This article includes discussion of ulnar neuropathies, Guyon canal neuropathy, ulnar neuropathy at the wrist, and flexor carpi ulnaris exit compression.
Jun. 07, 2021
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This article reviews the neurobiology of vitamin E, neurologic disorders considered to be due to vitamin E deficiency, and the role of vitamin E in the management of neurologic disorders. Vitamin E is a scavenger of free radicals; it plays a role in the control of brain prostaglandin synthesis, regulation of nucleic acid synthesis, and gene expression. Neurologic and muscle dysfunction due to vitamin E deficiency may result from lack of antioxidant protection in susceptible tissues. Vitamin E has been used therapeutically in several neurologic disorders wherein oxidative stress is implicated in pathophysiology, such as in neurodegenerative disorders. Vitamin E exerts antioxidant effects in combination with other antioxidants, including carotene, vitamin C, and selenium.
• Deficiency of vitamin E can produce neurologic disorders, some of which can improve following administration of vitamin E.
• Vitamin E has antioxidant and neuroprotective effects.
• Vitamin E has been found to be beneficial in the management of some neurologic disorders not characterized by deficiency of vitamin E.
• Vitamin E is effective as a prophylactic in preventing neurologic complications of some disorders where its deficiency has been proven to play a causative role.
Vitamin E, or tocopherol, is 1 of the fat-soluble vitamins. The term tocopherol (which in Greek, tokos meaning childbirth, and phero meaning to bring forth) was first used to describe something found in lettuce that prevented fetal resorptions and enabled an animal to have offspring (07). To indicate the alcohol nature of the molecule, “ol” was added to the ending. This unknown substance was designated vitamin E. The neurologic role of vitamin E was first reported in 1928 when suckling offspring of vitamin E–deficient mother rats developed paralysis (08). Degeneration of the brain in a vitamin E–deficient rat was reported a few years later (25). The antioxidant properties of vitamin E were demonstrated in the 1940s, and applications in several human disorders believed to be due to free radical damage were suggested. The first documentation of the effect of vitamin E deficiency on the human nervous system was in patients with abetalipoproteinemia, in which beta-lipoprotein cannot be secreted, resulting in severe malabsorption and vitamin E deficiency. Vitamin E deficiency was shown to be the cause of ataxic neuropathy in these patients (18). In 1981, Burck and colleagues first reported neurologic abnormalities resulting from vitamin E deficiency in a patient without abnormalities of gastrointestinal function or lipid malabsorption and with normal plasma proteins. This was subsequently labeled familial isolated vitamin E deficiency.
This article will briefly review the neurobiology of vitamin E, neurologic disorders considered to be due to vitamin E deficiency, and the role of vitamin E in the management of neurologic disorders.
• Vitamin E is a fat soluble vitamin of plant origin; it is absorbed in the circulation after oral intake, crosses the BBB, and is taken up by the brain for neuroprotection.
• It is a scavenger of free radicals and acts as an antioxidant.
• Vitamin E deficiency can produce neurologic disorders where it has therapeutic applications.
Biochemistry. The term vitamin E applies to a family of structurally related compounds, the tocopherols and tocotrienols. Tocotrienols are natural compounds found in select vegetable oils, such as palm oil, as well as oils derived from certain nuts and grains. Biological activity differs considerably among the 4 forms of each of the phenols: alpha, beta, delta, and gamma. The synthetic form of vitamin E is termed “alpha-tocopherol” because it is an equal mixture of 8 possible isomers. In animals as well as in humans, vitamin E is distributed exclusively in the cellular membranes, adipocytes, and circulating lipoproteins. Vitamin E is localized primarily in the mitochondrial, microsomal, and synaptosomal subcellular fractions of the brain.
Dietary vitamin E is usually in the form of alpha- and gamma-tocopherol, and 20% to 40% of this is normally absorbed from the intestine. The uptake, transport, and tissue delivery of vitamin E involves molecular, biochemical, and cellular processes closely related to overall lipid and lipoprotein homeostasis. Absorption of vitamin E depends on the individual's ability to absorb fat. Bile acids from the liver and lipases from the pancreas solubilize it into micelles prior to reaching the surface of the absorptive enterocytes. The absorption into the intestine is by a passive diffusion process. The lymphatics carry the absorbed vitamin E into the blood as chylomicrons. Most of the vitamin E in the blood circulation is in low density. It is transported by a carrier through the blood-brain barrier. The concentrations of alpha tocopherol in CSF correlated significantly with its concentration in serum. Among the various vitamin E components, only alpha-tocopherol is actively taken up by the brain and is directly involved in protecting neural membranes.
