Superficial siderosis
Encyclopedia
Superficial hemosiderosis
of the central nervous system is a disease of the brain resulting from chronic iron deposition in neuronal tissues associated with cerebrospinal fluid
. This occurs via the deposition of hemosiderin
in neuronal tissue, and is associated with neuronal loss, gliosis
, and demyelination
of neuronal cells. This disease was first discovered in 1908 by R.C. Hamill after performing an autopsy. Detection of this disease was largely post-mortem until the advent of MRI technology, which made diagnosis far easier. Superficial siderosis is largely considered a rare disease, with less than 270 total reported cases in scientific literature as of 2006, and affects people of a wide range of ages with men being approximately three times more frequently affected than women. The number of reported cases of superficial siderosis has increased with advances in MRI technology, but it remains a rare disease.
of the brain, which releases erythrocytes, or blood cells, into the cerebrospinal fluid. The chronic bleeding can come from many sources such as from an arteriovenous malformation
, from chronic subdural hematoma
, from a ventricular shunt, or from chronic subarachnoid hemorrhage
. Chronic bleeding sources can also be a result of past brain surgery or CNS
trauma, which may be the most common cause of superficial siderosis, with superficial siderosis showing up many years later. In up to as many as half of all described cases the source of bleeding was never found.
containing protein hemoglobin
. Hemoglobin breaks down and releases iron-containing heme into the cerebrospinal fluid. In response to this upsurge in heme levels, Bergmann glia and microglia
produce heme oxygenase 1. Heme oxygenase 1 breaks down free heme into biliverdin
, carbon monoxide, and iron. It is this breakdown of heme that is the source of iron deposition that ultimately causes superficial siderosis. The excess free iron is circulated in the cerebrospinal fluid and deposited in neuronal tissues, where it catalyzes the formation of reactive oxygen species which can damage DNA, RNA, proteins, and is otherwise toxic to the cells.
Iron deposition is prevalent in siderotic brain tissues, with iron concentrations of 1.79 to 8.26 times normal levels. Ferritin
, an iron storage protein, is over-produced in response to excess heme by glial cells in order to sequester iron, with production ranging from 20.1 to 27.4 times normal levels. Excess iron, ferritin, and red blood cells may result in xanthochromia of the cerebrospinal fluid. Amongst neuronal cells types, iron deposition appears to be preferential for oligodendroglial cells, which is supported by the belief that they can act as iron sinks in the central nervous system. Schwann cells are also frequently damaged, contributing to demyelination.
Iron deposition is most prevalent in the inferior temporal lobes, the brainstem, the cerebellum
, periventricular
structures, the spinal cord
, and cranial nerve VIII. Iron deposition is also present in cranial nerves I & II, but this damage less frequently presents symptoms when compared to cranial nerve VIII, which can be explained by cranial nerve VIII’s notable segment of glial cells, which are preferentially affected by iron deposition.
The presence of ‘foamy’, ‘spheroid’, or ‘cytoid’ bodies in affected neuronal tissues has been noted but what they are and their origin remains somewhat unclear. They are believed to be swollen axonal bodies, but some evidence exists that they may be astrocytic
in origin.
Early detection of superficial siderosis is usually via MRI. The iron deposition that is characteristic of superficial siderosis shows up as a hypointense band in affected tissues, with a characteristic rim of intensity appearing on the cerebellum; a hyperintense rim is rarely seen. Taking samples of cerebrospinal fluid may also reveal siderosis through xanthochromia, elevated presence of red blood cells, high iron and ferritin concentrations, and elevated levels of the proteins Tau, beta amyloid (Aβ42), neurofilament light protein (NFL), and glial fibrillary acidic protein (GFAP), but the CSF is sometimes normal. Detection is complicated by the fact that superficial siderosis is a rare disease and is not well described in neurological texts, so it may go unnoticed until noticeable symptoms appear.
The use of drugs to treat superficial siderosis is still being investigated. The use of iron chelating
drugs and steroids have been explored but they have proven to be largely unsuccessful thus far.
Alleviation of the most common symptom, hearing loss, has been varyingly successful through the use of cochlear implant
s. Most people do not notice a large improvement after successful implantation, which is most likely due to damage to the vestibulocochlear nerve (cranial nerve VIII) and not the cochlea itself. Some people fare far better, with a return to near normal hearing, but there is little ability to detect how well a person will respond to this treatment at this time.
