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The Lancet Neurology 05/2013; 12(5):425-6. · 23.46 Impact Factor
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Thaís Armangue,
Maarten J Titulaer,
Lidia Sabater,
Javier Pardo-Moreno,
Nuria Gresa-Arribas,
Natalia Barbero-Bordallo,
Gordon R Kelley,
Noh Kyung-Ha,
Akitoshi Takeda,
Takahiro Nagao,
Yukitoshi Takahashi,
Angélica Lizcano,
Aisling S Carr,
Francesc Graus, Josep Dalmau
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ABSTRACT: Among 249 patients with teratoma-associated encephalitis, 211 had N-methyl-D-aspartate receptor antibodies and 38 were negative for these antibodies. While antibody-positive patients rarely developed prominent brainstem-cerebellar symptoms, 22 (58%) antibody-negative patients developed a brainstem-cerebellar syndrome, which in 45% occurred with opsoclonus. The median age of these patients was 28.5 years (12-41), 91% were women, and 74% had full recovery after immunotherapy and tumor resection. These findings uncover a novel phenotype of paraneoplastic opsoclonus which until recently was likely considered "idiopathic" or post-infectious". The triad, young age (teenager- young adult), systemic teratoma, and high response to treatment characterize this novel brainstem-cerebellar syndrome. ANN NEUROL 2013. © 2013 American Neurological Association.
Annals of Neurology 04/2013; · 11.09 Impact Factor
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ABSTRACT: 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.
JAMA neurology. 02/2013;
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ABSTRACT: The goal of this study is to determine whether patients with paraneoplastic cerebellar degeneration (PCD) and small-cell lung cancer (SCLC) have a specific repertoire of antibodies, if SOX1 antibodies (SOX1-ab) can predict the presence of SCLC, and if antibodies to cell surface antigens occur in this syndrome. Antibody analysis was done using immunohistochemistry on rat brain, immunoblot with recombinant antigens, screening of cDNA expression libraries, and immunolabeling of live neurons in 39 patients with PCD and SCLC. VGCC-ab were measured by RIA, and SOX1-ab, Hu-ab, and ZIC4-ab by immunoblot. Lambert-Eaton myastenic syndrome (LEMS) was present in 10 of 23 patients with electrophysiological studies. At least one antibody was detected in 72% of patients. The individual frequencies were: 49% SOX1-ab, 44% VGCC-ab, 31% Hu-ab, and 13% ZIC4-ab. SOX1-ab occurred in 76% of patients with VGCC-ab and 27% of those without VGCC-ab (p = 0.0036). SOX1-ab were not found in 39 patients with sporadic late-onset cerebellar ataxia, 23 with cerebellar ataxia and glutamic acid decarboxylase antibodies, and 73 with PCD and cancer types other than SCLC (31 without onconeural antibodies, 25 with Yo-ab , 17 with Tr-ab). Five patients (13%) had antibodies against unknown neuronal cell surface antigens but none of them improved with immunotherapy. One serum immunoreacted against the axon initial segment of neurons and another serum against ELKS1, a protein highly expressed in the cerebellum that interacts with the beta4-subunit of the VGCC. In conclusion, 72% of patients with PCD and SCLC had one or more antibodies that indicate the presence of this tumor. In these patients, VGCC-ab and SOX1-ab occur tightly associated. SOX1-ab are predictors of SCLC in ataxia patients with a specificity of 100% and sensitivity of 49%. Unlike limbic encephalitis with SCLC, antibodies to cell surface antigens other than VGCC-ab, are infrequent and do not predict response to treatment.