Neurophysiology. The generally accepted physiological function of vitamin E is its role as a scavenger of free radicals. It is a component of enzymatic and nonenzymatic antioxidant systems that detoxifies the reactive oxygen species and prevents oxidant injury to the polyunsaturated fatty acids, other constituents of the cell membrane, the cytoskeleton, and nucleic acids. It is efficiently re-reduced from its free radical form (the form it takes after quenching free radicals) to its native state. Other important functions of vitamin E in the nervous system include its role in the control of brain prostaglandin synthesis, regulation of nucleic acid synthesis, and gene expression. The nervous tissues try to conserve vitamin E during deficiency states and show higher levels of this vitamin compared to other tissues. There is interaction between vitamin E and vitamin C--another antioxidant. Neuronal cells concentrate vitamin C intracellularly, which directly or indirectly protects them against oxidant stress by conserving vitamin E.
Neurologic disorders due to vitamin E deficiency. Vitamin E deficiency rarely occurs on a dietary basis in developed countries. The most common causes are malabsorption due to intestinal, hepatic, and pancreatic disorders that interfere with the digestion or absorption of lipids.
Pathomechanism. Neurologic and muscle dysfunction due to vitamin E deficiency may result from lack of antioxidant protection in susceptible tissues. Peroxidation of mitochondrial membrane lipid constituents may interfere with mitochondrial respiration, resulting in impairment of adenosine triphosphate production. In the developing nervous system, oxidation of the fatty acid component of the growth cone may alter the expression of membrane proteins and second messengers. The immature nervous system of young animals and human infants is, thus, more susceptible to vitamin E deficiency.
Impaired axonal transport may play a role in vitamin E–induced neuropathy. Vitamin E deficiency leads to swelling of distal axons and “spheroid” formation, which is observed in other conditions associated with impaired axonal transport. Defects of fast axonal transport produce a selective axonal degeneration of “dying back” type, which is also the finding in vitamin E deficiency neuropathy. Low tocopherol content has been demonstrated in peripheral nerves in vitamin E–deficient patients, who subsequently developed peripheral neuropathy.
Causes of vitamin E deficiency are listed in Table 1:
Malabsorption syndromes associated with:
Familial isolated vitamin E deficiency
• Mutations in the gene for alpha-tocopherol-transfer proteins
Prolonged total parenteral nutrition
Intestinal malabsorption disorders are common causes of vitamin E deficiency. In cholestatic liver disease, bile flow from the liver to the intestine is reduced, which impairs the morcellation process of vitamin E prior to absorption. In cystic fibrosis, failure of secretion of the pancreatic enzymes occurs. Lengthy intestinal resections for the treatment of Crohn disease or intestinal obstruction have been associated with vitamin E deficiency and neurologic manifestations.
In familial isolated vitamin E deficiency, the patients absorb vitamin E normally, but their conservation of plasma alpha-tocopherol is poor due to impaired secretion of alpha-tocopherol into the low-density lipoproteins. Tocopherol transfer protein regulates vitamin E status by facilitating the secretion of tocopherol from liver to circulating lipoproteins. Heritable mutations in the TTPA gene, tocopherol transfer protein, result in ataxia with vitamin E deficiency syndrome, typified by low vitamin E levels and a plethora of neurologic disorders. The physiological role of tocopherol transfer protein lies in its ability to direct vitamin E trafficking from the endocytic compartment to transport vesicles that deliver the vitamin to the site of secretion at the plasma membrane. Alpha-tocopherol transfer protein is found not only in the liver but also in cerebellar Purkinje cells in patients having vitamin E deficiency states or diseases associated with oxidative stress.
