This is the third in a series of essays devoted to Hillary Clinton's neuropathology. As I have stated in the prior two essays, much of this should be considered speculative, if only for the absence of verifiable medical records. In this essay, I will provide much more documentation than in the first two essays. The links will be to full text articles published in peer-reviewed medical journal. In order to save some time for you digging around inside the article, pertinent portions will be quoted. But I guarantee you, that everything I have abstracted from these articles will be found in those articles.

Bias: As you all know, I dislike Hillary Clinton and do not want to see her as President, or even dog-catcher
Request (plea, perhaps being a more appropriate word), please disseminate my essay(s) if you think them worthy. The experts most fitting would be those with no ties to the Clintons, DNC, or CGI. Specialties appropriate for this review include epileptologists, neurosurgeons, neuroradiologists, stroke specialists, physiatrists, neuropsychologists. Of course, sending these articles to any certified neurologic--or psychological--specialist would be just fine. I welcome factually based criticism.

There is considerable skepticism about the alleged note from Dr. Bardack's office, which was referred to in the previous post. Although the formatting of the letter is like hundreds I have read from other physicians, of course the veracity of which is open to question.

As stated in the prior essay, the diagnosis of subcortical vascular dementia (SVD) surprised me. This essay will be written from the standpoint that the suspicious office note never existed. There will be NO reference to SVD in this essay.

What do we know for sure about Hillary Clinton's health in December, 2012? There is absolutely NO controversy about her sustaining a concussion due to fall and a cerebral dural sinus thrombosis (DST). This essay will NOT discuss the DST. I'm reserving that for another post.

Let's review some terminology:
Concussion most often implies but not all concussions are associated with loss of consciousness. Concussions are defined as transient loss of neurological function secondary to applied external force(s).

Traumatic brain injury. This is a very broad term which includes the neurological/neuroanatomical/neurochemical loss of function with or without intracranial lesions.

TBI comes in three flavors: mild, moderate, or severe. The distinguishing features include: longer duration of unresponsiveness (unconsciousness), lower Glasgow Coma Scale (GCS), length of post-traumatic amnesia. A traumatic intracranial bleed also called intracranial hemorrhage (ICH) does not necessarily affect the severity rating of the TBI. A patient with an mTBI could legitimately be said to have a "complicated mTBI" if the patient qualifies for the mild status by virtue of the 3 factors just mentioned.

Glasgow Coma Scale (GCS) is a rating scale developed by two Scottish neurosurgeons in 1974, Drs. Jennett and Teasdale. As imperfect as it is, and there are many other coma scales, GCS is the standard concussion rating scheme both in clinical use and in research use.

GCS consists of three items. A perfect score is 15. A person who is brain dead gets a 3. Coma is usually defined as an 8.
The three items on the scale are 1) eye opening (maximum score 4); verbalization (maximum score 5); movements (maximum score 6).

These terms are introduced here because they will be very commonly used in the rest of this essay.

Layperson's knowledge of mTBI and whiplash

It is well-recognized that even a mild head injury resulting in only momentary loss of consciousness (LOC) can be followed by symptoms that include physical, affective, and memory problems.

Although over 80% of the participants thought that the common physical symptoms were a likely outcome, less than 50% believed that cognitive symptoms were likely. Moreover, the speeds thought to be necessary to cause cognitive symptoms were as extreme as those thought requisite for the distractor symptoms that are rarely or never reported. Cognitive dysfunctions are, however, commonly reported. These findings suggest that laypeople may show little little understanding for memory problems, loss of concentration, and similar cognitive symptoms. Secondly, the findings suggest also that these symptoms are unlikely to be simulated by malingerers if they are basing their simulations on common knowledge.
Distractor symptoms included items such as heart trouble and occasional bouts of uncontrollable laughter. The list also included five outcome items: difficulty with social relationships, financial difficulties, poor performance at work, loss of interest in sex, and brain damage.
Conclusions
First it seems unlikely that patients with persistent complaints (especially regarding cognitive dysfunctions) derive their symptoms from common knowledge about minor head or whiplash injuries. Secondly, lay persons, such as jury members, judges, lawyers, friends, family members and social workers may be sympathetic to physical complaints expressed by the accident victim but they may be less tolerant or accepting of cognitive, sexual, and or consequent social problems. A description of the relation between accident conditions and symptoms as well as the nature of the symptoms may facilitate understanding of victim’s situation.

