Nerve ultrasound in CANVAS-spectrum disease: Reduced nerve size distinguishes genetically confirmed CANVAS from other axonal polyneuropathies.

BACKGROUND AND AIMS: Ultrasound nerve cross-sectional area (CSA) of patients affected with axonal neuropathy usually shows normal value. Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) seems to represent an exception, showing smaller CSA, but previous reports did not test for biallelic RFC1 gene repeat expansions. METHODS: We compared nerve CSA from CANVAS patients (tested positive for biallelic RFC1 gene repeat expansions) with the CSA from a group of patients with chronic idiopathic axonal polyneuropathy (CIAP) who tested negative for RFC1 gene repeat expansions, hereditary axonal neuropathy (Charcot-Marie-Tooth type 2, CMT2), and Friedreich ataxia (FRDA). RESULTS: We enrolled 15 CANVAS patients (eight men, mean age 66.3 ± 11.5 years, mean disease duration 9.3 ± 4.1 years), affected with sensory axonal neuronopathy. Controls consisted of 13 CIAP (mean age 68.5 ± 12.8 years, seven men), seven CMT2 (mean age 47.9 ± 18.1 years, four men), 12 FRDA (mean age 33.7 ± 8.8, five men). Nerve ultrasound was performed at median, ulnar, sciatic, sural, and tibial nerves and brachial plexus, bilaterally. The nerve CSA from CANVAS patients was significantly smaller than the one from the other cohorts at several sites with significant and high accuracy at Receiver-operating characteristic (ROC) curve analyses. RFC1 AAGGG pentanucleotide expansion, disease duration, and disability did not correlate with CSA at any site, after Bonferroni correction. INTERPRETATION: Decreased sonographic nerve sizes, in arms and legs, in patients with sensory neuropathy and normal motor conduction studies could point to CANVAS-spectrum disease and help guide appropriate genetic testing.

Peripheral neuropathy as clinical onset of monoclonal IgM/k-related amyloidosis.

AIM: Neuropathy is a frequent complication of Waldenström's macroglobulinemia (WM), the most common being a demyelinating polyneuropathy with anti-myelin associated glycoprotein (MAG) antibodies, but also cryoglobulins, vasculitis, neurolymphomatosis, and amyloidosis. We describe a patient with IgM/kappa WM who presented with a severe, not length-dependent, peripheral neuropathy as clinical onset of IgM/kappa-related amyloidosis. METHODS: A 69-year-old woman came to our attention for weight loss, gait imbalance and sensory loss at upper limbs. In her medical history, she was in hematological follow-up for WM, and had undergone left carpal tunnel release. At neurological evaluation she had weakness and loss of sensation at upper limbs up to the elbows, more at the left side, gait was unsteady with right foot drop. Hypotrophy and areflexia were present at four limbs. Sensory loss and vibration sense were dramatically reduced. She underwent extensive diagnostic workup. RESULTS: Laboratory workup revealed an IgM/kappa monoclonal paraprotein of 16 g/L and increased NT-proBNP; anti-MAG antibodies were absent. Bone marrow biopsy demonstrated a population of neoplastic B-lymphocytes. Total-body CT scan and echocardiogram were negative. Neurophysiology revealed a symmetric, no length dependent sensory-motor polyneuropathy Periumbilical fat biopsy was positive for amyloid. Sural nerve biopsy detected amyloid in the wall of an epineurial vein. CONCLUSIONS: This case report describes a rare and unusual manifestation of IgM-related AL amyloidosis in WM. The patient presented with a subacute clinically asymmetric neuropathy with no pain or dysautonomic features as clinical onset of IgM/kappa-related amyloidosis. Sural nerve biopsy was crucial for the diagnosis.

Caspr1 antibodies autoimmune paranodopathy with severe tetraparesis: Potential relevance of antibody titers in monitoring treatment response.

