Observational Study

. 2023 Oct 10;101(15):e1560-e1566.

doi: 10.1212/WNL.0000000000207609. Epub 2023 Jul 24.

Clinical, Radiologic, and Immunologic Features of Patients With CTLA4 Deficiency With Neurologic Involvement

Cyrille Coustal¹, Radjiv Goulabchand¹, Pierre Labauge¹, Philippe Guilpain¹, Clarisse Carra-Dallière¹, Edouard Januel¹, Eric Jeziorski¹, Valery Salle¹, Jean-François Viallard¹, David Boutboul¹, Claire Fieschi¹, Delphine Gobert¹, Nathalie Aladjidi¹, Patricia Rullier¹, Julie Graveleau¹, Marie Piel-Julian¹, Felipe Suarez¹, Benedicte Neven¹, Nizar Mahlaoui¹, Xavier Ayrignac²

Affiliations

¹ From the Department of Internal Medicine and Multi-Organic Diseases (C.C., P.G., P.R.), Local Referral Center for Rare Autoimmune Diseases, Montpellier University Hospital; University of Montpellier (C.C., R.G., P.L., P.G., E. Jeziorski, X.A.); Internal Medicine Department (R.G.), CHU Nîmes; Department of Neurology (P.L., C.C.-D., X.A.), Montpellier University Hospital; INM (P.L., X.A.), INSERM; Institute of Regenerative Medicine and Biotherapy (P.G.), INSERM U1183, Montpellier; Sorbonne Université (E. Januel); Institut Pierre Louis d'Epidémiologie et de Santé Publique (E. Januel), Département de Santé Publique; Département de Neurologie (E. Januel), Hôpital Pitié Salpêtrière, AP-HP, Paris; Pediatrics Department (E. Jeziorski), Montpellier University Hospital; Department of Internal Medicine (V.S.), Amiens University Medical Center; Internal Medicine Department (J.-F.V.), Bordeaux University Hospital Centre, Hôpital Haut-Lévêque, Pessac; Clinical Immunology Department (D.B., C.F.), National Reference Center for Castleman Disease; UMR 1149 CRI INSERM (D.B.), Hôpital Saint Louis, Assistance Publique Hôpitaux de Paris (APHP); Université Paris Diderot (D.B., C.F.); Inserm U1126 (C.F.), Centre Hayem, Hôpital Saint-Louis; Internal Medicine Department (D.G.), Hôpital Saint Antoine, APHP, Paris; Pediatric Oncology Hematology Unit (N.A.), Bordeaux University Hospital; Plurithématique CIC (CICP) (N.A.), Centre d'Investigation Clinique (CIC) 1401, INSERM; Centre de Référence National des Cytopénies Autoimmunes de l'Enfant (CEREVANCE) (N.A.), Bordeaux; Department of Internal Medicine (J.G.), Saint-Nazaire Hospital; Department of Internal Medicine (M.P.-J.), Purpan University Hospital, Toulouse; Department of Hematology (F.S.), Necker-Enfants Malades University Hospital, AP-HP; INSERM UMR 1163 and CNRS ERL 8254 (F.S.), Imagine Institut; Descartes University (F.S., B.N.); Pediatric Hematology-Immunology and Rheumatology Department (B.N., N.M.), Hôpital Necker-Enfants Malades, AP-HP; Laboratory of Immunogenetics of Pediatric Autoimmunity (B.N.), INSERM UMR 1163, Imagine Institute; and French National Reference Center for Primary Immune Deficiencies (CEREDIH) (N.M.), Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
² From the Department of Internal Medicine and Multi-Organic Diseases (C.C., P.G., P.R.), Local Referral Center for Rare Autoimmune Diseases, Montpellier University Hospital; University of Montpellier (C.C., R.G., P.L., P.G., E. Jeziorski, X.A.); Internal Medicine Department (R.G.), CHU Nîmes; Department of Neurology (P.L., C.C.-D., X.A.), Montpellier University Hospital; INM (P.L., X.A.), INSERM; Institute of Regenerative Medicine and Biotherapy (P.G.), INSERM U1183, Montpellier; Sorbonne Université (E. Januel); Institut Pierre Louis d'Epidémiologie et de Santé Publique (E. Januel), Département de Santé Publique; Département de Neurologie (E. Januel), Hôpital Pitié Salpêtrière, AP-HP, Paris; Pediatrics Department (E. Jeziorski), Montpellier University Hospital; Department of Internal Medicine (V.S.), Amiens University Medical Center; Internal Medicine Department (J.-F.V.), Bordeaux University Hospital Centre, Hôpital Haut-Lévêque, Pessac; Clinical Immunology Department (D.B., C.F.), National Reference Center for Castleman Disease; UMR 1149 CRI INSERM (D.B.), Hôpital Saint Louis, Assistance Publique Hôpitaux de Paris (APHP); Université Paris Diderot (D.B., C.F.); Inserm U1126 (C.F.), Centre Hayem, Hôpital Saint-Louis; Internal Medicine Department (D.G.), Hôpital Saint Antoine, APHP, Paris; Pediatric Oncology Hematology Unit (N.A.), Bordeaux University Hospital; Plurithématique CIC (CICP) (N.A.), Centre d'Investigation Clinique (CIC) 1401, INSERM; Centre de Référence National des Cytopénies Autoimmunes de l'Enfant (CEREVANCE) (N.A.), Bordeaux; Department of Internal Medicine (J.G.), Saint-Nazaire Hospital; Department of Internal Medicine (M.P.-J.), Purpan University Hospital, Toulouse; Department of Hematology (F.S.), Necker-Enfants Malades University Hospital, AP-HP; INSERM UMR 1163 and CNRS ERL 8254 (F.S.), Imagine Institut; Descartes University (F.S., B.N.); Pediatric Hematology-Immunology and Rheumatology Department (B.N., N.M.), Hôpital Necker-Enfants Malades, AP-HP; Laboratory of Immunogenetics of Pediatric Autoimmunity (B.N.), INSERM UMR 1163, Imagine Institute; and French National Reference Center for Primary Immune Deficiencies (CEREDIH) (N.M.), Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France. x-ayrignac@chu-montpellier.fr.

