ログイン
ランキング
お知らせ
ログイン
文献詳細
特集 辺縁系脳炎
文献概要
はじめに
Anti-Ma2-associated encephalitis（本稿では，抗Ma2抗体陽性脳炎と表記する）は，細胞内のonconeuronal antigenであるMa2に対する抗体の存在を特徴とする傍腫瘍性神経症候群（paraneoplastic neurological syndromes：PNS）の1つであり，辺縁系脳炎をはじめとした特徴的な症候群を呈する。抗Ma2抗体は，同様に傍腫瘍性辺縁系脳炎に関連し，神経細胞内抗原と結合する抗Hu抗体，抗CV2/CRMP5抗体，抗amphiphysin抗体などとともに，いわゆるwell-characterized onconeuronal antibodies1）に分類され（最近はPNS-related onconeuronal antibodiesという分類も提唱されている2）が，本稿では文字数の関係もあり古典的抗体と表記する），PNSにおける診断的意義が確立しているが，病態における抗体の役割は未解明である。
一般に細胞内抗原を標的とする抗体を伴う傍腫瘍性脳炎の場合には，神経伝達物質受容体などの細胞表面抗原に対する抗体を伴う自己免疫性脳炎の場合と異なり，治療による神経症状の改善が期待できないと考えられている。しかし，抗Ma2抗体陽性脳炎は，早期治療に反応する症例が少なくない点で際立っている3）。特に治療効果が期待されるのは原発腫瘍が限局性の精巣腫瘍の場合であるが，性別や年齢などの患者背景がそろえば精巣腫瘍の存在を極めて正確に予測できる点も大きな特徴である。しかし，臨床診断が極めて困難な上皮内癌の段階でも重篤な神経傷害をきたし得るというジレンマも抱えている4）。
このように，抗Ma2抗体陽性脳炎は早期の診断治療を必要とする，辺縁系脳炎の重要な鑑別診断の1つであるが，PNSとしての古典的症候群と異なる臨床像を呈する場合が多い点に注意が必要である。本稿では，自験例の提示とともに，本疾患の臨床的特徴について概説する。
Anti-Ma2-associated encephalitis（本稿では，抗Ma2抗体陽性脳炎と表記する）は，細胞内のonconeuronal antigenであるMa2に対する抗体の存在を特徴とする傍腫瘍性神経症候群（paraneoplastic neurological syndromes：PNS）の1つであり，辺縁系脳炎をはじめとした特徴的な症候群を呈する。抗Ma2抗体は，同様に傍腫瘍性辺縁系脳炎に関連し，神経細胞内抗原と結合する抗Hu抗体，抗CV2/CRMP5抗体，抗amphiphysin抗体などとともに，いわゆるwell-characterized onconeuronal antibodies1）に分類され（最近はPNS-related onconeuronal antibodiesという分類も提唱されている2）が，本稿では文字数の関係もあり古典的抗体と表記する），PNSにおける診断的意義が確立しているが，病態における抗体の役割は未解明である。
一般に細胞内抗原を標的とする抗体を伴う傍腫瘍性脳炎の場合には，神経伝達物質受容体などの細胞表面抗原に対する抗体を伴う自己免疫性脳炎の場合と異なり，治療による神経症状の改善が期待できないと考えられている。しかし，抗Ma2抗体陽性脳炎は，早期治療に反応する症例が少なくない点で際立っている3）。特に治療効果が期待されるのは原発腫瘍が限局性の精巣腫瘍の場合であるが，性別や年齢などの患者背景がそろえば精巣腫瘍の存在を極めて正確に予測できる点も大きな特徴である。しかし，臨床診断が極めて困難な上皮内癌の段階でも重篤な神経傷害をきたし得るというジレンマも抱えている4）。
このように，抗Ma2抗体陽性脳炎は早期の診断治療を必要とする，辺縁系脳炎の重要な鑑別診断の1つであるが，PNSとしての古典的症候群と異なる臨床像を呈する場合が多い点に注意が必要である。本稿では，自験例の提示とともに，本疾患の臨床的特徴について概説する。
参考文献
1) Graus F, Delattre JY, Antoine JC, Dalmau J, Giometto B, et al: Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry, 75: 1135-1140, 2004
2) Graus F, Saiz A, Dalmau J: Antibodies and neuronal autoimmune disorders of the CNS. J Neurol 257: 509-517, 2009
3) Dalmau J, Graus F, Villarejo A, Posner JB, Blumenthal D, et al: Clinical analysis of anti-Ma2-associated encephalitis. Brain 127: 1831-1844, 2004
4) Mathew RM, Vandenberghe R, Garcia-Merino A, Yamamoto T, Landolfi JC, et al: Orchiectomy for suspected microscopic tumor in patients with anti-Ma2-associated encephalitis. Neurology 68: 900-905, 2007
5) Burton GV, Bullard DE, Walther PJ, Burger PC: Paraneoplastic limbic encephalopathy with testicular carcinoma. A reversible neurologic syndrome. Cancer 62: 2248-2251, 1988
6) Ahern GL, O'Connor M, Dalmau J, Coleman A, Posner JB, et al: Paraneoplastic temporal lobe epilepsy with testicular neoplasm and atypical amnesia. Neurology 44: 1270-1274, 1994
7) Dalmau J, Furneaux HM, Rosenblum MK, Graus F, Posner JB: Detection of the anti-Hu antibody in specific regions of the nervous system and tumor from patients with paraneoplastic encephalomyelitis/sensory neuronopathy. Neurology 41: 1757-1764, 1991
8) Gultekin SH, Voltz RD, Gerstner ER, Hoard RV, Posner JB, et al: Characterization of a Novel Antineuronal Antibody (Anti-Ta) in the Serum of 6 Patients with Testicular Cancer and Paraneoplastic Limbic Encephalopathy (PLE). Neurology 50 (Supple4): A383 (abstract), 1998
