Peripheral nerve regeneration in galactosaemic rats.

The use of galactosaemia as a model for some aspects of diabetic polyneuropathy allows the influence of glycation to be studied independently of other effects. There are well-studied abnormalities of the peripheral nerves in galactosaemic rats, one of which is that the efficiency of regeneration is initially reduced. One possible cause could be that glycated myelin debris in macrophages is less degradable and interferes with macrophage function. Macrophage recognition and ingestion of myelin glycosylated in vitro increases with the duration of incubation in a sugar-rich medium. This study was performed to investigate a possible correlation between galactosaemia and regeneration, together with the role of macrophages. Galactosaemia was induced by adding galactose to the rats' diet for 2 months before injury. Following a crush lesion to the sciatic nerve, regeneration was found to be delayed, demonstrated by a reduction in mean myelinated fibre size and density 1 month after crush, although, 2 and 3 months later, the differences did not reach statistical significance. There were also more macrophages in the galactosaemic rats than in the control animals at all time points. The initial delay in regeneration in galactosaemic rats was therefore only temporary and there was little evidence of long-term deleterious effects. In addition to the morphometric results, immunohistochemistry showed that there were more macrophages in the galactosaemic rats than in the control animals at all time points. Correlating macrophage and myelinated fibre counts suggests that the persistence of debris-containing macrophages does not appear to have a significant inhibitory effect on nerve regeneration. No evidence was found for persistent basal laminal tubes around the regenerating clusters.

Hypertrophic perineurial dysplasia in multifocal and generalized peripheral neuropathies.

Two cases are described, one with a multifocal cranial and limb neuropathy of adult onset associated with optic neuropathy, and the other with a diffuse demyelinating neuropathy characterized by congenital cataract, mental retardation and progressive lower limb paresis with an onset in childhood. Extensive investigation in both failed to establish the causation. No family history of similar disorder was obtained in either case. Nerve biopsy in both showed similar perineurial abnormalities, the endoneurium being compartmentalized by hypertrophic perineurial cells that exhibited dysplastic features. The appearances resemble those described in a previously reported case of multifocal neuropathy and probably represent an unusual but non-specific response to a peripheral neuropathy.

Neurological manifestations in chronic mountain sickness: the burning feet-burning hands syndrome.

OBJECTIVE: To characterise the clinical features and nerve biopsy findings in patients with chronic mountain sickness (CMS) living in the Peruvian Andes, with particular attention to the occurrence of the "burning feet-burning hands" syndrome. METHODS: Symptoms and signs were documented clinically in 10 patients with CMS and compared with those in five healthy subjects all living at 4338 metres altitude. Sural nerve biopsies were obtained from three patients with CMS. The nerve fibre population and endoneurial microvessels were analyzed morphometrically. RESULTS: All patients with CMS experienced burning and tingling paraesthesiae in the distal parts of their limbs. Similar but milder symptoms confined to the feet occurred in four of five controls. Three patients with CMS had a mild sensory neuropathy on examination, controls were clinically normal. Nerve biopsies showed a mild demyelinating neuropathy in all three with a reduction in the unmyelinated axon population in one. The endoneurial blood vessels showed a reduced thickness in the basal laminal zone compared with control values but were otherwise normal. CONCLUSIONS: Apart from well recognised symptoms and signs of CMS, the study has shown that such patients may also exhibit a mild sensory neuropathy. Its relation to the burning feet-burning hands syndrome, which was not confined to the patients but was also found in controls at altitude, is uncertain. The time course and pattern of the centrifugal resolution of the burning paraesthesiae complex on low altitude sojourn of high altitude natives raises the possibility that a mechanism involving altered axonal transport may be involved. The reduced thickness of the basal laminal zone of microvessels implies that adaptive structural changes to hypobaric hypoxia may also occur in peripheral nerve and are similar to those reported in other tissues of high altitude natives.

Focal upper limb demyelinating neuropathy.

Observations are presented on nine selected patients with chronic upper limb demyelinating neuropathy to illustrate the range of manifestations that may be observed. In three, the involvement was purely motor, in five, mixed motor and sensory and, in one, virtually purely sensory; in seven the symptoms were unilateral and in two bilateral. The presence of reduced nerve conduction velocity and conduction block and the response to treatment in seven of the cases indicate that they represented examples of chronic inflammatory demyelinating polyneuropathy (CIDP) with focal involvement. This was confirmed by nerve biopsy in two cases. The presentation in one patient was accompanied by forearm swelling initially suspected of being a tumour but shown to be due to muscle hypertrophy. This was probably the consequence of recurrent muscle cramps and fasciculation and possibly neuromyotonia. The patient with predominant sensory involvement restricted to the upper limbs demonstrates that sensory CIDP can present focally. In one patient with monomelic motor and sensory involvement, nerve biopsy showed multifocal areas of hypertrophic demyelinating neuropathy distally in the ulnar nerve without inflammatory infiltration. This patient failed to respond to therapy. Response in the others was satisfactory, although one patient with a monomelic motor neuropathy showed a severe deterioration after being given corticosteroids; he subsequently improved with intravenous human immunoglobulin therapy.

