Cerebral Superficial Siderosis

Superficial siderosis (SS) of the central nervous system constitutes linear hemosiderin deposits in the leptomeninges and the superficial layers of the cerebrum and the spinal cord. Infratentorial (i) SS is likely due to recurrent or continuous slight bleeding into the subarachnoid space. It is assumed that spinal dural pathologies often resulting in cerebrospinal fluid (CSF) leakage is the most important etiological group which causes iSS and detailed neuroradiological assessment of the spinal compartment is necessary. Further etiologies are neurosurgical interventions, trauma and arteriovenous malformations. Typical neurological manifestations of this classical type of iSS are slowly progressive sensorineural hearing impairment and cerebellar symptoms, such as ataxia, kinetic tremor, nystagmus and dysarthria. Beside iSS, a different type of SS restricted to the supratentorial compartment can be differentiated, i.e. cortical (c) SS, especially in older people often due to cerebral amyloid angiopathy (CAA). Clinical presentation of cSS includes transient focal neurological episodes or “amyloid spells”. In addition, spontaneous and amyloid beta immunotherapy-associated CAA-related inflammation may cause cSS, which is included in the hemorrhagic subgroup of amyloid-related imaging abnormalities (ARIA). Because a definitive diagnosis requires a brain biopsy, knowledge of neuroimaging features and clinical findings in CAA-related inflammation is essential. This review provides neuroradiological hallmarks of the two groups of SS and give an overview of neurological symptoms and differential diagnostic considerations.


Introduction
Superficial siderosis (SS) of the central nervous system (CNS) constitutes linear hemosiderin in the leptomeninges and the superficial layers of the cerebral and cerebellar cortices, the brainstem and the spinal cord [1][2][3]. Infratentorial (i) SS was first described by Hamill in 1908 as a "case of melanosis of the brain, cord and meninges", particularly involving the infratentorial structures in the posterior fossa and the spinal cord [4]. An iSS is often caused by chronic intermittent or continuous slight bleeding into the subarachnoid space [5][6][7][8]. The most common etiology is spinal Fig. 1 Algorithm of different types of superficial siderosis (SS) and the corresponding assumed etiologies. ARIA-H: amyloid-related imaging abnormalities, hemorrhagic type, AVM arteriovenous malformation, CAA cerebral amyloid angiopathy, CSF cerebrospinal fluid, ICH intracerebral hemorrhage, RCVS reversible cerebral vasoconstriction syndrome, SAH subarachnoid hemorrhage ious etiologies other than in iSS [2,9,[15][16][17][18][19][20][21][22][23][24][25]. Especially in older patients cSS is often due to cerebral amyloid angiopathy (CAA) [2,18,19]; however, not only the neuroradiological findings and the causes but also the clinical symptoms clearly differ between the two types of iSS [2,9,10,15,21]. This review deals with the characteristic neuroimaging features in iSS and cSS and also gives an overview of clinical symptoms and differential diagnostic considerations.

