problems with non-restorative sleep (due to TBI, depression and/or pain),

major depression and/or anxiety disorder (which are frequently accompanied by fatigue as a manifestation of the primary psychiatric illness) and chronic pain (which has clearly been shown to be of high prevalence in persons after TBI).

Individuals with TBI, families and clinicians must also remain aware of the potential for iatrogenically (physician) induced fatigue related to medication side effects. This latter problem can be minimized by facilitating adequate communication between all parties and by the clinical practice of instituting new medications in a "start low, go slow" paradigm.

Clinicians have a limited armamentarium of assessment instruments by which to evaluate fatigue. The Fatigue Impact Scale (FIS), Fatigue Severity Scale (FSS) and the Visual Analog Scale for Fatigue (VAS-F) have all been utilized to assess fatigue complaints. The FIS may provide the most multidimensional and holistic approach to assessment of the three scales mentioned. The FIS is divided into three main sections including incidence of fatigue, factors affecting fatigue and functional impact of fatigue. The functional categories assessed by the FIS include cognitive, social and physical functioning. One must acknowledge, however, that all of the aforementioned batteries are subjectively based without internal response bias measures to rate out exaggeration or under-reporting of fatigue related symptoms. The best assessment tool in guiding the diagnostic approach to fatigue is the history.

There is one study that this author is aware of that utilized electrophysiologic testing to "objectify" complaints of mental fatigue. This study demonstrated prolonged P300 latencies (post-task) on auditory evoked potential testing in their population of healthy men asked to perform simple calculations. I would note, however, that prolonged latencies on P300 testing is certainly not specific for fatigue and may be seen in a number of other conditions including traumatic brain injury.

There are several neurologic disorders that have historically been associated with fatigue including multiple sclerosis, post-polio syndrome and traumatic brain injury. In post-concussive disorders, fatigue is one of the most commonly reported symptoms, particularly beyond the first few months post-injury. Based on a limited amount of information and in conjunction with significant clinical experience, one can state that the natural history of fatigue post TBI tends to be one of overall improvement without necessarily a resolution of the problem. Interestingly, there has been little research attempting to correlate subjective reports of fatigue with objective evidence of this condition. One study attempted to correlate subjective reports of fatigue/depression with quadriceps strength and found no correlation between the two. A more recent study found that persons with TBI experienced greater level of fatigue on a finger-tapping test than a healthy control group.

As far as etiologic factors are concerned, there is no research that I am aware of in persons with TBI that has examined this issue. From a hypothetical standpoint, neurogenic fatigue is likely related to alterations in catecholaminergic (noradrenaline and dopamine) transmission and/or relative imbalances between catecholaminergic and serotonergic neurotransmission. In 1996, Newsome and Blomstrand theorized that increased concentrations of 5-HT result in physical and mental fatigue during prolonged exercise. The entry of tryptophan into the brain is influenced by the plasma level of free tryptophan (e.g., not bound to albumin) and is inhibited by increased plasma levels of branched chain amino acids. They theorized that oral administration of branched chain amino acids could prevent the increase in S-HT level during exercise and therefore delay physical and mental fatigue. What relevance this may have to treatment of neurogenic fatigue is as yet unclear.

Fatigue as previously defined needs to be differentiated from excessive daytime sleepiness (EDS). EDS manifests with daytime drowsiness and tiredness even after getting enough nighttime sleep. People with EDS frequently doze, nap or fall asleep in situations where they need or want to be fully awake and alert. EDS generally interferes with concentration and performance of activities of daily living (ADLs). Various medical conditions may produce EDS and it is characteristic of several different sleep disorders. Medical conditions that have been associated with EDS include narcolepsy, sleep apnea (peripheral and/or central), periodic leg movements in sleep (PLMS), restless leg syndrome (RLS) and circadian rhythm disorders. Circadian rhythm disorders are further subdivided into delayed sleep phase syndrome (DSPS) and advanced sleep phase syndrome (ASPS). True EDS is rarely if ever caused by psychological or psychiatric disorders such as depression. The Epworth Sleepiness Scale (ESS) is a reliable measure of risk factors/symptoms for EDS and involves a 0 to 3 rating scale with eight rating categories. Scores range from 0 - 24 with scores greater than 10 suggesting a need for further evaluation for FDS.

