Paraneoplastic Encephalomyelitis Research Articles

Autoimmune diseases and cancers overlapping with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): A systematic review.

BackgroundMyelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) has various similarities with AQP4-IgG-seropositive Neuromyelitis Optica Spectrum Disorder (AQP4-IgG + NMOSD) in terms of clinical presentations, magnetic resonance imaging (MRI) findings, and response to treatment. But unlike AQP4-IgG + NMOSD, which is known to coexist with various autoimmune diseases and cancers, an association of MOGAD with these conditions is less clear.MethodsWe conducted a systematic search in PubMed, Scopus, Web of Science, and Embase based on the preferred reporting items for systematic reviews and meta-analysis (PRISMA). Duplicates were removed using Mendeley 1.19.8 (USA production) and the citations were uploaded into Covidence systematic review platform for screening.ResultsThe most common autoimmune disease overlapping with MOGAD was anti-N-Methyl-D-Aspartate receptor encephalitis (anti-NMDAR-EN), followed by autoimmune thyroid disorders, and the most common autoantibody was antinuclear antibody (ANA), followed by AQP4-IgG (double-positive MOG-IgG and AQP4-IgG). A few sporadic cases of cancers and MOG-IgG-associated paraneoplastic encephalomyelitis were found.ConclusionUnlike AQP4-IgG + NMOSD, MOGAD lacks clustering of autoimmune diseases and autoantibodies associated with systemic and organ-specific autoimmunity. Other than anti-NMDAR-EN and perhaps AQP4-IgG + NMOSD, the evidence thus far does not support the need for routine screening of overlapping autoimmunity and neoplasms in patients with MOGAD.

Pick your poison: Neurobehçet or central nervous system paraneoplastic syndrome?

The diagnosis of rhomboencephalomyelitis is often challenging, with a wide variety of etiologies to be considered, some potentially fatal in the absence of early diagnosis and treatment, like Neurobehçet and paraneoplastic encephalomyelitis.

Autoimmune Encephalitis–Related Seizures and Epilepsy: Diagnostic and Therapeutic Approaches

