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Headache in mitochondrial disorders
Clinical Neurology and Neurosurgery 166 (2018) 44–49
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Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Headache in mitochondrial disorders Josef Finsterer a b
a,1,⁎
, Sinda Zarrouk-Mahjoub
T
b,1
Krankenanstalt Rudolfstiftung, Vienna, Austria University of Tunis El Manar and Genomics Platform, Pasteur Institute of Tunis, Tunisia
A R T I C L E I N F O
A B S T R A C T
Keywords: Mitochondrial Headache Cephalalgia Pain mtDNA Respiratory chain
Headache is a prominent feature in mitochondrial disorders (MIDs) but no comprehensive overview is currently available. This review aims at summarising and discussing findings concerning type, frequency, pathogenesis, and treatment of headache in MIDs. The most frequent headache types in MIDs are migraine and migraine-like headache (MLH). MLH is classified as secondary headache. More rarely, tension-type headache, trigemino-autonomic headache, or different secondary headaches can be found. Migraine or MLH may manifest with or without aura. MLH is frequently associated with an ongoing or previous stroke-like episode (SLE) or a seizure but may also occur independently of other neurological features. MLH may be associated with prolonged aura or visual phenomena after headache. Except for MLH, treatment of headache in MIDs is not at variance from other causes of headache. Beyond the broadly accepted subtype-related headache treatment, diet, cofactors, vitamins, and antioxidants may provide a supplementary benefit. Midazolam, L-arginine, or L-citrulline may be beneficial for MLH. The pathogenesis of headache in MIDs largely remains unsolved. However, since migraine and MLH respond both to triptanes, a shared pathomechanism is likely. In conclusion, migraine and MLH are the prominent headache types in MIDs. MLH may or may not be associated with current or previous SLEs. MLH is pathophysiologically different from migraine and requires treatment at variance from that of migraine with aura.
1. Introduction Mitochondrial disorders (MIDs) are frequently multisystem disorders or develop from a mono-organ disease to mitochondrial multiorgan disorder syndrome (MIMODS) during the disease course [1]. Potentially affected organs are brain, nerves, muscles, eyes, ears, endocrine organs, heart, lungs, intestines, kidneys, bones, and skin [2]. Among the cerebral abnormalities in MIDs, headache is a well appreciated manifestation [3]. A shortcoming of most reports about headache in MIDs, however, is that a classification and a detailed description of the intensity, localisation, regional radiation, quality, quantity, duration, recurrence frequency, or triggering factors of headache are missing [4]. This review aims at summarising and discussing previous and recent findings concerning frequency, diagnosis, and treatment of headache in MIDs. 2. Methods Data for this review were identified by searches of MEDLINE for
⁎
1
references of relevant articles. Search terms used for this database were “headache”, “cephalalgia”, “migraine”, “migraine-like”, “cluster”, “tension-type”, and “thunderclap”, in combination with “MELAS”, “MERRF”, “CPEO”, “Kearns-Sayre syndrome”; “Pearson syndrome”, “NARP”, “LHON”, “MIDD”, “MNGIE”, “IOSCA”, “LBSL”, “GRACILE”, “SANDO”, MIRAS“, “MEMSA”, “AHS”, “MCHS”, Leigh syndrome, “PCH”, “MLASA”, “Barth syndrome”, “cardio-facio-cutaneous syndrome”, “Mohr-Tranebjaerg syndrome”, “XLASA”, “ADOA”, “ADOAD”, “DISMOAD”, “SCAE”, “HUPRA”, “RARS”, “DARS2”, “mtDNA”, “mitochondrial”, “depletion”, and “stroke-like episode”. Results of the search were screened for potentially relevant studies by application of inclusion and exclusion criteria for the full texts of the relevant studies. Included were original articles (randomized controlled trials (RCTs) and observational studies with controls) and reviews about humans, published between 1966 and 2017. Editorials and letters were not included. For the paucity of epidemiological data also case reports and small case series, and studies whose reports were published only as an abstract were included. Reference lists of retrieved studies were checked for reports of additional appropriate studies.
Corresponding author at: Postfach 20, 1180, Vienna, Europe, Austria. E-mail address: fifi[email protected] (J. Finsterer). These authors contributed equally.
https://doi.org/10.1016/j.clineuro.2018.01.020 Received 28 June 2017; Received in revised form 12 January 2018; Accepted 15 January 2018 0303-8467/ © 2018 Elsevier B.V. All rights reserved.
Clinical Neurology and Neurosurgery 166 (2018) 44–49
J. Finsterer, S. Zarrouk-Mahjoub
Table 1 Types of headache according to ICHD3-beta so far reported in mitochondrial disorders. Headache type
Mitochondriopathy
Reference
Migraine
MELAS, CPEO, MERRF. LS
[13,15,42]
Tension-type headache Trigeminal autonomic headhace
MERRF
[22]
Cluster headache Paroxysmal hemicranias SUNCT Hemicrania continua
nsMIMODS nr nr nr
[17] nr nr nr
Primary cough headache Primary exercise headache Headache during sexual activity Thunderclap headache Cold-stimulus headache External pressure headache Stabbing headache Nummular headache Hypnic headache New daily persistent headache
nr nr nr nr nr nr nr nr nr nr
nr nr nr nr nr nr nr nr nr nr
Trauma to head or neck Cranial/cervical vascular disorder Non-vascular intracranial disorder Substance abuse or withdrawal Infection Homeostasis Disorders of cranium, neck eyes, Ears, nose, sinuses, teeth, mouth Psychiatric disorders
nr nr nr MELAS (steroids) MELAS nr MELAS (sinusitis, otitis) nr nr
nr nr nr [30] [25] nr [25] nr nr
nr nr
nr nr
Primary
Others
Secondary
Painful cranial neuropathies Other facial pains
MELAS: mitochondrial encephalopathy, lactic acidosis and stroke-like episodes, CPEO: chronic progressive external ophthalmoplegia, MERRF: myoclonic epilepsy with ragged-red fibers, LS: Leigh syndrome. MIMODS: mitochondrial multiorgan disorder syndrome, SUNCT: short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing, MLH: migraine-like headache, ns: non-specific, nr: not reported.
