An adult case of leukoencephalopathy with intracranial calcifications and cysts Abstract—We describe a 44-year-old woman with progressive headache, ataxia, and seizures in association with multifocal cerebral and cerebellar leukoencephalopathy, intracranial calcifications, and cysts. The cause of death was intracerebellar hemorrhage while taking warfarin. Pathologic features on biopsy included angiomatous-like blood vessels, intense gliosis, and Rosenthal fiber formation in the white matter. Genetic analyses did not identify any significant mutations in two candidate genes. NEUROLOGY 2006;67:1890–1892 John R. Corboy, MD; Judith Gault, PhD; and B.K. Kleinschmidt-DeMasters, MD Leukoencephalopathies are generally volume-losing processes, although several variants, such as Alexander disease and Canavan disease, may cause megalencephaly. Leukoencephalopathies that generate severe edema, are mass producing, and mimic neoplasms are rare. In 1996, a new cerebral disorder was described in three unrelated children who had onset in early infancy to adolescence of slowed cognitive performance, seizures, and extrapyramidal, cerebellar, and pyramidal signs.1 Neuroimaging studies demonstrated a striking triad of findings: progressive calcifications in the basal ganglia, cerebellar nuclei, and deep white matter; diffuse abnormal signal on MRI in the white matter; and large, space-occupying parenchymal brain cysts generating mass effect.1 Neuropathologic examination of surgically resected material from one patient revealed “angiomatous-like rearrangements of the microvessels . . .” that “suggest a constitutional, diffuse cerebral microangiopathy . . .”1 Profuse numbers of Rosenthal fibers were identified around the “pseudoangiomatous” blood vessels. The disease did not fit descriptions for any previously known phakomatosis or dysgenetic syndrome. A descriptive name was given to this new syndrome, which was initially thought to be a leukodystrophy. Three more patients were subsequently reported, all of whom also had onset in childhood between the ages 9 and 14 years.2 More extensive neuroimaging studies suggested that the white matter abnormalities were due to “increased water content rather than a demyelinating process,” consistent with a leukoencephalopathy, rather than a leukodystrophy. We From the Departments of Neurology (J.R.C., B.K.K.-D.), Pathology (B.K.K.-D.), and Neurosurgery (J.G., B.K.K.-D.), University of Colorado Health Sciences Center, Denver, CO; and Department of Neurology (J.R.C.), Denver Veterans Affairs Medical Center, Denver, CO. Disclosure: The authors report no conflicts of interest. This case was presented in abstract form at the XVI International Congress of Neuropathology, San Francisco, CA, September 9 –15, 2006. Received May 1, 2006. Accepted in final form August 3, 2006. Address correspondence and reprint requests to Dr. John R. Corboy, Department of Neurology, Box B-183, University of Colorado at Denver and Health Sciences Center, 4200 E. Ninth Avenue, Denver, CO 80262; e-mail: john.corboy@uchsc.edu 1890 Copyright © 2006 by AAN Enterprises, Inc. now present an adult patient with clinical and pathologic findings nearly identical to these six previously reported children. Because this disorder seemed somewhat similar to adult-onset Alexander disease and was associated with apparent microangiopathy, we also searched for polymorphisms in glial fibrillary acidic protein (GFAP) and cerebral cavernous malformation (CCM) genes. Methods. Methods include the case report and DNA sequence analysis of GFAP and CCM genes. Results. In April 1999, a previously healthy 44-year-old woman presented with generalized, daily headaches that rapidly worsened over a short interval. Over the next 6 years, she developed ataxia, seizures, and mild cognitive dysfunction, with episodic headache that was partially responsive to oral corticosteroids, but there were never signs of systemic illness. Her family history was negative for neurologic or ophthalmologic illnesses, and no consanguinity was known. Extensive evaluation, including brain MRI scans in 1999, showed diffuse cerebral and cerebellar leukoencephalopathy (figure 1, A and B), mass effect with right-to-left shift (figure 1B), with cysts and enhancing lesions in the subcortical white matter of the cerebrum (figure 1C). The mass effect fluctuated over time to include both sides of the brain. Also noted were a Type I Chiari malformation and a cervical syrinx. CT scans of the chest and abdomen were negative. An echocardiogram showed questionable vegetations on several heart valves; however, all cultures were negative, and a repeat echocardiogram was normal. Serologic