R. H. M. King

Sural nerve pathology in diabetic patients with minimal but progressive neuropathy

Aims/hypothesisThe early pathological features of human diabetic neuropathy are not clearly defined. Therefore we quantified nerve fibre and microvascular pathology in sural nerve biopsies from diabetic patients with minimal neuropathy.MethodsTwelve diabetic patients underwent detailed assessment of neuropathy and fascicular sural nerve biopsy at baseline, with repeat assessment of neuropathy 8.7±0.6 years later.ResultsAt baseline, neuropathic symptoms, neurological deficits, quantitative sensory testing, cardiac autonomic function and peripheral nerve electrophysiology showed minimal abnormality, which deteriorated at follow-up. Myelinated fibre density, fibre and axonal area, and g-ratio were normal but teased fibre studies showed paranodal abnormalities (p<0.001), segmental demyelination (p<0.01) and remyelination (p<0.01) without axonal degeneration. Unassociated Schwann cell profile density (p<0.04) and unmyelinated axon density (p<0.001) were increased and axon diameter was decreased (p<0.007). Endoneurial capillaries demonstrated basement membrane thickening (p<0.006), endothelial cell hyperplasia (p<0.004) and a reduction in luminal area (p<0.007).Conclusions/interpretationThe early pathological features of human diabetic neuropathy include an abnormality of the myelinated fibre Schwann cell and unmyelinated fibre degeneration with regeneration. These changes are accompanied by a significant endoneurial microangiopathy.

Changes with age in the peripheral nerves of the rat

SummaryUltrastructural observations have been made on the tibial and plantar nerves of Wistar rats aged 18–24 months. Changes indicative of segmental demyelination and remyelination and axonal degeneration and regeneration were prominent in the plantar nerves. Both in the plantar and tibial nerves, but particularly in the former, axonal abnormalities were frequent. These included the occurrence of multiple intra-axonal vacuoles containing glycogen and polyglucosan bodies. Axonal sequestration by adaxonal Schwann cell processes was also increased. The Schwann cell cytoplasm in relation to this activity contained bundles of filaments with the ultrastructural features of Hirano bodies. The changes in the plantar nerves probably indicate a pressure neuropathy, but the possibility of a superimposed distal axonal degeneration related to aging cannot be excluded on the present evidence. Such changes must be taken into consideration in experimental studies performed on rats of this age.

Myelinated nerve fibre regeneration in diabetic sensory polyneuropathy: correlation with type of diabetes

Observations were made on myelinated fibre regeneration in diabetic sensory polyneuropathy assessed in sural nerve biopsy specimens. These confirmed that regenerative clusters initially develop within abnormally persistent Schwann cell basal laminal tubes. The number of regenerating fibres, identified by light microscopy, was found to decline in proportion to the reduction in total myelinated fibre density. The relative number of regenerating fibres was significantly greater in patients with insulin-dependent as compared with those with non-insulin-dependent diabetes after correction for age. There was a slight negative correlation between the relative proportion of regenerating fibres and age, but this was not statistically significant. The progressive reduction in the number of regenerating fibres with declining total fibre density indicates that axonal regeneration fails with advancing neuropathy. The production of nerve growth factor (NGF) and NGF receptors by denervated Schwann cells is likely to be important for axonal regeneration. To investigate whether the failure of axonal regeneration could be related to a lack of NGF receptor production by Schwann cells, we examined the expression of p75 NGF receptors by Büngner bands immunocytochemically. In comparison with other types of peripheral neuropathy, p75 NGF receptor expression appeared to take place normally. It is concluded that failure of axonal regeneration constitutes an important component in diabetic neuropathy. Its explanation requires further investigation.

Electron microscope observations on aberrant regeneration of unmyelinated axons in the vagus nerve of the rabbit.

