Pathological Observation of Blood Stasis Syndrome in Non-diabetic Peripheral Neuropathies: A Retrospective Analysis Based on Nerve Biopsy.

OBJECTIVE: To investigate the pathological features of blood stasis syndrome (BSS) in non-diabetic peripheral neuropathy. METHODS: Clinical data of 31 patients with non-diabetic peripheral neuropathy who had undergone nerve biopsy during December 2004 and December 2010 in Xuanwu Hospital Capital Medical University were retrospectively analyzed. According to Chinese medicine (CM) syndrome differentiation and signs, 26 patients were blood stasis type and 5 patients were non-blood stasis type. Clinical and pathological data were compared in detail. RESULTS: Clinically, although both groups shared similar symptoms of limb numbness, weakness and sensory disturbances, the prevalence of neuralgia was much grievous in BSS group (73.1%, 26/31) compared with the non-BSS group (0%, 0/5). As for signs, dermal nutrients disturbance (84.6%, 22/26), dark or purple tongue (100.0%, 26/26), and sublingual varices (80.7%, 21/26) were more common in the BSS group than the non-BSS group (0%, 60%, 20%, respectively). The prevalence of qi deficiency cases (19/26) in the BSS group was significantly higher compared with the non-BSS group (1/5). The unique histological manifestations of BSS were axonal degeneration (16/26 vs 2/5 in non-BSS group), which was the hallmark of ischemia. Cases with BSS had prominent microangiopathy (61.5%, 16/26), manifested as epineurium vasculitis (inflammatory cell infiltrated to the vessel wall, obliteration and recanalization, vascular proliferation, extravascular hemosiderin deposition), angiotelectasis, proliferation and hyaline degeneration of endoneurium capillary. In the BSS group, impaired blood-nerve barrier was indicated by sub-perineurial edema (46.2%, 11/26) and endoneurial edema (15.4%, 4/26). The Renaut body (15.4%, 4/26) and amyloid deposition (3.8%, 1/26) found in the BSS group were absent in the non-BSS group. CONCLUSIONS: BBS was common in non-diabetic peripheral neuropathies. The nerves exhibited ischemic alteration of primary axon degeneration and secondary demyelination. The interstitial tissue revealed microcirculation impairment, blood-nerve barrier disturbance, amyloid deposition and proliferation changes. The high prevalence of qi deficiency also highlights the therapy of promotion of blood circulation and removal of blood stasis.

Effect of low-level laser therapy (LLLT) on peripheral nerve regeneration using fibrin glue derived from snake venom.

OBJECTIVES: The purpose of this study was to assess whether the adhesive permits the collateral repair of axons originating from a vagus nerve to the interior of a sural nerve graft, and whether low-level laser therapy (LLLT) assists in the regeneration process. MATERIALS AND METHODS: Study sample consisted of 32 rats randomly separated into three groups: Control Group (CG; n=8), from which the intact sural nerve was collected; Experimental Group (EG; n=12), in which one of the ends of the sural nerve graft was coapted to the vagus nerve using the fibrin glue; and Experimental Group Laser (EGL; n=12), in which the animals underwent the same procedures as those in EG with the addition of LLLT. Ten weeks after surgery, the animals were euthanized. Morphological analysis by means of optical and electron microscopy, and morphometry of the regenerated fibers were employed to evaluate the results. RESULTS: Collateral regeneration of axons was observed from the vagus nerve to the interior of the autologous graft in EG and EGL, and in CG all dimensions measured were greater and presented a significant difference in relation to EG and EGL, except for the area and thickness of the myelin sheath, that showed significant difference only in relation to the EG. CONCLUSIONS: The present study demonstrated that the fibrin glue makes axonal regeneration feasible and is an efficient method to recover injured peripheral nerves, and the use of low-level laser therapy enhances nerve regeneration.

Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2.

