Can you describe a few of Dr. Geller’s initially unresponsive patients who have profoundly improved at his rehabilitation program?
Henry suffered a massive stroke after a ruptured aneurysm, and much of his brain was destroyed. For months doctors told his family that he would never ascend from coma or leave the nursing home. Appropriate medications were started during his stay at the rehabilitation unit, and Henry spoke and wrote his name several weeks after admission. Henry remains cognitively impaired, but he now is employed in a limited capacity earning an income, eats dinner with his family, and sleeps in his own bed in his own home.

Mrs. B visited his wife for eight months after her brain infection rendered her vegetative. Her MRI and CAT scan had been interpreted as predictive of irreversible unresponsiveness. At the rehabilitation facility, multiple different dopaminergic and noradrenergic psychostimulants had unsuccessfully been delivered, including Protriptyline, Amantadine, Dexedrine, Sinemet, and methylphenidate. Several days after the psychostimulant medication Permax dose was increased, the patient began to speak and use her arms functionally. Mrs. B and Mr. B smiled and laughed together for the first time in what had seemed an eternity.

Evelyn suffered damage to her brainstem and developed locked in syndrome. She could move only her eyes to communicate. She could neither move her limbs nor speak, and was truly imprisoned in her body. Her sister feared that she would pass away from the same pneumonia, embolism, or other fatal event which so commonly happens to the comatose, vegetative, or locked in person within months of injury. Sinemet, a common anti-Parkinsonian medication, was delivered as a psychostimulant. Evelyn’s sister began to cry with joy two hours after the first dose was delivered and Evelyn began to speak and pull herself from her wheelchair back to bed. It had been five weeks since Evelyn had last spoken or moved. Over the next two months of intensive treatment, Evelyn regained full independence in self care and ambulation.

What is coma?
From a medical perspective, an unresponsive patient is in coma when his eye opening, verbal response, and motor response on the Glasgow Coma Scale total 8 or less. From a family’s perspective, patient’s eyes are closed and the loved one is never awake.

What is meant when a patient is described as being vegetative?
This is a condition in which the awake unresponsive patient’s eyes are open and sleep wake cycles are intact, but the patient neither speaks nor exhibits any behavioral evidence of awareness of loved ones or of his environment.

What is the locked in syndrome?
Locked in syndrome is a state of being awake and aware ("conscious"), but quadriplegic and mute such that one appears unresponsive. The patient is truly imprisoned in his body. Communication is only possible by eye blinking or isolated eye movements unless the condition is reversed.

What causes coma, vegetative states, and locked in syndrome?
These conditions are most commonly caused by stroke, traumatic traumatic brain injury, aneurysm ruptures, intoxication, medications, and infections.

Can coma, the vegetative state, or locked in syndrome be reversed?
Unfortunately, not everybody responds. In Dr. Geller’s experience, approximately 70% of patients in coma, vegetative states, or locked-in states can be successfully treated with advancement to higher levels of consciousness, awareness, arousal, communication, mobility, and, most importantly, higher quality of life for themselves and their families. For the unfortunate few who exhibit lack of response, this does not suggest permanence or the lack of hope. It simply reflects the enormous need for newer medications and treatments to be researched and developed.

Will all patients respond?
In Dr. Geller’s experience, the vast majority of patients improve. Some do not, but ALL patients deserve a chance. There are never any guarantees, and sometimes miracles do happen.

How is the comatose, vegetative, or stuporous patient made awake and aware?
Medical conditions such as hydrocephalus, hyponatremia, infection, and dozens of other dyshomeostatic states must be corrected. Offensive medications which perpetuate the comatose and vegetative states must be discontinued and substituted for safe alternatives. Psychostimulants must not only be started, but diligent dosing changes must occur every 2-4 days by a physician trained and experienced in coma stimulation. Physical, occupational, and speech therapy sensory stimulation and a host of additional interventions enormously supplements the medical management.

If coma or the vegetative state have persisted for years, can the situation still be reversed?
Patients may be in coma or vegetative for years, and appropriate treatment may bring them "back to the living."

Other doctors have told me that the condition was hopeless. How is that which you describe possible?
Turning the key in the ignition of a car left in the garage for a week will activate the engine. If the car is left in the garage for a month, then a jumper to the battery may be required. Similarly, despite being silent and inactive, patients who are non-interactive may be jump-started back to their families and a much higher quality life with appropriate medications and treatments.

My loved one’s neurologist stated that the head CT and MRI scans of the brain indicate too much damaged tissue for recovery to be possible. Is this a true assessment?
NO!!! It is impossible with any current technology to accurately predict prognosis based on CT or MRI. Clinical presentation, however, may suggest that anoxic patients, people older than 65, and individuals with undrained subdural hematomas have a less favorable likelihood of responding to psychostimulants. Patients with cardiac disease may also be less likely to tolerate stimulants, but cardioprotective medications can be given. EVERY PATIENT DESERVES A CHANCE!!!

My HMO stated that my loved one is not appropriate for a rehabilitation hospital, and that we should send him to a nursing home ‘to see’ if he awakens on his own and then consider rehabilitation. Is this appropriate?
NO!!! Here are the reasons:
1. Patients are significantly less likely to awaken spontaneously without psychostimulants. You could “wait and see” forever at the nursing home with no awakening. Unlike at a rehabilitation facility, at the nursing home it is extremely uncommon for psychostimulant agents to be changed in dose or type every 2-4 days.
2. Patients in comatose, vegetative, and locked in states have poor control over salivary secretions, enormously predisposing them to aspiration pneumonia, typically the fatal event at the nursing home. Usually fewer medical doctors and registered nurses are present on a daily basis at nursing homes relative to rehabilitation facilities. Awakening patients sooner than later decreases the likelihood that they will develop and succumb to pneumonia.
3. A ‘window of opportunity’ may exist in which psychostimulants can successfully awaken individuals from comatose, vegetative, or locked in states early after the brain injury or stroke. It may be that stimulants are less effective if prescribed later in time after the ‘window’ has closed in the nursing home.

--------------------

 
OBJECTIVES:
An appreciation that;

The comatose, vegetative, and locked-in-states are treatable conditions. 

The medications used to treat these conditions are safe for most patients, though cardiac disease may significantly increase risks with sympathomimetics and this class of psychostimulants should be considered a tertiary option in this population.  Psychostimulants are broadly classified in terms of neurotransmitter agonism, including noradrenergic, dopaminergic, and serotonergic.

The vast majority of patients that have been inappropriately designated as being “untreatable” or “irreversibly impaired” based on lack of spontaneous recovery may, in fact, respond to psychostimulants.

MRI and CT scans cannot predict who will or will not recover, independent of the improper confidence of the otherwise distinguished appearing, highly credentialed clinician who would suggest otherwise.

Different mechanisms of action of different psychostimulant classes, distinct effects at different receptor subtypes, differential effects at low and high doses, unique patient premorbid biophysiology, and diversity of intracranial lesions mandates that multiple trials and combination of psychostimulant trials be effected to return the loved one to their families.

Novel psychostimulants are constantly being developed, usually to treat depression, chronic fatigue, hypersomnia, and other medical conditions.

Comprehensive care of the comatose, vegetative, and locked-in patient mandates proper medical care, including attention directed towards minimizing evolution of new pathologies such as contractures, pneumonia, urinary infections, sepsis, decubitus ulcers, osteomyelitis, and other conditions which could lead to impairments in progression once arousal, initiation, and attention have been maximized.  Inattentiveness to medical conditions may result in early death as opposed to decades of productive, happy life.

Once a patient is awake, profound cognitive deficits characteristically are appreciated as sequelae of the initial neurologic insult.  Disinhibited aggressive and emotional behavior may preclude return to the community if untreated, even after the patient is no longer comatose or vegetative.  Psychostimulants, beta blockers, and a host of medications may SELECTIVELY extinguish disinhibited behavior without the considerable proconvulsant, globally sedating, and extensive side effects of treatment with antipsychotic neuroleptics.

EVERY PATIENT DESERVES A CHANCE!!!
 OUTLINE OF CHAPTERS

EPIDEMIOLOGY – SCOPE OF THE CONDITION
DEFINITIONS
PATHOPHYSIOLOGY
DIFFERENTIAL DIAGNOSIS
CLINICAL ASSESSMENT
CLINICAL IMPLICATIONS
INITIAL TREATMENT
TREATMENT - NONPHARMACEUTICAL
TREATMENT - DRUG SUBSTITUTION/TAPER
MEDICATION TRIALS - GENERAL CONCEPTS
MEDICATION TRIALS - SPECIFIC AGENTS
MEDICATIONS - NORADRENERGICS
MEDICATIONS - DOPAMINERGICS
MEDICATIONS – Tricyclic Antidepressants (TCA's)
MEDICATIONS - SEROTONERGICS
MEDICATIONS - MONOAMINE OXIDASE (MAO) INHIBITORS
MEDICATIONS - CHOLINERGIC AGONISTS
MEDICATIONS - ATYPICAL AGENTS
INFORMED CONSENT
FOLLOW-UP
FUTURE DIRECTIONS
MEDICAL MANAGEMENT IN THE INTERIM
MEDICAL MANAGEMENT IN THE INTERIM – VASCULAR
MEDICAL MANAGEMENT IN THE INTERIM – GASTRO-INTESTINAL
MEDICAL MANAGEMENT IN THE INTERIM – GENITO-URINARY
MEDICAL MANAGEMENT IN THE INTERIM – PULMONARY
MEDICAL MANAGEMENT IN THE INTERIM – CARDIAC
MEDICAL MANAGEMENT IN THE INTERIM – HEMATOPOETIC
MEDICAL MANAGEMENT IN THE INTERIM – SKIN
MEDICAL MANAGEMENT IN THE INTERIM – MUSCLE, TENDON CONTRACTURES
CONCLUSION


ABBREVIATIONS
 
AAI – arousal, attention, and initiation
TBI – traumatic brain injury
TCA – tricyclic antidepressant


 COGNITION - SUBOPTIMAL AROUSAL, ATTENTION, and INITIATION

EPIDEMIOLOGY – SCOPE OF THE CONDITION
    Arousal, attention, and initiation (AAI) are fundamental to cognition, behavior, and quality of life.  AAI may be profoundly impaired after acquired brain injury from stroke, anoxic or traumatic brain injury (TBI), encephalitis, hydrocephalus, Alzheimer's dementia,(82) or brain tumor.  This heterogenous population encompasses vast numbers of people.  The annual incidence of new head injury patients in the U.S. is 7.6 million, and more than one million of these are severe, with 400,000-500,000 hospitalized and 70,000-100,000 afflicted with significant disability.(25)  Institutionalization and failures of rehabilitation after TBI most consistently occur secondary to suboptimal AAI or disinhibition.(116)
    The potential complications of coma include pneumonia, pulmonary embolus, and a vast number of potentially fatal sequelae which may be obviated by induced ascension from coma or by facilitating the rate at which patients ascend from coma.  Deficits in AAI frequently respond to psychostimulants.  Chronically impaired patients may emerge from coma or vegetative states within days of initiating psychostimulants, even if the condition pre-existed for many months.(15,22)  Similarly low levels of attention and intitiation which preclude optimal quality of life may respond after numerous months.(119) 
    Impaired AAI markedly compromises quality of life for the patient and family, and institutionalization imposes extensive financial resource consumption.  Impaired attention promotes confusion, predisposing to disinhibited behavior.(34)  Enhancing AAI deficits often affords functional participation, home living, and employment restoring quality of life and benefits to patients, families, and society.  Prognosis has been undeservably grim for comatose and vegetative patients greater than one year from injury.(150,155) Arousal and awareness are amenable to clinical intervention, and the inestimable value of returning a conversive patient to their families, even with dependence for mobility and activities of daily living must be appreciated. 

DEFINITIONS
    Arousal is the state of readiness(35) to respond to internal and external stimuli.  If an individual is not aroused, then he cannot engage in activities, even if evolutionarily more advanced physioanatomic mediators of awareness and attention are preserved.  Arousal may be viewed in descending states by the amount of external stimulation required to confer wakefulness, a continuum from awake, lethargic, stuporous, obtunded, and unarousable/coma.  Alternatively, coma has been defined as those with Glasgow Coma Scale ratings of 8 or less. 
    Vegetative patients are individuals whose eyes are open, are akinetic or intermittently spontaneously move their arms in nonfunctional ways, and are mute or intermittently state inappropriate words.  Eyes do not move to command, but occasionally track objects.(163)  As such, their Glasgow Coma Scale intermittently ascends to 12.  Pupillary, corneal, and brainstem reflexes are characteristically preserved in vegetative patients.(150)  Vegetative patients are not categorized as being comatose, as they are awake, but they exhibit limited or no behavioral awareness of their external environment, similar to comatose patients.  Wakefulness merely implies sufficient integrity of the reticular activating system of the brainstem.  Awareness implies recognition of distinctiveness between self and environment as well as functioning within the cerebral hemispheres.(150)  Vegetative patients are also referred to as being in coma vigil, abulia, apallic,(154) indifference, akinetic mutism, nonsentient,(155) and post-comatose cortical unresponsiveness.(157)  The condition is characterized by flat affect, intact sleep-wake cycles,(153) occasional nonsustained visual pursuit eye tracking and limb movement, but absence of response to verbal commands.(50)  The constellation of grimacing, altered respiratory pattern, and stereotypic limb flexion may occur as well as automatisms including spontaneous chewing and sucking(150) as well as swallowing when fed.(163)  Vegetative patients do not respond consistently or at all to painful, loud, or threatening visual stimuli.(102,104)  Painful stimuli may produce slow withdrawal, and the delayed rate of movement is not accompanied by dystonia, rigidity, or spasticity.(163)  Medicine's limited understanding of the vegetative state reflects an inference of clinical observations, and may be incompletely accurate in that behavioral unresponsiveness cannot be unequivocally equated with cortical unawareness.(157)  Indeed, the EEG has been frequently reported as being normal in vegetative patients.(150)  Similarly, though not comatose, it is impossible to state whether these patients are "conscious." 
     The vegetative state is defined by some clinicians as a step in the continuum towards being awake.  Other practitioners, however, subscribe to the philosophy that the vegetative state is a distinct path.  It is not unlikely that the clinical presentation of vegetative state consists of both subpopulations, and some of these individuals will ascend to embark on the journey towards greater interaction with external stimuli if appropriately treated. 
    Persistent vegetative state is a distasteful and unacceptable term which must be discarded, as patients so distinguished may simply be those who have had a suboptimal trial with psychostimulants.  In addition, medicine is in its early maturation stage with respect to development of novel arousing pharmaceutical options.  Use of the word "persistent" at 6 months, one year, or ten years remote from the pathological event inappropriately suggests the absence of hope and the interminable futility of psychostimulant trials.  It remains anecdotal to suggest that the longer a patient is in the vegetative state, the less the potential for improvement.  Proof of a restricted therapeutic window has not been definitively issued.  Potential for improvement is not restricted by time, and not always by effort, but often by the current and evolving status of pharmacotherapy.  "Persistent" is a term whose use should be deferred indefinitely.
    The absence of speech and movement which characterizes the locked in state after pontine CVA, central pontine myelinolysis, and other pathologies affecting the pons is a condition in which cortical cognitive activity is entirely preserved, yet behavior is almost fully extinguished secondary to motor blockade.  Patients characteristically communicate appropriately with eye movements as well as blinking as these motor functions are usually preserved.

