Traumatic Brain Injury(TBI)

1. Traumatic Brain Injury(TBI) MONA ELSAYED, MD, MSc Clinical Assistant Professor Of Neurology and Epilepsy Comprehensive Epilepsy Center Neurology department Wayne state university(SOM)-DMC

2. Objectives • Definition and Types of TBI. • Pathophysiology of TBI and PostTraumatic Epilepsy(PTE). • Types of seizures in TBI. • Management of seizures and PTE due to TBI.

3. TBI • Traumatic brain injury (TBI) is an acquired condition from an external force/mechanical, which can cause significant effects to the brain vasculature and neighboring neuronal cells. • The traumatic brain injury (TBI) is the leading cause of death and severe disability among affected people. • Over 55 million people affected internationally. About 1,7 million people are affected in USA. • Epidemiology of TBI: The younger patients are more likely suffering TBI as the result of motor vehicle accidents (most common cause), sports, or battlefield exposure to blast waves, whereas the elderly population is generally affected by falls (neurogenic or cardiogenic in origin). 

8. TBI TYPES and classifications -Two anatomical types of TBI: 1- Closed head injury. 2- Penetrating head injury . -ALSO TBI can be classified into: 1- Focal injury causes brain contusion (impact TBI; Acute primary phase), 2- Diffuse/generalized injury (Blast injury; Subacute secondary phase) causes diffuse axonal shearing {DAI} means diffuse axonal tear/diffuse separation of axons from neuron cell bodies}, and damage brain small blood vessels. 3-Chronic phase: Tau kinase/phosphatase imbalance leads to hyperphosphorylation of tau. The Tau hyperphosphorylation forms neurofibrillary tangles near perivascular regions; promoting neurodegenerative disease and cognitive decline. In addition, Increased amyloid precursor protein promotes the toxic oligomerization of amyloid beta, causing cognitive decline.

10. -TBI is classified depending on the level of severity into: 1-Mild (unnoticed initially or exhibit SDH, but might develop later emotional and cognitive impairment), 2-Moderate, 3-Severe (can cause SAH; Severe TBI is often life-threatening and requires immediate care, its effects are more likely irreversible in both the short-term and the long-term). -TBI is classified clinically into: 1- Sub-concussive injury can have no initial symptoms, 2--Concussive injury (acute) presents with dizziness, confusion or seeing stars, having loss of consciousness or having post-traumatic amnesia. 3-Post-concussive syndrome involves concussive symptoms(cognitive, emotional, headache, dizziness/vertigo, and sleep symptoms) lasting >3 months, and chronic traumatic encephalopathy (common also with repeated mild TI) , and years later, might followed by onset of neuropsychiatric symptoms. -TBI has a predilection for the frontal and temporal lobes.

11. Subdural Hemorrhage

12. Epidural Hemorrhage

13. Contusions

14. Subarachnoid Hemorrhage

15. Pathogenesis of TBI and PTE1-primary acute phase2-secondary subacute phase3-chronic phase

16. The physical forces of TBI can cause acute immediate 1ry effects (response with in few hours) such as shear axons apart from the neuron bodies, break down plasmalemma(BBB), and rupture brain microvessels (this will release cytotoxic levels of iron into the brain parenchyma). • The Iron promotes Ca2+-dependent mechanisms, which can stimulate cell survival, or trigger cell death depending on severity and duration of iron exposure, this will LEAD TO subacute delayed 2ry effects (response within hours >7 hrs to days) as the neurons/astrocytes can rapidly depolarize, increase glutamate extracellular (Reduced glutamate uptake activates NMDA receptors) causing Glutamate Excitotoxicity, and activate voltage gated Ca2+ channels; • Thereby, increasing intracellular Ca2+, then will binds to calmodulin forming calpain kinase that cleaves normal p35 into toxic unfolded p25, causes energy failure and formation of toxic reactive oxygen species(ROS) due to damage of important cell organelles such as the endoplasmic reticulum (the main source of normal protein formation), and mitochondria (the main source of fat metabolism and energy production) respectively, • This will lead to irreversible cell damage and neuron cell death in lesional and peri-lesional areas, and which in turn lead to long-term changes in neural network organization, particularly in the hippocampus and neocortex .

