Superficial siderosis

INTRODUCTION — Superficial siderosis (SS) of the central nervous system (CNS) is a chronic condition consisting of hemosiderin deposition in the subpial layers of the brain (and spinal cord) due to chronic or intermittent low-grade extravasation of blood into the subarachnoid space. Several underlying conditions lead to the development of SS. It is most commonly identified on magnetic resonance imaging (MRI) of the brain [1-5]. The cortical and cerebellar surfaces are preferentially involved.

The clinical features, evaluation, management, and prognosis of SS will be discussed here. Other aspects of brain hemorrhage are discussed elsewhere. (See "Cerebral amyloid angiopathy" and "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis" and "Nonaneurysmal subarachnoid hemorrhage".)

CLASSIFICATION — SS can be categorized by the brain regions impacted. Two distinct forms of SS are recognized:

●Cortical SS (cSS) – Superficial hemorrhage in cortical sulci results in hemosiderin deposition on localized areas of the supratentorial cerebral convexities (image 1) [6,7]. Symptoms may include episodic and focal neurological symptoms related to the underlying brain regions impacted. cSS is most often associated with cerebral amyloid angiopathy (CAA) in older patients [8,9].

●Infratentorial SS (iSS) – Brainstem and cerebellar-predominating or infratentorial SS most often presents with gait ataxia, myelopathy, or impaired hearing [1-5,10-13]. It results from recurrent or persistent bleeding in the subarachnoid space with hemosiderin deposition in the subpial layers of posterior fossa structures (image 2).

•Classical iSS – Also termed type 1, classical iSS is characterized by hemosiderin deposition predominantly in the posterior fossa in patients with no overt source or history of hemorrhage. After directed evaluation, it is most commonly attributed to a spinal, or less commonly, a cranial dural defect as the source of recurrent bleeding [4,5,12-17]. These patients typically present with ataxia, myelopathy, or hearing loss [1-4,10-12].

•Secondary iSS – Also termed type 2, secondary iSS is characterized typically by hemosiderin deposition in patients with an attributable history of prior intracranial hemorrhage, angioinvasive tumors, or a vascular malformation. Siderosis may be found in the cortical sulci in addition to the posterior fossa and may also be focal, at the site of the bleeding source. Attributed symptoms may be focal, caused by siderosis at the source of the bleeding [12].

EPIDEMIOLOGY — Before routine use of MRI, approximately 40 cases were reported by biopsy or autopsy [18]. However, with widespread use of MRI (particularly with iron-sensitive sequences like susceptibility-weighted imaging and gradient-echo imaging), SS has been increasingly identified [1-4,11,12].

Cortical superficial siderosis (cSS) is frequently identified on imaging studies performed on older adults and is most commonly associated with cerebral amyloid angiopathy (CAA) [19]. In population-based studies of older adults in the United States and Europe, cSS was found in 0.4 to 0.7 percent (mean age 70 years) [20,21]. By contrast, in one German series of patients with histopathologically proven CAA, cSS was identified in 23 of 38 patients (61 percent) [22].

Patients often present with iSS in the fourth to sixth decades [1,10,12,18], but it can occur at any age depending on the underlying etiology [11]. Onset in the early teens has been reported in patients after intradural surgery [23]. A higher prevalence in males reported in three series may reflect a higher historical male predisposition to significant trauma [1,10,12].

PATHOGENESIS — Cortical superficial siderosis (cSS) on brain MRI represents iron-containing deposits in the superficial cortical layers due to prior focal convexity subarachnoid hemorrhage [7,24-26]. Several conditions may cause convexity subarachnoid hemorrhage, with cerebral amyloid angiopathy (CAA) being the most common. (See "Nonaneurysmal subarachnoid hemorrhage", section on 'Other associated conditions'.)

CAA is caused by beta-amyloid deposition within the walls of small cortical and leptomeningeal arteries [7,24,25]. cSS represents subpial deposits of hemosiderin in the cerebral convexities or cerebellar folia and, like cerebral microbleeds and lobar intracerebral hemorrhages in this context, is a hemorrhagic marker of CAA on MRI. (See "Cerebral amyloid angiopathy", section on 'Pathophysiology'.)

