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Original Article
Aura status: A not so frequent aura
Cephalalgia 0(0) 1–13 ! International Headache Society 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0333102414530525 cep.sagepub.com
Ana Alagoa Joa˜o1, Tomas B Goucha2,3 and Isabel P Martins1 Abstract Background: Migraine aura status is a variety of migraine aura with unvalidated research criteria. Aim and methods: We conducted a systematic review of published cases and a retrospective analysis of 500 cases of migraine with aura to evaluate the applicability and clinical features of ICHD-III beta criteria, compared to a more liberal definition for its diagnosis: 3 aura episodes for up to three consecutive days. Results: Many publications under this title correspond to persistent or formerly designated prolonged auras. Nine cases fulfilled ICHD-III beta status criteria. In our series, either 1.7% or 4.2% cases fulfilled ICDH-III beta or our definition, respectively. Regardless of the criteria, aura status patients were older at onset of status than those with typical aura, had a predominance of visual symptoms, normal neuroimaging and no sequelae. Status recurred in a few. Conclusion: Both criteria identify a similar population in terms of age, gender, main symptoms, imaging and outcome. Since patients with closely recurring auras might raise the same approach independently of the criteria, the use of more liberal criteria will allow more cases for detailed diagnosis and therapeutic analysis, eventually leading to the identification of subtypes. Keywords Migraine aura status, migraine diagnosis, ICHD-III beta, headache classification Date received: 6 September 2013; revised: 1 January 2014; accepted: 12 March 2014
Introduction Migraine auras might assume unusual temporal profiles, namely as recurrent bursts of attacks during a short period of time. This phenomenon, designated migraine aura status, was mentioned at least 30 years ago by Haas, 1982 (1) and described as aura episodes occurring ‘‘ . . . several times in a row over several days in a ‘flurry’ and then disappear for several weeks only to recur in another ‘flurry’’’ (2). As previously underlined by some authors (3), this syndrome should not be confused with status migranosus, a debilitating migraine headache lasting for more than 72 hours (with or without aura), with persistent aura without infarction nor with syndromes characterized by probable migraine with prolonged aura, as there are no aura-free intervals in those conditions. Since migraine auras frequently involve visual and sensory symptoms and are not always followed by a headache, their presentation can be confused with visual epilepsy or clustering transient ischemic attacks (TIAs), particularly in older patients with additional sensory symptoms or speech disturbances. Migraine aura status is listed in the Appendix of the International Classification of Headache Disorders-III
beta (ICHD-III beta) (4) as a novel entity that has not been sufficiently validated by research. Indeed, the criteria proposed seem to have little empirical basis, particularly regarding the precise cut-off in terms of the frequency of attacks required for its diagnosis (at least two auras occurring per day, for three or more days). Given the rarity of this syndrome, it is possible that published reports might have been biased toward the most severe cases and that the proposed criteria might be too strict. The aim of this article is to analyze the extant published data on aura status and to challenge the 1 Department of Clinical Neurosciences, Instituto de Medicina Molecular (IMM), Faculty of Medicine (IMM) University of Lisbon, Portugal 2 Max Planck Institute for Human Cognitive and Brain Sciences, Department of Neuropsychology, Germany 3 Berlin School of Mind and Brain, Humboldt University, Germany
Corresponding author: Isabel Pavao Martins, Department of Neurosciences, Lisbon Faculty of Medicine, Instituto de Medicina Molecular, Hospital de Sta Maria 1600 Lisboa, Portugal. Email: [email protected]
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2 proposed diagnostic criteria, comparing them with a broader definition, resulting from our clinical experience, previous studies on late-life aura—an age group in whom repeated auras often occur (5)—and on the recurrence of transient neurological phenomena (6). With that purpose, we conducted a systematic review of published cases of aura status and performed a retrospective analysis of a personal series of patients with migraine with aura (MA) in order to identify cases with status and estimate its frequency, demographic and clinical features. Additionally, we compared cases defined according either to the ICHD-III beta criteria or fulfilling our definition, with cases of typical migraine aura or probable migraine with prolonged aura, to determine if a change in criteria resulted in a significantly different clinical profile.
Methods Systematic review of migraine aura status cases We conducted a systematic review of the literature published in English and French up to July 2013 through a search of Medline/PubMed and the Cochrane Library, using the terms aura status, repeated or recurrent migraine aura and repeated or recurrent aura attacks. Among those describing cases in adults (above 18 years of age), articles were selected by title and abstract. Selected abstracts were then reviewed by two authors and full articles were accessed for data collection. Cases identified by their authors as migraine aura status or presenting with frequently recurring aura attacks during a short period of time were gathered and the following data were collected: patient’s gender, age at consultation and at aura onset, type of aura symptoms (categorized as visual, sensory, speech disturbances, other or multiple), frequency of attacks, underlying pathology and sequelae.
Retrospective review of personal clinical data Our study population consists of the last 500 adult patients clinically diagnosed with MA by a neurologist (IPM) in the setting of a tertiary headache outpatient clinic. Patients’ files were checked for the diagnostic criteria of MA according to the ICHD-III beta (4), and the following data were collected from the clinical records: patient’s gender, age at consultation and at aura onset [categorized as early (0–14 years), youth (15–29 years), adult (30–44 years) and late (45 or more years)], aura type (visual, sensory, speech disturbances or other symptoms) and duration. Cases were distributed into five categories according to the type and duration of aura symptoms: typical (five to 60 minutes), prolonged (more than 60 minutes and
Cephalalgia 0(0) less than one week per symptom), persistent aura without infarction (lasting for one week or more without evidence of infarction on neuroimaging), hemiplegic (including motor weakness) and aura status. Although the latest ICHD-III beta classification does not include the diagnosis of prolonged aura and those episodes are now included under the code 1.5.2., ‘‘probable migraine with aura (prolonged aura)’’, we kept that designation in this study as it has been extensively used in previous publications. Furthermore, a recent systematic review indicates that nonhemiplegic auras lasting more than 60 minutes might occur occasionally among subjects with typical auras (7). Patients were additionally classified as having aura status if the following operational criteria were present: there should be a minimum number of three aura episodes distributed in up to three consecutive days (3 episodes in 3 days). This statement comprises two possibilities: 1) if the episodes cluster in a single day, there should be, at least, three episodes in that day; 2) if they are distributed in a larger period of time, there should be, at least, three consecutive days with a total number of three or more episodes. For example, two attacks in one day plus some more in the following days (3 þ 0 þ 0, 2 þ 1 þ 0, 1 þ 2 þ 0, 1 þ 1 þ 1, minimum). Compared to the ICHD-III beta criteria, these are more liberal concerning the number of episodes per day and the duration of the status period, admitting a shorter duration and adjusting the number of episodes to the number of days (for example six in a single day). Demographic features were compared among aura syndromes and individual cases of aura status were further described in detail. In addition, we compared cases fulfilling our operational criteria for aura status and those fulfilling the ICHD-III beta criteria with cases of migraine with typical or prolonged auras.
Statistical analysis Patients with aura status were compared with those with typical aura using either diagnostic criteria. Continuous variables were compared with the Student’s t test for independent samples and Chi Square test or Wilcoxon-Mann-Whitney test for categorical variables, with a significance level 2/day for at least 5 days
Intermittent (‘‘several times an hour, hour after hour, day after day’’), for 5 weeks Up to 100/day, for 8 weeks
Frequency of aura episodes
Episodes up to the age of 76
No episodes at 10-month follow-up
No episodes at 18-month follow-up
Unknown
No episodes after oral acetazolamide treatment
No episodes at 2-month follow-up
Rare momentary visual symptoms
Recurrence of status
Normal ophthalmological and neurological exams, bMRI and bMRA
Hyperhomocysteinaemia Normal bCT, bMRI and tDoppler
aHT (treated with ACEi) Hyperhomocysteinemia Normal bCT and transcranial Doppler (tDoppler) bMRI showed subcortical white matter hyperdensities (T2)
Normal bCT EEG showed occipital slow waves
Normal neuroimaging, (bCT or bMRI) and EEG
Normal ophthalmological and neurological exams, bCT and EEG Normal ophthalmological and neurological exams
Other clinical findings
bCT: brain computed tomography; EEG: electroencephalogram; bMRI: brain magnetic resonance imaging scan; aHT: arterial hypertension; ACEi: angiotensin-converting-enzyme inhibitor; bMRA: brain magnetic resonance angiography scan. aAura symptoms listed in order of appearance.
