infections Encephalitis, encephalomyelitis, meningitis, polyradiculitis or polyneuritis Immune responses to infectious agent Some viruses induce immunosuppression (e.g. HIV, EBV, Herpes simplex virus) 23 Leucodystrophies e.g. X‐ALD: progressive cognitive and motor function impairment and eventually total disability. Accumulated levels of very long chain fatty acids (VLCFA) X‐ALD: severe lymphocytic response. VLCFA impair monocytes. Activated microglia and astrocytes become dystrophic 24, 25 MS Relapsing remitting or progressive neurological dysfunction. Oligoclonal cerebrospinal fluid bands Demyelination and axonal loss in CNS associated with innate and adaptive immune cell activation 26 MG and other channel‐opathies Clinical features depend on antibody e.g. synaptic dysfunction, neuronal excitability due to inhibition of ion channel function Antibody‐mediated disorders of the neuromuscular junction, e.g. antibodies to AChR in MG 27, 28 Neuromyelitis optica (Devic’s disease) Inflammatory disorder affecting optic nerves and spinal cord Presence of antibodies to aquaporin 4 in 80% cases damage astrocytes 29 Paraneoplastic disorders Immune mediated disorders triggered by tumour expressing neuronal antigens. Clinical manifestations depend on target of antibody Disease associated with antibody deposits on neuromuscular junction, Purkinje cell or peripheral nerves. T cells and immunoglobulin in cerebrospinal fluid 30 Parkinson’s disease Progressive movement disorder associated with loss of dopaminergic neurones Microglia and astrocyte activation associated with neuronal loss. IL‐1b gene polymorphisms associated with early onset. CD4+ and CD8 T cells in animal models 31 SLE, PSS, diabetes, gluten ataxia SLE: cognitive decline, depression, seizures, chorea. PSS: optic neuritis, vasculitis, results neurological syndrome. Gluten ataxia: cerebellar ataxia and atrophy SLE: vasculitis, autoantibodies, immune complexes 30 PSS: inflammation mimicking MS. Gluten ataxia: loss of Purkinje cells associated with immune activation Stroke Blockage of blood vessel or haemorrhage deprives CNS of oxygen resulting in various levels of unconsciousness Systemic and local inflammation triggered to clear debris 32 Traumatic spinal injury Contusions and bruising due to fracture or dislocation leading to paralysis, or degrees of dysfunction below level of injury Injury triggers inflammation that may contribute to secondary tissue damage 33 Neuroinfections Virus Clinical characteristics Neuroimmune involvement Ref HIV dementia Cognitive changes HIV‐infected monocytes and T cells produce chemokines and cytokines 34 Arbovirus Depends on infection Virus infects neurones, local immune response, microglia and macrophages present viral antigens to T cells. Antibodies may control spread 35, 36 TBE, e.g. Zika Depends on infection, e.g. Zika virus: microcephaly, GBS and CNS disorders Role of myeloid cells in facilitating viral spread and pathology 37 Rabies Encephalitis Immune responses crucial to clear neurotrophic virus 38 HSV Fever can induce anti‐NMDAR encephalitis Innate and adaptive immune responses control infection. Virus evades CD8+ T cells. TLR‐3 polymorphisms associated with susceptibility 39 EBV Febrile illness, meningeal signs, epileptic insults, depression polyradiculomyelitis, cognitive disorders, encephalitis EBV‐related lymphomas in CNS. Increased mononuclear leucocytes. Evidence that EBV infection is linked to MS and CFS 40, 41 SSPE Fatal complication of measles infection. Latency period of 4–10 years leading to coma Immaturity of immune response leads to widespread infection 42 CFS = chronic fatigue syndrome; HSV = herpes simplex virus; NMDAR = N‐methyl‐D‐aspartate receptor; PSS = primary Sjögren’s syndrome; SSPE = subacute sclerosing panencephalitis; TBE = tick‐borne encephalitis virus; AChR = acetylcholine receptor; AD = Alzheimer’s disease; ADEM = acute demyelinating encephalomyelitis virus; ALS = amyotrophic lateral sclerosis; CNS = central nervous system; CSF = cerebrospinal fluid; EBV = Epstein–Barr virus; GBS = Guillain–Barré syndrome; HD = Huntington’s disease; MS = multiple sclerosis; MG = myasthenia gravis; SLE = systemic lupus erythematosus; TLR = Toll‐like receptor. One of the greatest misconceptions that impeded progress in neuroimmunology was the idea that the blood–brain barrier (BBB) and the perceived immunological privilege of the brain prevent cross‐talk between the CNS and immune systems. This long‐standing dogma has been challenged by recent studies and the discovery of glymphatics and meningeal lymphatic vessels 43. Although this paradigm shift is a recent advancement in thinking of nervous‐immune system cross‐talk, such changes in the field, beginning over 150 years earlier, have been generally linked to technological advances, some of which have yielded Nobel Prizes in neuroimmunology (Table 2), including the development of mutant and transgenic mice to examine disease mechanisms, stem cell technologies and the novel CRISPR/cas9 system, that allows gene editing enabling personalized treatments. Year Recipient Topic Influence on neuroimmunology field 1901 Emile A. Behring Serum therapy Opened a new road in medical science for treating diseases 1906 Camillo Golgi and Santiago Ramón y Cajal Structure of the nervous system Impregnation method allowed microscopy of neuroglia 1908 Ilya I. Metchnikoff and Paul Ehrlich Recognition of work on immunity. Metchnikoff discovered types and functions of phagocytes. Ehrlich identified types of blood leucocytes Formulating the concept of antibody: antigens complexes Antibodies are the foundation for immunohistochemistry and for some therapies 1919 Jules Bordet Discoveries relating to immunity Interaction of antibodies and complement. Of diagnostic importance and understanding mechanisms of cell death 1927 Julius Wager‐Jauregg Therapeutic value of malaria inoculation in the treatment of dementia paralytica The link between infection, inflammation and neurological diseases 1945 Alexander Fleming, Ernst B. Chain and Howard W. Florey Discovery of penicillin and treatment for various infectious diseases Key approach to managing bacterial infections