Hemosiderosis
Idiopathic pulmonary haemosiderosis is a lung disease of unknown cause that is characterized by alveolar capillary bleeding and accumulation of haemosiderin in the lungs...
of the central nervous system is a disease of the brain resulting from chronic iron deposition in neuronal tissues associated with cerebrospinal fluid
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
. This occurs via the deposition of hemosiderin
Hemosiderin
thumb|Hemosiderin image of a kidney viewed under a microscope. The brown areas represent hemosiderinHemosiderin or haemosiderin is an iron-storage complex. It is always found within cells and appears to be a complex of ferritin, denatured ferritin and other material...
in neuronal tissue, and is associated with neuronal loss, gliosis
Gliosis
Gliosis is a proliferation of astrocytes in damaged areas of the central nervous system . This proliferation usually leads to the formation of a glial scar....
, and demyelination
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
of neuronal cells. This disease was first discovered in 1908 by R.C. Hamill after performing an autopsy. Detection of this disease was largely post-mortem until the advent of MRI technology, which made diagnosis far easier. Superficial siderosis is largely considered a rare disease, with less than 270 total reported cases in scientific literature as of 2006, and affects people of a wide range of ages with men being approximately three times more frequently affected than women. The number of reported cases of superficial siderosis has increased with advances in MRI technology, but it remains a rare disease.
Cause
The most commonly described underlying cause of superficial siderosis is chronic bleeding into the subarachnoid spaceSubarachnoid space
In the central nervous system, the subarachnoid cavity is the interval between the arachnoid membrane and pia mater....
of the brain, which releases erythrocytes, or blood cells, into the cerebrospinal fluid. The chronic bleeding can come from many sources such as from an arteriovenous malformation
Arteriovenous malformation
Arteriovenous malformation or AVM is an abnormal connection between veins and arteries, usually congenital. This pathology is widely known because of its occurrence in the central nervous system, but can appear in any location. An arteriovenous malformation is a vascular anomaly. It is a...
, from chronic subdural hematoma
Subdural hematoma
A subdural hematoma or subdural haematoma , also known as a subdural haemorrhage , is a type of haematoma, a form of traumatic brain injury. Blood gathers within the outermost meningeal layer, between the dura mater, which adheres to the skull, and the arachnoid mater, which envelops the brain...
, from a ventricular shunt, or from chronic subarachnoid hemorrhage
Subarachnoid hemorrhage
A subarachnoid hemorrhage , or subarachnoid haemorrhage in British English, is bleeding into the subarachnoid space—the area between the arachnoid membrane and the pia mater surrounding the brain...
. Chronic bleeding sources can also be a result of past brain surgery or CNS
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
trauma, which may be the most common cause of superficial siderosis, with superficial siderosis showing up many years later. In up to as many as half of all described cases the source of bleeding was never found.
Symptoms
Superficial siderosis is characterized by many symptoms resulting from brain damage:- Sensorineural hearing lossSensorineural hearing lossSensorineural hearing loss is a type of hearing loss in which the root cause lies in the vestibulocochlear nerve , the inner ear, or central processing centers of the brain....
- This is the most common symptom associated with superficial siderosis and its absence is rare. The highest tones are often lost first, and over a period of one to twelve years hearing loss progresses to total deafness or loss of all hearing but low tones. - AtaxiaAtaxiaAtaxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
- The impairment of gait, which is the second most common symptom. - Pyramidal signs- Various signs that indicate a condition of the pyramidal tracts.
- DementiaDementiaDementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
- Occurs in approximately one-quarter of those affected by superficial siderosis. - Disturbances of the bladderBladderBladder usually refers to an anatomical hollow organBladder may also refer to:-Biology:* Urinary bladder in humans** Urinary bladder ** Bladder control; see Urinary incontinence** Artificial urinary bladder, in humans...
- AnosmiaAnosmiaAnosmia is a lack of functioning olfaction, or in other words, an inability to perceive odors. Anosmia may be either temporary or permanent. A related term, hyposmia, refers to a decreased ability to smell, while hyperosmia refers to an increased ability to smell. Some people may be anosmic for one...
- Loss of sense of smell. - AnisocoriaAnisocoria-Causes:In the absence of the iris or eyeball proper, anisocoria is usually the result of a defect in efferent nervous pathways controlling the pupil traveling in the oculomotor nerve or the sympathetic pathways...
- Unequal size of pupils.