3. Results
also occur in other MIDs, such as MERRF, chronic progressive external ophthalmoplegia (CPEO), Leigh syndrome, Leber’s hereditary optic neuropathy (LHON), Alpers-Huttenlocher disease, and in non-specific MIMODS (Table 2). In a study of 40 patients with late-onset CPEO, 40% had a history of migraine [12]. Migraine was also reported in 52% of 34 patients carrying the m.8344A > G mutation [13]. In a study of four MELAS patients, migraine was the initial clinical manifestation in two [14]. Frequencies of migraine in MID patients in other studies are listed in Table 3. In patients carrying the m.3243A > G mutation, SLEs may be associated with MLH and homonymous hemianopsia [15]. MLH has been also reported in LHON due to the mutation m.14484T > C [16]. Complications of migraine may be adrenergic stimulation, cell stress, or ischemic stroke. Stress from migraine may even precipitate epilepsy [14].
3.1. Headache types Only a few types of headache according to the classification of the international headache society (IHS) (Table 1) have been described in MIDs [5]. These include migraine, cluster headache, tension-type headache, and headache secondary due to arterial hypertension, glaucoma, subarachnoid bleeding, infection, and central vein occlusion. 3.1.1. Migraine and migraine-like headache (MLH) Migraine in MIDs refers to migraine with aura or to MLH. There are several features upon which migraine with aura in MIDs can be delineated from MLH. Some authors regard MLH exclusively as a manifestation of a stroke-like episode (SLE) but some authors use the term also in the absence of SLEs [6]. Thus, MLH can be primary or secondary. Some authors even use both terms synonymously [7]. According to the ICHD-II and ICHD-III [5,8], MLH is a symptomatic headache secondary to the MID. MLH may not only occur in association with a current or previous SLE but also in association with seizures or without other neurological compromise [9]. Duration of visual phenomena prior to headache may be prolonged compared to migraine with aura (prolonged aura) [3]. Prolonged aura is characterised by aura-like visual disturbance after the headache attack, which may last up to 6 months [10]. Interestingly, the prevalence of MIDs is not increased among migraine patients with prolonged aura [11]. MLH may be the initial manifestation of a MID [9]. MLH may be associated with a worse outcome as compared to MID patients with migraine with aura [9]. Among syndromic MIDs, migraine or MLH has been most frequently reported in MELAS syndrome (Table 2). However, migraine or MLH
3.1.2. Trigemino-autonomic headache The term trigemino-autonomic headache includes cluster headache, the paroxysmal hemicranias, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), and hemicrania continua (Table 1). Trigemino-autonomic headache has been only rarely reported in MIDs. Only cluster headache has been described in a patient carrying a tRNA(Leu) mutation [17]. Additionally, cluster headache was described in patients carrying mtDNA deletions [18,19]. Some authors even regarded cluster headache exclusively as a manifestation of MIDs since they found P-MRS abnormalities in the brain and muscle in 14 patients with cluster headache [20]. 3.1.3. Tension-type headache Though myopathy affecting the axial muscles is frequent among the various MIDs [21], tension-type headache associated with axial 45
Clinical Neurology and Neurosurgery 166 (2018) 44–49
J. Finsterer, S. Zarrouk-Mahjoub
Table 2 Headache in mitochondrial disorders. Mutation mtDNA m.6597C > A m.5243A > G mtDNAdel m.8344A > G uk m.8344A > G mtDNAdel m.3291T > C m.13513G > A m.3291T > C m.3243A > G m.4336A > G m.14484T > C m.3243A > G nuclear DNA ch p.W748S c.347C > A c.1399G > A, c.2243G > C c.1491G > C, c.2243G > C
Gene
BC defect
Mt syndrome
Headache type
Reference
COXI tRNA(Leu) nm tRNA(Lys) uk tRNA(Lys) nm MT-TL1 ND5 tRNA(Leu) tRNA(Leu) tRNA(Gln) ND6 tRNA(Leu)
IV nm nm nm I/III, II/III nm nm nm nm nm nm nm nm nm
MELAS-like MELAS CPEO MERRF Leigh syndrome Leigh syndrome nsMIMODS MELAS/MERRF LHON/MELAS nsMIMODS CPEO nsMIMODS LHON nsMIMODS
Migraine Migraine Migraine Migraine Migraine Migraine Cluster headache MLH “Headache” “Headache” MLH Migraine MLH periorbital migraine
[51] [52] [12] [13] [53] [54] [18] [55] [28] [56] [57] [58] [16] [59]
POLG1 POLG1 POLG1 POLG1 POLG1
nm nm nm nm nm
nsMIMODS AHS nsMIMODS nsMIMODS nsMIMODS
sudden onset?? MLH Migraine “Headache” MLH
[60] [9] [36] [45] [61]
BC: biochemical, ch: compound heterozygous, MELAS: mitochondrial encephalopathy, lactic acidosis and stroke-like episodes, CPEO: chronic progressive external ophthalmoplegia, MERRF: myoclonic epilepsy with ragged-red fibers, LS: Leigh syndrome. MIMODS: mitochondrial multiorgan disorder syndrome, LHON: Leber’s hereditary optic neuropathy, AHS: Alpers Huttenlocher syndrome, mt: mitochondrial, uk: unknown, nm: not mentioned, ns: non-specific.
3.1.5. Secondary headache Secondary headache is frequent in MID patients since these patients usually suffer from a multisystem disease (MIMODS). The most frequent secondary headache in MIDs is headache due to arterial hypertension. Headache due to high blood pressure is a frequent secondary type of headache, since arterial hypertension can be a phenotypic manifestation of a MID [24]. Headache associated with the presentation of a meningoencephalitis has been reported in a single patient with MELAS syndrome [25]. This patient also had sinusitis and otitis, other causes of secondary headache [25]. Glaucoma is a common phenotypic feature of MIDs and has been particularly described in Kearns-Sayre syndrome [26] and LHON [27]. Glaucoma may go along with secondary frontal headache. Central retinal vein occlusion in patients carrying primary LHON mutations has been associated with subsequent headache and SLEs [28]. Since MIDs may go along with ectasia or aneurysms of cerebral arteries [1], there is an increased probability that MID patients experience subarachnoid bleeding and thus previously not experienced sudden onset strong permanent headache more frequently than the general population. However, no reports about thunderclap headache are currently available, most likely because patients with subarachnoid bleeding are not systematically investigated for MID. In rare cases, MIDs may manifest as arteriopathy due to affection of cells constituting the arterial wall [1]. In such a case spontaneous dissection of intracranial arteries may ensue [1]. Dissection has been reported to be accompanied by pain, including headache [29]. In a 12 year-old male with MELAS, SLEs responded favorably to steroids and each time steroids were tapered or withdrawn he experienced a relapse, including headache [30]. In a 12 year-old male with MELAS syndrome manifesting as headache and epilepsy, headache and seizures could be triggered by application of valproic acid [31]. Headache in MIDs may be also due to relative hypoxia since MIDs cannot sufficiently utilize oxygen.
