Department of
Neurology, Bowman Gray School of Medicine,
Winston-Salem and the Alfred Hospital,
Melbourne
A patient with postanoxic action
myoclonus (Lance-Adams syndrome) was severely
disabled with this movement disorder. Valproate
sodium was administered orally, with complete
resolution of the myoclonus. This favorable
response has been maintained for two years.
Excessive yawning, the only side effect
encountered, was dose related and was abolished
with the addition of pimozide to the drug
regimen.
Lance and Adams in 1963 described four cases
of action myoclonus in chronic postanoxic
states. Since that time, considerable interest
has been shown in this condition, particularly
since it may result in part from serotonin
deficiency in the brain. These cases are
clinically similar in that they demonstrate (1)
a very mild intellectual deficit; (2) action
myoclonus; (3) mild to moderate cerebellar
ataxia; and (4) resistance to conventional forms
of therapy.
REPORT OF A CASE : In November 1973, a
26-year-old woman nearly drowned in a swimming
pool. When found, she had suffered a respiratory
arrest and had a profound sinus bradycardia. She
was successfully resuscitated, but suffered a
prolonged period of anoxia. Her course was
stormy. A tracheostomy was done and artificial
ventilation was necessary for one week. Her
recovery was slow and was severely, hampered by
action myoclonus. This involuntary movement
disorder prevented the patient from walking
alone and she was confined to a wheelchair. The
patient had been unconscious for three days
postictally. In April 1974, she underwent a
thoracotomy for the repair of a tracheal
stenosis.
In March 1975, she was admitted to the
Neurology Unit of the Alfred Hospital,
Melbourne, for investigation and treatment. At
that time, examination disclosed a modest,
softly spoken woman with many bruises over the
extremities a legacy of many falls. The striking
abnormality wasthe violent jerking movements
involving truncal and proximal musculature; even
the muscles of respiration were not spared.
These movements were absent when the patient was
relaxed and supine, but appeared with
anxiety-producing situations and whenever an
erect, sitting, or standing posture was
attempted. Any effort to walk was in vain,
leading to falls, rapid labored respirations,
profuse sweating, and tachycardia, and
eventually terminated in physical exhaustion.
These movements were absent during sleep. There
was profound hypotonia of all extremities,
withnormal power and symmetrical muscle stretch
reflexes. The knee jerks were pendular. The
plantar responses were flexor. Sensation was
normal. There was mild impairment of
finger-to-nose and heel-to-shin testing, and
rapid alternating movements were moderately
impaired. There was no clinical evidence of
dementia, but according to her close friends the
patient had suffered a mincir intellectual
decline, and retained a period of five months
postanoxic amnesia.
The following investigations gave normal
findings: complete blood cell count, urinalysis,
liver function tests, blood urea nitrogen level,
blood glucose level, chest and skull
roentgenograms, EEG, electromyography, and
peripheral nerve conduction studies. Serial EEGs
were not performed.
Therapy was initiated along traditional
lines. The following drugs were administered
singly and sequentially: diazepam,nitrazepam,
carbamazepine, levodopa, and methysergide; only
levodopa had a transient beneficial effect. As
hydroxytryptophan was not available in this
conntry, a trial of valproate sodium (Epilim
[GreatBritain]; Depakene, comparable US
product) was begun orally. Initially, 200 mg was
given twice daily; this was gradually increased
to a total of 1,600 mg in four daily doses. At
this dosage, the myoclonus abated and the
patient for the first time in two years was able
to walk unaided. The patient was discharged on
this dosage and reviewed monthly with
neurological assessment, complete blood cell
count, prothrombin time, and liver and renal
function tests.Drug levels were also measured
regularly.
The patient remained free of and became more
communicative and cheerful. She attended a
rehabilitation center and was generally able to
care for herself. The final maintenance dose was
800mg daily; on this dosage, the serumlevels
were 50 to 80 µg/mI. In February 1976,
she began to yawn excessively. This
proved to be a dose-related side effect. In
order to maintain control of the myoclonus and
to eliminate the excessive yawning, we added
pimozide, 4 mg daily, to the regimen.The
yawning disappeared.
In October 1976, the patient was admitted for
further assessment, and the drug therapy was
stopped. After the drugs had been withdrawn for
12 hours, the patient returned to her status of
March 1975 with severe myoclonus. The only
additional feature was a moderate degree of
hypomania. After the medication had been
discontinued for five days, CSF was collected
for 5-hydroxyindole acetic acid(5-HIAA)
estimation after 24 hours of probenecid therapy.
These levels were low (less than 10 ng/ml).
Valproate was again administered, with complete
resolution of the myoclonus. Computerized
tomography (CT) was performed (Figure). This
therapeutic response has been maintained.