PLoS ONE 01/2013; 8(3):e60438. · 4.09 Impact Factor
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ABSTRACT: Onconeural antibodies are diagnostic markers for paraneoplastic neurological syndromes and indicate the underlying tumor type. Recently, a new antibody against protein-kinase Cγ (PKCγ) was detected in a patient with paraneoplastic cerebellar degeneration (PCD). We report here a second patient. A 70-year-old woman presented with cerebellar ataxia, dysdiadochokinesia, and dysarthria. Her serum showed immunoreactivity against the cytoplasm, dendrites and axons of Purkinje cells in tissue-based screening, later confirmed by immunoblot and phage plaques as anti-PKCγ. Tumor search revealed an adenocarcinoma of hepatobiliary origin. Detection of PKCγ antibodies should be considered in PCD and adenocarcinoma without typical onconeural antibodies.
Journal of neuroimmunology 12/2012; · 2.84 Impact Factor
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ABSTRACT: 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 immunologic 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 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 2 patients, 1 at onset of encephalitis and the other 1 year later. Two novel observations (1 patient each) include, the identification of an electroencephalographic pattern ("extreme delta brush") considered characteristic of this disorder, and the development of anti-NMDAR encephalitis as post herpes simplex encephalitis choreoathetosis. 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 herpes simplex encephalitis choreoathetosis and anti-NMDAR encephalitis.
The Journal of pediatrics 11/2012; · 4.02 Impact Factor
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ABSTRACT: 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.
Archives of neurology 10/2012; · 6.31 Impact Factor
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ABSTRACT: PURPOSE OF REVIEW: This review describes relevant advances in paraneoplastic neurological syndromes (PNS) with emphasis on particular syndromes and the impact of antibodies against surface antigens in their management. RECENT FINDINGS: PNS may present with symptoms that do not raise the suspicion of a paraneoplastic origin. The best example is anti-N-methyl-D-aspartate receptor encephalitis that in adult women frequently associates with ovarian teratoma. An electroencephalogram pattern described as 'extreme delta brush' was recently identified in 30% of patients with this disorder. Isolated myelopathy may have a paraneoplastic origin associated with amphiphysin or CV2 (CRMP5) antibodies. Jaw dystonia and laryngospasm can be the predominant symptom of the brainstem encephalitis associated with Ri antibodies. γ-Aminobutyric acid (GABA)B receptor antibodies are the most common antibodies found in patients with limbic encephalitis and small cell lung cancer, and contactin-associated protein 2 antibodies in patients with Morvan's syndrome and thymoma. Lastly, a recent study identified delta/notch-like epidermal growth factor-related receptor (DNER) as the target antigen of Tr antibodies, a marker of cerebellar ataxia and Hodgkin's lymphoma. SUMMARY: The number of antibodies relevant to PNS is now expanded to those against surface antigens. These antibodies do not confirm the paraneoplastic origin of the syndrome but predict a better response to immunotherapy.
Current opinion in neurology 10/2012; · 5.43 Impact Factor
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Anna Boronat,
Jeffrey M Gelfand,
Nuria Gresa-Arribas,
Hyo-Young Jeong,
Michael Walsh,
Kirk Roberts,
Eugenia Martinez-Hernandez,
Myrna R Rosenfeld,
Rita Balice-Gordon,
Francesc Graus,
Bernardo Rudy, Josep Dalmau
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ABSTRACT: 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 (1 case with prominent startle response). All patients had pleocytosis, and 3 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 back-propagation of action potentials), we determined the epitope distribution in DPPX, DPP10 (a protein homologous to DPPX), and Kv4.2. Patients' antibodies were found to be specific for DPPX, without reacting with DPP10 or Kv4.2. The unexplained diarrhea led to a demonstration of 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 during decreasing immunotherapy. Long-term follow-up showed substantial improvement in 3 patients (1 was lost to follow-up). INTERPRETATION: Antibodies to DPPX are associated with a protracted encephalitis characterized by central nervous system hyperexcitability (agitation, myoclonus, tremor, seizures), pleocytosis, and frequent diarrhea at symptom onset. The disorder is potentially treatable with immunotherapy. ANN NEUROL 2012;00:000-000.
Annals of Neurology 09/2012; · 11.09 Impact Factor
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ABSTRACT: 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.
Clinical neuropathology 09/2012; 31(5):337-41. · 1.04 Impact Factor
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ABSTRACT: 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.
