References 1. Schwartz RB. Hyperperfusion encephalopathies: hypertensive encephalopathy and related conditions. The Neurologist 2002;8:22–34. 2. Hinchey J, Chaves C, Appignami B, et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med 1996;334:494 –500. 3. Schwartz RB, Mulkern RV, Gudbjartsson H, Jolesz F. Diffusionweighted MR imaging in hypertensive encephalopathy: clues to pathogenesis. Am J Neuroradiol 1998;19:859 – 862. 4. Ay H, Buonanno FS, Schaaefer PW, et al. Posterior leukoencephalopathy Tacrolimus leukoencephalopathy: A neuropathologic confirmation Catherine M. Lavigne, MEd; David A. Shrier, MD; Manoj Ketkar, MD; and James M. Powers, MD Tacrolimus leukoencephalopathy has well documented clinical and neuroradiologic features.1 The latter suggest endothelial dysfunction as the underlying etiology.2 Confirmatory neuropathologic data have been lacking. Case reports. A 40-year-old woman with biopsy-proven acute rejection was admitted 3 weeks after an orthotopic liver transplant for alcoholic cirrhosis. Alanine aminotransferase was elevated at 226 IU/L (⬍50 IU/L). She also had elevated cholesterol levels (237– 411 IU/L) and was hypertensive (approximately 160/ 90). Erythrocytes showed anisocytosis and poikilocytosis (spiculated, fragmented, and targets). Tacrolimus 4 mg BID had been started the day after transplantation. The patient had 2 days of toxic tacrolimus levels of 25 ng/mL and 29 ng/mL (⬎20 ng/mL), followed 4 days later by new onset seizures and mental status changes (lethargy to agitation). BP just after the seizure was 172/104. The last reading prior to her seizure was 144/88. MRI revealed two large white matter lesions in the right frontal lobe without mass effect (figure 1A). There was minimal peripheral enhancement, as well as scattered white matter lesions in the frontal and parieto-occipital lobes bilaterally (figure 1B). Her condition continued to deteriorate over the next 2 days with increasing seizure activity culminating in unresponsiveness. Brain biopsy was performed to exclude a treatable infectious process. Her platelet count at this time was 329,000/␮L (445,000/␮L upon admission); her prothrombin time and partial thromboplastin time were normal. However, that same day bleeding at the biopsy site necessitated a craniotomy for evacuation of a hematoma. The patient remained unresponsive for the next few days, and she died 2 months after her admission as a result of transplant rejection and hemorrhagic necrosis of the entire right centrum semiovale. Neuropathologic findings. The small biopsy sample consisted of abnormal white matter that had no evidence of infection even with an antibody to cytomegalovirus (DAKO Envision Plus System; DAKO, Carpenteria, CA; 1:100 with proteinase K pretreatment). There was a diffuse decrease in the staining of myelin with Luxol Fast Blue, but not with an antibody to myelin basic protein (Research Diagnostics, Flanders, NJ; Monoclonal, 1:300, no pretreatment), and without appreciable periodic acid-Schiff (PAS)- or CD68-positive macrophages (DAKO Envision Plus System; Monoclonal, 1:100) (figure 1C). A comparable decrease in Bodian stained axons was observed (figure 1D). Oligodendrocytes appeared to be numerically reduced but were not activated caspase3-positive (R & D Systems, Minneapolis, MN; Polyclonal, 1:1000). A mild increase in glial fibrillary acidic protein-positive astrocytes (GFAP) (DAKO Envision Plus System; 1:1000 with proteinase K pretreatment) and CD68-positive microglia was noted. Several small veins were surrounded by PAS-positive material that was present within the vascular lumen (figure 1E). Another vessel showed a marked perivascular decrease in myelin and axonal staining with replacement by a pale PAS-positive background stain (figure 1F). That same vessel showed strongly positive intravascular and extravascular PAS-positive droplets, focal endothelial hyperplasia, and swelling with prominent nucleoli and fibrin transudation (figure 1G). The endothelium was immunoreactive without severe hypertension: utility of diffusion-weighted MRI. Neurology 1998;51:1369 –1376. 5. Oliveira-Filho J, Silva SCS, Trabuco CC, Pedreira BB, Sousa EU, Bacellar A. Detrimental effect of blood pressure reduction in the first 24 hours of acute stroke onset. Neurology 2003;61:1047–1051. 6. Fischberg GM, Lozano E, Rajamani K, Ameriso S, Fisher MJ. Stroke precipitated by moderate blood pressure reduction. J Emerg Med 2000;19:339–346. 