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Drenching sweats as an off phenomenon in parkinson's disease Treatment and relation to plasma levodopa profile.

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gests that the Apo E risk factor is independent of ethnic background. Apo E studies of the Nigerian population, now in progress, will be important in verifying
these findings.
This study was supported by the National Institute o n Aging grant
PHS 3R01 AG09956-04.
We acknowledge the assistance of our clinical nurses, Patricia Nurnberger, RN, Mary Williams, RN, and Nicki Coleman, R N , and the
technical help of Ms Dawn Davis with this study.
References
1. Saunders AM, Stritrmatrer WJ, Schmechel D, et al. Association
of apolipoprotein E allele ~4 with late onset familial and sporadic
Alzheimer’s disease. Neurology 1993;43:1467-1472
2. Corder EH, Saunders AM, Strittmatter WJ, er al. Gene dose of
apolipoprotein E type 4 allele and the risk of Alzheimer’s disease
in late onset families. Science 1973;261:921-923
3 . Saunders AM, Schmader K, Breirner JCS, et al. Apolipoprotein
E €4 allele distributions in late-onset Alzheimer’s disease and in
other amyloid-forming diseases. Lancet 1993;342:710-7 11
4. Peacock ML, Fink JK. Apo E-€4 allelic association with Alzheimer’s disease: independent confirmation using denaturing gradient gel electrophoresis. Neurology 1994;44:339-34 1
5. Tsai MS, Tangalor EG, Petersen RC, et al. Apolipoprotein E:
risk factor for Alzheimer disease. Am J Hum Genet 1994;54:
643-649
6 . Kamboh MI, Sepehrnia B, Ferrell RE. Genetic studies of human
apolipoproteins. VI. Common polymorphism of apolipoprotein
E in blacks. Dis Markers 1989;7:49-55
7. Osuntokun BO, Hendrie HC, Ogunniyi AO, et al. Crosscultural studies in Alzheimer’s disease. Ethnic Dis 1992;2:352357
8. Hall KS, Hendrie HC, Rodgers D D , et al. The development
of a dementia screening interview in two distinct languages. Int
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manual of mental disorders. 3rd ed, revised. Washington, DC:
American Psychiatric Association, 1987:97- 163
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In: International statistical classification of diseases and related
health problems. 10th revision (ICD- 10). Geneva: World
Health Organization, 1992:chapter V, categories F00-F99
11. McKhann G , Drachman D, Folsrein M, et al. Clinical diagnosis
of Alzheimer’s disease: report of the NINCDS-ADRDA work
group under the auspices of the Department of Health and
Human Services Task Force on Alzheimer’s Disease. Neurology
1984 ;34 939-944
12. Emi M, Wu LL, Robertson MA, e t d. Genotyping and sequence
analysis of apolipoprotein E isoforms. Genomics 1988;3:373377
13. Mayeux R, Stern Y ,Ortman R, er al. The apolipoprotein €4
allele in patients with Alzheimer’s disease. Ann Neurol 1993;34:
752-754
14. Davignon J, G r e g RE, Sing CF. Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis 1988;8:1-2 1 (Review)
15. Schachter F, Faure-Delanef L, GuCnor F, et al. Genetic associations with human longevity at the Apo E and ACE loci. Nature
Genet 1994;6:29-32
16. Scott J. Apolipoprotein E and Alzheimer’s Disease. Lancet
1993;342:696 (Commentary)
Drenching Sweats as an
Off Phenomenon in
Parkinson’s Disease:
Treatment and Relation to
Plasma Levodopa Profile
Jacob I. Sage, MD, and Margery H. Mark, MD
We followed 4 patients with Parkinson’s disease and severe, intermittent, drenching sweats. One patient was
studied with serial plasma levodopa levels anti simultaneous clinical examinations. She was observed during a
severe sweating episode; this was associated with subtherapeutic plasma levodopa levels (low dopa state). All
4 patients’ sweats responded favorably to the institution
of agonist therapy. Drenching sweats should be considered part of the spectrum of off-period levodopa-related
fluctuations in Parkinson’s disease.