Table 3 Studies reporting frequencies of headache types in cohorts of patients with a MID. Study
NOP
Migraine
MLH
Cluster
NSH
%HA
[62] [44] [43] [42] [12] [13] [45] [63] [64] [61] [65] [66] [67] [9]
98 66 57 42 40 34 26 24 8 6 5 4 4 3
35 0 33 4 16 18 6 0 0 2 3 0 3 0
0 0 0 0 0 0 0 0 0 0 0 0 0 2
0 0 0 0 0 0 0 0 0 0 0 0 0 0
0 33 0 0 0 0 7 24 5 2 0 2 0 0
35.7% 50% 58% 10% 40% 52% 50% 100% 62.5% 66.7% 60% 50% 75% 67.7%
NOP: number of included patients, NSH: non-specific headache, %HA: percentage of patients with headache.
myopathy, cervical hyperlordosis, or scoliosis has been hardly addressed. According to our own experience, however, tension-type headache is a common feature in patients with MIMODS. The reason for the low prevalence might be that patients have to be actively asked for headache and adequately investigated upon the clinical exam. In a young male with MERRF syndrome, tension-type headache with nausea was the predominant clinical manifestation at presentation [22]. Tension-type headache was also reported in a 24 year-old female carrying the m.3243A > G mutation which manifested as vomiting, phonophobia, photophobia, and focal motor seizures with oculocephalic deviation at onset [23].
3.1.4. Unclassified headache Though headache is a frequent phenotypic feature of MIDs (Table 3), headache was not classified according to the IHS headache classification in most MID studies. Nonetheless, unclassified headache needs to be included in the discussion about headache in MIDs. Readers should be encouraged to apply the IHS [5,8] also to MIDs patients. Studies in which headache in MID patients remained unclassified are listed in Table 3.
3.2. Pathogenesis 3.2.1. Migraine, MLH The pathogenesis of migraine and MLH in MIDs is unknown [32] but neuronal hyperexcitability and trigemino-vascular activation are regarded to play an important role [15]. There are indications that the brainstem activates the trigemino-vascular system, which then 46
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studies about headache in MIDs might be that headache is frequently not regarded as a manifestation of a MID. This is why the frequency of headache in MIDs may be underestimated. However, the frequency of migraine or MLH, the most frequent types of headache in MIDs, has been investigated in some specific MIDs. Among patients carrying the m.8344A > G mutation in the tRNA(Lys) gene, 52% developed migraine [13]. In a study of 42 patients carrying the m.8344A > G mutation in the tRNA(Lys) gene 10% manifested with migraine at the last evaluation [42]. The number of MERRF patients > 16y with migraine increased from 6% at onset to 10% during a period of 24y [42]. In a study of 40 patients with CPEO, 40% had a history of migraine [12]. The prevalence of migraine is particularly high in MELAS [43]. In a study of 57 patients carrying the m.3243A > G mutation, 58% presented with a history of migraine [43]. Migraine without aura was found in 47% of these patients and migraine with aura in 18% of the cases [43]. There are also a few studies about the frequency of non-specific headache in MIDs. In a study of 66 patients carrying the m.3243A > G mutation, 50% were reported who had a history of “headache” [44]. In a study of 26 patients carrying a POLG1 mutation, unclassified headache was the initial manifestation at onset in seven patients and migraine was diagnosed in six [45]. Frequency of headache among patients with definite MID varies considerably depending on the subtype of MID, ranging from 10 to 100% (Table 3).
stimulates perivascular trigeminal sensory afferent nerves with release of vasoactive neuropeptides, resulting in vasodilation and transduction of central nociceptive information [33]. Afterwards, a relay of pain impulses to central second- and third-order neurons and activation of brain stem autonomic nuclei may induce associated symptoms [33]. Another pathomechanism of migraine is cortical spreading depression (CSD) triggered by mitochondrial dysfunction resulting in calcium release to the cytosol, excessive production of reactive oxygen species (ROS), and deficient oxidative phosphorylation with consecutive energy failure [34]. Since MLH is associated with SLEs, metabolic disruption, epileptic activity, or vasculopathy may play an additional role in the pathogenesis of MLH. However, the role of SLEs in the pathogenesis of MLH in MIDs is currently unsolved [32]. Since MIDs are frequently associated with lactic acidosis, lactic acidosis may have a role in the development of headache. Whether migraine in non-MID patients is associated with particular haplotypes, polymorphisms, or mtDNA mutations is under debate. Some studies found a relation between mtDNA variants and migraine but others did not [32]. Recently, it has been proposed that non-MID patients with migraine may carry variants in nuclear genes involved in mitochondrial function [35]. Why POLG1 mutations show intrafamilial phenotypic heterogeneity with regard to headache is unknown [36]. One member of a family may present with migraine whereas the other may present without headache but with an arteriovenous malformation nidus [36]. There are some indications that fasting may trigger the development of migraine [37]. In a rat model of migraine mitochondrial dysfunction was implicated in the pathomechanism of migraine.
3.4. Treatment of headache in MIDs Therapy of headache in MIDs is usually not at variance compared to headache due to other causes. However, MLH requires treatment different from that of classical migraine. Additionally, care has to be taken to avoid any compounds known or suspected to be mitochondriontoxic. Beyond the broadly accepted subtype-related headache treatment, the medical therapy depends on organ manifestations (e.g., in hepatic failure valproic acid cannot be administered).
