Hadden RDM, Andersen H, Bril V
… +7 more, Basta I, Rejdak K, Duff K, Greco E, Hasan S, Anderson-Smits C, Ay H
J Peripher Nerv Syst
· 2024 Dec · PMID 39523874
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BACKGROUND AND AIMS: Hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) consists of subcutaneous human immunoglobulin G (IgG) 10% with recombinant human hyaluronidase (rHuPH20) and can be administered at the s...BACKGROUND AND AIMS: Hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) consists of subcutaneous human immunoglobulin G (IgG) 10% with recombinant human hyaluronidase (rHuPH20) and can be administered at the same dose and interval as intravenous IgG (IVIG). fSCIG recently received US approval as maintenance therapy for adults with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and European approval for adults and children with CIDP after stabilization with IVIG. METHODS: ADVANCE-CIDP 3 (NCT02955355) was an open-label long-term extension of the Phase 3 double-blind randomized placebo-controlled ADVANCE-CIDP 1 study (NCT02549170) that examined fSCIG safety and efficacy as maintenance CIDP therapy. Primary outcomes were safety, tolerability, and immunogenicity. Efficacy was an exploratory outcome. RESULTS: The study provided 220 patient-years of follow-up data from 85 patients. Median (range) exposure was 33 (0-77) months. Patients received fSCIG every 4 weeks (88.2%) or every 3 weeks (11.8%). Median (range) 4-weekly IgG dose equivalent was 64.0 (28.0-200.0) g. Mean (standard deviation) infusion duration was 135.5 (62.8) minutes. Most adverse events (AEs) were mild or moderate and self-limiting. Of the 1406 AEs, only 48 were severe and 30 were serious. fSCIG-related AEs (n = 798) included infusion site reactions such as pain, redness, and pruritus. Three infusions (0.1%) were reduced in rate, interrupted, or stopped due to intolerability. Relapse occurred in 10 of 77 patients (13.0%); annual relapse rate was 4.5%. An anti-rHuPH20 antibody titer ≥1:160 was detected in 14 of 84 patients (16.7%); patients who tested positive (≥1:160) had similar relapse rates versus those who tested negative (16.7% vs. 12.3%, respectively). INTERPRETATION: ADVANCE-CIDP 3 demonstrated favorable fSCIG long-term safety and tolerability consistent with its established safety profile, and a low relapse rate, supporting use as maintenance CIDP treatment.
J Peripher Nerv Syst
· 2024 Dec · PMID 39523026
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BACKGROUND AND AIMS: Charcot-Marie-Tooth (CMT) type 1 neuropathies are the most common inherited diseases of the peripheral nervous system. Although more than 100 causative genes have been identified so far, therapeutic...BACKGROUND AND AIMS: Charcot-Marie-Tooth (CMT) type 1 neuropathies are the most common inherited diseases of the peripheral nervous system. Although more than 100 causative genes have been identified so far, therapeutic options are still missing. We could previously identify that early-onset physical exercise (voluntary wheel running, VWR) dampens peripheral nerve inflammation, improves neuropathological alterations, and clinical outcome in Cx32def mice, a model for CMT1X. We here investigate the clinical and histopathological effect of late-onset exercise in Cx32def mice at an advanced disease stage. METHODS: Nine-month-old Cx32def mice were allowed to run for 4 days/week on a commercially available running wheel for 3 months, with timely limited access to running wheels, representing a running distance of ~2000 m. Control mutants had no access to running wheels. Afterward, mice were investigated by distinct functional tests and by immunohistochemical and electron microscopical techniques. RESULTS: We found that late-onset physical exercise (late VWR) prevented the robust functional decline in 12-month-old Cx32def mice. This was accompanied by improved neuromuscular innervation of distal muscles and axonal preservation in femoral quadriceps nerves. In contrast to a "pre-symptomatic" start of physical exercise in Cx32def mice, late-onset VWR did not alter nerve inflammation and myelin thickness at 12 months of age. INTERPRETATION: We conclude that VWR has robust beneficial effects on nerve function in Cx32def mice, even when applied at a progressed disease stage. These results have important translational implications, suggesting that physical exercise might be an effective treatment option for CMT1 patients, even when disease symptoms have already progressed.
