UMMC Pharmacy Newsletter May June 2013 Considerations for Migraine Headache Prevention In April 2012, new recommendations for the treatment of episodic migraine prevention in adults were released from the collaborative efforts of the American Academy of Neurology (AAN) and the American Headache Society (AHS). Cannabinoid Hyperemesis Cannabis, also known as marijuana, is the third most commonly used drug following tobacco and alcohol and the most commonly used illicit drug in the United States. Cannabis is recognized for antiemetic effects when used acutely. Chronic cannabis use occasionally leads to cyclical episodes of nausea, vomiting, and abdominal pain, which has been called cannabinoid hyperemesis. Balamuthia Mandrillaris A Rare Amebic Infection A fatal amebic infection, with low disease state awareness, nonspecific clinical presentation and no readily available treatment has twice been encountered at the University of Mississippi Medical Center (UMC). FDA Updates for Zolpidem Zolpidem (Ambien ) is a commonly prescribed sedative-hypnotic indicated for the treatment of insomnia and is frequently used by patients suffering from shift work insomnia, such as hospital employees. In January 2013, the FDA informed healthcare providers of new dose and safety information regarding zolpidem. Considerations for Migraine Headache Prevention Emily White, PharmD, Kris Harrell, PharmD, and Deborah Minor, PharmD In April 2012, new recommendations for the treatment of episodic migraine prevention in adults were released from the collaborative efforts of the American Academy of Neurology (AAN) and the American Headache Society (AHS). 1,2 These guidelines build upon the previous standards and review contemporary evidence supporting the use of pharmacologic, nonsteroidal anti-inflammatory drug (NSAID) and complementary therapies for migraine prevention. 1,2
INTRODUCTION Headache is one of the most common complaints encountered by healthcare practitioners and among the top three reasons given by adults for visiting United States emergency departments. Migraine headache, one of the most common primary headache disorders, affects approximately 6% of men and 18% of women. Despite the high prevalence of migraine headaches, studies indicate that most headache sufferers do not seek appropriate medical care. Furthermore, patients with migraines are both underdiagnosed and undertreated. 3,4 In 2004, it was found that only one-half of patients with evident symptoms of migraine had been formally diagnosed by a physician. 4 Appropriate care with an individualized approach to treatment can result in a reduction in attack frequency and severity, thus minimizing headache-related disability and emotional distress and improving the patient s quality of life. 3,4 Treatment strategies for migraine must address both immediate and long-term goals. Acute migraine therapies should provide consistent, rapid relief and enable the patient to resume normal activities at home, school, or work. Recurrence of symptoms and treatment-related adverse effects should be minimal. When migraine attacks occur frequently or symptomatic therapies are ineffective, preventive therapy should be considered. 4 CONSIDERATIONS FOR PREVENTIVE TREATMENT Approximately 25% of patients who suffer from severe migraines experience four or more attacks over a month. 5 Frequent use of acute treatments is less than optimal management and can exacerbate headaches, leading to the development of medication-overuse or rebound headaches. To prevent medication-overuse headaches from occurring, it is recommended that acute treatments be limited and prophylactic therapy be considered. 4 Unfortunately, it is estimated that only 3% to 13% of the 38% of patients who qualify for migraine preventive therapy actually receive it. 3 Preventive therapy should be considered in the setting of: recurring migraines that produce significant disability frequent attacks requiring symptomatic medication more than twice per week symptomatic therapies are ineffective, intolerable, or contraindicated migraines that are more severe and/or have a risk of neurological damage patient preference Preventive therapy also may be administered preemptively or intermittently when headaches recur in a predictable pattern (e.g., exercise-induced migraine or menstrual migraine). The preventive management of migraine should begin with the identification and avoidance of factors that consistently provoke migraine attacks in susceptible
