Updated Jan 31, 2023
SUPERFICIAL SIDEROSIS SUBVARIANTS
Infratentorial Superficial Siderosis, Type 1 (Classical) (iSS1)
Infratentorial superficial siderosis, type 1 (classical) (iSS), or superficial siderosis of the central nervous system, is a profoundly disabling degenerative subvariant of superficial siderosis affecting the brain and spinal cord. iSS affects all races, ethnicities, and genders, with onset manifesting at any age. Persistent long-term hemorrhage into the subarachnoid space results in a neuro-toxic accumulation of free iron products on the brain and pia mater from circulating cerebrospinal fluid. This circulation distribution process may also result in hemosiderin deposition in the supratentorial region. Bergman glia and microglia cells in the cerebellar cortex function as conduits for iron entering the tissue, facilitating ferritin biosynthesis resulting in accumulation within the superficial layer of astrocytes, the gray matter of the brain, oligodendroglia, and sub-ependymal tissue.
Clinical features are related to sensorineural hearing loss, ataxia, and myelopathy with pyramidal signs. Characteristically, patients clinically manifest a diverse number of symptoms, including tinnitus, anosmia, nystagmus, diplopia, anisocoria, neurogenic bladder, constipation, urinary or fecal incontinence, decreased sensation during micturition or defecation, neuropathy, headache, hyperreflexia, cerebellar dysarthria, dysdiadochokinesia, autonomic nervous dysfunction, dysregulation of blood pressure and vessels, spasticity, myoclonus, seizure, gait/truncal ataxia, radicular pain, intracranial hypotension, cognitive impairment, mood/behavior changes, and dementia.
INFRATENTORIAL SUPERFICIAL SIDEROSIS, TYPE 2 (SECONDARY)(iSS2)
Infratentorial superficial siderosis, type 2 (secondary), displays radiologically in an infratentorial region but is restricted to a single area extensively involving intracranial hemorrhage with only a thin rim of hemosiderin in adjacent areas. Iron and heme products are introduced from a major acute intracranial hemorrhagic event and are not distributed via cerebral spinal fluid circulation. Clinical features will be restricted to the affected region. For example, a patient may present with symptoms of gait/truncal ataxia or balance issues, but their hearing may never display any impairment beyond the normal aging process.
(Kharytaniuk N. et al, Practical Neurology 2022; 22:274-284)
CORTICAL SUPERFICIAL SIDEROSIS (CSS)
Cortical superficial siderosis (cSS) radiologically presents only in the supratentorial region of the cerebrum, limited to cortical sulci favoring cerebral convexities of the cerebral hemispheres. It is most often associated with cerebral amyloid angiopathy (CAA), where rupture of amyloid-laden leptomeningeal arterioles results in subarachnoid bleeding over the cerebral convexities, resulting in subpial cortical hemosiderin. The etiology is primarily recognized as an age-related cerebral small vessel disorder.
Patients with Alzheimer’s disease are nearly seven times more likely than other patients to radiologically display a serpentine pattern of cortical superficial siderosis (cSS) hemosiderin deposition across the brain’s surface.
(Zonneveld et al, Feb 25, 2014, Neurology)
While progression moves slowly in the pre-symptomatic or initial stage, the time from the clinical manifestation of early signs and symptoms such as tinnitus, complaints of dizziness, or phantosmia to the diagnosis of superficial siderosis may be as long as ten years. This is partly due to a disproportionate number of treating clinicians’ inability to distinguish between superficial siderosis variations or grasp the severe progressive nature. The past absence of clinical data impedes care management, resulting in delayed or no intervention until course progression reaches a point of profound disability. The clinical investigation of patient complaints should be reviewed against the long-term medical history focusing on previous surgical procedures, aneurysms, traumatic contusions, or accidents occurring as long as thirty to forty years in the past with older patients.
MRI sequencing is required to confirm the diagnosis. Superficial siderosis will be characterized as a rim of low signal covering the subpial surfaces of the brain, brainstem, and spinal cord, particularly on the gradient-echo (GRE) or susceptibility-weighted (SWI) sequences. Ependymal hypointensity may also occur in severe forms of superficial siderosis.
Clinical care relies on the coordinated management of progressive underlying symptoms.
- Patients may require extended periods to regulate new medications
- Surgical procedures, anesthesia, infections, or severe illness may require an extended recovery period
- Long-term oral anticoagulation therapy before surgical closure of the hemorrhagic source can act as a contributing and possible causative agent.
