Pyridoxine-induced sensory ataxic neuronopathy and neuropathy: revisited.

High dose pyridoxine is neurotoxic. Previous case reports were sparse and little is known about the clinical and electrodiagnostic findings. Three patients with pyridoxine-induced sensory ataxic neuropathy were studied and a review of the involved literature was performed. Three patients, aged 80, 83 and 83 years old, presented with sensory ataxia for 3-8 months. Examination showed signs of polyneuropathy and sensory ataxia. Six hundred milligrams of pyridoxine was consumed each day for 3-10 years, in the form of vitamin B1-6-12 combination tablet. Investigations for other causes of neuropathy were unremarkable. Blood levels of vitamin B6 were markedly elevated at 104.6, 81.4 and 66.9 times of upper normal limits. Electrodiagnostic tests showed symmetric axonal sensory polyneuropathy in two patients. Two years after vitamin discontinuation, all patients showed no significant improvement in the neuropathy and gait. In conclusion, consumption of high dose pyridoxine can cause sensory neuronopathy and axonal sensorimotor polyneuropathy, leading to sensory ataxia which may not be reversible.

Ginkgo nut intoxication in a 2-year-old male.

This report describes a case of ginkgo nut intoxication in a 2-year-old male. The patient presented with vomiting and afebrile convulsion 4 hours after eating a large number of roasted gingko nuts. There was a large volume of ginkgo nuts in his vomited matter, and on admission the concentrations of 4-O-methoxypyridoxine in his serum and urine were elevated. The patient was diagnosed as having ginkgo nut intoxication, and diazepam and pyridoxal phosphate were administered intravenously. After the treatment, his symptoms were resolved. The neurotoxicity of ginkgo nuts should be recognized by pediatricians and parents who have infants.

Ginkgo seed poisoning.

A 2-year-old girl presented with vomiting and diarrhea 7 hours after eating a large quantity of ginkgo seeds. She exhibited an afebrile convulsion 9 hours after ingestion. The serum concentration of 4-metoxypyridoxine was as high as 360 ng/mL. Although reported cases of ginkgo seed poisoning usually involve children who exhibit repetitive seizures that can be fatal, prompt administration of pyridoxal phosphate (2 mg/kg) may have prevented additional seizures. This is the first English-language case report measuring 4-metoxypyridoxine concentration during ginkgo seed poisoning. Awareness of the potential danger of overconsumption of this traditional food and its prompt treatment with pyridoxal phosphate may hasten recovery.

Pyridoxine-induced neuropathy in rats: a sensory neuropathy that responds to 4-methylcatechol.

Sensory neuropathies are frequently associated with diabetes or with antimitotic treatments in humans suffering from cancer, and are in this case the most important limitation to the use of antimitotic drugs. For this reason, there is a need to establish and validate animal models of sensory neuropathies that could be routinely used, together with the already known models, for studying and evaluating the effects of putative neuroprotective compounds. In the present study, we prove by behavioral and electromyographical analyses that (a) it is possible to induce a nonlethal, exclusively sensory, reversible neuropathy by intoxicating rats with large amounts of pyridoxine, using a new schedule of intoxication; (b) 4-methylcatechol, a drug known to induce nerve growth factor synthesis, improves the clinical status of pyridoxine-intoxicated animals, shortens the duration of the disease, and restores the morphological integrity of the sensory fibers. Owing to its mode of installation and its clinical features, we propose that this model be used as an additional model for preclinical studies of neuroprotective drugs.

Neurotrophin-3 administration attenuates deficits of pyridoxine-induced large-fiber sensory neuropathy.

