Observational Study of Deferiprone (Ferriprox®) in the Treatment of Superficial Siderosis
Condition: Superficial Siderosis
MeSH terms: Siderosis
Study type: Observational

Summary: 
      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.
    

Detailed description: 
      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.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        All patients with MRI-confirmed superficial siderosis currently residing in the United
        States.
      
Keywords: superficial siderosis