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ORIGINAL RESEARCH
Autonomic Function Tests, Heart Rate Variability, and
Electrophysiological Evaluation in Patients With a Primary Episodic
Headache: An Observational Study
Abdul Qavi,* Rajani Bala Jasrotia,†Pradeep Kumar Maurya,* Ajai Kumar Singh,* Dinkar Kulshreshtha,*
Arshi Ansari,‡Anup Kumar Thacker,* and Arvind Kanchan§
Departments of
*
Neurology,
†
Physiology, and
‡
Community Medicine, Dr Ram Manohar Lohia Institute of Medical Sciences, Lucknow, India; and
§
Department
of Physiology, Hind Institute of Medical Sciences, Lucknow, India.
Purpose: Cranial autonomic symptoms are typically associated
with the trigeminal autonomic cephalalgias and also present in
substantial cases of migraine. Autonomic nervous system
dysfunctions are also been reported in headache disorders and
postulated to promote headache attacks. This study was aimed
to evaluate the parasympathetic and sympathetic autonomic
functions tests in patients with a episodic primary headache and
to investigate, if any, electrophysiological abnormalities in the
blink reflex test and sympathetic skin response test in these
patients.
Methods: In this cross-sectional study, a total of 100 patients, 50
patients each of migraine and tension-type headache attending
the neurology OPD and fulfilling the diagnostic criteria of
headache disorders were enrolled. Autonomic functions tests
were performed in the Department of Physiology, whereas
electrophysiological tests were powered by the Editorial
Manager and ProduXion Manager from Aries Systems
Corporation performed in the Department of Neurology.
Results: Significant association (P,0.05) was observed in
“blood pressure response to sustained handgrip”(sympathetic
activity) and “heart rate response to Valsalva maneuver”
(parasympathetic activity) among patients with migraine.
Although the mean sympathetic skin response latency of
patients with migraine was within the normal range, it was
significantly prolonged in comparison with the control group.
“Blood pressure response to sustained handgrip”and “heart rate
variability”were found to be significantly (P,0.05) different in
patients with a tension-type headache. The blink reflex test was
observed to be normal in all patients with a headache. Patients
with migraine showed a significant dysautonomia in category
three of the Ewing battery for autonomic functional disability.
Conclusions: Autonomic functional abnormality, both
sympathetic and parasympathetic, does exist in patients with a
primary episodic headache.
Key Words: primary episodic headache, migraine, tension type
headache, autonomic function tests, Ewing's battery, blink reflex,
sympathetic skin response test, trigeminovascular reflex, sym-
pathetic skin response test, blink reflex, heart rate variabilty.
(J Clin Neurophysiol 2022;00: 1–9)
Headache is one of humanity’s most common afflictions
associated with significantly decreased functioning ability
during headache periods, imposing huge costs to health care and
indirectly to the economy in general.
1
Headache affects people of
all ages, races, ethnicity, and socioeconomic status, but it is more
prevalent in women and in younger age groups. Primary
headache disorders are classified as migraine, tension-type
headache (TTH), trigeminal autonomic cephalalgias, and other
primary headache disorders such as the new daily persistent
headache according to the International Classification of
Headache Disorder third edition beta.
2
Various mechanisms
explaining the pathophysiology of migraine and other episodic
primary headache disorders are hypothesized, but these clinical
researches are inconclusive in explaining the basic mechanisms
of this disorder because of variability in involved factors.
Activation of the trigeminovascular system and sensitization of
trigeminal brainstem nuclei are proposed to be possible basic
mechanisms.
3
Various functional imaging studies have shown
that during migraine headache attack, the brainstem is activated
and abnormalities are seen in ascending and descending
nociceptive pathways during ictal and interictal phases.
4
The
trigeminovascular system provides sensory innervation of extra
cranial and intracranial arteries, as well as afferent fibers of
nociceptive transmission.
3
The contribution of the trigeminovas-
cular system to pathogenesis of migraine has been detected in
experimental animal and human studies.
Autonomic nervous system (ANS) dysfunctions are also been
reported in headache disorders and postulated to promote the
attacks.
5
Cranial autonomic symptoms (CAS) are typically associ-
ated with the TAC, such as a cluster headache but also present in
substantial cases of migraine.
6
Systemic manifestations of ANS
involvement including nausea, diarrhea, constipation, coldness in
the extremities, and paroxysmal tachycardia are present in these
episodic headaches. It has been postulated that migraine episodes
are precipitated by chronic and excessive sympathetic nervous
system activation by rapidly depleting norepinephrine stores while
increasing the release of dopamine, adenosine, and prostaglandins.
7
However, in previous studies, it has been reported that migraine is
associated with sympathetic and parasympathetic hypofunction,
hyperfunction, or sympathetic instability.
7,8
The authors have no funding or conflicts of interest to disclose.
Address correspondence and reprint requests to Abdul Qavi, MBBS, MD,
Department of Neurology, Dr Ram Manohar Lohia Institute of Medical
Sciences, Lucknow 0226010, India; e-mail; drqavi2008@gmail.com.
