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Early Morning Off-Medication Dyskinesias, Dystonia, and Choreic Subtypes
Esther Cubo, MD;
Jean-Michel Gracies, MD, PhD;
Reina Benabou, MD, PhD;
Charles Warren Olanow, MD;
Rema Raman;
Sue Leurgans, PhD;
Christopher G. Goetz, MD
Arch Neurol. 2001;58:1379-1382.
ABSTRACT
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Background Abnormal involuntary movements (dyskinesias) are common in patients
with Parkinson disease (PD) as a consequence of the disease and dopaminergic
replacement therapy. Early morning off-medication choreic dyskinesias have
been recently reported after fetal dopaminergic cell transplantations in patients
with advanced PD.
Objective To determine the frequency and severity of the early morning off-medication
dyskinesias in consecutive patients with advanced PD and an insufficient response
to medical management before they undergo neurosurgery.
Methods Consecutive patients with advanced idiopathic PD were examined and videotaped
before undergoing neurosurgery that included pallidotomy, fetal transplantation,
or deep brain stimulation. The examination took place in the morning in the
practically defined off state, at least 12 hours after the last dose of dopaminergic
drugs. Parkinson disease was characterized using the Unified Parkinson's Disease
Rating Scale and the Hoehn and Yahr stage. Dyskinesias were rated with the
Abnormal Involuntary Movements Scale and the Rush Dyskinesia Rating Scale.
Patients' characteristics and medications were compared using the Wilcoxon
rank sum and the Fisher exact tests.
Results Of 68 consecutive patients (44 [65%] men and 24 [35%] women), 11 (16%)
had early morning off-medication dyskinesia, with a 95% upper confidence limit
of 24%. Focal dystonia was the most common off-medication dyskinesia, and
occurred in 10 patients (15%), with a 95% upper confidence limit of 22%; and
off-choreic dyskinesia occurred in 1 patient (1.5%), with a 95% upper confidence
limit of 4%. There was no difference in PD medications between the patients
with and those without dyskinesias.
Conclusions The most common form of off-medication dyskinesia seen in patients with
advanced PD is dystonia. Early morning off-medication choreic dyskinesias
are rare but do occur in patients with advanced PD before surgical intervention.
The presence and type of off-medication dyskinesias should be monitored in
clinical and surgical studies in patients with PD as part of the safety and
evaluation of clinical benefits.
INTRODUCTION
DYSKINESIAS in patients with Parkinson disease (PD) have various forms,
related in part to the underlying dopaminergic denervation and to drugs.1 Dyskinesias are usually classified into 2 categories,
off-period dyskinesias and on-period dyskinesias, based on the patient's clinical
state (on or off) and relationship with the medication intake (before the
first dose of morning medication, at peak medication intake, and at the end
of the dose). On-period dyskinesias, such as levodopa peak-dose dyskinesias,
occur during the period of maximal relief of parkinsonian symptoms and are
predominantly choreic, usually involving the upper more than the lower limbs,
the face, and the trunk.2, 3 Peak-dose
on-period dystonia may also occur.
Off-period dyskinesia include dystonia, usually seen in patients when
they are akinetic and rigid before the first daily dose of levodopa, and end-of-dose
dyskinesias, seen during the day as drug effects wear off, which predominate
in the lower extremities.4, 5 Recently,
a third type of off-period dyskinesia, which is primarily choreic, has been
reported before the intake of morning medication following fetal dopaminergic
cell transplantations in patients with advanced PD. This type of dyskinesia
was posited to be the result of transplantation.6
The occurrence of off-medication dyskinesias before surgical intervention
in patients with advanced PD has not been systematically studied. This study
determines the frequency, phenomenology, and severity of dyskinesias that
occur in patients with advanced PD before surgical intervention, specifically
those that occur in the early morning before the first daily dose of PD medications.
PATIENTS AND METHODS
Consecutive patients with advanced idiopathic PD7
who underwent neurosurgery, including pallidotomy, deep brain stimulation,
and fetal transplantation, at the Movement Disorder Section of the Department
of Neurological Sciences, Rush-Presbyterian-St Luke's Medical Center, Chicago,
Ill, and at the Mt Sinai Medical Center, New York, NY, were examined preoperatively
with a standardized videotape. The taping protocol documented the patients'
scores on the motor section of the Unified Parkinson's Disease Rating Scale
(UPDRS), following the recommendations of the Core Assessment Program for
Intracerebral Transplantations,8 at baseline
in the practically defined off state (no PD medications for at least 12 hours).