testing for rheumatologic and thrombogenic disorders was undertaken, including testing for antinuclear antibody, rheumatoid factor, anticardiolipin antibodies, erythrocyte sedimentation rate, C-reactive protein, protein S, protein C, dilute Russell venom viper test, and antithrombin III, all of which were negative. A lumbar puncture, including cytologic analysis, was normal. A repeat brain MRI in 2001 showed more extensive leukoencephalopathy (figure 1D). In 2002, a cerebral arteriogram, repeat lumbar puncture, and brain MR venogram were normal. Because the diagnosis remained unclear, the patient underwent three brain biopsies between 1999 and 2003. The initial review in 1999 suggested a questionable vascular malformation or “angiomatosis.” A second biopsy at the same institution 3 months later showed virtually identical features. The biopsy slides were referred to our institution and showed white matter blood vessels with fibrinoid vascular necrosis and thrombosis; vessels lacked the close jux- Figure 1. (A) Coronal fluid-attenuated inversion recovery (FLAIR) MRI scan from 1999 showing diffuse cerebral and cerebellar leukoencephalopathy, as well as one of the large cysts in the right parieto-occipital lobe. (B) Coronal FLAIR MRI scan from 1999 demonstrated the right-to-left shift and mass effect caused by the cyst and leukoencephalopathy. (C) T1-weighted MRI scan from 1999, with contrast, illustrating one of the large cysts and multifocal bilateral enhancement. (D) T2weighted MRI scan from 2001 best illustrates the extent of the bilateral cerebral white matter changes. (E) T2weighted MRI scan from 2 years later in 2003 shows that the left-sided leukoencephalopathy has progressed to involve virtually the entire left cerebral hemispheric white matter, causing a shift in the opposite direction, i.e., left to right, compared with 1999. (F) Head CT scan from 2005 just before the patient’s demise, highlighting the calcifications in the basal ganglia; note biopsy site in left frontal lobe. taposition of true cavernous angiomas (figure 2A). The intensely gliotic surrounding brain tissue contained Rosenthal fibers and astrocytes with mild nuclear atypia but no mitoses (figure 2B). White matter not immediately adjacent to the abnormal blood vessels demonstrated mild myelin pallor but no active demyelination, macrophage influx, or lymphocytic inflammation; there were focal hemosiderin deposits and prominent microcalcifications (figure 2C). Because we suspected a progressive CNS vasculitis/ Figure 2. (A) Low-power photomicrograph of the biopsy showing angiomatous vessels with fibrinoid vascular necrosis; vessels lack the close juxtaposition of true cavernous angiomas. Hematoxylin and eosin, 100⫻. (B) High-power photomicrograph of the biopsy shows the moderately hypercellular surrounding brain tissue that contained numerous Rosenthal fibers (arrows). These features are indistinguishable on morphology alone from a pilocytic astrocytoma. Hematoxylin and eosin, 600⫻. (C) High-power photomicrograph demonstrating brown hemosiderin deposits around vessels as well as small microcalcifications (arrow). Hematoxylin and eosin, 600⫻. (D) The third, and largest, biopsy included more of the surrounding white matter, which was devoid of abnormal blood vessels but was punctuated by tiny microcalcifications. Hematoxylin and eosin, 100⫻. (E) The myelinstained surrounding white matter demonstrated subtle, ill-demarcated white myelin pallor, unlike the overt myelin breakdown seen in either leukodystrophies or demyelinating disorders. Luxol fast blue–periodic acid-Schiff for myelin, 100⫻. (F) Immunostaining for glial fibrillary acidic protein showed that the greatest degree of chronic gliosis was situated immediately adjacent to the abnormal vessels (upper left) but also extended into the surrounding white matter (lower right). Immunostaining for GFAP, with light hematoxylin counterstain, 100⫻. November (2 of 2) 2006 NEUROLOGY 67 1891 vasculopathy, the patient was treated with oral cyclophosphamide and prednisone, and her headache dissipated. An outside expert neuropathologist diagnosed pilocytic astrocytoma based on the morphologic features. By September 2003, her headaches had worsened, and the MRI now demonstrated left-sided edema (figure 1E). A larger excisional biopsy of the left frontal lobe in November 2003 better illustrated the widespread leukoencephalopathy (figure 2D) characterized by subtle ill-defined myelin pallor on Luxol fast blue–periodic acid-Schiff stain for myelin (figure 2E) but neither macrophage influx nor swollen axons on modified Bielschowsky staining. Numerous microcalcifications were evident; intense gliosis