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Blink rates in parkinsonism.

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male hormone or protein-assimilating hormone induces thrombosis of a cortical vein or dural sinus, or
both.
Blink Rates
in Parkinsonism
References
Craig N . Karson, MD," Peter A. LeWitt, MD,+
Donald B. Calne, M D , t and Richard Jed Wyatt, MD"
1. Busetta BC, Courseille C, Precigoux G , Hospital M: Some
hypotheses about interactions between estrogen and androgen and their possible receptors. J Steroid Biochem 8:63-67,
1977
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in Japanese. In Hibino S (ed): Aplastic Anemia. Baltimore,
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5. Kalbag RM, Woolf A L Thrombosis and thrombophlebitis of
cerebral veins and dural sinuses. In Vinken PJ, Bruyn GW
(eds): Handbook of Clinical Neurology. Vol 12, part 2: Vascular Diseases of the Nervous System. Amsterdam, NorthHolland, 1972, pp 422-446
6. Kendall D: Thrombosis of intracranial veins. Brain 71:386402, 1948
7. Kennedy RJ, Yarbro JW: Effect of methenolone enanthate
(NSC-64967) in advanced cancer of the breast. Cancer
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9. Najean Y, Pecking A, Le Danvic M: Androgen therapy of
aplastic anemia-a prospective study of 352 cases. Scand J
Haematol 22:343-356, 1979
10. Nakao J, Chang WC, Murota S, Orimo H: Testosterone inhibits prosracyclin production by rat aortic smooth muscle
cells in culture. Atherosclerosis 39:203-209, 1981
11. Novak E, Hendrix JW, Seckman CE, Penner JA: A pharmacologic evaluation of fluoxymesterone in normal men. Curr
Therapeut Res 16:251-260, 1974
12. Poltera AA: The pathology of intracranial venous thrombosis
in oral contraception. J Pathol 106:209-219, 1972
13. Prakash C, Arya RK, Singla KP, Bansal BC: Study of platelet
adhesiveness and serum lipids in cerebral venousivenous
sinus thrombosis during pucrperium. J Assoc Physicians India
18:815-819, 1970
14. Sanchez-Medal L: The hemopoietic action of androstanes.
Prog Hematol 7:111-136, 1971
15. Sanchez-Medal L, Pizzuto J, Torre-Lopez E, Derbez R: Effect
of oxymetholone in refractory anemia. Arch Intern Med
113:721-729, 1964
16. Shahidi NT, Diamond LK. Testosterone-induced remission in
aplastic anemia. AMA J Dis Child 98:293-302, 1959
17. Shahidi NT, Diamond LK: Testosterone-induced remission in
aplastic anemia of both acquired and congenital types. Further
observations in 24 cases. N Engl J Med 264953-967, 1961
18. Shinohara K, Matsumoto N , Tajiri M, et al: Oxymetholone
treatment in aplastic anemia. Nippon Ketsueki Gakkai Zasshi
37:255-265, 1974
19. Wright HP: Changes in the adhesiveness of blood platelets
following parturition and surgical operations. J Pathol Bacteriol 54:461-468, 1942
20. Ygge J, Brody S, Korsan-Bengtsen K, Nilsson L: Changes in
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104187-98, 1969
Spontaneous eye blink rates were counted in 54 parkinsonian patients, 5 2 of whom were receiving
levodopa. The mean blink rate of the more disabled
patients, 7 per minute, was significantly less than the
17 blinks per minute observed in mildly disabled ( p <
0.02) and 22 blinks per minute (p < 0.001) in moderately disabled patients. Drug-induced dyskinesia in 2 1
patients was associated with an elevated blink rate, 32
per minute, as compared with 12 per minute for nondyskinetic patients ( p < 0.01).