There is very little research to date examining treatment options for post-TBI related neurogenic fatigue. Clearly, if after TBI, an individual has other contributory factors to fatigue, those should be addressed in the context of holistic, functionally oriented treatment. Before treating an individual with post-traumatic fatigue with pharmacologic agents such as stimulants, I would recommend first ascertaining the following questions:

Is the individual obtaining a regular, restorative sleep pattern?

Has the individual been adequately assessed to rule out psychiatric problems that may be accompanied by fatigue (e.g. depression, anxiety-related disorders and/or certain personality traits (neuroticism and "negative" perfectionism)?

Have endocrine and/or metabolic problems (e.g. diabetes mellitus, hypothyroidism and Addison's disease) been considered and, if deemed likely, ruled out?

Have chronic pain issues been adequately addressed (e.g. has pain management been optimized?)

Has drug induced sedation and/or fatigue been ruled-out?

Have nutritional or hematologic deficiencies such as low B12, anemia and/or blood cancers (e.g. leukemia) been ruled out?

Have the effects of chronic stress or stress intolerance (both of which may be adversely affected by traumatic brain injury) been taken into consideration as potential mediators of fatigue?

Have renal and/or hepatic conditions such as renal failure and/or hepatitis been assessed?

Have neoplastic (malignant) and/or infectious etiologies of fatigue been considered?

(10) Has cardiopulmonary disease been excluded?

The diagnostic work-up for fatigue, when clinically indicated, should include: complete blood count, erythrocyte sedimentation rate (ESR) (Westergren version), urinalysis, biochemical screening, thyroid panel, two hour post-prandial glucose or glucose tolerance test, chest X-ray and electro-cardiogram. If any of the aforementioned clinical issues have not been adequately considered and addressed then this should occur before making the assumption that the fatigue being reported is neurogenic. It is my opinion as a practicing clinician who sees many patients with fatigue that neurogenic fatigue should be a diagnosis of exclusion and not automatically assumed when a patient reports fatigue following a presumptive or established brain injury.

Given that there is a lack of good science to convey treatment recommendations specifically for neurogenic fatigue, I will share with you our approach to this problem when the differential diagnostic process leads us to conclude that we are indeed dealing with neurogenic fatigue. First, I recommend that all the aforementioned issues are explored as clinically indicated and that any issues that exist be treated. I am a big advocate on the role of a "wellness model" for persons after ABI and aggressively pursue recommendations for regular aerobic exercise (e.g., 20-30 minutes, at least three times per week). Regular sleep with fixed hours for going to sleep and waking up, good nutrition, avoidance of alcohol and development of compensatory strategies for fatigue including pacing, energy conservation techniques and task analysis can all contribute to modulating the severity of neurogenic fatigue symptoms and their functional impact.

As patients are interested and good clinical judgement dictates, pharmacologic approaches can be considered, including herbal stimulants such as gotu kola and/or guarana, caffeinated beverages and prescription medications, some of which are controlled. Many clinicians have had success with prescription of certain types of dopamine agonists such as Amantadine for neurogenic fatigue. Stimulant medications such as Ritalin, Dextroamphetamine, Pemoline and Aderall may also be considered. Other drugs that have not received as much attention but may hold some promise for treatment of neurogenic fatigue include activating antidepressants such as Effexor (venlafaxine) and nootropes such as piracetam. Somewhat surprisingly, there is actually a 1996 study indicating that chicken extract had the potential to metabolize stress-related substances such as cortisol in blood and promote recovery from mental fatigue. (Mother's chicken soup may yet be found to be a panacea!) Other experimental treatment options that have not been evaluated as applied to TBI include biofeedback and electromagnetic therapy.

Fatigue remains a common yet often complex and multi-factorial problem for persons with traumatic brain injury. Further research examining assessment and treatment is clearly warranted. Nonetheless, there are some basic common sense guidelines that clinicians should follow with regard to evaluation of subjective complaints of fatigue, as well as, some "tried and true" treatment strategies for this condition.