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Background and purpose: Whether the Lewis–Sumner syndrome (L‐SS) is a distinct entity from other types of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP‐ot) remains controversial. Method: The clinical/electrophysiological characteristics and long‐term outcomes of 45 L‐SS and 35 CIDP‐ot patients were retrospectively compared. Results: The CIDP‐ot group was composed of 11 patients with a typical CIDP, 17 with a pure sensory form, four with a distal form and three with a pure motor form. In the L‐SS group, asymmetric (P < 0.001) and monomelic involvement (P = 0.04) of the upper limbs (P < 0.001) was significantly more frequent; paucisymptomatic forms (Overall Neuropathy Limitations Scale ≤ 1) were less frequent (P < 0.001); electroneuromyography showed that conduction block in intermediate nerve segments was the main demyelinating feature, with frequent F‐wave abnormalities on nerves without conduction block (44%). Long‐term prognosis was globally poorer in the L‐SS group with more frequent aggravation during treatment (P = 0.02), less frequent treatment withdrawal (P = 0.03) and longer time to achieve successful withdrawal (39 vs. 15 months). Conclusions: Our study suggests that L‐SS patients have a less favourable therapeutic response rate and long‐term outcomes. Rapid differentiation of L‐SS from other forms of CIDP is important in order to anticipate a more complicated disease course management, with from one side the inefficacy or even harmfulness of corticosteroids and from the other side a difficult weaning procedure. A prospective study is necessary to confirm these results. [ABSTRACT FROM AUTHOR]

Background and purpose: The usefulness of plexus magnetic resonance imaging (MRI) in the diagnosis of chronic inflammatory demyelinating polyradiculopathy (CIDP) without definite European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) electrodiagnostic criteria is currently unclear. Methods: Data from consecutive patients with clinical manifestations suggesting CIDP, with or without (CIDP‐D and CIDP‐ND, respectively) definite EFNS/PNS electrodiagnostic criteria, and referred for plexus MRI in our imaging centre were retrospectively analysed. An expert committee of neurologists compared the level of suspicion of CIDP in CIDP‐ND patients to the blinded/unblinded MRI findings. Plexus MRI was reviewed by a neuroradiologist blinded to the final diagnosis. Results: In all, 38 patients were assessed with suspected CIDP‐ND [7/38 (18%) probable; 13/38 (34%) possible; 18/38 (47%), no EFNS/PNS electrodiagnostic criteria], plus 10 with CIDP‐D. Thirty‐six of the 38 (95%) fulfilled clinical criteria of CIDP variants, including pure sensory neuropathy in 22/36 (61%). Plexus MRI showed abnormalities in 22/38 (58%) patients including increased nerve signal intensity on T2‐weighted images in 22/22 (100%), nerve enlargement in 20/22 (91%) and contrast enhancement in 8/22 (36%). Plexus MRI enabled the expert committee's final diagnosis to be adjusted in 7/38 (18%) patients, and in conjunction with nerve conduction studies was a supportive criterion to classify 7/24 (29%) patients as definite CIDP. MRI abnormalities were more asymmetrical (P = 0.03) and less diffuse (P = 0.1) in CIDP‐ND than in CIDP‐D. Conclusions: Our observations suggest that plexus MRI makes a valuable contribution to the diagnosis of CIDP‐ND patients. Further studies are needed to investigate inter‐rater reliability of clinical and imaging criteria of CIDP in these patients, and the impact on outcomes. [ABSTRACT FROM AUTHOR]