Infratentorial superficial siderosis (iSS) most commonly results from an insidious low-volume but protracted or repetitive "leak" of red blood cells into the subarachnoid space. Exudation of blood from engorged, friable, or damaged intradural or epidural vessels are the likely source of chronic bleeding that results in classical iSS [1,4,27-32]. Case reports have identified rupture of engorged or fragile bridging veins within the dura by direct surgical inspection [33,34].

The process by which subarachnoid bleeding results in the hallmark hemosiderin deposition and neuronal damage of SS is complex and not well understood [35-39]. However, the capacity of the brain to synthesize ferritin in response to prolonged contact with iron is important in the pathogenesis of SS. Hemoglobin in red blood cells in the cerebrospinal fluid (CSF) breaks down into globin and neurotoxic heme [12]. In response to the presence of neurotoxic heme, Bergmann glia and microglia release heme oxygenase-1 and apoferritin. Heme oxygenase-1 breaks heme into free iron and biliverdin. Once the excess intrathecal free-iron overloads the ferritin biosynthesis capacity of the microglial cells, unbound iron results in free radical damage, lipid peroxidation, and resultant neuronal injury (figure 1) [35,36,38].

Hemosiderin deposition in SS is seen in those parts of the central nervous system (CNS) that are adjacent to the CSF: the pial, subpial, and subependymal regions [37,38,40]. Preferential cerebellar involvement in iSS may be explained by accelerated ferritin synthesis by the abundant Bergmann glia in the cerebellum [36,38]. In the erect and supine position, blood in the subarachnoid space spreads to the superior cerebellar cistern [41,42]. The vulnerability of the eighth cranial nerve may be attributed to its long glial segment in contact with the CSF.

While CNS glia and astrocytes respond to the presence of hemoglobin, this process does not occur in the Schwann cells of the peripheral nervous system. There is a sharp cut-off in the spinal roots and cranial nerves at the junction between the peripheral Schwann cell segment and central glial segment [38,43].

ETIOLOGY — There are many potential sources for the underlying bleeding in SS, but, in many cases, the actual source may not be readily apparent. Underlying etiologies can be divided into sources predominantly associated with cortical superficial siderosis (cSS), sources associated with predominantly infratentorial superficial siderosis (iSS), and sources that cause diffuse siderosis or are regionally nonspecific. In some instances, etiology remains unidentified after evaluation [12].

Regionally nonspecific or diffuse siderosis — Trauma, tumor, vascular lesion, prior intracranial bleeding, and history of radiation can all cause cSS or iSS [1,2,6,7,10-12].

●Trauma – A prior history of trauma is a well-recognized risk factor for the development of SS [1,2,44-46]. Such history may be remote. The connection to SS may not be immediately apparent, as in instances of prior brachial plexus injury with associated nerve root avulsion (image 3) [1,10,44,46-54].

●Tumor – Several primary and metastatic tumors have been reported in association with SS [10,55-59]. Most malignant cranial or spinal tumors should generally be considered the cause of SS when detected during imaging of the entire neuraxis; however, other common CNS neoplasms such as meningioma and pituitary microadenoma may be incidental findings. Bleeding from surgical resection or associated dural defects may also be responsible for SS (image 4). Postoperative surveillance brain MRI that includes T2*-weighted (eg, gradient-echo or susceptibility-weighted) sequences may facilitate early detection of SS following resection of pediatric posterior fossa tumors [60].

●Vascular abnormality with occult bleeding – Vascular malformations or abnormalities that may be associated with SS include cerebral arteriovenous malformation (AVM), spinal AVM, spinal arteriovenous fistula, aneurysm (including unruptured aneurysm), cavernous malformation, hematoma, venous thrombosis, and cerebrospinal fluid (CSF)-venous fistula [1,11,12,61-67]. However, vascular malformations may also be an incidental (ie, nonhemorrhagic) finding.

●Prior intracranial bleeding – Patients with SS may have a history of clinically apparent intracranial hemorrhage, typically subarachnoid bleeding, although intracerebral hemorrhage and perinatal germinal matrix hemorrhage have been reported [62,68-72]. Additionally, a history of severe headache suggestive of symptomatic prior subarachnoid hemorrhage has infrequently been reported [1,10].

●Radiation – Some patients who have undergone radiotherapy may develop SS possibly related to bleeding after the development of posttreatment telangiectasia or cavernous angiomas [73-75].

