Semin Neurol 2015; 35(03): 245-258
DOI: 10.1055/s-0035-1552625
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Autoimmune Epilepsy

Michel Toledano
1   Departments of Neurology and Mayo Clinic, College of Medicine, Rochester, Minnesota
,
Sean J. Pittock
1   Departments of Neurology and Mayo Clinic, College of Medicine, Rochester, Minnesota
2   Departments of Laboratory Medicine and Pathology, Mayo Clinic, College of Medicine, Rochester, Minnesota
› Author Affiliations
Further Information

Publication History

Publication Date:
10 June 2015 (online)

Abstract

Seizures are recognized as a common manifestation of autoimmune limbic encephalitis and multifocal paraneoplastic disorders, but accumulating evidence supports an autoimmune basis for seizures in the absence of syndromic manifestations of encephalitis. Autoimmune encephalitis and epilepsy have been linked to neural-specific autoantibodies targeting both intracellular and plasma membrane antigens. The detection of these antibodies can serve as a diagnostic marker directing physicians toward specific cancers and can assist in therapeutic decision-making, but are not necessary to establish the diagnosis. Response to an immunotherapy trial can support the diagnosis and help establish prognosis. Early recognition is important because expedited diagnosis can facilitate recovery. In this review, the authors summarize the clinical presentation, pathophysiology, and management of autoimmune epilepsies for which neural antigen-specific autoantibodies serve as diagnostic aids.