Morrison AH, Hoke M, Thomas S
… +4 more, Chaudhry V, Polydefkis M, PNRR Study Group, Höke A
J Peripher Nerv Syst
· 2024 Dec · PMID 39506207
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BACKGROUND AND AIMS: Peripheral neuropathy (PN) is a common neurological condition in elderly adults. Vitamin D deficiency has been associated with diabetic and chemotherapy-induced neuropathy, but its role in idiopathic...BACKGROUND AND AIMS: Peripheral neuropathy (PN) is a common neurological condition in elderly adults. Vitamin D deficiency has been associated with diabetic and chemotherapy-induced neuropathy, but its role in idiopathic PN, in which no underlying cause of neuropathy can be identified, has not been investigated. METHODS: Two hundred thirty patients with idiopathic PN enrolled in the Peripheral Neuropathy Research Registry (PNRR) at Johns Hopkins University School of Medicine had vitamin D testing information on record. Linear and logistic regressions were used to investigate the relationship between absolute vitamin D level or vitamin D insufficiency (<20 ng/mL) and both the severity of neuropathy as measured by the reduced total neuropathy score (TNSr) and severity of neuropathic pain. RESULTS: Sixteen (7%) patients were vitamin D insufficient (<20 ng/mL). Controlling for factors known to correlate with severity of neuropathy, there was no correlation between absolute vitamin D levels and TNSr (correlation coefficient 0.01, 95% CI -0.03 to 0.07, p = .59) and no association between vitamin D insufficiency and TNSr (correlation coefficient 0.3, 95% CI -2.8 to 3.4, p = .86). Vitamin D insufficiency was not associated with the presence of neuropathic pain (OR 4.1, 95% CI 0.6-26.0, p = .13), and there was no correlation between vitamin D levels and pain score (correlation coefficient 0.01, 95% CI -0.02 to 0.03, p = .59). INTERPRETATION: In a single-center cohort of patients with idiopathic PN, there was no correlation between vitamin D levels and the severity of neuropathy or neuropathic pain.
Wiersma M, van der Star GM, Notermans NC
… +3 more, van Doorn PA, Vrancken AFJE, EXPRESS Study Consortium
J Peripher Nerv Syst
· 2024 Dec · PMID 39473054
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The prevalence of chronic polyneuropathy will increase due to the aging population, and therefore, it becomes ever so important to optimize the diagnostic process. However, it is uncertain which blood tests are required...The prevalence of chronic polyneuropathy will increase due to the aging population, and therefore, it becomes ever so important to optimize the diagnostic process. However, it is uncertain which blood tests are required and when nerve conduction studies (NCS) should be done in the workup of chronic polyneuropathy. We aimed to investigate the methodology used to develop national polyneuropathy guidelines and to provide an overview and strength of evidence of the recommendations. We searched PubMed and websites of national neurological associations as listed on the website of the World Federation of Neurology to identify national guidelines pertaining to the workup of chronic polyneuropathy by neurologists in an outpatient clinic setting. We identified three national guidelines in the United States and seven national guidelines in Denmark, France, Germany, the Netherlands, Norway, Spain, and Turkey. The methodology used to develop the guidelines differed greatly. All guidelines recommend a series of blood tests. Some guidelines advise to conduct NCS in all patients, while other guidelines advise to conduct NCS when certain symptoms are present. There is variation in recommendations about the extensiveness of NCS, but all mention measuring the sural nerve and the motor peroneal nerve. The evidence for the recommendations is graded as low. Despite some overlap, there are disparities between guidelines regarding the workup that is advised to do in patients with chronic polyneuropathy. It remains unclear which combination of blood tests are to be strongly recommended. Furthermore, it is undetermined whether NCS are always necessary.