Copyright Ó2022 by the American Clinical Neurophysiology Society
ISSN: 0736-0258/22/0000-0001
DOI 10.1097/WNP.0000000000000943
Copyright © by the American Clinical Neurophysiology Society. Unauthorized reproduction of this article is prohibited.
clinicalneurophys.com Journal of Clinical Neurophysiology Volume 00, Number 00, Month 2022 1
The question whether migraine and tension-type headaches
occur by central, peripheral, or combined mechanisms remained
unresolved. The clinical phenomenon such as increased skin
sensitivity, hyperalgesia, and allodynia in primary headache
disorders possibly attribute to the modified trigeminocervical
nociceptive system for facilitation or sensitization of central
nociceptive neurons.
9
Direct assessment of brainstem structures such as the trigemi-
novascular system and some of the autonomic dysfunctions is
virtually not possible because of the involvement of a variety of
nuclei and there integrating pathways as well as different neuro-
modulators involvement. However, with performing certain facial
reflexes electrophysiologically, assessment of brainstem dysfunc-
tions can be obtained indirectly. One of these is the blink reflex test
for evaluation of brainstem dysfunction and the sympathetic skin
response (SSR) test for peripheral sympathetic autonomic system
assessment. Blink reflex is an objective neurophysiological method
for determining the status of trigeminal system, facial nerve, and
pons through its central reflex pathway. Early component of blink
reflex (R1) is transmitted by the pontine pathway recorded by
unilateral stimulation, whereas late component (R2) is a poly-
synaptic response passing through lateral reticular formation, and it
is recorded bilaterally.
10
The sympathetic skin response test is also a
noninvasive and easy-to-perform electrophysiological test to analyze
the sympathetic nervous system. The sympathetic skin response
reflects sympathetic cholinergic pseudo motor function which
induces changes in skin resistance to electrical conduction. This
test is a result of the activation of the polysynaptic reflex arch
involving eccrine sweat glands.
11
Other autonomic functions including both sympathetic and
parasympathetic can also be performed such as Valsalva
maneuver, deep breathing test, orthostatic hypotension, sustained
handgrip, and heart rate variability tests.
Various studies are conducted on electrophysiological tests
specially blink reflex and some studies on SSR in patients with a
primary headache in particular reference with migraine. In this
study, patients with a primary headache of both migraine and TTH
were included. This study was planned to help in understanding the
pathophysiology of different types of primary headache disorders
and abnormalities in autonomic functions which may help in
diagnosis and further better treatment plans for reducing morbidity
and functional loss due to these headaches.
This study was aimed to evaluate the parasympathetic and
sympathetic autonomic functions in patients with a episodic primary
headache and to investigate, if any, electrophysiological abnormal-
ities in the blink reflex test and sympathetic skin response test in
patients with migraine and tension-type headache.
MATERIAL AND METHODS
This cross-sectional observational study was conducted in
the Department of Neurology, in collaboration with the Depart-
ment of Physiology, Dr. Ram Manohar Lohia Institute of
Medical Sciences, Lucknow, India. The ethical approval was
taken from the institutional ethics committee (IEC No. 26/17).
Written informed consent was obtained from all cases regarding
the study, their participation, regarding publication, and use of
study data for research purposes. Patients seen in Neurology
OPD from June 2018 to June 2020 were enrolled in the study. A
total of 100 patients were enrolled in the study, 50 patients each
of migraine and TTH.
Inclusion Criteria
1. Cases of episodic migraine and episodic tension-type head-
ache were selected according to the International Classifica-
tion of Headache Disorder third edition beta.
2. Patients in the age group of 14 to 50 years
Exclusion Criteria
1. Evidence of systemic illness such as DM, HTN, hypothy-
roidism, primary malignancy, neuropathy, medical comorbid-
ities, and other chronic infections and on chemoradiation
therapy.
2. Previous cranial neuropathy, Bell palsy, facial trauma, and
leprosy.
3. Denial of consent.
Controls
Age and sex-matched healthy controls.
Data Collection
Detailed history taking and examination were conducted in all
included patients after taking informed written consent. The
subjective review of autonomic systems was performed in each
patient in the study group as per their clinical signs and symptoms.
In the study, both the autonomic function tests and
electrophysiological evaluation were performed during the
interictal period of the headache when the patient was headache
free. There is a possibility that the sympathetic and parasympa-
thetic tone might fluctuate during and then after a headache till
returning to a typical baseline level. Functional imaging studies
and studies based on a neurotransmitter are lacking regarding the
exact duration of how long the postdromal phase persists. So, for
the safer side, in this study, autonomic functions and electro-
physiological tests were performed at least 7 days after headache
to avoid the effect on ictal and postdromal sympathovagal tone.
At the time of the tests, these patients were off from any
prophylactic drugs for two or more weeks and were also not
taken any abortive/acute treatment of headache on the day of the
test to avoid the effects of medication on autonomic function
tests. Neither the cases nor the controls were taking any
medications such as antihistamines, antidepressant medications,
and antihypertensive medications with anticholinergic properties
that might have impact on autonomic functions.