    Attention is the capacity of focusing on isolated, specific tasks or stimuli.  It is a multifaceted concept governed by an integrated network of diverse brain structures.(133)  Many different subcomponents of attention exist, including resistance to distraction, sustained attention, capacity to shift attention as desired, speed of cognitive thought processing, visuospatial neglect, and self-regulatory avoidance of disinhibited outbursts.(133)  Many of these manifestations of impaired attention  improve with psychostimulant treatment,(29,133) but improvement in hemispatial neglect is often incomplete.(33,120,129)   Bradyphrenia and psychic akinesia are alternative names for delayed rate of mental thought processing.(93)  This is to be contrasted with nigrostriatal slowed motor processing of Parkinson's disease.(93)  Without sufficient attention, patients cannot learn new skills or optimally interact with their environment.  Quality of thought processing is impaired, as the patient lacks sufficient attention to organize concepts to achieve a plan of action. 
    Vigilance is a state of perseveration in which inordinate attention focused on a single stimulus with inability to readily deviate attention to another stimulus.  Vigilance is to be contrasted with conscious states of suppressing extraneous stimuli with a goal of dismissing distractions without shifting attention.  Vigilant preoccupation with a single stimulus may reflect diminished attention in that insufficient attention is commandable to deviate the focus of consciousness.  Alternatively, vigilance may reflect hyper-attentiveness in which attention is so intensively focused that it cannot be shifted to another stimulus.  The second state may reflect excessive delivery of psychostimulants, and the former condition suggests possible insufficient delivery of these medications. 
    Compromised memory and learning are closely linked to impairments in attention, and psychostimulants may facilitate recovery of compromised memory.  In addition, disinhibited behavior is commonly a manifestation of impaired AAI, and is often responsive to psychostimulants.(52,137)  

    Initiation is the will to respond to internal and external stimuli and goals.  Impaired initiation is also referred to as amotivational syndrome, docility, global apathy, placidity, anergia, anhedonia, indifference, abulia, poverty of interests, impoverished affective life, loss of psychic autoactivation, and pure psychic akinesia.(161)  Patients may intermittently summon the will to act, and deny mood depression as the cause for their "lack of will."  This condition may exist as a mild state of akinetic mutism.(161)  Patients may never speak unless questioned.(161) 
    Diminished initiation has been attributed to lesions of frontothalamic connections, including lenticular nucleus, lacunes of the caudate and putamen of the neostriatum, orbital and mesial frontal cortex.(161)  Different pathways mediate initiation and a patient with Parkinson’s disease without dementia may be unable to initiate motor activity despite intact cognition, but if one approaches the patient from behind and yells “Fire!  Move!” then the patient may activate alternative secondary pathways and promptly move to an exit.

PATHOPHYSIOLOGY
    Arousal is significantly mediated by dopamine and norepinephrine neurotransmitters of the reticular activating system in the midbrain, pons,(149) and limbic structures with projections to the thalamus(116) and then to the cortex.  Lesions of this site or of the projecting axons causes suboptimal arousal.  Extensive cortical lesions may also suppress arousal.  Serotonin may also mediate AAI, and levels of homovanillic acid and 5-hydroxyindolacetic acid, biometabolites of dopamine and serotonin degradation, are decreased in cerebrospinal fluid after head injury,(69) suggesting potential disruption of synthesis of these neurotransmitters.  Depletion of catecholamines following CVA and TBI may be remediated by exogenously delivering these agents to augment and amplify function of surviving structures.  Attention and initiation are higher executive functions, mediated by the cerebral cortex.  Disorders of attention likely represent complex interactions amongst several cognitive mechanisms.(45) 
    TBI causes shear damage to axial brain structures, disrupting monoamine neurotransmitter systems which project to the cortex and striatum to mediate arousal.(64) 
    It is of paramount importance to appreciate that the vegetative state is a behavioral syndrome rather than a specific anatomy.(150)  A heterogenous distribution of head CT identified lesions induce coma as well as  the vegetative state, and patients with anoxia or other metabolic toxic dyshomeostatic insuls as well as the sheared axons of diffuse axonal injury often results in a normal head CT.  Some clinicians suggest that vegetative patients have preserved brainstems and severely damaged cerebral hemispheres,(150) whereas others report identical behavioral states with isolated brainstem pathology or global anoxia.(154)  Lesions of the mesencephalic tegmentum, lateral hypothalamus of the medial forebrain bundle, posterior diencephalon, medial thalamus, globus pallidus, cingulate cortex, and septal areas have all been described in association with causation of akinetic mutism.(163)  The nigrocortical dopamine bundle courses through the median forebrain bundle.(163)  CLINICIANS AND PATIENTS MUST APPRECIATE THAT IT IS IMPOSSIBLE TO PREDICT ASCENSION FROM THE COMATOSE OR VEGETATIVE STATES BASED ON HEAD CT OR CRANIAL MRI.  Even brains “necrotic on MRI” of patients in deep coma may awaken.  Families often prefer to deal with awake loved ones with care needs as opposed to turning off respiratory support and allowing loved ones to die.
    Psychostimulants may be used to "jump start" AAI by stimulating the reticular activating system,(149) or they may be required chronically to maintain a state of adequacy for more complex executive function to proceed.  In the former situation, "jump starting" can be viewed as analogous to an intact automobile engine which works fine after the ignition key is turned, after which time the engine remains active.  Subsequent discontinuation of the medication does not reverse enhances achieved in AAI.(22,35,98)  Similarly, dramatic improvement in locked-in-syndrome with Sinemet persists after drug discontinuation.(50)  Conversely, other patients may require months to years of psychostimulant delivery that is accompanied by abrupt decompensation when the agent is tapered,(15) convincingly supporting a cause-effect relationship, especially when improvement occurs within days of drug initiation in patients in whom AAI was impaired for months preceding medication trial.  Marked improvement in expressive aphasia reversed when bromocriptine is discontinued in post-stroke patients.(12) 
    Medical knowledge is in its infancy with respect to identifying neurotransmitters, receptor polymorphism, and brain pathways which mediate AAI and specifically target desired areas.  Amino acids, neuropeptides, cholinergics, and catecholamines are some of the classes of known synaptically active messenger molecules.  To further expand potential neurodiversity, each neurotransmitter may differentially stimulate a host of receptor subtypes located at different sites in the brain.  For example, at least seven families of serotonin receptor have so far been identified in the brain, with subtypes within families.(96)  To introduce further complexity, receptor agonists may exert preferentially antagonistic effects at low doses and behave as agonists only at higher doses.
    Dopamine is the precursor neurotransmitter to norepinephrine.  Norepinephrine is produced by the locus coeruleus, and the ascending coeruleo-cortical noradrenergic system is extremely divergent and involved in improving signal to noise in multiple structures such that small brainstem lesions can effect considerable compromise throughout brain centers of AAI.(15)  Dopaminergic structures are frequently affected in chronic TBI.(52)  Dopaminergic projections to the striatum, limbic cortex, and the frontal cortex modulate motor control, arousal, attention, memory, and emotional regulation.(2) Dopamine influences motor behavior of the nigrostriatal pathways as well as motivation via the mesolimbic system.(34) Striatofrontal dopaminergic tracts are felt to mediate delayed cognitive thought processing whereas compromised nigrostriatal dopaminergic tracts cause slowed motor thought processing.(93)  Serotonin is a brain neurotransmitter which exhibits inconsistent effects on arousal.(52)
    Lesion sites which compromise AAI are diffuse or heterogenously discrete,(44,163) and enhanced arousal has been identified in patients with bifrontal contusions,(35) left parietal contusions,(35) basal ganglia CVA,(35) thalamic CVA,(70) posterior circulation CVA,(35) diffuse axonal injury, subdural hematoma, epidural hematoma, diffuse herpes encephalitis, and hydrocephalus,(33,44). Akinetic mutism has been described as affecting individuals with hypothalamic pathology,(102) globus pallidus,(102) bilateral damage to the frontal lobes, small lesions of the paramedian reticular formation in the diencephalon and midbrain, and diffuse cerebral leukoencephalopathy.(104)  Hydrocephalus secondary to shunt malfunction and compression of ascending dopaminergic input tracts to the striatum, cingulate, and frontal cortex has been described as a cause of akinetic mutism.(163)  Both white and grey matter micro and macroscopic lesion etiology of suboptimal AAI may be amenable to improvement with psychostimulants. 
    The spectrum of anatomic and neurochemical lesions is an obstacle to accurate predictions regarding responsiveness to drug trials.(106)  In light of the considerable safety of most of the psychostimulants and the inestimable potential benefit in fortunate patients who do respond, it is inapproriate and presumptuous to deny drug trials to patients solely on the basis of head CT/MRI radiologically identified pathology.  It may not be possible to identify patterns of injury which may account for clinical variations,(45) and considerable large scale randomized research is necessary to direct trial agents in varied populations.  Although various investigators and clinicians have advanced theoretical perspectives on the manner in which specific clinical presentations should guide drug selection, no systematically validated neurochemical measurement systems currently exist to guide drug selection.(106)  Until comparative trials are performed, it is impossible to confirm assertions of anatomic predictors of drug trials as anything greater than mythology.(106)  IN SHORT, ALL PATIENTS DESERVE A CHANCE. 

DIFFERENTIAL DIAGNOSIS
    Suboptimal AAI is a diagnosis of exclusion.  Other entities must be considered in a comprehensive differential diagnosis, as different interventions are pursued to treat different conditions.  Infectious encephalopathies secondary to herpes simplex virus, lyme disease, syphilis, and other bacterial and fungal invasions must be excluded.  Occult cancer with normal MRI’s and CT scans may present in a paraneoplastic state with quadriplegia and encephalopathy with full resolution following a course of chemotherapy.  Toxic etiologies must also be investigated.  Trimethoprim,(136) ibuprofen,(121,125,126) naproxen,(111) tolmetin,(130) and diclofenac(127) have all been reported as causing aseptic meningitis, a condition of fever, confusion, neck stiffness, photophobia, headache, and cerebrospinal fluid pleocytosis without organisms on culture or gram stain, precipitated within hours by drug ingestion usually with resolution with drug discontinuation.  Status epilepticus and frequent petit mal seizures may need to be excluded as a cause of unresponsiveness to the environment.  Thyroid failure should also be considered, especially in TBI.  Hydrocephalus shunt malfunction must also be considered as a cause of impaired AAI.(163) 
    Brain death is characterized by absence of brain stem function, including respiration, seizure activity, posturing, motor response to pain, and light, oculovestibular, oculocephalic, gag, and corneal reflexes.(150)  EEG's are frequently performed to confirm the clinical diagnosis.  CLINICIANS COMMONLY INAPPROPRIATELY INVOKE THE TERM “BRAIN DEATH” TO THE COMATOSE OR VEGETATIVE PATIENT WITHOUT EEG CONFIRMATION.
    Apraxia is a parietal and frontal cortically mediated motor planning disorder in which, independent of preserved strength, sensation, tone, posture, comprehension, intelligence, arousal, attention, and motivation,(156) movements cannot be executed because the synthesis of innumerable minor steps cannot be processed to direct skilled coordinated activity.  As such, this may be confused by some with a vegetative state.
    Locked-in states may follow central pontine myelinolysis, infarction of the ventral pons, and other causes.  Cognition and volitional blinking and vertical eye movements are usually fully intact, despite quadriplegia and lower cranial nerve paralysis.(50)  Preservation of appropriate and reproducible yes/no eye blinking responses alerts the clinician to the condition.  Similarly, occult cervical spinal cord injury can result in quadriplegia, potentially misinterpreted as diminished motion secondary to cognitive impairment, particularly if comorbid TBI has occurred.  Profound peripheral sensory or motor neuropathy may also be misdiagnosed as a primary deficit in AAI.
    Schizophrenic catatonia may present with an inability to physically interact with the environment.  However, the patient may be suffering from persecutory delusions, and dopaminergics exacerbate the condition.  Dopamine receptor antagonists are used treat the disorder.   Premorbid history from the family is often invaluable in ascertaining the diagnosis.  It must be appreciated that differentiation of catatonia from akinetic mutism may be impossible, and consideration for dopaminergic antagonists to treat occult catatonia may be indicated, particularly in a young person with abrupt social decline. 
    Mood depression has been described to exhibit cognitive slowing(93) accompanied by psychomotor retardation, and it may impersonate primary disorders of attention or initiation.
    Mania may be a sequelae of head trauma(135), and flight of ideas must not be misinterpreted as impaired sustained attention capacity, as dopaminergics may exacerbate mania associated with psychosis.   The presence of elation, grandiose delusions, and insomnia should elevate considerations for a diagnosis of mania. 
    Parkinsonian rigidity and bradykinesia should be considered in the differential diagnosis of impaired response to the environment.
    Spasticity, in its most severe form, may mask volitional motor control and environmental engagement, especially if aphasia is comorbid.
    Global aphasia may be occasionally misinterpreted as lack of initiation.  If the patient cannot understand spoken or written language, then he may appear to lack motivation to follow simple commands.  Frustration and secondary mood depression may be co-existant and exacerbate the functional deficits.   The patient characteristically exhibits frustration, unlike those with impaired AAI who prefer to sit and watch the world without engagement.