AIM: Nodopathies and paranodopathies are autoimmune neuropathies associated with antibodies to nodal-paranodal antigens (neurofascin 140/186 and 155, contactin-1, contactin-associated protein 1 [Caspr1]) characterized by peculiar clinical features, poor response to standard immunotherapies (e.g., intravenous immunoglobulins, IVIg). Improvement after anti-CD20 monoclonal antibody therapy has been reported. Data on Caspr1 antibodies pathogenicity are still preliminary, and longitudinal titers have been poorly described. METHODS: We report on a young woman who developed a disabling neuropathy with antibodies to the Caspr1/contactin-1 complex showing a dramatic improvement after rituximab therapy, mirrored by the decrease of antibody titers. RESULTS: A 26-year-old woman presented with ataxic-stepping gait, severe motor weakness at four limbs, and low frequency postural tremor. For neurophysiological evidence of demyelinating neuropathy, she was diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy and treated with IVIg without benefit. MRI showed symmetrical hypertrophy and marked signal hyperintensity of brachial and lumbosacral plexi. Cerebrospinal fluid showed 710 mg/dL protein. Despite intravenous methylprednisolone, the patient progressively worsened, and became wheelchair-bound. Antibodies to nodal-paranodal antigens were searched for by ELISA and cell-based assay. Anticontactin/Caspr1 IgG4 antibodies resulted positive. The patient underwent rituximab therapy with slow progressive improvement that mirrored the antibodies titer, measured throughout the disease course. CONCLUSIONS: Our patient had a severe progressive course with early disability and axonal damage, and slow recovery starting only a few months after antibody-depleting therapy. The close correlation between titer, disability, and treatment, supports the pathogenicity of Caspr1 antibodies, and suggest that their longitudinal evaluation might provide a potential biomarker to evaluate treatment response.

Peripheral nerve involvement in wild-type transthyretin amyloidosis.

INTRODUCTION AND AIMRPOSE: Neurological involvement other than carpal tunnel syndrome (CTS) has rarely been observed in wild-type transthyretin amyloidosis (ATTRwt). The aim of our study was to investigate peripheral nerve involvement in ATTRwt. METHODS: Patients diagnosed with ATTRwt (negative molecular testing, confirmed cardiac uptake at bone scintigraphy, Perugini score 2 or 3) were considered. Sixteen men (mean age 75 ± 6.2, range 65-86 years) were enrolled. Neurological examination (Neuropathy Impairment Score, NIS), questionnaires on autonomic function and quality of life (QoL), electrodiagnostic studies (EDX), nerve ultrasound, and Sudoscan (electrochemical skin conductance, ESC) were performed. The presence of peripheral neuropathy was defined according to the detection of any abnormal finding at lower limbs other than CTS at EDX studies, regardless of NIS scores. RESULTS: Ten (62.5%) ATTRwt had abnormal NIS scores. At EDX, CTS was observed in 13/16 (81.2%), with 3/16 (18.8%) presenting also axonal peripheral neuropathy. Extensive workup ruled out common causes of neuropathy. Eight (50%) ATTRwt patients had orthostatic hypotension (OH). Abnormal ESC was observed in 9/14 (64%) ATTRwt patients. DISCUSSION: Despite being uncommon, we observed peripheral nervous system involvement in ATTRwt (large and small fiber dysfunction). Being elderly, ATTRwt patients may have age-related conditions acting as confounding factors for the diagnosis of neuropathy that however can be detected with a careful examination and use of specific tests, including those for autonomic dysfunction.

Comparison of the diagnostic accuracy of the 2021 EAN/PNS and 2010 EFNS/PNS diagnostic criteria for chronic inflammatory demyelinating polyradiculoneuropathy.

OBJECTIVES: To compare the sensitivity and specificity of the 2021 European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) diagnostic criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with those of the 2010 European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS). METHODS: Sensitivity and specificity of the two sets of criteria were evaluated in 330 patients with CIDP and 166 axonal peripheral neuropathy controls. Comparison of the utility of nerve conduction studies with different number of nerves examined and of the sensitivity and specificity of the two criteria in typical CIDP and its variants were assessed. RESULTS: EFNS/PNS criteria had a sensitivity of 92% for possible CIDP and 85% for probable/definite CIDP, while the EAN/PNS criteria had a sensitivity of 83% for possible CIDP and 74% for CIDP. Using supportive criteria, the sensitivity of the EAN/PNS criteria for possible CIDP increased to 85% and that of CIDP to 77%, remaining lower than that of the EFNS/PNS criteria. Specificity of the EFNS/PNS criteria was 68% for possible CIDP and 84% for probable/definite CIDP, while the EAN/PNS criteria had a specificity of 88% for possible CIDP and 98% for CIDP. More extended studies increased the sensitivity of both sets of criteria by 4%-7% but reduced their specificity by 2%-3%. The EFNS/PNS criteria were more sensitive for the diagnosis of typical CIDP while the EAN/PNS criteria were more specific for the diagnosis of distal and sensory CIDP. CONCLUSIONS: In our population, the EAN/PNS criteria were more specific but less sensitive than the EFNS/PNS criteria. With the EAN/PNS criteria, more extended nerve conduction studies are recommended to obtain an acceptable sensitivity while maintaining a high specificity.

