Clinical utility of AQP4-IgG titers and measures of complement-mediated cell killing in NMOSD.

OBJECTIVE: To investigate whether aquaporin-4-immunoglobulin G (AQP4-IgG) titers and measures of complement-mediated cell killing are clinically useful to predict the occurrence of relapse, relapse severity, and/or disability in neuromyelitis optica spectrum disorder (NMOSD). METHODS: We studied 336 serial serum specimens from 82 AQP4-lgG-seropositive patients. NMOSD activity at blood draw was defined as preattack (24 [7.1%], drawn within 30 days preceding an attack), attack (108 [32.1%], drawn on attack onset or within 30 days after), or remission (199 [59.2%], drawn >90 days after attack onset and >30 days preceding a relapse). For each specimen, we documented the attack type and severity and immunotherapy status. Complement-mediated cell killing was quantitated by flow cytometry using an M23-AQP4 cell-based assay. RESULTS: The estimated logarithmic means of AQP4-IgG titers in preattack, attack, and remission samples were 3.302, 3.657, and 3.458, respectively, p = 0.21. Analyses of 81 attack/remission pairs in 42 patients showed no significant titer differences (3.736 vs 3.472, p = 0.15). Analyses of 13 preattack/attack pairs in 9 patients showed no significant titer differences (3.994 vs 3.889, p = 0.67). Of 5 patients who converted to seronegative status, 2 continued to have attacks. Titers for major and minor attacks (n = 70) were not significantly different (3.905 vs 3.676, p = 0.47). Similarly, measures (titers) of complement-mediated cell killing were not significantly associated with disease course, attack severity, or disability at 5 years. CONCLUSIONS AND RELEVANCE: AQP4-IgG titer and complement-mediated cell killing lack significant prognostic or predictive utility in NMOSD. Although titers may drop in the setting of immunotherapy, seroconversion to negative status does not preclude ongoing clinical attacks. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with NMOSD, AQP4-IgG titers and measures of complement-mediated cell killing activity do not predict relapses, relapse severity, or disability.

Autoimmune CRMP5 neuropathy phenotype and outcome defined from 105 cases.

OBJECTIVE: To establish the phenotype and clinical outcomes of collapsin response-mediator protein-5 (CRMP5) autoimmune neuropathy in comparison with anti-neuronal nuclear antibody type 1 (ANNA1)-immunoglobulin G (IgG) neuropathy. METHODS: Patients with CRMP5-IgG and/or ANNA1-IgGs were identified in our service-line testing, and medical records were reviewed. RESULTS: One hundred five patients with CRMP5-IgG neuropathy (88% smokers; 69% having cancer, most commonly small cell lung cancer [75%]) were identified and compared to 51 patients with ANNA1-IgG neuropathy, 27 with coexisting CRMP5-IgG. Patients with CRMP5 had painful axonal polyradiculoneuropathy (65%), mostly asymmetric onset (84%), with neuropathy predating cancer diagnosis by 185 days (range 60-540 days). Most cases (79%) had moderate to severe neuropathic pain, all on neuropathic medications (median 2, range 1-4), opioids in 39%. Nerve biopsies (n = 2) showed microvascular inflammation with axonal degeneration. Compared to ANNA1 alone, CRMP5 neuropathy has a higher prevalence of pain (79% vs 46%, p = 0.008), asymmetric polyradiculoneuropathy (54% vs 12%, p < 0.001), and inflammatory spinal fluids (elevated CSF protein or nucleated cell count 92% vs 60%, p = 0.022). Cerebellar ataxia (21%), myelopathy (19%), and optic neuritis and/or retinitis (11%) were common neurologic accompaniments. CRMP5 cases had significant pain reduction by immunotherapy (p < 0.001). Specifically, high-dose corticosteroid administration was associated with improvement/stabilization in neuropathy impairment scores (p = 0.012) (Class IV). Patients with CRMP5 had better 5-year survival than patients with ANNA1 (67% vs 32%, p = 0.012). CONCLUSION: Painful axonal asymmetric polyradiculoneuropathy is established as the major CRMP5 autoimmune neuropathy presentation and is distinguishable from other paraneoplastic neuropathies, including by ANNA1 autoimmunity. Patients with this phenotype should be prompted for CRMP5-IgG testing to assist in early cancer diagnosis.

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

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.