The pathology of superficial siderosis of the central nervous system

Abstract

Chronic or intermittent extravasations of blood into the subarachnoid space, and dissemination of heme by circulating cerebrospinal fluid, are the only established causes of superficial siderosis of the central nervous system (CNS). We studied the autopsy tissues of nine patients by iron histochemistry, immunocytochemistry, single- and double-label immunofluorescence, electron microscopy of ferritin, and high-definition X-ray fluorescence. In one case, frozen brain tissue was available for quantitative assay of total iron and ferritin. Siderotic tissues showed extensive deposits of iron and ferritin, and infiltration of the cerebellar cortex was especially severe. In addition to perivascular collections of hemosiderin-laden macrophages, affected tissues displayed iron-positive anuclear foamy structures in the neuropil that resembled axonal spheroids. They were especially abundant in eighth cranial nerves and spinal cord. Double-label immunofluorescence of the foamy structures showed co-localization of neurofilament protein and ferritin but comparable merged images of myelin-basic protein and ferritin, and ultrastructural visualization of ferritin, did not allow the conclusion that axonopathy was simply due to dilatation and rupture of fibers. Heme-oxygenase-1 (HO-1) immunoreactivity persisted in macrophages of siderotic cerebellar folia. Siderosis caused a large increase in total CNS iron but high-definition X-ray fluorescence of embedded tissue blocks excluded the accumulation of other metals. Holoferritin levels greatly exceeded the degree of iron accumulation. The susceptibility of the cerebellar cortex is likely due to Bergmann glia that serve as conduits for heme; and the abundance of microglia. Both cell types biosynthesize HO-1 and ferritin in response to heme. The eighth cranial nerves are susceptible because they consist of CNS axons, myelin, and neuroglial tissue along their subarachnoid course. The persistence of HO-1 protein implies continuous exposure of CNS to free heme or an excessively sensitive transcriptional response of the HO-1 gene. The conversion of heme iron to hemosiderin probably involves both translational and transcriptional activation of ferritin biosynthesis.

Iron chelation in the treatment of neurodegenerative diseases

“…Cerebral hemorrhage can undoubtedly supply large amounts of iron from the degraded heme prosthetic group. Repetitive subarachnoid bleeding may lead to iron deposition in the pial surface and cause superficial siderosis of the central nervous system (CNS) [6]. Microbleeding due to microangiopathies may be a source of parenchymal iron deposition.…”

“…The concentration of iron in siderotic tissue may be increased by a factor of 2-14 and ferritin protein by a factor 20-30, particularly in the cerebellar cortex [6]. Increased iron and ferritin levels are detectable also in the cerebrospinal fluid (CSF) [106] and may be thus helpful for monitoring the chelation therapy [107].…”

Superficial siderosis following trauma to the cervical spine: Case series and review of literature

“…It typically presents with sensorineural hearing loss, cerebellar ataxia, and pyramidal signs [1][2][3]. Other features include cognitive impairment, bladder dysfunction, anosmia, myelopathy, back pain, bilateral sciatica, and lower motor neuron signs [4][5][6].…”

“…This may be as a result of intracranial or spinal neoplasm, subarachnoid hemorrhage, subdural hematoma, hemorrhagic meningitis, head injury, and spinal trauma with nerve root avulsion [3,6]. Iatrogenic damage during surgery is a further possible cause [1,5].…”

Superficial siderosis associated with aceruloplasminemia. Case report

“…Hemosiderin is found in the subpial and subependymal regions and leptomeninges, where it is observed as coarse deposits in macrophages and astrocytes [2]. SS usually presents with hearing loss, ataxia, and pyramidal tract signs.…”