Abstract
Objective:
Describe the characteristics and prevalence of headache in patients with mitochondrial diseases (MDs), as well as sleep quality, trying to observe possible associations. To assess whether these patients are more likely to suffer headaches in relation to poorer quality of sleep.
Background:
Sleep disorders and headache are considered to be common in MDs. We present the largest sample analyzed to date.
Methods:
Observational, descriptive, cross-sectional study that analyzed a database of 232 patients with MDs, including age, sex, genotype, phenotype, presence and characteristics of headache. All patients fulfilled the Epworth Sleepiness Scale (ESS), the Pittsburgh Sleep Quality Index (PSQI) and, in migraine, the Migraine Disability Assessment questionnaire (MIDAS). Headache was divided into two groups: migraine headache, according to criteria of the International Classification of Headache Disorders (ICHD-III beta), and non-migraine headache.
Results:
A total of 203 cases were analyzed, 124 women (61%) and 79 men (39%). Average age was 46 years. Most frequent DNA mutation was m.3243 A > G in MITL1 gene (33%). Most frequent phenotype was MELAS syndrome: 28 patients (13.8%). Ninety-two patients (45.3%), reported headache, 44 fulfilling migraine criteria (21.7%). Headache was more frequent in MELAS syndrome (p < 0.01). Statistically significant differences were found in the number of disabling episodes per month in patients with migraine (p < 0.001). Patients with headache scored higher in Epworth (p = 0.01) and Pittsburgh scales (p < 0.001).
Conclusions:
A higher prevalence of migraine is observed in patients with mitochondrial diseases, independent of genotype and phenotype. MD-associated migraine tends to be chronic and more disabling. A higher frequency of headache, not specifically migraine, has also been observed in patients with MELAS syndrome. Mitochondrial dysfunction could be one of the pathophysiological mechanisms of migraine and a factor of chronification and severity. Poor sleep quality could also be associated with headache in patients with MDs. Assessment of headache and sleep disturbances should be part of the routine workup of patients with mitochondrial disease.
Trial registration:
N/A.
Introduction
Mitochondrial diseases (MDs) are a heterogeneous group of diseases in which mitochondrial respiratory chain function is affected, and cellular energy production is compromised. These diseases are the most common cause of inherited metabolic disease 1 and, due to the presence of mitochondria in all nucleated cells, they can show a wide spectrum of symptoms, affecting one or more organs and systems at any age and with a variable phenotypic expression. Diagnosis of mitochondrial diseases is often arduous and complicated, and so much clinical variability can lead to a delay in their recognition which, in addition, can increase the suffering of these patients.
Among the systems most affected by this group of diseases, the nervous system stands out, mainly given its high dependence on aerobic metabolism. In this sense, sleep disorders and headache are common in MDs, 2,3 being even one of the cardinal symptoms that define some of the subtypes of these diseases, such as headache in mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS). Both symptoms are treatable and have their own characteristics in these groups of patients, so they must be recognized and categorized as part of the clinical practice when dealing with this pathology. Furthermore, recent studies have shown a complex relationship between headache, mostly migraine, and sleep disorders, not only based on an epidemiological association but also sharing anatomical pathways and having a bidirectional relation in their clinical expression. 4
In regard to headache, it is still unclear whether headache is a primary disorder associated or coincident with MDs, mainly manifested as migraine, 5 or a secondary migraine-like headache caused by mitochondrial disease. 6 The current edition of the International Classification of Headache Disorders (ICHD-3 beta) only includes headache in MELAS among headache attributed to genetic vasculopathy, without other references to headache in the context of MDs. However, it seems that the prevalence of migraine in MDs is higher than in the general population and is independent of phenotype or genotype, 5 which, together with dysfunction of mitochondrial metabolism in migraine observed in several studies, 6 supports the hypothesis that mitochondrial dysfunction could play an important role in the pathophysiology of migraine. Moreover, there is emerging evidence that monoclonal antibodies acting on CGRP (CGRP-mAbs), widely used in the treatment of patients with migraine, are also safe and effective in the treatment of refractory headache associated with mitochondrial diseases, 7 also supporting common pathophysiological pathways between MDs and migraine.