 
  • References

  • 1 McKeon A, Pittock SJ. Paraneoplastic encephalomyelopathies: pathology and mechanisms. Acta Neuropathol 2011; 122 (4) 381-400
  • 2 Vincent A, Bien CG, Irani SR, Waters P. Autoantibodies associated with diseases of the CNS: new developments and future challenges. Lancet Neurol 2011; 10 (8) 759-772
  • 3 Lancaster E, Martinez-Hernandez E, Dalmau J. Encephalitis and antibodies to synaptic and neuronal cell surface proteins. Neurology 2011; 77 (2) 179-189
  • 4 Wilkinson PC, Zeromski J. Immunofluorescent detection of antibodies against neurones in sensory carcinomatous neuropathy. Brain 1965; 88 (3) 529-583
  • 5 Darnell RB, Posner JB. Paraneoplastic syndromes involving the nervous system. N Engl J Med 2003; 349 (16) 1543-1554
  • 6 Albert ML, Darnell JC, Bender A, Francisco LM, Bhardwaj N, Darnell RB. Tumor-specific killer cells in paraneoplastic cerebellar degeneration. Nat Med 1998; 4 (11) 1321-1324
  • 7 Tanaka M, Tanaka K, Tokiguchi S, Shinozawa K, Tsuji S. Cytotoxic T cells against a peptide of Yo protein in patients with paraneoplastic cerebellar degeneration and anti-Yo antibody. J Neurol Sci 1999; 168 (1) 28-31
  • 8 Dalakas MC. The role of IVIg in the treatment of patients with stiff person syndrome and other neurological diseases associated with anti-GAD antibodies. J Neurol 2005; 252 (1) (Suppl. 01) I19-I25
  • 9 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
  • 10 Kwan P, Schachter SC, Brodie MJ. Drug-resistant epilepsy. N Engl J Med 2011; 365 (10) 919-926
  • 11 Low NL. Infantile spasms with mental retardation. II. Treatment with cortisone and adrenocorticotropin. Pediatrics 1958; 22 (6) 1165-1169
  • 12 Sinclair DB. Prednisone therapy in pediatric epilepsy. Pediatr Neurol 2003; 28 (3) 194-198
  • 13 Sinclair DB, Snyder TJ. Corticosteroids for the treatment of Landau-Kleffner syndrome and continuous spike-wave discharge during sleep. Pediatr Neurol 2005; 32 (5) 300-306
  • 14 Rasmussen T, Olszewski J, Lloydsmith D. Focal seizures due to chronic localized encephalitis. Neurology 1958; 8 (6) 435-445
  • 15 Bien CG, Granata T, Antozzi C , et al. Pathogenesis, diagnosis and treatment of Rasmussen encephalitis: a European consensus statement. Brain 2005; 128 (Pt 3) 454-471
  • 16 Heida JG, Moshé SL, Pittman QJ. The role of interleukin-1beta in febrile seizures. Brain Dev 2009; 31 (5) 388-393
  • 17 Ong MS, Kohane IS, Cai T, Gorman MP, Mandl KD. Population-level evidence for an autoimmune etiology of epilepsy. JAMA Neurol 2014; 71 (5) 569-574
  • 18 Vezzani A, Granata T. Brain inflammation in epilepsy: experimental and clinical evidence. Epilepsia 2005; 46 (11) 1724-1743
  • 19 Vezzani A, French J, Bartfai T, Baram TZ. The role of inflammation in epilepsy. Nat Rev Neurol 2011; 7 (1) 31-40
  • 20 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
  • 21 Majoie HJ, de Baets M, Renier W, Lang B, Vincent A. Antibodies to voltage-gated potassium and calcium channels in epilepsy. Epilepsy Res 2006; 71 (2-3) 135-141
  • 22 Barajas RF, Collins DE, Cha S, Geschwind MD. Adult-onset drug-refractory seizure disorder associated with anti-voltage-gated potassium-channel antibody. Epilepsia 2010; 51 (3) 473-477
  • 23 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
  • 24 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
  • 25 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
  • 26 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
  • 27 Peltola J, Kulmala P, Isojärvi J , et al. Autoantibodies to glutamic acid decarboxylase in patients with therapy-resistant epilepsy. Neurology 2000; 55 (1) 46-50
  • 28 Quek AM, Britton JW, McKeon A , et al. Autoimmune epilepsy: clinical characteristics and response to immunotherapy. Arch Neurol 2012; 69 (5) 582-593
  • 29 Liimatainen S, Peltola M, Sabater L , et al. Clinical significance of glutamic acid decarboxylase antibodies in patients with epilepsy. Epilepsia 2010; 51 (5) 760-767
  • 30 Toledano M, Britton JW, McKeon A , et al. Utility of an immunotherapy trial in evaluating patients with presumed autoimmune epilepsy. Neurology 2014; 82 (18) 1578-1586
  • 31 Suleiman J, Brilot F, Lang B, Vincent A, Dale RC. Autoimmune epilepsy in children: case series and proposed guidelines for identification. Epilepsia 2013; 54 (6) 1036-1045
  • 32 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
  • 33 Iorio R, Lennon VA. Neural antigen-specific autoimmune disorders. Immunol Rev 2012; 248 (1) 104-121
  • 34 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
  • 35 Roberts WK, Deluca IJ, Thomas A , et al. Patients with lung cancer and paraneoplastic Hu syndrome harbor HuD-specific type 2 CD8+ T cells. J Clin Invest 2009; 119 (7) 2042-2051
  • 36 Graus F, Cordon-Cardo C, Posner JB. Neuronal antinuclear antibody in sensory neuronopathy from lung cancer. Neurology 1985; 35 (4) 538-543