CLINICAL ASSESSMENT
    Arousal is readily assessed via the Glasgow Coma Scale in which eye opening, movement, and verbalization are scored on a fifteen point scale.  With respect to eye opening, 4 points are accumulated for spontaneous eye opening, 3 points for eye opening to verbal command or to other sound, 2 to pain, and one point if the patient does not open his eyes.  With respect to best motor response, 6 points are accumulated if the patient obeys commands to move, 5 if the patient pushes a painful stimulus away, 4 if flexion withdrawl is the response to pain, 3 if decorticate movement occurs in response to pain, 2 if decerebrate positioning occurs, and one point if no response occurs in response to pain in the absence of anatomic lesion which would preclude movement or sensation, as with a hemiplegic limb.  With respect to best verbal response, 5 points are accumulated if a patient is oriented and converses, 4 if the patient is disoriented and converses, 3 if incomprehensible sounds are vocalized, and one point if the patient neither verbalizes nor vocalizes.  A cumulative score of less than or equal to 8 is defined as coma. 
    The spectrum of awake, lethargic, stuporous, obtunded, and comatose is less distinct.  A lethargic person readily autonomously compels himself to remain awake, occasionally requiring TV, radio, or other external stimulation.  A stuporous individual may require more potent external stimulation, such as gentle nudging.  An obtunded person requires considerable external effort to remain conscious, and forceful effort may be necessitated.
    Attention can be assessed with numerous tests, including serial counting one to twenty, twenty to one, twenty to one by subtracting 3's, one hundred to one by subtracting 7's,...  Hemispatial neglect can be assessed by asking the patient to name left and right body parts or draw a clock.  The rate of thought processing can be scrutinized in conversation as well as mathematical calculation and other problem solving tasks.  Neuropsychological battaries of tests are often helpful to optimally define precise levels of attention to identify baseline function and extent of improvement with various medication trials.
    The extent of impaired initiation is witnessed clinically when the patient cannot motivate himself to request a urinal to void, remove a painful stimulus, stand to dress, feed himself, or otherwise participate in therapies or other desirable tasks.  The patient may refuse therapies and simply wish to sit and stare out the window or lie in bed. 

CLINICAL IMPLICATIONS
    Treatment of patients within days to weeks after TBI with Ritalin(35) allows patients to participate more actively in rehabilitation efforts.  Psychostimulants may also accelerate rehabilitation by extinguishing behavioral dyscontrol,(9,25,44,83,87,114) possibly via enhancing processing capacity such that interpretation of stimuli is more lucid, prompting a more socially appropriate response.  Enhanced behavioral control directly translates into improved therapy participation and functional status,(25) facilitating efforts towards a home discharge.  Psychostimulants facilitate neurologic recovery after TBI and CVA.(30)  Even a modest improvement in AAI may substantially enhance quality of life. 
    Patients with suboptimal arousal may not ascend from coma or vegetative states after TBI or stroke.  Nursing care needs are consequently far more extensive, and the patient is at higher risk for DVT, aspiration pneumonia, decubitii, contractures, and osteoporosis.  Physical restraints with attendant risks of strangulation, respiratory impairment, and neurovascular compromise may be necessary to protect the obtunded patient from falling out of bed.  The psychologic trauma to the family cannot be overstated.  Sinemet, within days of drug initiation, precipitated emergence from vegetative state of six months.(     )  Desipramine and amitriptyline(15) have exhibited similar efficacy.  The merits of psychostimulants in enhancing AAI in both acute as well as chronic conditions cannot be overstated, but the value with respect to enhancing cortical recovery with respect to "windows of opportunity" must independently be thoroughly investigated. 
    Impaired selective attention during transfers and ambulation predisposes to falls, fractures, and subdural hematomas.  Suboptimal attention limits new learning in therapies, limiting the probability that the patient will be able to live in a noninstitutionalized environment.  Ability to follow commands is improved.  Memory is enhanced by psychostimulants, both secondary to enhanced attention(    ) as well as secondary to independent mediators.(    )  Even two years post-TBI, patients exhibit improved attention within weeks of psychostimulant trial.(44) 
    Impaired initiation prevents home discharge of patients who may otherwise require only minimal assistance for basic mobility and daily care skills.  Psychostimulants may obviate the need for frequent external prompts, allowing patients to complete tasks independently.  Improved initition secondary to protriptyline may enhance eating behavior.(114) 
    The importance of implementing pharmacotherapy as soon as possible after the onset of an acquired brain disorder of AAI cannot be overemphasized to ensure the economy of use of resources of the patient.(2) 

INITIAL TREATMENT
    Initial treatment of suboptimal arousal, attention, or initiation requires medical investigation for occult electrolyte dyshomeostasis, hypoglycemia, hypovolemia, anemia, infection, evolving stroke, seizures,...   Dilantin toxicity secondary to drug interactions has been identified as an insidious cause of vegetative depression.(24)  Hyponatremia occurs in up to one-third of patients following severe TBI, and patient's with sodium levels less than 128 mEq/L may exhibit impaired cognition.(53)  The danger of missing occult pathology in early, readily treatable stages cannot be overemphasized.  A sudden decline or plateau in neurologic recovery in a stroke or TBI patient may alert the clinician to consider hydrocephalus, subdural hematoma, intracranial abscess, meningitis, and additional medical conditions.
    Caloric, mineral, fluid, and protein malnutrition will negatively impact cognition.  Folate, thiamine, and other vitamins are requisite to cortical processing, and may require supplementation.  Body weights, pre-albumin levels, hemoglobin levels, vitamin levels, and calorie counts require monitoring and may suggest the indication for gastrostomy placement.
    Sensory function must be maximized. If visual acuity and audition are at optimal capacity, then already variably compromised cognitive status will be less burdened, and less likely to contribute to impaired attention.  External auditory canals should be assessed for middle ear infections, cerumen impaction,...  Cataracts, glaucoma, and other causes of impaired visual acuity must be addressed.   A low threshhold should be assumed to consult ophthalmology, ENT, and audiology, especially if comorbid aphasia is present. 
    Sensory overstimulation should be minimized to maximize attention capacity as complex information processing is often deficient.  In contra-distinction to awakening the comatose or reversing the vegetative state, patients should be placed in quiet, single rooms, not in the hallway or near a busy nursing station.  The patient should not be fully isolated, as inadequate sensory stimulation may impair arousal.  Lights should be neither too bright nor too dim.  If lights are too dim then patients with impaired attention may misinterpret dimly lit objects and respond to these illusions.  As cognition improves, meals with other patients should occur in a central, monitored dining area to facilitate social integration.  Home visits on weekends and frequent family visits further enhances socialization.
    Frustration can be diminished by facilitating communication.  Word boards, gestures, and simple yes/no finger movements, head nods, and eye blinks can greatly diminish frustration in aphasic patients.
    Re-establishment of regular sleep-wake cycles to maximize a full night's sleep will promote alertness and improved attention.  Delivery of medications and vital sign assessment should be scheduled such that the frequency of awakenings is minimized.  Scheduled daytime naps may be required, but excessive daytime sleep may reduce the patient's ability to sleep at night.  Caffeine and psychostimulants should not be given after noontime.
    A predictable schedule should be established with consistent times of wakening, meals, therapies, bathing, dressing, naps, bedtime,...  This will help the patient differentiate from his internal and external environments.
    Orientation will be enhanced with a clock and calendar in the patient's room as well as a daily schedule chart.  If placed on a large chart on the wall in his room, he can frequently refer to it.  This will also generate feelings of stability as he senses that his environment is well ordered.  Placing family pictures and familiar personal belongings (blankets, pillows, stuffed animals, posters,...) in his room will also contribute to security, as will visits from friends and family.  Attempt to have the same nurse care for the patient to establish continuity and familiarity for the patient.
    Avoid complex, stressful activities to which the disinhibited patient may combatively respond.  Explain activites slowly and answer questions before asking the patient to attempt them.  Attempt to simplify tasks or break complex tasks into less challenging subcomponents.  Performance will be enhanced if psychologic demands are limited.  Patients may be more likely to participate in PT and OT if family is present and encouraging. 
    Neuropsychologists can be fundamental to construct behavior programs which may enhance cognition.(16)  For example, positive reinforcement through liberal praise, rewards with cookies after staying awake for an entire therapy session will increase the frequency of cooperative behavior with therapists and nurses. 
        When chemical restraints are used, the smallest dose necessary should be selected.  Potent chemical restraints include antipsychotic/neuroleptics and benzodiazepines.  Neuroleptics are grossly overutilized in the management of disruptive behavior.  They globally suppress all aspects of cognition, including new learning.(38,39)   They can cause anhedonia, akathisia, irreversible tardive dyskinesia, parkinsonian symptoms, dystonia, neuroleptic malignant syndrome, cholestatic jaundice, depression, apathy, motor dyscoordination, attention deficits, emotional dyscontrol,(4) and memory impairment.(55) 
    Long term utility of neuroleptics is best reserved for patients with true psychotic thought process disorders.  Psychosis which may accompany acute TBI or acute delirium in a demented patient often resolves after only a few days of neuroleptics, and chronic treatment is often not necessary.  A trial taper of antipsychotics is indicated.
    If the goal is the control of delusions and/or hallucinations, Haldol is a superior agent since it is far less sedating at equipotent doses relative to most other antipsychotics.  Haldol has a lower risk of epileptogenic activity and less cardiopulmonary suppression than phenothiazines.  If sedation is the goal, however, then phenothiazines are better than haloperidol as the former class of antipsychotics has less risks for tardive dyskinesia at equipotent sedative doses.  Newer antipsychotics with less extrapyramidal side effects are generally preferred to the older less receptor specific classes of neuroleptics. 
    Benzodiazepines have profound side effects in terms of impairing new learning via the anticholinergic properties of this class.  In addition, benzodiazepines not uncommonly result in rebound mood depression, anxiety disorder, and insomnia.  Though successfully marketed as being different from all other benzodiazepines, clonazepam has similar untoward risks and should be considered contra-indicated in the vast majority of patients.
    Clinicians are encouraged to employ behavioral techniques to treat disinhibited behavior and not benzodiazepines or neuroleptics as they may cause paradoxical disinhibition when the drug eventually is cleared, and sedation when the agent is bioactive.  This is particularly important when these drugs are ordered as "prn" and nursing staff unfamiliar with the patient or overly responsive to behavior which neither threatens the safety of the patient or others.

TREATMENT - NONPHARMACEUTICAL
    If shunt malfunction is suspected, then lumbar puncture can be attempted to produce regression of akinetic mutism or other states of impaired AAI.(163)  Mechanical reversible extrinsic compression of fundamental tracts must be excluded prior to pharmaceutical augmentation of dopaminergic or noradrenergic projections.
    Neuropsychologists and occupational and speech therapists can train patients to use internal cueing systems to enhance AAI.  Patients can be taught to repeatedly ask themselves if they are sufficiently aroused or attentive, and compel themselves to become more so.  Similarly, they can ask themselves if they are initiating sufficient conversation during a social encounter, and subsequently assume corrective action.  Successfully employed compensatory strategies include self-cueing, and self-monitoring.(116) 

