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Treatment of Ballism and Pseudobulbar Affect With Sertraline
Michael S. Okun, MD;
Alonso R. Riestra, MD;
Stephen E. Nadeau, MD
Arch Neurol. 2001;58:1682-1684.
ABSTRACT
Background The pathogenesis of ballism is uncertain and may involve more than one
mechanism; treatment is not always efficacious.
Objective To provide evidence of a nondopaminergic mechanism and the potential
for a prompt and nearly complete response to a serotonergic agent.
Methods Report of 2 separate trials of sertraline hydrochloride in a single
patient.
Results Complete remission of symptoms within 48 hours of each drug trial.
Conclusion Sertraline may offer an alternative with a better adverse effect profile
than dopamine receptor blockers in the treatment of patients with ballism.
INTRODUCTION
THE MECHANISM of ballism is uncertain, and its response to treatment
with neuroleptics is frequently slow, fraught with adverse effects, and occasionally
so unsatisfactory as to motivate surgical treatment. We report a case that
suggests that an alternative treatment, sertraline hydrochloride, may be rapidly
effective and associated with few adverse effects. This and other reported
cases also suggest that the mechanism of ballism may be complex and susceptible
to different treatments in different patients.
REPORT OF A CASE
A 73-year old, previously healthy right-handed man had a 10-day history
of right-sided weakness, unpredictable jerking of his right upper extremity
and, to a lesser extent, his right lower extremity, and uncontrollable crying
spells. He also complained of recent difficulty with short-term memory, mild
slurring of speech, an inability to see objects on his right side, and a several-month
history of intermittent palpitations. He had no double vision, dysphagia,
dysarthria, dizziness, or sensory symptoms. He had a history of hypertension
and type 2 diabetes mellitus that was diet controlled, and he had undergone
coronary artery bypass surgery. There was no history of stroke. He had a 60
pack-year smoking history but had not smoked in 25 years. He was a former
railroad worker now practicing television evangelism.
Although the patient's vital signs were normal, he had an irregularly
irregular heartbeat. He recalled none of 3 objects after several minutes of
distraction, and he had an anomic aphasia. He had a depressed mood and flattened
affect, and he frequently exhibited pseudobulbar crying. When asked, he denied
that he was sad on these occasions. Cranial nerve examination results were
normal with the exception of an incongruous right homonymous hemianopia, saccadic
breakdown of ocular smooth pursuit movements, and a mild right supranuclear
palsy of the seventh cranial nerve. During a motor examination, there was
facilitatory paratonia in the right upper and lower extremities, a mild right
hemiparesis (4/5 in the deltoid, distal upper extremity muscles, and hip flexors),
and pronation drift of the right upper extremity. At rest he exhibited frequent,
irregular, high-amplitude ballistic movements of his proximal right upper
extremity. Adventitious movements of the right lower extremity were of much
lower amplitude. These movements were worse during intentional activity, including
finger-to-chin and toe-to-target maneuvers and ambulation. He also had mild,
nearly continuous choreiform movements of the right upper and lower extremities,
both at rest and with intentional activity, that were present between the
episodes of ballistic movement. There was mild, symmetric impairment in all
sensory modalities extending to the ankles, and there was a decrease in pinprick
and temperature sensation in the right upper and lower extremities. Cerebellar
function was intact. Reflexes were slightly more brisk on the right, and plantar
responses were equivocal.
The results of a complete blood cell count, measures of electrolytes,
a metabolic profile, and liver function studies were normal. An electrocardiogram
revealed atrial fibrillation. An echocardiogram revealed an ejection fraction
of 25%. A 4-hour electroencephalogram did not reveal any epileptiform activity,
even during the patient's involuntary movements and pseudobulbar episodes.
Goldmann perimetry of the left eye demonstrated a right hemianopia detectable
only with the smallest, least intense target. Perimetry of the right eye revealed
a dense right superior quadrantanopia extending inferiorly as far as the 330°
radian in the right inferior quadrant.
The lesion was mapped using axial 3-mm sections from a magnetic resonance
imaging (MRI) study of the brain (Figure 1) onto plates from the Schaltenbrand and Bailey1
atlas with a modified camera lucida technique. The lesion involved posterior
portions of the posterior limb of the internal capsule, posterolateral portions
of the pulvinar, portions of the body and tail of the caudate, portions of
the lateral geniculate nucleus, the hippocampus and adjacent parahippocampal
gyrus, and posteroinferior portions of the amygdala and periamygdaloid cortex.
There was a small region of hemorrhage in the area of infarction. The locus
and extent of the lesion were entirely consistent with a left anterior choroidal
artery distribution infarct even though involvement of the entire territory
of the artery was not evident. No other lesions appeared on the MRI.
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Magnetic resonance imaging study (fluid-attenuated inversion recovery
sequences) obtained 15 days after the onset of symptoms.
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A dose of 50 mg/d of sertraline was initiated 10 days after the onset
of symptoms. Marked improvement in depression, pseudobulbar symptoms, and
ballism was noted within 24 hours, and these problems had completely resolved
following 48 hours of treatment. The only residual movement disorder was a
subtle, intermittent chorea of the arm at rest that increased during walking.
The sertraline was then stopped, and within 48 hours the patient again became
morose, exhibited uncontrollable crying episodes, and experienced a return
of the ballism. Symptoms resolved within 48 hours of resumption of treatment.