When siderosis is predominately cortical — The most common source of cSS in patients over age 55 years is cerebral amyloid angiopathy (CAA), even in the absence of a history of intracerebral hemorrhage. In younger patients, cSS is rare and may be due to other causes such as the reversible cerebral vasoconstriction syndrome (RCVS), trauma, or a brain vascular malformation. However, consideration of alternative underlying causes is warranted in all age groups as imaging features are not specific to an underlying cause and management of distinct causes differs (table 1). (See 'Evaluation' below.)

●Cerebral amyloid angiopathy – Particularly in older adults, the presence of cSS is frequently an indicator of underlying CAA. Patients with CAA can present with lobar intracerebral hemorrhage, focal transient neurological episodes (often referred to as "amyloid spells"), chronic cognitive impairment, or progressive neurological symptoms with inflammatory leukoencephalopathy [6,7,24,25,76,77]. Brain MRI performed for an unrelated reason may also show cSS or cerebral microbleeds indicative of asymptomatic CAA. (See "Cerebral amyloid angiopathy", section on 'Cortical superficial siderosis'.)

●Reversible cerebral vasoconstriction syndrome – cSS may be seen as the sequelae of convexity subarachnoid hemorrhage in patients with a history of RCVS [24,76-78]. RCVS describes a group of conditions characterized by transient symptoms of acute thunderclap headache sometimes with neurologic deficits and associated cerebrovascular imaging showing reversible segmental narrowing of the cerebral arteries. Acute brain imaging may be normal or may show acute injury including ischemic stroke or convexity subarachnoid hemorrhage [79,80]. RCVS may be the most common cause of convexity subarachnoid hemorrhage in patients below age 60 [77]. (See "Reversible cerebral vasoconstriction syndrome".)

●Others – cSS may infrequently be identified as the sequelae of other conditions whose acute presentation may include convexity subarachnoid hemorrhage.

•Primary angiitis of the central nervous system [24] (see "Primary angiitis of the central nervous system in adults", section on 'Clinical manifestations')

•Bacterial endocarditis [81,82] (see "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis", section on 'Clinical manifestations')

•Hyperperfusion syndrome [24] (see "Complications of carotid endarterectomy", section on 'Hyperperfusion syndrome')

•Cerebral venous sinus thrombosis [76] (see "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis")

•Posterior reversible encephalopathy syndrome [76] (see "Reversible posterior leukoencephalopathy syndrome")

When siderosis is predominately infratentorial — The source of bleeding in patients with idiopathic or classical iSS is typically inapparent and requires detailed history and testing. Case series have identified dural tear and spinal fluid collection, tumor, prior trauma or surgery, rarely vascular malformation, and, in several instances, no etiology [1,10-12]. However, as imaging features are not specific to an underlying cause and management of distinct causes differs, thorough evaluation is warranted to identify attributable cause to the bleeding. (See 'Evaluation' below.)

●Dural defects – The most common etiology that results in iSS is a spinal dural defect (image 5 and image 6) [1,10,12,16,83]. Ventral epidural fluid collections adjacent to osteophytes are more common than dorsal fluid collections [1,28]. In some cases, the dural defect may be due to an osteophyte or disc herniation [4,16,84-88]. In one reported case of an osteophyte-associated dural tear, a perforating artery bleeding into the subarachnoid space was noted [86].

The defect is typically spinal, but cranial defects are reported [1,3,4,12,14-16,89-95]. Cranial defects may be associated with an epidural fluid collection. The fluid collection may also be intradural, due to a tear in the inner dural layer that leads to fluid accumulation between the outer fibrous and inner dural layers [34,96,97].

Dural ectasia or localized outpouching without an obvious defect may also be present in some patients with SS [98]. SS and dural ectasia have been reported in Marfan syndrome [12,99], neurofibromatosis type 1 [12,98,100], and ankylosing spondylitis [12]. Prior to more routine evaluation of SS with spinal imaging, some patients classified as having an idiopathic SS may have had a spinal dural defect.

●Craniospinal surgery – A history of intradural cranial or spinal surgery as a risk factor for later development of SS is well recognized (image 7) [1,10,23,73,101-107]. Posterior fossa surgery seems to be particularly common. Spine surgery may be complicated by a dural tear with subsequent development of a pseudomeningocele and SS (image 8) [105]. Rarely, bone marrow may be exposed to the CSF following spinal surgery and provides a chronic source of low-grade bleeding [108]. The development of SS has also been reported after placement of a ventriculoperitoneal shunt [109].