3.2.2. Cluster headache Though cluster headache is frequently regarded as vascular headache, the striking circadian rhythmicity of the strictly unilateral pain syndrome cannot readily be explained by the vascular hypothesis [38]. Studies using positron emission tomography (PET) suggest that a central nervous system (CNS) dysfunction in the region of the hypothalamus as the primum movens in the pathophysiology of cluster headache [38].
3.4.1. Acute headache treatment Treatment of acute headache in MIDs or non-MIDs does not differ, except for headache associated with SLEs or epilepsy. Migraine attacks in MIDs usually respond favorably to all recommended agents for migraine attacks in non-MIDs. Frequently applied analgesics for acute headache in MIDs include nonsteroidal-antiinflammatory drugs, opioids, opiates, triptans, steroids, or antiepileptic drugs. In patients with MLH associated with a SLE application of midazolam has been reported immediately beneficial for headache [15]. Whether migraine or MLH respond to the NO-precursors L-arginine or L-citrulline is under debate. In a Japanese girl with MELAS syndrome, infusions with L-arginine were effective for headache during all four SLEs but only if administered within four hours after onset of a SLE [46]. In a 12 year-old boy with MELAS, MLH disappeared immediately after oral administration of L-arginine (0.4 mg/kg/d) [6]. In a Japanese girl L-arginine was ineffective for severe headache during a SLE [15]. Oxygen is frequently beneficial for mitochondrial cluster headache.
3.2.3. Mitochondrial dysfunction in migraine Mitochondrial dysfunction may not only occur in patients with a definite MID but also in patients with migraine but without a MID. There is increasing evidence for mitochondrial dysfunction in the pathogenesis of migraine [39]. There is some evidence that migraine attacks trigger oxidative stress [40]. Oxidative stress may elicit neurogenic inflammation via signals from the TRPA1 channels to meningeal pain receptors [40]. From in vitro research and animal and human studies on ischemia it is known that a number of mechanisms are activated to decrease the production of reactive oxidative species ROS during migraine attacks, such as CSD, platelet activation, plasma protein extravasation, endothelial NO synthesis, upregulation of antioxidative enzymes, and release of serotonine, substance P, calcitonine gene-related peptide, and brain-derived neurotrophic factor [40]. Activation of these mechanisms, may stimulate neurogenesis, prevents apoptosis, facilitates mitochondrial biogenesis, and releases cerebral growth factors [40]. In a rat model of migraine, migraine caused fragmentation of mitochondria, increased the mitochondrial fission protein Drp1, reduced the mitochondrial fusion protein Mfn1, and reduced the neuronal mtDNA copy number and the levels of regulatory factors involved in mitochondrial biogenesis, such as PGC-1alpha [39].
3.4.2. Prophylactic treatment Prophylactic treatment of mitochondrial migraine is largely not at variance from non-MIDs and includes beta-blockers (propranolol, bisoprolol, metoprolol), flunarizine, and topiramate. Additionally, supplementary medication, such as vitamins, co-factors, or antioxidants can be tried. For prophylaxis of mitochondrial migraine riboflavin has been proposed with level B evidence [47]. However, no RCTs have been undertaken to provide evidence for such a treatment. Anti-CGRP antibodies have not been tried for headache in MIDs. Since some drugs used in migraine (e.g. CoQ, magnesium) may influence mitochondrial functions, they may be beneficial for MHL as well. A mainstay of prophylactic treatment for primary headache in MIDs is the adherence to a certain diet, such as the ketogenic diet or the general avoidance of glucose-rich food [48]. Dietary measures can be particularly helpful in
3.3. Frequency of headache types in MIDs There are only few epidemiological studies about the frequency of headache in MIDs available. In a study of 93 patients with a MID, 35.5% had headache (Table 3) [41]. On multivariate analysis, MID patients with headache had less frequently myopathy and epilepsy than those without headache [41]. One reason for the lack of epidemiological 47
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mitochondrial migraine [Finsterer, submitted]. In a MID patient with a > 20y history of migraine onset of weakness of facial and cervical muscles resulted in resolution of migraine for at least 10 months [49]. The authors attributed the effect to the concept that nerve or muscle compression cause migraine in a subset of these patients [49]. Though neuromodulation invasive techniques (occipital nerve stimulation (ONS), ganglion phenopalatine stimulation, deep brain stimulation (DBS)) or non-invasive techniques (supraorbital nerve stimulation (SONS), vagal nerve stimulation (VNS), or transcranial magnetic nerve stimulation (TMS) [50] have not been tried in mitochondrial headache, they could be useful and should be tried.
[9]
[10] [11]
[12]
[13]
4. Conclusions This review shows that headache can be a prominent manifestation of MIDs. The most frequent types of headache in MIDs are migraine and MLH. More rarely, tension-type headache, trigemino-autonomic headache, or different secondary headaches can be found. Migraine may manifest with or without aura and with or without a concomitant SLE. The term MLH refers to migraine with prolonged aura or prolonged visual phenomena after headache in association with or without an ongoing or previous SLE. MLH may be the initial manifestation of a SLE. However, the clinical characteristics of MLH are frequently not mentioned. Treatment of headache in MIDs is not at variance compared to other causes of headache, but diet, cofactors, vitamins, or antioxidants may have a supplementary beneficial effect. Midazolam, L-arginine, or L-citrulline may be beneficial in MLH associated with SLEs. Treatment of headache in MIDs is frequently not specified. Though causes of headache in MIDs are heterogeneous, they must be recognised. Important is to differentiate between classical migraine and MLH since MLH is not only pathophysiologically different from migraine but also requires treatment at variance from that of classical migraine. However, since migraine and MLH respond both to triptanes, a shared pathomechanism is likely. MLH should be diagnosed if MRI shows a strokelike lesion and if there is a prolonged aura or long-term visual, aura-like phenomena after headache. To overcome the lack of epidemiological data about headache in MIDs it is recommended that future studies use the ICHD-III classification [5].
[14] [15]
[16]
[17]
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[21]
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[24]
[25]
Conflict of interest There are no conflicts of interest.
[26]
Funding
[27]
No funding was received.
