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1.  Anti–N-Methyl-D-Aspartate Receptor Encephalitis 
JAMA neurology  2013;70(12):1566-1568.
IMPORTANCE
N-methyl-D-aspartate receptor (NMDAR) antibody encephalitis is an autoimmune encephalitis that can be paraneoplastic and usually responds to treatment. It is quickly becoming the most common paraneoplastic encephalitis.
OBSERVATIONS
We present a case of a woman in her late 30s who developed psychiatric symptoms that progressed to encephalopathy, seizures, autonomic instability, and hyperkinetic movements. The patient was found to have an ovarian teratoma and serum and cerebrospinal fluid NMDAR antibodies. Despite resection of the teratoma and treatment with immunosuppressive therapy, the patient progressed to a minimally conscious state. She was supported medically in our institution for 25 months. During her hospitalization, she was treated with multiple immunosuppressive agents. With each treatment, we analyzed the serum and cerebrospinal fluid for NMDAR antibodies. While there was some initial reduction in the serum antibodies, the spinal fluid antibodies remained persistently elevated. The patient did not have any clinical improvement and eventually died after the family decided to withdraw care.
CONCLUSIONS AND RELEVANCE
As far as we know, this case represents the longest active treatment without improvement of a patient with anti-NMDAR encephalitis. The patient had persistently high cerebrospinal fluid and serum antibody titers, which may be of prognostic significance.
doi:10.1001/jamaneurol.2013.3205
PMCID: PMC4065571  PMID: 24166348
2.  Anti-NMDA Receptor Encephalitis in Psychiatry 
Current psychiatry reviews  2011;7(3):189-193.
Anti-NMDA receptor encephalitis is an autoimmune disorder in which antibodies attack NMDA (N-methyl-D-aspartate)-type glutamate receptors at central neuronal synapses. Symptoms include a highly characteristic set of neurologic deficits, but also prominent psychiatric manifestations that often bring mental health professionals into the course of care. Distinct phases of illness have become increasingly appreciated, and include a range of psychotic symptoms early in the course of the disease followed by more severe fluctuations in consciousness with neurologic involvement, and ultimately protracted cognitive and behavioral deficits. Young women are most commonly impacted and an ovarian teratoma is sometimes associated with the syndrome. Patients respond well to immunotherapy, but psychiatric symptoms can be challenging to manage. We provide an up to date review of this disorder and highlight the role of psychiatry in diagnosis, symptomatology, and treatment.
doi:10.2174/157340011797183184
PMCID: PMC3983958  PMID: 24729779
NMDA receptor; autoimmune; synapse; paraneoplastic; schizophrenia
3.  Ophelia syndrome with metabotropic glutamate receptor 5 antibodies in CSF 
Neurology  2013;80(14):1349-1350.
A 35-year-old man developed progressive memory problems and personality changes over the course of 6 months. This amnesia culminated in overt functional impairment as he began getting lost in familiar places and paid his rent multiple times in one day. He then displayed increased aggression and was admitted to hospital after assaulting a family member.
doi:10.1212/WNL.0b013e31828ab325
PMCID: PMC3656459  PMID: 23486886
4.  Pediatric Anti-NMDAR encephalitis-Clinical analysis and novel findings in a series of 20 patients 
The Journal of pediatrics  2012;162(4):850-856.e2.
Objective
To report the clinical features of 20 pediatric patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis.
Study design
Review of clinical data, long-term follow-up, and immunological studies performed in a single center in Spain in the last 4 years.
Results
The median age of the patients was 13 years (range, 8 months-18 years), 70% were female. In 12 patients (60%) the initial symptoms were neurologic, usually dyskinesias or seizures, and in the other 40% psychiatric. One month into the disease, all patients had involuntary movements and alterations of behavior and speech. All patients received steroids, intravenous immunoglobulin (IVIG) or plasma exchange, and 7 rituximab or cyclophosphamide. With a median follow up of 17.5 months, 85% had substantial recovery, 10% moderate or severe deficits, and 1 died. Three patients had previous episodes compatible with anti-NMDAR encephalitis, 2 of them with additional relapses after the diagnosis of the disorder. Ovarian teratoma was identified in two patients, one at onset of encephalitis and the other one year later. Two novel observations (one patient each) include, the identification of an electroencephalographic pattern (“extreme delta brush”) considered characteristic of this disorder, and the development of anti-NMDAR encephalitis after herpes simplex encephalitis (HSE).
