CASE REPORT Posterior Encephalopathy Subsequent to Cyclosporin A Presenting as Irreversible Abulia Makoto Nishie, Kozo KURAHASHI,Masaya Ogawa, Yasuji YOSHIDA*and Hiroshi MlDORIKAWA** Abstract A case of cyclosporin A (Cys A)-induced posterior encephalopathy developed into persistent abulia despite rapid and marked improvement of abnormal T2- and FLAIR MRI hyperintense regions. Diffusion-weighted MRIsignal intensity was also high at the onset. This change is atypical in Cys A-induced encephalopathy and was thought to predict poor recovery from the encephalopathy. Persistent abulia was probably due to marked hypoperfusion in the whole cortex including bilateral frontal lobes and basal ganglia as detected by SPECT. Apart from the breakdown of the blood-brain barrier, direct toxicity of Cys A to the brain may play a role in the pathogenesis of chronic, irreversible encephalopathy. (Internal Medicine 42: 750-755, 2003) Key words: toxic encephalopathy, reversible posterior leukoencephalopathy, apoptosis, cortical diffusion-weighted matitis laminar necrosis, MRI, atopic der- reflecting vasogenic edema caused by disturbance of cerebral blood flow autoregulation (3). However, conversion to irreversible cytotoxic damage from RPLEhas recently been reported (5). Case Report A 57-year-old man was admitted to a hospital 2001, complaining of loss of appetite on May 7, and reduced activity for around 6 months. He was diagnosed as having acute gastritis and treated with an H2-inhibitor and intravenous fluids. On June 3, he had an episode of unconsciousness. Although he was unresponsive for the following three days, he could walk on June 6. On June 21, after he had consulted a doctor in a dermatology clinic, he developed a twilight condition for several hours before developing a generalized tonic-clonic seizure over 30 minutes. Hewas transported to a hospital, and was administered diazepam and phenytoin by infusion to arrest paroxysmal seizures. After arrest of the seizures, he became unresponsive to stimulation, mimicking akinetic mutism from June 22 to June 25, so he was transferred to our hospital. At the age of 45, he had developed Introduction atopic dermatitis, spreading to his whole body with severe itchiness, was resistant to various anti-allergic which medications and local steroid ointments. The patient was administered Cys A for Cyclosporin A (Cys A) is frequently used for patients intractable dermatitis from April 2000 with remarkable efwith autoimmunediseases. This drug mayinduce acute or fect. Cys A was taken in oral doses of between 150 mg and subacute encephalopathy classified as reversible posterior 250 mg per day based on blood serum concentrations, which leukoencephalopathy (RPLE) (1 , 2). Although rapid progress had been relatively high for the therapeutic range of Cys A to generalized seizure or cortical blindness are typical symp- (100 to 150 ng/ml). Serum concentrations of Cys A were 335 toms, the initial complaints may be subtle symptoms, such as ng/ml on April 20, 749 ng/ml on May 25, 289 ng/ml on July headache or reduced vitality (3). Transient high intensity sig- 19 and 202 ng/ml on September 14. After September 2000, nals in bilateral parieto-occipital lobes in T2-weighted or around when he had reduced activity and fine finger and posFLAIR sequence MRI with no lesions detected by diffusiontural tremor, Cys A (200 mg/day) was administered without weighted imaging (DWI) is a typical finding of RPLE (2, 4), monitoring its serum concentration. After the first seizure From the Departments of Neurology, **Radiology, Aomori Prefectural Central Hospital, Aomori and *the Department of Pathology, Research Institute for Brain and Blood Vessels, Akita Received for publication November 1 1, 2002; Accepted for publication April 9, 2003 Reprint requests should be addressed to Dr. Makoto Nishie, the Department of Neuropathology, Institute of Brain Science, Hirosaki University School of Medicine, 750 5-Zaifu-cho, Hirosaki 036-8562 Internal Medicine Vol. 42, No. 8 (August 2003) Posterior Encephalopathy Subsequent episode, at the beginning of June 2001, he had not regularly September 29 (Fig. 2B). From August 21, smaller doses of taken