The purpose of this work is to describe the characteristics and prevalence of headache in the largest sample of patients with MDs analyzed to date, also referring to some of the aspects of sleep quality in these patients, trying to observe possible associations between both entities and MDs which also help us to better understand their etiopathogenesis and in the development of new treatment strategies. In addition, the description of headache in this type of patients could help us to reach a consensus on its description and classification, which could also be useful in clinical practice.
Materials and methods
Study design and data collection
This is a cross-sectional study performed at the Neuromuscular, Metabolic and Sleep units of “Hospital Universitario 12 de Octubre,” in Madrid, during April and May 2022. Specifically, the Neuromuscular Unit is a national reference center for rare neuromuscular diseases in Spain.
A total of 203 patients were finally enrolled from a database of 232 individuals, all of them with proven MD on the basis of molecular genetics or an MD criteria score ≥8 in the NMDAS classification, suggestive of definite mitochondrial disorder in cases without a genetic characterization. 8 The study was approved by the Medical Investigation Commission and the Ethics Committee of the “Hospital 12 de Octubre.” All patients had been previously evaluated by a specialist in mitochondrial disorders.
Data collection regarding the diagnosis, history, and clinical characteristics of the patients was carried out through the electronic medical record and clinical database of the “Hospital 12 de Octubre,” meanwhile sleep and headaches characteristics were obtained through structured telephone interviews, prior verbal informed consent and, in case of minor patients, authorization from parents or legal guardian. A telephone interview was carried out by a specialist in headache disorders. All patients fulfilled two validated and adapted to Spanish language questionnaires or scales: the Epworth Sleepiness Scale (ESS) and the Pittsburgh Sleep Quality Index (PSQI) and, in the case of patients fulfilling the criteria of migraine, the Migraine Disability Assessment questionnaire (MIDAS). 9 -12 Thus, headache in these patients was classified as migraine or non-migraine, analyzing in all cases the characteristics of the headache, frequency, presence of aura, and its intensity.
The inclusion criteria were (1) confirmed mitochondrial disease (MD) according to genetic, histochemical, and/or clinical criteria 8 and (2) being able to read and understand the questionnaires. Exclusion criteria were: (1) not being able to give verbal informed consent, (2) declining phone interview, (3) insufficient clinical data, and (4) not having access or availability for telephone contact.
Measures
Demographic information
Demographic data were obtained from the electronic medical record, clinical database, and through the telephone interview, and included age, gender, clinical phenotype, genetic characteristics, and past medical history oriented to headache and sleep disorders.
Headache characteristics
Headache-related symptoms were asked through a structured telephone survey in which patients were interrogated about the presence or absence of headache, its characteristics, frequency, and duration of episodes, as well as the presence of prodromal or postdrome symptoms. Headache was diagnosed and classified according to revised criteria of the International Classification of Headache Disorders (ICHD-III beta). 12
Sleep and migraine test
Sleepiness was evaluated with the Epworth Sleepiness Scale (ESS), which is a self-administered questionnaire of 8 questions, each of them scoring from 0 to 3 points, with 24 being the maximum score. Commonly, scores of 11–24 are considered above the “normal” daytime sleepiness, so we assume it as suggestive of excessive daytime sleepiness. The Pittsburgh Sleep Quality Index (PSQI) is also a self-reported questionnaire that assesses sleep quality over a 1-month interval. The scale contains seven components (subjective sleep quality, sleep duration, sleep latency, habitual sleep efficiency, use of sleep medications, sleep disturbance, and daytime dysfunction), and the score for each component ranges from 0 to 3 points. The global PSQI score ranges from 0 to 21, with higher scores indicating more severe sleep disorders. We assume a score of 7 or higher as indicative of poor sleep quality. In our study, both tests were administered over the phone, allowing the patient to respond autonomously once the information and instructions were provided.
