Chronic migraine characterized by prolonged bilateral visual and brainstem aura: a case report and literature review

Abstract

Migraine aura manifests as various neurological symptoms, which may occur before, during, or persist throughout the headache phase. We report a case of a 30-year-old female patient whose initial symptoms included persistent bilateral photopsia and ophthalmoplegia, accompanied by headache, with a medical history spanning over four years. The duration of her auras was up to one month. After admission, through detailed inquiry into her medical history and extensive etiological screening, the patient was diagnosed with chronic migraine (CM). Following preventive treatment for CM, her symptoms significantly improved. This case serves to encourage neurologists to expand their diagnostic thinking in clinical practice. When encountering sudden and unexplained persistent neurological symptoms, the possibility of migraine with persistent aura should be considered.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12883-026-04732-9.

Introduction

Migraine is a highly prevalent and disabling neurological disorder, with a prevalence that is two to three times higher in women than in men [1]. The typical manifestations of this disease include unilateral, pulsating moderate to severe headache, often accompanied by symptoms such as nausea, vomiting, photophobia, and phonophobia, with a duration of 4 to 72 h. This condition often affects people during their most productive years, exerting substantial costs on both individuals and society [2]. In the Global Burden of Disease (GBD) study 2019, migraine ranked as the second leading cause of disability and topped the list for women under 50 years of age [3]. However, correct diagnosis and standardized treatment for migraine remain inadequate in China. A population-based survey of headache disorders in China revealed that, while the clinic attendance rate among migraine patients is nearly a half, the correct diagnosis rate is only 13.8% [4]. Another study investigated the utilization of preventive medications in neurology outpatient clinics and found that only 2.7% of migraine patients had received preventive treatment [5].

According to the International Classification of Headache Disorders, third edition (ICHD-3), migraine can be divided into episodic migraine (EM) and chronic migraine (CM) [6]. The former is further classified into migraine without aura (MwoA) and migraine with aura (MwA). MwoA is a clinical syndrome characterized by typical headache features and associated symptoms, while MwA is distinguished by transient focal neurological deficits occurring before or during the headache phase [6]. CM may develop from either MwoA or MwA, and is defined as headache occurring on at least 15 days per month for 3 months, with at least 8 of these days fulfilling the criteria for migraine [6]. Compared with MwoA, MwA is clinically less common. Data from a population-based study in Denmark shows that the annual prevalence of MwA is 4.1%, while MwoA is 8.2% [7]. Furthermore, the annual prevalence of MwA in females (5.3%) is also significantly higher than that in males (1.9%) [8]. Migraine auras typically include six types: visual, sensory, speech, motor, brainstem, and retinal. Among these, visual aura is the most common, followed by sensory aura, while other types of auras are relatively rare [8]. Additionally, visual, sensory, and speech auras are considered typical aura symptoms, most of which resolve spontaneously within 1 hour. When an aura lasts ≥ 1 week and neuroimaging shows no infarction, it is diagnosed as persistent aura without infarction (ICHD-3 1.4.2) [6]. It is worth noting that, although rare, a small number of patients may experience the persistent presence of multiple aura symptoms. Herein, we report a case of a migraine patient who simultaneously exhibited visual and brainstem auras. We also review and summarize relevant literature on migraines with persistent auras, aiming to provide new insights for the diagnosis and treatment of such migraines.

Case report

A 33-year-old female patient was admitted due to headache, bilateral photopsia, and ophthalmoplegia, all of which had been present for more than 4 years. She had no prior history of migraine and other diseases. In early January 2019, the patient suddenly developed blurred vision in both eyes without identifiable triggers, subjectively describing bright light sensations across the entire bilateral visual fields, and difficulty moving eyes in all directions. Approximately 10 minutes later, the patient experienced right temporal distending pain without other accompanying symptoms. The patient subsequently sought care at a hospital in Heze City, where cranial MRI and laboratory tests showed no abnormalities. A preliminary diagnosis of “immune-mediated inflammatory disorder” was made. After receiving methylprednisolone 1 g pulse therapy (exact treatment duration unknown), the patient’s visual abnormalities and ophthalmoplegia showed no improvement, though the headache resolved spontaneously (single episode duration ≤ 2 days). By mid-January 2019, the patient was transferred to a hospital in Weifang City. Lumbar puncture results revealed no significant abnormalities (medical records incomplete), and a possible diagnosis of “depression” was considered. Treatment with valproate and venlafaxine (specific regimen unknown) led to gradual complete resolution of symptoms. Notably, the visual symptoms and ophthalmoplegia persisted from onset to complete resolution for up to one month. In July 2019, the patient experienced symptom recurrence with similar but more severe manifestations. Detailed history-taking at our hospital revealed that recurrent headache episodes were frequently accompanied by nausea (without vomiting), photophobia, phonophobia, and emotional irritability, exacerbated by fatigue and cold exposure (Visual Analog Scale score: 7–8). Since symptoms remained relatively stable with attack frequencies of 5–6 episodes/month in winter and 1–2 episodes/month in summer (each episode lasting several minutes), the patient did not seek further treatment. Beginning in March 2023, the patient’s condition significantly worsened with headache frequency increasing to daily episodes. Each attack was accompanied by 2–4 h of bilateral photopsia and ophthalmoplegia, with the headache resolving immediately upon symptom cessation. The patient had intermittently used Fenbid (ibuprofen, < 15 days/month) for pain relief with suboptimal effect. During this period, 2–3 transient tinnitus episodes occurred (each episode lasting 5–10 minutes). In May, the patient presented to our outpatient clinic with a provisional diagnosis of migraine. Although naproxen provided partial pain relief, the disease progressed with daily episodes lasting 4–6 hours. By mid-July admission, symptom duration had further extended to 9 hours per episode. The patient had never received standardized prophylactic treatment. The visualization of the disease progression is shown in Fig. 1.

