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Treatment of Abulia with Carbidopa/Levodopa

Daniel A. Drubach, M.D., Gabriel Zeilig, M.D., Julio Perez, P.A.,


Ligia Peralta, M.D., and Michael Makley, M.D.

Abulia is a clinical syndrome manifested by lack of spontaneity of action and speech,

deficiency in initiation, apathy, inertia, mental and motor slowness, reduction in excur-
sion of motion, poor attention, and easy distractibility. Abulia has been conceptualized
as laying in a continuum of motivational and emotional deficit in which apathy is at one

extreme and akinetic mutism at the other, more severe extreme. Lesions in the frontal
lobes have been most often implicated in the causality of abulia, but other areas of
involvement have also been described. Some authors have reported the beneficial effect
of dopaminergic agents in the treatment of abulia and other related disorders. We report
on four patients with various disorders of the CNS and abulic symptoms who had a ben-
eficial response to administration of a carbidopa/levodopa (Sinemet) compound many
months after the CNS insult responsible for the symptoms. We hypothesize that lev-
odopa may be beneficial in the treatment of abulia by increasing the availability of
dopamine to the prefrontal cortex or related areas in the brain. Key Words: Abulia—
Levodopa—Brain injury—Prefrontal cortex.

The term cil~itlici is derived from the Greek &dquo;buul&dquo; reduced ability to persist with a task. Marin (3) concep-
(will) and isusually defined as a lack of will or motivation, tualizes abulia as one extreme of a continuum in which
or an inability to decide. From a clinical perspective, abu- apathy lies at the opposite, less severe extreme. Fisher ( 1 )
lia refers to a specific neurotonic syndrome manifested by places abulia in a continuum in which all~lllL1 minor and
lack of spontaneity of action and speech, deficiency in ini- akinetic mutism are on opposite extremes, and other
tiation, apathy, inertia, mental and motor slowness, authors (4) have also conceptualized akinetic mutism as
reduction in excursion of I110Cl~ln, poor attention, and a severe term of abulia. Abulia can be canceptuali=eLi as

easy distractibility ( 1 ). Patients with this disorder display laying in a continuum of motivational and emotional1
late, terse, incomplete, and emotionally tlat verbal deficit in which apathy is at one extreme and akinetic
responses, but the intellectual content is normal if they mutism at the other, more severe extreme.
are prodded repeatedly ( 1 ). Caplan (2) establishes three Lesions in the frontal lobes have most often been
criteria for the diagnosis of abulia: ( 1 ) decreased sponta- implicated in the etiology of abulia, but other areas of
neous activity and speech; (2) prolonged latency in involvement have been described in the literature. Luria
responding to queries, directions, and other stimuli; (3) (5) suggested that the &dquo;apathetico-akinetico-abulic&dquo; syn-
drome is most typical of massive frontal lobe damage,
proposing that the most extreme form (true akinetic
mutism) results from bilateral posterior-medial orbital
frontal damage. Blumer and Benson (6) found abulia to
From the Department of Neurology and Rehabilitation Medicine, be present in patients with lesions in the dorso-lateral-
University of Maryland School of Medicine, Baltimore, Maryland. frontal convexity, especially with bilateral involvement.
Address correspondence and reprint requests to: Daniel A. Drubach, Forstl (7) described prominent abulia in three patients
M.D., Department of Neurology and Rehabilitation Medicine, Univer-
with left frontal ischemia and atrophy. Fisher ( 1 )
sity of Maryland School of Medicine, 22 South Greene Street,. Balti-
more, MD 21201, telephone (410) 328-6484, fax (410) 328-5899.
described thirty-seven cases with abulia and akinetic

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mutism; eleven had bilateral cingulate lesions, eighteen severe decreased verbal output and a dense right hem-
had midbrain or medial diencephalic lesions, nine had plegia. Although able to follow complex commands, the
hydrocephalus, and three had third ventricle cysts. patient did not initiate any activities and did not partic-
Caplan (2) reviewed the clinical features of eighteen ipate in her activities of daily living (ADL). She did not
patients with caudate infarcts and found that ten had initiate her own feeding and ate only when assisted. She
symptoms of abulia. Of those ten, four had lesions con- would not initiate verbal communication, although she
fined to the caudate nucleus, four had extension to the did verbalize for brief periods when prodded. Neuropsy-
anterior limb, and only one had spread to the putamen. chological tests showed decreased attention span. The
Tatemichi (8) described six patients with abrupt change patient appeared to have good auditory comprehension as
in behavior after infarction involving the inferior genu of demonstrated by her performance in the Token test. Fur-
the internal capsule. The acute syndrome featured fluctu- thermore, her naming skills were judged to be adequate
ating alertness, inattention, memory loss, apathy, abulia, using an alphabet board. Her symptoms remained
and psychomotor retardation. unchanged over the following weeks. A seven week trial
Case studies of patients with various neurological and on methylphenidate, with dosages as high as 25 mg per

