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Mild Traumatic Brain Injury and my journey toward understanding it (7/2/07)

Note: I am not a doctor. This article is just based on my own experience and observations. It should not be taken as medical advice.

Walk into a doctor's office with a list of complaints and you're almost sure to get some odd looks, and I sure got my fair share of them. I was just out of college and finally had time to look into a few things I thought were a bit odd but not quite worthy of the ER. I could hear high pitched noises that no one else seemed to such as fluorescent lights and dimmer switches, I'd feel like someone was drilling into my head, my eyes would burn on exposure to dim lights, I always seemed to be the first to smell some odd smell, and when tired I seemed to be pretty good at forgetting basic words like "chair", "sink", and "home".

Such a list doesn't just happen to a person without something major going wrong such as a tumor. The MRIs didn't reveal one so what there wasn't much to go on except for the vague hunch I had that went back to a few concussions I had as a child. Without something solid, like a tumor, a diagnosis is hard and a doctor is forced to go hunting for the problem, sometimes through blind guesses alone. Since the concussions didn't seem likely we tried an allergist and then a neurologist, and eventually a few psychologists. I made marginal progress and found it hard to navigate "the system". A lot of doctors just didn't seem interested in helping me beyond keeping me in their office for billing purposes. I was continually being sent to specialists for everything under the sun, and then some.

That entire time was a rollercoaster for me. The specialists would run down a list of problems, all with the end result of an early death or being completely insane. As I made my way through all of the tests, most of which seemed to have a needles or strange devices strapped to my head, I did a lot of reading. The first time I was told I should see a psychologist I was so worried I read the DSM-IV cover to cover in one sitting, which is a bit like reading an encyclopedia but one that only contained mental health information. Fortunately I was fine.

Slowly progress was made. A Leahy neurologist tried an off label prescription for amitriptyline (Elavil) that had worked in similar cases in the past. The thing about these drugs is you have to build up and, if you want to quit taking them, peter off of them. Everything is done very slowly, and we won't really know if they are working or not for several months. Finally, after a few years without side effects the migraines went away. Why was the big question, and no one seemed to have the slightest clue!

As a last ditch effort I got tested for an anxiety condition by another psychologist. After she had finished with me and told me, yet again, that I was sane, I broke down (no crying thankfully) and asked her to listen to everything and serve as an independent ear since the doctors were out of places to poke, stab, and/or scan. She patiently listened to me describe all of my symptoms and then out of nowhere made the observation that mentally I seemed fine, but that my body gets out of whack when I'm stressed, almost as though I have an anxiety condition but without the anxiety. She called it a "biological sensitivity to stress".

So I did what any stubborn person would do and set out to become an expert... in my spare time of course! I wrote every doctor who had ever seen me asking for my medical records so I could get an idea of what had happened to me, what had been done already, and their thoughts over those times. I also read everything I could get my hands on, including:

  1. "The Cambridge Illustrated History of Medicine", which was very helpful in understanding where the medical field is at this point in time. It doesn't spend much time addressing neurology, which says a bit about how old (read: young) the field is.
  2. "Coping With Mild Traumatic Brain Injury" by Stoller and Hill, which did a great job of explaining all of the issues and methods for addressing them. It's still the best thing I've seen on MTBI.
  3. "The Merck Manual", which became invaluable in looking up all of the conditions the doctors were suspecting throughout all of this.
  4. "Physician's Desk Reference" (PDR), which was great for looking up treatments for all of those conditions and learning what drugs would be good to stay away from and what ones were ok. Drug company marketing does a good job of ensuring doctors take risks we patients don't always need.

Electronic resources ran the gamut but three stand out:

  1. Pubmed (http://www.pubmed.gov) - for looking up research.
  2. Clinical Evidence (http://www.clinicalevidence.com) - which takes a bit to get your hands on but is entirely case based, so all of the advice is basically what worked and what didn't work in clinical trials, making it a solid voice of reason in an otherwise quirky world.
  3. PainClinic.org (http://www.painclinic.org) - which skirts the line between established medicine and unestablished, but none the less has a great reference section and seems to be run by folks focused on ending pain, not making money.

Of course at the time my reading plans weren't nearly as logical as I have laid out above, but slowly a picture began to emerge. The Rosetta Stone was a journal article from some doctors in Copenhagen published in 2004 concerning that off label prescription that got rid of my headaches. In it the doctors prove amitriptyline's headache suppressing ability isn't due to its effect on serotonin (called 5-HT in the article), which is why it is used as an antidepressant, but to something as yet unidentified. Like any good journal article of this type the authors closed with further research hints:

"This suggests that the analgesic effect of amitriptyline in CTTH is not solely due to 5-HT reuptake inhibition and that other mechanisms such as norepinephrine reuptake inhibition, NMDA receptor antagonism, blockade of muscarinic receptors and ion channels should be addressed in the future research."
 
