Journal of Neuro-Ophthalmology, September 1994, Volume 14, Issue 3

Folate responsive optic neuropathy.

We examined six patients who presented with bilateral, progressive visual loss. Each patient had a bilateral decrease in visual acuity, poor color vision, and central or cecocentral scotomas. Optic nerve head appearance varied from normal to diffusely pale. All patients consumed tobacco, ethanol, or both. Each patient was folate deficient and had normal vitamin B12 levels. Patients were treated with oral folic acid, 1 mg per day. Visual acuity improved bilaterally in all patients (mean: five lines in 2 months). Folate deficiency should be considered in any patient with progressive bilateral optic neuropathy of unknown etiology. Treatment with folic acid can result in significant improvement in visual function.

journal of Neuw- Ophthalmolow 14( 3): 163- 169. 1994. © 1994 Raven Press, Ltd., New York Folate- Responsive Optic Neuropathy Karl C. Golnik, M. D. and Eric R. Schaible, M. D. We examined six patients who presented with bilateral, progressive visual loss. Each patient had a bilateral de­crease in visual acuity, poor color vision, and central or cecocentral scotomas. Optic nerve head appearance var­ied from normal to diffusely pale. All patients consumed tobacco, ethanol, or both. Each patient was folate defi­cient and had normal vitamin B, 2 levels. Patients were treated with oral folic acid, 1 mg per day. Visual acuity improved bilaterally in all patients ( mean: five lines in 2 months). Folate deficiency should be considered in any patient with progressive bilateral optic neuropathy of unknown etiology. Treatment with folic acid can result in significant improvement in visual function. Key Words: Folate- Optic neuropathy- Tobacco-alcohol amblyopia. Tobacco- alcohol amblyopia ( TAA) is characterized by a symmetric, bilateral optic neuropathy that oc­curs in association with tobacco and alcohol con­sumption ( 1). Vitamin B, 2 ( cobalamin) deficiency has been reported in patients thought to have TAA ( 2- 5). Although observed by Knox and others ( 5- 7), optic neuropathy associated with " isolated" fo­late deficiency has not been well documented, and many investigators believe folate deficiency has lit­tle significance in the development of TAA ( 5,7). The mechanism of optic neuropathy in TAA is un­known. Cyanide accumulation ( 7,8) and nutri­tional deficiencies ( 9- 11) are thought to be impor­tant factors. We report six patients who consumed ethanol and tobacco and had normal vitamin B12 levels. Each patient was folate deficient and had bilateral optic neuropathy. Oral folic acid supplementation corrected the folate deficiency and improved visual function. A mechanism is proposed to explain how folate deficiency, vitamin B12 deficiency, or cya­n i d e accumulation could decrease a d e n o s i ne triphosphate ( ATP) production and produce optic neuropathy. From the Department of Ophthalmology, Storm Eye Institute Medical University of South Carolina, Charleston, South Caro­lina, U. S. A. This study was supported in part by an unrestricted grant from Research to Prevent Blindness, Inc., New York, New York. This study was presented in part at the annual meeting of the Association for Research in Vision and Ophthalmology, Sara­sota, Florida, May 6, 1993. Address correspondence to Dr. Karl C. Golnik, Department of Ophthalmology, Medical University of South Carolina, 171 Ashley Avenue, Charleston, South Carolina, 29425, U. S. A. PATIENTS AND METHODS All patients evaluated at the Storm Eye Institute over a 20- month period who had bilateral optic neuropathy of " unknown etiology" and folate de­ficiency were included in this study. Each patient underwent thorough neuro- ophthalmic evaluation both before and after therapy. Color vision was tested with Hardy- Rand- Rittler pseudoisochro-matic plates ( numbers 1- 10). Visual fields were evaluated with Goldmann kinetic perimetry ( Cases 2 and 3) or Humphrey static perimetry ( Cases 