Peripheral nerve involvement in children with chronic cholestasis and vitamin E deficiency. A clinical, electrophysiological and morphological study

Seven children with early onset cholestasis who developed signs of peripheral neuropathy were investigated before and after one and a half to three years of treatment by vitamin E. This neuropathy appeared to be due to neuronoaxonal degeneration, but unusual Schwann cell inclusions were also observed. Although the treatment stabilized or improved the condition of all patients, no striking changes were noted neither in the EMG nor in the second nerve biopsy of a patient treated for three years. As the pathological process concerned it is probably both a developmental disorder and a degenerative phenomenon, substitutive vitamin E treatment should be proposed very early in life.     

Familial idiopathic vitamin E deficiency associated with cerebellar atrophy

Sibling cases of familial vitamin E deficiency accompanied by ataxia, polyneuropathy and mental retardation were reported. Case 1 was a 37-year-old male who developed progressive gait disturbance, deformity of the feet and head tremor from childhood, after normal delivery and development of early childhood. On physical examination, he had cataract, high arched palate and pes cavus. Neurological examination revealed mental retardation (WAIS 68), scanning speech, muscular atrophy of the face and extremities with predominance in the lower limbs, absent Achilles tendon reflex, disturbance of superficial and deep sensation predominant in distal limbs, and marked gait ataxia. Ataxia was both cerebellar and sensory in nature. Laboratory data of the blood showed no significant abnormalities including blood glucose and vitamin B12 except a markedly low level of serum vitamin E. The brain CT scan revealed severe cerebellar atrophy and marked dilatation of the cisterna magna and the subarachnoid space around the cerebellum. Motor nerve conduction velocity in the leg was decreased. Biopsy specimen from the quadriceps muscle showed neurogenic atrophy. Sural nerve biopsy revealed decrease in large myelinated fibers with axonal degeneration and regeneration. Oral administration of alpha-tocopherol acetate, 600 mg per day, diminished ataxia significantly. Based on lysosomal enzyme activity in leukocytes, clinical and laboratory examination, lipidosis or spinocerebellar degeneration was excluded. Chronic lipid malabsorption or beta lipoprotein deficiency which can cause decrease in vitamin E absorption, was not recognized. On oral loading with 2 g of alpha-tocopherol acetate, the decrease rate of serum vitamin E was normal. Consequently the low vitamin E was considered to have resulted from selective impairment of vitamin E absorption.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prostaglandin E1 in conjunction with high doses of vitamin B12 improves nerve conduction velocity of patients with diabetic peripheral neuropathy

BACKGROUND： Prostaglandin El improves diabetic peripheral neuropathy in symptoms and sensory threshold. Vitamin Bi and methyl-vitamin BI2 improve microcirculation to peripheral nerve tissue and promote neurotrophy. OBJECTIVE： To observe motor nerve and sensory nerve conduction velocity in patients with diabetic peripheral neuropathy, prior to and after treatment with prostaglandin El, vitamin B I and different doses of vitamin B 12. DESIGN, TIME AND SETTING： Randomized, controlled experiment, performed at the Department of Neurology, Beijing Hantian Central Hospital, between February 2002 and September 2007. PARTICIPANTS： A total of 122 patients with type 2 diabetic peripheral neuropathy; 73 males and 49 females were included. All patients met the diagnostic criteria of diabetes mellitus, as determined by the World Health Organization in 1999 and 2006, and also the diagnostic criteria of diabetic peripheral neuropathy. For each subject, conduction disorders in the median nerve and in the common peroneal nerve were observed using electromyogram. Also, after diet and drug treatment, the blood glucose level of subjects was observed to be at a satisfactory level for more than two weeks, and the symptoms of diabetic peripheral neuropathy were not alleviated. METHODS： All patients were randomly divided into the following three groups. A control group （n = 40）, in which, 100 mg vitamin B1 and 500 μg vitamin BI2 were intramuscularly injected. A vitamin B12 low-dose treated group （ n = 42）, in which 10 μ g prostaglandin E1 in 250 mL physiological saline was intravenously injected once a day and 100 mg vitamin BI and 500 11 g vitamin BI2 was intramuscularly injected once a day. Lastly, a vitamin B12 high-dose treated group （n = 40）, in which administration was the same as in the vitamin B12 low-dose treated group, except that 500 11 g vitamin BI2 was replaced by 1mg vitamin B12. Administration was performed for four weeks for each group. MAIN OUTCOME MEASURES： The motor nerve and sensory nerve con     