Blink reflex and SSR were performed in all patients with
migraine and TTH during headache-free periods in the Nerve
Conduction Study (NCS) Lab, Department of Neurology, Dr
RMLIMS. These tests were performed using the Nicolet EDX
machine with the Synergy software.
A. Qavi, et al. AFT and Electrophysiology of Primary Episodic Headache
Copyright © by the American Clinical Neurophysiology Society. Unauthorized reproduction of this article is prohibited.
2 Journal of Clinical Neurophysiology Volume 00, Number 00, Month 2022 clinicalneurophys.com
Supraorbital nerve stimulation procedure was used for blink
reflex,
12
and latency of both sides R1, R2 ipsilateral, and R2
contralateral was recorded and analyzed.
Sympathetic skin response was recorded in both upper limbs
by median nerve stimulation at the wrist.
13
The latencies and
amplitudes were recorded bilaterally placing an active electrode at
the palm as per standard protocols. On both sides of median nerve
stimulation, three values were taken and the average was used as
final values to avoid error. The stimuli were delivered at irregular
intervals at least 20 seconds apart to avoid SSR habituation.
Autonomic functions tests including both sympathetic and
parasympathetic functions were performed in the Experimental
Lab, Department of Physiology, Dr.RMLIMS
Parasympathetic Function Tests
1. Heart rate response to deep breathing
2. Heart rate response to Valsalva maneuver
3. Heart rate response to standing (30: 15 Ratio)
Sympathetic Function Tests:
1. Blood pressure response to the sustained handgrip test
2. Blood pressure response to standing
These five autonomic function tests were performed as per the
standard protocol described by Ewing et al.
14
All the study
participants were called to the Department of Physiology in the
morning hour. They were specially instructed prior to come prepared
to keep in hand; about 2 hours will be spent during autonomic
function tests. They were asked to remain abstained from coffee, tea,
chocolates, or cola for at least 12 hours before the test. However, a
light breakfast was allowed minimum 2 hours before the test. All the
tests were performed between 9.30 AM and 12.30 PM in a quiet
environment. The temperature of laboratory was maintained at 258C.
All the participants were tested under abovementioned similar
laboratory conditions. They were allowed to adapt the experimental
and environmental conditions for 1 hour. During that period, the
nature of the tests was explained to the subjects beforehand and
informed consents were taken.
Details of the Methods of Autonomic
Functions Tests
1. Heart rate response to deep breathing: This test was performed
in a supine posture with electrocardiogram (ECG) being
recorded. The patients were advised to follow the command of
observer as such that he/she will take deep and slow breathing
at the rate of 6 breaths per minute. The difference between
maximum and minimum heart rate $15 beats/min was
considered normal, 11 to 14 beats/min was considered
borderline, and #10 beats/min was considered abnormal.
2. Heart rate response to Valsalva maneuver: This test was
performed in a sitting posture. The patients were demon-
strated first to follow the procedure, in which he/she had
blown into a manometer tube and maintain holding the
pressure of 40 mm Hg for 15 seconds. The continuous ECG
was being recorded. The Valsalva ratio is derived from the
ratio of the maximum heart rate after the maneuver to
the minimum heart rate during the maneuver. Valsalva ratios
$1.21 were considered normal, 1.11 to 1.20 were consid-
ered borderline, and #1.10 were considered abnormal.
3. Heart rate response to standing (30: 15 ratio): In this test, first
the patient was asked to lie supine with ECG being recorded.
After a minute, he/she was asked to stand up suddenly, with
ECG leads attached. The maximum HR at or around the 15th
beat and the minimum HR at around the 30th beat after
standing were taken as the 30:15 ratio. The 30:15 ratios $
1.04 were considered normal, 1.01 to 1.03 were considered
borderline, and #1.00 were considered abnormal.
4. Blood pressure (BP) response to the sustained handgrip test:
In this test, the patient was advised to press a hand grip
dynamometer with force of about 30% of maximum voluntary
effort. BP was measured before the grip and at the one-minute
intervals during handgrip. The increase in diastolic blood
pressure $16 mm Hg was considered normal, 11 to 15 mm
Hg was considered borderline, and #10 mm Hg was
considered abnormal.
5. Blood pressure response to standing: This test was performed
by measuring the patient’s BP while he/she was lying down
quietly and again when he/she stands up for continuously
3 minutes. The decrease in systolic blood pressure #10 mm
Hg was considered normal, 11 to 29 mm Hg was considered
borderline, and $30 mm Hg was considered abnormal.
On the basis of these five autonomic functions test, the
Ewing score was calculated. As in our study, results for each
autonomic test were classified as normal, borderline, and
abnormal.
14
On the basis of scoring performed in the Ewing
classification of autonomic failure, patients were classified
among five categories as follows:
Category (1) normal: all tests normal or one borderline.
Category (2) early: one of the three heart rate tests abnormal or
two borderlines.
Category (3) definite: two or more of the heart rates tests
abnormal.