individuals. Patients should be encouraged to keep a headache diary to document the frequency, severity, and duration of attacks as well as responses to medications and potential trigger factors. Patients also can benefit from adherence to a general wellness program that includes regular sleep, exercise, and eating habits, avoidance of headache triggers, smoking cessation, and limited caffeine intake. 4-8 Preventive migraine therapies are usually administered on a daily basis with the goal of reducing the frequency, severity, and duration of attacks and improving responsiveness to symptomatic therapies. 1,5 The lowest effective dose should be used for initiation and then gradually titrated upward until a therapeutic effect is achieved or side effects become intolerable. Drug doses for migraine prophylaxis are often lower than those necessary for other indications. 5,6 Though some reduction in attack frequency may be evident after the first month, 2 to 3 months is usually necessary to achieve an observable clinical benefit. An adequate therapeutic trial (usually 6 months) should be given to judge maximal efficacy. Patients should be counseled and monitored closely for therapeutic response, adverse reactions, abortive therapy needs, and management compliance. 1,5,6 Overuse of acute headache medications can interfere with the effects of preventive treatment. 8 Prophylactic treatment should usually be continued for at least 6 to 12 months after the frequency and severity of headaches have diminished. Gradual dosage reduction or discontinuation of therapy may be reasonable after a prolonged headache-free interval. Many patients with migraines experience less severe and fewer attacks over a lengthy period following discontinuation of prophylactic medications or taper to a lower dose. 1,5 The selection of an agent for migraine prophylaxis should be based on patient response, tolerability, convenience of the drug formulation, and coexisting conditions. 1,8 The recent guideline updates provide recommendations as to the level of efficacy for particular agents, though there is insufficient evidence as to how to choose one therapy over another. Those with the highest level of efficacy should be used for treatment, with consideration of individual patient factors. 1,2 RECOMMENDATIONS FOR PREVENTIVE TREATMENT To develop the recent guidelines, the AAN and AHS reviewed and evaluated studies of preventive migraine therapies. To be included in the analysis, trials had to be randomized, controlled studies with masked outcome assessments of safety and efficacy (considered class I or II studies). 1,2 Results of the included studies were then categorized into levels based upon the proven efficacy of each therapy. Agents were considered effective if they reduced migraine frequency, the number of migraine days, or the severity of migraine attacks. Therapies with definitive evidence of treatment efficacy were assigned a Level A recommendation and Level B where evidence indicated probable effectiveness. 1,2 Therapies recognized with Level A and B recommendations, along with dosages and general medication comments, are summarized in the table included. 1,2,4 Further information regarding the specific details from their evaluation can be found within the published updates and at the website, www.neurology.org. 1,2
Of note, though other agents have established or probable efficacy, only propranolol, timolol, divalproex sodium, and topiramate are currently approved by the Food and Drug Administration for migraine prophylaxis. 4 CONCLUSION Many migraineurs receive inadequate care and experience substantial levels of pain and disability. Improvements in migraine diagnosis and treatment can improve the quality of life for these patients and those around them. Recent guideline updates for preventive therapy identify agents with established and probable efficacy. These recommendations should be considered when selecting an agent and medications with the highest level of efficacy should be used. There is insufficient evidence as to how to choose one therapy over another. Selection of an agent should be based on individual patient response, tolerability, convenience of dosing, coexisting conditions, and preference. Patient counseling and careful monitoring are essential in initiating the most appropriate