Journal of Neuro-Ophthalmology, March 2000, Volume 20, Issue 1

Transient Visual Loss after Licorcie Ingestion

The authors present a spectrum of clinical presentations of transient visual loss/aberrations and show that these occurrences were attributable to ingestion of significant amounts of licorice. A case series of five patients was seen at Geisinger Medical Center between October 1986 and May 1996. Details of patient presentation, treatment, and outcome are discussed. The literature on the effects of licorice derivatives on vascular smooth muscle function is reviewed. Of the five patients, two had documented visual loss by visual acuity testing and visual fields. All patients reported a recent ingestion of significant amounts of licorice (1/4-2 lbs.). All patients had resolution of their visual symptoms; the aid of hyperbaric oxygen was required for one patient. Thorough review of the literature shows recent in vitro and in vivo evidence of glycyrrhetinic acid (the active component of licorice) and carbenoxolone (the hemisuccinate derivative of glycyrrhetinic acid) directly and indirectly enhancing vasoconstrictor action in vascular smooth muscle. It is believed that licorice derivatives can cause retinal or occipital vasospasm, giving rise to transient monocular or binocular visual loss/aberrations. This has not been described before in the literature. It is important to ask about licorice ingestion with patients who present with these visual symptoms.

Journal of Neuro- Ophthalmology 20( 1): 38- 41, 2000. © 2000 Lippincott Williams & Wilkins, Inc., Philadelphia Transient Visual Loss After Licorice Ingestion » Kendall R. B. Dobbins, MD, and Robert F. Saul, MD The authors present a spectrum of clinical presentations of transient visual loss/ aberrations and show that these occur­rences were attributable to ingestion of significant amounts of licorice. A case series of five patients was seen at Geisinger Medical Center between October 1986 and May 1996. Details of patient presentation, treatment, and outcome are discussed. The literature on the effects of licorice derivatives on vascular smooth muscle function is reviewed. Of the five patients, two had documented visual loss by visual acuity testing and visual fields. All patients reported a recent ingestion of significant amounts of licorice (! A- 2 lbs.). All patients had resolution of their visual symptoms; the aid of hyperbaric oxygen was re­quired for one patient. Thorough review of the literature shows recent in vitro and in vivo evidence of glycyrrhetinic acid ( the active component of licorice) and carbenoxolone ( the hemisuc-cinate derivative of glycyrrhetinic acid) directly and indirectly enhancing vasoconstrictor action in vascular smooth muscle. It is believed that licorice derivatives can cause retinal or occipi­tal vasospasm, giving rise to transient monocular or binocular visual loss/ aberrations. This has not been described before in the literature. It is important to ask about licorice ingestion with patients who present with these visual symptoms. Key Words: Carbenoxolone- Glycyrrhetinic acid- Licorice- Vasospasm- 11 @- hydroxysteroid dehydrogenase. Licorice extract comes from the root Glycyrrhiza gla­bra. It is a sweet substance that is used as a flavoring agent in foods and beverages. The largest importer of licorice in the United States is the tobacco industry for use as a conditioning and flavoring agent. Licorice cures tobacco and thus has been used for a century in cigars, pipe tobacco, cigarettes, and chewing tobacco ( 1). It was used by the ancient Egyptians, Greeks, Romans, and Chi­nese for various medicinal purposes. More recently, lico­rice has been shown to have the pharmacologic proper­ties of a gastric mucosal protectant, an antitussive agent, a sedative, an anti- inflammatory/ anti- allergy agent, an Manuscript received May 11, 1999; accepted October 7, 1999. From the Department of Ophthalmology, Penn State Geisinger Medical Center, Danville, Pennsylvania. Dr. Dobbins is now in practice at the Corneal Consultants of Indiana, Indianapolis, Indiana. Dr. Saul is now in practice at Rappahannock Neurology Ltd., Kilmarnock, Vir­ginia. Address correspondence and reprint requests to Kendall R. B. Dobbins, MD, 9002 North Meridian Street, Suite 100, Indianapolis, IN 46260. immunoregulator ( beneficial effect in immunosup-pressed), and an antitoxin agent ( 2). Excessive licorice ingestion can cause hypermineralo-corticoidism, leading to sodium retention, potassium loss, edema, hypertension, and suppression of the renin-angiotensin- aldosterone system. Glycyrrhizic acid, a natural constituent of licorice, is hydrolyzed in the intes­tine to two molecules of glucuronic acid and one mol­ecule of glycyrrhetinic acid ( the pharmacologically ac­tive component). The enzyme 11 ( i- hydroxysteroid dehy­drogenase ( ll( 3- OHSD) interconverts Cortisol ( the more active form) and cortisone ( the more inactive form). In the kidney and other mineralocorticoid- selective tissues, 11 ( i- OHSD has a greater