Target Health Blog

First Contributors to an Understanding of the Blood Brain Barrier

May 30, 2017

History of Medicine

Paul Ehrlich

Paul Ehrlich MD (1854-1915): Photo credit: Harris & Ewing - This image is available from the United States Library of Congress' s Prints and Photographs division under the digital ID hec.04709. Public Domain, Wikipedia Commons

‍Paul Ehrlich' s work illuminated the existence of the blood-brain barrier, and in1908, he was awarded The Nobel Prize in Physiology or Medicine for his work on immunity.


Paul Ehrlich, a German Jewish physician, was a bacteriologist studying staining, a procedure that is used in many microscopic studies to make fine biological structures visible using chemical dyes. As Ehrlich injected some of these dyes (notably the aniline dyes that were then widely used), the dye stained all of the organs of some kinds of animals except for their brains. At that time, Ehrlich attributed this lack of staining to the brain simply not picking up as much of the dye. However, in a later experiment in 1913, Edwin Goldman (one of Ehrlich' s students) injected the dye into the cerebro-spinal fluids of animals' brains directly. He found that in this case the brains did become dyed, but the rest of the body did not. This clearly demonstrated the existence of some sort of compartmentalization between the two. At that time, it was thought that the blood vessels themselves were responsible for the barrier, since no obvious membrane could be found. The concept of the blood-brain barrier (then termed hematoencephalic barrier) was proposed in 1900 by a Berlin physician, Lewandowsky. It was not until the introduction of the scanning electron microscope to the medical research fields in the 1960s that the actual membrane could be observed and proved to exist.


Edwin Goldmann

Edwin Goldmann MD (1862-1913)  Credit: Von unbekannt - [1] M?nchen. med. Wchnschr. lx, 2735, 1913, PD-alt-100,

Edwin Ellen Goldmann (born November 12, 1862 in Burgherdorp, South Africa), was a German Jewish surgeon. He studied medicine in London, and in 1888 he received the Doctor of Medicine and PhD degrees. He got his first job at Karl Weigert in Frankfurt. He stayed there for six months and then went to Freiburg to join Eugen Baumann, where he devoted himself to physiological-chemical studies. In his work he dealt with the cystine, sulfur-containing compounds of urine and iodothyrine. His Habilitationsschrift from the year 1895 dealt with the doctrine of the neurons. In 1898 he became an extraordinary professor and later a full honorary professor. He headed the surgical department of the Diakonissenkrankenhaus in Freiburg and worked mainly in the field of cancer research.


Goldmann made a significant contribution to the discovery of the blood-brain barrier. In 1913, he injected Trypan blue, a water-soluble azo dye stuff first synthesized by Paul Ehrlich in 1904, directly into the cerebrospinal fluid of dogs. The result showed staining of the entire central nervous system (brain and spinal cord) but no other organ.

In 1913 Goldmann died of cancer in Freiburg.


Rudolph Virchow

Rudolph Virchow (1821-1902); Photo credit: Unknown -; Public Domain, Wikipedia Commons

‍The appearance of perivascular spaces was first noted in 1843 by Durant-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. The spaces were called Virchow-Robin spaces and are still also known as such. The immunological significance was discovered by Wilhelm His, Sr. in 1865 based on his observations of the flow of interstitial fluid over the spaces to the lymphatic system. For many years after Virchow-Robin spaces were first described, it was thought that they were in free communication with the cerebrospinal fluid in the subarachnoid space. It was later shown with the use of electron microscopy that the pia mater serves as separation between the two. Upon the application of MRI, measurements of the differences of signal intensity between the perivascular spaces and cerebrospinal fluid supported these findings. As research technologies continued to expand, so too did information regarding their function, anatomy and clinical significance.


A perivascular space, also known as a Virchow-Robin space, is an immunological space between an artery and a vein (not capillaries) and the pia mater that can be expanded by leukocytes. The spaces are formed when large vessels take the pia mater with them when they dive deep into the brain. The pia mater is reflected from the surface of the brain onto the surface of blood vessels in the subarachnoid space. Perivascular cuffs are regions of leukocyte aggregation in the spaces, usually found in patients with viral encephalitis. Perivascular spaces are extremely small and can usually only be seen on MRI images when dilated. While many normal brains will show a few dilated spaces, an increase in these has been shown to correlate with the incidence of several neurodegenerative diseases, making the spaces a popular topic of research. One of the most basic roles of the perivascular space is the regulation of fluid movement in the central nervous system and its drainage. The spaces ultimately drain fluid from neuronal cell bodies 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 the perivascular space. By acting as a sort of sponge, they are essential for signal transmission and the maintenance of extracellular fluid. Another function is as an integral part of the blood-brain barrier (BBB). 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. Perivascular spaces also play an important role in immunoregulation; they 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. VNs serve to prevent inflammation by activating the enzyme adenylate cyclase which then produces cAMP.

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