Clinical Neuropharmacologv 5 Vol. 22, N 2. pp.67 73 ©: 1999 Lippincott Williams & Wilkins, Inc., Philadelphia Cyclosporine A Neurotoxicity Among Bone Marrow Transplant Recipients Aashit K. Shah Wayne State University School of Medicine, Detroit Medical Center, Detroit, Michigan, USA Summary: Cyclosporine A (CsA) neurotoxicity is an iatrogenic disease with signifi- cant morbidity and occasional mortality. We retrospectively reviewed the cases of CsA neurotoxicity among bone marrow transplant recipients at our institution, and summa- tized the current literature on the subject. The neurologic presentation is varied and the neurologic manifestations are reversible, even after prolonged toxicity, in most in- stances. Serum CsA level is useful in evaluation, as the level is high in most instances. However, in a case of suspected neurotoxicity, withdrawal of the drug is the only way of determining presence or absence of such toxicity. The electrophysiologic studies, espe- cially electroencephalogram (EEG), is very sensitive in identifying the problem, but lacks specificity. On the other hand, the neuroimaging studies are helpful in making a diagnosis if they show characteristic findings of hyperintense lesions affecting posterior cerebral regions on T2 weighted magnetic resonance images (MRI) or white matter hypodensities on computed tomographic (CT) scan. These lesions are probably due to breakdown of blood-brain barrier resulting in leakage of fluid in interstitial space. The breakdown could be serious enough to cause microhemorrhages that may coalesce to produce macrohemorrhages. Key Words: Cyclosporine A toxicity —EEG findings— Triphasic waves—Periodic lateralizing epileptiform discharges—MRI findings— Intracerebral hemorrhage Cyclosporine A is one of the most widely used drugs for immunosuppression in patients with solid organ or bone marrow transplants. Neurologic complications are an important cause of morbidity and mortality in these patients. Various types of neurologic dysfunction are encountered in Cyclosporine A (CsA) neurotoxic- ity; including encephalopathy, coma, seizure, blind- ness, and hemiparesis. The neurotoxicity is usually transient, but difficult to diagnose because of unfamil- iarity and the lack of specific diagnostic testing. We report five new cases of CsA neurotoxicity and review the literature. METHODS The charts of bone marrow transplant (BMT) recipi- ents with neurologic symptoms or diagnosis recorded among discharge diagnoses were reviewed retrospec- tively. A total of 327 patients underwent bone marrow transplantation at Harper Hospital in Detroit over Address correspondence and reprint requests to Aashit K. Shah, 6B, UHC, Dept. of Neurology, 4201 St. Antoine, Detroit, MI-48201, USA. 67 28 months. A total of 26 patients’ chart were selected for further review. Patients with neurologic deficits as a part of a process other than BMT itself were excluded. CsA toxicity was considered to exist when: 1) neurologic deterioration occurred with an increase in the dose of CsA or rise in serum CsA level, and 2) neurologic improvement occurred following a dose reduction or cessation of CsA, concomitant meta- bolic variables being stable, and when known side effects of other medications could not explain the neurological deficits. A total of 5 patients fulfilled the criteria. A detailed chart review was done on each patient. The clinical, neuroimaging, laboratory and electrophysiologic data were gathered and analyzed. RESULTS Table 1 summarizes the clinical, electrophysiologic, neuroimaging, and laboratory data of 5 patients with ‘Jenuayod payoaa jensia ‘g]A ‘asesajsueNouluE sulUele * | TY ‘aseiajsuroutwe ajeuedse ‘| Sy ‘saszeyasip wWoyndayida pazipesaye] 1potied “SQA Td :tuo[> duo) paziyesqudd *D | H serwaynay snousdojadus Stuosys “T)D setay4NI] SnsejqoydwA] StuoIyD “TTD ‘ewoyduwA] wyBpoH-uOU "FPN #D UlNgojZounumu *H 49] ‘uN0d poojg pas" gy yUNOD 1129 poojg ary “DEA ‘piny jeutdsosgasas +459 ‘Surdeun adueuosai snousew ;YW :AydesZouro) pandwod * 1D vw auodsod49 “ys_D :wesBojeydoouaonda|a *NqAq ‘uonewue;dsuey moueul 2u0q "LW Tea ‘eam STG snd :¢7 :ulaiord Jane spy JepnsuuaAtiad 3) UI suoIsay asudTULadAY Ajasnyytp (o3ues B1QY} UL) SOARM sisazediuay Y2| padojarag “enuaue “ASD tyeuuou dqA Jo sease ajdujnur pamoys PY JurBu 61S MOIS JO SS39x9 YTS Jeu0oN onseyde roy | We paatacay +e W $ viuowue pue “LTV “LSV wmes feuuou tnim Tp/sur $-7Z wlqnuTyig seose esoduia) pue jeioued TROL ‘DLO ‘V7 Jo anew ayy pur ) bp) PU “Rage pesodway “VJ ur [PuOIsed90 pue ay) ‘sainzias 315 oma pey eiuajosaysajoyoodAy Ausuapodéy Sursueyua-uou J) qw,3u pps saaeM BIayR Jo sszoxq yeuuouqy quaned “TWD 10} LW pasiesay we Ww + ayqeysewiaun (jeuaioeq pue jesuny ‘jeqa) snondayida = aunynd ?Z1 (ay 29 SOINZIIS snyeys Xq pomojjog Sounzias x LDA NLS culajoid SOINZIOS OMI Jeotutps0299[9 DLO pue uoisnyuo “TWD JO a cP :asoon]s 45D JeuLOU YIOg JD PUE YW uaaniag Ju, Fu 60S aydnyjnu pur sqaqd yeunougy quauNeay ay) Joy [Wg paaiasay of d € x xapul sammjonys ~ pue sisayjuds [eigaza9 Joaisod Jo Jaye Ajaaodal 31Zojoinau apew 93] jeuuou anys pue Aesd Butajoaur pue Ayjeonewresp paaoidut “spur jeu0]I031[0 sadeun Z] Uo suorsa] quaned :azed WosWos jeuTULAL ON ‘9/qeyewozUN asuajuuadcy :;Yy “vounjosas JoJ ‘UMBIPYIIM soisadjeue (qeuaieq lenpead yin ‘ewapa qdaoxa sSrup jy "ew0a pure yeduny *jeata) Sulpunouns pur sadeyuoursy daap owut pasde| ‘uonrjuau auMIND QS -DAY 20 (jersued “J ‘e229 7e]1q Jo uonesolayap jenperd 400 ng/mL) at the time of neurologic complications. Serum cholesterol level was low in one patient. Electrographically, frontally dominant triphasic waves without phase-lag were noted at the peak of clinical neurologic toxicity in 2 patients. The EEG abnormalities resolved slowly on withdrawal of the drug, along with clinical improvement (Fig. 1). An- other patient revealed periodic lateralizing epilepti- form discharges (PLEDs) and multiple focal electro- clinical seizures with secondary generalization (Fig. 2). A third patient had focal excess of delta Clin, Neuropharmacol., Vol. 22, No. 2, 1999 70 A. K. SHAH activity over the left hemisphere, superimposed on more generalized slowing of the background activity. The remaining patient showed an excess of slow activ- ity (4~7 Hz) with relatively preserved background rhythms. MRI abnormalities were present in 3 of the 5 patients (60%) and included multifocal hyperintense cerebral lesions on T2-weighted magnetic resonance (MR) im- ages (Fig. 3). Magnetic resonance imaging (MRI) was normal in 2 patients. A brain computed tomographic (CT) scan was obtained in 4 patients and was abnormal in 2 (50%). It showed multiple intracerebral hemor- rhages (Fig. 4) in one patient, and hypodense areas in the other. No clear enhancement was seen when intra- venous contrast material was utilized. The electrophysiologic abnormalities preceded the neuroimaging abnormalities in one patient (patient #2) and in 2 other patients (patients #1 & 3) neuroimaging studies were normal with electrophysiologic studies being the only ancillary corroboration of neurotoxicity. CASE REPORTS Case 1 A 38-year-old male with stage IV non-Hodgkin lym- phoma (NHL) on combination chemotherapy, relapsed 4 months prior to the admission. He was treated with allogenic bone marrow transplantation and 2 months later developed graft vs. host disease (GVHD). He re- ceived combination of CsA and methyl prednisone for its treatment. He was admitted to the hospital for intra- venous (IV) acyclovir treatment to receive a resistant gluteal herpes simplex virus II infection. CsA was held, as serum creatinine was rising. His condition deterio- rated because of profuse diarrhea related to worsening of colonic GVHD, and CsA treatment was reinstituted via intravenous route. Seven days later he developed altered sensorium. His neurological exam revealed as- terixis and moderate global cognitive deficits. Brain CT and MRI scans as well as cerebrospinal fluid (CSF) analysis were unremarkable. Serum creatinine levels remained stable and no other significant metabolic ab- normalities such as hepatic enzyme or electrolyte alter- ations were seen. CsA was held for 2 days and restarted at a lower dose, but discontinued again 3 days later. He steadily improved thereafter, returning to baseline over a week. Serum CsA level at the onset of neurologic symptoms was 844 ng/mL and dropped to 126 ng/mL a week after the discontinuation of CsA, corroborating with clinical recovery. Serial EEGs were obtained on day 4, day 13, and day 27 after the onset of neurologic symptoms (Fig. 1). Clin, Neuropharmacol., Vol. 22. No. 2. 