Conclusions
The initial symptoms of pediatric anti-NMDAR encephalitis vary from those of the adults (more neurologic and less psychiatric in children), the development of a mono-symptomatic illness is extremely rare (except in relapses), and most patients respond to treatment. Our study suggests a link between post-HSE choreoathetosis and anti-NMDAR encephalitis.
doi:10.1016/j.jpeds.2012.10.011
PMCID: PMC3582718  PMID: 23164315
Autoimmune encephalitis; Choreoathetosis; Herpes simplex encephalitis; Child; Extreme delta brush
5.  Frequency and characteristics of isolated psychiatric episodes in anti-NMDA receptor encephalitis 
JAMA neurology  2013;70(9):10.1001/jamaneurol.2013.3216.
Importance
Patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis often develop prominent psychiatric manifestations. The frequency and type of isolated psychiatric episodes (pure psychiatric symptoms without neurological involvement) either as initial presentation of the disease or as relapse are unknown.
Objective
To determine the frequency, symptoms, and outcome of isolated psychiatric episodes in a cohort of patients with anti-NMDAR encephalitis.
Design
Observational cohort of patients diagnosed over a 5 year period (median follow-up 2 years).
Patients and setting
571 patients with IgG antibodies against the NR1 subunit of the NMDAR were included in the study. Antibody studies were performed at the Universities of Pennsylvania and Barcelona, and clinical information was obtained by the authors or referring physicians.
Main Outcome Measures
Frequency, type of symptoms, and outcome of patients with anti-NMDAR encephalitis and isolated psychiatric manifestations.
Results
23/571 patients (4%) developed isolated psychiatric episodes, 5 at disease onset and 18 during relapses. For all 23 patients, age (median 20 years), gender (91% female), and tumor association (43%, ovarian teratoma) were similar to the population at large. Predominant symptoms included, delusional thinking (74%), mood disturbances (70%, usually manic), and aggression (57%). Brain MRI was abnormal in 10/22 (45%) and CSF showed pleocytosis in 17/22 (77%). Eighty three percent of the patients had full/substantial recovery after immunotherapy and tumor resection when appropriate. After relapse, 17/18 (94%) patients returned to a similar or better pre-relapse functional level.
Conclusions
Isolated psychiatric episodes are rare but can occur as initial onset or relapse of anti-NMDAR encephalitis. Recognition of these episodes is important because they respond to immunotherapy. In patients with new onset psychosis, history of encephalitis, subtle neurological symptoms, and/or abnormal ancillary tests should prompt screening for NMDAR antibodies.
doi:10.1001/jamaneurol.2013.3216
PMCID: PMC3809325  PMID: 23877059
6.  Treatment and prognostic factors for long-term outcome in patients with anti-N-Methyl-D-Aspartate (NMDA) receptor encephalitis: a cohort study 
Lancet neurology  2013;12(2):157-165.
Background
Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder in which the use of immunotherapy and the long-term outcome have not been defined.
Methods
In this multi-institutional observational study (2007-2012), all patients with GluN1 antibodies were assessed at symptom onset and 4, 8, 12, 18, and 24 months using the modified Rankin Scale (mRS). Treatment included first-line immunotherapy (steroids, intravenous immunoglobulin, plasmapheresis), second-line immunotherapy (rituximab, cyclophosphamide), and tumor removal. Predictors of outcome were determined at the Universities of Pennsylvania and Barcelona using generalized linear mixed models with binary distribution.