Take away message: this article was linked in the first essay but I repost it here to correct some common misunderstandings. The article itself lists a number of symptoms often reported in mTBI. The use of "distractor items" is confusing because, except for heart trouble, the other "distractors do indeed occur. People commonly underestimate the cognitive sequelae of a "simple" mTBI.

minimizing complications in sports concussions

The usual sign of traumatic brain injury in sports is an acute alteration in mental status that may or may not involve loss of consciousness after the traumatic event. The hallmarks of concussion are confusion and amnesia, often without preceding loss of consciousness. Signs and symptoms of a concussion may immediately follow the head trauma or evolve gradually over several minutes to hours. (10)
Early symptoms may include headache, dizziness, nausea or vomiting, slurred or incoherent speech, and imbalance or incoordination. Signs of confusion may include a vacant stare, disorientation, delayed ability to follow instructions or answer questions, and poor concentration or attention. Signs of disorientation include a loss of sense of time or place. For example, signs would be evident in a dazed-appearing athlete walking in the wrong direction on the playing field.
Pathologic Features
Axonal shear injury is the primary pathologic feature of traumatic brain injury in all levels of severity.14 The extent of axonal injury is suggested by the duration of loss of consciousness and post-traumatic amnesia. (9)
With uncomplicated brain concussion, limited structural axonal injury may be present but not evident on diagnostic computed tomographic (CT) scanning or magnetic resonance imaging (MRI). However, concussion can be complicated by coexistent cortical contusions and the development of intracranial hemorrhage.

Take away messages here: the study was done on athletically fid athletes with no pre-existing neuropathology. Study participants were excluded if they had prior TBI. Despite excellent physical and neurologic health pre-concussion, brain pathology may develop after a delay, hours, from the inciting event. This is why some mTBI victims may look and act perfectly fine for up to several hours and then have neurologic deterioration. The propensity to brain damage increases with age. Link to follow.

neurological evaluation in dx and mgmt of sports concussions

The vast majority of concussions in athletes fall at the mild end of the mild traumatic brain injury severity continuum. Loss of consciousness typically is not present, and post-traumatic amnesia is typically brief. This injury is likely associated with low levels of axonal stretch resulting in temporary changes in neurophysiology. Giza and Hovda (2004) described the complex interwoven cellular and vascular changes that occur following concussion as a multilayered neurometabolic cascade. The primary mechanisms include ionic shifts, abnormal energy metabolism, diminished cerebral blood flow, and impaired neurotransmission. Fortunately, for the vast majority of affected cells, there appears to be a reversible series of neurometabolic events. The majority of athletes appear to recover fully within one-month post-injury (Collins, Lovell, Iverson, Ide, & Maroon, 2006), but some athletes can have lingering problems...The interpretation of neuropsychological test data should be conducted by a clinical neuropsychologist who is uniquely qualified to translate the test data into recommendations for clinical management.

Take away message: axonal stretch injuries are likely involved in temporary functional changes. The axon is the part of the nerve cell leading from the nerve cell body and connecting with receptors (dendrites) on another nerve cell. The destination neuron can be almost in direct contact with with projecting neuron or it may be many inches away. Notice the use of the word "stretching" when applied to axonal damage. More severe injuries can and do occur, including complete axonal disruption, micro hemorrhages, neural die back (if the axon damage is close to the projecting neuron). Finally, as will be discussed elsewhere, neuropsychological tests, of which there are many, are best performed, graded, and interpreted by a trained neuropsychologist. A neuropsychologist is a psychologist who has received advanced training in understanding neuroanatomy, neurochemistry, and testing. Neuropsychologists may do some counseling, but this task is primarily done by psychologists.

