Porphyric neuropathy: a clinical, neurophysiological and morphological study

A case of neuropathy in the course of an attack of acute intermittent porphyria was studied from the neurophysiological and morphological points of view. The neurophysiological findings (acute neuropathy with almost complete denervation despite normal or slightly reduced conduction velocity) and the morphological findings (no segmental demyelination after teasing, conservation of the linear fiber diameter/internodal distance ratio, mainly axonal damage on ultrastructural study) seem to indicate that the disease process is chiefly an axonal neuropathy.

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Somario Gli autori descrivono un caso di neuropatia nel corso di un attacco di porfiria acuta intermittente. Il caso è stato studiato dal punto di vista neurofisiologico e morfologico. I dati neurofisiologici (neuropatia acuta con denervazione pressochè completa, malgrado una velocità di condizione normale o poco ridotta) e morfologici (assenza di demielinizzazione segmentale all'esame tramite teasing, conservazione del rapporto lineare fra il diametro delle fibre e la distanza internodale, prevalente sofferenza assonale allo studio ultrastrutturale) sembrano indicare che il processo patologico è soprattutto una neuropatia assonale.

     

Acute ataxic neuropathy: a clinical, electrophysiological and morphological study

Sensory ataxia as the chief manifestation of acute neuropathy is rather rare. Of the 224 cases of acute polyneuropathy seen over 6 years (1984-1990) only 10 patients (M:F 3:7) had disabling ataxia as the presenting feature. Their ages ranged from 14-61 years. Antecedent febrile illness was present in 6 patients and the peak deficit evolved over 2-25 days. Severe ataxia, paresthesia, distal areflexia and predominant joint sense loss were common to all, motor weakness was either absent or insignificant. CSF was acellular and revealed elevated protein in 3 subjects. All patients had electrophysiological evidence of severe sensory neuropathy with mild or no motor neuropathy. Sural nerve biopsy in one patient showed loss of large, as well as small, diameter myelinated fibres, secondary demyelination, but no evidence of inflammation. At follow up marginal to moderate improvement in ataxia was noted in only 5 patients. Absence of ophthalmoplegia and motor weakness, poor prognosis and characteristic electrophysiological and histopathological observations suggest that acute ataxic neuropathy may be a distinct entity.     

Painful diabetic neuropathy (pdn): a morphological study of capsaicin receptor distribution

Capsaicin receptor TRPV1 is a non‐selective ligand‐gated channel activated by different noxious stimuli. Previous studies suggested that an increased density of TRPV1 positive axons in the skin could be involved in the pathogenesis of neuropathic pain. To investigate the expression of TRPV1 in PDN patients, skin biopsies from 6 patients with PDN and 10 controls, and sural nerve biopsies from 2 patients with PDN and 2 controls were studied using the polyclonal anti‐human TRPV1 antibody. Skin nerve fibers widely expressed TRPV1 immunoreactivity. The density of TRPV1 positive dermal and intra‐epidermal nerve fibers (IENF) did not differ from that obtained using the PGP 9.5 antibody (the standard marker for IEFN recognition). Confocal analysis demonstrated that TRPV1 and anti unique‐tubulin‐1 antibody (TuJ1) co‐localized in all axons. In PDN patients IENF density was significantly reduced, but no difference in immunostaining was detectable using TRPV1, PGP 9.5 and TuJ1 antibodies. Sural nerve unmyelinated fibers and few small‐myelinated fibers were intensely stained by TRPV1. DPN patients disclosed a severe reduction in unmyelinated fiber density, but residual fibers were recognized by TRPV1. These data suggest that TRPV1 is widely expressed in skin and sural nerve unmyelinated axons, but its expression is not increased in PDN. Other mechanisms, such as changes in proximal axon or neuron excitability, are more likely involved in the pathogenesis of neuropathic pain in diabetic neuropathy.     