More than 50 million people worldwide have epilepsy, and approximately 30% of these patients continue to experience seizures despite management with antiseizure medications (ASMs).1EpilepsyWorld Health Organization website.www.who.int/news-room/fact-sheets/detail/epilepsyDate accessed: November 10, 2020Google Scholar Acute symptomatic seizure secondary to autoimmune encephalitis (ASSAE) is a common symptom in patients with autoimmune encephalitis, particularly when the limbic system is involved. Autoimmune-associated epilepsy (AAE) refers to chronic seizures determined to be secondary to autoimmune brain diseases.2Steriade C. Britton J. Dale R.C. et al.Acute symptomatic seizures secondary to autoimmune encephalitis and autoimmune-associated epilepsy: conceptual definitions.Epilepsia. 2020; 61: 1341-1351Crossref PubMed Scopus (36) Google Scholar The detection of neural autoantibodies is essential in establishing the diagnosis of autoimmune encephalitis.3Graus F. Titulaer M.J. Balu R. et al.A clinical approach to diagnosis of autoimmune encephalitis.Lancet Neurol. 2016; 15: 391-404Abstract Full Text Full Text PDF PubMed Scopus (1495) Google Scholar Most of these antibodies target neuronal cell surface antigens, including synaptic neurotransmitter receptors, ion channels, or related proteins (eg, glioma inactivated 1 protein [LGI1],4Irani S.R. Michell A.W. Lang B. et al.Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis.Ann Neurol. 2011; 69: 892-900Crossref PubMed Scopus (563) Google Scholar,5van Sonderen A. Schreurs M.W. de Bruijn M.A. et al.The relevance of VGKC positivity in the absence of LGI1 and Caspr2 antibodies.Neurology. 2016; 86: 1692-1699Crossref PubMed Scopus (99) Google Scholar N-methyl-d-aspartate receptor [NMDAR],6Titulaer M.J. 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: 157-165Abstract Full Text Full Text PDF PubMed Scopus (1647) Google Scholar,7Dalmau J. Gleichman A.J. Hughes E.G. et al.Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies.Lancet Neurol. 2008; 7: 1091-1098Abstract Full Text Full Text PDF PubMed Scopus (2066) Google Scholar γ-aminobutyric acid type A receptor,8Petit-Pedrol M. Armangue T. Peng X. et al.Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies.Lancet Neurol. 2014; 13: 276-286Abstract Full Text Full Text PDF PubMed Scopus (351) Google Scholar and γ-aminobutyric acid B receptor9Lancaster E. Lai M. Peng X. et al.Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen.Lancet Neurol. 2010; 9: 67-76Abstract Full Text Full Text PDF PubMed Scopus (602) Google Scholar). Another group of antibodies targets neuronal intranuclear or cytoplasmic antigens (eg, glutamic acid decarboxylase 65-kDa isoform [GAD65]10Malter M.P. Helmstaedter C. Urbach H. Vincent A. Bien C.G. Antibodies to glutamic acid decarboxylase define a form of limbic encephalitis.Ann Neurol. 2010; 67: 470-478Crossref PubMed Scopus (332) Google Scholar and Ma1/2).11Dalmau J. Graus F. Villarejo A. et al.Clinical analysis of anti-Ma2-associated encephalitis.Brain. 2004; 127: 1831-1844Crossref PubMed Scopus (492) Google Scholar Table 1 summarizes the best known currently identified antibodies associated with autoimmune encephalitis.12Joubert B. Kerschen P. Zekeridou A. et al.Clinical spectrum of encephalitis associated with antibodies against the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor: case series and review of the literature.JAMA Neurol. 2015; 72: 1163-1169Crossref PubMed Scopus (66) Google Scholar, 13Lancaster E. Huijbers M.G. Bar V. et al.Investigations of caspr2, an autoantigen of encephalitis and neuromyotonia.Ann Neurol. 2011; 69: 303-311Crossref PubMed Scopus (320) Google Scholar, 14Spatola M. Sabater L. Planagumà J. et al.Encephalitis with mGluR5 antibodies: symptoms and antibody effects.Neurology. 2018; 90: e1964-e1972Crossref PubMed Scopus (47) Google Scholar, 15Carvajal-González A. Leite M.I. Waters P. et al.Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes [published correction appears in Brain. 2014;137(pt 12):e315].Brain. 2014; 137: 2178-2192Crossref PubMed Scopus (256) Google Scholar, 16Graus F. Keime-Guibert F. Reñe R. et al.Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients.Brain. 2001; 124: 1138-1148Crossref PubMed Scopus (661) Google Scholar The true incidence of AAE remains unknown; however, some reports suggest that approximately 6% to 10% of patients with late-onset seizures may have AAE.17von Podewils F. Suesse M. Geithner J. et al.Prevalence and outcome of late-onset seizures due to autoimmune etiology: a prospective observational population-based cohort study.Epilepsia. 2017; 58: 1542-1550Crossref PubMed Scopus (16) Google Scholar Identifying an immune-mediated cause opens up a new avenue of therapy (immunotherapy), which can drastically alter the course of ASM-resistant epilepsy. This commentary is intended to highlight the concept of immune-mediated seizures to primary care, internal medicine, and emergency medicine clinicians.Table 1Autoimmune Encephalitis–Associated Acute Symptomatic Seizures and Autoimmune-Associated EpilepsyAntibody-targeting antigenMost common seizure typeCommon nonseizure symptomAcute symptomatic seizure prevalenceRisk of AAEPrevalence of malignant neoplasmMain type(s) of malignant neoplasmResponse to immunotherapyCell surface antigensNMDAR6Titulaer M.J. 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: 157-165Abstract Full Text Full Text PDF PubMed Scopus (1647) Google Scholar,7Dalmau J. Gleichman A.J. Hughes E.G. et al.Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies.Lancet Neurol. 2008; 7: 1091-1098Abstract Full Text Full Text PDF PubMed Scopus (2066) Google Scholar•Tonic-clonic•Focal•EPC•Behavioral and psychiatric changes•Dyskinesia70%-80%<5%Varies with sex30%-40%Ovarian teratomaGoodAMPAR12Joubert B. Kerschen P. Zekeridou A. et al.Clinical spectrum of encephalitis associated with antibodies against the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor: case series and review of the literature.JAMA Neurol. 2015; 72: 1163-1169Crossref PubMed Scopus (66) Google Scholar•Temporal lobe•Opsoclonus•Cognitive dysfunction30%-40%<5%50%-60%•SCLC•Thymoma•BreastGoodGABAaR8Petit-Pedrol M. Armangue T. Peng X. et al.Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies.Lancet Neurol. 2014; 13: 276-286Abstract Full Text Full Text PDF PubMed Scopus (351) Google Scholar•Refractory status epilepticus•EPC•Behavioral changes•Cognitive dysfunction80%-90%<5%20%-30%ThymomaGoodGABAbR9Lancaster E. Lai M. Peng X. et al.Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen.Lancet Neurol. 2010; 9: 67-76Abstract Full Text Full Text PDF PubMed Scopus (602) Google Scholar•Focal onset impaired awareness•Focal to bilateral tonic-clonic seizures•Behavioral changes•Cognitive dysfunction90%-95%20%-30%50%-60%SCLCGoodLGI14Irani S.R. Michell A.W. Lang B. et al.Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis.Ann Neurol. 2011; 69: 892-900Crossref PubMed Scopus (563) Google Scholar,5van Sonderen A. Schreurs M.W. de Bruijn M.A. et al.The relevance of VGKC positivity in the absence of LGI1 and Caspr2 antibodies.Neurology. 2016; 86: 1692-1699Crossref PubMed Scopus (99) Google Scholar•Faciobrachial dystonic seizures•Focal aware•Focal to bilateral tonic-clonic seizures•Hyponatremia•Cognitive dysfunction80%15%<5%ThymomaGoodCASPR25van Sonderen A. Schreurs M.W. de Bruijn M.A. et al.The relevance of VGKC positivity in the absence of LGI1 and Caspr2 antibodies.Neurology. 2016; 86: 1692-1699Crossref PubMed Scopus (99) Google Scholar,13Lancaster E. Huijbers M.G. Bar V. et al.Investigations of caspr2, an autoantigen of encephalitis and neuromyotonia.Ann Neurol. 2011; 69: 303-311Crossref PubMed Scopus (320) Google Scholar•Focal onset impaired awareness•Morvan syndrome•Cognitive dysfunction40%-50%<10%<20%ThymomaGoodmGluR514Spatola M. Sabater L. Planagumà J. et al.Encephalitis with mGluR5 antibodies: symptoms and antibody effects.Neurology. 2018; 90: e1964-e1972Crossref PubMed Scopus (47) Google Scholar•Myoclonic•Psychiatric changes•Cognitive dysfunction50%-60%5%50%-60%Hodgkin lymphomaGoodGlyR15Carvajal-González A. Leite M.I. Waters P. et al.Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes [published correction appears in Brain. 2014;137(pt 12):e315].Brain. 2014; 137: 2178-2192Crossref PubMed Scopus (256) Google Scholar•Refractory SE•EPC•Myoclonus•PERM•SPSD-plus phenotype10%-40%Unclear10%-15%•Thymoma•B-cell lymphoma•Hodgkin lymphoma•Breast•MelanomaGoodIntracellular antigensGAD6510Malter M.P. Helmstaedter C. Urbach H. Vincent A. Bien C.G. Antibodies to glutamic acid decarboxylase define a form of limbic encephalitis.Ann Neurol. 2010; 67: 470-478Crossref PubMed Scopus (332) Google Scholar•TLE•Stiff person SPSD•Cerebellar ataxia•Cognitive dysfunction10%-50%>80%<10%•Very rare, adenocarcinoma, thymomaPoorMa211Dalmau J. Graus F. Villarejo A. et al.Clinical analysis of anti-Ma2-associated encephalitis.Brain. 2004; 127: 1831-1844Crossref PubMed Scopus (492) Google Scholar•TLE•Cognitive dysfunction hypersomnia•Ataxia40%-50%>60%>90%•Testicular germ cell•SCLC•BreastPoorHu/ANNA-116Graus F. Keime-Guibert F. Reñe R. et al.Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients.Brain. 2001; 124: 1138-1148Crossref PubMed Scopus (661) Google Scholar•TLE•Dysphagia•Dysarthria•Hypoventilation•Ataxia40%-50%>60%>95%•SCLCPoorAAE, autoimmune-associated epilepsy; AMPAR, alpha amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; ANNA-1, type 1 antineuronal nuclear antibody; CASPR2, contactin-associated protein 2; EPC, epilepsia partialis continua; GABAaR, γ-aminobutyric acid A receptor; GABAbR, γ-aminobutyric acid B receptor; GAD65, glutamic acid decarboxylase 65-kDa isoform; GlyR, glycine receptor; LGI1, leucine-rich glioma-inactivated 1; mGluR5, metabotropic glutamate receptor 5; NMDAR, N-methyl-d-aspartate receptor; PERM, progressive encephalomyelitis with rigidity and myoclonus (stiff person syndrome with rigidity, stimulus-sensitive spasms, myoclonus, hyperekplexia, autonomic disturbance, plus additional brainstem or other neurological deficits); SCLC, small cell lung cancer; SE, status epilepticus; SPSD, stiff person spectrum disorder; TLE, temporal lobe epilepsy. Open table in a new tab AAE, autoimmune-associated epilepsy; AMPAR, alpha amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; ANNA-1, type 1 antineuronal nuclear antibody; CASPR2, contactin-associated protein 2; EPC, epilepsia partialis continua; GABAaR, γ-aminobutyric acid A receptor; GABAbR, γ-aminobutyric acid B receptor; GAD65, glutamic acid decarboxylase 65-kDa isoform; GlyR, glycine receptor; LGI1, leucine-rich glioma-inactivated 1; mGluR5, metabotropic glutamate receptor 5; NMDAR, N-methyl-d-aspartate receptor; PERM, progressive encephalomyelitis with rigidity and myoclonus (stiff person syndrome with rigidity, stimulus-sensitive spasms, myoclonus, hyperekplexia, autonomic disturbance, plus additional brainstem or other neurological deficits); SCLC, small cell lung cancer; SE, status epilepticus; SPSD, stiff person spectrum disorder; TLE, temporal lobe epilepsy. Autoantibodies against surface antigens are hypothesized to directly mediate neurological changes that lead to acute symptomatic seizure development (by antigenic modulation or by recruitment of immune cells or complement activation).18Fang Z. Yang Y. Chen X. et al.Advances in autoimmune epilepsy associated with antibodies, their potential pathogenic molecular mechanisms, and current recommended immunotherapies.Front Immunol. 2017; 8: 395Crossref PubMed Scopus (9) Google Scholar Therefore, cases with these antibodies are often reversible with good immunotherapy response and do not require lifelong ASM. The risk of AAE is generally higher in patients with intracellular neuronal antibodies (suspected to be a T cell–mediated process) than in those with cell surface antibodies (often directly pathogenic). However, in experimental animal models, autoantibodies against surface antigens have exhibited robust effects on the target proteins, resulting in hyperexcitability and impairment of synaptic function and plasticity, leading to ASSAE.19Taraschenko O. Fox H.S. Pittock S.J. et al.A mouse model of seizures in anti-N-methyl-d-aspartate receptor encephalitis.Epilepsia. 2019; 60: 452-463Crossref PubMed Scopus (20) Google Scholar Autoimmune encephalitis–related seizures present with acute or subacute seizures, often frequent from the onset. A history of preceding viral prodrome is common. Frequent seizures can be the first symptom that raises initial suspicion of ASSAE or AAE, especially in patients who do not have a history or risk factors. Seizures are often multifocal and refractory to ASMs. Certain seizure types can be pathognomonic of an underlying immune etiology, for example, faciobrachial dystonic seizures in LGI1 antibody–associated autoimmune encephalitis.4Irani S.R. Michell A.W. Lang B. et al.Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis.Ann Neurol. 2011; 69: 892-900Crossref PubMed Scopus (563) Google Scholar Additional neurological symptoms, including autonomic disturbances, neurobehavioral problems, memory decline, and movement disorders, are also common. Some patients may present with new-onset refractory status epilepticus (NORSE) or febrile infection-related epilepsy syndrome (FIRES). Autoimmune encephalitis is the most common cause of NORSE (37%),20Gaspard N. Foreman B.P. Alvarez V. et al.New-onset refractory status epilepticus: etiology, clinical features, and outcome.Neurology. 2015; 85: 1604-1613Crossref PubMed Scopus (200) Google Scholar which is no longer considered a diagnosis but a clinical presentation. When the etiology remains unknown despite extensive work-up, it is labeled as cryptogenic new-onset refractory status epilepticus (cNORSE), which makes up around half of all NORSE cases.21Yanagida A. Kanazawa N. Kaneko J. et al.Clinically based score predicting cryptogenic NORSE at the early stage of status epilepticus.Neurol Neuroimmunol Neuroinflamm. 