Aura status: A not so frequent aura

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.

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 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 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 + 0 + 0, 2 + 1 + 0, 1 + 2 + 0, 1 + 1 + 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 <0.05. Data were analyzed with the IBM Statistical Package for the Social Sciences (SPSS) version 20 for Windows (8).

Results

Systematic review of migraine aura status cases

Using the research terms mentioned above, we found a total of 220 articles. Among those, we selected 29 articles reporting patients with aura-like episodes/recurrent stereotyped transient neurological symptoms, based on title and abstract. Of those, seven articles referred to hemiplegic migraine and one to a patient with cluster-like headache with aura. Only 11 articles (a total of 19 case reports) described patients with a large number of consecutive migrainous auras during a short period of time, thus leading to full text assessment for data collection.

Published cases fulfilling these criteria are summarized in Table 1. Altogether there were nine patients fulfilling ICHD-III beta criteria without underlying pathology (Table 1(a)). Most had a previous history of MA and experienced a sudden increase in frequency of mostly visual auras, which was unexplained with no identified triggers. In all of these, physical examination and neuroimaging revealed no pathologic findings. The 10 patients with identified pathology presented different etiologies (Table 1(b)). It is worth noticing that in this group of patients, only one reported a previous history of MA whereas in all others MA first presented as status. Patients with underlying pathology were significantly older at migraine onset, categorized as (<18), (18–45) and (>45) years old (χ²= 10.8, p = 0.004) and at status onset (66.6 vs. 43.1 years, t = −2.6, p = 0.02), presented vascular risk factors more frequently (χ²= 10.4, p = 0.005), had identical frequency of aura episodes (Mann and Whitney U test n.s.), and more sensory and motor auras (χ²= 8.35 (2) p = 0.015), when compared with those without pathology. There were no gender differences between these two groups.

Table 1(a).

Systematic review: Status patients without underlying pathology.

Author, year	Case nr.	Gender, age at aura onset	Age at status onset	Aura typea	Frequency of aura episodes	Recurrence of status	Other clinical findings
Haas, 1982 (1)	1	Male, adulthood	70	Visual, sensory	Intermittent (“several times an hour, hour after hour, day after day”), for 5 weeks	Rare momentary visual symptoms	Normal ophthalmological and neurological exams, bCT and EEG
	2	Male, early adolescence	18	Visual	Up to 100/day, for 8 weeks	No episodes at 2-month follow-up	Normal ophthalmological and neurological exams
Haan et al., 2000 (3)	3	Female, youth	Under 30	Visual	>2/day for at least 5 days	No episodes after oral acetazolamide treatment	Normal neuroimaging, (bCT or bMRI) and EEG
	4	Female, unknown	50	Visual
	5	Male, unknown	53	Visual, sensory			Normal bCT EEG showed occipital slow waves
	6	Female, unknown	23	Visual		Unknown
Cupini and Stipa, 2007 (9)	7	Male, 12	57	Visual, sensory	2–4/day for two weeks	No episodes at 18-month follow-up	aHT (treated with ACEi) Hyperhomocysteinemia Normal bCT and transcranial Doppler (tDoppler) bMRI showed subcortical white matter hyperdensities (T2)
	8	Female, 25	28	Visual, sensory	3/day for 10 days	No episodes at 10-month follow-up	Hyperhomocysteinaemia Normal bCT, bMRI and tDoppler
Reinecke and Silberstein, 2007 (10)	9	Male, 24	60	Visual	Up to 8–10/day for a few weeks	Episodes up to the age of 76	Normal ophthalmological and neurological exams, bMRI and bMRA

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.

Table 1(b).

Systematic review: Status patients with underlying pathology.

