Within the past few decades brain injury, or traumatic brain injury (TBI), has gained widespread attention. Early focus was on more severe forms of TBI; severity typically measured using the Glasgow Coma Scale. In more recent years, however, mild traumatic brain injury (mTBI), most notably concussions, has gained increasing interest due to the high frequency of concussions suffered in athletes of all levels and, recently, in military personnel due to blast injuries. Studies being performed have focused not only on ways to help minimize the incidence of concussion as well as treating concussive symptoms, but also on detecting concussions. Many concussions go unreported due to inadequate knowledge of concussive symptoms amongst the general population. Because many concussions go unnoticed and hence unreported the individual who has sustained a concussion is at risk for a more serious injury in the future. One such injury is Second Impact Syndrome (SIS). Second Impact Syndrome is essentially a synergistic event where the sum of two seemingly mild concussions combine to create an event that is potentially fatal. The findings during the autopsy are that there is insignificant damage to the brain to cause death. The damage that occurs, however, is on a molecular level causing a strain on the metabolic processes of the brain called dysautoregulation. Without an understanding of the changes that have occurred on a molecular level in SIS the assignment of cause and manner of death is difficult for the medical examiner. Currently, in order to diagnose SIS, a thorough scene investigation, along with the documentation of a previous head injury is needed. Without a full understanding of SIS and the pathophysiology changes that take place a medical examiner (ME) could misclassify the cause and manner of death in a death due to SIS. In the future, eliminating the prerequisite of identification and documentation of previous head injuries in order to diagnose SIS is needed. This paper evaluates the literature on the current knowledge of TBI and concussions in an attempt to create a protocol on how a medical examiner should approach a case where autopsy findings are unremarkable.