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REGULAR ARTICLES

Effect of Amantadine
Hydrochloride on Symptoms of
Frontal Lobe Dysfunction in
Brain Injury: Case Studies and
Review
Marilyn F. Kraus, M.D.
Pauline M. Maki, Ph.D.

Symptoms consistent with dysfunction of the fron- Traumalic brain injury (TB!) is a significant cause of
mortality and morbidity. More than 2,000,000 peo-
tal lobes can occur following traumatic brain in-
ple in the U.S. will sustain a TBI, and 500,000 will require
jury (TBI) or other types of acquired brain injury
hospitalization. Of those who survive, up to 90,000 will
(stroke, aneurysm). These symptoms can include have chronic disability.’ Brain injury from trauma as
problems with short-term memory, attention, plan- well as other causes, such as a stroke, can result in
ning, problem solving, impulsivity, disinhibition, disability due to persistent cognitive, behavioral, or
poor motivation, and other behavioral and cogni- mood disturbances. Commonly, these changes in men-

tive deficits (“frontal lobe syndrome”). These symp- tal functioning prevent the patient from successful so-
cial and occupational reintegration. Interventions such
toms may respond to certain drugs, such as
as the use of certain pharmacologic agents may substan-
dopaminergic agents. This case series describes re- tially improve the level of functioning these patients
sults of using amantadine in 7 patients with this achieve.
type of symptom profile (6 with TBI, 1 with menin- Although most of the patients in this series had Se-
gitis following sinus surgery). Patients received quelae of TBI, we have found that other types of brain
injury with similar symptom profiles can respond to the
neuropsychiatric examinations and serial neuropsy-
same pharmacologic interventions. There are often
chological testing. All patients showed some degree
complicating factors in a clinical setting, such as a his-
of positive response. One had side effects that re- tory of psychiatric problems or developmental disor-
solved upon discontinuation of drug. The rationale ders. This series attempts to reflect some of this diversity
for using dopaminergics is discussed, and perti- while showing the common factor of frontal lobe dys-
nent literature is reviewed. function. Amantadine hydrochloride and other dopa-
(The Journal of Neuropsychiatiy and Clinical minergic agents appear to be promising means of
Neurosciences 1997; 9:222-230) treating these types of sequelae in brain injury.
One rationale for the use of amantadine and other

Received February 15, 1996; revised July 2, 1996; accepted July 8, 1996.
From the Department of Psychiatry and Behavioral Sciences, Johns
Hopkins School of Medicine, Baltimore, Maryland. Address correspon-
dence to Dr. Kraus, University of Pittsburgh Medical Center, Western
Psychiatric Hospital and Clinic, Neuropsychiatry Division, 3811 O’Hara
Street, Pittsburgh, PA 15213.
Copyright © 1997 American Psychiatric Press, Inc.