and Rosenthal fiber formation were concentrated around the abnormal vessels (figure 2F), and the pattern was further verified to be inconsistent with a pilocytic astrocytoma. The patient underwent a head CT scan showing basal ganglia and cerebellar calcifications (figure 1F), and this and the brain MRIs were reviewed by Dr. Marjo van der Knapp, who raised the possibility of leukoencephalopathy with intracranial calcifications and cysts. Re-review of the pathology was compatible with this diagnosis. Because of the known association of retinal abnormalities with this syndrome in children, neuro-ophthalmologic examination was performed in July 2005. There was no evidence of Coats retinopathy, and fluorescein angiography was negative, but the patient was noted to have papilledema. The opening pressure was normal after lumbar puncture, but increased pressure was noted after placement of an intracranial pressure monitor. The patient had headache relief with ventricular drainage; however, placement of a ventriculoperitoneal shunt resulted in worsening of ataxia and confusion. She entered a rehabilitation hospital and developed a deep vein thrombosis in her leg. After being placed on warfarin, she had intracerebellar hemorrhage and died. No autopsy was performed. Before her death, the patient gave consent for buccal swab and blood samples to be evaluated for known genetic mutations within GFAP3 and CCM4,5 genes using previously described techniques. The institutional review boards at the University of Wisconsin and University of Colorado approved these studies. A single mutation in Exon 1, P47L, was found in the GFAP gene. This polymorphism has been seen in patients with Alexander disease, but only in conjunction with other potential diseasecausing mutations. It also has been detected in the unaffected parents of patients with Alexander disease, but not in 50 other control patients (Michael Brenner, personal communication). Thus, it has not been associated with 1892 NEUROLOGY 67 November (2 of 2) 2006 known pathology. No mutations were found in the CCM genes tested. Discussion. This is an example of adult onset of leukoencephalopathy with intracranial calcifications and cysts. This case manifested several clinical features that further expand the phenotype of the disorder, including fluctuating cerebral edema leading to severe intracranial hypertension and papilledema, moderate response to steroid treatment, and syringomyelia and tonsillar herniation, which were presumably due to mass effect of the cerebellar lesions. The cause of this disorder remains unknown. From the studies conducted in our patient, we would concur with the two original reports that this condition represents a cerebral microangiopathy.1,2 The exact cause of the deep vein thrombosis that led to anticoagulation remains unknown, but the unfortunate outcome here suggests the blood vessels in these patients may be prone to intracranial hemorrhage, as has been noted in three of the previous six reported cases.1,2 Based on the abnormal vasculature and profuse Rosenthal fibers in this case, we undertook extensive genetic analyses for possible Alexander disease and familial cerebral cavernous malformation syndromes. All were negative, although a mutation of unknown importance was identified in the gene for GFAP. Acknowledgment The authors thank Ms. Lisa Litzenberger for photographic assistance and Ms. Susan Peth for manuscript preparation. They also thank Drs. Albee Messing, Ron Li, and Robert Brenner for the genetic analysis of the GFAP gene. The MRI and CT scan review by Dr. Marjo van der Knaap was in instrumental in making the diagnosis. References 1. Labrune P, Lacroix C, Goutieres F, et al. Extensive brain calcifications, leukodystrophy, and formation of parenchymal cysts: a new progressive disorder due to diffuse cerebral microangiopathy. Neurology 1996;46: 1297–1301. 2. Nagae-Poetscher LM, Bibat G, Philippart M, et al. Leukoencephalopathy, cerebral calcifications, and cysts: new observations. Neurology 2004; 62:1206–1209. 3. Brenner M, Johnson AB, Boespflug-Tanguy O, et al. Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease. Nat Genet 2001;27:117–120. 4. Gault J, Shenkar R, Recksiek P, Awad IA. Biallelic somatic and germ line CCM1 truncating mutations in a cerebral cavernous malformation lesion. Stroke 2005;36:872–874. 5. Denier C, Goutagny S, Labauge P, et al. Mutations within the MGC4607 gene cause cerebral cavernous malformations. Am J Hum Genet 2004;74: 326–337. An adult case of leukoencephalopathy with intracranial calcifications and cysts John R. Corboy, Judith Gault and B. K. 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