Central JSM and Spine

Case Report *Corresponding author Mohsin Khan, Hamilton General Hospital, 8 North: Room 8N-06, 237 Barton St. E., Hamilton, ON L8L 2X2, Superficial of the Tel: 204-297-2226; Email: [email protected] Submitted: 11 November 2014 Accepted: 11 December 2014 Published: 12 December 2014 Copyright Secondary to Chronic Bleeding © 2014 Khan et al. From a Lumbar Paraganglioma OPEN ACCESS Keywords Mohsin Khan1*, Boleslaw Lach2, Ahmed Al Jishi1 and Naresh K. • Superficial siderosis Murty1 • Paraganglioma • Central nervous system tumors 1 Department of Neurological , McMaster University, Canada • Spine tumors 2Department of and Molecular , McMaster University, Canada

Abstract Superficial Siderosis (SS) is a rare neurological condition which results from deposition on the leptomeninges, subpial and ependymal surfaces of the central nervous system (CNS). Patients commonly present with the classic triad of hearing loss, cerebellar and pyramidal signs. We report clinical, radiological and pathological findings in a patient with SS due to chronic haemorrhages from a paraganglioma of cauda equina.

ABBREVIATIONS CLINICAL HISTORY

SS: Superficial Siderosis; CNS: Central Nervous System; CSF: A 73‐year‐old Caucasian male presented to the Hamilton Cerebro‐Spinal Fluid; ROS: Reactive Oxygen Species; TNF: Tumor General Hospital Emergency Room with confusion, slurred NecrosisINTRODUCTION Factor speech, lower extremity weakness and gait ataxia. According to the patient’s family, his symptoms began five years prior to this episode, when they noticed behavioral changes. He became aloof Superficial siderosis (SS) is a rare, chronic and progressive and introverted. He also complained of ‘ringing’ in his ears. An neurological condition due to deposition of hemosiderin on the auditory examination at that time demonstrated hearing loss, for leptomeningial, subpial and the ependymal surfaces of the CNS which he started wearing hearing aids. Subsequently, there was a [1]. SS is associated with repetitive, low‐grade hemorrhages in progressive decline in his functional mobility and other activities to the cerebro‐spinal fluid (CSF). There have been approximately of daily living. 270 cases of SS reported in the literature from 1908 to 2006 [2]. Upon physical examination, the patient was uncooperative. The most common causes of bleeding were CNS tumors (21%), He had a short attention span with brief moments where he head and neck trauma (13%), Arterio‐venous malformations demonstrated mental competence. A Folstein mini mental status (AVM) and aneurysms (9%), neurosurgery (7%) and brachial exam revealed baseline cognitive decline most likely due to his plexus injury (6%), as well as amyloid angiopathy and chronic (13/30). The cranial nerves examination demonstrated subdural hematomas (3%) [2]. The vast majority of SS cases bilateral hearing loss. He had lower extremity weakness (more present with sensorineural hearing loss (95%), cerebellar ataxia pronounced on the right than on the left), hyper‐reflexia and (88%) and pyramidal signs such as tremor, muscle weakness, Babinski sign bilaterally. No sensory deficits were noted. loss of muscle control, and paralysis (76%) [1,3]. The reported Disdiadokokinesia, finger‐nose and heel‐shin dysmetria were cases show preponderance towards males versus females, and present. the most common age of manifestation is in the sixth and seventh The patient had a past medical history of hypertension, decades of life [2]. cerebellar strokes, left ventricular ejection fraction of 46%, dyslipidemia, prostatic hyperplasia, and gastroesophageal reflux We present a unique patient with the classic clinical disease. He was retired after 33 years of working as steel plant symptoms of SS, subsequently confirmed by MRI findings. worker and a truck driver. Extensive investigation revealed a paraganglioma of the cauda equina as source of chronic bleeding. An MRI of the head showed a diffuse, superficial hypointense Cite this article: Khan M, Lach B, Al Jishi A, Murty NK (2014) Superficial Siderosis of the Central Nervous System Secondary to Chronic Bleeding From a Lumbar Paraganglioma. JSM Neurosurg Spine 2(6): 1046. Khan et al. (2014) Email: Central

A B C coating of the cerebral hemispheres and the , as well as significant atrophic and cavitary changes in the cerebellum (Figure 1A and 1B). The thick, hypointense layer extended from the cerebellar hemispheres to the rest of the and the (Figure 2A); based on these findings a diagnosis of SS was made. An MRI of the spine showed a well‐delineated intradural 12 x 14 mm space‐occupying lesion at the level of L3‐L4, displacing the lumbosacral roots. There was trace enhancement post‐gadolinium injection (Figure 2B and 2C). A spinal angiogram showed no evidence of vascular malformations. Figure 2