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dopaminergics is based on current knowledge of acute is rapidly absorbed after oral administration, and steady
neurotransmitter alterations in brain injury. Specifical- state can be achieved within 48 to 72 hours. Interactions
ly, lowered levels of dopamine metabolites have been with other drugs appear to be uncommon.9 Compared
found in brain injur’3 and may be involved in cogni- with other antiparkinsonian agents, amantadine is rela-
tive, mood, and behavioral changes. It appears from tively free of side effects. Those that do occur are gener-
acute studies that disturbances of neurotransmitter ally mild and transient and are always reversible. Side
function may persist in symptomatic patients years after effects tend to be dose-dependent and may be worse in
an injury, although this has not been studied. Anatomi- Parkinson’s disease patients and others receiving a con-
cal studies have shown the significant role of dopamine comitant anticholinergic agent. Possible effects include
in the frontal regions.4 Trauma also commonly affects insomnia, jitteriness, poor concentration, depression,
the prefrontal regions, either directly or indirectly.5 and gastrointestinal effects such as dyspepsia. Psychosis
General “frontal lobe” dysfunction, including symp- and other severe side effects are uncommon and seem
toms of behavioral dyscontrol such as impulsivity and to occur only when plasma concentrations are high.9
aggression, amotivation, apathy, disorganization, at- The drug is not recommended for patients with renal
tentional and memory deficits, other features of execu- dysfunction because it is eliminated primarily via the
tive dysfunction, and mood disregulation, is commonly kidneys.
observed in brain-injured patients. Hence, dopaminer-
gic agents may be a rational choice for treatment of these Clinical Uses of Amantadine
sequelae.6 Currently, the literature consists of mostly small or un-
controlled studies of use in neuropsychiatric conditions.
Characteristics and Properties of Gualtieri et al.’3 treated 30 TBI patients who were 2 to
Amantadine Hydrochloride 144 months postinjury with amantadine for severe
Amantadine was originally introduced for its antiviral neurobehavioral symptoms in an uncontrolled study.
properties in the 1960s,7 and later it was found to be Response was assessed by clinical staff and family, and
effective in treating parkinsonism.8 It is a water-soluble only those patients rated by observers as having a clear
acid salt that can penetrate all cell membranes, includ- positive response were considered “responders.” Nine-
ing those in the central nervous system. Its precise teen patients (63%) were noted to have reductions in
mechanism has not yet been defined, but it clearly has agitation, physical aggressiveness, distractibility, and/or
a dopaminergic effect. It facilitates dopamine (DA) re- mood swings; 14 of these were considered responders
lease from central neurons and delays DA reuptake.9 and 5 were considered partial responders. All had ex-
Amantadine may also have a more direct, postsynaptic tensive frontal and temporal lobe injuries. Although the
effect of increasing the number of postsynaptic DA re- majority had closed head injuries, 1 had an open head
ceptors10 or altering their conformation.11 Other neuro- injury and 1 had a stroke. Four patients had to discon-
transmitter systems do not appear to be affected by the tinue drug secondary to side effects. The mean dose was
drug. 288.3 ± 87.3 mg/day, and the optimum dose ranged
Other properties of amantadine might offer addi- from 50 to 400 mg/day. Improvement was sustained
tional benefits in the treatment of brain injury. Aman- over several months of follow-up.
tadine is an N-methyl-D-aspartate (NMDA) glutamate More recently, Van Reekum et al.14 reported a double-
receptor antagonist, and accordingly might provide blind placebo-controlled case study of 1 severely brain
protection against secondary damage resulting from injured patient who was 6 months posttrauma. On
release of this excitotoxic neurotransmitter.12 NMDA amantadine 100 mg tid, the patient improved on many
receptor inhibition reduces cholinergic transmission behavioral ratings, including apathy, amotivation,
and also indirectly enhances dopaminergic transmis- slowness, and perseveration.
sion. Amantadine and other glutamate agents have the Andersson et al.15 reported 2 cases of improved cogni-
potential to restore the balance between glutamatergic tive function in patients with histories of severe TB! who
and dopaminergic systems. This potential has were given daily doses of 200 to 400 mg. Improvements
prompted researchers to advocate the use of these in visual attention, speed of information processing,
agents in neuroleptic malignant syndrome when DA attentional span, learning, and alertness were attributed
transmission has been antagonized by neuroleptics.’2 to dopaminergic facilitation.
However, clinical implications of this finding are not yet Nickels et al.16 reviewed the charts of 12 brain injury
clear. patients treated with amantadine. Nine patients had
Clinical effects of amantadine can be observed fairly injuries due to trauma, 2 had hemorrhages resulting
quickly, usually within a few days to a week. The drug from aneurysms, and I had encephalitis. Ten of the 12

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AMANTADINE AND FRONTAL LOBE SYNDROME