Author, year	Case nr.	Gender, age at aura and status onset	Previous MA	Aura-like symptomsa	Frequency of aura episodes	Other clinical findings	Treatment and recurrence of status
Verma et al., 1996 (11)	10	Female, 60	No	Visual	1–3 attacks/day for some weeks (followed by headache)	aHT, diabetes Normal neurologic, ophthalmological exams and bCT bMRI revealed a right occipital lobe tumor	Phenytoin 300 mg/day Corticosteroids (patient refused surgery) No episodes, on a 6-month follow-up
Klingbiel et al., 2008 (12)	11	Male, 62	No	Paresis, aphasia, visual	Up to 10 attacks/day (not followed by headache)	aHT, obesity bCT normal on admission, later showed hypodensity in the left frontal region Duplex US and DSA showed 95% left ICA stenosis	Clearance of symptoms after thrombendarterectomy
Kleinig et al., 2008 (13)	12	Male, 81	No	Paresis	Up to 10 in 3 days (not followed by headache)	aHT, AF on warfarin bMRI showed SH and WM disease; microbleeds demonstrated by GE sequences Normal MRA, DWI and EEG	Valproate (symptoms decreased) Prednisolone (episodes ceased)
	13	Male, 73	No	Sensory	7 in 2 days (not followed by headache)	aHT, diabetes, previous TIAs on warfarin bMRI showed acute SH and WM disease; Microbleeds evident on GE sequences Normal DWI and EEG	Valproate, no recurrence after 6 months
	14	Male, 82	No	Sensory, paresis, dysarthria	6 in 2 days (not followed by headache)	aHT, on antiplatelet therapy bMRI showed SH, WM disease and cortical hemorrhages; GE showed cortical siderosis Normal DWI	No episodes, after antiplatelet therapy cessation
Izenberg et al., 2009 (14)	15	Male, 85	No	Sensory	6 in 2 days (not followed by headache)	aHT, coronary disease and dyslipidemia Normal neurological exam, EEG and EcoCG bCT and bMRI showed SH	Phenytoin Continued aspirin and clopidogrel No episodes, on a 16-month follow-up
	16	Male, 79	No	Sensory, paresis	3 in 2 days (not followed by headache)	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	Clopidogrel No episodes, on a 7-month follow-up
Holzer et al., 2009 (15)	17	Female, 28	Yes, since the age of 17	Visual, sensory	Daily attacks for 6 weeks (followed by headache)	Smoker CD, on prednisolone 20 mg/day Minor ataxia of left arm and gait instability Neuroimaging and CSF findings compatible with cerebral vasculitis	Full recovery after prednisolone 1000 mg/day and anticoagulation with heparin
Field and Kleinig, 2010 (16)	18	Female, 81	No	Sensory, paresis	4 in 4 days	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	Phenytoin Valproate (no recurrence)
Italiano, 2011 (17)	19	Female, 35	No	Visual	Several times/day for one week	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	Lysine acetylsalicylate 500 mg (no improvement) Gradual resolution on dexamethasone 8 mg/day and phenobarbital 100 mg/day

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: diffusion-weighted imaging; EEG: electroencephalography; TIA: transient ischemic attack; EcoCG: echocardiography; CD: Crohn’s disease; CSF: cerebral spinal fluid. ^aAura symptoms listed by order of appearance.

Personal clinical data

Review of clinical records

We reviewed the files of the last 500 consecutive patients clinically diagnosed as MA observed in an outpatient clinic for tertiary care specializing in headache. A total of 23 cases were excluded because, according to the clinical records, patients did not fulfill International Headache Society (IHS) diagnosis criteria for MA, most of them because of a single aura attack. Their mean age at the time of first consultation was 37.4 ± 12.9 years (range 18–89 years) and the majority (364), 76.3%, were women. MA onset had occurred before the age of 14 years in 29.7% of patients, between 15 and 29 years of age in 41.2.% and between 30 and 44 years in 19.4%. Only 9.7% of patients had aura with typical migraine headache beginning after the age of 45 years.

As shown in Table 2, a detailed retrospective review of the patients’ files revealed that up to the time of their first consultation most individuals (85.5%) had only typical migraine aura attacks, while about 5.9% had experienced episodes of migraine with prolonged aura (the second most common subtype). Migraine with persistent aura without infarction was less commonly reported, with only four patients (0.8%), half of whom are men, describing aura attacks lasting for at least one week. There were 17 patients (3.6%) with hemiplegic migraine and nearly two-thirds were familial. Among the 477 patients with MA, there were either eight (1.7%) by ICDH-III beta or 20 (4.2%) by our proposed criteria, with aura status.

Table 2.

Migraine with aura subtypes: Patients’ diagnosis according to ICHD-III criteria.