pharmacotherapy, documenting therapeutic successes and failures, identifying medication contraindications, and preventing or minimizing adverse events. Table : Preventive Migraine Therapies Drug Initial Dose Usual Range Comments β-adrenergic antagonists Atenolol B 50 mg/day 50 200 mg/day Metoprolol A 100 mg/day in 100-200 mg/day in Nadolol B 40-80 mg/day 80 240 mg/day Propranolol A 40 mg/day in 40 160 mg/day in Dose short-acting 4 times a day and long-acting 2 times a day; available as extended release Dose short-acting 2-3 times a day and long-acting 1-2 times a day; available as extended release Timolol A 20 mg/day in 20 60 mg/day in Antidepressants Amitriptyline B 10 mg at bedtime 20 50 mg at bedtime Venlafaxine B 37.5 mg/day 75-150 mg/day Available as extended release; increase dose after 1 week Antiepileptics Topiramate A 25 mg/day 50-200 mg/day in As effective as amitriptyline, propranolol or valproate; increase by 25 mg/week Valproic acid/ 250-500 mg/day 500 1,500 mg/day Monitor levels if compliance is
divalproex sodium A in, or daily for extended release Nonsteroidal anti-inflammatory drugs Ibuprofen B 400-1,200 mg/day in Ketoprofen B 150 mg/day in Naproxen 550-1,100 mg/day sodium B in Triptans Frovatriptan A 2.5 mg/day or 5 mg/day in divided doses Naratriptan B Zomitriptan B 2 mg/day in 5-7.5 mg/day in Miscellaneous Histamine B 1-10 ng 2 times/week in, or daily for extended release Magesium 400 mg/day 800 mg/day in gluconate B MIG-99 B (feverfew) 10-100 mg/day in an issue Use intermittently, such as for menstrual migraine prevention; daily or prolonged use may lead to medication-overuse headache and is limited by potential toxicity Taken in the perimenstrual period to prevent menstrual migraine Subcutaneous route of administration; may cause transient itching and burning at injection site May be more helpful in migraine with aura and menstrual migraine Withdrawal may be associated with increased headaches Petasites A 100-150 mg/day in 150 mg/day in Riboflavin B 400 mg/day in 400 mg/day in A Level A - established efficacy; should be used (> 2 Class I studies) B Level B - probably effective (1 Class I or 2 Class II studies) References Use only commercial preparations, plant is carcinogenic Benefit only after 3 months 1. Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology 2012;78:1337-1345. 2. Holland S, Silberstein SD, Freitag F, et al. Evidenced-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in
adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology 2012;78:1346-1353. 3. Lipton RB, Bigal ME, Diamond M, et al. The American Migraine Prevalence and Prevention Advisory Group. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology 2007;68:343-349. 4. Minor DS. Headache Disorders. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 8th ed. New York City: McGraw- Hill;April 2011, 1061-1075. 5. Bigal ME, Lipton RB. The preventative treatment of migraine. Neurologist 2006;12(4):204-213. 6. Silberstein SD, Dodick D, Freitag F, et al. Pharmacological approaches to managing migraine and associated comorbidities clinical considerations for monotherapy versus polytherapy. Headache 2007;47:585-599. 7. Bajwa ZH, Sabahat A. Preventive treatment of migraine in adults. UpToDate 2012;14:1-13. www.uptodate.com. 8. Buse DC, Rupnow FT, Lipton RB. Assessing and managing all aspects of migraine: migraine attacks, migraine-related functional impairment, common comorbidites, and quality of life. Mayo Clin Proc 2009;84(5):422-435. Return to top Cannabinoid Hyperemesis Emily Calongne, PharmD Cannabis, also known as marijuana, is the third most commonly used drug following tobacco and alcohol and the most commonly used illicit drug in the United States. Cannabis is recognized for antiemetic effects when used acutely. Chronic cannabis use occasionally leads to cyclical episodes of nausea, vomiting, and abdominal pain, which has been called cannabinoid hyperemesis. The major features of cannabinoid hyperemesis are chronic cannabis use, severe cyclic nausea and vomiting, and symptom cessation when cannabis use is stopped. The hallmark sign of cannabinoid hyperemesis is relief of symptoms after a hot shower or bath. Other common symptoms are abdominal pain, weight loss, symptom predominance in the morning, and vomiting not relieved by antiemetic medications. The length between episodes of nausea and vomiting varies, but episodes usually recur every 2-3 months.
