AJNR Am J Neuroradiol 20:1245±1248, August 1999 Case Report

Super®cial of the CNS Associated with Multiple Cavernous Malformations

Wendy C. Hsu, Laurie A. Loevner, Mark S. Forman, and Erica R. Thaler

Summary: Super®cial siderosis of the CNS due to chronic, resulted in the siderosis responsible for his hearing recurrent is an uncommon and loss. potentially debilitating disorder. The classic clinical mani- festation is progressive bilateral sensorineural hearing loss (SNHL), although and pyramidal signs also are ob- Case Report served frequently. Cavernous malformations rarely present A 32-year-old man presented with a 15-year history of pro- with subarachnoid hemorrhage. We describe an unusual gressive, bilateral hearing loss. No had ever evalu- case of a young patient who presented with progressive, ated extensively his hearing loss before this visit. He denied vertigo and tinnitus. On occasion, he noted episodic twitching bilateral SNHL who was found to have super®cial CNS of the ®ngers of his right hand, which lasted up to several siderosis associated with multiple cavernous malformations. days. His medical history was signi®cant for mild headaches and at 3 years of age to correct esotropia. His family history was noncontributory. The results of a neurologic ex- Super®cial siderosis of the CNS is an unusual amination were notable for bilateral hearing loss and were oth- cause of progressive sensorineural hearing loss; erwise unremarkable, with normal motor strength, symmetric however, bilateral SNHL is the most common clin- re¯exes, intact sensation, and steady gait without ataxia. Au- ical presentation of CNS siderosis. diometric testing revealed bilateral, high-frequency sensorineu- deposition along the leptomeninges, subpial tissues, ral hearing loss, which was symmetrical. and subependyma of the ventricles as a result of MR imaging of the brain was performed to determine the presence of retrocochlear disease. The results of an evaluation chronic, recurrent subarachnoid hemorrhage induc- of the cerebellopontine cistern and internal auditory canals es intracellular uptake of iron, leading to damage were unremarkable. Nonetheless, MR imaging revealed mul- of neural tissue (1Ϫ3). Traumatic cervical nerve tiple cavernous malformations in the cerebrum, , root avulsion, neoplasms, and vascular abnormali- brain stem (midbrain, pons, and cerebral peduncles), right per- ties are causes of siderosis. Nevertheless, in as iventricular and subependymal region, and the deep gray mat- many as 46% of the patients, no source for the ter (Fig 1). These were not associated with edema or mass effect. Several of the cavernous malformations were super®- siderosis is identi®ed (3Ϫ6). cial, including lesions in the left parietal and temporal lobes We present a report of a patient with a 15-year as well as in the pons. Gradient-echo MR imaging showed history of progressive, bilateral hearing loss whose hypointensity consistent with siderosis along the pial surface MR imaging evaluation revealed CNS siderosis as- of the brain stem and along the folia of the cerebellar vermis sociated with multiple intracranial cavernous mal- (Fig 1). The patient's history of ®nger twitching was inter- formations. Although intra- and perilesional hem- preted as myoclonus owing to the focal effect of a cavernous orrhages may occur with cavernous malformations, malformation in his left motor cortex. The patient was ®tted for hearing aids and will return for regular follow-up with a resulting in seizures or focal neurologic de®cits, neurologist and otorhinolaryngologist. subarachnoid hemorrhage is an unusual sequela of these lesions. Rare cases of subarachnoid hemor- rhage associated with optic nerve or Discussion cavernous malformations have been reported (7). Super®cial CNS siderosis is a relatively uncom- Several of the cavernous malformations in the pa- mon but underdiagnosed cause of progressive bi- tient we present are super®cial, and we speculate lateral SNHL. The largest review of the literature that recurrent bleeding into the subarachnoid space to date (published in 1995), reported that patients with super®cial siderosis most often present with progressive, bilateral sensorineural hearing loss Supported by the RSNA Research and Education Fund Scholar Grant and Medical Student/Scholar Assistant Program. (95%), ataxia (88%), and pyramidal signs (76%) (4). Other manifestations may include , bladder incontinence, , anisocoria, and sen- sory de®cits. The disorder has been identi®ed in patients of all ages, with men affected more often than women at a ratio of approximately 3:1 (4). Address reprint requests to Laurie A. Loevner, MD, De- partment of , University of Pennsylvania Medical Close questioning of patients often reveals that Center, 3400 Spruce Street, Philadelphia, PA 19104. their symptoms began years before they sought medical attention. Analysis of CSF intermittently ᭧ American Society of Neuroradiology may yield xanthochromia, elevated

