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Home , Cerebrovascular disease, Cluster headache, Meningeal biopsy, Thunderclap headache

Open access Review Vasc Neurol: first published as 10.1136/svn-2020-000333 on 26 March 2020. Downloaded from in cerebrovascular

Jiajie Lu ‍ , Wei Liu, Hongru Zhao

To cite: Lu J, Liu W, Zhao H. Abstract In fact, the relationship between headache Headache in cerebrovascular Headache is a common accompanying symptom of and cerebrovascular diseases is very compli- diseases. Stroke & Vascular cerebrovascular diseases. The most common patterns of cated. Headache can be the prodromal or 2020;0. doi:10.1136/ headache for different cerebrovascular disorders, aetiology svn-2020-000333 core symptom, and also a risk factor of them. and pathogenesis and diagnostic workup are reviewed In this paper, we will discuss the clinical with emphasis on distinguishing characteristics. It will JL and WL are joint first authors. characteristics of common cerebrovascular be a clinical guide for physicians who treat patients with diseases that may be associated with head- Received 10 January 2020 headache or cerebral vascular . Revised 3 March 2020 ache, and hope to provide a reference for Accepted 9 March 2020 clinical practice. are divided into primary head- aches, secondary headaches, painful cranial neuropathies, other facial pain and other Headache can manifest as a major headaches according to the Third Edition of symptom of craniocervical vascular the International Classification of Headache disease 1 Diseases (ICHD-3). In many of these conditions, such as ischaemic , tension-­type headache and or haemorrhagic stroke, headache is over- are major primary head- shadowed by focal signs and/or disorders of aches (table 1). consciousness. Headaches associated with Item 6 in ICHD-3 is the headache attributed ischaemic stroke have no special features, to cranial and/or cervical vascular disorder. which can be ipsilateral or bilateral, mild to It includes headaches attributed to cerebral moderate intensity and often recover within ischaemic events, non-­traumatic intracranial 3 months.2 It is more common in posterior haemorrhage, unruptured vascular malfor- circulation than in anterior circulation. In mation, arteritis (such as giant cell arteritis, haemorrhagic stroke, headache is usually primary or secondary angiitis of the central severe and torturous. It can be maximal on (CNS)), cervical carotid or the day of its onset and localised in accord- vertebral disorder (such as cranial ance with the site of the haemorrhage. Some venous disorder, other acute intracranial cerebrovascular diseases can cause headache http://svn.bmj.com/ arterial disorder, chronic intracranial vascu- and stroke simultaneously, such as subarach- lopathy (eg, cerebral autosomal dominant noid haemorrhage (SAH), CNS vasculitis, arteriopathy with subcortical infarcts and artery , cerebral venous leucoencephalopathy (CADASIL) or mito- (CVT), and so on, in which headache is usually chondrial encephalomyopathy, lactic acidosis a warning symptom. Therefore, it is essential and stroke-­like episode syndrome (MELAS)) to be aware of the relationship between head- and . ache and cerebral vascular diseases, so that on October 1, 2021 by guest. Protected copyright. Headache attributed to cranial and/or we can timely identify causes and intervene cervical vascular disorder is usually acute in as soon as possible to avoid serious conse- onset, throbbing or thunderclap in nature, quences (table 2). peaking rapidly and sometimes does not accompany any other local symptoms and Subarachnoid haemorrhage signs. Therefore, it is very important to collect rupture is the major cause of non-­ © Author(s) (or their detailed history, such as the way of onset, the traumatic SAH, accounting for 85% of all employer(s)) 2020. Re-­use site, the nature and the intensity of headache SAHs, whereas 10% of SAH cases are classi- permitted under CC BY-­NC. No fied as idiopathic perimesencephalic haemor- commercial re-­use. See rights and whether it is accompanied with nausea or and permissions. Published by . In addition, history, family history rhage. The remaining cases include intracra- BMJ. and history of are also crucial. nial arterial dissection, vascular malformation, Neurology, First Affiliated CT or MRI of , CVT and reversible cerebral vasoconstriction Hospital of Soochow University, (TCD), digital subtraction angiography syndrome (RCVS).3 is Suzhou, Jiangsu, China (DSA), and genetic testing the most common symptom of SAH, in which 4 Correspondence to are other optional examinations that may be mortality is 30%–40%. It is a sudden, severe, Dr Hongru Zhao; needed for identifying the possible under- usually stabbing pain, reaching maximal tiantan11@​ ​163.com​ lying causes. intensity in less than 1 hour and lasting for