Reinecke and Silberstein, 2007 (10)
Female, 25
8
Female, unknown
6 Male, 12
Male, unknown
5
7
Female, unknown
4
Under 30
18
70
Age at status onset
(CEP)
Cupini and Stipa, 2007 (9)
Female, youth
2
3
Male, early adolescence
1
Haas, 1982 (1)
Haan et al., 2000 (3)
Male, adulthood
Case nr.
Author, year
Gender, age at aura onset
Table 1(a). Systematic review: Status patients without underlying pathology.
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4 Cephalalgia 0(0)
Male, 73
Male, 82
11
12
13
14
Klingbiel et al., 2008 (12)
Kleinig et al., 2008 (13)
Male, 85
Male, 79
15
16
Male, 62
No
No
No
No
No
No
No
Previous MA
Sensory, paresis
Sensory
Sensory, paresis, dysarthria
Sensory
Paresis
Paresis, aphasia, visual
Visual
Aura-like symptomsa
3 in 2 days (not followed by headache)
6 in 2 days (not followed by headache)
6 in 2 days (not followed by headache)
7 in 2 days (not followed by headache)
Up to 10 in 3 days (not followed by headache)
Up to 10 attacks/day (not followed by headache)
1–3 attacks/day for some weeks (followed by headache)
Frequency of aura episodes
Lung cancer, coronary and peripheral vascular disease, heart failure and essential thrombocytosis, high grade left carotid stenosis on aspirin Normal neurological exam, EEG and EcoCG bCT revealed SH
aHT, coronary disease and dyslipidemia Normal neurological exam, EEG and EcoCG bCT and bMRI showed SH
aHT, on antiplatelet therapy bMRI showed SH, WM disease and cortical hemorrhages; GE showed cortical siderosis Normal DWI
aHT, AF on warfarin bMRI showed SH and WM disease; microbleeds demonstrated by GE sequences Normal MRA, DWI and EEG aHT, diabetes, previous TIAs on warfarin bMRI showed acute SH and WM disease; Microbleeds evident on GE sequences Normal DWI and EEG
aHT, obesity bCT normal on admission, later showed hypodensity in the left frontal region Duplex US and DSA showed 95% left ICA stenosis
aHT, diabetes Normal neurologic, ophthalmological exams and bCT bMRI revealed a right occipital lobe tumor
Other clinical findings
Alagoa Joa˜o et al. (continued)
Clopidogrel No episodes, on a 7-month follow-up
Phenytoin Continued aspirin and clopidogrel No episodes, on a 16-month follow-up
No episodes, after antiplatelet therapy cessation
Valproate, no recurrence after 6 months
Valproate (symptoms decreased) Prednisolone (episodes ceased)
Clearance of symptoms after thrombendarterectomy
Phenytoin 300 mg/day Corticosteroids (patient refused surgery) No episodes, on a 6-month follow-up
Treatment and recurrence of status
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Izenberg et al., 2009 (14)
Male, 81
10
Verma et al., 1996 (11)
Female, 60
Case nr.
Author, year
Gender, age at aura and status onset
Table 1(b). Systematic review: Status patients with underlying pathology.
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5
17
18
19
Holzer et al., 2009 (15)
Field and Kleinig, 2010 (16)
Italiano, 2011 (17)
Female, 35
Female, 81
Female, 28
Gender, age at aura and status onset
No
No
Yes, since the age of 17
Previous MA
Visual
Sensory, paresis
Visual, sensory
Aura-like symptomsa
Several times/day for one week
4 in 4 days
Daily attacks for 6 weeks (followed by headache)
Frequency of aura episodes
Previous history of visual symptoms followed by generalized tonic-clonic seizures Right hemianopia on neurological exam EEG recorded occipital seizures, simultaneous with the visual symptoms
Breast cancer, aHT, dyslipidemia Normal neurological exam, except for preexisting altitudinal field loss bMRI and bCT showed subdural hematoma, extending into the subarachnoid space; focal slowing on EEG
Smoker CD, on prednisolone 20 mg/day Minor ataxia of left arm and gait instability Neuroimaging and CSF findings compatible with cerebral vasculitis
Other clinical findings
Lysine acetylsalicylate 500 mg (no improvement) Gradual resolution on dexamethasone 8 mg/day and phenobarbital 100 mg/day
Phenytoin Valproate (no recurrence)
Full recovery after prednisolone 1000 mg/day and anticoagulation with heparin
Treatment and recurrence of status
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MA: migraine with aura; aHT: arterial hypertension; bCT: brain computed tomography; bMRI: brain magnetic resonance imaging scan; Duplex US: duplex ultrasonography; DSA: digital subtraction angiography; ICA: internal carotid artery; AF: atrial fibrillation; SH: subarachnoid haemorrhage; GE: gradient echo; WM: white matter; bMRA: brain magnetic resonance angiography scan; DWI: diffusionweighted imaging; EEG: electroencephalography; TIA: transient ischemic attack; EcoCG: echocardiography; CD: Crohn’s disease; CSF: cerebral spinal fluid. aAura symptoms listed by order of appearance.
Case nr.
Author, year
Table 1(b). Continued.
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6 Cephalalgia 0(0)
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7 ICHD-III: International Classification of Headache Disorders – III beta; MA: migraine with aura; V: visual symptoms; SS: sensory symptoms; LA: language and speech disturbances. aProbable MA (prolonged aura).
10.8 21.4 0 11.8 5 – 44 6 0 2 1 – 11 17.9 25 5.9 20 – 45 5 1 1 4 – 68.6 46.4 75 0 45 – 280 13 3 0 9 – 36.9 12.4 35.2 10.3 30 12.2 34.4 10 54.5 16.7 – 77.2 75 50 58.8 80 – 315 21 2 10 16 364 22.8 25 50 41.2 20 – 408 28 4 17 20 477 Only typical Prolongeda Persistent Hemiplegic Status Total
85.5 5.9 0.8 3.6 4.2 100
93 7 2 7 4 113
n n MA subtypes
%
n
%
%
0 0 0 17 0 – 9.6 14.3 0 82.4 30 – 39 4 0 14 6 –
0 0 0 100 0 –
% n n % n n % n
V
Age at first consultation (years) Female Male Total
Table 2. Migraine with aura subtypes: Patients’ diagnosis according to ICHD-III criteria.
Aura symptoms
VþS
%
Motor V þ S þ LA
%
Any other
Alagoa Joa˜o et al.
throbbing headache with nausea and intolerance to light, movements or effort, which lasted between 48 and 72 hours. There were no vascular risk factors, except for arterial hypertension, detected two years later and controlled with telmisartan. Neurological examination and computed tomography (CT) scan were normal. She improved considerably with sodium valproate. Four years later, she experienced repeated typical auras during one week: three attacks in one day followed, six days later, by four attacks in a single day. Auras were not followed by headache. At the age of 84, she still suffered from repeated episodes of aura followed by typical migraine headache once every three months.
Case 6 A 62-year-old woman reported episodes of MA since her youth. On the first consultation the auras were described as consisting on a scintillating scotoma followed by a unilateral intense headache with photo- and phonophobia that was relieved with local cold application and bed rest. There were no vascular risk factors. Neurological examination, carotid and vertebral ultrasound were within normal limits but CT scan showed mild periventricular leukoaraiosis. Four years later, she reported a sudden increase in attack frequency with two to three daily attacks of visual aura for several months. Each attack lasted about 15 minutes and was occasionally followed by headache. She described a particular period of two weeks with several attacks per day. After each aura there was a symptom-free stage of a few minutes and then it began again following the same stereotyped path. An ophthalmological observation could not find any significant abnormality in the retina, fundi, ocular pressure or in visual acuity. An MRI showed white matter hyperdensities (WMH) within normal limits.
Case 8 A 37-year-old man had been diagnosed with MA at the age of 8 years. Over adolescence and early adulthood, he experienced sporadic attacks with visual aura (about four per year). Between the ages of 37 and 43, auras became more complex and appeared in clusters on successive days. The episodes began with visual symptoms (scintillating scotoma spreading in a visual hemifield) for five minutes, followed by unilateral paresthesiae and cognitive symptoms—either aphasia or prosopagnosia—and lastly a unilateral headache with nausea, photophobia and intolerance to movement and minor exertion. The patient suffered from arterial
Gender, age
F, 45
F, 77
F, 41
F, 44
F, 55
F, 62
F, 63
M, 37
F, 39
F, 46
Case nr.
