NeuroRehabilitation An InterdilCiplinary Journal
ELSEVIER
NeuroRehabilitation 5 (1995) 197-204
Differential diagnosis of agitation following brain injury W. Jerry Mysiw*a, Rebecca D. Jackson b aDepartment of Physical Medicine
and Rehabilitation. The Ohio State University. Columbus. all 43210. USA Division of Endocrinology and Metabolism and Department of Physical Medicine and Rehabilitation. The Ohio State University. Columbus. OH 43210. USA
b Department of Medicine.
Accepted 17 April 1995
Abstract
Posttraumatic agitation is perhaps the most dramatic behavioral consequence of severe traumatic brain injury. The mechanism for this behavior remains to be determined. The development of effective management strategies has been hampered at least in part by the lack of a consensus definition for posttraumatic agitation. The diagnosis of posttraumatic agitation is a diagnosis of exclusion. Concurrent neurologic or medical decline during the recovery from an acute traumatic brain injury may precipitate delirium, which has many clinical features that overlap with posttraumatic agitation. Hence, the differential diagnosis of posttraumatic agitation includes all medical and neurologic etiologies for transient declines in consciousness and cognition. Keywords: Brain injury; Agitation; Diagnosis
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-------------------------------
1. Introduction
The efficient evaluation, diagnosis and management of any disorder is predicated on a clear understanding of the observed condition. Yet, the development of management strategies, for agitation, and to a lesser extent a differential diagnosis, has been hampered by the absence of a clear
*Corresponding author, Dodd Hall, The Ohio State University, 480 W. 9th Avenue, Columbus, OH 43210, USA. Tel: + 1 614 293-3801.
and consistent definition in the rehabilitation literature. In the psychiatric literature, agitation is defined as any emotion associated with severe anxiety (feeling of apprehension caused by anticipation of danger, which may be internal or external) and motor restlessness [1]. Perhaps the first description of agitation secondary to brain injury appeared in 1945 where Denny-Brown described restlessness as a natural sequela after a traumatic brain injury (TBI) [2]. In 1978, Levin and Grossman described agitation as some combination of
1053-8135/95/$09.50 © 1995 Elsevier Science Ireland Ltd. All rights reserved. SSDI 1053-8135(95) 00117-0
191'
WJ. Mysiw, R.D. Jackson / NeuroRehabilitation 5 (1995) 197-204
combativeness, thrashing, truncal rocking, screaming or signs of sympathetic activation [3]. By the 1980s, references to agitation secondary to brain injury frequented the rehabilitation literature but without a clear consensus definition. In 1980, the Rancho Los Amigos Levels of Cognitive Functioning Scale was designed, where Rancho level IV was described as the confused agitated period [4]. Specifically, Rancho level IV is characterized by a heightened state of activity where a patient demonstrates a diminished capability of processing new information and associated behaviors that include aggressiveness, attempts to remove restraints or tubes, and inability to cooperate with treatment and confabulation [4]. In 1981, Reyes et a1. differentiated restlessness and agitation in that restlessness implied consistent activity but the patient was capable of briefly inhibiting a movement, whereas agitation was defined as constant uninhibited movement [5]. In 1988, our working group at The Ohio State University defined agitation as 'subjective evidence of one or more of the following behaviors: restlessness, derogatory or threatening demands, verbal abusiveness, sexually inappropriate comments or actions, or threats or attempts at physical violence of sufficient severity to disrupt nursing care or therapy' [6]. Later that year, agitation was defined by our group as achieving a score ~ 21 on the Agitated Behavior Scale (a 14 item-scale that rates the degree of specific observed behaviors, where total scores can range from 14 to 56) [7]. More recent trends in the brain injury literature appear to argue for an interdisciplinary definition of agitation. In 1992, Brooke et a1. utilized an instrument validated in the psychiatric population, the Overt Aggression Scale, to evaluate the efficacy of pharmacologic interventions of agitation after traumatic brain injury [8]. Also, at the 1994 American Academy of Physical Medicine and Rehabilitation meeting of the Brain Injury Special Interest Group, the term delirium was proposed as an appropriate alternative to agitation [9]. At our institution, agitation is presently conceptualized as a behavior during posttraumatic amnesia that is characterized by a combination of aggression, disinhibition and/or emotional labil-
ity [10]. This definition remains more specific to the traumatic brain injury population for several reasons. First, the present DSM-IV (Diagnostic and Statistical Manual of Mental Disorders) criteria for delirium describes disturbances in consciousness and changes in cognition but the criteria for delirium does not require a heightened state of activity that is typical of the Rancho Level IV patient [11]. Our proposed definition of agitation also accounts for the observations that: agitation is a discrete stage during the cognitive recovery after traumatic brain injury; agitation is not unique to Rancho level IV, but persists through late stages of posttraumatic amnesia; and that cognition improves before agitation diminishes [7]. 2. Differential diagnosis