Oligoclonal IgG bands in chronic inflammatory polyradiculoneuropathies.

BACKGROUND: Cerebrospinal fluid (CSF) albumincytologic dissociation represents a supportive diagnostic criterion of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).Few studies have investigated possible systemic or intrathecal humoral immune response activation in CIDP.Aim of our study was to investigate whether the search of oligoclonal IgG bands (OCBs) might provide additional data helpful in CIDP diagnostic work-up. METHODS: Forty-eight consecutive patients with CIDP (34 men, mean age 59.4, range 16-83) were recruited. CSF analysis included nephelometric measurement of albumin and IgG concentrations, calculation of QALB, QAlbLIM and intrathecal IgG synthesis, and OCBs detection with isoelectric focusing. Data were compared with those from CSF and serum of 32 patients with Guillain-Barré syndrome (GBS), 18 patients with anti-myelin associated glycoprotein (MAG) antibody neuropathy, 4 patients with multifocal motor neuropathy and 32 patients with non-inflammatory neuropathies (NINPs). RESULTS: Patients with CIDP and anti-MAG antibody neuropathy had significantly higher CSF albumin concentrations and QALB values than NINPs (p=0.0003 and p=0.0095, respectively). A total of 9 (19%) patients with CIDP presented identical serum and CSF OCBs ('mirror pattern') versus 3 patients (16.6%) with anti-MAG antibody neuropathy, 13 patients (40.6%) with GBS and 12.5% patients with NINPs. Only one patient with CIDP showed unique-to-CSF OCBs. First-line therapy was effective in 80.4% of patients with CIDP, irrespective of CSF findings. CONCLUSIONS: Compared with NINP, CIDP, GBS and anti-MAG antibody neuropathies had a significantly increased CSF protein and blood-spinal nerve root barrier damage. Intrathecal humoral immune response is rare in our patients with CIDP. Systemic oligoclonal activation is more frequent, but not significantly different from what was detected in the control groups.

Neurolymphomatosis, a rare manifestation of peripheral nerve involvement in lymphomas: Suggestive features and diagnostic challenges.

Neurolymphomatosis, the infiltration of the peripheral nervous system from lymphoid cells, represents an uncommon manifestation of lymphomas. We describe the challenging diagnostic work-up in a patient with neurolymphomatosis. A 58-year-old woman with previous breast diffuse large B-cell lymphoma treated with chemo- and radiation-therapy, presented with dysesthesias, neuropathic pain at left abdomen and thigh, and weakness at left lower limb 9 years after disease remission. Neurophysiology revealed left T10-L4 radiculo-plexopathy with no abnormalities at cerebrospinal fluid (CSF), nerve ultrasound, and 18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT). MR-neurography disclosed left rectus abdominis muscle atrophy, neurogenic edema, and denervation. Radiation-induced damage, paraneoplastic, infectious radiculo-plexopathies, and atypical chronic inflammatory demyelinating polyradiculoneuropathy were ruled out. Neurolymphomatosis was suspected, and the patient treated with rituximab with improvement. Despite treatment, the radiculo-plexopathy eventually extended to the right side and sacral roots. Later in the disease course, sural nerve biopsy confirmed the diagnosis. Maintenance therapy was continued, until cutaneous localizations occurred, requiring salvage therapy and autologous stem cell transplant. Although rare, neurolymphomatosis should be considered in all patients with lymphomas and unexplained peripheral nervous system involvement. Hematological, CSF, and neuroimaging findings may be unremarkable, and a high index of suspicion required in order to achieve the diagnosis.

Sporadic hereditary neuropathies misdiagnosed as chronic inflammatory demyelinating polyradiculoneuropathy: Pitfalls and red flags.