Functional recovery and vitamin E level following sciatic nerve crush injury in normal and diabetic rats

Extensive biochemical data document the involvement of oxygen derived free radicals (ODFR) in recovery following neurotrauma as well as diabetic neuropathy. Vitamin E is considered as one of the principle protective mechanism against oxidative damage in neuronal tissue. The present study was undertaken to determine the association between functional recovery and vitamin E levels following sciatic nerve crush injury in normal and diabetic rats. The sciatic nerve of normal and streptozotocin (STZ) induced diabetic rats was crushed using a haemostat. The walking track analysis and vitamin E levels were recorded on 10, 20 and 30th day. Maximum functional deficiency and depletion of vitamin E in sciatic nerve was observed on 10th day following crush injury in both normal and diabetic animals. A progressive motor recovery and repletion of vitamin E was observed on day 20 and 30 following injury in both diabetic and normal rats. The functional recovery was slower whereas vitamin E level was higher in diabetic animals as compared to normal injured rats during healing phase suggesting that vitamin E alone may not be an efficient indicator of oxidative stress during regeneration of axons following trauma in diabetic rats.     

Electrophysiologic features of abetalipoproteinemia: functional consequences of vitamin E deficiency

We performed electrophysiologic testing in 10 patients with abetalipoproteinemia (ABL). Peripheral nerve studies implied an axonal disorder. Visual evoked potentials demonstrated prolonged P100 latency in three patients and abnormal electroretinograms in six. Somatosensory evoked potentials indicated dorsal column dysfunction in eight patients. Brainstem auditory evoked potentials were normal. Findings were consistent with the known neuropathology of ABL and of experimental vitamin E deficiency. Stabilization or improvement in electrophysiologic findings occurred with vitamin E supplementation. Neurophysiologic tests document retinal, central somatosensory and peripheral nerve lesions in vitamin E deficiency and provide an objective indication of response to treatment.     

STUDIES ON THE NEUROBIOLOGY OF VITAMIN E (ALPHA-TOCOPHEROL) AND SOME OTHER ANTIOXIDANT SYSTEMS IN THE RAT

To understand why nervous tissue should be particularly affected by severe deficiency of vitamin E, the distribution of vitamin E (alpha-tocopherol) and some other antioxidant systems was investigated. The concentration of vitamin E and the activities of glutathione peroxidase and superoxide dismutase were determined in different regions of the nervous system in male Wistar rats. The cerebral cortex had the highest, and the cerebellum the lowest concentration of alpha-tocopherol (P less than 0.02). Activity of glutathione peroxidase tended to show an inverse relationship to the alpha-tocopherol concentration, whereas superoxide dismutase activity was evenly distributed through the nervous tissue. Vitamin E concentrations were also determined in spinal cord, sciatic and tibial nerves and in epineurial, myelin and non-myelin fractions of the sciatic nerve. Uptake of intravenously injected tritiated alpha-tocopherol was studied after 6 h and found to be greater in brain and peripheral nerve than cervical and thoracic regions of the spinal cord. Uptake of tocopherol varied along the sciatic and tibial nerve, being greatest where the sciatic nerve divided into tibial, sural and common peroneal nerves. This corresponded to an area of increased vasculature which was visualized by an angiographic technique using barium sulphate.     