The diagnosis of posttraumatic agitation should be considered a diagnosis of exclusion, largely because the anatomic and neurochemical basis of agitation remains undefined. Towards this goal, the delirium literature lends itself to close scrutiny for its applicability in the diagnosis and management of posttraumatic agitation. Again, it is not the intent of this section to imply that posttraumatic agitation and delirium are synonymous, but, because the very hallmark of delirium involves a transient impairmeht of both consciousness and cognition, the two syndromes possess numerous overlapping features. The correct diagnosis of delirium is in fact important because as previously stated, cognition tends to improve before there is an observed decrement in agitation [7]. Hence the removal of all potential impediments to cognitive recovery may facilitate the resolution of agitation. Perhaps a more important reason to exclude delirium as a source for problematic behaviors observed after traumatic brain injury is that this may in fact be the first or only indication of concurrent medical or neurologic decline. For example, the incidence of delirium on general medical and surgical services has been estimated at rates of 15-25% and 10-15%, respectively [12]. This incidence increases to 30% if the patient is in an intensive care unit or if there is a prior
WI. Mysiw, R.D. Jackson / NeuroRehabilitation5 (1995) 197-204
history of substance abuse, a preexisting central nervous system injury, medical illnesses such as diabetes or malnutrition and sensory impairments (i.e. blindness) [12,13]. The importance of correctly diagnosing delirium is underscored by the fact that the mortality of all patient populations with a diagnosis of delirium approaches 33% at 3 months and 50% at 1 year [12]. The mortality rate amongst TBI survivors who develop delirium is unknown but in view of the relative youth and premorbid good health of most survivors, it is unlikely to approach the mortality rates documented in general medical and surgical patients. Nevertheless, concurrent medical illness has been documented to adversely affect cognitive recovery during posttraumatic amnesia. Jackson et al. demonstrated that etiologies as diverse as medication adverse reactions, surgery, febrile illness, hydrocephalus, chronic subdural hematoma and seizures could account for declines in the cognitive function that persisted for days to weeks [14]. Furthermore, during posttraumatic amnesia, the decline in cognitive function was the first indication of concurrent medical illness in 60% of the cohort [14]. An evaluation of the literature reveals that delirium has been referred to by a wide variety of other names including: acute confusional state, acute brain syndrome, metabolic encephalopathy, toxic psychosis, acute brain failure and sundowning [12]. This in part contributes to the previously mentioned observations that delirium is an under recognized and under diagnosed disorder. Retrospective studies of TBI survivors during acute inpatient rehabilitation reveal that survivors are subject to a host of medical and neurologic complications that place them at risk from delirium [15]. It has been observed that 56% of TBI survivors develop neurologic complications during acute inpatient rehabilitation that are of sufficient severity to warrant additional investigation and intervention [15]. The most common category of neurologic complications is ventricular dilatation, occurring in 37% of survivors. The important distinction in this subpopulation is between hydrocephalus ex vacuo, normal pressure hydrocephalus or obstructive hydrocephalus. The oc-
199
currence of normal pressure hydrocephalus after traumatic brain injury is relatively common with estimated incidences ranging between 29 and 72% [16]. Although normal pressure hydrocephalus is more likely to present as a dementia, with an insidious rather than acute or subacute onset, less fluctuation over the course of a day, psychomotor retardation and apathy, symptoms suggestive of delirium or posttraumatic agitation such as anxiety, delusional thinking, hallucinations, emotional lability and paranoia have been reported [17]. Posttraumatic seizures account for the second largest category of neurologic complications during posttraumatic amnesia, with 13% of survivors having a documented event prior to the completion of their inpatient rehabilitation stay [15]. Epilepsy may be associated with delirium in one of four ways: (1) as an ictal event; (2) as a post-ictal event; (3) as an interictal event; and (4) as an adverse reaction to anti-epileptic medication [13]. Other potential CNS events during inpatient rehabilitation with a known predisposition to present as delirium include delayed subdural hematoma or hygroma, meningitis and other CNS infections [12,13,15]. Finally, posttraumatic headaches are among the most common sequela of mild through severe traumatic brain injury. The fact that migraine features are common to these posttraumatic headaches is salient, in that, it has been estimated that 8% of patients suffering from severe migraine headaches occasionally develop delirium [13,18,19]. Gastrointestinal problems account for the second largest category of medical complications during inpatient rehabilitation, with 50% of TBI survivors developing problems [15]. Elevations in liver function tests account for the majority of gastrointestinal related complications with an estimated 43% of survivors demonstrating abnormal values. The incidence of hepatic encephalopathy after traumatic brain injury is unknown but this diagnosis is worth considering as hepatic encephalopathy may feature delirium. However, the presentation of that delirium is much more likely to be somnolent rather than activated, and thus, the potential for confusing posttraumatic agita-
200
WI. Mysiw, R.D. Jackson / NeuroRehabilitation 5 (1995) 197-204
