Peter James Dyck

Natural history of 46 patients with multifocal motor neuropathy with conduction block

We studied 46 consecutive patients with multifocal motor neuropathy with conduction block (MMN‐CB). Typically, asymmetric weakness and atrophy of the hands or arms developed insidiously, but spontaneous improvement (without treatment) or death from this disease did not occur and 94% remained employed. For 18 patients examined on multiple occasions using the weakness subscore of the neuropathy impairment score [NIS(W)] for a median time of 2.3 years, worsening of 1.3 points per year was observed; many patients, however, had received intensive immunomodulating therapy. Median worsening to our first evaluation (generally without treatment) was estimated at 4.2 points per year, perhaps suggesting that treatment had influenced course. Three criteria for conduction block (CB) were compared, but the least stringent was sensitive for the diagnosis. Conduction block accompanied by weakness and atrophy typically affected only motor fibers, especially of midforearm nerves, and these sites of dysfunction persisted for months or years. Neurological signs and electrodiagnostic features were consistent with CB, axonal degeneration, a variable degree of reinnervation, and segmental demyelination. Although this study did not focus on therapy, intravenous gammaglobulin and cyclophosphamide appeared to be associated with neurological improvement, which was seldom complete or sustained. Axonal degeneration and faulty regeneration may in part explain this muted response. Possibly, treatment must be earlier, more intense, or different.

Double-blind, placebo-controlled study of the application of capsaicin cream in chronic distal painful polyneuropathy

&NA; We have completed a 12‐week double‐blind, placebo‐controlled randomized study on the efficacy of the application of capsaicin (CAPS) cream (0.075%) in the treatment of chronic distal painful polyneuropathy. Forty patients were enrolled and 39 completed the study. The 2 limbs were randomly assigned to CAPS or placebo (PLAC). The cream was applied 4 times a day. The first tube contained the active PLAC, methyl nicotinate. In the final 4 weeks (single‐blind wash‐out phase), PLAC was administered bilaterally. Efficacy was evaluated using the following scales: (1) investigator global, (2) patient global, (3) visual analog (VAS) of pain severity, (4) VAS of pain relief, (5) activities of daily living, and (6) allodynia. Patients were examined at onset and at monthly intervals using a neurologic disability scale, nerve conduction studies, computer‐assisted sensory examination for vibration and thermal cooling and warming, QSART (quantitative sudomotor axon reflex test) and quantitative flare response. There was no statistical evidence of efficacy of CAPS cream over PLAC for any of the pain indices. At early time points (1–4 weeks), there were a small number of indices that favored the PLAC. The percent of limbs that improved on the investigators global scale were 51.3 vs. 53.8 at 4 weeks, 56.4 vs. 64.1 at 8 weeks and 59 vs. 66.7 at 12 weeks for CAPS vs. PLAC; no statistically significant difference was found. All the safety indices showed no difference between sides. We interpret the early hyperalgesia on the CAPS side as being responsible for the better performance of PLAC at early time points. The large percentage of limbs that improved may be a pronounced PLAC response.

Axonal Atrophy from Permanent Peripheral Axotomy in Adult Cat

The peripheral axons of lower motor and spinal ganglion neurons were permanently transected and not allowed to regrow to target tissue in adult cats by amputation of the hind limb at the hip. The number and sizes of L-7 lower motor neurons at two levels (cell bodies of lateral group motor neurons and myelinated fibers [MFs] of ventral root) and of L-7 spinal ganglion neurons at two levels (cell bodies of L-7 spinal ganglion and MFs of dorsal root) were morphometrically evaluated in groups of cats at 3 months, 9 months, and 18 months after amputation and compared with the number and sizes of neurons in controls or with those on the opposite side. The number of neurons decreased only minimally after amputation. The diameter of neuron cell bodies was only equivocally reduced. By contrast, the median diameter and the peak diameter of both large and small MFs of dorsal and ventral nerve roots were significantly (approximately 30%) less than those of controls. This reduction in diameter of MFs is judged to be related to chronic axonal atrophy rather than to selective loss of large fibers. Permanent transection of distal axons should therefore prove to be a good model of chronic axonal atrophy.

Lumbar motoneurons of man II: the number and diameter distribution of large- and intermediate-diameter cytons in "motoneuron columns" of spinal cord of man.