Friedreich-like ataxia with retinitis pigmentosa caused by the His101Gln mutation of the α-Tocopherol transfer protein gene

The α-tocopherol transfer protein (α-TTP) is a cytosolic liver protein that is presumed to function in the intracellular transport of α-tocopherol, the most biologically active form of vitamin E. We studied 4 unrelated patients with autosomal recessive Friedreich-like ataxia who had isolated vitamin E deficiency. A point mutation was identified in all of them at position 101 of the gene for α-TTP, where histidine (CAT) was replaced with glutamine (CAG). Three of the 4 patients developed retinitis pigmentosa subsequent to the onset of ataxia. Neurological symptoms included ataxia, dysarthria, hyporeflexia, and decreased proprioceptive and vibratory sensations. Electrophysiological and pathological examinations showed that the cardinal sites affected were the central axons of dorsal root ganglion cells and the retina, with minor involvement of the peripheral sensory nerve, optic nerve, and pyramidal tract. The vitamin E tolerance test performed showed that the absorption of vitamin E was normal but that its decrease from the serum was accelerated. Oral administration of vitamin E appeared to halt the progression of visual and neurological symptoms. We propose a new treatable syndrome of Friedreich-like ataxia and retinitis pigmentosa caused by a defect in the α-TTP gene.     

Vitamin E deficiency in acquired fat malabsorption

Summary Thirteen patients with adult-onset vitamin E deficiency due to fat malabsorption were investigated clinically and electrophysiologically. These patients had slightly or moderately decreased serum vitamin E (1.7–4.8 g/ml, normal <6.0) or vitamin E/cholesterol ratio (0.21–0.31 mg/g, normal <0.35). Only one patient had typical neurological manifestations of vitamin E deficiency, which improved with supplementary vitamin E. The pathological findings in this patient were also compatible with vitamin E deficiency. This patient had poorly controlled diabetes mellitus due to advanced chronic pancreatitis. Reviewing previously reported cases of vitamin E deficiency with diabetes mellitus in chronic pancreatitis, the duration of deficiency until the onset of symptoms was shorter than in those cases without complications. Although adult patients with early, slight deficiency of vitamin E are generally asymptomatic, patients with diabetes mellitus tend to have early neurological symptoms. The vitamin E tolerance test should be used, because even in some patients with vitamin E deficiency due to malabsorption, the deficiency can be overcome by large oral doses of vitamin E.     

Isolated vitamin E deficiency

Since the detection of vitamin E in 1922, nearly 50 years passed until the recognition that there is a pathogenic vitamin E deficiency in humans. Such a deficiency can be found mostly in a disturbed resorption or transport of the vitamin (mucoviscidosis, chronic cholestasis, abetalipoproteinaemia) and leads typically to a progredient spinocerebellar ataxia in combination with a polyneuropathy. Substitution of the vitamin may hinder a further progression or even lead to an amelioration of the symptoms. Prophylactic treatment in abetalipoproteinaemia prevents the otherwise unavoidable neurological deficits. Isolated vitamin E deficiency is a rare syndrome and the causes are still obscure. We observed a 26 year old male patient with such a isolated vitamin E deficiency who was hitherto thought to suffer from Friedreich's ataxia. The clinical feature showed in addition to the "classical" symptoms of vitamin E deficiency cranial nerve involvement, perioral dystonia and pyramidal signs. Histologically (M. gastrocnemius) we saw the described typical but not specific changes (neurogenic atrophy, phosphatase-positive vacuoles with myelin bodies, cores). An oral vitamin E resorption test yielded a very shortened serum half life. These results support the hypothesis that in the pathophysiology of isolated vitamin E deficiency malelimination plays an important role in addition the known malresorptions models.     