psychiatric disorders have reported some success in treat- day, was begun six weeks after her acute event and dis-
ing various disorders of attention and motivation ( includ- continued because of lack of beneticial response. Sixteen
ing abulia) with dopaminergic agents. Levodopa was used weeks after her injury she was started on bromocriptine at
successfully to arouse a patient in a coma of six months a dose of 2.5 mg per day and the dosage was titrated up

duration secondary to a traumatic brain injury (9). to 30 mg per day over a four week period. The patient still

Methylphenidate, a dopaminergic agonist, has been used demonstrated no significant improvement in behavior or
in the treatment of akinetic mutism (10). The same drug cognition. Twenty-eight weeks after the acute event she
was used successfully in treatment of apathy in geriatric was started on carbidopa/levodopa (Sinemet), with the

patients (11). Bromocriptine, a dopaminergic agonist, has dosage being titrated over the following three weeks to a
been used with success in the treatment of neglect ( 12 ) daily total of 100 mg carbidopa and 1000 mg levodopa. A
and in the treatment of akinetic mutism in four young week after starting the Sinemet the patient became much
patients (4). Bromocriptine and lergotrile were used suc- more active and motivated in therapy and more involved

cessfully in treatment of akinetic mutism resulting from in self-care including feeding and dressing. She began
hypothalamic damage in one patient (13). Bromocriptine communicating with an alphabet board and initiating
and lisuride, another dopaminergic agent, have also been verbal communication. Her affect became much brighter.
used successfully in the treatment of abulia in a small The repeated Digit Span Test showed an impressive
number of patients ( 14). improvement in her attention span. Over the following
We report on four patients with prominent symptoms weeks she continued to improve and by discharge she was
of abulia who responded favorably to treatment with car- propelling her wheelchair independently and making
bidopa/levodopa. We also discuss possible mechanisms for independent transfers. She was discharged on bromocrip-
the utility of dopaminergic agents in abulia and rationale tine 30 mg daily and carbidopa/levodopa (25/250) four
for their use in the management of this condition. times a day.

Case Reports Case 2

Case I A 26-year-old right-handed male with obstructive


hydrocephalus secondary to aqueductal stenosis of
A 35-year-old right-handed woman was admitted to unknown origin was admitted to a rehabilitation hospital
the emergency department after the abrupt onset of three weeks after multiple surgical procedures for shunt
headache soon after loss of consciousness. Computed placement and revisions. There was no significant past
tomography of the brain showed subarachnoid hemor- medical, neurological, or psychiatric histories in the
rhage with massive bilateral frontal lobe injury, corre- patient or in family members. On admission the patient
sponding to bilateral anterior cerebral artery territory was lethargic with a left hemiparesis and no spontaneous

infarctions. She underwent a craniotomy and clipping of speech. He did not initiate feeding, nor did he initiate any
a right anterior communicating artery aneurysm. There other activities of self-care. His affect was blunted. Neu-
was no significant past medical, neurological, or psychi- ropsychological testing showed markedly decreased atten-
atric histories in the patient or in family members. On tion span, decreased verbal fluency, and increased prob-
admission to a rehabilitation hospital ten days after her lem-solving response time. His symptoms remained
acute event, the neurological exam was remarkable for unchanged over the following weeks. Six weeks after
152
admission he was started on methylphenidate (Ritalin), of starting therapy he showed prominent improvement in
which was titrated to a maximum daily dosage of 20 mg spontaneous speech and in initiation and participation
without significant effect on his abulic symptoms, in activities of daily living, including feeding, grooming,
although he was noted to be more alert. Twenty weeks and dressing. He was discharged on Sinemet 100/1000
after admission he was started on carbidopa/levodopa, mg daily.
which was titrated until an effective therapeutic dose was
achieved ( 125 mg of carbidopa and 500 mg of levodopa
a day). Within two weeks of initiating levodopa therapy Case 4
he showed prominent improvements in motivation, alert-
ness, participation in therapies and activities of daily liv- A 44-year-old right-handed male was found unre-
ing, and spontaneous speech. Although his blunted affect sponsive in his home and brought to an emergency
remained, his spontaneity and responsiveness improved department, where a toxicology screen was positive for
dramatically. Neuropsychological tests of attention, benzodiazepine, methadone, and opiates. Magnetic reso-
specifically Digit Span and Trail Making, showed marked nance imaging showed periventricular white matter high

improvement. The patient also demonstrated improved signal changes. The patient had a long history of sub-
verbal fluency on the Verbal Associative Fluency Test stance abuse. There was no other significant past med-
and decreased response time in problem solving on the ical, neurological, or psychiatric histories in the patient
Arithmetic Age Corrected Scale score and on Block or in family members. Five weeks later he was transferred