including central nervous system (CNS) diseases, e.g. brain abscesses 1951 Max Theiler Yellow fever and how to combat it Controlling arboviruses using live attenuated viruses. Paved the way for controlling neurotrophic viruses 1953 Watson and Crick Structure of DNA Understanding genetic disorders and potential of gene therapy 1954 John F. Enders, Thomas H. Weller and Frederick C. Robbins Ability of poliomyelitis viruses to grow in cultures of various types of tissue In‐vitro testing of vaccines, neutralizing antibodies, typing infectious agents and cytopathic effects 1960 Frank Macfarlane Burnet and Peter B. Medawar Acquired immunological tolerance Self/non‐self‐discrimination led to approaches to induce tolerance to self‐antigens in neuroinflammatory diseases 1972 Gerald M. Edelman and Rodney R. Porter Discoveries concerning the chemical structure of antibodies Role of antibodies in disease, use in technologies, e.g. vaccine development, enzyme‐linked immunosorbent assay 1976 Baruch S. Blumberg and D. Carleton Gajdusek New mechanisms for the origin and dissemination of infectious diseases Idea of persistent infections and slow viruses (spongiform encephalopathies) 1980 Baruj Benacerraf, Jean Dausset and George D. Snell Genetically determined structures on the cell surface regulating immunological reactions Relevance of major histocompatibility complex (MHC) to developing neuroinflammatory disorders, e.g. DR2 in multiple sclerosis 1984 Niels K. Jerne, Georges J.F. Köhler and César Milstein Specificity in development and control of the immune system. Principle for production of monoclonal antibodies Development of monoclonal antibody (mAb) for therapies in neuroinflammatory diseases. mAb for characterizing immune molecules and role in diseases using immunohistochemistry 1987 Susumu Tonegawa Genetic principle for generation of antibody diversity Autoantibodies to peripheral nervous system (PNS) and CNS surface proteins, e.g. ion channels, receptors, myelin, axons 1996 Peter C. Doherty and Rolf M. Zinkernagel specificity of the cell mediated immune defence MHC class I and II restricted immune response applicable to infections and autoimmunity 1997 Stanley B. Prusiner Prions: a new biological principle of infection Modes of action may be applicable to neurodegenerative diseases 2002 Sydney Brenner, H. Robert Horvitz and John E. Sulston Genetic regulation of organ development and programmed cell death Cell death mechanism key to regulating neuronal development, neurodegeneration and control of immune responses 2003 Paul C. Lauterbur and Sir Peter Mansfield Magnetic resonance imaging Imaging neuroinflammatory diseases and response to therapy 2006 Andrew Z. Fire and Craig C. Mello RNA interference: gene silencing by double‐stranded RNA Therapeutic approaches targeting aberrant gene associated with neurological disorders 2007 Mario R. Capecchi, Martin J. Evans and Oliver Smithies Principles for introducing gene modifications in mice using embryonic stem cells The approach allows the study specific gene function and to create animal models for, e.g. neuroinflammatory diseases 2011 Bruce A. Beutler, Jules A. Hoffmann and Ralph M. Steinman Discoveries concerning activation of innate immunity (B.A.B., J.A.H.). Role of dendritic cells in adaptive immunity (R.M.S.) How innate and adaptive immune responses are activated are key to understanding and manipulation of immune responses to control diseases 2012 John B. Gurdon and Shinya Yamanaka Mature cells can be reprogrammed to become pluripotent Stem cells will facilitate regeneration within the nervous system to replace damaged cells and tissues Here, we review the developments in neuroimmunology since its roots in the first descriptions of immunological processes and neurological diseases, as well as the development of technologies and clinical trials for such diseases. Important events are given in major timelines or eras, along with the Nobel Prizes considered relevant by their impact on the field of neuroimmunology. The review also includes a perspective on the future of neuroimmunology that should herald prospective approaches to understanding these diseases, and we address several outstanding questions in the field. The long‐term goal of this rapidly developing field of neuroimmunology is to further the understanding of how immune responses shape the nervous system during development and ageing, how such responses lead to neurological diseases, and ultimately to develop new pharmacological treatments. These aspects are thus the major topics of the International Society of Neuroimmunology meetings (ISNI) (Fig. 1) and the educational topics of the global schools in neuroimmunology. Historical beginnings The first descriptions of many neuroinflammatory disorders come from personal notes, early authors and diarists. The earliest report purported to be MS was in an Icelandic woman (in approximately 1200) and Saint Lidwina of Schiedam (1380–1433), while the detailed personal diaries of Sir Augustus d’Esté, born in 1794 (grandson of King George III of England) and the British writer W. N. P. Barbellion (1889–1919) reveal their daily struggle with symptoms of MS 44, 45. Examples of early reports of other neuroinflammatory diseases include Sir Thomas Willis, credited with the first description of myasthenia gravis (MG) in 1672 46 (Fig. 2), as well as in early medical documents and diaries descriptions of encephalitis. Neuroinflammatory disorders were also documented in (albeit) fictional characters in novels such as those by Charles Dickens 47, 48. Early detailed descriptions of many neurological diseases expanded in the early 1800s (Fig. 2), due in part to Jean‐Martin Charcot (1825–1893), who systematically identified many neurological diseases including Charcot–Marie–Tooth, MS, Parkinson’s disease (PD; only later in 1872 was Parkinson credited for his earlier description, Fig. 2) and amyotrophic lateral sclerosis (ALS), by linking the clinical disease in patients with detailed studies of the anatomy and microscopy of diseased tissues 49. The link between neurology and immunology gained momentum with the refinement of the microscope and