TREATMENT - DRUG SUBSTITUTION/TAPER
    A significant number of medications have been identified which adversely affect cognition.  The clinician must initially assess if the pharmaceutical is even necessary.  If the drug is required then assessment without delay must commence to determine if a less cognitively detrimental medication can be substituted to achieve identical efficacy.
    Haloperidol, a dopamine receptor blocking agent, has been known for many years to delay the rate of motor recovery after cortical injuries.(38)  Neuroleptics impair attention, memory, and other aspects of cognition.(44)  Antipsychotics are also proconvulsant,(105) and cause akathisia and predispose to behavioral disinhibition.  Akathisia is a cognitive and motor restlessness that greatly impairs capacity to maximally utilize attention faculties.  It is also extremely distressing to the patient and may result in attempted suicide.(138)  Though usually dose and duration dependent, a single dose of neuroleptics may precipitate irreversible tardive dyskinesia.(108)  In addition, dopamine antagonists may induce fatal neuroleptic malignant syndrome and torsade de pointes ventricular dysrhythmia.(6,40,94,113)  Torsade may not universally be predicted by a prolonged QT interval.(40)  The clinician must simultaneously recall that neuroleptics can enormously enhance quality of life in people with premorbid psychotic thought processing disorders such as schizophrenia. 
    Clonidine and prazosin have been identified as agents which retard motor recovery because of their alpha-adrenergic antagonism,(15) and consideration for substitution for less cognitively offensive antihypertensives such as ACE inhibitors or calcium channel blockers should be pursued. 
    Spasticity is a common sequelae of acquired brain injury.  Phenol or botulinum toxin injections are entirely bereft of cognitive side effects, and control spastic hypertonus quite effectively.  If the principal manifestation of the triad of spasticity is that of mass spasms, then a systemically active agent may be more efficacious as a conservative intervention to ameliorate symptoms.  Dantrolene is felt to be least cognitively offensive, but dose and duration dependent hepatotoxicity may preclude delivery to young patients.  Baclofen in low doses is often well tolerated, especially if restricted to nocturnal dosing.  Valium and other benzodiazepines have significant central nervous system toxicity, and baclofen intrathecal pump implantation should be considered before prescription of Valium is entertained. 
    In the treatment of gastritis, famotidine (Pepcid) may have less cognitive depression than ranitidine (Zantac) which may have less CNS depression than cimetidine (Tagamet).(37)  Carafate and antacids are drugs that have far less CNS effects than H2 receptor blockers.  Proton pump inhibitors are far more desirable with respect to cognitive side effects, and newer agents have less drug-drug interactions.
    In the treatment of mood depression, potent anticholinergic medications can impair memory and be sedating, contributing to confusion.  Neuroleptics, benzodiazepines, and some antidepressants have potent anticholinergic effects.  Serotonergic, dopaminergic, and MAO inhibitor antidepressants are alternatives to treat mood depression.  Trazodone may cause daytime sedation,(4) and substitution or earlier ingestion may be required.   Trazodone is relatively contra-indicated in males given the risks for priapism and emergent surgical decompression.
    Benzodiazepines are sedating and impair AAI as well as memory.  Chronic use of benzodiazepines results in aggressiveness, anxiety, mood depression, and additional cognitive deficits.  If anxiety is the indication for treatment with benzodiazepines, then serotonergic and GABA-ergic medications are more desirable alternatives.
    Buspirone (BuSpar) is a serotonin 1A receptor modulator.  It does not impair memory,(74) unlike benzodiazepines.  Also unlike benzodiazepines, it does not cause dependence or withdrawal symptoms.(77)  Potential uncommon side effects include dizziness, nausea, headache, and nervousness.  Dosing is 5 mg po TID - 20 mg TID. 
    For treatment of nausea, the antipsychotic derived metoclopramide (Reglan) and Compazine can suppress cognition, and should be changed to trimethobenzamide (Tigan), Zofran, Anzemet, or other less offensive medications.  Not only is Tigan free of sedation, but it is unaccompanied by risks to cause  irreversible tardive dyskinesia.  Reglan is a proconvulsant agent.(46)  It can cause irreversible tardive dyskinesia after a single dose.(100)  The incidence of adverse extrapyramidal reactions from Reglan is as high as 1 in 500, and the spectrum encompasses not just irreversible tardive dyskinesia, but also orofacial dyskinesias, akathisia, chorea, tremor, dystonia, and parkinsonism.(100)  Involvement of the diaphragmatic respiratory and buccolingual deglutition muscles may cause life threatening dyspnea and dysphagia, necessitating gastrostomy tube placement for nutritional support.(159)  This is truly regrettable if the intracranial pathology improves, allowing a 20 year old to return to independent living with the iatrogenic condition of irreversible tardive dyskinesia, precluding optimal socialization and quality of life. 
    For analgesia, opioid narcotics can suppress cognition, and should be second options to Tylenol, NSAID's, and ice, heat, or TENS modalities.
    Antihypertensive agents which are sedating and otherwise cognitively offensive include clonidine,(55) alpha-methyldopa,(109) and lipophilic beta blockers.(89)  Reserpine is proconvulsant.(46)  More desirable alternatives include hydrophilic beta blockers, ACE inhibitors,(19) calcium channel blockers, and thiazide diuretics.(19)  Beta blockers have particular utility to selectively extinguish aggressive disinhibited behavior. 
    Lipophilic beta blockers cross the blood brain barrier and can induce sedation, depression, insomnia, visual illusions, spatial memory compromise, hallucinations, psychosis, and perceptual motor deficits.(89)  Hydrophilic agents do not cross the blood brain barrier, and are the indicated agents if the sole goal of delivering the beta blockers is control of systemic cardiovascular function.  The most highly lipophilic beta blocker is propranolol.  Those with moderate lipophilicity include timolol, metoprolol, pindolol, and labetolol.  Those which are most hydrophilic include nadolol, acebutolol, and atenolol.  Acebutolol and atenolol are also cardioselective(10) with decreased risk of exacerbating bronchospasm at lower doses.
    Restoration of impaired sleep-wake cycles may be achieved safely with melatonin.  Foods with high contents of tryptophan such as milk and turkey may promote sleep.  Avoidance of daytime naps and abstaining from coffee, tea, and other caffeine containing foods close to bedtime may also promote faster falling asleep, avoidance of nocturnal wakenings, and restorative sleep quality with refreshed awakening.  Sleeping in a cool room decreases core body temperatures and may promote sleep by increasing endogenous melatonin concentrations.(145) 
    Melatonin 0.3-75 mg po qhs may promote high quality sleep, especially in the elderly, a population in whom endogenous melatonin secretion is often diminished.(145)  Onset of effect may be delayed 1-3 days, but melatonin may increase daytime alertness, reduce sleep fragmentation, diminish time to sleep onset, decrease nocturnal awakenings, without changing REM quality sleep, inducing morning hangovers, causing mood depression, or next day sedation.(145)  As an endogenous substance, melatonin is extremely safe.  The FDA chose to classify melatonin as a nutritive/dietary supplement, and so products are poorly regulated with unidentifiable impurities in products from some manufacturers.(145)  Patients with major allergies or autoimmune disorders may also wish to abstain from melatonin as it may stimulate the immune system.(145)
    Trazodone is an excellent second option in females, but should not be given to males in light of well documented risks of iatrogenic, idiopathic priapism which may require emergent surgical reduction with accompanying risks for irreversible impotence.  Reports indicate incidences ranging from 1 in 23,000 male users(4) to 1 in 6000, with abrupt manifestation within 3 days -18 months of use.(61)  Trazodone (Desyrel) dosing is 75 mg po qd to 600 mg po qd.(55)  Trazodone requires further investigation, as transient delay in motor recovery occurred in rats with use of this agent.(30)  Chloral hydrate, 250-1500 mg qhs is another choice, but should be used with caution in the patient with hepatic or renal compromise. Short term use of an ultra-short acting benzodiazepine such as Restoril may re-establish sleep-wake cycles, as a desirable third line agent in an older patient with impaired drug clearance.  To promote sleep in the cognitively impaired, neuroleptics should be the last agents considered.  Neuroleptics are well documented as impairing neurologic recovery after intracranial events.
    The clinician must reassess the indication for anticonvulsants.  If such drugs are necessary, more sedating agents should be tapered after therapeutic levels of less offensive agents are achieved.   A taper of phenobarbitol faster than 15 mg a month may precipitate withdrawal siezures.
    The clinician should assess if the anticonvulsant is still necessary or if it can be projected to be tapered in 1-3 months while the patient is observed in the hospital.  Maximal cognition and antiseizure efficacy can be achieved if monotherapy is pursued instead of cumulative toxicity of polytherapy.(158)  Clinicians should strive to prescribe dosing such that the lowest level in the therapeutic window is achieved, as anticonvulsants impair speed of thought processing, attention, and memory more extensively at higher therapeutic window serum levels relative to lower serum levels.(103,110,131) These effects may be more pronounced after initiation of drug therapy(110) at the time when patients are attempting to achieve the maximal benefit from rehabilitation therapies.  Many patients, however, become sedated when anticonvulsants just reach the low end of the "therapeutic window."  If antiseizure efficacy is appreciated with negligible cognitive side effects despite "subtherapeutic" serum levels, then clinicians should seek informed consent to maintain patients "subtherapeutic" yet seizure free. 
    Patients are often placed on Dilantin or phenobarbital in the acute care hospitals to take advantage of their capacity for rapid I.V. loading.  However, phenobarbital has been conclusively proven to be amongst the most cognitively offensive anticonvulsants.  Dilantin impairs arousal, concentration, memory, and speed of mental processing.(35,110)  In addition, chronic delivery of Dilantin predisposes to cerebellar degeneration, sensory peripheral neuropathy,(35) and gingival hyperplasia with consequent dental caries.   Dilantin induced impairment in folate transport and biologic utilization predisposes to mood depression and macrocytic anemia.(35)  In patients receiving Dilantin, carbamazepine should be added and Dilantin tapered when the carbamazepine is therapeutic, as Dilantin has been shown to adversely affect cognition more than carbamazepine.(140,143,152)  If treatment with Dilantin cannot be substituted for alternative agents, then the clinician should supplement the diet with folate to avoid deficiency effects on cognition and red cell synthesis.  Also, Dilantin should be given in one large evening oral dose up to 500 mg to facilitate sleep and limit daytime sedation.  Some individuals may also find valproate to be less sedating than phenytoin.  An occasional individual may exhibit paradoxically improved cognition on Dilantin relative to carbamazepine. 

MEDICATION TRIALS - GENERAL CONCEPTS
    Benefits of early treatment with psychostimulants to enhance AAI should be viewed favorably as the same agents may mediate motor and speech recovery.  In addition, these agents may successfully prevent disinhibited behavior from manifesting, presumably by enhancing attention quality as the patient ascends from lower levels of consciousness.  AAI as well as disinhibited behavior may be responsive to amantadine.(64)
    If the aforementioned more conservative interventions are suboptimally effective in enhancing suboptimal cognition, then active drug trials are indicated.  Documented consent for these trials should be sought.  Though miraculous clinical improvement often occurs, the FDA has not yet approved many of these drugs for treatment of deficits in AAI.  Documentation must include indication for drug trial, specific short and long term target goals, and manner of monitoring for side effects.  A number of additional general considerations must be recognized;
    If the clinician has the luxury of waiting an entire week after dose changes, this should be embraced as it may more clearly support a direct cause effect relationship in improving AAI.  If a limited inpatient stay is expected and rapid dosing to maximize AAI does precipitate psychosis, then the clinician should slowly taper the stimulants.  Antidopaminergic neuroleptics should be prescribed only as a last resort.  Patients with premorbid histories of psychotic thought disorders may require more careful monitoring.
    Patients must be monitored for the effects of excessive psychostimulation, including perseveration, psychosis, and increased inaccuracies as the speed of processing and the error frequency of data manipulation may occur.
    Inefficacy or intolerance of a medication does not preclude similar response to other psychostimulants and patients deserve multiple trials at ascending dosing.  Protriptyline may enhance AAI despite inefficacy of another noradrenergic agent, methylphenidate.(114)  Bromocriptine may effectively treat akinetic mutism refractory to high doses of methylphenidate and Sinemet.(102)  Efficacy of Sinemet to dramatically enhance motor function in locked-in-syndrome despite an unsuccessful trial with the dopaminergic bromocriptine has been reported.(50)  These reports should be recognized as a reflection of the infancy of medical knowledge of synaptic neurophysiology.  It has been suggested that only 5% of central nervous system neurotransmitters have been identified.(   )  This also describes postsynaptic receptor subclassifications and receptor interactions.  As such, it is entirely unsurprising that agents have numerous as yet undefined bioactive properties despite classical oversimplified classification as dopaminergics, noradrenergics, serotonergics,...  This schema, however, is a valuable foundation apon which to expand as knowledge accumulates.  Investigation of dopamine 1,2,3,.. receptors, alpha or beta adrenergic receptors, and muscarinic and nicotinic receptors is invaluable to direct pharmaceutical engineering of specific pre- and post-synaptic agonists and antagonists.
    Psychostimulants may cause paradoxical sedation.  However, if cognition abruptly declines, then a delirium workup must be emergently repeated, as syndrome of inappropriate ADH secretion, meningitis, appendicitis, urinary tract infection, or other potentially life threatening medical condition must be excluded prior to attribution of the decline to the psychostimulant.  This may save the patient's life as well as avoid documentation of intolerance to a particular psychostimulant.  Although numerous drug options exist, the selection is finite, and recording an adverse drug reaction may preclude delivery of that agent for the entirety of the patient's life.
    Because inpatient lengths of stay are markedly abbreviated relative to prior years, aggressive psychostimulant drug trials are often indicated before a baseline low level of cognition has been established.  In addition, psychostimulants may facilitate neurologic recovery of cognition.
    Excessive psychostimulation may result in perseveration and/or disinhibition.(116) 
    Patients often spontaneously improve over time.  As such, drugs should slowly be tapered after a month or two of use to assess if administration is still necessary.  Worsening of cognition during a trial taper is an indication to reinstitute drug delivery. 
    Add only one new medication at a time.  Otherwise, improvements or side effects cannot be attributable to any single drug.  Paradoxical impairments in cognition with psychostimulants may occur.  At doses of bromocriptine presynaptic activity exceeds postsynaptic activity, and antidopaminergic activity prevails.(  )
    Tachycardia with resultant increased risk for myocardial ischemia or fatal arrhythmia may accompany treatment with several  psychostimulants, in particular noradrenergics agents.  Atenolol or nadolol are cardioselective with low lipophilicity and accompanying low risk to enter the brain.  These beta blockers may be delivered with psychostimulants for their cardioprotective properties.  Beta blockers also exhibit prophylactic efficacy to diminish cardiac irritability from potential proarrhythmic psychostimulants. 
    Anorexia is a common side effect of psychostimulants.  Treatment with Megace or other appetite stimulants may afford tolerability of drugs to enhance AAI.  Similarly, nausea may accompany prescription of psychostimulants, and use of trimethobenzamide (Tigan), Kytrel, Zofran, Anzemet, or other agents may be dosed prophylactically.  Alternatively, if the clinician has the luxury of slow escalation in dosing, these transient side effects may be avoided.
    Chorea and tics may occur at higher doses, as may perseveration.
    Allow days to a week for medication dose increases to effect improvement.
    Nurses and therapists often spend more time with patients than do physicians, and they can give a more extensive input with respect to response to pharmaceutical agents and dose levels.  The final test whether or not the drug is effective can be conducted by the clinician tapering the drug and asking the therapists and nurses if they note any change.  Therapists assume the role of being blind to knowledge of medication changes, and their observations may become more objective.  At an unpredictable dose, cognitive improvement fails to continue with serially elevated dose, but dose dependent toxicity continues to accumulate.  In addition, excessive delivery of psychostimulants may engender cognitive toxicity, manifested as hyperattentiveness to environmental distractors, perseveration, psychosis, and disinhibited behavior.  The clinician must assume a leadership role to educate the team that the drug is not "bad," and maintenance at a slightly lower level may be beneficial to the patient.  Neuropsychological testing may be helpful before and during drug trials to provide objective test data to guide ongoing treatment.
    A patient who may have failed one psychostimulant may be very responsive to one of the same or different class, not unlike the efficacy of a different NSAID in relieving the pain of muscle strains when minimally structurally different compounds have proven ineffective.  The optimal course of action is a clinical trial.
    Drug trials are individualized to the patient's medical history and current status.  Seizure disorder, neurogenic bladder, hepato-renal dysfunction, coronary artery atherosclerosis, and other aspects of systemic medical status are critically assessed in terms of drug side effect profiles.  Dosing must also be considered after assessment of bioavailability, drug clearance, pharmacokinetics, and pharmacodynamics. 
    Drugs with high anticholinergic properties may induce urinary retention.  This is especially a concern in patients with prostatic enlargement anatomic barrier to voiding as well as in patients with pathophysiologic external sphincter spasticity.  Co-treatment with Urecholine, Baclofen, and other interventions may be required to facilitate bladder contractility to counter urinary retention related to noradrenergic mediated increased smooth muscle internal sphincter tone.
    Orthostasis may occur as a result of dopaminergic effects on arterial vasocontractility.  Cotreatment with Proamitine or Flurinef may be required if refractory to thigh high stockings, corsets, positioning, isometrics, and other non-pharmacologic pursuits.
    Side effects which occur with initial rapid increase titration in dosing may remit when the dose of the agent is lowered.  Subsequent retrial after a one to two week intake of a lower dose may enhance tolerability.
    Patients with seizure disorders or significant risks for development of post-traumatic seizures may preferentially be treated with bromocriptine,(18,117) doxepin,(21) valproic acid, and carbamazepine, as these drugs have anticonvulsant properties.  Amantadine has been described as being proconvulsant(25,43) as well as anticonvulsant.(   )  Ritalin may be anticonvulsant(17) or have no effect on seizure threshhold.(17,43)  Sinemet may have weak proconvulsant properties.(    )  Amitriptyline, desipramine, and protriptyline are tricyclic antidepressants which are proconvulsant.(20)  Amitriptyline may be less so than other tricyclics.(4,54)  Secondary amines may be safer antidepressants than tertiary amines.(61)  Bupropion, at doses greater than 450 mg qd, increases the risk for seizures.(11)  Fluoxetine and MAOI's do not markedly increase seizure risk.(43)  Concomitant dosing with anticonvulsants for posttraumatic seizure prophylaxis may reassure the clinician that the patient is at lower risk for seizures.  Use of lower doses of potentially proconvulsant psychostimulants should be pursued, if possible.  Patients must be educated to fully abstain from even small amounts of alcohol to avoid lowering the seizure threshhold. 
    Less severely brain injured patients exhibit improved memory, attention, and initiation with psychostimulants, and those with severe injuries respond with improved levels of arousal. 
    Excessive dosing may result in perseveration,(34) aggression,(34) emotional lability,(34) psychosis, auditory hallucinations, or agitation.  Choreaform movements and tics may result from psychostimulants.(34)   If this occurs, then dosing should be minimally reduced such that maximal benefit is achieved.  Stimulant induced irreversible Gilles de la Tourette's syndrome may occur in predisposed individuals,(68) and these agents are relatively contra-indicated in patients with personal or family histories of tics.  Side effects relative to dosing are individually variable.  Ritalin greater than 10 mg a day may decrease therapy participation in one individual,(114) but may be suboptimal to effect psychostimulant efficacy in a second individual who might maximally benefit from 40 mg a day.
    Patients may exhibit variable patterns of response to medications.  Some individuals may slowly and progressively respond to greater and greater doses.  Other patients may remain unresponsive until a modest dose increase suddenly precipitates a marked positive response. 
    Research has not advanced enough to be able to predict which head injured patients should be treated with which psychostimulants, and symptomatic considerations must guide prescriptions, pending controlled trials.(2) 

