Painter, Sally L MB, BChir, MA; Mathew, Liberty MB, ChB, MRCP; Quaghebeur, Gerardine FRCR; Esiri, Margaret M DM, FRCPath; Elston, John S MD, FRCOphth
Department of Ophthalmology (SLP, JSE), Oxford Eye Hospital, Oxford, United Kingdom; Department of Neurophysiology (LM), John Radcliffe Hospital, Oxford, United Kingdom; Department of Neuroradiology (GQ), John Radcliffe Hospital, Oxford, United Kingdom; and Department of Clinical Neurology (MME), University of Oxford, Oxford, United Kingdom.
No authors have any conflicting interests or receive any funding.
Address correspondence to Sally L. Painter, MB, BChir, MA, Oxford Eye Hospital, John Radcliffe Hospital, Headley Way, Headington, Oxford, United Kingdom; E-mail: email@example.com
Superficial intracranial siderosis is a progressive degenerative condition characterized by sensorineural deafness (95%), cerebellar ataxia (88%), and pyramidal signs (76%) (1). It is secondary to repeated, often occult, subarachnoid hemorrhage over months to decades. A review of all previously reported cases found that only 54% had a demonstrable bleeding point (1). In these cases, 47% of bleeding sources were secondary to dural pathology, 35% had vascular tumors, and 18% were attributable to vascular abnormalities (1). Focal metabolism of hemoglobin by central nervous system structures adjacent to the subarachnoid space results in deposition of hemosiderin, which causes neuronal loss and demyelination.
Janss et al (2) has reviewed the correlation among the clinical features, MRI findings, and histopathological findings. Hemosiderin can be detected on T2 MRI as a hypointense signal. The only proven treatment is to prevent further hemorrhages by identifying the bleeding source. Systemic chelation of iron has not been shown to be effective in preventing disease progression (3,4).
Ophthalmic features in superficial intracranial siderosis are rare. Nystagmus due to cerebellar involvement is most common. Optic nerve dysfunction has been described in 3 adult patients after treatment for childhood cerebellar tumors (5). Two of these patients had reduced visual acuities preoperatively, and all had had previous intracranial hypertension or intracranial surgery. It is therefore not possible to conclude that their optic neuropathy was secondary to siderosis.
There is only one case of documented optic nerve dysfunction in superficial intracranial siderosis in a patient who also had glaucoma (6). Visual evoked potentials (VEPs) have rarely been recorded in this condition. Stevens et al (3) and River et al (4) reported patients with advanced disease to have normal visual function and VEPs. Indeed, Koeppen et al (7) reported that “visual failure strictly due to siderosis does not seem to occur.”
We report two cases of idiopathic superficial intracranial siderosis with evidence of optic neuropathy and visual electrophysiological studies suggesting demyelination. We also show histological evidence, from a postmortem case, of iron deposition on the optic chiasm with associated demyelination.
A 69-year-old retired nurse was diagnosed with primary (idiopathic) superficial intracranial siderosis at the age of 61 years after a period of progressive hearing loss and increasing ataxia. The diagnosis was confirmed by brain MRI. No bleeding point was found. Currently, she retains full mental capacity but is paraplegic with an indwelling catheter. Ocular history consists of hypermetropia and a convergent squint, for which she had surgery at an age of 4 years.
Seven years after the diagnosis was made, she complained of progressive deterioration in vision. Our examination disclosed that visual acuity was 0.60 in the right eye and 0.58 in the left eye on a scale of logarithm of the minimum angle of resolution (20/80 Snellen equivalent in both eyes). She identified 17/17 Ishihara plates in both eyes and had no relative afferent pupillary defect. Kinetic visual field testing showed superotemporal field constriction bilaterally.
Anterior segment examination with intraocular pressures was normal. Extraocular eye movements confirmed reduced abduction bilaterally, likely secondary to her previous strabismus surgery, but no nystagmus. Ophthalmoscopy through clear media revealed no abnormalities. Optical coherence tomography of the macula was normal.
MRI showed T2 hypointense signals involving the intraorbital optic nerve, optic chiasm, and optic tracts, indicative of hemosiderin deposition (Fig. 1). Visual evoked potentials were significantly delayed; the latencies of the main positive deflections were 134 milliseconds and 126 milliseconds in the left and right eyes, respectively; the waveforms were well defined and of normal amplitude (Fig. 2). Flash electroretinographic responses to bright white stimulation were normal.
A 53-year-old man presented with progressive balance problems and tinnitus. Following appropriate investigations, a diagnosis of primary superficial intracranial siderosis was made. No specific bleeding source was identified. He became wheelchair bound due to debilitating ataxia and developed profound deafness.
Fifteen years after symptoms began, he presented to us with diplopia, preventing him from being able to lip-read. Visual acuities were 20/120 in both eyes. He had a comitant esotropia, controllable with a 16 prism-diopter base-out prism, and downbeat nystagmus.
Visual field tests to confrontation were normal. Ophthalmoscopy showed bilateral symmetrical optic disc pallor. MRI showed hemosiderin staining of the intraorbital optic nerves (Fig. 3). VEPs could not be recorded on either pattern-reversal or flash stimulation (Fig. 4). Flash electroretinographic responses were normal.