Karson C N , LeWitt P A , Calne DB, Wyatt RJ
Blink rates in parkinsonism. A n n Neurol
12:580-583, 1982
A decreased rate of spontaneous blinking is characteristic of parkinsonism [9]. Along with improvement of other motor symptoms, infrequent blinking
may return to normal in some patients with institution of levodopa therapy. Since the most striking
pathophysiological feature of idiopathic parkinsonism is related to loss of nigroscriatal neurons, the
decrease in spontaneous blinking may also be related
to diminished dopaminergic activity in this pathway
[ 121. Recent observations support a role for central
dopamine activity in mediating the rate of blinking.
First, increased blink rates are associated with
schizophrenia [ 14, 261 and Tourette syndrome [6],
conditions both postulated to involve an increase in
central dopamine activity [ I , 251. Second, apomorphine, a potent dopamine agonist, increases blink
rates in monkeys [3, 161, whereas neuroleptic medications, which block dopaminergic activity, decrease
blinking in nonhuman primates [16] and in schizophrenic patients [ 141. In monkeys, the apomorphine
effect is dose related; prior treatment with haloperidol for three weeks results in greater sensitivity to a low dose of apomorphine [15].
This report explores the relationship between
blink rates and parkinsonism, including the extent of
From the "Adult Psychiatry Branch, Division of Special Mental
Health Research, Intramural Research Program, National Institute
of Mental Health, Saint Elizabeths Hospital, Washington, DC
20032, and the tExperimental Therapeutics Branch, National Institute of Neurological and Communicative Disorders and Stroke,
Berhcsda, M D 20205.
Received Mar 8, 1982. Accepted for publication Apr 10, 1982.
Address reprint requests to D r Karson.
580 0364-5 134/82/120580-04$0 1.25 @ 1082 by t h e American Neurological Association
Using criteria modified from Hoehn and Yahr [lo],
each patient was rated with a five-point scale as to the overall severity of parkinsonian disability. The ratings were as
follows: (I) patients show minimal o r no functional impairment, tremor at rest may be a prominent symptom, and
parkinsonism may be restricted to one side; (11) patients
have a mild degree of disability with bilateral or midline
involvement but no impairment of balance; (111) there is
moderate functional disability from parkinsonism, righting
reflexes are impaired, and patients may be restricted in activities requiring walking, dexterity, and rapid movements;
(IV) fully developed, severely disabling disease; the patient
may walk and stand unassisted in a precarious state; and (V)
severe disability with inability to walk. Other disabilities,
such as impaired speech, self-feeding, rigid state, and so on,
may be present. Patients with stage I11 or IV disease were
grouped together because of the small number in each category, and there were no stage V patients in this study. The
blink observer was not involved in the clinical staging of
these patients.
Each patient was carefully observed for dyskinetic
movements. If present, these were scored by a modified
version of the Abnormal Involuntary Movement Scale [ 8 ] ,
omitting the use of the blinking index rating as one of the
criteria for dyskinesia. With a rating of “2 o r more in any
of seven major motor groups (muscles of facial expression,
lips, jaw, tongue, arm, leg, and trunk), a patient was designated as dyskinetic. There were no noteworthy differences
between age or mean duration of illness among patients in
various stages of parkinsonism o r between the dyskinetic
versus the nondyskinetic groups.
disability, and the presence or absence of levodopainduced dyskinetic symptoms among treated parkinsonian patients. The most severely bradykinetic parkinsonian subjects, in whom nigrostriatal dopamine
is likely to be greatly depleted, might be expected to
demonstrate the slowest rates of spontaneous blinking. Furthermore, if dyskinesia induced by levodopa is derived from postsynaptic supersensitivity
to dopamine, as proposed by Klawans [19], then a
similar phenomenon may be found with respect to
blink rate as a manifestation of hyperkinesia. Hence,
depression of blink rate should correlate with the degree of parkinsonian disability, and patients with
levodopa-induced dyskinesia should have an increased spontaneous blink rate. To test this hypothesis, blink rates were examined in a group of parkinsonian subjects with varying degrees of disability.