Hereditary neuropathies may be misdiagnosed with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). A correct diagnosis is crucial for avoiding unnecessary therapies and access genetic counseling. We report on nine patients (seven men, mean age 49.2 ± 16.1) diagnosed with and treated as CIDP, in whom mutations or variants of unknown significance (VUS) in genes associated with hereditary neuropathies were reported. All underwent neurological and neurophysiological examination, eight also cerebrospinal fluid (CSF) analysis. In 4/9, nerve ultrasound and/or MR-neurography were performed. All the patients complained of progressive upper or lower limbs sensory-motor symptoms, with heterogeneous disease duration (1-34 years, mean 8.6 ± 10.8). Neurophysiology showed demyelinating signs in seven patients, mixed findings with predominant axonal damage in two patients. Neuroimaging disclosed diffuse abnormalities at proximal and distal segments. Molecular screening showed PMP22 duplication in two patients, mutations in the MPZ, EGR2, and GJB1 genes were reported in each of the remaining patients. The two patients with mixed neurophysiological findings had p.Val30Met mutation in the transthyretin gene. Two patients had VUS in the MARS and HSPB1 genes. Four patients had partial response to immunomodulant therapies, and CSF and neurophysiological features suggesting an inflammatory condition concomitant with the hereditary neuropathy. Hereditary neuropathy may be misdiagnosed with CIDP. The most common pitfalls are CSF (high protein levels and oligoclonal bands), incorrect interpretation of neurophysiology, and transient benefit from therapies. Neuroimaging may be helpful in cases with atypical presentations or when severe axonal damage complicate the neurophysiological interpretation.

Idelalisib plus rituximab is effective in systemic AL amyloidosis secondary to chronic lymphocytic leukaemia.

Light chain amyloidosis is characterized by the progressive deposition of immunoglobulin light chains into the extracellular tissue, leading to organ dysfunction. Usually, it is associated with an underlying clonal plasma cell dyscrasia and rarely with chronic lymphocytic leukaemia. Herein, we described the first report of a patient with relapsed chronic lymphocytic leukaemia harbouring TP53 abnormalities who developed, histologically proven, systemic light chain amyloidosis who was treated with the PI3K inhibitor, idelalisib, and rituximab. Unfortunately, the patient had sudden death during sleep, likely caused by arrhythmia secondary to amyloid cardiomyopathy. Idelalisib was at least effective in reducing secretory free light chain, chronic lymphocytic leukaemia burden, and to improve the survival of patient.

Different nerve ultrasound patterns in charcot-marie-tooth types and hereditary neuropathy with liability to pressure palsies.

INTRODUCTION: Nerve ultrasound in Charcot-Marie-Tooth (CMT) disease has focused mostly on the upper limbs. We performed an evaluation of a large cohort of CMT patients in which we sonographically characterized nerve abnormalities in different disease types, ages, and nerves. METHODS: Seventy patients affected by different CMT types and hereditary neuropathy with liability to pressure palsies (HNPP) were evaluated, assessing median, ulnar, fibular, tibial, and sural nerves bilaterally. Data were correlated with age. RESULTS: Nerve dimensions were correlated with CMT type, age, and nerve site. Nerves were larger in demyelinating than in axonal neuropathies. Nerve involvement was symmetric. DISCUSSION: CMT1 patients had larger nerves than did patients with other CMT types. Patients with HNPP showed enlargement at entrapment sites. Our study confirms the general symmetry of ultrasound nerve patterns in CMT. When compared with ultrasound studies of nerves of the upper limbs, evaluation of the lower limbs did not provide additional information. Muscle Nerve 57: E18-E23, 2018.

Risk stratification of oxaliplatin induced peripheral neurotoxicity applying electrophysiological testing of dorsal sural nerve.

PURPOSE: We aimed to verify the predictiveness of dorsal sural nerve neurophysiological monitoring in obtaining risk stratification for oxaliplatin-induced peripheral neurotoxicity (OXAPN). METHODS: We conducted a secondary analysis on a cohort of 110 colorectal cancer patients who were evaluated clinically and neurophysiologically before chemotherapy, at mid-treatment and at discontinuation. We applied the classification tree analysis method to predict the end-of-treatment OXAPN neurophysiological diagnosis, using data recorded at mid-treatment. We then ascertained the correlation between the obtained classes and neurological impairment at the end of treatment (Fisher's exact test). RESULTS: Dorsal sural nerve monitoring enabled us to stratify oxaliplatin-treated patients into risk classes with an implemented approach to neurophysiology application in this setting. Neurological outcome at discontinuation was predicted by neurophysiological monitoring performed during chemotherapy administration. CONCLUSIONS: We demonstrated the role that neurophysiology may play in clinical trials as an early surrogate marker that can predict OXAPN development at the end of treatment. Specifically, we propose abnormal dorsal sural sensory nerve testing as an early biomarker in identifying patients at high risk of eventually developing OXAPN.