MEDICATION TRIALS - SPECIFIC AGENTS
    Drugs which improve AAI can be classified into major groups, including noradrenergics, dopaminergics, serotoninergics.  Some medication classes with variable neurotransmitter agonism and antagonism include tricyclic antidepressants (TCA's), amphetamines, antiParkinsonian agents, selective serotonin reuptake inhibitor antidepressants (SSRI's), and monamine oxidase inhibitors (MAOI's).  Paradoxical sedation may occur with any agent, but inopportune onset is rarest with noradrenergics, occasional with dopaminergics, and not uncommon with serotonergics, especially in the elderly.

MEDICATIONS - NORADRENERGICS
    Noradrenergic agents such as amphetamine facilitate AAI via enhancing presynaptic release(15) of endogenous stores and decreasing presynaptic reuptake(34) of dopamine and norepinephrine catecholamines.  Dextroamphetamine, methylphenidate, desipramine, protriptyline, and pemoline are therapeutic options.
    Noradrenergics not uncommonly cause tachycardia and other potentially more malignant dysrhythmias.  The clinician should not be reluctant to co-prescribe a lipophobic/hydrophilic beta blocker such as nadolol or atenolol to attenuate cardiac responsiveness and facilitate rhythm stabilization.  This may allow escalation in dosing with informed consent beyond manufacturer recommendations.
    If insomnia occurs, the clinician should consider iatrogenic etiologies, and perform a trial taper of the noontime dose while monitoring for diminished AAI coincident with the intervention. 
    Advantages of desipramine and protriptyline over dextroamphetamine and methylphenidate include a longer duration of action as well as lower probabilities of anorexia, insomnia, on-off sudden inefficacy, abuse, or dependency.(7)  In addition, serum levels can be monitored for protriptyline and other antidepressants.  This is valuable in that patients with impaired hepatorenal function may accumulate drug with toxic effects if dosing is not adjusted in accord with serum levels.  Similarly, many medications speed hepatic drug clearance via biodegradative enzyme systems such as cytochrome P-450, and so doses which may otherwise be therapeutic will exhibit unexpected inefficacy if dosing is not increased in correlation with plasma levels.

    Dextroamphetamine (Dexedrine) is felt to directly enhance endogenous presynaptic release of dopamine(46,148) and norepinephrine,(109) decrease presynaptic catecholamine reuptake,(109) and reduce catecholamine biodegradation.(52)  Dextroamphetamine is a weak monamine oxidase (MAO) inhibitor.(109)  It is a potent psychostimulant.(65,79,119)  Amphetamine promotes recovery of motor function after cortical, internal capsule, and brainstem CVA,(3,38,72,134) and also has been used to enhance language function.(30)  
    Amphetamines have anticonvulsant properties.(46) 
    Dexedrine has more dependency, risk of withdrawal craving, and psychostimulant potency(44) relative to  Ritalin.  As such, it is not the optimal agent in patients with premorbid histories of substance abuse.  It may cause paranoid psychosis.(46)  As an alpha agonist(42) Dexedrine may promote internal sphincter contraction and urinary retention as well as arrhythmias, hypertension, and secondary bradycardia.  Post-void residuals, blood pressure, and heart rate and rhythm should be monitored after starting Dexedrine.  Anorexia and insomnia are additional potential side-effects(52) which should be monitored.
    Concomitant dosing of amphetamine with tricyclic antidepressants may block amphetamine induced release of dopamine,(148) a considerable potential concern in the optimal treatment of akinetic mutism. 
    Initial dosing is 5 mg po q7AM, advanced every 3-5 days to 5 mg po q7AM, 5 mg po q12PM.  Time to peak effect is 2-4 hours, and half-life is 7-10 hours.  Dose range is 10-60 mg qd.(61)  Tabs are available in 5 and 10 mg sizes. 
    Time released once a day spansules are available in 10 and 15 mg formulations, but continuous delivery and potential secondary receptor downregulation and clinical inefficacy remains suboptimally investigated to fully endorse long acting preparations as psychostimulants. 
    Additional amphetamine products include Adderall.
    Benzphetamine (Didrex) is a sympathomimetic amine available in 50 mg tabs with maximal dosing of 150 mg qd.

    Methylphenidate (Concerta, Metadate, Methylin, Ritalin), has a similar monoamine liberating mechanism as Dexedrine, except that Ritalin has also been reported to increase catacholamine degredation.(52)  Other sources report that methylphenidate weakly inhibits MAO.(109)  Ritalin is a nonselective monoamine reuptake inhibitor,(46) and acts at both the reticular activating system as well as in the cerebral cortex.(35)  It potentiates both noradrenergic as well as dopaminergic neurotransmitter activity.(133)  Ritalin induces the presynaptic release and inhibits presynaptic reuptake of catecholamines, particularly dopamine.(149)  Ill-defined serotonergic neurotransmission modulation is affected by methylphenidate.(91) 
    Delivery within 4 days(35) to several months after TBI effects enhanced rate of improved attention relative to the rate identified with natural recovery.(35)  Ritalin is well documented as a potent psychostimulant.(35,113,123,149,164)  It improves arousal and significantly speeds the rate of thought processing, but may be less helpful to improve sustained attention, resistance to distractions, and motor speed.(133)  Others, however, have found marked improvement in attention as well as motor performance.(123)  It has been successfully used in the treatment of coma secondary to TBI,(149) unevacuated subdual hematoma,(149) encephalopathy, and glutethimide intoxication.(164)
    Ritalin also has been described as enhancing memory(85), improving language, and selectively extinguishing aggressive disinhibition.(137)  It also exhibits analgesic properties(91) and capacity to rapidly ameliorate mood depression.(133) 
    As with Dexedrine, methylphenidate may cause hypertension, tachycardia, anorexia, insomnia, hyperarousal, and psychosis, and patients should be monitored for these sequelae during the initial days and weeks of treatment.  Despite the hemodynamic and increased cardiac oxygen consumption, patients with atherosclerosis tolerate methylphenidate well without evidence of ischemia, pulmonary edema, or arrhythmia.(149)  Methylphenidate has been described as being proconvulsant,(46) but other authors suggest that it may have anticonvulsant properties or neither protect nor prevent seizures.(17,43)  Excessively abrupt taper can increase agitation.  Side effects of Ritalin may include motor restlessness.(31)  Tachycardia(35) may result from use of this agent, suggesting that alternative psychostimulants may be more preferable first choices in patients with significant coronary atherosclerosis.
    Food enhances absorption.(42)  Onset of effect is usually within 15-60 minutes, with maximum effect in 2-4 hours and full elimination in most patients in 6-8 hours.  A delay in onset may range from 24 hours(149) to several days, occurring only after an appreciable dose is delivered.  The rapid onset of effect is one of the reasons why this agent is frequently chosen amongst the earliest agents delivered in trials to enhance AAI.  Time to peak effect is 1-2 hours, and half-life is 2-4 hours.(52)  Initial dose 2.5 to 10(149) mg po q8AM and q12PM.  Afternoon dosing may impair sleep.  The dose can be advanced by 2.5mg qd(35) daily or every two(149) to three days to a maximum dose of 45 mg q8AM, 45 mg po q12PM.(61)  One clinician, however, identified no side effects with dosing of 50 mg IM every half hour with 500 mg over one day and 1550 mg over seven days(164) in his successful efforts to awaken a 45 year old patient from coma.  Approximately 95% of the drug is eliminated within 72 hours.(123)  Tabs are available as 5, 10, 20 mg sizes.  A sustained release 20 mg formulation is available for q8AM delivery to maintain arousal once awakening or vegetative reversal has been successfully effected. 
    If ineffective to enhance AAI, the drug should be tapered.  
    Dexmethylphenidate (Metadate) is available as 10mg, 20 mg, and 30 mg tabs with a maximum suggested dose of 60 mg/day. It remains to be fully investigated for utility for coma awakening and reversal of the vegetative state.
   
    Desipramine (Norpramin), a secondary amine tricyclic antidepressant, which inhibits presynaptic noradrenergic presynaptic reuptake and decreases noradrenergic biodegredation.(7)  It enhances motor recovery in hemiparesis,(30) improves memory,(7) and is also efficacious as a psychostimulant.(15,58)   Delivery of 75 mg improved ability to verbalize within four days of ingestion in a patient nineteen  months post-TBI.(15) 
    As with other tricyclic antidepressants, these agents have been reported to block amphetamine induced release of DA,(148) a considerable potential concern in the optimal management of akinetic mutism and other states of impaired AAI. 
    Desipramine has significant theoretical benefits over protriptyline, including mildly more noradrenergic activity than protriptyline, 800% less anticholinergic properties, and 700% less antihistamine properties.  However, desipramine has mildly less dopaminergic and serotonergic properties than protriptyline. 
    Initial dose is 10 mg qd and is increased every 1-5 days to 50 mg after one week.(15) 

    Protriptyline (Vivactil), a secondary amine tricyclic antidepressant, has exhibited efficacy to enhance arousal in narcolepsy,(95) and also exhibits significant potency in TBI,(114) anoxic brain injury,(114) and stroke.  It may be effective when methylphenidate, levodopa, amantadine, bromocriptine, nortriptyline, and fluoxetine are incompletely effective psychostimulants.(114) 
    Protriptyline is slightly less noradrenergic than desipramine with considerably more anticholinergic and antihistaminergic activity.  However, it does have a mildly greater dopaminergic and serotonergic effect than desipramine. 
    The significant anticholinergic properties of protriptyline warrants monitoring for urinary retention and tachycardia via vagal inhibition.  As with all tricyclics, the seizure threshold may be lowered.  This does not warrant prescription of anticonvulsants unless new tonic-clonic or petit mal seizure activity is identified clinically or by EEG.  Alternatively, the clinician may wish to reduce dosing if seizure activity occurs as seizures are expected to occur as a dose related effect.  Concomitant prescription of psychostimulants with anticonvulsant properties may be considered. 
    Protriptyline may block dopamine postsynaptic receptors.(     ) Given this fact in addition to its proconvulsant properties, this agent may not be the optimal first adrenergic agent chosen to enhance AAI.
    It may take 6-14 days(114) for psychostimulant efficacy to develop.
    Initial dose is 10 mg po qhs, and dose is increased every 3-5 days to a maximum of 30 mg qhs.  Doses higher than 40 mg have been reported as increasing motor restlessness and irritability.(114)  At higher doses stimulant efficacy is not enhanced, and side effects and antidepressant properties manifest within 3-4 weeks.(114)   Protriptyline levels should be assessed, as co-delivered drugs which enhance biometabolism of protriptyline will decrease serum levels with accompanying decreased delivery to the brain and suboptimal psychostimulant efficacy. 

    Atomoxetine (Strattera) is a fairly newly released selective norepinephrine reuptake inhibitor available in 10 mg, 18 mg, 25 mg, 40 mg, and 60 mg tabs with a maximum recommended dosage of 100 mg qd.  It may demonstrate itself to have considerable efficacy for coma awakening and reversal of the vegetative state. 