Infratentorial Superficial Siderosis (iSS)
From a neuropathological point of view the hemosiderin deposits and especially the neurotoxic iron in the leptomeninges and the subpial structures lead to demyelination, axonal loss and subsequent atrophy [1,3,5,6]. There is a sharp delineation of hemosiderin deposits in the cranial nerves and the spinal nerve roots directly at the transition zone of central glial cells and peripheral Schwann cells [1,3,5,6,13]. Therefore, the olfactory nerve and the vestibu- year-old man with SS due to ongoing hemorrhage from a melanoma metastasis in the right frontal cortex. In T2*-GRE (f) and susceptibility-weighted imaging (SWI) (b,g), SS is revealed by dark rims on the surface of affected structures, e.g., the mesencephalon (arrow), with SWI being more sensitive. Minimum intensity projections (mIPs) of SW images (c,h) further enhance the conspicuousness of SS. In addition, filtered phase image of SWI (a) can be used to distinguish paramagnetic (hemorrhage/iron, dark here) from diamagnetic substances (calcification, bright here), as they have opposite signal intensities. In general, susceptibility effects are more pronounced on images acquired at 3 T (f-j) than on images acquired at 1.5 T (a-e). Whereas at 3 T a hypointense rim around the mesencephalon is seen in T2WI and fluid attenuated inversion recovery (FLAIR) images (i,j, arrow), SS is almost undetectable at 1.5 T in T2WI and FLAIR (d,e, arrow). a-e 1.5 T (Achieva dStream, Philips); a-c SWI, TR/α 52 ms/20°, 4 echoes TE1 = 12 ms, TE = 11 ms; d T2, TR/TE/α = 5762 ms/110 ms/90°; e FLAIR, TR/TE/TI/α = 11000 ms/140 ms/2800 ms/90°; f-j 3 T (Skyra fit, Siemens); f T2*-GRE, TR/TE/α = 631 ms/20 ms/20°; g, h SWI, TR/TE/α = 27 ms/20 ms/15°; i T2, TR/TE/α = 4980 ms/92 ms/150°, j FLAIR: TR/TE/TI/α = 8500 ms/81 ms/2440 ms/150°. TR repetition time, TE echo time, TI inversion time, α flip angle locochlear nerve are preferentially involved, because both are pure glial nerves with close contact to the cerebrospinal fluid (CSF). Although the optic nerve represents the glial type, clinical signs of involvement are rare, possibly due to the shorter course through the subarachnoid space [7].
For many years a definitive diagnosis of SS could be established only by biopsy or post-mortem; however, due to the iron sensitive T2* gradient recalled echo (GRE) sequences or the more sensitive susceptibility weighted imaging (SWI) especially at higher field strength, SS exhibits characteristic imaging features with signal loss, i.e. dark rims on the surface of the affected structures [2,18,[26][27][28][29][30][31]. The paramagnetic blood breakdown products, also including hemosiderin as a stable final product, cause local magnetic field inhomogeneity [2,30,31]. The radiological appearances of SS with different sequences and field strengths are illustrated in Fig. 2.
The most common etiology is spinal dural disease, often coming along with ventral dural tears, less commonly intracranial dural abnormalities inducing classical type of iSS (type 1) (see Figs. 3 and 4). Dural tears may be caused by at times calcified disc herniation and occasionally spiculated osteophytes, often associated with a ventrally accentuated epidural fluid collection due to CSF leakage [10-12, 14, 15]. Dural ventral tears are preferentially located in the upper thoracic spinal levels [8,14,15]. Further pathologies are intrinsic dural diseases caused by connective tissue abnormalities, spinal CSF venous fistula or nerve root diverticula, traumatic nerve root avulsion (see Fig. 5) and postoperative pseudo-meningoceles [8,14,15,32]. Spontaneous intracranial hypotension (SIH) due to CSF leakage with similar intraspinal epidural fluid collection is associated with leptomeningeal hemosiderosis on MRI in 5-10% of patients [14,33,34]. Other less common etiologies for classical iSS are neurosurgical craniospinal interventions, trauma, cranial or spinal tumors and AVM [1,8,15]. Chronic ongoing or repetitive low-volume bleeding in the subarachnoid space can occur before the diagnostic conformation of a CNS tumor (see Fig. 2; [11]) or may be due to postoperative residual tumor tissue or a postsurgical cavity. There is evidence that AVMs found in the diagnostic work-up of SS are often incidental [8].
In type 2 iSS (secondary iSS) [5][6][7][8][9][10][11][12][13]15] evidence of a causative often single SAH or parenchymal bleeding is radiologically present; however, in contrast to classical iSS MRI may disclose asymmetric iSS predominantly focused in the neighborhood of the bleeding site [8,15]. It is worth noting that parenchymal bleeding may be caused by a ve- nous outflow disorder. In rare cases venous thrombosis can occur as a result of decreased intracranial pressure in so far undetected spinal dural CSF leakage [10,12]. Therefore, it seems recommendable that the etiology of the bleeding event has to be clarified before the assignment to type 1 or 2 iSS is made (see Fig. 1).