showed improvement in cognitive and/or physical METHODS


function. Most were within several months of the injury
and were treated in an inpatient rehabilitation setting. Subjects
Chart notes suggested that TB! patients experienced Seven patients, 6 with TB! and I with meningitis, were
decreases in agitation, anxiety, rigidity, and fatigue and included. Patients were at least 1 year postinjury. Each
improvements in attention, concentration, alertness, case report included neuropsychiatric and neuropsy-
motor speed, and response time. One TB! patient and chological evaluations. Table 1 summarizes the cases.
the encephalitis patient did not respond to the medica- Three cases that we feel represent some of the premor-
tion. Five patients showed possible side effects, includ- bid and etiologic diversity of brain-injured patients who
ing hypomania, pedal edema, generalized seizures, and demonstrate symptoms of frontal lobe dysfunction are
visual hallucinations, but the exact relationship of these described in detail (pp. 226-228).
effects to amantadine is unclear.
Amantadine has also been preliminarily shown to Clinic Protocol
improve clinical status in dementia patients,172#{176} al- For each case, baseline neuropsychiatric and neuropsy-
though these studies were also mostly uncontrolled or chological evaluations are completed. Amantadine is
small-sample studies. Improvements were noted in then begun at a low dose, 50-100 mg bid, and titrated
alertness, activity level, mood, response time, and EEC. up at weekly intervals as tolerated to a maximum of 400
In a controlled study, young normal subjects given mg/day in divided doses. This dose is based on the
amantadine 100 mg showed a decrease in slow activity available literature on dosage and side effects and on
associated with an increase of higher alpha activity and clinical experience. Patients are reevaluated following
lower fast activity on EEC. A similar effect was found treatment. The final daily dose for each case in the
for bromocriptine 1.25 mg. This effect was thought to present series is included in Table 1.
reflect enhanced vigilance.21 To decrease the effects of practice on neuropsycho-
Moryl et al2 demonstrated potential antidepressant logical test performance in this series, an interval of 3 to
effects in an animal study. Amantadine may also be 6 months was imposed between neuropsychological
useful in treating the fatigue and depression of multiple evaluations. Six cases include data at baseline and fol-
sclerosis.23 lowing treatment.
A patient in a persistent vegetative state for 3 years All patients were continuing with treatment after our
due to progressed olivopontocerebellar atrophy became assessment except Case 7. This patient did not complete
responsive and began to follow commands after being a follow-up neuropsychological evaluation because
treated with amantadine 300 mg/day.24 After with- amantadine was discontinued owing to side effects, but
drawal of the drug the patient regressed, but with rein- clinical follow-up was obtained. At baseline, Case 7’s
stitution of the drug she again became responsive. neuropsychological test performance was notable for a
Interestingly, a trial of levodopa did not have any effect. higher MMSE score and poorer naming than the other
This disparity could reflect the different mechanism of 6 cases. Otherwise, his performance was similar to that
amantadine, which has both direct and indirect effects. of the 6 patients who continued to receive amantadine.
The efficacy of amantadine as an adjunct treatment of We include this case as an example of the side effects
epilepsy has also been investigated in both adults and that may cause discontinuation in spite of initial posi-
children, with mixed results. tive response.
In summary, amantadine has primarily been used
clinically for the treatment of Parkinson’s disease. Its Neuropsychiatnc Evaluation
use in other disorders, such as epilepsy, dementia, and A neuropsychiatnst performed the evaluation, which
brain injury, has been prompted by case studies or included patient and caretaker interviews, a neurologic
small controlled studies showing improvements in cog- examination, and a mental status examination. A similar
nitive functioning, EEC records, activity levels, or de- format was used for follow-up visits to assess any
pressive symptoms. To date, however, no case series change in symptoms or functioning. All evaluations and
involving both clinical and neuropsychological out- follow-up exams were performed by the same investi-
comes in brain injury has been reported. Below, we gator (M.K.).
report 7 cases, most of them several years postinjury,
that lend further support to the efficacy of amantadine Neuropsychological Evaluation
in treating cognitive and behavioral sequelae of brain The 1-hour neuropsychological evaluation included
injury patients. tests selected to measure a variety of cognitive func-

