Superficial Siderosis

Etiology

The potential sources of bleeding vary based on the classification of cortical versus iSS. 

Cortical Superficial Siderosis

Cortical superficial siderosis most commonly occurs due to iron deposits in the superficial cortical layers following bleeding from leptomeningeal vessels, most often from cerebral amyloid angiopathy in patients aged 55 or older.[3] Cortical superficial siderosis has been strongly associated with brain amyloid-β (Aβ) deposition.[4] Other etiologies of cortical SS include reversible cerebral vasoconstriction syndrome, vasculitis, trauma, radiation, cerebral venous sinus thrombosis, amyloid β-targeting antibody treatment, or vascular malformations.[5][6]

Infratentorial Superficial Siderosis

The classification of iSS is further divided into classic and secondary types (cases with a history of spontaneous or traumatic intracranial hemorrhage based on etiology).[7] The most common etiology for classic or primary iSS is spinal dural defects, often dural tears.[1][7][8] Dural tears are frequently ventral and preferentially caused by osteophytes or calcified disc herniation. iSS can also result from dural ectasia (connective tissue disorder), traumatic nerve root avulsion, or a postoperative pseudomeningocele, causing intracranial hypotension.[9] The most common source of bleeding is fragile, leaky bridging veins with trabeculae around dural tears.[1] Secondary iSS may result from trauma, craniospinal surgery, tumors, or vascular lesions.[1][5] Almost 35% of cases of superficial siderosis are idiopathic.[10]

Epidemiology

Superficial siderosis affects all races and age groups, with males affected more often than females. It is unclear why there is a higher prevalence of superficial siderosis in males, but a higher predisposition to cranial trauma may explain this.[11] Patients typically present with superficial siderosis in the fourth to sixth decade of life, but the condition can occur at any age, depending on the etiology.[12][13] The Mayo Clinic Study of Aging (MCSA) showed a prevalence of 0.21% in those aged 50 to 69 and 1.43% in those older than 69.[12] The prevalence of superficial siderosis has been increasing over the years due to the more widespread use of MRI and iron-sensitive sequences like GRE and SWI. 

Pathophysiology

The most common etiology for classic or primary iSS is spinal dural defects, often dural tears.[1][7][8] The typical source of bleeding is fragile, leaky bridging veins with trabeculae around dural tears.[1] Intracranial hypotension leads to epidural venous plexus engorgement. iSS also results from stretching superior cerebellar bridging veins due to brain sagging.[1] On the contrary, cortical superficial siderosis is due to iron deposits in the superficial cortical layers following bleeding from leptomeningeal vessels, mostly following cerebral amyloid angiopathy.[3] 

Due to persistent and recurring bleeding into the subarachnoid space, superficial siderosis results from the toxic buildup of hemosiderin on the surface of the brain and pia mater from the circulating cerebrospinal fluid (CSF). In the CSF, hemoglobin in red blood cells is broken down into globin and neurotoxic heme. Bergman glia and microglia cells are conduits for iron entry into the tissue, facilitating ferritin biosynthesis. Neuroglial cells produce heme oxygenase and apoferritin.[1] Heme oxygenase breaks down heme into free iron and biliverdin. Apoferritin binds the free iron produced from heme oxygenase to form ferritin and, subsequently, hemosiderin. The persistence of blood in the subarachnoid space eventually overwhelms the ferritin production capacity, and overloading this pathway results in subsequent free radical damage and lipid peroxidation-mediated neuronal injury.[1][11] Hemosiderin causes gliosis, demyelination, and neuronal loss, causing permanent damage to the involved structures except for the olfactory nerve.[14][15]

Preferential involvement of the cerebellum is likely explained by accelerated ferritin synthesis from the abundant Bergmann glia in the cerebellum.[1][16] Blood in the subarachnoid space also tends to spread to the superior cerebellar cistern when supine, and this continuously renewed contact may play a role in the pathogenesis of superficial siderosis.[17] Moreover, the cerebellum has large folded surfaces, harbingering susceptibility for iron deposition. The vermis is also close to the fourth ventricle.[18] Clinically, this manifests into superficial siderosis typically presenting as an ataxic disorder.