development of staining techniques to allow detailed studies of tissue. For example, the identification of different types of glial cells in the CNS and peripheral nervous system (PNS) was aided by the use of chemicals to enhance the microscopic visibility of nerve cells 50, 51, approaches for which Camillo Golgi and Santiago Ramon y Cajal received the Nobel Prize for Medicine in 1906 (Table 2). It was also with these new staining techniques that Alois Alzheimer identified the pathology underlying dementia that later became known as Alzheimer’s disease (AD) (1906) 52, and allowed Dawson to perform detailed microscopic examinations of MS (1916) 53 showing inflammation around blood vessels in CNS lesions. Purkinje is credited for the first descriptions of neurones in 1837 54, and only later did Golgi describe glial cells (1871), although Virchow had introduced the name ‘neuroglia’ and created the concept that nerve cells are held together by ‘glia’ (meaning glue) in 1856 55. Alongside the descriptions of neurological disease, various aspects of immunology were also investigated (Fig. 2). Metchnikoff revealed the rudimentary immune cells in freshwater starfish (1880) 56, and used the term ‘phagocytosis’, which became the basis of his research for which he was awarded the Nobel Prize in 1908 with Paul Ehrlich for discovery of blood leucocytes (Table 2). Later, Rio‐Hortega showed that cells in the brain (microglia) were able to phagocytose (1919) 57. In the same year, Jules Bordet was awarded the Nobel Prize for identifying factors (antibodies) in blood arising after vaccination 58, although it was not until 70 years ago that B cells were found to be important producers of antibodies in 1948 59. Immunology at the time was focused on the vaccine development for infectious diseases after the published work on the first vaccine for smallpox by British physician Edward Jenner in 1796 60. More relevant for the neuroimmunological field was the discovery of the vaccine for the neurotrophic rabies virus by Louis Pasteur (1885) 61 and the vaccine for polio by Jonas Edward Salk (1953) 62. Importantly, Pasteur used dried virus‐infected rabbit spinal cord for immunization which occasionally induced a post‐vaccine encephalomyelitis in humans. That the disease did not reflect rabies indicated that brain components in the vaccine were antigenic. In the 1940s adjuvants were developed to potentiate vaccines, and several vaccines as well as infections have been linked to neuroinflammatory diseases such as, for example, e.g. MS and acute disseminated encephalomyelitis (ADEM) (Table 1). The serendipitous finding of post‐rabies vaccination encephalitis was later exploited for immunization strategies to deliberately induce experimental autoimmune diseases (Fig. 2). Of relevance to the immune privilege nature of the CNS, in 1890 Gilman Thomson showed that brain cells can be transplanted without being rejected, many years before Sir Frank Macfarlane Burnet and Peter B. Medawar’s seminal studies, for which they received the Nobel prize in 1960 (Table 2). 1960–1980 Further to the identification and description of diseases, this era prompted the development of precise criteria for diagnosis of neuroinflammatory diseases, as well as examining the pathological mechanisms underlying disease and testing therapeutic approaches (Fig. 3). Technically, the development of computed tomography scans, positron emission spectroscopy (PET) and magnetic resonance imaging (MRI) allowed the first images of living brain, revolutionizing the diagnosis of neuroinflammatory diseases and allowing non‐invasive monitoring of disease progression as well as response to therapy. There was a surge in discoveries related to antibodies after the antibody structure was discovered (1959) 63. In this era associations were made linking antibodies to diseases such as MG and other neuroinflammatory diseases 64. For some diseases the target of the antibodies were identified 65, and the impact of pathogenic antibodies shown in vitro 66. A key development in the immunology field was the generation of monoclonal antibodies (mAb) 67. Not only were mAb key to the development of assays such as enzyme‐linked immunosorbent assay and other techniques key to linking immune cells to neurological diseases 68, this advancement also allowed development of specific therapeutic approaches in which mAb were designed to block or deplete specific cells of the immune system. The involvement of immune responses in neurological diseases prompted new approaches to treat disease and development of animal models of human diseases. While adjuvants developed in the 1940s were essential for inducing clinical disease in the case of experimental autoimmune encephalitis (EAE) 69 and experimental autoimmune neuritis (EAN), injection of antibodies to acetylcholine receptor (AchR) and from patients with myasthenia gravis (MG) induced experimental disease in rabbits. The therapy used for antibody‐mediated diseases included plasma exchange 70, while broad immunosuppressive approaches, e.g. adrenocorticotrophic hormone, were implemented for MS [Food and Drug Administration (FDA)‐approved in 1978]. Study of the immune system differentiated between cellular and humoral immunity and recognized T and B cell interactions, as well as the discovery of the first interleukins. Key to further developments in immune‐mediated diseases was Zinkernagel and Doherty’s finding (1974) that elimination of virus‐infected cells killer T cells required not only to recognize the virus but also the major histocompatibility complex (MHC) molecule of the host 71. Around this time the realization grew that cells later named as dendritic cells, due to their morphology, were intricately linked with adaptive immune responses, a notion that would later earn Steinman the Nobel Prize 72. Studies in this era supporting Cajal’s idea, that glia assist neurones, were aided by the development of the electron microscope and electrophysiological studies, although how this impacted on neuroinflammatory disease was as yet unknown. 