Results
577 patients (1-85 years, median 21) were studied, 212 were children (<18 years). Treatment effects and outcome were assessable in 501 (median follow-up 24 months): 472 (94%) underwent first-line immunotherapy or tumor removal, resulting in improvement within four weeks in 251 (53%). Of 221 patients who failed first-line therapy, 125 (57%) received second-line immunotherapy resulting in better outcome than those who did not (OR 2·69, CI 1·24-5·80, p=0·012). During the first 24 months, 394/501 reached good outcome (mRS 0-2; median 6 months), and 30 died. At 24 month follow-up 204/252 (81%) had good outcome. Outcomes continued to improve for up to 18 months after symptom onset. Predictors of good outcome were early treatment (OR 0·62, CI 0·50-0·76, p<0·0001) and lack of ICU admission (OR 0.12, CI 0·06-0·22,p<0·0001). 45 patients had one or multiple relapses (representing a 12% risk within 2 years); 46/69 (67%) relapses were milder than previous episodes (p<0·0001). In 177 children, predictors of good outcome and the magnitude of effect of second-line immunotherapy were comparable to those of the entire cohort.
Conclusions
Patients with anti-NMDAR encephalitis respond to immunotherapy. Second-line immunotherapy is usually effective when first-line therapies fail. Recovery can take more than 18 months.
doi:10.1016/S1474-4422(12)70310-1
PMCID: PMC3563251  PMID: 23290630
anti-NMDA-receptor antibodies; encephalitis; paraneoplastic; teratoma; behavior; seizures; treatment; outcome
7.  Encephalitis and antibodies to DPPX, a subunit of Kv4.2 potassium channels 
Annals of neurology  2012;73(1):120-128.
Objective
To report a novel cell-surface autoantigen of encephalitis that is a critical regulatory subunit of the Kv4.2 potassium channels.
Methods
Four patients with encephalitis of unclear etiology and antibodies with a similar pattern of neuropil brain immunostaining were selected for autoantigen characterization. Techniques included immunoprecipitation, mass spectrometry, cell-base experiments with Kv4.2 and several dipeptidyl-peptidase-like protein-6 (DPPX) plasmid constructs, and comparative brain immunostaining of wild-type and DPPX-null mice.
Results
Immunoprecipitation studies identified DPPX as the target autoantigen. A cell based assay confirmed that all 4 patients, but not 210 controls, had DPPX antibodies. Symptoms included agitation, confusion, myoclonus, tremor, and seizures (one case with prominent startle response). All patients had pleocytosis, and three had severe prodromal diarrhea of unknown etiology. Given that DPPX “tunes up” the Kv4.2 potassium channels (involved in somatodendritic signal integration and attenuation of dendritic backpropagation of action potentials), we determined the epitope distribution in DPPX, DPP10 (a protein homologous to DPPX) and Kv4.2. Patients’ antibodies were found specific for DPPX, without reacting with DPP10 or Kv4.2. The unexplained diarrhea led to demonstrate a robust expression of DPPX in the myenteric plexus, which strongly reacted with patients’ antibodies. The course of neuropsychiatric symptoms was prolonged and often associated with relapses while decreasing immunotherapy. Long-term follow-up showed substantial improvement in 3 patients (1 is lost to follow-up).
Interpretation
Antibodies to DPPX associate with a protracted encephalitis characterized by CNS hyperexcitability (agitation, myoclonus, tremor, seizures), pleocytosis, and frequent diarrhea at symptom onset. The disorder is potentially treatable with immunotherapy.
doi:10.1002/ana.23756
PMCID: PMC3563722  PMID: 23225603
Antibodies; encephalitis; autoimmune; DPP6; DPPX; potassium channels
8.  An Optimized Immunohistochemistry Technique Improves NMO-IgG Detection: Study Comparison with Cell-Based Assays 
PLoS ONE  2013;8(11):e79083.