Childhood onset motor neuron diseases or neuronopathies are a clinically heterogeneous group of disorders. A particularly severe subgroup first described in 1894, and subsequently called Brown-Vialetto-Van Laere syndrome, is characterized by progressive pontobulbar palsy, sensorineural hearing loss and respiratory insufficiency. There has been no treatment for this progressive neurodegenerative disorder, which leads to respiratory failure and usually death during childhood. We recently reported the identification of SLC52A2, encoding riboflavin transporter RFVT2, as a new causative gene for Brown-Vialetto-Van Laere syndrome. We used both exome and Sanger sequencing to identify SLC52A2 mutations in patients presenting with cranial neuropathies and sensorimotor neuropathy with or without respiratory insufficiency. We undertook clinical, neurophysiological and biochemical characterization of patients with mutations in SLC52A2, functionally analysed the most prevalent mutations and initiated a regimen of high-dose oral riboflavin. We identified 18 patients from 13 families with compound heterozygous or homozygous mutations in SLC52A2. Affected individuals share a core phenotype of rapidly progressive axonal sensorimotor neuropathy (manifesting with sensory ataxia, severe weakness of the upper limbs and axial muscles with distinctly preserved strength of the lower limbs), hearing loss, optic atrophy and respiratory insufficiency. We demonstrate that SLC52A2 mutations cause reduced riboflavin uptake and reduced riboflavin transporter protein expression, and we report the response to high-dose oral riboflavin therapy in patients with SLC52A2 mutations, including significant and sustained clinical and biochemical improvements in two patients and preliminary clinical response data in 13 patients with associated biochemical improvements in 10 patients. The clinical and biochemical responses of this SLC52A2-specific cohort suggest that riboflavin supplementation can ameliorate the progression of this neurodegenerative condition, particularly when initiated soon after the onset of symptoms.

Arsenical peripheral neuropathy.

A 49-year-old white man returned urgently to the UK after spending 3 months in Goa. He had a several week history of vomiting, weight loss, a widespread desquamating skin rash, and symptoms and signs of a progressive painful sensorimotor neuropathy. He had a mild normocytic anaemia and lymphopenia. Nerve conduction studies revealed a severe predominantly axonal large fibre sensorimotor neuropathy, confirmed on subsequent sural nerve biopsy. Once he had left Goa most of his symptoms started to rapidly settle although the neuropathic symptoms remained severe. Arsenic poisoning was suspected. A spot urine arsenic concentration was 300 microg/l, confirming the diagnosis. He was treated with chelation therapy. Deliberate arsenic poisoning was highly likely.

Effect of oral curcumin on Déjérine-Sottas disease.

Curcumin is the newest therapeutic agent for ameliorating the clinical and neuropathologic phenotype of a mouse model of Déjérine-Sottas disease. We undertook a 12-month dose-escalation safety trial of oral curcumin in a 15-year-old Caucasian girl with Déjérine-Sottas disease (point mutation, Ser72Leu) complicated by severe weakness, scoliosis, and respiratory impairment. The patient received 50 mg/kg/day oral curcumin for the first 4 months and 75 mg/kg/day thereafter, to complete a 12-month trial. Outcome measures included muscle strength, pulmonary function, upper/lower extremity disability, neurophysiologic studies, and health-related quality of life. After 12 months, the patient experienced no adverse events, and reported good compliance. There was little improvement in objective outcome measures. Knee flexion and foot strength increased slightly, but hand and elbow strength decreased. Pulmonary function, hand function, and measures of upper/lower extremity disability were stable or reduced. Her neurophysiologic findings were unchanged. Parent-reported quality of life improved for most domains, especially self-esteem, during the 12 months of treatment. Child-reported quality of life, assessed at the final visit, mirrored these results, with overall feelings of happiness and contentment. Further studies are required to explore the efficacy and safety of curcumin for severe demyelinating neuropathies of infancy and early childhood.

Long-term course and mutational spectrum of spatacsin-linked spastic paraplegia.