2020; 7: e849Crossref PubMed Scopus (6) Google Scholar Table 2 summarizes clinical clues that should raise suspicion of ASSAE.Table 2Clues Suggestive of Autoimmune Encephalitis–Related Acute Symptomatic SeizureClinical symptoms and history•Subacute onset (rapid progression of <3 mo) of ≥1 of the following symptoms:○Short-term memory loss○Altered level of consciousness, lethargy, or personality change○Psychiatric symptoms (eg, psychosis and hallucination)○Brainstem symptoms (eg, ataxia, dysarthria, and dysphagia)○Eye movement disorder○Autonomic dysfunction○Exaggerated startle response○Dyskinesia○Dystonia•New focal neurological finding•New seizure (eg, status epilepticus [NORSE] and faciobrachial dystonic seizures) without previously diagnosed seizure disorder•Prodromal symptoms such as headache, fever, or flu-like symptoms•Signs of cancer (eg, unintended weight loss, night sweats, and fatigue)•Personal history of autoimmune condition•Family history of autoimmune or cancerOther supportive laboratory or imaging findings•Cerebrospinal fluid with a white blood cell count of >5 cells/mm3 and protein elevation•Detection of IgG autoantibodies in the cerebrospinal fluid or serum (not IgA or IgM)•Brain MRI showing hyperintensity involving 1 or both medial temporal lobes (limbic encephalitis) on T2-FLAIR or involving multiple foci in the gray matter, white matter, or both that are compatible with demyelination or inflammation•Electroencephalogram showing frequent bilateral temporal lobe seizures or extreme delta brushMRI, magnetic resonance imaging; NORSE, new-onset refractory status epilepticus; T2-FLAIR, T2-weighted fluid-attenuated inversion recovery sequence. Open table in a new tab MRI, magnetic resonance imaging; NORSE, new-onset refractory status epilepticus; T2-FLAIR, T2-weighted fluid-attenuated inversion recovery sequence. A key to ASSAE’s or AAE’s diagnosis is obtaining serum and cerebrospinal fluid (CSF) autoimmune neuronal antibody panel to test for autoantibodies’ presence because the detection of neural autoantibody helps establish the diagnosis.3Graus F. Titulaer M.J. Balu R. et al.A clinical approach to diagnosis of autoimmune encephalitis.Lancet Neurol. 2016; 15: 391-404Abstract Full Text Full Text PDF PubMed Scopus (1495) Google Scholar However, reliance on antibody testing might delay the diagnosis. Recently, an international group developed diagnostic criteria for early diagnosis of autoimmune encephalitis in adults, which require (1) subacute onset over less than 3 months of working memory deficits, altered mental status, or psychiatric symptoms; (2) at least 1 of the following: new focal central nervous system (CNS) findings, seizures not explained by a preexisting disorder, CSF pleocytosis, and/or magnetic resonance imaging (MRI) features suggestive of encephalitis; and (3) reasonable exclusion of alternative cause.3Graus F. Titulaer M.J. Balu R. et al.A clinical approach to diagnosis of autoimmune encephalitis.Lancet Neurol. 2016; 15: 391-404Abstract Full Text Full Text PDF PubMed Scopus (1495) Google Scholar When there is suspicion of ASSAE or AAE, urgent neurology consultation is warranted because antibody testing, diagnosis, and treatment may be esoteric to clinicians without a neuroimmunology background. Generally, panel testing of multiple autoantibodies rather than single antibody testing is recommended. In some cases, antibodies may be present only in the CSF or serum. For instance, anti-LGI1 IgG is more commonly detected in serum whereas up to 15% NMDAR IgG has detectable antibodies only in the CSF.3Graus F. Titulaer M.J. Balu R. et al.A clinical approach to diagnosis of autoimmune encephalitis.Lancet Neurol. 2016; 15: 391-404Abstract Full Text Full Text PDF PubMed Scopus (1495) Google Scholar The electroencephalogram may have variable findings, including normal, focal, or diffuse slowing; epileptiform discharges; or frank seizures. The scalp electroencephalogram may also be normal (including during faciobrachial dystonic seizures) when the epileptic focus is deep or involves too small a neuronal aggregate for a synchronized activity to register on the scalp. Brain MRI can be normal (between 30% and 50%),22Quek A.M. Britton J.W. McKeon A. et al.Autoimmune epilepsy: clinical characteristics and response to immunotherapy.Arch Neurol. 2012; 69: 582-593Crossref PubMed Scopus (239) Google Scholar especially at the onset, but abnormalities, including bilateral and asymmetric mesial temporal lobe or limbic T2 hyperintensity, are commonly seen later. Findings of brain positron emission tomography are nonspecific but may detect focal areas of hyper- or hypometabolism. Tumor screening with whole body computed tomography or positron emission tomography scan is usually warranted, especially if antibodies that are known to be associated with specific tumors are present (Table 1). The modified Antibody Prevalence in Epilepsy and Encephalopathy (APE2) score, a 10-item, 16-point index, primarily based on clinical evaluation (such as new-onset epilepsy, neuropsychiatric manifestations, and autonomic dysfunction) (Table 2), has been developed to predict specific neuronal presence autoantibodies.23Dubey D. Pittock S.J. McKeon A. Antibody prevalence in epilepsy and encephalopathy score: increased specificity and applicability.Epilepsia. 2019; 60: 367-369Crossref PubMed Scopus (17) Google Scholar The sensitivity and specificity of the APE2 score greater than but not equivalent to 4 in predicting neuronal autoantibody (thereby AAE) were 98% and 84%, respectively.23Dubey D. Pittock S.J. McKeon A. Antibody prevalence in epilepsy and encephalopathy score: increased specificity and applicability.Epilepsia. 2019; 60: 367-369Crossref PubMed Scopus (17) Google Scholar Most clinicians could easily use this score, even in a primary care setting or emergency departments. However, it should be noted that the APE2 score is likely most useful to pick up ASSAE rather than AAE. Importantly, the score may not be sensitive enough to diagnose patients with chronic epilepsy and underlying intracellular antibodies such as GAD65 antibodies in which features of limbic encephalitis may be lacking. To address these issues, recently, de Bruijn et al24de Bruijn M.A.A.M. Bastiaansen A.E.M. Mojzisova H. et al.Antibodies contributing to focal epilepsy signs and symptoms score.Ann Neurol. 2021; 89: 698-710Crossref PubMed Scopus (10) Google Scholar have created the Antibodies Causing Epilepsy Syndromes (ACES) score, a 6-item (cognitive symptoms, behavioral changes, autonomic symptoms, speech problems, autoimmune diseases, and temporal MRI hyperintensities) and a 6-point index. This score (cutoff ≥ 2) can be used to select patients requiring neuronal antibody screening.24de Bruijn M.A.A.M. Bastiaansen A.E.M. Mojzisova H. et al.Antibodies contributing to focal epilepsy signs and symptoms score.Ann Neurol. 2021; 89: 698-710Crossref PubMed Scopus (10) Google Scholar Although the items for ACES and APE2 scores partially overlap, the ACES score is more sensitive for patients with focal epilepsy without overt encephalitis. Also, because this score assigns a 1 point for each risk factor, it is much easier to score than APE2 (a value-weighted score), thus more likely to be used in clinical settings.24de Bruijn M.A.A.M. Bastiaansen A.E.M. Mojzisova H. et al.Antibodies contributing to focal epilepsy signs and symptoms score.Ann Neurol. 2021; 89: 698-710Crossref PubMed Scopus (10) Google Scholar Treatment recommendation is inferred from the autoimmune encephalitis literature, and currently, little is known about the efficacy of immunotherapy in patients with AAE without signs and symptoms of encephalitis. Observational studies and a clinical trial suggest that early immunotherapy can shorten the time to seizure cessation or reduce and improve long-term outcomes, including cognition.25Thompson J. Bi M. Murchison A.G. et al.Faciobrachial Dystonic Seizures Study GroupThe importance of early immunotherapy in patients with faciobrachial dystonic seizures.Brain. 2018; 141: 348-356Crossref PubMed Scopus (146) Google Scholar Although evidence is still limited, the current recommended first-line management is immunotherapy with either intravenous methylprednisolone (1 g/d for 3-5 days), intravenous immunoglobulin (0.4 g/kg per day for 5 days), or plasmapheresis (plasma exchange [PLEX], every alternate day for 5 sessions).22Quek A.M. Britton J.W. McKeon A. et al.Autoimmune epilepsy: clinical characteristics and response to immunotherapy.Arch Neurol. 2012; 69: 582-593Crossref PubMed Scopus (239) Google Scholar,26Toledano M. Britton J.W. McKeon A. et al.Utility of an immunotherapy trial in evaluating patients with presumed autoimmune epilepsy.Neurology. 2014; 82: 1578-1586Crossref PubMed Scopus (134) Google Scholar If there is no response, minimal response (<50% of seizure reduction), or subsequent relapse after initial improvement with the first-line treatment, it is reasonable to initiate second-line immunosuppressive therapies such as rituximab or cyclophosphamide.6Titulaer M.J. 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: 157-165Abstract Full Text Full Text PDF PubMed Scopus (1647) Google Scholar,26Toledano M. Britton J.W. McKeon A. et al.Utility of an immunotherapy trial in evaluating patients with presumed autoimmune epilepsy.Neurology. 2014; 82: 1578-1586Crossref PubMed Scopus (134) Google Scholar Typically, patients with antibodies against surface antigens are more likely to respond to immunotherapy, especially when diagnosed early.26Toledano M. Britton J.W. McKeon A. et al.Utility of an immunotherapy trial in evaluating patients with presumed autoimmune epilepsy.Neurology. 2014; 82: 1578-1586Crossref PubMed Scopus (134) Google Scholar A recent study by McGinty et al27McGinty R.N. Handel A. Moloney T. et al.Clinical features which predict neuronal surface autoantibodies in new-onset focal epilepsy: implications for immunotherapies.J Neurol Neurosurg Psychiatry. 2021; 92: 291-294Crossref PubMed Scopus (10) Google Scholar suggests that immunotherapy is generally effective in patients with seizures as part of autoimmune encephalitis and not in those with epilepsy related to positive neuronal antibody results (AAE); that is, the clinical phenotype is paramount in guiding the relevance of autoantibody results, including the decision on a trial of immunotherapy. Antiseizure medications should be initiated in adjunct with immunotherapy. It should also be noted that antibody testing may be falsely negative if testing is done after immunotherapy administration, especially PLEX or rituximab. Therefore, it is a good practice to communicate with the laboratory to save initial CSF samples to be used for future testing. This further underscores the need for early neurology or neuroimmunology consultation when ASSAE or AAE is suspected. There are ongoing discussions on the proper terminology, especially surrounding the term epilepsy in autoimmune encephalitis, given many patients who suffer from encephalitis-associated seizures achieve seizure freedom after treatment with immunotherapy.2Steriade C. Britton J. Dale R.C. et al.Acute symptomatic seizures secondary to autoimmune encephalitis and autoimmune-associated epilepsy: conceptual definitions.Epilepsia. 2020; 61: 1341-1351Crossref PubMed Scopus (36) Google Scholar,26Toledano M. Britton J.W. McKeon A. et al.Utility of an immunotherapy trial in evaluating patients with presumed autoimmune epilepsy.Neurology. 2014; 82: 1578-1586Crossref PubMed Scopus (134) Google Scholar Although most patients with intracellular antibodies, including GAD65 and Ma1/2 require lifelong ASM therapy, most patients with cell surface antibodies (eg, NMDAR [>80%] and LGI1 [>70%]) require only short-term ASM therapy, typically 6 to 24 months.25Thompson J. Bi M. Murchison A.G. et al.Faciobrachial Dystonic Seizures Study GroupThe importance of early immunotherapy in patients with faciobrachial dystonic seizures.Brain. 2018; 141: 348-356Crossref PubMed Scopus (146) Google Scholar,28Feyissa A.M. López Chiriboga A.S. Britton J.W. Antiepileptic drug therapy in patients with autoimmune epilepsy.Neurol Neuroimmunol Neuroinflamm. 2017; 4: e353Crossref PubMed Scopus (44) Google Scholar, 29Vogrig A. Joubert B. André-Obadia N. Gigli G.L. Rheims S. Honnorat J. Seizure specificities in patients with antibody-mediated autoimmune encephalitis.Epilepsia. 2019; 60: 1508-1525Crossref PubMed Scopus (33) Google Scholar, 30de Bruijn M.A.A.M. van Sonderen A. van Coevorden-Hameete M.H. et al.Evaluation of seizure treatment in anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis.Neurology. 2019; 92: e2185-e2196Crossref PubMed Scopus (82) Google Scholar The International League Against Epilepsy Autoimmunity and Inflammation Taskforce has recently proposed conceptual definitions for 2 main diagnostic entities: (1) ASSAE and (2) AAE, the latter of which suggests an enduring predisposition to seizures.2Steriade C. Britton J. Dale R.C. et al.Acute symptomatic seizures secondary to autoimmune encephalitis and autoimmune-associated epilepsy: conceptual definitions.Epilepsia. 2020; 61: 1341-1351Crossref PubMed Scopus (36) Google Scholar Although the previously discussed APE2 and ACES scores were initially designed and validated to predict the likelihood of neural antibody positivity, there is currently no consensus on the established criteria for diagnosing ASSAE or AAE.31Dubey D. Singh J. Britton J.W. et al.Predictive models in the diagnosis and treatment of autoimmune epilepsy.Epilepsia. 2017; 58: 1181-1189Crossref PubMed Scopus (72) Google Scholar Only a small subpopulation with neuronal surface antibody positivity develops intractable AAE. Most patients in this population report an excellent response to immunotherapy and have a better overall prognosis than do patients with antibodies targeting nuclear or cytoplasmic proteins. The resolution of symptoms after immunotherapy for patients with cell surface antibodies might point toward an argument for their pathogenicity. Recently, intracerebroventricular infusion of anti-NMDAR IgG in mice has been found to induce seizures, suggesting a possible direct pathogenic role for surface neuronal antibodies.19Taraschenko O. Fox H.S. Pittock S.J. et al.A mouse model of seizures in anti-N-methyl-d-aspartate receptor encephalitis.Epilepsia. 2019; 60: 452-463Crossref PubMed Scopus (20) Google Scholar To date, there have been mixed findings with regard to intracellular antibodies’ direct pathogenic role.2Steriade C. Britton J. Dale R.C. et al.Acute symptomatic seizures secondary to autoimmune encephalitis and autoimmune-associated epilepsy: conceptual definitions.Epilepsia. 2020; 61: 1341-1351Crossref PubMed Scopu