Parkinson disease motor impairment and therapy motor complications were characterized
by using the motor section of the UPDRS; the Hoehn and Yahr stage; and the
fourth section of the UPDRS, focusing on dyskinesias.9
Dyskinesias were rated using the modified Abnormal Involuntary Movements Scale
during the UPDRS motor subscale filming and using the Rush Dyskinesia Rating
Scale.10 Information on patients' levodopa
and agonist (equivalent pergolide mesylate)11
doses was also collected.
Patient characteristics were analyzed as percentages or as means ±
SDs, with results expressed with 95% confidence limits for the percentage
of patients with dyskinesias. To compare medications and characteristics in
patients with and without dyskinesias, we used Wilcoxon rank sum tests for
continuous variables and Fisher exact tests for discrete variables.
RESULTS
Sixty-eight patients were included (44 [65%] men and 24 [35%] women),
and underwent different neurosurgical procedures for PD. These procedures
included pallidotomy in 30 patients, the fetal transplantation program in
34, and deep brain stimulation in 4. The mean age of the patients was 60 ±
9 years (range, 39-75 years), and the mean PD duration was 14 ± 7 years
(range, 2-41 years). All received levodopa (mean dose, 962.02 ± 507.00
mg), and 51 patients (75%) received agonist (mean dose, 2.18 ± 2.10
mg). In accordance with the guidelines of the Core Assessment Program for
Intracerebral Transplantations,8 all subjects
were videotaped in the morning at least 12 hours after the last dose of medication,
in the "practically defined" off state. At the time of the videotape, the
patients' mean total score on the motor section of the UPDRS was 50 ±
13 (range, 37-65), and the patients' median Hoehn and Yahr stage was 4 (range,
2-5).
The mean score on the fourth section of the UPDRS was 9 ± 3 (range,
2-19), taken on the day of the videotape.
Based on the videotape examinations, 11 patients (16%) were found to
have early morning dyskinesias in the off state, with a 95% upper confidence
limit of 24% (Table 1). Dystonia
occurred in 10 patients (15%), with a 95% upper confidence limit of 22%. Focal
and segmental dystonias, including foot (5 patients), arm (2 patients), and
cervical (3 patients) dystonias, were the more common form of off-medication
dyskinesia. The mean Abnormal Involuntary Movements Scale score was 2 ±
1, and the mean Rush Dyskinesia Rating Scale score was 1 ± 1. There
were no differences in patients' characteristics or scores on the fourth section
of the UPDRS between the group of patients with and the group without off-medication
dyskinesias (Table 1). There was
also no difference in the levodopa dose between the group of patients with
and the group without off-medication dyskinesias, nor was there a difference
in the proportion of patients taking levodopa and agonist between the 2 groups
(Table 2).
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Table 1. Early Morning Dyskinesias in the Off State*
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Table 2. Patients' Therapy*
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Off-medication choreic dyskinesias involving the orofacial muscles,
the trunk, and the lower extremities occurred in 1 patient (1.5%), with a
95% upper confidence limit of 4% (Table
1), despite confirmed abstinence from dopaminergic drugs for 12
hours. The patient experienced repetitive lifting of the right leg off the
ground with the foot inverted and the knee flexed. He also showed mild but
continuous pouting, smacking, and sucking movements of the lips and rocking
movements of his back. His Abnormal Involuntary Movements Scale score was
7, and his Rush Dyskinesia Rating Scale score was 1. The patient was clinically
in the off state otherwise, with a total score on the motor section of the
UPDRS of 48. Although our study's focus was on off-medication dyskinesias,
because of the particularly choreic character of these dyskinesias, we also
looked at the on-medication videotape assessment. At peak medication effect,
his score on the motor section of the UPDRS was 35, the dyskinesias were more
intense than the dyskinesias in the off state, and there was spread to the
contralateral side and neck.