Why patients return to ERs post-mTBI

Traumatic brain injury (TBI) occurs when an outside force, such as a blow to the head, alters brain function;1 it remains a leading cause of injury-related death and disability in developed countries. 2 In the U.S. alone, TBI accounts for 1.4 million case presentations to the emergency department (ED) annually, with 80% of these cases categorized as mild TBI (mTBI). 3 Despite its high prevalence, optimal ED management strategies for patients presenting with mTBI remain controversial, and no standardized protocol has been introduced. Additionally, clinicians make little effort to identify patients at high risk for poor outcomes, such as ED return visits, when designing a treatment plan. Identification of positive predictors for patients at risk of returning to the ED within 72 hours of discharge could lead to improved patient outcomes and conserve hospital resources.
The incidence of unplanned ED return after trauma is not insignificant. Previous estimates of trauma-related ED return visits range from 0.38% to 44%, but incidence of unplanned ED return following mTBI has not been reported, even though one of the most common reasons for it is failure to improve after discharge.
Patients most commonly returned to the ED for symptoms of post-concussion syndrome (46.0%), including headache, altered mental status, and vomiting. Twenty-three patients (18.7%) reported pain and 14.6% were recalled to the ED after discharge for further evaluation, while 9.76% returned for evaluation of a repeat head injury.
We suspect that the significant rate of return ED visits associated with bleed on head CT is driven by two factors. First, neurological symptoms do not appear immediately with intracranial hemorrhage, so patients may be discharged before clinical assessment can identify anything of medical concern.

Take away message: even when properly initially diagnosed, the predominant reason for unplanned ER return is due to delayed development of symptoms, or aggravation of symptoms present more mildly after mTBI. The second most common for re-presentation is the delayed development of intracranial bleeding.

Exercise intolerance in PCS

Key Points
All patients with postconcussion syndrome (PCS) reported increased symptoms or the appearance of additional symptoms from baseline that led to exercise cessation.
Patients with symptoms of PCS had limited ability to exercise when compared with uninjured control participants.
Whereas physical exertion is contraindicated in symptomatic patients after head injury, patients with PCS may be able to safely perform low-level exercise without risk of symptom exacerbation.

When the brain loses itself

Quite paradoxically, during truly intense sensory perceptual states—such as watching an absorbing movie, or being involved in a highly demanding sensory task—the strong subjective feeling is of ‘‘losing the self,’’ i.e., of disengagement from self-related reflective processes....
Some of these studies point to a clear hemispheric specialization within the broad spectrum of self-related functions, with the right hemisphere engaged during self-image processing, such as watching self-face images compared to popular faces…the left hemisphere is engaged during internally cued responses.
…self-related representations are associated with a consistent and reproducible set of brain structures...
Behavioral measurements verified that indeed a high level of self-awareness was experienced during the introspection task, while the rapid categorization virtually abolished any subjective self-awareness experience...
To conclude, the picture that emerges from the present results is that, during intense perceptual engagement, all neuronal resources are focused on sensory cortex, and the distracting self-related cortex is inactive. Thus, the term ‘‘losing yourself’’ receives here a clear neuronal correlate. This theme has a tantalizing echoing in Eastern philosophies such as Zen teachings, which emphasize the need to enter into a ‘‘mindless,’’ selfless mental state to achieve a true sense of reality...

