INTRODUCTION
Migraine
is a common neurovascular disorder characterized by severe episodes of headache
and autonomic-neurological symptoms.1
Visual
symptoms and photophobia are common features of migraine, but are not
exclusively confined to attacks.
Hypersensitivity
to environmental light has been demonstrated to persist even between attacks2, and visual
stimulus can precipitate the migraine attacks.3 Moreover, the aura
in migraine is usually visual in 80–90% of cases.4 Therefore, it is
suggested that visual system may play a role in the pathophysiology of
migraine.3
Previous studies showed visual evoked potential changes
between migraineurs and normal subjects, but results were often conflicting. In
the headache free interval, some authors showed difference of amplitude or
latencies of P100 between migraineurs and healthy control subjects; others did
not show any difference.1,4-7
Aim of work: To
compare VEP (P100) in patients with migraine with and without aura to normal
subjects, and the effect of prophylactic treatment on VEP.
SUBJECTS
AND METHODS
The
present study included 32 patients with migraine, presented to neurology clinic
at a regional hospital, KSA, during the period from June 2012 to May 2013 with
age range from 19 to 54 years (27 females and 5 males) and 15 sex and age
matched control subjects. The diagnosis
of migraine was in accordance with the International Headache Society (IHS) classification.8 Migraine patients
with ocular disorders or other neurological diseases were excluded from the
study.
Patients
were recorded in the headache-free interval; at least 72 hours before or after
an attack. Patients were informed to contact us if attack occurred within 72
hours after the test, and the test was repeated. Recordings were performed in a
quiet room with dimmed light, patients seated in an armchair, 1 minute in front
of a television monitor (mean luminance 240 cd/m2). Stimuli were presented as a
checkerboard pattern of black and white squares subtending 4° 0.5’ of arc (contrast 100%) at
a reversal frequency of 3 Hz. With one eye patched, subjects were instructed to
fixate on a point in the middle of the screen. VEPs were recorded with
silver-silver chloride electrodes applied to the scalp. A standard transverse
chain of three electrodes was sited at 5 cm above the inion (MO), while one electrode
was placed on the midline and one on each side at an inter-electrode distance
of 5cm (LO and RO). All electrodes were referred to a common mid-frontal
electrode 12 cm
above the nasion. During uninterrupted stimulation, sequential blocks of 100
responses were averaged for a total duration of 9 min. We studied the
amplitudes and latencies of the P100 (peak latency of the point of maximal
positivity (Pl00) and amplitude measured from the preceding negative peak (N75)
to trough of the Pl00).
Statistical Analysis
SPSS
software (Version 11.0) was used for statistical evaluation. Analysis of variance
with repeated measures (ANOVA) was performed to compare P100 amplitude and
latency between patients’ subgroups and control subjects. Post hoc analysis was
done by using paired t-test with Bonferroni corrections. Age of patients and
control subjects, and P100 parameters between right and left eye were compared
using paired T-tests. The Pearson correlation analysis was used to
determine the correlation between duration of migraine and P100 parameters.
RESULTS
The
present study included 32 patients with migraine with mean age of 31±8.9.
Twenty-seven (84.4%) of our patients were females, and 5 (15.6 %) were males.
Fifteen
patients had migraine with visual aura (MA) 13 of them were female, and 17
patients diagnosed as migraine without aura (MO) 14 of them were female.
No
significant difference (P=0.378) was present between age of patients with
migraine with aura (30.3±6), and those with migraine without aura (33±10.8).
The
mean disease duration was 28.8±12.3 months for migraine with aura, and for
migraine without aura, it was 31.8±14.9 months. There was no significant
difference (P=0.543) regarding the disease duration between the two groups.
Migraine without aura
Fourteen
migraineurs, 6 migraine without aura (MO) and 8 migraine with aura (MA), had a
prophylactic migraine treatment and 18 (11 MO and 7 MA) had no prophylactic
therapy. The drugs used were: beta blockers, antiepileptic drugs (topiramate),
5-HT receptor antagonists (pizotifen), calcium channel blockers (flunarizine)
and antidepressants (amitriptyline), and treatment was effective regarding
severity and frequency of headache
We
studied the amplitudes and latencies of the P100 component of the VEP. We first
compared VEP latencies and amplitudes between the right and the left eyes
within each population. Because t-test revealed non-significant
differences between the two eyes, we subsequently calculated mean values from
both eyes for each subject.
The
amplitude of P100 component was significantly higher (P<0.001) in patients
with migraine (11.4±1.3) than control subjects (9.7±0.9). This significant
difference still present in patients subgroup with aura 11.7±1.4 (P<0.001)
and without aura 11.1±1.2 (P<0.01) compared to control subjects; (Table 1).
The significant difference disappeared (P=0.164) in patients on regular
prophylactic treatment (10.5±0.9) compared to healthy subjects (Table 2).
Regarding
the latency of P100, it was significantly (P<0.01) longer in patients
(103.7±4.7) than control (100.3±3.2) groups. Patients with migraine with aura
(105.2±4.8) had significantly (P<0.01) longer P100 latency compared to
control subject while the difference was not significant (P=0.517) between
patients with migraine without aura (102.3±4.3) compared to control subjects.