Using a methodology which corrects for split cell error, and for the linear relationship between diameter of nucleolus and of cell body (cyton) and using semi-automatic methods of counting and sizing and programmed calculation and plotting, the number and diameter histograms of cytons of L-3, L-4, and L-5 motoneuron columns of 18 reference spinal cords of man (ages 17 to 82 years) have been evaluated. The number and frequency distribution of diameters (diameter histograms) of myelinated fibers of L-3, L-4 and L-5 ventral spinal roots (VSRs) had been determined in a preceding study as a control to validate the estimated number of alpha and gamma motoneuron cytons determined in this study from the same segment of spinal cord. The diameter histograms of cytons of motoneuron columns consistently contain three discrete peaks: a large-diameter peak (CL), an intermediate-diameter (CI) and small-diameter peak (CS). To illustrate, on the average, there were 4874 ± 585 large cytons and 1700 ± 564 → intermediate cytons in the L5 segment of spinal cord. A reasonably close concordance was found between the average number of large cytons of spinal cord segments and the number of large-diameter myelinated fibers of ventral spinal roots (VSRs) (0.91, 0.94, and 0.98 for L3, L4 and L5 spinal cord segments and ventral spinal roots, respectively). For the ratio of the number of intermediate cytons to the number of intermediate axons the concordance was not as good (0.77, 0.85, and 1.14 for L3, L4 and L5 segments, respectively). Assuming that a cyton provides only one axon to VSR it is reasonable to infer from our studies that most large-diameter cytons are those of alpha motoneurons and that most of the intermediate-diameter cytons are those of gamma motor neurons. The greater number of axons than of cytons for the intermediate diameter group may be from a spurious inclusion of small-diameter axons (possibly pre-ganglionic autonomic fibers) with the intermediate-diameter group. On the average, the range of diameters of large-diameter cyton population in motoneuron col

Lumbar motoneurons of man: I) Number and diameter histogram of alpha and gamma axons of ventral root

The numbers of large and intermediate diameter myelinated fibers of 17 ventral lumbar (L3, L4 and L5) spinal roots (vsr) of man (ages 17–81 years) have been evaluated using the improved methods of histologic processing and morphometry now available, semi-automatic methods of measurement and programmed calculation and plotting. A population of small diameter myelinated fibers as found in thoracic (T11) vsr, which are presumed to be preganglionic sympathetic fibers, were essentially absent from L3, L4 and L5 roots. On the average, there were 5716 (70%) large diameter fibers and 2625 (30%) intermediate diameter fibers in the L3 ventral spinal root. Comparable figures for L4 vsr were 4900 (70%) and 2152 (30%) and for L5 vsr were 5043 (75%) and 1559 (25%). On the assumption that these lumbar roots contain few if any small diameter myelinated pre-ganglionic sympathetic axons, the large diameter fibers correspond to alpha motoneuron axons and the small diameter fibers to gamma motoneuron axons. With age, a decrease in the number of myelinated fibers was estimated to be 350 fibers per decade (∼5% per decade).

Sudden cardiac death in diabetes mellitus: risk factors in the Rochester diabetic neuropathy study

Objectives: To determine risk factors for sudden cardiac death and the role of diabetic autonomic neuropathy (DAN) in the Rochester diabetic neuropathy study (RDNS) Methods: Associations between diabetic and cardiovascular complications, including DAN, and the risk of sudden cardiac death were studied among 462 diabetic patients (151 type 1) enrolled in the RDNS. Medical records, death certificates, and necropsy reports were assessed for causes of sudden cardiac death. Results: 21 cases of sudden cardiac death were identified over 15 years of follow up. In bivariate analysis of risk covariates, the following were significant: ECG 1 (evolving and previous myocardial infarctions): hazard ratio (HR)u200a=u200a4.4 (95% confidence interval (CI), 1.6 to 12.1), pu200a=u200a0.004; ECG 2 (bundle branch block or pacing): HRu200a=u200a8.6 (2.9 to 25.4), p<0.001; ECG 1 or ECG 2: HRu200a=u200a4.2 (1.3 to 13.4), pu200a=u200a0.014; and nephropathy stage: HRu200a=u200a2.1 (1.3 to 3.4), pu200a=u200a0.002. Adjusting for ECG 1 or ECG 2, autonomic scores, QTc interval, high density lipoprotein (HDL) cholesterol, 24 hour microalbuminuria, and 24 hour total proteinuria were significant. However, adjusting for nephropathy, none of the autonomic indices, QTc interval, HDL cholesterol, microalbuminuria, or total proteinuria was significant. At necropsy, all patients with sudden cardiac death had coronary artery or myocardial disease. Conclusions: Sudden cardiac death was correlated with atherosclerotic heart disease and nephropathy, and to a lesser degree with DAN and HDL cholesterol. Although DAN is associated with sudden cardiac death, it is unlikely to be its primary cause.