[28]
Author contribution [29]
JF: design, literature search, discussion, first draft, SZM: literature search, discussion, critical comments.
[30] [31]
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49
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Headache in mitochondrial disorders Josef Finsterer a b
a,1,⁎
, Sinda Zarrouk-Mahjoub
T
b,1
Krankenanstalt Rudolfstiftung, Vienna, Austria University of Tunis El Manar and Genomics Platform, Pasteur Institute of Tunis, Tunisia
A R T I C L E I N F O
A B S T R A C T
Keywords: Mitochondrial Headache Cephalalgia Pain mtDNA Respiratory chain
Headache is a prominent feature in mitochondrial disorders (MIDs) but no comprehensive overview is currently available. This review aims at summarising and discussing findings concerning type, frequency, pathogenesis, and treatment of headache in MIDs. The most frequent headache types in MIDs are migraine and migraine-like headache (MLH). MLH is classified as secondary headache. More rarely, tension-type headache, trigemino-autonomic headache, or different secondary headaches can be found. Migraine or MLH may manifest with or without aura. MLH is frequently associated with an ongoing or previous stroke-like episode (SLE) or a seizure but may also occur independently of other neurological features. MLH may be associated with prolonged aura or visual phenomena after headache. Except for MLH, treatment of headache in MIDs is not at variance from other causes of headache. Beyond the broadly accepted subtype-related headache treatment, diet, cofactors, vitamins, and antioxidants may provide a supplementary benefit. Midazolam, L-arginine, or L-citrulline may be beneficial for MLH. The pathogenesis of headache in MIDs largely remains unsolved. However, since migraine and MLH respond both to triptanes, a shared pathomechanism is likely. In conclusion, migraine and MLH are the prominent headache types in MIDs. MLH may or may not be associated with current or previous SLEs. MLH is pathophysiologically different from migraine and requires treatment at variance from that of migraine with aura.
1. Introduction Mitochondrial disorders (MIDs) are frequently multisystem disorders or develop from a mono-organ disease to mitochondrial multiorgan disorder syndrome (MIMODS) during the disease course [1]. Potentially affected organs are brain, nerves, muscles, eyes, ears, endocrine organs, heart, lungs, intestines, kidneys, bones, and skin [2]. Among the cerebral abnormalities in MIDs, headache is a well appreciated manifestation [3]. A shortcoming of most reports about headache in MIDs, however, is that a classification and a detailed description of the intensity, localisation, regional radiation, quality, quantity, duration, recurrence frequency, or triggering factors of headache are missing [4]. This review aims at summarising and discussing previous and recent findings concerning frequency, diagnosis, and treatment of headache in MIDs. 2. Methods Data for this review were identified by searches of MEDLINE for
⁎
1
references of relevant articles. Search terms used for this database were “headache”, “cephalalgia”, “migraine”, “migraine-like”, “cluster”, “tension-type”, and “thunderclap”, in combination with “MELAS”, “MERRF”, “CPEO”, “Kearns-Sayre syndrome”; “Pearson syndrome”, “NARP”, “LHON”, “MIDD”, “MNGIE”, “IOSCA”, “LBSL”, “GRACILE”, “SANDO”, MIRAS“, “MEMSA”, “AHS”, “MCHS”, Leigh syndrome, “PCH”, “MLASA”, “Barth syndrome”, “cardio-facio-cutaneous syndrome”, “Mohr-Tranebjaerg syndrome”, “XLASA”, “ADOA”, “ADOAD”, “DISMOAD”, “SCAE”, “HUPRA”, “RARS”, “DARS2”, “mtDNA”, “mitochondrial”, “depletion”, and “stroke-like episode”. Results of the search were screened for potentially relevant studies by application of inclusion and exclusion criteria for the full texts of the relevant studies. Included were original articles (randomized controlled trials (RCTs) and observational studies with controls) and reviews about humans, published between 1966 and 2017. Editorials and letters were not included. For the paucity of epidemiological data also case reports and small case series, and studies whose reports were published only as an abstract were included. Reference lists of retrieved studies were checked for reports of additional appropriate studies.
Corresponding author at: Postfach 20, 1180, Vienna, Europe, Austria. E-mail address: fifi[email protected] (J. Finsterer). These authors contributed equally.
https://doi.org/10.1016/j.clineuro.2018.01.020 Received 28 June 2017; Received in revised form 12 January 2018; Accepted 15 January 2018 0303-8467/ © 2018 Elsevier B.V. All rights reserved.
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Table 1 Types of headache according to ICHD3-beta so far reported in mitochondrial disorders. Headache type
Mitochondriopathy
Reference
Migraine
MELAS, CPEO, MERRF. LS
[13,15,42]
Tension-type headache Trigeminal autonomic headhace
MERRF
[22]
Cluster headache Paroxysmal hemicranias SUNCT Hemicrania continua
nsMIMODS nr nr nr
[17] nr nr nr
Primary cough headache Primary exercise headache Headache during sexual activity Thunderclap headache Cold-stimulus headache External pressure headache Stabbing headache Nummular headache Hypnic headache New daily persistent headache
nr nr nr nr nr nr nr nr nr nr
nr nr nr nr nr nr nr nr nr nr
Trauma to head or neck Cranial/cervical vascular disorder Non-vascular intracranial disorder Substance abuse or withdrawal Infection Homeostasis Disorders of cranium, neck eyes, Ears, nose, sinuses, teeth, mouth Psychiatric disorders
nr nr nr MELAS (steroids) MELAS nr MELAS (sinusitis, otitis) nr nr
nr nr nr [30] [25] nr [25] nr nr
nr nr
nr nr
Primary
Others
Secondary
Painful cranial neuropathies Other facial pains
MELAS: mitochondrial encephalopathy, lactic acidosis and stroke-like episodes, CPEO: chronic progressive external ophthalmoplegia, MERRF: myoclonic epilepsy with ragged-red fibers, LS: Leigh syndrome. MIMODS: mitochondrial multiorgan disorder syndrome, SUNCT: short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing, MLH: migraine-like headache, ns: non-specific, nr: not reported.