CLINICAL PRESENTATIONS AND DIAGNOSIS — The clinical presentation in SS is dependent on the location and extent of hemosiderin deposition. Patients may also have symptoms attributable to the underlying syndrome/condition that caused the siderosis. Others may also be asymptomatic, with SS being discovered incidentally on imaging obtained for an unrelated indication.

Clinical presentations — − Clinical presentations may be organized as either asymptomatic, symptomatic, or syndromic (ie, symptoms due to underlying etiology rather than to the SS).

Asymptomatic — The diagnosis of SS may be made incidentally on MRI performed for other indications (eg, screening evaluation for headache) [62,64].

Symptomatic — Patients may present with symptoms attributed to the brain regions affected by the hemosiderin deposition.

Patients with classical infratentorial superficial siderosis (iSS) who harbor an occult underlying bleeding source may become symptomatic years after the onset of siderosis. In one series of patients with classical iSS, the median latency between the presumed causal event and onset of first symptoms was 19 years [12]. Symptoms are likely related to the duration of bleeding and amount of hemosiderin deposition.

Common symptoms — Patients with iSS may present with gait ataxia, myelopathy, or hearing impairment in varying combinations [1,10,12]. In a series of 48 patients with classical iSS, hearing loss was seen in 31, ataxia in 31, and myelopathy in 20; 83 percent had at least one of the three clinical features [12].

●Gait ataxia – Gait ataxia may be accompanied by appendicular ataxia. Nystagmus is generally absent, but dysphagia or cerebellar dysarthria may be seen in later stages [73,110,111], which can be misdiagnosed as a degenerative cerebellar ataxia [112].

●Hearing loss – Sensorineural hearing loss is common, progressive, may have both retrocochlear and cochlear components, is often accompanied by tinnitus, involves high tones, and is generally bilateral but asymmetric [113,114]. The hearing loss may be accompanied by vestibular failure and may be the first symptom [115].

●Myelopathy – A myelopathic presentation in SS is well recognized [12,42,44,116]. Pyramidal signs, sensory signs, and bladder dysfunction are common and may relate to brainstem or spinal cord involvement. The epidural fluid collections seen in those cases of SS who have a dural defect may compress the cord and cause a myelopathy [1,12]. Rarely, a sensory level may be present [1,50]. Dural defects can also cause cord herniation, and the resulting myelopathy may have features of a Brown-Sequard syndrome, which is often seen with cord herniation [44,117].

Other neurologic symptoms

●Seizures may occur in patients with SS but have been reported in less than 5 percent of cases [24,118,119].

●Isolated lower motor neuron involvement is rare. In some cases, lower motor neuron signs like wasting and fasciculations may be accompanied by preserved or brisk reflexes [10,111,120,121]. Lower motor neuron involvement may result from inflammation due to arachnoiditis from blood products in the cerebrospinal fluid or stretch injury from a ventral epidural fluid collection [10,44,51,111,120-126]. Bibrachial amyotrophy associated with SS has also been reported in patients with cerebrospinal fluid leaks and intraspinal fluid collections [125,127].

●Dementia may be present [10]. Patients with cortical superficial siderosis (cSS) attributable to cerebral amyloid angiopathy (CAA) and others with widespread disseminated cSS may have cognitive impairment [24]. A distinct pattern of cognitive and social impairment in patients with iSS has been recognized [128]. Areas affected include speech production, executive functions, visual recall memory, and ability to represent the mental state of others. However, the extent of hemosiderin deposition does not necessarily correlate with the severity of cognitive impairment, suggesting that the hemosiderin is not directly toxic [129].

●Anosmia or hyposmia is likely common but underreported and rarely evaluated [10,73,130,131]. In a small study of 10 patients with iSS, olfactory dysfunction was present in all and severe hyposmia was also correlated with hearing loss [131].

●Optic neuropathy has been reported to occur in patients with SS who have a remote history of intracranial surgery [132].

Syndromic — Patients may have symptoms related to the underlying cause of the chronic bleeding in SS. Imaging pursuant to these syndromic symptoms may identify the underlying cause of bleeding or may show only the hemosiderin deposition diagnostic of SS. (See 'Etiology' above.)