early cortical thickness changes post-MVA

Introduction
In the United States, approximately 1.7 million traumatic brain injuries (TBIs) occur each year. Of these, approximately 75% are categorized as mild (mTBI) (http://www.cdc.gov/traumatic braininjury/causes.html). Symptoms that characterize mTBI include brief loss of consciousness (LOC; . mTBI survivors, however, show minimal abnormalities on conventional neuroradiological examinations or none at all. Relative to non-mTBI survivors, mTBI survivors experience significantly more subjective physical, emotional, and cognitive symptoms, possibly associated with brain changes caused by mTBI. Although most symptoms resolve spontaneously in the majority of survivors 3 to 6 months after a single mTBI, about 5% of survivors continue having some symptoms years after trauma, suggesting sustained changes in brain structure or function in these chronic mTBI survivors. In addition, those who experience mTBIs repeatedly over their lifetime may develop a progressive neurodegenerative condition known as chronic traumatic encephalopathy....
Forty-four MVC survivors who were recruited from EDs completed the initial scan session within 2 weeks after the MVC. The majority experienced a frontal/rear collision. All survivors reported dramatic acceleration/deceleration of the head during the MVC, and 16 also reported the head striking an object. None had a GCS of The affected region is located at the junction of BA 21, 20, and 37. This region has been linked to higher-level modality-nonspecific language processing and word generation, as well as reasoning. Thinning in this region might affect language generation and similar functions in mTBI survivors, which in turn could contribute to impairment of cognitive and social functions in mTBI survivors.

Take away message: This study used special MRI protocols but run on standard MRI trauma-screening sequences on patients who had normal GCS scores = 15. The average interval from MVA to scan was 7 days. Only patients without history of pre-existing neurological disease were included in the study. Yet specific areas of brain damage were found in very localized areas. The consequences of these injured areas on function are described.

early emotional and neuropsychological sequelae after mTBI

Impairments in episodic memory and processing speed have been reported in prospective studies that used eligibility criteria similar to the present study, including GCS 13–15 and normal CT scans when available. Our findings confirm these as among the most important cognitive domains to assess after injury from a clinical perspective. Additional study is also needed to establish the relation between these cognitive domains and changes that may be apparent on advanced forms of neuroimaging, symptom report, and aspects of specialized physical examination (e.g., vestibular system, eye movements, etc.).

Take away message: although not quoted directly here, this article lists an extensive number of neuropsychological tests utilized in mTBI assessment. One weakness of this study is the failure to mention any imaging results.

Review of MRI and DTI in mTBI

Mild traumatic brain injury (mTBI), also referred to as concussion, remains a controversial diagnosis because the brain often appears quite normal on conventional computed tomography (CT) and magnetic resonance imaging (MRI) scans. Such conventional tools, however, do not adequately depict brain injury in mTBI because they are not sensitive to detecting diffuse axonal injuries (DAI), also described as traumatic axonal injuries (TAI), the major brain injuries in mTBI. Furthermore, for the 15 to 30% of those diagnosed with mTBI on the basis of cognitive and clinical symptoms, i.e., the “miserable minority,” the cognitive and physical symptoms do not resolve following the first three months post-injury. Instead, they persist, and in some cases lead to long-term disability. The explanation given for these chronic symptoms, i.e., postconcussive syndrome, particularly in cases where there is no discernible radiological evidence for brain injury, has led some to posit a psychogenic origin. Such attributions are made all the easier since both post-traumatic stress disorder (PTSD) and depression are frequently co-morbid with mTBI.

TBI is a heterogeneous disorder and there is no one single imaging modality that is capable of characterizing the multifaceted nature of TBI. Advances in neuroimaging are, nonetheless, unprecedented and we are now able to visualize and to quantify information about brain alterations in the living brain in a manner that has previously not been possible. These advances began with computed axial tomography (CT) in the 1970’s, and then with magnetic resonance imaging (MRI) in the mid-1980’s, with more refined and advanced MR imaging over the last 25 years, including

perfusion weighted imaging (useful for measuring abnormal blood supply and perfusion),

susceptibility-weighted imaging (SWI; useful for measuring micro-hemorrhages),

magnetization transfer MRI (useful for measuring traumatic lesions)

diffusion weighted imaging (DWI; useful for measuring edema and developed initially for studies of stroke –

diffusion tensor imaging (DTI; useful for measuring white matter integrity

functional MRI (fMRI; useful for measuring altered cortical responses to controlled stimuli)

Other neuroimaging tools, although not a complete list, include

positron emission tomography (PET; useful for measuring regional brain metabolism using 2-fluro2-deoxy-d-glucose, both hyper and hypo metabolism observed in TBI),
single photon emission tomography (SPECT; useful for measuring cerebral blood flow but less sensitive to smaller lesions that are observed on MRI
magnetic resonance spectroscopy (MRS; useful for measuring brain metabolites/altered brain chemistry).

