User:Horowitr/Virchow Robin Spaces Draft

Virchow-Robin spaces (VRS) are perivascular, fluid-filled canals that surround perforating arteries and veins in the parenchyma of the brain. These spaces are separated from the subarachnoid space by a thin pia layer. VRS are extremely small and can usually only be seen on MR images when dilated. While many normal brains will show a few dilated VRS, an increase in dilated VRS has been shown to correlate with the incidence of several neurodegenerative diseases, making the spaces a popular topic of research.

History
The appearance of Virchow-Robin spaces was first noted in 1843 by Durand Fardel. In 1851, Rudolph Virchow was the first to provide a detailed description of these microscopic spaces between the outer and inner/middle lamina of the brain vessels. Charles-Philippe Robin confirmed these findings in 1859 and was the first to describe the perivascular spaces as channels that existed in normal anatomy. For many subsequent years it was thought that VRS were in free communication with the cerebrospinal fluid in the subarachnoid space, but it was later shown with electron microscopy that pia matter serves as separation between the two. The immunological significance was discovered by Wilhelm His, Sr. in 1865 based on his observations of the flow of interstitial fluid over VRS to the lymphatic system.

Anatomy
Virchow-Robin spaces are the interstitial fluid-containing gaps between blood vessels and the brain matter which they penetrate. Like the blood vessels around which they form, Virchow-Robin spaces are part of the subarachnoid space. Virchow-Robin spaces may be enlarged to a diameter of five millimeters in healthy humans and are usually harmless. When enlarged even further, they can disrupt the function of the brain regions into which they project. Dilation can occur on one or both sides of the brain.

Virchow-Robin spaces are categorized into three types: Virchow-Robin spaces are most commonly located in the basal ganglia, thalamus, midbrain, cerebellum, hippocampus, insular cortex, the white matter of the cerebrum, and along the optic tract. The ideal method used to visualize Virchow-Robin spaces is T2-weighted MRI. The MRI images of dilated Virchow-Robin spaces must be distinguished from MRI images of other neurological maladies that are similar in appearance. These illnesses are specifically: Virchow-Robin spaces can often be distinguished by their signal intensity which is visually equivalent to that of cerebrospinal fluid.
 * Type 1 VRS are located on the lenticulostriate arteries projecting into the basal ganglia
 * Type 2 VRS are located in the cortex following the path of the medullary arteries
 * Type 3 VRS are located in the midbrain
 * cystic neoplasms
 * lacunar infarctions
 * cystic periventricular leukomalacia
 * cyptococcosis
 * multiple sclerosis
 * mucopolysaccharidoses
 * neurocysticercosis
 * arachnoid cysts
 * neuroepithelial cysts

Function
One of the most basic roles of the VRS is the regulation of CNS fluid movement and drainage. Virchow-Robin spaces ultimately drain fluid from neuronal cell bodies in the CNS to the cervical lymph nodes. In particular, the “tide hypothesis” suggests that the cardiac contraction creates and maintains pressure waves to modulate the flow to and from the subarachnoid space and VRS. By acting as a sort of sponge, the VRS are essential for signal transmission and maintenance of extracellular fluid (ECF).

Another role of the VRS is as an integral part of the blood-brain barrier (BBB). While the BBB is often described as the gap junctions between the endothelial cells, this is an oversimplification that neglects the intricate role that perivascular spaces take in separating the venous blood from the parenchyma of the brain. Often times, cell debris and foreign particles, which are impermeable to the BBB will get through the endothelial cells, only to be phagocytosed in the VR spaces. This holds true for many T and B cells, as well as monocytes, giving this small fluid filled space an important immunological role.

VR spaces not only contain interstitial and cerebrospinal fluid, but they also have a constant flux of macrophages, which is regulated by blood-borne mononuclear cells, but do not pass the basement membrane of the glia limitans. Similarly, as part of its role in signal transmission, perivascular spaces contain vasoactive neuropeptides (VNs), which, aside from regulating blood pressure and heart rate, have an integral role in controlling microglia. When inflammation by T cells begins, astrocytes begin to undergo apoptosis, due to their CD95 receptor, to open up the glia limitans and let T cells into the parenchyma of the brain. Because this process is aided by the perivascular macrophages, these tend to accumulate during neuroinflammation and cause dilation of the VRS.

Clinical Significance
The clinical significance of Virchow-Robin spaces comes primarily from their tendency to dilate. The importance of dilation is hypothesized to be based on changes in shape rather than size. Enlarged Virchow-Robin spaces have been observed most commonly in the basal ganglia, specifically on the lenticulostriate arteries. They have also been observed along the paramedial mesencephalothalamic artery and the substantia nigra in the mesencephalon, the brain region below the insula, the dendate nucleus in the cerebellum, and the corpus callosum, as well as the brain region directly above it, the cingulate gyrus. Upon the clinical application of MRI, it was shown in several studies that VRS dilation and lacunar infracts are the most commonly observed histological correlates of signaling abnormalities.