Ponirakis G, Al-Janahi I, Elgassim E
… +25 more, Hussein R, Petropoulos IN, Gad H, Khan A, Zaghloul HB, Siddique MA, Ali H, Mohamed FFS, Ahmed LHM, Dakroury Y, El Shewehy AMM, Saeid R, Mahjoub F, Al-Thani SN, Ahmed F, Homssi M, Mahmoud S, Hadid NH, Obaidan AA, Salivon I, Mahfoud ZR, Zirie MA, Al-Ansari Y, Atkin SL, Malik RA
J Peripher Nerv Syst
· 2024 Dec · PMID 39439079
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AIM: Obesity is a major risk factor for diabetic peripheral neuropathy (DPN) in type 2 diabetes (T2D). This study investigated the effect of glucose lowering medication associated with weight change on DPN. METHODS: Part...AIM: Obesity is a major risk factor for diabetic peripheral neuropathy (DPN) in type 2 diabetes (T2D). This study investigated the effect of glucose lowering medication associated with weight change on DPN. METHODS: Participants with T2D were grouped based on whether their glucose lowering medications were associated with weight gain (WG) or weight loss (WL). They underwent clinical, metabolic testing and assessment of neuropathic symptoms, vibration perception threshold (VPT), sudomotor function and corneal confocal microscopy (CCM) at baseline and follow-up between 4 and 7 years. RESULTS: Of 76 participants, 69.7% were on glucose lowering medication associated with WG, and 30.3% were on glucose lowering medication associated with WL. At baseline, participants in the WG group had a significantly longer duration of diabetes (p < .01), higher douleur neuropathique en 4 (DN4) score (p < .0001) and VPT (p = .01) compared with those in the WL group. Over a 56-month period, participants in the WG group showed no significant change in body weight (p = .11), HbA1c (p = .18), triglycerides (p = .42), DN4 (p = .11), VPT (p = .15) or Sudoscan (p = .43), but showed a decline in corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD) and corneal nerve fiber length (CNFL) (p < .0001). Participants in the WL group showed a reduction in weight (p = .01) and triglycerides (p < .05), no change in DN4 (p = .30), VPT (p = .31) or Sudoscan (p = .17) and a decline in the corneal nerve branch density (p < .01). CONCLUSIONS: Participants treated with glucose lowering medication associated with weight gain had worse neuropathy and greater loss of corneal nerves during follow-up, compared to patients treated with medication associated with weight loss.
Zippo AG, Rodriguez-Menendez V, Pozzi E
… +14 more, Canta A, Chiorazzi A, Ballarini E, Monza L, Alberti P, Meregalli C, Bravin A, Coan P, Longo E, Saccomano G, Paiva K, Tromba G, Cavaletti G, Carozzi VA
J Peripher Nerv Syst
· 2024 Dec · PMID 39434652
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BACKGROUND AND AIMS: Chemotherapy-induced peripheral neurotoxicity (CIPN), with paraesthesia, numbness, dysesthesia and neuropathic pain ranks among the most common dose-limiting toxicity of several widely used anticance...BACKGROUND AND AIMS: Chemotherapy-induced peripheral neurotoxicity (CIPN), with paraesthesia, numbness, dysesthesia and neuropathic pain ranks among the most common dose-limiting toxicity of several widely used anticancer drugs. Recent studies revealed the microvascular angiogenesis as a new important actor, beside peripheral neurons, in the neurotoxicity and neuropathic pain development and chronicisation. The aim of this work is to elucidate the role of vascular alterations in CIPN. METHODS: We evaluated the severity of CIPN with neurophysiological, behavioural and neuropathological analysis together with the microvascular network in central and peripheral nervous systems of rats in order to correlate the features of the CIPN and the vascular abnormalities. The vascular network was quantitatively evaluated through synchrotron radiation-based X-ray phase-contrast micro-tomography imaging, measuring four specific parameters: vascular density, vessel diameter, vessel tortuosity and branching. RESULTS: Rats exposed to paclitaxel and affected by a severe painful sensory axonopathy showed an increased vascular density (putative sprouting angiogenesis) in the crucial districts of the central (somatosensory cortex and lumbar spinal cord) and peripheral nervous system (lumbar dorsal root ganglia). In addition, the complexity of the vascular network and the size of neo-formed vessels were significantly decreased in specific regions. On the other hand, less significant changes were observed in rats exposed to cisplatin, affected by a painless peripheral neuropathy, suggesting a specific involvement of neo-angiogenesis in the development of severe neurotoxicity and neuropathic pain. INTERPRETATIONS: These new ground-breaking results can shed light on new pathogenetic mechanisms and potential novel therapeutic approaches for painful-CIPN.