Analgesic effect of amitriptyline in chronic tension-type headache is not directly related to serotonin reuptake inhibition.
Ashina S, Bendtsen L, Jensen R.
Danish Headache Center, Department of Neurology, University of Copenhagen, Glostrup University Hospital, DK-2600 Glostrup, Copenhagen, Denmark.
Pain. 2004 Mar;108(1-2):108-14.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=15109513&query_hl=2&itool=pubmed_docsum

Aha! Direction! The information on the NMDA receptors proved to be the watershed event:

"Amitriptyline and clozapine at 10 mumol/l both decreased the maximum effect of NMDA by around 17%, but left its EC50 unchanged. This suggests a "classical" non-competitive antagonism and excludes an uncompetitive or "use-dependent" antagonism. Considering the important role of NMDA receptor-mediated effects in spinal nociception the analgesic properties of tricyclic antidepressants may partly be explained by their inhibitory action on spinal NMDA receptors, in addition to their enhancement of monoaminergic transmissions in the dorsal horn."
 
Effects of amitriptyline, amitriptylinoxide, doxepine and clozapine on N-methyl-D-aspartate-evoked release of [3H]-acetylcholine in rat caudatoputamen.
Kiefer G, Fischer W, Feuerstein TJ.
Sektion Klinische Neuropharmakologie, Neurologischen Universitatsklinik, Freiburg, Germany.
Arzneimittelforschung. 1999 Oct;49(10):820-3.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=10554658&query_hl=2&itool=pubmed_docsum

This is where all of that background material proved useful. After some digging it was apparent all of these articles are looking into the mechanisms of pain surrounding a theory known as "Central Sensitization". First described in a Nature article in 1983, Dr. Clifford J Woolf outlined his theory which would shortly come to be known as "Central Sensitization" (CS):

"Because sensitization of peripheral receptors [nerves in the arms, legs, etc. -JRW] occurs following injury, a peripheral mechanism is widely held to be responsible for post-injury hypersensitivity. To investigate this I have now developed an animal model where changes occur in the threshold and responsiveness of the flexor reflex following peripheral injury that are analogous to the sensory changes found in man. Electrophysiological analysis of the injury-induced increase in excitability of the flexion reflex shows that it in part arises from changes in the activity of the spinal cord. The long-term consequences of noxious stimuli result, therefore, from central as well as from peripheral changes."
 
Evidence for a central component of post-injury pain hypersensitivity.
Woolf CJ.
Nature. 1983 Dec 15-21;306(5944):686-8.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=6656869&query_hl=8&itool=pubmed_DocSum

Woolf has a good synopsis of pain hypersensitivity, of which CS plays a part, on the Wellcome Trust website:

"Pain systems need to be sensitive enough to detect potentially harmful stimuli. But often they become too sensitive, causing us pain that provides no benefit. This hypersensitivity arises because our pain pathways actually increase in sensitivity when they relay pain messages, and the mechanisms of this sensitization are beginning to be revealed." ...
 
"Pain hypersensitivity after an injury helps healing by ensuring that contact with the injured tissue is minimized until repair is complete - an adaptive response. However, pain hypersensitivity may persist long after an injury has healed or occur in the absence of any injury. In this case, pain provides us with no benefits, and is a manifestation of pathological change in the nervous system."
 
Pain hypersensitivity
Clifford J Woolf
http://www.wellcome.ac.uk/en/pain/microsite/science4.html

Step into any bookstore's health section and you'll see a variety of books on disorders and syndromes which have no known medical cause, and diseases with poorly understood causes. It's a bit like reading a tabloid since many of these books purport to offer a solution for something that is poorly understood. CFS, Fibromyalgia, IBS, even migraines and to a certain degree Alzheimers, fall into this category. These are all problems that wouldn't crop up in significant numbers until modern medicine and sanitation practices (medical and community based) came along and helped us escape communicable diseases in the late 1800s and 1900s. Life expectancy and population boomed and suddenly the focus turned to the new primary killers such as heart disease and cancer. It's only now that we are coming to understand problems like Fibromyalgia, and CS plays an important part in all of this, along side regular old peripheral sensitivity.

The main mechanisms feature some medical terms that should sound familiar: NMDA and Cox-2, along with AMPA, Substance P, and dynorphin. Quite a lot of them, NMDA included, center on a system in the brain called the "glutamatergic system" which features the neurotransmitter glutamate. Here are some examples of places this theory is being applied:

"Both glutamate release from stimulated platelets and plasma concentrations of the amino acid were assessed by high-performance liquid chromatography, and were increased in both types of migraine, [with aura, MA, and without, MoA] although more markedly in MA. Platelet glutamate uptake, assessed as 3H-glutamate intake, was increased in MA, while it was reduced in MoA with respect to the control group."
 