Early, progressive, and sustained dysfunction of sensory axons underlies paclitaxel-induced neuropathy

Paclitaxel is used in the adjuvant treatment of breast cancer. It induces disabling and potentially long-lasting sensory neuropathy. This study systematically and prospectively investigated sensory function, using clinical grading scales, quantitative sensory testing, and neurophysiological and nerve excitability studies in 28 patients with early-stage breast cancer. After administration of 529 ± 41 mg/m(2) paclitaxel, 71% of patients developed neuropathic symptoms by 6 weeks of treatment. Early and progressive increases in stimulus threshold (P < 0.05) and reduction in sensory amplitudes from 47.0 ± 3.3 μV to 42.4 ± 3.4 μV (P < 0.05) occurred by 4 weeks, with a further reduction by final treatment (33.7 ± 3.0 μV, P < 0.001). The majority of patients (63%) did not experience recovery of neuropathic symptoms at follow-up. Axonal disruption did not relate to membrane conductance dysfunction. We found that paclitaxel produces early sensory dysfunction and leads to persistent neuropathy. Importantly, significant axonal dysfunction within the first month of treatment predated symptom onset, suggesting a window for neuroprotective therapies.     

Perhexiline neuropathy: a clinicopathological study.

Five patients developed a mild to severe polyneuropathy while under treatment with perhexiline maleate, a drug used in long-term treatment of angina pectoris. Recovery took place within a few months after drug withdrawal. We performed qualitative and quantitative light and electron microscopical studies, including teased fiber preparations, in different patients; 16 to 90% of the fibers showed segmental demyelination, an unusual feature in drug-induced neuropathies, and 3 to 20% were undergoing wallerian degeneration. Severe loss of myelinated axons was noted in all 5 patients. In these patients clinical symptoms occurred only when a great number of fibers had already been lost and most of the surviving fibers showed demyelination.     

Methanol optic neuropathy: a histopathological study

The histopathologic effects of methanol on the optic nerve were studied in four patients. Circumscribed myelin damage occurred behind the lamina cribrosa in each nerve. Axons were preserved. Demyelination also occurred in cerebral hemispheric white matter in one patient. This selective myelinoclastic effect of methanol metabolism is probably caused by histotoxic anoxia in watershed areas of the cerebral and distal optic nerve circulations. Juxtabulbar demyelination may cause optic disk edema in methanol poisoning by compressive obstruction of orthograde axoplasmic flow. Visual loss may be due to disruption of saltatory conduction. Retrolaminar demyelinating optic neuropathy is an early morphologic correlate of visual loss in methanol intoxication.     

Vasculitic neuropathy in HIV infection: a clinicopathological study

Vasculitis causing peripheral neuropathy may be the first sign of HIV infection. We report four such cases in whom the onset of peripheral neuropathy led to the detection of HIV infection. Two patients presented with features of mononeuritis multiplex, while the other two had a lumbosacral polyradiculopathy. A prior history of blood transfusion was forthcoming in one of the patients. Sural nerve biopsies in all the four cases and the muscle biopsy in two, histologically showed evidence of vasculitis. Immunohistochemically, the viral antigen was not demonstrable in any of the biopsies, but on electron microscope, virus-like particles were identifiable in the Schwann cell cytoplasm and the perivascular macrophages in one case. To the best of our knowledge, this is the only report that has documented the virus in the Schwann cells as well as the perivascular macrophages lending credence to the fact that these viruses are neurotropic as well as lymphotropic. Immunoglobulin deposits were not demonstrable in any of the cases, suggesting that direct viral invasion may have a role in the pathogenesis of peripheral nerve vasculitis.     

Peptidergic intraepidermal nerve fibers in the skin contribute to the neuropathic pain in paclitaxel-induced peripheral neuropathy

