Tobacco Optic Neuropathy

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Article initiated by:

Wendy.Brazon

All contributors:

Andrew Go Lee, MD, Nagham Al-Zubidi, MD, Noor Laylani, MD, Pamela Davila-Siliezar, MD, Wendy.Brazon, Nagham Al-Zubidi, MD, Noor Laylani, MD, Mary Labowsky, MD

Assigned editor:

Mary Labowsky, MD

Review:

Assigned status Up to Date

 by Mary Labowsky, MD on November 6, 2024.

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Disease Entity

Tobacco optic neuropathy (TON), also called in the past, “tobacco–alcohol amblyopia” is part of a large group of toxic optic neuropathies. It is typically found in middle–aged and elderly individuals who smoke pipe or cigars. The disorder is characterized by painless, slowly progressive, and bilateral dyschromatopsia with visual loss. The typical visual field defect is a central or cecocentral scotoma due to damage in the papillomacular bundle. Initially, the optic discs appear normal, but they become pale overtime.

According to a CDC report on TON, visual loss occurs due to the use of tobacco, with or without concomitant alcohol abuse or nutritional deficits.

Epidemiology

TON has low incidence and prevalence in the 21st century. Morbidity depends mostly on related risk factors, the degree of exposure to the agent (tobacco) and the period between the first visual function changes and the beginning of treatment.

Per the CDC: as of 2021, 11.5% of U.S. adults (28.3 million people) current smoked cigarettes. Over 16 million people live with one complication related to smoking cigarettes, and 58 million non-smokers are exposed to secondhand smoke. Each year 8.6 million suffer from serious illnesses from smoking, including blindness.

Etiology

TON is acquired after chronic smoking habit and consequent exposure to cyanide. Additionally, concomitant alcohol abuse leading to malnutrition could be a contributing factor. Smoking and alcoholism play an important role in increasing mitochondrial oxidative stress and decreasing ATP production, which ultimately is the responsible mechanism of TON.

Risk Factors

Risk Factors may include:

• Smoking (cigar or pipe in large quantities for long periods of time).
• Alcoholism.
• Nutritional deficiencies or malnourishment (due to the abuse of both tobacco and alcohol which leads to vitamin B12 and folate (B9) deficiencies).

Pathophysiology

The mechanism of TON is incompletely understood and controversial, and may be multifactorial:

Direct metabolic damage. Chronic exposure to cyanide (a neurotoxin) and free radicals present in the tobacco cause direct damage to the highly metabolic "type-P" ganglion cell axons in the papillomacular bundle by impairing the mitochondria respiratory cycle, leading to a decrease of ATP production and increase of oxidative stress, leading to apoptosis.

Secondary deficiencies. Cyanide, chronic exposure to tobacco, and alcohol produce metabolic deficiencies of vitamin B12 and folate (B9), leading to accumulation of formic acid, which also contributes to demyelination of the optic nerve.

Ischemic damage. Nicotine from cigars causes indirect ischemic optic nerve damage by its vasoconstrictive effect and reduction in blow flow.

In summary, the mechanism could be produced by the synergistic impairment of the optic nerve’s vascular supply and the metabolism of toxic substances or their metabolites, which ultimately causes this acquired mitochondrial optic neuropathy.

Diagnosis

TON is a diagnosis of exclusion since it clinically presents similar to nutritional, toxic, and congenital optic neuropathies, such as Leber’s hereditary optic neuropathy (LHON).

History

• Social history and habits (amount and type of tobacco/cigars and alcohol used, even if habits ended over 10 years ago).
• Any gradual onset of visual acuity decreased (over the last 20 years or more).
• Family history of hereditary optic nerve disorders (LHON).
• Metabolic diseases (DM, kidney failure, thyroid, which might influence the disorder due to the accumulation of toxins).
• Patients’ complaints surrounding any loss of visual acuity, reduced contrast perception, a blur in the center when reading, faded colors (mainly red) without ocular pain. Patients present with a central and cecocentral scotoma as an early symptom due papillomacular bundle damage.

Physical Examination

• Humphrey (static) or Goldman (kinetic) visual fields evaluations
• Best corrected visual acuity.
• Swinging flashlight test for relative afferent pupillary defect (RAPD).
• Slit-lamp examination.
• Fundoscopy.

Signs

Visual Field

• Central scotoma: 5° to 20° surrounding fixation. Enlarged blind spot.
• Cecocentral scotoma: smaller and typically dumbbell shaped.

Pupils

Sluggish. RAPD is present if optic neuropathy is worse in one eye than the other. Absence if both eyes are affected.

Optic Disc

• Early stages: normal, swollen, or hyperemic
• Late stages: optic atrophy, loss of the papillomacular bundle and consequent temporal pallor disc.