Sage JI, Mark MH. Drenching sweats as an off
phenomenon in Parkinson’s disease: treatment
and relation to plasma levodopa profile.
Ann Neurol 1395;37:120-122
Sweating abnormalities have been noted in patients
with Parkinson’s disease (PD) since the early descriptions of Gowers [l] and Charcot [2). After levodopa
came into widespread use to treat PD, profuse sweating was noted in fluctuating patients [3]. Excessive intermittent head and neck sweating [ 4 ] and patchy impairment of thermoregulatory sweating [ S ] in P D
patients supports the notion that the sweating is primarily disease related 161. There is controversy about
whether severe, whole-body, intermittent sweating in
treated P D patients is related to excessive chorea during on periods or is associated with offs. To elucidate
the relationship between these drenching sweats and
state of dopaminergic stimulation, we examined the
clinical state and simultaneous plasma levoclopa concentrations in a patient who had drenching sweats during the time she was under observation. W e treated
her, along with 3 clinically similar patients, b y adding
From the Department of Neurology, University of Medicine and
Dentistry of New Jersey-Robert Wood Johnson Medical School,
New Brunswick, NJ
Received Mar 3 1 , 1994, and in revised form Jun 10. Accepted for
publication Jun 1 5 , 1994.
Address correspondence to D r Mark, Department of Neurology,
Robert Wood Johnson Medical School, C N - 19, New Brunswick,
NJ 08903.
120 Copyright 0 1935 by the American Neurological Association
direct-acting dopamine receptor agonists to the existing therapeutic regimen.
Patients and Methods
Patient I
A 68-year-old woman with P D for 7 years developed fluctuations over a 6-year period. She experienced end-of-dose
wearing off 2 to 3 hours after each dose of carbidopa/levodopa (CD/LD). To maintain reasonable “on” time, she took
between 12.5/50 and 50/200 mg of CD/LD at 2- to 3-hour
intervals throughout the waking day, and selegiline, 5 mg
twice daily. To minimize high-dopa (peak-dose) chorea in the
afternoon and evenings, the lower doses were taken in the
afternoon, reserving the higher doses for the morning. On
this regimen, she had severe, drenching sweats that occurred
once or twice daily in what appeared to be an end-of-dose
pattern.
Patient 2
A 48-year-old woman with P D for 10 years developed motor
fluctuations over an 8-year period. She experienced end-ofdose wearing off as well as abrupt on/off fluctuations, most
of which did not occur in a predictable pattern. She had
undergone a right pallidotomy, which resulted in an apparent
decrease of high-dopa chorea. Liquid CD/LD, taken every
1.5 to 2.5 hours during the waking day, gave her approximately 80% on time. She was virtually unable to move during “off’ periods, although she was able to sleep through the
night without levodopa. The onset of some offs during each
day was associated with severe, painful arm and shoulder
dystonia; the onset of other offs was unpredictably associated
with drenching sweats lasting up to 30 minutes.
Patient 3
A 78-year-old man with PD for 13 years developed motor
fluctuations ovcr a %year period. H e experienced end-ofdose wearing off 3 to 3.5 hours after each dose. The offs
were associated with painful leg dystonia, which also occurred
each morning prior to his first levodopa dose. On a CD/LD
schedule of 20/200 mg to 25/250 mg every 3 hours for 6 to
7 doses per day, he also had intermittent drenching sweats
occurring just as he went off each dose and lasting for approximately 20 minutes.
Patient 4
A 65-year-old woman with PD for 14 years developed motor
fluctuations over a 10-year period. She had end-of-dose wearing off o n a regimen that included a combination of sustained
release and standard CD/LD (individual levodopa doses varied between 100 mg and 300 mg) every 3 hours during the
daytime. Offs consisted of severe akinesia. Some offs were
unpredictably associated with drenching sweats lasting up to
1 hour.