This difference disappeared in patients with regular prophylactic treatment (Tables
1 and 2).
There
was no correlation between age of the patients, or the duration of migraine and
the P100 amplitude (Figure 1) or latency (Figure 2) in patients with migraine
and in patient's subgroups (all of them: p>0.05).
DISCUSSION
This
study was planned to compare VEP (P100) in migraine patients - with and without
aura - to normal subjects, and the effect of prophylactic treatment on VEP.
We
found high P100 amplitude in patients with migraine either with or without aura
compared to controls; however, the amplitude of P100 was normal in patients
with migraine with regular prophylactic treatment. The latency of P100 was
delayed in patients with migraine with aura, but it was normal in patients with
migraine without aura, and patients on regular prophylactic treatment.
There
was no correlation between P100 parameters (amplitude, and latency) and disease
duration, and age of the patients in any of patient's subgroups. In accordance
with our findings, higher P100 amplitude was reported in many previous studies
either in children or in adult patients with migraine either with or without
aura.9-14
Shibata
and colleagues (1997, and 1998) reported higher P100 amplitude in patients with
migraine than control subject, especially on the contralateral side of the visual
aura independent on duration or severity of the illness.7, 15
On the
other hand, Khalil and colleagues (2000) reported high P100 amplitude in
patients with migraine without aura of any duration of the disease, and
migraine with aura of short duration (less than 10 years), the amplitude
decline in patients with migraine with aura of long duration.14 More recently,
Unay and colleagues (2008) reported similar tendency with significantly higher
P100 amplitude in children with migraine compared to healthy subjects, and
patients with tension type headache.3
Prolonged
P100 latency in patients with migraine had been reported by several previous
studies.3,13,14,16
However,
Spreafico and colleagues (2004) reported short P100 latency in patients with
migraine compared to control subjects, and it was normal in patients on prophylactic treatment, he suggested that a different responsiveness
of the visual system in migraineurs due to a dysmodulation of sensor input,
leading to facilitation of visual processing.4
The
absence of correlation between disease duration and age of the patients on one
hand, and the P100 parameters on the other hand was in accordance with many
previous studies.3,7,11,15
However, Khalil and colleagues (2000), reported a decline in P100 amplitude in
patients with migraine with aura of more than 30 years duration, but there was
no correlation between P100 parameters and disease duration in patients with
migraine without aura (of any duration) and migraine with aura of less than 10
years duration. they concluded that, the low amplitude in migraine with aura of
prolonged duration is an acquired phenomenon, related to the events of the
aura.14 The results were similar to our
results especially with disease duration of less than 10 years.
Abnormalities
in VEP strengthen the idea of hyperexcitability of the brain, which is
consistent with previous studies in migraine patients. In previous studies it
was claimed that neuronal hyperexcitability in migraine patients leads to
increased sensitivity to light and other stimuli, so that light discomfort
could emerge in headache-free periods.17 Chronicle and
Mulleners (1994) stated that migraine attacks with or without drug treatment
induces interneuron losses (loss of inhibitory inter-neuron) in the visual
cortex, leading to hyperexcitability.18 Hyperexcitability
status, which can be confirmed with
electrophysiological studies, can explain the basis of VEP response
abnormalities.17 It has been
suggested that this input modulation mechanism (lack of inhibition or increase
in excitation) may occur at any point in the visual pathway.12
Prolonged
P100 latency in these patients cannot be interpreted with one factor. Some
authors noted that recurrent cerebral edema and ischemia cause latency
prolongation provoking demyelination and neuronal hyperexcitability. Increased
stroke incidence in migraine patients strengthens the role of ischemia in the
pathophysiology of migraine.1,3 It has
also been postulated that these electrophysiologic abnormalities can be related
to a central neurotransmitter alteration involving the input modulation
mechanism, such as lack of inhibition or increase in excitation. Another
hypothesis implies an instability of the neural control of cerebral vascular
supply, predisposing the individual to transient episodes of lateralized cortical
oligemia.14
In this
study, prophylactic treatment associated with normalization of P100 parameters.
In recent years many studies investigated
electrophysiological parameters in migraine.19 Following
beta-blocker treatment amplitudes and latencies of pattern reversal visual
evoked potentials were reported to normalize.20 Also in the study
of Gerwig and colleagues (2012), in patients with prophylactic (Beta-blocker)
treatment, the mean Phosphene threshold (PT) increased to values corresponding
to that in healthy controls as assessed by transcranial magnetic stimulation
(TMS).21 At the same time,
topiramate treatment22,
and valporic acid treatment23, had the same effect on PT studied by TMS.
These
findings suggest that prophylactic treatment in migraine may reduce the
excitability of the visual cortex.
Consistent
with earlier findings, the data suggest that modified central excitability may
be one factor of prophylactic efficacy in migraine and that dysfunction of
cortical excitability is at least associated with mechanisms underlying the
pathophysiology of migraine.