1
2
3
4
5
6
7
8
9
10
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
MA, 39
MA, youth
MA, youth
MA, 12
MWoA, 16 MA, >45 MA, youth
1/day for 6 days
3/day for 1 day
1–2/day for 4 days
1/day for 4 days
2–10/day for 15 days
2/day for >1 day
3/day over 3–4 days/week 2/day for 3–7 days
4/day for 1 day
MA, >45
MWoA, youth MA, 40 MA and acephalgic migraine, 14
1/day for 8 days
Frequency and duration of status period
MA, 42
Migraine type, age at onset
Visual (30 min)
Visual, sensory, language (5– 15 min) Visual (40– 120 min)
Visual, sensory, language (30 min)
Visual, language (30 min) Visual (15–30 min)
Visual, language, sensory (2–3 hours)
Visual (30 min)
Visual, language (30 min)
Visual, sensory, language (25– 30 min)
Aura type (duration)a
Yes
Not always
Not always
Yes
Not always
Not always
Not always
Yes
Not always
Yes
Associated headache
6 years
None
9 years
10 years
8 years
11 years
11 years
9 years
8 years
1 year
Duration of follow-up period
Yes
Unknown
Yes
Yes
Yes
Yes
Yes
Yes
No
No (after treatment)
Recurrence of status
None
None
aHT, dyslipidemia
None
None
None
Prolonged use of OC Smoking, dyslipidemia
aHT
Smoking
Vascular risk factors
No
No
Yes
No
Yes
No
Yes
No
No
No
8 (continued)
Normal cUS and vertebral US, EEG and visual evoked potentials WMH (within normal limits)
Normal bCT and cUS WMH (within normal limits)
Normal bCT
Normal ophthalmological and neurological exam
Normal cUS and bCT Parkinson’s disease Normal ophthalmological exam and bCT WMH (within normal limits)
WMH (within normal limits)
Normal EEG and bCT
Normal ECG, cUS and bCT
Normal bMRI, except for mild tonsillar ectopia
Other clinical findings
ICHDIII beta criteria for status
(CEP)
Yes
No
Family history
Table 3. Aura status cases.
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Cephalalgia 0(0)
F, 40
F, 49
F, 44
F, 89
M, 48
F, 27
M, 69
F, 74
F, 81
M, 63
11
12
13
14
15
16
17
18
19
20
No
Yes
No
Yes
No
No
Yes
Yes
Yes
Yes
Family history
MA, 30
MWoA, youth MA, 50
MWoA, youth aura, 73
MA, 62
MA, 22
MA, 39
MA, 30
MA and acephalgic migraine, 41
MWoA, 14 MA, 49
MWoA, 15 MA, 25
Migraine type, age at onset
2/day for a few days
2/day for 2 days
2/day for 3 days
3/day for 1 day
Intermittent for 3 days
3/day for a few days
2/day for 2 days
1/day for 3 days
3/day for 1 day
3/day for 3–8 days
Frequency and duration of status period
Visual (30 min)
Visual (10–15 min)
Visual, language (20 min)
Visual
Visual
Visual (15–20 min)
Visual, sensory, language
Sensory, language, visual (20 min)
Visual (30 min)
Visual, sensory
Aura type (duration)a
No
Not always
No
Not always
Yes
Not Always
Yes
Not always
Not always
Not always
Associated headache
1 year
10 years
2 years
None
None
None
2 years
None
None
4 years
Duration of follow-up period
No
No
Yes
Unknown
Unknown
Yes
No
Yes
Unknown
Yes
Recurrence of status
aHT, dyslipidemia
Dyslipidemia
Smoking, aHT, dyslipidemia
aHT
None
None
aHT, dyslipidemia
None
Smoking, dyslipidemia
None
Vascular risk factors
Mitral valve prolapse
Normal cUS and bCT
Normal ophthalmological and neurological exam Normal cUS and bCT
Normal ophthalmological and neurological exam
Normal bCT, bMRI and cUS
Normal bCT and bMRI
Normal bMRI
Normal ophthalmological exam, bCT and EEG
Normal bMRI and cUS
Other clinical findings
Yes
No
Yes
No
Yes
Yes
No
No
No
Yes
ICHDIII beta criteria for status
(CEP)
F: female; M: male; MA: migraine with aura; MWoA: migraine without aura; bMRI: brain magnetic resonance imaging scan; aHT: arterial hypertension; ECG: electrocardiography; US: ultrasound; cUS: carotid ultrasound; bCT: brain computed tomography; OC: oral contraceptives; EEG: electroencephalography; WMH: white matter hyperintensities. aAura symptoms listed by order of appearance.
Gender, age
Case nr.
Table 3. Continued.
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9
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(CEP)
10
Cephalalgia 0(0)
Table 4. Comparison between proposed and ICHD-III beta criteria for aura status. Proposed criteria
N Gender
Male Female Age at first consultation Age at aura onset
Aura symptoms
(0–14) (15–29) (30–44) (>44) V V þ SS V þ SS þ LA Any other
ICHD-III beta criteria
Yes
No
Sig.
Yes
No
Sig.
20 (4.4%) 4 (20%) 16 (80%) 54.5 16.7
436 (95.6%) 100 (22.9%) 336 (77.1%) 36.8 12.3
2 ¼ 0.096 (1) p ¼ n.s.
8 (1.8%) 3 (37.5%) 5 (62.5%) 49.1 15.3
448 (98.2%) 101 (22.5%) 347 (77.5%) 37.4 12.9
2 ¼ 0.89 (1) p ¼ n.s.
5 2 7 6 9 4 6 1
91 (30.3%) 130 (43.3%) 54 (18%) 25 (8.3%) 293 (67.2%) 50 (11.5%) 43 (9.8%) 50 (11.5%)
3 2 2 1 4 1 2 1
93 (29.8%) 130 (41.7%) 59 (18.9%) 30 (9.6%) 298 (66.5%) 53 (11.8%) 47 (10.5%) 50 (11.2%)
(25%) (10%) (35%) (30%) (45%) (20%) (30%) (5%)
t ¼ 4.68 (19.95) p < 0.000 2 ¼ 15.68 (3) p ¼ 0.001
2 ¼ 8.42 (3) p ¼ 0.038
(37.5%) (25%) (25%) (12.5%) (50%) (12.5%) (25%) (12.5%
t ¼ 2.55 (451) p < 0.011 2 ¼ 0.953 (3) p ¼ n.s.
2 ¼ 0.804 (1) p ¼ n.s.
ICHD-III beta: ICHD-III: International Classification of Headache Disorders – III beta; V: visual symptoms; SS: sensory symptoms; LA: language and speech disturbances; n.s.: not significant.
hypertension and dyslipidemia. He was recently contacted again and reported a maximum of six episodes in four days. In summary, cases classified as migraine aura status according to our proposed criteria were mostly women with a long-standing history of MA (fulfilling ICHD criteria for aura with typical migraine headache). More than half reported a positive family history, typically mothers and/or sisters. The status periods appeared at a rather late age, with no apparent triggering factors. Patients described a sudden increase of the frequency of aura attacks, often without headache (all auras according to the IHS criteria). Nevertheless, the typical progression of symptoms was similar to their previous auras of classic migraine. Visual phenomena—chiefly positive, like bright lines and flashing lights—were collectively reported, frequently followed by paresthesiae and/or speech disturbances, such as aphasia or dysarthria. Although the majority of patients stated that the attacks resolved within up to 30 minutes, two female patients reported aura episodes lasting for two and three hours. These aura status episodes clustered in 2 to 10 attacks per day for a few days and unexpectedly disappeared until the beginning of another bout, days or weeks later. Between the episodes the patients were asymptomatic. On a followup consultation afterward (average was 5.8 years later), less than half the patients were still experiencing aura status bouts. Neurological and ophthalmological examination, neuroimaging, electroencephalogram (EEG) and Doppler were normal,
revealing no underlying pathology or sequelae, even though a thorough standard investigation has not been conducted in all patients.
Comparison of the two sets of criteria for migraine aura status We performed a comparison between patients with migraine aura status and patients with typical or prolonged aura (excluding cases of persistent aura and hemiplegic migraine) using either the ICHD-III beta or our proposed criteria. Results are presented in Table 4. With both criteria, gender distribution was not significantly different between patients with status and other auras. Patients with status were significantly older at first consultation than other patients with aura, but more so with our own criteria (54.5 16.7 years vs. 36.8 12.3 years). Comparing the frequency in the oldest patients (>44 years) with the other age groups, those with status are older than patients without status, when using our criteria (2 ¼ 10.29 (1) p ¼ 0.001) but not with ICHD-III beta criteria (2 ¼ 0.08 (1) p ¼ n.s.). We also noted that aura symptoms have a different distribution in the two groups, as patients with aura status seem to have more complex auras. This is not evident with the ICHD-III beta criteria since there are only eight subjects, but in our definition, it is possible to observe that the dominance of visual symptoms is lower in status patients.