Cannabinoid hyperemesis has been compared to cyclical vomiting syndrome (CVS), but these two conditions are different. Like cannabinoid hyperemesis, patients with CVS experience cycles of severe nausea and vomiting that lasts hours to days. Unlike cannabinoid hyperemsis, hot showers do not relieve their symptoms. CVS most commonly occurs in children aged 3-7, but can occur at any age. Of course, cannabinoid hyperemesis does not usually occur in children. CVS can be triggered by infection, emotional stress, or migraines. Antiemetics are sometimes useful in the treatment of CVS, but are not effective in cannabinoid hyperemesis. In the largest published case series, the majority of patients developed symptoms within 1 to 5 years after beginning to use cannabis on a regular basis. Many patients used cannabis more than once per week, with the majority of patients using it daily. The majority of patients report at least 7 episodes of cyclic nausea and vomiting per year. The intervals between these cyclical episodes were generally less than 2 months. Many patients reported relief of symptoms after a hot shower. Of the patients that stopped using cannabis, the majority had complete resolution of symptoms. The mechanism behind cannabinoid hyperemesis is unknown, but there are some proposed theories. One theory is that chronic cannabis use can disturb the hypothalamic-pituitary-adrenal axis leading to autonomic instability to cause the symptoms of cannabinoid hyperemesis. Another theory is that after several years of use, susceptible individuals may develop a reaction to cannabis due to delayed gastric emptying, the fat solubility, and long half-life of cannabis when chronically used. Cannabinoid hyperemesis is a newly described condition, but is something to consider if a patient complains of cyclical nausea and emesis with relief of symptoms after a hot shower. References: 1. Allen JH, de Moore GM, Heddle R, Twartz JC. Cannabinoid hyperemesis: cyclical hyperemesis in association with chronic cannabis abuse. Gut [Internet]. 2004;53: 1556-70. Available from: http://gut.bmj.com/content/53/11/1566.full.pdf 2. Simonetto DA, Oxentenko AS, Herman ML, Szostek JH. Cannabinoid hyperemesis: a case series of 98 patients. Mayo Clin Proc [Internet]. 2012 Feb; 87(2): 114-9. Available from: http://download.journals.elsevierhealth.com/pdfs/journals/0025-6196/piis0025619611000267.pdf
3. Sontineni SP, Chaudhary S, Sontineni V, Lanspa SJ. Cannabinoid hyperemesis syndrome: clinical diagnosis of an underrecognised manifestation of chronic cannabis use. World J Gastroenterol [Internet]. 2009 Mar 14; 15(10): 1264-6. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/pmc2658859/pdf/wjg-15-1264.pdf 4. Cyclic vomiting syndrome. The National Digestive Diseases Information Clearinghouse [Internet]. 2008 Dec [updated 2012 Apr 23]. Available from: http://digestive.niddk.nih.gov/ddiseases/pubs/cvs/ Return to top FDA Updates for Zolpidem Emily White, PharmD Zolpidem (Ambien ) is a commonly prescribed sedative-hypnotic indicated for the treatment of insomnia and is frequently used by patients suffering from shift work insomnia, such as hospital employees. In January 2013, the FDA informed healthcare providers of new dose and safety information regarding zolpidem. This announcement added to a previous FDA warning issued in 2008 regarding abnormal thinking and behavioral changes found patients taking sedative hypnotics such as zolpidem. Specific activities reported in the previous alert included driving, preparing and eating food, making phone calls, and having intercourse, all of which were usually not recalled by the patient. The more recent FDA warning was prompted by newly submitted data demonstrating the potential for elevated drug concentrations the morning following zolpidem use. Persistent elevated blood concentrations could lead to impairment while performing activities requiring alertness, such as driving, even when feeling fully awake. As of this publication, the data has not been published but has been summarized and released by the FDA. Additionally, the FDA has provided dosing recommendations and labeling changes. Driving simulation studies have revealed that zolpidem blood concentrations exceeding 50 ng/ml could produce impairment sufficient to increase the risk of a motor vehicle collision. In pharmacokinetic studies, approximately 3% of males and 15% of females taking immediaterelease Ambien 10 mg had blood concentrations exceeding this amount approximately eight hours after administration. One male and three females had concentrations exceeding 90 ng/ml after eight hours. In comparable pharmacokinetic studies of the extended-release formulation, similar results were found. In studies of the 12.5 mg extended-release product, 25% of males and 33% of females had blood concentrations exceeding 50 ng/ml approximately eight hours after administration. Approximately 5% of patients experienced concentrations greater than 100 ng/ml. When evaluating the 6.25 mg extended-release dose, approximately 5% of males and 15% of females had blood concentrations of 50 ng/ml or greater eight hours following administration. Elevated concentrations occurred in 10% of elderly patients, both male and female.