Hearing impairment, another hallmark symptomatology in superficial siderosis, likely results from the long glial segment of the eighth cranial nerve exposed to the CSF during its transit through the pontine cisterns.[1][18] Spinal fluid collection (spinal hydrops) following spinal anterior dural dissection (SADD) results in a feature of myeloradiculopathy.[19] 

Histopathology

Hamill, an American neurologist and psychiatrist, first described the histopathological findings of superficial siderosis in 1908.[18] Gross examination of affected brains from patients with superficial siderosis reveals brownish discoloration of the spinal cord, cerebellum, brainstem, and cerebral cortices. Atrophy and necrosis of the cerebellum may also be present. Prussian blue staining shows hemosiderin deposits in the superficial cortical layers and subarachnoid space.[17] Nadol et al also noted severe degeneration of the organ of Corti, spiral ligament, stria vascularis, spiral ganglion cells, and neuroepithelium of the vestibular system, as well as atrophy of both the superior and inferior vestibular nerves.[18]

History and Physical

Patients often present in the fourth to sixth decade of life.[1] Patients may become symptomatic years after the onset of superficial siderosis, with 1 series of patients having a median interval of 19 years between the inciting event and the onset of the first symptoms.[11] The average time from onset to diagnosis of iSS was 1 to 10 years.[7] The first presentation usually appears after at least 6 months of subarachnoid hemorrhage from injury in 97% of cases.[10] Rarely has acute superficial siderosis syndrome been described.[1] 

Patients with iSS most commonly present with hearing impairment, often with slowly progressive cerebellar ataxia. Cerebellar ataxia and deafness occur in 90% of cases.[10] Sensorineural hearing loss is the most common symptom of superficial siderosis that progressively leads to complete deafness in 1 to 12 years.[10] Progressive sensorineural hearing loss, which can be both cochlear or retro-cochlear, is commonly associated with tinnitus and sometimes with bilateral peripheral vestibular loss.[1] Hearing loss is usually bilateral and asymmetric, with involvement of high tones.[20] The classic triad of superficial siderosis includes hearing loss, ataxia, and myelopathy, although patients rarely have all 3 symptoms at the same time. Gait ataxia is often more common than appendicular ataxia, which may be explained by preferential cerebellar vermis involvement.[1] Other cerebellar symptoms that can be seen include nystagmus, saccadic dysmetria, kinetic tremor, and cerebellar dysarthria. Cerebellar signs are obligatory in iSS, whereas signs of cranial nerve dysfunction and myeloradiculopathy are facultative.[21] Myelopathy with spinal cord involvement in superficial siderosis can present with pyramidal signs, sensory symptoms, bladder dysfunction, and spasticity. This can also enigmatically present as Brown-Sequard syndrome, motor-predominant compressive polyradiculopathy (owing to epidural hydrops causing “duropathy”), or lower motor neuron involvement from arachnoiditis.[1]

Other neurologic symptoms include mild cognitive impairment, anosmia or hyposmia (olfactory nerve comprising of glial cells), headaches, and seizures.[7] Cognitive impairment in superficial siderosis has a distinct pattern with deficits in executive function, visual recall, and speech production.[2] Executive dysfunction is due to hemosiderin deposition in the medial and inferior frontal cortex.[1] There is no correlation between the extent of hemosiderin deposition and the severity of cognitive impairment.[22] Seizures may occur in superficial siderosis but have been reported in less than 5% of cases.[23] Rarely, extraocular nerve palsies, optic neuropathy, and trigeminal neuropathy can occur.[1][24]

In cases of superficial siderosis secondary to dural defects, symptoms of intracranial hypotension due to a CSF leak may occur but rarely dominate the clinical presentation. The median latency between the onset of orthostatic headaches and symptoms is 9.5 years.[25] This lag is likely explained by the chronicity of the process associated with superficial siderosis and the compensation that occurs.[26] Cortical superficial siderosis is primarily due to cerebral amyloid angiopathy and presents most commonly in patients aged 60 or older as chronic memory impairment or transient focal neurological episodes (“amyloid spells”).[27][28] 

Evaluation

In patients with symptoms concerning for superficial siderosis, an extensive medical history focusing on potential sources of bleeding should be reviewed. Given the slow progression of the disease, this should include relatively remote histories that may seem “inconsequential.” Particular attention should be paid to prior intracranial surgeries, vascular malformations, aneurysms, cranial trauma, or tumors.