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Alagoa Joa˜o et al. When we performed a direct comparison between patients fulfilling both criteria (eight patients) and those fulfilling only our criteria (12 individuals), the only significant difference is a female predominance in our series (100% vs. 50%).
Discussion Migraine aura is a neurogenic phenomenon corresponding to the cortical spreading depression (18) described in rodent’s brain in 1944 (19). In experimental conditions, it can be triggered by physical, chemical or other noxious stimuli or spontaneously in transgenic animals with channelopathies. In humans, it is known to occur in ischemia and traumatic brain disease (20–22) or spontaneously in migraine. Aura status is a recognized presentation of migraine with unknown frequency. Using two operational definitions, we found that though rarely reported in literature, its frequency may range between 1.7% and 4.2% in a consecutive series of patients observed in a tertiary headache outpatient center. Most cases previously presented under this diagnosis did not describe the entity of frequent and repetitive aura symptoms. Additionally, various reports included patients with underlying pathology that might not be migrainous in nature, such as epileptic disorders and cerebral primary vascular lesions. It is of particular notice that individuals with secondary aura-like status presented as such from the onset and did not report a previous history of MA. Nonetheless, future studies are needed to confirm these findings. The frequency of episodes required for aura status diagnosis has decreased from the ICHD-II (at least two auras per day for 5 consecutive days) (23) to the ICHD-III beta (at least two auras per day for 3 consecutive days). However, these are still rather strict, leading both to the exclusion of many cases and a bias toward male gender and lower mean age. Even though a more rigorous approach may be useful in research because of the selection of more extreme cases, in daily practice, a clinician will possibly have an identical attitude if a patient has six attacks in three days or four attacks in only one day. Undoubtedly, the focus should be on how to investigate unusual cases and distinguish benign cases from those presenting with signs of a brain catastrophe. In addition, in the literature review, the frequency of aura episodes in secondary cases was not higher than in those patients with no identified underlying pathology. Concerning the analysis of our own series of patients, we found no major differences in the demographic and clinical profile of patients with aura status, when applying the two sets of criteria (stricter ones proposed by the ICHD-III beta and a broader
11 definition allowing less-frequent attacks per day). Our criteria, though less strict concerning attack frequency, resulted in more conservative aura symptoms as most of our patients presented with the typical recognized symptoms of this syndrome (visual and sensory disturbances). This might be a clinical advantage since patients with secondary status gathered from the literature often experienced isolated sensory or motor symptoms. Moreover, our criteria produced a female predominance, which is the usual gender distribution of migraine. However, the number of subjects fulfilling ICHD-III beta criteria is too limited to reach any definitive conclusion. In this report, we concluded that aura status may be more common than previously thought, that most patients had a previous history of MA and were older than patients with typical aura at first consultation (this event usually follows closely the onset of status). Gender distribution, age at MA onset and aura symptoms were identical in both groups, as was the absence of sequelae on brain imaging, suggesting that status may be a benign late manifestation of classic migraine. Our hypothesis is that status aura and MA are the same disorder, as proposed by others (3), and these ‘‘flurries’’ (2) or temporary aura attacks may express an increased pathophysiological vulnerability to migraine stimuli, as if the occipital cortex develops a very low threshold required to trip the sensitive mechanisms involved. In fact, animal studies (24–26) showed amplified long-term potentiation (LTP, a form of synaptic plasticity) and decreased inhibitory adenosine effect on the brain of elderly individuals, both heralding increased cortical excitability with aging. These attacks may also represent a state of amplified vasomotor instability, with transient and spatially restricted changes in cerebral blood flow (27) being more frequent in these older individuals. Additionally, an association with hyperhomocysteinemia is possible (9).The focal and stereotyped nature of aura status, with mainly positive symptoms, suggests that the phenomenon is rather circumscribed and does not spread to neighboring regions, as if the normal inhibitory phenomena were intact in the neighboring cortex. However, its pattern of temporal profile can suggest clustering TIAs or status epilepticus, conditions where a neurological symptom (negative or positive) repeats itself in a short period of time. According to Fisher, 1980 (28) and Haas, 1982 (1) the characteristics that favor migraine attacks are luminous visual images, build-up of images, progression from one aura to another, limited character, benign outcome and the migrainous predisposition of most of the patients; the separate occurrences of various types of attacks (visual, paresthetic and language), the absence of additional epileptic
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Cephalalgia 0(0)
features throughout the episodes and the negative encephalogram weigh against an epileptic pathogenesis. We acknowledge some limitations to this study. Firstly, our series of patients was analyzed retrospectively. Although the descriptions were detailed enough to allow the gathering of data, we believe that prospective studies with standardized questionnaires and investigation are necessary to corroborate the presented hypothesis. Secondly, this study presents the personal experience of a single neurologist, therefore multicentric prospective studies are desirable in order to adequately validate our proposed criteria.
Conclusion Patients with recurring auras in a short period of time will probably raise the same doubts and diagnostic approach independently of the set of criteria applied. Furthermore, two different criteria identified a similar
population in terms of age, symptoms, imaging and outcome from a clinical perspective. Therefore we suggest that the use of a more liberal definition can be valuable, since larger samples of cases will allow diagnostic and therapeutic studies, leading eventually to further knowledge of this syndrome or even its subdivision in subtypes. Since differential diagnosis is imperative in clinical practice, it is important to describe and systematically report these events in order to understand their nature, triggering factors and resolution. The comprehension of these cases may help to understand migraine aura and possibly lead to therapeutic trials and neurophysiologic or functional imaging studies. Additionally, it would be interesting to study the prevalence of vascular risk factors, white matter changes and other possible findings in migraine aura status cases, comparing them to patients with migraine with typical aura.
Clinical implications . Migraine aura status is a transient state characterized by multiple recurring migraine auras in a period of hours or days, with a tendency to occur in older subjects with a previous history of migraine with aura. . The number and frequency of episodes required by International Classification of Headache Disorders-III beta (ICHD-III beta) for this diagnosis is possibly too strict and exclude most cases. . The use of less strict criteria, with a minimum number of 3 episodes in 3 days, resulted in a similar sample of patients and may allow the development of knowledge about this infrequent condition. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest None declared.
References 1. Haas DC. Prolonged migraine aura status. Ann Neurol 1982; 11: 197–199. 2. Spierings E. Flurries of migraine (with) aura and migraine aura status. Headache 2002; 42: 326–327. 3. Haan J, Sluis P, Sluis LH, et al. Acetazolamide treatment for migraine aura status. Neurology 2000; 55: 1588–1589. 4. Headache Classification Committee of the International Headache Society. The International Classification of Headache Disorders, 3rd ed. (beta). Cephalalgia 2013; 33: 629–808. 5. Martins IP, Goucha T, Mares I, et al. Late onset and early onset aura: The same disorder. J Headache Pain 2012; 13: 243–245. 6. Crespo M, Melo TP, Oliveira V, et al. Clustering transient ischemic attacks. Cerebrovasc Dis 1993; 3: 213–220.
7. Viana M, Sprenger T, Andelova M, et al. The typical duration of migraine aura: A systematic review. Cephalalgia 2013; 33: 483–490. 8. IBM Corp. Released 2011. IBM SPPS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp. 9. Cupini LM and Stipa E. Migraine aura status and hyperhomocysteinaemia. Cephalalgia 2007; 27: 847–849. 10. Reinecke RD and Silberstein SD. Migrainous visual auras: A life history. Headache 2007; 47: 123–127. 11. Verma A, Rosenfeld V, Forteza A, et al. Occipital lobe tumor presenting as migraine with typical aura. Headache 1996; 36: 49–52. 12. Klingebiel R, Friedman A, Shelef I, et al. Clearance of a status aurae migraenalis in response to thrombendarterectomy in a patient with high grade internal carotid artery stenosis. J Neurol Neurosurg Psychiatry 2008; 79: 89–90. 13. Kleinig TJ, Kiley M and Thompson PD. Acute convexity subarachnoid haemorrhage: A cause of aura– like symptoms in the elderly. Cephalalgia 2008; 28: 658–663. 14. Izenberg A, Aviv RI, Demaerschalk BM, et al. Crescendo transient aura attacks: A transient ischemic attack mimic caused by focal subarachnoid hemorrhage. Stroke 2009; 40: 3725–3729.
