Paraneoplastic and Autoimmune Encephalopathies

 

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Abstract

Immune-mediated encephalitis is an increasingly recognized cause of neurologic dysfunction including behavioral change, psychosis, movement disorders, seizures, autonomic instability, and coma. Associated antineuronal antibodies are of two main subtypes, those targeting neuronal cell surface antigens, which are pathogenic, and nonpathogenic antibodies targeting intracellular antigens. Antibody identification aids in screening for underlying cancers and prediction of outcome. Cancer is found most commonly with antibodies targeting intracellular neural components. Certain cancers, such as small-cell lung carcinoma, and breast and ovarian cancer are particularly immunogenic. When cancer is detected, oncologic treatment should be followed with immunotherapy. Nonpathogenic antibody disorders respond poorly to treatment, whereas pathogenic antibodies predict a favorable response to immune treatment. If no cancer is identified, then ongoing surveillance is recommended for 5 years after detection of most antineuronal antibodies.

• References

• 1 McKeon A, Pittock SJ. Paraneoplastic encephalomyelopathies: pathology and mechanisms. Acta Neuropathol 2011; 122 (4) 381-400
  CrossrefPubMedGoogle Scholar
• 2 Graus F, Delattre JY, Antoine JC , et al. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry 2004; 75 (8) 1135-1140
  CrossrefPubMedGoogle Scholar
• 3 Yu Z, Kryzer TJ, Griesmann GE, Kim K, Benarroch EE, Lennon VA. CRMP-5 neuronal autoantibody: marker of lung cancer and thymoma-related autoimmunity. Ann Neurol 2001; 49 (2) 146-154
  CrossrefPubMedGoogle Scholar
• 4 Pittock SJ, Lucchinetti CF, Lennon VA. Anti-neuronal nuclear autoantibody type 2: paraneoplastic accompaniments. Ann Neurol 2003; 53 (5) 580-587
  CrossrefPubMedGoogle Scholar
• 5 Pittock SJ, Kryzer TJ, Lennon VA. Paraneoplastic antibodies coexist and predict cancer, not neurological syndrome. Ann Neurol 2004; 56 (5) 715-719
  CrossrefPubMedGoogle Scholar
• 6 McKeon A, Tracy JA, Pittock SJ, Parisi JE, Klein CJ, Lennon VA. Purkinje cell cytoplasmic autoantibody type 1 accompaniments: the cerebellum and beyond. Arch Neurol 2011; 68 (10) 1282-1289
  CrossrefPubMedGoogle Scholar
• 7 Lucchinetti CF, Kimmel DW, Lennon VA. Paraneoplastic and oncologic profiles of patients seropositive for type 1 antineuronal nuclear autoantibodies. Neurology 1998; 50 (3) 652-657
  CrossrefPubMedGoogle Scholar
• 8 Bernal F, Shams'ili S, Rojas I , et al. Anti-Tr antibodies as markers of paraneoplastic cerebellar degeneration and Hodgkin's disease. Neurology 2003; 60 (2) 230-234
  CrossrefPubMedGoogle Scholar
• 9 Chan KH, Vernino S, Lennon VA. ANNA-3 anti-neuronal nuclear antibody: marker of lung cancer-related autoimmunity. Ann Neurol 2001; 50 (3) 301-311
  CrossrefPubMedGoogle Scholar
• 10 Cross SA, Salomao DR, Parisi JE , et al. Paraneoplastic autoimmune optic neuritis with retinitis defined by CRMP-5-IgG. Ann Neurol 2003; 54 (1) 38-50
  CrossrefPubMedGoogle Scholar
• 11 Folli F, Solimena M, Cofiell R , et al. Autoantibodies to a 128-kd synaptic protein in three women with the stiff-man syndrome and breast cancer. N Engl J Med 1993; 328 (8) 546-551
  CrossrefPubMedGoogle Scholar
• 12 Graus F, Cordon-Cardo C, Posner JB. Neuronal antinuclear antibody in sensory neuronopathy from lung cancer. Neurology 1985; 35 (4) 538-543
  CrossrefPubMedGoogle Scholar
• 13 Hetzel DJ, Stanhope CR, O'Neill BP, Lennon VA. Gynecologic cancer in patients with subacute cerebellar degeneration predicted by anti-Purkinje cell antibodies and limited in metastatic volume. Mayo Clin Proc 1990; 65 (12) 1558-1563