propensity for converting Cor­tisol to cortisone, preventing Cortisol from gaining access to nonspecific mineralocorticoid receptors. However, 113- OHSD is inhibited by glycyrrhetinic acid, thus caus­ing a Cortisol excess. Because Cortisol binds to miner­alocorticoid receptors with the same affinity as aldoste­rone, there is a resulting hypermineralocorticoid effect of Cortisol. This causes sodium and water retention, leading to hypervolemia and, thus, hypertension. From the 1940s to the 1980s, the consensus had been that hypermineralocorticoidism was the primary mecha­nism for how licorice caused hypertension. However, there is recent evidence that glycyrrhetinic acid and car­benoxolone ( the hemisuccinate derivative of glycyrrhe­tinic acid) enhance vasoconstrictor action in vascular smooth muscle ( 3- 14). It is now believed that this is most likely the primary cause of hypertension with lico­rice ingestion. We propose that the vasospastic properties of licorice can cause transient visual loss/ aberrations, similar to those seen with migraines. PATIENTS AND METHODS Five patients with transient visual loss/ aberrations af­ter ingestion of significant amounts of licorice are re­viewed. The case histories, treatments, and outcomes are discussed. CASE REPORTS Case 1 A 62- year- old man with a history of hypertension, treated with lisinopril 10 mg each day, and no previous 38 TRANSIENT VISUAL LOSS AFTER LICORICE INGESTION 39 history of transient visual loss, experienced a prolonged loss of vision OS ( described as a centripetal collapse phenomenon) for 3.5 hours the day before presentation. When he saw his family doctor, the symptoms had com­pletely resolved, and he was prescribed acetylsalicylic acid, 325 mg/ d. The next day, the patient woke up with no light perception in his left eye, which improved mod­estly by the time he arrived at the hospital. His visual acuity was 20/ 20 OD and 20/ 400 OS. There was a posi­tive afferent pupillary defect ( APD) OS. Funduscopy showed very mild narrowing of the retinal vessels OS, with mild retinal pigment epithelial ( RPE) changes OU. Formal visual fields were not measured at this point. Results of the rest of the ophthalmic examination were normal. Results of the physical examination were normal except for a blood pressure of 160/ 102 mm Hg. Because it was thought that this may have been a vasospastic phenomenon, it was decided to treat the patient with hyperbaric oxygen ( 90 minutes at 2.4 atmospheres of breathing 100% oxygen). After the first dive, his visual acuity improved to 20/ 25 OS. A second dive was at­tempted; however, the patient became claustrophobic af­ter 20 minutes. Twelve hours after initial presentation, his visual acuity was 20/ 20 OS. Intravenous sodium hep­arin was administered until carotid stenosis of a critical nature or the presence of significant carotid artery plaques as a source of embolization were ruled out. Re­sults of carotid duplex studies were normal. A complete blood count ( CBC) was normal and the erythrocyte sedi­mentation rate ( ESR) was 15 mm/ h. The patient had ingested about 8 ounces of black jel­lybeans flavored with licorice throughout the 3 days be­fore presentation. After 2 days of no licorice consump­tion, his blood pressure decreased to 145/ 75 mm Hg. This occurred without the addition of any antihyperten­sive medications. His visual acuity remained 20/ 20 OU. Formal visual field testing showed some mild nonspe­cific constriction OS. There was a trace APD OS. Color vision was normal. There was no evidence of narrowing of the retinal vasculature at this time. The patient was discharged with the diagnosis of resolving retinal and optic nerve ischemia probably on the basis of licorice-induced vasospasm. Acetylsalicylic acid, 325 mg/ d orally, was prescribed. On 1- month follow- up, the patient described some continued " blotchiness" in his field of vision OS. His color vision was normal, and there was no APD. On follow- up after 4 months, the patient reported his vision to be almost completely back to normal with occasional episodes of " a piece of a jig- saw puzzle missing." Formal visual fields were now normal. Case 2 A 67- year- old radiation oncologist with a medical his­tory of benign prostatic hypertrophy and hypercholester­olemia experienced the sudden onset of scintillating pe­ripheral scotomas on his way to work one morning. His central vision was minimally affected. On further ques­tioning, the patient gave the history that he had stayed up until 3: 00 AM reading a novel the night before, during which time he consumed about a half pound of licorice. He also remembered that he had similar episodes of vi­sual disturbances in the past, which were much shorter in duration, and were also accompanied by licorice inges­tion. He did not recall having any incidents not accom­panied by licorice ingestion. Because of the strong sus­picion that licorice ingestion was the cause for the pa­tient's visual disturbance, he was advised to stop its consumption. Further workup was not thought to be