Chronic treatment of adult rats for 2-3 weeks with high doses of pyridoxine (vitamin B6) produced a profound proprioceptive loss, similar to that found in humans overdosed with this vitamin or treated with the chemotherapeutic agent cisplatin. Pyridoxine toxicity was manifest as deficits in simple and precise locomotion and sensory nerve function and as degeneration of large-diameter/large-fiber spinal sensory neurons. As assessed quantitatively in a beam-walking task and by EMG recording of H waves evoked by peripheral nerve stimulation, coadministration of the neurotrophic factor neurotrophin-3 (NT-3; 5-20 mg . kg-1 . d-1, s.c.) during chronic pyridoxine treatment largely attenuated the behavioral and electrophysiological sequelae associated with pyridoxine toxicity. Furthermore, NT-3 administration prevented degeneration of sensory fibers in the dorsal column of the spinal cord. These data are consistent with the evidence that NT-3 is a target-derived neurotrophic factor for muscle sensory afferents and suggest that pharmacological doses of NT-3 may be beneficial in the treatment of large-fiber sensory neuropathies.

[Pyridoxine neuropathies. Review of the literature]. / Neuropathies à la pyridoxine. Revue de la littérature.

Daily needs of vitamin B6 are very low (2 mg per day) and widely covered by normal feeding. Pyridoxine deficiencies are exceptional (congenital metabolic abnormalities, drug or toxic-induced perturbations). First described in animal models, human cases of neuropathy had been encountered in the "megavitamin"-syndrome. They are confirmed by rare case-reports of very high doses given in toxic indication. Sensory peripheral neuropathies can also occur with lower doses taken over a long period of time.

Sensory and motor neuropathy caused by excessive ingestion of vitamin B6: a case report.

We describe a patient who developed a severe sensory and a mild motor neuropathy. This syndrome was due to massive and prolonged ingestion of vitamin B6 (10 g daily for 5 years). To our knowledge this is the first published case of motor neuropathy caused by chronic abuse of vitamin B6.

Dose-dependent expression of neuronopathy after experimental pyridoxine intoxication.

We examined the sequence of nervous system abnormalities that resulted when rats were given excess amounts of vitamin B6 (pyridoxine). High doses of pyridoxine (1,200 or 600 mg/kg/d) for 6 to 10 days caused a neuronopathy with necrosis of dorsal root ganglion (DRG) sensory neurons, accompanied by centrifugal axonal atrophy and breakdown of peripheral and central sensory axons. Large diameter neurons with long processes and large cytoplasmic volumes were especially affected. Smaller doses (300 to 150 mg/kg/d) for up to 12 weeks had minor effects on DRG neurons, but produced a neuropathy with axonal atrophy and degeneration. Guinea pigs given 1,800 mg/kg/d developed sensory neuronopathy, whereas mice given similar or higher doses did not have neuropathologic abnormalities. Multiple factors including rate of administration, differential neuronal vulnerability, and species susceptibility have bearing on the final expression of pyridoxine neurotoxicity.

Alteration of neuronal cytoskeletal organization in dorsal root ganglia associated with pyridoxine neurotoxicity.

The pathogenesis of the sensory neurotoxicity arising from high doses of pyridoxine is obscure. Beagle dogs were fed 200 mg pyridoxine/kg per day and killed at 4, 10, 14 and 16 days. Dorsal root ganglia (DRG) and their processes were processed for electron microscopy and teased-fiber preparation following perfusion of anesthetized animals with heparinized saline and a fixative solution of 3% paraformaldehyde, 1% glutaraldehyde. Four days after initiation of treatment a striking accumulation of neurofilament (NF) in proximal unmyelinated axons of the DRG was observed. Domains of altered NF cytoskeleton consisting of well-demarcated zones of higher packing density and anomalous orientation were observed, mainly in the myelinated part of the DRG segment. In addition, aggregates of microtubules (MT) were noted. In the cyton the Golgi complexes were abundant and the Nissl bodies together with the NF appeared increased in numbers. At 10 days NF and MT aggregations were readily apparent in both perikarya and proximal cell processes. This phenomena was diminished in the 14- and 16-day-treated animals and retrogressive histological features appeared in the soma and in axons. Degeneration of NF with subsequent reduction in size of the axonal swellings and axonal breakdown with phagocytosis were prominent in central and peripheral processes of DRG. Cytons distended by NF were less prominent. Necrotizing changes, evidenced by disruption of the soma with the proliferation of satellite cells, were present. These results indicate that an early morphological correlate of pyridoxine neurotoxicity is the accumulation of NF with MT-NF dissociation in the unipolar process of the DRG in the absence of extensive vacuolization, and that the observed cytoskeletal disruption may be related to an increased rate of NF protein synthesis together with mechanical obstruction of transport phenomena.