The above findings could be expected when evaluating the pharmacokinetic properties of zolpidem. Per package inserts, the half-life for both immediate-release and extended-release zolpidem ranges from 2.5 2.8 hours in healthy adult subjects. If allowing for 7-8 hours of sleep and taking the medication immediately before bedtime as recommended, only 2.5-3 half-lives will have passed before wakening. This translates to approximately 10-20% of the drug remaining in the blood upon wakening. It is important to note that this scenario does not take into account the biphasic absorption property of the extended-release formulation; therefore the resulting percentages could be underestimated. As supported by the pharmacokinetic studies described above, the risk of impairment is higher in females due to decreased rates of elimination. The risk of impairment is also higher in patients taking an extended-release formulation as opposed to those taking an immediaterelease formulation. To diminish risk, caution should always be used when prescribing zolpidem and patients should be thoroughly educated about the risks associated with its use. The FDA has placed a strong emphasis on prescribing the lowest effective dose and recommends patients taking either dose of the extended-release formulation avoid driving or carrying out other tasks that require alertness the day after medication administration. Manufacturers have been required to change the wording in product labels to reflect these warnings and recommendations. A summary of both previous and current recommendations can be found in table 1. Warnings and precautions listed in the package insert can be found in Table 2. Medications listing zolpidem as an active ingredient include generic versions of the medication, as well as the branded products Ambien, Ambien CR, Edluar, Intermezzo, and Zolpimist. Of these products, Intermezzo did not have labeling changes implemented since it was already recommended to be given at lower doses for difficulty falling asleep after night-time awakenings. Although this data is specific to zolpidem, the FDA warns that other sleep aids may have this risk as well. Studies evaluating other medications are currently ongoing. Table 1: Previous and Updated Zolpidem Dosing Recommendations Immediaterelease zolpidem Extendedrelease zolpidem Previous Labeling Adults: 10 mg once daily at bedtime Elderly: 5mg once daily at bedtime Adults: 12.5 mg once daily at bedtime Elderly: 6.25 mg once daily at bedtime Updated Labeling Women: initially 5 mg once daily at bedtime Men: initially 5-10 mg once daily at bedtime Elderly: 5 mg once daily at bedtime Women: initially 6.25 mg once daily at bedtime Men: initially 6.25-12.5 mg once daily at bedtime Elderly: 6.25 mg once daily at bedtime
Table 2: Summary of Zolpidem Warnings and Precautions CNS depressant effects and next-day impairment o Potential additive effects with other CNS depressants Need to evaluate co-morbid diagnoses o Determine underlying cause of insomnia Severe anaphylactic and anaphylactoid reactions o Angioedema, dyspnea, throat closing, nausea, vomiting Abnormal thinking and behavioral changes o Decreased inhibition, bizarre behavior, agitation, depersonalization, hallucinations, sleep-activities Use in patients with depression o May worsen depression; suicidal thoughts and actions have been reported Respiratory depression o Use caution in patients with compromised respiratory function Withdrawal effects o Withdrawal signs and symptoms have been reported following rapid dose decrease or abrupt discontinuation. Monitor for tolerance, abuse, and dependence. Withdrawal signs and symptoms have been reported following rapid dose decrease or abrupt discontinuation. Monitor for tolerance, abuse, and dependence. Patients using extended release zolpidem should be cautioned against driving or engaging in other hazardous activities or activities requiring complete mental alertness the day after use. References: 1. FDA Drug Safety Communication: Risk of next-morning impairment after use of insomnia drugs: FDA requires lower recommended doses for certain drugs containing zolpidem (Ambien, Ambien CR, Edluar, and Zolpimist). 