  CrossrefPubMedGoogle Scholar
• 14 Luque FA, Furneaux HM, Ferziger R , et al. Anti-Ri: an antibody associated with paraneoplastic opsoclonus and breast cancer. Ann Neurol 1991; 29 (3) 241-251
  CrossrefPubMedGoogle Scholar
• 15 Peterson K, Rosenblum MK, Kotanides H, Posner JB. Paraneoplastic cerebellar degeneration. I. A clinical analysis of 55 anti-Yo antibody-positive patients. Neurology 1992; 42 (10) 1931-1937
  CrossrefPubMedGoogle Scholar
• 16 Pittock SJ, Lucchinetti CF, Parisi JE , et al. Amphiphysin autoimmunity: paraneoplastic accompaniments. Ann Neurol 2005; 58 (1) 96-107
  CrossrefPubMedGoogle Scholar
• 17 Pittock SJ, Parisi JE, McKeon A , et al. Paraneoplastic jaw dystonia and laryngospasm with antineuronal nuclear autoantibody type 2 (anti-Ri). Arch Neurol 2010; 67 (9) 1109-1115
  CrossrefPubMedGoogle Scholar
• 18 Vernino S, Lennon VA. New Purkinje cell antibody (PCA-2): marker of lung cancer-related neurological autoimmunity. Ann Neurol 2000; 47 (3) 297-305
  CrossrefPubMedGoogle Scholar
• 19 Vernino S, Tuite P, Adler CH , et al. Paraneoplastic chorea associated with CRMP-5 neuronal antibody and lung carcinoma. Ann Neurol 2002; 51 (5) 625-630
  CrossrefPubMedGoogle Scholar
• 20 Wilkinson PC, Zeromski J. Immunofluorescent detection of antibodies against neurones in sensory carcinomatous neuropathy. Brain 1965; 88 (3) 529-583
  CrossrefPubMedGoogle Scholar
• 21 Graus F, Keime-Guibert F, Reñe R , et al. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain 2001; 124 (Pt 6) 1138-1148
  CrossrefPubMedGoogle Scholar
• 22 McKeon A, Lennon VA, Pittock SJ. Immunotherapy-responsive dementias and encephalopathies. Continuum (Minneap Minn) 2010; 16 (2 Dementia ) 80-101
  PubMedGoogle Scholar
• 23 Rosenfeld MR, Dalmau JO. Paraneoplastic disorders of the CNS and autoimmune synaptic encephalitis. Continuum (Minneap Minn) 2012; 18 (2) 366-383
  PubMedGoogle Scholar
• 24 Vernino S, O'Neill BP, Marks RS, O'Fallon JR, Kimmel DW. Immunomodulatory treatment trial for paraneoplastic neurological disorders. Neuro-oncol 2004; 6 (1) 55-62
  PubMedGoogle Scholar
• 25 Titulaer MJ, Soffietti R, Dalmau J , et al; European Federation of Neurological Societies. Screening for tumours in paraneoplastic syndromes: report of an EFNS task force. Eur J Neurol 2011; 18 (1) 19-e3
  CrossrefPubMedGoogle Scholar
• 26 Lancaster E, Martinez-Hernandez E, Dalmau J. Encephalitis and antibodies to synaptic and neuronal cell surface proteins. Neurology 2011; 77 (2) 179-189
  CrossrefPubMedGoogle Scholar
• 27 Dalmau J, Gleichman AJ, Hughes EG , et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 2008; 7 (12) 1091-1098
  CrossrefPubMedGoogle Scholar
• 28 Dalmau J, Tüzün E, Wu HY , et al. Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol 2007; 61 (1) 25-36
  Google Scholar
• 29 Hutchinson M, Waters P, McHugh J , et al. Progressive encephalomyelitis, rigidity, and myoclonus: a novel glycine receptor antibody. Neurology 2008; 71 (16) 1291-1292
  CrossrefPubMedGoogle Scholar
• 30 Irani SR, Alexander S, Waters P , et al. Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan's syndrome and acquired neuromyotonia. Brain 2010; 133 (9) 2734-2748
  CrossrefPubMedGoogle Scholar
• 31 Klein CJ, Lennon VA, Aston PA , et al. Insights from LGI1 and CASPR2 potassium channel complex autoantibody subtyping. JAMA Neurol 2013; 70 (2) 229-234
  CrossrefPubMedGoogle Scholar
• 32 Lai M, Hughes EG, Peng X , et al. AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location. Ann Neurol 2009; 65 (4) 424-434
