Perivascular space

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Perivascular space
A perivascular space as seen on CT
Anatomical terms of neuroanatomy
CT image showing extensive low attenuation in the right hemispheric white matter due to dilated Type 2 perivascular spaces
Axial fat-suppressed T2-weighted MRI image in the same patient as above demonstrating extensive dilated Type 2 perivascular spaces in the right hemisphere
Perivascular space is depicted in the inset box.

A perivascular space, also known as a Virchow–Robin space, is a fluid-filled space surrounding certain

subarachnoid space. In the brain, perivascular cuffs are regions of leukocyte aggregation in the perivascular spaces, usually found in patients with viral encephalitis
.

Perivascular spaces vary in dimension according to the type of blood vessel. In the brain where most capillaries have an imperceptible perivascular space, select structures of the brain, such as the circumventricular organs, are notable for having large perivascular spaces surrounding highly permeable capillaries, as observed by microscopy. The median eminence, a brain structure at the base of the hypothalamus, contains capillaries with wide perivascular spaces.[3]

In humans, perivascular spaces surround arteries and veins can usually be seen as areas of

neurodegenerative diseases, making the spaces a topic of research.[4]

Structure

Perivascular spaces are gaps containing

subpial space.[6]

Perivascular spaces surrounding

desmosomes.[8]

Perivascular spaces, especially around fenestrated capillaries, are found in many organs, such as the thymus, liver, kidneys, spleen, bones, and pineal gland.[9][10][11][12] Particularly within the brain circumventricular organs – subfornical organ, area postrema, and median eminence – large perivascular spaces are present around fenestrated capillaries, indicating that the spaces serve a dispersive role for brain- or bloodborne messengers.[2]

Perivascular spaces may be enlarged to a diameter of five millimeters in healthy humans and do not imply disease. When enlarged, they can disrupt the function of the brain regions into which they project.[5] Dilation can occur on one or both sides of the brain.[7]

Dilated perivascular spaces are categorized into three types:[7]

Perivascular spaces are most commonly located in the basal ganglia and white matter of the cerebrum, and along the optic tract.[13] The ideal method used to visualize perivascular spaces is

disorders can be similar to those of the dilated spaces. These disorders are:[7]

Perivascular spaces are distinguished on an MRI by several key features. The spaces appear as distinct round or oval entities with a signal intensity visually equivalent to that of cerebrospinal fluid in the subarachnoid space.[7][14][15] In addition, a perivascular space has no mass effect and is located along the blood vessel around which it forms.[14]

Function

One of the most basic roles of the perivascular space is the regulation of fluid movement in the central nervous system and its drainage.[13] The spaces ultimately drain fluid from neuronal cell bodies to the cervical lymph nodes.[5] 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 the perivascular space.[16] By acting as a sort of sponge, they are essential for signal transmission and the maintenance of extracellular fluid.[16]

Another function is as an integral part of the blood–brain barrier (BBB).[17] While the BBB is often described as the tight 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, cell debris and foreign particles, which are impermeable to the BBB will get through the endothelial cells, only to be phagocytosed in the perivascular spaces. This holds true for many T and B cells, as well as monocytes, giving this small fluid filled space an important immunological role.[17]

Perivascular spaces also play an important role in immunoregulation; they not only contain

T cells by regulatory T cells. .[19] The perivascular space is susceptible space for VN compromise and when their function is reduced in the space, immune response is adversely affected and the potential for degradation increases.[18][19] 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.[17] Because this process is aided by the perivascular macrophages, these tend to accumulate during neuroinflammation and cause dilation of the spaces.[18]

Clinical significance

The clinical significance of perivascular spaces comes primarily from their tendency to dilate. The importance of dilation is hypothesized to be based on changes in shape rather than size.