Manifestations. The role of vitamin E in the nervous system is well established. Neurologic manifestations of vitamin E deficiency are listed in Table 2. The primary manifestations of prolonged vitamin E deficiency are spinocerebellar ataxia, myopathy, and retinopathy.
• Syndrome resembling Friedrich ataxia
Role of vitamin E in pathophysiology of ataxia. Vitamin E deficiency is a significant cause of ataxia. However, not all the patients show the spectrum of neurologic disorders listed in Table 2. The neurologic manifestations vary according to the cause of vitamin E deficiency. Ophthalmoplegia and pigmentary retinopathy are unusual in patients with isolated vitamin E deficiency, but loss of vibration sense may be marked. In children with chronic cholestatic hepatobiliary disease, spinocerebellar ataxia has an early onset and is marked. The progression of neurologic deficits is slower in patients with abetalipoproteinemia and cystic fibrosis.
Familial isolated vitamin E deficiency manifesting as cerebellar ataxia and dysarthria can mimic Friedrich ataxia. However, in Friedrich ataxia, plasma alpha-tocopherol levels are normal, and vitamin E supplementation is unresponsive.
Mutation of the gene for alpha-tocopherol transfer protein causes ataxia with isolated vitamin E deficiency (AVED), a disorder usually stabilized or improved after vitamin E supplementation (23). Ataxia with isolated vitamin E deficiency is caused by a mutation in the α-tocopherol transfer protein gene (TTPA) and resembles Friedreich ataxia but is associated with low plasma vitamin E levels. Decreased visual acuity, likely due to retinitis pigmentosa, has been reported in ataxia with isolated vitamin E deficiency. A patient with ataxia with isolated vitamin E deficiency and progressive macular degeneration carried a novel mutation in the TTPA gene, resulting in severely low serum vitamin E levels (17). Another case of ataxia with vitamin E deficiency was reported to be caused by heterozygous missense mutations: c.173C>A in exon 1 and c.457G>A in exon 3 of the TTPA gene leading to amino acid p.A58D and p.G153R substitutions, respectively (33). Serum vitamin E levels were 47 µg/dL (normal values 500 to 1800 µg/dL). A case of sensory ataxic neuropathy and cognitive decline resulting from severe vitamin E deficiency due to pancreatic exocrine insufficiency was reported in which dietary supplementation with high-dose vitamin E produced rapid and significant improvement (32).
A study of patients with ataxia and peripheral neuropathy with vitamin E deficiency has recommended that any patient displaying an autosomal recessive cerebellar ataxia phenotype with absent tendon reflexes and minor nerve abnormalities should first be screened for the 744delA mutation in the gene for alpha-tocopherol transfer protein, even in the absence of a serum vitamin E measurement (06).
Role of vitamin E in myopathy. Severe vitamin E deficiency causes lethal myopathy in animal models. Failure of membrane repair leads to loss of myocytes and muscular dystrophy. An experimental study has shown that myocytes in intact muscle cannot repair membranes when exposed to an oxidant challenge but show enhanced repair when supplemented with vitamin E (16). This indicates a role for vitamin E in prevention of myopathy. Statins decrease blood levels of vitamin E, and a hypothesis states this as a possible mechanism of statin-induced myopathy (10). This needs further investigation.
Role of vitamin E in neurodegenerative disorders. Vitamin E exerts its antioxidative effects via direct scavenging of free radicals, prevents damage to biomolecules, indirectly stimulates the endogenous antioxidative enzymes and gene expressions, inhibits activation of pro-oxidant enzymes, and chelates metals (26). Vitamin E is particularly effective in preclinical stages as it attenuates oxidative stress underlying Alzheimer and Parkinson diseases.
• Vitamin E supplementation prevents neurologic complications of intestinal malabsorption.
• Vitamin E has some therapeutic effect in a number of neurologic disorders where its deficiency has been demonstrated.
• Vitamin E has a neuroprotective effect in some neurodegenerative disorders.
Vitamin E is clearly needed in conditions where its deficiency has been demonstrated. Vitamin E is valuable in preventing neurologic complications of intestinal malabsorption. Oral vitamin E supplementation can improve neurologic disturbance resulting from low serum vitamin E levels following gastrectomy. Its usefulness has also been demonstrated in isolated familial deficiency of vitamin E. Vitamin E deficiency neuropathy is reversible, and electrophysiologic recovery can occur with vitamin E therapy.