OBJECTIVE: Hereditary spastic paraplegias (HSPs) comprise a heterogeneous group of neurodegenerative disorders resulting in progressive spasticity of the lower limbs. One form of autosomal recessive hereditary spastic paraplegia (ARHSP) with thin corpus callosum (TCC) was linked to chromosomal region 15q13-21 (SPG11) and associated with mutations in the spatacsin gene. We assessed the long-term course and the mutational spectrum of spatacsin-associated ARHSP with TCC. METHODS: Neurological examination, cerebral magnetic resonance imaging (MRI), 18fluorodeoxyglucose positron emission tomography (PET), nerve biopsy, linkage and mutation analysis are presented. RESULTS: Spastic paraplegia in patients with spatacsin mutations (n = 20) developed during the second decade of life. The Spastic Paraplegia Rating Scale (SPRS) showed severely compromised walking between the second and third decades of life (mean SPRS score, >30). Impaired cognitive function was associated with severe atrophy of the frontoparietal cortex, TCC, and bilateral periventricular white matter lesions. Progressive cortical and thalamic hypometabolism in the 18fluorodeoxyglucose PET was observed. Sural nerve biopsy showed a loss of unmyelinated nerve fibers and accumulation of intraaxonal pleomorphic membranous material. Mutational analysis of spatacsin demonstrated six novel and one previously reported frameshift mutation and two novel nonsense mutations. Furthermore, we report the first two splice mutations to be associated with SPG11. INTERPRETATION: We demonstrate that not only frameshift and nonsense mutations but also splice mutations result in SPG11. Mutations are distributed throughout the spatacsin gene and emerge as major cause for ARHSP with TCC associated with severe motor and cognitive impairment. The clinical phenotype and the ultrastructural analysis suggest a disturbed axonal transport of long projecting neurons.

Isolated vitamin E deficiency with demyelinating neuropathy.

A 22-year-old man, with a past history of generalized tonic-clonic seizures treated with phenobarbital, presented with spinocerebellar ataxia. The electrophysiological studies revealed a demyelinating motor-sensory neuropathy. The serum vitamin E level was low. Sural nerve biopsy revealed loss of large myelinated fibers with evidence of remyelination. Vitamin E supplementation led to clinical and electrophysiological recovery of sensory conduction and evoked potentials. Motor nerve conduction, however, showed only partial recovery. Vitamin E deficiency leading to a demyelinating neuropathy, as in the present case, suggests that the full spectrum of the disease entity is not fully defined.

Clinical diagnosis in Karwinskia humboldtiana polyneuropathy.

Intoxication by Karwinskia humboldtiana presents a neurological picture similar to that for Guillain-Barré syndrome or other polyradiculoneuropathies. Clinical diagnosis in poisoned humans may be difficult if no evidence of previous fruit ingestion is available. We present our experience in the clinical diagnosis of Karwinskia humboldtiana polyneuropathy, as confirmed by toxin detection in blood. We designed an open trial at the Pediatric Neurology service and included all cases with acute ascending paralysis that were admitted to our hospital in the last two years. In all cases, we performed hematological, immunological and biochemical profiles, CSF analysis including immunological studies, oligoclonal bands and myelin basic protein determinations. Electrodiagnostic studies were performed, including motor conduction velocities, distal latencies, F-wave latency and compound muscle action potential (CAMP) amplitude. The presence of Karwinskia humboldtiana toxins in blood were determined by thin layer chromatography. In six cases, T-514 Karwinskia humboldtiana toxin was detected. These cases had a symmetric motor polyneuropathy with the absence of tendon reflexes and no sensory signs or cranial nerve involvement. Only one patient required assisted ventilation due to bulbar paralysis. In two of these cases, a sural nerve biopsy revealed a segmental demyelination with swelling and phagocytic chambers in Schwann cells and without lymphocytic infiltration. All six cases survived, with complete recovery in five. We conclude that this intoxication is common in Mexico. The availability of toxin detection in blood samples allows the clinician to establish an accurate diagnosis and should be included in the study of children with polyradiculoneuropathy, especially in countries where this poisonous plant grows.

Chronic inorganic mercury induced peripheral neuropathy.

We report the clinical features, electrophysiological studies, and morphometric analysis of sural nerve pathology in a patient with polyneuropathy due to inorganic mercury intoxication. He developed slowly progressive generalized paralysis of all limbs after 3 months ingestion of herb drugs which contained mercuric sulfate. Electrophysiologic studies revealed axonal polyneuropathy involving both motor and sensory fibers. Sural nerve biopsy demonstrated axonal degeneration with demyelination and a predominant loss of large myelinated fibers. His muscle strength showed only mild improvement after 2 years' follow-up. We concluded that inorganic mercury exposure may induce severe axonal sensorimotor polyneuropathy in humans and that neurological deficits may persist in severe cases.