COMMENT : The cause of the movement
disorder in the present case was undoubtedly
hypoxia and this is reflected in the widespread
abnormalities in the CT scan (Figure). These
findings were quite unexpected. The location of
the area of reduced attenuation in the anterior
aspect of the left temporal lobe must have
spared the language area, as at no time did this
righthanded patient demonstrate any disorder of
language. We have not found any previous
examples of the CT findings of this condition in
the literature.The pathological substrate of the
Lance-Adams syndrome is not clear, although
Richardson et all stated that a detailed
postmortem study of their case failed to
disclose any significant lesion in the midline
structures of the brain stem-the site of the
highest concentration of serotonin-containing
structures. They postulated a functional
alteration in serotoninergic activity. Lance and
Adams stated that the myoclonus may be produced
by the repetitive firing of thalamocortical
fibers, mainly from the ventrolateral nucleus,
wich is the principal relay nucleus from the
cerebellum to the sensorimotor cortex. However,
Lhermitte et all in a stereotactic study, were
unable to verify this hypothesis. Lhermitte et
all have shown that hydroxytryptophan, the
precursor of serotonin was therapeutically
successful in the Lance-Adams syndrome in a
single patient. The CSF levels of 5-HIAA in some
patients with this condition have been low. The
therapeutic responses in the above cases were
reflected in significant rises in the CSF of
5-HIAA after the hydroxytryptophan therapy. The
following pharmacological agents have been
reported to be of benefit in the Lance Adams
syndrome: intravenously given hydroxytryptophan,
orally given hydroxytryptophan and carbidopa,`
tryptophan, trytophan and a monoamine oxidase
inhibitor, levodopa, methysergide,
carbamazepine, diazepam, clonazepam,
chlorpromazine, and valproate.
Valproate has been found to be of benefit in
many different kinds of epilepsy, particularly
in the myoclonic varieties. This drug is thought
to inhibit both glutamic acid decarboxylase and
gamma-aminobutyric acid (GABA) alpha
ketoglutarate. Tomlinson postulated that the
prevention of GABA degradation might restore
inhibition and provide a beneficial effect in
myoclonus. The drug is administered orally;
common early side effects are nausea, vomiting,
and diarrhea. Transient loss of scalp hair bas
also been reported. Frequently, patients
demonstrate an increased mental alertness,
almost hypomania as well. This has led to the
suggestion that valproate may also have some
effect on serotonin inetabolism. Pimozide is a
useful antipsychotic agent that is thought to
act as a dopa antagonist. Pimozide bas also been
used in several different movement disorders.
Valproate therefore may provide another less
expensive, relatively safe form of therapy for
this disabing condition.
References
Lance JW, Adams RD: The syndrome of
intention or action myoclonus as a sequel to
hypoxic encephalography. Brain 86:111-134,
1963.
Van Woert M, Sethy V: Therapy of intention
myoclonus vvith L-5-hydroxytryptophan and a
peripheral decarboxylase inhibitor, MK 486.
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Guilleminault C, Tharp B, Cousin D: HVA and
5HIAA CSF measurernents and 5HTP trials in some
patients with involuntary movements. J Neurol
Sci 18:435-441, 1973.
Richardson JC, Rewcastle B, De Lean J:
Hypoxic myoclonus: Clinical and pathological
observations, in Proceedings of the Sir Gordon
Holwes Centennial Meeting, London, March, 1976.
Edinburgh, William Blackwood & Sons Ltd, to
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1976
Arch
Neurol
april 1979; vol 36;
p253
Drug-induced
yawning successfully treated with
pimozide
RD Rollinson, WS Wiggins, BS
Gilligan
Department of
Neurology, Bowman Gray School of Medicine,
Winston-Salem and the Alfred Hospital,
Melbourne
We recently had a patient who had postanoxic
action myoclonus (Lance-Adams syndrome). This
severe movement disorder was completely
suppressed with the oral administration of
valproate sodium (Epilim [Britain];
Depakene, comparable US product) at a dosage of
1000 mg daily, with corresponding serum levels
of 50 to 80 µg/ml. At these serum levels
and while receiving no other therapy, severe
uncontrollable yawning developed. This
was occurring every two to three minutes.
Lowering the dosage of the valproate sodium
abolished the yawning, and its reinstitution at
the previous level led to its return. Pimozide
(Orap), 400 mg daily, was added to the regimen
of full dosage of valproate sodium, and the
yawning disappeared within one day. Withdrawal
of the pimozide caused the yawning to
reappear.
Computarized tomography of the brain
demonstrated mild généralized
cortical atrophy with area of infarction in the
left inferior temporal lobe. Serotonin
deficiency was demonstrated.
This pathological yawning seemed to be a
dose-related side effect of valproate sodium
that has not been previously reported. Pimozide,
a dopamine antagonist, was used by Mogilnicka
and Klimek to reduce the yawning in rats
produced by dopamine agonists; a theorical
possibility is that valproate sodium led to the
stimulation of dopaminergic neurons, thereby
producing the yawning that in turn alleviated by
administration of pimozide.
