J Headache Pain (2002) 3:51–53 © Springer-Verlag 2002 BRIEF REPORT

Bruno M. Fusco A case of MELAS syndrome with typical cluster Mario Giacovazzo headache attacks: is it a causal or coincindental association?

Received: 7 June 2001 Abstract Many findings relate diagnosis was confirmed when a Accepted in revised form: 4 December 2001 migraine and cluster headaches to a point mutation (Leu mutation at genetic alteration, even if the site of position 3423 of mitochondrial the defect has not been identified. RNA) was found in the mitochondri- Some of these findings indicate an al gene. The recurrent periods, char- involvement of mitochondrial DNA, acterized by attacks of unilateral pain although some contrasting results and accompanied by homolateral B.M. Fusco ( ) have been reported. We describe a symptoms (e.g. tearing, palpebral Department of Pharmaceutical Science, University of Salerno, case of cluster headache occurring in ptosis, rhinorrea), did not leave any Via del Ponte Don Melillo, a patient with MELAS syndrome. doubt as to the diagnosis of cluster I-84084 Fisciano (SA), Italy The diagnosis of MELAS was sup- headache. We discuss whether the e-mail: [email protected] ported by the familiar anamnesis (the co-existence of MELAS and cluster Tel.: +39-089-962726 mother suffered from a similar headache was coincidental or causal. form), by the laboratory reports M. Giacovazzo Institute of Internal Medicine, (lacto-acidosis), by instrumental Key words Cluster headache • Second Faculty of Medicine, analysis (signs of encephalopathy on mtDNA • Lacto-acidosis • MELAS • La Sapienza University of Rome, magnetic resonance imaging) and by Mitochondrial disease Rome, Italy biopsy findings (myopathy). The