Symptoms

• Bilateral, painless, symmetrical, and progressive loss of visual acuity. Initially manifest as a blur in the center.
• Dyschromatopsia: blue-yellow defect preceding a characteristic red-green defect. Usually, it is manifested as the 1st symptom.

Diagnostic Procedures

A detailed medical history and a thorough eye exam provide enough information to make a presumptive diagnosis. However, the following exams could be considered for differential diagnosis:

• MRI of the optic nerves and chiasm with and without gadolinium enhancement. Usually used to exclude any compressive lesion.
• Optical coherence tomography – OCT can detect early toxicity by quantifying the loss of retinal nerve fiber layer (RNFL) in the papillomacular bundle. In some patients even presenting visual loss, the RNFL defect might not be evident because the defect is masked by RNFL edema.
• Ishihara plates or Panel D15 test to evaluate the dyschromatopsia. Useful to identify early toxicity since this is the first symptom patients manifest before the gradual visual acuity loss.
• Electrophysiological tests: Visual-evoked potentials (VEP) or the patter electroretinography (PERG). These tests are useful to identify early optic neuropathy in patients with normal pupillary response but no evident optic disc changes on clinical examination. Also, it is helpful to rule out demyelinating disease, retinal disease, or macular lesions.

Laboratories

Performed to rule out other toxic or nutritional etiologies:

• Complete blood cell count (CBC) with peripheral blood smear to discard anemia, macrocytosis, and neutrophil hyper-segmentation (Nutritional neuropathy).
• Blood levels of vitamin B12, its metabolites (methylmalonic acid and homocysteine) and serum cobalamin levels (Nutritional neuropathy).
• Urinalysis to rule out specific toxins (methanol, heavy metal screening).
• Blood vitamin deficiencies (niacin, riboflavin, pyridoxine, and thiamine).

Differential diagnosis

1. Nutritional neuropathy: alcohol, malnutrition, and vitamin deficiencies (group B).
2. Mitochondrial optic neuropathies: Leber’s hereditary optic neuropathy (LHON) caused by mtDNA mutations, m.3460g>A, m.11778G>A and m.14484T>C, and Dominant optic atrophy (DOA) caused by a nuclear mutation in the OPA1 gene. Both with degeneration of retinal ganglion cells that leads to loss of central vision. Tobacco and alcohol could be the trigger for the threshold effect in these patients with predisposing mitochondria genetic disorders.
3. Toxic optic neuropathies: Ethambutol, Isoniazid, Methanol, and Amiodarone.
4. Non-arteritic anterior ischaemic optic neuropathy (NAION) caused by infarction of the laminar or retrolaminar portion of the optic nerve head supplied by the short posterior ciliary arteries (SPCAs). This ultimately leads to axonal degeneration and loss of retinal ganglion cells via apoptosis, therefore clinically shows the same symptoms as (TON).
5. General pathologies: Ischemic stroke, intracranial tumor, acephalgic migraine, demyelinating disease, and rapidly progressive neurodegenerative disorder.
6. Ophthalmic pathologies: macular degeneration, neuromyelitis optica, ischemic optic neuropathy disorders.

Management

Treatment

• Discontinue use of tobacco and alcohol: removal of the social trigger translates into significant improvement in the visual field within a period of 3-12 months.
• Adoption of a healthy and nutritive lifestyle.
• Vitamin supplementation: it has been proposed as an adequate therapy for toxic and nutritional optic neuropathies regardless of the etiology.
• Oral therapy with B group vitamins, thiamine (vitamin B1/100mg twice a day), riboflavin (vitamin B2) folic acid (Vitamin B9 / 1mg once a day/ involved in detoxification of formate (13) cyanocobalamin (Vitamin B12).
• Intramuscular therapy with hydroxocobalamin (vitamin B12) has proven efficacy in visual recovery in tobacco amblyopia patients due to the conversion of free cyanide to cyanocobalamin.
• Psychotherapy and Rehab programs: focus on abstinence and relapse prevention. Since these patients are mostly heavy smokers and drinkers, therapy might be helpful to assure patients maintain healthy habits and avoid long term relapses.

It is advisable to follow up patients every 3 to 4 weeks, soon after initial diagnosis. Future follow-ups every 6 to 9 months is acceptable once tobacco use has been discontinued, any associated vitamin deficiencies corrected, and the vision and optic nerve thinning have stabilized. In each visit assessment of visual acuity, color vision, optic disc appearance and visual field are considered necessary.

Prognosis

The prognosis of tobacco optic neuropathy varies depending on the length of smoking exposure and degree of vision loss at the time of diagnosis. Therefore, the earlier neuropathy is diagnosed, the higher the probabilities of fully recovering vision function.

The recovery of vision might take anywhere from weeks to a period between 3 -12months after tobacco abstinence, but residual permanent damage to the optic nerve might sometimes persist. Usually, visual acuity recovers before color vision, the opposite of what happens when the patient is first diagnosed.