PMID: 37487754
PMCID: PMC10585684
DOI: 10.1212/WNL.0000000000207609

Observational Study

Clinical, Radiologic, and Immunologic Features of Patients With CTLA4 Deficiency With Neurologic Involvement

Cyrille Coustal et al. Neurology. 2023.

. 2023 Oct 10;101(15):e1560-e1566.

doi: 10.1212/WNL.0000000000207609. Epub 2023 Jul 24.

Authors

Affiliations

¹ From the Department of Internal Medicine and Multi-Organic Diseases (C.C., P.G., P.R.), Local Referral Center for Rare Autoimmune Diseases, Montpellier University Hospital; University of Montpellier (C.C., R.G., P.L., P.G., E. Jeziorski, X.A.); Internal Medicine Department (R.G.), CHU Nîmes; Department of Neurology (P.L., C.C.-D., X.A.), Montpellier University Hospital; INM (P.L., X.A.), INSERM; Institute of Regenerative Medicine and Biotherapy (P.G.), INSERM U1183, Montpellier; Sorbonne Université (E. Januel); Institut Pierre Louis d'Epidémiologie et de Santé Publique (E. Januel), Département de Santé Publique; Département de Neurologie (E. Januel), Hôpital Pitié Salpêtrière, AP-HP, Paris; Pediatrics Department (E. Jeziorski), Montpellier University Hospital; Department of Internal Medicine (V.S.), Amiens University Medical Center; Internal Medicine Department (J.-F.V.), Bordeaux University Hospital Centre, Hôpital Haut-Lévêque, Pessac; Clinical Immunology Department (D.B., C.F.), National Reference Center for Castleman Disease; UMR 1149 CRI INSERM (D.B.), Hôpital Saint Louis, Assistance Publique Hôpitaux de Paris (APHP); Université Paris Diderot (D.B., C.F.); Inserm U1126 (C.F.), Centre Hayem, Hôpital Saint-Louis; Internal Medicine Department (D.G.), Hôpital Saint Antoine, APHP, Paris; Pediatric Oncology Hematology Unit (N.A.), Bordeaux University Hospital; Plurithématique CIC (CICP) (N.A.), Centre d'Investigation Clinique (CIC) 1401, INSERM; Centre de Référence National des Cytopénies Autoimmunes de l'Enfant (CEREVANCE) (N.A.), Bordeaux; Department of Internal Medicine (J.G.), Saint-Nazaire Hospital; Department of Internal Medicine (M.P.-J.), Purpan University Hospital, Toulouse; Department of Hematology (F.S.), Necker-Enfants Malades University Hospital, AP-HP; INSERM UMR 1163 and CNRS ERL 8254 (F.S.), Imagine Institut; Descartes University (F.S., B.N.); Pediatric Hematology-Immunology and Rheumatology Department (B.N., N.M.), Hôpital Necker-Enfants Malades, AP-HP; Laboratory of Immunogenetics of Pediatric Autoimmunity (B.N.), INSERM UMR 1163, Imagine Institute; and French National Reference Center for Primary Immune Deficiencies (CEREDIH) (N.M.), Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
² From the Department of Internal Medicine and Multi-Organic Diseases (C.C., P.G., P.R.), Local Referral Center for Rare Autoimmune Diseases, Montpellier University Hospital; University of Montpellier (C.C., R.G., P.L., P.G., E. Jeziorski, X.A.); Internal Medicine Department (R.G.), CHU Nîmes; Department of Neurology (P.L., C.C.-D., X.A.), Montpellier University Hospital; INM (P.L., X.A.), INSERM; Institute of Regenerative Medicine and Biotherapy (P.G.), INSERM U1183, Montpellier; Sorbonne Université (E. Januel); Institut Pierre Louis d'Epidémiologie et de Santé Publique (E. Januel), Département de Santé Publique; Département de Neurologie (E. Januel), Hôpital Pitié Salpêtrière, AP-HP, Paris; Pediatrics Department (E. Jeziorski), Montpellier University Hospital; Department of Internal Medicine (V.S.), Amiens University Medical Center; Internal Medicine Department (J.-F.V.), Bordeaux University Hospital Centre, Hôpital Haut-Lévêque, Pessac; Clinical Immunology Department (D.B., C.F.), National Reference Center for Castleman Disease; UMR 1149 CRI INSERM (D.B.), Hôpital Saint Louis, Assistance Publique Hôpitaux de Paris (APHP); Université Paris Diderot (D.B., C.F.); Inserm U1126 (C.F.), Centre Hayem, Hôpital Saint-Louis; Internal Medicine Department (D.G.), Hôpital Saint Antoine, APHP, Paris; Pediatric Oncology Hematology Unit (N.A.), Bordeaux University Hospital; Plurithématique CIC (CICP) (N.A.), Centre d'Investigation Clinique (CIC) 1401, INSERM; Centre de Référence National des Cytopénies Autoimmunes de l'Enfant (CEREVANCE) (N.A.), Bordeaux; Department of Internal Medicine (J.G.), Saint-Nazaire Hospital; Department of Internal Medicine (M.P.-J.), Purpan University Hospital, Toulouse; Department of Hematology (F.S.), Necker-Enfants Malades University Hospital, AP-HP; INSERM UMR 1163 and CNRS ERL 8254 (F.S.), Imagine Institut; Descartes University (F.S., B.N.); Pediatric Hematology-Immunology and Rheumatology Department (B.N., N.M.), Hôpital Necker-Enfants Malades, AP-HP; Laboratory of Immunogenetics of Pediatric Autoimmunity (B.N.), INSERM UMR 1163, Imagine Institute; and French National Reference Center for Primary Immune Deficiencies (CEREDIH) (N.M.), Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France. x-ayrignac@chu-montpellier.fr.