KNOCK KNOCK, HU'S THERE? POSITIVE ANTI-HU ANTIBODY IN EXTRAPULMONARY SMALL CELL CARCINOMA OF LYMPH NODE

SESSION TITLE: Tuesday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/22/2019 01:00 PM - 02:00 PM INTRODUCTION: To date, small cell carcinoma (SCC) has been primarily recognized as a pulmonary malignancy and research has been skewed towards this area. Extrapulmonary SCC is rare, accounting for 2.5% of SCC, out of which lymph node SCC are far and few between. CASE PRESENTATION: A 59-year-old gentleman was initially admitted to neurology for sensory neuropathy and weight loss. He was referred to the respiratory medicine team after imaging revealed subcarinal and left hilar lymphadenopathy. He is a chronic smoker and there was a concern for malignancy. Initial endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) using 22 gauge needle showed lymphoid yield. Serum paraneoplastic panel (Hu, Yo, Ri, CV2, Amphiphysin, PNMA2/Ta, recoverin, SOX1, titin, zic4, GAD65, Tr(DNER)) was performed as part of the diagnostic work up. Anti-Hu antibody was 1:101 (strongly positive); reference titer 1:<10. Fluorodeoxyglucose-positron emission tomography-computed tomography (FDG-PET-CT) scan revealed FDG avid subcarinal (SUVmax:11.1) and left hilar (SUVmax:13.2) nodes. In view of the anti-Hu antibody results and FDG-PET-CT findings, a repeat EBUS-TBNA using 19 gauge needle was performed and histology confirmed SCC. DISCUSSION: Paraneoplastic syndrome was first described by M. Auché in 1890 and is known to affect up to 8% of patients with cancer; most notably small cell lung cancer. Anti-Hu is an onconeural antibody first discovered by F. Grouse in 1985. Its moniker is type I anti-neuronal nuclear antibody (ANNA-1) and has been a signpost for paraneoplastic sensory neuropathy or encephalomyelitis. (Positive anti-Hu antibody titers have a reported specificity of 99% and sensitivity of 82%). It is recognized as a distinct clinical disease, “anti-Hu syndrome”, with characteristic clinical picture and imaging findings. A Dutch study in 2002 found that 85% of patients with positive anti-Hu antibody also have a tumor. Of note, anti-Hu antibodies can also be positive in antecedent inflammatory diseases like systemic lupus erythematosus or Sjogren’s syndrome which can confound the diagnosis. Thus, positive anti-Hu antibody levels should prompt further evaluation and follow up even in absence of concurrent malignancy. Early diagnosis of lymph node SCC has prognostic implications when compared to pulmonary and extrapulmonary SCC, thus making the distinction necessary. CONCLUSIONS: This study highlights the diagnostic implications of an abnormal paraneoplastic panel, emphasizing the role of anti-Hu antibody in its specificity for SCC. The presence of FDG avid thoracic lymph nodes with elevated anti-Hu antibody titers warrants a repeat biopsy. It is imperative for clinicians to identify occult neoplasms in the setting of paraneoplastic syndromes. Reference #1: Koike H, Sobue G. Paraneoplastic neuropathy. Handb Clin Neurol. 2013;115:713-26. Reference #2: Graus F, Cordon-Cardo C, Posner JB. Neuronal antinuclear antibody in sensory neuronopathy from lung cancer. Neurology. 1985 Apr;35(4):538–43. Sehgal IS, Kaur H, Dhooria S, et al. Extrapulmonary small cell carcinoma of lymph node: Pooled analysis of all reported cases. World J Clin Oncol. 2016;7(3):308-20. Graus F, Keime-Guibert F, Reñe R, Benyahia B, Ribalta T, Ascaso C, Escaramis G, Delattre JY. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain. 2001;124(6):1138-1148. Senties-Madrid H, Vega-Boada F. Paraneoplastic syndromes associated with anti-Hu antibodies. Isr Med Assoc J. 2001 Feb;3(2):94-103. Reference #3: Benyahia B, Amoura Z, Rousseau A, Le Clanche C, Carpentier A, Piette JC, Delattre JY. Paraneoplastic antineuronal antibodies in patients with systemic autoimmune diseases. J Neurooncol. 2003 May;62(3):349-51. Sillevis Smitt P, Grefkens J, de Leeuw B, van den Bent M, van Putten W, Hooijkaas H, Vecht C. Survival and outcome in 73 anti-Hu positive patients with paraneoplastic encephalomyelitis/sensory neuronopathy. J Neurol. 2002 Jun;249(6):745-53. Kim KO, Lee HY, Chun SH, et al. Clinical overview of extrapulmonary small cell carcinoma. J Korean Med Sci. 2006;21(5):833-7. Kannoth S. Paraneoplastic neurologic syndrome: A practical approach. Ann Indian Acad Neurol. 2012;15(1):6-12. DISCLOSURES: No relevant relationships by John Abisheganaden, source=Web Response No relevant relationships by Caroline Choong, source=Web Response No relevant relationships by Sharlene Ho, source=Web Response No relevant relationships by Chuen Peng Lee, source=Web Response No relevant relationships by Ziqin Ng, source=Web Response No relevant relationships by Ser Hon Puah, source=Web Response No relevant relationships by HUIJIA WANG, source=Web Response No relevant relationships by Kim Hoong Yap, source=Web Response

Neuroimmunology of OMS and ANNA-1/anti-Hu paraneoplastic syndromes in a child with neuroblastoma.