Background and purpose: The aim is to describe an uncommon phenotype of hereditary ATTR neuropathy with upper limb onset. Methods: The French TTR Familial Amyloid Polyneuropathy database was used for a retrospective evaluation of 32 consecutive patients with upper limb onset of the neuropathy (study group) and they were compared to 31 Portuguese early‐onset patients and 99 late‐onset patients without upper limb onset. Results: Initial upper limb symptoms were mostly sensory. Lower limb symptoms began 2.3 ± 3 years after upper limb symptoms. Twenty‐four (75%) patients were initially misdiagnosed, with 15 different diagnoses. More patients in the study group had a Neuropathy Impairment Score upper limb/lower limb ratio > 1 compared to the late‐onset patient group. The study group had significantly more pronounced axonal loss in the median and ulnar motor nerves and the ulnar sensory and sural nerves. On radial nerve biopsies (n = 11), epineurial vessels were abnormal in six cases, including amyloid deposits in vessel walls (3/11), with vessel occlusion in two cases. Conclusion: Upper limb onset of hereditary ATTR neuropathy is not rare in non‐endemic areas. It is important to propose early TTR sequencing of patients with idiopathic upper limb neuropathies, as specific management and treatment are required. [ABSTRACT FROM AUTHOR]

Background and Purpose: Small-fiber neuropathy (SFN) affects only unmyelinated and thin myelinated fibers. It may be caused by amyloidogenic mutations of the transthyretin (TTR) gene, but not all TTR gene variants are pathogenic. The nonamyloidogenic c.76G>A (rs1800458) and c.337-18G>C (rs36204272) variants of TTR were recently reported to be associated with SFN. We investigated this putative association by analyzing TTR gene sequencing data retrospectively for two cohorts of patients, one with SFN and a control group., Methods: In this retrospective single-center study, we analyzed the frequency of the c.76G>A and c.337-18G>C TTR gene variants in a cohort of patients meeting a strict definition of SFN, with or without dysautonomia, a control cohort of patients investigated for nonneurological conditions, and the gnomAD international database., Results: We included 55 SFN patients in this study, 17 of whom had dysautonomia. The allelic frequencies of the two variants in our cohort of 55 SFN patients were 7.27% for c.76G>A TTR and 5.25% for c.337-18G>C. The frequencies of both variants were statistically similar in the 337 control patients and the gnomAD database., Conclusions: The c.76G>A and c.337-18G>C TTR gene variants are not associated with SFN., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Purpose: Hereditary transthyretin-mediated amyloidosis with polyneuropathy (ATTRv-PN [v for variant]) is a rare, progressive disease associated with multisystemic impairments. This study assessed the real-world outcomes of patients with ATTRv-PN who switched from tafamidis to patisiran, as well as the reasons for the treatment switch., Methods: This was a retrospective chart review study at a large expert referral center. Data were extracted from medical charts of patients with ATTRv-PN who switched from tafamidis to patisiran on or before 30 August 2019. Data elements included demographic and clinical characteristics, rationale for switch, and disease measures evaluated from tafamidis initiation through the 12-month patisiran treatment period., Results: Among the 24 patients with ATTRv-PN included in the study, 50.0% had a V30M variant, and the mean (SD) age was 67.3 (8.0) years. During tafamidis treatment (mean [SD] = 30.1 [17.5] months) before switching to patisiran, patients worsened across multiple polyneuropathy measures, including walking ability, Neuropathy Impairment Score, and autonomic function. Neuropathic disease progression on tafamidis was the principal reason for switching to patisiran. After 12 months on patisiran (mean [SD] = 11.7 [1.4] months), patients experienced attenuated disease progression or improvement in the aforementioned measures of polyneuropathy., Conclusions: Switching from tafamidis to patisiran attenuated the rate of functional decline, and most patients experienced stabilization or improvement of at least one polyneuropathy measure within 12 months of patisiran treatment. Timely switch from tafamidis to patisiran can be beneficial to avoid rapid disease progression in patients with ATTRv-PN., (© 2024 Analysis Group, Alnylam Pharmaceuticals and The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Purpose: In this retrospective study involving 14 university hospitals from France and Switzerland, the aim was to define the clinicopathological features of chronic neuropathies with anti-disialosyl ganglioside immunoglobulin M (IgM) antibodies (CNDA)., Results: Fifty-five patients with a polyneuropathy evolving for more than 2 months and with at least one anti-disialosyl ganglioside IgM antibody, that is, anti-GD1b, -GT1b, -GQ1b, -GT1a, -GD2 and -GD3, were identified. Seventy-eight percent of patients were male, mean age at disease onset was 55 years (30-76) and disease onset was progressive (82%) or acute (18%). Patients presented with limb sensory symptoms (94% of cases), sensory ataxia (85%), oculomotor weakness (36%), limb motor symptoms (31%) and bulbar muscle weakness (18%). Sixty-five percent of patients had a demyelinating polyradiculoneuropathy electrodiagnostic profile and 24% a sensory neuronopathy profile. Anti-GD1b antibodies were found in 78% of cases, whilst other anti-disialosyl antibodies were each observed in less than 51% of patients. Other features included nerve biopsy demyelination (100% of cases), increased cerebrospinal fluid protein content (75%), IgM paraprotein (50%) and malignant hemopathy (8%). Eighty-six percent of CNDA patients were intravenous immunoglobulins-responsive, and rituximab was successfully used as second-line treatment in 50% of cases. Fifteen percent of patients had mild symptoms and were not treated. CNDA course was progressive (55%) or relapsing (45%), and 93% of patients still walked after a mean disease duration of 11 years., Conclusion: Chronic neuropathies with anti-disialosyl ganglioside IgM antibodies have a recognizable phenotype, are mostly intravenous immunoglobulins-responsive and present with a good outcome in a majority of cases., (© 2022 European Academy of Neurology.)

