Phenotypes of headache in patients with obstructive sleep apnea

Abstract

Obstructive sleep apnea (OSA), characterized by repeatedly collapse of upper airway while sleeping, is a common disease; estimated to have a prevalence of 57% in adults. Headache is a common neurological symptom and can be bothersome. A meta-analysis found that 33% of patients with OSA may have headaches. There is limited data on risk factors for having headache in patients with OSA. This study aimed to find risk factors or phenotypes of headache in patients with OSA. This was a retrospective analytical study. The inclusion criteria were adult patients with age of 18 years or over and diagnosed as OSA by polysomnography. The primary outcome of this study was a symptom of headache. Predictors for headache in patients with OSA were executed by stepwise method of multivariable logistic regression analysis. There were 213 patients with OSA met the study criteria. Of those, 52 patients (24.41%) had headache. The most common type of headache was tension type (27 patients; 51.92%), followed by non-specific type (22 patients; 42.31%), and migraine type (3 patients; 5.77%). There were four significant factors including dyspnea, fatigue, dizziness, and macroglossia. Dyspnea had the highest adjusted odds ratio at 3.29 (95% confidence interval of 1.25, 8.54), while macroglossia had the lowest adjusted odds ratio at 2.10 (95% confidence interval of 1.01, 4.43). Patients with OSA who had the following phenotypes of dyspnea, fatigue, dizziness, and macroglossia may have a higher chance of having headache.

Background

Obstructive sleep apnea (OSA), characterized by repeatedly collapse of upper airway while sleeping, is a common disease; estimated to have a prevalence of 57% in adults¹. Additionally, 80% of patients with OSA may be underdiagnosed². It can lead to several long term consequences including hypertension, diabetes, stroke, cardiac arrhythmia, or coronary artery disease^3–5. OSA is closely related with hypertension and resistant hypertension^6–8. The prevalence of OSA in patients with hypertension may be high as 81.9% which were again undiagnosed⁹. Other than long term consequences, OSA can cause several symptoms such as sleepiness or headache¹⁰.

Headache is a common neurological symptom and can be bothersome. A meta-analysis found that 33% of patients with OSA may have headache¹¹. The characteristics of headache in patients with OSA are varied including morning headache (33%), sleep apnea headache (25%), tension-type headache (19%), and migraine (16%). A previous study found that a continuous positive airway pressure machine (CPAP) can improve headache in patients with OSA significantly¹². Among patients with OSA who had headache, those who used CPAP regularly had an improvement of headache (78%) compared with those who did not use CPAP (33%) or did not titrate CPAP (42%); p = 0.045). Predictors of having OSA in patients with headache were increasing age, female gender, and chronic migraine with odds ratio of 1.2, 19, and 20.8 times, respectively¹². However, there is limited data on risk factors for having headache in patients with OSA. These may indicate a phenotype of headache in patients with OSA. Knowing these phenotypes may assist physicians to encourage the patients to have a good CPAP adherent which may improve headache. Therefore, this study aimed to find risk factors or phenotypes of headache in patients with OSA.

Methods

This was a retrospective analytical study conducted at Srinagarind Hospital, Khon Kaen University, Thailand. The inclusion criteria were adult patients with age of 18 years or over and diagnosed as OSA by presence of an apnea-hypopnea index of five events or more/hour by polysomnography (Polysmith^®, Nihon Kohden, USA & Alice PDx, Philips, USA). Scoring of AHI was performed in accordance with AASM criteria¹³. Those who were pregnant were excluded. The study period was between January and December 2023. This study was a part of OSA project, Khon Kaen University, Thailand. The study protocol was approved by the ethics committee in human research, Khon Kaen University, Thailand (HE641504) and all methods were conducted following the principles of the Declaration of Helsinki. An informed consent was waived by the ethics committee in human research, Khon Kaen University, Thailand.

