Seizures after Heart Transplantation - Annals of Transplantation

CASE REPORT ISSN 1425-9524 © Ann Transplant, 2014; 19: 417-420 DOI: 10.12659/AOT.890743 Received: Accepted: Published:

Seizures after Heart Transplantation – Two Cases of Non-Immunosuppressant Drug Interactions in Young Patients

2014.03.23 2014.05.08 2014.08.22

Authors’ Contribution: Study Design A Data Collection B Statistical Analysis C Data Interpretation D Manuscript Preparation E Literature Search F Funds Collection G

ABCDEF 1 BCF 1 DEF 1 BF 1 EF 2 EF 2 AEF 1

Corresponding Author: Source of support:

Background:

Case Reports:

Conclusions:

MeSH Keywords: Full-text PDF:

Tomasz Urbanowicz Magdalena Pawłowska Piotr Buczkowski Bartłomiej Perek Hanna Baszyńska-Wachowiak Ewa Straburzyńska-Migaj Marek Jemielity

1 Department of Cardiac Surgery and Transplantology, Chair of Cardio-Thoracic Surgery, Poznań University of Medical Sciences, Poznań, Poland 2 Department of Cardiology, Poznań University of Medical Sciences, Poznań, Poland

Tomasz Urbanowicz, e-mail: [email protected] None

Neurological complications occur in 30–80% of patients following heart transplantation, and seizures account for 2–20% of these sequelae. The main risk factors are toxicity due to immunosuppression, infections, and brain lesions. We present 2 cases of grand mal type attacks that occurred on the 7th and 15th postoperative days. The origin of the attacks was an unusual interaction between 2 non-immunosuppressive drugs (metoclopramide and theophylline). We present 2 cases of seizure episodes during the early postoperative period in young heart transplant recipients (a 26-year-old female and a 33-year-old man). Grand mal type attacks occurred on the 7th and 15th postoperative day, respectively. Both patients were treated with standard triple immunosuppressive therapy including tacrolimus, mycophenolate mofetil, and steroids. Therapy with metoclopramide was started because the patients reported gastrointestinal disturbances. Theophylline was administered due to postoperative bradycardia. Serum theophylline levels were 33 and 34 mcg/ml, respectively. There were no neurological deficits noticed thereafter. The magnetic resonance imaging (MRI) was negative for stroke and central nervous system infection in both cases. We conclude that theophylline overdose combined with metoclopramide may provoke new-onset seizures, especially in young patients following heart transplantation. Drug Interactions • Epilepsy • Heart Transplantation • Metoclopramide • Theophylline http://www.annalsoftransplantation.com/abstract/index/idArt/890743

1660

—

1

417

31

Indexed in: [Science Citation Index Expanded] [Index Medicus/MEDLINE] [Chemical Abstracts] [Scopus]

Urbanowicz T. et al.: Seizures after heart transplantation – two cases… © Ann Transplant, 2014; 19: 417-420

CASE REPORT

Background Various neurological complications occur in 30–80% of patients after heart transplantation, including seizures, which occur in 2–20% of heart transplant recipients [1–5]. The most common risk factors for neurological complications are toxicity of immunosuppressants, rapid electrolyte or osmolar changes, central nervous system infections, and ischemic/hemorrhagic brain lesions. We present 2 cases of an unusual interaction of theophylline and metoclopramide during the early posttransplant period in 2 young patients.

Case Reports The first patient was initially diagnosed with dilated cardiomyopathy and was awaiting urgent surgery. Clinical symptoms appeared in the 3rd trimester of pregnancy. Her past medical history was positive for hypothyroidism. The patient was listed on an urgent transplantation list for 5 months. She was operated on using the Lower-Shumway technique with ischemic time of 211 min and cross-clamping time of 184 min. Good left ventricular function was found postoperatively on echocardiography. There were 2 episodes of ventricular tachycardia followed by 3rd degree atrioventricular block 1 day after transplantation. Because a retrospective cross-match was positive, she was treated with anti-thymocyte globulin (ATG). During ATG therapy, the atrioventricular block was resolved. The patient reported heartburn, constipation, nausea, and vomiting postoperatively. Metoclopramide (a daily dose of 20 mg given parenterally) was started to treat gastrointestinal disturbances. Due to postoperative bradycardia, she was treated with theophylline; prior to this she had taken no inotropic medications. Theophylline serum concentration was monitored once a day. The first seizure occurred on postoperative day 7, during the 4th day of the ATG course. The seizure was characterized as a grand mal type episode and was effectively treated with benzodiazepines. Serum tacrolimus concentration was 9 ng/L and theophylline level was 36 mcg/ml. There were no neurological deficits noticed thereafter. Thyroid hormones were within the normal range. Magnetic resonance imaging (MRI) performed on the following day indicated no stroke or central nervous system infection (Figure 1). The second patient was initially diagnosed with ischemic cardiomyopathy and was awaiting urgent surgery. The patient reported 2 prior episodes of myocardial infarction treated by percutaneous interventions. He was operated on using the Lower-Shumway technique with an ischemic time of 121 min and a cross-clamping time of 98 min. Good left ventricular function was found postoperatively on echocardiography. The patient reported postoperative nausea and vomiting. Consequently, metoclopramide (a daily dose of 20 mg given parenterally) was started to treat gastrointestinal disturbances.