7. Semplicini A, Maresca A, Boscolo G, et al. Hypertension in acute ischemic stroke: a compensatory mechanism or an additional damaging factor? Arch Intern Med 2003;163:211–216. for tumor necrosis factor-alpha (Santa Cruz Biotechnology, Santa Cruz, CA; Monoclonal, 1:5) but not for interleukin-1 (Genzyme, Cambridge, MA; Polyclonal, 1:300). Discussion. Tacrolimus leukoencephalopathy has been included within the reversible posterior leukoencephalopathy syndrome (RPLS), which is also caused by cyclosporin, eclampsia, malignant hypertension, renal failure, and drug-induced thrombotic thrombocytopenic purpura (TTP).1 The most common clinical features include the sudden onset of seizures, headache, altered mental status, visual abnormalities, aphasia, and hemiparesis.1 Neuroradiologic findings are most commonly located in white matter of the posterior cerebrum, but also in the white matter of the cerebellum, frontal lobes, and brainstem.1 Radiologic imaging provides evidence of vasogenic edema and generalized cerebrovascular dysregulation.2 Neuropathologic confirmation of the neuroradiologic interpretations, however, has been lacking. Cortical and subcortical infarcts, areas of diffuse neuronal necrosis, coagulative necrosis containing numerous macrophages, neutrophilic invasion of small cortical arteries and perivascular space, thrombi with perifocal edema3, and areas of “demyelination” with minimal reactive astrocytosis have been reported.4 Our patient had toxic levels of tacrolimus and neuropathologic evidence of endothelial damage with vasogenic edema in white matter in the absence of infarcts or demyelination. The myelin pallor in our patient and in a previous report does not constitute active demyelination (i.e., myelin breakdown with phagocytosis of myelin debris), and is more consistent with vasogenic edema as has been reported in HIV leukoencephalopathy.5 The precise etiology of tacrolimus leukoencephalopathy is not known. Tacrolimus toxicity has been implicated in cases of druginduced thrombotic thrombocytopenic purpura (TTP); nephrotoxicity also has been reported in both animal and human studies. The precipitating event for both is most likely endothelial cell damage, which includes a microangiopathy with fibrinoid degeneration and endothelial swelling,6 comparable to that seen in our patient. Further evidence for endothelial dysfunction in our patient can be deduced from her erythrocytic abnormalities. Polymorphisms in the ABCD1 gene that encodes the P glycoprotein transporter, a multidrug efflux pump acting to exclude tacrolimus from the brain, may render some patients genetically susceptible to the adverse neurologic effects of tacrolimus.7 One common precursor of RPLS is hypertension and hypocholesterolemia. The posterior circulation is purportedly more vulnerable to alterations in blood pressure because of its relative paucity of sympathetic innervation.3 In our patient, neither hypocholesterolemia nor the sympathetic innervation seem operative because at least some of the leukoencephalopathy and endothelial damage was located in the frontal lobe and she was hypercholesterolemic. The temporal linkage of her leukoencephalopathy to toxic drug levels suggests that tacrolimus was the main determinant for the endothelial lesions, but mild hypertension may have played a synergistic role in the genesis of the vasogenic edema. Additional references may be found on line at www.neurology.org. Acknowledgment The authors thank Marshall Lichtman, MD, for hematologic discussion. From the University of Rochester School of Medicine and Dentistry, Rochester, NY. Received March 26, 2004. Accepted in final form May 20, 2004. Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the September 28 issue to find the title link for this article. 1132 NEUROLOGY 63 September (2 of 2) 2004 Address correspondence and reprint requests to Dr. James M. Powers, Professor of Pathology and Neurology, University of Rochester School of Medicine and Dentistry, Box 626, 601 Elmwood Avenue, Rochester, NY 14642; e-mail: james_powers@urmc.rochester.edu Figure. Neuroradiologic and neuropathologic features. (A) Axial T2-weighted image shows focal high intensity lesions in right frontal subcortical white matter and bilateral occipito-parietal, deep and subcortical white matter lesions. (B) Axial proton density weighted image shows bilateral deep and subcortical fronto-parietal white matter lesions. (C) Myelin pallor in the absence of periodic acid-Schiff (PAS)-positive macrophages, but a few reactive astrocytes (arrowheads). Luxol Fast Blue– PAS, original magnification, ⫻90. (D) A comparable decrease in stainable axons in a serial section of A, without axonal abnormalities (e.g., spheroids). Bodian, original magnification, ⫻90. (E) Small vein with a rim of PASpositive material and both intravascular and extravascular PAS-positive droplets, probably composed of serum glycoproteins (arrowheads); some of these are within glial cells, presumably astrocytes (arrow). Diastase-PAS, original magnification, ⫻150. (F) Another small vein with both intravascular and extravascular PAS-positive droplets (arrowheads) and linear material (arrow), the absence of perivascular myelin staining and replacement by a faint PAS-positivity. Duplicated, swollen endothelial cells with prominent nucleoli. Luxol Fast Blue–PAS, original magnification, ⫻150. (G) Fibrin transudation in wall of same vessel as in D (arrow). Phosphotungstic acid-hematoxylin; original magnification, ⫻150. Copyright © 2004 by AAN Enterprises, Inc. References 1. Hinchey J, Chaves C, Appignani B, et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med 1996;334:494 –500. 