Typical neurological manifestations of classical iSS (type 1) are slowly progressive sensorineural hearing impairment and cerebellar symptoms, such as ataxia, kinetic tremor, nystagmus and dysarthria (see Figs. 3 and 4; [7][8][9]13]). Preferential affection of the cerebellar vermis results in severe ataxic gait disturbance up to inability to stand and walk [8]. In addition, spinal cord symptoms may occur, especially corticospinal tract signs with spasticity, rarely also anterior horn signs (see Figs. 4 and 5; [6,8,12]). In contrast, in patients suffering from iSS type 2 these neurological symptoms are lacking [8,15]. Contrariwise, predominately focal neurological deficits are often present depending on the localization and etiology of the pathologic process.
Patients suffering from SIH as sequelae of spinal dural CSF leakage often show orthostatic headache, dizziness and auditory disturbance, nausea and vomiting. Impressive amnestic hint is the statement "the day it all began" [10,12,14,34]. Characteristic focal neurological symptoms are cranial nerve palsies, especially abducens nerve failure [14,34]. Brain sagging results in consecutive mechanical stress of the abducens nerve due to the fixation within Dorello's canal when entering the clivus [34].
Beside MRI with thin slices, e.g. constructive interference in steady-state (CISS) and 3D T2 sampling perfection with application optimized contrasts using different flip angle evolutions (SPACE) [35], myelographic computed tomography (CT) and especially if indicated dynamic subtraction myelography are necessary to identify the circumscribed dural defect in classical iSS (see Fig. 1; [14,[36][37][38]). Overall, in more than 80% of patients with iSS a potentially causal spinal or cranial dural abnormality can be identified [8,10,15,35]. An additional supportive therapeutic option in iSS is the administration of iron chelates [39].

CAA Related Inflammation (CAA-ri)
CAA related inflammation (CAA-ri) is a disease subtype associated with autoantibodies against Aß deposits in the vessel walls of cortical and leptomeningeal small and medium sized arteries, arterioles and capillaries [103][104][105][106]. The vascular and perivascular inflammation cause vasogenic edema and sulcal effusions with hyperintense signal changes on T2 WI and FLAIR images, i.e. amyloid related imaging abnormalities-edema (ARIA-E) (see Fig. 9; [48,49,107,108]). The hemorrhagic type (ARIA-H) shows cerebral MB and cSS [40,41,108]. Neurological presentation of CAA-ri is characterized by rapidly progressive cognitive decline with  impairment of consciousness, headache, seizures and variable focal neurological deficits depending on the localization of the autoimmune process [104,[109][110][111]. Diagnostic criteria differentiate between probable and possible CAAri [104]. In probable CAA-ri MRI discloses uni-or multifocal subcortical or deep white matter hyperintensities that are asymmetric and extend to the immediately subcortical white matter, and asymmetry is not due to past ICH [48,104,105,110]. The patients are of age ≥ 40 years and neoplastic, infectious or other etiologies must be excluded. Because definitive diagnosis requires brain biopsy, knowledge of neuroradiological features in CAA-ri is essential [104,110,112]; however, from a histological point of view CAA-ri summarizes perivascular inflammation with histiocytes and also vessel wall inflammation with lymphocytes, and changeover to Aß related angiitis (ABRA) is not further differentiated [113][114][115][116].
There is evidence that intravenous (i.v.) high-dose corticosteroid pulse therapy with slow oral tapering is effective in spontaneous CAA-ri with neurological recovery in 84% within 1 year (see Fig. 8; [104,110,117,118]); however, especially when i.v. corticosteroid therapy is stopped suddenly, in 34% recurrence within 24 months was observed. Focal brain atrophy is a likely consequence in nonresponders to anti-inflammatory treatment [104,112].