Paraneoplastic neurologic disorders have been at the frontier of neuroimmunology for decades and remain urgent. Newer tools for the diagnosis and treatment of neuroinflammation include autoantibody screening, lymphocyte subset analysis, oligoclonal bands, and profiling of chemokines/cytokines and brain-related proteins in CSF and blood/serum. Opsoclonus-myoclonus syndrome (OMS), a paraneoplastic disorder without a known diagnostic antibody marker, is associated with remote neuroblastoma and is often relapsing.1 Paraneoplastic encephalomyelitis with type 1 antineuronal nuclear antibodies (ANNA-1) (alias anti-Hu)2 also may occur in children with neuroblastoma3–5 and exhibits intrathecal B- and T-cell inflammation in adults.6 We now provide a detailed neuroimmunologic profile of a child with both relapsing OMS and ANNA-1 paraneoplastic syndromes and neuroblastoma. Acknowledgment: Dr. Pranzatelli is a clinician-scientist; President and Founder of the National Pediatric Neuroinflammation Organization, Inc.; and an Adjoint Professor of Neurology at the University of Colorado School of Medicine. The National Pediatric Myoclonus Center relocated from Springfield, IL (SIU School of Medicine) to Orlando, FL, in 2014 to become the current independent, nonprofit organization. The authors thank Elizbeth D. Tate, MN, ARNP, C-FNP, who participated in clinical care, the patient, her family, and referring and treating physicians.

A case of confusion: paraneoplastic encephalomyelitis in an elderly patient suspected of having urinary tract infection-associated delirium

Acute confusion is a common symptom of physical illness in the older patient. In the majority, it is transient and resolves on treatment of precipitants. In a subset of patients,...

ANNA-1 Paraneoplastic Encephalomyelitis Presenting as Rapidly Progressing Dementia in a Man With Undiagnosed Small Cell Lung Cancer

Back to table of contents Previous article Next article Case ReportFull AccessANNA-1 Paraneoplastic Encephalomyelitis Presenting as Rapidly Progressing Dementia in a Man With Undiagnosed Small Cell Lung CancerPatrick K. Reville, M.P.H., Catherine Steingraeber, M.D.Patrick K. RevilleSearch for more papers by this author, M.P.H., Catherine SteingraeberSearch for more papers by this author, M.D.Published Online:16 Mar 2017https://doi.org/10.1176/appi.ajp-rj.2016.111106AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail Patients with paraneoplastic encephalomyelitis may present with cognitive dysfunction, memory loss, confusion, psychiatric disturbances, rapidly progressive dementia, myoclonic jerks, and/or seizures. The present case report is of an elderly man with rapidly progressive cognitive decline and positive anti-neuronal nuclear antibody-1 prior to small cell lung carcinoma diagnosis.Case“Mr. B” is a 64-year-old man with a past medical history of hypertension presented to our emergency department with his wife for safety concerns in context of rapid behavioral changes, mood lability, impulsivity, and memory problems. Review of his outside records showed that he initially presented to his primary care physician 2 months prior due to a 1-month history of memory deficits, confabulations, confusion, and executive function deficits in the context of an unintended 20-pound weight loss. Additionally, he had alternating irritability and euphoria, psychomotor agitation, nonspecific paranoia, increased speech, and impaired judgment. Neurologic examination was concerning for frontal and temporal lobe deficits. The patient’s Montreal Cognitive Assessment score was 12/30. His vitamin B12 and thyroid-stimulating hormone levels were normal. His primary care physician started him on bupropion (150 mg twice daily) and mirtazapine (7.5 mg at night) for mood. An MRI of the patients’ head revealed several foci of T2 hyperintensity within the periventricular white matter and centrum semiovale. Subsequently, an [18F]FDG PET [18F-fluorodeoxyglucose positron emission tomography] scan of the brain showed reduced metabolic activity in the posterior cingulate, precuneus, and lateral temporal-parietal lobes suggestive of Alzheimer’s disease. Two days prior, the patient was seen at an outside emergency department because he was becoming too difficult to manage; olanzapine (5 mg a day) was added to his medication regimen.The patient is a former smoker with a 50-pack/year history and drinks alcohol occasionally. He lives at home with his wife and worked as a repairman until 2 months prior when he had to resign due to cognitive decline. His family history is significant for a mother with depression, anxiety, and acute lymphoblastic leukemia as a child, as well as a sister with depression and anxiety.Laboratory investigation in the emergency department revealed a hemoglobin level of 12.1 g/dl with normal mean corpuscular volume, hyponatremia with a sodium level of 134 mEq/L, a negative toxicology screen, an unremarkable urinalysis, and Montreal Cognitive Assessment score of 12/30. The patient was admitted for further workup. The consulting psychiatry service recommended discontinuing bupropion, mirtazapine, and olanzapine in favor of 50 mg of quetiapine at night.Initially, the patient had episodes of increasing agitation and confusion that was managed with an as-needed quetiapine dose of 50 mg. About a week into his hospitalization, his agitation worsened, necessitating the addition of haloperidol (2 mg p.r.n.) to control his agitation. As his delirium was subsequently better controlled, it remained clear that his major neurocognitive disorder remained, with serial Montreal Cognitive Assessment examinations demonstrating consistent levels of cognitive impairment.An initial EEG demonstrated focal spike and wave discharges from the right temporal chain, but a 24-hour video EEG re-demonstrated epileptiform abnormalities without clear electrographic seizures. Levetiracetam was loaded but discontinued after the results of the video EEG. Initial head CT was unremarkable, and a head MRI showed T2-fluid attenuated inversion recovery hyperintensity in the bilateral mesial temporal lobes. Initial laboratory workup included a heavy metal screen that was negative; iron studies demonstrating elevated ferritin, normal iron, total iron binding capacity, and transferrin indicating anemia of inflammation; and CSF analysis. Basic CSF analysis demonstrated normal cell count and glucose and an elevated level of CSF protein to 75 mg/dl. CSF gram stain and cultures were negative. CSF polymerase chain reaction tests were negative for herpes simplex virus, enterovirus, and Epstein-Barr virus. CSF angiotensin converting enzyme levels were normal. CSF serology demonstrated positive anti-neuronal nuclear antibody-1 (ANNA-1), with a titer of 1:512, no anti-N-methyl-d-aspartate receptor antibodies, and a normal Creutzfeldt-Jakob screen. A prostate-specific antigen screen was normal. Given the positive ANNA-1 antibody, a CT of the chest, abdomen, and pelvis was performed, which showed enlarged right paratracheal lymph nodes but no other abnormalities. Subsequent bronchoscopy with endobronchial ultrasound-guided fine-needle aspiration of the paratracheal lymph nodes was performed. Initial cytology smear was suspicious for malignancy. Final pathology demonstrated cells positive for synaptophysin, chromogranin, and thyroid transcription factor-1 consistent with small cell lung carcinoma. A subsequent PET-CT performed showed hypermetabolic activity in the right paratracheal lymph nodes, mildly hypermetabolic nodes involving the right hilum, pretracheal, and paraesophageal nodes, and moderate uptake in the right fourth and tenth rib with sclerosis, suggestive of extensive-stage small cell lung carcinoma.The patient’s paraneoplastic syndrome was initially managed with 5 daily doses of intravenous immunoglobulin (400 mg/kg/day) and five plasmapheresis treatments three times weekly. His first cycle of chemotherapy with cisplatin and etoposide was started in the hospital. He was discharged home after a 23-day hospital stay. During initial follow-up with a lung oncologist, the decision was made to pursue curative intent with chemotherapy plus radiation. The patient’s behavioral agitation is improved; however, his cognitive function remains diminished.DiscussionParaneoplastic syndromes are autoantibody-mediated disorders associated with underlying tumors (1). Neurological paraneoplastic syndromes occur in approximately 1 in 10,000 cancer patients (2). These conditions arise when systemic tumors express antigens normally found on neural tissue. Tumor directed immune responses recognize these antigens as non-self, leading to production of antibodies against the neural antigen. Paraneoplastic encephalomyelitis symptoms are often subacute and often precede detection of the tumor (2). Cancers associated with paraneoplastic encephalomyelitis include small cell lung carcinoma, ovarian carcinoma, breast carcinoma, thymoma, Hodgkin’s lymphoma, and, rarely, prostate cancer (3).The patient in the above case presented with records showing imaging suggestive of Alzheimer’s dementia. On PET, the metabolic pattern characteristic of Alzheimer’s disease is hypometabolism in parietotemporal areas, the posterior cingulate cortex, and the precuneus, as well as medial temporal lobes, mostly the entorhinal cortex and hippocampus (4). Interestingly, PET has utility in the diagnosis of paraneoplastic neurologic syndromes as well. In clinically suspected paraneoplastic encephalomyelitis, PET has a sensitivity and specificity of 75% and 87%, respectively, in diagnosing paraneoplastic encephalomyelitis (5). Clear indications for PET in patients with major neurocognitive disorder are not currently established, but the American College of Radiology and the American Society for Neuroradiology suggest it can be useful in patients with unexplained major neurocognitive disorder (6).A case series of patients with ANNA-1 paraneoplastic encephalomyelitis shows similarities with the above case (7). The authors reported that the median age was 63 years old, 75% were men, and paraneoplastic encephalomyelitis preceded diagnosis of the malignancy in 73% of cases (7). Treatment of the primary tumor with or without immunotherapy was a predictor of improvement or stabilization of the neurologic sequelae (7). Similarly, in another case series of ANNA-1 paraneoplastic encephalomyelitis, tumor complete response was the only predictor of paraneoplastic encephalomyelitis stabilization, and immunotherapy did not modify the outcome regarding the tumor or paraneoplastic encephalomyelitis (8). The probability of survival at 30 months has been shown to be higher in small cell lung carcinoma patients with paraneoplastic encephalomyelitis than those without paraneoplastic encephalomyelitis (8). Similarly, a report in patients without clinically evident paraneoplastic encephalomyelitis showed that small cell lung carcinoma patients with detectable ANNA-1 antibodies in their serum were more likely to have: limited stage disease, a complete response to therapy, and longer overall survival compared with patients without ANNA-1 antibodies (9). Despite more positive prognosis for small cell lung carcinoma with ANNA-1 paraneoplastic encephalomyelitis, reports suggest that up to 65% of patients with ANNA-1 paraneoplastic encephalomyelitis and small cell lung carcinoma die of neurological complications rather than tumor progression (9). It is unclear whether paraneoplastic encephalomyelitis preceding small cell lung carcinoma diagnosis allows for earlier detection of disease and a potential survival benefit through lead-time bias or there is a biological relationship between these autoimmune processes and small cell lung carcinoma outcomes.Despite the initial uncertainty in the above case, a relatively rapid diagnosis of small cell lung carcinoma was made. Initial diagnostic workup for rapidly progressive dementia should be broad and include testing for metabolic, infectious, and autoimmune causes through blood, urine, and CSF; neuroimaging with MRI is also recommended (10). This workup can be expanded based on results of a complete initial evaluation. Early diagnosis of paraneoplastic encephalomyelitis and tumor and early tumor treatment are necessary. However, the overall functional outcome is poor, and >50% of patients are confined to bed or a wheelchair in the chronic phase of the disease, highlighting the therapeutic challenge these patients face (7, 8).Key Points/Clinical PearlsPatients with paraneoplastic encephalomyelitis may present with cognitive dysfunction, memory loss, confusion, psychiatric disturbances, rapidly progressive dementia, myoclonic jerks, and/or seizures.Paraneoplastic encephalomyelitis occurs commonly in small cell lung, ovarian, and breast carcinomas, as well as thymomas and Hodgkin’s lymphomas.While uncommon, paraneoplastic encephalomyelitis is an important diagnostic consideration in patients presenting with rapidly progressing dementia, as the cognitive symptoms usually present prior to detection of the malignancy.Mr. Reville is currently a fourth-year medical student at the University of Wisconsin School of Medicine and Public Health, Madison, Wisc., and Dr. Steingraeber is currently a first-year child and adolescent psychiatry fellow at the University of Minnesota, Minneapolis, Minn.The authors thank their mentors, Drs. Burr Eichelman and Michael Peterson, for assistance with caring for the patient in this case report, as well as for their editorial assistance. The authors also thank all medical professionals that played a role in the complex management of this patient, as well as the patient and his family for allowing us to take part in his care.