Figure 1. Brain magnetic resonanse imaging performed after seizure attack.

Due to postoperative bradycardia, he was treated with theophylline; he had previously been inotrope free. Theophylline serum concentration was monitored once daily. He experienced a self-limiting grand mal type seizure 15 days after transplantation. The serum tacrolimus concentration was 10.2 ng/L and theophylline level was 34 mcg/ml. There were no neurological deficits noticed thereafter and an MRI showed no other complications. Based on these 2 cases, we suggest that theophylline combined with metoclopramide may cause new-onset seizures, especially in young patients after heart transplantation.

Discussion Neurological complications occur in as many as 30–80% of patients after heart transplantation. The peak of neurological incidence occurs within first 3 months after transplantation and includes seizure, stroke, intracranial hemorrhage, and central nervous system (CNS) infections [6]. In the majority of cases there is only a single attack requiring no further treatment. However, neurological complications may be related to multiple pre-, intra-, and postoperative risk factors. Neurological complications can be related to pretransplant risk factors such as low cardiac output with hypotension, watershed infarction, or cerebral emboli from a dilated left ventricle [7]. It is most likely related to diffuse neuronal loss within the cerebral cortex or thalamus location. Neurological disturbances may also be related to clinical manifestations of drugs adverse effects. Beta blockers may cause confusion and depression and calcium channel blockers are associated with vertigo, headache, tremor and confusion. Tremor and neuropathy have been reported during amiodarone treatment. Digoxin was reported to cause visual disturbances, seizures and syncope. These different drugs adverse effects may be intensified by renal/hepatic dysfunctions.

418



CASE REPORT

Postoperative causes include drug neurotoxicity, vascular events, infections, de novo encephalopathy, and any neoplasmic process in the CNS. Neurotoxicity caused by immunosuppressive drugs is less common than that related to either hypertension or nephrotoxicity [8,9]. There are 3 spectrums of clinical presentation of neurological complications: focal deficit, encephalopathy, and epileptic seizures. Focal deficits are usually related to embolic events, thus diagnostics by computer tomography (CT) scan should be performed within 48 h of any related symptoms. Encephalopathy may vary from mild confusion to coma and, when diagnosed within the first 48 h after surgery, is probably associated with the intraoperative hypoxic/ischemic insult. Prompt investigation should be considered in patients who experience new-onset seizures. Brain CT scan or MRI can exclude newly-evolved lesional pathologies. Cerebrospinal fluid (CSF) examination may be necessary to exclude primary CNS infection. Electroencephalography (EEG) may be necessary in some encephalopathic patients to exclude non-convulsive status epilepticus. On EEG most patients with new-onset seizures following heart transplantation have a focal-onset seizure mechanism [10]. Exclusion and correction of common seizure-provoking electrolyte imbalances such as hyponatremia, hypomagnesemia, hypocalcemia, and hypoglycemia should be considered in all patients with new-onset seizures [11,12]. Heart transplant patients may be especially vulnerable to specific dyselectrolytemias. CNS infections occur in 5–10% of patients, especially caused by Aspergillus fumigatus, Listeria monocytogenes, and Cryptococcus [13]. Early detection and initiation of treatment is crucial to increase the likelihood of successful treatment and survival. Most post-transplant brain abscesses are fungal, of which Aspergillus is most common [14,15]. Microbiology tests consist of blood cultures for encephalitis (HSV, HHV-6, and Pp65) and CNS fluid assays for the responsible meningitis. It is well known that calcineurin inhibitors are associated with neurotoxicity as well as with complications in liver, kidney, bone marrow, and in rare situations in heart transplant patients. These patients may be affected by a wide range of clinical symptoms, including seizures, altered mental status with confusion, hallucinations, tremor, headache, encephalopathy, cortical blindness, and coma, as well as any combination thereof [16]. These complications occur in up to 40% of patients, with a peak in the early postoperative time [17]. The clinically and radiologically defined syndrome called posterior reversible encephalopathy (PRES) is secondary to calcineurin inhibitors intake. PRES was found to be associated with the neurotoxicity of cyclosporine immunosuppressive treatment. It can be demonstrated by bilateral lesions in half of all patients with seizures. A brain MRI typically shows involvement