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Alagoa Joa˜o et al. 15. Holzer K, Esposito L, Stimmer H, et al. Cerebral vasculitis mimicking migraine with aura in a patient with Crohn’s disease. Acta Neurol Belg 2009; 109: 44–48. 16. Field DK and Kleinig TJ. Aura attacks from acute convexity subarachnoid haemorrhage not due to cerebral amyloid angiopathy. Cephalalgia 2010; 31: 368–371. 17. Italiano D, Grugno R, Calabro` RS, et al. Recurrent occipital seizures misdiagnosed as status migrainosus. Epileptic Disord 2011; 13: 197–201. 18. Hadjikhani N, Sanchez Del Rio M, Wu O, et al. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci U S A 2001; 98: 4687–4692. 19. Lea˜o AAP. Spreading depression of activity in cerebral cortex. J Neurophysiol 1944; 7: 359–390. 20. Fabricius M, Fuhr S, Willumsen L, et al. Association of seizures with cortical spreading depression and peri– infarct depolarisations in the acutely injured brain. Clin Neurophysiol 2008; 119: 1973–1984. 21. Dreier JP, Major S, Manning A, et al. Cortical spreading ischaemia is a novel process involved in ischaemic damage in patients with aneurysmal subarachnoid haemorrhage. Brain 2009; 132: 1866–1881. 22. Lauritzen M, Dreier JP, Fabricius M, et al. Clinical relevance of cortical spreading depression in neurological
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27. 28.
disorders: Migraine, malignant stroke, subarachnoid and intracranial haemorrhage and traumatic brain injury. J Cereb Blood Flow Metab 2001; 31: 17–35. Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders, 2nd ed. Cephalalgia 2004; 24: 1–160. Sebastia˜o AM, Cunha RA, De Mendonc¸a A, et al. Modification of adenosine modulation of synaptic transmission in the hippocampus of aged rats. Br J Pharmacol 2000; 131: 1629–1634. Dio´genes MJ, Assaife-Lopes N, Pinto-Duarte A, et al. Influence of age on BDNF modulation of hippocampal synaptic transmission: Interplay with adenosine A2a receptors. Hippocampus 2007; 17: 577–585. Dio´genes MJ, Costenla AR, Lopes LV, et al. Enhancement of LTP in aged rats is dependent on endogenous BNDF. Neuropsychopharmacology 2011; 36: 1823–1836. Aurora SK and Welch KM. Migraine: Imaging the aura. Curr Opin Neurol 2000; 13: 273–276. Fisher CM. Late-life migraine accompaniments as a cause of unexplained transient ischemic attacks. Can J Neurol Sci 1980; 7: 9–17.
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Original Article
Aura status: A not so frequent aura
Cephalalgia 0(0) 1–13 ! International Headache Society 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0333102414530525 cep.sagepub.com
Ana Alagoa Joa˜o1, Tomas B Goucha2,3 and Isabel P Martins1 Abstract Background: Migraine aura status is a variety of migraine aura with unvalidated research criteria. Aim and methods: We conducted a systematic review of published cases and a retrospective analysis of 500 cases of migraine with aura to evaluate the applicability and clinical features of ICHD-III beta criteria, compared to a more liberal definition for its diagnosis: 3 aura episodes for up to three consecutive days. Results: Many publications under this title correspond to persistent or formerly designated prolonged auras. Nine cases fulfilled ICHD-III beta status criteria. In our series, either 1.7% or 4.2% cases fulfilled ICDH-III beta or our definition, respectively. Regardless of the criteria, aura status patients were older at onset of status than those with typical aura, had a predominance of visual symptoms, normal neuroimaging and no sequelae. Status recurred in a few. Conclusion: Both criteria identify a similar population in terms of age, gender, main symptoms, imaging and outcome. Since patients with closely recurring auras might raise the same approach independently of the criteria, the use of more liberal criteria will allow more cases for detailed diagnosis and therapeutic analysis, eventually leading to the identification of subtypes. Keywords Migraine aura status, migraine diagnosis, ICHD-III beta, headache classification Date received: 6 September 2013; revised: 1 January 2014; accepted: 12 March 2014
Introduction Migraine auras might assume unusual temporal profiles, namely as recurrent bursts of attacks during a short period of time. This phenomenon, designated migraine aura status, was mentioned at least 30 years ago by Haas, 1982 (1) and described as aura episodes occurring ‘‘ . . . several times in a row over several days in a ‘flurry’ and then disappear for several weeks only to recur in another ‘flurry’’’ (2). As previously underlined by some authors (3), this syndrome should not be confused with status migranosus, a debilitating migraine headache lasting for more than 72 hours (with or without aura), with persistent aura without infarction nor with syndromes characterized by probable migraine with prolonged aura, as there are no aura-free intervals in those conditions. Since migraine auras frequently involve visual and sensory symptoms and are not always followed by a headache, their presentation can be confused with visual epilepsy or clustering transient ischemic attacks (TIAs), particularly in older patients with additional sensory symptoms or speech disturbances. Migraine aura status is listed in the Appendix of the International Classification of Headache Disorders-III
beta (ICHD-III beta) (4) as a novel entity that has not been sufficiently validated by research. Indeed, the criteria proposed seem to have little empirical basis, particularly regarding the precise cut-off in terms of the frequency of attacks required for its diagnosis (at least two auras occurring per day, for three or more days). Given the rarity of this syndrome, it is possible that published reports might have been biased toward the most severe cases and that the proposed criteria might be too strict. The aim of this article is to analyze the extant published data on aura status and to challenge the 1 Department of Clinical Neurosciences, Instituto de Medicina Molecular (IMM), Faculty of Medicine (IMM) University of Lisbon, Portugal 2 Max Planck Institute for Human Cognitive and Brain Sciences, Department of Neuropsychology, Germany 3 Berlin School of Mind and Brain, Humboldt University, Germany
Corresponding author: Isabel Pavao Martins, Department of Neurosciences, Lisbon Faculty of Medicine, Instituto de Medicina Molecular, Hospital de Sta Maria 1600 Lisboa, Portugal. Email: [email protected]
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2 proposed diagnostic criteria, comparing them with a broader definition, resulting from our clinical experience, previous studies on late-life aura—an age group in whom repeated auras often occur (5)—and on the recurrence of transient neurological phenomena (6). With that purpose, we conducted a systematic review of published cases of aura status and performed a retrospective analysis of a personal series of patients with migraine with aura (MA) in order to identify cases with status and estimate its frequency, demographic and clinical features. Additionally, we compared cases defined according either to the ICHD-III beta criteria or fulfilling our definition, with cases of typical migraine aura or probable migraine with prolonged aura, to determine if a change in criteria resulted in a significantly different clinical profile.
Methods Systematic review of migraine aura status cases We conducted a systematic review of the literature published in English and French up to July 2013 through a search of Medline/PubMed and the Cochrane Library, using the terms aura status, repeated or recurrent migraine aura and repeated or recurrent aura attacks. Among those describing cases in adults (above 18 years of age), articles were selected by title and abstract. Selected abstracts were then reviewed by two authors and full articles were accessed for data collection. Cases identified by their authors as migraine aura status or presenting with frequently recurring aura attacks during a short period of time were gathered and the following data were collected: patient’s gender, age at consultation and at aura onset, type of aura symptoms (categorized as visual, sensory, speech disturbances, other or multiple), frequency of attacks, underlying pathology and sequelae.
Retrospective review of personal clinical data Our study population consists of the last 500 adult patients clinically diagnosed with MA by a neurologist (IPM) in the setting of a tertiary headache outpatient clinic. Patients’ files were checked for the diagnostic criteria of MA according to the ICHD-III beta (4), and the following data were collected from the clinical records: patient’s gender, age at consultation and at aura onset [categorized as early (0–14 years), youth (15–29 years), adult (30–44 years) and late (45 or more years)], aura type (visual, sensory, speech disturbances or other symptoms) and duration. Cases were distributed into five categories according to the type and duration of aura symptoms: typical (five to 60 minutes), prolonged (more than 60 minutes and
Cephalalgia 0(0) less than one week per symptom), persistent aura without infarction (lasting for one week or more without evidence of infarction on neuroimaging), hemiplegic (including motor weakness) and aura status. Although the latest ICHD-III beta classification does not include the diagnosis of prolonged aura and those episodes are now included under the code 1.5.2., ‘‘probable migraine with aura (prolonged aura)’’, we kept that designation in this study as it has been extensively used in previous publications. Furthermore, a recent systematic review indicates that nonhemiplegic auras lasting more than 60 minutes might occur occasionally among subjects with typical auras (7). Patients were additionally classified as having aura status if the following operational criteria were present: there should be a minimum number of three aura episodes distributed in up to three consecutive days (3 episodes in 3 days). This statement comprises two possibilities: 1) if the episodes cluster in a single day, there should be, at least, three episodes in that day; 2) if they are distributed in a larger period of time, there should be, at least, three consecutive days with a total number of three or more episodes. For example, two attacks in one day plus some more in the following days (3 þ 0 þ 0, 2 þ 1 þ 0, 1 þ 2 þ 0, 1 þ 1 þ 1, minimum). Compared to the ICHD-III beta criteria, these are more liberal concerning the number of episodes per day and the duration of the status period, admitting a shorter duration and adjusting the number of episodes to the number of days (for example six in a single day). Demographic features were compared among aura syndromes and individual cases of aura status were further described in detail. In addition, we compared cases fulfilling our operational criteria for aura status and those fulfilling the ICHD-III beta criteria with cases of migraine with typical or prolonged auras.