Applications where some evidence, but no conclusive proof, exists include many conditions. The non-neurologic applications include prevention of cataracts and cardiovascular disease, supplementary treatment for cancer and burns, acute respiratory distress syndrome, and boosting the immune system. Neurologic conditions where vitamin E has been proposed or used and that are seldom associated with vitamin E deficiency are listed in Table 3. The rationale proposed in some of these conditions, particularly neurodegenerative disorders, is that free radicals play a part in the pathogenesis, and vitamin E (an antioxidant) is a part of free radical scavenging system.
• Decline of mental function with aging
Decline of mental function with aging. Several studies have shown that consumption of foods and supplements containing vitamin E may help slow the decline in mental functioning that occurs with age. A possible explanation for this effect is that the antioxidant effect of vitamin E may counteract the damage done to brain cells by free radicals. Results of a randomized controlled trial of vitamin E in adults aged 60 to 85 years at a dose of 900 IU/day for 6 months showed no effect on cognitive function as evaluated by event-related potentials (01).
Alzheimer disease and other dementias. Vitamin E has been proposed as a treatment for Alzheimer disease because it protects neurons against the oxidative toxicity of amyloid beta and other adenosine diphosphate-related oxidative insults. Although earlier clinical trials showed beneficial effects of vitamin E in slowing functional deterioration in Alzheimer disease, a Cochrane Database review found no evidence that the alpha-tocopherol form of vitamin E given to persons with mild cognitive impairment prevents progression to dementia or that it improves cognitive function in people with mild cognitive impairment or dementia due to Alzheimer disease (09). One explanation of lack of efficacy is the use of alpha tocopherol supplementation in these studies, which significantly reduces serum gamma-tocopherol -- the form that is more effective in scavenging free radicals in the neuroinflammation component of neurodegenerative diseases (29). Contrary to this finding, a double-blind, placebo-controlled, parallel-group, randomized clinical trial involving patients with mild to moderate Alzheimer disease showed that 2000 IU/d of alpha tocopherol compared with placebo resulted in slower functional decline, whereas there were no significant differences in the groups receiving memantine alone or memantine plus alpha tocopherol (05). Although some randomized controlled studies have shown that treatment with vitamin E could delay functional decline in patients with mild to moderate Alzheimer disease, there were no cognitive benefits in patients with mild cognitive impairment (27). Despite functional improvement, value of vitamin E as a treatment for Alzheimer disease remains unproven because of a lack of established effect on cognition (02). A review of trials of vitamin E in animal models of Alzheimer disease and clinical use in older patients has concluded that vitamin E may be a good strategy to improve cognitive and memory deficits, and combination with other antioxidant or antiinflammatory compounds may increase its efficacy (13). Another review has suggested that the loss of neuronal networks and their replacement, wide variation in the nutritional status of patients at the baseline of studies, and different antioxidant effects of vitamin E in each person are some of the reasons for failure in treatment (20).
Amyotrophic lateral sclerosis. Dietary supplementation with vitamin E delays onset of clinical disease and slows progression in the transgenic models of amyotrophic lateral sclerosis but does not prolong survival. Vitamin E did not ameliorate the progression of amyotrophic lateral sclerosis for Lou Gehrig, after whom the disease is named, but more recent advances may identify subpopulations of patients that may respond to this therapy. A clinical trial of vitamin E in the treatment of amyotrophic lateral sclerosis showed no effect on survival and motor skills, but high intake of polyunsaturated fatty acids and vitamin E is associated with a 50% to 60% decreased risk of developing amyotrophic lateral sclerosis. In a large prospective study, long-term vitamin E supplement use was associated with lower amyotrophic lateral sclerosis rates, indicating a possible neuroprotective effect that should be investigated further (31).