cate metabolic process, disruption of any mitochondrial or Introduction nuclear gene by mutation is likely to have impact on that organism. mtDNA is particular vulnerable to mutations [3]. MELAS, a syndrome characterized by myopathy, The inheritance of mitochondria-related diseases is more encephalopathy, lactic acidosis and stroke-like episodes, has complex than that of diseases due to genetic alterations of been related to an alteration in mitochondrial DNA the nucleus. A zygote receives a large number of organelles (mtDNA). Mitochondria are intracellular organelles which through the egg. Only few of them contain a mutation. are the sites of the oxidative phases of cell respiration [1]. During the early phases of life, cell division disperses the Mitochondria have their own DNA. In most eukaryotes, initial population of the mitochondria and new populations mtDNA exists as a double-stranded, closed circle which has of the organelles are reproduced by the original. Therefore, the capability to replicate. Mitochondrial genes have been if a mutation is present in some of the initial populations of identified to code 13 proteins that are essential to the cellu- mitochondria, the adult cell will have a variety of lar respiratory functions of the mitochondria [2]. Protein organelles, both normal and abnormal. This condition is encoded by intra-organelle genes act, along with proteins of called heteroplasmy [4]. nuclear origin, to guarantee the respiratory function of the Human disorders that are attributable to mutations of the mitochondria. Because cellular respiration is such an intri- mtDNA have to meet several criteria. They can be either 52 sporadic, when mutations occur in somatic cells, or inherit- and spread to the maxillary area. Pain was described as ed when the gene alteration is present in oocytic organelles. excruciatingly sharp. Accompanying symptoms usually Inheritance must exhibit a maternal rather than a mendelian described for cluster headache occurred, along with other pattern. The mtDNA alteration must produce a deficit in the (stroke-like) symptoms not usually associated. In particular, bio-energetic function of the organelle [5]. On the other conjunctival hyperemia, tearing, palpebral ptosis, and nasal hand, a disruption of mitochondrial function could also arise obstruction were always present on the same side as the from a nuclear gene alteration. Mitochondrial disorders can pain. These episodes matched the diagnostic crteria outlined be categorized as due to: primary mutations of DNA, either by the Ad Hoc Committee of the International Headache sporadic or maternally inherited; nuclear mutations which Society (IHS). In addition, hemiplegia, aphasia, and blind- provoke either direct alterations in mtDNA or intergenomic ness often occurred during the crises, and disappeared at the signalling defects; mendelian defects that affect the respira- end of the attacks. He reported that his mother suffered from tory chain in the absence of mtDNA mutations. The differ- an analogous form, with cluster headache-like attacks (even ence (if one exists) in the pathophysiology of these three if the pain intensity was described as significantly lighter) possibilities has not been determined [6]. accompanied by the same stroke-like symptoms (hemiple- MELAS is one of the major mitochondria-related gia, aphasia, amaurosis). It was not possible to evaluate if encephalomyopathies. MELAS has been related to a point other analogous cases occurred in his pedigree mutation resulting in the presence of leucine in position The personal anamnesis showed that before the occur- 3234 of mitochondrial tRNA [7]. rence of the cluster period, the patient had suffered from MELAS has been related to migraine, in as much as the stroke-like attacks that had the same duration as that of the symptomatology is often characterized by migraine-like accompanying headache. The chronological pattern of attacks (i.e. headache with nausea and vomiting). The rela- these pre-cluster episodes was not determined, occurring tionship between MELAS and migraine-like attacks and 5–6 times during a year. No other important pathologies the consideration that migraine could have a familiar were referred. The stroke-like attacks which occurred inheritance with a preferential maternal line have suggest- before the onset of the cluster headache-like disease were ed possible common elements at the basis of the two clin- similar to those present during the headache attacks. The ical entities [8]. One study showed that there was a high patient referred transitory (5–10 min) episodes of amauro- frequency of mitochondrial gene alterations (same Leu sis, with loss of coordination, hemiplegia and, sometimes, mutation) in a population of migraine patients [9]. These aphasia. findings were not confirmed by a subsequent investigation The general clinical investigation revealed a light [10], nor was an alteration in mtRNA found in cluster hypotrophy of the muscles with relative weakness. headache patients [11]. On the other hand Montagna [12] Neurological examination was normal. Neuroimaging tech- demonstrated, with spectroscopy resonance, an alteration niques documented the presence of encephalopathy, partic- of the neuronal cell respiratory function in cluster ularly at the posterior level (Fig. 1). No lesions were found headache patients, while Montagna et al. [13] described a in the hypothalamus. Electromyographic examination case of cluster headache with an extensive deletion of the demonstrated the myopathic alteration. Laboratory investi- mitochondrial genome. These findings support the hypoth- gation did not reveal any abnormal values. A significant esis of the hereditability of migraine and cluster headache. increase of lactic acid in the blood was found during the We described a case of a typical cluster headache feature in attacks. The basal values were 15 mg/dl 2 hours after the a subject with MELAS. crisis. They increased to 80–110 mg/dl during the crisis, and descended to 20 mg/dl at the end of the crisis Electrocardiographic features were not altered. A muscular biopsy was carried out in order to examine the mtDNA Case report along with the leucocytic mtDNA. The polymerase chain reaction (PCR) technique was applied to sequence the A 37-year-old man came to our observation at the headache DNA. A point mutation was found (cytosine to thymine). centre of Rome. He reported episodes of headache which The mutation was related to the Leu alteration in the tRNA occurred over a period of about 2 months. These periods re- at position 3243. occurred with a frequency of twice a year for 7 years. The last cluster headache-like period was treated with During these periods the occurrence of the headache attacks verapamil (oral dose of 80 mg, 3 times a day), which had an impressive chronological pattern: the attacks appeared to shorten the length of the florid phase (40 days). occurred every day at 1:00 a.m. and 4:00 p.m. Each attack The attacks were treated with oxygen, which only partially lasted about 45 minutes. The pain was localized in the left (30% as reported by the patient) attenuated the intensity of side, involved the orbit and the facial and parietal regions, the attack, whereas the duration was unaffected. 53

attacks were also characterized by an increase in lactic acid well above the normal level. The instrumental investiga- tion indicated the presence of encephalopathy and myopa- thy. The patient’s mother was affected by an analogous form of headache. The presence of a point mutation in the mtDNA confirmed the diagnosis of MELAS, with a possi- ble maternal inheritance. MELAS is often characterized by migraine-like attacks, and this had encouraged studies on the possible involvement of mtDNA in migraine. The only study which described an elevated frequency of mitochon- drial alterations was not confirmed by others which have followed. A survey carried out on cluster headache patients showed that their mtDNA was normal. Thus, an alteration of mtDNA in the common pathogenesis of migraine and cluster headache was excluded. On the other hand, evi- dence that the syndromes characterized by altered mtDNA could sometimes show migraine or cluster headache-like characteristics indicates that a dysfunction of the mito- chondria could contribute to the headache attacks. Our case is significant in this sense, as it occurred in a patient who has features of MELAS syndrome with typical cluster headache attacks. The high blood level of lactic acid observed only during the headache attacks is suggestive of an involvement of acidosis in the genesis of cluster headache. Acidosis could participate in the pathogenesis of Fig. 1 MR image showing an ischemic-like lesion at the cerebellar cluster headache at either a peripheral or central level. level (arrow) Peripherally, a decrease in pH could stimulate the nocicep- tive fibers that are putatively involved in genesis the clus- ter headache attacks. The proton (H+) is a potent activating Discussion stimulus of nocicpetive fibers. On the other hand, meta- bolic acidosis could interfere with central nervous system We described a patient with typical cluster headache function, in this case by evidentiating a hypothetical alter- attacks co-existing with stroke-like symptomatology. The ation of some central structures.

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