DTI differs from conventional MRI in that it is sensitive to microstructural changes, particularly in white matter, whereas CT and conventional MRI (including also FLAIR) reveal only macroscopic changes in the brain. Thus subtle changes using DTI can reveal microstructural axonal injuries, which are potentially responsible also for persistent postconcussive symptoms.
Longitudinal studies are needed to understand the dynamic nature of mTBI and how it may reflect changes in brain alterations over time.
TBI is a heterogeneous disorder and there is no one single imaging modality that is capable of characterizing the multifaceted nature of TBI.

Take away message: this article is the best review of neuromiaging techniques I have read. Although it is very technical, I highly recommend readers to review the linked article simply for the pictures. The illustrations will undoubtedly help you understand the vocabulary, even if you don't understand the techniques.

Are mTBIs as mild as we think?

Method: 38 patients with a single MTBI that had occurred at least 12 month prior to testing, and 38 matched controls, participated in the experiment. A combination of questionnaires and neuropsychological test batteries were used to assess the extent of PCS and related deficits in neurobehavioral performance.
Results: 11 out of 38 MTBI participants (29%) were found to suffer from PCS. This subgroup of MTBI patients performed poorly on neuropsychological test batteries. Thereby, a correlation was found between PCS symptom severity and test performance suggesting that participants with more pronounced PCS symptoms performed worse in cognitive tasks. In contrast, MTBI patients with no PCS showed performed similar to matched control. We further found that loss of consciousness, a key criterion for PCS diagnosis, was not predictive of sustained PCS.
Conclusion: The results support the idea that MTBI can have sustained consequences, and that the subjectively experienced symptoms and difficulties in everyday situations are related to objectively measurable parameters in neurocognitive function.
Background
Mild traumatic brain injury (MTBI) represents 70 - 90% of all treated brain injuries. It is by far most common in teen- agers and young adults, and typically caused by falls and motor-vehicle collisions. The estimated population-based incident rate ranges above 600/100000 [1].
MTBI typically induces a range of symptoms such as: headaches, blurred vision, poor concentration, sleep disturbance, depressed mood or irritability. These post- injury effects are referred to as Post-Concussion Syndrome (PCS), a transient condition which is thought to reflect a fully recoverable disturbance of neural function [2-5]. However, long beyond the typical recovery interval of one to three months, at least 15% of persons with a history of MTBI continue to see their GPs because of persistent prob- lems [6-10].
The view that MTBI leads to transient disturbances only is further supported by the absence of structural brain dam- age in diagnostic MRI images acquired with standard recording sequences[12]. However, the combination of high resolution MRI with specifically tailored scanning protocols provides evidence for microstructural abnor- malities in MTBI patients [13-15]. Ultra-structural studies further indicate that MTBI may damage the structure of neurofilaments and cause traumatic axonal injury [16,17].
We propose that the inconsistent findings on the relation- ship of neurobehavioural performance and PCS might, in part, be due to the fact that most experiments investigated long-term MTBI consequences by studying a cohort of MTBI participants without taking the status of PCS specifically into account.
For PCS ICD-10 suggests guidelines for research purposes only.
Participants
Thirty eight head injured and 38 healthy control participants, with a mean age of 23.8 and 23.1 years respectively, were tested. The groups were further matched for handedness, gender and education. Recruitment was conducted through advertisement posters, which invited persons with MTBI as well as healthy controls to contact the laboratory. Posters were distributed in 150 general practitioner surgeries in Merseyside, a local Brain Injury Community Centre, and the University of Liverpool campus. Participants were tested at least 12 months post-incident. Only those who had not been involved in or considered litigation were included in the study. All participants were in employment or studying for at least six month when tested.
Both the MTBI and the control cohort were screened for general well-being, which included questions on mood, depression and anxiety, sleep disturbances, previous psy- chological or neurological problems, medication, and pain. Those with poor screening outcome were excluded from the experiment. The age range was set to 18–65 years.