Regarding migraines, the MIDAS questionnaire was used, which evaluates the functional impact of migraine through seven questions and a score between 0 and +21, considering a value above 11 as a moderate disability.
Statistical analysis
Data analysis was performed using the IBM SPSS Statistics 28.0.1.1 program for Mac. Variable normality was checked using the Kolmogorov–Smirnov test. Qualitative variables are expressed as absolute frequency and percentage. Quantitative variables with normal distribution are expressed as mean ± standard deviation, while those without normal distribution are expressed as the median and interquartile range (IQR). Hypothesis testing was performed using the χ2 test in the case of qualitative variables, the Student’s t test for independent variables in the case of quantitative variables with normal distribution, and the Mann–Whitney U test in the case of quantitative variables with non-normal distribution. A difference with a p-value of less than 0.05 was considered statistically significant.
Results
Demographic data
Based on an initial database of 232 patients with confirmed mitochondrial disease, a total of 203 individuals could finally be enrolled after applying the inclusion and exclusion criteria. This sample included 124 women (61%) and 79 men (39%), with an average age of 46 ± 17 years, ranging from 13 to 89 years (Table 1). Of the 232 patients registered in our database, only 29 did not participate in the study due to logistical or personal causes. No patient was excluded due to medical criteria.
Summary of the characteristics of the study population.
CPEO: chronic progressive external ophthalmoplegia.
Distribution of mtDNA/nuclear mutations and phenotypes of mitochondrial diseases
The most frequent DNA mutation in our sample was m.3243 A > G in MITL1 gene, present in 67 patients (33%), followed by a single large-scale deletion in mitochondrial DNA within 16 patients (7.9%) and pathogenic variants in the TK2 gene in 15 cases (7.4%). A total of 51 patients (25%) did not obtain a definitive genetic result, so they were diagnosed as probable MD based on clinical criteria and muscle biopsy.
Headache frequency in patients with mitochondrial disease.
Phenotypically, the most common manifestation was myopathy, present in 35 patients (17.2%). Among the syndromic phenotypes, the most frequent was MELAS syndrome, with 28 patients (13.8%). Of the 28 patients with MELAS, 20 (71.4%) presented the m.3243 A > G mutation in the MTTL1 gene. Twenty patients (29.8%) with the m.3243 A > G mutation in the MTTL1 gene presented the MELAS syndrome phenotype, the rest being patients with other clinical manifestations such as diabetes mellitus, myopathy, and sensorineural hearing loss. Six of these patients (8.9%) were asymptomatic (Table 2).
Headache
Of the 203 patients interviewed, 92 (45.3%) reported suffering regularly from headache of any type (at least one headache day per month), the prevalence being more frequent in women than in men (53.2% vs. 32.9% respectively). Within the group of 92 patients with headache, 44 (47.8%) had headaches classified as migraine according to the 2018 International Headache Society criteria, 12 while the remaining 48 patients (52.2%) had non-migraine headache (Figure 1). Therefore, 21.7% of all patients suffered from migraine according to the ICHD-III criteria (Figure 2).
Patients with the pathogenic variant m.8344 A > G in the MTTK gene were those with the highest prevalence of headache, three out of five cases (60%). A total of 39 patients with the m.3243 A > G mutation in the MTTL1 gene (58.2%) presented headache, with 69% of cases fulfilling migraine criteria. On the other hand, none of the five patients with alterations in the TWNK gene reported suffering from headaches. In addition, a higher proportion of migraine compared to non-migraine headache was observed in patients without a definitive genetic diagnosis, in addition to patients with the m.3243 A > G mutation as mentioned above, though these differences were not statistically significant.
In the same way, no statistically significant differences were found in the presence of headache, both migraine and non-migraine type, in patients with m.3243 A > G mutation in the MTTL1 gene compared to the rest of genetic alterations related to mitochondrial diseases in our sample (p = 0,10). However, based on the phenotype of the patients with MD in our database, a statistically significant relationship was found between the MELAS syndrome and the presence of headache, in contrast with other phenotypes, with a p-value of less than 0.01. In this group of patients (MELAS syndrome with headache), no statistically significant differences were found between the presence of migraine and non-migraine type headache (p = 0.629).