Neurosurgical intervention to prevent fresh heme from entering the CNS is the primary method of interrupting hemosiderin deposition. *The “classic triad” of ataxia, bilateral sensorineural hearing loss, and myelopathy are well-reported in the literature. iSS patients may clinically manifest an endless combination of associated symptoms, including but not limited to:
- bilateral sensorineural hearing* impairment
- bladder dysfunction
- bowel dysfunction
- cerebellar dysarthria
- autonomic nervous dysfunction
- impairment of the nervous system control of blood pressure and vessels
- craniospinal hypotension
- cognitive impairment
- mood and behavior changes
- dementia (late-stage iSS1)
- radicular pain
- balance impairment
- wide-based gait
- loss of sexual function
- impaired neurological reserve
Koeppen AH., et al. Acta Neuropathol (2008) 116:371–382
Gross neuropathology of superficial siderosis. Cerebellar cortex (a, b), brain stem (a), eighth cranial nerve (VIII in b), spinal cord (c), and filum terminale (arrow in d) display a dark brown to orange color of variable intensity. Incrustation of the cerebellum is most severe in the upper vermis, the superior hemispheres, and the cortex surrounding the cerebellopontine angle (a and b). The facial and glossopharyngeal nerves (VII and IX, respectively, in b) do not show intense brown discoloration of the adjacent eighth nerve (VIII in b). Anterior and dorsal spinal roots (arrows in c), including those of the cauda equina (d), are also devoid of iron pigment. The cross-sectional areas of the siderotic spinal cord are abnormally small.
The pathophysiology of iSS reflects a failure within a small subset of the population to curb heme products within ferritin proteins. Hemolysis rupturing blood cells circulating through the CNS results in a heme overload activating Bergman glia and microglial cells into heme oxygenase 1(HO-1) production. Heme oxygenase is an endoplasmic reticulum enzyme that oxidizes heme to biliverdin, free ferrous iron, and carbon monoxide. In a critical biochemical step, astrocytes release ferritin protein to curb Fe2+ molecules. Ferritin controls the reversibility of the transition phase between Fe2+ (soluble) and Fe3+ (insoluble) mineralized inside the protein. Cerebrospinal fluid circulation of heme products results in hemosiderosis on the surface of the macrophages, cortical sulci, cerebellar cortex, and pia mater. Bergman glia and microglia in the cerebellar cortex act as conduits for heme entering the tissue facilitating ferritin biosynthesis resulting in accumulation within the superficial layer of astrocytes, gray matter oligodendroglia, and sub-ependymal tissue.
HO-1 up-regulation in the compartments created by glial cells surrounding neuronal endings required for neuronal function facilitates bioenergetics failure, pro-toxin bioactivation, macroautophagy, and corpora amylacea formation, by affecting iron metabolism and mitochondrial activity. The Fenton/Haber-Weiss reaction has significant effects on pathophysiological conditions. Fe2+ reacts with hydrogen peroxide to create the hydroxyl ion (OH−), the hydroxyl radical (OH•), and ferric Fe3+ iron. The OH• radical is an indiscriminate, highly toxic oxidant. As mitochondria initiate the production of adenosine triphosphate ATP through glycolysis ->Krebs Cycle -> Electron Transport Chain (ETC) by oxidative phosphorylation (OXPHOS), the ROS superoxide is one of the by-products produced from the ETC. Superoxide radicals can unbind Fe3+ from ferritin and Fe2+ from Iron-sulfur (Fe-S) clusters.
iSS principally presents radiologically in the infratentorial region, but deposition may be concurrent in the supratentorial region of the cerebrum, brain stem, basilar cisterns, and spinal cord. Dural defects are considered a predominant originating source of heme in iSS1.
EXISTING THERAPEUTIC INTERVENTIONS
Superficial siderosis: a case report and review of the literature (Levy et al. 2007), Pilot safety trial of deferiprone in 10 subjects with superficial siderosis (Levy et al. 2012), and Two-year observational study of deferiprone in superficial siderosis (Kessler et al. 2018) provided evidence for hemosiderin reduction through chelation. This method is still the only viable pharmacological intervention to date, but its efficacy continues to be debated by clinicians. In addition, neural dysfunction continues during an elimination process that may take years if successful for patients undergoing chelation.
SUPERFICIAL SIDEROSIS: A CASE REPORT AND REVIEW OF THE LITERATURE, (LEVY ET AL., 2007)
A 48-year-old male patient with a history of a past auto accident-induced coma was identified through MRI sequencing to present with iSS. This solo case study demonstrated the safety and therapeutic efficacy of deferiprone, a lipid-soluble iron chelator, to cross the blood–brain barrier. This was the first proof-of-concept showing that reduction of hemosiderosis and neuro-toxic iron products could stabilize or reverse the disorder process.
PILOT SAFETY TRIAL OF DEFERIPRONE IN TEN PARTICIPANTS WITH SUPERFICIAL SIDEROSIS (LEVY ET AL., 2012)
Based on the single iSS patient’s response to deferiprone, approval was obtained from the Food and Drug Administration to investigate the safety of deferiprone in a cohort of ten participants with iSS. Although efficacy was not the primary endpoint of the investigation, brain MRI sequencing was conducted to radiologically evaluate the hemosiderosis accumulation and clinical data collected to assess the potential benefits of deferiprone on the clinical manifestations of iSS.
The primary objective was to assess the tolerability and safety of deferiprone in iSS participants. Because deferiprone has been associated with agranulocytosis in patients with thalassemia major, weekly blood counts were monitored for evidence of episodes of neutropenia in this study cohort.