●Dural defects may cause orthostatic headache from spontaneous intracranial hypotension due to cerebrospinal fluid leak [4,14,16,17,28,30,133,134]. Symptoms related to intracranial hypotension such as orthostatic headaches may be seen but rarely dominate the clinical presentations. Clinical symptoms of spontaneous intracranial hypotension are discussed separately. (See "Spontaneous intracranial hypotension: Pathophysiology, clinical features, and diagnosis", section on 'Clinical features'.)

●CAA is the most common underlying source of cSS in patients age 60 years and older. Such patients may present with acute intracerebral hemorrhage or chronic memory impairment or dementia. Additionally, patients with CAA may include transient focal neurologic episodes ("amyloid spells") [8]. CAA is discussed in further detail separately [119,135]. (See "Cerebral amyloid angiopathy".)

●Reversible cerebral vasoconstriction syndrome (RCVS) is more common in females than males and typically in the fifth decade of life. Acute, often recurrent, thunderclap headaches occurring either spontaneously or from a potential trigger characterize the syndrome. (See "Reversible cerebral vasoconstriction syndrome", section on 'Clinical presentation and course'.)

Diagnosis and imaging features — The diagnosis of SS is made when characteristic imaging findings of hemosiderin deposition are found on iron-sensitive MRI sequences like susceptibility weighted or gradient echo [136-138]. The magnetic susceptibility effects of blood degradation products such as ferritin and hemosiderin are more pronounced at high field strength [41,110,139]. Though the MRI findings showing hemosiderin deposition in SS are pathognomonic, occasionally they may be overlooked because the symmetric and confluent hypointensity follows the contours of the brain and spinal cord (image 9).

Involvement of the cortical sulci, sylvian fissure, and interhemispheric fissure are common in cSS and may be secondarily involved in iSS. The cerebellum and brainstem are preferentially involved in classical iSS, most commonly the superior vermis, quadrigeminal plate, and basal cerebral surfaces. Occasionally, hemosiderin deposition may be seen along the eighth cranial nerve.

Additional MRI features characteristic of SS include T2-weighted sequences showing a marginal rim of hypointensity around the ventral and dorsal surfaces of the brainstem and at times the spinal cord. The presence of subarachnoid blood can cause clumping of nerve roots and related imaging features of arachnoiditis. Secondary gliosis, atrophy in cerebellar tissue, or spinal cord atrophy adjacent to the hemosiderin deposition may result in high T2 signal [41,42].

Though head computed tomography (CT) is generally unremarkable in SS, cerebellar atrophy or a structural abnormality suggesting the potential etiology of SS may be evident [110,140]. Additionally, evidence of bony injury due to prior trauma may be better seen on CT than MRI. Rarely, a rim of hyperdensity may be seen around the brainstem on CT [41].

EVALUATION

Approach to identifying the underlying cause — Identification of the source of bleeding relies on clinical evaluation and multimodality neuroimaging. In patients with cortical superficial siderosis (cSS), the underlying etiology can often be identified by syndromic symptoms of the clinical presentation. (See 'Clinical presentations and diagnosis' above and 'When siderosis is predominately cortical' above.)

However, many patients with infratentorial superficial siderosis (iSS) and some patients with cSS may lack an overt history of hemorrhage or clinical syndrome to correlate with the SS findings. In these patients, diagnostic imaging evaluation may help uncover occult underlying cause. If the history and initial MRI do not reveal the source of the bleeding or are of uncertain significance, we suggest:

●Contrast-enhanced MRI of the neuraxis (brain and spinal cord) to evaluate for structural lesions including epidural fluid collections, tumors, and vascular lesions.

If MRI of the neuraxis shows an attributable structural lesion, subsequent treatment of SS is directed toward management of the attributed cause. (See 'Source-specific management' below.)

●If MRI of the neuraxis shows an epidural fluid collection or is unrevealing, we suggest CT or magnetic resonance (MR) myelogram to identify occult dural defects.

●Digital-subtraction angiography (DSA) may be performed when results of MRI or myelography suggest a vascular etiology may be the cause. While cerebral angiography is appropriate for some patients with cSS, cerebral and spinal angiography may also be appropriate for rare patients with iSS.

