Observational Study of Deferiprone (Ferriprox®) in the Treatment of Superficial Siderosis
Superficial siderosis is a progressive neurological disease caused by iron deposition in the central nervous system from chronic subarachnoid bleeding. Until 2011, there has been no effective treatment for this progressive condition that leads to hearing loss, spasticity, weakness, loss of bowel/bladder function, incoordination, dementia and ultimately death.
Last year, we demonstrated that a lipid soluble iron chelator, deferiprone, can reduce hemosiderin deposition in patients with superficial siderosis by MRI in as little as 3 months. As the only therapy that can improve this condition, chelation with deferiprone is the standard of care for treatment of superficial siderosis. Now that the FDA has approved deferiprone in the United States for thalassemia, we propose documenting the clinical effect of deferiprone over 2 years in superficial siderosis patients. Our goal is to understand how the clinical course of this disease is altered using standard of care chelation therapy with deferiprone.
Patients with superficial siderosis who are taking deferiprone for chelation therapy at doses consistent with the standard of care will be offered enrollment into this observational study. Patients will be treated and monitored locally by participating neurologists who have agreed to help us collect information for this study. We are interested in documenting the clinical effect of deferiprone on hearing, ataxia and myelopathy using standardized scales performed and documenting the effect of deferiprone on hemosiderin deposition in the CNS by MRI, all performed according to standard of care.
|Study Design:||Observational Model: Cohort
Time Perspective: Prospective
|Official Title:||Phase IV Observational Study of Deferiprone (Ferriprox®) in the Treatment of Superficial Siderosis|
- Efficacy -- Improvement in hearing audiology exam [ Time Frame: 2 years ] [ Designated as safety issue: No ]Standard audiology exam to examine severity and frequency and hearing loss in both ears.
- Ashworth Spasticity Scale score as a measure of muscle spasticity [ Time Frame: 2 years ] [ Designated as safety issue: No ]Standardized score to measure changes in limb muscle spasticity
- Scale for the Assessment and Rating of Ataxia [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]Standardized outcome measure to measure changes in coordination function including ability to stand, walk, talk and move the arms and legs in a coordinated manner.
- MRI of the brain and spinal cord [ Time Frame: every 6 months for 2 years ] [ Designated as safety issue: No ]MRI of the brain and spinal cord without contrast to monitor for changes in hemosiderin deposition.
|Study Start Date:||March 2012|
|Estimated Study Completion Date:||June 2016|
|Estimated Primary Completion Date:||March 2016 (Final data collection date for primary outcome measure)|
All patients must have MRI evidence of superficial siderosis and be treated with deferiprone according to standard of care guidelines.
First described over 100 years ago, superficial siderosis is a rare neurodegenerative disease caused by iron toxicity in the CNS due to chronic subarachnoid bleeding. Iron from red blood cells in the subarachnoid space is preferentially taken up by the Bergmann glia in the cerebellum, brainstem, spinal cord, eighth cranial nerve and the cerebral cortex; the iron is stored as ferritin within the glial cells. With continued subarachnoid bleeding, the glia are overwhelmed by the ferritin load and die. Their loss exposes neurons to free iron which is toxic to cells because it catalyzes the breakdown of hydrogen peroxide to superoxide, a reactive oxygen species that can cause lipid peroxidation, membrane dysfunction, and neuronal cell death.
Neurological consequences of iron overload depend on the area of the brain exposed to free iron. With chronic subarachnoid bleeding, the blood tends to pool around the brainstem, cerebellum and spinal cord thus leading to the classic triad of hearing loss, ataxia and myelopathy that is seen in more than 50% of patients with superficial siderosis. The eighth cranial nerve courses through the subarachnoid space until it reaches the inner ear exposing it to the toxic blood; in contrast, the other cranial nerves are protected by the peripheral Schwann cells within 1 mm of exiting the brainstem. Compared to the other CNS structures affected in superficial siderosis, the eighth cranial nerve is the most susceptible because it exposes the most surface area to volume. Thus, the most common and often the first symptom patients get is sensorineural hearing loss. This is followed by ataxia due to dysfunction of both the vestibular component of the eighth cranial nerve and neurodegeneration of the cerebellum. Myelopathy develops when the brainstem and spinal cord are involved. With continued bleeding, other areas of the brain can degenerate leading to a myriad of other symptoms seen in superficial siderosis including urinary problems headaches, anosmia, diplopia, bowel problems, ageusia, cranial nerve palsies, and dementia.
The etiologies of chronic subarachnoid bleeding are (in order of incidence): Idiopathic, Head/back trauma, A/V malformations, Current CNS tumor, Previously resected CNS tumor, CNS post-surgical (non-tumor), Amyloid angiopathy, Brachial plexus/root injury. Currently, there are fewer than 50 patients world-wide with the diagnosis of superficial siderosis. In the United States, there are an estimated 50-60 patients.
Iron chelators, other than deferiprone, used in other iron-overload disorders such as hemochromatosis are not expected to be effective in superficial siderosis because they do not cross the blood brain barrier. Copper chelators used in Wilson's disease can permeate the brain-blood barrier, but are unfortunately not effective in superficial siderosis, as they do not bind iron. Surgical intervention is thought to be key to slowing the disease by stanching the leak of blood into the subarachnoid space. However, once the neurodegenerative process has begun, surgical intervention does not prevent the neurodegenerative disease from progressing.
Recently, we have demonstrated that deferiprone, a lipid-soluble iron chelator, at a dose of 30 mg/kg/day administered over 90 days is safe in a population of 10 superficial siderosis patients. Although not designed to assess efficacy, we also found that 4 of 10 patients showed reduced hemosiderin deposition in the CNS after the trial, which is very different from the natural course of disease in which hemosiderin deposition either remains the same over 3 months or increases over time. This suggests that deferiprone may be effective in chelating hemosiderin in patients with superficial siderosis.
|United States, Maryland|
|Johns Hopkins University|
|Baltimore, Maryland, United States, 21287|
|Principal Investigator:||Michael Levy, MD, PhD||Johns Hopkins University|