Expanded phenotypes and outcomes among 256 LGI1/CASPR2-IgG–positive patients

Avi Gadoth, Sean J Pittock, Divyanshu Dubey, Andrew McKeon, Jeff W. Britton, John E. Schmeling, Aurelia Smith, Amy L. Kotsenas, Robert E. Watson, Daniel H Lachance, Eoin Flanagan, Vanda A Lennon, Christopher Jon Klein

Research output: Contribution to journalArticle

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Abstract

Objective: To describe an expanded phenotypic spectrum and longitudinal outcome in 256 LGI1-IgG–seropositive and/or CASPR2-IgG–seropositive patients. Methods: Patients were identified through service neural autoantibody evaluation. Ninety-five had longitudinal follow-up (7–456 months; median = 35). Results: Among 3,910 patients tested, 196 were LGI1-IgG positive, 51 were CASPR2-IgG positive, and 9 were dual positive. Cerebrospinal fluid testing was less sensitive than serum testing, detecting only 24 of 38 (63%) LGI1-IgG–positive and 5 of 6 (83%) CASPR2-IgG–positive patients. LGI1-IgG–positive specimens had higher voltage-gated potassium channel–IgG immunoprecipitation values (0.33nmol/l, range = 0.02–5.14) than CASPR2-IgG–positive specimens (0.10nmol/l, range = 0.00–0.45, p < 0.001). Of patients presenting with pain or peripheral nervous system (PNS) manifestations, 39% were LGI1-IgG seropositive (7% had solely neuropathy or pain). Multivariate analysis identified age as the only significant predictor of central nervous system (CNS) versus PNS involvement (>50 years; odds ratio = 15, p < 0.001). Paroxysmal dizziness spells (PDS), a unique LGI1-IgG accompaniment (14% of patients), frequently delayed the diagnosis. T2-mesiotemporal hyperintensity was more common in LGI1-IgG–positive (41%) than in CASPR2-IgG–positive patients (p = 0.033). T1-bright basal ganglia were confined to LGI1-IgG–positive patients with faciobrachial–dystonic seizures (9 of 39, 31%). Cancer was found in 44% of LGI1-IgG/CASPR2-IgG dual seropositive patients (one-third thymoma). Response to initial immunotherapy was favorable in 97%; mean modified Rankin score was 3 (range = 1–5) at onset and 1.74 (range = 0–6) at last follow-up, with 9% having severe refractory disability, 20% being asymptomatic, 28% receiving immunotherapy, and 58% receiving antiepileptic medication. Interpretation: Older age is a strong predictor of CNS involvement in patients seropositive for CASPR2-IgG or LGI1-IgG. Pain, peripheral manifestations, and stereotypic paroxysmal dizziness spells are common with LGI1-IgG. Response to initial immunotherapy is often favorable, but some patients remain severely disabled, requiring long-term immunotherapy and/or antiepileptic medications. Ann Neurol 2017;82:79–92.

Original languageEnglish (US)
Pages (from-to)79-92
Number of pages14
JournalAnnals of Neurology
Volume82
Issue number1
DOIs
StatePublished - Jul 1 2017

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Phenotype
Immunoglobulin G
Immunotherapy
Dizziness
Anticonvulsants
Thymoma
Delayed Diagnosis
Basal Ganglia
Immunoprecipitation
Autoantibodies
Cerebrospinal Fluid
Potassium
Seizures
Odds Ratio
Pain
Serum
Neoplasms

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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Expanded phenotypes and outcomes among 256 LGI1/CASPR2-IgG–positive patients. / Gadoth, Avi; Pittock, Sean J; Dubey, Divyanshu; McKeon, Andrew; Britton, Jeff W.; Schmeling, John E.; Smith, Aurelia; Kotsenas, Amy L.; Watson, Robert E.; Lachance, Daniel H; Flanagan, Eoin; Lennon, Vanda A; Klein, Christopher Jon.

In: Annals of Neurology, Vol. 82, No. 1, 01.07.2017, p. 79-92.