Category (4) severe: two or more of the heart rates tests abnormal
plus one or both of the blood pressure tests abnormal or both
borderlines.
Category (5) atypical: any other combination.
Along with these typical autonomic functions tests, the heart
rate variability testda test of sympathovagaldbalance was also
performed using LabChart 8 Pro software on the ADInstrument.
Statistical Analysis
Statistical analysis was performed by using SPSS version
16.0 version (Chicago, Inc). The results are presented as mean 6
SD and percentages. The chi-square test was used to compare the
categorical variables. The unpaired t-test was used to compare
discrete variables. The mean values for normally distributed data
were compared using paired and unpaired 2-tailed t-tests. Values
were considered to be significant at P,0.05.
AFT and Electrophysiology of Primary Episodic Headache A. Qavi, et al.
Copyright © by the American Clinical Neurophysiology Society. Unauthorized reproduction of this article is prohibited.
clinicalneurophys.com Journal of Clinical Neurophysiology Volume 00, Number 00, Month 2022 3
OBSERVATIONS & RESULTS
This study was conducted among 100 patients with a
episodic primary headache comprising 50 patients each of
migraine and TTH along with 50 healthy age and sex-matched
controls. Most of the patients with headache in this study were
females (69%). Almost half (42%) of the patients with migraine
and one fifth (18%) of the patients with TTH were in the age
group of 15 to 25 years. About half of the patients had 5 to 10
episodes of headache per month. Headache was primarily
hemicranial (76%) in patients with migraine, whereas it was
global in TTH (60%). Cranial autonomic symptoms were present
in 72% cases of migraine (Table 1).
A significant association (P,0.05) was observed in “blood
pressure response to sustained handgrip”and “heart rate response
to Valsalva maneuver”among patients with migraine in
TABLE 1. Demographic and Clinical Profile of Study Participants
Characteristics Migraine (N ¼50), n (%) Tension Type Headache (N ¼50), n (%) Control (N ¼50), n (%)
Gender
Male 14 (28) 17 (34) 14 (28)
Female 36 (72) 33 (66) 36 (72)
Age (in completed years)
15–25 21 (42) 9 (18) 20 (40)
26–35 17 (34) 18 (36) 20 (40)
36–50 12 (24) 23 (46) 10 (20)
Mean 6SD 27.7 68.3 34.6 68.8 28.3 68.7
Residence
Urban 23 (46) 30 (60) 26 (52)
Rural 27 (54) 20 (40) 24 (48)
Religion
Hindu 45 (90) 42 (84) 42 (84)
Muslim 5 (10) 8 (16) 8 (16)
Clinical features
Family history 14 (28) 0 (0) NA
Duration of illness
,5 years 23 (46) 16 (32) NA
5–10 yeas 27 (54) 27 (54)
.10 years 0 7 (14)
Frequency of headache attacks
,5 per month 19 (38) 12 (24) NA
5–10 per month 31 (62) 32 (64)
.10 per month 0 (0) 6 (12)
Location of headache
Hemicranial 38 (76) 0 (0) NA
Bifrontal 1 (2) 17 (34)
Global 7 (14) 30 (60)
Occipital 4 (8) 3 (6)
Premonitory symptoms 5 (10) 1 (2)
Aura 6 (12) 0 (0)
Cranial autonomic symptoms 36 (72) 1 (2)
Severity of pain (VAS)
Mild 0 (0) 19 (38) NA
Moderate 15 (30) 30 (60)
Severe 35 (70) 1 (2)
Associated symptoms
Nausea 42 (84) 3 (6) NA
Vomiting 32 (64) 0 (0)
Photophobia 44 (88) 9 (18)
Phonophobia 39 (78) 6 (12)
Vertigo 12 (24) 0 (0)
Aggravating factors
Sunlight 45 (90) 6 (12) NA
Noise 37 (74) 5 (10)
Fasting 18 (36) 1 (2)
Travel 9 (18) 11 (22)
Stress 9 (18) 40 (80)
A. Qavi, et al. AFT and Electrophysiology of Primary Episodic Headache
Copyright © by the American Clinical Neurophysiology Society. Unauthorized reproduction of this article is prohibited.
4 Journal of Clinical Neurophysiology Volume 00, Number 00, Month 2022 clinicalneurophys.com
comparison with healthy controls (Table 2). The mean values of
“blood pressure response to sustained handgrip”were signifi-
cantly lower (15.640 612.368) in patients with migraine in
comparison with controls (21.160 68.988) with pvalue ,
0.012. In the same way, mean values of “heart rate response to
Valsalva maneuver”were also found to be significantly (P,
0.002) lower among patients with migraine (1.424 60.392) as
compared with controls (1.662 60.344) (Table 3).
“Blood pressure response to sustained handgrip”and “heart
rate variability”(mean values of HRV in TTH patients vs.
controls 2.095 61.334 vs. 1.435 61.4, respectively, with p
value of 0.019) were found to be significantly (P,0.05)
different in patients with TTH and healthy controls (Table 2).