During this 90-day open-label trial, there was no indication of patient bone marrow involvement. There was no change in white blood cell counts, absolute neutrophil counts, percentage of neutrophils, or hemoglobin levels. Monthly liver function tests indicated three participants had transient elevations in liver function test results over the course of the trial. These two participants discontinued deferiprone therapy for seven days, during which the liver enzymes declined. Both participants resumed deferiprone after seven days and experienced no further liver enzyme elevations. Monthly ferritin levels underwent a modest decline in all participants over the course of the 90-day trial, but none was below the low reference range of 5 ng/mL.
MRI sequencing was completed at the conclusion for the evaluation of hemosiderosis. An ad hoc comparison between the participant’s pre-intervention and post-intervention MRI scans was conducted to evaluate deferiprone’s efficacy in reducing the participants’ brain hemosiderin deposition. Although the time between the last pretrial MRI and the post-trial MRI varied in this ad-hoc analysis, investigators were able to determine a 90-day course of chelation therapy with deferiprone was associated with a decrease in hemosiderin deposition by MRI in 4 of the 9 participants.
TWO-YEAR CLINICAL TRIAL OF DEFERIPRONE IN SUPERFICIAL SIDEROSIS (KESSLER ET AL., 2018)
The aims of this observational study were to assess the clinical and radiological outcomes of iSS patients using deferiprone, a cell-permeant iron chelator. The results determined 63% of participants reported either symptom stability or an improvement in at least one neurological domain, with 40% of patients reporting a stabilization in hearing function and 30% reporting stable or improved coordination and walking.
MRI scans were objectively analyzed for changes in the iron deposition. In half of the participants, there was an overall mean increase in T2 hyperintensity of the whole brain (reduced iron) of 1-13% over the 24-month time, indicating a reduction in hemosiderosis. There were no cases of agranulocytosis, and declines in white blood cell counts and neutrophils averaged < 10%. Fatigue was the most common side effect.
QUANTITATIVE CLINICAL AND RADIOLOGICAL RECOVERY IN POST-OPERATIVE PATIENTS WITH SUPERFICIAL SIDEROSIS BY AN IRON CHELATOR (NOBUO ET AL., OCTOBER 2021)
35 participants were identified with iSS based on clinical manifestations and MRI findings of hemosiderin deposition on the surface of the brain at the Tokyo Medical and Dental University Hospital between September 2007 and December 2019. Fifteen postsurgical bleed repair participants were recruited, with eight participants (control group) receiving only surgical intervention and seven participants receiving chelation therapy with deferiprone (case group) administration. Quantitative changes in the hypointense signals on T2*-weighted magnetic resonance images, cerebellar ataxia, and audiometry were acquired for both groups and comparatively assessed.
Considerable improvements in signal contrast ratios were observed in the lateral orbitofrontal gyrus, superior temporal lobe, insular lobe, brainstem, lingual gyrus, and cerebellar lobe in the case group. Case group participants’ cerebellar ataxia scale scores also significantly improved. The degree of signal improvement in the cerebellar lobe correlated with the improvement of cerebellar ataxia scores. Early deferiprone administration after disorder onset and long-term administration were correlated with greater signal improvements in magnetic resonance imaging. No adverse effects were observed in the clinical or laboratory parameters. The trial concluded deferiprone administration significantly improved radiological and clinical outcomes in patients with postoperative bleed abatement iSS. Earlier and longer courses of deferiprone could result in better patient prognosis.
TREATMENT RESPONSE OF DEFERIPRONE IN INFRATENTORIAL SUPERFICIAL SIDEROSIS: A SYSTEMATIC REVIEW. THE CEREBELLUM. (MARTIN, ANDREAS ET AL., 2021)
Case studies of deferiprone as a therapeutic intervention in infratentorial superficial siderosis were included in a systematic review based on PRISMA guidelines.
Eleven papers met the review criteria.
- 69 patients in total were identified.
- Seventeen patients (25%) discontinued the drug.
- The most encountered adverse effect was anemia (21.7%).
- Neutropenia was observed in 8.7% of patients.
- Agranulocytosis was observed in 5.8% of patients.
Clinically, while the outcome was diverse, stability or improvement was seen across neurological domains in six studies, while five showed a mixed response. On imaging, 13 (28.9%) patients improved, 24 (53.3%) stabilized, and 8 (17.8%) deteriorated.
Ideally, large-scale, multicentre, placebo-controlled, randomized studies should be performed using a standardized protocol which includes treatment dose, duration of follow-up and outcome measures (audiometry, scale for the assessment and rating of ataxia (SARA) scores and adverse effect monitoring) to provide further evidence of the role of deferiprone in the treatment of infratentorial superficial siderosis. There is also a need for further detailed stratification of patients to accurately identify factors which alter patient outcomes such as underlying cause of superficial siderosis, disease duration and severity. A prospective international centralized register of patients should be developed to inform the design and conduct of a multicentre, placebo-controlled, randomized clinical trial to evaluate the efficacy of deferiprone. The evidence from this systematic review is that deferiprone is a promising intervention. (Martin, A et al., 2021)