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Superficial
hemosiderosis Hemosiderosis is a form of iron overload disorder resulting in the accumulation of hemosiderin. Types include: * Transfusion hemosiderosis * Idiopathic pulmonary hemosiderosis * Transfusional diabetes Organs affected: * Hemosiderin deposi ...
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 (CSF) is a clear, colorless Extracellular fluid#Transcellular fluid, transcellular body fluid found within the meninges, meningeal tissue that surrounds the vertebrate brain and spinal cord, and in the ventricular system, ven ...
. This occurs via the deposition of
hemosiderin Hemosiderin image of a kidney viewed under a microscope. The brown areas represent hemosiderin Hemosiderin or haemosiderin is an iron-storage complex that is composed of partially digested ferritin and lysosomes. The breakdown of heme gives ri ...
in neuronal tissue, and is associated with neuronal loss,
gliosis Gliosis is a nonspecific reactive change of glial cells in response to damage to the central nervous system (CNS). In most cases, gliosis involves the proliferation or hypertrophy of several different types of glial cells, including astrocytes ...
, and
demyelination A demyelinating disease refers to any disease affecting the nervous system where the myelin sheath surrounding neurons is damaged. This damage disrupts the transmission of signals through the affected nerves, resulting in a decrease in their con ...
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 Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to generate pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and rad ...
technology, but it remains a rare disease.


Symptoms

Superficial siderosis is characterized by many symptoms resulting from brain damage: *
Sensorineural hearing loss Sensorineural hearing loss (SNHL) is a type of hearing loss in which the root cause lies in the inner ear, sensory organ (cochlea and associated structures), or the vestibulocochlear nerve (Cranial nerves, cranial nerve VIII). SNHL accounts for a ...
- This is the most common symptom associated with superficial siderosis and its absence is rare. The highest pitches 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 pitches. *
Ataxia Ataxia (from Greek α- negative prefix+ -τάξις rder= "lack of order") is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in e ...
- The impairment of gait, which is the second most common symptom. *
Pyramidal signs Pyramidal signs indicate that the pyramidal tract is affected at some point in its course. Pyramidal tract dysfunction can lead to various clinical presentations such as spasticity, weakness, slowing of rapid alternating movements, hyperreflexi ...
- Various signs that indicate a condition of the pyramidal tracts. *
Dementia Dementia is a syndrome associated with many neurodegenerative diseases, characterized by a general decline in cognitive abilities that affects a person's ability to perform activities of daily living, everyday activities. This typically invo ...
- Occurs in approximately one-quarter of those affected by superficial siderosis. *Disturbances of the
bladder The bladder () is a hollow organ in humans and other vertebrates that stores urine from the kidneys. In placental mammals, urine enters the bladder via the ureters and exits via the urethra during urination. In humans, the bladder is a distens ...
*
Anosmia Anosmia, also known as smell blindness, is the lack of ability to detect one or more smells. Anosmia may be temporary or permanent. It differs from hyposmia, which is a decreased sensitivity to some or all smells. Anosmia can be categorized int ...
- Loss of sense of smell. *
Anisocoria Anisocoria is a condition characterized by an unequal size of the eyes' pupils. Affecting up to 20% of the population, anisocoria is often entirely harmless, but can be a sign of more serious medical problems. Causes Anisocoria is a common cond ...
- Unequal size of pupils.


Cause

The most commonly described underlying cause of superficial siderosis is chronic bleeding into the subarachnoid space of the brain, which releases
erythrocytes Red blood cells (RBCs), referred to as erythrocytes (, with -''cyte'' translated as 'cell' in modern usage) in academia and medical publishing, also known as red cells, erythroid cells, and rarely haematids, are the most common type of blood cel ...
, or blood cells, into the cerebrospinal fluid. The chronic bleeding can come from many sources such as from an
arteriovenous malformation An arteriovenous malformation (AVM) is an abnormal connection between arteries and veins, bypassing the capillary system. Usually congenital, this vascular anomaly is widely known because of its occurrence in the central nervous system (usually ...
or cavernous malformation, myxopapillary ependymoma of the spinal cord, from chronic
subdural hematoma A subdural hematoma (SDH) is a type of bleeding in which a collection of blood—usually but not always associated with a traumatic brain injury—gathers between the inner layer of the dura mater and the arachnoid mater of the meninges surrou ...
, from a ventricular shunt, or from chronic
subarachnoid hemorrhage Subarachnoid hemorrhage (SAH) is bleeding into the subarachnoid space—the area between the arachnoid (brain), arachnoid membrane and the pia mater surrounding the human brain, brain. Symptoms may include a thunderclap headache, severe heada ...
. 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.