17. The Effects of Traumatic Brain Injury on the Blood-Brain-Barrier. TBI can cause disruptions of tight junction proteins connecting endothelial cells. Astrocytes can undergo astrogliosis and the basement membrane can become disrupted. Ultimately these changes increase the likelihood of red blood cell extravasations.

18. Depiction of a Vasospasm Resulting from Traumatic Brain Injury. Vasospasm can be triggered by subarachnoid hemorrhage or blood pressure spikes. Pericytes near vessels release endothelin-1, which triggers vasoconstriction.

20. Pathophysiology of Neuronal Cell Death Following Traumatic Brain Injury. An intracranial pressure spike, axonal shearing, and brain contusion contribute to secondary mechanisms that lead to an increase in Ca2+channel opening. The generation of reactive oxygen species can ultimately contribute to cell death

21. Brain edema leading to an expansion of brain volume has a crucial impact on morbidity and mortality following traumatic brain injury (TBI) as it increases intracranial pressure, impairs cerebral perfusion and oxygenation, and contributes to additional ischemic injuries. • Classically, two major types of traumatic brain edema exist: First “cytotoxic/cellular” due to sustained intracellular water collection. • Then vasogenic” due to blood–brain barrier (BBB) disruption resulting in extracellular water accumulation. • And a third type, “osmotic” brain edema is caused by osmotic imbalances between blood and tissue.

22. The chronic phase of TBI has been shown to hyperphosphorylate tau protein, and produce amyloid beta proteins. • These neurodegenerative factors are activated immediately following TBI and can advance profoundly over time. • Cortical tissue loss and white matter atrophy resulting from TBI are associated with cognitive deficits.

23. The Chronic Effects of Traumatic Brain Injury. Some individuals experiencing TBI are more susceptible to chronic effects than others. Environmental and genetic factors play a role. Pathologic changes that may develop include neurofibrillary tangles, axonal shearing, and amyloid plaques to name a few. Neuropsychiatric symptoms may also develop such as depression, impulsivity, cognitive decline, and confusion. This area of chronic deficits following TBI is a topic of growing importance receiving renewed research focus and funding

24. Post‐traumatic epilepsy (PTE) • Post‐traumatic epilepsy (PTE) is a serious and disabling delayed consequence of a traumatic brain injury (TBI). • Immediate PTS occurs within first 24 of TBI and is provoked with incidence of 1-4%, • Early PTS occur within first week (1-7d) of TBI, that provoked by head injury with incidence of 4-25%, • Late PTS occur at any time after first week of TBI and characterized by one or more unprovoked seizures and determine the occurrence of PTE with incidence of 9-42%. • PTE is one of the most common types of acquired (or secondary) epilepsies, which are due to a brain insult, such as trauma(TBI), tumors, stroke, and infections, and accounts for 5% of all epilepsies and about 20% -30 of acquired epilepsy in the general population. • People with PTE commonly experience a latent or silent period of at least 6 months, and sometimes up to 20 years, between the causative injury and the onset of seizures.

26.  The types of seizures experienced by people with PTE are: • 1- Focal onset seizures with or without secondary generalization to bilateral tonic‐clonic convulsive activity, • 2-Focal nonconvulsive seizures only. • 3- Subclinical seizures is common as well, and is even higher in penetrating injuries than in non-penetrating injuries. •  Early seizures are often of the generalized tonic‐clonic convulsive type in comparison to late seizures, which are mostly focal and nonconvulsive in nature. • The risk of PTE is the highest within the first 2 years of TBI.However, the risk of developing PTE is still high for more than 10 years later in people with moderate TBI, and more than 20 years later in people with severe TBI. • There is stronger evidence for a high risk of seizure recurrence subsequent to the first late seizure: 47% within a month after TBI, and 86% after 2 years following TBI.