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MS 1246 HSU AJNR: 20, August 1999

FIG. 1. Images of a 32-year-old male patient with CNS siderosis associated with multiple cavernous malformations. A, Axial spin-echo 3500/98/1 (TR/TE/excitations) T2-weighted MR image, centered at the level of the pons, suggests mild hypointensity along the ventral surface of the pons, particularly on the left. B, Axial gradient-echo 750/40/2 susceptibility MR image with a ¯ip angle of 10Њ, obtained at the same level as that shown in A, shows focal regions of hypointensity in the ventral left pons (solid arrow) as well as the central pons (arrowhead), consistent with cavernous malformations. In addition, hypointensity along the ventral surface of the pons is better appreciated, as is hypointensity along the folia of the vermis of the cerebellum (open arrows). C, Axial spin-echo 3500/98/1 T2-weighted MR image, obtained at the level of the upper pons, raises the possibility of mild hypointensity along the surface of the brain stem (open arrows), as well as a small focal region of hypointensity within the left upper pons (solid arrow). D, Axial gradient-echo 750/40/2 susceptibility MR image with a ¯ip angle of 10Њ, acquired at the identical level as that shown in C, shows ``blooming'' of the hypointensity within the left side of the brain stem, consistent with cavernous malformations that are super®cial, as well as markedly improved visualization of hypointensity consistent with siderosis along the cerebellar folia and surface of the brain stem, as compared with the T2-weighted image shown in C. E, Axial gradient-echo 750/40/2 susceptibility MR image with a ¯ip angle of 10Њ, obtained at a more cephalad level, shows hypointensity consistent with siderosis along the folia of the superior vermis (open arrows). F, Axial gradient-echo 750/40/2 susceptibility MR image with a ¯ip angle of 10Њ, obtained at the level of the lateral ventricles, shows cavernous malformations along the ependymal/subependymal region (solid arrows) but no hemosiderin staining of the ependyma. count, and elevated iron and ferritin levels (4, 6). and there are varying degrees of neuronal loss, re- Nevertheless, normal CSF ®ndings are occasionally active , and demyelination. The super®cial encountered. folia of the cerebellum almost always are involved The pathologic changes of super®cial siderosis with loss of Purkinje cells and Bergmann gliosis. are characterized well (1Ϫ3). Macroscopically, In addition, cranial nerve VIII and, to a lesser ex- there is dark brown discoloration of the leptomen- tent, cranial nerves I and II exhibit dense accu- inges and super®cial CNS parenchyma as well as mulation of hemosiderin, which is often associated the subependymal lining throughout the neuroaxis. with demyelination and atrophy. Often, there is associated hydrocephalus. Micro- Animal models of super®cial siderosis have scopically, there is extensive hemosiderin deposi- shown that recurrent subarachnoid hemorrhage re- tion in the leptomeninges and subpial and subepen- sulting in the prolonged contact of these tissues dymal regions. The leptomeninges are thickened, with iron is crucial to the development of the dis- AJNR: 20, August 1999 SUPERFICIAL SIDEROSIS OF THE CNS 1247 order (1). Within the cerebellum, as well however, there is little evidence to support their ef- as Bergmann glia are uniquely sensitive to iron- fectiveness (3, 6). mediated cell damage. The terminal processes of Super®cial siderosis has been associated with a Bergmann glia that interface with the subarachnoid spectrum of lesions, including trauma (such as cer- space mediate iron uptake from the CSF, inducing vical nerve root avulsions), neoplasms (ependy- the synthesis of ferritin within these cells. Because momas, oligodendrogliomas, and astrocytomas), ferritin sequesters iron and is thus thought to play and vascular abnormalities (arteriovenous malfor- a role in iron detoxi®cation, intracellular iron may mations, aneurysms, and fragile capillary regrowth not cause toxicity until ferritin biosynthesis is over- after brain surgery) (4). When super®cial siderosis whelmed by a large iron load. Excess free iron may is diagnosed using imaging, efforts must be direct- then stimulate lipid peroxidation, leading to local- ed at identifying a source of recurrent subarachnoid