COMMENT
Dyskinesias in patients with PD are difficult to assess because they
are phenomenologically variable, transient, and often poorly appreciated by
the patient.12 We restricted our study to objective
examinations based on videotapes focused on the practically defined off state,
defined by the recommendations of the Core Assessment Program for Intracerebral
Transplantations. Although we maximized the rigor of our examinations, we
only had one preoperative videotape for each subject. To our knowledge, no
publications have reported on the temporal stability of dyskinesia assessments
in the off state using videotapes taken at repeated time points. Therefore,
although we document both off medication dystonia and choreic-dystonic movements
in this group of patients with PD who have severe motor impairment, we cannot
comment on whether these behaviors would be reproducibly seen in frequency
or severity on other days or during other off cycles.
Limb dystonia is a well-characterized form of early morning off-medication
dyskinesia, occurring in 20% to 30% of patients with PD receiving long-term
treatment with levodopa, usually documented by the patient's report. It takes
the form of a static posture, involving the feet and, less often, the whole
leg, the upper limb, and the neck, and usually disappears on withdrawal of
levodopa for more than 24 hours.13, 14
Other studies14, 15 have found
that those patients with early morning off-medication dyskinesias have taken
levodopa for 5 to 12 years, have coexisting peak-dose and diphasic dyskinesias,
and exhibited dystonia before the initiation of levodopa treatment. In our
sample, dystonia was the most frequent off-medication dyskinesia.
Choreic movements with dystonic features, especially involving the legs,
can be seen typically in patients with PD during the day, after they have
taken at least one dose of medication and before their next dose, as medication
effects wane. These dyskinesias often are a component of the dyskinesia–improvement
dyskinesia syndrome, and are most prominent on the more parkinsonian side.14 They typically improve with dopaminergic drugs and
are not a regularly described feature in the early morning before the first
dose of medication.
Off-medication choreic-dystonic dyskinesias have been described by Freed
et al6 as a phenomenon in patients who previously
underwent fetal transplantation. They described disabling dyskinesias including
dystonia in 15% of the patients,6 and suggested
that fetal transplantation may play a role in causing or enhancing this phenomenon.
In one subject from our series of patients with advanced PD, early morning
off-medication choreic-dystonic dyskinesias occurred in one leg, closely resembling
the movements seen in the wearing-off dyskinesias during the day (although
these usually occur in both legs), but this subject also had choreic-dystonic
dyskinesias in the face and trunk, which are not typically described in patients
with the wearing-off dyskinesias. They occurred before surgery, demonstrating
that this phenomenon cannot be solely ascribed to surgical intervention. This
form of off-medication dyskinesias was uncommon and much less frequently encountered
than dystonia. It was not reported or appreciated by the patient and, because
it was not painful like dystonia in the off state, we doubt that patients
can reliably report these choreic movements. There was no difference in the
total score on the fourth section of the UPDRS between the group of patients
with and the group without dyskinesias, supporting the idea that the patient's
accuracy of perception of the presence of dyskinesias, especially when mild,
is poor.12
Off-medication choreic-dystonic dyskinesias are not likely to be addressed
outside of research protocol because patients are rarely seen in clinical
practice before taking their first dose of medication. Because they occurred
so rarely in our series, the higher prevalence of 15% in the report by Freed
et al6 suggests that surgical intervention
may exacerbate or produce these movements. Comparisons of films before surgery
and afterwards would be necessary to permit more solid conclusions.
In treatment trials for PD, continued improvement in bradykinesia, tremor,
rigidity, and gait impairment function is usually the primary outcome variable
of interest. Information about dyskinesias, including dystonia in the off
state and choreic dyskinesias in the on state, is usually collected by patient
report or investigator examination, and choreic-dystonic movements in the
off state are not specifically sought. Surgical protocols such as the Core
Assessment Program for Intracerebral Transplantations8
and the Core Assessment Program for Surgical Interventional Therapies in Parkinson's
Disease16 include videotape assessment of patients
at baseline and after treatment in the on and off states. Our observations
on consecutive patients being treated with neurosurgical intervention for
PD cannot be extrapolated to all subjects with PD. These patients were relatively
young and had severe motor impairment poorly controlled with available pharmacological
therapies. Nevertheless, because the group included all patients from 2 centers
that enrolled patients from 2 neurosurgical programs, we consider them representatives
of the population undergoing neurosurgical treatments for PD. Our data document
that choreic-dystonic dyskinesias, partially resembling wearing-off dyskinesias,
can occur in the early morning before medication ingestion in patients with
advanced PD, and should be recorded as a form of dyskinesia in the off state.