Lu J, et al. Stroke & Vascular Neurology 2020;0. doi:10.1136/svn-2020-000333 1 Open access Stroke Vasc Neurol: first published as 10.1136/svn-2020-000333 on 26 March 2020. Downloaded from Table 1 Primary headaches and characteristics Types Characteristics Migraine Unilateral location, pulsating quality, moderate or severe intensity, aggravation by routine physical activity, association with nausea and/or and phonophobia, lasting from 4 to 72 hours. Tension-­type Bilateral, pressing or tightening in quality and mild-­to-­moderate intensity, lasting from 30 min to 7 days. headache Cluster Severe in intensity, strictly unilateral to the orbital, supraorbital and temporal area or in any combination of headache these sites, lasting 15–180 min and occurring from once every other day to eight times a day. days or weeks. However, initial misdiagnosis occurs in one-­ thickening of vessel walls with alternating segments of quarter to one-half­ of patients, which is usually misdiag- stenosis can occur, resulting in poor blood circulation. nosed as migraine. So great attention must be paid to the On the other hand, weakened vessel walls can lead to sudden onset, high intensity and the description of the ruptured vessels due to an inflammatory process. extreme pain. The attack of thunderclap headache may PACNS is a rare and severe inflammatory disease. also be associated with nausea or vomiting (77% of cases), Retrospective analysis showed that there was no signifi- transient loss of consciousness (53% of cases) and nuchal cant difference in prevalence between men and women. 5 rigidity (35% of cases). SAH occurs during stressful It accounts for about 1% of all vasculitis, its annual inci- events, such as physical exertion or emotional stress, in dence is around 2.4 cases per 1 million people and has about half of the patients. However, these features are not no gender differences.6 The clinical features of PACNS specific to SAH. Following , analysis are non-­specific, which increases the difficulty of diag- of the , CT scan and lumbar puncture nosis. Patients may start with acute stroke, one or more help us get final diagnosis. episodes, or subacute onset with chronic headache, 7 CNS vasculitis , chronic or changes in personality. CNS vasculitis is a kind of disease that causes inflamma- Headache is characterised by insidious or subacute onset. tion and destruction of brain, and meningeal The pain usually manifests as a chronic process that lasts vessels. It is divided into primary vasculitis and secondary for months as the disease progresses. Initially, the inten- vasculitis. Primary angiitis of the sity is usually of mild to moderate, but it can deteriorate (PACNS) is defined when vasculitis is confined to the or improve over time; sometimes, headache is associated CNS and no other system is involved. Vasculitis is consid- with cervical pain. Thunderclap headache is almost never ered secondary when it occurs during systemic inflamma- reported, and the absence of such sudden attack helps tion or infection. The pathophysiological mechanism is distinguish PACNS from acute neurological conditions

that infiltration of immune cells within CNS like RCVS and SAH. Headache alone is of little diag- http://svn.bmj.com/ walls leading to destruction of the vessel walls. As a result, nostic value, but PACNS should be considered in young