Theuriet J, Gerfaud-Valentin M, Durel CA
… +2 more, Gouya L, Pegat A
J Peripher Nerv Syst
· 2024 Dec · PMID 39425488
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BACKGROUND AND AIMS: Porphyrias are inherited metabolic disorders caused by mutations in genes encoding enzymes involved in the heme biosynthetic pathway, leading to the accumulation of heme precursors. Acute hepatic por...BACKGROUND AND AIMS: Porphyrias are inherited metabolic disorders caused by mutations in genes encoding enzymes involved in the heme biosynthetic pathway, leading to the accumulation of heme precursors. Acute hepatic porphyrias (AHP), including acute intermittent porphyria (AIP), can present with predominant peripheral neurological manifestations, often leading to a misdiagnosis as Guillain-Barré syndrome. METHODS: We report a case of AIP initially presenting as a peripheral neuropathy mimicking Parsonage-Turner syndrome (neuralgic amyotrophy, NA). Clinical and electrophysiological evaluations were conducted, including nerve conduction studies and needle electromyography (EMG). RESULTS: A 41-year-old woman presented with burning pain and electric shock-like sensations in the shoulders and trunk, alongside asymmetrical motor weakness in the upper limbs affecting arm abduction and finger extension. Electrophysiological evaluation revealed involvement of the superior trunk of the brachial plexus and the posterior interosseous nerve. Initially diagnosed with NA, she showed significant improvement in proximal strength over nine months but relapsed at fourteen months with severe finger extension weakness. Concurrent severe abdominal pain with constipation led to the identification of elevated urinary porphobilinogen (PBG) and delta-aminolevulinic acid (ALA) levels, confirming AHP and specifically AIP via genetic and biochemical testing. The patient received hemin and givosiran infusions, resulting in decreased ALA levels, improvement of motor weakness, and no further attacks. INTERPRETATION: This case underscores the need to consider AIP in the differential diagnosis of acute neuropathies like NA, especially when accompanied by abdominal pain and severe constipation. Early recognition and appropriate testing for PBG and ALA can prevent misdiagnosis and enable targeted treatment.
Wilhelmy B, Gerzanich V, Simard JM
… +1 more, Stokum JA
J Peripher Nerv Syst
· 2024 Dec · PMID 39402795
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BACKGROUND AND AIMS: After peripheral nerve stretch injury, most degenerating axons are thought to become disconnected at the time of injury, referred to as primary axotomy. The possibility of secondary axotomy-a delayed...BACKGROUND AND AIMS: After peripheral nerve stretch injury, most degenerating axons are thought to become disconnected at the time of injury, referred to as primary axotomy. The possibility of secondary axotomy-a delayed and potentially reversible form of disconnection-has not been evaluated. Here, we investigated secondary axotomy in a rat model of sciatic nerve stretch injury. We also evaluated whether axon sparing and functional improvement results from pharmacological blockade of the sodium-calcium exchanger 1 (NCX1), which is widely believed to contribute to traumatic axon degeneration but was previously only investigated in vitro. METHODS: We studied peripheral nerve secondary axotomy in a clinically relevant rat model of sciatic nerve rapid stretch injury with immunolabeling and fluorescence microscopy. The role of NCX1 in secondary axotomy was studied with pharmacological inhibition with SEA0400 and immunolabeling, immunoblot, and behavioral assays. RESULTS: We found that early after injury, many axons remained in-continuity and that degeneration of axons was delayed, consistent with the occurrence of secondary axotomy. βAPP, a marker of secondary axotomy, accumulated at regions of axon swelling and disconnection, and NCX1 was upregulated and co-localized to βAPP axonal swellings. Pharmacological blockade of NCX1 after injury reduced calpain activation, proteolytic degradation of neurofilaments, βAPP accumulation, distal axon degeneration, and improved hindlimb function. INTERPRETATION: Our data demonstrate a major role for secondary axotomy in peripheral nerve stretch injury and identify NCX1 as a promising therapeutic target to reduce secondary axotomy and improve functional outcome after nerve injury.