MRI of entire neuraxis — Contrast-enhanced MRI of the entire neuraxis (brain and spinal cord) is the investigation of choice for the diagnosis and initial workup in patients with SS of inapparent etiology [3,5,13,141]. Imaging of the neuraxis is indicated to define the extent of the SS and to localize a potential bleeding source. This may include a neoplasm, vascular malformation, or signs of a cerebrospinal fluid (CSF) leak [1,4,142]. Brain MRI should include a sequence sensitive to the magnetic-susceptibility property of blood products (eg, susceptibility-weighted imaging). Imaging should be performed with contrast administration since the presence of diffuse pachymeningeal enhancement may suggest intracranial hypotension from an underlying dural defect and associated CSF leak as the etiology of SS. Additional findings that may be identified include myelomalacia or encephalomalacia indicative of a remote injury.

Conventional MRI may demonstrate epidural fluid collections but generally does not identify the precise site of the associated dural defect. The epicenter of the fluid collection is generally not at the location of the dural defect [143]. High-resolution constructive interference in steady-state sequence or three dimensional fast imaging employing steady-state acquisition sequences accentuate the tissue contrast between dura and CSF and is more sensitive for the detection of dural defects than standard T2-weighted MRI [27,144-146].

Myelography — If contrast-enhanced MRI does not identify the cause, CT myelography or MR myelography may identify the source of bleeding or site of a suspected dural defect [1,3-5,13,45,133,141,147]. For most patients, CT myelography is preferred. An epidural fluid collection and associated dural defect is best characterized on CT myelography [3,45]. A CT myelogram shows a leak when intrathecal contrast fills an epidural fluid collection. This confirms free communication with the subarachnoid space, and the presence of a dural defect is inferred.

Rarely, the opacification of a paraspinal vein sign in patients with spontaneous intracranial hypotension suggests the presence of a CSF-venous fistula [148].

Other myelographic techniques may be preferred by local practice or performed when initial CT myelogram is not diagnostic.

●Dynamic CT myelography may help identify the precise location of a small dural leak associated with an epidural fluid collection [1,45,143]. In dynamic CT myelography, contrast is injected during active scanning and the patient may be positioned in ways to enhance the identification of the site of communication between the fluid collection and thecal sac.

●MR myelography is performed as an alternative to CT-based imaging in patients where a CSF leak due to a dural defect is suspected [149].

●Intrathecal contrast administration or positive pressure application can enhance the yield from MR myelography [150] as can positive-pressure application during CT myelography.

●Reverse CT myelography is a technique that uses contrast injected directly into the fluid collection to identify the site of communication with the CSF [151].

●Digital-subtraction myelography is performed by some institutions and may reflect a personal preference by the performing radiologist [133].

Adjunctive diagnostic tests — Further testing may be performed in symptomatic patients to clarify equivocal results from MRI of the neuraxis or myelography. Such tests may also be used in select patients when initial tests are unrevealing. Specific test selection is guided by suspected etiology based on patient symptoms. (See 'Etiology' above.)

●Angiography – Vascular imaging, including computed tomography angiography (CTA), magnetic resonance angiography (MRA), and DSA are generally unrevealing in patients with SS [3,12,41]. We do not recommend DSA unless MRI, CTA, or MRA suggests a spinal or cranial vascular malformation. In most other circumstances, if a vascular abnormality like a small aneurysm or venous angioma is identified, it is likelier an incidental finding. While cavernous angiomas have been reported with SS, these are angiographically occult and unaccompanied by the classical clinical presentation of iSS. (See "Vascular malformations of the central nervous system", section on 'Clinical presentation'.)

●Lumbar puncture (LP) – LP may be infrequently useful to assess whether SS is associated with active subarachnoid bleeding. The presence of increased red blood cells in patients with SS suggests ongoing bleeding. However, due to its intermittent nature, red blood cells may be absent [11]. Chronic bleeding may also result in an elevation in CSF protein or xanthochromia from arachnoiditis and a resulting elevated CSF protein. Resolution of elevated red blood cells and xanthochromia months after repair of the dural defect can provide indirect evidence of successful repair of the dural defect.

MANAGEMENT

Source-specific management — Some sources of SS may be amenable to treatment to arrest symptoms related to further deposition of hemosiderin or to reduce the risk of morbidity related to the source.