war­ranted. In the past 9 years, he has significantly reduced his licorice intake and has had only one milder visual disturbance, which occurred after significant coffee con­sumption. Case 3 A 26- year- old woman was hit by a rock in her right eye at age 13, resulting in a cataract, iridodialysis, sig­nificant foveal pigmentation, and count fingers vision. She also had a long history of typical vascular headaches. Four years before presentation, with the birth of her first child, the severity of the headaches increased. They were typically bitemporal and throbbing. Four months before her introduction to our clinic, she gave birth to her sec­ond child, and, again, her headaches worsened. In the 13 days before presentation, she had daily headaches that were interrupted with spells of visual loss. She noted a " fuzzy" expanding spot in her left eye that became a moon- shaped dark defect in the nasal aspect and then spread into the right visual field. Even though she had significant central visual loss OD secondary to past trauma, she was certain that the remaining vision she had on the right was also darkened. This would last 30 min­utes to several hours, at which time the headache inten­sified. The patient reported eating 1 to 2 pounds of lico­rice per week, and consuming about 20 cups of coffee and a pot of iced tea per day. Ophthalmic examination showed a visual acuity of counting fingers OD and 20/ 20 OS. The visual field of the left eye showed constriction of the entire visual field, with a preponderance of the deficit favoring the nasal field ( Fig. 1). Results of a CBC, electrolytes panel, ESR, antinuclear antibodies, and coagulation studies were all normal. Magnetic resonance imaging was normal. The patient was advised to stop eating licorice and decrease her caffeine intake, and she was placed on verapamil hydrochloride, 80 mg, three times per day by mouth. A repeat visual field 4 days after presentation was im­proved ( Fig. 2). It was believed that occipital vasospasm was causing her to have vascular headaches and visual disturbances, exacerbated by licorice and caffeine intake. In the past 7 years, she has stopped all licorice ingestion and de­creased caffeine consumption. She continues to have an occasional headache, but only two have been associated with mild visual auras. Case 4 A 65- year- old man experienced 4 months of intermit­tent left- sided headaches that would become generalized, preceded by some visual aberrations in the left eye, de- J Neuro- Ophlhalmol, Vol. 20, No. 1. 2000 40 K. R. B. DOBBINS AND R. F. SAUL FIG. 1. Automated visual field ( Humphrey 30- 2) of the left eye of patient 3 after significant licorice ingestion. There is constriction of the entire visual field, with a preponderance of the deficit fa­voring the nasal field. scribed as " pinwheels" that were red and white and fluc­tuating. At some times his headaches were throbbing in nature; at other times, however, they were steady and lancinating into the left eye. He also experienced in­creased lacrimation and nasal stuffiness on the left side. He stated that he liked to eat " a lot" of black licorice and ate a quarter pound the night before presentation. On the day of presentation, the patient experienced a severe left-sided headache and " pinwheel" vision, which was pre­ceded by numbness of his left neck and face. His medical history was significant for basilar artery ischemic attacks and a brainstem stroke for which he regularly took so­dium warfarin. He also had a history of aortic sclerosis without stenosis. Results of physical examination and neuroophthalmic examination were normal. Computed tomography of the head was unremarkable. A CBC was normal, and an ESR was 5 mm/ h. Verapamil hydrochloride SR 180 mg, once per day, was prescribed. The patient was then given intravenous prochlorperazine, with resolution of the headache within 24 hours. The patient was discharged on verapamil and sodium warfarin and was told to cease licorice ingestion. It was thought that he probably had a cluster- migraine variant headache, which was conceivably exacerbated by licorice ingestion. The patient did well and was eventually taken off the verapamil and sodium warfarin. He has reported no fur­ther licorice consumption. In the 2 years after this event, he has only had some occasional mild headaches and has not had any further visual aberrations. Case 5 A 39- year- old intensive care unit physician presented with a history of multiple episodes of binocular scintil­lating scotomas lasting 20 to 30 minutes each, all during approximately a 7- hour period ( about 2: 30 PM to 9: 30 PM). The patient experienced no headache and had no history of migraines. He was an otherwise healthy indi­vidual. On further questioning, it was discovered that he had ingested " about half of a bag" of licorice- flavored candy during that morning and afternoon. Results of complete ophthalmic and neurologic examinations were normal. It was thought that this was occipital vasospasm, precipitated by licorice intake, and further