Correspondence
A Reversible Posterior Leukoencephalopathy Syndrome
N Engl J Med 1996; 334:1743-1746June 27, 1996
- Article
To the Editor:
In their article “A Reversible Posterior Leukoencephalopathy Syndrome,” Hinchey et al. (Feb. 22 issue)1 described several cases of a condition that is clinically and radiographically similar to hypertensive encephalopathy2,3 and the related syndrome of cyclosporine-induced neurotoxicity.4 These disorders have previously been well characterized.2-4
Several points in the paper require clarification. Of greatest concern are the methodologic flaws in the study design that led the authors to conclude that the syndrome is always reversible. They retrospectively selected only patients with white-matter abnormalities who subsequently recovered from their neurologic event. This bias effectively excluded any patient with unusual findings or serious sequelae. In our published series of 30 patients with hypertensive encephalopathy, 4 had intracranial hemorrhages, which resulted in a persistent deficit in 1 and death in another.3,4 I have since encountered two other patients, one being treated with cyclosporine and another with eclampsia, who had hypertensive encephalopathy and then fatal intracranial hemorrhages. Clinicians must be cognizant of this potential complication, particularly in patients with thrombocytopenia or other clotting abnormalities. However, the authors' selection criteria ensured that patients with these abnormalities would not be identified.
Clinicians should also be aware that the syndrome of hypertensive encephalopathy can occur even in patients with apparently normal blood-pressure readings. In a patient being evaluated for neurologic dysfunction, a single blood-pressure reading may be deceptive. Unless pressures are recorded frequently and compared with base-line values, gradual increases or transient spikes in blood pressure may be overlooked. This is particularly applicable to young or pregnant patients, in whom base-line pressures are normally low. More important, preexisting dysfunction of the vascular endothelium, as has been reported with immunosuppressive therapy or in preeclampsia and eclampsia,4-6 may predispose patients to failure of autoregulation and encephalopathy after relatively slight increases in blood pressure. In such patients, one should monitor and control blood pressures as aggressively as one would in patients with obviously elevated pressures.
Finally, the name the authors have chosen for the syndrome is inaccurate. The condition they describe is not always reversible, nor, as they have noted, are the lesions confined to the posterior white matter. Therefore, the term “reversible posterior leukoencephalopathy” could be misleading. If the existing name of hypertensive encephalopathy is thought to be too restrictive, the term “hyperperfusion encephalopathy” might be considered as an alternative.
6 ReferencesRichard B. Schwartz, M.D., Ph.D.
Brigham and Women's Hospital, Boston, MA 021151
Hinchey J ,Chaves C ,Appignani B , et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med 1996;334:494-500
Full Text | Web of Science | Medline2
Hauser RA ,Lacey DM ,Knight MR . Hypertensive encephalopathy: magnetic resonance imaging demonstration of reversible cortical and white matter lesions. Arch Neurol 1988;45:1078-1083
Web of Science | Medline3
Schwartz RB ,Jones KM ,Kalina P , et al. Hypertensive encephalopathy: findings on CT, MR imaging, and SPECT imaging in 14 cases. AJR Am J Roentgenol 1992;159:379-383
Web of Science | Medline4
Schwartz RB ,Bravo SM ,Klufas RA , et al. Cyclosporine neurotoxicity and its relationship to hypertensive encephalopathy: CT and MR findings in 16 cases. AJR Am J Roentgenol 1995;165:627-631
Web of Science | Medline5
Reece DE ,Frei-Lahr DA ,Shepherd JD , et al. Neurologic complications in allogeneic bone marrow transplant patients receiving cyclosporin. Bone Marrow Transplant 1991;8:393-401
Web of Science | Medline6
Rodgers GM ,Taylor RN ,Roberts JM . Preeclampsia is associated with a serum factor cytotoxic to human endothelial cells. Am J Obstet Gynecol 1988;159:908-914
Web of Science | Medline
To the Editor:
The report by Hinchey et al. recalled to mind a patient whom I saw several years ago who had incompletely resolving posterior leukoencephalopathy that was not associated with hypertension, uremia, or chemotherapy.
A 41-year-old previously healthy woman was admitted because of a 48-hour history of confusion. She could not find her way around the house, could not figure out how to operate the spigot, and asked questions repetitively. During hospitalization, systolic blood pressure typically ranged from 110 to 120 mm Hg, and diastolic blood pressure ranged from 70 to 80, with a maximal blood pressure of 140/92 mm Hg. The patient had severe amnesia, global aphasia, constructional apraxia, right hemianopia, lateral pulsion of saccades to the right, ataxia, and bilateral clumsiness. The creatinine concentration was 0.8 mg per deciliter, and the blood urea nitrogen concentration was 12 mg per deciliter. Examination of the cerebrospinal fluid showed no serious abnormalities. Magnetic resonance imaging (MRI) of the head (Figure 1A, 1B, and 1CFigure 1
MRI Scans Obtained at the Onset of Symptoms and Six Weeks and Seven Months after Onset.) showed areas of increased signal intensity in the parieto-occipital white matter bilaterally, which was worse on the left, and at the pontomesencephalic junction. All deficits except the amnesia improved with dexamethasone (Decadron) therapy.The dexamethasone was tapered, and six weeks later the patient was able to care for herself and recall her friends' names. Her speech was more fluent, but she was once again unable to find her way around the house. Examination revealed severely impaired memory, dyscalculia, and constructional apraxia. The visual fields were full, lateral pulsion was again present, and new findings had developed: slight weakness of the left side of the face, decreased position sense on the left side, and a right extensor plantar response. MRI showed a marked increase in the size and intensity of the white-matter lesions, which were now nearly symmetric.