After informed consent was obtained, Patient 1 was followed in the Neurology Department Clinical Observation
unit from approximately 9 AM to 5 PM; during this time, she
went through a sweating period. She took CD/LD at the
3-
/
I
\ on
2-’
2
-
1-
%
1
%
3
44
5
time (hrs)
Plasma letlodopa concentration (pglml) in Patient 1 (graph).
Cliniial state at the giren time periods is indicated in the boxes.
Each arrou’ denotes a dose of iarbidopallwodopa (12.5/125 tng).
“Freezing”refers to gait-specific immobility.
usual frequency, but at a uniform dose of 12.5/125 mg. Parkinson motor ratings (using the Unified Parkinson Disease
Rating Scale [ 7 ] )and simultaneous venipuncture for plasma
levodopa measurements were carried out approximately
hourly, with additional measurements during and after her
sweating period [8). Plasma levodopa was measured by high
performance liquid chromatography 191.
Results
During the monitoring of clinical state and simultaneous plasma levodopa profile in Patient 1, she experienced severe, drenching sweats (Fig). The on state was
associated with plasma levodopa concentrations above
1.5 kg/ml. Sweating began just before the patient went
off at plasma concentrations of approximately 1.5 kg/
ml. Chorea accompanied the sweats (low-dopa chorea).
The severity of the movements, however, was n o
greater than on many other occasions during which no
sweating occurred. Clinical state lagged behind plasma
levodopa by about 45 minutes. As plasma levodopa
fell further (below 1 pg/ml), sweating stopped, but the
patient became further immobilized with severe freezing of gait.
Pergolide (0.25 mg, 5 times per day) was added to
control motor fluctuations and the sweating was abolished. Twenty-eight months later, she developed hallucinations on this medication. The pergolide was discontinued and the drenching sweats reappeared.
Patient 2 had previously not tolerated bromocriptine
due to nausea. Pergolide in doses up to 2 mg/day failed
to benefit her motor fluctuations. The patient was
Brief Communication: Sage and Mark: Drenching Sweats in P D
121
placed on cabergoline, a new long-acting agonist (up
to 4 mg/day); the swcating disappeared. She remains
improved at 6 months of follow-up. Patient 3 was
started on bromocriptine (2.5 mg 4 times daily) with
resolution of the sweating. After 4 months, he developed hallucinations and the bromocriptine was
stopped. Within several weeks, intermittent, drenching
sweats reappeared. Patient 4 was placed on bromocriptine (1.25 mg at 8 AM and 2 PM). The sweating resolved
and she continues to do well at 1 year.
Discussion
Drenching sweats must be considered part of the spectrum of off-period levodopa-related fluctuations in PD
[lo]. These sweating episodes must be distinguished
from the sweating accompanying excessive motor activity during periods of high-dopa chorea. Sweating associated with severe chorea is usually not as profound
as the off-period drenching sweats. Profuse sweating
during periods of subtherapeutic plasma levodopa concentrations strongly suggests that this clinical phenomenon results from inadequate central dopaminergic
stimulation [8].Clinical manifestations associated with
low-dopa phenomena (in this case, sweating) begin at
a certain threshold plasma levodopa concentration (but
not zero) and then disappear above another higher
threshold concentration. Low-dopa dystonia and lowdopa chorea are similar examples [8, 11, 121. Sweating,
like dyskinesias, may not occur each time the plasma
levodopa concentrations drop to the critical levels; the
reasons are not known.
Low-dopa-related events theoretically should be
noted in a biphasic pattern at the beginning and the
end of a dose (in what has been called the dyskinesiaimprovement-dyskincsia [D-I-D] pattern [ 131). More
often, however, they are seen at the end of a dose. The
most likely reason is that most methods of levodopa
administration produce a rapid rise to a peak in plasma
levodopa concentrations, followed by a much more
gradual return to baseline. The concentration window
at which these events occur, therefore, may be
achieved for too brief a time as levodopa levels are
rising just before a dose becomes effective. Low-dopaassociated symptoms and signs, such as profuse sweats,
therefore, are usually too fleeting to notice or may not
occur at all in the moments just prior to most on states
and only develop as the patient is wearing off.