tion with delirium secondary to hepatic encephalopathy is small [20]. Peptic ulcer disease-related symptoms account for the second largest category of gastrointestinal disorders documented during inpatient rehabilitation with an incidence of less than 10% of TBI survivors [15]. The management of these disorders with a Hz-receptor antagonist may induce delirium; cimetidine, for example, has an incidence of 1.1 per 100000 patients treated for developing subsequent delirium [13]. Unrecognized peptic ulcer disease may also present as a delirium secondary to anemia [13]. Finally, acute pancreatis may present as a co-morbid diagnosis with TBI secondary to blunt abdominal trauma; secondary pancreatic encephalopathy may feature delirium [13]. The third largest category of medical complications after traumatic brain injury involves respiratory problems· with approximately 39% of survivors developing either problems with colonization of the airway, pneumonia or atalectasis [15]. Potential secondary sources of delirium then include fever, hypoxia, carbon dioxide narcosis and adverse reactions to antibiotics [12,13]. The overall incidence of pulmonary emboli after traumatic brain injury has been estimated at 3%; the estimated mortality rate secondary to pulmonary emboli is 1% [15,21]. This incidence is salient in that a pulmonary emboli can present with delirium [13]. Cardiovascular disorders represent the fourth largest category of medical issues noted during the acute stages of recovery after traumatic brain injury with an overall incidence estimated at 32% of survivors. The majority, approximately twothirds, are non-specific EKG changes [15]. In primarily a young population of TBI survivors, delirium may present as the consequence of arrhythmias, hypertension, or hypotension secondary to prolonged bedrest, complications of pharmacologic intervention or neuroendocrine etiologies such as hypothalamic or pituitary disorders [22]. Endocrine disorders most likely to occur concurrently with a traumatic brain injury include the
syndrome of inappropriate antidiuretic hormone secretion, hypothyroidism and panhypopituitarism. The overall incidence of endocrine disorders after TBI has been estimated at 20% of acute survivors [23]. All of these conditions may present with delirium [12,13]. Metabolic disorders such as infection and fever affect the brain to the extent that secondary widespread cerebral dysfunction may present as a delirium. Most likely sources of infection among brain injury survivors during the rehabilitation phase of recovery include urinary tract infections in approximately 40% of survivors [15], respiratory complications that predispose to infection in approximately 34% of survivors [15], and sinusitis secondary to intubation in approximately 26% of survivors [24,25]. Adverse reactions to medication may include febrile responses with perhaps the most life threatening being the neuroleptic malignant syndrome. This rare, but potentially fatal complication of dopamine antagonist medication presents with a combination of extrapyramidal signs, autonomic disturbances and altered levels of consciousness [26]. Numerous other medications are linked to adverse reactions that include behavioral and cognitive changes consistent with delirium. Acetylcholine is the neurotransmitter system hypothesized to be most closely linked with delirium, hence, anticholinergic agents, such as numerous antidepressants and antipsychotics, are among the most common causes of delirium [12]. Antipsychotic agents may also result in the development of akathisia, where the subsequent motor restlessness can be mistaken for a worsening of agitation [27]. Other medications with specific rehabilitation implications that are known to occasionally induce delirium include anticonvulsants, antiparkinsonian agents, opiates, lithium, clonidine, cimetidine and ranitidine [12,13]. It is noteworthy that a number of the medications successfully utilized in the management of posttraumatic agitation involve adverse reactions such as delirium [6,28-31]. Approximately 40% of TBI patients are intoxicated at the time of admission [32]. The prepon-
WJ. Mysiw, RD. Jackson / NeuroRehabilitation 5 (1995) 197-204
derance of survivors with a history of substance abuse is similarly high, placing them at risk for behavioral disturbances and delirium secondary to withdrawal. [12,13]. Similarly, the evaluation of the confused agitated patient should include some of the known vitamin deficiencies known to accompany substance abuse (Table 1) [12,13]. 3. Evaluation
The physical examination of the confused agitated patient therefore involves a careful, syste-
matic evaluation to exclude all neurologic and metabolic etiologies for a decline in mental status. The physical examination as outlined in Table 2 can be used as a framework to begin the evaluation and guide the selection of additional diagnostic studies (Table 3). In the event that the physical examination fails to suggest specific etiologies for observed problematic behaviors, the baseline studies as outlined in Table 3 should be considered. The additional studies described in Table 3 are more appropriate if suggested by the history and physical examination, or if the behav-
Table 1 Known causes of delirium with potential implications for causing or worsening posttraumatic agitation Central nervous system epilepsy and post-ictal states space-occupying lesions hematoma/hygroma neoplasm - primary or remote effects aneurysm abscess infection encephalitis meningitis vascular disease thrombosis embolism hemorrhage migraine Drugs aminophyline anticholinergic agents (ex tricyclic antidepressants) antiarrythmics antibiotics anticonvulsants antiparkinsonian drugs antipsychotics cardiac glycosides cimetidine, ranitidine, etc. clonidine disulfiram insulin lithium opiates phencyclidine salicylate sedative /hypnotics (barbiturates, benzodiazepines, etc.) steroids
201
Intoxication alcohol carbon monoxide Drug withdrawl alcohol sedatives /hypnotics / amphetamines Metabolic endocrine (hypo or hyperfunction) adrenal parathyroid pancreas pituitary thyroid Hepatic encephalopathy Renal encephalopathy Pulmonary carbon dioxide nacrosis hypoxia Cardiac failure arrythmia hypo /hpertension Vitamin deficiency thiamine nicotinic acid folate
Bl2
Anemia Fluid, electrolyte, acid-base balance disturbances Systemic infection AIDS Postoperative states
Table adapted from Kaplan and Sadock's Synopsis of Psychiatry: Behavioral Sciences, Clinical Psychiatry (7th Ed.).
202
w.J. Mysiw, R.D. Jackson / NeuroRehabilitation 5 (1995) 197-204
ior persists despite an otherwise unremarkable evaluation. Finally, it is prudent to exclude all noxious stimuli as potential sources of restlessness in a patient who otherwise has limited communication options.