●Surgical options for dural defects – Treatment of dural defects is important to minimize the impact of irreversible neurologic injury [16,48,51,144,152]. Even in relatively asymptomatic patients with SS and an active leak, we routinely pursue treatment since the natural history is generally one of slow progression with the potential for significant neurologic injury.

Dural defects have been closed with sutures, patches, collagen sponge, fibrin glue, or muscle/fat grafting [153].

Spinal endoscopy with CT myelography [154] and intraoperative ultrasonography [155] have also been used to aid in detection and repair of small dural defects in SS. Surgical techniques to repair dural defects are discussed separately. (See "Spontaneous intracranial hypotension: Treatment and prognosis", section on 'Interventional options for patients with refractory symptoms'.)

Postoperative resolution of the fluid collection and resolution of cerebrospinal fluid (CSF) xanthochromia and increased red cell count in CSF is well documented following such repairs. Regression of SS following surgical repair is rare but has been reported following repair of a spontaneous spinal CSF leak. The clinical outcome is more variable. Syndromic symptoms associated with craniospinal hypovolemia often resolve, and the clinical progression attributable to SS may be halted. However, given the slowly progressive nature of the disorder, long-term follow-up is necessary to be confident about clinical stabilization. Additionally, reversal of symptoms attributed to the longstanding siderosis is less common. Patients with longstanding SS often have irreversible neural tissue damage, and this may limit potential benefit of the dural closure [61,144,156].

In our experience, patients with SS who have a longitudinally extensive epidural fluid collection in association with a dural defect do not benefit from less invasive closure options such as an epidural blood patch, likely due to the chronicity of the process in SS. Some patients at surgery may have an osteophyte adjacent to or protruding through a dural defect that needs excision in addition to repairing the dural defect.

●Treatment of cranial or spinal tumors – Additional details to guide the management of brain or spinal cord tumors are discussed separately. (See "Overview of the clinical features and diagnosis of brain tumors in adults" and "Spinal cord tumors".)

●Management of vascular malformations – Management of a vascular malformations of the central nervous system is discussed separately. (See "Overview of the clinical features and diagnosis of brain tumors in adults", section on 'Surgical resection or biopsy' and "Vascular malformations of the central nervous system".)

●Cerebral amyloid angiopathy – Additional details regarding the treatment of cerebral amyloid angiopathy are discussed separately. (See "Cerebral amyloid angiopathy".)

●Reversible cerebral vasoconstriction syndrome – Management of reversible cerebral vasoconstriction syndrome is discussed separately. (See "Reversible cerebral vasoconstriction syndrome", section on 'Management'.)

●Cerebral cortical venous thrombosis – Treatment and prognosis of cerebral venous thrombosis are discussed separately. (See "Cerebral venous thrombosis: Treatment and prognosis".)

Symptomatic management — Infratentorial superficial siderosis (iSS) may impact quality of life in multiple domains [157]. Most symptoms of SS such as ataxia or myelopathy cannot be effectively reversed with treatment. However, supportive treatments may help patients accommodate and minimize further neurologic impairment. Patients with gait ataxia, weakness, or myelopathy may benefit from physical and occupational therapy. Referral to a specialist with expertise in managing specific symptoms can be helpful. (See "Overview of cerebellar ataxia in adults", section on 'Management' and "Chronic complications of spinal cord injury and disease".)

Patients with SS and hearing impairment can be evaluated for cochlear implantation [158,159]. Despite the predominantly retrocochlear nature of the hearing impairment, variable degrees of benefit with cochlear implantation have been reported in some patients [158,160-167]. In some cases, the improvement was minimal, but further deterioration was prevented and maintenance of speech perception likely contributed to the perceived benefit [162]. Rapid deterioration in hearing thresholds and speech discrimination before implantation may be an indicator of an actively progressing case of SS, which may suggest possibly limited benefit from cochlear implantation [162].

Chelation — Because they have not been shown to provide meaningful clinical benefit, we do not routinely prescribe chelating agents to patients with SS. Observational studies in SS patients have shown decreased hemosiderin deposition on MRI, but clinical courses were variable. Some patients reported improvement, but, in others, symptoms continued to worsen [5,13,156,168-173].