1981–2000 This era saw major steps in putting neuroimmunology on the map as a new field with the launch of the Journal of Neuroimmunology by Cedric Raine and colleagues (1981), the first PubMed term of neuroimmunology (1981), the initiation of Neuroimmunology Congresses in Stresa, Italy (1982), the foundation of the ISNI (1987) and the launch of the Journal of Clinical and Experimental Neuroimmunology in 1988. If the previous era was dedicated to the role of antibodies in disease for which Tonegawa received the Nobel Prize in 1987 (Table 2) 73, this era was that of T cells in neuroimmunology and the recognition of the importance of innate immunity (Fig. 3). Following Doherty and Zinkernagel’s discovery in 1974, for which they were awarded the Nobel Prize in 1996, major steps were made in identifying the T cell receptor (1983–1987) 74, 75 (Table 2), classification of T cells (1986) 76, the role of MHC peptide complex in triggering T cell responses (1991) 77 and how T cells are regulated (1995) 78 or modified using altered peptide ligands (1998) 79. Models also made use of the emerging field of transgenic mice designed to express human proteins such as human leucocyte antigens (HLA), T cells expressing specific T cell receptors (TCRs), markers such as green fluorescent protein (GFP) to allow tracking of cells or generated to lack specific molecules (knock‐out or deficient mice). Many of the studies examining the pathogenic role of T cells focused on the EAE model of MS (1981–1984) 80-82 although inflammation was also reported in depression (1983) 83 and neurodegenerative diseases, e.g. AD, which up to that point had been widely assumed to be due to neuronal degeneration. While many studies focused on immune‐mediated damage, studies also revealed the importance of the immune response in shaping neuronal development. For example, while microglia were reported to be crucial for synaptic pruning, new studies from the Shatz laboratory revealed that neuronal expression of MHC class I was key to long‐term structural and synaptic modifications 84. The focus on pathogenic T cells in EAE models of MS increased and experiments using antibodies to block TCRs were performed 85, 86. Further studies highlighted the importance of other myelin antigens as targets for the demyelinating response and induction of chronic relapsing clinical disease to model the disease course in MS more clearly 87. Although T cells were at the forefront of many studies, therapeutic approaches targeting pathogenic antibodies such as trials using intravenous immunoglobulin (IVIg) in GBS, or use of therapeutic mAB to block adhesion molecules on immune cells, revealed the importance of cell trafficking across the BBB 88. Although such approaches were effective in animal models, blocking immune cell entry in the CNS in humans had serious side effects. Other strategies focused on repairing damage in the nervous systems were examined. These strategies included transplanting oligodendrocyte progenitor cells for remyelination 89 and stem cells that, although originally designed to replace damaged cells, they were later recognized to be neuroprotective via the release of growth factors and immune modulatory molecules (i.e. therapeutic plasticity) 90. This era saw the emergence of the human immunodeficiency virus (HIV), the isolation of HTLV‐1‐like retrovirus from tropical spastic paraparesis cases, the link between Campylobacter jejuni infection and GBS and the Nobel Prize to Prusiner for his studies on prions as new infectious particles promoting neurological disease (Table 2). These findings clearly highlighted the role of infectious agents in triggering neuroinflammatory disorders, although it was unclear how the different infections triggered disease. One innovative concept at the time was proposed by Janeway (1989) 91, suggesting that microbes act via receptors on innate immune cells. Only later was this concept validated by the discovery of Toll‐like receptors (TLR) and other innate receptors, as well as dendritic cells (Nobel Prize: Beutler, Hoffman, Steinman 2011). Further revelations were made in 1994, when Matzinger proposed the ‘danger model’ (1994) to include the concept that changes in the host’s tissues due to ‘dangerous’ situations, i.e. trauma or disease, could also activate innate immunity 92. Another technological leap during this era was the use of genetic engineering that enabled the generation of mice expressing antigen‐specific TCR, such as against the myelin basic protein, and humanized mice expressing certain HLA haplotypes in an attempt to understand how human genes contributed to neuroinflammmatory diseases. 2001–2018 Accumulating evidence during the last two decades shows that immune senescence is associated with late‐onset neurodegenerative diseases such as AD, PD, spinal cerebellar ataxia, ALS and Huntington’s disease, thus broadening the range of diseases falling within the neuroimmunology field (Table 1). Further evidence that the immune response is also key to neuronal development was highlighted by the finding that the complement component C1q is expressed by synapses of postnatal but not adult neurones 93 (Fig. 4). Studies in this era have also expanded ideas of how microbes, such as the newly emerging Zika virus, the re‐emergence of Ebola and the gut microbiome, influence susceptibility to neuroinflammatory disease. In line with this, clinical trials have highlighted the need to develop more specific approaches in neuroimmune diseases other than broad immunosuppression or blocking cells from entering into the CNS, in order to avoid the emergence of opportunistic infections. Thus, specific approaches such as cell depletion therapies (e.g. of B cells in MS), tolerance‐inducing strategies and the use of stem cells have been a major focus in MS, while gene therapy approaches have been initiated in an attempt to correct genetic mutations in ALS 94 (Fig. 4). Probing neuroinflammatory diseases has been aided with improved higher‐resolution MRI, single photon emission computed tomography and PET ligands 95, 96, and optical coherence tomography to visualize the progression of disease in patients and for some modes the contribution of inflammation. Similarly, in‐vivo optical imaging, for