Table 2 Headache attributed to cerebrovascular diseases with clinical and diagnostic features Types Headache features Diagnostic features SAH Thunderclap, acute, severe, long-­ Non-­contrast-­enhanced CT: sensitivity 99% in the first on October 1, 2021 by guest. Protected copyright. lasting 6 hours, CSF: erythrocytes or PACNS Chronic, moderate, diffuse, long-­ CSF: lymphocyte and protein increases, MRI: ischaemic lasting lesions in subcortical and deep and grey matter CAD Thunderclap, acute, unilateral CT or MRA: long, irregular stenosis, an occlusion or a dissecting aneurysm CVT Acute or subacute, diffuse, long-­ MRI: detect brain parenchymal lesions; CT/CTV: high density lasting consistent with the position of venous sinus MELAS Migrainous headaches, short-lasting,­ MRI: lace sign or ribbon sign mild or moderate CADASIL Migraine with (atypical) MRI: white matter hyperintensities in the anterior temporal pole, lacunes; genetic testing: NOTCH3 mutation RCVS Thunderclap, acute, severe, relapsing Angiography: segmental narrowing of branches of cerebral

CAD, cervical artery dissection; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy; CSF, ; CTV, CT venography; CVT, cerebral venous thrombosis; MELAS, mitochondrial encephalomyopathy, lactic acidosis and stroke-­like episode syndrome; MRA, magnetic resonance angiography; PACNS, primary angiitis of the central nervous system; RCVS, reversible cerebral vasoconstriction syndrome; SAH, subarachnoid haemorrhage.

2 Lu J, et al. Stroke & Vascular Neurology 2020;0. doi:10.1136/svn-2020-000333 Open access Stroke Vasc Neurol: first published as 10.1136/svn-2020-000333 on 26 March 2020. Downloaded from adults without cerebrovascular risk factors when they CAD can be identified by a variety of different imaging present a history of subacute or chronic headache with modalities including CT angiography (CTA), MRI and focal deficits, , altered cognition or disorders of DSA. Each of them offers their own advantages and consciousness. disadvantages based on the clinical scenario. Therefore, At present, no specific laboratory indicators are used the final diagnosis of carotid artery dissection should be to diagnose PACNS. Cerebrospinal fluid examination is made by combining the medical history, clinical manifes- an important diagnostic tool. In most cases of PACNS tations and dynamic imaging findings. confirmed by tissue biopsy, the content of lymphocyte and protein in cerebrospinal fluid increases, and the sugar Cerebral venous thrombosis content is normal.8 The most common imaging mani- CVT is a special type of charac- festation is , which usually develops terised by obstruction of cerebral venous reflux, often on both sides, involving the cortex, subcortex and accompanied by intracranial . The annual 15 . White matter hyperintensities are common incidence of CVT is 1/250 000. CVT is a common cause in the T2-weighted­ image/fluid attenuated inversion of cerebrovascular diseases in young people. The age of recovery phase of magnetic resonance. The gold standard onset is mostly between 20 and 50 years old. The ratio of diagnosis of PACNS is that subcortical combined with of male to female is 1–1.5:5, which is the result of sex-­ soft meningeal biopsy finds primary vascular transmural specific risk factors such as oral contraceptives, preg- damage and vascular destructive inflammatory response. nancy and puerperium. About 85% of patients have one or more risk factors, including hereditary or secondary 16 Artery dissection thrombogenic tendency (eg, factor V Leiden mutation, thrombin G20210A mutation, protein C, protein S or Cervical artery dissection (CAD) is divided into internal antithrombin III deficiency), pregnancy, postpartum or carotid artery dissection and dissection oral contraceptives, acute or chronic infections or inflam- (VAD), in which blood flows into the wall of the cervical matory diseases, blood system diseases, tumours or inju- artery to form an intramural haematoma, which leads to ries, but some patients have unknown causes. stenosis, occlusion or aneurysmal changes of the artery. CVT can present four clinical syndromes: isolated Carotid dissection is the cause of stroke in 20% of young intracranial hypertension, focal neurological deficit, people. The average age of onset is 44 years.9 The patho- diffuse and cavernous sinus syndrome. physiological mechanism of dissection is still unclear. Severe headache is the first and most common symptom Hypertension, migraine (especially migraine without 17 of CVT and reported by 60%–90% of patients. aura), neck trauma and new infections (intracranial or Headache associated with CVT is elicited by intracra- systemic infections) are considered risk factors for carotid 10 nial hypertension. It has no specific features, but it is artery dissection. In most cases, headache and neck pain usually diffuse, progressive and severe, and associated can be the initial symptoms. The headache or neck pain with other signs of intracranial hypertension. It can be is likely caused by the direct tear in the blood vessel wall. unilateral and sudden (even thunderclap), or mild, and http://svn.bmj.com/ Blood vessels, like arteries, have many nerves surrounding sometimes mimics migraine. It worsens with manoeu- them. Irritation of the vessel wall likely leads to a series vres that increase and is usually of events, including proinflammatory neurotransmitters refractory to common analgesics.18 Headache often from the perivascular nerve terminals. This may cause 11 accompanies with focal neurological symptoms, but in pain away from the area of the dissection. A retrospec- 10% of patients can be the only symptom.19 Thirty to tive study of carotid artery dissection and VAD found that forty per cent of patients develop acute symptomatic on October 1, 2021 by guest. Protected copyright. 12 57% of patients had headache symptom. Headache asso- seizures, with approximately 80% of seizures occur- ciated with CAD has no special manifestation and some- ring actually before the diagnosis has been established. times it mimics other headaches such as migraine, cluster Superficial venous system thrombosis and brain paren- headache or thunderclap headache. Headache is often chymal lesions generally have focal neurological deficit acute and continuous for days or longer, and located at while deep venous system thrombosis often presents the same side of the affected cervical vessel. If the patient mental disorder, gaze paralysis, diffuse encephalopathy only suffers from neck pain, the degree is often mild to or coma.20 Given the absence of specific characteristics moderate, and if he has headache with or without neck of headache caused by CVT, it should be considered in 13 pain, the intensity is usually moderate to severe. Head- the patients with recently persistent headache, espe- ache is more common in posterior circulation stroke than cially in the presence of a potential prethrombotic state. in anterior circulation, and the reasons have been spec- The diagnosis of CVT depends more on imaging. ulated as follows. First, there are more dense vessels and Magnetic resonance venography (MRV) and CT venog- abundant distribution in the posterior raphy (CTV) are both appropriate for diagnosis of CVT, circulation system; second, the posterior cerebral arteries but the former has more advantages for the visualisation and superior cerebellar arteries supply part of the dura of brain parenchymal lesions. In theory, DSA is still the mater; third, the posterior circulation vessels might be gold standard for the diagnosis of CVT. However, it is not more susceptible to spreading depolarisations.14 routinely used because of its invasiveness and the risk