大剂量维生素C和维生素E对急性颅脑损伤病人神经损伤、神经营养及氧化应激的影响

目的 探讨大剂量维生素C和维生素E对急性颅脑损伤病人神经损伤、神经营养及氧化应激的影响。方法 2018年1月至2018年11月前瞻性收集84例急性颅脑损伤并随机分为对照组（n=42,接受常规治疗）和观察组（n=42,接受大剂量维生素C和维生素E联合常规治疗）。治疗前、治疗后4、7 d,采用酶联免疫吸附法测定血清神经损伤指标[包括神经元特异性烯醇化酶（NSE）、S100蛋白、脑红蛋白（NGB）、泛素羧基末端水解酶L1（UCH-L1））、神经营养指标[包括神经营养因子-α（NTF-α）、脑源性神经营养因子（BDNF）、神经生长因子（NGF）、胰岛素样生长因子-1（IGF-I）,采用放射免疫沉淀法测定氧化应激指标[包括超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GPx）、过氧化氢酶（CAT）、丙二醛（MDA）、晚期氧化蛋白产物（AOPP）]。结果 治疗后4、7 d,两组血清NSE、S100B、NGB、UCH-L1、MDA、AOPP含量均显著降低（P<0.05）,血清NTF-α、BDNF、NGF、IGF-I、SOD、GPx、CAT含量均显著增高（P<0.05）,而且,观察组均明显优于对照组（P<0.05）。结论 大剂量维生素C和维生素E治疗能够减轻急性颅脑损伤病人神经损伤程度、氧化应激反应并改善神经营养状态。     

Effect of vitamin E supplementation in patients with ataxia with vitamin E deficiency

Ataxia with vitamin E (Vit E) defciency (AVED) is an autosomal recessive disorder caused by mutations of the alpha tocopherol transfer protein gene. The Friedreich ataxia phenotype is the most frequent clinical presentation. In AVED patients, serum Vit E levels are very low in the absence of intestinal malabsorption. As Vit E is a major antioxidant agent, Vit E deficiency is supposed to be responsible for the pathological process. Twenty-four AVED patients were fully investigated (electromyography, nerve conduction velocity (NVC) studies, somatosensory evoked potentials, cerebral computed tomography scan, sural nerve biopsy, genetic studies) and supplemented with Vit E (800 mg daily) during a 1-year period. Clinical evaluation was mainly based on the Ataxia Rating Scale (ARS) for cerebellar ataxia assessment and serum Vit E levels were monitored. Serum Vit E levels normalized and ARS scores decreased moderately but significantly suggesting clinical improvement. Better results were noted with mean disease duration < or = 15 years. Reflexes remained abolished and posterior column disturbances unchanged. Vitamin E supplementation in AVED patients stabilizes the neurological signs and can lead to mild improvement of cerebellar ataxia, especially in early stages of the disease.     

Effects of vitamin E and electrical stimulation on the denervated rat gastrocnemius muscle malondialdehyde and glutathione levels

Effects of vitamin E treatment and local electrical stimulation on progression of atrophy in the denervated rat gastrocnemius muscle were studied. Denervation was performed by right leg sciatic nerve axotomy. Electrical stimulation (3-10 mA ms(-1), 10 min per day for 7 days) was applied to the right gastrocnemius muscle starting from day 1 of denervation. The muscle samples were assayed for malondialdehyde (MDA) and glutathione levels, as well as the histological appearance after 8 days of denervation. MDA levels were markedly increased following denervation. However, electrical stimulation, vitamin E treatment (30 mg kg(-1), i.m., everyday for 7 days), and combination of electrical stimulation and vitamin E treatment markedly reduced MDA levels. Glutathione levels were significantly decreased in the denervation group. Electrical stimulation, vitamin E treatment, and electrical stimulation plus vitamin E treatment prevented these reductions in glutathione levels. In the vitamin E treatment group, glutathione levels were markedly higher than in the control group. These results indicate that electrical stimulation and vitamin E treatment alone, or in combination, were able to prevent the effects of denervation on muscle atrophy.     