Cerebral ischemia. Generation of oxygen radicals occurring during reperfusion is an important aspect of the pathophysiological mechanism in brain infarction. Vitamin E has been shown to prevent apoptosis in hippocampal neurons caused by cerebral ischemia and reperfusion in rat models and can be expected to have a beneficial effect in acute stroke. A randomized clinical trial of vitamin E tocotrienols have shown neuroprotective effect as judged by lack of increase of volume of white matter due to cerebral small vessel disease (11). An experimental study on rat stroke models has shown that treatment with vitamin E has a neuroprotective effect by preventing increased permeability of the blood-brain barrier and reduction of cerebral edema following an ischemic stroke occurrence, possibly by increase of antioxidant activity (14). Clinical trials, however, have mostly failed to show beneficial effects of vitamin E on stroke patients.
Down syndrome. Vitamin E has been shown to delay onset of cognitive and morphological abnormalities in a mouse model of Down syndrome and may represent a safe and effective treatment early in the progression of neuropathology of this disease (21). No controlled study has been reported using vitamin E as monotherapy.
Duchenne muscular dystrophy. Oxidative stress has been implicated in the pathogenesis of muscular dystrophies. Vitamin E has been shown to alleviate skeletal muscle injury in a mouse model of muscular dystrophy by promoting membrane repair through its antioxidant and antiinflammatory effects, suggesting potential therapeutic use for muscular dystrophy (22).
Epilepsy. Vitamin E levels are frequently decreased in epileptic children receiving antiepileptic drugs and may be associated with an increase in frequency of seizures. Supplementation with vitamin E has not been proven to improve seizure control in such children.
Fetal alcohol syndrome. Oxidative stress is involved in the pathophysiology of this syndrome. Prophylactic vitamin E has been suggested for the alcoholic mother during pregnancy to prevent this syndrome. The evidence is based on the demonstration of neuroprotective effect of vitamin E (reduced neuronal loss) in cells in hippocampal cultures exposed to ethanol.
In experimental animals, mitochondrially targeted vitamin E (MitoVit E), which is designed to accumulate in the mitochondria, has been shown to ameliorate toxic effects of alcohol by modulations of endogenous cellular proteins and antioxidant means.
Intraventricular hemorrhage prevention in premature infants. Vitamin E supplementation reduces the frequency of periventricular hemorrhages in premature babies. A concern, however, is about the use of vitamin E, as it increases the chance of intracerebral hemorrhage in children with vitamin K deficiency.
Multiple sclerosis. A study on multiple sclerosis patients has shown that elevated oxidation levels in circulating leukocytes are associated with serum lipid peroxidation as well as shortening of telomere length, and treatment with vitamin E 400 mg/day for 3 months showed significant reduction of serum lipid oxidation level with maintenance of telomere length (12). Therefore, antioxidants such as vitamin E are potential therapeutic agents for multiple sclerosis.
Myotonic dystrophy. Increased levels of free radicals and decreased antioxidants are found in the blood of patients with myotonic dystrophy, but vitamin E treatment of such patients has not produced any conclusive results.
Neuronal ceroid lipofuscinoses. Neuronal ceroid lipofuscinoses are a group of recessively inherited neurodegenerative lysosomal storage disorders. The occurrence of fluorescent pigments in these disorders suggests the peroxidation of lipids as an etiologic factor. These patients also have low selenium, coenzyme Q10, and vitamin E levels, indicating an impaired antioxidant protection. Antioxidant therapy (vitamin E plus selenium) has been used for these disorders, but there is no proof that the disease course is slowed.
Parkinson disease. The rationale for use of vitamin E in Parkinson disease is based on the hypothesis that it attenuates the dopaminergic neuronal degeneration of the disease. The DATATOP clinical trial was initiated to examine the benefits of deprenyl and vitamin E in slowing the progression of Parkinson disease, but after more than a decade of inquiry in this field, no definite evidence emerged for this approach. High dose vitamin E (2000 mg/day) continued to be used empirically by some neurologists in their patients with Parkinson disease. The trend, however, is to use lower doses of vitamin E, and further studies continue to investigate the neuroprotective in Parkinson disease.
Microtubule-associated protein tau (MAPT) is a susceptibility gene for idiopathic Parkinson disease, and hypermethylation of the MAPT gene is neuroprotective by reducing MAPT expression. The effect of vitamin E on MAPT, an example of gene-environment interaction, represents a possible explanation of beneficial effect of vitamin E (03).
