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Effects of blockade on contingent negative variation in migraine.

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2. Munsat TL, Poussaint AF: Clinical manifestations and diagnosis
of amyloid polyneuropathy. Report of three cases. Neurology
(Minneap) 12:413-422, 1962
3. Schiff S , Bateman T, Maffatt R, et ak Diagnostic considerations in
cardiomyopathy: unique scinrigraphic pattern of diffuse biventricular technetium-9%-pyrophosphate uptake in amyloid heart
disease. Am Heart J 103:562-563, 1982
4. Sobol SM, Brown JM, Bunker SR, et al: Noninvasive diagnosis
of cardiac amyloidosis by technetium-99m-pyrophosphate myocardial scintigraphy. Am Heart J 103:563-566, 1982
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Effects of p Blockade
on Contingent Negative
Variation in Migraine
A. Maertens de Noordhout, MD,X M. Timsit-Berthier, MD,t
M. Timsit, MD,? and J. Schoenen, MD*
Technetium-99m-diphosphonate scintigram exhibiting intense
and diffuse myocardial uptake.
rophosphate 13-51, and this scintigraphic approach is now
thought to have diagnostic usefulness. Autoradiographic
studies indicate that the radiopharmaceutical is associated
with amyloid itself [11. Although the mechanism of localization of technetium-labeled phosphate compounds in amyloid
deposits is not well understood, it has been suggested that
uptake is related to the high calcium content of amyloid [ 1).
Our case shows that scintigraphy with technetium-99mdiphosphonate or pyrophosphate may be useful in the diagnosis of primary amyloid polyneuropathy even in the
absence of clinical evidence of heart disease. Myocardial
scintigraphy with technetium-99m-diphosphonate or pyrophosphate may provide a practical and noninvasive means
of diagnosing primary systemic amyloidosis in patients with
unexplained chronic progressive polyneuropathy.
Department of Neurology
Japanese Red Cross Medical Center
4-1-22, Hiroo
Shibuya, Tokyo 150, Japan
1. Kula RW, Engel WK, Line BR: Scanning for soft tissue amyloid.
Lancet 1:92-93, 1977
Contingent negative variation (CNV) is an event-related
slow cerebral potential that is modulated by central catecholaminergic systems [ 5 , 8, lo]. In previous studies [4, 71, we
reported that CNV amplitude is significantly increased in
migraineurs undergoing no prophylactic treatment and that
the clinical efficacy of @-blockersis positively correlated with
baseline CNV amplitude. Since the exact mechanism of action of @-blockersin migraine remains controversial [b],it
seemed worthwhile to monitor the evolution of CNV in
patients undergoing treatment with these drugs.
Twelve patients (mean age, 34 years; 11 females, 1 male)
suffering from common migraine, according to the
classification of the Ad Hoc Committee [2] and Vahlquist’s
191 criteria, were considered for treatment with @-blockers
because they experienced frequent attacks (at least three per
month). They had not undergone any antimigraine prophylaxis during the previous 3 months, but had used ergot
derivatives or analgesics for relief during attacks.
Before starting @-blockers, CNV was recorded in all patients, according to the standardized procedure 141. Metoprolol, a selective @lantagonist, was then prescribed at a
dosage of 50 mg twice daily, which has proved effective in a
recent controlled study C37. After 3 months of p blockade,
the patients again underwent CNV recording. The CNV
features taken into account were pre-Sz amplitude (M2) and
habituation. All CNV recordings were performed at least 7
days after the last migraine attack.
To allow comparisons between CNV modifications and
the clinical efficacy of metoprolol, a monthly migraine severity score was calculated for each patient, as described elsewhere 171. At the first visit, the score for the preceding
month was retrospectively evaluated from the patient’s history. During therapy with metoprolol, patients were asked to
record their migraine attacks in a diary. The severity score
during the month preceding the study was compared to the
one during the third month of treatment. The response to
metoprolol was graded as follows: a reduction by 0 to 20%
Annals of Neurology
Vol 21 N o 1 January 1987 111
treatment with metoprolol. This finding would support a direct effect of metoprolol on the neural generators of CNV.
In order to validate this hypothesis, we are currently studying CNV before and after treatment with other antimigraine
drugs, such as the calcium antagonist flunarizine, which
presumably has no direct influence on catecholaminergic
In conclusion, our results suggest that a-blockers might
normalize central catecholaminergic overactivity in migraineurs, and thus the increased CNV amplitude characteristic of attack-free intervals. It remains to be demonstrated
whether this effect of P-blockers on the central nervous system is involved in their antimigraine properties.