A longitudinal study of somatosensory, brainstem auditory and peripheral sensory-motor conduction during vitamin E deficiency in the rat

A severe deficiency of vitamin E causes a characteristic neurological syndrome in man and experimental animals. In this study a number of electrophysiological modalities in vitamin E deficient and control rats have been investigated over a period of one year to define the time of onset and severity of the abnormalities associated with vitamin E deficiency in the rat. The mean velocities (n = 10) of the sensory evoked potentials were slower at all time points in the vitamin E deficient rats, with the central conduction velocities being more severely affected than the peripheral. Central conduction velocities, following both tibial and median nerve stimulation, were significantly delayed (P less than 0.005) after 8 months of deficiency. Differences in peripheral conduction following tibial stimulation became significantly delayed (P less than 0.005) after 11 months of deficiency. There were no significant differences in the brainstem auditory evoked potentials or peripheral sensory motor responses between the vitamin E deficient and control rats over the 1 year period. These results in the rat are essentially similar to those previously reported in vitamin E deficient man.     

Nigrostriatal function in vitamin E deficiency: Clinical,experimental, and positron emission tomographic studies

Four patients with vitamin E deficiency and sensory ataxia were studied using [¹⁸F]dopa positron emission tomography. The 2 most disabled patients, who had severe and prolonged vitamin E deficiency due to abetalipoproteinemia, showed reduced [¹⁸F]dopa uptake in both putamen and caudate. Putaminal uptake was in a similar range to that seen in Parkinson's disease. Studies of [³H]mazindol binding in the striatum of vitamin E–deficient rats indicated a reduced number of dopamine terminals, which was most severe in ventrolateral striatum. These observations suggest that severe and prolonged vitamin E deficiency results in loss of nigrostriatal nerve terminals, and support the hypothesis that oxidative stress may contribute to the etiology of Parkinson's disease.     

Alteration of the α-tocopherol content in the brain and peripheral nervous tissue of dysmyelinating mutants

In the brain of quaking and shiverer mutants, vitamin E content was normal when related to both wet weight and dry weight. When related to lipid extract, phosphorus, and polyunsaturated fatty acids, vitamin E was slightly increased only in the quaking mutant. In the sciatic nerve from trembler mutants, vitamin E was 134% of control values in the dry material, but normal in relation to wet weight. It was 260% in the lipid extract and 716% based on phosphorus. In relation to total fatty acids, there was a threefold increase in trembler mutants. Interestingly, it was increased approximately three times when related to 18∶2 n?6, 20∶4 n?6, and 20∶5 n?3, and seven times when related to 22∶6 n?3. The fact that the amount of vitamin E in fresh weight was normal, suggests that vitamin E plays a role in some nonmembrane material, such as the extracellular matrix or the basal lamina.     

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.     

Vitamin D and Nerve Conduction In Pediatric Type-1 Diabetes Mellitus

IntroductionThe aim of this study is to investigate a possible association between vitamin D deficiency and diabetic peripheral neuropathy in pediatric patients with type 1 diabetes mellitus.Materials-methodsTwenty-nine patients with type 1 diabetes mellitus and 19 healthy controls were included to the study. All individuals were evaluated for diabetic peripheral neuropathy with nerve conduction studies. Complete blood cell count, biochemical investigations, serum vitamin D levels, hemoglobin A1c levels were recorded.ResultsNo statistically significant differences between the diabetes and control groups in terms of gender, age, body weight, height, body mass index, systolic and diastolic blood pressures, laboratory investigations, serum vitamin D levels and nerve conduction studies was found. Patients with diabetes were grouped as patients with normal serum vitamin D levels and patients with vitamin D deficiency. Sensory nerve action potential of sural nerve and motor peroneal nerve velocity were statistically significantly lower in diabetic patients with vitamin D deficiency compared to diabetic patients with normal vitamin D levels (p 0.009 and 0.005 respectively).ConclusionOur results suggested that hypovitaminosis D might lead to development of neuropathic changes particularly on the lower limb nerves even in the early stages of the disease. It should be kept in mind that patients with hypovitaminosis D should be elaborately examined and closely followed up for the development of diabetic neuropathic changes, even if glucose control is achieved.     

