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) 

EVERY PATIENT DESERVES A CHANCE!!!