EVOLVING CONCEPTS ARTICLE
Familiarity with the anatomy and physiology of the cerebrospinal venous system (CSVS) is necessary to understand the therapeutic potential of perispinal injection for treatment of central nervous system (CNS) disorders [1, 2]. The CSVS is composed of the confluence of the venous systems of the spine and the brain, which together constitute a unique, large-capacity valveless venous network in which flow is bidirectional [1, 2]. Detailed examination of the medical literature reveals that seminal work in this area was performed by the scientists Gilbert Breschet, James Leonard Corning and Oscar Batson in the 19th and 20th centuries. Careful reading of their publications is necessary scientific background to understand the scientific basis for perispinal delivery of CNS drugs. Recent work with perispinal etanercept (PSE) highlights the significance of this topic with respect to treatment of CNS disorders.
Brief History – Corning, Breschet and Batson
In 1885, James Leonard Corning, a New York neurologist who had received his medical training in Europe, shocked the world with the first successful report of spinal anesthesia . Corning accomplished this milestone utilizing cocaine as a local anesthetic, based in part upon the 1884 publications of Carl Kollar and his colleague Sigmund Freud [2, 4]. To this day it remains an obscure fact that Corning achieved rapid spinal anesthesia by giving cocaine by perispinal injection [1, 2]. Perispinal delivery enabled cocaine to cross the physiological barriers (ligamentum flavum and dural membranes) protecting the spinal cord by carriage in the CSVS [1, 2]see Footnote 1. Corning understood that needle passage through these connective tissue barriers was not necessary, as the perispinal veins pass through them without difficulty:
...in order to obtain the most immediate, direct, and powerful effects upon the cord with a minimum quantity of a medicinal substance, it is by no means necessary to bring the substance into direct contact with the cord …. 
As Corning described in his experiment:
I decided to inject the anesthetic between the spinous processes of the lower dorsal vertebrae. I was led to resort to this expedient from a knowledge of the fact that in the human subject numerous small veins (venae spinosae) run down between the spinous processes of the vertebrae, and, entering the spinal canal, join the more considerable vessels of the plexus spinalis interna. From these theoretical considerations I reasoned that it was highly probable that, if the anaesthetic was placed between the spinous processes of the vertebrae, it (the anaesthetic) would be rapidly absorbed by the minute ramifications of the veins referred to, and, being transported by the blood to the substance of the cord, would give rise to anesthesia of the sensory and perhaps also of the motor tracts of the same….
Corning’s experiment was successful, and in both dog and man he proved that perispinal injection of cocaine was able to achieve rapid spinal anesthesia [3, 5-10]. Corning’s ground-breaking use of perispinal cocaine was likely based upon knowledge of the pioneering anatomical studies of the leading French anatomist Gilbert Breschet [11, 12] (Figure 1).
Figure 1. The cerebrospinal venous system, detail of Plate 5 from Breschet, G., Recherches anatomiques physiologiques et pathologiques sur le systeme veineux. 1829, Paris,: Rouen fráeres. Courtesy of the Sidney Tobinick Collection. Copyright 2016 Edward Tobinick MD, all rights reserved.
Breschet’s work was well-known in Europe in the middle of the 19th century. The description of the CSVS in the First Edition of Gray’s Anatomy was entirely based on Breschet’s findings (Figure 2):
The veins of the spine are described and illustrated from the well-known work of Breschet (Gray 1858, Preface )….The Dorsi-Spinal Veins commence by small branches, which receive their blood from the integument of the back of the spine, and from the muscles in the vertebral grooves. They form a complicated net-work, which surrounds the spinous processes, laminae, and the transverse and articular processes of all the vertebrae. At the bases of the transverse processes, they communicate, by means of ascending and descending branches, with the veins surrounding the contiguous vertebrae, and with the veins in the interior of the spine, in the intervals between the arches of the vertebrae, perforating the ligamenta subflava [ligamentum flavum]….
Figure 2. The Spinal Veins, from Gray 1858. Figure 223, from Gray, H. and H.V. Carter, Anatomy, descriptive and surgical. First ed. 1858, London: John W. Parker and Son.(reference 13): after Breschet (1829) (reference 12).
It took more than a century for Breschet’s elegant and accurate descriptions of the CSVS to be confirmed by the injection and radiologic experiments of American anatomist Oscar Batson [14, 15]. As Batson observed,
It seems incredible that a great functional complex of veins would escape recognition as a system until 1940….In the first four decades of the last century, our knowledge of the vertebral veins was developed and then almost forgotten .