his Cys A medication, with consequent relapse and ex- Cys A (150 mg/day) were necessarily administered to the paacerbation of his atopic eruptions. tient because of severe exacerbation of atopic eruptions that On admission, his face was apathetic. He was unrespon- was unresponsive to other medications; this markedly imsive to verbal orders or painful stimuli, consistent with the proved his dermatitis without exacerbation of his neurologicondition of akinetic mutism. Although he opened his eyes, cal condition or reappearance of MRIabnormalities. There he had cortical blindness. His posture mimicked paraplegia had not been remarkable changes in the EEG findings flexion and muscles of four extremities showedparatonia. through the course. The patient had been abulic and bedThere were no meningial signs, increase of deep reflexes or ridden with only stereotyped verbal responses and echolalia, pathological reflexes. He had numerous reddish and con flu- until his transfer to a rehabilitation hospital on December 13, ent eruptions with an inflammatory exudate over his entire 2001. His neurological condition had not improved by July body. Atopic eruptions were also seen on the lower dorsal extremities. His blood pressure was 120/80; heart rate 110 beats per min with a sinus rhythm; body temperature 37.4°C. Laboratory studies on June 26 revealed that his WBCcount was 17,200/mm3 with 13.2% eosinophils on a differential count; serum CRP was 6.1 mg/dl (normal: <0.2 mg/dl) and IgE 3,642 mg/dl (normal: <170 mg/dl). Specific IgE was highly positive for Candida and Japanese cedar pollen. Soluble interleukin-2 receptor level was also high at 4,460 31, 2002. Discussion Cys A is one of the essential immunosuppressive drugs in the treatment of various intractable autoimmune diseases, including refractory atopic dermatitis. This drug has a potent neurotoxicity and maycause various neurological side effects in up to 40%of patients (3). RPLESis the most serious complicationand accounts for severe symptomssuch as sei- U/ml (normal: 145-519 U/ml). Other serum data, including total cholesterol and magnesium, were within normal range. zure, cortical blindness, or decreased level of consciousness. Markers for various collagen diseases were all negative. Cys The principle etiology of the neurotoxic mechanisminduced A concentration was less than 25 ng/ml. CSF contained 3 by Cys A is thought to be transient breakdown of the autoregulation of cerebral blood flow through endothelial damcells/mm3 and 25 mg/dl protein. IgG index was 0.38 (<0.75), age, leading to brain edema. The experimental finding that myelin basic protein and oligoclonal bands were not detected arteries lack adrenergic in CSF. Both bacterial culture and generic herpes virus DNA endothelial cells of vertebral-basilar were negative in both serum and CSF. The CSF and blood receptors that control vasodilatation is consistent with the levels of pyruvate and lactate were within normal range. posterior predominance of this syndrome (6). Because tran- EEG revealed diffuse slowing of background activities and sient brain edema underlies the condition in most patients, associated with Cys A-induced bursts of delta waves in the area of the bilateral temporo- neurological deficits parieto-occipital regions without definite epileptic dis- encephalopathy usually resolve within two weeksafter cescharges. MRI on June 26 revealed extensive abnormal sation or dose-reduction of Cys A (1). lesions with high signal intensity on the right temporal and However, reports concerning poor recovery from this synbilateral parieto-occipital lobes on DWI(Fig. 1) and T2 WI drome have been published recently (5, 7, 8). The present paand FLAIRsequence. 