28. Management of Post Traumatic Epilepsy (PTE) and TBI

29. Seizure prophylaxis protocol in neuro-ICU

30. Current prophylactic treatment options. Anticonvulsant drug Mechanism Adverse reactions • Phenytoin Stabilize inactive form of sodium channel Fever, nystagmus leukocytosis, rash, hypersensitivity reactions • Carbamazepine Stabilize sodium channels in inactive state Aplastic anemia, pancytopenia, Stevens Johnson syndrome • Phenobarbital Activate GABA receptors, inhibit calcium channels Dizziness, fatigue, ataxia, aplastic anemia, • Valproate Inhibit sodium channels and GABA transaminase, Thrombocytopenia, hypofibrinogenemia, pancytopenia, hair loss activate GABA-synthetic enzyme glutamic acid decarboxylase, alter the conductance of calcium and potassium

31. Other recommendations relevant to the management of PTE in adults include the following: • Phenytoin increases the refractory period and reversibly inhibits action potentials. • In severe TBI, phenytoin has been found to reduce the incidence of early seizures from 14.2% to 3.6% . Also, this drug should only be used within the first 48 h post-trauma because a randomized control trial showed a trend toward higher mortality when used at later time points . • In a separate study, the use of this anticonvulsant beyond 1 week was associated with skin rash as side effects. • “Adults presenting with an unprovoked first seizure should be informed that the chance for a recurrent seizure is greatest within the first 2 years after a first seizure (21–45%) (Level A).

32. Current clinical practice guidelines • Several recommendations have been produced by the American Academy of Neurology for the management of epilepsy both in adults and in children. There is only one clinical practice guideline containing recommendations for seizure prophylaxis following TBI. • “For adult patients with severe TBI (typically with prolonged loss of consciousness or amnesia, intracranial hematoma or brain contusion on CT scan, and/or depressed skull fracture): • Prophylactic treatment with phenytoin, beginning with an IV loading dose, should be initiated as soon as possible after injury to decrease the risk of posttraumatic seizures occurring within the first 7 days (Level A). However, early PTS is not associated with worse outcomes. Phenytoin increases the refractory period and reversibly inhibits action potentials. • In severe TBI, phenytoin has been found to reduce the incidence of early seizures from 14.2% to 3.6% [41]. Also, this drug should only be used within the first 48 h post-trauma because a randomized control trial showed a trend toward higher mortality when used at later time points. Valproate inhibits GABA transaminase increasing GABA levels in the synaptic cleft [40]. Studies have demonstrated a similar efficacy as compared to phenytoin. • Prophylactic treatment with phenytoin, carbamazepine, or valproate should not routinely be used beyond the first 7 days after injury to decrease the risk of post‐traumatic seizures occurring beyond that time; late PTE (Level B). • Levetiracetam (LEV) is an anticonvulsant which binds synaptic vesicle glycoprotein 2A (SV2A) and likely inhibits presynaptic Ca2+ channels

33. Clinicians should also advise such patients that clinical factors associated with an increased risk of seizure recurrence include a prior brain insult such as a stroke or trauma (Level A), an EEG with epileptiform abnormalities (Level A), a significant brain‐imaging abnormality (Level B), or a nocturnal seizure (Level B). • Clinicians should advise patients that, although immediate AED therapy, as compared with delay of treatment pending a second seizure, is likely to reduce the risk of a seizure recurrence in the 2 years subsequent to a first seizure (Level B), it may not improve QOL (Level C). • Clinicians should advise patients that over the longer term (3 years), immediate AED treatment is unlikely to improve the prognosis for sustained seizure remission (Level B). Patients should be advised that their risk for AED adverse effects (AEs) ranges from 7% to 31% (Level B) and that these AEs are predominantly mild and reversible”.

34. A surgical option for treatment of post-traumatic epilepsy is implantation of a vagal nerve stimulator (VNS). • Generally, a small stimulator is implanted in the chest wall in the vicinity of the vagus nerve; it is believed the stimulator acts by altering norepinephrine and elevating GABA levels.

35. Continuous electroencephalography (CEEG) monitoring is commonly used in critically ill patients. CEEG is tightly linked to cerebral metabolism and, thus, sensitive to changes in cerebral blood flow. Several patterns on CEEG are of diagnostic and prognostic significance in patients with cerebral edema that lie on the ictal-interictal continuum . EEG patterns that correlate with increased intracranial pressure (ICP) include focal slowing of underlying rhythms or global EEG suppression progressing to burst suppression or flat EEG. CEEG monitoring provides real-time dynamic information about brain functioning and allows for detection of any early change in neurological status of a patient that may not be evident on neurological examination alone . J Intensive Care. 2018

36. PTE can have a significant negative effect on the quality of life (QoL) of people with TBI. Following a return to the community, people with TBI have to learn to cope with and adjust to major changes in their life, including the reestablishment of their self‐identity. • PTE adds a complexity to the existing consequences of TBI, making reintegration into the community difficult and challenging. • The development of epilepsy represents a serious setback that can affect people's independence, job opportunities, recreational pursuits, mental health, and safety. • Furthermore, PTE usually requires the taking of AEDs on a long‐term basis, and these can have negative side effects that influence a person's QoL and neuropsychiatric symptoms.