    Ephedrine is a noradrenergic agonist which acts as a direct and indirect sympathomimetic.(165)  
Ephedrine started at 25 mg TID and increased over 5 days to 50 mg q4 hours with concomitant dosing with bromocriptine 100 mg/day resulted in ascension of a patient from akinetic mutism secondary to hydrocephalus.(165)  The clinician safely increased the dose to 525 mg/day to take advantage of arousing projections from the brainstem which ascend adjacent to the third ventricle.(165) 

    Phentermine (Adipex, Ionamin) is a sympathomimetic amine available in 37.5 mg scored tabs, but primary pulmonary hypertension and valvular heart disease may occur with its use such that it is clearly a tertiary option.  It remains to be fully investigated for utility for coma awakening and reversal of the vegetative state. 

    Phendimetrazine (Bontril) is a sympathomimetic amine available in 35 mg scored tabs with maximum recommended daily dosing of 210 mg a day. It remains to be fully investigated for utility for coma awakening and reversal of the vegetative state.

    Sibutramine (Meridia) is a dopamine, norepinephrine, and serotonin reuptake inhibitor available in 5 mg, 10 mg, and 15 mg tabs with maximum recommended dose of 15 mg qd.  It remains to be fully investigated for utility for coma awakening and reversal of the vegetative state.

    Diethylpropion (Tenuate) is a sympathomimetic amine available in 25 mg tabs with maximum recommended dosing of 75 mg qd.  It remains to be fully investigated for utility for coma awakening and reversal of the vegetative state.

    Cylert (Pemoline) is felt to enhance the release of dopamine and reduce catecholamine turnover.(52)  It is associated with life threatening hepatic failure and is a final option in terms of medication trials.
    Time to peak onset is two to three weeks.(34)  Half life is twelve hours.(52) 
    It is a less potent psychostimulant and sympathomimetic than Dexedrine or Ritalin,(34) and so it does not have the same heart rate and blood pressure risks, a benefit in patients with coronary artery disease or hypertension.  Cylert has potential hepatotoxicity, and is relatively contra-indicated in patients with histories or baseline liver testing suggestive of liver pathology.  Serial liver testing should be followed.  Nutritional intake should also be monitored, as anorexia may also follow its use.
    Cylert is available in 18.75, 37.5, and 75 mg tabs.  Starting dose is 18.75 mg tab po q8AM.  Dose should be changed at a rate of one 18.75 mg tab q3-7 days.  Maximum dose is 112.5 mg po q8AM,(114) but doses greater than 200 mg a day have been used in the treatment of narcolepsy.(160) 


MEDICATIONS - DOPAMINERGICS
    Dopaminergics enhance AAI by stimulating dopamine (DA) dependent pathways via several different mechanisms.  Dopamine synthesis may be enhanced, dopamine presynaptic release and degradation may be modulated, and different dopamine receptors can be stimulated.  Additionally, DA is converted by noradrenergic neurons to norepinephrine,(15) so delivery of exogenous DA may mediate psychostimulation via enhanced noradrenergic bioactivity.  
    Regions of the brain that are rich in DA receptors include the basal ganglia nucleus accumbens, olfactory tubercle, ventral tegmental area, retina, hypothalamus, central nucleus of the amygdala, median eminence, and the neocortical and prefrontal cortices.(96)  It is felt that the long projections between the substantia nigra and the ventral tegmental area to the striatum (nigrostriatal), limbic (mesolimbic), and frontal cortex (mesocortical) structures mediates at least a component of anhedonia(96) as well as impaired attention and initiation.(29)  Additional central tracts include the mesopiriform, tuberoinfundibular, and tuberohypophyseal paths.(29)
    At least five unique dopamine receptors have thus far been identified, and subtypes also exist.(162) Pharmaceuticals exhibit variable selectivity for different sites.  DA-1, DA-3, and DA-4 have been identified in the mesolimbic and mesocortical systems, and DA-2 has been found in the nigrostriatal and tuberoinfundibular tracts.(96)  DA-1 receptors have been identified in the internal globus pallidus and substantia nigra whereas DA-2 receptors are located in the external globus pallidus.(162)  DA-1 and DA-5 are mediated by activation of adenylate cyclase, and DA-2, DA-3, and DA-4 inhibit this enzyme.(96)  It may have been premature to classify DA receptors relative to adenylate cyclase activity as a DA-1 receptor subtype might be linked to another transduction mechanism.(162)  Efficacy and side effects of different medications are linked to receptor site agonism and antagonism. 
    DA-2 and DA-3 agonists may induce psychosis,(162) and so selectivity of agents is to be valued.
    Ritalin and Dexedrine are indirect dopamine agonists, as they enhance endogenous stored DA release, a function dependent on the presynaptic neuron to synthesize DA.  Direct receptor agonists have the advantage that they stimulate the postsynaptic membrane, even if the presynaptic neuron exhibits anatomic disruption or biochemical subcellular dysfunctional enzymatic conversion of L-dopa to DA.  Conditions such as large strokes or extensive traumatic injury, therefore, may more readily respond to receptor agonists.(64)  However, receptor agonists, in contrast to L-dopa of Sinemet, do not increase DA levels, so they do not undergo bioconversion to norepinephrine to concomitantly facilitate function of the noradrenergic system.  While nigrostriatal DA-2 agonism has been identified as a principal receptor mediating symptomatic improvement in Parkinson's Disease,(96) the most potent dopaminergic receptor mediator of psychostimulation remains undefined.  An additional consideration as alluded to above is that different medications stimulate different DA receptors and so postsynaptic agonists may not optimally address the spectrum of receptor deficits.
    DA agonism has been found to improve memory(114) and speech, while DA antagonism at DA-2 (e.g. haloperidol) and DA-4 (e.g. clozapine) have been means by which psychosis is extinguished.  Antagonistic potency at DA-2, however, is also associated with likelihood of development of extrapyramidal side effects.(96)  In addition DA antagonists may retard motor recovery after stroke or brain injury.
    Dopaminergics must be prescribed with caution in patients with premorbid history of schizophrenia or other psychotic thought processing disorders.(86)  First generation neuroleptics such as haloperidol and thioridazine are felt to exhibit efficacy via DA-2 receptor antagonism whereas D-4 blockade may mediate clozapine's antipsychotic potency.  It may be wisest to deliver dopaminergics in such patients only to awaken such patients from coma and states of akinetic mutism, and then taper the drug once consciousness has been obtained with subsequent monitoring for psychosis. 
    Dopaminergics commonly induce nausea during the initial days of delivery.  The clinician may consider prophylaxis with several days of Tigan, Anzemet, Zofran, or Kitrel, but not Reglan or Compazine or other dopaminergic antagonist. 
    Abrupt withdrawal of dopaminergics has been described as potentially precipitating neuroleptic malignant syndrome, a potentially fatal condition characterized by hyperthermia, rigidity, and delirium.  As such, a gradual taper of all dopaminergic agents should be performed if agents do not exhibit efficacy to treat coma awakening and reversal of the vegetative state.  
    Dopaminergic agents which can be prescribed to enhance AAI include amantadine, carbidopa/levodopa, bromocriptine, selegiline, and Mirapex. 

    Bromocriptine (Parlodel), 2-bromo-alpha-ergocryptine methanesulfonate, is a direct receptor agonist at DA-2,3,4, and 5 receptors and mild antagonist at DA-1.(162)  Bromocriptine also exhibits some agonism at alpha adrenergic, and serotonin receptors.(141)  It has demonstrated considerable psychostimulant efficacy,(33,70,90,102,112,129,144) particularly in akinetic mutism(33,102,112) with abrupt onset of effect usually within 1-7 days after a dose of 25 mg BID or higher is achieved.  Hemispatial neglect may also improve.(33,120,129)  Bromocriptine is also efficacious in post-traumatic parkinsonism,(33) akathisia,(139) and aphasia.   It has not yet been the subject of substantial investigation in terms of potential for motor restoration of hemiplegia.
    Presynaptic damage to the anterior medial forebrain bundles after separation of the nigrostriatal tract may suggest that biosynthetic capacity is compromised, and direct dopamine postsynaptic agonists may be more efficacious than Sinemet or methylphenidate presynaptic agonists.(102)  Conversely, it has been suggested that damage to the anterior cingulate gyri may indicate lessened efficacy of bromocriptine.(102)  The parietal cortex is felt to be devoid of dopaminergic receptors.(141) 
     The mesolimbic and nigrostriatal regions possess presynaptic autoreceptors which function to reduce presynaptic DA release.(151)  At doses greater than 7.5-10 mg/day, postsynaptic DA agonist effects outweigh presynaptic autoreceptor effects,(151) suggesting potential greater psychostimulant efficacy at higher doses and alerting the clinician to the importance of not documenting a failed trial if the patient does not exhibit improved AAI in terms of coma awakening and reversal of the vegetative state at lower bromocriptine doses.
    Bromocriptine has strong(46) anticonvulsant(18,117) properties.  This may be attributable to DA-2 postsynaptic receptor stimulation(46) or to the absence of DA-1 agonism.(46)  Bromocriptine was efficacious in the treatment of akinetic mutism in a patient in whom Sinemet 25/250 QID and methylphenidate 40 mg qd was without significant effect.(102)  With ephedrine, bromocriptine promoted ascension from akinetic mutism in a patient with hydrocephalus.(165)  Bromocriptine also has antidepressant properties(151) and is safe in pregnancy.
    Unlike pramipexole, bromocriptine lacks cytoprotective antioxidant properties.(141) 
    Potential dose dependant side effects requiring monitoring include hallucinations, delusions, headache, dizziness, nausea, dyskinesias, paradoxical sedation, and gastric stasis(33) with increased risks for reflux and aspiration.  Side effects are greater in the elderly, at initial dosing, and with doses greater than 20 mg/day.(151)  Orthostatic hypotension may also occur, and patient blood pressure must be monitored, as cerebral perfusion autoregulation is often dyshomeostatic after CVA and TBI.  Side effects may be less prominent when bromocriptine is ingested with food.(151)  Presyncope and hepatitis may also occur.(33)  It has been suggested that bromocriptine may paradoxically lower the seizure threshold.(50)  Bromocriptine is an ergot derivative and so chronic use may cause pulmonary infiltrates, pleural effusion, or pleural thickening, findings of which may remit towards normal with drug discontinuation.(33)  The percentage of patients who develop these complications is unknown, and a patient receiving bromocriptine for at least 2.5 years has been reported to be free of complications or tolerance.(102)  Dysesthesias(33) and pericardial effusion has also been reported.  Although dystonia has been reported,(33)  bromocriptine may also be used to reverse dystonia.
    Metabolism is hepatic, and so dosing may be decreased in hepatic failure and potentially increased more quickly in patients who are receiving medications which speed hepatic metabolism.
    Half-life of bromocriptine is 7 hours.(33)  Dosing is 2.5 mg po q8AM, q12 PM and increased q3-5 days to a maximum dose of  110 mg BID.(151)  One clinician reported increasing bromocriptine safely over 7 days to 27.5 mg q6 hours.(165)  A triphasic response has been identified with maximal dopamine agonism only at the mid-range doses.(33)  Tablets are available in 2.5 and 5 mg sizes.
    Concomitant dosing of anti-emetics and gastropropulsive agents may diminish symptoms, allowing patients to appreciated the enormous benefits of psychostimulation. 

    Pergolide (Permax) is a DA-2 postsynaptic receptor agonist.(52)  It exhibits some agonism at DA-3, DA-4, alpha adrenergic, and serotonin receptors.(141)  Pergolide is distinct from Bromocriptine in that it exhibits considerable DA-1 agonism.(162)  In Parkinson's disease, this agonism is appreciating more recognition to improve bradykinesia.(162)  In addition, repeated administration of pergolide markedly attenuates dyskinesias.(162)  Pergolide, like bromocriptine, is an ergot derivative, and has risks for iatrogenic causation of pericardial, pleural, and retroperitoneal fibrosis.  Pergolide has less DA-3 agonism than bromocriptine, potentially suggesting a lesser risk of iatrogenic psychosis with pergolide.(162) 
    Pergolide acts on presynaptic autoreceptors to reduce DA release and lower oxidative stress formed as a result of DA metabolism via MAO-B to form hydrogen peroxide.(162) 
    Pergolide strongly protects against seizures,(46) theoretically allowing patients to be tapered from their cognitively offensive anticonvulsants in favor of a cognitively beneficial psychostimulant. 
    Unlike pramipexole, pergolide lacks cytoprotective antioxidant properties.(141) 
    It is available in 0.05, 0.25, and 1 mg tabs.  Initial dosing is 0.05 mg qd or BID with increase in dose by 0.1 mg-0.25 mg q3 days to a maximum dosing 4mg(52) to 6.5 mg qd, usually in 3 divided doses.
    One patient treated by Dr. Geller (yet to be published) was unresponsive to numerous psychostimulants over six months and remained vegetative.  Her Permax dose was increased and after six months of not moving, speaking, or interacting with her husband she abruptly began to speak, smile, and throw a ball two feet back and forth to her husband within two days of a dose escalation of Permax.

    Pramipexole (Mirapex) is a newer non-ergot dopaminergic which exhibits DA3>DA2>DA4  receptor agonism with negligible DA-1 activity.(73)  It exhibits 700% greater DA3 binding affinity relative to its considerable DA2 and DA-4 agonism.(141)  The extent of pramipexole's DA-2 and DA-3 agonism is greater than at both receptor sites relative to bromocriptine.(    )  Mirapex also has alpha-2 and 5HT-1A affinity.(141) 
    Mirapex has very potent antioxidant properties and can even reduce tocopherol.(141)  Investigation for cytoprotective efficacy to ameliorate the cascade of events contributing to secondary injury after CVA and TBI must be defined.  An important concern is the role of DA-3 agonism with respect to treatment of diminished AAI in terms of coma awakening and reversal of the vegetative state. 
    Common potential side effects include orthostatic hypotension, nausea, and constipation.
    It remains to be fully investigated for utility for coma awakening and reversal of the vegetative state.

    Ropinirole (Requip) is a newer non-ergot dopaminergic. It remains to be fully investigated for utility for coma awakening and reversal of the vegetative state.

    Selegiline (Eldepryl) is a selective MAO type B inhibitor.  It has exhibited psychostimulant efficacy in Alzheimer's disease.(52)  As with other dopaminergics, selegiline may result in manic behavior.(146)  Initial dosing is 5 mg q7AM or 5 mg q7AM and q12 PM.  At doses of 5 mg po BID it may improve alertness over a 3-6 month period.(1)  It is free of the beer, wine, and cheese potential hypertensive crisis effects of nonselective MAO-A inhibitors.