2013 Jan 10. Available from: http://www.fda.gov/drugs/drugsafety/ucm334033.htm 2. FDA Drug Safety Communication: FDA approves new label changes and dosing for zolpidem products and a recommendation to avoid driving the day after using Ambien CR. 2013 May 14. Available from: http://www.fda.gov/drugs/drugsafety/ucm352085.htm 3. Ambien [package insert]. Sanofi-Aventis U.S. LLC, Bridgewater, New Jersey, February 2008 4. Ambien [package insert]. Sanofi-Aventis U.S. LLC, Bridgewater, New Jersey, April 2013 5. Ambien CR [package insert]. Sanofi-Aventis U.S. LLC, Bridgewater, New Jersey, December 2007
6. Ambien CR [package insert]. Sanofi-Aventis U.S. LLC, Bridgewater, New Jersey, April 2013 Return to top Balamuthia Mandrillaris A Rare Amebic Infection Bradley Wagner, PharmD A fatal amebic infection, with low disease state awareness, nonspecific clinical presentation and no readily available treatment has twice been encountered at the University of Mississippi Medical Center (UMC). Balamuthia mandrillaris (BM) is an extremely rare amebic infection producing granulomatous amebic encephalitis. BM is prevalent in soil and water, growing best in warm climates such as the southern United States and Peru. It enters human hosts through inhalation of BM cysts (dormant phase) or through penetration of ulcerated, broken skin. Once in the body, the cyst can transition or excyst to a trophozoite phase, where it actively grows, feeds and replicates. Once in the body, BM is a relatively slow killer, disseminating through the vasculature at 3.37 x 10-7 mph or ½ inch/ day. Upon reaching the brain, it causes brain tissue necrosis and is fatal in greater than 90% of cases. Balamuthia, a free-living ameba of the Acanthamoeba genus, is pathogenic in humans, primates, horses, sheep and dogs. In 1986, the first documented BM infection was in a pregnant baboon with fatal hemorrhagic encephalitis. The first human incidences occurred in 1991. Since 1991, 200 cases have occurred worldwide with only 11 known survivors. Twenty-nine of the 35 United States cases have been fatal. Interestingly, 80% of humans have Acanthamoeba antibodies, demonstrating its ubiquity in nature. In the United States, most infectious BM cases have occurred in immunocompromised patients, unlike in Peru where most have occurred in immunocompetent hosts. Patients may present with symptoms of headache, seizures, altered mental status, skin lesions and neurologic deficits. Imaging studies, laboratory findings and physical assessment are abnormal, but nonspecific in patients with Balamuthia. Lumbar puncture will typically reveal lymphocytic pleocytosis. MRI of the brain may demonstrate numerous ring enhancing lesions. Neurologic decline is precipitated by amebic induced thrombotic angeitis, development of ring like lesions, or intracranial hypertension that lead to brain tissue necrosis. Balamuthia s nonspecific presentation requires an expansion of diagnostic tests. The gold standard of testing is indirect
immunofluorescence of brain tissue. There are currently only 2 research centers that are capable of performing this test, the Centers for Disease Control in Atlanta, Georgia and the California Department of Public Health. Additional tests include polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA). Multiplex PCR is able to detect amebic DNA in human tissue at a high degree of sensitivity and specificity in 5 hours time and can be used as a confirmatory test. The ELISA test may turn seropositive due to asymptomatic infection from BM s ubiquity in nature and therefore has limited specificity. The CDC currently recommends a 5-6 drug treatment