Introduction

Traumatic brain injury (TBI) is a leading cause of disability throughout the world ( ).

An estimated 3.2–5.3 million Americans (1.1–1.7%) live with long-term mental and/or physical impairments as a result of TBIs ( ). Due to an increase in patients surviving a TBI, it is imperative for novel treatments and therapies to be tested and used for this vulnerable population. Traumatic brain injuries cost the United States approximately $60 billion dollars ( ). This includes the costs for medical treatment and rehabilitation therapies and the indirect costs to society ( ).

Chronic neurological dysfunction following moderate to severe traumatic brain injury is characteristic ( ). Chronic neurological dysfunction after TBI may include motor dysfunction; sensory dysfunction; chronic central pain syndromes; visual dysfunction; hearing loss; speech and language dysfunction, including aphasia and apraxia of speech; and incontinence ( ). Cognitive impairment is common and may be long-lasting and progressive ( ). Neuropsychiatric disturbances are common; they can include depression, impulsivity, fatigue, and behavioral changes ( ). There is currently no drug treatment that is specifically approved to treat the spectrum of chronic neurological, cognitive, and behavioral dysfunction that affects the 5.3 million Americans who live with long-term mental or physical impairments due to TBI ( ).

Excess Tumor Necrosis Factor as a Therapeutic Target for Treatment of Traumatic Brain Injury

Tumor necrosis factor (TNF) is an immune signaling molecule produced by glia, neurons, macrophages, and other immune cells ( ). TNF exerts its physiological effects by binding to two cell-surface receptors, the p55 and p75 TNF receptors (TNFR), now more commonly referred to as TNFR1 and TNFR2 ( ). TNFR are found on all nucleated cells, including neurons in the brain ( ). Constitutive expression of p55 TNFR messenger RNA has been detected in the brain in the circumventricular organs, choroid plexus, leptomeninges, ependymal lining cells in the walls of the cerebral ventricles, and along the blood vessels ( ). Among other functions, TNF serves as a gliotransmitter, secreted by glial cells that envelope and surround synapses in the brain ( ). TNF is known to regulate synaptic communication between both neurons and neuronal networks ( ).

TNF plays a key role in regulating synaptic network function in the normal brain, through its control of synaptic scaling, a neuronal network homeostatic regulatory mechanism ( ). Thus the finding, surprising perhaps to those unfamiliar with TNF’s critical regulatory function in the brain, that the immune signaling molecule TNF, in addition to functioning as the master regulator of the inflammatory response in the periphery, plays an essential role in regulating brain function, in both health and disease ( ).

In , Goodman, Robertson, Grossman, and Narayan, measured levels of TNF in the serum of 21 patients admitted in coma to a neurosurgical intensive care unit after head injury and found their mean serum TNF levels were more than 30 times normal. In a later study, studied TNF levels in the cerebrospinal fluid (CSF) in TBI patients and in controls. They found high levels of CSF TNF in 65% of subjects who had sustained a severe TBI and that “normal” CSF does not contain measurable concentrations of TNF ( ). The authors postulated that elevated CSF TNF levels might contribute to the vasogenic edema of head injury ( ). In various models of closed head TBI in rats, early elevation of TNF was detected in the contused cerebral hemisphere and cerebral cortex ( ). Subsequent basic science experiments provided further data implicating excess TNF in the pathophysiology of TBI ( ). Genetic analysis examining single nucleotide polymorphisms in the promoter region of the TNF gene has discovered a correlation between TNF genetic makeup and clinical outcome at 6 months after TBI ( ). The authors of this genetic study concluded that this data suggested that neuroinflammation has an impact on clinical outcome after TBI and that TNF plays an important role in this process ( ).

