Vitamins in Neuro-ophthalmology

From EyeWiki

Vitamins in Neuro-ophthalmology


  1. Vitamin A
  2. Vitamin B1 (Thiamine)
  3. Vitamin B9 and B12
  4. Vitamin D
  5. Vitamin E


Vitamins are essential for biochemical metabolic function. Deficiencies (or in some cases excess) of these vital amines can produce neuro-ophthalmic disease. This chapter reviews the major vitamins and their various clinical presentations.

Vitamin A

General Pathology

Vitamin A is essential for various life processes such as reproduction, embryo development, growth, cell differentiation, immune function, and vision.1 Preformed vitamin A sourced from animal foods (e.g., liver, egg yolks) and provitamin A carotenoids sourced from plant foods (e.g., dark green leafy vegetables, carrots, papaya) or supplements undergo metabolism in the intestine resulting in conversion into retinol. Other forms of retinol are found in retinal pigment epithelium cells, such as 11-cis-retinal and all-trans-retinal, who both hold an essential role in the visual system. 11-cis-retinal binds opsin and holds the photoreceptor in its stable, inactive form. Photo isomerization of 11-cis-retinal to all-trans-retinal causes conformational alterations in the receptor, consequently producing meta-rhodopsin II. Meta-rhodopsin II production leads to a sequence of events resulting in a change in neurotransmitter release that is communicated to other retinal neurons and ultimately the brain.2

Vitamin A Deficiency


Worldwide, vitamin A deficiency is the leading cause of preventable blindness in children, mainly affecting countries in Southeast Asia and Africa. Over 250 million preschool children are deficient across the globe.3 In developing countries, Vitamin A deficiency is because of malnutrition meanwhile in developed countries, although rare, is due to malabsorption following intestinal and bariatric surgery.4 Other causes of vitamin A deficiency include inadequate liver stores, liver disease, and the acute phase response.5


Vitamin A deficiency can cause a spectrum of eye diseases including xerophthalmia (dryness of the conjunctiva and cornea). In the early stages of Vitamin A deficiency, nyctanopia, also known as night blindness, may develop. In severe stages of Vitamin A deficiency, keratomalacia may develop and this ulceration of the cornea can lead to blindness. Vitamin A deficiency also may cause squamous metaplasia of the conjunctiva and the formation of a Bitot’s spot (a well-demarcated area of keratinizing squamous metaplasia on the nasal bulbar or temporal conjunctiva). Serum vitamin A concentrations are used to determine deficiency defined as less than 0.7 μmol/L in children, and less than 1.05 μmol/L in adults.5


High-dose of oral vitamin A supplements are recommended for children to treat xerophthalmia and lower prophylactic dosing can be given for prevention of vitamin A deficiency. Women of reproductive age who are deficient may also need supplementation.5 If oral supplements are inefficient, then IV or intramuscular injections may be considered.

Hypervitaminosis A

Causes and Disease

Several case reports over the past few decades have reported a correlation between secondary pseudotumor cerebri (PTC) and hypervitaminosis A or chronic lower doses of retinoid. In various reports, PTC, although rare, is attributed to the use of retinoids for acne (e.g., isotretinoin), psoriasis, and in leukemia6, excessive dietary7 (e.g., liver ingestion) and supplement intake.8 All-trans retinoic acid used for acute promyelocytic anemia has also been linked to the presentation of IIH.9


The potentially causative medication may be discontinued and the patient should seek medical attention for a detailed evaluation.

Vitamin B1 (Thiamine)

General Pathology

Vitamin B1, also known as thiamine, has a role in pyruvate dehydrogenase multiple enzyme complex in the Kreb’s cycle, enzymatic processes in brain function and interneuonal communication, and the regulation of immune cells and proteins. Given its multiple roles, adequate thiamine levels are essential. Thiamine is absorbed in the jejunum and transported in erythrocytes and plasma in the blood.10,11


In less developed countries, malnutrition is the source of thiamine deficiency. In industrialized countries, such as the U.S., thiamine intake is high because of the abundance of enriched, fortified and whole-grain products. We see thiamine deficiency in patients with heavy alcohol consumption with limited food intake, gastric surgery, excessive loss from vomiting (e.g., hyperemesis gravida) or diarrhea, or eating disorders.11


Thiamine deficiency is most concerning for Wernicke Encephalopathy (WE), which classically has been described as a triad of encephalopathy, ophthalmoplegia, or nystagmus, and gait ataxia. If not treated appropriately, WE can progress to Korsakoff syndrome, resulting in permanent anterograde and retrograde memory impairment.12


Management of Wernicke Encephalopathy and thiamine deficiency can be found here.

Vitamin B9 and Vitamin B12

General Pathology and Causes

Vitamin B9, also known as folate acid, serves as a coenzyme and is involved in various reactions including DNA and purine synthesis, and amino acid catabolism, specifically the conversion of homocysteine to methionine. Folate is found in green leafy vegetable, fruits, fortified cereals, and meats. A serum folate concentration of less than 3ng/mL and an increased plasma homocysteine level of greater than 16 μmol/L indicates deficiency. Folate deficiency can develop in the setting of malabsorptive diseases, excess alcohol, medications (e.g., antiepileptics), and pregnancy.11

Vitamin B12, also known as cobalamin, serves as a coenzyme in reaction that converts homocysteine to methionine and in the production of succinyl-CoA. Therefore, solely measuring plasma homocysteine levels would not differentiate between a folate or cobalamin deficiency. Cobalamin is absorbed with intrinsic factor, a glycoprotein of stomach cells, in the terminal ileum. Cobalamin deficiency most typically develops in patients following a vegetarian or vegan diet, with a history of bariatric surgery, and those with malabsorptive diseases. Elevated serum homocysteine and methylmalonic acid are an indicator of cobalamin deficiency.11

Disease and Treatment

Decreased levels of both vitamin B9 and B12 have been linked with age-related macular degeneration,13 a degeneration of the retina that results in central visual acuity and visual field loss (central scotoma) due to neovascular and non-neovascular derangements. Incorporating foods rich in folate and vitamin B12 is encouraged in patients with age-related macular degeneration due to its potential contribution to slowing its progression.13 More details regarding the management of age-related macular degeneration can be found here.