of the occipito-parietal regions, but lesions could diffuse as far as the frontal lobes. They are located both in the white matter and the cortex. Symptoms reverse promptly after changing the immunosuppressive treatment. Some data report that PRES related to supratherapeutic levels of cyclosporine may be easily reversed by reducing the drug dose [18]. Theophylline is a member of the xanthine family and bears structural and pharmacological similarity to caffeine. Theophylline is a competitive nonselective phosphodiesterase inhibitor, which raises intracellular cAMP and thus activates protein kinase A (PKA). Theophylline has a stimulatory effect and is metabolized extensively via cytochrome P450 in the liver (up to 70%). It can cause nausea, diarrhea, increase in heart rate, arrhythmias, and central nervous system excitation (headaches, insomnia, irritability, dizziness, and lightheadedness). Theophylline does not trigger seizures as such but potentiates brain hyperexcitability [19]. The dominant role of adenosine and its receptor (A1R) in seizure prevention has been documented [20]. Seizures can also occur in severe cases of toxicity and are considered to be a neurological emergency. Theophylline can reach toxic levels when taken with fatty meals. Metoclopramide is an antiemetic and gastroprokinetic agent primarily used to treat nausea and vomiting, and to facilitate gastric emptying. Metoclopramide is an antagonist of dopamine D-2 receptors in the chemoreceptor trigger zone (CTZ) of the CNS, where it prevents nausea and vomiting. It also has 5-HT3 antagonist activity, which at higher doses may contribute to the antiemetic effect. Common adverse drug reactions (ADRs) associated with metoclopramide therapy include restlessness, drowsiness, and dizziness. Metoclopramide is known to produce dystonic reactions and induce Parkinsonism [21]. Up to 1% of patients receiving metoclopramide have seizures as an adverse effect [22]. lnfrequent ADRs include headache and/or depression. The risk of extrapyramidal effects is increased in young adults and children, particularly those with high-dose or prolonged therapy. Metoclopramide blocks central dopaminergic receptors and can induce biochemical and behavioral changes as neuroleptics [23]. This drug is metabolized at least in part by the cytochrome P450 system [24]. Tardive dyskinesia has been linked to gene polymorphism of CYO2D6, CYP3A, and CYP1A2 [25]. Tardive dyskinesias, frequently associated with metoclopramide use, are estimated to occur in 1–15% of patients and may be persistent and irreversible in some [26]. Metabolic involvement of the cytochrome P450 system and its inhibition by metoclopramide may influence cytochrome effectiveness on theophylline metabolism. Metoclopramide is postulated to be a dopamine 2 (D2R) receptor antagonist. Based on mouse experiments, D2R activation

419



CASE REPORT

exerts a neuroprotective effect against excitotoxicity [27]. The opposite action of D2R and D1R has been described and proconvulsant effect compounding with seizure threshold lowering by D1R activation was found [28]. The prominent role of dopaminergic receptors in epileptogenesis has been established in a previous study [29]. Dopamine neurotransmission in epileptic patients has been confirmed in human studies [30]. Metoclopramide can lower seizure threshold and acts in a proconvulsant manner (simultaneously to D1R activation) but also lowers neuroprotective effect by D2R inhibition.

(53±5 mcg/ml) [31]. This situation may be explained by adverse effects caused by metoclopramide co-administration.

The inhibition of dopamine D2R receptors by metoclopramide and possible impairment of theophylline by the cytochrome P450 system can explain the seizures attacks in the present study. Theophylline serum concentrations (33 and 34 mcg/ml) were lower compared to previously reported mean values

Conclusions

Treatment for seizures includes benzodiazepines. Most singleseizure attacks do not require any further treatment. Drugs, like Phenytoin and Phenobarbital, which are metabolized by the cytochrome P450 system, may accelerate CNI metabolism. Among patients after heart transplantation, valproic acid and gabapentin seem to be the drugs of choice.

Theophylline overdose combined with metoclopramide may provoke new-onset seizures, especially in young patients following heart transplantation.