Dr J. Schoenen is a research associate of the National Fund for
Scientific Research (Belgium).
Individual amplitudes in contingent negative variation (CNV)
before and 3 months after starting treatment with metoprolol,
SO mg twice daily.
was scored as poor, by 20 to 50% as moderate, by 50 to
80% as good, and over 80% as excellerit.
Mean CNV amplitude for the 12 patients before starting
meroprolol was -26.42 t 5.31 pV, a value comparable to
that observed in another group of 29 untreated migraineurs
[4}.Ten subjects showed no habituation of CNV during
successive sequences, while weak habituation was observed
in the other 2 . The mean baseline migraine severity score
was - 2 1.9 f 5.9. Mean CNV amplitude after the 3-month
treatment period was - 16.49 ? 5.05 pV, which is in the
normal range {43. The reduction of amplitude between the
first and second recording was highly significant (p c: 0.001,
paired Student’s t test). Simultaneously, habituation of CNV
reappeared in 11 patients: it was normal in 6 and weak in 5.
The Figure illustrates the modifications of CNV amplitude
following metoprolol therapy in each pati.ent. The mean migraine severity score during the third month of treatment
decreased 6.9 t 4.6, i.e., a reduction by 68%. A weak
nonsignificant correlation (r = 0.59) was :found between the
reduction of CNV amplitude following rnetoprolol therapy
and the clinical efficacy of this drug.
This study demonstrates that CNV tends to normalize,
i.e., decreases in amplitude and recovers .habituation, in migraineurs after 3 months of treatment with metoprolol. Similar results were obtained with propranolol in a few patients
not included here. The reduction of amplitude is by far
superior to that described in normal subjects undergoing
successive CNV recordings at similar time intervals [ t } . The
question arises, however, whether it is due to decreased attack frequency, i.e., clinical improvement, or merely to a
direct pharmacological effect of the @-blocker.The finding
that reduction of CNV amplitude is only weakly correlated
with the clinical efficacy of the treatment does not favor the
former hypothesis, but the number of patients might have
been too small to determine such a correlation. Conversely,
we have also observed a markedly reduced CNV amplitude
in 3 migraineurs studied as early as 2 weeks after the onset of
112 Annals of Neurology
Vol 21 No 1 January 1987
*Headache Clinic
Department of Neurology and Clinical Neurophysiology
University of Liege,
H6pital de Baviere,
Bd de la Constitution 66
4020 Liege, Belgium
fLaboratoirede Neurophysiologie Clinique et de Psychopathologie
University of Liege
Bd de la Constitution 153
4020 Liege (Belgium)
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pilot study of CNV in mental illness. Prog Brain Res 54:535542, 1980
2. Ad Hoc Committee on Classification of Headache: Classification of headache. JAMA 179:717-718, 1962
3. Louis P, Schoenen J, Hedman C: Metoprolol v. clonidine in the
prophylactic treatment of migraine. Cephalalgia 5(3):159-164,
4. Maertens de Noordhout A, Timsit-Berthier M, Timsit M,
Schoenen J: Contingent negative variation in headache. Ann
Neurol 19:78-80, 1986
5. Marczynski TJ: Neurochemical mechanisms in the genesis of
slow potentials: a review and some clinical implications. In Otto
D (ed): Multidisciplinary Perspectives in Event-Related Brain
Potential Research. Washington, DC, U.S. Government Printing Office, 1978, pp 25-35
6. Schoenen J: Place des P-bloquants dans le traitement de la migraine. Migraine et Cbphalees, Sandoz Pharmaceuticals, 1984,
pp 85-95
7. Schoenen J, Maertens de Noordhout A, Timsit-Berthier M,
Timsit M: Correlations between contingent negative variation
(CNV) and clinical efficacy of @-blockersin migraine. (submitted for publication)
8. Thompson JW,
Newton P, Pocock PV, et al: Preliminary study
of pharmacology of CNV in man. In Otto D (ed): Multidisciplinary Perspectives in Event-Related Brain Potential Research.
Washington, DC, U.S. Governmenr Printing Office, 1978, pp
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contingency, effect, migraine, variation, blockade, negativa
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