Lu J, et al. Stroke & Vascular Neurology 2020;0. doi:10.1136/svn-2020-000333 3 Open access Stroke Vasc Neurol: first published as 10.1136/svn-2020-000333 on 26 March 2020. Downloaded from of increased intracranial pressure caused by improper the ages of 20 and 30. Motor dysfunction, apathy, execu- operation. Diagnostic accuracy of CTV and MRV for the tive dysfunction and dementia caused by ischaemic stroke cerebral venous system diseases is higher. MRV with GRE often occur between the ages of 40 and 70.26 Although (gradient recalled echo) or SWI (susceptibility weighting other types of migraine have been reported, the most imaging) sequences can maximise diagnostic accuracy, common type of headache in 40% of cases is migraine especially in patients with acute CVT and suspected with aura (MA).27 MA in CADASIL is the most commonly isolated cortical venous thrombosis.21 typical aura with visual or sensory symptoms. Frequency of migraine can vary, but a majority of patients have less Mitochondrial encephalomyopathy, lactic acidosis and stroke- than one attack per month, as high as 80% in one 2015 like episode syndrome study.28 Women with CADASIL are more likely to have MELAS is the most common maternal hereditary mito- migraine aura than men. The characteristics of migraine chondrial encephalomyopathy. It is associated with mito- are different from those of the general population. The chondrial DNA and nuclear DNA (nucleus) gene aura period is longer and more complex. Nowadays it mutations, which causes the disorder of mitochondrial is recognised that MA is an undisputed risk factor for protein synthesis and oxidative phosphorylation. The age ischaemic stroke. Several mechanisms like genetic predis- 22 of onset is generally under 45 years old. Eight-­four to position, hypercoagulability, increased platelet aggre- ninety-­nine per cent of patients have stroke-like­ seizures. gability, hyperviscosity, and so on are speculated to be Fifty-­four to ninety-one­ per cent of patients present with involved.29 In CADASIL, up to 70% biopsy-­confirmed pulsatile headache accompanied with frequent vomiting. patients have ischaemic events, which tend to occur The migrainous headaches can precipitate stroke-like­ repeatedly and manifest in many ways. episodes. On the other hand, the headache attack is The diagnosis of CADASIL in patients with head- more severe during the stroke-­like episodes. In most of ache can be particularly challenging, as headache may the patients, headaches were short-lasting­ and often mild 23 precede other clinical or radiographic clues. For young or moderate intensity. The high prevalence of migraine patients with MA, ischaemic events, psychiatric symp- in MELAS is independent of sex, phenotype or genotype. toms and progressive cognitive impairment, CADASIL , and stroke-like­ episodes are more should be fully considered. The latest diagnostic frequent in MELAS cases with migraine than without criteria proposed by Japan are that the age of onset migraine. Moreover, migraine is a phenotype of MELAS is less than 55 years old; at least two clinical manifes- and an early manifestation of mitochondrial respiratory 24 tations are accorded with: subcortical dementia, long chain dysfunction in the CNS. bundle sign, , stroke-­like attacks with The level of lactic acid in blood and cerebrospinal fluid focal neurological deficits, mood disorders, migraine; and the lactic acid peak in magnetic resonance spectros- autosomal dominant inheritance; white matter lesions copy are important evidence for patients suspected of involving the anterior temporal lobe detected by MRI MELAS. The brain MRI of patients with MELAS often

