Transient blindness due to posterior reversible encephalopathy syndrome following ephedra overdose.

Abstract: Posterior reversible encephalopathy syndrome (PRES), also known as reversible posterior leukoencephalopathy syndrome (RPLS), is most often associated with hypertensive emergencies and is characterized by seizures, mental status changes and visual disturbances. We report a case of a previously healthy young man who developed multiorgan failure and transient cortical blindness following ingestion of a performance-enhancing ephedra-based supplement. Neuroimaging findings confirmed the clinical suspicion of PRES. Radiographic abnormalities and neurologic dysfunction subsequently resolved with correction of his systolic blood pressure. This case emphasizes the need for prompt treatment and consideration of toxic ingestions in patients presenting with hypertension-related end-organ dysfunction.

Key Words: posterior reversible encephalopathy syndrome, reversible posterior leukoencephalopathy syndrome, hypertensive encephalopathy, cortical blindness, ephedra

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The amphetamine-like properties of ephedra have been linked with several adverse effects, including seizure, myocardial infarction and hepatotoxicity. (1,2) Even at recommended doses, this agent can result in an abrupt rise of systemic blood pressure with resultant end-organ dysfunction. (1) Posterior reversible encephalopathy syndrome (PRES) is an uncommon manifestation of hypertensive emergencies that classically presents with seizures, mental status changes and visual impairment. (3) We present a case of transient cortical blindness secondary to PRES following ingestion of the ephedra-based weight-loss supplements, Stacker 3 and Ripped Fuel Extreme.

Case Report

A 29-year-old previously healthy man presented following a generalized tonic-clonic seizure that occurred while playing basketball. He had no medical illnesses and had never experienced seizure-like activity before this event. The patient initially complained of the abrupt onset of a severe headache associated with confusion and lethargy. By report, the patient had recently initiated a weight loss program using the ephedra-containing supplements, Stacker 3 and Ripped Fuel Extreme. He was not taking prescription medications or other supplements and denied the use of illicit drugs.

On presentation, the patient was stuporous and combative. He was noted to have a systolic blood pressure of 220 mm Hg, sinus tachycardia with a heart rate of 117 and a core body temperature of 103.2[degrees]F. His physical examination was otherwise unremarkable. Dynamic electrocardiographic changes and elevated cardiac enzymes confirmed an acute myocardial infarction. Initial laboratory values revealed fulminant hepatic failure, acute renal failure and rhabdomyolysis. A urine drug screen was negative. Hypertensive emergency with multiorgan dysfunction was diagnosed and a labetalol drip was initiated to normalize the systemic blood pressure. The patient developed anuric renal failure requiring hemodialysis. Over the course of the next several days, the patient improved clinically and was transferred to a nearby facility for physical rehabilitation.

One week later, the patient returned to the emergency department after developing complete, bilateral visual loss without nystagmus, consistent with cortical blindness. Blood pressure was markedly elevated, and the patient was diagnosed with a second episode of hypertensive emergency. No precipitating etiology for his subsequent blood pressure elevation was identified, and the patient did not resume taking his ephedra-containing supplements. Magnetic resonance imaging (MRI) revealed T2 hyperintensity in the subcortical white matter of the occipital, posterior parietal, and posterior temporal lobes bilaterally (Figs. 1 and 2). There was no abnormal enhancement or restricted diffusion. His clinical presentation, along with the radiographic findings, was suggestive of PRES. Visual loss and cognitive depression resolved with normalization of his blood pressure. Repeat MRI one week later demonstrated near resolution of the abnormalities noted on initial imaging (Figs. 3 and 4). Upon discharge, his neurologic status remained stable, and he was transferred to a subacute rehabilitation facility for continued physical therapy. At his two week follow-up visit, the patient was normotensive, and no neurologic dysfunction was identified.

Discussion

Ephedra, also referred to as ma huang, is an over-the-counter, amphetamine-like alkaloid. Initially approved and regulated by the US Food and Drug Administration (FDA) as an alternative asthma medication, it is now commonly found in many dietary supplements, including both the Stacker 3 and Ripped Fuel Extreme used in the presented patient. (1) Both supplements are based on the "ECA stack" containing ephedrine, caffeine and aspirin which are used for their synergistic thermogenic properties. (4)

Between January 1993 and October 2000, the FDA received 1,398 reports of adverse health events and 81 deaths attributed to ephedra supplements. (5) Although ephedra-related products accounted for less than 1% of all dietary supplement sales, it resulted in 64% of adverse event reactions reported to poison control centers. (6) Supplements containing ephedra constituted 42% of all complaints and 59% of all reported deaths involving nutritional supplements during this time period. (5) The most common significant reactions included hypertension, seizures, cerebrovascular accidents, cardiac arrhythmias, myocardial infarctions, psychosis, and cognitive impairments. (5) In December 2003, the FDA issued a consumer alert warning regarding the safety of ephedra. Its sale was prohibited in February 2004.

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Posterior reversible encephalopathy syndrome, first described in 1996 by Hinchey et al., (3) is a clinical syndrome characterized by headache, mental status changes, generalized seizures and visual impairment, most commonly transient cortical blindness. The development of PRES, especially cortical blindness, may be delayed up to several weeks after the initial insult, as seen in the presented case. (7) Bilateral vasogenic edema without infarction involving the white matter of the occipital and posterior parietal lobes is a common presentation. (3,8,9) Vasogenic edema has also been reported to occur to a lesser degree in the posterior frontal and temporal lobes, the corona radiata, the pons and the cerebellum. (10) Symptoms and radiographic changes typically resolve, and most patients experience complete neurologic recovery with rapid treatment of the underlying disorder.