Eligible patients were evaluated for baseline characteristics, comorbidities, symptoms/signs of OSA, STOPBANG questionnaire, and the apnea-hypopnea index. Symptoms of OSA were assessed prior to treatment with a continuous positive airway pressure machine or other treatments. The STOPBANG questionnaire was based on the previous published study¹⁴. The primary outcome of this study was symptoms of headache. Headache was defined by unexplained headache which occur in any period of time and classified as tension type, migraine type, cluster type, or non-specific. Diagnosis of tension type and migraine type were made based on the ICD-10.

Sample size calculation. The meta-analysis found that the prevalence of headache in patients with OSA was 33%¹¹, the estimated prevalence of headache in this study was lower at 20%. Based on the confidence of 95% and power of 80%, the estimated sample size was 94.

Statistical analyses. Patients were categorized into two groups: with and without headache. Descriptive statistics were used to calculate mean (SD) and number (percentage) for numerical and categorical variables, respectively. Inferential statistics were used to compare the differences between both groups. Predictors for headache in patients with OSA were executed by stepwise method of multivariable logistic regression analysis. Studied variables were computed for a p value by univariable logistic regression analysis. Those with a p value of less than 0.20 were included in the stepwise, multivariable logistic regression analysis¹⁵. The model was tested for a goodness of fit by the Hosmer-Lemeshow method. A p value by the Hosmer-Lemeshow Chi square of more than 0.05 indicated a goodness of fit. Statistical analyses were performed by STATA software, version 18.0 (College Station, Texas, USA).

Results

There were 213 patients with OSA met the study criteria. Of those, 52 patients (24.41%) had headache symptoms. The most common type of headache was tension type (27 patients; 51.92%), followed by non-specific type (22 patients; 42.31%), and migraine type (3 patients; 5.77%). Most patients had headache in the morning (33 patients; 64.71%), while 17 patients had headache in other times of the day: afternoon (9 patients; 17.65%) or at all times (8 patients; 15.69%). Regarding baseline characteristics and symptoms of OSA (Table 1), there were three significant factors between those with and without headache: fatigue, dyspnea, and dizziness. Those with headache had higher proportions of fatigue (67.31% vs. 40.37%; p = 0.001), dyspnea (25.00% vs. 7.45%; p = 0.002), and dizziness (34.62% vs. 17.39%; p = 0.012) than those without headache. For physical signs, there was only a significant factor between those with and without headache (Table 2): macroglossia. Those with headaches had a higher proportion of macroglossia than those without headache (73.08% vs. 56.52%; p = 0.035). Both groups had comparable STOPBANG score (4.05 vs. 4.07; p = 0.958) and apnea-hypopnea index (27.41 vs. 24.55; p = 0.341); the first number was from those with headache group.

Table 1.

Baseline characteristics, comorbities, and symptoms of patients with obstructive sleep apnea categorized by presence of headache.

Factors	No headache n = 161	Headache n = 52	p value
Mean (SD) age, years	50.62 (17.19)	48.84 (15.14)	0.505
Male sex	79 (49.07)	26 (50.00)	0.999
Comorbidities
Hypertension	105 (65.22)	27 (51.92)	0.101
Diabetes	41 (25.47)	12 (23.08)	0.854
Coronary artery disease	2 (1.24)	0	0.999
Atrial fibrillation	2 (1.24)	1 (1.92)	0.570
Heart failure	4 (2.48)	0	0.574
Allergic rhinitis	17 (10.56)	6 (11.54)	0.802
Symptoms
Snoring	142 (88.20)	46 (88.46)	0.999
Stop breathing	51 (31.87)	15 (28.85)	0.733
Fatigue	65 (40.37)	35 (67.31)	0.001
Dyspnea	12 (7.45)	13 (25.00)	0.002
GERD	43 (26.71)	20 (38.46)	0.118
Nocturia	83 (51.55)	29 (55.77)	0.634
Insomnia	75 (46.58)	24 (46.15)	0.999
Dizziness	28 (17.39)	18 (34.62)	0.012
Sleepiness	72 (44.72)	29 (55.77)	0.202
STOPBANG	4.07 (1.53)	4.05 (1.50)	0.958

Data presented as number (percentage) unless indicated otherwise; GERD: gastroesophageal reflux disease.