Rehbein T, Purks J, Dilek N
… +12 more, Behrens-Spraggins S, Sowden JE, Eichinger KJ, ACT‐CMT Study Group, Burns J, Pareyson D, Scherer SS, Reilly MM, Shy ME, McDermott MP, Heatwole CR, Herrmann DN
J Peripher Nerv Syst
· 2024 Dec · PMID 39390667
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BACKGROUND AND AIMS: The Charcot-Marie-Tooth Disease Health Index (CMT-HI) is a disease-specific, patient-reported disease burden measure. As part of an international clinical trial readiness study, individuals with CMT1...BACKGROUND AND AIMS: The Charcot-Marie-Tooth Disease Health Index (CMT-HI) is a disease-specific, patient-reported disease burden measure. As part of an international clinical trial readiness study, individuals with CMT1A (ages 18-75 years) underwent clinical outcome assessments (COAs), including the CMT-HI, to capture their longitudinal perspective on the disease burden. METHODS: Two hundred and fifteen participants underwent serial COAs including the CMT-HI, CMT Functional Outcome Measure (CMT-FOM), CMT Neuropathy Score (CMTNSv2R), and CMT Exam Score (CMTES/CMTES-R). Correlations between the total and subscale scores for the CMT-HI and other COAs were determined. Changes in the CMT-HI scores over 12 months were assessed using paired t-tests. The minimum clinically important difference (MCID) for the CMT-HI and its subscales were calculated by anchoring to a participant global impression of change scale. RESULTS: At baseline, CMT1A participants were 44.5 ± 15 years old (range: 18-75) and 58% were women. The mean CMT-HI was 25.7 ± 18.8 (range: 0-91.9; 100 reflecting maximal disease burden). The CMT-HI correlated with the CMT-FOM (r = .54, p < .0001), CMTNSv2R (r = .48, p < .0001), and CMTES/CMTES-R (r = .52/r = .54, p < .0001). Disease burden was greater in women than in men (CMT-HI 29.1 ± 19.1 vs. 21.2 ± 17.3, p = .001). Over 12 months, there was a nonsignificant mean increase in CMT-HI of 0.40 ± 10.0 (n = 189, p = .89). The MCID for the CMT-HI total score was 3.8 points (95% CI: 1.7-5.9). DISCUSSION: Patient-reported disease burden in CMT1A as measured by the CMT-HI is associated with measures of neurologic impairment and physical functioning. Women reported a higher disease burden than men. These data will inform the design of clinical trials in CMT1A.
Xie J, Yu H, Lv W
… +12 more, Li K, Li H, Ji Y, Cai Y, Cheng Y, Luo L, Wu C, Xu Y, Du L, Chen Y, Pang C, Deng B
J Peripher Nerv Syst
· 2024 Dec · PMID 39343764
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BACKGROUND AND AIMS: Little is known about the ability of serological biomarkers to monitor clinical outcomes in patients with Guillain-Barré syndrome (GBS). The objective of this study was to determine the associations...BACKGROUND AND AIMS: Little is known about the ability of serological biomarkers to monitor clinical outcomes in patients with Guillain-Barré syndrome (GBS). The objective of this study was to determine the associations of liver function, easily available and convenient biomarkers, with the clinical course and outcome of severe GBS in patients. METHODS: A prospective data collection was conducted in a cohort of 343 GBS patients from multi-centers between September 2019 and December 2023. Serum samples were obtained at four-time points for mechanical ventilation (MV) patients and two-time points for non-MV patients. The primary endpoint was the need for MV during hospitalization, while secondary outcomes included the ability to walk independently and the mortality at 26-week follow-up. RESULTS: (i) A total of 208 patients were eligible, of whom 50 required MV with a median (interquartile range) ventilation duration of 15 (8-27) days. (ii) Hypohepatia, as evidenced by reduced total protein (OR 0.913 [95% CI 0.862-0.967]) and albumin (0.775 [0.679-0.884]) 1 week after treatment, along with raised liver enzymes (2.732 [1.007-7.413]), was associated with the risk of MV after adjusting for confounders. (iii) After 26-week follow-up, patients with hypohepatia were less likely to regain independent walking and exhibited higher mortality in survival analysis (all log-rank p < .05). (iv) In a cross-sectional study spanning up to 4 years of follow-up, patients with prolonged MV (≥15 days) experienced a longer time to regain independent ambulation than those with shorter MV (167 [46-316] vs. 69 [24-106], p = .036). However, no relationships between liver function and prolonged MV were revealed. INTERPRETATION: Dynamically monitoring hepatic metabolism and promptly adjusting, it can aid the improvement of GBS in patients.