Prostate cancer, Hu antibodies and paraneoplastic neurological syndromes.

Prostate cancer is the most common cancer among American and European men. Nervous system affection caused by local tumor growth or osseous metastases are the main causes of neurological symptoms in prostate cancer patients. Prostate cancer is rarely reported in association with paraneoplastic neurological syndromes (PNS). We have, therefore, studied clinical and paraclinical findings of a series of patients with prostate cancer and PNS, and reviewed cases reported in the literature. Case histories of 14 patients with definite PNS from the PNS Euronetwork database and from the authors' databases were reviewed. A PubMed literature search identified 23 patients with prostate cancer and PNS. Thus, a total of 37 case histories were reviewed with respect to syndrome type, cancer evolution, paraclinical investigations, antibody status, treatment and outcome. The three most frequent isolated PNS were paraneoplastic cerebellar degeneration, paraneoplastic encephalomyelitis (PEM)/limbic encephalitis and subacute sensory neuronopathy (SSN). Onconeural antibodies were detected in 23 patients, in most cases the Hu antibody (17 patients, 74% of all antibody-positive cases). Other well-characterized onconeural antibodies (Yo, CV2/CRMP5, amphiphysin, VGCC antibodies) were found in a minority. PNS was diagnosed prior to prostate cancer diagnosis in 50% of the cases. The association of PNS with prostate cancer is quite infrequent, but clinically important. PNS often heralds prostate cancer diagnosis. Syndromes associated with Hu antibodies predominate. Another tumor more prone to associate with PNS should always be excluded.

Pediatric anti-Hu-associated encephalitis with clinical features of Rasmussen encephalitis.

Anti-Hu antibodies (anti-neuronal nuclear antibodies, type 1) are associated with paraneoplastic encephalomyelitis in adults, especially those with small cell lung cancer. Anti-Hu antibodies are extremely rare in children, but they have been observed in neuroblastoma with or without opsoclonus-myoclonus syndrome or in limbic encephalitis without associated malignancy.1 However, anti-Hu antibodies are not typically associated with clinical features of Rasmussen encephalitis (RE). Acknowledgment: The authors thank Sean J. Pittock, MD, for his assistance in the interpretation of serum and CSF anti-Hu antibody titers and for explaining the methodologic processes involved in the Mayo Clinic Paraneoplastic Antibody Panel.

Paraneoplastic Neurological Syndromes and Glutamic Acid Decarboxylase Antibodies.

Little is known of glutamic acid decarboxylase antibodies (GAD-abs) in the paraneoplastic context. Clinical recognition of such cases will lead to prompt tumor diagnosis and appropriate treatment. To report the clinical and immunological features of patients with paraneoplastic neurological syndromes (PNS) and GAD-abs. Retrospective case series study and immunological investigations conducted in February 2014 in a center for autoimmune neurological disorders. Fifteen cases with GAD65-abs evaluated between 1995 and 2013 who fulfilled criteria of definite or possible PNS without concomitant onconeural antibodies were included in this study. Analysis of the clinical records of 15 patients and review of 19 previously reported cases. Indirect immunofluorescence with rat hippocampal neuronal cultures and cell-based assays with known neuronal cell-surface antigens were used. One hundred six patients with GAD65-abs and no cancer served as control individuals. Eight of the 15 patients with cancer presented as classic paraneoplastic syndromes (5 limbic encephalitis, 1 paraneoplastic encephalomyelitis, 1 paraneoplastic cerebellar degeneration, and 1 opsoclonus-myoclonus syndrome). When compared with the 106 non-PNS cases, those with PNS were older (median age, 60 years vs 48 years; P = .03), more frequently male (60% vs 13%; P < .001), and had more often coexisting neuronal cell-surface antibodies, mainly against γ-aminobutyric acid receptors (53% vs 11%; P < .001). The tumors more frequently involved were lung (n = 6) and thymic neoplasms (n = 4). The risk for an underlying tumor was higher if the presentation was a classic PNS, if it was different from stiff-person syndrome or cerebellar ataxia (odds ratio, 10.5; 95% CI, 3.2-34.5), or if the patient had coexisting neuronal cell-surface antibodies (odds ratio, 6.8; 95% CI, 1.1-40.5). Compared with the current series, the 19 previously reported cases had more frequent stiff-person syndrome (74% vs 13%; P = .001) and better responses to treatment (79% vs 27%; P = .005). Predictors of improvement in the 34 patients (current and previously reported) included presentation with stiff-person syndrome and the presence of a thymic tumor. Patients with GAD-abs must be screened for an underlying cancer if they have clinical presentations different from those typically associated with this autoimmunity or develop classic PNS. The risk for cancer increases with age, male sex, and the presence of coexisting neuronal cell-surface antibodies.