example of GFP‐labelled T cells, glia or transplanted human induced pluripotent stem cells (iPSC), in experimental models has greatly influenced our knowledge of the cross‐talk between the immune and nervous systems 97. Although mainly limited to in‐vitro and animal studies, genetic modification has proved to be an indispensable tool to study gene function in normal development and disease and has yielded several Nobel Prizes in this area (2006, Fire and Mello; 2007, Capecchi, Evans, Smithies). Breakthroughs in this era include the generation of human iPSCs for which Gurdon and Yamanaka received the Nobel Prize in 2012; gene‐targeting approaches and genome‐editing tools, the most effective for interrogation of neuroimmune disease being the CRISPR/Cas9 system (derived from clustered regularly interspaced short palindromic repeats) originating from early discoveries in bacteria 98. While yet to prove applicable to human disorders, such gene editing has allowed genetic manipulation of iPSC from humans, ALS models and elimination of viral infections by targeting viral genomes. Future perspectives While current therapies aim to modulate neuroinflammation arising during the disease, future approaches should aim at disease prevention. For some diseases, the aetiological agents are known, and thus vaccination strategies are key for disease prevention. In other cases, the specific genes or environmental agents triggering disease require clarification. Prophylactic approaches for genetic disorders could exploit genetic modification during development, while cell therapy strategies may aid regeneration of the damaged nervous system. Exploitation of infections agents may also be beneficial, as demonstrated by the recent clinical trial using a non‐pathogenic poliovirus for treating glioblastomas 99. For disease prevention, rapid and specific diagnosis as well as adequate ways to monitor the disease course and response to therapy are crucial. Thus, advancements in biomarker research will be key to faster diagnosis and more efficient monitoring in clinical trials, speeding up drug development and reducing costs. Biomarkers of neuroimmunological diseases may include markers of BBB disruption, demyelination, oxidative stress and excitotoxicity, axonal/neuronal damage, gliosis, remyelination and repair, but should also focus on markers of altered immune function such as cytokines, chemokines, antibodies, adhesion molecules, antigen presentation and changes in cellular subpopulations 100. Ideally, detection and collection of new biomarkers will be minimally invasive, specific for the disease and reflect response to therapy Additionally, well‐characterized tissue biobanks will be crucial to these advancements in biomarkers. Another important aspect of future neuroimmunology research and developments will be in disease modelling. The highly effective CRISPR/cas9 system will allow precision engineering of the genome, and has the potential to speed up the generation of transgenic animal models, generating single‐gene mutations in adult animals. Model systems making use of iPSCs from patients will also allow better translation of fundamental research data to the clinic. Further advances in CRISPR/cas9 or similar systems to increase transgene efficiency or to regulate gene expression using inducible expression systems will allow genes to be regulated once gene editing is completed. Such approaches will herald better treatments in the form of personalized medicine, gene editing (taking into account the ethical issues) and improved clinical trial design. The increase in data generated by next‐generation sequencing is expected to aid identification of genetic variants in neuroimmunological diseases. Such data are already contributing to designing algorithms, development of pharmacogenomics and personalized medicine. These approaches will be fundamental in reducing risks in drug development by avoiding adverse drug reactions, and minimizing cost by limiting drug administration solely to those patients who will benefit 101. While drug discovery is increasingly costly and prolonged, artificial intelligence (AI) may be key to reversing this trend. AI will use previously collected data and molecular dynamic predictions to reduce the number of compounds to be screened, repurpose compounds, predict interactions between compounds and their target and refine clinical trial populations 102. Advancements in targeted drug delivery will also reduce side‐effect profiles of compounds and aid in those compounds that will readily cross the BBB 103. Both Big Pharma and academia have the potential to increase drug discovery efficiency by embracing AI, pharmacogenomics, personalized medicine and targeted drug delivery to provide future treatments of neuroimmunological diseases. Conclusions The field of neuroimmunology has evolved from early studies recognizing that immune responses are present in the CNS and PNS during disease, to sophisticated approaches for manipulation of the immune system. The list of neuroimmune diseases has expanded from the prototypical cases of MS, GBS and MG to incorporate diseases considered to be purely neurological such as AD, PD, ALS as well as behavioural and mood disorders. Neuroimmunology has evolved to encompassed less disease‐orientated fields by addressing how the immune system impacts upon the developing nervous systems during pregnancy, how neural stem cells play an immune regulatory role, the contribution of immune‐senescence to ageing, how microbiota influence the immune system, and how this impacts upon development and susceptibility to neurological diseases. Understanding the delicate balance between the beneficial and pathological effects of the immune system with neuronal development and diseases has already allowed the development of rational approaches for treating neuroimmune disorders. Further advances are expected to address the following points. How pathogenic (auto)antibodies arise and how they contribute to immune‐mediated neurological disorders While the source of pathogenic antibodies in paraneoplastic neurological syndrome (PNS) are well described, a significant