MA subtypes	Total		Male		Female		Age at first consultation (years)	Aura symptoms
	n	%	n	%	n	%		V		V + S		V + S + LA		Motor		Any other
								n	%	n	%	n	%	n	%	n	%
Only typical	408	85.5	93	22.8	315	77.2	36.9 ± 12.4	280	68.6	45	11	39	9.6	0	0	44	10.8
Prolongeda	28	5.9	7	25	21	75	35.2 ± 10.3	13	46.4	5	17.9	4	14.3	0	0	6	21.4
Persistent	4	0.8	2	50	2	50	30 ± 12.2	3	75	1	25	0	0	0	0	0	0
Hemiplegic	17	3.6	7	41.2	10	58.8	34.4 ± 10	0	0	1	5.9	14	82.4	17	100	2	11.8
Status	20	4.2	4	20	16	80	54.5 ± 16.7	9	45	4	20	6	30	0	0	1	5
Total	477	100	113	–	364	–	–	–	–	–	–	–	–	–	–	–	–

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).

Aura status case description

All cases classified as aura status according to our operational criteria are presented in Table 3. Below, we present a detailed description of four illustrative cases, focusing on the type of symptoms and their temporal profile.

Table 3.

Aura status cases.

Case nr.	Gender, age	Family history	Migraine type, age at onset	Frequency and duration of status period	Aura type (duration)a	Associated headache	Duration of follow-up period	Recurrence of status	Vascular risk factors	Other clinical findings	ICHD- III beta criteria for status
1	F, 45	No	MA, 42	1/day for 8 days	Visual, sensory, language (25–30 min)	Yes	1 year	No (after treatment)	Smoking	Normal bMRI, except for mild tonsillar ectopia	No
2	F, 77	Yes	MA, >45	4/day for 1 day	Visual, language (30 min)	Not always	8 years	No	aHT	Normal ECG, cUS and bCT	No
3	F, 41	Yes	MWoA, youth MA, 40	≥3/day over 3–4 days/week	Visual (30 min)	Yes	9 years	Yes	Prolonged use of OC	Normal EEG and bCT	No
4	F, 44	Yes	MA and acephalgic migraine, 14	≥2/day for 3–7 days	Visual, language, sensory (2–3 hours)	Not always	11 years	Yes	Smoking, dyslipidemia	WMH (within normal limits)	Yes
5	F, 55	Yes	MWoA, 16 MA, >45	2/day for >1 day	Visual, language (30 min)	Not always	11 years	Yes	None	Normal cUS and bCT Parkinson’s disease	No
6	F, 62	Yes	MA, youth	2–10/day for 15 days	Visual (15–30 min)	Not always	8 years	Yes	None	Normal ophthalmological exam and bCT WMH (within normal limits)	Yes
7	F, 63	Yes	MA, 12	1/day for 4 days	Visual, sensory, language (30 min)	Yes	10 years	Yes	None	Normal ophthalmological and neurological exam	No
8	M, 37	Yes	MA, youth	1–2/day for 4 days	Visual, sensory, language (5–15 min)	Not always	9 years	Yes	aHT, dyslipidemia	Normal bCT	Yes
9	F, 39	Yes	MA, youth	3/day for 1 day	Visual (40–120 min)	Not always	None	Unknown	None	Normal bCT and cUS WMH (within normal limits)	No
10	F, 46	No	MA, 39	1/day for 6 days	Visual (30 min)	Yes	6 years	Yes	None	Normal cUS and vertebral US, EEG and visual evoked potentials WMH (within normal limits)	No
11	F, 40	Yes	MWoA, 15 MA, 25	≥3/day for 3–8 days	Visual, sensory	Not always	4 years	Yes	None	Normal bMRI and cUS	Yes
12	F, 49	Yes	MWoA, 14 MA, 49	3/day for 1 day	Visual (30 min)	Not always	None	Unknown	Smoking, dyslipidemia	Normal ophthalmological exam, bCT and EEG	No
13	F, 44	Yes	MA and acephalgic migraine, 41	1/day for 3 days	Sensory, language, visual (20 min)	Not always	None	Yes	None	Normal bMRI	No
14	F, 89	Yes	MA, 30	2/day for ≥2 days	Visual, sensory, language	Yes	2 years	No	aHT, dyslipidemia	Normal bCT and bMRI	No
15	M, 48	No	MA, 39	≥3/day for a few days	Visual (15–20 min)	Not Always	None	Yes	None	Normal bCT, bMRI and cUS	Yes
16	F, 27	No	MA, 22	Intermittent for 3 days	Visual	Yes	None	Unknown	None	Normal ophthalmological and neurological exam	Yes
17	M, 69	Yes	MA, 62	3/day for 1 day	Visual	Not always	None	Unknown	aHT	Normal ophthalmological and neurological exam	No
18	F, 74	No	MWoA, youth aura, 73	≥2/day for 3 days	Visual, language (20 min)	No	2 years	Yes	Smoking, aHT, dyslipidemia	Normal cUS and bCT	Yes
19	F, 81	Yes	MWoA, youth MA, 50	2/day for 2 days	Visual (10–15 min)	Not always	10 years	No	Dyslipidemia	Normal cUS and bCT	No
20	M, 63	No	MA, 30	≥2/day for a few days	Visual (30 min)	No	1 year	No	aHT, dyslipidemia	Mitral valve prolapse	Yes