Supplemental myo-inositol prevents L-fucose-induced diabetic neuropathy.

Nerve myo-inositol depletion, which has been implicated in the pathogenesis of acute experimental diabetic neuropathy, can be reproduced in normal rats by feeding diets enriched in L-fucose, a competitive inhibitor of sodium-dependent myo-inositol transport. Previously, we reported that L-fucose feeding for 6 weeks reproduces the effect of experimental diabetes on nerve Na+-K+-ATPase activity and conduction velocity, which can be prevented by simultaneous dietary myo-inositol supplementation. To further validate this model of myo-inositol depletion, we examined the effects of long-term (24-week) L-fucose feeding and dietary myo-inositol supplementation on nerve Na+-K+-ATPase, nerve conduction velocity, and myelinated nerve fiber pathology. After 24 weeks of L-fucose enriched (10 or 20%) diets, nerve myo-inositol levels and Na+-K+-ATPase activity decreased significantly (P < 0.05) and were associated with a 25-30% reduction in nerve conduction velocity, all of which were completely prevented by 1% dietary myo-inositol. Twenty percent L-fucose diet resulted in significant axonal atrophy, paranodal swelling (P < 0.001), and paranodal demyelination (P < 0.005), without increasing Wallerian degeneration or nerve fiber loss, a pattern qualitatively similar to that seen in early murine diabetic neuropathy. Dietary myo-inositol supplementation prevented these structural changes and increased nodal remyelination, supporting a role of myo-inositol depletion in the genesis of early diabetic neuropathy. The L-fucose model system may therefore serve as an experimental tool to elucidate the pathophysiological role of isolated myo-inositol depletion and its consequences in the multifactorial pathogenesis of diabetic neuropathy.

"Sunbath polyneuritis": subacute axonal neuropathy in perazine-treated patients after intense sun exposure.

This article aims at drawing attention to the peculiar association of intense exposure to sunlight and subacute development of sensory neuropathy which was seen in 7 psychiatric patients treated with the phenothiazine derivative, perazine. Three patients additionally developed bilateral VII nerve palsy. Symptoms followed a monophasic course with almost complete remission. Routine neurophysiology suggested axonal neuropathy confirmed by sural nerve biopsy in 1 patient. A toxic origin of neuropathy is supposed, possibly induced by phenothiazine photoproducts, which may cause cell damage via lipid peroxidation.

Human adjuvant disease: presentation as a multiple sclerosis-like syndrome.

Twenty-six women had a systemic disease with central nervous system (CNS) involvement at a mean age of 39.2 years (range, 23 to 64 years) after receiving silicone breast implants (n = 25) or silicone fluid injections into breasts (n = 1). The median latency period between breast surgery and onset of symptoms was 5.71 years (range, 3 months to 15 years). All patients had evidence of disseminated CNS lesions; 20 patients also had evidence of peripheral neuropathy. Additional problems included myalgia (n = 24), joint stiffness (n = 23), arthralgia (n = 22), sicca complex (dry eyes and dry mouth) (n = 19), headache (n = 16), skin rash (n = 15), joint swelling (n = 14), Raynaud's phenomena (n = 14), fever (n = 13), hair loss (n = 12), allergies (n = 11), sensitivity to sunlight (n = 10), and lymphadenopathy (n = 9). Magnetic resonance imaging brain scans were abnormal in 22 of 26 patients (21, white matter lesions; 1, ischemic lesions; 4, cerebral atrophy). Spinal tap revealed oligoclonal bands in 18 of 23 patients. Visual evoked responses were delayed in 14 of 23 patients, and autodirected antibodies were detected in 16 of 26. Sural nerve biopsy results showed loss of myelinated fibers in 15 of 15. Seventeen of 24 patients (71%) who had implant removal were found to have grossly ruptured implants. We believe our patients had a new syndrome triggered by the foreign material in their body. This syndrome appears as a systemic inflammatory autoimmune disease with central nervous system involvement resembling multiple sclerosis.