In addition to its role in age-related macular degeneration, patients with vitamin B12 deficiency have neurological manifestations. B12 deficiency particularly affects the dorsal spinal column clinically presenting as diminished vibratory and positional sense in the extremities, especially the lower limbs. Gait abnormalities and cognitive disturbances, such as decreased concentration and memory loss, are also noted.11

Vitamin D

General Pathology

Vitamin D, also known as calciferol, is a fat-soluble vitamin that is photosynthesized in the skin as well as found in fortified foods. The major source of vitamin D is sunlight. Deficiency is typically due to limited sunlight exposure. Vitamin D enters the circulation from the skin or lymphatic system and goes to the liver for processing. The major circulating metabolite of vitamin D is 25-hydroxy vitamin D (25(OH)D) is further hydroxylised to 1,25-dihydroxy vitamin D (1,25(OH)2 D) or calcitriol by the kidney. Overall, vitamin D plays a role in the maintenance of serum calcium and phosphorus levels by increasing their absorption in the small intestine. Excessive amounts of vitamin D metabolites are catalyzed and excreted by the kidneys in the form of calcitroic acid. When the body is exposed to excessive sunlight, photolysis of the vitamin D skin metabolites occurs to prevent hypervitaminosis.14

Vitamin D and Multiple Sclerosis

Multiple sclerosis (MS) is a neurodegenerative disease caused by immune-mediated inflammation and demyelination of axons leading to various neurologic symptoms. Ocular manifestations are common in multiple sclerosis with 20% initially presenting with optic neuritis. Internuclear ophthalmoplegia (INO) is another common ocular manifestation of MS.15 Many studies have established vitamin D deficiency as a risk factor for multiple sclerosis.14,16

Management and Treatment

Vitamin D is thought to be associated with multiple sclerosis. Some authors feel that higher levels of vitamin D may potentially lead to better outcomes.16,17

Thyroid Eye Disease and Vitamin D

Grave’s disease is an autoimmune thyroid disorder that most commonly affects women (6:1). In Grave’s disease, the thyroid-stimulating immunoglobulins bind to the thyroid gland, causing the stimulation of the thyroid-stimulating hormone receptor. As a result, there is an overproduction of thyroid hormones resulting in symptoms such as tachycardia, unintended weight loss, anxiety, irregular menstrual cycles, and heat intolerance. Grave’s disease is treated with antithyroid medications or partial or total removal of the thyroid. A portion of Grave’s disease patients may develop thyroid eye disease (TED). In TED, there is an enlargement of the orbital tissues, such as the extraocular muscles and orbital fat, resulting in diplopia, eyelid retraction, proptosis, excessive tearing, and more rarely, compressive optic neuropathy.18 Several studies have studied vitamin D’s role in Grave’s disease and found that patients typically had a lower vitamin D level than the general population.19,20 Heisel et al. investigated the difference in vitamin D levels between Grave’s disease patients with TED and those without. They found that Grave’s disease patients with TED had a lower 25(OH)D levels than Grave’s disease patients without TED. Therefore, vitamin D supplementation should be considered in the management of Grave’s disease.18

Vitamin E

General Pathology

Vitamin E is believed to serve as a chain-breaking antioxidant that stops the oxidative degradation of lipids, thus preventing free radical production and harm to the cell. It is absorbed in the intestinal lumen, which is dependent upon various factors such as pancreatic secretions, micelle formation, and most importantly, chylomicron secretions. Chylomicron secretion is necessary for vitamin E absorption. Vitamin E is found in sunflower seeds, nuts, some oils, spinach, butternut squash, and many other food sources. Vitamin E deficiency has been linked to peripheral neuropathy in addition to spinocerebellar ataxia, skeletal myopathy and pigmented retinopathy. Interestingly, studies have reported vitamin E level in association to the development of cataracts.21

Albetalipoproteinemia (ABL) and Vitamin E

Hypobetalipoproteinemias (HBLs) are a group of rare disorders that cause low or absent plasma levels of LDL-cholesterol and apoB in the circulation. This group of disorders include abetalipoproteinemia (ABL), familial HBL (FHBL), familial combined hypolipidemia, and chylomicron retention disease.22,23 ABL, also known as Bassen-Kornzweig syndrome, results from mutations in the MTP gene in charge of forming a protein that assists in transferring lipids onto apoB. As a result, ApoB is degraded preventing the secretion of chylomicrons and VLDL. This fat malabsorption symptomatically results in steatorrhea, vomiting, and failure to thrive in early childhood, and later on, leads to spinocerebellar ataxia. Common ophthalmic findings include nyctalopia, dyschromatopsia and atypical retinitis pigmentosa.23


Vitamin deficiencies can present with neuro-ophthalmic complaints that may be afferent or efferent. Patients at high risk for vitamin deficiency either from decreased intake (e.g., malnutrition or eating disorder) or poor absorption (bariatric surgery) or excess loss (e.g., vomiting) should be evaluated for vitamin deficiencies. Early recognition and prompt vitamin replacement may be vision or lifesaving.


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