1, 4, 5, and 6). Visual evoked responses ( Cases 2, 3, and 6), magnetic resonance images ( Cases 1, 2, and 6), and computed tomographic scans ( Case 4) had been previously obtained and were reviewed. Lab­oratory evaluation included complete blood count, serum vitamin B12 ( microparticle radioimmunoas- 163 164 K. C. GOLNIK AND E. R. SCHA1BLE say), and folate, erythrocyte folate, rapid plasma reagin, Lyme antibody titers, and antinuclear an­tibody. Mitochondrial deoxyribonucleic acid ( DNA) analysis for point mutations found in pa­tients with Leber's hereditary optic neuropathy was obtained in four patients ( Cases 2, 3, 5, and 6). Each patient was treated with oral folic acid ( 1 mg per day) alone. Patients were not instructed to stop smoking, drinking, or to change their diet un­til 2 to 4 months after starting folate supplementa­tion. Each patient underwent at least two follow-up evaluations between 1 and 4 months after be­ginning treatment. RESULTS Six patients with bilateral optic neuropathy and folate deficiency were evaluated between October 1991 and June 1993. Each patient was referred with bilateral unexplained visual loss. Four men and two women with an average age of 43 ( range: 28- 53) were evaluated ( Table 1). Each patient either regularly drank alcohol ( Case 5, 3 oz per day) or drank alcohol ( range: 3- 24 oz per day) and smoked tobacco ( range: 20- 60 cigarettes per day or 1 oz pipe tobacco per week). Family history was nega­tive for unexplained visual loss except for one pa­tient ( Case 3) whose father and sister were re­ported to have decreased vision of unknown etiol­ogy. These relatives were not available for examination. Every patient had bilaterally reduced visual acuity ( range: 20/ 30- 8/ 200), color vision, and central or cecocentral scotomata ( Fig. 1) in each eye ( Table 1). Visual loss was typically symmetric, al­though Case 4 had visual acuity of 20/ 400 and 20/ 50 at presentation. Although pupillary response var­ied from briskly to moderately reactive, no patient had a relative afferent pupillary defect. Presum­ably the lack of a relative afferent pupillary defect was due to relatively symmetric optic nerve dam­age. Optic nerve heads were either normal ( Cases 3, 4, and 5), showed mild temporal pallor ( Cases 1 and 6), or were diffusely pale ( Case 2). Visual acu­ity was not predictable on the basis of optic nerve head appearance and vice versa. None of the pa­tients had abnormalities on external, motility, or anterior segment examination. Intraocular pres­sure was normal in all eyes. No abnormalities were noted in the peripheral retina, macula, or retinal blood vessels. The consulting neurologist reported " mild peripheral neuropathy and long tract signs compatible with subacute combined degeneration of the spinal cord" in one of five patients exam­ined. Pattern visual evoked responses were unrecord-able ( no P- 100 wave could be identified) in each case tested ( Cases 2, 3, and 5). Magnetic resonance images ( Cases 1, 2, and 6) and computed tomo­graphic scans ( Case 4) revealed no anterior visual system abnormalities. Serum folate was low in all but two patients ( Cases 3 and 6) but these individ­uals had low erythrocyte folate ( Table 1). When evaluated, erythrocyte folate was low ( Cases 2, 3, and 6). Despite folate deficiency, only three pa­tients ( Cases 1, 2, and 4) had macrocytic erythro­cytes ( 101.4, 99.3, 101.3 CUMIC, respectively; nor­mal: 80.0- 94.0) and two patients ( Cases 4 and 6) were anemic ( hemoglobin 11.8, 11.5 g/ dl, respec­tively; normal: 14.0- 18.0). Serum vitamin B12 was normal in each patient. Lyme antibody titers, an­tinuclear antibody, and rapid plasma reagin were negative in each patient. Mitochondrial DNA test­ing ( Cases 2, 3, 5, and 6) revealed no point muta­tions at positions 11778, 3460, 15257, and 14484. TABLE 1. Clinical data of patients pre- and post- folic acid treatment Case no./ age/ gender 1/ 38/ M 2/ 28/ F 3/ 52/ M 4/ 39/ M 5/ 53/ F 6/ 51/ M Serum folate ( ng/ ml)° 4.1 3.8 6.3 4.4 1.9 8.1 Pretreatment Erythrocyte folate ( ng/ ml)" - 131 100 - - 98 Visual acuity 20/ 40 20/ 30 20/ 400 20/ 300 20/ 400 20/ 200 20/ 400 20/ 50 20/ 800 8/ 200 20/ 70 20/ 25 Hardy- Rand- Rittler color platesc 1 1.5 0 0 0 0 1 1.5 0 0 3 3.5 Treatment interval ( months) 4 2.5 4 3 2 2 Serum folate ( ng/ ml) 47.5 > 21.0 46.3 > 21.0 > 21.0 6.3 Posttreatment Erythrocyte folate ( ng/ ml) - 390 283 - - 238 Visual acuity 20/ 20 20/ 20 20/ 80 20/ 70 20/ 50 20/ 50 20/ 25 20/ 25 20/ 30 20/ 60 20/ 20 20/ 15 Hardy- Rand- Rittler color plates 2 2 0 0 0 0 8 8 0 0 7 7 " Normal serum folate - 5.0- 21.0 ng/ ml. " Normal erythrocyte folate = 169- 707 ng/ ml. c Number of correctly identified plates of 10 tested. / Neum- Ophthalmol, Vol. 14, No. .3, 1994 FOLATE- RESPONSIVE OPTIC NEUROPATHY 165 > V 4*# m FIG. 1. Automated static perimetry, Humphrey program 24- 2, demonstrates central scotomas OU in Case 1 ( OD on right, OS on left). Foveal sensitivity is 28 DB OD and 29 DB OS. Patients noted improvement in vision within 1 week after starting folate replacement. Examina­tion 4- 12 weeks later revealed visual acuity im­provement in each eye of all patients. Range of improvement was 2- 11 Snellen lines ( mean = 5 lines ± 2.8 lines). Perimetry showed improvement of the central of cecocentral scotomata in each case ( Fig. 2). Optic nerve head appearance did not change appreciably during the follow- up period. At follow- up, each patient indicated compliance with treatment. Serum folate was supranormal in Cases 1 to 5 and normal in Case 6 ( Table 1). Eryth­rocyte folate normalized in each patient with ini­tially low levels ( Cases 2, 3, and 6). Macrocytosis resolved in one patient ( Case 1) and persisted in two patients ( Cases 2 and 4). The two anemic pa­tients ( Cases 4 and 7) had mild increases in hemo­globin ( 12.0 and 11.8 g/ dl, respectively), but re­mained anemic. DISCUSSION Patients thought to have tobacco- alcohol ambly­opia ( TAA) typically present with painless, pro­gressive, bilateral visual loss and are found to have diminished visual acuity and color vision ( 1). The characteristic visual field defect is either a central or cecocentral scotoma. Temporal optic nerve head pallor is often apparent. However, both optic nerve heads may initially appear normal. A rela­tive afferent pupillary defect is typically not present because the optic neuropathy is usually symmetrical. The lack of objective findings ( absent relative afferent pupillary defect, normal nerve heads) may lead to the " diagnosis" of unexplained visual loss. Visual evoked responses can be helpful in demonstrating an optic neuropathy by either showing decreased amplitude of the P- 100 wave ( 12- 14) or by showing both decreased amplitude and prolonged latency of the P- 100 wave ( 12,13). Each of our patients was a diagnostic dilemma for the referring physician. Presenting complaints were similar in each case: an insidious, bilateral visual loss. Variable quantities of alcohol, tobacco, or both were consumed. The patients had rela­tively symmetric optic neuropathies and no rela­tive afferent pupillary defect. Each patient had normal serum vitamin B12 but were deficient in folate. It is difficult to control the various factors thought important in the development of TAA; the patients may spontaneously change their con­sumption habits. Without hospitalization and strict control of diet, ethanol intake, and tobacco consumption, it cannot be certain that these vari­ables are constant. We did not hospitalize our pa­tients, but we did not instruct the patients to alter their diet, ethanol intake, or tobacco use during the short trial of folic acid supplementation. At fol­low- up, patients indicated no change in consump­tion habits. Thus, we feel that folate deficiency can be an important factor in the development of TAA. The etiology of optic neuropathy in TAA is con­troversial. In 1958, Heaton and associates ( 2) found patients with TAA to have low vitamin B12 levels. They reported improvement in visual acuity after parenteral administration of this vitamin. Subse­quently, other investigators have verified that a significant proportion of patients with TAA are de­ficient in vitamin B12 and respond to supplemen­tation ( 3- 5). Despite the frequent association be- / Neuro- Ophthalmol. Vol. 14, No. 3, 1994 266 K. C. GOLNIK AND E. R. SCHAIBLE 30°. • A.:-**?