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An acute rise in systemic blood pressure resulting in hypertensive encephalopathy is the most commonly reported etiology of PRES. Other etiologies include eclampsia both with and without hypertension and renal dysfunction. (3,11) PRES has also been commonly associated with immunosuppressive agents, most notably cyclosporine (7) and tacrolimus. (12) Malignancies, vasculitides and recombinant human erythropoietin have been infrequently reported as precipitants to PRES. (13-15)

PRES has not been previously reported with use of ephedra. Ephedra has been associated with an abrupt increase in systemic blood pressure with resultant end-organ dysfunction. Its sympathomimetic effects, especially when combined with the additive thermogenic properties of caffeine, likely resulted in the hypertensive encephalopathy and development of PRES in the presented case. In this instance, cortical blindness, mental status changes and radiographic abnormalities resolved with prompt control of the patient's blood pressure.

Conclusions

Hypertensive encephalopathy is a common cause of PRES. Toxic effects of prescription and over-the-counter medications should be considered early in patients, especially young individuals, presenting with hypertension-related end-organ dysfunction. Prompt treatment of hypertensive emergency is essential to prevent progression and the development of irreversible organ dysfunction.

References

1. Miller SC. Safety concerns regarding ephedrine-type alkaloid-containing dietary supplements. Mil Med 2004;169:87-93.

2. Stevens T, Qadri A, Zein NN. Two patients with acute liver injury associated with use of the herbal weight-loss supplement Hydroxycut. Ann Intern Med 2005;142:477-478.

3. Hinchey J, Chaves C, Appignani B, et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med 1996;334:494-500.

4. Daly PA, Krieger DR, Dulloo AG, et al. Ephedrine, caffeine and aspirin: safety and efficacy for treatment of human obesity. Int J Obes Relat Metab Disord 1993;17(suppl 1):S73-S78.

5. U.S. Food and Drug Administration Center for Food Safety and Applied Nutrition.

6. Bent S, Tiedt TN, Odden MC, et al. The relative safety of ephedra compared with other herbal products. Ann Intern Med 2003;138:468-471.

7. Jarosz JM, Howlett DC, Cox TC. Cyclosporine-related reversible posterior leukoencephalopathy: MRI. Neuroradiology 1997;39:711-715.

8. Hauser RA. Lacey DM, Knight MR. Hypertensive encephalopathy: magnetic resonance imaging demonstration of reversible cortical and white matter lesions. Arch Neurol 1988;45:1078-1083.

9. Bakshi R, Bates VE, Mechtler LL, et al. Occipital lobe seizures as the major clinical manifestation of reversible posterior leukoencephalopathy syndrome: magnetic resonance imaging findings. Epilepsia 1998:39: 295-299.

10. Casey SO, Sampaio RC, Michel E, et al. posterior reversible encephalopathy syndrome: utility of fluid-attenuated inversion recovery MR imaging in the detection of cortical and subcortical lesions. AJNR Am J Neuroradiol 2000;21:1199-1206.

11. Ozcakar ZB, Ekim M, Fitoz S, et al. Hypertension induced reversible posterior leukoencephalopathy syndrome: a report of two cases. Eur J Pediatr 2004;163:728-730.

12. Lacaille F, Hertz-Pannier L, Nassogne MC, et al. Magnetic resonance imaging for the diagnosis of acute leukoencephalopathy in children treated with tacrolimus. Neuropediatrics 2004;35:130-133.

13. Miyazaki Y, Tajima Y, Sudo K, et al. Hodgkin's disease-related central nervous system angiopathy presenting as reversible posterior leukoencephalopathy. Intern Med 2004;43:1005-1007.

14. Primavera A, Audenino D, Mavilio N, et al. Reversible posterior leucoencephalopathy syndrome in systemic lupus and vasculitis. Ann Rheum Dis 2001;60:534-537.

15. Delanty N, Vaughan C, Frucht S, et al. Erythropoietin-associated hypertensive posterior leukoencephalopathy. Neurology 1997;49:686-689.

To win without risk is to triumph without glory
--Pierre Corneille

Fouad J. Moawad, MD, Joshua D. Hartzell, MD, Timothy J. Biega, MD, and Christopher J. Lettieri, MD

From the Department of Medicine, Walter Reed Army Medical Center, Washington, DC; the Department of Neuroradiology, George Washington University Medical Center, Washington, DC; the Pulmonary, Critical Care and Sleep Medicine Service, Washington, DC; and the Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD.

Reprint requests to Fouad J. Moawad, MD, Department of Medicine, Walter Reed Army Medical Center, 6900 Georgia Avenue, NW, Washington, DC 20307. Email: [e-mail]

The authors have no potential financial or proprietary conflicts of interests. The opinions expressed herein are not to be construed as official or as reflecting the policies of either the Department of the Army or the Department of Defense.

Accepted January 17, 2006.

RELATED ARTICLE: Key Points

* Posterior reversible encephalopathy syndrome (PRES) is an uncommon manifestation of hypertensive emergencies that classically presents with seizures, mental status changes and visual impairment.

* Hypertensive encephalopathy has not been previously reported with use of ephedra.

* Prompt treatment of hypertensive emergency is essential to prevent progression and the development of irreversible organ dysfunction.