4. Conclusion
Despite the preponderance of posttraumatic agitation and the subsequent significant rehabilitation implications, the development of manage-
Table 2 Physical examination of the confused, agitated patient Parameter 1. Pulse
Finding
Clinical implications
Bradycardia
Hypothyroidism Stokes-Adams syndrome Inc intracranial pressure Hyperthyroidism Infection Heart failure
Tachycardia
2. Temperature
Fever
3. Blood pressure
Hypotension Shock
Hypertension 4. Respiration
5. Carotid vessels
Tachypnea
Sepsis Thyroid storm Vasculitis Hypothyroidism Addison's disease Encephalopathy Intracranial mass
Shallow
Diabetes Pneumonia Cardiac failure Fever Acidosis {metabolic} Alcohol/substance abuse
Bruits
TIA
6. Scalp and face
Evidence of trauma
7. Neck
Evidence of nuchal rigidity
Meningitis SAH a
8. Eyes
Papilledema
Tumor Hypertensive encephalopathy
Lacerations
Seizures
10. Thyroid
Enlarged
Hyperthyroidism
11. Heart
Arrhythmia Cardiomegaly
Cardiac output, emboli Heart failure Hypertensive disease
12. Lungs
Congestion
Pulmonary failure Pulmonary edema Pneumonia
13. Breath
Alcohol Ketones
Diabetes
14. Liver
Enlargement
Cirrhosis Liver failure
9. Mouth
W:J. Mysiw, RD. Jackson / NeuroRehabilitation5 (1995) 197-204
203
Table 2 (Continued) Parameter
Finding
Clinical implications
15. Nervous system a. Reflexes muscle stretch
Asymmetry with Babinski sign
Mass lesion Cerebrovascular disease Preexisting dementia Frontal mass Bilateral PCAb occlusion Inc. intracranial pressure Mass lesion Cerebrovascular disease Anxiety Delirium
c. Limb strength
Snout Weakness in lateral gaze Asymmetrical
d. Autonomic
Hyperactivity
b. Abducens nerve
a Subarachnoid
hemorrhage. cerebral artery. Table from R.L. Strub, FW. Black: Neurobehavioral Disorders: A Clinical Approach, p. 120, Davis, PA, 1981. Used with permission. b Posterior
ment strategies remains hampered by the failure to develop the consensus definition necessary to foster thoughtful and meaningful investigation concerning its etiology and treatment. In our institution, posttraumatic agitation is conceptualized as a behavior during posttraumatic amnesia that consists of a combination of aggression, disinhibition and/or emotional lability [10]. Delirium is not sufficient as a synonmous term with
Table 3 Medical evaluation of the confused-agitated patient Baseline tests complete blood count electrolytes, glucose, BUN, creatinine, liver function tests T4 , TSH urinalysis electrocardiogram chest X-ray Additional tests blood, urine, cerebrospinal fluid cultures B12 , folic acid levels CT or MRI of brain lumbar puncture electroencephalogram (EEG) serologic tests for syphilis HIV antibody test Table adapted from Kaplan and Sadock's Synopsis of Psychiatry: Behavioral Sciences, Clinical Psychiatry (7th Ed).
posttraumatic agitation because delirium is a syndrome with a host of potential etiologies and presentations; it is for example not necessary to be agitated to meet the diagnostic criteria for delirium. Because we have no known anatomic or neurochemical mechanism to explain posttraumatic agitation, the diagnosis of posttraumatic agitation remains a diagnosis of exclusion. Despite the fact that delirium and posttraumatic agitation are not synonymous, the respective presentations of these disorders overlap sufficiently to warrant the exclusion of delirium as a source of observed disruptive behaviors. References [1] Typical signs and symptoms of psychiatric illness defined. In: Kaplan HI, Sadock BJ, Grebb JA, eds. Kaplan and Sadock's Synopsis of Psychiatry: Behavioral Sciences Clinical Psychiatry, 7th Ed. Baltimore: Williams and Wilkins, 1993;300-308. [2] Denny-Brown D. Disability arising from closed head injury. JAmMed Assoc 1945;127:429-436. [3] Levin HS, Grossman RG. Behavioral sequelae of closed head injury: A quantitative study. Arch Neurol 1978;35:720-27. [4] Malkmus D, Booth BJ, Kodimer C. Rehabilitation of the head injured adult: Comprehensive congitive management. Downey, CA, Professional Staff Association of Rancho Los Amigos Hospital, Inc., 1979. [5] Reyes RL, Bhattacharyya AK, Heller D. Traumatic head injury: Restlessness and agitation as prognosticators of
204
[6] [7]
[8]
[9]
[10]
[11] [12]
[13] [14]
[15] [16] [17]
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physical and psychologic improvement in patients. Arch Phys Med Rehabil 1981;62:20-23. Mysiw WJ, Jackson RD, Corrigan JD. Amitriptyline for posttraumatic agitation. Am J Phys Med Rehabil 1988;67:29-33. Corrigan JD, Mysiw WJ. Agitation following traumatic head injury: Equivocal evidence for a discrete stage of cognitive recovery. Arch Phys Med Rehabil 1988;69:487-492. Brooke MM, Questad KA, Patterson DR et al. Agitation and restlessness after closed head injury: A prospective study of 100 consecutive admissions. Arch Phys Med Rehabil 1992;73:320-323. Sandel ME. Evaluation and management of the confused and agitated brain injured patient: Definitions and differential diagnosis. Paper presented at the annual meeting of the American Academy of Physical Medicine and Rehabilitation. Los Angeles, CA, November 1994. Mysiw WJ, Fugate L, Clinchot D. Assessment, early rehabilitation intervention and tertiary prevention. In: Hom U and Zasler ND, eds. Medical Rehabilitation of Traumatic Brain Injury. Philadelphia: Hanley and Belfus, in press. Diagnostic and Statistical Manual of Mental Disorders, 4th Ed. Washington, DC, Copyright American Psychiatric Association, 1994. Delirium. In: Kaplan HI, Sadock BJ and Grebb JA, eds. Kaplan and Sadock's Synopsis of Psychiatry: Behavioral Sciences Clinical Psychiatry, 7th Ed. Baltimore: Williams and Wilkins, 1993;338-344. Lipowski ZJ. Delirium (acute confusional state). In: Fredericks JAM, ed. Handbook of Clinical Neurology, vol. 2. New York: Elsevier, 1985;523-559. Jackson RD, Mysiw WJ, Corrigan JD. Orientation group monitoring system: An indicator for reversible impairments in cognition during posttraumatic amnesia. Arch Phys Med Rehabil1989;70:33-36. Kalisky Z, Morrison DP, Meyers CA et al. Medical problems encountered during rehabilitation of patients with head injury. Arch Phys Med Rehabil1985;66:25-29. Beyerl B, Black PM. Posttraumatic hydrocephalus. Neurosurgery 1984;15:257-260. Moss R, D'Amico S, Maletta G. Mental dysfunction as a sign of organic illness in the elderly. Geriatrics 1987;42:35-40.