Research output: Contribution to journalArticle

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title = "Expanded phenotypes and outcomes among 256 LGI1/CASPR2-IgG–positive patients",
abstract = "Objective: To describe an expanded phenotypic spectrum and longitudinal outcome in 256 LGI1-IgG–seropositive and/or CASPR2-IgG–seropositive patients. Methods: Patients were identified through service neural autoantibody evaluation. Ninety-five had longitudinal follow-up (7–456 months; median = 35). Results: Among 3,910 patients tested, 196 were LGI1-IgG positive, 51 were CASPR2-IgG positive, and 9 were dual positive. Cerebrospinal fluid testing was less sensitive than serum testing, detecting only 24 of 38 (63{\%}) LGI1-IgG–positive and 5 of 6 (83{\%}) CASPR2-IgG–positive patients. LGI1-IgG–positive specimens had higher voltage-gated potassium channel–IgG immunoprecipitation values (0.33nmol/l, range = 0.02–5.14) than CASPR2-IgG–positive specimens (0.10nmol/l, range = 0.00–0.45, p < 0.001). Of patients presenting with pain or peripheral nervous system (PNS) manifestations, 39{\%} were LGI1-IgG seropositive (7{\%} had solely neuropathy or pain). Multivariate analysis identified age as the only significant predictor of central nervous system (CNS) versus PNS involvement (>50 years; odds ratio = 15, p < 0.001). Paroxysmal dizziness spells (PDS), a unique LGI1-IgG accompaniment (14{\%} of patients), frequently delayed the diagnosis. T2-mesiotemporal hyperintensity was more common in LGI1-IgG–positive (41{\%}) than in CASPR2-IgG–positive patients (p = 0.033). T1-bright basal ganglia were confined to LGI1-IgG–positive patients with faciobrachial–dystonic seizures (9 of 39, 31{\%}). Cancer was found in 44{\%} of LGI1-IgG/CASPR2-IgG dual seropositive patients (one-third thymoma). Response to initial immunotherapy was favorable in 97{\%}; mean modified Rankin score was 3 (range = 1–5) at onset and 1.74 (range = 0–6) at last follow-up, with 9{\%} having severe refractory disability, 20{\%} being asymptomatic, 28{\%} receiving immunotherapy, and 58{\%} receiving antiepileptic medication. Interpretation: Older age is a strong predictor of CNS involvement in patients seropositive for CASPR2-IgG or LGI1-IgG. Pain, peripheral manifestations, and stereotypic paroxysmal dizziness spells are common with LGI1-IgG. Response to initial immunotherapy is often favorable, but some patients remain severely disabled, requiring long-term immunotherapy and/or antiepileptic medications. Ann Neurol 2017;82:79–92.",
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T1 - Expanded phenotypes and outcomes among 256 LGI1/CASPR2-IgG–positive patients

AU - Gadoth, Avi

AU - Pittock, Sean J

AU - Dubey, Divyanshu

AU - McKeon, Andrew

AU - Britton, Jeff W.

AU - Schmeling, John E.

AU - Smith, Aurelia

AU - Kotsenas, Amy L.

AU - Watson, Robert E.