number of neurological diseases in which pathogenic antibodies directed to neuronal structures are not related to cancer. Uncovering how these antibodies arise, how they enter the nervous systems and approaches to inhibit antibody formation will be key to developing effective therapeutic approaches. The role of memory B cells in autoimmune diseases For several autoimmune disorders, e.g. MS, rheumatoid arthritis and Graves’ disease, among others, an association has been made between Epstein–Barr virus (EBV) and development of disease. The recent awareness that effective therapies target memory B cells makes the hypothesis that EBV triggers autoreactive B cells and/or antibodies is very compelling. Exactly how EBV triggers autoimmune neurological diseases will be an important step in understanding neuroimmunological diseases such as MS. Inflammaging and neurological diseases The term ‘inflammaging’ has been used to describe the chronic, low‐grade inflammation associated with ageing. Senescence in the immune and nervous systems covers a multitude of factors, including lowered response to vaccination, decline in effective autophagy and increased susceptibility to cancer and autoimmune diseases. Why such changes occur will be aided by studying healthy aged cohorts of different backgrounds and races and highlight how environmental factors such as diet, gut microbiota or genes and lifestyle contribute to the immune imbalance associated with ‘inflammaging’. A key question will thus be: ‘Can we manipulate the immune response to combat the effects of ageing?’. Neuroimmunology of pregnancy and development Maternal stress or infections during pregnancy have been linked to impaired cognitive development and psychiatric disorders in the offspring. The recent emergence of Zika virus has underscored not only how the brain may be shaped by infections during development, but that such infections may predispose to autoimmune diseases later in life. A future challenge will thus be to understand how maternal immune factors, including immune cells and cytokines, influence brain development in utero and modulate the beneficial factors to enhance brain development to prevent and limit the detrimental effects of the immune system that may contribute to behavioural and mood disorders. Human stem cell technology and personalized medicine The advances in reprogramming somatic cells into iPSCs has allowed the culture of patient‐specific stem cells, e.g. neuronal stem cells (NSC), to study the disease specific pathways. This technology will allow the development of human in‐vitro models to study disease and patient‐specific pathways. More importantly, these models should also allow approaches to modulate disease‐specific factors aiding personalized medicine. For some neuroimmunological diseases the use of NSC has already proved effective in experimental settings to not only repair the nervous system but examine an unexpected trait by which NSC modulate immune responses. While in its infancy, gene‐editing approaches are expected to develop to the point that genetic neurological diseases may be treatable and modulate the immune and nervous systems to combat neuroimmunological disease, and in the meantime allow standardization of iPSC cells. Acknowledgements This review was written in celebration of the 60 years’ anniversary of the foundation of the British Society of Immunology, and following the 13th ISNI meeting in 2018 in Brisbane. We thank our colleagues in the neuroimmunology field who have contributed to this review in terms of discussions and their invaluable insight into neuroimmune diseases. Specifically, we thank Dr Hans van Noort and Dr Gareth Pryce for their input with critical feedback on the paper. To the neuroimmunologists whom we have not mentioned due to lack of space, we warmly encourage them and readers to make suggestions of omissions. Disclosures None. References Citing Literature
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John Libbey Eurotext - Epileptic Disorders - A Rasmussen encephalitis, autoimmune encephalitis, and mitochondrial disease mimicker: expanding the DNM1L-associated intractable epilepsy and en...

John Libbey Eurotext - Epileptic Disorders - A Rasmussen encephalitis, autoimmune encephalitis, and mitochondrial disease mimicker: expanding the DNM1L-associated intractable epilepsy and en... | AntiNMDA | Scoop.it
Illustrations Auteurs Danielle A. Nolan 1 * Baibing Chen 2 Anne Marie Michon 1 Emily Salatka 1 Daniel Arndt 1 1 Department of Pediatric Epilepsy, Beaumont Health, Royal Oak, MI 48073 2 Oakland University William Beaumont School of Medicine, Rochester, MI 48309, USA * Correspondence: Danielle A. Nolan Beaumont Children's, Neuroscience Center, 3555 West 13 Mile Rd, Suite N120, Royal Oak, MI 48073, USA Mots-clés : developmental delay, seizure, refractory epilepsy, cerebral atrophy, encephalopathy congenital, DNM1L DOI : 10.1684/epd.2019.1036 Page(s) : 112-6 Année de parution : 2019 Dynamin-1-like protein (DNM1L) gene variants have been linked to childhood refractory epilepsy, developmental delay, encephalopathy, microcephaly, and progressive diffuse cerebral atrophy. However, only a few cases have been reported in the literature and there is still a limited amount of information about the symptomatology and pathophysiology associated with pathogenic variants of DNM1L. We report a 10-year-old girl with a one-year history of mild learning disorder and absence seizures who presented with new-onset focal status epilepticus which progressed to severe encephalopathy and asymmetric hemispheric cerebral atrophy. Differential diagnosis included mitochondrial disease, Rasmussen's encephalitis, and autoimmune encephalitis. Disease progressed from one hemisphere to the other despite anti-seizure medications, hemispherectomy, vagus nerve stimulator, ketogenic diet, and immunomodulators. Continued cerebral atrophy and refractory seizures evolved until death four years after initial presentation. Post-mortem whole-exome sequencing revealed a pathogenic DNM1L variant. This paper presents a novel case of adolescent-onset DNM1L-related intractable epilepsy and encephalopathy.