    Amantadine (Symmetrel) is a 1-aminoadamantane derivative tricyclic amine.(46)  It directly stimulates presynaptic dopamine release(25) and synthesis(82) as well as directly stimulates postsynaptic dopamine receptors.(52)  Others believe that amantadine may alter DA receptor morphology to high affinity states.(29)  If this is so, then the distinct mechanism of action would suggest potential synergism between amantadine and other DA receptor agonists.  Additionally, amantadine reduces presynaptic dopamine reuptake,(29) allowing dopamine to remain liberated in the synapse for a longer time.  It has been suggested that amantadine may also increase the number of dopamine receptors.(25)  The dual pre- and postsynaptic agonism of amantadine suggests that it is a potent agent.  Ability to rapidly titrate dosing makes amantadine an attractive option to enhance AAI.  Antiseizure efficacy has been described at low doses of 100 mg BID, whereas proconvulsant properties may dominate at higher doses.(64)
    It has exhibited efficacy as a psychostimulant(25,28,64,82,84,92,107,122) with additional capacity to enhance arousal,(64) attention,(64) and memory,(25,28) attenuate mutism,(64) and selectively extinguish disinhibited behavior.(64,87)  Amantadine may also improve appetite,(92) posttraumatic tremor,(29) and rigidity and bradykinesia.(25)  Benefit has been reported in patients with TBI(28,107,122) stroke,(122) and Alzheimer's dementia.(82,122)
      Side effects include dose dependent agitation, anxiety, delusions, hallucinations, hypomania, dysarthria, mood depression, paradoxical lethargy,(64) dependent edema, and irritability.(64)  Amantadine may cause livedo reticularis as peripheral DA is released.(29)  Some clinicians report that amantadine is desirably unique amongst the pre- and post-synaptic dopaminergic psychostimulants in that it does not have the potential for paradoxical sedation.(    )  Though anticonvulsant properties have been described(66,82) in up to 3% of patients,(75) seizures on 200 mg po BID may resolve with decreased dosing at 100 mg po BID.(25)  Proconvulsant(29,43,64,66) side effects of amantadine have also been described, and the clinician may harbor some reluctance to deliver trials in patients who are receiving neither prophylactic anticonvulsants nor monitoring in the inpatient setting, especially in individuals with penetrating brain injury or other significant risk factors for seizures.  As an influenza antiviral used in hundreds of thousands of people, amantadine has been proven to be a very safe agent.
    Clearance of this agent is mediated by the kidney, and 90% of the drug is excreted unchanged in the urine.(32)  Drug half-life is 9.7(32)-16(29) hours, but 8 days in patients receiving hemodialysis.(32)  Amantadine induced coma,(32) psychosis,(101) and torsade de pointes ventricular arrhythmia(124)  may occur if the clinician does not increase the dosing interval in patients with severe renal failure. 
    Amantadine is available as 100 mg capsules, and can be given as 50 mg po q7AM and q12PM.  Peak plasma levels are achieved within 1-4 hours of ingestion,(64) and steady state is achieved within 48-72 hours,(82) so dose can be advanced q4 days to a maximum of 200 mg po q7AM and q12PM.  Onset of therapeutic action is within 4-7 days of each dose increase, and the drug should be discontinued if no distinct benefit is identified within 6 weeks of drug initiation.(64)  Onset of effect to enhance AAI is usually within 1-7 days,(28) but peak beneficial effect may be realized only after 10 days,(82) presumably reflected responsive subcellular anatomic receptor changes.  The potential for rapid upward titration of dose relative to other dopaminergics is another distinct benefit of amantadine. 

    Rimantadine (Flumadine) is available in 100 mg tabs described as having a superior side effect profile relative to the first generation drug amantadine.  It remains to be fully investigated for utility for coma awakening and reversal of the vegetative state.

    Apomorphine is a direct dopamine agonist(102) which merits further investigation as a psychostimulant.

    Bupropion (Wellbutrin) is a aminoketone antidepressant that improves attention that is relatively free of anticholinergic effects.  Less orthostatic hypotension and tachycardia may accompany its use relative to tricyclic antidepressants.  It is hypothesized that it may exert its psychostimulant effect via enhancement of dopaminergic transmission.(52)  Seizure risk is a very low 0.4%(71), but at doses greater than 450 mg qd it has proconvulsant properties.(4)  Dosing is 75-150 mg po BID. It remains to be fully investigated for utility for coma awakening and reversal of the vegetative state.

    Carbidopa/levodopa (Sinemet).  Carbidopa is a peripheral DA decarboxylase inhibitor which diminishes peripheral levodopa conversion to bioactive DA.  Levodopa subsequently enters the brain and is metabolized within the neuron to DA.  L-dopa stimulates DA-1 and DA-2 receptors indirectly by releasing endogenous dopamine.(46)  L-dopa has been described as a blunt pharmacologic tool, as it enhances dopamine activity at all sites in addition to being biotransformed to DA and then to noradrenaline.(46)  If the brain is unable to synthesize its own DA then providing exogenous substrate may compensate for diminished post-insult biosynthetic capacity.  This is undesirable in light of its lack of selectivity towards minimization of side effects, but potentially welcome in terms of its global activity at all DA receptors which may enhance AAI to treat coma awakening and reversal of the vegetative state. 
    If intracellular enzymatic biosynthetic machinery is intact, then the additional enormous potential benefit of  biotransformation of DA substrate to noradrenaline is also invaluable.  Presynaptic damage to the anterior medial forebrain bundles after separation of the nigrostriatal tract may suggest that biosynthetic capacity is compromised, and direct DA postsynaptic agonists may be more efficacious.(102)  This assertion may be as premature, however, as is the ridiculous contention that MRI or CT scan may predict candidacy for psychostimulant trials.  Presynaptic neuronal down-regulation in response to Sinemet with consequent inefficacy has also been suggested.(98)  If this is experimentally proven to occur, then it may suggest superiority of postsynaptic receptor agonists.  It has also been suggested that Sinemet may functionally activate dormant cells, resulting in new neural pathways.(69)  It remains to be proven if Sinemet exhibits greater efficacy with more extensive intracranial lesions in which dopaminergic activity is diffusely compromised.
    Sinemet has exhibited efficacy as a psychostimulant in TBI.(69,76,166)  It has improved alertness,(98) initiation for movement, disinhibited violence and emotional lability, sialorrhea, hypertension, comprehension, and conversation in patients within 18 months of head injury.(69)  Within 3 days of initiation of treatment with Sinemet, a patient who had been in a vegetative state for 6 months ascended to a higher level of consciousness.  A few days later he stated his mother's name, and months later he was independent in basic activities of daily living with independent wheelchair propulsion and subsequent discharge to home with his family.(22)  Akinetic mutism has also been reported by others to respond to Sinemet.(166)  It has been suggested that individuals treated closer in time to their head injury may respond to a greater extent.(69)  L-dopa may also have antidepressant properties.(151) 
    Delivery to patients on dialysis may require vitamin B6 supplementation to avoid Sinemet induced B6 deficiency induced secondary epilepsy.(62)  The risk of Sinemet induced seizures is low, but may occur 6 weeks to 2.5 years after drug initiation.(63)  Although L-dopa has been reported as protective against seizures,(97) it has also been suggested that DA-1 agonism enhances seizure predisposition,(46) and the nonselective effects of L-dopa may potentiate seizures in high risk patients, especially if they are not on anticonvulsants.  Similarly, DA-2 receptor antagonists are used to treat psychosis,(46) so L-dopa stimulation of all DA receptor sites in the absence of agents which may selectively block DA-2 receptors may be a concern in patients with premorbid histories of schizophrenia or other psychiatric conditions with psychosis. 
    Sinemet may cause nausea, hypotension, dyskinesias, sedation, and delirium.  The pro-oxidant properties of Sinemet(162) must also be further investigated with respect to potentiating the deleterious cascade following TBI and stroke.  
     Initial dose is one 10/100 tab po q7AM, q12 AM.  Patients may respond as early as 48 hours after initiation of treatment.  The dose can be increased every 4-7 days to a maximum of Sinemet 25/250 eight tabs a day in four divided doses. 
    Sinemet CR is a controlled release formulation of carbidopa/levodopa, and has been explored favorably in Parkinson's disease to increase motor "on time" without dyskinesias.(147)  However, it also exhibited a disappointing slower response to initial morning dosing, reflecting peak blood levels two hours after morning ingestion as opposed to one hour for the normal release formulation.(147)  The extended release formulation remains to be investigated as a psychostimulant. 

    COMT - inhibitors include tolcapone (Tasmar) and entacapone (Comtan).  Levodopa can be metabolized centrally to DA or it can be metabolized peripherally, decreasing bioavailability by preventing levodopa from access to centrally depleted sites to serve as a psychostimulant for coma awakening and reversal of the vegetative state.  Peripheral bioconversion via dopa decarboxylase may be prevented with carbidopa, and conversion via catechol-o-methyl-transferase can be blocked by (COMT) inhibitors.  Addition of COMT inhibitors to Sinemet may enhance delivery of DA to the brain and decrease peripheral side effects.  Stalevo is a single pill combination of carbidopa, levodopa, and entacapone.

    Modafinil (Provigil) is FDA approved to treat narcolepsy.  It is not an amphetamine, and is an exciting potential new dopaminergic agent which remains to be investigated to facilitate coma awakening and reversal of the vegetative state.  Modafinil's novel pharmacology is exciting as its mechanism is distinct from previously available agents, acting not via altering the release of dopamine or norepinephrine.(160)  An intact alpha adrenergic system, however, is necessary for modafinil to exert its wake promoting activity.(160)  The absence of sympathomimetic properties makes this agent particularly desirable in the elderly and in individuals with cardiac dysrhymthmias or coronary artery disease.  It is available in 100 mg tabs to be delivered as 100-200 mg po BID at q 7AM, q12 PM.  Considerably higher doses have proven safe in non-FDA approved uses, and high doses may be required to address coma awakening and reversal of the vegetative state. 

    Carbamazepine (Tegretol) is most commonly characterized as being mildly sedating, but it may have some limited efficacy to enhance AAI.(41)  Tegretol may exercise its clinical effect via its ability to facilitate dopamine agonists, reduce dopamine turnover, and enhance presynaptic dopamine release.(46) 
    Tegretol has an incidence of bone marrow suppression is 1:40,000 - 1:125,000.(61)  "It is not at all clear that carbamazepine is likelier than valproate... to cause agranulocytosis or thrombocytopenia."(4)  Risk of severe blood dyscrasias is similar for phenytoin and carbamazepine,(132) amd so a CBC with differential needs to be followed.  Because of these potentially lethal side effects, carbamazepine should be prescribed for its anticonvulsant, analgesic, anti-bipolar disorder properties, but not for the indication of enhancing AAI.  A “safer, newer carbamazepine” has been released in the form of oxcarbazepine (Trileptal).

MEDICATIONS – Tricyclic Antidepressants (TCA's)
    TCA's enhance AAI by inhibiting presynaptic terminal norepinephrine reuptake from the synaptic cleft, thereby increasing the exposure of the postsynaptic membrane to the stimulating effects of the neurotransmitter.  Norepinephrine is felt to be the critical neurotransmitter promoting recovery after brain damage,(15) but studies still must be designed to identify if TCA's share the beneficial properties of amphetamines(38) in potentiating recovery. 
    A baseline ECG may be obtained prior to starting TCA's, as torsade de pointes ventricular dysrhythmia has been reported with heterocyclic antidepressants.(40) 
    Side effects of strongly noradrenergic TCA's to monitor include anticholinergic induced urinary retention secondary to increased smooth muscle alpha noradrenergic mediated tone, and confusion.  TCA's with potent anticholinergic properties may cause confusion and impair memory as well as relax detrusor contractility and predispose to urinary retention.  Similarly, anticholinergic mediated vagal blockade may cause tachycardia in excess of coronary perfusion capacity in patients with coronary artery disease, causing myocardial ischemia.  Though not a TCA, the antidepressant trazodone may impair motor recovery or temporarily reinstate paralysis in patients with acquired brain injuries, and this is felt to be alpha mediated.(    )  Proconvulsant properties of TCA's are dose dependant and felt to occur with an incidence of less than 1%.(78)  Other sources report a proconvulsant range of 0.1-1%.(71)  Maprotiline is a semi-tetracyclic antidepressant with a high incidence of seizures at doses greater than 225 mg/day.(78)  Amoxapine is associated with adverse extrapyramidal side effects as well as a high incidence of seizures relative to TCA's.(78)  The risk for seizures is 2.2% for tricyclic antidepressants in general, and .7% for imipramine.(81)
    TCA's which are more selective towards noradrenergic agonism with minimal anticholinergic, alpha antagonistic, and antihistamine properties are most desirable as psychostimulants.

        Amitriptyline (Elavil), within several days, 50 mg po qd improved motor and speech initiation after several months of plateau.(15)  This may suggest a fundamental role of serotonergic deficiency in responsive patients, as amitriptyline, relative to protriptyline, has approximately 4% of the noradrenergic stimulant properties, similar stimulating dopaminergic activity, 265 times as much sedating antihistamine activity, but 400% of the seratonergic agonism.(   )  This is speculative, and the etiology of amitriptyline's psychostimulant efficacy remains indeterminate.  If the etiology of a patient's suboptimal AAI is that of serotonergic system dysfunction, then amitriptyline may be a efficacious agent. 
    Amitriptyline has potent antihistaminergic properties which are often sedating and anticholinergic properties which predispose to urinary retention via detrusor relaxation.  It also has alpha antagonist properties which may predispose to urinary retention via internal urethral sphincter stimulation and to delayed neurologic healing in brain pathology.(   )   As with other tricyclic antidepressants, Elavil has potential proconvulsant properties.

