Traumatic Brain Injury
- Background
- Consequences of TBI
- Pathophysiology of TBI
- Economic Burden
- The Need
- Current Treatments
- Our Solution
Background
Injury to the central nervous system (CNS) is one of the leading causes of death and invalidity among all people below the age of 45, for which there are no specific treatments. In terms of mortality, morbidity and cost to modern society injuries to the CNS (traumatic brain injury – TBI and spinal cord injury – SCI) are some of the most severe and widespread public health problems, not only because of the high incidence of deaths they cause (22% of all TBI cases result in death), but also owing to the large number of individuals who are left with some kind of disability.
According to epidemiology studies of the National Center for Injury Prevention and Control at the Center for Disease Control approximately 5.3 million Americans live with disabilities caused by TBI. Furthermore, of approximately 1.3 million traumatic brain injuries that occur annually, more than 250,000 are severe enough to require hospitalization. If all types of head injuries are included, the incidence jumps from 2 to 12.5 million head injuries per year.
Comparison of Annual Incidence of Traumatic Brain Injury and other Leading Injuries or Diseases
A traumatic brain injury (TBI) is caused by a blow or jolt to the head or a penetrating head injury that disrupts the normal function of the brain. In terms of severity TBI is classified as "mild", "moderate", or "severe".
The leading causes of TBI are: Falls (28%); Motor vehicle-traffic crashes (20%); Struck by/against events (19%); and Assaults (11%). It is estimated that by the year 2020, 8.4 million people will die every year from injury, and injuries from road traffic accidents will be the third most common cause of disability worldwide and the second most common cause in the developing world. Additionally, an increase in combat casualties with TBI from current conflicts is observed.
Consequences of TBI
Medical complications of TBI vary greatly. Its complications range from minor sensory or motor problems that resolve quickly without medical intervention, to severe injuries that involve a prolonged loss of consciousness and lifelong physical and cognitive disabilities. Effects/consequences of a brain injury will depend on the location of the injury and the amount of damage to particular brain parts. This is because different parts of the brain control different functions. Therefore, every brain injury is different, and no two people will have identical symptoms from a brain injury. Thus, one person may have problems with memory and concentration while another may have weakness or paralysis of muscles. Cognitive and neurological complications may be apparent immediately after the injury, but may also develop and change over time. The heterogeneous nature of TBI requires the cooperation of many different disciplines and services: clinical activities as neurological assessment, acute medical and neurosurgical treatment, psychiatric intervention, behavioral therapies, occupational and physical rehabilitation.
One of the prolonged consequences occurring following head trauma is the development of abnormal electrical activity in the brain that induces the genesis of epileptic seizures. Epileptic seizures induced by TBI are especially debilitating because patients afflicted with them frequently lose consciousness as a result of this abnormal neuronal hyperactivity. Due to the effects of these seizures, patients are often unable to fully partake in normal daily life or work activities, such as driving vehicles or operating machinery. Patients usually experience their first seizure a year or two after the original trauma.
Briefly, severity of TBI is highly variable and is typically categorized as mild, moderate, or severe. In mild TBI, a brief change in mental status or consciousness occurs that may be followed by temporary symptoms associated with concussion, such as headache, blurred vision, and confusion. The symptoms of mild TBI generally resolve quickly, but optimal recovery may require patients to temporarily limit their activity to prevent further injury or harm to others.
In moderate TBI, longer periods of loss of consciousness (LOC) and posttraumatic amnesia (PTA) follow the traumatic event. Patients with moderate TBI may experience a variety of symptoms, including mood and memory disturbances and physical and emotional problems that may persist for months. Moderate TBI requires increased clinical intervention but generally responds to medication, psychotherapy, and compensatory strategies.
Severe TBI can be characterized by a coma that lasts longer than 24 hours or PTA for longer than 7 days. The Glasgow Coma Score can also be used to describe the severity of TBI, with severe patients falling between 3 and 8 on the scale. Patients with severe TBI may remain in a vegetative state for an extended time period. Severe TBI most often results in long-term problems with independent functioning and can result in moderate to severe disability in some patients. Most patients with severe TBI require comprehensive nursing care and ongoing rehabilitation.
There are two major categories of brain injury: focal injuries and diffuse injuries.
Focal brain injuries are usually caused by direct blows to the head and comprise contusions, brain accelerations and haemorrhage leading to the formation of haematoma in the extradural, subarachnoid, subdural, or intracerebral compartments within the head. Diffuse brain injuries are usually caused by a sudden movement of the head, and cause diffuse axonal injury.