ized tissue necrosis (1). hemorrhage. In the absence of an intracranial ab- The preferential involvement of cranial nerve normality, further evaluation should include MR VIII is partly because of its extensive lining with imaging of the spine to look for a spinal cord le- central , which is supported by siderosis-sus- sion. If no source is identi®ed, further evaluation ceptible microglia. In addition, its course through with conventional catheter angiography may be the pontine cistern exposes the nerve to an abun- warranted to exclude a vascular lesion. In 25% to dance of iron. Cranial nerve I also is affected sim- 46% of the patients, a source of siderosis is not ilarly for the same reasons; therefore, it is specu- identi®ed (3Ϫ6). lated that anosmia is underreported in association Cavernous malformations are well-demarcated with siderosis because this symptom often is not vascular lesions consisting of a honeycomb array sought or documented clinically. It is not clear why of compact vessels lined by a single endothelial symptoms of optic nerve involvement also are not layer and separated by a collagenized or ®brous found as often as hearing loss, but it is speculated stroma. The vessels characteristically lack smooth that cranial nerve II comes into contact with sig- muscle and elastic lamellae. In addition, there is ni®cant CSF volumes over only a short distance in typically no intervening neural tissue. Cavernous its course (4). malformations are estimated to occur in approxi- In the past, super®cial siderosis was diagnosed mately 0.5% to 0.9% of the population, with men almost exclusively at autopsy (2, 3). With the ad- and women affected equally (9, 10). Multiple le- vent of MR imaging, the diagnosis has been made sions may be the result of genetic predisposition or increasingly premortem. MR imaging has identi®ed they may occur sporadically. They also have been siderosis in reportedly asymptomatic patients. In associated with radiation and stereotactic one series, which examined 8843 consecutive MR biopsy (11). Most are asymptomatic. Clinical man- studies, 0.15% of patients had MR ®ndings consis- ifestations may include seizures with lesions locat- tent with super®cial siderosis. Eighty-®ve percent ed in the cortex or focal neurologic de®cits in le- of these patients reported no symptoms (5). This sions associated with acute hemorrhage or both. supports the theory of a presymptomatic phase (4). Rare cases of subarachnoid hemorrhage have been There are studies now in progress that will follow reported with cavernous malformations of the optic asymptomatic patients to determine whether and nerve or spinal cord (7). In one case, a periventri- when they develop symptoms (5). cular cavernous malformation was associated with MR imaging ®ndings of siderosis are pathogno- siderosis and intraventricular hemorrhage (12). monic. T2-weighted and, in particular, gradient- MR imaging is sensitive and speci®c for diag- echo susceptibility imaging reveals characteristic nosing occult vascular malformations (13). Uncom- hypointensity along the pial surface/subarachnoid plicated lesions are circumscribed with a complete space of the brain (Fig 1) and spinal cord as well hemosiderin ring, which is hypointense on T2- as the ependyma of the ventricles (8). This ®nding weighted images. Gradient-echo images reveal is detected classically along the surface of the brain marked ``blooming'' of these lesions (Fig 1). The stem and cerebellar vermis. Frequently, there is as- central sinusoids may be hyperintense on unen- sociated cerebellar atrophy. Although a pathologic hanced T1- and T2-weighted images and may en- examination reveals that the cranial nerves are hance after the administration of contrast material. coated with hemosiderin, this is detected by MR Mass effect and edema in the surrounding paren- imaging in only 25% of cases (4). The extent or chyma are unusual. Variable signal intensity indi- distribution of siderosis does not necessarily cor- cating recurrent subclinical bleeds of different ages relate with the severity of clinical disease (4, 5). may be present with some malformations. Some patients with diffuse ®ndings revealed by im- Super®cial CNS siderosis and cavernous malfor- aging have minimal symptoms, whereas others mations are not common causes of SNHL. For the with less severe ®ndings may be debilitated signif- patient who presents with bilaterally symmetric icantly. Management of super®cial siderosis is SNHL, workup includes audiologic testing that aimed at eliminating the cause of recurrent sub- may be followed by cross-sectional imaging if the arachnoid hemorrhage either by surgical