Early predictors of oxaliplatin-induced cumulative neuropathy in colorectal cancer patients.

OBJECTIVES: Peripheral neuropathy ranks among the most common dose-limiting and disabling side-effect of oxaliplatin (OXA)-based chemotherapy. The aim of this prospective, multicentre study was to define early clinical and neurophysiological markers that may help to identify patients at risk of developing severe, treatment emergent, cumulative OXA-induced peripheral neuropathy (OXAIPN). METHODS: 200 colorectal cancer patients, scheduled to receive OXA-based chemotherapy, were prospectively followed. Detailed neurological assessment employing the clinical Total Neuropathy Score (TNSc), oncological rating scales (National Common Institute-Common Toxicity Criteria V.3) and nerve conduction studies (NCS) were performed at baseline, mid-treatment and at the end of chemotherapy. Symptoms of OXA-induced acute neurotoxicity were systematically recorded. RESULTS: According to TNSc, 36 (18%) patients developed grade 3 OXAIPN. These patients were predominantly men (p=0.005), presented a significant decrease in all NCS (p<0.001), reported more acute neuropathic symptoms (p<0.001) and received higher OXA cumulative dose (p=0.003). Multivariate analysis showed that three variables obtained at intermediate follow-up, namely, the number of acute symptoms (OR 1.9; CI 95% 1.2 to 3.2; p=0.012) and the >30% decrease in sensory nerve action potential amplitude from the baseline value in radial (OR 41.4; CI 95% 4.98 to 343.1; p=0.001) and dorsal sural nerves (OR 24.96; CI 95% 2.6 to 239.4; p=0.005) were independently associated with the risk of developing severe OXAIPN. CONCLUSIONS: High-grade OXA neurotoxicity can be predicted by clinical and neurophysiological information obtained at mid-treatment. Neurological assessment of acute neuropathy symptoms and radial and dorsal sural nerves NCS should be carefully monitored to predict and hopefully prevent the induction of severe OXAIPN.

Long-term course of oxaliplatin-induced polyneuropathy: a prospective 2-year follow-up study.

This prospective study sought to identify the potential reversibility of oxaliplatin-induced peripheral neuropathy (OXAIPN) by following-up its long-term course 2 years after discontinuation of oxaliplatin (OXA)-based chemotherapy. Participants were 91 colorectal cancer patients treated with OXA-based chemotherapy. Neurological assessment, clinical Total Neuropathy Score© (TNSc©) and nerve conduction studies were performed at baseline (T0), the end of chemotherapy (T1) and 2 years (T2) after discontinuation of chemotherapy. A total of 73 of 91 (80%) patients experienced OXAIPN at T1. At a median follow-up of 25 months, persistence of chronic OXAIPN was present in 61 of 73 patients (84%) and complete resolution was present in 12 patients (17%). Longitudinal comparison of TNSc© values between T1 and T2 revealed that the overall severity of OXAIPN in those 61 patients significantly decreased over time. Median TNSc© values were nine (range: 2-15) at T1 vs. four (range: 2-12) at T2 (P < 0.001). Likewise, sensory nerve conduction measures at T2 significantly improved in all sensory nerves tested, compared with T1. Severity of OXAIPN at T2 was significantly associated (P < 0.001) with high severity of OXAIPN at T1. In conclusion, persistence of OXAIPN beyond 2 years after finishing chemotherapy is common. Clinical and neurophysiological improvement is observed, although recovery is often incomplete.

Assessment of Neuropathic Pain in Erosive Hand Osteoarthritis.