References: 1. PlessM, Zivkovic SA: Neurologic complications of transplantation. Neurologist, 2002; (8): 107–20 2. Cemillan CA, Alonso-Pulpon L, Burgos-Lazaro R et al: Neurological complications in a series of 205 orthotopic heart transplant patients. Rev Neurol, 2004; 38: 906–12 3. Zierer A, Melby SJ, Voeller RK et al: Significance of neurologic complications in the modern era of of cardiac transplantation. Ann Thorac Surg, 2007; 83: 1684–90 4. Perez-Miralles F, Sanchez-Manso JC, Almenar-Bonet L et al: Incidence and risk factors for neurologic complications after heart transplantation. Transplant Proc, 2005; 37: 4067–70 5. Cemillan CA, Alonson-Pulpon L, Burgos-Lazaro R et al: Neurological complications in a series of 205 orthotopic heart transplant patients. Rev Neurol, 2004; 38: 906–12 6. Senzolo M, Ferronato C, Burra P: Neurologic complications after solid organ transplantation-review. Tansplan Inter, 2009; 22: 269–78 7. Jarquin-Valdivia AA, Wijddicks EFM, McGregor C: Neurologic complications following heart transplantation in the modern era: decrease incidence, but postoprative stroke remains prevalent. Transplant Proc, 1999; 31: 2161–62 8. Jemenez-Perez M, Lozano Rey JM, Marin Garcia D et al: Efficancy and safety of monotherapy with mycophenolate mofetil in liver transplantation. Transplant Proc, 2006; 38: 2480–81 9. Eidelman BH, Abu-Elmagd K, Wilson J et al: Neurological complications of FK 506. Transplan Proc, 1991; 93: 3175–78 10. Shepard PW, St. Louis KE: Seizure Treatment in Transplant Patients. Curr Treat Options Neurol, 2012; 14(4): 332–47 11. Sarnaik AP, Meert K, Hackbarth R et al: Management of hyponatremic seizures in children with hypertonic saline: a safe and effective strategy. Crit Care Med, 1991; 19: 758–62 12. Thompson CB, June CH, Sullivan KM et al: Association between cyclosporin neurotoxicity and hypo-magnesaemia. Lancet, 1984; 2: 1116–20 13. Conti DJ, Rubin RH: Infection of the central nervous system in organ transplant patients. Neurol Clin, 1988; 6(2): 241–60 14. Bonham CA, Dominguez EA, Fukui MB et al: Central nervous system lesions in liver transplant recipients: prospective assessment of indications for biopsy and implications for management. Transplantation, 1998; 66(12): 1596–604

15. Selby R, Ramirez CB, Singh R et al: Brain abscess in solid organ transplant recipients receiving cyclo-sporine-based immunosuppression. Arch Surg, 1997; 132: 304–10 16. Miller LW: Cyclosporine-associated neurotoxicity: the need for a better guide for immunosuppressive therapy. Circulation, 1996; 94: 1209–11 17. Gijtenbeek JM, Van den Bent MJ, Vecht CJ: Cyclosporine neurotoxicity: a review. J Neurol, 1999; 246: 339–46 18. Singh N, Bonham A, Fukui M: Immunosuppressive-associated leukoencephalopathy in organ transplant recipients. Transplantation, 2000; 69: 467–72 19. Lado FA, Moshe SL: How do seizures stop? Epilepsia, 2008; 49: 1651–64 20. Boison D: 10 Methylxanthines, seizures and excitotoxicity. Handb Exp Pharmacol, 2011; 200: 251–66 21. Leopold NA: Prolonged metoclopramide – induced dyskinetic reaction. Neurology, 1984; 34: 238–39 22. Al Zaben AA, Al Herbish AS: Neurological side effects associated with unnecessary use of metoclopramide in children. Ann Saudi Med, 1995; 15(2): 183–84 23. Grimes JD, Hassan MN, Preston DN: Adverse neurologic effects of metoclopramide. Can Med Assoc J, 1982; 126: 23–25 24. Desta Z, Wu GM, Morocho AM et al: The gastroprokinetic and antiemetic drug metoclopramide is a substrate and inhibitor of cytochrome P450 2D6. Drug Metab Dispos, 2002; 30: 336–43 25. Muller DM, Shinkai T, De Luca V, Kennedy JL: Clinical implications of pharmacogenomics for tardive dyskinesia. Pharmacogenomics J, 2004; 4: 77–87 26. Abell TL, Bernstein RK, Cutts T et al: Treatment of gastroparesis: a multidisciplinary clinical review. Neurogastroenteral Motil, 2006; 18: 263–83 27. Bozzi Y, Borrelli E: Dopamine in neurotoxicity and neuroprotection: what do D2 receptors have to do with it? Trends Neurosci, 226; 29: 167–74 28. Starr MS: The role of dopamine in epilepsy. Synapse, 1996; 22(2): 159–94 29. Gangarossa G, Di Benedetto M, O’Sulivan Gdunleavy M et al: Consulvant doses of dopamine D1 receptor agonist result in Erk-dependent increasea in Zif268 and Arc/Arg3.1 expression in mouse dentate gyrus. PLoS One, 2011; 6(5): e19415 30. Rocha L, Alonso-Vanegas M, Villeda-Hernandez J et al: Dopamine abnormalities i the neocortex of patients with temporal lobe epilepsy. Neurobiol Dis, 2012; 45: 499–507 31. Zwillich CW, Sutton FD, Neff TA et al: Theophylline-induced seizures in adults. Ann Intern Med, 1975; 82: 784–87

420