Characteristics of pyridoxine overdose neuropathy syndrome.

A newly recognised neurotoxic syndrome due to pyridoxine (B6) overdose is described. It is the largest series of B6 intoxication hitherto reported. A raised serum B6 level was present in 172 women of whom 60% had neurological symptoms, which disappeared when B6 was withdrawn and reappeared in 4 cases when B6 was restarted. The mean dose of B6 in the 103 women with neurological symptoms was 117 +/- 92 mgs, compared with 116.2 +/- 66 mgs in the control group. There was a significant difference (P less than 0.01) in the average duration of ingestion of B6 in the neurotoxic group of 2.9 +/- 1.9 years compared with 1.6 +/- 2.1 years in controls. The symptoms were paraesthesia, hyperaesthesia, bone pains, muscle weakness, numbness and fasciculation, most marked on the extremities and predominantly bilateral unless there was a history of previous trauma to the limb. These women were taking a lower dose of B6 than previously described (1,2), which may account for the complete recovery within 6 months of stopping B6.

[Peripheral sensory neuropathy produced by a megadose of vitamin B6].

Clinical cases of sensory neuropathy produced by a megadose of vitamin B6 have been reported in English literatures. We investigated the ordinary daily dosage and maximal dose of vitamin B6 widely adopted in Japan, and the amount of vitamin B6 per unit (per tablet, capsule or ampule) available in our medical practice. We concluded that in Japan it is very rare to administer such a large dose of vitamin B6 that produced sensory neuropathy described in the literatures. In our experimental study, Sprague-Dawley rats were intraperitoneally given a total amount of 14,000 mg/kg of body weight of pyridoxine hydrochloride in ten separate doses. They developed an ataxic gait. The occurrence of the degeneration of nerve cell bodies and peripheral axons of lumbar primary sensory neurons were histologically demonstrated. Although in Japan no clinical cases of neuropathy produced by a megadose of vitamin B6 have been reported to our knowledge, it is necessary to be aware of the possible occurrence of such neuropathy among patients with polyneuropathy of unknown etiology or who have been receiving vitamin B6 for a long time.

[Acute renal failure caused by acute oxalosis after massive ingestion of pyridoxilate]. / Insuffisance rénale aiguë par oxalose aiguë après ingestion massive de piridoxilate.

The authors report a case of acute renal failure with hyperoxaluria and intratubular deposits of oxalate crystals, following a massive ingestion of piridoxilate. Cases of calciumoxalate urolithiasis have also been reported after chronic administration of piridoxilate.

Pyridoxine neuropathy: correlation of functional tests and neuropathology in beagle dogs treated with large doses of vitamin B6.

Neurologic examination, electrophysiologic testing and microscopic post-mortem examination was used to study the neuropathy induced in the beagle dog by administration of excessive amounts of vitamin B6. Two female dogs received repeated daily oral doses of 3 g. The treatment was ceased when the dogs developed severe general morbidity, including uncoordinated gait and abnormal neurologic symptoms. The symptoms were most severe during and early after cessation of treatment, and in general they regressed during the subsequent 2 months of treatment-free observation. Sensory central and peripheral maximum nerve conduction velocity started to decrease after a considerable delay; the decrease progressed until late after termination of treatment and failed to fully regress. Morphologic lesions were confined to large, first order sensory neurons. The neurologic examination thus revealed the early changes, while electrodiagnostics and microscopic neuropathology were indicators of more advanced stages of toxic neuropathy and disclosed selective lesions in individuals whose gait appeared to be unremarkable.