Baseline prevalence rates will permit a safety-and-benefit assessment of the
role of interventions like fetal transplantation in the induction, exacerbation,
or amelioration of these dyskinesias in patients with PD.
AUTHOR INFORMATION
Accepted for publication May 14, 2001.
We thank Teresa Chmura for her assistance.
From the Departments of Neurological Sciences (Drs Cubo and Goetz)
and Preventive Medicine (Ms Raman and Dr Leurgans), Rush-Presbyterian-St Luke's
Medical Center, Chicago, Ill; and the Department of Neurology, Mt Sinai Medical
Center, New York, NY (Drs Gracies, Benabou, and Olanow). Dr Cubo is now with
Hospital Mutua de Terrassa, Terrassa, Spain.
Corresponding author and reprints: Esther Cubo, MD, Calle Maria Odlaga
64, B-D, 28025, Madrid, Spain (e-mail: 35350ecd{at}comb.es).
REFERENCES
| |
1. Marsden CD. "On-off" phenomena in Parkinson's disease. In: Rinne UK, Linger M, Stamm G, eds. Parkinson's
Disease: Current Progress, Problems and Management. New York, NY: Elsevier
North–Holland Biomedical Press; 1980:241-254.
2. Luquin MR, Scipioni O, Vaamonde J, et al. L-Dopa–induced dyskinesias in Parkinson's disease: clinical and
pharmacological classification. Mov Disord. 1992;7:117-124.
FULL TEXT
|
ISI
| PUBMED
3. Nutt JG. L-Dopa–induced dyskinesias: review, observations, and speculations. Neurology. 1990;40:340-345.
FREE FULL TEXT
4. Melamed E. Early-morning dystonia: a late side effect of long-term levodopa therapy
in Parkinson's disease. Arch Neurol. 1979;36:308-310.
FREE FULL TEXT
5. Lees AJ, Shaw KM, Stem GM. "Off period" dystonia and "on period" choreoathetosis in levodopa-treated
patients with Parkinson's disease [letter]. Lancet. 1977;12:1034.
6. Freed CR, Greene PE, Breeze RE, et al. Transplantation of embryonic dopamine neurons for severe Parkinson's
disease. N Engl J Med. 2001;344:710-719.
FREE FULL TEXT
7. Hughes AJ, Daniel SE, Kilford L, et al. Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a
clinicopathological study of 100 cases. J Neurol Neurosurg Psychiatry. 1992;55:181-184.
FREE FULL TEXT
8. Langston JW, Widner H, Goetz CG, et al. Core Assessment Program for Intracerebral Transplantations (CAPIT). Mov Disord. 1992;7:2-13.
ISI
| PUBMED
9. Fahn S, Elton RI and members of the UPDRS Development Committee. Unified Parkinson's Disease Rating Scale. In: Fahn S, Marsden CD, Calne DB, eds. Recent Developments
in Parkinson's Disease. London, England: Macmillan; 1987:153-163.
10. Nutt J. A unified dyskinesias rating scale for L-dopa–induced dyskinesias
[editorial]? Mov Disord. 1999;14(suppl 1):74.
11. Lang AE, Lozano AM, Montgomery E, et al. Posteroventral medial pallidotomy in advanced Parkinson's disease. N Engl J Med. 1997;337:1036-1042.
FREE FULL TEXT
12. Goetz CG, Stebbins GT, Blasucci LM, et al. Efficacy of a patient-training videotape on motor fluctuations for
on-off diaries in Parkinson's disease. Mov Disord. 1997;12:1039-1041.
FULL TEXT
|
ISI
| PUBMED
13. Kidron D, Melamed E. Forms of dystonia in patients with Parkinson's disease. Neurology. 1987;37:1009-1011.
FREE FULL TEXT
14. Currie LJ, Harrison MB, Trugman JM, et al. Early morning dystonia in Parkinson's disease. Neurology. 1998;51:283-285.
FREE FULL TEXT
15. Vidailhet M, Bonnet AM, Marconi R, et al. Do parkinsonian symptoms and levodopa-induced dyskinesias start in
the foot? Neurology. 1994;44:1613-1616.
FREE FULL TEXT
16. Defer GL, Widner H, Marie RM, Remy P, Levivier M. Core Assessment Program for Surgical Interventional Therapies in Parkinson's
Disease (CAPSIT-PD). Mov Disord. 1999;14:572-584.
FULL TEXT
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ISI
| PUBMED
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