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tions, with particular emphasis on tests sensitive to connect a spatial array of numbers as quickly as possi-
frontal lobe function. The investigator (P.M.) was not ble, a task requiring graphomotor speed and coordina-
blind to treatment condition at the second evaluation. tion. On part B, they attempt to alternate between
The Mini-Mental State Examination27 (MMSE) and the numbers and letters in a similar spatial array, a task
Test for Severe Impairment were administered as requiring mental flexibility. The latter two tests serve as
global measures of mental status. Constructional praxis measures of frontal lobe functioning.3233 A 30-item Bos-
was assessed with the Clock Drawing Test, which re- ton Naming Test assessed confrontation naming.TM
quires subjects to draw a clock to command, and then
to copy one.29 The Hopkins Verbal Learning Test3#{176}
as-
sessed immediate recall, delayed recall, and delayed RESULTS
recognition of 12 words from 3 categories. Sustained
attention was measured with the Hopkins Attention Global Rating
Screening Test, which requires subjects to attend to, and All of the patients showed some degree of positive
then reproduce, a visuospatial pattern. The task is akin clinical response, 3 being rated by the investigators as
to a visuospatial digit-span test. The Brief Test of Atten- responders and 4 as partial responders. This rating was
tion31 served as a measure of auditory divided attention. an overall rating based on clinical evaluation, family
In each of 20 trials, patients heard a list of numbers and and patient report, and testing. A responder was one
letters, and attempted to attend to the number of times who had positive effects on clinical evaluation and care-
they heard one type of stimulus (e.g., number). Patients taker interview (the neuropsychiatric evaluation) and
were administered verbal fluency tests for letter (S and who showed a significant improvement (at least two
P) and category (animals and supermarket items).32 The standard deviations) on at least one neuropsychological
Trail Making Test was also administered.33 The test is test. Partial responders showed gains on clinical assess-
composed of two parts. On part A, subjects attempt to ment and caretaker interviews (such as improved mood

TABLE 1. Brief summary of case histories and results

Age!
Patient Sex Brief History Final Dose/Results R Side Effects

Ms. A. 43/F Birth brain injury resulting in MR, SZ; 25 mg/day R +


2nd TBI in 1976 resulting in significant T response in speech, motor ability, See case text
decrease in function, mutism activity level, cognition

Ms. B. 50/F Severe brain injury due to MVA in 1990; 400mg/day R


5 mos in coma; severe cognitive, behavioral, response in attention, executive function,
physical difficulties behavior, mood, motivation

Ms. C. 39/F Meningitis secondary to CSF leak 400mg/day PR


during surgery; persistent cognitive, I response in motivation, energy,
mood, behavioral problems executive function

Case 4 29/M Severe brain injury due to MVA in 1993; 400 mg/day PR
2 wks in coma; persistent cognitive, I response in memory, mood, motivation,
mood problems psychomotor speed

Case 5 37/M Severe brain injury due to MVA in 1977; 300 mg/day PR
45 days in coma; severe behavioral I executive function, memory, attention;
disturbance and occasional manic episodes; calmer, less dyscontrol
multiple psychiatric hospitalizations

Case 6 27/F Severe brain injury due to MVA in 1985; 400mg/day PR


I mo in coma; persistent cognitive, behavioral, 1’ executive function, attention; less
and affective symptoms; self-injury dyscontrol, improved mood

Case 7 36/M TB! due to MVA in 1991; 1 wk in coma; Pt reported initially I response in alertness PR +
mild cognitive deficits; MMSE and other and energy on 300 mg/day, but side effects Light-headedness,
cognitive functions were higher than resulted in decreased dosage resolved with
those of other patients at baseline decreased dosage

Note: MR = mental retardation; SZ = seizures; TB! = traumatic brain injury; MVA = motor vehicle accident; CSF = cerebrospinal fluid;
MJvISE = Mini-Mental State Examination; R = responder: clear and significant benefit, including gains on testing results; PR = partial responder:
clear, but lesser, benefit that may not include significant gains on testing; I = increased; + = present; - = absent.

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AMANTADINE AND FRONTAL LOBE SYNDROME

or behavior), but any changes on neuropsychological A performance (Z = 1.75, 2.02, and 1.6, respectively).
testing did not reach significant levels. Table 1 summa- Three cases are described in detail below.
rizes all cases.