1999 FIG. 3. A T2-weighted brain scan of a patient with Cyclosporine A neurotoxicity showing hyperintense lesions involving gray and white matter of both hemispheres, most prominent posteriorly. Case 2 A 21-year-old female received BMT for recurrence of chronic lymphocytic leukemia, a year after initial chemotherapy. She was discharged home with good bone marrow engraftment. Twenty-eight days post- BMT she was readmitted with nausea, vomiting, fever and chills due to staphylococcus epidermidis septice- mia from an infected indwelling catheter. She also suf- fered from GVHD of colon, which was treated with in- creasing doses of CsA and steroids. She suffered a single generalized tonic clonic seizure on day 41 post- BMT. The neurological exam following the seizure showed postictal state without focal deficits. A brain CT and CSF studies obtained on the same day were unremarkable. She became lethargic the next day and later lapsed into coma. T2 weighted magnetic reso- nance images of the brain on day 43 post-BMT, re- vealed hyperintense lesions in the gray and white mat- ter of the cerebral cortex, most strikingly in the oc- cipito-parietal regions without any hemorrhagic features (Fig. 3). A CT scan of brain obtained 2 days later, revealed 3 areas of intracerebral hemorrhages CYCLOSPORINE A NEUROTOXICITY 71 FIG. 4. ACT scan without enhancement showing two areas of intracerebral hemorrhages in the same patient as in Figure 3. (Fig. 4). Aggressive treatment for the presumed in- creased intracranial pressure with hyperventilation and 1V mannitol had no impact on the clinical situation. No other significant abnormalities of metabolic parameters were apparent. After many days of unsuccessful thera- peutic interventions including CsA throughout, a deci- sion to provide only comfort care measures in a hospice setting was made in consultation with her family. All treatment, except for a morphine drip, was withdrawn. Two days later she started to show improvement with spontaneous movements of her limbs and some re- sponse to family members’ voices. She was transferred back to the intensive care unit and over the next several weeks continued to recover. She was discharged home with only a footdrop due to peroneal nerve injury. Case 3 A 39-year-old female was diagnosed with chronic lymphocytic leukemia and received chemotherapy. She underwent allogenic bone marrow transplantation a year later and treatment with CsA was initiated. She developed jaundice 2 weeks later due to hemolysis and hepatic veno occlusive disease. Three wecks post- BMT, she became confused and the following day she had a single generalized tonic clonic seizure. Her EEG on the same day showed a mild diffuse excess of theta waves. No significant changes in her metabolic vari- ables, including renal and liver function tests, were seen. Neuroimaging studies on the same day, and sub- sequently on 3 separate occasions, were unremarkable. CSF examination after the initial seizure showed mini- mally elevated protein at 57 mg/dL, 17 RBC/mm*? and 6 WBC/mm*. She continued to suffer from seizures de- spite treatment and became increasingly lethargic. Fol- low up EEG showed PLEDs and multiple electrical sei- zures with focal onset (Fig. 4). A full course of IV acy- clovir was of no benefit. Because of continued seizures, pentobarbital was administered until burst suppression pattern became evident on the EEG. The CSF abnor- malities resolved completely on repeat testing a few days later, and remained normal at a later date in the illness. On withdrawal of pentobarbital, she was sei- zure free, but remained in semicoma and expired a few weeks later due to hepatic failure. The autopsy revealed hepatomegaly and bile