Amyloid beta (Aß) Targeting Monoclonal Antibody Therapies
Different randomized clinical trials within the investigational use of monoclonal antibodies targeting Aß including aducanumab and bapineuzumab showed ARIA-E and ARIA-H. This suggests that immunotherapy related ARIA is an iatrogenic version of CAA-ri [40,59,81,82,108,119,120]. Due to increased parenchymal trafficking of Aß to the perivascular pathway during immunization with monoclonal antibodies the Aß overflow may lead to a disruption of smooth cells in the vessel wall [54,60]. The extravasation of fluid with elevated protein content causes ARIA-E with edema and sulcal effusions, depending on the location of affected intraparenchymal and/or leptomeningeal vessels ( Fig. 9; [40,48,60,81,82]). Whereas a single hyperintense lesion on FLAIR images smaller than 5 cm reflects mild severity, lesions > 5 and ≤ 10 cm are classified as moderate and lesions > 10 cm reflect severe ARIA-E [48]. Extravasation of blood cells causes ARIA-H, whereas up to 4 MB are considered as mild, 5-9 MB reflects moderate and ≥ 10 MB reflects severe ARIA-H [50]. In addition, also new areas of cSS (1, 2 or > 2) represent a mild, moderate or severe stage, respectively [40,81]. The number of MB at baseline and the APO-E©4 allele are risk factors for ARIA-E and ARIA-H. The risk of ARIA-E also depends on the antibody dosage and patients suffering from ARIA-E are at higher risk for additional ARIA-H [40,108]. In the EMERGE and ENGAGE phase 3 randomized clinical trials of aducanumab, ARIA-H associated cSS occurred in total in 14.7% of patients treated with a dose of 10 mg/kg and in APO-E©4 carriers in 19.1% [108].
However, it is noteworthy that despite possible impressive imaging features the most common associated neurological symptom was headache [108]. Whereas ARIA-E was transient and resolved within 12-16 weeks after initial detection, ARIA-H tends to persist over time (see Fig. 10). It is hypothesized that vascular remodelling after Aß clearance might reduce further risk of ARIA over time [60,108].
In conclusion, iSS is likely due to recurrent or continuous slight bleeding into the subarachnoid space, commonly due to spinal dural abnormalities, often dural tears (classical or type 1 iSS). Dural tears may be caused by at times calcified disc herniation and occasionally spiculated osteophytes, often associated with a ventrally accentuated epidural fluid collection due to CSF leakage. Further pathologies are intrinsic dural diseases caused by connective tissue abnormalities, CSF-venous fistula or nerve root diverticula, traumatic nerve root avulsion and postoperative pseudo-meningoceles. In consequence, detailed neuroradiological assessment of the spinal compartment is necessary, including MRI with thin slices, e.g. CISS and SPACE sequences, myelographic computed tomography (CT) and dynamic subtraction myelography. In SIH due to CSF leakage with similar intraspinal epidural fluid collection MRI concomitantly disclosed leptomeningeal hemosiderosis in 5-10% of patients.
In contrast, cSS especially in older patients is often due to CAA, encompassing a genetic and biochemical inhomogeneous group of pathologies in which the reduced perivas-cular clearance of Aß from the interstitial fluid has a key role in the pathogenesis. Typical clinical presentation of cSS in CAA includes transient focal neurological episodes or "amyloid spells". Knowledge of this neurological feature in CAA and associated cSS is essential to avoid clinical misinterpretation and subsequent wrong therapeutic interventions. In addition, CAA-ri may occur spontaneously or caused by Aß immunotherapy. In contrast to several grades of neuropsychological disturbances due to spontaneous CAA-ri, Aß immunotherapy associated ARIA-E and ARIA-H neurologically is often present with headache. In contrast, slowly progressive sensorineural hearing impairment and cerebellar symptoms up to severe ataxic gait disturbance reflect the neurological key symptoms in the classical type of iSS.
Funding Open Access funding enabled and organized by Projekt DEAL.
Conflict of interest S. Weidauer, E. Neuhaus and E. Hattingen declare that they have no competing interests.
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