Subsequently the patient had fluctuating signs with overall improvement in her condition. Follow-up MRI scans done four and seven months after the onset of symptoms showed progressive but incomplete resolution of the abnormalities (Figure 1C). When seen 21 months after the onset of symptoms, the patient was still unable to return to work but was able to care for herself and to do some typing and volunteer work. She still had severe memory impairment and dyscalculia but could copy figures. Her neurologic examination was otherwise normal.
This case illustrates that deficits from posterior leukoencephalopathy may persist and that the condition may have causes other than hypertension, uremia, and chemotherapy.
John M. Eaton, M.D.
University of Nevada School of Medicine, Reno, NV 89502To the Editor:
Hinchey et al. described 15 patients with reversible “posterior” leukoencephalopathy. However, five of nine patients with diastolic blood pressures >100 mm Hg (Patients 1 through 7, 11, and 12) also had frontal-lobe abnormalities on MRI. These findings are in accordance with reports in the literature that hypertensive encephalopathy produces more diffuse white-matter abnormalities, resulting in confusion, cognitive changes, seizures, and sometimes cortical blindness.1,2 Leukoencephalopathy restricted to the posterior areas seems to be especially correlated with cyclosporine therapy.3 We would like to describe a patient who had multiple episodes of cortical blindness, to illustrate the difference between these two types of leukoencephalopathy.
A 39-year-old woman with chronic myeloid leukemia who was taking cyclosporine and prednisone was admitted in May 1995 because of vertigo, headache, and rapidly diminishing vision. She had three generalized epileptic seizures. Examination showed a blood pressure of 180/100 mm Hg, mild hypertensive retinopathy, and strongly impaired vision with only light perception. Cranial T2-weighted MRI showed diffuse areas of high signal intensity only in the occipital gray and white matter. The serum cyclosporine level was 447 μg per liter (therapeutic range, 100 to 250); the serum creatinine level was normal. Cyclosporine therapy was interrupted, and vision was fully restored within two days. Two weeks later, an MRI scan revealed no abnormalities. In September 1995, the patient had a second episode of cortical blindness accompanied by confusion in the absence of cyclosporine therapy. Her blood pressure was 210/120 mm Hg. An MRI scan showed bi-occipital areas of high signal intensity on T2-weighted images in parasagittal and mesencephalic white matter. After the blood pressure was lowered with enalapril and nifedipine, the confusion disappeared and vision fully recovered in six days. In February 1996, the patient experienced a third attack of acute cortical blindness followed by a generalized tonic–clonic seizure over a five-minute period. When she recovered 30 minutes later her blindness had disappeared. Her blood pressure was normal (150/80 mm Hg). An attempt at MRI two days later failed because the patient would not cooperate. As of this writing no further seizures have occurred.
Our patient had three episodes of cortical blindness. The first was probably due to the cyclosporine, although hypertensive encephalopathy cannot be ruled out. The second episode was caused by hypertensive encephalopathy. The abnormalities found on MRI during these two episodes clearly differed. The third time the patient was neither hypertensive nor taking cyclosporine, but she probably had an epileptic aura. This indicates that although the MRI scans revealed no abnormalities, the occipital cortex of this patient and patients like her remains more susceptible to epileptic seizures.
3 ReferencesEdo P.J. Arnoldus, M.D., Ph.D.
Teus Van Laar, M.D., Ph.D.