[18] Zasler ND. Mild traumatic brain injury: Medical assessment and intervention. J Head Trauma Rehabil 1993;8:13-29. [19] Hom U, Zasler ND, eds. Rehabilitation of Post-concussive Disorders. Philadelphia, Hanley and Be1fus, 1992. [20] Ross CA, Peyser CE, Shapiro I et al. Delirium: Phenomenologic and etiologic SUbtypes. Int Psychogeriatr 1991;3:135-147. [21] Consensus Conference: Prevention of venous thrombosis and pulmonary embolism. JAmMed Assoc 1986;256(6):744-749. [22] Zeigler MG, Morrissey EC, Marshall LF. Catecholamine and thyroid hormones in traumatic injury. Crit Care Med 1990;18:253-58. [23] Hom U, Glenn MB. Update in pharmacology: Pharmacological and interventions in neuroendocrine disorders following traumatic brain injury, Part II. J Head Trauma Rehabil 1988;3:86-90. [24] O'Reilly MI, Reddick EJ et al. Sepsis from sinusitis in nasotracheally intubated patients. Am J Med 1979;66:463-467. [25] Bell RM, Page GV, Bynoe RP et al. Posttraumatic sinusitis. J Trauma 1988;28:923-930. [26] Vincent FM, Zimmerman JE, Van Haren J. Neuroleptic malignant syndrome complicating closed head injury. Neurosurgery 1986;18:190-193. [27] Sachdev P, Loneragan C. The present status of akathisia. J Nerv Ment Dis 1991;179:381-391. [28] Whyte J, Rosenthal M. Rehabilitation of the patient with traumatic brain injury. In: DeLisa JA, ed. Rehabilitation Medicine: Principals and Practice, 2nd Ed. Philadelphia: JB Lippincott, 1993;825-260. [29] Chandler NC, Barnhill JL, Gualtieri T. Amantadine for the agitated head injury patient. Brain Inj 1988;2:309-311. [30] Rowland T, Mysiw WJ, Bogner JA et al. Trazodone for posttraumatic agitation. Arch Phys Med Rehabil 1992;73:963. [31] Hale MS, Donaldson JO. Lithium carbonate in the treatment of organic brain syndrome. J Nerv Ment Dis 1982; 170:362-365. [32] Gurney JG, Rivara FP, Mueller BA et al. The effects of alcohol intoxication on the initial treatment and hospital course of patients with acute brain injury. J Trauma 1992;33:709-713.
ELSEVIER
NeuroRehabilitation 5 (1995) 197-204
Differential diagnosis of agitation following brain injury W. Jerry Mysiw*a, Rebecca D. Jackson b aDepartment of Physical Medicine
and Rehabilitation. The Ohio State University. Columbus. all 43210. USA Division of Endocrinology and Metabolism and Department of Physical Medicine and Rehabilitation. The Ohio State University. Columbus. OH 43210. USA
b Department of Medicine.
Accepted 17 April 1995
Abstract
Posttraumatic agitation is perhaps the most dramatic behavioral consequence of severe traumatic brain injury. The mechanism for this behavior remains to be determined. The development of effective management strategies has been hampered at least in part by the lack of a consensus definition for posttraumatic agitation. The diagnosis of posttraumatic agitation is a diagnosis of exclusion. Concurrent neurologic or medical decline during the recovery from an acute traumatic brain injury may precipitate delirium, which has many clinical features that overlap with posttraumatic agitation. Hence, the differential diagnosis of posttraumatic agitation includes all medical and neurologic etiologies for transient declines in consciousness and cognition. Keywords: Brain injury; Agitation; Diagnosis
----_._----- -------
-------------------------------
1. Introduction
The efficient evaluation, diagnosis and management of any disorder is predicated on a clear understanding of the observed condition. Yet, the development of management strategies, for agitation, and to a lesser extent a differential diagnosis, has been hampered by the absence of a clear
*Corresponding author, Dodd Hall, The Ohio State University, 480 W. 9th Avenue, Columbus, OH 43210, USA. Tel: + 1 614 293-3801.