Platelet glutamate uptake and release in migraine with and without aura.
Vaccaro M, Riva C, Tremolizzo L, Longoni M, Aliprandi A, Agostoni E, Rigamonti A, Leone M, Bussone G, Ferrarese C.
Cephalalgia. 2007 Jan;27(1):35-40.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17212681&query_hl=23&itool=pubmed_docsum

"We studied 20 chronic migraine patients, with and without fibromyalgia, compared to age-sex matched controls. ... CSF [cerebrospinal] glutamate demonstrated significantly higher levels in patients with fibromyalgia compared to those without fibromyalgia. Patients overall had higher CSF glutamate levels than controls. Mean pain score correlated with glutamate levels in chronic migraine patients."
 
Cerebrospinal fluid glutamate levels in chronic migraine.
Peres MF, Zukerman E, Senne Soares CA, Alonso EO, Santos BF, Faulhaber MH.
Cephalalgia. 2004 Sep;24(9):735-9.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=15315529&query_hl=4&itool=pubmed_DocSum

"Of the former players, 61% sustained at least one concussion during their professional football career, and 24% sustained three or more concussions. Statistical analysis of the data identified an association between recurrent concussion and clinically diagnosed MCI [mild cognitive impairment] (chi = 7.82, df = 2, P = 0.02) and self-reported significant memory impairments (chi = 19.75, df = 2, P = 0.001). Retired players with three or more reported concussions had a fivefold prevalence of MCI diagnosis and a threefold prevalence of reported significant memory problems compared with retirees without a history of concussion. Although there was not an association between recurrent concussion and Alzheimer's disease, we observed an earlier onset of Alzheimer's disease in the retirees than in the general American male population."
 
Association between recurrent concussion and late-life cognitive impairment in retired professional football players.
Guskiewicz KM, Marshall SW, Bailes J, McCrea M, Cantu RC, Randolph C, Jordan BD.
Neurosurgery. 2005 Oct;57(4):719-26; discussion 719-26.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16239884

The topic of Alzheimer's brings up and important aspect of this discussion. The mechanisms we are focusing on are just that, mechanisms. CS doesn't guarantee a person will get any or all of these things, nor does it completely explain all of the diseases, disorders, and symptoms we broached earlier. It does go a long way towards explaining them. Alzheimer's clearly has something else going on that produces the plaque in the brain, but since it is such a widespread disease there are drugs for it that should help anyone with these sort of medical problems. As an example, memantine (Namenda), a drug approved for Alzheimers and not much else, is a strong NMDA receptor antagonist, the same mechanism by which amitriptyline helps me by reducing glumate levels in my brain. It also targets serotonin and choline.

Interestingly, looking at a person's glutamate and choline levels shortly after major head trauma can directly predict their outcome:

"We found that glutamate/glutamine (Glx) and choline (Cho) were significantly elevated in occipital gray and parietal white matter early after injury in patients with poor long-term (6-12-month) outcomes. Glx and Cho ratios predicted long-term outcome with 94% accuracy and when combined with the motor Glasgow Coma Scale score provided the highest predictive accuracy (97%)."
 
Proton MRS in acute traumatic brain injury: role for glutamate/glutamine and choline for outcome prediction.
Shutter L, Tong KA, Holshouser BA.
J Neurotrauma. 2004 Dec;21(12):1693-705.
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=15684761

Why? Paradoxically, while glutamate serves an essential role in the brain it is also a neurotoxin! Increase the amount too much and neurons die. With Central Sensitization the levels of glutamate will fluctuate more, and have a higher average amount of it in the brain and spine. Now perhaps it's easier to see why we see the neurological deficits we see in people with brain damage and the other problems we've touched on. Sadly cat scans and MRIs aren't capable of seeing this sort of damage and so it is commonly missed.

There are many sources of hope however:

  1. The drugs that act on these mechanisms are appearing finally, although it may take some digging to find them since they are targeted to specific medical problems and not the spectrum I have outlined above.
  2. fMRI and Proton MRS scans can see the problems and damage. The trick is finding one, a doctor who can order the scan, and a doctor to interpret the results who is aware of all of the above.
  3. It turns out we aren't born with all the brain cells we'll ever have - we produce new neurons all the time, and that combined with the new science of "neuroplasticity" means we have the ability to recover from damage to the brain. The big question is how long it will take to do so, and what can be done to speed up the process.

Many mysteries remain and will continue to for some time, however we are making progress. If you know of anything noteworthy along these lines please feel free to contact me and I will mention it here.

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