    Imipramine (  ) can be given up to 300 mg qd.(57)   Imipramine is a nonselective monoamine reuptake inhibitor.(46) 

MEDICATIONS - SEROTONERGICS
    SSRI's improve AAI by interfering with presynaptic neural reuptake of serotonin.  The effect is within 1-3 days, in contradistinction with antidepressant efficacy and receptor protein synthesis alteration which takes 1-2 weeks.  However, serotonin has inconsistent effects on arousal.(52)  Many patients are aroused, but more are paradoxically sedated relative to noradrenergics or dopaminergics.  This most likely reflects the nonselectivity of currently available agents in terms of serotonin receptor subtype agonism and antagonism.  Over eleven distinct serotonin receptors have thus far been identified.(      ) 
    The risk for SSRI induced seizures is low, but secondary cytochrome P450 inhibition may enhance the levels of concomitantly delivered tricyclic antidepressants, increasing the risk for seizures.(78)  It is a safe drug in patients with cardiovascular disease, a benefit in the elderly in whom the clinician may have reservations regarding prescription of noradrenergics such as dextroamphetamine or the tricyclic antidepressants.  Anorexia is not uncommon after SSRI's are delivered.  It remains to be investigated whether Megace and other appetite stimulants are efficacious to afford continued SSRI delivery when psychostimulation is achieved.
    SSRI's may rarely induce extrapyramidal side effects,(4) including tardive dyskinesia,(    ) akathisia,(     ) and bradykinesia.(    )

    Fluoxetine (Prozac) dose is 10 mg po qAM.  Max. dose is 80 mg po qd.(55)  Effects may be seen very quickly, within 3-14 days.(5,8) 


MEDICATIONS - MONOAMINE OXIDASE (MAO) INHIBITORS
    Nonselective MAO inhibitors strongly impair MAO-A and B from oxidatively inactivating norepinephrine, dopamine, and serotonin neurotransmitters after presynaptic reuptake.(96)  Efficacy to enhance attention and memory(109,114) has been appreciated.  The immediacy of effect, in contrast to the delayed antidepressant properties, argues against a role for receptor alteration.(109) 
    A benefit of using MAO inhibitors is their anticonvulsant properties.(78)  Patients who have exhibited idiosyncratic allergy to dextroamphetamine and other classic psychostimulants may be optimal candidates for trials with MAO inhibitors.  These agents may also be beneficial in the patient with baseline hypotension who may not tolerate dopaminergic agonists.  The nonselective diffuse increase in multiple biogenic amines suggests that these agents may be viable options in patients who demonstrate unresponsiveness to traditional psychostimulants. 
    The undesirable aspect of utilizing MAO inhibitors is the potential for hypertensive crisis if beer, wine, cheese, or other tyramine containing substances are ingested.  These medications should be used with great caution if sympathomimetics are also being delivered.  This suggests that delivery of MAO inhibitors may need to be reserved for use in the inpatient setting if compliance with strict dietary restrictions is not a realistic expectation.
    Tranylcypromine (Parnate) and phenelzine (Nardil) are MAO options.  Tolerance to psychostimulation is rare, but may occur.(109) 


MEDICATIONS - CHOLINERGIC AGONISTS
    Physostigmine, an anticholinesterase inhibitor, has been used to reverse intrathecal baclofen overdose induced coma.(67) 
    Donepezil (Aricept) is a piperidine derivative reversible acetylcholinesterase inhibitor.
    Rivastigmine (Exelon) is a carbamate derivative reversible acetylcholinesterase inhibitor.
    Galantamine (Reminyl) is a benzazepine derivative reversible acetylcholinesterase inhibitor.
    Though cholinergic agonists clearly enhance memory after TBI or stroke, this class of medications  remains to be fully investigated for utility for coma awakening and reversal of the vegetative state.  As each medication is derived from a different parent compound and has a different molecular structure, each has different efficacy based on each patient’s individual receptor profile and morphology, reflecting genetic diversity.

MEDICATIONS - ATYPICAL AGENTS

    Valproic acid(4) is an anticonvulsant which usually have mild sedating properties but occasionally has paradoxical potential to enhance AAI.

    Flumazenil has treated hepatic encephalopathy and benzodiazepine intoxication.(80)  It may or may not have efficacy for coma awakening and reversal of the vegetative state. 


INFORMED CONSENT
Patients with loved ones in coma or the vegetative state must understand that all medications utilized to reverse the state are utilized in an off-label manner.  The pharmaceutical manufacturing companies have not found it cost effect to petition the FDA for official approval for psychostimulants to be used for the indication of coma awakening or reversal of the vegetative state. 

As such, many clinicians are not trained in this off-label use of these medications.  Given this fact, the epidemic of frivolous litigation, and the rare but valid potential dangers accompanying use of any medication including psychostimulants, many clinicians will refuse to participate in coma awakening or vegetative state reversal unless patient’s family members sign detailed and all inclusive informed consent.

Patients families must document that they understand the risks for everything from the spectrum of retroperitoneal fibrosis, pleural fibrosis/thickening, pulmonary infiltrates, pericardial effusion, myocardial infarction, cardiac arrhythmia, hepatorenal failure, status epilepticus with further brain damage, pulmonary hypertension, valvular heart, and death.  These outcomes are extremely rare, but comprehensive informed consent may reassure clinicians to provide care without concern for litigation despite the most admirable of intentions.

Informed consent must extend to encompass the institution, as the “deeper pockets” may be enticing for easy money.  Informed consent must include trials with supra-maximal dosing which may be required to effect coma awakening and reversal of the vegetative state. 


FOLLOW-UP
Diminished AAI is a dynamic condition, and evolves with time from the intracranial event.  The patient should be assessed every few months with a trial taper to determine if psychostimulants are still required, as anatomically intact but physiologically "stunned" neurons may recover.  Clinical decompensation must also be investigated, as post-traumatic hydrocephalus, aneuryms, meningitis, abscess, and other conditions may occur and require definitive medical or surgical management. 

Rechallenge of psychostimulants previously documented as inefficacious should also be considered, as edema resolution and neurologic anatomic regrowth or unmasking of preserved systems may imbue new responsiveness to psychostimulants previously documented as inefficacious in a particular individual at a particular stage in healing.  Selegiline given to a patient receiving concomitant bromocriptine and Sinemet resulted within 7 months in mania,(146) and illustrates the importance of continued clinical monitoring of patients receiving dopaminergics.

Development of irritability may occur with long term use,(64) and dose reduction may be required to maximize quality of life and social performance.  A retrial at a higher dose after the irritability has subsided may afford resumption of previously maximized AAI without recurrence of irritability.(64) 

Though the long term efficacy and safety of psychostimulants has been well established,(2) a small subpopulation of patients may develop tolerance(109) and require higher doses as the brain heals and better processes data.  Efficacy of amantadine may decrease after months of continued use.(4)  "Tolerance" to the beneficial effects of psychostimulants may occur, as described after a year of  protriptyline(114) or one to two months of methylphenidate.(114)  Just as some patients with Parkinson's disease exhibit a decline in clinical efficacy over the first few months,(64) so too may psychostimulant efficacy fade in an undefined subpopulation of patients with the passage of time.(2)  Follow-up is invaluable to evaluate patients for alternative drug options.


FUTURE DIRECTIONS
Further research is required to define if a critical period exists during after which pharmacological intervention is no longer efficacious to enhance AAI.   Alternatively, a therapeutic window of maximal efficacy may be identified.  Serial PET scans may correlate cerebral hemodynamic and metabolic responsivity of various lesions and clinical expressions to individual drug trials.  The phenomenon of tolerance to TCA's(7) must be investigated.  Presynaptic neuron down-regulation in response to Sinemet with consequent inefficacy has been suggested(98) and must be further explored. 

A therapeutic maximum dose may exist in which excessive dosing may precipitate post-synaptic receptor downregulation or diminished presynaptic neurotransmitter synthesis.  Identification of such a dose or excessive daily frequency or protracted duration of delivery may enormously benefit patients who might otherwise be designated nonresponders or rapid acclimators.  Potential synergism between agents of different classes and those of the same class, such as amantadine and bromocriptine must also be investigated. 

If dopaminergic psychostimulant efficacy is felt to be mediated by DA-3 or other non-DA-2 or DA-4 activity, then future molecular engineering may synthesize receptor specific agents which can be used safely in patients with premorbid histories of psychosis and need for psychosis suppression via DA-2 or DA-4 blockade.  The value of DA-1 agonism remains to be defined.  Effects of different agents on various subcomponents of attention must continue to be investigated in randomized prospective studies.  It will also be of valuable clinical interest to identify if an optimal duration of initial psychostimulant treatment influences whether the system can be reset to eventually achieve functional autonomy without exogenous intervention.

A triphasic response to bromocriptine has been identified with maximal dopamine agonism only at the mid-range doses.(33)  The etiology of this remains to be identified as receptor saturation, downregulation, metabolism kinetics, or other etiology.  Similar occurrences for other psychostimulants remains to be investigated. 

Earlier delivery of the medication may promote recovery and restoration of neurologic integrity with consequent improved function rather than enhance function of irreversably damaged neurones.  If this is true, then the former intervention may afford greater eventual function and potentially less dependency on continued drug delivery for maintenance of function.(123) 


MEDICAL MANAGEMENT IN THE INTERIM
A great number of organ systems can decompensate in the comatose, vegetative, and locked in patient if not properly treated.

MEDICAL MANAGEMENT IN THE INTERIM – VASCULAR
During the inpatient stay and for 6 weeks – 6 months, heparin should be given daily to prevent deep venous thrombosis and potentially fatal pulmonary embolus.  Aspirin does not prevent thrombosis or embolus.

MEDICAL MANAGEMENT IN THE INTERIM – GASTRO-INTESTINAL
All patients who suffer an acute neurologic insult are at heightened risks for peptic ulceration and potentially fatal bleeding.  Proton pump inhibitors such as Aciphex should be given to greatly diminish risks.  This author prefers Aciphex over Nexium, Prevacid, Protonix, and Prilosec as Aciphex reportedly is the only proton pump inhibitor which blocks all four acid channels in the stomach.

Patients with low levels of AAI still require general medical care in terms of cancer screening with colonoscopy, pap smears, testicular exams, prostatic specific antigen (PSA), breast exams, and mammograms.

Patients whose TBI was felt to be related to alcohol and other substance abuse should be tested with a hepatitis panel as diagnosis of this condition will dictate safety of psychostimulant medication trials as well as permit treatment of the hepatitis itself.  HIV testing should also be entertained.

MEDICAL MANAGEMENT IN THE INTERIM – GENITO-URINARY
Bladder emptying should be performed with suprapubic tapping and scheduled straight catheterization.  Males should use condom catheters if low post-void residuals can be confirmed.  Indwelling urethral catheters enormously increase the risks for sepsis and death.  Methenamine decreases the risks for urinary tract infections unless the patient is inappropriately managed with an indwelling catheter.  Cranberry juice fed via the G-tube may decrease the likelihood that E. coli bacteria will adhere to the bladder wall to cause infection.

Patients with low levels of AAI still require general medical care in terms of cancer screening with pap smears, testicular exams, prostatic specific antigen testing (PSA), breast exams, mammograms, and colonoscopy.

Urodynamic testing may be required to identify external sphincter dyssynergia.

MEDICAL MANAGEMENT IN THE INTERIM - PULMONARY
Chest percussion, good hydration, and frequent suctioning decreases the risks for atalectasis and pneumonia.  Pneumococcus vaccination should be given in the acute care hospital and repeated every five years to reduce the risks for pneumonia.  Influenza vaccination should be given annually, early in the season.

MEDICAL MANAGEMENT IN THE INTERIM – CARDIAC
Premorbid medical conditions are often neglected in the TBI, stroke, and otherwise neurologically devastated.  Aspirin, Plavix, and Aggrenox should be delivered to prevent potentially fatal myocardial ischemia or recurrent stroke. 

MEDICAL MANAGEMENT IN THE INTERIM – HEMATOPOETIC
Folic acid should be given to 100% of patients consuming chronic Dilantin therapy to prevent macrocytic anemia.

MEDICAL MANAGEMENT IN THE INTERIM - SKIN
Patients should be repositioned to rest on their sides as well as back every few hours.  Skin overlying superficial bone such as the greater trochanters, heels, elbows, and ischial tuberosities are prone to decubitii which may erode into bone and necessitate amputation or death from sepsis.  Elbow pads should be worn.  Multipodus L’Nard boots should be worn to elevate the heel from the bed such that it is suspended in air and unable to rapidly develop a pressure ulcer.  Bunny foam boots are fully inadequate. 

MEDICAL MANAGEMENT IN THE INTERIM – MUSCLE, TENDON CONTRACTURES
Family members should be taught stretching exercises to prevent knee flexion, elbow flexion, shoulder adduction, wrist flexion, and finger flexion contractures.  Botulinum and phenol spastic hypertonus reducing injections may be required.  Resting wrist splints, knee extension, and other splinting interventions are enormously helpful.


CONCLUSION
Suboptimal arousal, attention, and initiation profoundly impair quality of life and predispose to conditions which endanger duration of life.  The earliest step in the management of suboptimal cognition is confirmation that no dangerous medical condition is ongoing.  Confirmation that mood depression, locked in states, schizophrenic catatonia, or other conditions are not mimicking primary disorders of arousal, attention, or initiation must be performed.  Offensive environmental and pharmaceutical agents must be addressed prior to trials with agents which may enhance cognition.  A host of drug options exist which may dramatically ameliorate disorders of arousal, attention, and initiation and be utilized in coma awakening and reversal of the vegetative state.  Severely neurologically traumatized patients may benefit more from psychostimulants to facilitate coma ascension whereas individuals with attention and initiation disorders may require medications to enhance subcomponents of these systems. 

New medications which positively modulate neurotransmitters related to AAI are constantly in development.  If the magic cure does not currently exist, then it may in the future.  Though coma awakening and reversal of the vegetative state require perseverance and patience in terms of psychostimulant trials, successful responses are extremely common, enormously satisfying to the clinician, and invaluable to the family. 

It is the pinnacle of arrogance to suggest that MRI and CT scan can be utilized to state that a patient will not respond to psychostimulants.  Only clinical trials with monitored dose escalation can result in such a conclusion for that patient at a specific stage of recovery.  The benefits of coma awakening and reversal of the vegetative state to the patient, patient's family, and society cannot be overly stressed.

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