and consistent definition in the rehabilitation literature. In the psychiatric literature, agitation is defined as any emotion associated with severe anxiety (feeling of apprehension caused by anticipation of danger, which may be internal or external) and motor restlessness [1]. Perhaps the first description of agitation secondary to brain injury appeared in 1945 where Denny-Brown described restlessness as a natural sequela after a traumatic brain injury (TBI) [2]. In 1978, Levin and Grossman described agitation as some combination of
1053-8135/95/$09.50 © 1995 Elsevier Science Ireland Ltd. All rights reserved. SSDI 1053-8135(95) 00117-0
191'
WJ. Mysiw, R.D. Jackson / NeuroRehabilitation 5 (1995) 197-204
combativeness, thrashing, truncal rocking, screaming or signs of sympathetic activation [3]. By the 1980s, references to agitation secondary to brain injury frequented the rehabilitation literature but without a clear consensus definition. In 1980, the Rancho Los Amigos Levels of Cognitive Functioning Scale was designed, where Rancho level IV was described as the confused agitated period [4]. Specifically, Rancho level IV is characterized by a heightened state of activity where a patient demonstrates a diminished capability of processing new information and associated behaviors that include aggressiveness, attempts to remove restraints or tubes, and inability to cooperate with treatment and confabulation [4]. In 1981, Reyes et a1. differentiated restlessness and agitation in that restlessness implied consistent activity but the patient was capable of briefly inhibiting a movement, whereas agitation was defined as constant uninhibited movement [5]. In 1988, our working group at The Ohio State University defined agitation as 'subjective evidence of one or more of the following behaviors: restlessness, derogatory or threatening demands, verbal abusiveness, sexually inappropriate comments or actions, or threats or attempts at physical violence of sufficient severity to disrupt nursing care or therapy' [6]. Later that year, agitation was defined by our group as achieving a score ~ 21 on the Agitated Behavior Scale (a 14 item-scale that rates the degree of specific observed behaviors, where total scores can range from 14 to 56) [7]. More recent trends in the brain injury literature appear to argue for an interdisciplinary definition of agitation. In 1992, Brooke et a1. utilized an instrument validated in the psychiatric population, the Overt Aggression Scale, to evaluate the efficacy of pharmacologic interventions of agitation after traumatic brain injury [8]. Also, at the 1994 American Academy of Physical Medicine and Rehabilitation meeting of the Brain Injury Special Interest Group, the term delirium was proposed as an appropriate alternative to agitation [9]. At our institution, agitation is presently conceptualized as a behavior during posttraumatic amnesia that is characterized by a combination of aggression, disinhibition and/or emotional labil-
ity [10]. This definition remains more specific to the traumatic brain injury population for several reasons. First, the present DSM-IV (Diagnostic and Statistical Manual of Mental Disorders) criteria for delirium describes disturbances in consciousness and changes in cognition but the criteria for delirium does not require a heightened state of activity that is typical of the Rancho Level IV patient [11]. Our proposed definition of agitation also accounts for the observations that: agitation is a discrete stage during the cognitive recovery after traumatic brain injury; agitation is not unique to Rancho level IV, but persists through late stages of posttraumatic amnesia; and that cognition improves before agitation diminishes [7]. 2. Differential diagnosis
The diagnosis of posttraumatic agitation should be considered a diagnosis of exclusion, largely because the anatomic and neurochemical basis of agitation remains undefined. Towards this goal, the delirium literature lends itself to close scrutiny for its applicability in the diagnosis and management of posttraumatic agitation. Again, it is not the intent of this section to imply that posttraumatic agitation and delirium are synonymous, but, because the very hallmark of delirium involves a transient impairmeht of both consciousness and cognition, the two syndromes possess numerous overlapping features. The correct diagnosis of delirium is in fact important because as previously stated, cognition tends to improve before there is an observed decrement in agitation [7]. Hence the removal of all potential impediments to cognitive recovery may facilitate the resolution of agitation. Perhaps a more important reason to exclude delirium as a source for problematic behaviors observed after traumatic brain injury is that this may in fact be the first or only indication of concurrent medical or neurologic decline. For example, the incidence of delirium on general medical and surgical services has been estimated at rates of 15-25% and 10-15%, respectively [12]. This incidence increases to 30% if the patient is in an intensive care unit or if there is a prior
WI. Mysiw, R.D. Jackson / NeuroRehabilitation5 (1995) 197-204
history of substance abuse, a preexisting central nervous system injury, medical illnesses such as diabetes or malnutrition and sensory impairments (i.e. blindness) [12,13]. The importance of correctly diagnosing delirium is underscored by the fact that the mortality of all patient populations with a diagnosis of delirium approaches 33% at 3 months and 50% at 1 year [12]. The mortality rate amongst TBI survivors who develop delirium is unknown but in view of the relative youth and premorbid good health of most survivors, it is unlikely to approach the mortality rates documented in general medical and surgical patients. Nevertheless, concurrent medical illness has been documented to adversely affect cognitive recovery during posttraumatic amnesia. Jackson et al. demonstrated that etiologies as diverse as medication adverse reactions, surgery, febrile illness, hydrocephalus, chronic subdural hematoma and seizures could account for declines in the cognitive function that persisted for days to weeks [14]. Furthermore, during posttraumatic amnesia, the decline in cognitive function was the first indication of concurrent medical illness in 60% of the cohort [14]. An evaluation of the literature reveals that delirium has been referred to by a wide variety of other names including: acute confusional state, acute brain syndrome, metabolic encephalopathy, toxic psychosis, acute brain failure and sundowning [12]. This in part contributes to the previously mentioned observations that delirium is an under recognized and under diagnosed disorder. Retrospective studies of TBI survivors during acute inpatient rehabilitation reveal that survivors are subject to a host of medical and neurologic complications that place them at risk from delirium [15]. It has been observed that 56% of TBI survivors develop neurologic complications during acute inpatient rehabilitation that are of sufficient severity to warrant additional investigation and intervention [15]. The most common category of neurologic complications is ventricular dilatation, occurring in 37% of survivors. The important distinction in this subpopulation is between hydrocephalus ex vacuo, normal pressure hydrocephalus or obstructive hydrocephalus. The oc-
199