3. Results
also occur in other MIDs, such as MERRF, chronic progressive external ophthalmoplegia (CPEO), Leigh syndrome, Leber’s hereditary optic neuropathy (LHON), Alpers-Huttenlocher disease, and in non-specific MIMODS (Table 2). In a study of 40 patients with late-onset CPEO, 40% had a history of migraine [12]. Migraine was also reported in 52% of 34 patients carrying the m.8344A > G mutation [13]. In a study of four MELAS patients, migraine was the initial clinical manifestation in two [14]. Frequencies of migraine in MID patients in other studies are listed in Table 3. In patients carrying the m.3243A > G mutation, SLEs may be associated with MLH and homonymous hemianopsia [15]. MLH has been also reported in LHON due to the mutation m.14484T > C [16]. Complications of migraine may be adrenergic stimulation, cell stress, or ischemic stroke. Stress from migraine may even precipitate epilepsy [14].
3.1. Headache types Only a few types of headache according to the classification of the international headache society (IHS) (Table 1) have been described in MIDs [5]. These include migraine, cluster headache, tension-type headache, and headache secondary due to arterial hypertension, glaucoma, subarachnoid bleeding, infection, and central vein occlusion. 3.1.1. Migraine and migraine-like headache (MLH) Migraine in MIDs refers to migraine with aura or to MLH. There are several features upon which migraine with aura in MIDs can be delineated from MLH. Some authors regard MLH exclusively as a manifestation of a stroke-like episode (SLE) but some authors use the term also in the absence of SLEs [6]. Thus, MLH can be primary or secondary. Some authors even use both terms synonymously [7]. According to the ICHD-II and ICHD-III [5,8], MLH is a symptomatic headache secondary to the MID. MLH may not only occur in association with a current or previous SLE but also in association with seizures or without other neurological compromise [9]. Duration of visual phenomena prior to headache may be prolonged compared to migraine with aura (prolonged aura) [3]. Prolonged aura is characterised by aura-like visual disturbance after the headache attack, which may last up to 6 months [10]. Interestingly, the prevalence of MIDs is not increased among migraine patients with prolonged aura [11]. MLH may be the initial manifestation of a MID [9]. MLH may be associated with a worse outcome as compared to MID patients with migraine with aura [9]. Among syndromic MIDs, migraine or MLH has been most frequently reported in MELAS syndrome (Table 2). However, migraine or MLH
3.1.2. Trigemino-autonomic headache The term trigemino-autonomic headache includes cluster headache, the paroxysmal hemicranias, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), and hemicrania continua (Table 1). Trigemino-autonomic headache has been only rarely reported in MIDs. Only cluster headache has been described in a patient carrying a tRNA(Leu) mutation [17]. Additionally, cluster headache was described in patients carrying mtDNA deletions [18,19]. Some authors even regarded cluster headache exclusively as a manifestation of MIDs since they found P-MRS abnormalities in the brain and muscle in 14 patients with cluster headache [20]. 3.1.3. Tension-type headache Though myopathy affecting the axial muscles is frequent among the various MIDs [21], tension-type headache associated with axial 45
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Table 2 Headache in mitochondrial disorders. Mutation mtDNA m.6597C > A m.5243A > G mtDNAdel m.8344A > G uk m.8344A > G mtDNAdel m.3291T > C m.13513G > A m.3291T > C m.3243A > G m.4336A > G m.14484T > C m.3243A > G nuclear DNA ch p.W748S c.347C > A c.1399G > A, c.2243G > C c.1491G > C, c.2243G > C
Gene
BC defect
Mt syndrome
Headache type
Reference
COXI tRNA(Leu) nm tRNA(Lys) uk tRNA(Lys) nm MT-TL1 ND5 tRNA(Leu) tRNA(Leu) tRNA(Gln) ND6 tRNA(Leu)
IV nm nm nm I/III, II/III nm nm nm nm nm nm nm nm nm
MELAS-like MELAS CPEO MERRF Leigh syndrome Leigh syndrome nsMIMODS MELAS/MERRF LHON/MELAS nsMIMODS CPEO nsMIMODS LHON nsMIMODS
Migraine Migraine Migraine Migraine Migraine Migraine Cluster headache MLH “Headache” “Headache” MLH Migraine MLH periorbital migraine
[51] [52] [12] [13] [53] [54] [18] [55] [28] [56] [57] [58] [16] [59]
POLG1 POLG1 POLG1 POLG1 POLG1
nm nm nm nm nm
nsMIMODS AHS nsMIMODS nsMIMODS nsMIMODS
sudden onset?? MLH Migraine “Headache” MLH
[60] [9] [36] [45] [61]
BC: biochemical, ch: compound heterozygous, MELAS: mitochondrial encephalopathy, lactic acidosis and stroke-like episodes, CPEO: chronic progressive external ophthalmoplegia, MERRF: myoclonic epilepsy with ragged-red fibers, LS: Leigh syndrome. MIMODS: mitochondrial multiorgan disorder syndrome, LHON: Leber’s hereditary optic neuropathy, AHS: Alpers Huttenlocher syndrome, mt: mitochondrial, uk: unknown, nm: not mentioned, ns: non-specific.
3.1.5. Secondary headache Secondary headache is frequent in MID patients since these patients usually suffer from a multisystem disease (MIMODS). The most frequent secondary headache in MIDs is headache due to arterial hypertension. Headache due to high blood pressure is a frequent secondary type of headache, since arterial hypertension can be a phenotypic manifestation of a MID [24]. Headache associated with the presentation of a meningoencephalitis has been reported in a single patient with MELAS syndrome [25]. This patient also had sinusitis and otitis, other causes of secondary headache [25]. Glaucoma is a common phenotypic feature of MIDs and has been particularly described in Kearns-Sayre syndrome [26] and LHON [27]. Glaucoma may go along with secondary frontal headache. Central retinal vein occlusion in patients carrying primary LHON mutations has been associated with subsequent headache and SLEs [28]. Since MIDs may go along with ectasia or aneurysms of cerebral arteries [1], there is an increased probability that MID patients experience subarachnoid bleeding and thus previously not experienced sudden onset strong permanent headache more frequently than the general population. However, no reports about thunderclap headache are currently available, most likely because patients with subarachnoid bleeding are not systematically investigated for MID. In rare cases, MIDs may manifest as arteriopathy due to affection of cells constituting the arterial wall [1]. In such a case spontaneous dissection of intracranial arteries may ensue [1]. Dissection has been reported to be accompanied by pain, including headache [29]. In a 12 year-old male with MELAS, SLEs responded favorably to steroids and each time steroids were tapered or withdrawn he experienced a relapse, including headache [30]. In a 12 year-old male with MELAS syndrome manifesting as headache and epilepsy, headache and seizures could be triggered by application of valproic acid [31]. Headache in MIDs may be also due to relative hypoxia since MIDs cannot sufficiently utilize oxygen.