stasis. Immunocytochemical staining of the brain did not show evidence of herpes infection. DISCUSSION Clinical Aspects The exact frequency of CsA Neurotoxicity is un- clear. Most studies are reported as case series and in fact majority are retrospective review like this. The in- cidence of neurotoxicity ranges from 0.5% to 35%, and of tremor up to 50%. A review of reported cases indi- cated selected neurologic manifestations in decreasing frequency as follows: seizures, confusion, disorienta- tion, psychiatric manifestations, headache, speech dis- order, decreased responsiveness, paralysis, coma, cor- tical blindness, akinesia, parkinsonism and pesudobul- bar palsy (1). A review of the data collected in 3,000 kidney trans- plant and 800 bone marrow transplant patients receiv- ing CsA, revealed the incidences of convulsions are 1.5% and 5.5%, respectively (2). The seizures occurred as a part of encephalopathy resulting from CsA neuro- toxicity. The toxicity occurs | day to 3 years after initiating the drug (1), but majority present after initiation or change in dose or route of administration from oral to IV. This is usually associated with sudden rise in serum CSA level. CsA induced encephalopathy is usually reversible upon discontinuing the drug or decreasing its dose. This was true in all our cases, excluding the patient who died. If the drug is discontinued, neurotoxicity may be reversible even after prolonged period of time, and without permanent neurologic damage. One of our pa- tients (patient #2) is a striking example of this. She Clin, Neuropharmacol., Vol. 22, No. 2. 1999 72 A. K. SHAH was transferred to the hospice setting given the pre- sumed irreversibility of her situation, and serendipi- tously improved as medications were withdrawn, lead- ing to almost full recovery. Electrophysiologic Aspects Electrophysiologic studies have revealed that EEG is a sensitive test to identify cerebral dysfunction, but lacks specificity. In our series, EEGs were abnormal in all patients. Varicty of EEG findings have been re- ported, and the abnormalities parallel the clinical neu- rologic functioning. The reported EEG findings in- clude diffuse slowing, focal slowing, focal epileptiform discharges, electrical and electroclinical seizures and status epilepticus (3,4). We are reporting two patients with triphasic waves, and one with PLEDs on their EEG during CsA neurotoxicity. As pointed out in our patients, EEG may be the only corroborative evidence of neurotoxicity and EEG abnormalities may precede imaging abnormalities. Thus, EEG may be a valuable adjunct for the diagnosis and follow-up in these cases. The evoked potentials in CsA neurotoxicity have not been studied consistently. The reported cases suggest abnormally prolonged P100 latency on visual evoked potentials (VEP), if the patient suffers from cortical blindness (4). In the same patients, somatosensory evoked responses and auditory evoked responses did not reveal any significant or consistent abnormalities. Abnormal VEP has not been reported consistently, and one of our patient (patient #5) without visual distur- bances had norma! VEP. Neuroimaging Aspects The characteristic neuroimaging findings in CsA neurotoxicity are hyperintense lesions on the T2- weighted MR images, involving cerebral white matter. The predominant involvement may be posterior and may also involve gray matter (5,6). However, the im- aging abnormalities usually extend anteriorly, and may only be present anteriorly. Jansen and associates re- ported increased signal intensity involving superficial cortical layers in proton density-weighted images in pa- tients with CsA toxicity (7). The abnormalities were limited to gray matter in some cases and enhanced after gadolinium administration. One of their reported cases exhibited hyperintensity involving superficial cortical layer on T1-weighted and proton density-weighted MR images, suggesting presence of methemoglobin due to petechial hemorrhages. It is conceivable that these cor- tical microhemorrhages coalesce and result in frank in- traparenchymal hemorrhage. However, intracerebral