and CT; excluding white matter malnutrition; muta- http://svn.bmj.com/ shows diffusion limited in temporal, parietal and occip- tions in exons 2–24 that result in the acquisition or ital cortex during stroke-­like attack, which means layered deletion of cysteine residues; and GOM (granular necrosis, also called ‘lace sign’ or ‘ribbon sign’. Some osmiophilic material) is found under pathological elec- patients had basal nucleus calcification, brain atrophy tron microscopy.30 and ventricular enlargement. The characteristic morpho- logical changes of muscle biopsy in patients with MELAS display typical ragged-­red fibres by modified Gomori Reversible cerebral vasoconstriction syndrome on October 1, 2021 by guest. Protected copyright. staining, and strong succinate dehydrogenase (SDH) RCVS was first reported in 1988 by Call and Fleming. It reactive blood vessels by SDH staining. From the molec- used to be called Call-­Fleming syndrome. RCVS often ular genetic mechanism, genetic mutation at site of presents as a recurrent episode of severe thunderclap A3243G in the MT-­TL1 gene encoding tRNA was found headache, and accompanied by diffuse segmental stenosis in 80% of patients with MELAS, and mutations at site of of intracranial artery, which can recover within 3 months. T3271C or A3252G can also cause MELAS.25 The pathogenesis of headache may include reversible dysregulation of cerebral arterial tone, autonomic over- 31 Cerebral autosomal dominant arteriopathy with subcortical activity, endothelial dysfunction and oxidative stress. infarcts and leucoencephalopathy The peak age of RCVS is 42 years old and is considered 32 CADASIL associated with subcortical infarction and a common cause of stroke in young adults. The under- leucoencephalopathy is a non-­atherosclerotic arteriop- lying causes of RCVS are unclear, but there are many athy caused by Notch 3 gene mutation and is the most triggers involved. Common causes include drug expo- common cause of hereditary stroke in adults. The clinical sure (selective serotonin reuptake inhibitors, phenyl- features include migraine, psychiatric symptoms, progres- propanolamine, pseudoephedrine, cyclophosphamide, sive cognitive decline and recurrent stroke. Migraine tacrolimus), marijuana use, pregnancy and puerperium, usually occurs before the age of 20, and white matter blood transfusion, head trauma, cervical or spinal cord abnormalities in T2 phase on MRI are common between injury, , and so on.33