Side Effects CASE REPORTS


Two patients had suspected side effects. The first was a
young TB! patient who complained of light-headed- Case 1. Ms. A. is a single, 43-year-old, right-handed
ness. He had reported a positive response to aman- woman with a history of seizure disorder since birth secon-
tadine, reporting improved alertness and energy level, dary to birth trauma, mental retardation, and hypothyroid-
ism. Her parents described her as placid and cooperative,
but the drug was discontinued. Side effects resolved
with no verbally or physically aggressive behavior. She at-
shortly after stopping drug, as did the positive effects.
tended special education classes until age 21, learned to read
Another case (Ms. A.), to be described in detail, had a
at the 4th grade level, and received vocational training. With
number of suspected side effects, but because of the supervision, she worked effectively at a book bindery for 2
complexity of her case it is not clear whether they were years.
related solely to the amantadine. Ultimately she was Almost 20 years ago, Ms. A. had a seizure, fell, and struck
able to tolerate a low dose (50 mg/day) with a lessened her head. She became comatose, with pupils dilated bilater-
degree of positive response. The other patients had no ally, and underwent surgical evacuation of a left parietal
reported adverse effects. epidural hematoma. After awaking from coma, the patient
was akinetic and mute, had spasticity in the extremities, and
Neuropsychological Test Results required total nursing care. For seizure control, she received
Table 2 shows the results of neuropsychological tests for phenytoin and carbamazepine; the latter was tapered and dis-
continued due to a leukopenia 10 years after the TB!. EEC
the 6 patients who completed neuropsychological test-
showed continuous slow wave discharge in the left anterior
ing before and after treatment with amantadine.
quadrant. Other laboratory values, including thyroid func-
Nonparametnc statistical analyses with P < 0.05, one-
tions, were normal. In September of the following year, 11
tailed, as the level of significance (Wilcoxon’s matched- years posttrauma, Ms. A. could ambulate only with two assis-
pairs signed-ranks test) were conducted on data from tants. A brain CT scan in August 1993 was read as normal. For
the 6 cases. Significant improvements were observed in 18 years following the trauma, she remained mute and could
letter and category fluency and in Trail Making Test part respond only by nodding or shaking her head.

TABLE 2. Summary of demographic data and neuropsychological test results for 6 cases before and after treatment with amantadine

Variable Ms. A. Ms. B.a Ms. C. Case 4 Case 5 Case 6

Age (yrs) 43 50 39 29 37 27
Education (yrs) l9’ 14 16 12 II 11
Intertest interval (mos) 3 6 4 4 4 6
MMSE 0/13 13/14 NA/26 21/19 24/21 24/26
Boston Namin 0/17 NAJ7 NA/30 27,28 28/28 30/30
Letter Fluency 0/5 5/10 30/NA 17,22 20/17 26/43
Category Fluency 0/1 12./15 NA/NA 31/32 25/30 31/47
Clock Copy 0/1 3/3 NA/NA 4/3 5/5 5/5
Clock Construction 0/1 2/1 NA/NA 3/3 5/5 5/5
Immediate Recall 0/3 11/11 NA/NA 14/13 15/15 20/17
Delayed Recall 0/0 1/NA NA/NA NA/0 0/1 2/0
Recognition Memory 0/0 5/NA NA/NA NA/P 7/4 4/3
Divided Attention 0/NA NA/0 8/13 NA/7 0/8 16/15
Sustained Attention 0/0 1/1 NA/NA 5/6 6/6 6/6
Trail Making part A 300/300 239/62 49/36 97/’71 44/62 49/38
Trail Making part B C 600/600 600/600 253/99 600/561 240/203 169/105

Note: Visit I data (before amantadine treatment) appear before the slash, and Visit 2 data (after amantadine treatment) appear after the slash.
MMSE = Mini-Mental State Examination; NA = not available.
‘First visit was on 100 mg amantadine and second visit was on 400 mg. Prior to Visit 1 the patient was unable to complete part A of the Trail
Making Test.
“Special education.
cValue of 600 indicates inability to complete in specified time.
‘Significant Wilcoxon’s matched-pairs signed-ranks test, P < 0.05, one-tailed.