Table 2.

Physical signs and an apnea-hypopnea index (AHI) of patients with obstructive sleep apnea categorized by presence of headache.

Factors	No headache n = 161	Headache n = 52	p value
Body mass index, kg/m2*	33.26 (20.50)	29.75 (9.17)	0.233
Systolic blood pressure, mmHg*	137.49 (15.55)	135.32 (16.54)	0.391
Diastolic blood pressure, mmHg*	75.53 (12.54)	78.03 (12.61)	0.212
Neck circumference, cm*	39.82 (4.25)	38.85 (4.66)	0.165
Retrognathia	34 (21.12)	9 (17.31)	0.692
Torus palatinus	42 (26.25)	14 (26.92)	0.999
Torus mandibularis	34 (21.12)	12 (23.08)	0.847
Macroglossia	91 (56.52)	38 (73.08)	0.035
Friedman classification*	2.23 (0.75)	2.08 (0.77)	0.235
Denture	20 (12.42)	5 (9.62)	0.805
Tonsillectomy	1 (0.62)	2 (3.85)	0.148
Thyroidomegaly	3 (1.86)	0	0.999
AHI, events/hour*	24.55 (16.71)	27.41 (24.19)	0.341

Data presented as number (percentage); * indicated mean (SD).

Among studied variable, there were eight factors with a p value of less than 0.20 included in the model plus other two factors: age, sex which may be related with headache. In total, there were 10 factors included in the model. Of those, six factors remaining in the model by stepwise logistic regression analysis (Table 3). There were four significant factors including dyspnea, fatigue, dizziness, and macroglossia. Dyspnea had the highest adjusted odds ratio at 3.29 (95% confidence interval of 1.25, 8.54), while macroglossia had the lowest adjusted odds ratio at 2.10 (95% confidence interval of 1.01, 4.43). The Hosmer-Lemeshow Chi square of the model was 4.44 (p = 0.815) indicating a goodness of fit of the model.

Table 3.

Factors predictive of headache in patients with obstructive sleep apnea by stepwise, multivariable logistic regression analysis.

Factors	Unadjusted odds ratio (95% confidence interval)	Adjusted odds ratio (95% confidence interval)
Dyspnea	4.13 (1.75, 9.78)	3.26 (1.25, 8.54)
Fatigue	3.04 (1.57, 5.87)	2.24 (1.10, 4.54)
Dizziness	2.51 (1.24, 5.07)	2.42 (1.12, 5.23)
Macroglossia	2.08 (1.04, 4.15)	2.10 (1.01, 4.43)
GERD	1.71 (0.88, 3.31)	1.56 (0.76, 3.22)
Hypertension	0.57 (0.30, 1.08)	0.53 (0.26, 1.06)

Factors included in the model including hypertension, fatigue, dyspnea, GERD (gastroesophageal reflux disease), dizziness, neck circumference, macroglossia, tonsillectomy, plus two factors (age and sex).

Discussion

This study found that phenotypes of patients with OSA who had headache; mostly tension type were those with dyspnea, fatigue, dizziness, and macroglossia.

The prevalence of headache in patients with OSA in this study was somewhat lower than a previous systematic review (24.41% vs. 33%)¹¹. As previously reported, morning headache was the most common type of headache (33%) which was compatible with this study (64.71%). However, this study found that tension type and non-specific headache were more common than migraine which was different from the previous systematic review: 51.92% in this study vs. 19% in the systematic review¹¹. These findings may be explained by difficulty to describe the headaches resulting in high prevalence of non-specific headache.