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 dentate nucleus in the cerebellum, and the corpus callosum, as well as the brain region directly above it, the cingulate gyrus.[5] Upon the clinical application of MRI, it was shown in several studies that perivascular space dilation and lacunar strokes are the most commonly observed histological correlates of signaling abnormalities.[13]

Senescence

Dilation is most commonly and closely associated with aging. Dilation of perivascular spaces has been shown to correlate best with age, even when accompanying factors including hypertension, dementia, and white matter lesions are considered.[20] In the elderly, such dilation has been correlated with many symptoms and conditions that often affect the arterial walls, including vascular hypertension, arteriosclerosis, reduced cognitive capacity, dementia, and low post-mortem brain weight.[13] In addition to dilation among the elderly, dilation in young, healthy individuals can also be observed. This occurrence is rare and there has been no observed association in such cases with reduced cognitive function or white matter abnormalities.[13] When dilated VRS 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.[21]

Symptoms of dilation

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,

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.[13] 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.[5]

Associated disorders

Dilation is a typical characteristic of several diseases and disorders. These include diseases from metabolic and genetic disorders such as

autism in children, megalencephalopathy, secondary Parkinson's disease, recent-onset multiple sclerosis, 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.[13]

Current research

Causes of dilated VRS

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. Further research has implicated 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.[13] 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.[5]Dilated VRS might also be linked to vascular damage, blood leakage and microaneurysm formation.[22]

Association of dilated VRS and other diseases

Recent and ongoing research has found associations between enlarged VRS and several disorders.

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, additional research is currently being performed in order to confirm or refute a direct connection between dilation of VRS and dementia.[15]

Analysis of VRS may distinguish dementia caused by

neurodegenerative disease. A 2005 study has evidenced that a substantial amount of VRS in the substantia innominata, lentiform nucleus, and the caudate nucleus of the basal ganglia may implicate dementia due to arteriosclerotic microvascular disease, in particular Ischemic Vascular Dementia, as opposed dementia due to neurodegenerative disease, specifically Alzheimer's disease and frontotemporal dementia. Thus, perhaps VRS dilation can be used to distinguish between diagnoses of vascular dementias and degenerative dementias.[23]

Alzheimer's disease

Some studies have assessed the spatial distribution and prevalence of VRS in people with Alzheimer's disease versus those without the disease. 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.[24]

Cerebral amyloid angiopathy (CAA), a blood vessel failure often associated with Alzheimer's disease, utilizes dilated VRS to spread inflammation to the parenchyma. Because the VRS often have an extra membrane in gray matter, the ischemic CAA response is often observed in white matter.[25]

It has been hypothesized that the structure of VRS in the

interstitial fluid less effectively than VRS in the basal ganglia. The less-effective drainage may lead to the development of the β-amyloid plaques that characterize Alzheimer's disease. In support of this hypothesis, studies have noted the greater frequency of β-amyloid plaques in the cerebral cortex than in the basal ganglia of Alzheimer's disease patients.[8]

Stroke

Because dilated perivascular spaces are so closely correlated with cerebrovascular disease, there is much current research on their use as a diagnostic tool. In a recent study of 31 subjects, abnormal dilation, along with irregular CSF pulsation, were correlated with those subjects having three or more risk factors for strokes. Therefore, perivascular spaces are a possible novel biomarker for hemorrhagic strokes.[26]

Notch 3 gene mutation on Chromosome 19. Studies have noted that in comparison to family members lacking the affected haplotype that leads to the condition, an increased number of dilated spaces is observed in individuals with CADASIL. These perivascular spaces are localized primarily in the putamen and temporal subcortical white matter and they appear to correlate with age of the individual with the condition rather than severity of the disease itself.[27]

There has been a high risk of

arterosclerosis. This remains, therefore, an important point of research in the field.[13]

Multiple sclerosis

Similar to the research concerning a potential connection between perivascular spaces and Alzheimer's, MRI scans of people recently diagnosed with

demyelination that characterizes MS also attack the perivascular spaces. Studies using advanced MRI techniques will be necessary to determine if the perivascular spaces can be implicated as a potential marker of the disease.[29]

Autism

Dilated perivascular spaces are common among the elderly and uncommon in children. Studies have noted the association between both

autism and enlarged or dilated perivascular spaces.[30][31] Non-syndromic autism categorizes autistic patients for which there is no known cause.[30]

History

The appearance of perivascular spaces was first noted in 1843 by Durant-Fardel.

Wilhelm His, Sr. in 1865 based on his observations of the flow of interstitial fluid over the spaces to the lymphatic system.[13]

For many years after Virchow-Robin spaces were first described, it was thought that they were in free communication with the

MRI, measurements of the differences of signal intensity between the perivascular spaces and cerebrospinal fluid supported these findings.[13]
As research technologies continued to expand, so too did information regarding their function, anatomy and clinical significance.

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