Most of the patients with migraine (56%) have normal sym-
pathovagal tone. Twenty-four percent of patients with migraine
presented with sympathetic dominance, whereas 20% have
parasympathetic overactivity. Contrary to migraine, patients with
TTH showed significant sympathetic dominance (48%,
p¼,0.05) in HRV values in comparison with healthy controls.
The mean value of LF/HF in patients with TTH was 2.095 6
1.334, which was significantly (P,0.05) higher than of controls
suggesting significant sympathetic predominance (P,0.05) in
patients with TTH (Table 3).
The mean SSR latency (right UL 1.433 60.129 and left UL
1.433 60.119) of patients with migraine was within the normal
range and was significantly (P,0.015 and ,0.005 in right and
left UL, respectively) prolonged in comparison with the control
group (right UL 1.376 60.095 and left UL 1.372 60.087)
(Table 3). In qualitative analysis, 8% of patients with migraine
had significantly (P,0.05) low SSR amplitude (right upper
limb) in comparison with the control group (Table 4). No
significant difference in mean sympathetic skin response values
was observed in patients with TTH in comparison with healthy
controls (Table 3). The latencies of both sides in blink reflex were
comparable in patients and controls suggesting no significant
abnormality regarding the blink reflex test in patients with a
headache (Table 3, 4).
A majority of patients with a headache, migraine 46% and
TTH 52%, were in category two of the Ewing score that is the
early phase of autonomic involvement. Among patients with a
headache, 22% of patients with migraine were in category 3
(definite involvement group) whereas patients with TTH have
only 6% in this group. Severe autonomic involvement (category
4) was found more in patients with migraine than in TTH (8 and
2%, respectively). These scoring suggested that patients with
migraine have more severe dysautonomia in comparison with
patients with TTH, where majority are in the early involvement
phase of ANS (Table 5).
DISCUSSION
The trigeminal autonomic cephalalgias, such as a cluster
headache, are a typical example of the presence of cranial
autonomic symptoms.
15
Trigeminal–autonomic reflex is well
understood and described anatomical as well as physiological
explanation behind these symptoms.
16
Recently in various
studies, it was noticed that cranial autonomic symptoms were
TABLE 2. Autonomic Function Tests in Patients With a Headache and Healthy Controls
Autonomic Function
Tests
Migraine
(N ¼50)
Tension Type Headache
(N ¼50)
Control
(N ¼50)
N, n (%) BL, n (%) AbN, n (%) *PN, n (%) BL, n (%) AbN, n (%) ‡PN, n (%) BL, n (%) AbN, n (%)
B. P. response to standing 40 (80) 10 (20) 0 (0) 0.806 37 (74) 12 (24) 1 (2) 0.578 39 (78) 11 (22) 0 (0)
B. P. response to handgrip 21 (42) 13 (26) 16 (32) 0.000 28 (56) 11 (22) 11 (22) 0.032 40 (80) 4 (8) 6 (12)
H. R. response to deep breathing 43 (86) 3 (6) 4 (8) 0.378 38 (76) 11 (22) 1 (2) 0.158 44 (88) 5 (10) 1 (2)
H. R. response to Valsalva maneuver 20 (40) 12 (24) 18 (36) 0.003 24 (48) 19 (38) 7 (14) 0.075 35 (70) 10 (20) 5 (10)
H. R. response to standing 15 (30) 8 (16) 27 (54) 0.078 19 (38) 12 (24) 19 (38) 0.600 24 (48) 10 (20) 16 (32)
H. R. variability LF/HF 12 (24)†28 (56)§ 10 (20)‡0.731 24 (48)†22 (44)§ 4 (8)‡0.003 9 (18) 29 (58) 12 (24)
*Chi-square test (migraine vs. control).
†Sympathetic.
‡Chi-square test (TTH vs. control); N-normal, BL-borderline, AbN-abnormal. Parasympathetic.
§Normal
AFT and Electrophysiology of Primary Episodic Headache A. Qavi, et al.
Copyright © by the American Clinical Neurophysiology Society. Unauthorized reproduction of this article is prohibited.
clinicalneurophys.com Journal of Clinical Neurophysiology Volume 00, Number 00, Month 2022 5
present in substantially high frequency, between 27 and 73% in
adult migraineurs.
5,6,17
In our study, 72% of patients with
migraine had cranial autonomic symptoms. The systemic mani-
festations of this autonomic nervous system involvement have
also been described in various studies. Rabner et al. found strong
associations of cold and clammy palms and soles among patients
with headache, whereas insomnia and dizziness were moderately
associated with a headache. He explained that these symptoms in
headache groups is possibly because of sympathetic hyperfunc-
tion, as increased sympathetic discharge may activate the small
nerve fibers connected to sweat glands to cause excessive
sweating.
18
Although numerous studies have documented the
presence of ANS dysfunction in primary episodic headaches with
special reference to migraine,
5–7
the results are conflicting. The
most common findings are sympathetic hypofunction, but higher
sympathetic tone or parasympathetic dysfunction had also been
reported.