99mTc ECDsingle photon emission CT tient had symptoms suggestive of chronic encephalopathy for (SPECT) showed slight hypoperfusion in the entire cortex, about nine months before the onset of acute encephalopathy with seizure and abnormal MRIfindings. Chronic and proparticularly in the bilateral parieto-occipital cortices on June 26 (Fig. 2A). longed universal damage to the cortical neurons besides the Considering the results of blood and CSF examinations in parieto-posterior regions was thought to be the cause of the addition to neuroimaging, we suspected that the pathological irreversible clinical course and abulic state, which did not process of the lesions was derived from Cys A-induced correspond to the rapid resolution of vasogenic edema deencephalopathy. As a diagnostic procedure, a brain biopsy tected by T2-and FLAIR MRI. In addition to the influence of from the right temporal lobe was performed on July 10. Cys A on arterial endothelial cells, McDonald et al reported Microscopic examination revealed mild brain edema and that Cys A induced both neuronal apoptosis and death of mild reactive astrocytosis consistent with a diagnosis of oligodendroglial cells (9). Direct neurotoxicity of Cys A is RPLE(Fig. 3). In this specimen, there were no findings sug- thought to play a crucial role in persistent brain damage. In addition, angiographic and SPECTstudies during the sympgestive of laminar necrosis or neuronal death. On July 30, T2WI, FLAIR and DW MRI images showed tomatic period of PRLESrevealed segmental narrowing of disappearance of the abnormal high intensity lesions. the posterior cerebral arteries, possibly resulting in ischemia However, Tl-weighted MRI showed high-signal linear lesions along with parieto-occipital cortices, suggesting cortical laminar necrosis that was not detected on MRIon June 26 (Fig. 4). In addition, SPECT showed marked progress of hypoperfusion in the entire cortex in contrast to improvement of FLAIR and DWIMRI findings on July 30 and Internal Medicine Vol. 42, No. 8 (August 2003) of the corresponding cortices (10). Chronic vasospasm in- duced by Cys A may have been another contributor to the permanent brain damage in this patient, because the most commoncause of cytotoxic edema, indicated as a high signal on DWI, is hypoxia eventually accompanied by vasogenic edema (ll). The pathological findings in our patient were 751 B C A NlSHIE et al Figure 1. MRI on June 26, 2001 showed abnormal hypersignal lesions on bilateral FLAIR image (A, B) but also diffusion-weighted imaging (C). 752 parieto-occipital Internal lobes with not only Medicine Vol. 42, No. 8 (August 2003) Posterior Encephalopathy Subsequent Figure 2. 9*"Tc-ECD SPECT showed hypoperfusion in the bilateral parieto-occipital cortices and right basal ganglia on June 26 (A). The study on September 29 showed marked hypoperfusion in the entire cortex in addition to the lesions detected by the previous study (B). Figure 3. Microscopic examinations biopsied from the right temporal cortex (A&Bx200, CxlOO). Hematoxylin and eosin staining revealed enlarged extracellular spaces around neurons and neuronal pyknosis in addition to porosity of neuropile (A). Periodic acid-Schiff (PAS) staining revealed many PASpositive granules, which suggested that there was plasma infiltrate because of a breach of the blood-brain barrier (B). The immunohistochemical stain for glial acid protein (GFAP) detected reactive astrocytes fibrillary with in- creased processes and GFAPexpression (C). Internal Medicine Vol. 42, No. 8 (August 2003) 753 NlSHlE et al Figure 4. MRIon July 30, 2001. The lesions detected by the previous study were almost completely diminished with both diffusion-weighted imaging and FLAIRimages (A, B) except the right temporo-parietal cortex from which biopsied specimens were taken. However, Tl-weighted image without Gadolinium contrast (C) showed cortical hyperintense lesions consistent with cortical laminar necrosis. 754 Internal Medicine Vol. 42, No. 8 (August 2003) Posterior Encephalopathy Subsequent consistent with increased permeability of the blood-brain barrier, which is much the same as the previous report con- activity, may have been the initial symptoms of Cys Ainduced encephalopathy that acutely deteriorated, and they cerning three patients whohad a post-mortem examination may not always be benign, 'reversible' (12). An interesting and major manifestation in this patient, abulia, is regarded as a behavioral change reflecting damage of the prefrontal cortex or disturbance of projections to the region via the basal ganglia circuit, especially the head of the caudate (13, 14). However, abulia is not a commonmanifestation of posterior encephalopathy, and there have been no reports that refer to persisting abulia as a main symptomof symptoms. References 1) Hinchey J, Chaves C, Appignani B, et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med 334: 494-500, 1996. 