Material and Methods
Fifty-four parkinsonian subjects (35 male, 19 female) were
seen as outpatients at the Experimental Therapeutics
Branch of the National Institute of Neurological and Communicative Disorders and Stroke. The mean age ( 2 SD)
was 56 t 13 years, and symptoms of parkinsonism had
been present for a mean of 12 2 9 years. Fifty-two of the
patients had been receiving treatment with levodopa and
carbidopa for several years, sometimes in combination with
other drugs (including anticholinergics, tricyclic antidepressants, and amantadine). Twenty-six of these patients received additional therapy with a D, agonist (either bromocriptine or lisuride). The regimen of dopamine agonists had
been unchanged for two weeks o r longer prior to assessment. Twenty-four controls (14 male, 10 female; mean age,
56 ? 12 years) were chosen from clinical staff, patient family members (spouses and siblings), and 3 patients with
nonparkinsonian neurological disorders.
Blinks were counted and timed by an experienced observer for the first five minutes of conversation during
routine examinations with a familiar interviewer: these
were calculated as the mean number of blinks per minute.
Although subjects sometimes were informed that “certain
movements” were under observation, blinking was not
specified.
+”
Results
The mean blink rate for each patient group appears in
the Table. The mean 2 SD for normal controls was
16 k 9 blinks per minute. The stage of illness had a
significant effect on blinking: F(3,74) = 3.78; p <
0.02, one-way analysis of variance (ANOVA) for independent measures [29].The means, compared in
a post-hoc fashion by the Scheffk test [ 2 9 ] , demonstrated that patients with advanced parkinsonism had
significantly decreased blinking as compared with
normal subjects (t = 2.37,p < 0.03) or with stage I ( t
Mean Blink Rates of Patients, Gvouped by Stage and Dyskinesia Statusa
~~
~
Stage
+ IV
Subjects
I
Dyskinetic
patients
Nondyskinetic
patients
24
&
14 (N
5)
32
5
14 ( N = 9)
11 2 11 ( N = 6)
32
2
16 (N
15
‘-t
8 ( N = 18)
1.5
-t
11 ( N = 10)
2
* 2 ( N = 5)
12
2
10 ( N = 34)
17
?
10 ( N
2.2
-t
16 (N
7 +. 10 (N = 11)
Overall mean
for patients
in each stage
111
I1
=
=
24)
=
19)
Overall Mean c SDb
=
21)
aValues are blinks pet minute.
”According to dyskinesia status.
Brief Communication: Karson et al: Blink Rates in Parkinsonism
581
(intraclass correlation coefficient = 0.58, p < 0.001
[27]. The mean difference per patient was 7 k 10
blinks per minute. Four patients with differences 2
standard deviations above the mean accounted for
more than half the total difference. If these patients
are omitted from analysis, the mean difference for
each of the remaining 26 patients decreased to 3 k 4
blinks per minute (intraclass correlation coefficient =
0.86,p = O.Op0).
50
40
0
c
.-
30
.
E
0
u)
3
.c
:
20
-
N
*:
rn
*-:
10
**
*
i
N.
..
.y
**
0..
C
Normals
(n=241
Non
dys k i n e t i c
patients
D y s k i n et i c
p a t ie n t s
(n=2l)
in-33)
Blink rates of normal controls and patient.c grouped according
t o dyskinesia status.
= 2.40,p < 0.02) or stage I1 patients ( t = 3.77,) <
0.001).
The presence of dyskinesia also significantly affected blinking: F(2,77) = 5.16;) < 0.01, one-way
ANOVA for independent measures. Dyskinetic patients had blink rates in excess of those in nondyskinetic (t = 3.18,p < 0.01) and normal subjects ( t =
1.97,p < 0.05) (Figure).