regimen for Balamuthia infections. Miltefosine (Impavido ), the only amebicidal agent against Balamuthia, is not available in the United States except through an Investigational New Drug (IND) application. It can be procured through Germany or India. Miltefosine is an alkylphosphocholine agent originally used for breast cancer cutaneous metastases. It penetrates the blood brain barrier with suspected activity against BM through inhibition of sterol and phospholipid synthesis. Miltefosine also has been used for visceral leishmaniasis, a protozoan parasite transmitted by the sand fly, in Brazil and India. Miltefosine is dosed at 2.5 mg/kg/day (max dose 150 mg/day) for an unknown duration. One survivor received 7 months of miltefosine therapy. Most common adverse drug reactions include GI upset (nausea, vomiting, diarrhea) and increases in serum transaminases and creatinine. The CDC s latest recommendation is to add Miltefosine to pentamidine, sulfadiazine, flucytosine, fluconazole and azithromycin - many of which have in-vitro amebistatic properties (see table). Additional management techniques may require placing an external ventricular drain to manage high intracranial pressures and avoidance of steroids to prevent dissemination of CNS lesions. The two cases of BM encountered at UMC were the first documented cases in solid organ transplant patients. These two patients developed BM in 2009 following their solid organ transplant. In November 2009, a 4 year-old deceased organ donor died from what was believed to be acute disseminated encephalomyelitis (ADEM) status post influenza A infection. Following his death, his kidneys, liver and heart were procured for organ transplantation. Both kidney recipients, a 31 year old female (kidney recipient A) and 27 year old male (kidney recipient B), developed neurologic symptoms consisting of seizures, headache and altered mental status at 21 and 22 days post transplant, respectively. Both patients were admitted to UMC. Magnetic resonance imaging revealed numerous ring-like lesions in both patients brains. In December 2009, post-mortem brain biopsy and histology was conducted on the 4-year-old organ donor and his cause of death was determined to be BM, not ADEM. He had no known immunocompromising conditions. He had lived in Kentucky, Florida and Mississippi during the 2 years prior to his death where he had frequent soil exposures and occasionally played in a wading pool of untreated well water. In December, kidney
recipient A underwent a brain biopsy. The brain histopathology revealed amebic infection, and PCR confirmed BM. Kidney recipient B received Balamuthia confirmation via PCR and CSF culture. Both patients were initiated on a drug regimen of miltefosine, pentamidine, sulfadiazine, flucytosine, fluconazole, and azithromycin. Miltefosine, unavailable in the States, was procured from Germany through an IND application. Despite weeks of intensive care, kidney recipient A died in February, 75 days posttransplant. Kidney recipient B, spent 2 months in a coma and 1 month in a rehabilitation facility and was able to make significant cognitive and motor function recovery. On post transplant day 203, he was discharged home from the rehabilitation facility with neurologic sequelae of right arm paralysis, bilateral leg weakness, and intermittent vision loss. Interestingly, neither the liver (7 y/o male) or heart transplant (2 y/o male) recipients developed BM. Both patients were given 6 week prophylactic courses of IV fluconazole, azithromycin and pentamidine and remain well at last documentation. Why both kidney recipients developed Balamuthia, but neither liver or heart recipients developed infection is unknown. Balamuthia is known to grow well on monkey kidney cells potentially explaining disease in both kidney recipients. In February 2013, UMC treated a patient 4 months status post renal transplant who developed