-:- +• FIG. 2. Automated static perimetry, Humphrey program 24- 2, four weeks after starting folate therapy in Case 1 ( OD on top, OS on bottom). The central scotomas have markedly improved. / Ncuro- Ophthalmol, Vol. U, No. ,3, 1994 FOLATE- RESPONS1VE OPTIC NEUROPATHY 167 tween nutritional deficiency and TAA, other inves­tigators report patients with bilateral optic neuropathy and normal nutrition, whose vision improves upon cessation of tobacco and alcohol consumption ( 7,8,15). The role of folate deficiency in TAA has not been well characterized. Bronte- Stewart and associates ( 7) reported several patients with TAA in whom " folate deficiency was the only abnormality found." These authors give no details regarding their patients examination or response to treat­ment. Chisholm ( 5) found great variation of serum folate levels in 77 patients with TAA. Neverthe­less, one patient is described with visual acuity of 6/ 24 OD and 6/ 18 OS, normal serum vitamin B, 2, and low serum folate (< 1 ng/ ml; normal; > 5 ng/ ml). Treatment with oral folic acid " fully restored visual function" over 8 months. Knox and associ­ates ( 6) studied 26 patients with TAA and found their serum folate and erythrocyte folate levels to be significantly lower than controls. They felt erythrocyte folate was a more reliable indicator of folate deficiency than serum folate because of the lability of folate in serum and the transient eleva­tion of serum folate observed after just one meal. The authors mention a patient who had a normal serum folate but low erythrocyte folate in whom oral folic acid " reversed the trend of visual fail­ure." Two of our patients ( Cases 3 and 7) also had normal serum folate levels but had reduced eryth­rocyte folate levels. We agree that patients in whom there is suspicion of folate deficiency should have both serum folate and erythrocyte fo­late determined. Although TAA was not men­tioned, a role for folate in visual function was sug­gested by a study of dyschromatopsia in 16 pa­tients with hepatic cirrhosis ( 16). Despite 20/ 20 visual acuity, 807c of the patients with low serum folate had abnormal error scores on the Farns-worth- Munsell 100 Hue Test. The dyschromatop­sia of these patients may represent subtle optic nerve dysfunction associated with folate defi­ciency. Thus, tobacco and alcohol use, vitamin B12 deficiency, and folate deficiency may each contrib­ute to development of optic neuropathy in TAA. Deficiency of vitamin B12 has been associated with macrocytic anemia and several neurologic syndromes, including peripheral neuropathy, global dementia, subacute combined degeneration of the spinal cord, and optic neuropathy ( 2,17,18). The recently recognized association of folate defi­ciency and congenital neural tube defects has re­newed interest in folate metabolism ( 19). Like vi­tamin B12 deficiency, folate deficiency has been re­ported in association with polyneuropathy and subacute combined degeneration of the spinal cord ( 20,21). the pathophysiology of these neurologic conditions is thought to be related to the role of vitamin B12 in methionine metabolism ( 18,22). It is interesting that folate is also required in methio­nine metabolism and isolated folate deficiency is associated with many of the neurologic conditions attributed to vitamin B12 deficiency. Vitamin B12 in the form of methylcobalamin is required as a cofactor for the enzyme methionine synthetase, which catalyzes the recycling of homo­cysteine to methionine ( Fig. 3). In this same reac­tion, folate ( in the form of methyltetrahydofolate) is required to donate a methyl