Cell-based assays (CBA) have increased the sensitivity of the neuromyelitis optica (NMO)-IgG/aquaporin-4-antibody detection compared to classical tissue-based indirect assays. We describe the sensitivity of an optimized immunohistochemistry (IHC-o) to detect NMO-IgG/aquaporin-4-antibody in comparison with that of two CBA: an in-house (CBA-ih) and a commercial (CBA-c) assay (Euroimmun, Germany). Coded serum from 103 patients with definite NMO and 122 inflammatory controls were studied by IHC-o, CBA-ih, and CBA-c. IHC-o used the same protocol described to detect antibodies against cell surface antigens. CBA-ih used live cells transfected with the aquaporin-4-M23-isoform. The sensitivity of the IHC-o was 74.8% (95% confidence interval [CI] 65-83) and was similar to that of the CBA-ih 75.7% (95% CI 66-84) and the CBA-c 73.8% (95% CI 64-82). The specificity of the three assays was 100% (95% CI 97-100). Interassay concordance was high, 100 of 103 samples were coincident in all techniques. The optimized immunohistochemistry proves to be as sensitive and specific as the cell-based assays. This assay extends the available tools for NMO-IgG/aquaporin-4-antibody detection.
doi:10.1371/journal.pone.0079083
PMCID: PMC3817095  PMID: 24223884
9.  Autoimmune Encephalitis in Children 
Journal of child neurology  2012;27(11):1460-1469.
The causes of encephalitis are numerous, and extensive investigations for infectious agents and other etiologies are often negative. The discovery that many of these encephalitis are immune mediated has changed the approach to the diagnosis and treatment of these disorders. Moreover, the broad spectrum of symptoms including, psychosis, catatonia, alterations of behavior and memory, seizures, abnormal movements, and autonomic dysregulation usually requires a multidisciplinary treatment approach. This review focuses in several forms of encephalitis that occur in children, and for which an autoimmune etiology has been demonstrated (eg, anti-N-methyl-D-aspartate receptor encephalitis) or is strongly suspected (eg, Rasmussen encephalitis, limbic encephalitis, opsoclonus-myoclonus). The authors also review several disorders that may be immune mediated, such as the rapid onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation (ROHHAD) syndrome and some encephalopathies with fever and status epilepticus. Recognition of novel immune-mediated encephalitis is important because some of these disorders are highly responsive to immunotherapy.
doi:10.1177/0883073812448838
PMCID: PMC3705178  PMID: 22935553
autoimmune; encephalitis; limbic; anti-NMDA receptor; NMDA
10.  Patient With Homer-3 Antibodies and Cerebellitis 
JAMA neurology  2013;70(4):506-509.
Importance
Homer proteins are a family of scaffolding proteins of the postsynaptic density. Homer-3 colocalizes and modulates the activity of group I metabotropic glutamate receptors (mGluR1 and mGluR5). Cerebellitis has been reported in association with antibodies to mGluR1. We describe the second patient with cerebellitis and Homer-3 antibodies and report a novel, highly specific immunoblot assay.
Observations
A 38-year-old man had acute onset of headache, nausea, vomiting, and confusion. He developed a pancerebellar syndrome during the ensuing week. Extensive studies did not reveal any tumor. Cerebrospinal fluid analysis showed a white blood cell count of 60/µL (to convert to ×109 per liter, multiply by 0.001). Brain magnetic resonance imaging findings were normal. For 2 years, the patient was treated with intravenous immunoglobulins and steroids, with partial improvement of the cerebellar ataxia. The patient was negative for onconeural (Hu, Yo, Ri, CV2, Tr, amphiphysin, and Ma2), glutamic acid decarboxylase, and mGluR1 antibodies. Immunohistochemistry on rat brain revealed immunostaining of the cerebellar molecular layer. Homer-3 antibodies were demonstrated by immunoblot of recombinant Homer-3. The clinical features of this patient and a previously described patient with Homer-3 antibodies are similar to those of patients with mGluR1 antibodies.
Conclusions and Relevance
We report the second case of autoimmune cerebellar ataxia associated with Homer-3 antibodies. The presence of Homer-3 autoantibodies should be considered in the differential diagnosis of patients with subacute cerebellar ataxia of unknown cause.
doi:10.1001/jamaneurol.2013.1955
PMCID: PMC3723144  PMID: 23400636
11.  Extreme delta brush 
Neurology  2012;79(11):1094-1100.
Objectives:
To determine continuous EEG (cEEG) patterns that may be unique to anti-NMDA receptor (NMDAR) encephalitis in a series of adult patients with this disorder.
Methods:
We evaluated the clinical and EEG data of 23 hospitalized adult patients with anti-NMDAR encephalitis who underwent cEEG monitoring between January 2005 and February 2011 at 2 large academic medical centers.