Crugeiras J, Calls A, Contreras E
… +6 more, Alemany M, Navarro X, Yuste VJ, Casanovas O, Udina E, Bruna J
J Peripher Nerv Syst
· 2024 Dec · PMID 39329299
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BACKGROUND AND AIMS: Cell culture is a fundamental experimental tool for understanding cell physiology. However, translating these findings to in vivo settings has proven challenging. Replicating donor tissue conditions,...BACKGROUND AND AIMS: Cell culture is a fundamental experimental tool for understanding cell physiology. However, translating these findings to in vivo settings has proven challenging. Replicating donor tissue conditions, including oxygen levels, is crucial for achieving meaningful results. Nevertheless, oxygen culture conditions are often overlooked, particularly in the context of chemotherapy-induced neurotoxicity. METHODS: In this study, we investigated the role of oxygen levels in primary neuronal cultures by comparing neuronal performance under cisplatin exposure (1 μg/mL) in supraphysiological normoxia (representing atmospheric conditions in a standard incubator; 18.5% O) and physioxia (representing physiologic oxygen conditions in nervous tissue; 5% O). Experiments were also conducted to assess survival, neurite development, senescence marker expression, and proinflammatory cytokine secretion. RESULTS: Under control conditions, both oxygen concentration conditions exhibited similar behaviors. However, after cisplatin administration, sensory neurons cultured under supraphysiological normoxic conditions show higher mortality, exhibit an evolutionarily proinflammatory cytokine profile over time, and activate apoptotic-regulated neuron death markers. In contrast, under physiological conditions, neurons treated with cisplatin exhibited senescence marker expression and an attenuated inflammatory secretome. INTERPRETATION: These results underscore the critical role of oxygen in neuronal culture, particularly in studying compounds where neuronal damage is mechanistically linked to oxidative stress. Even at identical doses of evaluated neurotoxic drugs, distinct cellular phenotypic fates can emerge, impacting translatability to the in vivo setting.
Geroldi A, La Barbera A, Mammi A
… +23 more, Origone P, Gaudio A, Ponti C, Sanguineri F, Matà S, Sperti M, Carboni I, Bellone E, Gotta F, Gemelli C, Massucco S, Valeria G, Marinelli L, Grandis M, Bisogni G, Sabatelli M, Piscosquito G, Esposito G, Schenone A, Manganelli F, Mandich P, Tozza S, Luigetti M
J Peripher Nerv Syst
· 2024 Dec · PMID 39251209
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BACKGROUND AND AIMS: Since 2016, biallelic mutations in the membrane metalloendopeptidase (MME) gene have been associated with late-onset recessive CMT2 (CMT2T). More recently, heterozygous mutations have also been ident...BACKGROUND AND AIMS: Since 2016, biallelic mutations in the membrane metalloendopeptidase (MME) gene have been associated with late-onset recessive CMT2 (CMT2T). More recently, heterozygous mutations have also been identified in familial and sporadic patients with late-onset axonal neuropathy, ranging from subclinical to severe. This indicates that the heterozygous MME variants may not be fully penetrant, or alternatively, that they may be a potential risk factor for neuropathy. Here, we describe the clinical, neurophysiological, and genetic findings of 32 CM2T Italian patients. METHODS: The patients were recruited from four different Italian referral centers. Following a comprehensive battery of neurological, electrophysiological, and laboratory examinations, the patients' DNA was subjected to sequencing in order to identify any variants in the gene. Bioinformatic and modeling analyses were performed to evaluate the identified variants' effects. RESULTS: We observe a relatively mild axonal sensory-motor neuropathy with a greater impairment of the lower extremities. Biallelic and monoallelic patients exhibit comparable disease severity, with an earlier onset observed in those with biallelic variants. When considering a subgroup with more than 10 years of disease, it becomes evident that biallelic patients exhibit a more severe form of neuropathy. This suggests that they are more prone to quick progression. INTERPRETATION: CM2T has been definitively defined as a late-onset neuropathy, with a typical onset in the fifth to sixth decades of life and a more rapidly progressing worsening for biallelic patients. CMT2T can be included in the neuropathies of the elderly, particularly if MME variants heterozygous patients are included.
Salvalaggio A, Cacciavillani M, Tierro B
… +11 more, Coraci D, Currò R, Ferrarini M, Pegoraro E, Bello L, Fabrizi GM, Filla A, Padua L, Manganelli F, Cortese A, Briani C
J Peripher Nerv Syst
· 2024 Dec · PMID 39219417
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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 r...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.
