SummaryBackgroundAscorbic acid reduced the severity of neuropathy in transgenic mice overexpressing peripheral myelin protein 22 (PMP22), a model of Charcot–Marie–Tooth disease type 1A (CMT1A) associated with the PMP22 duplication. However, in three 1-year trials, ascorbic acid had no benefit in human beings. We did a multicentre 2-year trial to test the efficacy and tolerability of ascorbic acid in patients with CMT1A.MethodsAdult patients (aged 18–70 years) with symptomatic CMT1A were enrolled from nine centres in Italy and the UK, and were randomly assigned (1:1 ratio) to receive 1·5 g/day oral ascorbic acid or matching placebo for 24 months. The randomisation sequence was computer generated by block randomisation, stratified by centre and disease severity, and patients were allocated to treatment by telephone. The primary outcome was change in the CMT neuropathy score (CMTNS) at 24 months. Secondary outcomes were timed 10 m walk test, nine-hole peg test, overall neuropathy limitations scale, distal maximal voluntary isometric contraction, visual analogue scales for pain and fatigue, 36-item short-form questionnaire, and electrophysiological measurements. Patients, treating physicians, and physicians assessing outcome measures were masked to treatment allocation. Analysis of the primary outcome was done on all randomised patients who received at least one dose of study drug. This study is registered, numbers ISRCTN61074476 () and EudraCT 2006-000032-27 ().FindingsWe enrolled and randomly assigned 277 patients, of whom six (four assigned to receive ascorbic acid) withdrew consent before receiving treatment; 138 receiving ascorbic acid and 133 receiving placebo were eligible for analysis. Treatment was well tolerated: 241 of 271 patients (89% in each group) completed the study; 20 patients (nine receiving ascorbic acid) dropped out because of adverse events. Mean CMTNS at baseline with missing data imputed was 14·7 (SD 4·8) in the ascorbic acid group and 13·9 (4·2) in the placebo group. Mean worsening of CMTNS was 0·2 (SD 2·8, 95% CI −0·3 to 0·7) in the ascorbic acid group and 0·2 (2·7, −0·2 to 0·7) in the placebo group (mean difference 0·0, 95% CI −0·6 to 0·7; p=0·93). We recorded no differences between the groups for the secondary outcomes at 24 months. 21 serious adverse events occurred in 20 patients, eight in the ascorbic acid group and 13 in the placebo group.InterpretationAscorbic acid supplementation had no significant effect on neuropathy compared with placebo after 2 years, suggesting that no evidence is available to support treatment with ascorbic acid in adults with CMT1A.FundingTelethon-UILDM and AIFA (Italian Medicines Agency) for CMT-TRIAAL, and Muscular Dystrophy Campaign for CMT-TRAUK.

We studied the frequency and clinical correlates of different IgM specificities in 75 patients with neuropathy associated with IgM monoclonal gammopathy. Patients were tested for IgM reactivity with the myelin-associated glycoprotein, P0, neurofilaments, and tubulin by immunoblot; with GM1, asialo-GM1, GM2, GD1a, GD1b, sulfatide, and chondroitin sulfate C by enzyme-linked immunosorbent assay; and with brain and nerve glycolipids by overlay high-performance thin-layer chromatography. Forty-two patients (56%) had high titers of IgM antibodies to MAG; 4 (5%), to sulfatide (1 also to myelin-associated glycoprotein); 4 (5%), to the 200-kd neurofilament (2 also to myelin-associated protein); and 1 each, to GD1b and chondroitin sulfate C. No reactivity was found in 26 patients (35%). More patients with anti-myelin-associated glycoprotein IgM (62%) than with unknown IgM reactivity (31%) had a predominantly sensory neuropathy (p < 0.025). Nerve conduction findings were consistent with a demyelinating neuropathy in 77% of patients reactive to myelin-associated glycoprotein and 24% with unknown reactivity (p < 0.0001) and the mean conduction velocity of peroneal nerve was lower in the former group (22.9 m/sec) than in the latter group (39.6 m/sec) (p < 0.000001). Patients with anti-sulfatide IgM had a sensorimotor neuropathy with morphological evidence of demyelination while anti-neurofilament IgM was not associated with homogeneous findings. Patients with anti-GD1b or anti-chondroitin sulfate C IgM had a predominantly motor impairment. The frequent occurrence of anti-neural IgM antibodies in neuropathy associated with IgM gammopathy, and their frequent, though not constant association with similar neuropathy features, support their possible pathogenetic role in the neuropathy.

(3 Neurol Neurosurg Psychiatry 1994;57:983-986)

We report the features of non-length dependent small fiber neuropathy (SFN) and compare them to those with distal length-dependent SFN. In a series of 224 consecutive neuropathy patients, we evaluated 44 patients with SFN diagnosed in the presence of both symptoms and signs. Eleven were classified as non-length dependent SFN. Disease associations were Sjögren's syndrome (two patients), impaired glucose tolerance, rheumatoid arthritis, hepatitis C virus, Crohn's disease, and idiopathic (five patients). In the 33 patients with distal SFN, the age of onset was significantly older and more had impaired glucose metabolism (16/33). In both groups, pain was mainly characterized as burning, but patients with non-length dependent SFN more often reported an "itchy" quality and allodynia to light touch.

of a levodopa-nonresponsive PD patient who failed to improve after pallidotomy also failed to improve after DBS STN. 10 Our patients were all levodopa-responsive and, aside from a single patient, improved after their pallidotomy.There are several reasons why postpallidotomy STN DBS may result in less robust motor improvement. First, there is an obvious referral bias toward patients who were not satisfied after their pallidotomy, either for objective or subjective reasons. This may represent a more aggressive disease process or more atypical course. The pre-and postpallidotomy off drug UPDRS scores, however, were similar in this group of pallidotomy DBS patients compared to our pallidotomy population in general (n ϭ 89). 1 Dyskinesia scores were also similar. Second, electrophysiological recordings, on which we greatly rely for placement, can be altered in the STN following GPi ablation, possibly resulting in suboptimal placement. 11 Random suboptimal placement is possible in either group. Third, there could be redundant physiological effects that would mitigate against subsequent improvement after the second procedure. A single study that simultaneously implanted GPi and STN DBS found that combined stimulation was no more effective than STN stimulation alone. 12 Fourth, we present a relatively small number of patients and the results could be different with a larger sample.Overall, the small corpus of literature on the efficacy and safety of postpallidotomy STN DBS is mixed. We recommend prudence when considering DBS in this population. REFERENCES