Headache according to the different genetic diagnoses.
In terms of frequency and impact of headache, the median number of days per month was 5 in patients with MDs suffering headache, with 25% of them reporting 15 or more days of pain per month in the last 6 months, thus meeting the criteria for chronic headache. Sixteen (69.6%) of these patients met the criteria of migraine, while the remaining 7 had non-migraine-type headache. Patients with migraine had a median of 10 headache days per month, while patients with non-migraine headache had a median of 3 headache days per month. However, when comparing the frequency of headache days per month between patients with migraine and patients with non-migraine-type headache, no statistically significant differences were found (p = 0.09).
Regarding disabling episodes, considered as not being able to reconcile headache with daily activities, patients with migraine reported a median of 2 per month versus a median of 0 per month in patients with non-migraine headache. Statistically significant differences were found in the number of disabling episodes per month depending on the type of headache, these being higher in patients with migraine (p-value <0.001). The average score on the MIDAS scale of the patients with migraine was 12. Moreover, 12 patients had moderate disability (score between 11 and 20), and nine patients had a severe disability (score ≥21). Five patients had a score of 0, while the maximum value obtained was 70 in one patient with the m.3243 A > G mutation.
Finally, with regard to the characteristics of the headache, only five patients with headache met the criteria of migraine with aura (5.4%), two of them presenting de m.3243 A > G mutation (40%). These patients scored higher on the MIDAS scale (mean 31.4) than patients with migraine without aura (mean 8.9), but no statistically significant differences were observed between both groups (p = 0.09).
Headache frequency according to phenotype.
CPEO: chronic progressive external ophthalmoplegia.
Sleep characteristics
The sleep characteristics of patients with MDs were indirectly analyzed using the Epworth and Pittsburgh scales. Normal distribution was observed only on the Epworth scale. Including the scores of all the patients, an average of 4.2 was obtained on the Epworth scale, indicative of low daytime sleepiness. Excessive daytime somnolence, considered a score greater than 10 on the Epworth scale, was observed in 20 patients (9.8%). On the Pittsburgh scale, the median was 5.5 (95% CI, 4.9–6.03). Patients with headache scored higher in both questionnaires, with a mean of 5.5 on the Epworth scale (4.2 in non-headache patients) and a mean of 7 on the Pittsburgh scale (4.2 in non-headache patients).
When analyzing these results both in the Epworth scale (p = 0.01) and in the Pittsburgh scale (p-value <0.001), statistically significant differences were observed. However, only the average score of the Pittsburgh scale was in the range of clinical relevance, as previously stated.
Discussion
In this large and clinically heterogeneous cohort of patients with MDs, ranging from asymptomatic carriers of different pathogenic mitochondrial disease mutations to patients with severe and limiting involvement, 45.3% reported suffering from headache of any type, which is similar to that of the general population 13 and previous studies, despite the fact that a great heterogeneity is observed in their results. 3,14 However, when characterizing the type of headache, a migraine prevalence of 21.7% was observed, which is higher than expected in the general population (15% worldwide). 15 In addition, 25% of the patients with migraine met the criteria for chronic migraine, this result being much higher than that observed in the general population (2–3%), 16 with a mean score of 12 on the MIDAS scale, indicative of moderate disability. Similar to what was observed in the general population, headache was more frequent in women. These results are in line with what was observed in previous studies, indicating a higher prevalence of migraine in MDs compared with general population-based data, independently from genotype or phenotype. 5 We have also observed that migraine in MDs tends to the chronic forms and be more severe and disabling than in the general population. Thus, mitochondrial dysfunction could be one of the pathophysiological mechanisms of migraine, mainly through the production of ROS, apoptosis, Ca2+ homeostasis, and global increased neuronal excitability, as previously hypothesized, 6 and it can also constitute one of the mechanisms of chronification and severity of migraine.