Statistical analysis Patients with aura status were compared with those with typical aura using either diagnostic criteria. Continuous variables were compared with the Student’s t test for independent samples and Chi Square test or Wilcoxon-Mann-Whitney test for categorical variables, with a significance level 2/day for at least 5 days
Intermittent (‘‘several times an hour, hour after hour, day after day’’), for 5 weeks Up to 100/day, for 8 weeks
Frequency of aura episodes
Episodes up to the age of 76
No episodes at 10-month follow-up
No episodes at 18-month follow-up
Unknown
No episodes after oral acetazolamide treatment
No episodes at 2-month follow-up
Rare momentary visual symptoms
Recurrence of status
Normal ophthalmological and neurological exams, bMRI and bMRA
Hyperhomocysteinaemia Normal bCT, bMRI and tDoppler
aHT (treated with ACEi) Hyperhomocysteinemia Normal bCT and transcranial Doppler (tDoppler) bMRI showed subcortical white matter hyperdensities (T2)
Normal bCT EEG showed occipital slow waves
Normal neuroimaging, (bCT or bMRI) and EEG
Normal ophthalmological and neurological exams, bCT and EEG Normal ophthalmological and neurological exams
Other clinical findings
bCT: brain computed tomography; EEG: electroencephalogram; bMRI: brain magnetic resonance imaging scan; aHT: arterial hypertension; ACEi: angiotensin-converting-enzyme inhibitor; bMRA: brain magnetic resonance angiography scan. aAura symptoms listed in order of appearance.
Reinecke and Silberstein, 2007 (10)
Female, 25
8
Female, unknown
6 Male, 12
Male, unknown
5
7
Female, unknown
4
Under 30
18
70
Age at status onset
(CEP)
Cupini and Stipa, 2007 (9)
Female, youth
2
3
Male, early adolescence
1
Haas, 1982 (1)
Haan et al., 2000 (3)
Male, adulthood
Case nr.
Author, year
Gender, age at aura onset
Table 1(a). Systematic review: Status patients without underlying pathology.
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Male, 73
Male, 82
11
12
13
14
Klingbiel et al., 2008 (12)
Kleinig et al., 2008 (13)
Male, 85
Male, 79
15
16
Male, 62
No
No
No
No
No
No
No
Previous MA
Sensory, paresis
Sensory
Sensory, paresis, dysarthria
Sensory
Paresis
Paresis, aphasia, visual
Visual
Aura-like symptomsa
3 in 2 days (not followed by headache)
6 in 2 days (not followed by headache)
6 in 2 days (not followed by headache)
7 in 2 days (not followed by headache)
Up to 10 in 3 days (not followed by headache)
Up to 10 attacks/day (not followed by headache)
1–3 attacks/day for some weeks (followed by headache)
Frequency of aura episodes
Lung cancer, coronary and peripheral vascular disease, heart failure and essential thrombocytosis, high grade left carotid stenosis on aspirin Normal neurological exam, EEG and EcoCG bCT revealed SH
aHT, coronary disease and dyslipidemia Normal neurological exam, EEG and EcoCG bCT and bMRI showed SH
aHT, on antiplatelet therapy bMRI showed SH, WM disease and cortical hemorrhages; GE showed cortical siderosis Normal DWI
aHT, AF on warfarin bMRI showed SH and WM disease; microbleeds demonstrated by GE sequences Normal MRA, DWI and EEG aHT, diabetes, previous TIAs on warfarin bMRI showed acute SH and WM disease; Microbleeds evident on GE sequences Normal DWI and EEG
aHT, obesity bCT normal on admission, later showed hypodensity in the left frontal region Duplex US and DSA showed 95% left ICA stenosis
aHT, diabetes Normal neurologic, ophthalmological exams and bCT bMRI revealed a right occipital lobe tumor
Other clinical findings
Alagoa Joa˜o et al. (continued)
Clopidogrel No episodes, on a 7-month follow-up
Phenytoin Continued aspirin and clopidogrel No episodes, on a 16-month follow-up
No episodes, after antiplatelet therapy cessation
Valproate, no recurrence after 6 months
Valproate (symptoms decreased) Prednisolone (episodes ceased)
Clearance of symptoms after thrombendarterectomy
Phenytoin 300 mg/day Corticosteroids (patient refused surgery) No episodes, on a 6-month follow-up
Treatment and recurrence of status
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Izenberg et al., 2009 (14)
Male, 81
10
Verma et al., 1996 (11)
Female, 60
Case nr.
Author, year
Gender, age at aura and status onset
Table 1(b). Systematic review: Status patients with underlying pathology.
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5
17
18
19
Holzer et al., 2009 (15)
Field and Kleinig, 2010 (16)
Italiano, 2011 (17)
Female, 35
Female, 81
Female, 28
Gender, age at aura and status onset
No
No
Yes, since the age of 17
Previous MA
Visual
Sensory, paresis
Visual, sensory
Aura-like symptomsa
Several times/day for one week
4 in 4 days
Daily attacks for 6 weeks (followed by headache)
Frequency of aura episodes
Previous history of visual symptoms followed by generalized tonic-clonic seizures Right hemianopia on neurological exam EEG recorded occipital seizures, simultaneous with the visual symptoms
Breast cancer, aHT, dyslipidemia Normal neurological exam, except for preexisting altitudinal field loss bMRI and bCT showed subdural hematoma, extending into the subarachnoid space; focal slowing on EEG
Smoker CD, on prednisolone 20 mg/day Minor ataxia of left arm and gait instability Neuroimaging and CSF findings compatible with cerebral vasculitis
Other clinical findings
Lysine acetylsalicylate 500 mg (no improvement) Gradual resolution on dexamethasone 8 mg/day and phenobarbital 100 mg/day
Phenytoin Valproate (no recurrence)
Full recovery after prednisolone 1000 mg/day and anticoagulation with heparin
Treatment and recurrence of status
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MA: migraine with aura; aHT: arterial hypertension; bCT: brain computed tomography; bMRI: brain magnetic resonance imaging scan; Duplex US: duplex ultrasonography; DSA: digital subtraction angiography; ICA: internal carotid artery; AF: atrial fibrillation; SH: subarachnoid haemorrhage; GE: gradient echo; WM: white matter; bMRA: brain magnetic resonance angiography scan; DWI: diffusionweighted imaging; EEG: electroencephalography; TIA: transient ischemic attack; EcoCG: echocardiography; CD: Crohn’s disease; CSF: cerebral spinal fluid. aAura symptoms listed by order of appearance.
Case nr.
Author, year
Table 1(b). Continued.
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6 Cephalalgia 0(0)
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7 ICHD-III: International Classification of Headache Disorders – III beta; MA: migraine with aura; V: visual symptoms; SS: sensory symptoms; LA: language and speech disturbances. aProbable MA (prolonged aura).
10.8 21.4 0 11.8 5 – 44 6 0 2 1 – 11 17.9 25 5.9 20 – 45 5 1 1 4 – 68.6 46.4 75 0 45 – 280 13 3 0 9 – 36.9 12.4 35.2 10.3 30 12.2 34.4 10 54.5 16.7 – 77.2 75 50 58.8 80 – 315 21 2 10 16 364 22.8 25 50 41.2 20 – 408 28 4 17 20 477 Only typical Prolongeda Persistent Hemiplegic Status Total
85.5 5.9 0.8 3.6 4.2 100
93 7 2 7 4 113
n n MA subtypes
%
n
%
%
0 0 0 17 0 – 9.6 14.3 0 82.4 30 – 39 4 0 14 6 –
0 0 0 100 0 –
% n n % n n % n
V
Age at first consultation (years) Female Male Total
Table 2. Migraine with aura subtypes: Patients’ diagnosis according to ICHD-III criteria.