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.

Case 1

A 45-year-old woman had suffered from MA for about three years, experiencing two to three attacks per year. The typical attack began with scintillating scotomata (“a shining golden chain”) on the right visual field, lasting 5 to 10 minutes and leaving an area of visual loss. Subsequently, she felt paresthesiae in her right fourth and fifth digits that spread upward to the arm and to the right side of the mouth and nose (in five to 10 minutes), followed by speech disturbances. As the aura cleared, she developed an intense throbbing headache on the right orbit and temple with nausea, pallor and photo- and phonophobia that lasted about two hours with nonsteroidal anti-inflammatory drug (NSAID) therapy. The episodes became more frequent two months before the first visit, with daily auras (without headache) for eight consecutive days. She was a heavy smoker but had no other vascular risk factors. Neurological examination was normal and magnetic resonance imaging (MRI) revealed a mild ectopia of the cerebellar tonsils. She was prescribed sodium valproate 500 mg twice daily with a decrease of aura frequency to three attacks per month. Two years later, when reducing that dose, she experienced seven attacks in 15 days that improved as she increased the dose.

Case 2

A 77-year-old woman described a long history of migraine with visual aura. Attacks began with a sensation of visual blurring followed by scintillating scotomata with geometric shapes that spread slowly (for 15 minutes) in one side of the visual field, leaving an area of poor vision behind. The aura changed side between attacks and was occasionally followed by speech disturbances, with all symptoms lasting for 30 minutes. Aura was followed by a generalized intense and 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 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 follow-up 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.

Table 4.

Comparison between proposed and ICHD-III beta criteria for aura status.

		Proposed criteria		Sig.	ICHD-III beta criteria		Sig.
		Yes	No		Yes	No
N		20 (4.4%)	436 (95.6%)		8 (1.8%)	448 (98.2%)
Gender	Male	4 (20%)	100 (22.9%)	χ2 = 0.096 (1) p = n.s.	3 (37.5%)	101 (22.5%)	χ2 = 0.89 (1) p = n.s.
	Female	16 (80%)	336 (77.1%)		5 (62.5%)	347 (77.5%)
Age at first consultation		54.5 ± 16.7	36.8 ± 12.3	t = −4.68 (19.95) p < 0.000	49.1 ± 15.3	37.4 ± 12.9	t = −2.55 (451) p < 0.011
Age at aura onset	(0–14)	5 (25%)	91 (30.3%)	χ2 = 15.68 (3) p = 0.001	3 (37.5%)	93 (29.8%)	χ2 = 0.953 (3) p = n.s.
	(15–29)	2 (10%)	130 (43.3%)		2 (25%)	130 (41.7%)
	(30–44)	7 (35%)	54 (18%)		2 (25%)	59 (18.9%)
	(>44)	6 (30%)	25 (8.3%)		1 (12.5%)	30 (9.6%)
Aura symptoms	V	9 (45%)	293 (67.2%)	χ2 = 8.42 (3) p = 0.038	4 (50%)	298 (66.5%)	χ2 = 0.804 (1) p = n.s.
	V + SS	4 (20%)	50 (11.5%)		1 (12.5%)	53 (11.8%)
	V + SS + LA	6 (30%)	43 (9.8%)		2 (25%)	47 (10.5%)
	Any other	1 (5%)	50 (11.5%)		1 (12.5%	50 (11.2%)

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.

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 (χ²= 10.29 (1) p = 0.001) but not with ICHD-III beta criteria (χ²= 0.08 (1) p = 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.

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 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 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.