Dilation is most commonly and closely associated with aging. Dilation of VRS has been shown to correlate best with age, even when accompanying factors including hypertension, dementia, and white matter lesions are considered. In the elderly, VRS dilation has been correlated with many symptoms and conditions which often affect the arterial walls. Such conditions associated with VRS dilation in the elderly include vascular hypertension, arteriosclerosis, reduced cognitive capacity, dementia, and low post-mortem brain weight. Additionally, there has been a high risk of stroke associated with VRS dilation in the elderly according to the Framingham Stroke Risk Score. In contrast, other studies have concluded that VRS dilation is a normal phenomenon in aging with no association with arthrosclerosis. This remains, therefore, an important point of research in the field. Interestingly, dilation in young, healthy individuals can be observed, but it is rare and there has been no observed association in such cases with reduced cognitive function or white matter abnormalities. When Dilated VR spaces are observed in the corpus callosum, there is generally no neurological deficit associated. They are often observed in this region as cystic lesions with cerebrospinal-like fluid.

There are several possible causes of dilation. These include shrinkage or atrophy of surrounding brain tissue, perivascular demyelination, coiling of the arteries as they age, altered permeability of the arterial wall and obstruction of lymphatic drainage pathways. Extreme dilation has been associated with several specific clinical symptoms. In cases of severe dilation in only one hemisphere, symptoms reported include a non-specific fainting attack, hypertension, positional vertigo, headache, early recall disturbances, and hemifacial tics. Symptoms associated with severe bilateral dilation include ear pain (which was reported to have resolved on its own), dementia, and seizures. Considering the anatomical abnormality presented in such cases, these findings were considered surprising in that the symptoms were relatively mild. In most cases there is in fact to mass effect associated with some VRS dilation. An exception to the mildness of clinical symptoms associated with VRS dilation is when there is extreme dilation in the lower mesencephalon at the junction between the substantia nigra and cerebral peduncle. In such cases, mild to moderate obstructive hydrocephalus was reported in most patients. Associated symptoms ranged from headaches to symptoms more severe than those just discussed in the cases of dilation in the cerebral hemispheres. Other general symptoms associated with VRS dilation include headaches, dizziness, memory impairment, poor concentration, dementia, visual changes, oculomotor abnormality, tremors, seizures, limb weakness, and ataxia.

Dilation is a typical feature in several diseases and disorders. These include diseases from metabolic and genetic disorders such as mucopolysaccharidosis types I, II, and III, mannosidosis, myotonic dystrophy, Lowe syndrome, and Coffin-Lowry syndrome. Dilation is also a typical feature in diseases or disorders of vascular pathologies, including CADSIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), hereditary infantile hemiparesis, retinal arteriolar tortuosity and leukoencephalopathy, migranes, and vascular dementia. A third group disorders typically associated with VRS dilation are neuroectodermal syndromes. This includes polycystic brains associated with ectodermal dysplasia, frontonasal dysplasia, and Joubert syndrome. There is a fourth miscellaneous group of disorders typically associated with dilation which include autism in children, Megalencephalopathy, Secondary Parkinson’s, recent-onset MS and chronic alcoholism. Because dilation can be associated with several diseases but also observed in healthy patients, it is always important in the evaluation of VRS to study the tissue around the dilation via MRI and to consider the entire clinical context.

Current Research
Much of the current research concerning Virchow-Robin spaces relates to their known tendency to dilate. Research is presently being performed in order to determine the exact cause of dilation in these perivascular spaces. Current theories include mechanical trauma resulting from cerebrospinal fluid pulsation, elongation of ectactic penetrating blood vessels, and abnormal vascular permeability leading to increased fluid exudation. In addition, insufficient fluid draining and injury to ischemic perivascular tissue resulting in an ex vacuo effect have been suggested as possible causes for dilated VRS.

A proposed hypothesis for the degradation of Virchow-Robin spaces concerns reduced functioning of vasocative neuropeptides found in the VRS. These molecules serve to prevent inflammation by activating the enzyme adenylate cyclase which then produces cAMP. The production of cAMP aids in the modulation of auto-reactive T cells by regulatory T cells. If vasoactive neuropeptide function is reduced in the VRS, immune response is adversely affected and the potential for degradation increases.

Alzheimer's
Some studies have assessed the spatial distribution and prevalence of VRS in people with Alzheimer's disease versus those without the disease, and researchers have found that while VRS appear to be correlated with natural aging, MR imaging reveals a greater prevalence of VRS in those with Alzheimer's.

Multiple Sclerosis
Similar to the research concerning a potential connection between VRS and Alzheimer's, MRI scans of people recently diagnosed with multiple sclerosis have been studied. Larger, more prevalent VRS have been observed in those with MS. Additional studies with similar findings have suggested that the inflammatory cells which contribute to the demyelination that characterizes MS also attack the VRS. Studies using advanced MRI techniques will be necessary to determine if VRS can be implicated as a potential marker of the disease.

Dementia
At one point in time, dilated Virchow-Robin spaces were so commonly noted in autopsies of persons with dementia, they were believed to cause the disease. However, more research must be performed in order to confirm or refute a direct connection between dilation of VRS and dementia.