Pathophysiology of TBI
After the acute physical insult to the brain, there are many harmful secondary effects, usually associated with three things: 1. ischemia (bleeding); 2. elevated intracranial pressure; 3; haematomas, contusions and brain swelling. This is followed by late-appearing neurodegeneration. Primary injury is the result of immediate mechanical damage of neural pathways that occurs at the time of injury and is irreversible.
Although much damage is caused by the initial impact or primary injury, additional factors can cause further damage to the brain. This is known as secondary injury and it evolves over a period of minutes to hours to days, even to several weeks following initial trauma. It appears therefore that CNS trauma triggers a cascade of events, which cause primarily unaffected neurons to degenerate at a later time-point. Most of the care that a person receives in the hospital after a brain injury is meant to minimize the effects of secondary injury since the primary injury (the impact) has already happened.
Importantly, the damaging consequences of TBI can be significantly exacerbated by the superimposition of secondary posttraumatic insults that may lead to ischemic brain damage. These secondary brain insults are extremely common after head injuries. Thus patients may suffer combination of various systemic (hypoxia, arterial hypotension, hypercarbia, pyrexia, anaemia, diffuse intravascular coagulopathy) and intracranial (haematomas, brain swelling/edema, intracranial hypertension, cerebral vasospasm, altered cerebral blood flow – CBF and blood-brain barrier status- BBB, intracranial infection, epilepsy) insults to the injured brain.
Finally, many other medical problems, which are common after trauma, can aggravate a brain injury. For instance, a period of low blood pressure or low blood oxygen that may be caused by breathing difficulty can cause further damage to the already-injured brain. Among other problems that can affect functioning of the brain are abnormalities of the blood’s chemical composition.
In summary, damage to the brain is caused by many factors, in addition to the original trauma. Therefore, brain injury represents all these different factors together.
Unlike the successful healing responses in the peripheral nervous system, adult CNS injury leads to permanent disability, because most severed axons fail to regenerate.
A phenomenon that adds to the complexity of regenerative failure is the process of glial scarring or reactive gliosis. Although the functional role of glial scarring is not completely understood, it has been suggested to be an attempt made by the CNS to restore homeostasis through isolation of the damaged region. This process involves proliferation and migration of glial cells (astrocytes and oligodendrocytes). Despite the fact that it is in the first moment helpful, the robust formation of the glial scar has been considered to be one of the major impediments to neuronal regeneration. Glial scarring is also the cause of postoperative problems after removing of brain tumours.
The understanding of the molecular pathophysiology of these brain dysfunctions will provide new clues that may lead to effective therapeutic approaches that will limit damage, slow cell death and promote repair. Considerable effort is being directed toward understanding the etiology of astrogliosis and the mechanisms by which the glial scar can be reduced.
Economic Burden
Direct medical costs and indirect costs such as lost productivity of TBI totaled an estimated $60 billion in the United States in 2000. The lifetime cost of treating and supporting an individual with a significant TBI is estimated at $600,000 to $1,875,000.
According to the European Brain Council, the average cost for a patient who suffers from a brain disorder is estimated at €829 per inhabitant per year in Europe. In 2004, the total cost of brain-related diseases was approximately €386 billion in Europe. In addition to these direct medical costs, brain-related diseases have major societal implications and indirect costs linked among others to a loss of productivity, and social dependency among others. These data refer to various disorders of the brain, (Parkinson’s disease, Migraine, TBI, Dementia, Alzheimer’s disease, Epilepsy, Brain aneurysm etc.). Taking into account that TBI can also cause epilepsy and increase the risk for conditions such as Alzheimer’s disease, Parkinson’s disease, and other brain disorders that become more prevalent with age, one may conclude that a significant proportion of the estimated economic burden can be attributed to TBI.
The Need
People suffering consequences of TBI had more and less serious cognitive impairments such as:
- short and long term memory loss
- slowed ability to process information
- trouble concentrating or paying attention for periods of time
- difficulty keeping up with a conversation
- other communication difficulties such as word finding problems
- spatial disorientation
- organizational problems and impaired judgment
- inability to do more than one thing at a time
mood disorders and personality changes such as:
- poor judgment,
- increased agitation,
- aggression, depression, and
- anxiety are also prevalent after brain injury
emotional consequences such as:
- a lack of initiating activities
- or once started, difficulty in completing tasks without reminders;
- denial of deficits,
- impulsive and egocentric behaviour, as well as difficulty seeing how such behaviour can affect others are also frequent
In addition, they had physical consequences that can include:
- muscle spasticity; double vision or low vision, even blindness; loss of smell or taste; speech impairments such as slow or slurred speech; headaches or migraines; fatigue, increased need for sleep; balance problems.