Design and Picture Arrangement tests. Reduction in car- to a rehabilitation hospital with a diagnosis of anoxic

bidopa/levodopa compound dosage one month after brain injury. Neurological exam was remarkable for hypo-
beginning therapy resulted in prominent worsening in the phonia and decreased verbal output as well as a spastic
initiation of self-care activities, with increased need for tetraparesis. There was no aphasia or apraxia. The
verbal cues in simple problem solving. Medication was patient demonstrated lack of spontaneous speech, flat
therefore resumed and the patient was discharged on affect, limited attention to task, and increased response
Sinemet 100/1000 mg daily. time in neuropsychological evaluation. He did not ini-
tiate self-care activities including grooming, dressing, and
bathing. The patient was treated with methylphenidate
. Case 3 with dosage as high as 20 mg per day over a four week
period but showed no improvement. He was subsequent-
A41-year-old right-handed male became unrespon- ly tried on amantadine at a dosage of 200 mg daily with
sive withina week of a hip revision. Magnetic resonance only slight improvement in function. At six months after
imaging of the brain was normal and he was presumed to brain injury carbidopa/levodopa (Sinemet) was added at
have suffered hypoxic brain damage secondary to a fat a dose of 10/100 tablets twice daily. Five days after initi-

embolus to the brain. He remained comatose for the fol- ation of therapy the rehabilitation team reported dra-
lowing four weeks. There was no significant past medical, matic improvements in the patient’s condition, includ-
neurological, or psychiatric histories in the patient or in ing increased attention on the Digit Span Test and
family members except for total hip replacement sec- increased speech output on the Verbal Associative Flu-
ondary to trauma sustained seventeen years prior. Four- ency Test, as well as motor improvements that allowed
teen weeks after the acute event he was admitted to a the patient to assist in his transfers and bed mobility. His
rehabilitation hospital. On admission his exam showed dose was titrated to 25 mg of carbidopa with 250 mg of
decreased but normal spontaneous speech, flat affect, levodopa three times a day. The patient continued to
impaired recall for both recent and remote events, right improve and by discharge he was initiating spontaneous
hemiparesis, and bilateral upper extremity cerebellar dys- conversation with fluency, asking and answering ques-
function. He did not initiate or participate in self-care tions, exhibiting humor, and demonstrating improve-
activities including feeding, grooming, dressing, or trans- ments in mobility and in ADL. After six weeks of ther-
fers. A three week trial of methylphenidate (maximum apy, the patient was tapered off carbidopa/levodupa.
dosage of 25 mg daily) did not improve his abulic symp- Approximately seven days after taper, the patient was
toms. A subsequent six week course of sertraline (Zoloft) noted to be less motivated and his spontaneity of speech
at a dosage of 50 mg daily was discontinued secondary to had diminished to a state similar to the admission level.
a lack of clinical response. Twenty-four weeks from onset Carbidopa/levodopa was restarted and by the hfth day the
of injury and without any improvement in his abulic patient returned to the level of spontaneity and func-
state, carbidopa/levodopa therapy was instituted and the tioning he demonstrated prior to interruption of Sinemet
dose was titrated within two weeks to 100 mg of car- therapy. The patient was discharged on Sinemet
bidopa and 1000 mg of levodopa a day. Within ten days 100/1000 mg daily.

153
Discussion an important role for the neurotransmitter dopamine in
the frontal and prefrontal areas includingthefinding of
All four patients displayed prominent symptoms of a high population of dopamine receptors (24-29). In pri-
abulia and met the clinical criteria proposed by Caplan. mates, the prefrontal cortex shows a high concentration
However, the etiology and location of lesions in each case and increased synthesis rates of catecholamines, particu-
were different. Abulic symptoms clearly improved in these larly dopamine (30). The role of the prefrontall cortex in
patients, some dramatically, after carbidopa/levodopa was the synaptic regulation of the subcortical dopamine sys-
administered, suggesting a hypodopaminergic state. All tems has also been hypothesized (31 ).