currence of normal pressure hydrocephalus after traumatic brain injury is relatively common with estimated incidences ranging between 29 and 72% [16]. Although normal pressure hydrocephalus is more likely to present as a dementia, with an insidious rather than acute or subacute onset, less fluctuation over the course of a day, psychomotor retardation and apathy, symptoms suggestive of delirium or posttraumatic agitation such as anxiety, delusional thinking, hallucinations, emotional lability and paranoia have been reported [17]. Posttraumatic seizures account for the second largest category of neurologic complications during posttraumatic amnesia, with 13% of survivors having a documented event prior to the completion of their inpatient rehabilitation stay [15]. Epilepsy may be associated with delirium in one of four ways: (1) as an ictal event; (2) as a post-ictal event; (3) as an interictal event; and (4) as an adverse reaction to anti-epileptic medication [13]. Other potential CNS events during inpatient rehabilitation with a known predisposition to present as delirium include delayed subdural hematoma or hygroma, meningitis and other CNS infections [12,13,15]. Finally, posttraumatic headaches are among the most common sequela of mild through severe traumatic brain injury. The fact that migraine features are common to these posttraumatic headaches is salient, in that, it has been estimated that 8% of patients suffering from severe migraine headaches occasionally develop delirium [13,18,19]. Gastrointestinal problems account for the second largest category of medical complications during inpatient rehabilitation, with 50% of TBI survivors developing problems [15]. Elevations in liver function tests account for the majority of gastrointestinal related complications with an estimated 43% of survivors demonstrating abnormal values. The incidence of hepatic encephalopathy after traumatic brain injury is unknown but this diagnosis is worth considering as hepatic encephalopathy may feature delirium. However, the presentation of that delirium is much more likely to be somnolent rather than activated, and thus, the potential for confusing posttraumatic agita-
200
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tion with delirium secondary to hepatic encephalopathy is small [20]. Peptic ulcer disease-related symptoms account for the second largest category of gastrointestinal disorders documented during inpatient rehabilitation with an incidence of less than 10% of TBI survivors [15]. The management of these disorders with a Hz-receptor antagonist may induce delirium; cimetidine, for example, has an incidence of 1.1 per 100000 patients treated for developing subsequent delirium [13]. Unrecognized peptic ulcer disease may also present as a delirium secondary to anemia [13]. Finally, acute pancreatis may present as a co-morbid diagnosis with TBI secondary to blunt abdominal trauma; secondary pancreatic encephalopathy may feature delirium [13]. The third largest category of medical complications after traumatic brain injury involves respiratory problems· with approximately 39% of survivors developing either problems with colonization of the airway, pneumonia or atalectasis [15]. Potential secondary sources of delirium then include fever, hypoxia, carbon dioxide narcosis and adverse reactions to antibiotics [12,13]. The overall incidence of pulmonary emboli after traumatic brain injury has been estimated at 3%; the estimated mortality rate secondary to pulmonary emboli is 1% [15,21]. This incidence is salient in that a pulmonary emboli can present with delirium [13]. Cardiovascular disorders represent the fourth largest category of medical issues noted during the acute stages of recovery after traumatic brain injury with an overall incidence estimated at 32% of survivors. The majority, approximately twothirds, are non-specific EKG changes [15]. In primarily a young population of TBI survivors, delirium may present as the consequence of arrhythmias, hypertension, or hypotension secondary to prolonged bedrest, complications of pharmacologic intervention or neuroendocrine etiologies such as hypothalamic or pituitary disorders [22]. Endocrine disorders most likely to occur concurrently with a traumatic brain injury include the
syndrome of inappropriate antidiuretic hormone secretion, hypothyroidism and panhypopituitarism. The overall incidence of endocrine disorders after TBI has been estimated at 20% of acute survivors [23]. All of these conditions may present with delirium [12,13]. Metabolic disorders such as infection and fever affect the brain to the extent that secondary widespread cerebral dysfunction may present as a delirium. Most likely sources of infection among brain injury survivors during the rehabilitation phase of recovery include urinary tract infections in approximately 40% of survivors [15], respiratory complications that predispose to infection in approximately 34% of survivors [15], and sinusitis secondary to intubation in approximately 26% of survivors [24,25]. Adverse reactions to medication may include febrile responses with perhaps the most life threatening being the neuroleptic malignant syndrome. This rare, but potentially fatal complication of dopamine antagonist medication presents with a combination of extrapyramidal signs, autonomic disturbances and altered levels of consciousness [26]. Numerous other medications are linked to adverse reactions that include behavioral and cognitive changes consistent with delirium. Acetylcholine is the neurotransmitter system hypothesized to be most closely linked with delirium, hence, anticholinergic agents, such as numerous antidepressants and antipsychotics, are among the most common causes of delirium [12]. Antipsychotic agents may also result in the development of akathisia, where the subsequent motor restlessness can be mistaken for a worsening of agitation [27]. Other medications with specific rehabilitation implications that are known to occasionally induce delirium include anticonvulsants, antiparkinsonian agents, opiates, lithium, clonidine, cimetidine and ranitidine [12,13]. It is noteworthy that a number of the medications successfully utilized in the management of posttraumatic agitation involve adverse reactions such as delirium [6,28-31]. Approximately 40% of TBI patients are intoxicated at the time of admission [32]. The prepon-
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derance of survivors with a history of substance abuse is similarly high, placing them at risk for behavioral disturbances and delirium secondary to withdrawal. [12,13]. Similarly, the evaluation of the confused agitated patient should include some of the known vitamin deficiencies known to accompany substance abuse (Table 1) [12,13]. 3. Evaluation
The physical examination of the confused agitated patient therefore involves a careful, syste-
matic evaluation to exclude all neurologic and metabolic etiologies for a decline in mental status. The physical examination as outlined in Table 2 can be used as a framework to begin the evaluation and guide the selection of additional diagnostic studies (Table 3). In the event that the physical examination fails to suggest specific etiologies for observed problematic behaviors, the baseline studies as outlined in Table 3 should be considered. The additional studies described in Table 3 are more appropriate if suggested by the history and physical examination, or if the behav-
Table 1 Known causes of delirium with potential implications for causing or worsening posttraumatic agitation Central nervous system epilepsy and post-ictal states space-occupying lesions hematoma/hygroma neoplasm - primary or remote effects aneurysm abscess infection encephalitis meningitis vascular disease thrombosis embolism hemorrhage migraine Drugs aminophyline anticholinergic agents (ex tricyclic antidepressants) antiarrythmics antibiotics anticonvulsants antiparkinsonian drugs antipsychotics cardiac glycosides cimetidine, ranitidine, etc. clonidine disulfiram insulin lithium opiates phencyclidine salicylate sedative /hypnotics (barbiturates, benzodiazepines, etc.) steroids
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Intoxication alcohol carbon monoxide Drug withdrawl alcohol sedatives /hypnotics / amphetamines Metabolic endocrine (hypo or hyperfunction) adrenal parathyroid pancreas pituitary thyroid Hepatic encephalopathy Renal encephalopathy Pulmonary carbon dioxide nacrosis hypoxia Cardiac failure arrythmia hypo /hpertension Vitamin deficiency thiamine nicotinic acid folate
Bl2
Anemia Fluid, electrolyte, acid-base balance disturbances Systemic infection AIDS Postoperative states
Table adapted from Kaplan and Sadock's Synopsis of Psychiatry: Behavioral Sciences, Clinical Psychiatry (7th Ed.).