The diagnosis of superficial siderosis was based on autopsies and biopsies before the use of neuroimaging.[10] Superficial siderosis is diagnosed when characteristic hemosiderin deposition is seen on iron-specific MRI sequences like SWI or GRE. MRI of the entire neuroaxis is the investigation of choice for the diagnosis and initial workup in patients with superficial siderosis to define the extent of superficial siderosis and to localize a potential bleeding source. The brain MRI should be performed with contrast as the presence of pachymeningeal enhancement may suggest a dural tear and associated CSF leak or intracranial hypotension. The contrast also aids in assessing for underlying vascular lesions or masses.[1] Brain MRI should include a sequence sensitive to the magnetic susceptibility property of blood products like GRE or SWI.[1] Hemosiderin deposition on MRI is seen as a T2 hypointensity and preferentially outlines the cerebellum and brainstem surface.[1][2] SWI is better than GRE-T2 for revealing iron deposits.[29] Constructive interference in steady state (3D-CISS) reveals an increment in caliber, and susceptibility-weighted imaging (SWI) shows characteristic hypointense linear bands.[18] Linear “pencil”-like hypointensities have also been described.[14] The cortical sulci, interhemispheric fissures, and Sylvian fissures may also be involved. These findings on MRI are pathognomonic but may be overlooked given the confluent hypointensity that follows the contours of the brain and spinal cord.

Classically, iSS involves the cerebellum and brainstem, most commonly the superior vermis, quadrigeminal plate, and basal cerebral surfaces. Cerebellar atrophy, particularly the superior vermis and anterior cerebellar hemispheres, can also be seen on a computed tomography (CT) scan of the head. The MRI of the spinal cord may reveal myelomalacia, syringomyelia, “owl-eyes,” or “snake-eyes” signs.[30][31] Imaging features of arachnoiditis can sometimes occur due to clumping or peripheralization of the nerve roots caused by subarachnoid blood.[2][5][32] A CT is not the imaging modality of choice but can show a hyperdense ring around the brainstem, suggesting superficial siderosis.[32]

If the MRI of the neuroaxis with contrast shows a structural lesion as an etiology for superficial siderosis, no further imaging is required. If the MRI of the neuroaxis shows an epidural fluid collection or is unrevealing, a CT or MR myelogram should be performed to identify potential dural defects.[1] A dural defect is shown on the CT myelogram when intrathecal contrast fills an epidural fluid collection, inferring communication with the subarachnoid space and a dural defect. Dynamic CT myelography and steady-state free precession (SSFP) sequence may help identify the location of a small dural leak with associated epidural fluid collection when an initial CT myelogram is not diagnostic.[1] CISS is also better at revealing dural defects.[1] Single photon emission CT (SPECT) with labeled red blood cells (RBCs) has also been described.[10] Digital subtraction angiography should only be pursued when CT or MR angiography suggests a spinal or cranial vascular malformation. A lumbar puncture may provide helpful information as increased RBCs in the CSF suggest active bleeding. A lumbar puncture that does not demonstrate RBCs does not rule out the diagnosis of SS.[33] Chronic bleeding can also result in an elevation in CSF protein, iron, and ferritin.[1]

Neurological findings include bilateral increment in P1 and N1 latencies in sacculocollic reflex, desynchronization in brainstem auditory evoked potentials (BAEP), and partial or complete loss of the visual suppression of vestibular-ocular reflex (vermian lesion).[18] Deep learning convolutional neural networks (CNN) and artificial intelligence (AI) can provide newer avenues for lesion detection and segmentation in superficial siderosis.[34][35]

Treatment / Management

Treatment depends on the etiology of superficial siderosis. If a dural defect is identified, regardless of whether the patient is asymptomatic, it is recommended to pursue treatment given the slow progression and potential for neurological injury.[36][37] Dural defects are often identified using CT myelography and repaired with sutures, patches, muscle/fat grafts, or fibrin glue.[1] Blood patches and minimally invasive repair of dural defects are other therapeutic options.[1] Spinal endoscopy and intraoperative ultrasonography can help identify and manage dural defects.[1] After the dural defect is repaired, markers of successful closure include the resolution of CSF xanthochromia and epidural fluid collection.[15] Symptoms of superficial siderosis after dural defects often do not regress after dural defect repair but have been reported to occur mainly in patients with symptomatic intracranial hypotension. Clinical progression of superficial siderosis can be halted, although long-term follow-up is still required. Patients with superficial siderosis often have irreversible damage, and dural closure often does not improve symptoms but rather prevents progression.[38][39](B2)

Treatment for other underlying causes of superficial siderosis, including vascular malformations, cerebral amyloid angiopathy, reversible cerebral vasoconstriction syndromes, cerebral cortical venous thrombosis, and central nervous system tumors, focuses on treating each specific disease to reduce bleeding in the subarachnoid space.[14] In most cases, an underlying etiology of superficial siderosis is not identified, and symptoms cannot be reversed with treatment. Management with supportive care can help patients acclimate and prevent falls and further injuries. Physical and occupational therapy can be helpful for individuals with gait ataxia, pyramidal symptoms, and balance issues and should be offered to every patient with superficial siderosis.(B3)