Peripheral neuropathy associated with chemotherapy. Supplementation of patients receiving cisplatin chemotherapy with vitamin E decreases the incidence and severity of peripheral neuropathy as an adverse effect. In animal experimental studies, vitamin E was shown to protect against neurotoxicity induced by cisplatin without interfering with its antitumor activity. A randomized phase III study has confirmed the neuroprotective role of vitamin E against cisplatin peripheral neurotoxicity (24).
These encouraging results were contradicted by a phase III, randomized, double-blind, placebo-controlled trial, which concluded that vitamin E did not appear to reduce the incidence of sensory neuropathy patients receiving neurotoxic chemotherapy that included taxanes, cisplatin, carboplatin, oxaliplatin, or a combination (19).
Neuroprotection against cisplatin-induced neurotoxicity and ototoxicity. Neurotoxicity is an adverse effect caused by cisplatin due to inflammation and oxidative stress in the central nervous system. Results of an experimental study on rats show that vitamin E could improve cisplatin-induced memory impairment possibly through affecting the hippocampal oxidative status (15).
Preliminary results from a randomized, placebo-controlled trial have confirmed the neuroprotective properties of vitamin E against cisplatin-induced ototoxicity in a cancer patient (30).
Spinal cord injury. Several experimental studies over the past decade have indicted the usefulness of antioxidant therapy in spinal cord injury. Studies in rat models of spinal cord injury indicate that long-term administration of vitamin E may be useful toward decreasing lipid peroxidation following acute spinal cord trauma. In a rat model of contusional injury to the spinal cord, use of vitamins C and E did not improve the neurologic performance, but histopathological examination showed that the inflammatory response was less intense following administration of this combination of vitamins (04). No clinical trials have been reported.
Tardive dyskinesia. The rationale of using vitamin E in tardive dyskinesia is based on the theory that persistent tardive dyskinesia is caused by free-radical toxicity in the basal ganglia. According to Cochrane Database of Systematic Reviews, small trials of limited quality suggest that vitamin E may protect against deterioration of tardive dyskinesia, but there is no evidence that vitamin E improves symptoms of this condition once it is established (28).
Sources and dose of vitamin E for prophylaxis. The best sources of vitamin E are wheat germ, whole grain cereals, eggs, and certain vegetable oils, such as almond oil. The recommended daily allowance for both men and women is 15 mg/day. Because it is impossible to obtain a high intake of vitamin E without consuming a high-fat diet, use of vitamin E supplements is often recommended. Higher doses are used for protection against chronic diseases; the most commonly used dose is 400 mg/day.
Vitamin E exerts antioxidant effects in combination with other antioxidants, including carotene, vitamin C, and selenium. Vitamin C can restore vitamin E to its natural reduced form. Vitamin E is necessary for the action of vitamin A and may protect against some of the adverse effects of excessive vitamin A.
Adverse effects and drug interactions of vitamin E. Vitamin E is generally safe, and few adverse effects are reported with daily intake below 400 mg. In some individuals, vitamin E may interfere with vitamin K metabolism, causing bleeding. High doses of alpha-tocopherol supplements can cause hemorrhage and interrupt blood coagulation in animals, and in vitro data suggest that high doses inhibit platelet aggregation. Two clinical trials have found an increased risk of hemorrhagic stroke in participants taking alpha-tocopherol. In some clinical trials of vitamin E in cardiovascular diseases, cancer, diabetes, or hypertension, some adverse events and worsening of preexisting diseases were reported, but these are difficult to evaluate.
Vitamin E might increase the hepatic production of cytochrome P450s and MDR1, which could potentially lower the efficacy of any drug metabolized by CYP3A4 or MDR1 that is administered concomitantly.
Safety of high doses of vitamin E. As safety guidance, a tolerable upper intake level has been established by the Food and Nutrition Board of Institute of Medicine at 1000 mg for vitamin E. There is controversy about the safety of high doses of vitamin E. In view of this uncertainty, caution is recommended in the use of high doses of vitamin E in patients with neurologic disorders.
K K Jain MD
Dr. Jain is a consultant in neurology and has no relevant financial relationships to disclose.See Profile
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