Importance of T1-MRI enhanced pyramidal tracts in differential diagnosis as to paraneoplastic encephalomyelitis

Department of Neurology, Hokkaido University Graduate School of Medicine, Sapporo, Japan Department of Neurology, Kushiro Rosai Hospital, Kushiro, Japan Department of Neurology, Brain Science Center, Sapporo City General Hospital, Sapporo, Japan Department of Clinical Research, Hokkaido Medical Center, Sapporo, Japan Department of Pathology, Kushiro Rosai Hospital, Kushiro, Japan Department of Neurology, Kanazawa Medical University, Uchinada, Japan

Paraneoplastic neurological syndromes in lung cancer patients with or without onconeural antibodies

BackgroundParaneoplastic neurological syndromes (PNS) are poorly described in patients without onconeural antibodies and in patients with non-small cell lung cancer (NSCLC). We compared the clinical characteristics of PNS in lung cancer patients with and without onconeural antibodies. MethodsMedical records from patients with lung cancer and neurological symptoms referred for onconeural antibody analysis in the period 1995–2004 were analyzed and well-established diagnostic criteria used for the retrospective diagnosis of PNS. Thirty-one patients were diagnosed with PNS and included in the study. Data from the Cancer Registry of Norway and follow-up medical data were analyzed. ResultsSmall-cell lung cancer (SCLC) was the most common lung cancer in the 31 PNS patients (77%, P<0.01). Onconeural antibodies were found in 18 of the PNS patients (58%). Paraneoplastic encephalomyelitis (PEM) was the most common PNS among the seropositive patients (11 of 18 patients), of which 10 had SCLC. Various types of PNS were found in the 13 seronegative patients. ConclusionApproximately 40% of PNS patients with lung cancer do not have onconeural antibodies. PEM was the most common PNS in the seropositive patients. Our results underline the importance of recognizing PNS in patients with NSCLC and those without onconeural antibodies.

CEREBRAL WHITE MATTER DISEASE IN PATIENTS WITH MALIGNANCY: PML VERSUS TOXIC LEUCOENCEPHALOPATHY DUE TO CHEMOTHERAPY

BackgroundSystemic malignancy and its treatment can produce a variety of cerebral abnormalities. Malignancy itself can lead to metastatic disease and paraneoplastic encephalomyelitis Patients on chemotherapy can develop the Posterior Reversible...

Paraneoplastic neurological syndromes in lymphoid neoplasms: a clinical and laboratorial challenge.

Dear Editor I had the great pleasure to read the very interesting paper published recently by Acharya et al. titled “Subacute Sensorimotor Polyneuropathy as Sole Manifestation of Occult Non Hodgkin’s Lymphoma: Infiltrative or Paraneoplastic?” in which the authors tried to ascertain whether the etiology of the neuropathy presented by a patient with a diagnosis of a non-Hodgkin’s lymphoma was due to neural infiltration by the tumor itself or, if it was a paraneoplastic manifestation, with the latter hypothesis being considered the most likely by a diagnosis of exclusion [1]. It was a very challenging case, and several factors hampered the final verdict. Some, were related to the lack/limitation of availability of specific diagnostic tests (no nerve biopsy or search for onconeural antibodies) while others were due to the inherent problems in diagnosing paraneoplastic syndrome itself. Paraneoplastic neurological syndromes (PNS) are a group of not yet fully understood rare disorders which affect about 0,01 % of cancer patients, with some exceptions such as the Lambert–Eaton myasthenic syndrome which can occur in up to 3 % of small-cell lung cancer [2]. PNS can affect any part of the central and peripheral nervous systems, the neuromuscular junction, or muscles. They are mostly encountered in small lung cancer followed by gynecological tumors (ovarian cancer), breast cancer, thymoma and in a minority of cases in lymphomas (mainly Hodgkin’s lymphomas) [3]. As a general rule, the neurological manifestations precede the clinical onset of cancer, and therefore can go unnoticed, risking to miss a gold opportunity to detect the cancer at an earlier and curable stage. So, a great index of clinical suspicion is necessary [4]. The very definition of PNS was not always clear. In the past, it was considered neurological syndromes of unknown cause that often associate with cancer, but that description was imprecise, since co-existence of neoplasm and neurological derangement can be merely coincidental, without a direct pathogenic cause-effect relationship. The recent observations that PNS are in many instances an immune mediated disorder, led to the increasing importance given to the onconeural antibodies (ONA) which recognize antigens expressed by the nervous system and by neoplastic cells as a key means to diagnose true paraneoplastic neurological syndromes [5]. This has refined the current definition of PNS to a heterogeneous group of nervous system dysfunctions in cancer patients, which are caused by an immune response to an underlying malignancy and not due to a local effect of the tumor or its metastases [6]. Regarding the ONA, the well characterized ONA (anti-Hu, anti-Yo, anti-CV2, anti-Ri, anti-Ma, anti-amphiphysin) target against intracellular antigens, have a high specificity (>90 %) and are associated with a restricted range of cancer, thus allowing directing the search of the underlying tumor at a stage where it is frequently not clinically overt. However, drawback of ONA, is that antibodies might be detected in the absence of a PNS; in 5–10 % an atypical antibody directed against cell surface antigens is present that is only partially characterized (anti-NMDA, VGKC, AChR, anti-Tr) and is less well linked to a tumor; in about one-third of PNS, no antibodies are even detected. As such, presence of ONA are not the only required condition to catalog a neurological syndrome as paraneoplastic [7]. The spectrum of entities that encompass the PNS can be split into two groups: The “classical syndromes” (the most well-known are encephalomyelitis, limbic encephalitis, subacute cerebellar degeneration, subacute sensory neuronopathy, Lambert–Eaton myasthenic syndrome and opsoclonus-myoclonus), which are often associated with cancer and whose diagnosis should not delay the search for an occult neoplasm; and the many other disorders such as Guillain–Barre syndrome, Stiff person syndrome and the subacute sensorimotor neuropathy as described in the case report by Acharya et al., are categorized as “non-classical syndromes”. Deciding whether a given neurological picture is paraneoplastic depends on the clinical syndrome, presence or absence of cancer and onconeural antibodies, and the time elapsed between onset of neurological symptoms and the detection of the cancer. In this regard, it was proposed two levels of diagnostic evidence (definite or possible) to consider a neurological syndrome as paraneoplastic [8]. A definite diagnosis includes the “classical syndromes” plus cancer (that develops within five years of the diagnosis of the neurological abnormalities) and presence or absence of ONA; or in the absence of cancer, the presence of well characterized ONA. In the “non-classical syndromes” setting, association with a tumor discovered within five years of diagnosis of PNS and presence of well/partially characterized ONA or, improvement after cancer therapy constitute a definite diagnosis. If no cancer is detected, presence of well characterized ONA is a sine qua non requisite for a definite diagnosis. The possible PNS cases involve the “classical syndromes” without detectable cancer plus absence of ONA or presence of only partially characterized antibodies; and “non-classical syndromes” without ONA plus cancer detected within two years of diagnosis (Tables 1, ​,22). Table 1 Diagnostic criteria for a “Definite PNS” Table 2 Diagnostic criteria for a “Possible PNS” Although extremely rare in lymphoid neoplasms, PNS involve a large range of central and peripheral nervous system manifestations. [9]. In Hodgkin’s lymphoma (HL), the central nervous system paraneoplastic subacute cerebellar degeneration (manifested as dysarthria, nystagmus, truncal ataxia, and appendicular ataxia) is the most common and best characterized PNS, with a strong correlation with the ONA anti-Tr and in very rare instances to autoantibodies against the metabotropic glutamate receptor (mGLuR1). Males are more affected than females, with a median age of 49 years and in almost all cases the PNS develops before the diagnosis of the lymphoma and the outcome appears to be good after cancer treatment. Other PNS that may occur in this lymphoid malignancy include: limbic encephalitis, which may be associated or not with the autoantibodies anti-NMDA; the peripheral nervous system paraneoplastic encephalomyelitis, chronic inflammatory demyelinating polyradiculoneuropathy, sensory neuropathy, sensory neuronopathy and myotonia, in all of which the neurologic syndrome antedates the cancer diagnosis and no onconeural antibodies were detected. [9, 10].While central nervous system paraneoplastic manifestations are more prevalent in HL, on the other side, peripheral nervous system demyelinating polyradiculopathies and motor neuron involvement are more predominant in non-Hodgkin’s lymphoma (NHL), followed by autonomic neuropathies and Lambert–Eaton myasthenic syndrome, and to date no association with ONA have been detected. Nonetheless, among the central nervous system paraneoplastic manifestations in this group of lymphoid neoplasms, cerebellar degeneration is the most frequent manifestation. Contrary to HL, it affects female sex predominantly, with a median age of 58 years and besides anti-Tr, the anti-GAD was also identified. It is followed by motor neuron disease, brainstem encephalitis, and limbic encephalitis. In most cases, the neurological symptoms precede the neoplasia diagnosis too. [9, 11]. In NHL, paraneoplastic peripheral nervous system diagnosis is more tricky since multiple etiologies might be responsible for the neuropathy and the differential diagnosis should exclude other more common factors such as neoplastic root infiltration, iatrogenic causes, infection, amyloid or paraprotein deposition, etc. Neurological improvement is more frequently seen in patients with HL than in NHL. However, in both groups, the survival rate appears to be good after cancer treatment. [9]. In the case reported by Acharya et al., the patient presented a non-classical syndrome and cancer that developed three months after the neurological manifestations. However, no nerve biopsy was performed, screening for ONA was not possible and also no documented neurological response after the first cycle of treatment for the cancer was observed. At this current state, the level of evidence of PNS is only possible. If no neoplastic nerve infiltration was documented or if either ONA were detected and neurological manifestations improved after cancer chemotherapy, PNS in that case would be upgraded to a definite level diagnosis. The cornerstone of therapy of PNS is the identification and treatment of the underlying malignancy. Rapid detection and immediate treatment of the underlying tumor appears to offer the best chance of stabilizing the patient and preventing further neurological deterioration [12, 13]. The chemotherapy regimen used in the case reported by Acharya et al. was CHOP instead of R-CHOP which is associated with a higher tumor response rates in B cell NHL. Furthermore, since many PNS are an auto-immune disease, adding a monoclonal antibody drug like Rituximab could have resulted in a rapid improvement of the neurological disease too [14].