  CrossrefPubMedGoogle Scholar
• 33 Lai M, Huijbers MG, Lancaster E , et al. Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series. Lancet Neurol 2010; 9 (8) 776-785
  CrossrefPubMedGoogle Scholar
• 34 Lancaster E, Huijbers MG, Bar V , et al. Investigations of caspr2, an autoantigen of encephalitis and neuromyotonia. Ann Neurol 2011; 69 (2) 303-311
  CrossrefPubMedGoogle Scholar
• 35 Lancaster 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 (1) 67-76
  CrossrefPubMedGoogle Scholar
• 36 Lancaster E, Martinez-Hernandez E, Titulaer MJ , et al. Antibodies to metabotropic glutamate receptor 5 in the Ophelia syndrome. Neurology 2011; 77 (18) 1698-1701
  CrossrefPubMedGoogle Scholar
• 37 Sillevis Smitt P, Kinoshita A, De Leeuw B , et al. Paraneoplastic cerebellar ataxia due to autoantibodies against a glutamate receptor. N Engl J Med 2000; 342 (1) 21-27
  CrossrefPubMedGoogle Scholar
• 38 Thieben MJ, Lennon VA, Boeve BF, Aksamit AJ, Keegan M, Vernino S. Potentially reversible autoimmune limbic encephalitis with neuronal potassium channel antibody. Neurology 2004; 62 (7) 1177-1182
  CrossrefPubMedGoogle Scholar
• 39 Vincent A, Buckley C, Schott JM , et al. Potassium channel antibody-associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis. Brain 2004; 127 (Pt 3) 701-712
  CrossrefPubMedGoogle Scholar
• 40 Tan KM, Lennon VA, Klein CJ, Boeve BF, Pittock SJ. Clinical spectrum of voltage-gated potassium channel autoimmunity. Neurology 2008; 70 (20) 1883-1890
  CrossrefPubMedGoogle Scholar
• 41 Irani SR, Michell AW, Lang B , et al. Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann Neurol 2011; 69 (5) 892-900
  CrossrefPubMedGoogle Scholar
• 42 Irani SR, Bera K, Waters P , et al. N-methyl-D-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes. Brain 2010; 133 (Pt 6) 1655-1667
  CrossrefPubMedGoogle Scholar
• 43 Schmitt SE, Pargeon K, Frechette ES, Hirsch LJ, Dalmau J, Friedman D. Extreme delta brush: a unique EEG pattern in adults with anti-NMDA receptor encephalitis. Neurology 2012; 79 (11) 1094-1100
  CrossrefPubMedGoogle Scholar
• 44 Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol 2011; 10 (1) 63-74
  Google Scholar
• 45 Flanagan EP, McKeon A, Lennon VA , et al. Autoimmune dementia: clinical course and predictors of immunotherapy response. Mayo Clin Proc 2010; 85 (10) 881-897
  CrossrefPubMedGoogle Scholar
• 46 Geschwind MD, Tan KM, Lennon VA , et al. Voltage-gated potassium channel autoimmunity mimicking Creutzfeldt-Jakob disease. Arch Neurol 2008; 65 (10) 1341-1346
  CrossrefPubMedGoogle Scholar
• 47 Prüss H, Höltje M, Maier N , et al. IgA NMDA receptor antibodies are markers of synaptic immunity in slow cognitive impairment. Neurology 2012; 78 (22) 1743-1753
  CrossrefPubMedGoogle Scholar
• 48 Quek AM, Britton JW, McKeon A , et al. Autoimmune epilepsy: clinical characteristics and response to immunotherapy. Arch Neurol 2012; 69 (5) 582-593
  CrossrefPubMedGoogle Scholar
• 49 Graus F, Boronat A, Xifró X , et al. The expanding clinical profile of anti-AMPA receptor encephalitis. Neurology 2010; 74 (10) 857-859
  CrossrefPubMedGoogle Scholar
• 50 Zuliani L, Graus F, Giometto B, Bien C, Vincent A. Central nervous system neuronal surface antibody associated syndromes: review and guidelines for recognition. J Neurol Neurosurg Psychiatry 2012; 83 (6) 638-645
  CrossrefPubMedGoogle Scholar
• 51 McKeon A, Pittock SJ, Lennon VA. CSF complements serum for evaluating paraneoplastic antibodies and NMO-IgG. Neurology 2011; 76 (12) 1108-1110
  CrossrefPubMedGoogle Scholar