Kohle F, Stark C, Klünter HD
… +6 more, Wernicke D, Wunderlich G, Fink GR, Klussmann JP, Schroeter M, Lehmann HC
J Peripher Nerv Syst
· 2024 Dec · PMID 39219364
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BACKGROUND/AIMS: Peripheral neuropathies perturbate the sensorimotor system, causing difficulties in walking-related motor tasks and, eventually, falls. Falls result in functional dependency and reliance on healthcare, e...BACKGROUND/AIMS: Peripheral neuropathies perturbate the sensorimotor system, causing difficulties in walking-related motor tasks and, eventually, falls. Falls result in functional dependency and reliance on healthcare, especially in older persons. We investigated if peripheral neuropathy is a genuine risk factor for falls in the elderly and if quantification of postural control via posturography is helpful in identifying subjects at risk of falls. METHODS: Seventeen older persons with a clinical polyneuropathic syndrome of the lower limbs and converging electrophysiology were compared with 14 older persons without polyneuropathy. All participants were characterized via quantitative motor and sensory testing, neuropsychological assessment, and self-questionnaires. Video-nystagmography and caloric test excluded vestibulocochlear dysfunction. For further analysis, all subjects were stratified into fallers and non-fallers. Overall, 28 patients underwent computerized dynamic posturography for individual fall risk assessment. Regression analyses were performed to identify risk factors and predictive posturography parameters. RESULTS: Neuropathy is an independent risk factor for falls in the elderly, while no differences were observed for age, gender, weight, frailty, DemTect test, timed "Up & Go" test, and dizziness-related handicap score. In computerized dynamic posturography, fallers stepped more often to regain postural control in challenging conditions, while the Rhythmic Weight Shift test showed a lack of anterior-posterior bidirectional voluntary control. INTERPRETATION: Our study confirms peripheral neuropathy as a risk factor for older persons' falls. Fallers frequently used stepping to regain postural control. The voluntary control of this coping movement was impaired. Further investigations into these parameters' value in predicting the risk of falls in the elderly are warranted.
Vittert AB, Daniel M, Svientek SR
… +7 more, Risch MJ, Nelson NS, Donneys A, Dehdashtian A, Sacks GN, Buchman SR, Kemp SWP
J Peripher Nerv Syst
· 2024 Dec · PMID 39180472
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INTRODUCTION: Radiation-induced peripheral neuropathy is a rare, but serious complication often resulting in profound morbidity, life-long disability, and chronic debilitating pain. Unfortunately, this type of peripheral...INTRODUCTION: Radiation-induced peripheral neuropathy is a rare, but serious complication often resulting in profound morbidity, life-long disability, and chronic debilitating pain. Unfortunately, this type of peripheral neuropathy is usually progressive, and almost always irreversible. To date, a standardized rat model of radiation-induced peripheral neuropathy has not been established. The purpose of the present study was to examine neuropathic pain, sensorimotor impairment, and muscle force parameters following the administration of a clinically relevant radiation dose in a rat model. METHODS: Ten rats were randomly assigned to one of two experimental groups: (1) radiation and (2) sham-radiated controls. Radiated animals were given a clinically relevant dose of 35 Gray (Gy) divided into five daily doses of 7 Gy/day. This regimen represents a human equivalent dose of 70 Gy, approximating the same dosage utilized for radiotherapy in oncologic patients. Sham-radiated controls were anesthetized and placed in the radiation apparatus but were not given radiation. All animals were tested for baseline values in both sensorimotor and pain behavioral tests. Sensorimotor testing consisted of the evaluation of walking tracks with the calculation of the Sciatic Functional Index (SFI). Pain-related behavioral measures consisted of mechanical allodynia (von Frey test), cold allodynia (Acetone test), and thermal allodynia (Hargreaves test). Animals were tested serially over an 8-week period. At the study endpoint, electrophysiological and muscle force assessments were completed, and histomorphometric analysis was performed on all sciatic nerves. RESULTS: Animals that underwent radiation treatment displayed significantly greater pain hypersensitivity to mechanical stimulation as compared to sham radiated controls from weeks 4 to 8 of testing. SFI values indicated sensorimotor impairments in the overground gait of radiated animals as compared to non-radiated animals. Furthermore, radiated animals displayed reduced twitch and tetanic muscle force when compared to sham radiated controls. CONCLUSIONS: A clinically relevant human equivalent dose of fractionated 35 Gy in rats established significant pain hypersensitivity, impairments in sensorimotor locomotion, and decreased muscle force capacity. This novel rodent model of radiation-induced peripheral neuropathy can be utilized to assess the potential efficacy of therapeutic treatments to either prevent or remediate this clinically debilitating condition.