Pathology & Diagnosis
Blood cells are not native to the cerebrospinal fluid, and their presence there is problematic. Once they eventually break down, they release the hemeHeme
A heme or haem is a prosthetic group that consists of an iron atom contained in the center of a large heterocyclic organic ring called a porphyrin. Not all porphyrins contain iron, but a substantial fraction of porphyrin-containing metalloproteins have heme as their prosthetic group; these are...
containing protein hemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
. Hemoglobin breaks down and releases iron-containing heme into the cerebrospinal fluid. In response to this upsurge in heme levels, Bergmann glia and microglia
Microglia
Microglia are a type of glial cell that are the resident macrophages of the brain and spinal cord, and thus act as the first and main form of active immune defense in the central nervous system . Microglia constitute 20% of the total glial cell population within the brain...
produce heme oxygenase 1. Heme oxygenase 1 breaks down free heme into biliverdin
Biliverdin
Biliverdin is a green tetrapyrrolic bile pigment, and is a product of heme catabolism. It is the pigment responsible for a greenish color sometimes seen in bruises.- Metabolism :...
, carbon monoxide, and iron. It is this breakdown of heme that is the source of iron deposition that ultimately causes superficial siderosis. The excess free iron is circulated in the cerebrospinal fluid and deposited in neuronal tissues, where it catalyzes the formation of reactive oxygen species which can damage DNA, RNA, proteins, and is otherwise toxic to the cells.
Iron deposition is prevalent in siderotic brain tissues, with iron concentrations of 1.79 to 8.26 times normal levels. Ferritin
Ferritin
Ferritin is a ubiquitous intracellular protein that stores iron and releases it in a controlled fashion. The amount of ferritin stored reflects the amount of iron stored. The protein is produced by almost all living organisms, including bacteria, algae and higher plants, and animals...
, an iron storage protein, is over-produced in response to excess heme by glial cells in order to sequester iron, with production ranging from 20.1 to 27.4 times normal levels. Excess iron, ferritin, and red blood cells may result in xanthochromia of the cerebrospinal fluid. Amongst neuronal cells types, iron deposition appears to be preferential for oligodendroglial cells, which is supported by the belief that they can act as iron sinks in the central nervous system. Schwann cells are also frequently damaged, contributing to demyelination.
Iron deposition is most prevalent in the inferior temporal lobes, the brainstem, the cerebellum
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...
, periventricular
Periventricular
Periventricular means around the ventricle and may refer to:*Periventricular leukomalacia, a disease characterized by the death of the white matter near the cerebral ventricles*Periventricular nucleus, a composite structure of the hypothalamus...
structures, the spinal cord
Spinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...
, and cranial nerve VIII. Iron deposition is also present in cranial nerves I & II, but this damage less frequently presents symptoms when compared to cranial nerve VIII, which can be explained by cranial nerve VIII’s notable segment of glial cells, which are preferentially affected by iron deposition.
The presence of ‘foamy’, ‘spheroid’, or ‘cytoid’ bodies in affected neuronal tissues has been noted but what they are and their origin remains somewhat unclear. They are believed to be swollen axonal bodies, but some evidence exists that they may be astrocytic
Astrocyte
Astrocytes , also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord...
in origin.
Early detection of superficial siderosis is usually via MRI. The iron deposition that is characteristic of superficial siderosis shows up as a hypointense band in affected tissues, with a characteristic rim of intensity appearing on the cerebellum; a hyperintense rim is rarely seen. Taking samples of cerebrospinal fluid may also reveal siderosis through xanthochromia, elevated presence of red blood cells, high iron and ferritin concentrations, and elevated levels of the proteins Tau, beta amyloid (Aβ42), neurofilament light protein (NFL), and glial fibrillary acidic protein (GFAP), but the CSF is sometimes normal. Detection is complicated by the fact that superficial siderosis is a rare disease and is not well described in neurological texts, so it may go unnoticed until noticeable symptoms appear.
Treatment
There is no current cure for superficial siderosis, only treatments to help alleviate the current symptoms and to help prevent the development of further symptoms. If a source of bleeding can be identified (sources are frequently not found), then surgical correction of the bleeding source can be performed; this has proved to be effective in halting the development of further symptoms in some cases and has no effect on symptoms that have already presented.The use of drugs to treat superficial siderosis is still being investigated. The use of iron chelating
Chelation
Chelation is the formation or presence of two or more separate coordinate bonds between apolydentate ligand and a single central atom....
drugs and steroids have been explored but they have proven to be largely unsuccessful thus far.
Alleviation of the most common symptom, hearing loss, has been varyingly successful through the use of cochlear implant
Cochlear implant
A cochlear implant is a surgically implanted electronic device that provides a sense of sound to a person who is profoundly deaf or severely hard of hearing...
s. Most people do not notice a large improvement after successful implantation, which is most likely due to damage to the vestibulocochlear nerve (cranial nerve VIII) and not the cochlea itself. Some people fare far better, with a return to near normal hearing, but there is little ability to detect how well a person will respond to this treatment at this time.