Results:
Twenty-three patients with anti-NMDAR encephalitis underwent a median of 7 (range 1−123) days of cEEG monitoring. The median length of hospitalization was 44 (range 2−200) days. Personality or behavioral changes (100%), movement disorders (82.6%), and seizures (78.3%) were the most common symptoms. Seven of 23 patients (30.4%) had a unique electrographic pattern, which we named “extreme delta brush” because of its resemblance to waveforms seen in premature infants. The presence of extreme delta brush was associated with a more prolonged hospitalization (mean 128.3 ± 47.5 vs 43.2 ± 39.0 days, p = 0.008) and increased days of cEEG monitoring (mean 27.6 ± 42.3 vs 6.2 ± 5.6 days, p = 0.012). The modified Rankin Scale score showed a trend toward worse scores in patients with the extreme delta brush pattern (mean 4.0 ± 0.8 vs 3.1 ± 1.1, p = 0.089).
Conclusions:
Extreme delta brush is a novel EEG finding seen in many patients with anti-NMDAR encephalitis. The presence of this pattern is associated with a more prolonged illness. Although the specificity of this pattern is unclear, its presence should raise consideration of this syndrome.
doi:10.1212/WNL.0b013e3182698cd8
PMCID: PMC3525298  PMID: 22933737
12.  Paraneoplastic Neurologic Disorders: A Brief Overview 
Memo  2012;5(3):197-200.
Immune-mediated paraneoplastic neurologic disorders (PND) may affect any part of the nervous system, and can mimic many non-cancer associated disorders. The availability of diagnostic tests based on the presence of specific anti-neuronal antibodies facilitates diagnosis and can suggest treatment strategies. Once thought to be poorly responsive to therapies, it is now recognized that there is a subgroup of PND, mostly associated with antibodies to antigens on the neuronal cell surface that are highly treatment responsive. For all PND, identification and treatment of the underlying tumor is the most effective step in the potential control or stabilization of the neurological disorder.
doi:10.1007/s12254-012-0034-z
PMCID: PMC3525357  PMID: 23264806
paraneoplastic; neurologic; autoimmunity; antibodies
13.  Paraneoplastic syndromes and autoimmune encephalitis 
Neurology. Clinical Practice  2012;2(3):215-223.
Summary
We review novel findings in paraneoplastic syndromes including the Lambert-Eaton myasthenic syndrome, and then focus on the novel disorders associated with antibodies against cell surface antigens, discussing the importance and caveats of antibody testing, and providing an algorithm for interpretation of results. In anti-NMDAR encephalitis 2 novel findings include the recognition of a characteristic EEG pattern (“extreme delta brush”) in 30% of patients and the demonstration of a fronto-temporo-occipital gradient of glucose metabolism that correlates with disease activity. In limbic encephalitis, antibodies to GABA(B) receptor are the most frequently detected in patients with small-cell lung cancer who are anti-Hu negative, and antibodies to mGluR5 distinctively associate with Hodgkin lymphoma (Ophelia syndrome). We also address the syndromes associated with “VGKC-complex antibodies,” a problematic term that groups well-characterized immune-mediated disorders (LGI1, Caspr2) with others that lack syndrome specificity, are less responsive to treatment, and for which the target antigens are unknown.
doi:10.1212/CPJ.0b013e31826af23e
PMCID: PMC3613202  PMID: 23634368
15.  Pseudo-Piano Playing Motions and Nocturnal Hypoventilation in Anti-NMDA Receptor Encephalitis: Response to Prompt Tumor Removal and Immunotherapy 
Internal medicine (Tokyo, Japan)  2011;50(6):627-630.