Paclitaxel in chemotherapy-induced peripheral neuropathy (CIPN) is predominantly with a dose-limiting effect on neuropathic pain in clinical strategy. In the present study, the relationship between the neuropathic pain and nerve degeneration in paclitaxel CIPN was investigated. Adult male Sprague–Dawley (SD) rats were divided into three paclitaxel groups (0.5, 1.0, 2.0 mg/kg) and a vehicle group with four intraperitoneal (i.p.) injections on alternating days. Our results demonstrated that the paclitaxel groups significantly exhibited the reductions of thermal hyperalgesia and mechanical allodynia. The neurotoxicity of paclitaxel conveyed the degeneration of intraepidermal nerve fibers (IENFs) in hindpaw glabrous skin. Nevertheless, the influence of paclitaxel to the peptidergic IENFs are even unknown. The skin innervation of protein gene product 9.5 (PGP 9.5)-immunoreactive (IR) IENFs in paclitaxel groups revealed the decreasing levels of density (73.54 ± 0.72%, 63.17 ± 1.77%, 61.79 ± 2.68%, respectively; vs. vehicle group, p < 0.05) throughout the entire experimental period. Additionally, the diminishing levels of density for peptidergic substance P (SP)-IR IENFs in paclitaxel groups were significantly shown (48.84 ± 1.74%, 30.02 ± 1.69%, 30.14 ± 0.37%, respectively; vs. vehicle group, p < 0.05). On the contrary, the density for peptidergic calcitonin gene-related peptide (CGRP)-IR IENFs in paclitaxel groups were revealed the similar decreasing levels (82.75 ± 0.91%, 84.34 ± 3.20%, 81.99 ± 0.25%, respectively; vs. vehicle group, p < 0.05). Linear regression analyses exhibited that densities of IENFs for PGP 9.5, SP, CGRP were correlated with withdrawal latencies (r² = 0.77, p < 0.0001; r² = 0.75, p < 0.0001; r² = 0.28, p = 0.0001, respectively) and mechanical thresholds (r² = 0.43, p < 0.0001; r² = 0.73, p < 0.0001; r² = 0.40, p < 0.0001, respectively). Therefore, the present results suggested that the development of neuropathic pain following paclitaxel injection induced the progressive degeneration of IENFs in skin and gave the evidence that the peptidergic IENFs may play an important role in therapeutic strategy of paclitaxe CIPN.     

Clinical and morphological features of gold neuropathy

Three cases of gold-related neuropathy are reported. Clinical features include an acute, symmetrically progressive polyneuropathy, focal or generalized myokymia and a tendency for initial neurological deterioration followed by improvement, after cessation of chrysotherapy. The degree of clinical recovery related to maximal disability. Morphological findings on sural nerve biopsies revealed both axonal degeneration and segmental remyelination. Similar peripheral nerve histology was seen in a parallel animal study in which the severity of the neuropathy was dose-related.     

Rheumatoid neuropathy: a histological and electrophysiological study

Peripheral nerves in five patients with rheumatoid neuropathy were examined electrophysiologically and by sural nerve biopsy. There was close correlation between the clinical severity of the disease and the degree of nerve damage found histologically and by EMG. Group 1 patients with a mild distal sensory neuropathy showed varying degrees of axonal degeneration in the large myelinated fibres and some segmental demyelination. Group 2 patients with a severe, rapidly progressive sensori-motor neuropathy had extensive loss of myelinated fibres. In one case all the large fibres had degenerated. The second case had lost both large and small myelinated fibres together with many of the non-myelinated axons. The major nerve damage in both groups appeared to be axonal degeneration but some segmental demyelination was detected. Occlusive vascular disease in the vasa nervorum was considered to be the major cause of the nerve damage.     

Leprous neuropathy: a clinical and neurophysiological study

Leprosy is one of the most common treatable causes of neuropathy in the world. Peripheral nerves and skin are commonly affected. We reported the clinical features and electrophysiological findings in 46 patients with leprosy. The aim of our study was to evaluate the nature of damage in the nerve fibres, especially in the first phase of disease. Forty‐six patients (mean age: 44.8 ± 17.8) with diagnosed leprosy were studied by neurological examination and nerve conduction studies (NCS). Twenty‐eight patients were examined for a mean period of 34.8 months. The number of tests for patients varied from 1 to 13 controls. Amplitude of sensory and motor action potentials (SNAP and MAP), sensory‐motor conduction velocity of median, ulnar, tibialis, peroneal and sural nerves were evaluated. Abnormalities were found in 282 of 647 nerves investigated (37.56%), sensory nerve abnormalities being more frequent than motor (50.16% 29.45). Of 282 nerves with neurophysiological abnormalities, 123 were clinically asymptomatic (43.62%). A statistically significant correlation between duration of disease and number of electrophysiological abnormalities was demonstrated. In 19 nerves partial "conduction‐block"(reduction of cMAP > 50% in the proximal response) was individuated. The first electrophysiological alteration, suggesting segmental demyelination, was detected in 41 nerves of 21 patients (33.3 %). According to this view, our data support the hypothesis that leprosy induces a neuropathy of demyelinating nature in the first phase.     