Pathology

Blood cells are not native to the cerebrospinal fluid, and their presence there is problematic. Once they eventually break down, they release the
heme Heme (American English), or haem (Commonwealth English, both pronounced /Help:IPA/English, hi:m/ ), is a ring-shaped iron-containing molecule that commonly serves as a Ligand (biochemistry), ligand of various proteins, more notably as a Prostheti ...
containing protein
hemoglobin Hemoglobin (haemoglobin, Hb or Hgb) is a protein containing iron that facilitates the transportation of oxygen in red blood cells. Almost all vertebrates contain hemoglobin, with the sole exception of the fish family Channichthyidae. Hemoglobin ...
. Hemoglobin breaks down and releases iron-containing heme into the cerebrospinal fluid. In response to this upsurge in heme levels,
Bergmann glia Radial glial cells, or radial glial progenitor cells (RGPs), are bipolar-shaped progenitor cells that are responsible for producing all of the neurons in the cerebral cortex. RGPs also produce certain lineages of glia, including astrocytes and ol ...
and
microglia Microglia are a type of glia, glial cell located throughout the brain and spinal cord of the central nervous system (CNS). Microglia account for about around 5–10% of cells found within the brain. As the resident macrophage cells, they act as t ...
produce heme oxygenase 1. Heme oxygenase 1 breaks down free heme into
biliverdin Biliverdin (from the Latin for green bile) is a green tetrapyrrolic bile pigment, and is a product of heme catabolism.Boron W, Boulpaep E. Medical Physiology: a cellular and molecular approach, 2005. 984–986. Elsevier Saunders, United States. ...
, 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, lipids and 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 is a universal intracellular and extracellular protein that stores iron and releases it in a controlled fashion. The protein is produced by almost all living organisms, including archaea, bacteria, algae, 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 Schwann cells or neurolemmocytes (named after German physiologist Theodor Schwann) are the principal glia of the peripheral nervous system (PNS). Glial cells function to support neurons and in the PNS, also include Satellite glial cell, satellite ...
are also frequently damaged, contributing to demyelination. Iron deposition is most prevalent in the inferior
temporal lobes The temporal lobe is one of the four Lobes of the brain, major lobes of the cerebral cortex in the brain of mammals. The temporal lobe is located beneath the lateral fissure on both cerebral hemispheres of the mammalian brain. The temporal lobe ...
, the
brainstem The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is conti ...
, the
cerebellum The cerebellum (: cerebella or cerebellums; Latin for 'little brain') is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as it or eve ...
, peri- ventricular structures, the
spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue that extends from the medulla oblongata in the lower brainstem to the lumbar region of the vertebral column (backbone) of vertebrate animals. The center of the spinal c ...
, and
cranial nerve VIII The vestibulocochlear nerve or auditory vestibular nerve, also known as the eighth cranial nerve, cranial nerve VIII, or simply CN VIII, is a cranial nerve that transmits sound and equilibrium (balance) information from the inner ear to the bra ...
. 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 Astrocytes (from Ancient Greek , , "star" and , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of end ...
in origin.


Diagnosis

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 Tau (; uppercase Τ, lowercase τ or \boldsymbol\tau; ) is the nineteenth letter of the Greek alphabet, representing the voiceless alveolar plosive, voiceless dental or alveolar plosive . In the system of Greek numerals, it has a value of 300 ...
,
amyloid beta Amyloid beta (Aβ, Abeta or beta-amyloid) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid-beta precursor prot ...
(Aβ42), neurofilament light chain (NFL), and
glial fibrillary acidic protein Glial fibrillary acidic protein (GFAP) is a protein that is encoded by the ''GFAP'' gene in humans. It is a type III intermediate filament (IF) protein that is expressed by numerous cell types of the central nervous system (CNS), including astro ...
(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. Patients with superficial siderosis are often treated with
deferiprone Deferiprone, sold under the brand name Ferriprox among others, is a medication that chelates iron and is used to treat iron overload in thalassaemia major. It was first approved and indicated for use in treating thalassaemia major in 1994 and ...
(brand name is Ferriprox), a lipid-soluble iron chelator, as this medication has been demonstrated to chelate iron in the central nervous system. Deferiprone use is associated with severe
neutropenia Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteria ...
, but this risk and associated complications are usually minimised by administering a weekly blood test that measures absolute neutrophil count. Alleviation of the most common symptom, hearing loss, has been varyingly successful through the use of
cochlear implant A cochlear implant (CI) is a surgically implanted Neuroprosthetics, neuroprosthesis that provides a person who has moderate-to-profound sensorineural hearing loss with sound perception. With the help of therapy, cochlear implants may allow for imp ...
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.


References


External links

{{Medicine, state=collapsed Central nervous system disorders Rare diseases