Neurology. Clinical practice. 09/2012; 2(3):215-223.
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ABSTRACT: 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.
memo - Magazine of European Medical Oncology 09/2012; 5(3):197-200.
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ABSTRACT: 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.
Journal of child neurology 08/2012; 27(11):1460-9. · 1.59 Impact Factor
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ABSTRACT: 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.
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.
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).
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.
Neurology 08/2012; 79(11):1094-100. · 8.31 Impact Factor
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ABSTRACT: Anti-NMDA receptor (NMDAR) encephalitis is a newly identified autoimmune disorder that targets NMDARs, causing severe neurological symptoms including hallucinations, psychosis, and seizures, and may result in death (Dalmau et al., 2008). However, the exact epitope to which these antibodies bind is unknown. A clearly defined antigenic region could provide more precise testing, allow for comparison of immunogenicity between patients to explore potential clinically relevant variations, elucidate the functional effects of antibodies, and make patients' antibodies a more effective tool with which to study NMDAR function. Here, we use human CSF to explore the antigenic region of the NMDAR. We created a series of mutants within the amino terminal domain of GluN1 that change patient antibody binding in transfected cells in stereotyped ways. These mutants demonstrate that the N368/G369 region of GluN1 is crucial for the creation of immunoreactivity. Mass spectrometry experiments show that N368 is glycosylated in transfected cells and rat brain regions; however, this glycosylation is not directly required for epitope formation. Mutations of residues N368/G369 change the closed time of the receptor in single channel recordings; more frequent channel openings correlates with the degree of antibody staining, and acute antibody exposure prolongs open time of the receptor. The staining pattern of mutant receptors is similar across subgroups of patients, indicating consistent immunogenicity, although we have identified one region that has a variable role in epitope formation. These findings provide tools for detailed comparison of antibodies across patients and suggest an interaction between antibody binding and channel function.
Journal of Neuroscience 08/2012; 32(32):11082-94. · 7.11 Impact Factor
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ABSTRACT: 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.
Nature Reviews Neurology 06/2012; 8(7):380-90. · 12.46 Impact Factor
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Anna Boronat,
María Sepúlveda,
Sara Llufriu,
Lidia Sabater,
Yolanda Blanco,
Iñigo Gabilondo,
Nuria Solà,
Pablo Villoslada, Josep Dalmau,
Francesc Graus,
Albert Saiz
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ABSTRACT: Contactin-2 was recently identified as an autoantigen targeted by T-cells and autoantibodies in multiple sclerosis (MS). Here we analyzed the frequency of antibodies to contactin-2 (contactin-2-ab) by a cell-based assay in the serum from 105 MS patients and at least 5 years of follow-up (19 clinically isolated syndromes, 51 relapsing-remitting, 20 secondary-progressive, and 15 primary-progressive). Contactin-2-ab were detected in 4 (7.8%) relapsing-remitting patients. Clinical and magnetic resonance imaging characteristics were not significantly different from the rest of relapsing-remitting patients. In conclusion, contactin-2-ab are identified in a minority of MS patients but their presence is not associated with a particular clinical-radiological profile.
Journal of neuroimmunology 03/2012; 244(1-2):103-6. · 2.84 Impact Factor
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Handbook of Clinical Neurology 01/2012; 105:853-64.
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The Lancet Neurology 01/2012; 11(1):17-9. · 23.46 Impact Factor
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ABSTRACT: Paraneoplastic neurological disorders can affect any part of the central or peripheral nervous system. Many of these syndromes
have an immunopathogenesis, and are mediated by immunological responses triggered by the presence of a cancer. In this chapter,
we focus on paraneoplastic disorders of the central and peripheral nervous system associated with leukemia or lymphoma. We
also review paraneoplastic syndromes related to plasma cell malignancies (myeloma, Waldenström’s macroglobulinemia), which
in contrast to leukemia and lymphoma, frequently cause paraneoplastic neuropathies.
12/2011: pages 329-344;