4 Lu J, et al. Stroke & Vascular Neurology 2020;0. doi:10.1136/svn-2020-000333 Open access Stroke Vasc Neurol: first published as 10.1136/svn-2020-000333 on 26 March 2020. Downloaded from Thunderclap headache is usually recurrent in a few and license their derivative works on different terms, provided the original work is days or weeks, often bilateral and lasting about 1–3 hours, properly cited, appropriate credit is given, any changes made indicated, and the use is non-­commercial. See: http://​creativecommons.org/​ ​licenses/by-​ ​nc/4.​ ​0/. accompanied by nausea and vomiting. Headaches are often caused by exertion, sexual activity, Valsalva ORCID iD manoeuvre, mood, bath and/or shower. Seventy-five­ Jiajie Lu http://orcid.​ ​org/0000-​ ​0002-0865-​ ​8240 per cent of patients have headache accompanied with fluctuating focal neurological dysfunction and epileptic seizures. Acute headache caused by RCVS may be a References warning sign before stroke.34 Although thunderclap 1 Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders. headache is similar to RCVS and SAH, a few details help In: Cephalalgia. . 3rd ed, 2018: 38. 1–211. distinguish between them: they have common onset and 2 Oliveira FAA, Sampaio Rocha-­Filho PA. Headaches attributed localisation, but in RCVS, headache lasts for up to 3 hours to ischemic stroke and transient ischemic attack. Headache 2019;59:469–76. while in SAH it can last for days or weeks; in contrast 3 Ducros A, Bousser M-­G. Thunderclap headache. BMJ to the numerous episodes of RCVS, single episodes are 2013;346:e8557. 4 Sherlock M, Agha A, Thompson CJ. Aneurysmal subarachnoid usually described in SAH. hemorrhage. N Engl J Med 2006;354:1755–7. DSA is still the gold standard for its diagnosis. The 5 Yang C-W­ , Fuh J-­L. Thunderclap headache: an update. Expert Rev sensitivity of brain CTA/magnetic resonance angiog- Neurother 2018;18:915–24. 6 Salvarani C, Brown RD, Christianson T, et al. An update of the Mayo raphy in the diagnosis of RCVS is about 80%. Typical clinic cohort of patients with adult primary central nervous system manifestations are multiple beaded stenosis of intracra- vasculitis: description of 163 patients. 2015;94:e738. 7 Hajj-­Ali RA, Calabrese LH. Diagnosis and classification of central nial vessels, most of which last 1–2 weeks after headache nervous system vasculitis. J Autoimmun 2014;48-49:149–52. attack. TCD can dynamically detect intracranial blood 8 Beuker C, Schmidt A, Strunk D, et al. Primary angiitis of the central flow rate, which is of great significance in displaying nervous system: diagnosis and treatment. Ther Adv Neurol Disord 35 2018;11:1756286418785071. cerebral vasospasm. 9 Giannini N, Ulivi L, Maccarrone M, et al. Epidemiology and In order to improve the diagnostic accuracy of RCVS, cerebrovascular events related to cervical and intracranial arteries dissection: the experience of the city of Pisa. Neurol Sci a new diagnostic score RCVS2 has been developed. The 2017;38:1985–91. scores include R (recurrent or single thunder-­like head- 10 Debette S. Pathophysiology and risk factors of cervical artery ache, positive predictor), C (intracranial involvement, dissection: what have we learnt from large hospital-­based cohorts? Curr Opin Neurol 2014;27:20–8. negative predictive factor), V (vasoconstriction, posi- 11 Sheikh HU. Headache in intracranial and cervical artery dissections. tive predictive factor) and S (gender and SAH, positive Curr Pain Headache Rep 2016;20:8. 12 Diamanti S, Longoni M, Agostoni EC. Leading symptoms in predictor), ranging from −2 to 10, and 10 means prob- cerebrovascular diseases: what about headache? Neurol Sci able RCVS. The combination of clinical features and 2019;40:147–52. imaging results is necessary for the diagnosis of RCVS.36 13 Gallerini S, Marsili L, Bartalucci M, et al. Headache secondary to cervical artery dissections: practice pointers. Neurol Sci 2019;40:613–5. 14 Wang Y, Cheng W, Lian Y, et al. Characteristics and relative factors