Vitamin E suppression of microglial activation is neuroprotective

Neurotoxic microglial-neuronal interactions have been implicated in the pathogenesis of various neurodegenerative diseases such as Alzheimer's disease, and vitamin E has been shown to have direct neuroprotective effects. To determine whether vitamin E also has indirect neuroprotective effects through suppression of microglial activation, we used a microglial-neuronal coculture. Lipopolysaccharide (LPS) treatment of a microglial cell line (N9) induced a time-dependent activation of both p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor-kappaB (NFkappaB), with consequent increases in interleukin-1alpha (IL-1alpha), tumor necrosis factor-alpha (TNF-alpha), and nitric oxide (NO) production. Differentiated neuronal cells (PC12 cells treated with nerve growth factor) exhibited marked loss of processes and decreased survival when cocultured with LPS-activated microglia. Preincubation of microglia with vitamin E diminished this neurotoxic effect, independently of direct effects of the antioxidant on the neuronal cells. Microglial NO production and the induction of IL-1alpha and TNFalpha expression also were attenuated by vitamin E. Such antiinflammatory effects of vitamin E were correlated with suppression of p38 MAPK and NFkappaB activation and were mimicked by an inhibition of either p38 MAPK (by SB203580) or NFkappaB (by decoy oligonucleotides). These results suggest that, in addition to the beneficial effects of providing direct antioxidant protection to neurons reported by others, vitamin E may provide neuroprotection in vivo through suppression of signaling events necessary for microglial activation.     

Appearance of amyloid beta-like substances and delayed-type apoptosis in rat hippocampus CA1 region through aging and oxidative stress

To elucidate whether oxidative stress induces cognitive deficit, and whether nerve cells in the hippocampus, which modulates learning and memory functions in the brain, are damaged by oxidative stress and during aging, the influence of hyperoxia as oxidative stress on either the cognitive function of rats or the oxidative damage of nerve cells was investigated. Young rats showed better learning ability than both old rats and vitamin E-deficient young rats. Vitamin E- supplemented young rats showed similar ability to young control rats. After they learned the location of the platform in the Morris water maze test, the young rats and vitamin E-supplemented young rats were subjected to oxidative stress for 48 h, and the old rats and vitamin E-deficient young rats were kept in normal atmosphere. The memory function of the old rats and vitamin E-deficient young rats declined even when they were not subjected to oxidative stress for 48 h. In contrast, the young rats maintained their memory function for 4 days after the oxidative stress. However, their learning abilities suddenly declined toward that of the normal old rats after 5 days. At this point, nerve cell loss and apoptosis were observed in the hippocampal CA 1 region of young rats. Vitamin E-supplementation in the young rats prevented either memory deficit or the induction of delayed-type apoptosis. The old rats and vitamin E-deficient young rats kept in normal atmosphere for 48 h also showed apoptosis in the hippocampus. Also, 10 days after oxidative stress, amyloid beta-like substances appeared in the CA-1 region of control young rats; these substances were also observed in the CA-1 region of the old rats and vitamin E- deficient young rats. These results suggest that reactive oxygen species (ROS) generated by oxidative stress induced amyloid beta-like substances and delayed-type apoptosis in the rat hippocampus, resulting in cognitive deficit. Since amyloid beta in Alzheimer's disease characterized by cognitive deficit induces neuronal cell death, it is reasonable to consider that amyloid beta deposition in the brain may be associated with memory dysfunction. The results of this study imply that age-related hippocampal neuronal damage is prevented by vitamin E supplementation due to the antioxidant effect of vitamin E.