AU - Lachance, Daniel H

AU - Flanagan, Eoin

AU - Lennon, Vanda A

AU - Klein, Christopher Jon

PY - 2017/7/1

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N2 - Objective: To describe an expanded phenotypic spectrum and longitudinal outcome in 256 LGI1-IgG–seropositive and/or CASPR2-IgG–seropositive patients. Methods: Patients were identified through service neural autoantibody evaluation. Ninety-five had longitudinal follow-up (7–456 months; median = 35). Results: Among 3,910 patients tested, 196 were LGI1-IgG positive, 51 were CASPR2-IgG positive, and 9 were dual positive. Cerebrospinal fluid testing was less sensitive than serum testing, detecting only 24 of 38 (63%) LGI1-IgG–positive and 5 of 6 (83%) CASPR2-IgG–positive patients. LGI1-IgG–positive specimens had higher voltage-gated potassium channel–IgG immunoprecipitation values (0.33nmol/l, range = 0.02–5.14) than CASPR2-IgG–positive specimens (0.10nmol/l, range = 0.00–0.45, p < 0.001). Of patients presenting with pain or peripheral nervous system (PNS) manifestations, 39% were LGI1-IgG seropositive (7% had solely neuropathy or pain). Multivariate analysis identified age as the only significant predictor of central nervous system (CNS) versus PNS involvement (>50 years; odds ratio = 15, p < 0.001). Paroxysmal dizziness spells (PDS), a unique LGI1-IgG accompaniment (14% of patients), frequently delayed the diagnosis. T2-mesiotemporal hyperintensity was more common in LGI1-IgG–positive (41%) than in CASPR2-IgG–positive patients (p = 0.033). T1-bright basal ganglia were confined to LGI1-IgG–positive patients with faciobrachial–dystonic seizures (9 of 39, 31%). Cancer was found in 44% of LGI1-IgG/CASPR2-IgG dual seropositive patients (one-third thymoma). Response to initial immunotherapy was favorable in 97%; mean modified Rankin score was 3 (range = 1–5) at onset and 1.74 (range = 0–6) at last follow-up, with 9% having severe refractory disability, 20% being asymptomatic, 28% receiving immunotherapy, and 58% receiving antiepileptic medication. Interpretation: Older age is a strong predictor of CNS involvement in patients seropositive for CASPR2-IgG or LGI1-IgG. Pain, peripheral manifestations, and stereotypic paroxysmal dizziness spells are common with LGI1-IgG. Response to initial immunotherapy is often favorable, but some patients remain severely disabled, requiring long-term immunotherapy and/or antiepileptic medications. Ann Neurol 2017;82:79–92.

AB - Objective: To describe an expanded phenotypic spectrum and longitudinal outcome in 256 LGI1-IgG–seropositive and/or CASPR2-IgG–seropositive patients. Methods: Patients were identified through service neural autoantibody evaluation. Ninety-five had longitudinal follow-up (7–456 months; median = 35). Results: Among 3,910 patients tested, 196 were LGI1-IgG positive, 51 were CASPR2-IgG positive, and 9 were dual positive. Cerebrospinal fluid testing was less sensitive than serum testing, detecting only 24 of 38 (63%) LGI1-IgG–positive and 5 of 6 (83%) CASPR2-IgG–positive patients. LGI1-IgG–positive specimens had higher voltage-gated potassium channel–IgG immunoprecipitation values (0.33nmol/l, range = 0.02–5.14) than CASPR2-IgG–positive specimens (0.10nmol/l, range = 0.00–0.45, p < 0.001). Of patients presenting with pain or peripheral nervous system (PNS) manifestations, 39% were LGI1-IgG seropositive (7% had solely neuropathy or pain). Multivariate analysis identified age as the only significant predictor of central nervous system (CNS) versus PNS involvement (>50 years; odds ratio = 15, p < 0.001). Paroxysmal dizziness spells (PDS), a unique LGI1-IgG accompaniment (14% of patients), frequently delayed the diagnosis. T2-mesiotemporal hyperintensity was more common in LGI1-IgG–positive (41%) than in CASPR2-IgG–positive patients (p = 0.033). T1-bright basal ganglia were confined to LGI1-IgG–positive patients with faciobrachial–dystonic seizures (9 of 39, 31%). Cancer was found in 44% of LGI1-IgG/CASPR2-IgG dual seropositive patients (one-third thymoma). Response to initial immunotherapy was favorable in 97%; mean modified Rankin score was 3 (range = 1–5) at onset and 1.74 (range = 0–6) at last follow-up, with 9% having severe refractory disability, 20% being asymptomatic, 28% receiving immunotherapy, and 58% receiving antiepileptic medication. Interpretation: Older age is a strong predictor of CNS involvement in patients seropositive for CASPR2-IgG or LGI1-IgG. Pain, peripheral manifestations, and stereotypic paroxysmal dizziness spells are common with LGI1-IgG. Response to initial immunotherapy is often favorable, but some patients remain severely disabled, requiring long-term immunotherapy and/or antiepileptic medications. Ann Neurol 2017;82:79–92.

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