SummaryAn electron microscope investigation has been made into the regeneration of unmyelinated axons in the vagus nerve of the rabbit. Following a localized crush injury of the vagus nerve in the neck at the level of the thyroid cartilage, the regenerating unmyelinated axons become diverted into the recurrent laryngeal branch, which is normally composed almost entirely of myelinated fibres. Here the regenerating unmyelinated axons become arrayed around the regenerating myelinated axons, but are associated with separate Schwann cells.The possible explanation for this aberrant regeneration of the unmyelinated axons is discussed, as is its significance for human neuropathology.ZusammenfassungEine elektronenmikroskopische Untersuchung über die Regeneration von marklosen Axonen wurde am N. vagus des Kaninchens durchgeführt. Als Folge einer lokalisierten Quetschverletzung des N. vagus am Hals in Höhe der Cartilago thyreoidea wurden die regenerierenden marklosen Axone in den laryngealen Recurrens-Ast abgelenkt, der normalerweise beinahe vollständig aus myelinreichen Fasern aufgebaut ist. Die regenerierenden marklosen Axone kommen um die regenerierenden myelinreichen Axone zu liegen, sind aber mit getrennten Schwannschen Zellen verbunden.Eine mögliche Erklärung für diese aberrierende Regeneration der myelinfreien Axone wird diskutiert, ebenso ihre Bedeutung für die Human-Neuropathologie.

Nerve biopsy findings in two cases of Tangier disease.

SummaryNerve biopsy findings are recorded for two previously reported patients with Tangier disease (hereditary high density lipoprotein deficiency). Both cases showed unusual clinical manifestations in comparison with other reported cases. The neurological disorder, symptoms from which began in the third decade, gave rise to a lower motor neuron deficit of unique distribution, which was accompanied by progressive sensory impairment limited for many years to loss of pain and temperature sensibility, ultimately involving all sensory modalities.Both biopsy specimens displayed similar features, with a gross loss of unmyelinated and myelinated axons, an extensive accumulation of lipid within Schwann cells, and excessive endoneurial collagenization. The axonal loss appeared to represent a primary axonal degeneration, there being no evidence of a demyelinating process.It is suggested that the accumulation of cholesterol within Schwann cells may be the result of a failure of cholesterol removal mechanisms or of intracellular lipid transport.

Comparative ultrastructural observations on peripheral nerve abnormalities in the late infantile, juvenile and late onset forms of metachromatic leukodystrophy

SummaryThe ultrastructural findings in nerve biopsies from two cases of late onset metachromatic leukodystrophy were compared with those in cases of late infantile and juvenile onset. Hypertrophic changes and regenerating clusters were more evident in the late onset cases, in which macrophages were less frequent, presumably reflecting the chronicity of the disorder in this form. Inclusions within Schwann cells and endoneurial macrophages were similar in all four cases. Myelin figures, in which the periodicity of major dense lines was 8 nm, were present in Schwann cells associated with myelinated axons. The electron lucent zones between the major dense lines were bisected by lines of lesser electron density. These inclusions were probably related to myelin breakdown. All other inclusions displayed a periodicity of 5.8 nm and consisted of zebra bodies, vacuoles containing irregularly orientated lamellar material and stacks of flattened discs. These inclusions represented the metachromatic sulphatide deposits. Occasional inclusion bodies were observed within axons.

Relative growth and maturation of axon size and myelin thickness in the tibial nerve of the rat

SummaryMorphometric observations have been made on the medial plantar division of the tibial nerve (MPD) and on the motor branches of the tibial nerve to the calf muscles (MBC) in rats ranging in age from weaning (3 weeks) to 12 months. Axon size, assessed by measurements of circumference and cross-sectional area, increased rapidly until 3 months with further slight increases between 3 and 9 months and a slight fall between 9 and 12 months. Axon size distributions were unimodal throughout in the MPD but bimodal for the MBC except at 3 weeks. Distributions of myelin thickness were bimodal throughout for both nerves. Scatter plots of g ratios (axon diameter: total fibre diameter) confirmed the presence of two fibre populations: a group of small fibres with relatively thin myelin sheaths, and a group of larger fibres within which sheath thickness was relatively less on the larger than on the smaller axons. These two fibres populations were less easily separable in the MBC than in the MPD nerves. These results document morphometrically the normal growth changes in the rat tibial nerve and also provide control data for the analysis of the effects of experimental procedures on the growth and maturation of peripheral nerve fibres.

Paranodal structure in diabetic sensory polyneuropathy

Abstract Observations have been made on the structure of the paranodal region at nodes of Ranvier in the sural nerve of patients with diabetic sensory polyneuropathy. The structure of the paranodes was examined with particular attention to the definition and assessment of axoglial dysjunction, which has been claimed to be a characteristic feature of both human and experimental diabetic neuropathy and which has been related to paranodal swelling. In the present series of cases it was not possible to confirm that axoglial dysjunction is a distinctive feature of diabetic polyneuropathy in fibres not undergoing active demyelination or wallerian-type degeneration, neither was excessive paranodal enlargement found.