Rivermead Post-Concussion Symptoms Questionnaire (RPQ) was classification tool.
Demographical analyses
Analysis of demographic variables and NART scores revealed no significant differences between groups. We further found that injury-related parameters, i.e. chronicity, loss of consciousness or hospitalisation, did not differ significantly between PCS+/PCS- groups
In the PCS+ group, significant correlations were found for 12 out of the 24 subtest scores. In all these cases symptom severity was positively correlated with test performance (table 2 and figure 3). 22 out of the 24 correlations were insignificant in the PCS- group and none of the correlations were significant in controls.
First, they highlight that mild head injury leads to a chronically elevated level of PCS symptoms in some persons with MTBI, while in others the experienced symptom level is no different from persons who did not have an MTBI. Second, they indicate that neurobehavioral deficits are related to high levels of PCS symptoms but not the MTBI per se.
The role of loss of consciousness in sustained PCS and/or its severity. According to ICD - 10, a 'history of head trauma with loss of consciousness preceding the onset of symptoms by a period of up to four weeks' represents one of the diagnostic criteria (criterion 'B'). However, in our experiment 4 out of 11 participants in the PCS+ group (36%) had not experienced loss of consciousness but nevertheless satisfied all other PCS criteria. At the same time, 14 out of 27 participants (52 in the PCS- group had lost consciousness during the incident but did not develop chronic PCS.
a correlational analysis of test performance and symptom severity, indexed by the RPQ scores, revealed positive correlations with error rates for 50% of the neurobehavioral subtests in the PCS+ group.
These results highlight the fact that only those MTBI participants who suffer from PCS show deficits in cognitive processing, and provide further evidence that the level of PCS severity and not the experience of MTBI per se is the critical factor.
Re hyperalertness: participants in the PCS+ group showed higher error rates than participants in both other groups, while reaction times were unaffected.
Peloso further argues that the simultaneous management of response accuracy and response speed becomes less efficient when the cognitive load exceeds a certain threshold level, and that this level may be lower following minor brain damage. This idea is well compatible with our finding that the highest error rates were found for the subtests with greatest cognitive demand. Furthermore, cognitive and emotional problems are known to persists longer after the incident than somatic symptoms. In line with this observation, the RPQ symptom profile shows that the experienced symptoms in the PCS+ group relate mostly to cognitive processing, with poor concentration and irritability receiving the highest scores.
Malingering is probably of negligable magnitude for several reasons. First and foremost, participants involved in litigation of any kind were excluded from the study. Secondly, our volunteers were in employment or studying, and generally in good health and spirits. Finally, the severity of PCS symptoms systematically varied with the level of performance across a range cognitive tasks, and such a data distribution across a group is unlikely to be explained by malingering or exaggerated responses in the RPQ.
The question regarding the neural origin and mechanisms underlying sustained PCS are not addressed in the present study, however the data is in line with these ideas.
While this behavioral fault theory could explain why common complaints reported in the PCS+ group are more psychological in origin than somatic, it falls short of a plausible explanation for the strong correlation of objectively measurable performance indices and symptom severity.

I don't know how that little guy snuck in there but he looks too confused to move.

This last article, which is heavily abstracted, is the key issue here. Is mild mTBI as mild as we think? The answer is no, but to go further into the subject we need to delve into the post-concussion syndrome.

My apology for the length of this essay and its technicality. However, I have been accused by some to not be the scholar that I am. If anyone wants the complete list of UTLs of journal articles, send me your email address by c99 mail.

Next projects on the near future: post-concussion syndrome, anatomic/functional relationships of PCS (planned next essay); dural sinus thrombosis; post-traumatic epilepsy; double impact syndrome and closing thoughts.