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In late 1993, the patient began receiving amantadine (for pen, write her name, or close her eyes. She showed no
flu prophylaxis) and valproate. An evaluation 3 months later change on scales of memory and conceptualization.
noted that Ms. A. had begun to speak single words and to re- A month later, Ms. A. was restarted on a low dose of 25 mg
spond in sentences to prompts or questions. Reports sug- bid with no recurrence of side effects and with a partial posi-
gested that her improved speech coincided with improved tive response compared with her initial response.
alertness and activity level. After another 3 months, the aman-
tadine was discontinued because of a rash. After discontinu- Case 2. Ms. B. is a 50-year-old, married, right-handed
ation, the rash resolved, but she again became mute. She woman with 14 years of education who sustained a severe
regressed to her state prior to amantadine and would re- brain injury in a motor vehicle accident 5 years ago. Her pre-
spond to questions only by shaking or nodding her head. senting Glasgow Coma Scale score was 4, and she was coma-
At this point, Ms. A. was referred to our clinic. Prior to her tose for 5 months. She suffered an open depressed skull
first visit, we suggested amantadine be restarted at a low fracture on the left, a blowout fracture of the left orbit, and
dose (100 mg bid), with careful monitoring for side effects. optic nerve damage, resulting in impaired vision in the left
Her other medications included valproic acid 400 mg (level eye. Premorbidly, she was a physically healthy, inde-
within therapeutic range at 73.7), iron supplement, and pendent, and high-functioning entrepreneur. With her hus-
levothyroxine 0.2 mg. Her thyroid status was stable. She was band’s persistent commitment to her recovery, she showed
receiving occupational, physical, and speech therapy, and she some improvement, but she remained impulsive, irritable,
was dependent in all activities of daily living (ADLs). Approxi- and, on occasion, physically aggressive. She performed tasks
mately 12 days after restarting the amantadine, Ms. A. began quickly and impulsively. For example, her handwriting was
to show an overall improvement in functioning. She gave re- scrawled, and she tended to gulp her food and on occasion
sponses of one to three words, knew her roommate’s name, almost choked. Other residual problems included
was more cooperative with ADLs, and began to assist staff dysarthria, incoordination, and gait problems. Psychological
with dressing and transfers. testing at another clinic in early 1994 revealed abilities in the
Ms. A. was initially seen in our clinic 15 days after restart- mentally retarded range (Wechsler Adult Intelligence Scale-
ing amantadine. On examination, she was wheelchair bound, Revised Full Scale IQ of 68) and comparable memory abili-
alert, pleasant, and cooperative. Her speech was coherent but ties. Significant impairments were also observed on tests of
nonfluent, monotone, and dysarthric. She responded in a executive functioning, attention, and concentration. Ms. B.
goal-directed manner with short sentences or single words, first visited our clinic in the fall of 1994. Her medications in-
and she followed her father’s prompt to join him in singing a cluded buspirone 10 mg tid for agitation, a variety of vita-
song she knew as a child. She described her mood as good, mins, and estrogen replacement. The buspirone was
but her affect was blunted and she seemed tired. Her discontinued after the caretakers reported no benefit. Her
neurologic examination was notable for brisk deep tendon re- mental status was significant for mild emotional lability, im-
flexes and for generalized weakness and spasticity that were pulsivity, distractibility, and perseveration. For example, con-
greater in the left upper extremity. Her toes were upgoing, sistent with her behavior at home, she repeatedly requested
with two to three beats of clonus bilaterally. On neuropsycho- to go to the bathroom. (A full urologic workup had been
logical examination, she wrote her name and followed com- negative.) Her speech was dysarthric, with paraphasic er-
mands but showed deficits in all areas tested. An area of rors. Ms. B. admitted to occasional episodes of low mood.
relative strength was her naming ability. She earned an age The impression was that cognitive, behavioral, and mood
equivalent of 4 years and 7 months on a test requiring her to problems were consistent with frontal lobe dysfunction re-
copy geometric figures. sulting from her ThI.
Within a month, drug was increased to 300 mg/day, di- Amantadine was begun at a dose of 50 mg bid. Although
vided doses. Two weeks later, Ms. A. became nauseated and the patient had already been through extensive therapies and
vomited, seemed more hyperactive, and occasionally exhib- was working with her caretaker on basic cognitive tasks at
ited a facial “twitch.” Her dose was reduced to 200 mg/d, then home, physical and speech therapy evaluations were recom-
to 100 mg/d, with resolution of her side effects but no loss of mended because of her persistent gait difficulties and
functional gains. dysarthric speech. Ms. B. tolerated the amantadine well and
Abnormal thyroid results prompted an endocrine consul- showed improvements in alertness and attention span. Her
tation. Although the patient had a history of chronic hema- dose was titrated to 100 mg bid.
tologic problems of unclear etiology, amantadine was In this case, because testing had been done previously the
discontinued due to concerns about leukopenia and thrombo- battery used in this series was first completed in late fall of
cytopenia. Her lab abnormalities did not normalize. On her 1994, after amantadine was started. At this time Ms. A. was
second neuropsychological examination, Ms. A. could com- very distractible, impulsive, and perseverative. She showed
plete only the Test of Severe Impairment because she was impaired phonemic and categorical verbal fluency, and she
again mute. Her score on this test dropped from 18 toll. She often repeated items in quick succession (for example, “meat,
performed poorly on scales of language production and com- bread, meat”). Constructional apraxia was evident in her
prehension, and she lost points in subtests of motor perfor- spontaneous clock construction and in her copy. Her perfor-
mance. She no longer followed commands to put a cap on a mance on a test of verbal memory was notable for impair-