Scientific evidence developed during the past decade has established the fact that TBI often results in a chronic intracerebral neuroinflammatory response that includes chronic microglial activation as an essential feature of this brain pathophysiology ( ). For example, in 2004, an international collaboration of neuroscientists found pathological evidence of a long-term intracerebral inflammatory response after TBI in a series of patients who had sustained a blunt head injury ( ). These scientists described microglial hyperplasia and hypertrophy with major histocompatibility complex (MHC) class II upregulation and inflammatory changes up to 16 years after the traumatic brain injury ( ). In another study that used positron emission tomographic (PET) brain imaging using a radioligand that binds to activated microglia, studied patients with moderate and severe TBI using (R)-[11C]-PK11195 brain PET, 6 months after trauma. In both whole-brain and regional analysis, increased (R)-[11C]-PK11195 binding potential was found in patients who had sustained a TBI compared with age- and sex-matched healthy controls ( ). Increased (R)-[11C]-PK11195 binding potential was found not only in the ipsilateral but also in the contralateral hemisphere in this patient series, indicating persistent and widespread microglial activation after TBI ( ). Earlier studies had documented intracerebral microglial activation at 6 months and 2 years after stroke ( ). In 2013, an international consortium of neuroscientists collaborated in the study of brain pathology sustained by a group of subjects who had sustained traumatic brain injury compared with controls ( ). In subjects surviving at least 3 months after injury, cases with TBI frequently displayed extensive, densely packed reactive microglia, a pathology not seen in control subjects or acutely injured cases ( ). Reactive microglia were present up to 18 years posttrauma ( ). The authors concluded that their data presented “striking evidence of persistent inflammation and ongoing white matter degeneration for many years after just a single traumatic brain injury in humans” ( ). performed [11C]-PK11195 brain PET and diffusion MRI imaging in 10 patients with a history of moderate-severe TBI a mean of 6.2 ± 5.3 years earlier. They documented significantly increased [11C]-PK11195 (PK) binding in the TBI patients relative to controls, with bilateral increase in PK binding seen in thalami ( ). Diffusion MRI was used to estimate axonal injury and showed that thalamic inflammation was correlated with thalamocortical tract damage, supporting a link between axonal damage and persistent inflammation after brain injury ( ).

Microglia are a constituent of the innate immune system of the brain. Microglial activation with resulting elaboration of cytokines and initiation of an inflammatory cascade are a characteristic response of the brain’s innate immune system to injury ( ). As discussed earlier, chronic microglial activation has been documented by multiple investigators to be a consequence of traumatic brain injury ( ). Although neurons themselves may release TNF, during neuroinflammation microglia are assumed to be the major source of TNF ( ). Considering that activated microglia release TNF and that TNF regulates synaptic function, targeting microglial activation is a therapeutic strategy that may result in amelioration of TNF excess and restoration of perturbed synaptic physiology in the brain ( ).

Excess TNF has been implicated as a common pathophysiologic mechanism that may be centrally involved in chronic brain dysfunction associated with a wide variety of clinical disorders, including Alzheimer’s disease, cerebral malaria, viral encephalopathies, after seizures, stroke, and TBI ( ). A shared feature of all of these forms of chronic brain dysfunction is cognitive dysfunction. Cognitive dysfunction after TBI may manifest as difficulties with attention, executive function, memory, planning, and judgment ( ). Improvement in cognition following perispinal etanercept (PSE) has been reported after TBI, stroke, and Alzheimer’s disease ( ).

Etanercept is Therapeutically Effective in Basic Science Models of Traumatic Brain Injury and Stroke

Etanercept is a recombinant DNA biologic therapeutic that was FDA-approved for treatment of rheumatoid arthritis in 1998. It is a dimeric fusion protein, composed of 934 amino acids with a molecular weight of 150,000 Da. It consists of the extracellular ligand-binding portion of the human p75 TNF receptor linked to the Fc portion of human IgG1. After administration of 25 mg of etanercept by a single subcutaneous injection to 25 patients with rheumatoid arthritis, a mean ± standard deviation serum half-life of 102 ± 30 h was observed [Enbrel (Amgen) package insert, revised 3/2015]. The half-life of etanercept after perispinal administration is not known. Because it is a drug that can modify immune function [eg, reduce microglial activation ( )], etanercept may have a pharmacodynamic effect in clinical neurological disorders that involve microglial activation that greatly exceeds its pharmacokinetic half-life ( ). Increasing basic science evidence suggests the efficacy of etanercept for treatment of various forms of experimentally induced brain injury ( ).

In and , Chio et al. and Cheong et al. studied etanercept in experimental models of TBI. They found that etanercept, 5 mg/kg intraperitoneally immediately after lateral fluid-percussion injury once every 12 h for 3 consecutive days caused attenuation of TBI-induced cerebral ischemia, reduction of motor and cognitive function deficits, and reduction of microglial activation in their first study ( ). In subsequent studies, found that neurological and motor deficits, cerebral contusion, and increased brain TNF content caused by TBI were attenuated by etanercept, 5 mg/kg intraperitoneally immediately after lateral fluid-percussion injury once every 12 h for 3 consecutive days.

In an experimental stroke model induced by middle cerebral artery occlusion (MCAO) with an intraluminal suture, etanercept (5 mg/kg) administered intraperitoneally 0 or 6 h after inducing ischemia was studied ( ). Etanercept significantly reduced stroke volume compared with nontreated MCAO rats 24 h after reperfusion ( ).