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ior persists despite an otherwise unremarkable evaluation. Finally, it is prudent to exclude all noxious stimuli as potential sources of restlessness in a patient who otherwise has limited communication options.
4. Conclusion
Despite the preponderance of posttraumatic agitation and the subsequent significant rehabilitation implications, the development of manage-
Table 2 Physical examination of the confused, agitated patient Parameter 1. Pulse
Finding
Clinical implications
Bradycardia
Hypothyroidism Stokes-Adams syndrome Inc intracranial pressure Hyperthyroidism Infection Heart failure
Tachycardia
2. Temperature
Fever
3. Blood pressure
Hypotension Shock
Hypertension 4. Respiration
5. Carotid vessels
Tachypnea
Sepsis Thyroid storm Vasculitis Hypothyroidism Addison's disease Encephalopathy Intracranial mass
Shallow
Diabetes Pneumonia Cardiac failure Fever Acidosis {metabolic} Alcohol/substance abuse
Bruits
TIA
6. Scalp and face
Evidence of trauma
7. Neck
Evidence of nuchal rigidity
Meningitis SAH a
8. Eyes
Papilledema
Tumor Hypertensive encephalopathy
Lacerations
Seizures
10. Thyroid
Enlarged
Hyperthyroidism
11. Heart
Arrhythmia Cardiomegaly
Cardiac output, emboli Heart failure Hypertensive disease
12. Lungs
Congestion
Pulmonary failure Pulmonary edema Pneumonia
13. Breath
Alcohol Ketones
Diabetes
14. Liver
Enlargement
Cirrhosis Liver failure
9. Mouth
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Table 2 (Continued) Parameter
Finding
Clinical implications
15. Nervous system a. Reflexes muscle stretch
Asymmetry with Babinski sign
Mass lesion Cerebrovascular disease Preexisting dementia Frontal mass Bilateral PCAb occlusion Inc. intracranial pressure Mass lesion Cerebrovascular disease Anxiety Delirium
c. Limb strength
Snout Weakness in lateral gaze Asymmetrical
d. Autonomic
Hyperactivity
b. Abducens nerve
a Subarachnoid
hemorrhage. cerebral artery. Table from R.L. Strub, FW. Black: Neurobehavioral Disorders: A Clinical Approach, p. 120, Davis, PA, 1981. Used with permission. b Posterior
ment strategies remains hampered by the failure to develop the consensus definition necessary to foster thoughtful and meaningful investigation concerning its etiology and treatment. In our institution, posttraumatic agitation is conceptualized as a behavior during posttraumatic amnesia that consists of a combination of aggression, disinhibition and/or emotional lability [10]. Delirium is not sufficient as a synonmous term with
Table 3 Medical evaluation of the confused-agitated patient Baseline tests complete blood count electrolytes, glucose, BUN, creatinine, liver function tests T4 , TSH urinalysis electrocardiogram chest X-ray Additional tests blood, urine, cerebrospinal fluid cultures B12 , folic acid levels CT or MRI of brain lumbar puncture electroencephalogram (EEG) serologic tests for syphilis HIV antibody test Table adapted from Kaplan and Sadock's Synopsis of Psychiatry: Behavioral Sciences, Clinical Psychiatry (7th Ed).
posttraumatic agitation because delirium is a syndrome with a host of potential etiologies and presentations; it is for example not necessary to be agitated to meet the diagnostic criteria for delirium. Because we have no known anatomic or neurochemical mechanism to explain posttraumatic agitation, the diagnosis of posttraumatic agitation remains a diagnosis of exclusion. Despite the fact that delirium and posttraumatic agitation are not synonymous, the respective presentations of these disorders overlap sufficiently to warrant the exclusion of delirium as a source of observed disruptive behaviors. References [1] Typical signs and symptoms of psychiatric illness defined. In: Kaplan HI, Sadock BJ, Grebb JA, eds. Kaplan and Sadock's Synopsis of Psychiatry: Behavioral Sciences Clinical Psychiatry, 7th Ed. Baltimore: Williams and Wilkins, 1993;300-308. [2] Denny-Brown D. Disability arising from closed head injury. JAmMed Assoc 1945;127:429-436. [3] Levin HS, Grossman RG. Behavioral sequelae of closed head injury: A quantitative study. Arch Neurol 1978;35:720-27. [4] Malkmus D, Booth BJ, Kodimer C. Rehabilitation of the head injured adult: Comprehensive congitive management. Downey, CA, Professional Staff Association of Rancho Los Amigos Hospital, Inc., 1979. [5] Reyes RL, Bhattacharyya AK, Heller D. Traumatic head injury: Restlessness and agitation as prognosticators of
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