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The Anti-NMDA Receptor Encephalitis Foundation Newsletter - June 17, 2019

The Anti-NMDA Receptor Encephalitis Foundation Newsletter - June 17, 2019 | AntiNMDA | Scoop.it
Anti-NMDA receptor (anti-NMDAR) encephalitis is a treatment-responsive autoimmune encephalitis, first described in 2007.1 Ovarian teratomas are found in one-third of the patients.2 The clinical features of this disorder vary between patients and age groups and usually include abnormal (psychiatric) behavior or cognitive dysfunction, speech dysfunction (pressured speech, verbal reduction, and mutism), seizures, movement disorders, dyskinesias, or rigidity/abnormal postures, decreased level of consciousness, autonomic dysfunction, or central hypoventilation.2 Cerebellar ataxia has been described as a symptom during the first months of the disease, especially in young children, in combination with other symptoms.2,3 It is extremely rare as the initial symptom, especially in adults. We report a case of a female adult with anti-NMDAR encephalitis presenting with cerebellar ataxia associated with recurrent mature ovarian teratomas. Case report A 32-year-old woman, born in South Korea and adopted at age 4 months, presented with vertigo, nausea, and vomiting for 4 days. Her medical history consisted of bilateral cystectomy revealing mature teratomas, discovered by ultrasound examination after a missed abortion at age 26 years. During cesarean sections afterward (ages 29 and 31 years), no macroscopic abnormalities were seen. Furthermore, she had had depressive symptoms, treated with venlafaxine for years. Neurologic examination showed a horizontal gaze-evoked nystagmus to the right without other neurologic signs or symptoms. Laboratory investigations on admission were normal, and brain CT showed no abnormalities. Initially, she improved after treatment with antiemetic drugs, but after 3 days, she deteriorated quickly, also complaining of headache. Neurologic examination showed nystagmus in all directions and dysarthric speech (cerebellar) that further worsened to impaired speech restricted to one-word sentences. She showed bilateral dysmetria of the lower and especially the upper limbs, truncal ataxia, and inability to stand and walk. Psychiatric evaluation showed rapid progression of depressive symptoms with suicidal ideation and labile affect. Brain MRI and MRV were normal. CSF analysis and extensive laboratory investigations showed pleocytosis (table). Anti-NMDAR antibodies were negative in serum, but positive in CSF,4 confirming the diagnosis of definite anti-NMDAR encephalitis.3 View inline View popup Table Overview of investigations The patient was treated with IV methylprednisolone 1,000 mg (day 13, 5 days) and IV immunoglobulins 0.4 g/kg (day 16, 5 days). Thorax/abdomen CT and transvaginal ultrasound revealed 2 lesions in the pelvic area with fat tissue and calcifications, suspect for teratomas. Bilateral laparotomic ovariectomy was performed (day 19). Pathologic examination showed mature cystic teratomas, without immature components, containing nervous tissue. Hormone replacement therapy was started. Her neurologic condition improved within a week, but the depressive mood remained. Recovery was hampered by urosepsis, treated with cefuroxime/amoxicillin. She was treated with a second course of methylprednisolone 4 weeks after the initial treatment and immunoglobulins at 8 weeks for remaining speech impairments and severe depression. This resulted in further improvement of both. After 6 weeks, the patient was transferred to a rehabilitation unit. After 6 months, the patient returned home. She was able to perform activities of daily living independently, but needed walking aids outside due to residual ataxia and had not returned to work (yet). Discussion This case with cerebellar ataxia as an initial symptom highlights an unusual presentation of anti-NMDAR encephalitis. If cerebellar ataxia is present in patients with anti-NMDAR encephalitis, it is almost exclusively found in (young) children, and most frequently, it appears later in the disease in combination with other symptoms.2 Different brainstem-cerebellar symptoms have been described, such as opsoclonus-myoclonus syndrome, ocular movement abnormalities, and low cranial nerve involvement in patients with ovarian teratomas, but these symptoms have more frequently been described in whom no NMDAR antibodies could be identified.5 Although 2 simultaneously occurring paraneoplastic neurologic syndromes, due to an ovarian teratoma, cannot be fully excluded, this is considered unlikely. The development of multiple symptoms quickly into diseases compatible with anti-NMDAR encephalitis (psychiatric symptoms and mutism), the confirmation of NMDAR antibodies by different tests,4 and the identification of an ovarian teratoma are suitable with a diagnosis of “definite anti-NMDAR encephalitis.”3 Although it is known that anti-NMDAR IgG antibodies bind to granular cells in the cerebellum (but not to Purkinje cells),6 it is unknown why only approximately 5% of patients show cerebellar complaints. MRI abnormalities of the cerebellum have been described in 6% of patients.7 A small study showed progressive cerebellar atrophy by follow-up MRI in 2 of 15 patients with anti-NMDAR encephalitis.6 In conclusion, cerebellar ataxia is unusual in adult patients and an extremely rare presenting symptom of