Myopathy in vitamin E deficient rats: muscle fibre necrosis associated with disturbances of mitochondrial function.

Vitamin E deficiency in rats gives rise to a neuromuscular syndrome that includes a peripheral neuropathy as well as generalised muscle wasting and weakness. This is probably related to damage by oxygen-derived free radicals. In the present study, histological examination of lower limb muscles showed widespread myopathic changes which included the presence of amorphous electron-dense inclusions and tubular aggregates in muscle fibres and muscle fibre necrosis. Histochemical observations suggested a reduction in the activity of oxidative enzymes. The mitochondria showed nonspecific degenerative changes on electron microscopy; no paracrystalline inclusions were observed. Polarographic analysis of isolated muscle mitochondria revealed statistically significant decreases in oxygen utilisation rates with both NADH and FADH2-linked substrates. In confirmation of a generalised respiratory chain abnormality, enzymatic analyses revealed decreases in the activities of complexes I, II/III and IV, although only the decreases in complexes I and IV activities were statistically significant. Measurements of membrane fluidity showed that this is reduced in mitochondria from vitamin E deficient rats, indicating reduced stability of their membranes. The respiratory control ratio, derived from the polarographic results, was also reduced in mitochondria from vitamin E deficient animals, suggesting membrane damage. An altered lipid environment, possibly secondary to a higher level of lipid peroxidation, could result in the inhibition of complexes I and IV. This could also be caused by oxidative damage to the complexes or to mitochondrial DNA. The preservation of citrate synthase activity is against any generalised defect of mitochondrial function. The question as to whether these defects of mitochondrial respiratory chain function are responsible for the muscle fibre damage and necrosis requires further investigation.

Abnormalities of the axonal cytoskeleton in giant axonal neuropathy.

Intermediate filaments accumulate abnormally in a variety of cell types in individuals with human inherited giant axonal neuropathy (GAN). A characteristic feature of this disorder is the occurrence of focal axonal enlargements filled with accumulations of neurofilaments. The minimum separations between neurofilaments in sural nerve axons of a patient with GAN were 12-30 nm compared with 24-60 nm in controls. The normal sidearm protrusions which cross-bridge adjacent filaments were rare in GAN. Average minimum neurofilament diameter was 12.4 nm in GAN compared with 10.1 nm in controls. Many axons were devoid of neurofilaments and contained an increased density of microtubules, many of which did not run longitudinally. This disorganization of microtubule alignment may reflect the lack of an associated neurofilament lattice. It is concluded that GAN involves abnormalities of neurofilament cross-linkage to one another and to adjacent microtubules. Mechanisms are discussed which could account for this inherited disorder of intermediate filament organization affecting various cell types.

Metabolic cost of walking: equation and model.

Twenty years of published experience with the Workman-Armstrong equation for predicting walking VO2 is reviewed. The equation is reexpressed in currently accepted terminology, and it is shown that the equation serves well as a basic model of normal walking. Employing this model to analyze VO2/step leads to the elaboration of a three-compartment model of the metabolic cost of walking. This three-compartment model provides a rational estimate of the fraction of walking's metabolic cost that powers the actual walking movement. Doubt is expressed that "comfortable speed of walking" is definable in energy terms. It is suggested that the requirements of maintaining balance while walking may determine both the comfortable speed of walking and the curvilinearity of the relationship between ground-speed and freely chosen step frequency of walking.

Behr's syndrome. A family exhibiting pseudodominant inheritance.

A family with the clinical features of Behr's syndrome is described that exhibited probable pseudodominant inheritance. The salient clinical manifestations consisted of mental retardation and dementia, optic atrophy, cerebellar ataxia, pyramidal signs and peripheral neuropathy. Nerve biopsy from the index case showed a chronic neuropathy with axonal degeneration and regeneration. A muscle biopsy from the same patient demonstrated multiple inclusions composed of spiral cylindrical structures possibly derived from the sarcoplasmic reticulum, and less obtrusive accumulations of mitochondria, some of which contained paracrystalline inclusions.