The deleterious effects of Infratentorial Superficial Siderosis (iSS), both type 1 (iSS1) and type 2 (iSS2), emanate from the pathological accumulation of iron, specifically free iron, in the cerebrospinal fluid (CSF) that subsequently leads to neurotoxic damage. It is posited that the therapeutic use of iron chelation could retard the progression of neurological dysfunction and related symptomology in iSS by mitigating the amount of free iron within the CSF, an approach rooted in the understanding of iron’s role in the central nervous system (CNS) and its effect on neuronal health.
In the physiological state, iron plays an integral role in the CNS, contributing to various essential biological processes such as myelin synthesis, neurotransmitter production, and mitochondrial function. However, when excessive hemosiderin is present, as is the case in iSS, excessive free iron can induce neurotoxic effects via oxidative stress, protein aggregation, and mitochondrial dysfunction.
As explained earlier, excessive free iron can catalyze the Fenton/Haber-Weiss reaction at the molecular level, producing reactive oxygen species (ROS), including hydroxyl radicals. These radicals are highly reactive and can cause oxidative damage to lipids, proteins, and nucleic acids, thus impairing the function of neurons and leading to cell death.
Iron chelation therapy sequesters the excessive free iron, rendering it inert and preventing its participation in the aforementioned Fenton reaction. This reduction in ROS production can alleviate oxidative stress, preserving the structural and functional integrity of neuronal cells. Moreover, by chelating iron, it may also prevent the aggregation of iron-binding proteins, which can disrupt cellular processes and contribute to neurodegeneration.
It is noteworthy that mitochondrial dysfunction is implicated in the pathophysiology of various neurodegenerative diseases, including iSS. Iron overload can disrupt mitochondrial function by generating ROS, damaging mitochondrial DNA, and interfering with the electron transport chain. By chelating iron, it may be possible to protect the mitochondria, preserving their function and promoting neuronal survival.
Taken together, the application of iron chelation therapy in managing iSS aims to slow the progression of neural dysfunction. This strategy holds potential as a targeted therapeutic approach; however, further research is necessary to elucidate the precise mechanisms and evaluate iron chelation’s clinical efficacy and safety in the context of iSS. 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 Literature Review (Levy et al., 2007) details a singular case study of a 48-year-old male who developed iSS following a vehicular accident. In this instance, deferiprone was used as an efficacious lipid-soluble iron chelator able to traverse the blood-brain barrier, providing the initial evidence for the capability of deferiprone in mitigating hemosiderosis and neurotoxic iron, thereby potentially halting or reversing the progression of the disorder.
Subsequently, the Pilot Safety Trial of Deferiprone in Ten Participants with Superficial Siderosis (Levy et al., 2012) extended the research on deferiprone to a larger cohort under the approval of the Food and Drug Administration. This investigation’s primary objective was to scrutinize deferiprone’s safety and tolerability in iSS patients due to its previous association with agranulocytosis in thalassemia major patients. Throughout the 90-day trial, there were no indications of adverse bone marrow involvement or significant alterations in blood cell counts. Transient elevations in liver function tests were noted in three participants, with two discontinuing and then resuming treatment with no further adverse outcomes. The trial observed a moderate reduction in ferritin levels among participants and identified a decrease in brain hemosiderin deposition via MRI in 4 out of 9 participants.
The Two-Year Clinical Trial of Deferiprone in Superficial Siderosis (Kessler et al., 2018) sought to assess deferiprone administration’s long-term clinical and radiological impact in iSS patients. The study determined that over half of the participants experienced symptomatic stability or improvements in various neurological domains, with reduced iron levels indicated in MRI scans for half of the participants. The trial did not report any cases of agranulocytosis, although fatigue was a common side effect.
The scholarly article “Quantitative Clinical and Radiological Recovery in Post-Operative Patients with Superficial Siderosis” (Nobuo et al. 2021) scrutinized a cohort of 35 post-operative iSS patients. Within this cohort, a subset of 15 patients was administered deferiprone subsequent to their surgical procedures. The empirical data gleaned from this study highlighted a discernible augmentation in MRI signal contrast ratios and a reduction in cerebellar ataxia scores for those treated with deferiprone. This evidence suggests that the iron chelator, deferiprone, is pivotal in ameliorating radiological and clinical trajectories. Furthermore, commencing deferiprone therapy expeditiously and sustaining its administration correlated with a more favorable prognosis, and the treatment exhibited an absence of substantial adverse reactions.
In the comprehensive systematic review titled “Treatment Response of Deferiprone in Infratentorial Superficial Siderosis: A Systematic Review” (Martin, Andreas, et al. 2021), a meticulous analysis was conducted on eleven pertinent studies, cumulatively involving 69 patients, and this yielded a spectrum of clinical outcomes. While anemia, neutropenia, and agranulocytosis were delineated as adverse reactions to the treatment, their incidence was relatively infrequent. The review underscored the imperative for robust, multicentric, placebo-controlled, randomized studies that rigorously adhere to a uniform protocol. Such an approach would be instrumental in crystallizing our comprehension of deferiprone’s therapeutic efficacy and tolerability in the context of iSS management. Additionally, the study advocated for the inception of an international patient registry, positing that this would be invaluable in streamlining the conceptualization and operationalization of subsequent investigative endeavors. Preliminary inferences are drawn from the review intimate that deferiprone might hold substantial promise as a therapeutic intervention for infratentorial superficial siderosis.