Superficial Siderosis Clinical Trial
Official title:
Phase IV 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 (CNS) 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, the investigators 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, the investigators propose documenting the
clinical effect of deferiprone over 2 years in superficial siderosis patients. The
investigators' 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 the investigators collect information for this study. The investigators 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.
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. Glial cell 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 iron
chelators 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 copper chelators 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, the investigators 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, the investigators
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.
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| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Not yet recruiting |
NCT04890808 -
Therapeutic Antioxidant Supplementation
|
N/A |