workup was not thought necessary. Over the last 13 years, he has almost completely ceased licorice consumption, rarely having only very small amounts, and has had no further episodes of visual disturbances. DISCUSSION We present five cases we believe represent visual dis­turbances related to licorice ingestion and offer review of the literature to support our conclusions. Licorice is known to cause hypertension. It has been thought that the primary cause for this was the hyper-mineralocorticoid action of licorice derivatives. There is increasing evidence that licorice derivatives have direct and indirect vasospastic effects, and thus, this is now being considered the main cause for hypertension after licorice ingestion. Funder et al. ( 3) and Walker et al. ( 4) have shown that 11 ( 3- OHSD is present in vascular smooth muscle. In the vasculature, the oxoreductase reaction of cortisone to Cortisol is nearly four times greater than the dehydroge­nase reaction of Cortisol to cortisone. Carbenoxolone, a semisynthetic hemisuccinate derivative of glycyrrhetinic acid, and also an inhibitor of 1 l( 3- OHSD, suppresses the dehydrogenase reaction to a greater degree than the re­verse oxoreductase reaction in the vasculature ( 5). There­fore, the increased amount of Cortisol yields a greater glucocorticoid effect. FIG. 2. Improvement of the visual field of the left eye of patient 3, 4 days after presentation, with cessation of licorice ingestion. J Neuw- Ophthalmol, Vol. 20, No. 1, 2000 TRANSIENT VISUAL LOSS AFTER LICORICE INGESTION 41 Hyperglucocorticoidism causes vasoconstriction in a number of different ways. Studies in rats show that glu­cocorticoids enhance the vascular smooth muscle con­tractile response to vasopressin and angiotensin II ( 6,7). Glucocorticoids also induce a supersensitivity of vascu­lar smooth muscle to noradrenaline by inhibiting the bio­synthesis of prostaglandins ( 8). Thus, the inhibition of 11 ( 3- OHSD by licorice derivatives causes an increase in Cortisol levels in vascular smooth muscle, which in turn leads to vasoconstriction by increasing the sensitivity of smooth muscle cells to these vasoconstrictors ( vaso­pressin, angiotensin II, and noradrenaline). This has been supported by oral treatment of carbenoxolone and skin treatment of glycyrrhetinic acid in humans, resulting in increased dermal constriction to endogenous pressors; and oral carbenoxolone potentiating forearm vasocon­striction and blood pressure readings during systemic infusion of exogenous norepinephrine ( 9,10). Further in­vestigation in rats shows evidence that glucocorticoids reduce the vasorelaxant effects of atrial natriuretic factor ( ANF). After binding of ANF to receptors on target cells, there is normally an increase in cyclic guanosine mono­phosphate concentration, indicating that it plays a role in vasodilation. Research by Yasunari et al. ( 11) suggests that glucocorticoids decrease ANF- induced cyclic gua­nosine monophosphate formation in vascular smooth muscle. Finally, as a result of the work done by Kornel et al. ( 12) in rabbits, they showed that increased levels of glucocorticoids also cause vasoconstriction by increasing the influx rate of calcium in vascular smooth muscle. Additionally, carbenoxolone has a direct effect on the vasculature, independent of 11 ( 3- OHSD. It potentiates noradrenaline- induced vasoconstriction ( 13). Further­more, concentrations of carbenoxolone greater than 10u, mol/ L enhance vasoconstrictor action by selective toxicity to the endothelium and significant reduction of endothelium- dependent relaxation ( 14). There is good evidence that licorice derivatives en­hance vasoconstrictor activity by multiple mechanisms. We believe that this is not manifested only as hyperten­sion physiologically. We think that licorice derivatives can cause vasospasm throughout the human body, mani­festing a multitude of symptoms. Five patients were pre­sented who experienced sudden visual loss/ aberrations after ingestion of significant amounts of licorice. Al­though patient 3 had a confounding factor of notable coffee consumption along with significant licorice inges­tion, and patient 4 could have conceivably had headaches and visual loss secondary to a cluster event not associ­ated with licorice ingestion, we believe that licorice con­sumption may have played a contributory role. There is little doubt, however, that licorice ingestion was associ­ated with the visual disturbances experienced by the other three patients, because they had no history of mi­graines, ischemic events, associated intake of other known vasoconstrictors, or previous visual disturbances unrelated to licorice consumption. We believe licorice derivatives play an active role in retinal and occipital vasospasm, and possibly vasospasm of vessels supplying the optic nerve. The authors recog­nize that licorice ingestion in the patients presented could be a confounding factor in a group of patients experienc­ing migrainous phenomena. 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