Zinc Optic Neuropathy

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Article initiated by:

Kathryn E. McAnnis, Sarah Eperjesi

All contributors:

Andrew Go Lee, MD, Nagham Al-Zubidi, MD, Noor Laylani, MD, Pamela Davila-Siliezar, MD, Nagham Al-Zubidi, MD, Noor Laylani, MD

Assigned editor:

Osama Al Deyabat, MBBS

Review:

Assigned status Up to Date

 by Osama Al Deyabat, MBBS on October 8, 2024.

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Clinicians should be aware that zinc deficiency can mimic other nutritional optic neuropathies and may present with bilateral painless, progressive visual acuity and visual field (e.g., central or cecocental scotomas) loss with eventual optic atrophy OU. Prompt recognition and testing for zinc is recommended in patients with risk factors for deficiency.

Disease Entity

Zinc is an important essential trace mineral in humans. Zinc deficiency is an uncommon cause of nutritional optic neuropathy but can result in bilateral, symmetric, progressive vision loss . Zinc is a crucial mineral for proper functioning of cellular and metabolic processes throughout the entire body, especially the visual pathway. The lack of zinc causes disruption of normal retina and retinal pigment epithelium functioning leading to vision loss, dyschromatopsia, loss of contrast sensitivity, and central or cecocentral scotoma. From an ocular standpoint, zinc maintains normal retina and retinal pigment epithelium where it interacts with taurine and Vitamin A, modifies photoreceptor plasma membranes, regulate the light-rhodopsin reaction, and modulates synaptic transmission.

Epidemiology: History

Zinc is the second most abundant mineral in the body. Due to its abundance, it plays important roles in proper functioning of cellular and metabolic processes throughout the entire body. Thus, when zinc deficiency occurs, it can affect many systems, including dermatologic, gastrointestinal/digestive, reproductive, and the central nervous system.

• Deficiency of zinc has become more common due to the increased popularity of plant-based diets and increased frequency of bariatric surgeries.
• Nutritional optic neuropathies were discovered when epidemics occurred during wars and famine, zinc optic neuropathy can also occur during this time.

Etiology

Iatrogenic

• Surgical: Zinc deficiency can be secondary to any bariatric or gastrointestinal surgery where the digestive system is altered. This includes bariatric procedures (e.g., Roux-en-Y gastric bypass, sleeve gastrectomy, and biliopancreatic diversion duodenal switch). Zinc deficiency has been seen to be more frequent in patients with duodenal switch (DS) bariatric surgery due to the duodenum being a major site of absorption for zinc.

• Medication:
  • Ethambutol: antibiotic commonly used for treatment of mycobacteria infections, such as mycobacterium tuberculosis (MTB), Mycobacterium avium complex (MAC), and Mycobacterium kansasii (MK). Ethambutol is a metal chelator which can decrease absorption of zinc and copper. Due to ocular tissue containing high concentrations of zinc, this increases the risk of ethambutol-induced zinc deficiency which can result in zinc optic neuropathy. For further information, view the Eyewiki on ethambutol optic neuropathy.
  • Calcium-containing antacids: Commonly taken to prevent osteoporosis or osteopenia to increase blood calcium levels or decreasing pH of stomach acid secondary to acid reflux. Research has shown that calcium supplements reduce zinc absorption by 50%. Due to this interaction, some calcium supplements include zinc in their formulation to combat this.
  • Thiazide diuretics (chlorthalidone, hydrochlorothiazide): Used for hypertension, congestive heart failure (CHD), edema, etc. In research studies, treatment with thiazide diuretics resulted in increased urine zinc excretion. This can result in decreased serum concentration of zinc. There is also limited evidence of furosemide, a loop diuretic, affecting urinary zinc excretion in humans. Research in rats showed increase urinary zinc excretion when used for short period.
  • Quinolone antibiotics: Fluoroquinolone absorption after oral administration can be impaired by the presence of zinc supplements (and vice versa).

Diet-based

• Strictly plant-based have higher rates of deficiency of zinc. Animal-based proteins, like meat, fish, and seafood, contain more bioavailable zinc. Oysters have the highest amount of zinc (mg) per serving, but beef contributes to the highest intake of zinc from food in the United State due to prevalence. Beans, nuts, and whole grain container lower bioavailability of zinc due to containing phytates. Phytate severely decreases intestinal zinc bioavailability due to formation of an insoluble complex that inhibits absorption.
• Breakfast cereals are often fortified with zinc which is a major source in the United States population, especially children and adolescents.

Risk Factors

Risk factors and age of presentation will help to distinguish acquired versus inherited forms of zinc deficiency. Acquired forms will present with risk factors of inadequate supply, regional and geographic risk factors, excess loss, or increased demand as described earlier. The inherited disease presents earlier in life.

Bariatric Surgery

• Reduced protein intake–to compensate for endogenous zinc loss, must supplement with food daily.
• Impaired zinc absorption from altered digestive system.

Dietary Restrictions

• Veganism, vegetarianism, Celiac disease, inflammatory bowel diseases.

Alcohol use disorder

• Ethanol consumption has been shown to decrease intestinal absorption of zinc and increase urinary zinc excretion.

Pathophysiology

Zinc acts as a co-factor for enzymes to protect cells against oxidative damage, stabilize cellular membranes and inhibit the enzyme nicotinamide adenine dinucleotide phosphate oxidase (NADPH-Oxidase). Zinc also induces the synthesis of metallothioneins, which are proteins effective in reducing hydroxyl radicals and sequestering reactive oxygen species (ROS) produced in stressful situations. The literature provides strong evidence for the role of zinc in the protection against oxidative stress in several diseases. No research has been conducted evaluating zinc and oxidative stress in the eye.