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AMANTADINE AND FRONTAL LOBE SYNDROME

ments in immediate memory, delayed recall, and delayed rec- difficulties in retrieving information suggested deficits in fron-
ognition. After recalling an item, she tended to make intru- tal lobe functioning, and she was referred to a neuropsychiat-
sion errors that were members of the same category (for rist for a medication consultation. Her neurological exam was
instance, after correctly recalling “cinnamon” she falsely re- unremarkable, and she was prescribed amantadine 100 mg
called “cherry, apple, water”). In contrast to her performance bid to treat prominent frontal lobe features.
on previous neuropsychological evaluation (prior to aman- Within 1 week of starting medication, Ms. C. noted in-
tadine), she completed the Trail Making Test part A without creased motivation. For example, she woke up earlier and felt
error, although slowly. She was unable to complete the sam- energized to get out of bed. The dose was gradually in-
ple of part B. Overall, the pattern of performances suggested creased to 400 mg/day with no side effects, and the patient re-
significant frontal lobe dysfunction and memory impairment. ported fewer headaches, more energy, and increased
Ms. B.’s dose was gradually increased to a total daily dose motivation. However, she still complained of memory diffi-
of 400 mg without side effects. Both her husband and the culty. Ms. C. again completed an evaluation in August 1995.
caretaker noted improvements in her general behavior, mem- Significant improvements were noted in divided auditory at-
ory, attentiveness, and concentration, and a decrease in im- tention, cognitive flexibility, and sustained attention. On the
pulsivity. For example, she no longer constantly asked to go Wechsler Memory she showed
Scale,35 improved verbal mem-
to the bathroom. She also showed improved motivation and ory for both easy-to-learn, semantically related word pairs,
motor ability, particularly in her handwriting and in her abil- and more difficult-to-learn, semantically unrelated word
ity to ambulate with a cane. Her speech was less dysarthric pairs. She also demonstrated improved visuospatial memory.
and easier to understand. Cognitive testing was repeated 5 However, her memory scores remained lower than expected
months after her previous testing. Her verbal fluency im- given her estimated premorbid ability. Ms. C.’ s improvement
proved, and her performance on part A of the Trail Making on objective testing confirmed her subjective belief that her
Test improved by 177 seconds. She was able to complete the attention had improved on amantadine.
sample of part B this time, but she could not complete the test
in the time allowed. Her performances on tests of memory, at-
tention, and construction did not change significantly.
DISCUSSION