or endo- SNHL does not ®t a pattern typical for age-induced vascular treatment. Iron chelators and antioxidants SNHL. In cases of suspected retrocochlear lesions, have been used to treat idiopathic CNS siderosis; MR imaging is the technique of choice in patients 1248 HSU AJNR: 20, August 1999 of all ages (14). Retrocochlear SNHL may result CSF interface. In particular, gradient-echo imaging from lesions in the internal auditory canal, cere- should be performed in search of CNS siderosis in bellopontine angle cistern, or brain parenchyma. In such patients because T2-weighted imaging is the cerebellopontine angle cistern, lesions include much less sensitive for detecting this complication. neoplasms, especially acoustic neuromas and men- Neurosurgical intervention in the management of ingiomas, as well as arachnoid and epidermoid cavernous malformations is aimed at treating only cysts. Bilateral acoustic neuromas are diagnostic of those lesions that are in clinically signi®cant op- neuro®bromatosis type 2. Leptomeningeal neo- erable locations. plasms (lymphoma and metastatic disease), in¯am- matory processes (sarcoidosis and meningitis), vas- References cular loops, and siderosis may cause SNHL (14). 1. Koeppen AH, Dickson AC, Chu RC, Thach RE. The pathogen- In the intra-axial pathway, SNHL may be due to esis of super®cial siderosis of the . Ann ischemia, neoplasms, trauma, or demyelinating dis- Neurol 1993;34:646±653 2. Hughes JT, Oppenheimer DR. Super®cial siderosis of the central eases (14). Intra-axial lesions are usually associated nervous system. Acta Neuropathol (Berl) 1969;13:56±74 with other neurologic sequelae, such as cranial 3. Koeppen, AH, Dentinger MP. Brain hemosiderin and super®cial nerve palsies, weakness, and respiratory symptoms. siderosis of the central nervous system. J Neuropathol Exp Neu- rol 1988;47:249±270 Vascular malformations strategically located may 4. Fearnley JM, Stevens JM, Rudge P. Super®cial siderosis of the also cause SNHL. central nervous system. Brain 1995;118:1051±1066 In our case, we attribute the patient's progressive 5. Offenbacher H, Fazekas F, Schmidt R, Kapeller P, Fazekas G. bilateral sensorineural hearing loss to siderosis Super®cial siderosis of the central nervous system. MRI ®nd- ings and clinical signi®cance. Neuroradiology 1996;38:S51ϪS56 caused by recurrent chronic subarachnoid hemor- 6. Bracchi M, Savoiardo M, Triulzi F, et al. Super®cial siderosis of rhage from multiple intracranial cavernous malfor- the CNS. MR diagnosis and clinical ®ndings. AJNR Am J Neu- mations, many of which were super®cial. Our case roradiol 1993;14:227±236 7. Ueda S, Saito A, Inomori S, Kim I. Cavernous angioma of the is unusual not only because siderosis is uncommon cauda equina producing subarachnoid hemorrhage. J Neuro- but also because cavernous malformations infre- surg 1987;66:134±136 quently present with subarachnoid hemorrhage and 8. Gomori JM, Grossman RI, Bilaniuk LT, Zimmerman RA, Gold- berg HI. High-Field MR imaging of super®cial siderosis of the their association with siderosis is virtually unre- central nervous system. J Comput Assist Tomogr 1985;9: ported. In a patient with multiple cavernous mal- 972±975 formations, it may be dif®cult to determine which 9. Simard JM, Garcia-Bengochea F, Ballinger WE, Mickle JP, Quis- ling RG. Cavernous angioma. A review of 126 collected and lesion(s) is responsible for the siderosis. The ab- 12 new clinical cases. 1986;18:162±172 sence of subependymal staining on images of our 10. Maraire JN, Awad IA. Intracranial cavernous malformations. patient (Fig 1) suggests that intraventricular hem- Lesion behavior and management strategies. Neurosurgery orrhage was not responsible but rather that one or 1995;37:591±605 11. Ogilvy CS, Moayeri N, Golden JA. Appearance of a cavernous more of the super®cial brain stem and parenchymal hemangioma in the cerebral cortex after a biopsy of a deep lesions were the source of subarachnoid lesion. Neurosurgery 1993;33:307±309 hemorrhage. 12. Hashimoto M, Hoyt WF. Super®cial siderosis and episodic fourth nerve paresis. J Neuro-Ophthalmol 1996;16:277±280 Because siderosis is a clinically debilitating and 13. Gomori JM, Grossman RI, Goldberg HI, Hackney DB, Zimmer- potentially irreversible complication of super®cial- man RA, Bilaniuk LT. Occult cerebral vascular malformations. ly positioned cavernous malformations, clinicians High-Field MR imaging. Radiology 1986;158:707±713 14. Swartz JD. Sensorineural hearing de®cit. A systematic ap- should maintain a high level of suspicion for sid- proach based on imaging ®ndings. Radiographics 1996;16: erosis with cavernous malformations that abut a 561±574