9) Voltz R, Gultekin SH, Rosenfeld MR, Gerstner E, Eichen J, et al: A serologic marker of paraneoplastic limbic and brain-stem encephalitis in patients with testicular cancer. N Engl J Med 340: 1788-1795, 1999
10) Dalmau J, Gultekin SH, Voltz R, Hoard R, DesChamps T, et al: Ma1, a novel neuron- and testis-specific protein, is recognized by the serum of patients with paraneoplastic neurological disorders. Brain 122 (Pt 1): 27-39, 1999
11) Schuller M, Jenne D, Voltz R: The human PNMA family: novel neuronal proteins implicated in paraneoplastic neurological disease. J Neuroimmunol 169: 172-176, 2005
12) Rosenfeld MR, Eichen JG, Wade DF, Posner JB, Dalmau J: Molecular and clinical diversity in paraneoplastic immunity to Ma proteins. Ann Neurol 50: 339-348, 2001
13) Giometto B, Grisold W, Vitaliani R, Graus F, Honnorat J, et al: Paraneoplastic neurologic syndrome in the PNS Euronetwork database: a European study from 20 centers. Arch Neurol 67: 330-335, 2010
14) Gultekin S, Rosenfeld M, Voltz R, Eichen J, Posner J, et al: Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumour association in 50 patients. Brain 123 (Pt 7): 1481-1494, 2000
15) Lancaster E, Lai M, Peng X, Hughes E, Constantinescu R, et al: Antibodies to the GABA (B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen. Lancet Neurol 9: 67-76, 2010
16) Graus F, Dalmou J, Rene R, Tora M, Malats N, et al: Anti-Hu antibodies in patients with small-cell lung cancer: association with complete response to therapy and improved survival. J Clin Oncol 15: 2866-2872, 1997
17) Monstad SE, Knudsen A, Salvesen HB, Aarseth JH, Vedeler CA: Onconeural antibodies in sera from patients with various types of tumours. Cancer Immunol Immunother 58: 1795-1800, 2009
18) Pittock SJ, Kryzer TJ, Lennon VA: Paraneoplastic antibodies coexist and predict cancer, not neurological syndrome. Ann Neurol 56: 715-719, 2004
19) Hoffmann LA, Jarius S, Pellkofer HL, Schueller M, Krumbholz M, et al: Anti-Ma and anti-Ta associated paraneoplastic neurological syndromes: 22 newly diagnosed patients and review of previous cases. J Neurol Neurosurg Psychiatry 79: 767-773, 2008
20) Mehta P, Fernando MM, Pickering MC, Wilson Y, Molloy S, et al: Lateral medullary syndrome with anti-neuronal antibodies (anti-Ta/Ma2) in primary Sjogren's syndrome. Rheumatology (Oxford) 48: 1174-1176, 2009
21) Desestret V, Didelot A, Meyronet D, Bruyas A, Jouvet A, et al: Neurosarcoidosis with diencephalitis and anti-Ma2 antibodies. Neurology 74: 772-774, 2010
22) Pruss H, Voltz R, Gelderblom H, Bohner G, Munz DL, et al: Spontaneous remission of anti-Ma associated paraneoplastic mesodiencephalic and brainstem encephalitis. J Neurol 255: 292-294, 2008
23) Matsumoto L, Yamamoto T, Higashihara M, Sugimoto I, Kowa H, et al: Severe hypokinesis caused by paraneoplastic anti-Ma2 encephalitis associated with bilateral intratubular germ-cell neoplasm of the testes. Mov Disord 22: 728-731, 2007
24) Psimaras D, Carpentier AF, Rossi C: Cerebrospinal fluid study in paraneoplastic syndromes. J Neurol Neurosurg Psychiatry 81: 42-45, 2010
25) Scheid R, Voltz R, Guthke T, Bauer J, Sammler D, et al: Neuropsychiatric findings in anti-Ma2-positive paraneoplastic limbic encephalitis. Neurology 61: 1159-1161, 2003
26) Landolfi JC, Nadkarni M: Paraneoplastic limbic encephalitis and possible narcolepsy in a patient with testicular cancer: case study. Neuro Oncol 5: 214-216, 2003
27) Kayser MS, Kohler CG, Dalmau J: Psychiatric Manifestations of Paraneoplastic Disorders. Am J Psychiatry, 2010［Epub ahead of print］
28) Kerling F, Blumcke I, Stefan H: Pitfalls in diagnosing limbic encephalitis - a case report. Acta Neurol Scand 118: 339-342, 2008
29) Bennett JL, Galetta SL, Frohman LP, Mourelatos Z, Gultekin SH, et al: Neuro-ophthalmologic manifestations of a paraneoplastic syndrome and testicular carcinoma. Neurology 52: 864-867, 1999
30) Bataller L, Dalmau J: Neuro-ophthalmology and paraneoplastic syndromes. Curr Opin Neurol 17: 3-8, 2004
31) Castle J, Sakonju A, Dalmau J, Newman-Toker DE: Anti-Ma2-associated encephalitis with normal FDG-PET: a case of pseudo-Whipple's disease. Nat Clin Pract Neurol 2: 566-572; quiz 573, 2006
32) Saiz A, Bruna J, Stourac P, Vigliani MC, Giometto B, et al: Anti-Hu-associated brainstem encephalitis. J Neurol Neurosurg Psychiatry 80: 404-407, 2009
33) Pruss H, Voltz R, Flath B, Rudolph B, Klingebiel R, et al: Anti-Ta-associated paraneoplastic encephalitis with occult testicular intratubular germ-cell neoplasia. J Neurol Neurosurg Psychiatry 78: 651-652, 2007
34) Compta Y, Iranzo A, Santamaria J, Casamitjana R, Graus F: REM sleep behavior disorder and narcoleptic features in anti-Ma2-associated encephalitis. Sleep 30: 767-769, 2007
35) Wagner J, Schankin C, Birnbaum T, Popperl G, Straube A: Ocular motor and lid apraxia as initial symptom of anti-Ma1/Ma2-associated encephalitis. Neurology 72: 466-467, 2009
36) Waragai M, Chiba A, Uchibori A, Fukushima T, Anno M, et al: Anti-Ma2 associated paraneoplastic neurological syndrome presenting as encephalitis and progressive muscular atrophy. J Neurol Neurosurg Psychiatry 77: 111-113, 2006
37) Dalmau J: Paraneoplastic disorders of the nervous system. Rinsho Shinkeigaku 48: 799-803, 2008
38) Tampoia M, Zucano A, Antico A, Giometto B, Bonaguri C, et al: Diagnostic accuracy of different immunological methods for the detection of antineuronal antibodies in paraneoplastic neurological syndromes. Immunol Invest 39: 186-195, 2010
39) Voltz R: Can antibodies in serum predict the presence of microscopic tumors? Neurology 68: 887-888, 2007
40) Stich O, Jarius S, Kleer B, Rasiah C, Voltz R, et al: Specific antibody index in cerebrospinal fluid from patients with central and peripheral paraneoplastic neurological syndromes. J Neuroimmunol 183: 220-224, 2007
41) Blumenthal DT, Salzman KL, Digre KB, Jensen RL, Dunson WA, et al: Early pathologic findings and long-term improvement in anti-Ma2-associated encephalitis. Neurology 67: 146-149, 2006
42) Basu S, Alavi A: Role of FDG-PET in the clinical management of paraneoplastic neurological syndrome: detection of the underlying malignancy and the brain PET-MRI correlates. Mol Imaging Biol 10: 131-137, 2008
43) Scheid R, Lincke T, Voltz R, von Cramon DY, Sabri O: Serial 18F-fluoro-2-deoxy-D-glucose positron emission tomography and magnetic resonance imaging of paraneoplastic limbic encephalitis. Arch Neurol 61: 1785-1789, 2004
44) Overeem S, Dalmau J, Bataller L, Nishino S, Mignot E, et al: Hypocretin-1 CSF levels in anti-Ma2 associated encephalitis. Neurology 62: 138-140, 2004
45) Jones TD, Ulbright TM, Eble JN, Cheng L: OCT4: A sensitive and specific biomarker for intratubular germ cell neoplasia of the testis. Clin Cancer Res 10: 8544-8547, 2004
46) van Casteren NJ, de Jong J, Stoop H, Steyerberg EW, de Bekker-Grob EW, et al: Evaluation of testicular biopsies for carcinoma in situ: immunohistochemistry is mandatory. Int J Androl 32: 666-674, 2008
47) Linke R, Schroeder M, Helmberger T, Voltz R: Antibody-positive paraneoplastic neurologic syndromes: value of CT and PET for tumor diagnosis. Neurology 63: 282-286, 2004
48) Younes-Mhenni S, Janier MF, Cinotti L, Antoine JC, Tronc F, et al: FDG-PET improves tumour detection in patients with paraneoplastic neurological syndromes. Brain 127: 2331-2338, 2004
49) Leyhe T, Schule R, Schwarzler F, Gasser T, Haarmeier T: Second primary tumor in anti-Ma1/2-positive paraneoplastic limbic encephalitis. J Neurooncol 78: 49-51, 2006
50) McKeon A, Apiwattanakul M, Lachance DH, Lennon VA, Mandrekar JN, et al: Positron emission tomography-computed tomography in paraneoplastic neurologic disorders: systematic analysis and review. Arch Neurol 67: 322-329, 2010
51) Vedeler CA, Antoine JC, Giometto B, Graus F, Grisold W, et al: Management of paraneoplastic neurological syndromes: report of an EFNS Task Force. Eur J Neurol 13: 682-690, 2006
52) Sahashi K, Sakai K, Mano K, Hirose G: Anti-Ma2 antibody related paraneoplastic limbic/brain stem encephalitis associated with breast cancer expressing Ma1, Ma2, and Ma3 mRNAs. J Neurol Neurosurg Psychiatry 74: 1332-1335, 2003
53) Takaji M, Komatsu Y, Watakabe A, Hashikawa T, Yamamori T: Paraneoplastic antigen-like 5 gene (PNMA5) is preferentially expressed in the association areas in a primate specific manner. Cereb Cortex 19: 2865-2879, 2009
54) Wen PY: Cerebral spinal fluid abnormalities in patients with paraneoplastic syndromes of the nervous system. J Neurol Neurosurg Psychiatry 81: 3, 2010
55) Hill KE, Clawson SA, Rose JW, Carlson NG, Greenlee J E: Cerebellar Purkinje cells incorporate immunoglobulins and immunotoxins in vitro: implications for human neurological disease and immunotherapeutics. J Neuroinflammation 6: 31, 2009
56) Pellkofer H, Schubart AS, Hoftberger R, Schutze N, Pagany M, et al: Modelling paraneoplastic CNS disease: T-cells specific for the onconeuronal antigen PNMA1 mediate autoimmune encephalomyelitis in the rat. Brain 127: 1822-1830, 2004
57) Dalmau J, Rosenfeld MR: Paraneoplastic syndromes of the CNS. Lancet Neurol 7: 327-340, 2008
58) Kimura M, Onozawa M, Fujisaki A, Arakawa T, Takeda K, et al: Anti-Ma2 paraneoplastic encephalitis associated with testicular germ cell tumor treated by carboplatin, etoposide and bleomycin. Int J Urol 15: 942-943, 2008
掲載誌情報