  • 37 Lawn ND, Westmoreland BF, Kiely MJ, Lennon VA, Vernino S. Clinical, magnetic resonance imaging, and electroencephalographic findings in paraneoplastic limbic encephalitis. Mayo Clin Proc 2003; 78 (11) 1363-1368
  • 38 Rudzinski LA, Pittock SJ, McKeon A, Lennon VA, Britton JW. Extratemporal EEG and MRI findings in ANNA-1 (anti-Hu) encephalitis. Epilepsy Res 2011; 95 (3) 255-262
  • 39 Dalmau J, Gultekin HS, Posner JB. Paraneoplastic neurologic syndromes: pathogenesis and physiopathology. Brain Pathol 1999; 9 (2) 275-284
  • 40 Jean WC, Dalmau J, Ho A, Posner JB. Analysis of the IgG subclass distribution and inflammatory infiltrates in patients with anti-Hu-associated paraneoplastic encephalomyelitis. Neurology 1994; 44 (1) 140-147
  • 41 Bernal F, Graus F, Pifarré A, Saiz A, Benyahia B, Ribalta T. Immunohistochemical analysis of anti-Hu-associated paraneoplastic encephalomyelitis. Acta Neuropathol 2002; 103 (5) 509-515
  • 42 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
  • 43 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
  • 44 Schmidt EF, Strittmatter SM. The CRMP family of proteins and their role in Sema3A signaling. Adv Exp Med Biol 2007; 600: 1-11
  • 45 Arimura N, Hattori A, Kimura T , et al. CRMP-2 directly binds to cytoplasmic dynein and interferes with its activity. J Neurochem 2009; 111 (2) 380-390
  • 46 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
  • 47 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
  • 48 Lichte B, Veh RW, Meyer HE, Kilimann MW. Amphiphysin, a novel protein associated with synaptic vesicles. EMBO J 1992; 11 (7) 2521-2530
  • 49 Dropcho EJ. Antiamphiphysin antibodies with small-cell lung carcinoma and paraneoplastic encephalomyelitis. Ann Neurol 1996; 39 (5) 659-667
  • 50 Pittock SJ, Lucchinetti CF, Parisi JE , et al. Amphiphysin autoimmunity: paraneoplastic accompaniments. Ann Neurol 2005; 58 (1) 96-107
  • 51 Wessig C, Klein R, Schneider MF, Toyka KV, Naumann M, Sommer C. Neuropathology and binding studies in anti-amphiphysin-associated stiff-person syndrome. Neurology 2003; 61 (2) 195-198
  • 52 Geis C, Weishaupt A, Hallermann S , et al. Stiff person syndrome-associated autoantibodies to amphiphysin mediate reduced GABAergic inhibition. Brain 2010; 133 (11) 3166-3180
  • 53 Lernmark A. Controlling the controls: GAD65 autoreactive T cells in type 1 diabetes. J Clin Invest 2002; 109 (7) 869-870
  • 54 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
  • 55 Solimena M, Folli F, Aparisi R, Pozza G, De Camilli P. Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiff-man syndrome. N Engl J Med 1990; 322 (22) 1555-1560
  • 56 Moersch FP, Woltman HW. Progressive fluctuating muscular rigidity and spasm (“stiff-man” syndrome); report of a case and some observations in 13 other cases. Proc Staff Meet Mayo Clin 1956; 31 (15) 421-427
  • 57 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
  • 58 Bien CG, Vincent A, Barnett MH , et al. Immunopathology of autoantibody-associated encephalitides: clues for pathogenesis. Brain 2012; 135 (Pt 5) 1622-1638
  • 59 Dalakas MC, Fujii M, Li M, Lutfi B, Kyhos J, McElroy B. High-dose intravenous immune globulin for stiff-person syndrome. N Engl J Med 2001; 345 (26) 1870-1876
  • 60 Vicari AM, Folli F, Pozza G , et al. Plasmapheresis in the treatment of stiff-man syndrome. N Engl J Med 1989; 320 (22) 1499
  • 61 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
  • 62 Benarroch EE. Potassium channels: brief overview and implications in epilepsy. Neurology 2009; 72 (7) 664-669
  • 63 Gutman GA, Chandy KG, Grissmer S , et al. International Union of Pharmacology. LIII. Nomenclature and molecular relationships of voltage-gated potassium channels. Pharmacol Rev 2005; 57 (4) 473-508
  • 64 Ogawa Y, Oses-Prieto J, Kim MY , et al. ADAM22, a Kv1 channel-interacting protein, recruits membrane-associated guanylate kinases to juxtaparanodes of myelinated axons. J Neurosci 2010; 30 (3) 1038-1048
  • 65 Oiso S, Takeda Y, Futagawa T , et al. Contactin-associated protein (Caspr) 2 interacts with carboxypeptidase E in the CNS. J Neurochem 2009; 109 (1) 158-167
  • 66 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
  • 67 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
  • 68 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
  • 69 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
  • 70 Tan KM, Lennon VA, Klein CJ, Boeve BF, Pittock SJ. Clinical spectrum of voltage-gated potassium channel autoimmunity. Neurology 2008; 70 (20) 1883-1890
  • 71 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
  • 72 McKeon A, Marnane M, O'connell M, Stack JP, Kelly PJ, Lynch T. Potassium channel antibody associated encephalopathy presenting with a frontotemporal dementia like syndrome. Arch Neurol 2007; 64 (10) 1528-1530
  • 73 Geschwind MD, Tan KM, Lennon VA , et al. Voltage-gated potassium channel autoimmunity mimicking Creutzfeldt-Jakob disease. Arch Neurol 2008; 65 (10) 1341-1346