hemorrhage is not a well recognized complication of Clin. Neuropharmacol., Vol. 22. No. 2, 1999 CsA neurotoxicity. One of our patients (patient #2) clearly suffered peripherally located cortical hemor- rhages, supporting this view. A CT scan may show hypodensities involving the cerebral white matter. Sensitivity of MR imaging is su- perior to that of CT scan in detecting abnormalities in these patients. The neuroimaging studies are less sen- sitive when compared to Electrophysiologic tests. However, imaging studies are more specific when characteristic findings are present, and also help to ex- clude other pathological processes, such as cerebral in- farction and cerebral abscess. Laboratory Tests Cyclosporine A neurotoxicity is not totally dose de- pendent, as patients with comparable serum CsA levels do not exhibit neurotoxicity consistently. It has been reported with different CsA serum levels or even with ‘therapeutic’ serum level of the drug. One of our pa- tients (patient #2) had a serum CsA level in the ‘thera- peutic range’ (maximum level of 339 ng/mL) despite being in deep coma. Alternatively, CsA neurotoxicity may be due to its toxic metabolite, the level of which may be higher in spite of a ‘therapeutic level’ of the parent drug (8). Cerebrospinal fluid exam is usually unremarkable, or shows mildly elevated protein. However, significant number may show CSF pleocytosis (1). Cyclosporine A causes renal tubular wasting of mag- nesium (9). Profound hypomagnesemia and renal mag- nesium wasting are associated with the use of CsA for bone marrow transplantation. Hypocholesterolemia is another abnormality associated with CsA therapy. Al- though, increased fasting level of triglycerides also re- ported in studies of patients with psoriasis treated with CsA (10). Cyclosporine A renal toxicity is much more common than neurotoxicity. In most instances, the signs of neph- rotoxicity precede those of neurotoxicity. The early findings may be limited to decreased creatinine clear- ance, and later a rise in blood urea nitrogen and creati- nine level. Pathogenesis The exact cause of Cyclosporine A neurotoxicity re- mains unknown. The brain has low concentration of the drug due to its poor ability to cross the blood-brain bar- rier. However, impairment of the blood-brain barrier has been demonstrated in patients receiving the drug (11). Sixty to seventy percent of Cyclosporine A is bound to red blood cell and the remaining is bound to plasma lipopro- teins. It is this binding that may be altered in patients with CYCLOSPORINE A NEUROTOXICITY 73 hypocholesterolemia, predisposing them to CsA toxicity (10). Lower serum cholesterol level is associated with CsA neurotoxicity in liver transplant patients (12). Low serum magnesium level due to renal wasting has been postulated as a potential complicating factor, at least for precipitating seizures. Cyclosporine A is also shown to be calcineurin in- hibitor. Calcineurin is an important regulator of Ca+2 signaling in the central nervous system, and effects of CsA may interfere with this process (13). Inhibitory ef- fects of CsA on nitrous oxide synthatase is another pro- posed mechanism of its neurotoxicity (14). Nitrous ox- ide is a potent vasodilator and lack of it may induce increased vascular tone. Another endogenous peptide implicated in possible etiologic role is endothelin, a po- tent vasoconstrictor. Increased level of circulating ent- dothelin or release of it from damaged endothelium caused by CsA may also result in increased vascular tone (15,16). The increase in vascular tone affecting arte- rioles may result in focal ischemia. Alternatively, sys- temic hypertension may cause loss of autoregulation of cerebral vessels leading to opening of tight junctions with resultant leak of water molecules and vasogenic edema. Systemic hypertension usually precedes neurotoxic- ity, prompting hypertensive encephalopathy as another potential candidate for etiology of CsA neurotoxicity. An interesting aspect of CsA neurotoxicity is that simi- lar clinical and neuroimaging findings are described in variety