PMID: 37487754
PMCID: PMC10585684
DOI: 10.1212/WNL.0000000000207609

Abstract

Objectives: CTLA4 deficiency (CTLA4d) is a disease with multisystem autoimmune features, including neurologic manifestations. We aimed to describe neurologic involvement in these patients.

Methods: We performed a cross-sectional observational study using the French Reference Centre for Primary Immunodeficiencies (CEREDIH) registry plus a surveillance in national society networks. Participants with confirmed CTLA4d and neurologic involvement were included. Clinical, laboratory, and radiologic features were collected, as well as treatments. Available MRI was double-reviewed.

Results: Among 70 patients with CTLA4d, 13 patients (21%) had neurologic involvement. Neurologic symptoms began at a median age of 18 [15-45] years, mostly occurring after systemic manifestations (median delay: 8.5 [4.5-10.5] years). Main symptoms included headaches, focal deficit (54% each), and seizures (38%). MRI detected at least 1 large contrast-enhancing lesion in 8 patients. Lesions reminiscent of multiple sclerosis lesions were found in 6 patients. Cerebellar (6 patients) and large spinal cord lesions (3 patients) were common. Ten patients were treated with abatacept, of whom 9 (90%) showed good clinical and radiologic response.

Discussion: Neurologic involvement is common among patients with CTLA4d. Despite its rarity, and considering the suspected efficacy of abatacept, neurologists should be aware of the characteristics of CTLA4d neurologic involvement.

PubMed Disclaimer

Conflict of interest statement

E. Jeziorski reports reimbursement for conference registration fees, travel expenses, and accommodation from Sanofi Genzyme, outside the submitted work. Go to Neurology.org/N for full disclosures.

Figures

**Figure 1. Clinical Course of All Patients**

**Figure 2. MRI Characteristics of CTLA4d Patients**
(A) Large supratentorial lesions (A.a: axial FLAIR; A.b: axial T1 with gadolinium; A.c: axial T2; A.d: axial T1 with gadolinium); (B) large infratentorial lesions (B.a: axial FLAIR; B.b: axial T1; with gadolinium; B.c: axial FLAIR; B.d: axial T1 with gadolinium); (C) small lesions (C.a: small leptomeningeal lesions; C.b: small nonspecific lesion; C.c-C.d: small MS-like lesions); (D) gadolinium enhancement (D.a-D.b: in supratentorial lesions; D.c-D.d: in infratentorial lesions); (E, F) large spinal cord lesions (gadolinium enhancement not shown); (G) diffuse leukoencephalopathy.

See this image and copyright information in PMC

References

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Clinical, Radiologic, and Immunologic Features of Patients With CTLA4 Deficiency With Neurologic Involvement

Affiliations

Clinical, Radiologic, and Immunologic Features of Patients With CTLA4 Deficiency With Neurologic Involvement

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical