FORENSIC SCIENCE NEWSLETTER Forensic Pathology and Neuropathology. William A. Cox, M.D., FCAP.

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1 NEUROPATHOLOGY FORENSIC SCIENCE NEWSLETTER Forensic Pathology and Neuropathology William A. Cox, M.D., FCAP May 15, 2016 This issue of the Forensic Science Newsletter will address the most recent scientific information regarding the acute effects of traumatic brain injury as represented by concussion in adults. Concussion refers to an immediate, usually reversible episode of brain dysfunction following traumatic brain injury (TBI), typically, but not always, with sudden brief impairment of consciousness and loss of memory. Concussion represents the mildest form of TBI. TBI comprises a clinical spectrum that extends from mild concussion, in which consciousness is often retained, to severe diffuse traumatic axonal injury (TAI) causing an unresponsive wakefulness state (UWS), which was formally referred to as a vegetative state. Patients with UWS have sleep wake cycles, intact cardiorespiratory function and primitive responses to stimuli but without evidence of inner or outer awareness present for at least one month. Concussions can occur by any traumatic etiology including falls from sufficient height, motor vehicular accidents, non-penetrating blast injuries, domestic violence, or other physical traumatic events, which occur during many contact sports, such as football, hockey, basketball, etc. They can also occur during combat sports, which have a specific goal of inducing a concussion in the opponent, such as boxing, mixed martial arts, etc. The word concussion is derived from the Latin concutere, which means to shake violently. In essence, concussion is due to the shaking of the brain inside the skull. Such shaking can be caused by either direct or indirect rapid movements of the brain, which results in extreme rotational and or translational brain acceleration or deceleration injury. Such acceleration or deceleration injury manifest with not only anterior-posterior movement of the brain within the skull, but also by rotation of the cerebral hemispheres on the relatively fixed upper brainstem, the midbrain, which serves as a fulcrum. The injury thresholds required to cause a concussion are believed to be at least 60 g of linear acceleration or at least 2,000-4,000 rad/s² of rotational acceleration. As stated above, loss of consciousness is not required to make a diagnosis of concussion. When unconsciousness does occur it is believed to be due to a transient electrophysiologic dysfunction of the reticular activating system in the upper midbrain.

2 Another alternate explanation for the loss of consciousness is the transmission of a wave of kinetic energy throughout the brain. Clinically, the concussion diagnosis is based on neurological symptoms and signs, which can be categorized as follows: " 1. Somatic: headache, nausea, vomiting, dizziness, imbalance, sound " sensitivity, transient visual disturbances or visual hallucinations referred to as " seeing stars, brief convulsion, and autonomic signs, such as facial pallor, " bradycardia, faintness with mild hypotension and sluggish pupillary reaction. Any localizing or lateralizing signs or symptoms should prompt a clinician to consider neuroimaging, such as a CT scan. " 2. Emotional: nervousness, irritability and sadness, which on occasion may lead " to depression. On a rare occasion you may see the development of " permanent neurobehavioral changes in a patient who before the traumatic " event had no evidence of psychiatric or neurologic problems. " 3. Sleep disturbances: sleeping more or less than usual and trouble falling " asleep. " 4. Cognitive: there are difficulties in concentration, feeling mentally slow " (described as brain fog), and memory impairment manifested as no memory " of the traumatic event, which is often associated with retrograde amnesia or " anterograde amnesia or both. Retrograde amnesia is the loss of memory to events that occurred or information that was learned, before the injury. This memory loss may involve only a few moments before the impact or it may extend to the previous days, weeks and rarely months. The extent of the retrograde amnesia typically correlates with the severity of the injury. Anterograde amnesia is the loss of ability to create new memories after the event that caused the amnesia, leading to a partial or complete inability to recall, retell, the recent past. There is also an entity referred to as Hysterical Post-traumatic Amnesia, which is not uncommon and should be suspected when there is unexplainable behavioral abnormalities. Current recommendations regarding the clinical evaluation and management of concussions, especially in sports, have moved away from grading systems. Part of the problem is the very definition of TBI has not been consistent and tends to vary according to the specialties involved in the evaluation of the patient and the circumstances. The grading systems which are currently being used by many clinicians as defined by the BrainLineMilitary.org are the Glasgow Coma Scale (GCS), Ronchos Los Amigos Scale of Cognitive Functioning and the Head Injury Interdisciplinary Special Interest Group of the American Congress of Rehabilitation Medicine. The GCS defines the severity of TBI within 48 hours of the injury. The GCS measures the following functions: eye opening, motor response and verbal response. Clinicians use the scale to rate the best eye opening response, the best verbal response, and the best motor response, with each response being assigned a numerical value. The highest score that can be attained for eye opening is 4, for verbal response 5, and for 2

3 motor response 6. The GCS represents the sum of the highest score in each category. A GCS of is consistent with mild TBI, which is where a concussion is categorized; moderate TBI has a GCS of 9-12, and severe TBI has a score of 3-8. Three is the lowest possible score under the GCS. Mild TBI can result in temporary or permanent neurological symptoms. Neuroimaging studies such as CT scans or MRIs may or may not show evidence of neuroanatomic damage. Before the more advanced imaging techniques were developed, such as Diffusion Tensor Imaging (DTI), it was thought there were no neuroanatomic changes following mild TBI (concussion), which was based on CT and MRI studies of patients with mild TBI. We now know that is not true in all cases of mild TBI. The Ronchos Los Amigos Scale of Cognitive functioning defines the severity of deficit in cognitive functioning. The scale extends from level I, which is no response, to level VIII in which the response is purposeful and appropriate. The Head Injury Interdisciplinary Special Interest Group of the American Congress of Rehabilitation Medicine defines mild TBI as a traumatically induced physiological disruption of brain function, as manifested by one of the following: " 1. Any period of loss of consciousness. " 2. Any loss of memory for events immediately before or after the accident. " 3. Any alteration in mental state at the time of the accident. " 4. Focal neurologic deficits, which may or may not be transient. There are other criteria for defining mild TBI, which include: " 1. GCS greater than 12. " 2. No abnormalities on CT scan (remember, this criteria differs from that listed " by other organizations, such as the BrainLineMilitary.org discussed above). " 3. No operative lesions. " 4. Length of stay in the hospital is less than 48 hours. Keep in mind, although a patient may have a normal CT scan or MRI, they often will have long term symptoms, such as problems with concentration, memory, sleep and anxiety. The recent development of two diagnostic tests based on the biomarkers, glial fibrillary acidic protein (GFAP) and ubiquitan C-terminal hydrolase (UCH-LI) has the potential to provide greater insight into the severity of the TBI, which will be discussed in greater detail shortly. For comparison, The Head Injury Interdisciplinary Special Interest Group of the American Congress of Rehabilitation Medicine defines moderate TBI as: " 1. Length of stay at least 48 hours. " 2. GCS of 9-12 or higher. " 3. Operative intracranial lesion. " 4. Abnormal CT scan. There has been a recent development, which may greatly aid the clinician in differentiating between those patients with a mild TBI from those with a more severe 3

4 TBI. In an article published on line in JAMA Neurology on March 28, 2016, a group led by Linda Papa M.D. of the Orlando Regional Medical Center, Florida, released the results of a study involving almost 600 trauma patients, 55% of whom had a mild or moderate TBI. This study showed the serum levels of two biomarkers, glial fibrillary acidic protein (GFAP) and ubiquitan C-terminal hydrolase (UCH-LI), correlated with the degree of TBI. Of the two biomarkers, GFAP appeared to be the most reliable. They found although UCH-LI was useful within the first two days, GFAP was a more accurate indicator of diagnostic accuracy and was able to predict brain injury severity up to 7 days after the traumatic event. GFAP is a protein expressed primarily by the astrocytes and UCH-LI by the neurons. In a head injury, both the astrocytes and neurons are damaged and thus will leak out their respective proteins. Not all astrocytes express GFAP. GFAP is also expressed by ependymal cells (ependymocytes are a type of glial cell that line the cerebral spinal fluid [CSF] filled ventricles in the brain and the central canal of the spinal cord). GFAP is also found in non-cns (central nervous system) cells, such as the glomeruli of the kidneys, Leydig cells of the testis, keratinocytes, osteocytes and chondrocytes. Although, UCH-LI is highly specific to neurons, it is also found in cells of the testis and ovary, as well as certain lung tumor cell lines. Typically, patients with a concussion (mild TBI) show no evidence of structural brain injury using conventional neuroimaging with CT or MRI and thus concussion has been considered a physiologic alteration, which does occur and will be discussed shortly. However, newer imaging studies, such as diffusion tensor imaging (DTI), have demonstrated microstructural axonal disruption in concussion. What is important to remember, even after resolution of all symptoms, there may be long lasting, ultrastructural and functional brain alterations. DTI has been used to study white matter tractography in the brain, including those patients with mild TBI. DTI studies have identified white matter changes in the posterior corpus callosum in patients with mild TBI. Other imaging techniques which have proved to be beneficial in the study of structural brain injury in TBI are: Susceptibility weighted imaging MRI, Functional MRI, Magnetic resonance spectroscopy MRI and Positron emission tomography MRI There is not much in the literature regarding neuropathologic changes in the brain in mild TBI. The only neuropathologic analysis of the brain in patients with mild TBI was done by Blumberg, et al and published in Lancet in Their study initially involved five patients with mild TBI (GCS 13-15) who died of other causes, 2-99 days following a traumatic head injury. Axonal β-app immunostaining (beta-amyloid precursor protein is a marker of traumatic axonal injury in infants, young children and adults), was seen in the fornices and corpus callosum of all cases, and occasionally within the brainstem and cerebral white matter. Blumberg et al extended their study to include six cases in a subsequent publication using an axonal index sector score (AISS), in which 116 separate sectors within each brain are assessed to derive an overall axonal injury score. The study identified a spectrum of axonal injury in patients with TBI, whether mild or severe, with those with severe TBI having a higher score than those with mild TBI. 4

5 As indicated above concussion can be associated with significant physiologic disturbances. Experimental models suggest metabolic changes including elevated tissue lactate, which peaks over the course of several days followed by gradual recovery of cerebral blood flow within the affected tissues, with the most significant changes resolving by 7-10 days. Other neurometabolic and neurochemical reactions, which can occur: activation of inflammatory responses, imbalance of ionic concentrations, increase in the excitatory amino acids, dysregulation of neurotransmitter release and synthesis, imbalance of mitochondrial functions and energy metabolism, and production of free radicals. 5