of headache caused by cervicocerebral artery dissection. J Neurol http://svn.bmj.com/ Summary 2019;266:298–305. In a word, we need to keep in mind the relationship 15 Devasagayam S, Wyatt B, Leyden J, et al. Cerebral venous between headache and cerebrovascular diseases. When it sinus thrombosis incidence is higher than previously thought: a retrospective population-­based study. Stroke 2016;47:2180–2. comes to the condition in which headache presents as a 16 Lauw MN, Barco S, Coutinho JM, et al. Cerebral venous thrombosis major symptom, especially acute in onset, throbbing or and thrombophilia: a systematic review and meta-­analysis. Semin Thromb Hemost 2013;39:913–27. thunderclap in nature and peaking rapidly, we need to 17 Silvis SM, de Sousa DA, Ferro JM, et al. Cerebral venous thrombosis. consider the possibility of following diseases such as SAH, Nat Rev Neurol 2017;13:555–65. on October 1, 2021 by guest. Protected copyright. 18 Cumurciuc R, Crassard I, Sarov M, et al. Headache as the only CAD, CVT, RCVS, and so on. A comprehensive combi- neurological sign of cerebral venous thrombosis: a series of 17 nation of characteristics of headache, detailed medical cases. J Neurol Neurosurg Psychiatry 2005;76:1084–7. history, physical examination and necessary laboratory 19 Mehta A, Danesh J, Kuruvilla D. Cerebral venous thrombosis headache. Curr Pain Headache Rep 2019;23:47. and imaging examinations are very important for identi- 20 Ferro JM, Canhão P, Bousser M-­G, et al. Early seizures in fying the aetiology. Good prognosis is based on clear aeti- cerebral vein and dural sinus thrombosis: risk factors and role of antiepileptics. Stroke 2008;39:1152–8. ology and individualised precise treatment. 21 Coutinho JM, Gerritsma JJ, Zuurbier SM, et al. Isolated cortical vein thrombosis: systematic review of case reports and case series. Contributors JL and WL proposed the overall structure and drafted the Stroke 2014;45:1836–8. manuscript. HZ provided critical feedback and helped shape the manuscript. All 22 Marques-Matos­ C, Reis J, Reis C, et al. Mitochondrial authors contributed to the final version of the manuscript. encephalomyopathy with lactic acidosis and strokelike episodes presenting before 50 years of age: when a stroke is not just a stroke. Funding The authors have not declared a specific grant for this research from any JAMA Neurol 2016;73:604–6. funding agency in the public, commercial or not-­for-­profit sectors. 23 Kraya T, Deschauer M, Joshi PR, et al. Prevalence of headache in patients with : a cross-­sectional study. Competing interests None declared. Headache 2018;58:45–52. Patient consent for publication Not required. 24 Vollono C, Primiano G, Della Marca G, et al. Migraine in Provenance and peer review Commissioned; externally peer reviewed. mitochondrial disorders: prevalence and characteristics. Cephalalgia 2018;38:1093–106. Open access This is an open access article distributed in accordance with the 25 El-Hattab­ AW, Adesina AM, Jones J, et al. Melas syndrome: clinical Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which manifestations, pathogenesis, and treatment options. Mol Genet permits others to distribute, remix, adapt, build upon this work non-commercially­ , Metab 2015;116:4–12.

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6 Lu J, et al. Stroke & Vascular Neurology 2020;0. doi:10.1136/svn-2020-000333