7,19–21
In this study, we evaluated autonomic functions
in detail using the Ewing autonomic functions test, heart rate
variability test, and electrophysiological evaluation in patients
with migraine and also in patients with TTH among which such
studies are lacking.
Autonomic Function Tests
In this study, it was observed that both sympathetic as well
as some parasympathetic dysfunctions were present in patients
with primary episodic headaches. S. J. Petroutka observed that
TABLE 3. Analysis of Autonomic Function Tests and Electrophysiological Evaluation in Patients With a Headache and Healthy Controls
Migraine (N ¼50) Tension Type Headache (N ¼50)
ControlMean 6SD *PMean 6SD †P
Autonomic function tests
B. P. response to standing 2.960 67.706 0.485 4.760 68.052 0.730 4.140 69.073
B. P. response to handgrip 15.640 612.368 0.012 18.160 611.298 0.145 21.160 68.988
H. R. response to deep breathing 27.481 611.018 0.957 23.519 611.640 0.125 27.620 614.693
H. R. response to Valsalva maneuver 1.424 60.392 0.002 1.535 60.317 0.058 1.662 60.344
H. R. response to standing 1.009 60.104 0.056 1.026 60.083 0.179 1.058 60.145
H. R. variability LF/HF 1.556 61.370 0.666 2.095 61.334 0.019 1.435 61.432
Electrophysiological tests
SSR latency (ms) Right UL 1.433 60.129 0.015 1.339 60.130 0.053 1.376 60.095
Left UL 1.433 60.119 0.005 1.346 60.166 0.315 1.372 60.087
SSR amplitude (mV) Right UL 1.388 60.759 0.125 1.639 60.746 0.719 1.592 60.537
Left UL 1.358 60.796 0.054 1.646 60.787 0.858 1.622 60.527
Blink reflex latency (ms) R1 right 11.333 60.967 0.898 11.426 60.906 0.672 11.355 60.774
R1 left 11.300 60.871 0.930 11.301 60.698 0.924 11.313 60.522
R2 I/L right 38.678 61.455 0.052 38.697 61.492 0.059 38.156 61.176
R2 I/L left 38.677 61.599 0.086 38.633 61.802 0.154 38.209 61.043
R2 C/L right 41.573 61.641 0.243 41.612 61.329 0.136 41.246 61.088
R2 C/L left 41.043 62.509 0.606 40.724 62.058 0.124 41.247 61.991
*T-test (migraine vs. control).
†T-test (TTH vs. control).
SSR, sympathetic skin response.
TABLE 4. Electrophysiological Studies in Patients with a Headache and Healthy Controls
Electrophysiological
Tests
Migraine
(N ¼50)
Tension Type Headache
(N ¼50)
Control
(N ¼50)
N, n (%) AbN, n (%) *PN, n (%) AbN, n (%) P†N, n (%) AbN, n (%)
SSR latency upper limb (ms) Right 41 (82) 9 (18) 0.065 47 (94) 3 (6) 1.000 47 (94) 3 (6)
Left 44 (88) 6 (12) 0.295 46 (92) 4 (8) 0.695 47 (94) 3 (6)
SSR amplitude upper limb (mV) Right 46 (92) 4 (8) 0.041 47 (94) 3 (6) 0.079 50 (100) 0 (0)
Left 45 (90) 5 (10) 0.092 47 (94) 3 (6) 0.307 49 (98) 1 (2)
Blink reflex latency (ms) R1 right 47 (94) 3 (6) 0.646 48 (96) 2 (4) 1.000 48 (96) 2 (4)
R1 left 47 (94) 3 (6) 0.307 49 (98) 1 (2) 1.000 49 (98) 1 (2)
R2 I/L right 48 (96) 2 (4) 1.000 48 (96) 2 (4) 1.000 48 (96) 2 (4)
R2 I/L left 48 (96) 2 (4) 1.000 48 (96) 2 (4) 1.000 48 (96) 2 (4)
R2 C/L right 46 (92) 4 (8) 0.400 48 (96) 2 (4) 1.000 48 (96) 2 (4)
R2 C/L left 48 (96) 4 (8) 1.000 48 (96) 2 (4) 1.000 48 (96) 2 (4)
*Chi-square test (migraine vs. control).
†Chi-square test (TTH vs. control); N-normal, AbN-abnormal; I/L- ipsilateral, C/L- contralateral.
SSR, sympathetic skin response.
A. Qavi, et al. AFT and Electrophysiology of Primary Episodic Headache
Copyright © by the American Clinical Neurophysiology Society. Unauthorized reproduction of this article is prohibited.
6 Journal of Clinical Neurophysiology Volume 00, Number 00, Month 2022 clinicalneurophys.com
migraine is a disorder of chronic sympathetic dysfunction, and it
shares many clinical and diagnostic characteristics with pure
autonomic failure and multiple system atrophy.