Conclusion
Visual
evoked potential (P100) is abnormal in patients with migraine with or without
aura, and it is normal in patients with migraine with regular prophylactic
treatment. It has been suggested that modified cortical excitability may be one
factor of prophylactic efficacy in migraine and that its dysfunction is at
least associated with mechanisms underlying the pathophysiology of migraine.
[Disclosure: Authors report no
conflict of interest]
REFERENCES
1.
Kennard
C, Gawel M, Rudolph Nde M, Rose FC. Visual evoked potentials in migraine
subjects. Res Clin Stud Headache. 1978; 6:73-80.
2.
Hay KM,
Mortimer MJ, Barker DC, Debney LM, Good PA. 1044 women with migraine: the
effect of environmental stimuli. Headache. 1994; 34:166-8.
3.
Unay B,
Ulas UH, Karaoglu B, Eroglu E, Akin R, Gokcay E. Visual and brainstem auditory
evoked potentials in children with headache. Pediatr Int. 2008; 50:620-3.
4.
Spreafico
C, Frigerio R, Santoro P, Ferrarese C, Agostoni E. Visual evoked potentials in
migraine. Neurol Sci. 2004; 25 Suppl 3:S288-90.
5.
Polich
J, Ehlers CL, Dalessio DJ. Pattern-shift visual evoked responses and EEG in
migraine. Headache. 1986; 26:451-6.
6.
Drake ME,
Pakalnis A, Hietter SA, Padamadan H. Visual and auditory evoked potentials in
migraine. Electromyogr Clin Neurophysiol. 1990; 30:77-81.
7.
Shibata
K, Osawa M, Iwata M. Pattern reversal visual evoked potentials in migraine with
aura and migraine aura without headache. Cephalalgia. 1998; 18:319-23.
8.
Classification
and diagnostic criteria for headache disorders, cranial neuralgias and facial
pain. Headache Classification Committee of the International Headache Society.
Cephalalgia. 1988; 8 Suppl 7:1-96.
9.
Lahat E,
Nadir E, Barr J, Eshel G, Aladjem M, Bistritze T. Visual evoked potentials: a
diagnostic test for migraine headache in children. Dev Med Child Neurol.
1997;39:85-7.
10.
Mariani
E, Moschini V, Pastorino GC, Rizzi F, Severgnini A, Tiengo M. Pattern reversal
visual evoked potentials (VEP-PR) in migraine subjects with visual aura.
Headache. 1990; 30:435-8.
11.
Afra J,
Cecchini AP, De Pasqua V, Albert A, Schoenen J. Visual evoked potentials during
long periods of pattern-reversal stimulation in migraine. Brain. 1998;
121:233-41.
12.
Aloisi
P, Marrelli A, Porto C, Tozzi E, Cerone G. Visual evoked potentials and serum
magnesium levels in juvenile migraine patients. Headache. 1997; 37:383-5.
13.
Sener
HO, Haktanir I, Demirci S. Pattern-reversal visual evoked potentials in migraineurs
with or without visual aura. Headache. 1997; 37:449-51.
14.
Khalil NM, Legg
NJ, Anderson DJ. Long term
decline of P100 amplitude in migraine with aura. J Neurol Neurosurg Psychiatry.
2000; 69:507-11.
15.
Shibata
K, Osawa M, Iwata M. Simultaneous recording of pattern reversal
electroretinograms and visual evoked potentials in migraine. Cephalalgia. 1997;
17:742-7.
16.
Oelkers
R, Grosser K, Lang E, et al. Visual evoked potentials in migraine patients:
alterations depend on pattern spatial frequency. Brain. 1999; 122:1147-55.
17.
Main A,
Dowson A, Gross M. Photophobia and phonophobia in migraineurs between attacks.
Headache. 1997; 37:492-5.
18.
Chronicle
E, Mulleners W. Might migraine damage the brain? Cephalalgia. 1994;
14(6):415-8.
19.
Schoenen
J, Ambrosini A, Sandor PS, Maertens de Noordhout A. Evoked potentials and
transcranial magnetic stimulation in migraine: published data and viewpoint on
their pathophysiologic significance. Clin Neurophysiol. 2003; 114:955-72.
20.
Diener
HC, Scholz E, Dichgans J, et al. Central effects of drugs used in migraine
prophylaxis evaluated by visual evoked potentials. Ann Neurol. 1989; 25:125-30.
21.
Gerwig
M, Niehaus L, Stude P, Katsarava Z, Diener HC. Beta-blocker migraine
prophylaxis affects the excitability of the visual cortex as revealed by transcranial
magnetic stimulation. J Headache Pain. 2012; 13:83-9.
22.
Artemenko AR, Kurenkov AL, Filatova EG, Nikitin SS, Kaube H, Katsarava Z.
Effects of topiramate on migraine frequency and cortical excitability in
patients with frequent migraine. Cephalalgia. 2008; 28:203-8.
23.
Mulleners
WM, Chronicle EP, Vredeveld JW, Koehler PJ. Visual cortex excitability in
migraine before and after valproate prophylaxis: a pilot study using TMS. Eur J
Neurol. 2002; 9:35-40.