group to homocys­teine; methionine and tetrahydrofolate result. Thus, deficiency of either vitamin B12, folate, or both could result in decreased production of tet­rahydrofolate. Formate metabolism is dependent on the availability of tetrahydrofolate ( Fig. 3). The ability to metabolize formate is important because the sequelae of methanol poisoning are thought to be due to formate accumulation ( 23). When in­gested, methanol is converted to formaldehyde and then to formate. Animal models of folate de­ficiency ( monkey) and B12 deficiency ( rat) show re­duced formate oxidation and increased formic ac­idemia after methanol administration as compared to animals with normal nutrition ( 24,25). Folic acid administration will reverse formic acidemia in the monkey model ( 26). Indeed, folic acid is now used in the treatment of patients with acute methanol FIG. 3. The relationship be­tween folate, vitamin B12, and formate. Methylcobalamin ( B12) is required as a cofactor for the enzyme methionine syn­thetase ( MS). Tetrahydrofolate production ( and subsequent formate detoxification) is de­pendent on adequate supply of both vitamin B12 and folate ( in the form of methyltetrahydrofo-late). methionine homocysteine tetrahydrofolate methvltetrahvdrofolate formate carbon dioxide ; Neuro- Ophthalmol, Vol. 14, No. 3, 1994 168 K. C. GOLNIK AND E. R. SCHAIBLE poisoning. Recently, Deacon and associates ( 27) demonstrated elevated serum formate in vitamin B12- deficient rats in the absence of exogenous meth­anol. Thus, deficiency of vitamin B12 or folate could result in inadequate detoxification of endog­enous formate and subsequent formic acidemia. The inability to detoxify formate is essential be­cause infusion of formate in monkeys has been shown to cause relatively selective optic nerve damage similar to that observed in methanol poi­soning ( 28). Several investigators have proposed that tobacco use contributes to the optic neuropathy of TAA by increasing body cyanide levels ( 3,7,8). Indeed, in­creased cyanide levels have been documented in three patients with TAA ( 8). Both formate and cy­anide inhibit cytochrome c oxidase ( complex IV in the mitochondrial electron transport chain). Inhi­bition of this enzyme results in both decreased ox­idative phosphorylation and ATP production. It has been suggested that the optic neuropathy oc­curring in methanol poisoning may be due to in­hibition of cytochrome c oxidase by formate accu­mulation ( 29). Additionally, Rizzo has suggested that TAA, Leber's hereditary optic neuropathy, and vitamin B12- deficiency optic neuropathy are each a type of ATP- deficiency optic neuropathy ( Rizzo paper presented at the North American Neuro- ophthalmology Society Meeting, February 1992). We agree with Rizzo, and suggest that the progressive optic neuropathy of TAA is due to ATP deficiency resulting from chronic inhibition of cytochrome c oxidase by accumulation of formate, cyanide, or both. Many people consume tobacco and alcohol and may have deficiencies of folate, vitamin B^, or both ( 30). However, only a small percentage will develop visual system dysfunction. In 1982, Knox and colleagues ( 6) suggested that patients with TAA may have a genetic predisposition for this condition. It is now known that Leber's hereditary optic neuropathy is associated with several mito­chondrial DNA mutations that effect synthesis of electron transport chain complexes I, III, and IV ( 31). However, not all patients with these mito­chondrial DNA mutations develop optic neuropa­thy. It has been suggested that optic neuropathy results when either a combination of mutations sufficiently decreases energy production or when subclinically damaged electron transport is further affected by environmental factors ( tobacco, alco­hol) ( 32). We believe it is possible that patients with TAA may have nuclear or mitochondrial DNA abnormalities which affect ATP production in a subclinical manner. 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