7
However,
contrary to these disorders, in migraine, sympathetic changes
are present with the anatomically intact system. It was proposed
that the sympathetic dysfunction in migraine reflects to an
imbalance of sympathetic cotransmitters. Thus, migraine attack
is a consequence of a relative depletion of sympathetic norepi-
nephrine stores in conjunction with an increase in the release of
other sympathetic cotransmitters such as dopamine, prostaglan-
dins, and adenosine triphosphate.
22
Thijs et al. executed a population-based CAMERA (Cerebral
Abnormalities in Migraine, an Epidemiologic Risk Analysis) study
in migraineurs with and without aura. They found in their study an
elevated prevalence of syncope and orthostatic intolerance in
migraineurs without clear interictal signs of autonomic nervous
system dysfunction.
23
They explained this slight sympathetic
dysfunction in migraineurs was possibly because of the reduced
plasma noradrenaline levels and alpha-adrenergic hypersensitivity.
1. Blood pressure response to standing was normal in our study
in both patients with migraine and TTH and comparable with
healthy controls. None of the patients with headache were
fulfilling the blood pressure criteria of orthostatic hypoten-
sion. Same findings were also noticed in previous studies,
although in some studies, there was blunting of blood pressure
response to standing, but no significant orthostatic hypoten-
sion identified in all these studies.
5,7,22–26
2. 2Blood pressure response to the sustained handgrip test in this
study showed significant abnormality in both patients with
migraine (32%) and TTH (22%). Among healthy controls,
this test was abnormal in 12% of cases. Patients with migraine
showed a significant failure in the rise of diastolic blood
pressure on sustained handgrip, suggesting sympathetic
hypofunctioning in these patients. Pogacnik et al. and Aron
Shechter
5,25
also reported sympathetic dysfunctions in
patients with migraine. Venkatesan et al. in his study found
out that the migraineurs showed a slightly decreased rise in
the diastolic blood pressure just before the release of the
handgrip when compared with that of healthy controls which
supported the presence of sympathetic hypofunction in
migraineurs, but the small difference between the two groups
was not proved to be statistically significant.
27
3. 3In this study, the results of the heart rate response to the
deep breathing test were comparable among patients with
migraine and TTH and control group without any significant
changes, supporting the presence of the intact parasympa-
thetic system in these patients with a headache as also found
by Venkatesan et al. and Pierangeli et al. in their study
conducted during headache-free periods.
27,28
The heart rate
response to the deep breathing test was also normal in
disabled as well as mild cases of migraine in the study of
Shechter et al.
5
4. The patients in the migraine group showed a significant
(p¼,0.05) abnormality in the HR response to the Valsalva
maneuver test, whereas in patients with TTH, the values are
comparable with the control group. This finding supports the
presence of parasympathetic hypofunctioning in migraineurs
as found in some previous studies which showed differences
in Valsalva ratios in patients with migraine.
5,21,24,25,27,29
Sanya EO et al. found that the autonomic nervous system
abnormality with special reference to parasympathetic abnor-
mality was present.
21
Mylius et al.
29
also showed that
migraine is associated with impairment of parasympathetic
nerve supply to the pupil. Parasympathetic abnormality was
also found in the study of Martín et al. while doing
cardiovascular reflexes in patients with a vascular headache.
24
Shechter et al. in their study showed lower nonsignificant
Valsalva ratios for disabled migraine cases compared with
controls.
5
This finding of our study is contrary to the findings
of Venkatesan R. et al., as they found no significant changes
in the heart rate response to the Valsalva maneuver test.
27
5. 5H. R. response to standing: No significant difference in the
HR response to standing was found in patients with migraine
and TTH and control in this study. This test of the para-
sympathetic activity was also found normal in studies
conducted during headache-free periods by Pogacnik et al.,
Venkatesan et al., and Pierangeli et al.
25,27,28
Autonomic Functions’Disability Scoring by the
Ewing Score
Patients with migraine showed a significant dysautonomia in
category 3 (definite involvement group) of the Ewing battery for
autonomic functional disability, in comparison with the control
group. Such type of studies has earlier been performed on
diabetic neuropathy, but no such study on headache is performed
so far.
14
A significantly lower proportion of patients with
migraine and TTH was found in category 1 (normal group) in
comparison with the control, suggesting both have more patients
with abnormal autonomic functions.
TABLE 5. Autonomic Functions’Disability Scoring by the Ewing Score
Ewing Score Migraine (N ¼50) n (%) *PTension Type Headache (N ¼50), n (%) †PControl (N ¼50), n (%)
Category 1 Normal 7 (14) 0.001 8 (16) 0.001 23 (46)
Category 2 Early involvement 23 (46) 0.42 26 (52) 0.16 19 (38)
Category 3 Definite involvement 11 (22) 0.002 3 (6) 0.31 1 (2)
Category 4 Severe involvement 4 (8) 0.17 1 (2) 1.00 1 (2)
Category 5 Atypical 5 (10) 1.0 12 (24) 0.062 5 (10)
*Chi-square test (migraine vs. control).
†Chi-square test (TTH vs. control).
AFT and Electrophysiology of Primary Episodic Headache A. Qavi, et al.