Tumor resection is recommended in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, however it is often difficult during an early stage of the disease. We report here the efficacy of early tumor removal in a patient with anti-NMDAR encephalitis. This 21-year-old woman was admitted to another hospital with rapidly progressive psychiatric symptoms, a decreased level of consciousness, and seizures. Abdominal CT showed a pelvic mass. On day 1 of admission to our center, she developed hypoventilation requiring mechanical support. She had orofacial dyskinesias with well-coordinated, pseudo-piano playing involuntary finger movements. Based on these clinical features, she was immediately scheduled for tumor resection on day 3. While awaiting surgery, she began to receive high-dose intravenous methylprednisolone. After tumor removal, she received plasma exchange, followed by intravenous immunoglobulin and additional high-dose methylprednisolone. Two weeks after tumor removal, she started following simple commands and progressive improvement, although she remained on mechanical ventilation for 10 weeks due to nocturnal central hypoventilation. Anti-NMDAR antibodies in serum/CSF were detected. Pathological examination showed immature teratoma with foci of infiltrates of B- and T-cells. Early tumor resection with immunotherapy facilitates recovery from this disease, but central hypoventilation may require long mechanical support. Non-jerky elaborate finger movements suggest antibody-mediated disinhibition of the cortico-striatal systems.
PMCID: PMC3740121  PMID: 21422691
paraneoplastic; encephalitis; ovarian tumor; NMDA receptor; early treatment
16.  Fluorodeoxyglucose positron emission tomography in anti-N-methyl-D-aspartate receptor encephalitis: distinct pattern of disease 
Background
Patients with encephalitis associated with antibodies against N-methyl-D-aspartate-receptor antibody (NMDAR-ab) encephalitis frequently show psychotic symptoms, amnesia, seizures and movement disorders. While brain MRI in NMDAR-ab encephalitis is often normal, abnormalities of cerebral glucose metabolism have been demonstrated by positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) in a few usually isolated case reports. However, a common pattern of FDG-PET abnormalities has not been reported.
Methods
The authors retrospectively identified six patients with NMDAR-ab encephalitis in two large German centres who underwent at least one whole-body FDG-PET for tumour screening between January 2007 and July 2010. They analysed the pattern of cerebral uptake derived from whole-body PET data for characteristic changes of glucose metabolism compared with controls, and the changes of this pattern during the course of the disease.
Results
Groupwise analysis revealed that patients with NMDAR-ab encephalitis showed relative frontal and temporal glucose hypermetabolism associated with occipital hypometabolism. Cross-sectional analysis of the group demonstrated that the extent of these changes is positively associated with clinical disease severity. Longitudinal analysis of two cases showed normalisation of the pattern of cerebral glucose metabolism with recovery.
Conclusions
A characteristic change in cerebral glucose metabolism during NMDAR-ab encephalitis is an increased frontotemporal-to-occipital gradient. This pattern correlates with disease severity. Similar changes have been observed in psychosis induced by NMDAR antagonists. Thus, this pattern might be a consequence of impaired NMDAR function.
doi:10.1136/jnnp-2011-301969
PMCID: PMC3740122  PMID: 22566598
17.  Clinical Reasoning: Agitation and psychosis in a patient after renal transplantation 
Neurology  2012;79(5):e41-e44.
doi:10.1212/WNL.0b013e3182616fad
PMCID: PMC3405246  PMID: 22851723
18.  N-Methyl-d-Aspartate Receptor Antibodies in Herpes Simplex Encephalitis 
Annals of neurology  2012;72(6):902-911.
Objective
To determine the presence and kinetics of antibodies against synaptic proteins in patients with herpes simplex virus encephalitis (HSE).
Methods
Retrospective analysis of 44 patients with polymerase chain reaction-proven HSE for the presence of a large panel of onconeuronal and synaptic receptor antibodies. The effect of patients’ serum was studied in cultures of primary mouse hippocampal neurons.
Results
N-Methyl-d-aspartate receptor (NMDAR) antibodies of the immunoglobulin (Ig) subtypes IgA, IgG, or IgM were detected in 13 of 44 patients (30%) in the course of HSE, suggesting secondary autoimmune mechanisms. NMDAR antibodies were often present at hospital admission, but in some patients developed after the first week of HSE. Antibody-positive sera resulted in downregulation of synaptic marker proteins in hippocampal neurons.