of other disorders, such as hypertensive enceph- alopathy, tacrolimus and interferon alpha toxicity, and eclampsia (17). It also shares features of accelerated hypertension preceding neurologic manifestation and similar prognosis of resolution of neurologic and neu- roimaging abnormalities in most instances. There may be similar underlying etiologic mechanisms of neuro- logical dysfunction for all of these conditions. It is possible that the combination of CsA and other unknown factors predispose an individual to manifest the neurotoxicity. In the absence of those confounding factors, similar dosage and serum level of CsA may not cause the neurotoxicity. In conclusion, Cyclosporine A neurotoxicity is a het- erogeneous disorder. High serum CsA level is a com- mon but not a constant finding. Patients with bone mar- row transplants have a multitude of problems, and a high index of suspicion is necessary to identify patients with CsA toxicity. If CsA neurotoxicity is suspected clinically, a trial of its withdrawal should be given to all patients, including patients with serum CsA level in the ‘therapeutic’ range. The potential for complete recov- ery should encourage the clinician to pay close atten- tion and to look for these patients. Acknowledgment: The author would like to thank R. P. Lisak for his help and guidance, without which this would not have been possible. REFERENCES 1. Hauben M. Cyclosporine neurotoxicity: Pharmacotherapy 1996:16 (4):576-83. 2. Walker RW, Brochstein JA. Neurologic complications of immuno- suppressive agents. Neurol Clin 1988:6:261-78. 3. Shah AK, Lisak RP. Neurological complications of immunomodu- lating therapy. In: de Wolff FA, ed. Handbook of Clinical Neurol- ogy, intoxicants of the Nervous system, Part Il; Vol 21(65), Amster- dam: Elsevier Science B.V. 1995: 547-66. 4. Edwards LL, Wszolek ZK, Normand MM. Neurophysiologic evalu- ation of cyclosporine toxicity associated with bone marrow trans- plantation. Acta Nerol Scand 1995;92:423-9, 5. Scheinman SJ, Reinitz G, Petro G, Schwartz RA, Szmalc FS. Cy- closporine central neurotoxicity following renal transplant. Trans- plantation 1990;49:215-6. 6. Truwit C, Denaro CP, Lake JR, DeMarco T. MR imaging of revers- ible cyclosporine neurotoxicity. AJNR 1991;12:651-9. 7. Jansen O, Krieger D, Krieger S, Sartor K. Cortical hyperintensity on proton density weighted images: An MR sign of cyclosporine- related encephalopathy. AJNR 1996;17:337-44 8. Kunzendorf U, Brockmoller J, Jochimsen F, et al. Neurotoxicity caused by a high cyclosporine metabolite level. Transplantation 1989;48:53 1-2. 9. June CH, Thompson CB, Kennedy MS, Nims J, Thomas ED. Pro- found hypomagnesemia and renal magnesium wasting associated with use of cyclosporine for marrow transplantation. Transplanta- tion 1985;39:620-4, 10. Faulds D, Goa K, Benfield P. Cyclosporine: A review of its phar- macodynamic and pharmacokinetic properties, and therapeutic use in immunoregulatory disorders. Drugs 1993;45(6):953-1040. 11. Stoane JP, Liven KY, Gore ME, et al. Disturbance of blood-brain barrier after bone marrow transplantation. Lancet 1985; ii:280. 12. De Goren PC: Cyclosporine, low density lipoprotein and choles- terol. Mayo Clin Proc 1988;63:1012-21, 13. Sugimoto T, Stewart S, Guan KL. The calcium/calmodulin- dependent protein phosphatase calcineurin is the major Elk-1 phos- phatase. J Biol Chem 1997;272(47):29415-8. 14. Rao MR, Kanji VK, Salahudeen MK, Wang C, Sekhar V. Inhibition of rat brain nitric oxide synthatase activity by cyclosporin-A. Ind J Exp Biol 1996;34(12):1265-7. 15. Meyer-Lehnert H, Bokemeyer D, Friedrichs U, Backer A, Kramer HJ. Cellular mechanisms of cyclosporine A-associated side effects: Role of endothelin. Kidney Int 1997;52(supp! 61):S27-31. 16, Haug C, Duell T, Voisard R, Lenich A, Kolb HJ, Mickley V, Hom- bach V, Grunert A. Cyclosporine A stimulates endothelin release. J Cardiovascular Pharmacol 1995;26(supp! 3)S239--41 17. Hinchey J, Chaves C, Appignani B et al. A reversible posterior leu- koencephalopathy syndrome. N Engl J Med 1996;334:494-S00. Clin. Neuropharmacol., Vol. 22, No. 2. 1999