BACKGROUND AND AIMS: Leprosy is a chronic infectious disease caused by Mycobacterium leprae (M. leprae), an intracellular bacillus that systematically invades the peripheral nerves. Diagnosing leprosy neuropathy is still...BACKGROUND AND AIMS: Leprosy is a chronic infectious disease caused by Mycobacterium leprae (M. leprae), an intracellular bacillus that systematically invades the peripheral nerves. Diagnosing leprosy neuropathy is still a defying skill, and late diagnosis and treatment are still a reality. Based on the biological characteristics of M. leprae, particularly its preference for invading the Schwann cells localized at the coldest areas of human body, we hypothesized that these areas have focal demyelination that may escape detection through standard nerve conduction studies (NCSs) protocols. METHODS: Twenty-five patients with confirmed multibacillary leprosy and 14 controls were accessed. A multisegmented NCS protocol (MP) was performed, targeting short segments through the coldest areas, to identify focal areas of slowed conduction velocity. The effectiveness of this multisegmented protocol was compared to the standard protocol (SP) to detect abnormalities. RESULTS: All leprosy patients presented an abnormal study with the MP, contrasting to 19 with the SP. The most frequent NCS pattern was an asymmetric neuropathy with focal slowing of conduction velocity, found in 23 out of 25 leprosy patients. Significant differences favoring the proposed method were observed when comparing the MP with the SP. Notably, the MP increased the sensitivity to detect abnormalities by 122%, 133%, and 257% for the median, peroneal, and tibial nerves, respectively. MP also increases sensitivity to detect focal abnormalities in the ulnar nerve. INTERPRETATION: The MP protocol significantly increases the sensitivity of NCSs to detect neurophysiological abnormalities in leprosy neuropathy.
AIMS: To develop a standardised, automated protocol for detecting protein gene product 9.5 (PGP9.5) positive intra-epidermal nerve fibres (IENFs) in skin biopsies, transitioning from the established manual technique to a...AIMS: To develop a standardised, automated protocol for detecting protein gene product 9.5 (PGP9.5) positive intra-epidermal nerve fibres (IENFs) in skin biopsies, transitioning from the established manual technique to an automated platform. This automated method, although currently intended for research applications, may improve the accessibility of this diagnostic test for small fibre neuropathy in clinical settings. METHODS: Skin biopsies (n = 274) from 100 participants (fibromyalgia syndrome n = 62; idiopathic small fibre neuropathy: n = 16; healthy volunteers: n = 22) were processed using an automated immunohistochemistry platform. IENF quantification was performed by blinded examiners, with reliability assessed via a two-way mixed-effects model to evaluate inter- and intra-observer variability. RESULTS: The automated staining system reproduced intra-epidermal nerve fibre density (IENFD) counts consistent with free-floating sections (mean ± standard deviation: free-floating: 5.6 ± 3.4 fibres/mm; automated: 5.9 ± 3.2 fibres/mm). A median difference of 0.3 with a lower bound 95% Confidence Interval (CI) at -0.00005 established non-inferiority against a margin of -0.4 (p = .08). Specifically, the inter-class correlation coefficient (class denotes consistency in measured observations) was 99% (95% CI: 0.9-1), indicating excellent agreement between free-floating and automated methods. The inter- and intra-class coefficient between examiners were both 99% (95% CI: 0.9-0.1) for IENFD, demonstrating high reliability using sections stained using the automated method. INTERPRETATION: Automated immunohistochemistry provides high-throughput reliable and reproducible intra-epidermal nerve fibre quantification. This method, although currently proof-of-concept, for research use only, may be more widely deployed in histopathology laboratories to increase the adoption of IENFD assessment for the diagnosis of peripheral neuropathies.