Leiden University Hospital, 2300 RC Leiden, the Netherlands1
Weingarten KL ,Zimmerman RD ,Pinto RS ,Whelan MA . Computed tomographic changes of hypertensive encephalopathy. AJNR Am J Neuroradiol 1985;6:395-398
Web of Science | Medline2
Weingarten K ,Barbut D ,Filippi C ,Zimmerman RD . Acute hypertensive encephalopathy: findings on spin-echo and gradient-echo MR imaging. AJR Am J Roentgenol 1994;162:665-670
Web of Science | Medline3
Truwit CL ,Denaro CP ,Lake JR ,DeMarco T . MR imaging of reversible cyclosporin A-induced neurotoxicity. AJNR Am J Neuroradiol 1991;12:651-659
Web of Science | Medline
To the Editor:
We are currently caring for an adolescent infected with the human immunodeficiency virus (HIV) who had a reversible episode of deteriorating mental status, seizures, hypertension, and posterior leukoencephalopathy, as observed on computed tomographic and MRI studies. His clinical course is consistent with the syndrome described by Hinchey et al. The patient is a congenitally infected boy who initially presented at the age of 12 1/2 years with fatigue, chronic otitis media, and a 13-lb weight loss. HIV infection was confirmed; the initial CD4+ T-lymphocyte count was 168 per microliter. Three days later, the patient had elevated levels of blood urea nitrogen (136 mg per deciliter) and creatinine (26.3 mg per deciliter), anemia (hematocrit, 22.4 percent), thrombocytopenia (platelet count, 40,000 per cubic millimeter), and evidence of microangiopathic hemolysis on examination of a blood smear. The patient required acute peritoneal dialysis. A presumptive diagnosis of thrombotic thrombocytopenic purpura was made, and plasmapheresis was initiated. The patient's condition eventually improved, though maintenance therapy with peritoneal dialysis was necessary. Approximately six weeks later, the patient presented at a city hospital with hypertension, disorientation, and lethargy followed by generalized tonic–clonic seizures. Although the hypertension was controlled medically and by dialysis, the patient became obtunded and then comatose, with Cheyne–Stokes respirations. T2-weighted MRI revealed hyperintensity in the posterior parietal and occipital lobes bilaterally and in the pons, changes thought to be consistent with progressive multifocal leukoencephalopathy. Unexpectedly, the patient's mental status improved dramatically over the next 72 hours and returned to base-line function within 4 days. His dramatic clinical recovery and the results of follow-up MRI four months later, which showed nearly complete resolution of the hyperintense areas, were thought to be inconsistent with the diagnosis of progressive multifocal leukoencephalopathy.
In retrospect, this patient's course appears to be compatible with the reversible posterior leukoencephalopathy syndrome. None of the patients in the report by Hinchey et al. were infected with HIV. We believe that the presence of this syndrome may explain many of the radiographic features that have sometimes been attributed to progressive multifocal leukoencephalopathy in both adults and older children with AIDS.
Jeffrey S. Kahn, M.D., Ph.D.
Sostena Romano, P.N.P.
Warren A. Andiman, M.D.
Yale University School of Medicine, New Haven, CT 06510Author/Editor Response
The authors reply:
To the Editor: Dr. Schwartz's main point concerns the reversibility of the leukoencephalopathy that we described in patients with severe hypertension, puerperal eclampsia, uremia, and immunosuppressive-drug treatment. The word reversible means “able to be reversed.” This does not mean that the condition will always be reversed. Reversibility is contingent on controlling the condition that caused the encephalopathy. Brain hemorrhage is a well-known and feared complication of uncontrolled hypertension, eclampsia, and potential bleeding disorders. Brain hemorrhage is not a sequela of the encephalopathy. It is due to the primary disease causing the encephalopathy or one of the complications of that disease. In our experience, controlling the primary condition and stopping therapy with the offending immunosuppressive drug will reverse the leukoencephalopathy.
Kahn and colleagues describe an adolescent with AIDS and wonder whether HIV infection, especially in youths, could be another cause of the leukoencephalopathy syndrome. Their patient had severe hypertension and uremia, well known causes of leukoencephalopathy. It is difficult to know whether the HIV infection had any additional contributory role.
Arnoldus and Van Laar posit that the distribution of white-matter abnormalities differs between hypertensive and cyclosporine-induced leukoencephalopathy. They may be correct, but there have been insufficient cases analyzed to test this hypothesis. The syndromes and location of abnormalities are quite variable in patients treated with cyclosporine and tacrolimus. Some patients have mutism with pseudobulbar palsy and basal ganglionic or no lesions on MRI scans. Other patients have predominantly frontal-lobe lesions. The explanation for the location of white-matter edema in any of the causative conditions is still obscure.
Dr. Eaton describes a patient with posterior periventricular white matter and brain-stem abnormalities and no known risk factors for the reversible predominantly posterior leukoencephalopathy syndrome who had persistent and recurrent symptoms and MRI abnormalities. She probably has multiple sclerosis or another form of demyelinative disease.
Clearly, there is much to be learned about the potentially reversible leukoencephalopathy, which we presume to be a capillary-leak syndrome related to abrupt hypertension, renal failure, puerperal eclampsia, immunosuppressant-drug treatment, and perhaps other systemic disorders and drug treatments. Once the medical community becomes aware of this condition, there should be many new insights into its pathogenesis.
Judith Hinchey, M.D.
Louis R. Caplan, M.D.
New England Medical Center, Boston, MA 02111- Citing Articles (23)
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John L. Moriarity, Michael Lim, Phillip B. Storm, Norman J. Beauchamp, Alessandro Olivi. (2001) Reversible Posterior Leukoencephalopathy Occurring during Resection of a Posterior Fossa Tumor: Case Report and Review of the Literature. Neurosurgery 49:5, 1237-1240
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