37. PTCPD • Survivors of traumatic brain injury (TBI) often develop chronic neurological, neurocognitive, psychological, and psychosocial deficits that can have a profound impact .on an individual’s wellbeing and quality of life. • Around 60% of people experience a psychiatric illness in the 12-months following a TBI, with affective disorders such as depression and anxiety the most common presentation. • After TBI, a psychological process of grief and adjustment can occur in response to sudden changes in personal circumstance caused by the injury. Such psychosocial changes can be temporary or permanent, 

38. TBI Guidelines • I. Blood Pressure and Oxygenation • II. Hyperosmolar Therapy • III. Prophylactic Hypothermia • IV. Infection Prophylaxis • V. Deep Vein Thrombosis Prophylaxis • VI. Indications for Intracranial Pressure Monitoring • VII. Intracranial Pressure Monitoring Technology • VIII. Intracranial Pressure Thresholds • IX. Cerebral Perfusion Thresholds • X. Brain Oxygen Monitoring and Thresholds • XI. Anesthetics, Analgesics, and Sedatives • XII. Nutrition • XIII. Antiseizure Prophylaxis • XIV. Hyperventilation • XV. Steroids

39. surgical management of TBI • A common treatment option for hemorrhagic change that infiltrates the ventricles is a ventriculostomy followed by ventriculoperitoneal shunt placement. • In severe cases of TBI with subarachnoid hemorrhage, brain edema, where herniation is anticipated, decompressive craniectomy can be performed. • decompressive craniectomy (DC) is a life-saving strategy for patients who suffer from severe TBI. • The most frequent complications early after DC are contusion or herniation of the cortex through the bone defect, and CSF leakage through the scalp incision, infection and hydrocephalus that can happen after 1 month.

40. acute rehabilitation following TBI • Studies of acute rehabilitation following TBI are: • (1) gains made during rehabilitation such as in ambulation, independence and cognition • (2) effects of early intervention • (3) effects of intensity of rehabilitation efforts. • Practice-Based Evidence (PBE) study methodology provides an efficient, comprehensive means of implementing comparative effectiveness research.The 5-year TBI rehabilitation project described in articles in this supplement used PBE research methodology to isolate specific components of rehabilitation treatments, as has been done in previous PBE rehabilitation inpatient treatment studies.

41. The specific aims of the TBI-PBE project were to: • (1) identify individual patient characteristics, including demographic data, severity of brain injury, and severity of illness (complications and comorbidities), that may be associated with significant variation in treatments selected and in outcomes of acute rehabilitation for TBI. • (2) identify medical procedures and therapy interventions, alone or in combination, that are associated with better outcomes, controlling for patient characteristics. • (3) determine whether specific treatment interactions with age, severity/impairment, or time are associated with better outcomes.

42. Individuals with traumatic brain injury (TBI) frequently present to acute inpatient rehabilitation facilities with pain, hypoarousal, sleep dysregulation, behavioral dysregulation, spasticity, confusion, slowed cognitive processing, impaired memory, and affective disorders prompting prescription of multiple psychotropic medications. • Some of medications are used for controlling behaviors to prevent harm and allow safer and more effective management of the patient (e.g. use of stimulants, benzodiazepine and antipsychotic agents to control agitation). • Other medication uses are aimed at preventing comorbidities (such as seizures), and some are aimed at enhancing function (such as sleep medications, stimulants, and antiparkinson agents

43. Neurobiology of Disease, Volume 123, March 2019, Pages 27-41 • Journal of Clinical Neuroscience, Volume 22, Issue 4, April 2015, Pages 627-631 • Journal of Neuroinflammation • December 2018, 15:144| The role of inflammation in the development of epilepsy • Seizure 33 (2015) 13–23

44. THANKS