No statistically significant differences were observed between the genotype and the presence of headache or migraine. However, in terms of phenotype, a higher frequency of headache was observed in patients with MELAS syndrome but without statistically significant differences in terms of the presence of migraine or non-migraine headache. Thus, contrary to what was observed in previous studies, 3,5 a higher prevalence of headache is found in patients with the MELAS syndrome compared to other mitochondrial diseases, including migraine and non-migraine type. This suggests the presence of a specific headache subtype in patients with this entity, as well as the need to further define its characteristics. Unfortunately, in this study, the characteristics of the headache in patients with MELAS syndrome have not been compared with the presence of other symptoms or signs of the disease. The clinical profile of patients with migraine and mitochondrial disease is similar to that of the general population with migraine, with no differences observed in clinical characteristics, prodromal or postdrome symptoms, and the presence of aura.
Regarding sleep characteristics in patients with MDs, no data was observed to suggest the presence of greater daytime sleepiness or worse sleep quality compared to the general population. Interestingly, the mean score on the sleep quality scale indicates a good sleep quality in these patients which, however, worsens significantly in patients presenting headache, reaching ranges of clinical relevance measured by the Pittsburg index. In this sense, as in previous studies, we have assumed a score equal to or greater than 7 on the PSQI as indicative of poorer sleep quality. 17 These data could show a bidirectional relationship between both entities, headache and sleep disorders, given that it is already known that there are more sleep complaints in patients with headache, and that sleep disorders could be an independent factor in its chronification. 18 Conversely, it is also known that patients with headache, specifically migraine, tend to present more sleep disorders, specifically insomnia. 4 Finally, common pathophysiological mechanisms have also been described between sleep disorders and headache, which mainly involve the brainstem nuclei, hypothalamus, and the orexinergic and melatoninergic systems. 19 However, in view of the results obtained in our study, in which no relevant differences were observed with respect to sleep between the general population and MDs, it seems that the association between headache and sleep would be independent of mitochondrial function or, in other words, mitochondrial dysfunction would not be one of the common physiopathogenic factors of both entities and having a more relevant role in the case of headache compared to sleep disorders. Unfortunately, given the design and purpose of this study, it has not been possible to investigate the presence of the different sleep disorders (e.g. sleep-disordered breathing), in this cohort of patients. In the same way, it has not been possible to identify possible associated confounding factors, such as comorbidity with other pathologies or frequent symptoms in patients with mitochondrial diseases, as well as drug use in this population. This fact could constitute a limitation in this study when drawing conclusions applied to clinical practice. Finally, as in other previously conducted studies, the great heterogeneity in the cohort of patients with MD may affect the generalization of the conclusions across all phenotypes and genotypes.
Conclusion
There is a higher frequency of migraine in patients with mitochondrial diseases, independent of genotype and phenotype. In addition, MD-associated migraine tends to be chronic and more disabling than in the general population. A higher frequency of headache, not specifically migraine, has also been observed in patients with MELAS syndrome, suggesting the presence of a characteristic headache subtype in these patients. In this way, mitochondrial dysfunction could be one of the pathophysiological mechanisms of migraine and constitute a factor of chronification and severity in this entity. Poor sleep quality could also be associated with the presence of headache and its chronification in patients with MDs, in a bidirectionally way but not clearly related to mitochondrial dysfunction. So, assessment of headache and, specifically, migraine, as well as sleep quality, is essential in patients with mitochondrial diseases in order to provide the most appropriate management and treatment of these disorders.
Clinical implications
A higher prevalence of migraine is observed in mitochondrial diseases (MDs), independent of genotype and phenotype. Mitochondrial dysfunction could be a factor in the chronification of migraine. There appears to be a specific subtype of headache in MELAS syndrome that has to be defined. Sleep disorders could have a bidirectionally relation to headache, independent of mitochondrial dysfunction.
Footnotes
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Ethic approval and patient consent
This study received approval from the ethics committee and all study patients gave their consent.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.