There is no compelling evidence that iron removal significantly benefits patients with SS or other disorders of central nervous system iron accumulation, despite some MRI evidence of reduction in brain iron [174]. Reduction of hemosiderin with chelation is a questionable surrogate marker of effect since the extent of hemosiderin deposition has not been shown to correlate with disease severity [12,129]. In addition, the pathophysiology of SS suggests that hemosiderin deposition may be a protective response. Detection and management of the source of bleeding should remain the priority in SS.

Deferiprone is an iron chelator used for iron overload syndromes such as thalassemia that has also been used in SS in a dose of 30 mg/kg/day orally, typically given in two or three divided doses. Deferiprone use in SS patients may carry a risk of anemia, neutropenia, neutropenic sepsis, and agranulocytosis [173,175,176].

Continued progression despite medical or surgical therapy may be related to longstanding siderosis triggering an irreversible neurodegenerative cascade, wherein reparative mechanisms fail after having passed a "point of no return" [144,156,174].

PROGNOSIS — The prognosis of SS depends upon being able to identify the underlying bleeding source and to arrest further hemosiderin deposition and progressivity of symptoms. Because SS is a heterogeneous disease, the management and natural history of the underlying etiologies contribute to long-term prognosis. (See 'Source-specific management' above and 'Etiology' above.)

Additionally, prognosis depends upon extent of the irreversible damage from hemosiderin deposition. Often patients are left with permanent deficits, which in part include deficits related to the underlying cause like nerve root avulsions. Some patients may continue to progress despite treatment of the bleeding source [61]. Patients with long-term SS often have irreversible neural tissue damage, which limits potential benefit of dural closure.

SUMMARY AND RECOMMENDATIONS

●Definition and classification – Superficial siderosis (SS) of the central nervous system (CNS) is a chronic condition consisting of hemosiderin deposition in the subpial layers of the brain (and spinal cord) due to chronic or intermittent low-grade extravasation of blood into the subarachnoid space. It is most frequently identified on MRI of the brain. (See 'Introduction' above.)

•Cortical superficial siderosis (cSS) describes hemosiderin deposition on relatively localized areas of the supratentorial cerebral convexities. (See 'Classification' above.)

•Infratentorial superficial siderosis (iSS) generally describes preferential brainstem and cerebellar deposition of hemosiderin and most often presents with gait ataxia, myelopathy, or impaired hearing. (See 'Classification' above.)

●Pathogenesis and etiologies – SS results from an insidious low-volume but protracted or repetitive "leak" of red blood cells into the subarachnoid space. (See 'Pathogenesis' above.)

•The most common source of cSS in patients over age 55 years is cerebral amyloid angiopathy, even in the absence of a history of intracerebral hemorrhage. (See 'When siderosis is predominately cortical' above.)

•The source of bleeding in patients with idiopathic or classical iSS may be due to dural tears and spinal fluid collections, tumors, prior trauma, or surgery. (See 'When siderosis is predominately infratentorial' above.)

●Clinical presentation – Patients with SS may present with symptoms attributable to the presence and location of the siderosis or from the underlying syndrome/condition that caused the siderosis. Patients may also be asymptomatic, with SS being discovered incidentally on imaging obtained for an unrelated indication. (See 'Clinical presentations' above.)

●Diagnosis – The diagnosis of SS is made by characteristic imaging findings on susceptibility-weighted or gradient-echo sequence images on brain MRI. (See 'Diagnosis and imaging features' above.)

●Evaluation and management – Identification of the source of bleeding relies on clinical evaluation and neuroimaging. The underlying etiology can often be identified by syndromic symptoms of the clinical presentation or findings on diagnostic brain MRI. For other patients, we perform a contrast-enhanced MRI of the entire neuraxis. Myelography or other testing may be performed in selected symptomatic patients to clarify equivocal results from MRI. (See 'Evaluation' above.)

•Treatment of an identified structural cause is warranted to arrest symptoms related to further deposition of hemosiderin. (See 'Source-specific management' above.)

•Symptomatic management with supportive treatments may help patients accommodate and minimize further neurologic impairment. We do not routinely prescribe chelating agents to patients with SS, as they have not been associated with a meaningful clinical benefit. (See 'Symptomatic management' above and 'Chelation' above.)

●Prognosis – The prognosis of SS is variable, depending on the underlying bleeding source and the ability to arrest further hemosiderin deposition and progressivity of symptoms with treatment. Symptoms due to cerebral damage from hemosiderin deposition may be irreversible. (See 'Prognosis' above.)