2. Ahn KJ, Lee JW, Hahn ST, et al. Diffusion-weighted MRI and ADC mapping in FK506 neurotoxicity. Br J Radiol 2003;76:916 –919. 3. Pizzolato GP, Sztajzel R, Burkhardt K, Megret M, Borisch B. Cerebral vasculitis during FK 506 treatment in a liver transplant patient. Neurology 1998;50:1154 –1157. Natural history of conservatively treated meningiomas Z. Herscovici, MD; Z. Rappaport, MD; J. Sulkes, PhD; L. Danaila, MD; and G. Rubin, MD Asymptomatic brain meningiomas are often diagnosed incidentally during investigations for minor neurologic symptoms. Their management is controversial because not enough data have been collected on the growth rate,1–7 and it may vary according to tumor location or patient age. We reviewed the natural history of conservatively treated brain meningiomas with a focus on the features associated with tumor growth. Patients and methods. The files of 43 patients with 51 brain meningiomas that were treated conservatively at Beilinson hospital between 1989 and 1999 were reviewed. The diagnosis was based on a finding of an extra-axial dural-based enhancing mass on CT or MRI. Follow-up was performed 6 to 9 months after 4. Small SL, Fukui MB, Bramblett GT, Eidelman BH. Immunosuppressioninduced leukoencephalopathy from tacrolimus (FK 506). Ann Neurol 1996;40:575–580. 5. Power C, Kong PA, Crawford TO, et al. Cerebral white matter changes in acquired immunodeficiency syndrome dementia: alterations of the bloodbrain barrier. Ann Neurol 1993;34:339 –350. 6. Kindt MV, Kemp R, Allen HL, Jensen RD, Patrick DH. Tacrolimus toxicity in rhesus monkey: model for clinical side effects. Transplant Proc 1999;31:3393–3396. 7. Yamauchi A, Ieiri I, Kataoka Y, et al. Neurotoxicity induced by tacrolimus after liver transplantation: relation to genetic polymorphisms of the ABCB1 (MDR1) gene. Transplantation 2002;74:571–572. diagnosis and yearly thereafter. Tumor size was calculated according to largest diameter in the anterio-posterior, medio-lateral, or oblique dimension (perpendicular analysis). Growth was defined as a change in tumor size of at least 2 mm. The tumors were classified as growing or nongrowing, and the groups were compared for the following features: patient age, sex, tumor location, size, calcification, and duration of follow-up. Statistical analysis. Student’s t-test was used to analyze the significant differences in mean continuous variables, and ␹2 or Fisher’s Exact Test was used, as appropriate, to analyze differences in categorical variables between groups. p Values ⱕ 0.05 were considered significant. Results. Patient and tumor data. The clinical data are reported in the table. The study group consisted of 8 men and 35 women aged 39 to 83 years (mean 65 years). Four patients had two tumors, and two patients had three. In all but two patients, the symptoms were not caused by the tumor itself. Average tumor size at diagnosis was 17 ⫾ 8 mm (range 3– 45 mm). Twelve tumors September (2 of 2) 2004 NEUROLOGY 63 1133 Tacrolimus leukoencephalopathy: A neuropathologic confirmation Catherine M. Lavigne, David A. Shrier, Manoj Ketkar, et al. Neurology 2004;63;1132-1133 DOI 10.1212/01.WNL.0000138568.60774.E4 This information is current as of September 27, 2004 Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright . All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X. Updated Information & Services including high resolution figures, can be found at: http://www.neurology.org/content/63/6/1132.full.html Supplementary Material Supplementary material can be found at: http://www.neurology.org/content/suppl/2004/09/07/63.6.1132.DC1 References This article cites 7 articles, 2 of which you can access for free at: http://www.neurology.org/content/63/6/1132.full.html##ref-list-1 Citations This article has been cited by 3 HighWire-hosted articles: http://www.neurology.org/content/63/6/1132.full.html##otherarticles Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): All Medical/Systemic disease http://www.neurology.org//cgi/collection/all_medical_systemic_disease All Toxicology http://www.neurology.org//cgi/collection/all_toxicology Cardiac http://www.neurology.org//cgi/collection/cardiac Hematologic http://www.neurology.org//cgi/collection/hematologic MRI http://www.neurology.org//cgi/collection/mri Permissions & Licensing Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions Reprints Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright . All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.