- seizures of all type. Epileptic seizures induced by TBI are especially debilitating because patients afflicted with them frequently lose consciousness as a result of this abnormal neuronal hyperactivity. Due to the effects of these seizures, patients are often unable to fully partake in normal daily life or work activities, such as driving vehicles or operating machinery. Patients usually experience their first seizure a year or two after the original trauma.
Additional psychosocial consequences usually emerge as individuals face the challenge of returning to routine daily activities. Even a "mild" TBI can increase the risk of chronic unemployment, substance abuse, and suicide. After traumatic brain injury, it is common for workplace performance to be disrupted, personal and professional relationships to deteriorate, and marriages to fail. Therefore, behavioural and psychosocial sequelae are the most disabling consequences of TBI.
Current Treatments
Anyone with signs of moderate or severe TBI should receive medical attention as soon as possible. Because little can be done to reverse the initial brain damage caused by trauma, medical personnel try to stabilize an individual with TBI and focus on preventing further injury. Primary concerns include ensuring adequate ventilation and proper oxygen supply to the brain and the rest of the body, maintaining adequate blood flow, and controlling blood pressure.
Imaging tests help in determining the diagnosis and prognosis of a TBI patient. Patients with mild to moderate injuries may receive skull and neck X-rays to check for bone fractures or spinal instability. For moderate to severe cases, the imaging test is a computed tomography (CT) scanning, which has been shown to reduce mortality in patients with acute extradural haematoma, as the time taken to diagnose and evacuate an intracerebral haematoma is critical in determining outcome.
Moderately to severely injured patients receive rehabilitation that involves individually tailored treatment programs in the areas of physical therapy, occupational therapy, speech/language therapy, physiatry (physical medicine), psychology/psychiatry, and social support.
The current treatment for epileptic seizures is based on anticonvulsant drugs. However, currently available drugs are, at the moment, aimed at arresting or reducing symptoms associated with the seizure of about 60 % of patients only. None of these drugs have been shown to be anti-epileptogenic. Since no current anticonvulsants have been shown to influence the natural history of epileptic seizures, there is no medical cure for the disease. Currently, there are no treatments to prevent epileptic seizures induced by traumatic brain injury.
Our Solution
Considerable effort is being directed toward understanding the etiology of astrogliosis and the mechanisms by which the glial scar can be reduced. Insight into the mechanisms underlying the process of reactive gliosis, led us to a novel therapeutic approach that involved application of an antiviral drug RIBAVIRIN.
The experiments were performed on adult male Wistar rats. Traumatic brain injury is induced by the stab lesion or by unilateral ablation of left or right sensorimotor cortex. The coordinates of the sensorimotor cortex stab lesion were as follows: 2 mm posterior to the bregma, 2 mm from the midline and 2 mm deep, while coordinations of ablation were: 2 mm anterior to the bregma, 4 mm posterior to the bregma, 4 mm lateral from the midline. The left/right sensorimotor cortex was removed by suction ablation through a polypropylene tip, to the depth of the white matter. Throughout the experiments minimal number of animals was utilized, and in order to minimize their suffering the animals were anesthetized throughout the whole procedure.
For in vitro experiments primary mixed glial cell cultures were prepared from newborn Wistar rat pups.
RIBAVIRIN (VIRAZOLE®, 1-b-D-ribofuranosyl-1,2,4-triazole-3-carboxamide), a purine nucleoside analogue, acts primarily by inhibition of inosine monophosphate dehydrogenase (IMPDH), a rate-limiting enzyme in de novo purine synthesis pathway. RIBAVIRIN produces IMPDH inhibition via its metabolite 5’-ribavirin monophosphate (RMP).
Diagrams showing the mechanism of RIBAVIRIN action i.e. how ribavirin attenuates de novo synthesis of purine nucleotides
RIBAVIRIN, by inhibiting de novo nucleic acid (DNA, RNA) synthesis, attenuated and delayed forming of the glial scar and reduced the number of glial cells (astrocytes, microglia and oligodendrocytes) around the lesion site.
Down-regulation of glial cells proliferation was retained even 30 days after the last RIBAVIRIN injection. Postponing of glial scarring could be one of the prerequisites for neurite outgrowth by primary undamaged neurons, and creation of new synaptic connections with denervated nerve cells at the lesion site. Thus, anti – proliferative potential of RIBAVIRIN, low toxicity, and disappearance of toxicity upon withdrawal of the drug recommend this nucleoside analogue as an attractive therapeutic tool for improving neurological recovery from head injury.
