NORD gratefully acknowledges Michael Levy, MD, PhD, Associate Professor, Harvard Medical School; Director, Neuromyelitis Optica Clinic and Research Laboratory; Research Director, Division of Neuroimmunology & Neuroinfectious Disease; Massachusetts General Hospital and the Superficial Siderosis Research Alliance, for the preparation of this report.
Summary
Infratentorial superficial siderosis, commonly identified as superficial siderosis, is a disabling degenerative disorder affecting the brain and spinal cord. Persistent or recurring long-term bleeding (hemorrhage) into the subarachnoid space in the brain results in a toxic build-up of hemosiderin (an important component of iron delivery) on the surface of the brain and pia mater from circulating cerebrospinal fluid. Patients will present with one or more of the classic triad of symptoms: hearing loss, movement abnormalities (ataxia), and motor difficulties due to suspected spinal cord injury (myelopathy) with pyramidal signs. Proper recognition and timely early diagnosis of superficial siderosis allow for early care planning.
Typically, the period between the onset of noticeable clinical symptoms and the trigger event ranges between 10-30 years. Symptoms and signs will present depending on the location of hemosiderin deposition and state of weakness of neural tissue. The intensity of deposition shown on imaging will not always correspond with the degree of disability due to the slow-moving progressive nature of the disorder. 95% of patients will exhibit progressive hearing impairment in both ears. 88% of patients will show signs of progressive ataxia with a focus on wide-based gait and balance issues. 76% will experience myelopathy with pyramidal signs. Additional signs include mild cognitive impairment, uncontrolled eye movements (nystagmus), poor coordination (dysmetria), difficulty swallowing (dysphagia), uncontrolled muscle movements (spasticity), loss of smell (anosmia), loss of taste (ageusia), different pupil sizes in the eyes (anisocoria) bladder or bowel dysfunction, sensory defects, small motor dysfunction, nerve pain (neuropathy), headache, autonomic nervous system dysfunction, inability to perform rapid, coordinated movements (dysdiadochokinesia), slurred speech (dysarthria), overactive reflexes (hyperreflexia) and abnormal foot reflexes (Babinski signs)
Cortical superficial siderosis (cSS) is a recognized variant of superficial siderosis. Hemosiderin deposition is limited to cortical sulci over the convexities of the cerebral hemispheres, sparing the cerebellum, brainstem and spinal cord affected in the classic iSS symptoms. Identified with gradient recalled echo (GRE) or susceptibility-weighted imaging (SWI) MRI as linear hypointensities, cortical superficial siderosis (cSS) is often due to cerebral amyloid angiopathy, an age-related cerebral small vessel disorder. Symptoms of amyloid angiopathy include transient focal neurological episodes, cognitive impairment, generalized seizures, headaches, and increased intracerebral hemorrhage risk.
Superficial siderosis is an acquired disorder caused by chronic long-term subarachnoid bleeding. A large percentage of the identifiable bleed sources are abnormalities resulting from recurring brain bleeds (chronic suboccipital hematomas), sacs protruding from the spinal column (meningoceles) or spinal surgery tears resulting in pseudomeningoceles. Other causes include root avulsions or epidural cyst removal, intradural cranial surgery, brain tumors, vascular abnormalities, fragile capillary regrowth after brain surgery, nerve damage (brachial plexus injury), head injury or bone marrow exposed to the spinal (intrathecal) space.
Ruptured blood cells (hemolysis) in the cerebrospinal fluid create a heme overload that triggers Bergman glia and microglial cells into producing the enzyme heme oxygenase-1. HO-1 breaks down the heme molecule resulting in the release of free-iron molecules, carbon dioxide, and biliverdin. Astrocytes release ferritin proteins to curb the free-iron molecules and the product is hemosiderin. Because hemosiderin is not soluble, gravity pulls it to the subpial surfaces in the infratentorium and spinal column where it attaches to the pia mater. Sleeping in the supine position leads to large accumulations in the cerebellum. Cranial nerve sections, brainstem, and the spinal cord may also become encased in hemosiderin. Long-term exposure to free-iron molecules released from the hemosiderin layer is toxic to the underlying neural tissue.
Superficial siderosis affects all races and age groups, with males affected at three times more often than females. The prevalence of superficial siderosis is estimated to be 1 in one million individuals. In the U.S., in 2020 there are an estimated 200 diagnosed cases, almost double the number of confirmed diagnosed patients in 2014. This increase is due to improved MRI techniques and neuro-radiologist awareness. The actual incidence of superficial siderosis is suspected to affect a larger population than is currently diagnosed.
The average time from the clinical manifestation of early symptoms such as ringing of the ears (tinnitus), complaints of dizziness, or reports of phantom odors to the diagnosis of superficial siderosis may be as long as ten years, partly due to the slow progression of the disease. Clinical investigation of patient complaints should be reviewed against the long-term medical history focusing on previous surgical procedures, aneurysm, 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.
The first step after a diagnosis is determining if a bleed source is present. Despite an investigation, a cause is not identified for a large percentage of patients. A CT myelogram is the preferred method to determine the location of a suspected bleed due to dural defect. The three suggested approaches for stopping a bleed are injection of fibrin glue into the dural tear site; for small leaks, an epidural blood patch may pull the dura from surrounding bone and immobilize the spinal cord long enough for healing to take place. Surgical closure of dural defects or other active bleed sites offers the best opportunity to stop additional hemosiderin deposition.
The progression of neurological deficits will continue as long as free-iron molecules continue to release from existing hemosiderin. Elimination of hemosiderin deposition off the subpial surface is fundamental to potentially stopping cerebellar atrophy and neural damage. This removal action must be accomplished through iron chelation. In order for a chelating agent to achieve its desired pharmacological effect, the drug must reach the target sites at sufficient concentration. Deferiprone is an orally active bidentate hydroxypyridinone iron chelator proven to cross the blood-brain barrier that binds to ferric ions (fe3+), forms a 3:1 chelator to iron stable complex, and is eliminated through urine. One reason for the limited efficacy of deferiprone in clinical use is its extensive metabolism in the liver. Patients prescribed deferiprone require close monitoring due to the severe nature of possible side effects, most notably being a low incidence of reversible agranulocytosis.
Patient care will rely on the coordinated treatment of the underlying symptoms through referral to appropriate specialties. The superficial siderosis patient in mid to late-stage progression lives in a state of compromised neurological reserve on a perpetual basis. They may require a longer than average recovery time from procedures, surgery, or illness. Consideration should be given for neuropsychological evaluation with increasing patterns of cognitive and social impairment, memory problems, or behavioral changes. 20% of those diagnosed with mild or progressive cognitive impairment initially may progress to neurodegenerative dementia.
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