To examine the combined effects of dyskinesia and
staging on patients’ blinking, we used a two-way
ANOVA for independent measures [29]. T h e stage
of parkinsonism (F(1,48) = 11.60,) < 0.1) and the
presence of dyskinesia (F(2,48) = 7.94, p < 0.01)
each affected blinking significantly, though these two
variables did not interact significantly (F(2,48) =
1.15, ) > 0.40). Severely affected patients had decreased blink rates compared with other patients in
both the dyskinetic ( t = 2.63,) < 0.02) and nondyskinetic groups (2 = 2.08,p < 0.05). While the presence of dyskinesia was associated with increased
blinking overall (t = 1.97,) = 0.05), this effect was
significant only in stage I1 patients ( t = 3.17, p <
0.01).
The constancy of the blink rate from one time period to another was tested by comparing blink rates
from the two most recent counts in 3 1 patients in
whom counts had been obtained previously on several occasions weeks apart. The mean blink rate for
the first count was 17 k 13 blinks per minute as
compared with 18 2 15 during the second count
582
Annals ofNeurology
Vol 12
Discussion
The marked decrease of blink rates in patients with
advanced parkinsonism, as compared with less affected patients and controls, supports the notion that
blink rates reflect hypokinesia in this disorder. Since
advanced parkinsonism involves extreme deterioration in the dopaminergic nigrostriatal pathways [ 111,
there may be a connection between decreased blink
rates and diminished dopamine activity. The finding
of relatively normal blink rates in patients with mild
disability may be the result of dopamine agonist
therapy. Alternatively, these mildly symptomatic patients may have nearly normal blink rates. This could
be confirmed by studying the blink rates of untreated
parkinsonians.
T h e association of increased blinking with dyskinesia leads to the hypothesis that both may be
manifestations of dopamine agonist therapy. However, while several dyskinetic patients had high blink
rates, some had low ones, thus precluding such a
simplistic explanation. Tardive dyskinesia, which is
produced by prolonged treatment with dopamine
blocking agents (neuroleptics), may not be associated
with increased blink rates [2,4, 51. This additional
evidence implies a characteristic difference between
the mechanisms that cause dyskinesias and those responsible for elevated blinking.
The neuroanatomy of spontaneous blinking has
not been elucidated. Another type, reflex blinking (as
elicited in Myerson’s sign), is regarded as a
trigeminofacial reflex [20, 231, though recent evidence suggests a role for the facial nerve in the afferent arch as well [7, 281. Two components of this
reflex have been identified, R, and R2. R, appears to
be a simple pontine reflex [24],while the later R,
travels a more complex route involving the spinal
pathway of the trigeminal nerve [lS, 201. Studies of
the brainstem-peripheral arc of the blink reflex in
parkinsonian patients suggest a delay in the central
pathways, although the site of impaired transmission
remains undefined [17].
Two lines of evidence point to an inverse relationship between the two types of blinking. First, while
spontaneous blinking is decreased in parkinsonism,
reflex blinking is increased [2 13, and this increase is
diminished by levodopa therapy [22], implying that
No 6 December 1982
reflex blinking involves dopaminergic mechanisms.
Second, spontaneous blinking increases steadily,
from infrequent blinking at birth to the normal adult
rate of 25 f 13 blinks per minute [13] by adolescence. Thereafter, the adult rate remains constant
[30].Reflex blinking behaves in the opposite fashion:
it is readily and persistently elicited in infancy but
steadily decreases during childhood. These relationships may be clues to the neuroanatomy involved in
spontaneous blinking, since they parallel an agerelated increase in the urinary excretion of dopamine
and its metabolites [ 2 7 ] .
Blink rates appear to be a promising tool in the
investigation of disturbances of central dopaminergic
processes. Further studies are under way investigating the influence of D, agonists to aid in the definition of the nature of dopaminergic impairment in
neurological disorders such as parkinsonism.
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Brief‘ Communication: Karson et al: Blink Rates in Parkinsonism 583
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