Familial autoimmunity in neurological patients with GAD65 antibodies: an interview-based study

Paraneoplastic Neurologic Syndromes

“…9,10 A family history of autoimmune disease is more common in patients with paraneoplastic syndromes. 11 An underlying immunogenetic predisposition to paraneoplastic neurologic disorders may be present, as seen with human leukocyte antigen-type and immune gene associations for NMDA-receptor encephalitis. 12 This is most suggestive in syndromes with a low incidence of associated tumors: 90% of patients with IgLON family member 5 (IgLON5)-related syndromes have the DQB1*05 allele and 60% also have the DRB1*10:01 allele; 90% of patients with contactin-associated proteinlike 2 (CASPR2)-related syndromes have the DRB1*11:01 allele; and 40% of patients with glutamic acid decarboxylase 65 (GAD65)-related syndromes have the DQB*02:01 allele.…”

“…incidence of tumors. 11 CSF markers of inflammation (eg, elevated white blood cell concentration, elevated IgG index versus serum, oligoclonal bands, 14-3-3 protein, elevated neurofilament light chains) are common but nonspecific, and they are absent in more than 20% of patients over 65 years old with paraneoplastic neurologic disorders and vary in different antibody disorders (abnormal in 90% of patients with NMDA, γ-aminobutyric acid B [GABA B ], and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid [AMPA] disorders, 40% of those with LGI1 disorders, and 20% of those with CASPR2 disorders). 13 In addition, CSF 14-3-3 protein is found in 12.5% of patients with paraneoplastic syndromes and some syndromes can overlap with Creutzfeldt-Jakob disease presentations, but patients with paraneoplastic syndromes show a double-banding pattern while patients with Creutzfeldt-Jakob disease have a single band.…”

“…36 It is estimated that up to 20% of patients with cerebellar ataxia who have an otherwise negative workup may have an autoimmune syndrome and lack a confirmatory diagnostic test, but the characteristic development of subacutely progressive gait ataxia (ie, developing over weeks, reaching a nadir at 6 months, with initially normal MRI but developing midline vermian atrophy) is very typical of all of these syndromes, and initial cerebellar hypermetabolism on PET followed by later hypometabolism has been reported. 11,54 Downbeat nystagmus (especially vibration-induced nystagmus) is a recently described manifestation that appears more often in paraneoplastic cerebellar syndromes compared with nonparaneoplastic syndromes. 11,55 When atrophy is already present on initial imaging, a nonimmune cause is much more likely (eg, toxic, genetic, metabolic) (TABLE 7-6) (CASE 7-3).…”

“…Polysomnography can also detect occult seizures including faciobrachial dystonic seizures and central sleep apnea 9,10 . A family history of autoimmune disease is more common in patients with paraneoplastic syndromes 11 . An underlying immunogenetic predisposition to paraneoplastic neurologic disorders may be present, as seen with human leukocyte antigen–type and immune gene associations for NMDA-receptor encephalitis 12 .…”

“…This is most suggestive in syndromes with a low incidence of associated tumors: 90% of patients with IgLON family member 5 (IgLON5)-related syndromes have the DQB1*05 allele and 60% also have the DRB1*10:01 allele; 90% of patients with contactin-associated proteinlike 2 (CASPR2)-related syndromes have the DRB1*11:01 allele; and 40% of patients with glutamic acid decarboxylase 65 (GAD65)-related syndromes have the DQB*02:01 allele. However, no genetic human leukocyte antigen–type associations were found for anti–Purkinje cell cytoplasmic antibody type 1 (PCA-1) (Yo) antibodies and other paraneoplastic syndromes with a high incidence of tumors 11 . CSF markers of inflammation (eg, elevated white blood cell concentration, elevated IgG index versus serum, oligoclonal bands, 14-3-3 protein, elevated neurofilament light chains) are common but nonspecific, and they are absent in more than 20% of patients over 65 years old with paraneoplastic neurologic disorders and vary in different antibody disorders (abnormal in 90% of patients with NMDA, γ-aminobutyric acid B [GABA B ], and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid [AMPA] disorders, 40% of those with LGI1 disorders, and 20% of those with CASPR2 disorders) 13 .…”