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Original Investigation |

Determination of Neuronal Antibodies in Suspected and Definite Creutzfeldt-Jakob Disease

Oriol Grau-Rivera, MD1; Raquel Sánchez-Valle, MD, PhD1,2; Albert Saiz, MD, PhD1,2; José Luis Molinuevo, MD, PhD1,2; Reyes Bernabé, MD3; Elvira Munteis, MD4; Francesc Pujadas, MD5; Antoni Salvador, MD6; Júlia Saura, MD7; Antonio Ugarte, MD7; Maarten Titulaer, MD, PhD2,8; Josep Dalmau, MD, PhD2,9,10; Francesc Graus, MD, PhD1,2
[+] Author Affiliations
1Service of Neurology, Hospital Clínic, Barcelona, Spain
2Neuroimmunology Program, Institut d’Investigació Biomèdica August Pi i Sunyer, Barcelona, Spain
3Oncology Department, Hospital de Valme, Sevilla, Spain
4Neurology Department, Hospital del Mar Parc de Salut Mar, Barcelona, Spain
5Neurology Department, Hospital Universitari Vall d’Hebrón, Barcelona, Spain
6Neurology Department, Hospital Clínico Universitario de Valencia, Valencia, Spain
7Neurology Department, Hospital Sant Joan de Déu de Manresa, Manresa, Spain
8Neurology Department, Erasmus Medical Center, Rotterdam, the Netherlands
9Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain
10Department of Neurology, University of Pennsylvania, Philadelphia
JAMA Neurol. 2014;71(1):74-78. doi:10.1001/jamaneurol.2013.4857.
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Importance  Creutzfeldt-Jakob disease (CJD) and autoimmune encephalitis with antibodies against neuronal surface antigens (NSA-abs) may present with similar clinical features. Establishing the correct diagnosis has practical implications in the management of care for these patients.

Objective  To determine the frequency of NSA-abs in the cerebrospinal fluid of patients with suspected CJD and in patients with pathologically confirmed (ie, definite) CJD.

Design, Setting, and Participants  A mixed prospective (suspected) and retrospective (definite) CJD cohort study was conducted in a reference center for detection of NSA-abs. The population included 346 patients with suspected CJD and 49 patients with definite CJD.

Main Outcomes and Measures  Analysis of NSA-abs in cerebrospinal fluid with brain immunohistochemistry optimized for cell-surface antigens was performed. Positive cases in the suspected CJD group were further studied for antigen specificity using cell-based assays. All definite CJD cases were comprehensively tested for NSA-abs, with cell-based assays used for leucine-rich glioma-inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2), N-methyl-d-aspartate (NMDA), and glycine (GlY) receptors.

Results  Neuronal surface antigens were detected in 6 of 346 patients (1.7%) with rapid neurologic deterioration suggestive of CJD. None of these 6 patients fulfilled the diagnostic criteria for probable or possible CJD. The target antigens included CASPR2, LGI1, NMDAR, aquaporin 4, Tr (DNER [δ/notch-like epidermal growth factor–related receptor]), and an unknown protein. Four of the patients developed rapidly progressive dementia, and the other 2 patients had cerebellar ataxia or seizures that were initially considered to be myoclonus without cognitive decline. The patient with Tr-abs had a positive 14-3-3 test result. Small cell lung carcinoma was diagnosed in the patient with antibodies against an unknown antigen. All patients improved or stabilized after appropriate treatment. None of the 49 patients with definite CJD had NSA-abs.

Conclusions and Relevance  A low, but clinically relevant, number of patients with suspected CJD had potentially treatable disorders associated with NSA-abs. In contrast, none of 49 patients with definite CJD had NSA-abs, including NMDAR-abs, GlyR-abs, LGI1-abs, or CASPR2-abs. These findings suggest that cerebrospinal fluid NSA-abs analysis should be included in the diagnostic workup of patients with rapidly progressive central nervous system syndromes, particularly when they do not fulfill the diagnostic criteria of probable or possible CJD.

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