• 52 Titulaer MJ, McCracken L, Gabilondo I , et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 2013; 12 (2) 157-165
  CrossrefPubMedGoogle Scholar
• 53 Castillo P, Woodruff B, Caselli R , et al. Steroid-responsive encephalopathy associated with autoimmune thyroiditis. Arch Neurol 2006; 63 (2) 197-202
  CrossrefPubMedGoogle Scholar
• 54 Psimaras D, Carpentier AF, Rossi C ; PNS Euronetwork Cerebrospinal fluid study in paraneoplastic syndromes. J Neurol Neurosurg Psychiatry 2010; 81 (1) 42-45
  CrossrefPubMedGoogle Scholar
• 55 McKeon A, Ahlskog JE, Britton JW, Lennon VA, Pittock SJ. Reversible extralimbic paraneoplastic encephalopathies with large abnormalities on magnetic resonance images. Arch Neurol 2009; 66 (2) 268-271
  CrossrefPubMedGoogle Scholar
• 56 Bien CG, Urbach H, Schramm J , et al. Limbic encephalitis as a precipitating event in adult-onset temporal lobe epilepsy. Neurology 2007; 69 (12) 1236-1244
  CrossrefPubMedGoogle Scholar
• 57 McKeon A, Apiwattanakul M, Lachance DH , et al. Positron emission tomography-computed tomography in paraneoplastic neurologic disorders: systematic analysis and review. Arch Neurol 2010; 67 (3) 322-329
  CrossrefPubMedGoogle Scholar
• 58 Gultekin SH, Rosenfeld MR, Voltz R, Eichen J, Posner JB, Dalmau J. Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumour association in 50 patients. Brain 2000; 123 (Pt 7) 1481-1494
  CrossrefPubMedGoogle Scholar
• 59 Keime-Guibert F, Graus F, Broët P , et al. Clinical outcome of patients with anti-Hu-associated encephalomyelitis after treatment of the tumor. Neurology 1999; 53 (8) 1719-1723
  CrossrefPubMedGoogle Scholar
• 60 Hansen HC, Klingbeil C, Dalmau J, Li W, Weissbrich B, Wandinger KP. Persistent intrathecal antibody synthesis 15 years after recovering from anti-N-methyl-D-aspartate receptor encephalitis. JAMA Neurol 2013; 70 (1) 117-119
  CrossrefPubMedGoogle Scholar
• 61 Dalmau J, Gultekin SH, Voltz R , et al. Ma1, a novel neuron- and testis-specific protein, is recognized by the serum of patients with paraneoplastic neurological disorders. Brain 1999; 122 (Pt 1) 27-39
  CrossrefPubMedGoogle Scholar
• 62 Adams C, McKeon A, Silber MH, Kumar R. Narcolepsy, REM sleep behavior disorder, and supranuclear gaze palsy associated with Ma1 and Ma2 antibodies and tonsillar carcinoma. Arch Neurol 2011; 68 (4) 521-524
  CrossrefPubMedGoogle Scholar
• 63 Dalmau J, Graus F, Villarejo A , et al. Clinical analysis of anti-Ma2-associated encephalitis. Brain 2004; 127 (Pt 8) 1831-1844
  CrossrefPubMedGoogle Scholar
• 64 Voltz R, Gultekin SH, Rosenfeld MR , et al. A serologic marker of paraneoplastic limbic and brain-stem encephalitis in patients with testicular cancer. N Engl J Med 1999; 340 (23) 1788-1795
  CrossrefPubMedGoogle Scholar
• 65 Bataller L, Wade DF, Fuller GN, Rosenfeld MR, Dalmau J. Cerebellar degeneration and autoimmunity to zinc-finger proteins of the cerebellum. Neurology 2002; 59 (12) 1985-1987
  CrossrefPubMedGoogle Scholar
• 66 Bataller L, Wade DF, Graus F, Stacey HD, Rosenfeld MR, Dalmau J. Antibodies to Zic4 in paraneoplastic neurologic disorders and small-cell lung cancer. Neurology 2004; 62 (5) 778-782
  CrossrefPubMedGoogle Scholar
• 67 Kerasnoudis A, Rockhoff M, Federlein J, Gold R, Krogias C. Isolated ZIC4 antibodies in paraneoplastic cerebellar syndrome with an underlying ovarian tumor. Arch Neurol 2011; 68 (8) 1073
  CrossrefPubMedGoogle Scholar
• 68 McKeon A, Lennon VA, LaChance DH, Klein CJ, Pittock SJ. Striational antibodies in a paraneoplastic context. Muscle Nerve 2013; 47 (4) 585-587
  CrossrefPubMedGoogle Scholar
