How to recognise and treat peripheral nervous system vasculitis.

Peripheral neuropathy can be the first and only manifestation of necrotising primary immune-mediated vasculitis which, carries a high mortality. A clear idea of how to both recognise and treat peripheral nervous system vasculitis is important. We provide a practical approach to immediate and longer term treatment protocols.

Clinical skills evaluation of trainees in a neurology department.

Three to 12 evaluations of clinical performance using the mini-clinical evaluation exercise (Mini-CEX) (n = 124) or direct observation of procedural skills (DOPS) (n = 21) were performed on 27 trainees working in an NHS neurology department. The communications/ counselling skills subdomain was scored in 64 evaluations. For Mini-CEX the focus was on gathering data (22%), diagnosis (31%), management (34%) and counselling (7%) (focus not recorded in 6%). For DOPS, lumbar puncture was the most common evaluated procedure (57%). Mini-CEX evaluations lasted 23.8 minutes (10.6) (mean, sd) and DOPS 25.9 minutes (12.6). Mini-CEX scores for overall competence and communication skills were mean 5.99 (sd 0.95, range 4-8) and 5.98 (sd 1.21, range 3-9) and for DOPS 5.71 (sd 0.90, range 4-8) both on scales of 1 to 9. Overall trainee competence and communication scores increased with year of training (p < 0.001, p < 0.004 univariate analysis). Assessors undertook up to three or four assessments in a session. Assessors and trainees considered that the observation and feedback had been 'very' or 'quite' useful in providing a relevant element of assessment. These assessments were feasible and useful in a neurology department and provided some evidence for increasing performance with trainee seniority. More assessor time (approximately one hour) than trainee time (24-26 min) was needed for each assessment undertaken.

Effects of ageing on touch.

A decline in the main sensory modalities is well reported to occur with ageing. This article outlines the normal pathways involved in touch sensation and includes a review of available evidence relating to the study of ageing and touch. The authors try to use what is known about the neuroanatomy and neurophysiology of ageing to explain the impact on some broad functional deficits seen in the elderly population. The importance of understanding how the normal ageing process affects touch sensation is emphasised.

Aldose reductase activity and myo-inositol levels in sciatic nerve and dorsal root ganglia of the diabetic mutant mouse [C57/BL/Ks (db/db)].

Glucose, polyol (sorbitol, fructose), and myo-inositol levels were estimated in peripheral nerve tissue of the diabetic mutant mouse [C57/BL/Ks (db/db)]. At 26 and 40 weeks of age, there was significant accumulation of glucose, sorbitol, and fructose. Tissue myo-inositol levels were lower than those in age-matched control animals at 40 weeks, but not at 26 weeks. Polyol changes in mouse nerve were less marked than those in rat nerve. In dorsal root ganglia, there was also an increase in glucose, sorbitol, and fructose, with a decrease in myo-inositol concentration. These findings show that there is increased aldose reductase activity in peripheral nerve tissue of the diabetic mutant mouse.

Rubidium (86Rb+) influx into dorsal root ganglia and sciatic nerve endoneurium of control and streptozotocin-diabetic rats: comparison with enzymatic Na,K-ATPase activity.

Streptozotocin (STZ)-induced diabetes in the rat causes a significant reduction in ouabain-sensitive Na,K-ATPase pumping activity measured by 86Rb+ influx, in sciatic endoneurium (by 54%) and dorsal root ganglia (by 22%). For endoneurium, the change is similar to that of ouabain-sensitive enzymatic Na,K-ATPase activity (42%), but in dorsal root ganglia, the decrease in enzymatic Na,K-ATPase activity was much greater. 86Rb+ efflux from dorsal root ganglia showed no difference between diabetic and control animals, confirming that the abnormal 86Rb+ influx reflects Na,K-ATPase function and not abnormal membrane permeability. The significance of these findings to pathogenetic mechanisms in diabetic neuropathy is discussed.

Epineurial microvasculitis in proximal diabetic neuropathy.

Amongst the focal and multifocal neuropathies that are associated with diabetes mellitus one of the most common is a proximal predominantly motor lower limb neuropathy. Recent evidence has indicated that, at least in a proportion of cases, this may have an inflammatory basis. We have examined a consecutive series of 15 cases of proximal diabetic neuropathy (diabetic amyotrophy). These were characterized by proximal pain and asymmetric proximal or generalized lower limb muscle weakness, associated in some cases with radicular sensory involvement. Two-thirds of the patients had an accompanying distal symmetric sensory polyneuropathy. Biopsy of the intermediate cutaneous nerve of the thigh, a sensory branch of the femoral nerve, showed epineurial microvasculitis in 3 patients and nonvasculitic epineurial inflammatory infiltrates in another case. In a further case, microvasculitis was found in both in the sural nerve and a quadriceps muscle biopsy specimen. The detection of inflammatory changes appeared to be correlated with the occurrence of sensory radicular involvement. Whether similar changes are present in muscle nerves in this predominantly motor syndrome requires further study. Nevertheless, the present observations confirm the view that secondary vasculitic or other inflammatory reactions may contribute to some forms of diabetic neuropathy.