Clinicopathologic features of nonsystemic vasculitic neuropathy and microscopic polyangiitis-associated neuropathy: a comparative study

OBJECTIVE: To compare clinicopathologic findings in nonsystemic vasculitic neuropathy (NSVN) and microscopic polyangiitis-associated neuropathy (MPAN). METHODS: Patients clinicopathologically confirmed to have NSVN (n=23) or MPAN (n=40) were compared with respect to clinical, electrophysiologic, and histopathologic features. RESULTS: Clinical features of neuropathy such as initial symptoms, progression, and distribution of sensory and motor deficits were similar in both groups, while functional compromise was greater in MPAN than NSVN. Abnormalities of laboratory data including those reflecting severity and extent of inflammation such as C-reactive protein were more conspicuous in MPAN than NSVN. Perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) were positive in two-thirds of patients with MPAN but negative in all NSVN. Electrophysiologic and histopathologic findings indicated axonal neuropathy in both groups, whereas the reduction of compound muscle action potentials in the tibial nerve and sensory nerve action potentials in the median nerve was significantly more profound in MPAN than NSVN. As for the epineurial perivascular infiltration, frequencies of cell-specific markers for T lymphocytes, macrophages, and B lymphocytes among cells infiltrating the vasculitic lesions were essentially similar between groups. CONCLUSIONS: Clinicopathologic profiles and vascular pathology were similar between NSVN and MPAN but the age at onset, severity, and presence of p-ANCA were clearly different. Further study is needed to clarify the pathogenesis of NSVN and its place in the vasculitic spectrum of diseases.     

Brachial plexus involvement in familial pressure-sensitive neuropathy: Electrophysiological and morphological findings

Two family members with hereditary pressure-sensitive neuropathy are reported. One patient presented atypically with acute brachial plexus neuropathy following transaxillary removal of the first rib. Electrophysiological studies showed slowing of motor nerve conduction in clinically affected and unaffected nerves. In vitro recording of the compound action potential of the subclinically involved sural nerve showed pronounced slowing in conduction of large and small myelinated fiber groups. These alterations correlated with morphological studies of the sural nerve that showed tomacula with acute and healed segmental demyelination. An inherited, generalized neuropathy manifested by a morphological abnormality of myelination may render peripheral nerves unduly susceptible to mechanical trauma, including positional pressure or traction effects during general anesthesia.     

Experimental thalidomide neuropathy: The morphological correlate of reduced conduction velocity

Summary Morphological studies of experimental thalidomide neuropathy have thus far failed to show any significant structural changes. The present investigation was performed on sural nerves of female New Zealand white rabbits showing a reduction of sensory conduction velocity after oral treatment with thalidomide (100 mg/kg b.wt. per day) for a period of 33 weeks. Rabbits of the same strain and equal sex, weight, and number served as controls. Very few nerve fibers were undergoing Wallerian degeneration in both groups, experimental animals and controls. Morphometry, however, revealed a statistically significant reduction of the mean myelin thickness of sural nerve fibers in the thalidomide group of rabbits as compared to controls. The mean myelin thickness of the largest nerve fibers was also significantly smaller than in the control group. On the other hand, axonal diameters were not significantly altered. The association between the decrease of the sensory conduction velocity, the reduction of the myelin sheath thickness, and the chronic thalidomide application is discussed.Presented in part at the Joint Meeting of the German and Scandinavian Neuropathologists in Turku, Finland, June 3–4, 1983     

Peripheral neuropathy in myotonic dystrophy: a nerve biopsy study

Sural nerve biopsies from 13 unselected myotonic dystrophy patients and 6 normal controls were studied morphometrically. The myelinated fiber density was reduced in 11 of the 13 myotonic dystrophy patients, with preferential loss of large myelinated fibers. Unmyelinated fiber densities and diameters were normal. Teased fiber studies commonly revealed focal areas of remyelination and abnormal wrinkling of the myelin sheath. Measurement of internodal length disclosed features of both axonal regeneration and focal demyelination-remyelination. These findings are consistent with a chronic axonopathy of moderate severity, possibly due to axonal atrophy.