In a murine model, the distal part of the left middle cerebral artery was permanently occluded with sham-operated mice acting as controls ( ). Etanercept was administered intravenously, at a dose of 10 mg/kg, 30 min after surgery. Etanercept was found to improve functional outcome, including neuromuscular asymmetry and motor learning skills, and improve altered microglial responses, without affecting infarct volume ( ).

In an experimental model of subarachnoid hemorrhage (SAH), etanercept administered by intracerebroventricular injection 1 h before SAH (12.5 μg/10 μL) significantly decreased the level of TNF in the cerebral cortex and hippocampus, reduced cellular apoptosis in the cerebral cortex and hippocampus, and improved neurological scores two days after experimental SAH ( ).

Delivery of Etanercept Using the Cerebrospinal Venous System

Appreciation of perispinal administration of etanercept as a method of therapeutic delivery for treatment of neuroinflammatory disorders requires knowledge and understanding of the anatomy and physiology of the cerebrospinal venous system (CSVS) ( Fig. 7.1 ) ( ).

The cerebrospinal venous system.

Adapted with permission from Tobinick, E. The Cerebrospinal Venous System. U.S. Copyright Registration Number VAu000736716, digital enhancement of Plate 5 by Breschet, G. (1829). Recherches anatomiques physiologiques et pathologiques sur le systáeme veineux . Paris, France: Rouen fráeres.

The rapid clinical effects of PSE are due to two of its fundamental characteristics: (1) its use of the CSVS to facilitate rapid and selective delivery of etanercept to the central nervous system and (2) the biological potency of etanercept, a recombinant DNA biotherapeutic that is effective in minute concentration ( ).

The CSVS extends from the head to the pelvis; it consists of the group of veins and venous plexuses of the spine and the brain that freely communicate because they lack valves ( ). The first of the two main divisions of this system, the intracranial veins, includes the cortical veins, the dural sinuses, the cavernous sinuses, and the ophthalmic veins ( ). The second main division, the vertebral venous system, includes the vertebral venous plexuses, which flow along the entire length of the spine ( ). The intracranial veins richly anastomose with the vertebral venous system in the suboccipital region. The CSVS constitutes a unique, large-capacity, valveless venous network in which flow is bidirectional. The CSVS plays important roles in the regulation of intracranial pressure with changes in posture and venous outflow from the brain. The CSVS is a unique venous system capable of bidirectional flow, which does not function to return blood directly to the heart, a characteristic that is essential to its physiologic functions in both health and disease. Blood flow within the CSVS may be conceptualized as generally linear, ie, from the brain to the spine or vice versa; in contrast to the circular blood flow (heart to periphery via the arteries; arteries to capillaries; capillaries to veins; veins to the heart) that is characteristic of the systemic venous system, as Harvey described centuries ago. It was not until Breschet’s detailed drawings were published in the second and third decades of the 19th century that the anatomic connection between the intracranial cerebrospinal venous system and the vertebral venous system was accurately depicted ( Fig. 7.1 ) ( ). Breschet’s work remains the definitive treatise on this venous system; his work has been confirmed by all investigators through the present ( ).

Etanercept injected posterior to the spine is absorbed into the CSVS, because the external vertebral venous plexus drains the anatomic region posterior to the spine ( ).

Perispinal Administration of Etanercept Produces Rapid Intracerebroventricular Delivery in an Experimental Model

In March 2007, the senior author wrote the following in an e-mail to a colleague:

Since etanercept works instantaneously [on a molecular level] it need only meet with free TNF for an instant to inactivate it. It is my belief that retrograde delivery via the CSVS results in etanercept flow into the cerebral veins which then, with the benefit of a brief reversal of the usual venous pressure gradient within the cerebral sinuses…allows etanercept to reach brain TNF momentarily. This may occur via reverse flow into the parenchyma/CSF through the choroid plexus/ arachnoid villi…

Following this e-mail communication, an animal experiment using PET imaging, performed at Stanford in July 2007, provided in vivo imaging evidence of rapid penetration of etanercept into the cerebral ventricles after peripheral perispinal administration followed by tail suspension (head-down positioning) ( ) ( Fig. 7.2 ). In this experiment, radiolabeling of etanercept with the PET emitter ( ) ⁶⁴ Cu was performed by DOTA (1,4,7,10-tetraazadodecane-N,N′,N″,N‴-tetraacetic acid) conjugation of etanercept, followed by column purification and ( ) ⁶⁴ Cu labeling, to enable the in vivo localization of radiolabeled etanercept after perispinal administration. MicroPET imaging revealed accumulation of ( ) ⁶⁴ Cu-DOTA etanercept in the CSF within the lateral and third cerebral ventricles within minutes of peripheral perispinal administration in a normal rat anesthetized with isoflurane anesthesia, with concentration within the choroid plexus and within the CSF ( ).