Table 3 Studies reporting frequencies of headache types in cohorts of patients with a MID. Study
NOP
Migraine
MLH
Cluster
NSH
%HA
[62] [44] [43] [42] [12] [13] [45] [63] [64] [61] [65] [66] [67] [9]
98 66 57 42 40 34 26 24 8 6 5 4 4 3
35 0 33 4 16 18 6 0 0 2 3 0 3 0
0 0 0 0 0 0 0 0 0 0 0 0 0 2
0 0 0 0 0 0 0 0 0 0 0 0 0 0
0 33 0 0 0 0 7 24 5 2 0 2 0 0
35.7% 50% 58% 10% 40% 52% 50% 100% 62.5% 66.7% 60% 50% 75% 67.7%
NOP: number of included patients, NSH: non-specific headache, %HA: percentage of patients with headache.
myopathy, cervical hyperlordosis, or scoliosis has been hardly addressed. According to our own experience, however, tension-type headache is a common feature in patients with MIMODS. The reason for the low prevalence might be that patients have to be actively asked for headache and adequately investigated upon the clinical exam. In a young male with MERRF syndrome, tension-type headache with nausea was the predominant clinical manifestation at presentation [22]. Tension-type headache was also reported in a 24 year-old female carrying the m.3243A > G mutation which manifested as vomiting, phonophobia, photophobia, and focal motor seizures with oculocephalic deviation at onset [23].
3.1.4. Unclassified headache Though headache is a frequent phenotypic feature of MIDs (Table 3), headache was not classified according to the IHS headache classification in most MID studies. Nonetheless, unclassified headache needs to be included in the discussion about headache in MIDs. Readers should be encouraged to apply the IHS [5,8] also to MIDs patients. Studies in which headache in MID patients remained unclassified are listed in Table 3.
3.2. Pathogenesis 3.2.1. Migraine, MLH The pathogenesis of migraine and MLH in MIDs is unknown [32] but neuronal hyperexcitability and trigemino-vascular activation are regarded to play an important role [15]. There are indications that the brainstem activates the trigemino-vascular system, which then 46
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studies about headache in MIDs might be that headache is frequently not regarded as a manifestation of a MID. This is why the frequency of headache in MIDs may be underestimated. However, the frequency of migraine or MLH, the most frequent types of headache in MIDs, has been investigated in some specific MIDs. Among patients carrying the m.8344A > G mutation in the tRNA(Lys) gene, 52% developed migraine [13]. In a study of 42 patients carrying the m.8344A > G mutation in the tRNA(Lys) gene 10% manifested with migraine at the last evaluation [42]. The number of MERRF patients > 16y with migraine increased from 6% at onset to 10% during a period of 24y [42]. In a study of 40 patients with CPEO, 40% had a history of migraine [12]. The prevalence of migraine is particularly high in MELAS [43]. In a study of 57 patients carrying the m.3243A > G mutation, 58% presented with a history of migraine [43]. Migraine without aura was found in 47% of these patients and migraine with aura in 18% of the cases [43]. There are also a few studies about the frequency of non-specific headache in MIDs. In a study of 66 patients carrying the m.3243A > G mutation, 50% were reported who had a history of “headache” [44]. In a study of 26 patients carrying a POLG1 mutation, unclassified headache was the initial manifestation at onset in seven patients and migraine was diagnosed in six [45]. Frequency of headache among patients with definite MID varies considerably depending on the subtype of MID, ranging from 10 to 100% (Table 3).
stimulates perivascular trigeminal sensory afferent nerves with release of vasoactive neuropeptides, resulting in vasodilation and transduction of central nociceptive information [33]. Afterwards, a relay of pain impulses to central second- and third-order neurons and activation of brain stem autonomic nuclei may induce associated symptoms [33]. Another pathomechanism of migraine is cortical spreading depression (CSD) triggered by mitochondrial dysfunction resulting in calcium release to the cytosol, excessive production of reactive oxygen species (ROS), and deficient oxidative phosphorylation with consecutive energy failure [34]. Since MLH is associated with SLEs, metabolic disruption, epileptic activity, or vasculopathy may play an additional role in the pathogenesis of MLH. However, the role of SLEs in the pathogenesis of MLH in MIDs is currently unsolved [32]. Since MIDs are frequently associated with lactic acidosis, lactic acidosis may have a role in the development of headache. Whether migraine in non-MID patients is associated with particular haplotypes, polymorphisms, or mtDNA mutations is under debate. Some studies found a relation between mtDNA variants and migraine but others did not [32]. Recently, it has been proposed that non-MID patients with migraine may carry variants in nuclear genes involved in mitochondrial function [35]. Why POLG1 mutations show intrafamilial phenotypic heterogeneity with regard to headache is unknown [36]. One member of a family may present with migraine whereas the other may present without headache but with an arteriovenous malformation nidus [36]. There are some indications that fasting may trigger the development of migraine [37]. In a rat model of migraine mitochondrial dysfunction was implicated in the pathomechanism of migraine.
3.4. Treatment of headache in MIDs Therapy of headache in MIDs is usually not at variance compared to headache due to other causes. However, MLH requires treatment different from that of classical migraine. Additionally, care has to be taken to avoid any compounds known or suspected to be mitochondriontoxic. Beyond the broadly accepted subtype-related headache treatment, the medical therapy depends on organ manifestations (e.g., in hepatic failure valproic acid cannot be administered).