Interpretation
Some patients with HSE develop IgA, IgG, or IgM autoantibodies against NMDAR. Sera from these patients alter the density of neuronal synaptic markers, suggesting a potential pathogenic disease-modifying effect. These findings have implications for the understanding of autoimmunity in infectious diseases, and prospective studies should reveal whether the subgroup of patients with HSE and NMDAR antibodies may benefit from immunotherapy.
doi:10.1002/ana.23689
PMCID: PMC3725636  PMID: 23280840
19.  CNS autoimmunity: new findings and pending issues 
Lancet neurology  2012;11(1):17-19.
doi:10.1016/S1474-4422(11)70280-0
PMCID: PMC3723139  PMID: 22172617
20.  Glycine Receptor Autoimmune Spectrum With Stiff-Man Syndrome Phenotype 
JAMA neurology  2013;70(1):44-50.
Objectives
To determine whether glycine receptor α1 subunit-specific autoantibodies (GlyRα1-IgG) occur in a broader spectrum of brainstem and spinal hyperexcitability disorders than the progressive encephalomyelitis with rigidity and myoclonus phenotype recognized to date, and to ascertain disease specificity.
Design
Retrospective, case-control study.
Settings
Mayo Clinic, Rochester, Minnesota, and University of Barcelona, Spain.
Patients
Eighty-one patients with stiff-man syndrome phenotype, 80 neurologic control subjects, and 20 healthy control subjects.
Intervention
Glycine receptor α1–transfected cells to test serum or cerebrospinal fluid from cases and control subjects.
Main Outcome Measures
Frequency of GlyRα1-IgG positivity among stiff-man syndrome phenotype cases and control subjects. Comparison of GlyRα1-IgG seropositive and seronegative cases.
Results
Seropositive cases (12% of cases) included 9 with stiff-man syndrome (4 classic; 5 variant; 66% were glutamic acid decarboxylase 65–IgG positive) and 1 with progressive encephalomyelitis with rigidity and myoclonus. Immunotherapy responses were noted more frequently in GlyRα1-IgG–positive cases (6 of 7 improved) than in seronegative cases (7 of 25 improved; P=.02). The single seropositive control patient had steroid-responsive vision loss and optic atrophy with inflammatory cerebrospinal fluid.
Conclusions
Glycine receptor α1–IgG aids identification of autoimmune brainstem/spinal cord hyperexcitability disorders and may extend to the glycinergic visual system.
doi:10.1001/jamaneurol.2013.574
PMCID: PMC3718477  PMID: 23090334
21.  Cognitive deficits following anti-NMDA receptor encephalitis 
Background
Anti-NMDA receptor (NMDAR) encephalitis is a recently characterised autoimmune disorder mainly affecting young women. Although the clinical features of the acute disease are well characterised, cognitive long-term outcome has not been examined in detail.
Methods
The authors investigated cognitive performance in nine patients with proven anti-NMDAR encephalitis after recovery from the acute disease period (median 43 months after disease onset, range 23 to 69). Patients underwent a comprehensive neuropsychological assessment, including memory tasks that have previously been shown to be sensitive for hippocampal dysfunction.
Results
Substantial persistent cognitive impairments were observed in eight out of nine patients that mainly consisted of deficits in executive functions and memory. The severity of these deficits varied inter-individually. Patients with early immunotherapy performed significantly better. The most severe deficits were observed with inefficient or delayed initial treatment.
Conclusion
Our results suggest that cognitive deficits constitute a major long-term morbidity of anti-NMDAR encephalitis. These deficits relate to the distribution of NMDARs in the human brain and their functional role in normal cognition. Good cognitive long-term outcome may depend on early and aggressive treatment.
doi:10.1136/jnnp-2011-300411
PMCID: PMC3718487  PMID: 21933952
22.  Neuronal autoantigens—pathogenesis, associated disorders and antibody testing 
Nature reviews. Neurology  2012;8(7):380-390.