Inflammation and neuropathic attacks in hereditary brachial plexus neuropathy

Objective: To study the role of mechanical, infectious, and inflammatory factors inducing neuropathic attacks in hereditary brachial plexus neuropathy (HBPN), an autosomal dominant disorder characterised by attacks of pain and weakness, atrophy, and sensory alterations of the shoulder girdle and upper limb muscles. Methods: Four patients from separate kindreds with HBPN were evaluated. Upper extremity nerve biopsies were obtained during attacks from a person of each kindred. In situ hybridisation for common viruses in nerve tissue and genetic testing for a hereditary tendency to pressure palsies (HNPP; tomaculous neuropathy) were undertaken. Two patients treated with intravenous methyl prednisolone had serial clinical and electrophysiological examinations. One patient was followed prospectively through pregnancy and during the development of a stereotypic attack after elective caesarean delivery. Results: Upper extremity nerve biopsies in two patients showed prominent perivascular inflammatory infiltrates with vessel wall disruption. Nerve in situ hybridisation for viruses was negative. There were no tomaculous nerve changes. In two patients intravenous methyl prednisolone ameliorated symptoms (largely pain), but with tapering of steroid dose, signs and symptoms worsened. Elective caesarean delivery did not prevent a typical postpartum attack. Conclusions: Inflammation, probably immune, appears pathogenic for some if not all attacks of HBPN. Immune modulation may be useful in preventing or reducing the neuropathic attacks, although controlled trials are needed to establish efficacy, as correction of the mutant gene is still not possible. The genes involved in immune regulation may be candidates for causing HBPN disorders.

Endoneurial oxygen tension and radial topography in nerve edema

Endoneurial edema occurs in numerous human and experimental neuropathies. We tested the hypothesis that the resultant increase in intercapillary distance (ICD) may result in endoneurial hypoxia. Experimental galactose neuropathy (EGN) was chosen since in this model, edema is due to the accumulation of galactitol, which does not directly damage nerve fibers, so that it was possible to study the role of endoneurial edema alone. We measured endoneurial oxygen tensions (PnO2) using oxygen-sensitive microelectrodes and related PnO2 radial topography to ICD. We also determined local oxygen consumption (VLO2) and critical PnO2(PcritO2). EGN and age-matched controls were studied at 4 months. (1) Caudal nerve conduction velocity was reduced in EGN. (2) The PnO2 values were reduced in EGN and the PnO2 histogram was shifted into the hypoxic range. These changes were paralleled by a significant increase in ICD in EGN. (3) The radial topography of PnO2 in EGN differed from the relatively uniform distribution in control nerves. In EGN the subperineurial PnO2 was significantly lower than the PnO2 at the center of the fascicle. These changes were paralleled by a significantly greater increase in ICD in the periphery. (4) That the PnO2 reduction in EGN was significant is suggested by the marked reduction in VLO2 and the large percentage (greater than 75%) of intrafascicular regions that fell below PcritO2 in EGN.

Effect of Serum Hyperosmolality on Morphometry of Healthy Human Sural Nerve

Fascicles of human sural nerve, fixed by immersion in isosmolar 2.5% glutaraldehyde solution and in isosmolar osmium tetroxide and embedded in epoxy, undergo a 10% shrinkage in area when compared with cryostal sections. By contrast, fascicles fixed in hyperosmolar solutions (whether 5.6% glutaraldehyde solution or 2.5% glutaraldehyde raised to the same level of hyperosmolality with sucrose) undergo a 43% shrinkage in area. Axis cylinders of myelinated fibers undergo a selective and severe shrinkage and assume noncircular shapes, the shapes allowing the transverse area to decrease when the perimeter remains unchanged. These studies raise the intriguing question of whether interstitial hyperosmolality in metabolic diseases, such as diabetes mellitus, or in uremia may cause osmotic axonal shrinkage, altered transverse fiber shape, and abnormality of function and structure of nerve.

Lead Neuropathy: 2. Random Distribution of Segmental Demyelination Among “Old Internodes” of Myelinated Fibers

One-hundred teased fibers of proximal and of distal sural nerve of five rats fed lead carbonate for 3 months were evaluated to see whether the pattern of segmental demyelination was random or clustered. If the evaluation was done by the length of the “territory of an old internode” (the region of one Schwann cell) a significant departure from randomness could not be shown for the majority of nerves. However, if the evaluation was by regions with and without myelin a highly clustered pattern of segmental demyelination was found. Since several remyelinated internodes form following internodal segmental demyelination, of one “old internode” the latter method of analysis would be expected to show clustering even though Schwann cell damage was random. Therefore the second method of analysis cannot be used to assess randomness of Schwann cell involvement in neuropathy. We interpret these studies as supporting the concept that Schwann cells are primarily and ubiquitously involved in lead neuropathy of the rat. Possible mechanisms of such primary Schwann cell injury are direct damage from lead of the intrafascicular interstitial fluid or from increased intrafascicular interstitial pressure.