• 69 McKeon A, Robinson MT, McEvoy KM , et al. Stiff-man syndrome and variants: clinical course, treatments, and outcomes. Arch Neurol 2012; 69 (2) 230-238
  CrossrefPubMedGoogle Scholar
• 70 Pittock SJ, Yoshikawa H, Ahlskog JE , et al. Glutamic acid decarboxylase autoimmunity with brainstem, extrapyramidal, and spinal cord dysfunction. Mayo Clin Proc 2006; 81 (9) 1207-1214
  CrossrefPubMedGoogle Scholar
• 71 Solimena M, Folli F, Denis-Donini S , et al. Autoantibodies to glutamic acid decarboxylase in a patient with stiff-man syndrome, epilepsy, and type I diabetes mellitus. N Engl J Med 1988; 318 (16) 1012-1020
  CrossrefPubMedGoogle Scholar
• 72 Graus F, Vincent A, Pozo-Rosich P , et al. Anti-glial nuclear antibody: marker of lung cancer-related paraneoplastic neurological syndromes. J Neuroimmunol 2005; 165 (1-2) 166-171
  CrossrefPubMedGoogle Scholar
• 73 Titulaer MJ, Klooster R, Potman M , et al. SOX antibodies in small-cell lung cancer and Lambert-Eaton myasthenic syndrome: frequency and relation with survival. J Clin Oncol 2009; 27 (26) 4260-4267
  CrossrefPubMedGoogle Scholar
• 74 McKeon A, Lennon VA, Lachance DH, Fealey RD, Pittock SJ. Ganglionic acetylcholine receptor autoantibody: oncological, neurological, and serological accompaniments. Arch Neurol 2009; 66 (6) 735-741
  CrossrefPubMedGoogle Scholar
• 75 Vernino S, Lennon VA. Neuronal ganglionic acetylcholine receptor autoimmunity. Ann N Y Acad Sci 2003; 998: 211-214
  CrossrefPubMedGoogle Scholar
• 76 Vernino S, Low PA, Fealey RD, Stewart JD, Farrugia G, Lennon VA. Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies. N Engl J Med 2000; 343 (12) 847-855
  CrossrefPubMedGoogle Scholar
• 77 Bataller L, Galiano R, García-Escrig M , et al. Reversible paraneoplastic limbic encephalitis associated with antibodies to the AMPA receptor. Neurology 2010; 74 (3) 265-267
  CrossrefPubMedGoogle Scholar
• 78 Boronat A, Sabater L, Saiz A, Dalmau J, Graus F. GABA(B) receptor antibodies in limbic encephalitis and anti-GAD-associated neurologic disorders. Neurology 2011; 76 (9) 795-800
  CrossrefPubMedGoogle Scholar
• 79 McKeon A, Martinez-Hernandez E, Lancaster E , et al. Glycine receptor autoimmune spectrum with stiff-man syndrome phenotype. JAMA Neurol 2013; 70 (1) 44-50
  CrossrefPubMedGoogle Scholar
• 80 Stern WM, Howard R, Chalmers RM , et al. Glycine receptor antibody mediated progressive encephalomyelitis with rigidity and myoclonus (PERM): a rare but treatable neurological syndrome. Pract Neurol 2013;
  PubMedGoogle Scholar
• 81 Iorio R, Lucchinetti CF, Lennon VA , et al. Syndrome of inappropriate antidiuresis may herald or accompany neuromyelitis optica. Neurology 2011; 77 (17) 1644-1646
  CrossrefPubMedGoogle Scholar
• 82 Lennon VA, Wingerchuk DM, Kryzer TJ , et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 2004; 364 (9451) 2106-2112
  CrossrefPubMedGoogle Scholar
• 83 Pittock SJ, Lennon VA, Krecke K, Wingerchuk DM, Lucchinetti CF, Weinshenker BG. Brain abnormalities in neuromyelitis optica. Arch Neurol 2006; 63 (3) 390-396
  CrossrefPubMedGoogle Scholar
• 84 Vernino S, Lennon VA. Autoantibody profiles and neurological correlations of thymoma. Clin Cancer Res 2004; 10 (21) 7270-7275
  CrossrefPubMedGoogle Scholar
• 85 Lennon VA, Kryzer TJ, Griesmann GE , et al. Calcium-channel antibodies in the Lambert-Eaton syndrome and other paraneoplastic syndromes. N Engl J Med 1995; 332 (22) 1467-1474
  CrossrefPubMedGoogle Scholar
• 86 Boronat A, Gelfand JM, Gresa-Arribas N , et al. Encephalitis and antibodies to dipeptidyl-peptidase-like protein-6, a subunit of Kv4.2 potassium channels. Ann Neurol 2013; 73 (1) 120-128
  CrossrefPubMedGoogle Scholar