Due to the high likelihood of further deterioration of the The sagittal T2‐weighted MRI image of head and neck reveals patient’s mobility from increasing leg weakness, the decision was cerebellar cavitary changes along with hypointense coat on the made to resect the tumor and eliminate the source of the bleeding. cerebellum, brainstem and the spinal cord (Fig. 2A). The sagittal T2‐ Intraoperatively, the lesion was round, firm, encapsulated and weighted MRI images of the spine show a well‐delineated intradural lumbar mass at the L3‐L4 levels of the spinal cord and heterogeneous tethered to the roots of the cauda equine and filum terminale enhancement post‐ gadolinium injection in the T1‐weighted MRI (Figure 3). Careful microsurgical dissection allowed complete sequence (Figure 2B and C). removal of the tumor. Microscopic examination revealed a monomorphic tumor composed of epithelioid neoplastic cells strongly positive for synaptophysin and chromogranin (Figure 4A-4C). The tumor contained many hyalinized vessels with hemosiderin‐ impregnated walls. The accumulation of hemosiderin in numerous macrophages and tumor cells was most pronounced in the subcapsular area at the tumour periphery, and associated with focal deposits of hematidin (Figure 5). Electron microscopy revealed osmiophilic intracellular bodies consistent with Figure 3 siderosomeDISCUSSION formation in the chief cells (Figure 6). Intradural, extramedullary tumor (12 mm x 14 mm) in the thecal sac tethered to the nerves of the cauda equina. There is subtle yellow‐tinged discoloration of the spinal nerves. There have been 17 case reports of SS associated with spinal tumors, most often myxopapillary ependymomas [1,4]. SS attributable to a spinal paraganglioma has only been described without documenting the source of bleeding [4,5]. The massive in two case reports [4,5]. Paragangliomas are rare, benign, highly accumulation of hemosiderin in the tumor cells, macrophages, vascular tumors of neural crest origin [6]. The slow subclinical vessel walls and connective tissues of the capsule, as well as the growth and rich vascularity of these tumors may explain the subcapsular deposits of hematidin, leave no doubt about the progression of clinically undetectable bleeding to full‐blown cause of SS in our patient. SS in some patients. Previous reports on paragangliomas SS of the CNS develops in patients with chronic, low‐grade associated with SS offered only limited descriptions of the hemorrhaging into the CSF. Under normal circumstances, the pathological changes, namely calcifications and ossifications, heme is degraded by hemeoxygenase, and the released iron is A B phagocytized and converted to ferritin, preventing oxidative stress [7]. However, repetitive low‐grade hemorrhages in the CNS may overwhelm the neurons ability to generate hemeoxygenase. The labile iron from hemosiderin is cytotoxic and triggers the production of mitochondrion‐driven reactive oxygen species (ROS) which leads to lipid peroxidation, membrane dysfunction and cell death [8]. The resulting inflammation also promotes the activation of tumor necrosis factor (TNF), which in turn generates more ROS [7]. These multiple mechanisms acting in concert are most likely responsible for the irreversible neurological damage, Figure 1 resulting in symptoms of SS.

Axial SWI MRI image of the head reveals a bilateral, diffuse, SS of the CNS has been associated with cognitive impairment. hypointense coating of the cortex consistent with hemosiderin Dementia has been noted in 24% of the patients with SS [9]. Six deposition, including involvement of the interhemispheric and sylvian patients with confirmed diagnoses of SS exhibited impairments fissures and the lateral ventricles (A). in speech production, visual recall, and executive function, as well The coronal T2‐weighted MRI sequence depicts atrophic changes and as inappropriate social interactions [10]. Our patient’s cognitive a hypointense coat of hemosiderin deposition on the cerebellum (B). decline is most likely attributable to SS. He scored a 13/30 on JSM Neurosurg Spine 2(6): 1046 (2014) 2/4 Khan et al. (2014) Email: Central

AA B a Folstein mini mental status examination due to deficits in attention, concentration and recall as well as short‐term memory loss. He was also easily irascible. One of the classic symptoms in the triad of SS is sensorineuroal hearing loss. The cochlear nuclei and the organ of Corti are susceptible to damage in SS [11]. The Vestibulococchlear nerve is particularly vulnerable to hemosiderin deposition because of C its long glial segment and exposure to the rapidly flowing pool of CSF in the cerebello‐pontine angle [11,12]. Due to our patient’s dementia, it was difficult to determine whether he had conductive or sensorineural hearing loss. However, his hearing impairment could also be attributed to years of work as a steel plant worker and truck driver with SS as a detrimental cofactor. Ataxia in SS is explained by damage to the cerebellum caused by hemosiderin deposition. However, our patient had a history Figure 4 of multiple cerebellar infarcts, which very likely also contributed to his ataxic gait. Although it has been demonstrated that High power view of epithelioid neoplastic cell arranged hemosiderin deposition on the pia mater may result in sclerosis in characteristic “Zellballen” pattern outlined by capillaries. Some neoplastic cells (single arrow) and perivascular macrophages of the intracranial veins, leading to venous hypertension, it is not (double arrow) contain brow pigment consistent with accumulation known whether hemosiderin deposition on arterial vasculature of hemosiderin (A). All the neoplastic cells are strongly positive for can account for our patient’s cerebellar infarcts. [13,14]. synaptophysin (B) and chromogranin (C). (H&E) The main objective in the treatment of SS is to stop the chronic hemorrhaging and thus prevent further progression of the disease. Surgical treatment can not reverse the symptoms such as ataxia, hearing loss and pyramidal signs. In some patients presenting with hearing loss, cochlear implantation can be a viable option [15]. Grover et al. reported successful cochlear implantation in a patient with progressive hearing loss over a 25‐year period due to SS. Although the short‐term results of such a treatment seem promising, long‐term data is lacking on the success of this [15]. Iron chelation therapy is another mode of treatment currently under investigation. A Figure 5 pilot trial of Deferiprone, a lipid‐ soluble Iron chelator, resulted in a decrease in hemosiderin deposition in four out of ten study Staining for iron (blue) shows accumulation of hemosiderin, participants [16]. Four other participants reported improvement concentrated at the subcapsular part of the tumor. The large deposits in neurological functioning, including better coordination and of hematoidin (orange) are consistent with old, poorly organized intratumoral haemorrhages. gait, better hearing, clearer thinking and reduced spasticity [16]. Our patient presented with classical, as well as some less‐ commonly reported, symptoms of SS such as dementia. He recovered well from the surgery however, due to the irreversible nature of the pathological process, his baseline mental function and other clinical manifestations remained unchanged three weeks postoperatively and he was subsequently transferred to a long‐termREFERENCES health care facility. 1.