2) Mukherjee P, McKinstry RC. Reversible posterior leukoencephalopathy syndrome: evaluation with diffusion-tensor MR imaging. Radiology 219: 756-765, 2001. 3) Gijtenbeek JM, van den Bent MJ, Vecht CJ. Cyclosporine neurotoxicity: a review. J Neurol 246: 339-346, 1999. Cys A-induced encephalopathy. Although Bird et al reported SC, Porter DA, Calamante F, Chong WK, Connelly A. Quantitathat three patients acutely developed akinetic mutism on the 4)tiveColeyMRdiffusion mappingand cyclosporin-induced neurotoxicity. Am third day after the introduction of intravenous Cys A, the symptom was temporary and completely resolved from 48 hours to few days after withdrawal of Cys A (15). They did not discuss in depth the mechanismof akinetic mutism induced by Cys A and associated changes of brain-imaging studies during the symptom. We consider that Cys A contributed to chronic subclinical encephalopathy before the acute exacerbation due to posterior encephalopathy because the first SPECTstudy already showed hypoperfusion in the bilateral frontal lobes and right basal ganglia including the caudate, which were regarded as lesions related to abulia in this patient. Hypoperfusion detected by SPECTwas widespread in the cortex, extending well beyond abnormal areas detected by MRIone month after the onset of acute encephalopathy. Although it is unknownwhyperfusion of the entire cortex detected by SPECTdecreased irrespective of improvement of high signal abnormalities in the posterior white matter, it is probable that overlap of chronic toxicity of Cys A and acute breakdownof posterior circulation brought about the J Neuroradiol 5) Covarrubias 20: 1507-1510, 1999. DJ, Luetmer PH, Campeau NG. Posterior encephalopathy syndrome: prognostic utility weighted MR images. 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Intern Med 38: 54-58, 1999. 1 1) Neurol Klatzo 26:I. Neuropathological aspects of brain edema. J Neuropathol Exp 1-14, 1967. doses of Cys A to prevent exacerbation of atopic dermatitis 12) Reece DE, Frei-Lahr DA, Shepherd JD, et al. Neurologic complications in allogeneic bone marrowtransplant patients receiving cyclosporin. Bone Marrow Transplant 8: 393-401, 1991. 13) CummingsJL. Frontal-subcortical circuits and human behavior. Arch tion. High signal regions on parieto-occipital (occasionally temporal) regions by T2-weighted and FLAIRimages with 14) Bhatia KP, Marsden CD. The behavioural and motor consequences of focal lesions of the basal ganglia in man. Brain 117: 859-876, 1994. 15) Bird GL, Meadows J, Goka J, Poison R, Williams R. Cyclosporin- most severe form of encephalopathy leading to irreversible abulia. In addition, necessary re-administration of small might have participated no abnormalities in the persisting on DWI is a typical pathologic condi- MRI finding of RPLES induced by Cys A, indicating vasogenic edema without cytological lesions damage (2, 4, 16). As seen in this patient, abnormal that were detectable with DWI at the onset are Neurol associated 50: 873-880, akinetic 1993. mutism and extrapyramidal syndrome after liver transplantation. J Neurol Neurosurg Psychiatry 53: 1068-1071, 1990. 16) Furukawa M, Terae S, Chu BC, Kaneko K, Kamada H, Miyasaka K. MRI in seven cases of tacrolimus FLAIR and diffusion-weighted (FK-506) encephalopathy: imaging. Neuroradiology utility of 43: 615-621 , thought to be a useful predictor of irreversibility (2) and poor 2001. prognosis of posterior encephalopathy. Tl-weighted MRI 17) Bargallo N, Burrel M, Berenguer J, Co fan F, Bunesch L, Mercader JM. findings which were similar to those associated with laminar Cortical laminar necrosis caused by immunosuppressive therapy and necrosis may also be a hallmark of irreversible encephalchemotherapy. Am J Neuroradiol 21: 479-484, 2000. opathy induced by Cys A (17). Finally, it is clinically tant that subtle symptoms, such as decrease of appetite Internal Medicine Vol. 42, No. 8 (August 2003) impor- and 755