Studies suggest that zinc deficiency leads to a decrease of myelination of the nerve fibers in the optic nerve. Destruction of the myelin and proliferation of the glial cells in the optic nerve is significantly decreased in zinc deficiency. This demyelination causes the nerve impulses (through the optic nerve) to slow and even stop, resulting in loss of vision.

If demyelination occurs before neuronal death and axial dysfunction, supplementation with zinc before neuronal death and axial dysfunction can potentially prevent irreversible damage.

Diagnosis

Clinical diagnosis

Zinc optic neuropathy is a subtype of nutritional optic neuropathy. Symptoms and signs on an ocular standpoint are not able to be distinguished within the different causes of nutritional optic neuropathy and zinc optic neuropathy. Evaluation of systemic symptoms of zinc deficiency and serum levels of zinc are necessary to confirm diagnosis.

Symptoms

Symptoms of zinc optic neuropathy include bilateral, symmetric, progressive painless visual loss, cecocentral or central scotoma, dyschromatopsia and loss of contrast sensitivity.

Due to zinc deficiency affecting multiple organ systems, this can cause systemic symptoms including, but not limited to, reproductive (hypogonadism, oligospermia), central nervous system (emotional lability, mental disturbances, impaired taste and smell, photophobia), immunological (delayed wound healing, increased susceptibility to infections), gastrointestinal (GI) (diarrhea), cutaneous disease (angular cheilitis, eczematous scaly plaques), nail involvement (paronychia, cuticle inflammation, Beau lines).

Physical examination

• Visual acuity loss OU
• Automated visual field testing may show bilateral central/cecocentral scotomas OU
• Relative afferent pupillary defect may be absent in bilateral and symmetric visual loss
• Color vision testing (e.g., Ishihara testing) may show dyschromatopsia OU
• Fundoscopic exam of the optic nerve and retina may be normal initially and then subsequently shows temporal optic nerve pallor in affected eyes.

Diagnostic

• Humphrey or Goldman visual field evaluation: central/cecocentral scotoma
• Visual Evoked Potentials (VEP): reduced amplitude, normal or near normal latency.
• Retinal nerve fiber layer (RNFL) Optical coherence tomography (OCT): RNFL thinning or bilateral optic atrophy.
• Electroretinography: performed to rule out retinal disease.
• MRI: performed to exclude other causes of bilateral, symmetric vision loss, such as compressive, radiation, infiltrative causes, and demyelinating diseases.

Laboratory tests

If zinc optic neuropathy is suspected, due to either risk factors or systemic symptoms of zinc deficiency, complete blood count (CBC), peripheral blood smear, and complete metabolic profile (CMP) is recommended. Zinc serum level should be evaluated. Zinc deficiency is defined as <70 mcg/dL in women and <74 mcg/dL in men (Ryu). Other factors can cause zinc serum levels to fluctuate, including response to infections, changes in steroid hormones, and muscle breakdown; this should take into account during evaluation of test results.

Testing for serum levels of other vitamins (B9, B12) and minerals (copper, magnesium, iron) is also recommended.

Differential diagnosis

All other causes of acquired optic neuropathy should be evaluated including, nutritional optic neuropathy, toxic optic neuropathy, compressive optic neuropathy, radiation optic neuropathy and infiltrative optic neuropathy as they all have similar presentations of progressive, bilateral, symmetric, painless vision loss with cecocentral or central scotoma.

History and appropriate testing are essential to rule out other pathologies. See table for evaluating bilateral, progressive, painless vision loss with central/cecocentral scotoma.

Disease	Onset	Etiology	Testing
Compressive optic neuropathy	Chronic	Midline lesions (pituitary adenoma, craniopharyngioma, meningioma, giant aneurysms) or bilateral orbital lesions (thyroid disease, sarcoidosis)	Neuroimaging
Infiltrative optic neuropathy	Acute, subacute	Systemic malignancies (lymphoma, leukemia, multiple myeloma, and carcinoma)	Neuroimaging, CSF, or vitreous analysis
Radiation optic neuropathy	Acute	Chemotherapy or radiation exposure to brain and orbit	Neuroimaging
Toxic optic neuropathy	Acute, subacute, or chronic	Drugs, metals, organic solvents, methanol, carbon dioxide, and tobacco	Lab work
Nutritional optic neuropathy	Acute, subacute, or chronic	Vitamin (B1, B6, B9, B12) or mineral (copper, magnesium, iron, zinc) deficiencies	Lab work

Primary prevention

To prevent zinc optic neuropathy, proper zinc supplementation is needed in patients at risk for mineral or vitamin deficiencies. Various zinc supplement formulations that can be used: zinc sulfate, zinc acetate, zinc aspartate, zinc orotate, and zinc gluconate. Additionally, zinc supplementation can also alter absorption of other minerals (i.e. magnesium) and medications (i.e. fluoroquinolones). Close monitoring in these cases is recommended.

Recommended daily elemental intake is:

• 9 mg/day for women (non-pregnant and non-lactating)
• 11 mg/day for men
• 11 to 12 mg/day in pregnant and lactating women

Management

Treatment:

Oral replacement

• Adults: 20-40 mg per day is recommended for 1-2 weeks for cure of clinical manifestations.
• Adults with malabsorption: oral replacement with 1-2 mg/kg per day is recommended for life-long supplementation.

• Recheck zinc levels after 3-6 months to see if adequate serum levels of zinc were reached. Can increase dose if levels are still low.
• Higher doses of 50 mg per day may be needed for patients with malabsorption; however, that dosing carries the risk of toxicity. Close monitoring would be required.

Prognosis

Full recovery of symptoms after supplementation. Development of optic atrophy in severe and/or prolonged cases of zinc deficiency cannot be reversed. Therefore, early intervention is essential to prevent long-term damage to the optic nerve.

References

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