anti-NMDAR encephalitis. This case shows that anti-NMDAR encephalitis should be considered in the differential diagnosis of cerebellar ataxia, especially in patients with previous teratomas and those developing other symptoms shortly afterward. Study funding No targeted funding reported. Disclosure M.J. Titulaer has filed a patent for methods for typing neurological disorders and cancer, and devices for use therein, and has received research funds for serving on a scientific advisory board of MedImmune LLC, for consultation at Guidepoint Global LLC, for teaching courses by Novartis, and an unrestricted research grant from Euroimmun AG. M.J. Titulaer has received funding from the Netherlands Organization for Scientific Research (NWO, Veni incentive), from the Dutch Epilepsy Foundation (NEF, project 14-19), and from ZonMw (Memorabel program). The other authors report no conflicts of interest. Go to Neurology.org/NN for full disclosures. Acknowledgment The authors thank J.J. Oudejans, pathologist, Tergooi, Blaricum, The Netherlands, and C.E. de Boer, physiatrist, Tergooi, Blaricum, The Netherlands, for their advice on this case. Appendix Authors Footnotes Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article. Informed consent: The patient gave informed consent. The Article Processing Charge was funded by the authors. Received January 3, 2019. Accepted in final form April 21, 2019. Copyright © 2019 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, Tuzun 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.↵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 3.↵Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016;15:391–404.OpenUrlCrossRefPubMed 4.↵Gresa-Arribas N, Titulaer MJ, Torrents A, et al. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol 2014;13:167–177.OpenUrlCrossRefPubMed 5.↵Armangue T, Titulaer MJ, Sabater L, et al. A novel treatment-responsive encephalitis with frequent opsoclonus and teratoma. Ann Neurol 2014;75:435–441.OpenUrl 6.↵Iizuka T, Kaneko J, Tominaga N, et al. Association of progressive cerebellar atrophy with long-term outcome in patients with anti-N-Methyl-d-Aspartate receptor encephalitis. JAMA Neurol 2016;73:706–713.OpenUrl 7.↵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
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Pediatric freezing of gait caused by anti‐NMDAR encephalitis | MyNeuroNews

Gaetano Cantalupo, Alfonso Fasano June 15, 2019 Read More... See Also: Elevated Plasma Homocysteine Levels in Anti-N-methyl-D-aspartate Receptor Encephalitis Objective: Homocysteine (Hcy) levels have been investigated in many diseases, such as neurodegenerative and autoimmune diseases. However, changes in Hcy levels in anti-N-Methyl-D-aspartate receptor (anti-NMDAR) encephalitis have not been investigated thus far. Methods: Case data were collected from 46 patients with anti-NMDAR encephalitis and 179 age- and sex-matched healthy controls... Novel Object Recognition in Rats With NMDAR Dysfunction in CA1 After Stereotactic Injection of Anti-NMDAR Encephalitis Cerebrospinal Fluid Purpose: Limbic encephalitis associated with autoantibodies against N-methyl D-aspartate receptors (NMDARs) often presents with memory impairment. NMDARs are key targets for memory acquisition and retrieval, and have been mechanistically linked to its underlying process, synaptic plasticity. Clinically, memory deficits are largely compatible with a predominantly hippocampus-dependent phenotype, which, in rodents,... Clinical Features, Treatment, and Outcomes Among Chinese Children With Anti-methyl-D-aspartate Receptor (Anti-NMDAR) Encephalitis Objective: Anti-N- methyl-D-aspartate receptor (anti-NMDAR) encephalitis is the most common form of autoimmune encephalitis in pediatric patients. In the present study, we aimed to investigate the clinical features and long-term outcomes of pediatric patients with anti-NMDAR encephalitis in China. Methods: We conducted a retrospective study of children (age range: 0–18... Elevation of YKL-40 in the CSF of Anti-NMDAR Encephalitis Patients Is Associated With Poor Prognosis Jinyu Chen, Yuewen Ding, Dong Zheng, Zhanhang Wang, Suyue Pan, Teng Ji, Hai-Ying Shen, Honghao Wang Read More...Read More......
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Hosts World’s Largest Gathering of Rare Disease Stakeholders

Hosts World’s Largest Gathering of Rare Disease Stakeholders | AntiNMDA | Scoop.it
Global Genes® Hosts World’s Largest Gathering of Rare Disease Stakeholders at the 8th Annual RARE Patient Advocacy Summit September 18-20 Author of Brain on Fire Susannah Cahalan Announced as 2019 Keynote Speaker Aliso Viejo, Calif.
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Catatonia in Adolescence: First Onset Psychosis or Anti-NMDAr Encephalitis? - PubMed - NCBI

Catatonia in Adolescence: First Onset Psychosis or Anti-NMDAr Encephalitis? - PubMed - NCBI | AntiNMDA | Scoop.it
Clin Neuropharmacol. 2019 May 30. doi: 10.1097/WNF.0000000000000348.[Epub ahead of print]...
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Catatonia and the immune system: a review

Catatonia is a psychomotor disorder featuring stupor, posturing, and echophenomena.
This Series paper examines the evidence for immune dysregulation in catatonia. Activation of the innate immune system is associated with mutism, withdrawal, and psychomotor retardation, which constitute the...
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