Aura symptoms
VþS
%
Motor V þ S þ LA
%
Any other
Alagoa Joa˜o et al.
throbbing headache with nausea and intolerance to light, movements or effort, which lasted between 48 and 72 hours. There were no vascular risk factors, except for arterial hypertension, detected two years later and controlled with telmisartan. Neurological examination and computed tomography (CT) scan were normal. She improved considerably with sodium valproate. Four years later, she experienced repeated typical auras during one week: three attacks in one day followed, six days later, by four attacks in a single day. Auras were not followed by headache. At the age of 84, she still suffered from repeated episodes of aura followed by typical migraine headache once every three months.
Case 6 A 62-year-old woman reported episodes of MA since her youth. On the first consultation the auras were described as consisting on a scintillating scotoma followed by a unilateral intense headache with photo- and phonophobia that was relieved with local cold application and bed rest. There were no vascular risk factors. Neurological examination, carotid and vertebral ultrasound were within normal limits but CT scan showed mild periventricular leukoaraiosis. Four years later, she reported a sudden increase in attack frequency with two to three daily attacks of visual aura for several months. Each attack lasted about 15 minutes and was occasionally followed by headache. She described a particular period of two weeks with several attacks per day. After each aura there was a symptom-free stage of a few minutes and then it began again following the same stereotyped path. An ophthalmological observation could not find any significant abnormality in the retina, fundi, ocular pressure or in visual acuity. An MRI showed white matter hyperdensities (WMH) within normal limits.
Case 8 A 37-year-old man had been diagnosed with MA at the age of 8 years. Over adolescence and early adulthood, he experienced sporadic attacks with visual aura (about four per year). Between the ages of 37 and 43, auras became more complex and appeared in clusters on successive days. The episodes began with visual symptoms (scintillating scotoma spreading in a visual hemifield) for five minutes, followed by unilateral paresthesiae and cognitive symptoms—either aphasia or prosopagnosia—and lastly a unilateral headache with nausea, photophobia and intolerance to movement and minor exertion. The patient suffered from arterial
Gender, age
F, 45
F, 77
F, 41
F, 44
F, 55
F, 62
F, 63
M, 37
F, 39
F, 46
Case nr.
1
2
3
4
5
6
7
8
9
10
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
MA, 39
MA, youth
MA, youth
MA, 12
MWoA, 16 MA, >45 MA, youth
1/day for 6 days
3/day for 1 day
1–2/day for 4 days
1/day for 4 days
2–10/day for 15 days
2/day for >1 day
3/day over 3–4 days/week 2/day for 3–7 days
4/day for 1 day
MA, >45
MWoA, youth MA, 40 MA and acephalgic migraine, 14
1/day for 8 days
Frequency and duration of status period
MA, 42
Migraine type, age at onset
Visual (30 min)
Visual, sensory, language (5– 15 min) Visual (40– 120 min)
Visual, sensory, language (30 min)
Visual, language (30 min) Visual (15–30 min)
Visual, language, sensory (2–3 hours)
Visual (30 min)
Visual, language (30 min)
Visual, sensory, language (25– 30 min)
Aura type (duration)a
Yes
Not always
Not always
Yes
Not always
Not always
Not always
Yes
Not always
Yes
Associated headache
6 years
None
9 years
10 years
8 years
11 years
11 years
9 years
8 years
1 year
Duration of follow-up period
Yes
Unknown
Yes
Yes
Yes
Yes
Yes
Yes
No
No (after treatment)
Recurrence of status
None
None
aHT, dyslipidemia
None
None
None
Prolonged use of OC Smoking, dyslipidemia
aHT
Smoking
Vascular risk factors
No
No
Yes
No
Yes
No
Yes
No
No
No
8 (continued)
Normal cUS and vertebral US, EEG and visual evoked potentials WMH (within normal limits)
Normal bCT and cUS WMH (within normal limits)
Normal bCT
Normal ophthalmological and neurological exam
Normal cUS and bCT Parkinson’s disease Normal ophthalmological exam and bCT WMH (within normal limits)
WMH (within normal limits)
Normal EEG and bCT
Normal ECG, cUS and bCT
Normal bMRI, except for mild tonsillar ectopia
Other clinical findings
ICHDIII beta criteria for status
(CEP)
Yes
No
Family history
Table 3. Aura status cases.
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F, 40
F, 49
F, 44
F, 89
M, 48
F, 27
M, 69
F, 74
F, 81
M, 63
11
12
13
14
15
16
17
18
19
20
No
Yes
No
Yes
No
No
Yes
Yes
Yes
Yes
Family history
MA, 30
MWoA, youth MA, 50
MWoA, youth aura, 73
MA, 62
MA, 22
MA, 39
MA, 30
MA and acephalgic migraine, 41
MWoA, 14 MA, 49
MWoA, 15 MA, 25
Migraine type, age at onset
2/day for a few days
2/day for 2 days
2/day for 3 days
3/day for 1 day
Intermittent for 3 days
3/day for a few days
2/day for 2 days
1/day for 3 days
3/day for 1 day
3/day for 3–8 days
Frequency and duration of status period
Visual (30 min)
Visual (10–15 min)
Visual, language (20 min)
Visual
Visual
Visual (15–20 min)
Visual, sensory, language
Sensory, language, visual (20 min)
Visual (30 min)
Visual, sensory
Aura type (duration)a
No
Not always
No
Not always
Yes
Not Always
Yes
Not always
Not always
Not always
Associated headache
1 year
10 years
2 years
None
None
None
2 years
None
None
4 years
Duration of follow-up period
No
No
Yes
Unknown
Unknown
Yes
No
Yes
Unknown
Yes
Recurrence of status
aHT, dyslipidemia
Dyslipidemia
Smoking, aHT, dyslipidemia
aHT
None
None
aHT, dyslipidemia
None
Smoking, dyslipidemia
None
Vascular risk factors
Mitral valve prolapse
Normal cUS and bCT
Normal ophthalmological and neurological exam Normal cUS and bCT
Normal ophthalmological and neurological exam
Normal bCT, bMRI and cUS
Normal bCT and bMRI
Normal bMRI
Normal ophthalmological exam, bCT and EEG
Normal bMRI and cUS
Other clinical findings
Yes
No
Yes
No
Yes
Yes
No
No
No
Yes
ICHDIII beta criteria for status
(CEP)
F: female; M: male; MA: migraine with aura; MWoA: migraine without aura; bMRI: brain magnetic resonance imaging scan; aHT: arterial hypertension; ECG: electrocardiography; US: ultrasound; cUS: carotid ultrasound; bCT: brain computed tomography; OC: oral contraceptives; EEG: electroencephalography; WMH: white matter hyperintensities. aAura symptoms listed by order of appearance.
Gender, age
Case nr.
Table 3. Continued.
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10
Cephalalgia 0(0)
Table 4. Comparison between proposed and ICHD-III beta criteria for aura status. Proposed criteria
N Gender
Male Female Age at first consultation Age at aura onset
Aura symptoms
(0–14) (15–29) (30–44) (>44) V V þ SS V þ SS þ LA Any other
ICHD-III beta criteria
Yes
No
Sig.
Yes
No
Sig.
20 (4.4%) 4 (20%) 16 (80%) 54.5 16.7
436 (95.6%) 100 (22.9%) 336 (77.1%) 36.8 12.3
2 ¼ 0.096 (1) p ¼ n.s.
8 (1.8%) 3 (37.5%) 5 (62.5%) 49.1 15.3
448 (98.2%) 101 (22.5%) 347 (77.5%) 37.4 12.9
2 ¼ 0.89 (1) p ¼ n.s.
5 2 7 6 9 4 6 1
91 (30.3%) 130 (43.3%) 54 (18%) 25 (8.3%) 293 (67.2%) 50 (11.5%) 43 (9.8%) 50 (11.5%)
3 2 2 1 4 1 2 1
93 (29.8%) 130 (41.7%) 59 (18.9%) 30 (9.6%) 298 (66.5%) 53 (11.8%) 47 (10.5%) 50 (11.2%)
(25%) (10%) (35%) (30%) (45%) (20%) (30%) (5%)
t ¼ 4.68 (19.95) p < 0.000 2 ¼ 15.68 (3) p ¼ 0.001
2 ¼ 8.42 (3) p ¼ 0.038
(37.5%) (25%) (25%) (12.5%) (50%) (12.5%) (25%) (12.5%
t ¼ 2.55 (451) p < 0.011 2 ¼ 0.953 (3) p ¼ n.s.
2 ¼ 0.804 (1) p ¼ n.s.