The work of Breschet, Corning and Batson together is entirely relevant today, as this knowledge, together, provides a scientific framework that helps one understand the rapid and sustained neurological improvement that may ensue after perispinal delivery of etanercept for treatment of selected neuroinflammatory disorders [1, 2, 17, 18, 20, 23-26, 28-37]. Etanercept, a biotechnology drug, is a potent inhibitor of TNF, an immune molecule that potentiates inflammation and regulates synaptic function . Etanercept was first approved for human use in 1998 for treatment of rheumatoid arthritis, with multiple additional indications to follow [20, 37]. Etanercept is both a biologic (a therapeutic derived from living organisms, in this case entirely human amino acid DNA sequences) and a macromolecule, with a molecular weight of 150,000 . The first published descriptions of neurological improvement in humans following etanercept administration were reports of improvement in neuropathic spinal pain following its use [28-30]. The first description of rapid improvement in intractable lumbar radiculopathy (sciatica) following PSE injection was published in U.S. patent 6,419,944, filed in 2001, followed by additional published reports in 2003 and 2004 of rapid improvement in intractable lumbar and cervical radiculopathy after PSE [28-30]. The rapid neurological effects of PSE in patients with intractable intervertebral disc-related pain were found to include not only improvements in pain but also rapid improvements in sensory disturbance (numbness and paresthesia), mood, affect and cognition [20, 24, 28-30]. As previously stated in a 2012 review,
It later became clear that there existed an essentially forgotten anatomic pathway that could explain these rapid spinal results: carriage of etanercept in the vertebral venous system, the interconnected plexuses of internal and external spinal veins. Bi-directional flow within the vertebral venous system, potentially enabling etanercept injected perispinally to rapidly reach the spinal nerve roots, dorsal ganglia, and spinal cord, was the only viable mechanism that could explain the rapid improvement in pain. 
In 2006-2008, the first published reports of improvement in Alzheimer’s disease (AD) following open-label administration of PSE were published [16, 17, 31-33]. These reports were followed by growing recognition of excess TNF as a therapeutic target in AD [17, 19, 26, 37-46]. In 2011, the first report of rapid improvement in chronic post-stroke neurological dysfunction after PSE published . Recently, through consideration of the anatomy and physiology of the CSVS; the history of perispinal injection; and the rapid CNS improvements produced by PSE after chronic stroke in larger numbers of patients, it has become obvious, when examining the broad spectrum of supporting evidence, that PSE can reliably produce improvement in chronic CNS dysfunction in selected patients [1-3, 16-37, 44, 47-56].
Patients, medicine and science will be best served if the publications, results and anatomical studies of Breschet, Corning, and Batson are appreciated for what we now know they reveal: a new anatomic route that may be utilized for delivery of CNS drugs, without the necessity of invasive neurosurgical procedures and without the necessity, time, expense and uncertainty of re-engineering existing molecules to facilitate their passage through the blood-brain barrier [2, 19, 23, 26]. While evidence of therapeutic effectiveness utilizing perispinal injection is currently limited to etanercept and cocaine, there is no reason why these are the only molecules that could benefit from the use of this relatively non-invasive delivery method. Positron emission tomographic and functional magnetic resonance imaging are ideal methods to study the effects and distribution of radiolabeled macromolecules after perispinal injection [2, 18, 20]. The unmet medical need produced by stroke, traumatic brain injury, chronic traumatic encephalopathy and Alzheimer’s disease, calls for funding perispinal injection studies without delay. Randomized controlled clinical trials of PSE for treatment of AD and chronic stroke are in process at Griffith University in Australia, but more funding for larger, multi-center trials is urgently needed. Further basic science studies of PSE in animal models merit initiation without delay.
Perispinal injection utilizes passage through the cerebrospinal venous system to facilitate CNS drug delivery without the necessity of neurosurgery or re-engineering of existing drugs. Perispinal injection of biologics, such as etanercept, provides a new modality to investigate brain-immune pathophysiology and address CNS disorders.
 It also remains widely unrecognized that Corning was also the first to achieve spinal anesthesia by intrathecal injection of cocaine, with publications in 1894 and 1897 (references 9,10); this distinction has historically been awarded to Bier for his 1899 publication (Bier, A., Versuche uber Cocainisirung des Ruckenmarkes. Dtsch Ztschr Chir 1899. 51: p. 361-369).
No funding was received in connection with this manuscript. Conflict of Interest Statement: The author has multiple patents, assigned to TACT IP LLC, describing methods of perispinal delivery of etanercept and other drugs for treatment of neuroinflammatory indications, including but not limited to U.S. patents 6419944, 6537549, 6982089, and 8900583. Dr. Tobinick is the CEO of TACT IP, LLC and founder of medical practices that utilize PSE as an off-label therapeutic modality and also train physicians in its use.
The contents of this article were adapted from: Tobinick, E Perispinal Delivery of CNS Drugs, an open-access article, CNS Drugs (2016) 30: 469. doi:10.1007/s40263-016-0339-2. Copyright 2016 Edward Tobinick MD, all rights reserved.
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