Case 3. Ms. C. is a 39-year-old divorced, right-handed


The aim of the present case series was to investigate the
woman who underwent surgery on her sinuses in late 1993
effects of amantadine on the neuropsychiatric function-
to relieve severe persistent headaches. During the proce-
dure, her dura was perforated, resulting in a CSF leak. She ing of patients with acquired brain injuries, primarily
developed meningitis and was hospitalized for 3 weeks. Fol- TBI. The cases described represent a rather hetero-
lowing this, Ms. C. reported persistent mood, behavior, and geneous group of patients with respect to their histories
cognitive changes. Prior to the surgery, she was in generally and the nature of their brain injuries. Their symptoma-
good health except for the chronic headaches. Following the tology, however, is similar in that they all had evidence
surgery, she began to experience cognitive and motivational of significant frontal lobe dysfunction.
changes that substantially affected her functioning at work Overall, the patients all showed some degree of posi-
and home. She complained of word-finding difficulty and tive response to amantadine. According to caregiver
forgetfulness. The most dramatic change, however, was a
reports and clinical findings, 4 patients were catego-
marked decrease in achievement and motivation. She had
rized as responders and 3 were partial responders.
been very ambitious and achieved great success in her pro-
fessional activities, but after the surgery she preferred to stay There were 2 patients with side effects that prompted
at home. She acknowledged having a low mood but denied discontinuation of the drug. In 1, the side effects were
any changes in sleep or appetite, self-blame, guilt, or other not clearly related to amantadine, and the patient was
depressive symptoms. Her medications included ibuprofen successfully placed back on a low dose with a lessened
(800 mg) to relieve persistent bilateral facial pain and head- degree of positive response. Clinically, we find that side
aches, which she experiences two to three times a week. effects are uncommon and that, ifpresent, they are mild
Ms. C. first completed a neuropsychological evaluation be- and reversible with discontinuation of the drug.
fore amantadine treatment. It was not known that she would The limitations of the present case series are apparent.
be referred to the study protocol, so she received only some Intervals between visits varied somewhat depending on
of the tests in the study battery. Ms. C.’s overall intellectual
the clinical situation. Response was judged by the
performance was significantly poorer than would be ex-
authors, who were not blind to treatment condition. No
pected given her demographic characteristics and her aca-
demic and career achievement (obtained Full Scale IQ 99; =
control subjects were evaluated, and the group studied
estimated FSIQ = 115). Testing revealed impairments in was small and represented a heterogeneous range of
memory, particularly in delayed recall, and in sustained atten- comorbid disorders and medication regimens.
tion, psychomotor speed, and cognitive flexibility. Ms. C.’s Because no control subjects were tested, the amount
loss of ambition, deficits on tests of sustained attention, and of neuropsychological improvement expected from

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KRAUS AND MAKI

practice effects, independent of the effects of aman- that frontal regions, particularly in the orbitofrontal and
tadine, is unknown. Practice effects likely contributed medial temporal lobes, are most vulnerable to injury.5
to the observed improvements, though it is unlikely that Second, acute neurotransmitter derangements follow
such effects can explain the magnitude of improvement. TBI,23 although the nature of these derangements in
One patient, who was mute for 18 years, began speaking chronic brain injury is unknown. Then there are the
in short sentences after receiving amantadine and lost preliminary studies reviewed in this article that suggest
those gains after amantadine was discontinued. Two that dopaminergic agonists improve functioning of
subjects, who before treatment with amantadine were brain-injured patients.
unable to complete the sample items of the Trail Making The apparent efficacy of amantadine in improving
Test part B, not only completed them while taking the functioning in patients with TBI underscores the need
drug, but also completed the test in less than the maxi- for larger, controlled studies. Although positive effects
mum time allotted. were seen in the present study in patients who were at
The specificity of the improvement to tests commonly least 1 year posttrauma, amantadine may be even more
used to assess frontal lobe functioning further suggests effective if given acutely after injury. The efficacy of
that the neuropsychological improvements are due to amantadine in TBI may be attributable to its effect on
amantadine.33’339 A more global neuropsychological dopamine transmission, its role as an NMDA antago-
improvement would have suggested that amantadine nist, its effects on the balance among different neuro-
works more indirectly to improve neuropsychological transmitter systems, or a combination of these
test performance, for example, by improving mood or attributes. A comparison of a variety of dopaminergic
motivation. That the neuropsychological improvement agonists on functioning in patients with TBI, along with
was limited to tests of executive function suggests that functional imaging studies, could also help to clarify this
amantadine exerted a specific effect on frontal function issue. Clinically, based on current evidence, dopaminer-
through its dopaminergic activity in these individuals. gic agents such as amantadine may provide a poten-
A final point is that all subjects were tested at least a year tially effective, safe, and inexpensive option for treating
following their injury, so the effects are not likely due the cognitive, mood, and behavioral disorders of indi-
to spontaneous recovery. viduals with brain injury. We feel further research is
Multiple lines of evidence suggest that dopamine certainly warranted.
neurotransmission plays a significant role in frontal lobe
syndromes associated with TBI. First, basic anatomical
studies demonstrate the significant role of DA in frontal This work was partially supported by National Institutes of
regions of the brain,4 and studies of TBI patients show Health Grant AG00149.

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