ICHD-III beta: ICHD-III: International Classification of Headache Disorders – III beta; V: visual symptoms; SS: sensory symptoms; LA: language and speech disturbances; n.s.: not significant.
hypertension and dyslipidemia. He was recently contacted again and reported a maximum of six episodes in four days. In summary, cases classified as migraine aura status according to our proposed criteria were mostly women with a long-standing history of MA (fulfilling ICHD criteria for aura with typical migraine headache). More than half reported a positive family history, typically mothers and/or sisters. The status periods appeared at a rather late age, with no apparent triggering factors. Patients described a sudden increase of the frequency of aura attacks, often without headache (all auras according to the IHS criteria). Nevertheless, the typical progression of symptoms was similar to their previous auras of classic migraine. Visual phenomena—chiefly positive, like bright lines and flashing lights—were collectively reported, frequently followed by paresthesiae and/or speech disturbances, such as aphasia or dysarthria. Although the majority of patients stated that the attacks resolved within up to 30 minutes, two female patients reported aura episodes lasting for two and three hours. These aura status episodes clustered in 2 to 10 attacks per day for a few days and unexpectedly disappeared until the beginning of another bout, days or weeks later. Between the episodes the patients were asymptomatic. On a followup consultation afterward (average was 5.8 years later), less than half the patients were still experiencing aura status bouts. Neurological and ophthalmological examination, neuroimaging, electroencephalogram (EEG) and Doppler were normal,
revealing no underlying pathology or sequelae, even though a thorough standard investigation has not been conducted in all patients.
Comparison of the two sets of criteria for migraine aura status We performed a comparison between patients with migraine aura status and patients with typical or prolonged aura (excluding cases of persistent aura and hemiplegic migraine) using either the ICHD-III beta or our proposed criteria. Results are presented in Table 4. With both criteria, gender distribution was not significantly different between patients with status and other auras. Patients with status were significantly older at first consultation than other patients with aura, but more so with our own criteria (54.5 16.7 years vs. 36.8 12.3 years). Comparing the frequency in the oldest patients (>44 years) with the other age groups, those with status are older than patients without status, when using our criteria (2 ¼ 10.29 (1) p ¼ 0.001) but not with ICHD-III beta criteria (2 ¼ 0.08 (1) p ¼ n.s.). We also noted that aura symptoms have a different distribution in the two groups, as patients with aura status seem to have more complex auras. This is not evident with the ICHD-III beta criteria since there are only eight subjects, but in our definition, it is possible to observe that the dominance of visual symptoms is lower in status patients.
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Alagoa Joa˜o et al. When we performed a direct comparison between patients fulfilling both criteria (eight patients) and those fulfilling only our criteria (12 individuals), the only significant difference is a female predominance in our series (100% vs. 50%).
Discussion Migraine aura is a neurogenic phenomenon corresponding to the cortical spreading depression (18) described in rodent’s brain in 1944 (19). In experimental conditions, it can be triggered by physical, chemical or other noxious stimuli or spontaneously in transgenic animals with channelopathies. In humans, it is known to occur in ischemia and traumatic brain disease (20–22) or spontaneously in migraine. Aura status is a recognized presentation of migraine with unknown frequency. Using two operational definitions, we found that though rarely reported in literature, its frequency may range between 1.7% and 4.2% in a consecutive series of patients observed in a tertiary headache outpatient center. Most cases previously presented under this diagnosis did not describe the entity of frequent and repetitive aura symptoms. Additionally, various reports included patients with underlying pathology that might not be migrainous in nature, such as epileptic disorders and cerebral primary vascular lesions. It is of particular notice that individuals with secondary aura-like status presented as such from the onset and did not report a previous history of MA. Nonetheless, future studies are needed to confirm these findings. The frequency of episodes required for aura status diagnosis has decreased from the ICHD-II (at least two auras per day for 5 consecutive days) (23) to the ICHD-III beta (at least two auras per day for 3 consecutive days). However, these are still rather strict, leading both to the exclusion of many cases and a bias toward male gender and lower mean age. Even though a more rigorous approach may be useful in research because of the selection of more extreme cases, in daily practice, a clinician will possibly have an identical attitude if a patient has six attacks in three days or four attacks in only one day. Undoubtedly, the focus should be on how to investigate unusual cases and distinguish benign cases from those presenting with signs of a brain catastrophe. In addition, in the literature review, the frequency of aura episodes in secondary cases was not higher than in those patients with no identified underlying pathology. Concerning the analysis of our own series of patients, we found no major differences in the demographic and clinical profile of patients with aura status, when applying the two sets of criteria (stricter ones proposed by the ICHD-III beta and a broader
11 definition allowing less-frequent attacks per day). Our criteria, though less strict concerning attack frequency, resulted in more conservative aura symptoms as most of our patients presented with the typical recognized symptoms of this syndrome (visual and sensory disturbances). This might be a clinical advantage since patients with secondary status gathered from the literature often experienced isolated sensory or motor symptoms. Moreover, our criteria produced a female predominance, which is the usual gender distribution of migraine. However, the number of subjects fulfilling ICHD-III beta criteria is too limited to reach any definitive conclusion. In this report, we concluded that aura status may be more common than previously thought, that most patients had a previous history of MA and were older than patients with typical aura at first consultation (this event usually follows closely the onset of status). Gender distribution, age at MA onset and aura symptoms were identical in both groups, as was the absence of sequelae on brain imaging, suggesting that status may be a benign late manifestation of classic migraine. Our hypothesis is that status aura and MA are the same disorder, as proposed by others (3), and these ‘‘flurries’’ (2) or temporary aura attacks may express an increased pathophysiological vulnerability to migraine stimuli, as if the occipital cortex develops a very low threshold required to trip the sensitive mechanisms involved. In fact, animal studies (24–26) showed amplified long-term potentiation (LTP, a form of synaptic plasticity) and decreased inhibitory adenosine effect on the brain of elderly individuals, both heralding increased cortical excitability with aging. These attacks may also represent a state of amplified vasomotor instability, with transient and spatially restricted changes in cerebral blood flow (27) being more frequent in these older individuals. Additionally, an association with hyperhomocysteinemia is possible (9).The focal and stereotyped nature of aura status, with mainly positive symptoms, suggests that the phenomenon is rather circumscribed and does not spread to neighboring regions, as if the normal inhibitory phenomena were intact in the neighboring cortex. However, its pattern of temporal profile can suggest clustering TIAs or status epilepticus, conditions where a neurological symptom (negative or positive) repeats itself in a short period of time. According to Fisher, 1980 (28) and Haas, 1982 (1) the characteristics that favor migraine attacks are luminous visual images, build-up of images, progression from one aura to another, limited character, benign outcome and the migrainous predisposition of most of the patients; the separate occurrences of various types of attacks (visual, paresthetic and language), the absence of additional epileptic
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Cephalalgia 0(0)
features throughout the episodes and the negative encephalogram weigh against an epileptic pathogenesis. We acknowledge some limitations to this study. Firstly, our series of patients was analyzed retrospectively. Although the descriptions were detailed enough to allow the gathering of data, we believe that prospective studies with standardized questionnaires and investigation are necessary to corroborate the presented hypothesis. Secondly, this study presents the personal experience of a single neurologist, therefore multicentric prospective studies are desirable in order to adequately validate our proposed criteria.
Conclusion Patients with recurring auras in a short period of time will probably raise the same doubts and diagnostic approach independently of the set of criteria applied. Furthermore, two different criteria identified a similar
population in terms of age, symptoms, imaging and outcome from a clinical perspective. Therefore we suggest that the use of a more liberal definition can be valuable, since larger samples of cases will allow diagnostic and therapeutic studies, leading eventually to further knowledge of this syndrome or even its subdivision in subtypes. Since differential diagnosis is imperative in clinical practice, it is important to describe and systematically report these events in order to understand their nature, triggering factors and resolution. The comprehension of these cases may help to understand migraine aura and possibly lead to therapeutic trials and neurophysiologic or functional imaging studies. Additionally, it would be interesting to study the prevalence of vascular risk factors, white matter changes and other possible findings in migraine aura status cases, comparing them to patients with migraine with typical aura.
Clinical implications . Migraine aura status is a transient state characterized by multiple recurring migraine auras in a period of hours or days, with a tendency to occur in older subjects with a previous history of migraine with aura. . The number and frequency of episodes required by International Classification of Headache Disorders-III beta (ICHD-III beta) for this diagnosis is possibly too strict and exclude most cases. . The use of less strict criteria, with a minimum number of 3 episodes in 3 days, resulted in a similar sample of patients and may allow the development of knowledge about this infrequent condition. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest None declared.
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![[Aura with a headache (cafaleia)].](/assets/img/hold.png)