An 8-year-old girl had a right cerebral hemispherectomy for infantile hemiplegia in 1954. She was well for 6 years after surgery but then developed progressive ataxia, nystagmus, and deafness in her left ear. Vision deteriorated and ultimately failed completely with unreactive pupils and bilateral optic disc atrophy.
Repeated lumbar punctures showed heavily blood-stained cerebrospinal fluid (CSF). Surgical exploration showed a brown surface of the cerebellar hemispheres due to hemosiderin deposition and yielded a diagnosis of superficial intracranial siderosis secondary to recurrent subarachnoid hemorrhage following hemispherectomy. She died 7 years after the original surgery.
At postmortem examination, the optic chiasm was stained deeply brown and there was leptomeningeal thickening (8). We recovered the archival tissue from this case and are reporting, for the first time, histopathology of the optic chiasm. Perl stain showed macrophages filled with iron in the pial region (Fig. 5A). The myelin stain showed the myelin sheaths to be absent (Fig. 5B).
Despite the rarity of superficial intracranial siderosis, the condition has been well documented due to its distinct symptoms, characteristic imaging, and histopathological features (1-13). It is becoming increasingly recognized due to its classical MRI findings, consisting of hypointense signal seen on T2 images. Symptomatic optic nerve involvement has not been a recognized feature.
Our Case 1 had relatively preserved visual function and no optic disc pallor, yet significantly delayed VEPs 7 years after the diagnosis of siderosis. Our Case 2 had poor visual acuity, optic disc pallor, and nonrecordable VEPs in both eyes 15 years after diagnosis. In both cases, MRI showed signal abnormalities of siderosis involving the anterior visual pathway. Our Case 3, a patient we did not examine, had reportedly lost all vision in both eyes with bilateral pale optic discs, and, on postmortem examination, had histological evidence of severe demyelination affecting the optic nerves and chiasm.
The pathology of superficial siderosis has been studied on postmortem brain tissue and in animal models (7,9,10). Multiple small subarachnoid hemorrhages over a sustained period cause persistent release of heme into the CSF, which deposits on all structures of central nervous system in contact with the CSF. Despite diffuse exposure to blood across the brain's surface, the cerebellum and eighth cranial nerve are particularly susceptible to heavy deposits and to subsequent functional damage. This susceptibility is partly explained by their physical location within the brain. Dynamic CSF studies show high-volume flow around the brain stem and cerebellum compared to other regions, increasing the exposure to hemorrhagic CSF. Even within the cerebellum, the deposition of heme is varied due to differential CSF flow, being most severe in the upper vermis and superior hemispheres (7). In addition, Bergmann glial cells, which are densely populated within the cerebellum, metabolize heme into free iron, ferritin, and finally hemosiderin. In cerebellar tissues, the biosynthesis of ferritin is particularly prolonged, causing delayed removal of heme and free iron from the CSF. The circulating heme and free iron damage neuronal tissue by causing necrosis and demyelination (11). The final product of heme removal is hemosiderin, an inactive compound that stains tissues brown (12).
The susceptibility of the vestibulocochlear nerve to damage by blood products is unexplained. In contrast to adjacent cranial nerves, the vestibulocochlear nerve consists of oligodendroglial myelin within its subarachnoid course (9). This feature may make it more susceptible to damage than cranial nerves whose axons contain myelin entirely of Schwann cell origin, such as the ocular motor or facial nerves.
On histological examination of the vestibulocochlear nerve in postmortem studies of superficial intracranial siderosis, Koeppen et al (7) described numerous foamy bodies containing ferritin. These were also found in the root exit zone of the facial nerve, indicating a preferential concentration in central nervous tissue. The presence of foamy bodies containing ferritin was inversely proportional to the density of myelin in these tissues, suggesting that they are implicated in the process of nerve damage and demyelination.
Although the optic nerve often has hemosiderin deposition on MRI and at autopsy (8,10), it appears to be relatively resistant to damage. Only 1 case has been reported wherein superficial intracranial siderosis was directly linked to a symptomatic bilateral optic neuropathy, but that patient also had glaucoma (6). Other cases of documented optic nerve involvement in siderosis also had additional potential causes of optic neuropathy (1,5). For example, 3 cases had undergone intracranial surgery and been documented to have poor vision or papilledema or had had cranial radiotherapy (5). None of our 3 cases had additional comorbidities, an identifiable bleeding point, or previous intracranial surgery to provide an alternative explanation for anterior visual pathway dysfunction apart from the deposition of hemosiderin as a result of recurrent subarachnoid hemorrhage.
The prolonged latencies on the VEP studies of our patients suggest that the mechanism of damage to the anterior visual pathways is demyelination. The relative resistance of these structures to recurrent exposure to subarachnoid blood may be due to the microstructure and protection afforded by oligodendrocytes encased within arachnoid tissue. Slowly progressive visual loss can be relatively asymptomatic, and subclinical damage to vision may be underrecognized in this patient group. As cognitive impairment is also a feature of the condition, self-reporting of visual difficulties may be reduced (13).
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