COMMENT
The anterior choroidal artery supplies anterior regions of the medial
temporal lobe (most consistently including the anterior hippocampus), dorsomedial
portions of the lateral geniculate nucleus and adjacent optic tract and radiations,
ventral and retrolenticular portions of the posterior limb of the internal
capsule, the medial globus pallidus, dorsal portions of the subthalamic nucleus,
the H2 field of Forel, the zona incerta, and in some cases, the middle portion
of the cerebral peduncle and adjacent substantia nigra.2, 3
On MRI studies of our patient, infarction was not visible through the entire
territory of the artery, presumably because of the limited sensitivity of
MRI in detecting ischemic damage short of complete infarction.4
Nevertheless, it may reasonably be inferred that the memory deficits seen
in our patient reflect involvement of mesial temporal structures; the hemianopia
reflects involvement of the optic tract, lateral geniculate nucleus, or proximal
portions of the geniculocalcarine tract; the language deficits, characteristic
of thalamic aphasia, reflect damage to thalamocortical pathways by the internal
capsule lesion4; and the ballism reflects disruption
of the subthalamopallidal pathway or damage to the subthalamic nucleus. The
origin of the depression and pseudobulbar affect is uncertain. The territory
of the anterior choroidal artery extends sufficiently medially below the thalamus
to include the ascending noradrenergic and serotonergic pathways traveling
in the median forebrain bundle.3, 5
Thus, the depression and pseudobulbar affect could reflect depletion of norepinephrine
and serotonin in the mesolimbic structures.
The treatment of pseudobulbar affect with selective serotonin reuptake
inhibitors (SSRIs) such as sertraline is well established in the literature,6 although there is some uncertainty about the mechanism
underlying its effects. Patients typically respond rapidly and to low doses.
The favorable response of pseudobulbar affect to sertraline in our case may
reflect the effect of this SSRI on serotonin levels in the limbic system,
the nucleus accumbens, or the cerebral cortex on the involved side.
Neuroleptics have been the mainstay of treatment for hemiballism.7 However, approximately 16% of affected patients fail
to respond to these or other antidopaminergic drugs or to clonazepam, and
the mean delay to response in one series was 15 days.8
In some patients, the disorder is so severe and refractory that it motivates
surgical treatment.9 Thus, there is a need
for alternative pharmacological approaches. The response to sertraline in
our patient was both dramatic and prompt. It is conceivable that the improvement
reflected a placebo effect, but this seems unlikely because we told the patient
that we were targeting only the emotional incontinence. It is unlikely that
the improvement reflected spontaneous resolution because symptoms recurred
following discontinuation of sertraline.
This may represent the first report of successful treatment of ballism
with sertraline. It is not the first report of a favorable response to a drug
that potentiates serotonergic activity10: Lenton
et al11 described successful treatment with
valproate sodium in 1981. The mechanism underlying the beneficial effect of
sertraline is uncertain, but there are several possibilities. First, serotonin
is known to play a role in modulating the presynaptic release of several neurotransmitters
via its action on serotonin (5-HT)1B and 5-HT2 receptors,
and SSRIs have been shown to reduce dopamine release in the striatum.12, 13 By this mechanism, sertraline could
have emulated the beneficial effects of dopamine receptor blockers in the
treatment of ballism. This same effect may account for the occasional development
of extrapyramidal features in patients given SSRIs,14
including sertraline,15 and in patients given
sumatriptan succinate, a specific 5-HT1B agonist.16
These characteristics most often consist of akathisia or dystonia but may
include more classical parkinsonian features.
Second, postsynaptic serotonergic effects of sertraline may have increased
the firing rate of neurons within the subthalamic nucleus17
that, via the globus pallidus pars interna, affected neurons of the pars oralis
of the ventral lateral thalamic nucleus (VLo) projecting to the supplementary
motor area and area 4. This also would have reduced the effects of the ischemic
lesion.
Finally, the potentiation by sertraline of interstitial serotonin levels
within VLo18 or the cerebral cortex could have
compensated for the apparent imbalance between the direct and indirect basal
ganglia pathways caused by the lesion.
Some patients with ballism resistant to haloperidol have improved following
treatment with risperidone, an atypical dopamine receptor blocker that is
also a 5-HT2 receptor blocker.19
These observations coupled with our report, as well as evidence of the variable
efficacy of valproate,20 suggest that there
may be more than one mechanism for ballism. Treatment with sertraline may
provide an alternative to haloperidol by virtue of its fast onset of action
and better adverse effect profile (low risk of parkinsonian effects or tardive
dyskinesia), or it could provide an alternative for patients in whom the mechanism
of ballism makes the disorder susceptible to treatment that potentiates serotonergic
activity. Because we did not test the merits of sertraline relative to typical
or atypical D2 (dopamine) receptor blockers, we can draw no conclusions
regarding these possibilities.
AUTHOR INFORMATION
Accepted for publication May 23, 2001.
From the Department of Neurology, Emory University (Dr Okun), Atlanta,
Ga; the Department of Neurology, University of Florida College of Medicine
(Drs Riestra and Nadeau), and the Geriatric Research, Education and Clinical
Center and the Brain Rehabilitation Research Center, Malcom Randall Department
of Veterans Affairs Medical Center (Dr Nadeau), Gainesville, Fla.
Corresponding author: Stephen E. Nadeau, MD, GRECC-182, Malcom Randall
DVA Medical Center, Gainesville, FL 32608-1197 (e-mail: snadeau{at}ufl.edu).
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