Background and Purpose: This study was undertaken to assess skin biopsy as a marker of disease onset and severity in hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN), a treatable disease., Methods: In this single center retrospective study, skin Congo red staining and intraepidermal nerve fiber density (IENFD) were evaluated in symptomatic ATTRv-PN patients and asymptomatic TTR gene mutation carriers between 2012 and 2019. Non-ATTRv subjects with suspected small fiber neuropathy who underwent skin biopsy during the same timespan were used as controls., Results: One hundred eighty-three symptomatic ATTRv-PN patients, 36 asymptomatic carriers, and 537 non-ATTRv patients were included. Skin biopsy demonstrated amyloid depositions in 80% of the 183 symptomatic cases. Skin amyloid deposits were found in 75% of early stage ATTRv-PN patients, and in 14% of asymptomatic carriers. All 183 symptomatic and 34 of 36 asymptomatic patients displayed decreased ankle IENFD with a proximal-distal gradient distribution, and reduced IEFND correlated with disease severity and duration., Conclusions: Our study demonstrates skin amyloid deposits are a marker of ATTRv-PN disease onset, and decreased IENFD a marker of disease progression. These results are of major importance for the early identification of ATTRv-PN patients in need of disease-modifying treatments., (© 2022 European Academy of Neurology.)

Background and Purpose: Preparations for clinical trials of unfolded protein response (UPR) inhibitors (such as Sephin1) that target the upregulated UPR in patients with Charcot-Marie-Tooth disease (CMT) carrying MPZ mutations are currently underway. The inclusion criteria for these trials are still being formulated. Our objective was to characterize the relation between genotypes and phenotypes in patients with CMT caused by MPZ mutations, and to refine the inclusion criteria for future trials., Methods: Clinical and neurophysiological data of CMT patients with MPZ mutations were retrospectively collected at 11 French reference centers., Results: Forty-four mutations in MPZ were identified in 91 patients from 61 families. There was considerable heterogeneity. The same mutation was found to cause either axonal or demyelinating neuropathy. Three groups were identified according to the age at disease onset. CMT Examination Score (CMTES) tended to be higher in the early (≤22 years) and adult (23-47 years) onset groups (mean CMTESv2 = 10.4 and 10.0, respectively) than in the late onset group (>47 years, mean CMTESv2 = 8.6, p = 0.47). There was a significant positive correlation between CMTESv2 and the age of patients in Groups I (p = 0.027) and II (p = 0.023), indicating that clinical severity progressed with age in these patients., Conclusions: To optimize the selection of CMT patients carrying MPZ mutations for the upcoming trials, inclusion criteria should take into account the pathophysiology of the disease (upregulated UPR). Recruited patients should have a mild to moderate disease severity and a disease onset at between 18 and 50 years, as these patients exhibit significant disease progression over time., (© 2021 European Academy of Neurology.)