Background/Objectives: Erosive hand osteoarthritis (EHOA) is an aggressive form of hand osteoarthritis (OA) and a severely disabling condition. Patients affected by OA frequently lament symptoms suggestive of neuropathic pain (NP). The aim of our study was to ascertain the presence and severity of NP in patients with EHOA and correlate its presence with EHOA clinical characteristics. Methods: In this retrospective study, we included all consecutive EHOA patients with NP symptoms who underwent upper limb electroneurography (ENoG) and nerve ultrasound. The presence of NP was screened using the ID pain neuropathic pain-screening questionnaire (ID-Pain). In addition, the following NP questionnaires were also used: Douleur Neuropathique en 4 Questions (DN4), PainDETECT, and Neuropathic Pain Symptom Inventory (NPSI). Moreover, patients completed the Australian/Canadian Osteoarthritis Hand Index (AUSCAN) and Dreiser's algofunctional finger index questionnaires assessing EHOA disease activity. The following clinical and laboratory data were collected: age, sex, BMI, disease duration, intensity of pain (VAS 0-10), painful and swollen joints, and inflammatory indices, as well as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Results: Of the 34 patients studied, 24 (70.6%) presented NP to the ID-Pain questionnaire. According to DN4, 14 (41.2%) patients had NP, while using the PainDETECT questionnaire, 67.6% had NP. Patients with NP were statistically younger and had a higher VAS pain score compared to subjects without NP. The ENoG and median nerve ultrasound were normal in 81% of patients, while four patients had carpal tunnel syndrome. The ID-Pain questionnaire correlated with the number of painful joints (r = 0.48, p = 0.03) and with the AUSCAN questionnaire (r = 0.37, p = 0.05). The DN4 questionnaire correlated with PainDETECT (r = 0.58, p < 0.01). The PainDETECT questionnaire correlated with VAS pain (r = 0.49, p = 0.02), the DN4 questionnaire (r = 0.58, p < 0.01), and AUSCAN (r = 0.51, p = 0.02). The NPSI questionnaire correlated negatively with BMI (r = -0.53, p = 0.01) and positively with the PainDETECT questionnaire (r = 0.49, p = 0.02). Conclusions: Our study revealed that 32% to 70% of EHOA patients exhibited symptoms consistent with NP, with observed variability depending on the questionnaire utilized. Despite patients frequently exhibiting symptoms compatible with NP, only 19% of patients presented alterations on ENoG and ultrasound examinations confirming CTS. This suggests a probable nociplastic component for pain in patients with EHOA, which warrants tailored treatment. In the present study, NP correlated with clinical and functional indices of EHOA.

Mutational Profile in 75 Patients With Anti-Myelin-Associated Glycoprotein Neuropathy: Clinical and Hematologic Therapy Response and Hints on New Therapeutic Targets.

BACKGROUND AND OBJECTIVES: Neuropathy with antibodies to myelin-associated glycoprotein (MAG) is the most common paraproteinemic IgM neuropathy. Recently, the mutational profile of the MYD88 and CXCR4 genes has been included in the diagnostic workup of IgM monoclonal gammopathies. The objective of our study was to assess the prevalence of MYD88 L265P and CXCR4 S338X gene variants in patients with anti-MAG antibody neuropathy. Secondary aims were to evaluate possible correlations between the mutational profile and neuropathy severity, antibody titers, and treatment response. METHODS: Seventy-five patients (47 men, mean age at molecular analysis 70.8 ± 10.2 years; mean disease duration 5.1 ± 4.9 years) with anti-MAG antibody neuropathy were recruited. Among them, 38 (50.7%) had IgM monoclonal gammopathy of undetermined significance, 29 (38.7%) Waldenstrom macroglobulinemia (WM), and 8 (10.6%) chronic lymphocytic leukemia/marginal zone lymphoma/hairy cell leukemia variant. Molecular analysis was performed on DNA from the bone marrow mononuclear cells in 55 of 75 patients and from peripheral mononuclear cells in 18 of 75 patients. Forty-five patients were treated with rituximab, 6 with ibrutinib, 2 with obinutuzumab-chlorambucil, and 3 with venetoclax-based therapy. All the patients were assessed with the Inflammatory Neuropathy Cause and Treatment (INCAT) Disability Scale, INCAT Sensory Sum Score, and MRC Sum Score at baseline and follow-up. We considered as responders, patients who improved by at least 1 point in 2 clinical scales. RESULTS: Fifty patients (66.7%) carried the MYD88L265P variant, with a higher frequency in WM and naive patients (77.2% vs 33.3%, p = 0.0012). No patients harbored the CXCR4S338X variant. There were no significant differences in hematologic data (IgM levels, M protein, and anti-MAG antibody titers), neuropathy severity, or response to rituximab in MYD88-altered and MYD88 wild-type patients. Nine of 11 (81.8%) patients treated with novel targeted drug, according to the MYD88 status, responded to treatments. DISCUSSION: MYD88L265P variant has a high prevalence (66.7%) in anti-MAG antibody neuropathy representing a potential effective mutational target for Bruton tyrosine kinase inhibitors. MYD88L265P variant, however, does not seem to be a prognostic factor of neuropathy severity or response to rituximab. In patients not responding or becoming refractory to rituximab, a tailored therapy with new effective target therapies should be considered.