Copyright © by the American Clinical Neurophysiology Society. Unauthorized reproduction of this article is prohibited.
clinicalneurophys.com Journal of Clinical Neurophysiology Volume 00, Number 00, Month 2022 7
Heart Rate Variability (HRV) by LF/HF
Heart rate variability (HRV) is the fluctuation in the time
intervals between adjacent heartbeats. Heart rate variability
indicates neurocardiac function and is generated by heart–brain
interactions and dynamic nonlinear autonomic nervous system
processes. The LF/HF ratio indexes the sympathovagal balance
of an individual. In previous studies, HRV has been shown to
produce a reliable quantitative estimate of the part of the ANS
controlling the heart rate, as well as the balance between its
sympathetic and parasympathetic parts.
5,25,26,30
Pogacnik et al. in
their study based on spectral analysis of HR variability showed
an impairment of the sympathetic function in patients with
migraine as they found a significantly reduced increase of the
middle frequency band after transition from the supine to the
standing posture.
25
In our study, 24% of patients with migraine
had sympathetic overactivity, whereas 20% had parasympathetic
dominance which is statistically insignificant. We could not find
any study based on the frequency domain of HRV in patients
with TTH.
Electrophysiological Tests
Sympathetic Skin Response (SSR)
During evaluation of SSR in our study, we found significant
abnormalities in the form of prolonged mean latencies in both
right and left upper limbs and reduced amplitudes in the right
upper limb in qualitative analysis among patients with migraine,
suggesting sympathetic hypofunctioning in these patients. In the
SSR study, no significant changes were found in either of the
latencies or amplitudes in patients with TTH. Yildiz S K et al.
found that the mean latencies were longer, and the maximum
amplitudes were smaller on the symptomatic side compared with
the asymptomatic side during headache attack and in interictal
periods.
19
During the postattack period, F-SSRs on the symp-
tomatic side had higher amplitudes and shorter latencies
compared with the asymptomatic side. Thus, they concluded
that there is an asymmetric sympathetic hypofunction on the
symptomatic side in attack and interictal periods, whereas there is
a hyperfunction in the postattack period. Huseyin T. et al. in their
study found that sympathetic skin response latencies in patients
with medication overuse headache and in migraineurs were
significantly longer than in controls.
31
Blink Reflex
No significant changes in blink reflex latencies of either of
the ipsilateral or contralateral side in patients with migraine as
well as TTH were found in the study. Joseph B. in his study on
160 patients of chronic migraine and healthy controls explained
that blink did not affect in migraine possibly because it is a
relatively simple and primitive reflex and is not affected unless
there is considerable damage to the brainstem.
32
Aktekin et al.
conducted BR tests on 20 patients with migraine and 20 patients
with TTH during the interictal phase using standard methods and
compared measurements of R1 and R2 latencies, R2 amplitudes,
and area with those of the control group without finding any
significant intergroup difference. They stated that these findings
can be considered evidence that migraine-specific trigeminal
dysfunction is a transient condition.
33
Contrary to our study,
Aktekin et al. in their study found that the recovery curve of the
R2 component of the blink reflex diminished in patients with
tension-type headache compared with the other groups suggest-
ing reduced excitability of the brainstem interneurons in patients
with tension-type headache. They explained that it is disturbed
brainstem interneuronal activity due to abnormal endogenous
pain control mechanisms responsible for the pathogenesis of
tension-type headaches. Avradimi TG et al. did the blink reflex
study in 19 patients with migraine, 10 patients with TTH, and 30
healthy controls. The blink reflex was normal in all the patients
with tension-type headache, whereas in patients with migraine,
there were significantly lower values of R2 and R2’s amplitude
and size compared with the healthy control group.
34
They
concluded from the study findings that the brainstem interneuron
of the blink reflex arc may be diffusely suppressed in migraine,
only during the headache phase. This phenomenon is believed to
emerge as a response to sensitization of cutaneous nociceptive
afferent arch or neurons in the trigeminal nucleus.
Limitations of our Study
Autonomic function tests and electrophysiological evalua-
tion was performed only during the headache-free period
(interictal), whereas these tests’study during headache (ictal)
and just after headache may further be helpful to clarify the
objectives and hypothesis.
CONCLUSION
This study indicates that autonomic functional abnormality,
both sympathetic and parasympathetic, does exist in patients with
a primary episodic headache. Patients with migraine were found
to have sympathetic abnormality both in autonomic function tests
as well as the sympathetic skin response test, whereas in patients
with TTH, sympathetic predominance in the autonomic function
test was found. Abnormality of SSR was found in patients with
migraine alone. Autonomic dysfunctions either may be a risk
factor for episodic headaches or be a consequence of frequent
disabling attacks, which requires a further evaluation in future
studies.
This study will help in understanding the association of the
presence of autonomic dysfunctions and their severity in patients
with a episodic headache, which may be associated with
additional functional disability and morbidity/complications
stipulating the prerequisite of a combative and preferred
treatment plan for reducing morbidity and functional loss due
to these headaches and associated dysautonomia.
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