Sweating abnormalities in P D are consistent with the
concept that many patients have Lewy body pathology
that is not restricted just to the substantia nigra and
related brainstem nuclei [ 141. Dopamine concentrations in the hypothalamus are markedly reduced in P D
[15]. It is possible that decreased dopaminergic activity
in the hypothalamus may, under certain as yet unknown circumstances, initiate drenching sweats. Such
an episode might occur in the untreated condition as
122
Annals of Neurology
Vol 37
No 1 January 1995
a result of disease progression or as a wearing-off reaction during the course of treatment, as seen in the
patients described here.
Direct-acting dopamine receptor agonists may benefit P D patients with drenching sweats by elevating the
underlying, subnormal dopaminergic stimulation in the
hypothalamus or other areas of the autonomic nervous
system. Agonists have been shown to help low-dopa
dyskinesias 11 1, 127. Thus, the addition of agonists in
the 4 patients described here may have raised dopaminergic input above the threshold needed to produce
sweats. One may predict, on the other hand, that increasing or adding agonists in other patients might precipitate or worsen sweats by keeping dopaminergic
stimulation within the critical window.
References
I . Gowers WR. A manual of diseases of nervous system. Philadelphia: Blakiston, 1888
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3. Barbeau A. The clinical physiology of side effects of long-term
L-DOPA therapy. Adv Neurol 1974;5:347-364
4. Appenzeller 0, Goss JE. Autonomic deficits in Parkinson’s syndrome. Arch Neurol 1971;24:50-57
5. Aminoff MJ, Wilcox CS. Assessment of autonomic function in
patients with a parkinsonian syndrome. Br Med J 1!)71;4:80-84
6. Goetz CG, Lutge W, Tanner CM. Autonomic dysfunction in
Parkinson’s disease. Neurology 1986;36:73-75
7. Fahn S, Elton RL,Members of the UPDRS Development Committee. Unified Parkinson’s disease rating scale. In: Fahn S,
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in Parkinson’s disease, vol 11. Florham Park, NJ: MacMillan
Healrhcare Information, 1987:153-163
8. Sage JI, Mark MH, McHale DM, et al. Benefits of monitoring
plasma levodopa in Parkinson’s disease oatients with druginduced chorea. Ann Neurol 199 1;29.623-628
9. McHale DM, Sage JI, Sonsalla PK, Vitagliano D. Complex dysronia of Parkinson’s disease; clinical features and relation to
plasma levodopa profile. Clin Neuropharmacol 1’290;13:164170
10. Riley DE, Lang AE. The spectrum of levodopa-related Auctua[ions in Parkinson’s disease. Neurology 1993;43:1459-1464
11. Mark MH, Sage JI. An analysis of treatment opticons and outcome in patients with Parkinson’s disease and severe dyskinesias.
Ann Clin Lab Sci 1994;24:12-21
12. Zimmerman TR Jr. Sage JI, Lang AE, Mark MH. Severe evening dyskinesias in advanced Parkinson’s disease. clinical description, relation to plasma levodopa, and treatment. Mov Disord 1994;9: 173- 177
13. Muenter MD, Sharpless NS, Tyce GM, Darley FI.. Patterns of
dystonia (“I-D-I” and “D-I-D’) in response to I-dopa therapy of
Parkinson’s disease. Mayo Clin Proc 1377;52:163-1 74
14. Sage JI, Mark MH. Diffuse Lewy body disease. In: Stern MB,
Koller WC, eds. Parkinsonian syndromes. New J’ork. Marcel
Dekker, 1933:393-411
15. Hornykiewicz 0, Kish SJ. Biochemical pathophysiology of Parkinson’s disease. Adv Neurol 1986;45:19-34
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