The discovery of disorders that are associated with antibodies to neuronal cell-surface proteins has led to a paradigm shift in our understanding of CNS autoimmunity. These disorders can occur in patients with or without cancer—often children or young adults who develop psychosis, catatonic or autistic features, memory problems, abnormal movements, or seizures that were previously considered idiopathic. The autoantigens in such cases have crucial roles in synaptic transmission, plasticity and peripheral nerve excitability. Patients can be comatose or encephalopathic for months and yet fully recover with supportive care and immunotherapy. By contrast, disorders in which the antibodies target intracellular antigens, and in which T-cell-mediated irreversible neuronal degeneration occurs, show a considerably poorer response to treatment. In this article, we review the various targets of neuronal antibodies, focusing predominantly on autoantigens located on the cell surface or synapses—namely, N-methyl-d-aspartate receptors, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, γ-aminobutyric acid receptors, leucine-rich glioma-inactivated protein 1, contactin-associated protein-like 2, and metabotropic glutamate receptors. We also provide an algorithm to identify and assess antibodies that bind to cell-surface and synaptic antigens.
doi:10.1038/nrneurol.2012.99
PMCID: PMC3718498  PMID: 22710628
23.  Clinical neuropathology practice guide 5-2012: Updated guideline for the diagnosis of antineuronal antibodies 
Clinical neuropathology  2012;31(5):337-341.
In recent years there is an increasing description of novel anti-neuronal antibodies that are associated with paraneoplastic and non-paraneoplastic neurological syndromes. These antibodies are useful in clinical practice to confirm the immunmediated origin of the neurological disorder and are helpful in tumor search. Currently, antineuronal antibodies can be classified according to the location of the recognized antigen into two groups, 1.) intraneuronal antigens and 2.) antigens located in the cell membrane. Different techniques are established for detecting these antibodies: tissue-based assay (TBA), cell-based assay (CBA), immunoblot, immunoprecipitation assay (IP), and ELISA. TBA detect most of the antibodies, however, different pretreatment methods of rat brain are necessary to visualize either Group 1 or 2 antibodies. Higher specificity is provided by immunoblots, applicable for Group 1 antibodies, and CBA, suitable for Group 2 antibodies. IP and ELISA may be useful for the detection of specific antibodies or to solve particular issues such as antibody titers. Diagnosis of paraneoplastic and non-paraneoplastic neurological syndromes has important implications on treatment and follow-up of patients. Selection and proper combination of test systems and appropriate knowledge of the clinical information will provide a maximum of sensitivity and specificity in identifying the associated antibody.
PMCID: PMC3663458  PMID: 22939174
anti-neuronal antibodies; diagnosis; tissue-based assay; cell-based assay; immunoblot; sensitivity; specificity
24.  Young girl with psychosis, cognitive failure and seizures 
Psychiatric symptoms combined with neurological disturbances should always arouse suspicion that the cause may be organic. We describe a young patient whose examination revealed a recently described condition for which there are precise diagnostics and in many cases effective treatment.
doi:10.4045/tidsskr.12.0092
PMCID: PMC3707140  PMID: 23038201
25.  Persistent Intrathecal Antibody Synthesis 15 Years After Recovering From Anti–N-methyl-d-aspartate Receptor Encephalitis 
JAMA neurology  2013;70(1):117-119.
Background
Anti–N-methyl-d-aspartate receptor (NMDAR) encephalitis is a severe autoimmune disorder characterized by high intrathecal antibody synthesis. Little is known about the long-term follow-up of the cerebrospinal fluid antibody status.
Objective
To describe persistent intrathecal antibody synthesis in a clinically healthy person 15 years after recovering from anti-NMDAR encephalitis.
Design
Case report.
Setting
Academic medical center.
Patient
A 40-year-old woman who had been diagnosed as having encephalitis of unknown origin in 1995.
Main Outcome Measures
Clinical evaluation and NMDAR antibody testing.
Results
On reexamination in 2011, the patient had fully recovered. Investigation of archived as well as follow-up serum and cerebrospinal fluid samples revealed intrathecal synthesis of NMDAR antibodies.
Conclusions
This is the longest follow-up on a patient with anti-NMDAR encephalitis. Our findings emphasize that intrathecal antibody synthesis does not necessarily reflect disease activity and that the significance of NMDAR antibody titers needs to be interpreted for each patient according to the clinical context.
doi:10.1001/jamaneurol.2013.585
PMCID: PMC3707142  PMID: 23318518

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