Glucose and leucine uptake by rat dorsal root ganglia is not insulin sensitive.

Dorsal root ganglia from rats were incubated with 3-O-methyl-[14C]glucose, and [3H]leucine in the presence or absence of insulin in order to determine whether insulin influences the uptake of glucose and amino acids by the cells of the ganglion. No effect was detected. A significant proportion (38%) of the uptake of [3H]leucine was shown to be inhibited by ouabain and therefore energy dependent, utilizing Na+K(+)-ATPase. The activity of this enzyme is known to be impaired in dorsal root ganglia in diabetic rats, as is the uptake of amino acids; these phenomena are therefore unlikely to be due to a direct effect of reduced circulating insulin levels. The relevance of these findings to theories as to the causation of diabetic neuropathy is discussed.

Water content, vasoactive intestinal polypeptide and substance P in intact and crushed sciatic nerves of normal and streptozotocin-diabetic rats.

Observations on streptozotocin-diabetic rats have confirmed overhydration of peripheral nerve. As in previous studies, the sorbitol and fructose content, when expressed in terms of wet weight of nerve was found to be increased and myo-inositol decreased. The reduction in myo-inositol content was less, although still significant, when expressed in terms of protein content. Nerve water content increased during Wallerian degeneration following a crush injury in both normal and diabetic animals, but was relatively less in the latter. Vasoactive intestinal polypeptide (VIP) concentrations were significantly increased in diabetic nerve, those for substance P being normal. Both became severely reduced during Wallerian degeneration following nerve crush and ligature. The significance of these findings is discussed. The accumulation of water in the endoneurial compartment may be related to impaired extraction by the perineurium, to which the increased VIP content may contribute. These changes are unlikely to be responsible for nerve fibre damage.

Polypeptide and glycoprotein abnormalities in dorsal root ganglia of streptozotocin-diabetic rats.

Observations were made on the polypeptide and glycoprotein composition of dorsal root ganglia from streptozotocin-induced diabetic rats by sodium dodecyl sulphate (SDS)-polyacrylamide gel electrophoresis (PAGE). Silver staining of one-dimensional gels failed to demonstrate any differences between diabetic and control animals. In two-dimensional studies, good resolution of polypeptides with a mass greater than 70 kDa was not obtained, but a number of important abnormalities in the polypeptide composition of diabetic ganglia were detected. Some polypeptides recognized in the gels from control ganglia were present in high concentrations in diabetic ganglia; other polypeptides, particularly a number of basic polypeptides of low molecular mass, were only identified in the diabetic rats. Three major polypeptides showed a small shift in their isoelectric point in the diabetic animals. The glycoprotein content of the ganglia was examined by lectin binding to both one- and two-dimensional gel separations. An increase in total glycoprotein content was evident in the diabetic ganglia. A number of polypeptides with a molecular mass between 70 and 110 kDa showed heavy glycosylation. Altered glycosylation of some specific polypeptides of lower molecular mass was also seen, 7 of these showing increased and 3 reduced glycosylation. The significance of these findings is discussed.

Spontaneous bilateral carotid and vertebral artery dissection presenting as a Collet-Sicard syndrome.

Spontaneous dissection of the internal carotid arteries usually presents with unilateral headache, neck pain, focal ipsilateral cerebral ischaemic symptoms and a Horner's syndrome. Lower cranial nerve palsies are only rarely observed. We report a case of carotid and vertebral dissections presenting as a unilateral palsy of the ninth to twelfth cranial nerves (Collet-Sicard syndrome).

Alemtuzumab in the treatment of IVIG-dependent chronic inflammatory demyelinating polyneuropathy.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an idiopathic immune mediated neuropathy causing demyelination and conduction block thought to occur as the result of an aberrant autoimmune response resulting in peripheral nerve inflammation mediated by T cells and humoral factors. Diagnosis commonly prompts initial treatment with steroids or intravenous immunoglobulin (IVIG) on which 5-35% subsequently become dependent to maintain function. Despite a number of small scale trials, the role for alternative long-term immunosuppression remains unclear. Alemtuzumab is a humanised monoclonal antibody targeting the CD52 antigen present on the surface of lymphocytes and monocytes. A single intravenous infusion results in rapid and profound lymphopoenia lasting >12 months. We report its use and clinical outcome in a small series of patients with severe IVIG-dependent CIDP. Seven patients (4 Males; 3 Females) who had failed to respond to conventional immunosuppression were treated in 5 centres receiving 9 courses of alemtuzumab (dose range 60-150 mg). Following treatment, mean monthly IVIG use fell 26% from 202 to 149 g and IVIG administration frequency from 22 to 136 days. Two patients had prolonged remission, two patients had a partial response and no clear benefit was observed in the remaining three patients (2 Males, 1 Females). Responding patients had a younger age at onset (19.5 years) and shorter disease duration than non-responders. Three patients developed autoimmune disease following treatment. Alemtuzumab may offer an alternative treatment for a subset of early onset IVIG dependent CIDP patients failing conventional immunosuppressive agents, but concerns about toxicity may limit its use.