Anti-Hu-associated Paraneoplastic Encephalomyelitis with Esophageal Small Cell Carcinoma

A 63-year-old woman had anti-Hu-associated paraneoplastic encephalomyelitis (anti-Hu syndrome) caused by esophageal small cell carcinoma (SCC). The patient developed bilateral limbic encephalitis, followed by myelitis, brain stem encephalitis, and autonomic failure. Extensive examination demonstrated SCC of the abdominal lymph nodes that was retrospectively diagnosed as metastasis of esophageal SCC on autopsy. The neuropathological findings were characterized by widespread neuronal loss and gliosis in the central nervous system, as well as patchy loss of myelin and axons in the spinal nerve roots with perivascular lymphocytic infiltration. This is the first detailed clinical and neuropathological report of anti-Hu syndrome caused by esophageal SCC.

Rare Association of Anti-Hu Antibody Positive Paraneoplastic Neurological Syndrome and Transitional Cell Bladder Carcinoma

Introduction. Paraneoplastic encephalomyelitis (PEM) and subacute sensory neuronopathy (SSN) are remote effects of cancer, usually associated with small-cell lung carcinoma and positive anti-Hu antibody. We describe the rare association of bladder transitional cell carcinoma (TCC) with anti-Hu antibody positivity resulting in this paraneoplastic neurological syndrome. Patient. A 76-year-old female presented with bilateral muscle weakness and paraesthesia of the upper and lower limbs in a length-dependent “glove and stocking” distribution. Central nervous system symptoms included cognitive problems, personality change, and truncal ataxia. Case notes and the literature were reviewed. Result. Autoantibody screening was positive for anti-Hu antibody (recently renamed antineuronal nuclear antibody 1, ANNA-1). The diagnosis of PEM and SSN was supported by MRI and lumbar puncture results. A superficial bladder TCC was demonstrated on CT and subsequently confirmed on histology. No other primary neoplasm was found on full-body imaging. The neurological symptoms were considered to be an antibody-mediated paraneoplastic neurological syndrome and improved after resection of the tumour. Discussion. The association of anti-Hu positive paraneoplastic neurological syndrome and TCC has not been described in the literature previously. We emphasize the need for detailed clinical examination and the importance of a multidisciplinary thought process and encourage further awareness of this rare association.

Current approaches to the treatment of paraneoplastic encephalitis.

Paraneoplastic neurological syndromes (PNSs) cover a wide range of diseases and involve both the central nervous system (CNS) and peripheral nervous system. Paraneoplastic encephalitis comprises several diseases such as paraneoplastic cerebellar degeneration (PCD), limbic encephalitis (LE), paraneoplastic encephalomyelitis (PEM), brainstem encephalitis, opsomyoclonus syndrome, in addition to other even less frequently occurring entities. LE was the first historically identified CNS PNS, and similarities between other temporal lobe diseases such as herpes encephalitis have been elucidated. In the past few decades several autoantibodies have been described in association with LE. These encompass the classical 'onconeuronal' antibodies (abs) such as Hu, Yo, Ri and others, and now additionally abs towards either ion channels or surface antigens. The clinical core findings in LE are various mental changes such as amnesia or confusion, often associated with seizures. Careful characterization of psychiatric manifestations and/or associated neurological signs can help to characterize the syndrome and type of ab. The treatment options in LE depend on the aetiology. In LE caused by onconeuronal abs, the treatment options are poor. In two types of abs associated with LE, abs against ion channels and surface antigens (e.g. NMDA), immunomodulatory treatments seem effective, making these types of LE treatable conditions. However, LE can also occur without being associated with cancer, in which case only immunomodulation is required. Despite effective treatments, some patients' residual deficits remain, and recurrences have also been described.

A myxoid chondrosarcoma associated with an anti-Hu-positive paraneoplastic encephalomyelitis

Extraskeletal myxoid chondrosarcoma is a rare tumor with less than 100 cases reported in the literature. The prevalence of anti-Hu positive myxoid chondrosarcoma-associated paraneoplastic subacute cerebellar degeneration is exceedingly rare. We present a report of a patient with confirmed myxoid chondrosarcoma-associated paraneoplastic subacute cerebellar degeneration, who exhibited marked improvement within 1 week of receiving chemotherapy, intravenous immunoglobulin (IVIG), and hydrocortisone treatment.

Paraneoplastic encephalomyelitis: Is it an oropharyngeal or a lung cancer complication?

This case report describes a patient with a locally advanced oropharyngeal cancer with a simultaneous paraneoplastic encephalomyelitis. To the best of our knowledge, a paraneoplastic neurological syndrome is a rare complication in head and neck cancer, and has previously not been reported in the literature. One year later, following initial treatment, a small cell lung cancer developed, a tumor frequently associated with this type of paraneoplastic syndrome. The dilemma, therefore, is whether this paraneoplastic symdrome was a secondary complication of the tonsilar concurrent cancer or a metachronous paraneoplastic syndrome prior to small cell lung cancer.

Brainstem and spinal cord involvement in a paraneoplastic syndrome associated with anti-Yo antibody and breast cancer

Paraneoplastic neurological syndromes (PNS) are associated with breast cancer in\1% of cases [1]. Anti-Yo/PCA1 antibody is usually detected in female patients with breast or gynaecologic cancer and is most commonly associated with progressive cerebellar degeneration (PCD) [2–5]. Here we describe a case of a 60-year-old woman who, in May 2008, complained of progressive weakness of lower limbs followed, after 2 months, by dysesthesias in the four limbs, dysphagia, diplopia and sensory ataxia. Total body computed tomography (CT) scan, brain and spinal cord magnetic resonance imaging (MRI) were normal, electromyography (EMG) showed evidence of acute and chronic denervation in the four limb muscles, oligoclonal bands were present in the cerebrospinal fluid and serum anti-onconeural antibodies were negative. She was treated with steroids for several months with partial benefit but soon after drug discontinuation her symptoms worsened. At our first neurological examination in January 2010, the patient was unable to walk for severe sensory ataxia and showed lower limb weakness and spasticity, mild dysarthria, dysphagia, diplopia and dysesthesias in the four limbs. Sensory and motor evoked potentials were altered both at upper and lower limbs and EMG showed evidence of acute and chronic denervation in the muscles of upper and lower extremities. At that time, serum anti-Yo/PCA-1 antibody was positive. Total body CT scan and mammography showed evidence of a nodular opacity associated with two clusters of retroareolar microcalcifications in the left breast. A total body 2-deoxy-2-F-fluoro-D-glucose positron emission tomography (FDG PET)/CT imaging showed high metabolic activity in the right axillary lymph nodes but ultrasound scan (US) and MRI confirmed the left breast calcifications with no evidence of axillary lymph node pathological alterations bilaterally. The left mammary lesion was surgically removed in March 2010. Histopathological examination revealed the presence of foci of ductal carcinoma in situ of G2 grade. Radiotherapy and hormonal therapy were started in April 2010. Soon after the surgery, the neurological symptoms progressively improved. At the last neurological examination in July 2010, the ataxia was reduced and the patient was ambulatory without aid or rest for about 10 m, with only a mild proximal weakness of the legs and diplopia persisting. The EMG evaluation showed improvement mainly at the lower limbs with reduction of acute denervation signs. Despite the fact that, in our patient, the clinical picture was not evocative of a classical PNS, we suspected a paraneoplastic encephalomyelitis; we repeated tests for anti-onconeural antibodies and diagnostic investigations for cancer, and we found serum positivity for anti-Yo/ PCA-1 antibody associated with a ductal breast carcinoma in situ. Very few cases of anti-Yo/PCA-1 antibody associated PNS, different from PCD, have already been described including several cases of peripheral neuropathy [6, 7] and a case of motor neuron disease involving both the upper and the lower motor neurons [8]. All patients with PNS and anti-Yo/PCA-1 antibody associated breast cancer previously reported showed axillary lymph node metastases [9]. D. Plantone P. Caliandro R. Iorio G. Frisullo V. Nociti A. K. Patanella A. Marti P. A. Tonali A. P. Batocchi (&) Department of Neurosciences, Institute of Neurology, Catholic University, Largo Gemelli 8, 00168 Rome, Italy e-mail: annapaola.batocchi@rm.unicatt.it