Even though several studies showed that CPAP significantly improved symptoms related with OSA particularly fatigue, sleepiness, or anxiety^16–20, the real mechanism of OSA associated with these symptoms are still unknown. A recent study found that only daytime sleepiness was associated with OSA severity, but not fatigue, anxiety, or depression¹⁹. OSA severity had adjusted odds ratio of 1.30 (95% confidence interval of 1.13, 1.49) for daytime sleepiness, but fatigue had adjusted odds ratio of 0.92 (95% confidence interval of 0.79, 1.08) for OSA severity¹⁹. We did a post-hoc analysis of apnea-hypopnea index and the significant factors: dyspnea, fatigue, dizziness, and macroglossia. We found only a significant association between apnea-hypopnea index and dizziness but not dyspnea, fatigue, or macroglossia. The median apnea-hypopnea index in those with dizziness was significantly higher than those without dizziness (21 vs. 15 events/hour; p value = 0.005), while p value for dyspnea, fatigue, and macroglossia was 0.628, 0.568, and 0.426, respectively.

A national database study found the correlation between OSA and peripheral vestibular disorders both dizziness and vertigo²¹. OSA had a significantly higher incidence rate ratio than the non-OSA group of 6.28 (95% confidence interval of 4.98–8.08), while OSA had an adjusted odds ratio of 6.64 (95% confidence interval of 5.20, 8.47) for development of peripheral vertigo²¹. There were several proposed mechanisms of dizziness from OSA including nocturnal cerebral ischemia, vascular insufficiency, defective otoconial hemostasis, and abnormal endolymph homeostasis²¹. These mechanisms of dizziness were similar to mechanisms of headache particularly sleep apnea apnea headache which is occurring in the morning.

A previous study found that hypertensive patients with OSA had a significantly higher proportion of macroglossia than those without OSA (41.5% vs. 8.2%; p < 0.001). These results may indicate that patients with OSA who had macroglossia are at risk for hypertension or hypertensive crisis which may cause headache^5,22,23.

A study from Poland showed that unrefreshing sleep was significantly associated with morning headache in patients with OSA with adjusted odds ratio of 1.42 ; 95% confidence interval of 1.19, 1.70²⁴. While, another study conducted a comparison study of sleep parameters in patients with fatigue versus non-fatigue patients²⁵. Those with fatigue had significantly slow wave sleep than the control (55.43 vs. 95.8 min; p = 0.01) indicating fatigue was associated with unrefreshed sleep and may result in morning headache.

Patients with OSA may develop dyspnea symptom from having pulmonary hypertension. A previous study found that patients with pulmonary hypertension with OSA had significantly lower minimum oxygen level than the non-OSA (75.8% vs. 83.52%; p = 0.002) as well as duration of oxygen saturation below 90% (166.30 vs. 74.97 min; p = 0.001)²⁶. Another study compared oxygen levels in patients with sleep apnea headache versus patients with morning headache²⁷. The sleep apnea headache group had significantly lower level of both oxygen parameters than the morning headache group: minimum oxygen level (80.9% vs. 88.5%; p < 0.001) and duration of oxygen saturation below 90% (23.1 vs1.9 min; p = 0.002). These results may indicate the linkage between dyspnea and sleep apnea headache via the mechanisms of low oxygen during sleep.

There are some limitations in this study. First, it might be some missing data due to retrospective data collection such as headache severity or duration. Second, no causal relationship was evaluated due to retrospective study design. Further cohort studies are needed to determine causal relationship between OSA and headache. Finally, no intervention of CPAP or other treatments were intervened^28–30.

In conclusion, patients with OSA who had the following phenotypes of dyspnea, fatigue, dizziness, and macroglossia may have a higher chance of having headache.

Abbreviations

CPAP

Continuous positive airway pressure machine

OSA

Obstructive sleep apnea

Author contributions

VT, SK, and KS conceived the study. SK and KS conducted the statistical analysis. All authors were involved in data acquisition and data interpretation. SK and KS wrote the first draft of the manuscript. All authors were involved in critically reviewing the manuscript for important intellectual content. All authors approved the final manuscript.

Data availability

The datasets used and/or analyzed during the current study are not publicly available but are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

The study protocol was approved by the ethics committee in human research, Khon Kaen University, Thailand (HE641504).

Consent for publication

Not applicable. The manuscript does not contain data from any individual participant.

Competing interests

The authors declare no competing interests.