Diabetic neuropathy.

The possible role of growth factors in diabetic neuropathy is under investigation and offers new insights into the effect of diabetes on nerve function. The search continues to identify the pathogenic mechanisms involved, many of which will be interlinked.

Perineurial sodium-potassium-ATPase activity in streptozotocin-diabetic rats.

Perineurial sodium-potassium-ATPase activity was estimated in streptozotocin-diabetic rats and compared with that in control animals. Total ATPase activity was found to be reduced by 34% and ouabain-sensitive ATPase activity by 53%. This finding is significant in relation to the putative role of the perineurium as a metabolically active perifascicular diffusion barrier that regulates the composition of the endoneurial fluid, as is its possible relevance to the occurrence of endoneurial edema in diabetes.

Acute painful diabetic neuropathy precipitated by strict glycaemic control.

A case of acute painful diabetic neuropathy that followed the establishment of strict glycaemic control using continuous subcutaneous insulin infusion is described. Sural nerve biopsy shortly after the onset of the acute painful syndrome showed no evidence of active nerve fibre degeneration; instead, the appearances were those of a chronic neuropathy with prominent regenerative activity. The suggestion is made that adequate diabetic control promoted regeneration and that the pain may have been related to the ectopic generation of impulses in regenerating axon sprouts.

Sural nerve morphometry in diabetic autonomic and painful sensory neuropathy. A clinicopathological study.

Observations have been made on a selected series of insulin-dependent patients with neuropathy, subdivided into three groups: (1) severe autonomic neuropathy with an accompanying painless sensory neuropathy; (2) severe autonomic neuropathy with a chronic painful sensory neuropathy; and (3) chronic or acute painful sensory neuropathy with no autonomic neuropathy. All three groups showed a loss of large and small myelinated nerve fibres in sural nerve biopsy specimens which was greater in Groups 1 and 2. Regenerative activity was prominent in all three groups, but least in Group 3. Teased fibre studies showed evidence both of axonal regeneration and remyelination. Active fibre degeneration was rare. Measurements of g ratio (axon diameter:total fibre diameter) gave no indication of axonal atrophy. The density of unmyelinated axons was reduced in all three groups, as was their median diameter. Vibration sense threshold was positively correlated with the total number of myelinated fibres and thermal sensory threshold with median unmyelinated axon diameter but not with total unmyelinated axon numbers. No correlation between the occurrence of pain and active degeneration of myelinated fibres or with regenerative activity either in myelinated or unmyelinated axons was detectable. Assessment of differential loss of large or small myelinated nerve fibres was difficult because of the presence of large numbers of small regenerating myelinated axons. The results are discussed in relation to the concept of 'diabetic small fibre neuropathy' and the causation of pain in diabetic neuropathy.

Changes in sorbitol, myo-inositol and lipid inositol in dorsal root and sympathetic ganglia from streptozotocin-diabetic rats.

Sorbitol, fructose, myo-inositol and lipid inositol concentrations were measured in excised dorsal root and sympathetic ganglia from rats with streptozotocin-induced diabetes, both in the acute stage (1 and 2 weeks after the induction of diabetes) and chronically (after 2 months of diabetes). In comparison with age-matched controls, myo-inositol concentrations were decreased by 26-32% after 1 and 2 weeks but had returned to normal levels at 2 months. Lipid inositol concentrations were normal both in the acutely and chronically diabetic animals. Sorbitol was not detectable in ganglia from diabetic or control animals except for a small quantity (0.05 mumol/g wet weight) in dorsal root ganglia at the 2-month stage. Fructose was present in dorsal root ganglia (1.71-3.53 mumol/g wet weight) at all stages and in sympathetic ganglia (2.18 mumol/g wet weight) at the 8-week stage. The differences in these results from those obtained in peripheral nerve trunks are possibly related to the lack of a blood-nerve barrier in sensory and autonomic ganglia.

Perineurial calcification.

A study of the occurrence of extracellular deposits of calcium in the perineurium of the human sural nerve demonstrated that there is a higher incidence in abnormal nerves than in normal material and that, of the conditions examined, nerves from cases of diabetic neuropathy showed the greatest incidence of calcification. It seems likely that the process of calcification is similar to that operating in other tissues, with deposition on matrix vesicles or lipid droplets, probably derived from the perineurial cells. The increased incidence in diabetic neuropathy is presumably related to metabolic abnormality consequent upon the diabetic state.