3.2.2. Cluster headache Though cluster headache is frequently regarded as vascular headache, the striking circadian rhythmicity of the strictly unilateral pain syndrome cannot readily be explained by the vascular hypothesis [38]. Studies using positron emission tomography (PET) suggest that a central nervous system (CNS) dysfunction in the region of the hypothalamus as the primum movens in the pathophysiology of cluster headache [38].
3.4.1. Acute headache treatment Treatment of acute headache in MIDs or non-MIDs does not differ, except for headache associated with SLEs or epilepsy. Migraine attacks in MIDs usually respond favorably to all recommended agents for migraine attacks in non-MIDs. Frequently applied analgesics for acute headache in MIDs include nonsteroidal-antiinflammatory drugs, opioids, opiates, triptans, steroids, or antiepileptic drugs. In patients with MLH associated with a SLE application of midazolam has been reported immediately beneficial for headache [15]. Whether migraine or MLH respond to the NO-precursors L-arginine or L-citrulline is under debate. In a Japanese girl with MELAS syndrome, infusions with L-arginine were effective for headache during all four SLEs but only if administered within four hours after onset of a SLE [46]. In a 12 year-old boy with MELAS, MLH disappeared immediately after oral administration of L-arginine (0.4 mg/kg/d) [6]. In a Japanese girl L-arginine was ineffective for severe headache during a SLE [15]. Oxygen is frequently beneficial for mitochondrial cluster headache.
3.2.3. Mitochondrial dysfunction in migraine Mitochondrial dysfunction may not only occur in patients with a definite MID but also in patients with migraine but without a MID. There is increasing evidence for mitochondrial dysfunction in the pathogenesis of migraine [39]. There is some evidence that migraine attacks trigger oxidative stress [40]. Oxidative stress may elicit neurogenic inflammation via signals from the TRPA1 channels to meningeal pain receptors [40]. From in vitro research and animal and human studies on ischemia it is known that a number of mechanisms are activated to decrease the production of reactive oxidative species ROS during migraine attacks, such as CSD, platelet activation, plasma protein extravasation, endothelial NO synthesis, upregulation of antioxidative enzymes, and release of serotonine, substance P, calcitonine gene-related peptide, and brain-derived neurotrophic factor [40]. Activation of these mechanisms, may stimulate neurogenesis, prevents apoptosis, facilitates mitochondrial biogenesis, and releases cerebral growth factors [40]. In a rat model of migraine, migraine caused fragmentation of mitochondria, increased the mitochondrial fission protein Drp1, reduced the mitochondrial fusion protein Mfn1, and reduced the neuronal mtDNA copy number and the levels of regulatory factors involved in mitochondrial biogenesis, such as PGC-1alpha [39].
3.4.2. Prophylactic treatment Prophylactic treatment of mitochondrial migraine is largely not at variance from non-MIDs and includes beta-blockers (propranolol, bisoprolol, metoprolol), flunarizine, and topiramate. Additionally, supplementary medication, such as vitamins, co-factors, or antioxidants can be tried. For prophylaxis of mitochondrial migraine riboflavin has been proposed with level B evidence [47]. However, no RCTs have been undertaken to provide evidence for such a treatment. Anti-CGRP antibodies have not been tried for headache in MIDs. Since some drugs used in migraine (e.g. CoQ, magnesium) may influence mitochondrial functions, they may be beneficial for MHL as well. A mainstay of prophylactic treatment for primary headache in MIDs is the adherence to a certain diet, such as the ketogenic diet or the general avoidance of glucose-rich food [48]. Dietary measures can be particularly helpful in
3.3. Frequency of headache types in MIDs There are only few epidemiological studies about the frequency of headache in MIDs available. In a study of 93 patients with a MID, 35.5% had headache (Table 3) [41]. On multivariate analysis, MID patients with headache had less frequently myopathy and epilepsy than those without headache [41]. One reason for the lack of epidemiological 47
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mitochondrial migraine [Finsterer, submitted]. In a MID patient with a > 20y history of migraine onset of weakness of facial and cervical muscles resulted in resolution of migraine for at least 10 months [49]. The authors attributed the effect to the concept that nerve or muscle compression cause migraine in a subset of these patients [49]. Though neuromodulation invasive techniques (occipital nerve stimulation (ONS), ganglion phenopalatine stimulation, deep brain stimulation (DBS)) or non-invasive techniques (supraorbital nerve stimulation (SONS), vagal nerve stimulation (VNS), or transcranial magnetic nerve stimulation (TMS) [50] have not been tried in mitochondrial headache, they could be useful and should be tried.
[9]
[10] [11]
[12]
[13]
4. Conclusions This review shows that headache can be a prominent manifestation of MIDs. The most frequent types of headache in MIDs are migraine and MLH. More rarely, tension-type headache, trigemino-autonomic headache, or different secondary headaches can be found. Migraine may manifest with or without aura and with or without a concomitant SLE. The term MLH refers to migraine with prolonged aura or prolonged visual phenomena after headache in association with or without an ongoing or previous SLE. MLH may be the initial manifestation of a SLE. However, the clinical characteristics of MLH are frequently not mentioned. Treatment of headache in MIDs is not at variance compared to other causes of headache, but diet, cofactors, vitamins, or antioxidants may have a supplementary beneficial effect. Midazolam, L-arginine, or L-citrulline may be beneficial in MLH associated with SLEs. Treatment of headache in MIDs is frequently not specified. Though causes of headache in MIDs are heterogeneous, they must be recognised. Important is to differentiate between classical migraine and MLH since MLH is not only pathophysiologically different from migraine but also requires treatment at variance from that of classical migraine. However, since migraine and MLH respond both to triptanes, a shared pathomechanism is likely. MLH should be diagnosed if MRI shows a strokelike lesion and if there is a prolonged aura or long-term visual, aura-like phenomena after headache. To overcome the lack of epidemiological data about headache in MIDs it is recommended that future studies use the ICHD-III classification [5].
[14] [15]
[16]
[17]
[18] [19] [20]
[21]
[22] [23]
[24]
[25]
Conflict of interest There are no conflicts of interest.
[26]
Funding
[27]
No funding was received.
[28]
Author contribution [29]
JF: design, literature search, discussion, first draft, SZM: literature search, discussion, critical comments.
[30] [31]
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