Vascular factors in diabetic neuropathy.

Despite considerable research we still do not have a comprehensive explanation for the pathogenesis of diabetic neuropathy. Although chronic hyperglycaemia is almost certainly involved, it is not known whether the primary pathology is metabolic, microvascular, or an interaction between the two. Hyperglycaemia-induced polyol pathway hyperactivity associated with nerve sorbitol accumulation and myo-inositol depletion may play a part in the genesis of diabetic neuropathy. The case for microvascular disease in diabetic neuropathy is now strong. Fibre loss in human sural nerve is multifocal, suggesting ischaemia. The degree of vessel disease has been related to the severity of neuropathy. People with chronic obstructive pulmonary disease develop the so called "hypoxic neuropathy" in which similar microvascular changes occur as in diabetic neuropathy. In rats with experimental diabetic neuropathy nerve blood flow is reduced and oxygen supplementation or vasodilator treatment improved the deterioration in conduction velocity and nerve blood flow. Similarly, in human diabetic neuropathy, there is impaired nerve blood flow, epineurial arterio-venous shunting and a reduction in sural nerve oxygen tension. At what stage during the development of nerve damage these changes occur is yet to be determined.

Expression of types I, III and IV collagen genes in fibrotic skin and nerve lesions of toxic oil syndrome patients.

We have studied the skin and nerve fibrosis in toxic oil syndrome by in situ hybridization using specific cDNA probes for types I, III, and IV collagens. Fibroblasts with high levels of type I and III collagen mRNA were observed in biopsies from fibrotic skin areas. Similarly, type IV collagen mRNA was abundant in cells within the fibrotic process of the nerves. These results suggest that the excessive accumulation of collagen in toxic oil syndrome results from transcriptional activation of collagen genes in a subpopulation of fibroblasts.

[Accidental poisoning with podophyllin: a case with study of peripheral nerve]. / Intoxication accidentelle à la podophylline: un cas avec étude du nerf périphérique.

A 53 year-old veterinary surgeon accidentally ingested 0.8 g of podophyllin. Twelve hours later, he was deeply comatose, with clinical and EMG signs of extensive axonal sensorimotor and autonomic peripheral neuropathy. In addition, transient bone marrow and hepatic toxicity occurred. The coma lasted 2 weeks. Systemic and neurological disturbances started to improve at 3 months post-onset, but the patient died four months later from gastro-intestinal bleeding. Sural nerve biopsy showed loss of myelinated fibers and signs of axonal degeneration with type E teased fibers. The cytoplasm of Schwann and endothelial cells was vacuolated and swelled. Diffuse interstitial aedema was noted. Podophyllin acts as a spindle poison, binds microtubular proteins and inhibits axoplasmic flow.

Neuropathy due to podophyllin intoxication.

A 22-year-old man developed a severe sensorimotor neuropathy following ingestion of podophyllin, which had been prescribed for genital condylomata. The initial toxic symptoms were vomiting and diarrhoea, followed by peripheral neuropathy. The neuropathy was still present 18 months later. Nerve conduction studies and sural nerve biopsy confirmed the presence of axonal degeneration.

Peripheral neuropathy following intentional inhalation of naphtha fumes.

Two adolescent native Canadians who presented with peripheral neuropathy secondary to the abuse of volatile hydrocarbons are described. They were initially thought to have been sniffing leaded gasoline fumes, but public health investigation revealed that they had been sniffing naphtha fumes. Naphtha contains a significant amount of n-hexane, a known inducer of neuropathy. Nerve conduction studies and nerve biopsy confirmed the diagnosis of naphtha abuse. These cases emphasize the need to specifically identify the formulation of hydrocarbons being abused.

Abetalipoproteinaemia. A case report with pathological studies.

The clinical and pathological features of a case of abetalipoproteinaemia in a 38-year-old patient are described in detail. A feature not previously recorded was a marked reduction in the velocity of ocular horizontal saccadic movements. Pathological studies revealed an active chronic demyelinating process. The patient showed no response to large doses of vitamin E. The rationale for this therapy, and the possible reasons for its failure are discussed.