III Meeting Neuroscienze Toscane 5-7 Aprile 2019 Viareggio POLINEUROPATIA ASSOCIATA A GAMMOPATIA MONOCLONALE: UNO STUDIO OSSERVAZIONALE Stefano Filippini, Sabrina Matà, Alessandro Barilaro, Luca Massacesi, Sandro Sorbi (Firenze)

Monoclonal gammopathy MGUS (monoclonal gammopathy of undetermined significance) is a common, age-related medical condition characterized by an accumulation of bone marrow plasma cells derived from a single abnormal clone without proliferation of malignant cells. There are three types of MGUS -IgM -non-IgM -light chains Paraproteins are detected in the serum of approximately 1 % of the general population. The prevalence of paraproteinemia rises with age, up to 5.3 % among individuals over 70 years and up to 10 % in people older than 80 years 

MGUS-associated neuropathies Distal demyelinating acquired symmetric neuropathy (DADS) Chronic inflammatory demyelinating polyneuropathy (CIDP) –like Axonal sensorimotor peripheral neuropathy Multifocal motor neuropathy Multifocal motor-sensory neuropathy POEMS CANOMAD Few treatment options are now available for these patients, which including IVIg, plasma exchange and, recently, Rituximab.

MGUS-associated neuropathy: a local experience Aim of this study was to investigate the clinical phenotype and long-term outcome of patients with MGUS-associated polyneuropathy Retrospective review of a consecutive series of patients with neuropathy and MGUS evaluated during a 15 year period who were seen at Neurology Unit of Careggi’s Hospital The patients were classified as having axonal neuropathy, demyelinating neuropathy, or a mixed neuropathy, according to EMG Antibodies against gangliosides, sulfatides and MAG were tested by ELISA. The modified Rankin disability scale was used to determine functional impairment at the time of the maximal neurological deficit and after treatment A treatment response was defined as improvement of at least one grade of the Rankin score for at least two months. Patients with malignancies, amiloidosis or other dysimmune or metabolic disorders were excluded.

Results: Demographic Data 75 MGUS PNP patients Demographic Data Male gender 51 (67%) Mean age at onset (yrs) 65 Male: 65.7 Female: 63.6 Median disease duration (yrs) 7.9 (range: 1-28)

Results: Clincal Findings 75 MGUS patients Clinical Data Neuropathy phenotype Polyneuropathy: 70 (93%) DADS: 27 CIDP-like: 15 Axonal: 17 Other: 11 Multifocal neuropathy: 5 (7%) Motor: 4 Sensory-motor: 1 mRS at disease onset 0= 1 2= 18 4= 16 1= 31 3= 6 5= 1 Therapy Steroids 21 Intravenous Ig 32 Rituximab 36 A total of 56 (75%) patients received one or more treatments; treated patients had mRS value at onset significantly higher (mean 2.4 vs 1.1, p<0.001)

Results: Haematologic Data 75 MGUS PN patients Haematologic data MGUS clonality Monoclonal: 68 patients (91%) 55 IgM 12 IgG 2 IgA Biclonal: 5 patients (6.5%) 3 IgM + IgG 1 IgM + IgA 1 IgG + IgA Three clonal: 2 patients (2.5%) 2 IgM + IgG + IgA Hematologic malignancy at follow-up 6 patients (8%) 0.75 pt/yr

Results: Immunological Findings 75 MGUS Neuropathy patients Immunological data (Ig reactivity) IgM M protein (n.61) MAG: 26 (42.6%) Gangliosides/Sulfatides: 19 (31.1%) No reactivity 16 (26.2%) IgG/IgA M protein (n. 14) MAG (IgM)/Sulfatides: 1 (7.1%) Gangliosides/sulfatides (IgG 1 (7.1%) No reactivity: 12 (85.5%) No differences were observed in age at onset, mRS, or neuropathy phenotype distribution between patients with and without IgM M protein.

Results: EMG vs Immunological findings

Results: Therapy vs Immunological findings

Results: Immune-based differences No reactivity MAG Gangliosides/Sulf No reactivity MAG Gangliosides/Sulf No reactivity MAG Gangliosides/Sulf

Conclusions - 1 Distribution of electrophysiological, haematologic and immunological findings in our patients mirror the data from literature MGUS neuropathies are often mildly disabling at presentation (mRS=1/2 in 70% of patients), but 20% of patients had a high mRS at onset (mRS=4 in 20% of cohort) Patients with reactivity to gangliosides/sulfatides had a higher burden of disability at onset, but showed marked benefit from therapy (the majority was treated with IVIg)

Conclusions - 2 Patients with reactivity to MAG and no reactivity had a lower burden of disability at onset, but showed less benefit from therapy (mostly treated with rituximab) An higher IgM titer and most severe deficit at presentation can be predictive of a better response to IGIv therapy in anti-ganglioside/sulfatide PNPs, as already described in literature for Rituximab in anti-MAG PNPs (Dalakas, 2009). Nevertheless, IgM titer and severity of disease are not correlated.

What’s next Is response to therapy in anti-GM/S patient influenced by EMG pattern? Do Anti-GM/S patients have the same benefit when treated with IVIG and then Rituximab vs. rituximab only? Is there an association between disability recovery and time from diagnosis to treatment?