  • 74 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
  • 75 Klein CJ, Lennon VA, Aston PA, McKeon A, Pittock SJ. Chronic pain as a manifestation of potassium channel-complex autoimmunity. Neurology 2012; 79 (11) 1136-1144
  • 76 Irani SR, Bien CG, Lang B. Autoimmune epilepsies. Curr Opin Neurol 2011; 24 (2) 146-153
  • 77 Irani SR, Stagg CJ, Schott JM , et al. Faciobrachial dystonic seizures: the influence of immunotherapy on seizure control and prevention of cognitive impairment in a broadening phenotype. Brain 2013; 136 (Pt 10) 3151-3162
  • 78 Diani E, Di Bonaventura C, Mecarelli O , et al. Autosomal dominant lateral temporal epilepsy: absence of mutations in ADAM22 and Kv1 channel genes encoding LGI1-associated proteins. Epilepsy Res 2008; 80 (1) 1-8
  • 79 Nobile C, Michelucci R, Andreazza S, Pasini E, Tosatto SC, Striano P. LGI1 mutations in autosomal dominant and sporadic lateral temporal epilepsy. Hum Mutat 2009; 30 (4) 530-536
  • 80 Sagane K, Hayakawa K, Kai J , et al. Ataxia and peripheral nerve hypomyelination in ADAM22-deficient mice. BMC Neurosci 2005; 6: 33
  • 81 Baulac S, Ishida S, Mashimo T , et al. A rat model for LGI1-related epilepsies. Hum Mol Genet 2012; 21 (16) 3546-3557
  • 82 Rho JM, Szot P, Tempel BL, Schwartzkroin PA. Developmental seizure susceptibility of kv1.1 potassium channel knockout mice. Dev Neurosci 1999; 21 (3-5) 320-327
  • 83 Strauss KA, Puffenberger EG, Huentelman MJ , et al. Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2. N Engl J Med 2006; 354 (13) 1370-1377
  • 84 Gregor A, Albrecht B, Bader I , et al. Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1. BMC Med Genet 2011; 12 (106) 106
  • 85 Lalic T, Pettingill P, Vincent A, Capogna M. Human limbic encephalitis serum enhances hippocampal mossy fiber-CA3 pyramidal cell synaptic transmission. Epilepsia 2011; 52 (1) 121-131
  • 86 Dunstan EJ, Winer JB. Autoimmune limbic encephalitis causing fits, rapidly progressive confusion and hyponatraemia. Age Ageing 2006; 35 (5) 536-537
  • 87 Park DC, Murman DL, Perry KD, Bruch LA. An autopsy case of limbic encephalitis with voltage-gated potassium channel antibodies. Eur J Neurol 2007; 14 (10) e5-e6
  • 88 Khan NL, Jeffree MA, Good C, Macleod W, Al-Sarraj S. Histopathology of VGKC antibody-associated limbic encephalitis. Neurology 2009; 72 (19) 1703-1705
  • 89 Kotsenas AL, Watson RE, Pittock SJ , et al. MRI findings in autoimmune voltage-gated potassium channel complex encephalitis with seizures: one potential etiology for mesial temporal sclerosis. AJNR Am J Neuroradiol 2014; 35 (1) 84-89
  • 90 Pinheiro PS, Mulle C. Presynaptic glutamate receptors: physiological functions and mechanisms of action. Nat Rev Neurosci 2008; 9 (6) 423-436
  • 91 Benarroch EE. NMDA receptors: recent insights and clinical correlations. Neurology 2011; 76 (20) 1750-1757
  • 92 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
  • 93 Vitaliani R, Mason W, Ances B, Zwerdling T, Jiang Z, Dalmau J. Paraneoplastic encephalitis, psychiatric symptoms, and hypoventilation in ovarian teratoma. Ann Neurol 2005; 58 (4) 594-604
  • 94 McCoy B, Akiyama T, Widjaja E, Go C. Autoimmune limbic encephalitis as an emerging pediatric condition: case report and review of the literature. J Child Neurol 2011; 26 (2) 218-222
  • 95 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
  • 96 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
  • 97 Hughes EG, Peng X, Gleichman AJ , et al. Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. J Neurosci 2010; 30 (17) 5866-5875
  • 98 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
  • 99 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
  • 100 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
  • 101 Tobin WO, Lennon VA, Komorowski L , et al. DPPX potassium channel antibody: frequency, clinical accompaniments, and outcomes in 20 patients. Neurology 2014; 83 (20) 1797-1803
  • 102 Wada K, Yokotani N, Hunter C, Doi K, Wenthold RJ, Shimasaki S. Differential expression of two distinct forms of mRNA encoding members of a dipeptidyl aminopeptidase family. Proc Natl Acad Sci U S A 1992; 89 (1) 197-201
  • 103 Nadal MS, Ozaita A, Amarillo Y , et al. The CD26-related dipeptidyl aminopeptidase-like protein DPPX is a critical component of neuronal A-type K+ channels. Neuron 2003; 37 (3) 449-461
  • 104 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
  • 105 McKnight K, Jiang Y, Hart Y , et al. Serum antibodies in epilepsy and seizure-associated disorders. Neurology 2005; 65 (11) 1730-1736
  • 106 McKeon A, Lennon VA, Pittock SJ. Immunotherapy-responsive dementias and encephalopathies. Continuum (Minneap Minn) 2010; 16 (2 Dementia): 80-101
  • 107 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
  • 108 Hacohen Y, Deiva K, Pettingill P , et al. N-methyl-D-aspartate receptor antibodies in post-herpes simplex virus encephalitis neurological relapse. Mov Disord 2014; 29 (1) 90-96