acanthamoeba amebic encephalitis, another free-living ameba that is phylogenetically and clinically similar to Balamuthia mandrillaris. This patient received the same medical regimen as the previously discussed kidney recipients A and B, but was unable to tolerate his transplant immunosuppressives or encephalitis treatment and expired after 1 month of care. Balamuthia mandrillaris remains an extremely rare and deadly amebic infection. With the advancements in organ recovery and increasing organ transplantation both locally and worldwide, clinicians and organ recovery organizations should be aware of Balamuthia infection as a possible cause of encephalitis of undetermined etiology. Questions regarding whether preliminary screening should be implemented prior to transplantation as a method to decrease potential spread of Balamuthia are unanswered. However, increased awareness may aid in providing the prompt evaluation and necessary treatment for Balamuthia mandrillaris infection. Organ donor: 4 year-old boy 31 F 27 M 2 M 7 M Kidney Kidney Heart Liver
Drug Mechanism Dose Side Effects Comments Amebicidal Agent Believed to inhibit 2.5 mg/kg/day GI: N/V/D BM sterol (max 150 mg/day) Hepatitis biosynthesis Nephrotoxicity Miltefosine (Impavido ) Flucytosine (oral) Converts to 5- Fluorouracil in vivo and interferes with protein synthesis Fluconazole (oral or IV) Azithromycin (oral or IV) Pentamidine (IV) Sulfadiazine (oral) Amebistatic Agents Penetrate Cerebrospinal Fluid 37.5 mg/kg q 6 hours (max 150 mg/kg/day) Alters cell membrane function leakage of intracellular components Inhibits protein synthesis by binding to 50S ribosome Believed to inhibit DNA, RNA and protein synthesis Competitively inhibits p- aminobenzoic acid (PABA) converting to folic acid 12 mg/kg/day in 1 dose GI: N/V Marrow Suppression (pancytopenia) CNS: confusion, ataxia Hepatitis GI: bloating, N/V Unknown duration for BM. One successful case report was treated for 7 months. Drug level monitoring and dose adjustment recommended with renal insufficiency Monitor LFTs Good CSF penetration 500 mg/day GI: N/V/abd pain Few drug interactions If administer oral tablet, take with food Additional Agents Utilized 4 mg/kg/day in 1 dose Nephrotoxicity (25-50%) Hyper- or hypoglycemia (effects insulin secretion) 1.5 g q 6 hours GI: N/V Bone marrow suppression May take 30 days to penetrate CNS Prevent crystalluria with azotemia by adequate hydration & alkalinization of urine
Ring enhancing lesion in left knee BM cutaneous lesion on right temporal lobe of patient with BM of Peruvian patient References: Bravo FG, Seas C. Balamuthia mandrillaris Amoebic Encephalitis: An Emerging Parasitic Infection. Curr Infect Dis Rep. 2012; 14:391-396. CDC Morbidity and Mortality Weekly Report (MMWR). Balamuthia mandrillaris Transmitted Through Organ Transplantation Mississippi 2009. CDC Morbidity and Mortality Weekly Report. September 17, 2010; 59(36);1165-1170. CDC Morbidity and Mortality Weekly Report (MMWR). Balamuthia Amebic Encephalitis California 1999-2007. CDC Morbidity and Mortality Weekly Report. July 18, 2008; 57(28);768-771. Kiderlen AF, Radam E, Lewin A. Detection of Balamuthia mandrillaris DNA by real-time PCR targeting the RNase P gene. BMC Microbiology 2008, 8:210. Kokko KE, Farnon E, Butt FK. First Report of Balamuthia mandrillaris Transmission Through Organ Transplantation- Non-Viral Infections in Transplantation. The Transplantation Society. http://www.tts.org/index.php? option=com_tts&view=presentation&id=1374. Accessed April 5, 2013. Martinez D, Seas C, Bravo F et al. Successful Treatment of Balamuthia mandrillaris Amoebic Infection with Extensive Neurological and Cutaneous Involvement. Clin Infect Dis 2010; 51(2):e7 e11. Orozco L, Hanigan W, Khan M, Fratkin J, Lee M. Neurosurgical Intervention in the Diagnosis and Treatment of Balamuthia mandrillaris encephalitis. J Neurosurg. 2011;114:636-40. Return to top