Hearing loss secondary to superficial siderosis is often progressive and irreversible. Cochlear implantation has shown some benefits, but the results of sustained benefits are mixed.[7][40][41] Given the possibility of improvement, it is reasonable to refer patients to an otologist for cochlear implantation, but further deterioration due to superficial siderosis is a potential factor in decision-making. When a referral is made for cochlear implantation, it is important to counsel the patient on the limited benefit of the surgery and the eventual decline of hearing due to the progressive course of superficial siderosis.(A1)

Chelation therapy has been studied in superficial siderosis due to the pathophysiology of hemosiderin deposition as the cause of superficial siderosis. Iron chelators such as deferiprone reduce the amount of hemosiderin and iron deposition on brain MRI. However, the reduction in hemosiderin has not been shown to correlate with clinical improvements and disease severity.[11][39] Currently, chelating agents are not recommended in patients with superficial siderosis as they have not been shown to provide a clinically meaningful benefit.[1] (B2)

Differential Diagnosis

The differential diagnosis for superficial siderosis is broad due to the wide range of symptoms. Given that the course of the disease is chronic and slowly progressive, acute pathologies are unlikely. Neurodegenerative conditions like parkinsonism can present similarly, given the long course of the disease and gait and coordination issues. An acoustic neuroma or vestibular schwannoma can present similarly with progressive hearing loss and balance issues. Differentiation of vestibular schwannoma and superficial siderosis can be made with a family history of neurological tumors and unilateral symptoms on the side of the tumor. Superficial siderosis will present with bilateral hearing loss and pyramidal signs, unlike vestibular schwannoma.

Normal pressure hydrocephalus (NPH) can present similarly with progressive gait abnormalities. Differentiating NPH and superficial siderosis can be difficult based on clinical features alone since bladder incontinence can occur in superficial siderosis. Hearing loss is not commonly seen in NPH, but most patients with SS and NPH have some degree of age-related hearing loss, given the age demographic affected. Once brain imaging is obtained, differentiating these 2 diagnoses is relatively easy, as 1 shows hemosiderin deposition and the other shows enlarged ventricles that are out of proportion to atrophy.

Vestibular neuritis and Meniere disease can also present with balance issues, tinnitus, and hearing loss. Vestibular neuritis often occurs after a viral illness and presents subacutely rather than chronically. Meniere disease can present similarly to superficial siderosis, given the chronic nature and degree of hearing loss. Audiometric evaluation in Meniere disease shows low-frequency unilateral sensorineural hearing loss compared to superficial siderosis, which shows bilateral, asymmetric, high-frequency hearing loss. Meniere disease will also have a more fluctuating course with spontaneous episodes of vertigo, while superficial siderosis will be constant rather than episodic.

Other radiological mimics of superficial siderosis include the following:

• Meningioangiomatosis
• Neurocutaneous melanosis
• Motor neuron disease like amyotrophic lateral sclerosis (snake eye sign) [1][30][31]

Prognosis

The prognosis depends on whether an identifying etiology or source of bleeding can be found. Even if the bleeding source is identified and treated, reversibility of symptoms is unlikely. Patients may continue to progress and have permanent disability even after the treatment of the underlying etiology. Patients usually have a “point of no return” pattern of hemosiderin-induced irreversible neurodegenerative cascade.[1] 

Spinal longitudinal intrathecal collections have a better prognosis.[25] Sealing spinal CSF leaks might halt and improve symptomatology, but the prognosis is time-dependent. The probability of developing superficial siderosis after CSF leakage ranges from 0% at 48 months to 32.7% at 144 months.[15][25] 

Cochlear implantation has mixed results in hearing impairments.[1]

Complications

Superficial siderosis can have various clinical manifestations but often leads to similar complications. The most frequent complications with superficial siderosis include hearing and peripheral vestibular loss and falls secondary to gait impairment. Other complications include anosmia, amyloid spells (transient neurological episodes that can mimic transient ischemic attacks), dementia, sensory deficits, bladder incontinence, and cranial nerve dysfunction. 

Cortical superficial siderosis progression was a predictor of incident symptomatic lobar intracerebral hemorrhage.[28] This also has a strong correlation with amyloid angiopathy and Alzheimer disease.[15] 

The most concerning complication of deferiprone chelating therapy is agranulocytosis.[1] Up to 25% to 40% of cases have been observed to withdraw from chelation treatment due to granulocytopenic sepsis.[7][42]