PET image, transverse section, of a living rat brain following perispinal extrathecal administration of ⁶⁴ Cu-DOTA-etanercept, imaged 5–10 min following etanercept administration.

The pattern is consistent with penetration of ⁶⁴ Cu-DOTA-etanercept into the CSF in the lateral and third ventricles. Note the horizontal linear enhancement within the lateral ventricles which is suggestive of accumulation of tracer within the choroid plexus.

Adapted with permission from Tobinick, E. L., Chen, K., & Chen, X. (2009). Rapid intracerebroventricular delivery of Cu DOTA-etanercept after peripheral administration demonstrated by PET imaging. BMC Research Notes , 2 , 28. Copyright 2008 by Tobinick et al.; licensee BioMed Central Ltd., Figure 1 .

The human experiment that was later completed, using nuclear medicine imaging of a radiolabeled molecule, confirmed that perispinal administration in the posterior neck followed by Trendelenburg positioning could result in retrograde delivery into the cerebral venous system ( ). Trendelenburg positioning involves placement of the patient flat on an examination table with the table inverted so that the legs are higher than the head of the patient (head-down tilt) ( ). Head-down tilt in a rabbit model has been shown to disrupt the blood–CSF barrier, allowing the passage of plasma proteins into the CSF ( ).

Rapid delivery of etanercept into the CSF following perispinal delivery may help explain the rapid neurological improvement seen in patients following PSE administration ( ).

Perispinal Etanercept—Clinical Development

More than a decade after PSE was first used clinically, it has now demonstrated favorable clinical effects for multiple neuroinflammatory disorders ( ) ( Table 7.2 ). PSE was developed for the treatment of neuroinflammatory disorders and first used clinically for intractable neuropathic pain more than a decade ago ( ). In observational studies published in 2003, the ability of PSE to produce rapid relief of pain and neurological dysfunction due to herniated nucleus pulposus and spinal pain due to bone metastases was reported ( ). The rapidity of relief of sciatic pain and associated sensory and motor dysfunction, often evident within minutes, was confirmed in additional patients in an observational study of 143 patients published in 2004 ( ). Prevailing concepts of drug distribution were unable to explain the novel pattern of clinical effects that rapidly ensued after PSE ( ). The pattern, rapidity, and distribution of clinical effects best fit with rapid delivery of etanercept via the CSVS, a novel concept ( ). Further study of the anatomy and physiology of the CSVS led to a new insight: the lack of venous valves enabling bidirectional flow and the anatomical continuity of Batson’s plexus with the cerebral venous system introduced the possibility that this unique vascular pathway might be used for delivery of etanercept, and other large molecules, into the brain ( ). More than a decade after clinical utility of PSE for intractable sciatica was first discovered, PSE was found to have clinical utility for treatment of patients with intractable neurological dysfunction after stroke and TBI ( ). Years after PSE was first reported to produce rapid pain improvement, blockade of TNF was documented to rapidly inhibit pain responses in the central nervous system using blood-oxygen level-dependent functional MRI ( ). Rapid neurological improvement after PSE has been confirmed by multiple, independent scientists through their first-hand observations ( ). This rapid improvement may be due to rapid effects of TNF on synaptic function, neuronal network function, or amelioration of mitochondrial dysfunction mediated by TNF-induced neurotoxicity ( ). TNF’s effects on neuronal function are likely to vary with concentration ( ). Low, physiological levels, of TNF appear necessary for normal neuronal function; conversely, elevated levels of TNF may disrupt synaptic function and be associated with clinically significant neurological dysfunction ( ). Specifically, it is hypothesized that the rapid effects of PSE may be mediated by changes in neural network function by signals transduced across the blood–CSF barrier, perhaps by tancyctes or CSF-contacting neurons with TNF receptors on their dendritic surfaces in contact with the CSF ( ). The pervasive involvement of TNF in modulation of neurological function continues to be unraveled ( ). ¹

1 For example, the improvement in taste perception following perispinal etanercept in chronic stroke patients first published in 2012 ( CNS Drugs , 2012. 26 (12), 1051–1070) is supported by basic science experiments documenting the regulation of bitter taste responses by TNF and the expression of TNFR1 and TNFR2 on taste buds (Feng, P., Jyotaki, M., Kim, A., Chai, J., Simon, N., Zhou, M., et al. (October 2015). Regulation of bitter taste responses by tumor necrosis factor. Brain Behavior, and Immunity , 49 , 32–42).

Table 7.2

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