patients were initially started on and later discontinued Alteration of dopamine alctivity in frontal lobes has
from methylphenidate, with little or nobeneficial effect. been implicated in disorders of attention and motivation
Although spontaneous recovery is apossible consid- in animal models. Severe depletion of dopamine by intra-
eration, it seems unlikely considering that all patients cortical administration of 6~hydwxydopamine in the pre-
were started on carbidopa/levodopa several months after frontal cortex of the monkey impairs performance on
the neurologic insult responsible for the symptoms. Also complex behavioral tasks that demand attention. This
against spontaneous recovery is the apparent return of deficit is ameliorated by treatment with nonselective
abulic symptoms in patients 2 and 4 when carbidopa/ dopamine agonist, apomorphine, and by levodopa, a
levodopa dosage was reduced or discontinued. dopamine precursor (32). Rogeness (33) hypothesized all
Our study has several limitations. No scale was uti- alteration in dopaminergic functioning in patients with
lized document improvement of abulia, since there are
to attention deficit disorders, and Shenker (34) has reviewed
not any validated scales currently in use. Improvement of the role of the neurotransmitter dopamine in attention-
abulia was determined from a consensus of opinion of a deficit hyperactivity disorder. A hypodopaminergic state
rehabilitation team consisting Of neurologists, neuropsy- involving the prefrontal areas of the brain has been
chologists, nurses, and speech, physical, and occupation- hypothesized by various authors (16,35) to be responsible
al therapists, and by patients’ family members. Neither the for the negative symptoms of schizophrenia, specifically
rehabilitation team nor family members were blinded as motivational difficulties, abulia, and flattening of affect.
to administration of medication. We thus postulate that dopaminergic agents may be
The mechanism for the beneticial effect of Liop91nin- beneficial in the treatment of abulia by increasing the
ergic drugs on abulia and other related disorders of atten- availability of dopamine in dopaminergic pathways, pri-
tion is still unclear. We postulate that certain neurologi- marily those ending in the prefrontal cortex. Specific path-
cal disorders may result in a hypodopaminergic state, ways discussed in literature include interconnections that
which may in turn result in abulia. Drugs that work on originate within the midbrain, spinal cord, and frontal
dopaminergic pathways might be considered in its treat- lobe. Using this model, damage to any of these intercon-
ment. It remains to be elucidated as to pathophysiology of nections could hypothetically result in abulia (36,37).
abulia. Although the anatomic lesion pattern is heteroge-
Research in recent years about the behavioral func- neous in our patient group, the symptom complex of abu-
tions of the frontal and prefrontal cortex suggests that its lia is uniform. Additionally, while no radiological evi-
dysfunction may result in motivational and attentional dence of anatomic frontal lobe damage was found in two
disorders, including abulia (6,7,15). Clinical, experimen- of our patients, it has been shown by other investigators
tal, and pathophysiologic data that link the neurotrans- that functional imaging studies can demonstrate abnor-
mitter dopamine to frontal and prefrontal lobe function malities in the absence of an anatomic lesion (38,39).
may give an important clue as to the beneficial effect of L- As discussed, many lines of evidence link this symp-
dopa in the treatment of abulia. tom complex with dysfunction of frontal and prefrontal
Prefrontal areas of the brain play a selective role in lobe dopaminergic pathways. Other authors, however,
mediating attentional, spatial, and mnemonic capacities have suggested that abulia may result from loss of
in primates, including humans (16,17) and are involved dopaminergic input to anterior cingulate cortex and the
in goal-oriented activities, including the initiation, plan- mesolimbic dopamine system rather than solely to pre-
ning, and sequencing of complex actions (18-22). frontal cortex (4,13). It may be argued, as well, that L-
The prefrontal cortex appears to be particularly dopa has a more general, nonspecific effect on activation
important in the planning of behavior in non-routine sit- and alertness. Alternatively, L-dopa may work on some
uations (18), and patients with frontal lesions frequently other pathway entirely. One hypothesis might be that the
display deficits and impaired flexibility in generating men- precursor L-dopa is further metabolized to norepineph-
tal plans and profit less from experience gained in a new rine. Perhaps the clinical effect we saw in our patients is
and unfamiliar situation (23). related to the augmentation of the noradrenergic rather
There is ample evidence in the literature to suggest than dopaminergic systems.

154
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pharmacotogic intervention is ~lls0 needed. a comparison of maze performance in routine and non-routine sit-

uations. Neuropsychologia 1991;29(4):271-90.


24. Tassin JP, Bockaert TJ, Blane G, Stinus L, Thierry AM, Lavielle
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