Boedeker CC, Ridder GJ, Schipper J. Paragangliomas of the head and 2. neck: diagnosis and treatment. Fam Cancer. 2005; 4: 55-59. Dubessy AL, Ursu R, Maillet D, Augier A, Le Guilloux J, Carpentier AF. 277.Superficial siderosis of the central nervous system: a rare cause of dementia with therapeutic consequences. Age Ageing. 2012; 41: 275- Figure 6

Electron micrograph of a chief cell with electron‐dense 3. Fearnley JM, Stevens JM, Rudge P. Superficial siderosis of the central osmiophilic intracytoplasmic bodies consistent with siderosomes nervous system. Brain. 1995; 118: 1051-1066. (blue arrow). Whorled collections of intermediate filaments represent cytokeratin (red arrow). Magnification 14,000. 4. Irving RM, Graham JM. Cochlear implantation in superficial siderosis. J Laryngol Otol. 1996; 110: 1151-1153. JSM Neurosurg Spine 2(6): 1046 (2014) 3/4 Khan et al. (2014) Email: Central

11.

5. Grover N, Whiteside OJ, Ramsden JD. Cochlear implantation in Levy M, Turtzo C, Llinas RH. Superficial siderosis: a case report and superficial siderosis: a viable option? Cochlear Implants Int. 2011; 12: 12. review of the literature. Nat Clin Pract Neurol. 2007; 3: 54-58. 241-243. Kinge NG, Paliwal VK, Neyaz Z, Verma R. Superficial siderosis in a 6. Kamata H, Honda S, Maeda S, Chang L, Hirata H, Karin M. Reactive patient with filum terminale paraganglioma. Neurol India. 2012; 60: oxygen species promote TNFalpha-induced death and sustained JNK 648-649. activation by inhibiting MAP kinase phosphatases. Cell. 2005; 120: 13. Sharma A, Gaikwad SB, Goyal M, Mishra NK, Sharma MC. Calcified 7. 649-661. filum terminale paraganglioma causing superficial siderosis. AJR Am J Koeppen AH, Borke RC. Experimental superficial siderosis of the Roentgenol. 1998; 170: 1650-1652. central nervous system. I: morphological observations. J Neuropath 14. Tosaka M, Sato K, Amanuma M, Higuchi T, Arai M, Aishima K, et al. Exper Neurol. 1991; 50: 579–594. Superficial Siderosis of the Central Nervous System Caused by 8. Koeppen AH, Hurwitz CG, Dearborn RE, Dickson AC, Borke RC, Chu Hemorrhagic Intraventricular Craniopharyngioma: Case Report and RC. Experimental superficial siderosis of the central nervous system: Literature Review. Neurol Med Chir (Tokyo). 2014. biochemical correlates. J Neurol Sci. 1992; 112: 38-45. 15. van Harskamp NJ, Rudge P, Cipolotti L. Cognitive and social 9. Kumar N. Superficial siderosis: associations and therapeutic impairments in patients with superficial siderosis. Brain. 2005; 128: 10. implications. Arch Neurol. 2007; 64: 491-496. 1082-1092. Levy M, Llinas R. Pilot safety trial of deferiprone in 10 subjects with 16. Wilden JA, Kumar N, Murali HR, Lindell EP, Davis DH. Unusual superficial siderosis. Stroke. 2012; 43: 120-124. neuroimaging in superficial siderosis. . 2005; 65: 489.

Cite this article Khan M, Lach B, Al Jishi A, Murty NK (2014) Superficial Siderosis of the Central Nervous System Secondary to Chronic Bleeding From a Lumbar Paraganglioma. JSM Neurosurg Spine 2(6): 1046.

JSM Neurosurg Spine 2(6): 1046 (2014) 4/4