Fig. 1.

The visualization diagram of the disease progression

The examinations performed after admission to our hospital are as follows:

Physical Examination: During the ictal period, the patient’s vision was limited to hand motion perception, accompanied by bilateral esotropia and restricted ocular motility in all directions (incomplete and episodic dysfunction). The pupil diameter was 3.5 mm with sluggish light reflex, and no other abnormalities were noted. During the interictal period, the patient appeared completely normal.

All auxiliary examination results were negative, including blood tests, liver and kidney function, thyroid function, antinuclear antibodies, pituitary-related hormones, electrocardiogram, echocardiography, transcranial Doppler ultrasound bubble test, and ophthalmological examination (including intraocular pressure, fundus examination, and optical coherence tomography). Visual evoked potentials were normal. Cerebrospinal fluid (CSF) analysis and autoimmune encephalitis-related tests were also normal. A sleep electroencephalogram (EEG) during the ictal period and magnetoencephalography (MEG, during the interictal period, Fig. 2) were both normal. The patient could not cooperate during the ictal period and did not complete the MEG scan during that time. Prior to treatment, positron emission tomography (PET) and non-contrast magnetic resonance imaging (MRI) revealed decreased metabolism in the left hippocampus, temporal lobe, and temporo-occipital junction. All MRI sequences, including T1-weighted, T2-weighted, fluid attenuated inversion recovery (FLAIR), diffusion weighted imaging (DWI), arterial spin labeling (ASL), magnetic resonance angiography (MRA), and magnetic resonance venography (MRV), were normal (during the ictal period, Fig. 3A). One week after treatment, a follow-up PET/MRI showed significant improvement in the reduced metabolism in the left hippocampus, temporal lobe, and temporo-occipital junction, with no other abnormalities (during the interictal period, Fig. 3B).

Fig. 2.

The MEG examination during the interictal period.

The patient’s interictal MEG showed no epileptiform discharges in the cerebral cortex. There were more low-amplitude fast waves visible in the bilateral frontal and temporal regions

Fig. 3.

Axial 18-FDG PET/MRI during the ictal and interictal period.ABefore initiating treatment, the 18-FDG PET scan during the ictal period of the patient revealed reduced radiotracer uptake in multiple brain regions, including the left hippocampus (blue arrow), left temporal lobe (white arrow). B After a re-examination on the fifth day of treatment, it was found that there was a significant improvement in the metabolism of the cortical brain region during the interictal period compared to before. 18 F-FDG PET, 18 F-fluorodeoxyglucose PET

Differential diagnosis

During the patient’s initial visit to a hospital in Heze City, although ancillary tests revealed no significant abnormalities, the persistent bilateral ophthalmoplegia led physicians to initially suspect an autoimmune inflammatory disorder. High-dose glucocorticoid pulse therapy was administered, but symptoms showed no improvement. After referral to another hospital in Weifang City, a lumbar puncture was performed, ruling out infectious or inflammatory neurological disorders, and the patient was ultimately diagnosed with depression. The presence of ophthalmoplegia significantly complicated the diagnostic process, as it can occur in various conditions, including Miller-Fisher syndrome, myasthenia gravis, brainstem lesions, and other immune-mediated or structural diseases [9–10]. Therefore, in patients with acute-onset ophthalmoplegia, secondary causes must be thoroughly investigated.

This patient had no history of infection, and the neurological examination only revealed involvement of the oculomotor nerves, allowing for the exclusion of Miller-Fisher syndrome. There were no fluctuations or fatigue, and not any bulbar symptoms, any limb weakness, thus ruling out the possibility of myasthenia gravis. Blood tests, CSF analysis, and MRI results were normal, and no brainstem or cavernous sinus lesions, nor intracranial vascular abnormalities, were found, further excluding Tolosa-Hunt syndrome, intracranial aneurysms, and other immune-inflammatory diseases. The patient had no history of diabetes, and ophthalmic examination revealed no structural damage, thus excluding diabetic ophthalmoplegia. Considering the sudden onset and complete reversibility of the patient’s symptoms, it was initially speculated that the symptoms might be related to paroxysmal brain diseases, including transient ischemic attack (TIA), recurrent painful ocular myopathy (RPON), epilepsy, and migraine [10–12]. The patient was young, had no risk factors for cerebrovascular disease, and no intracranial vascular stenosis was observed, thus ruling out TIA. RPON typically presents as unilateral ophthalmoplegia, and bilateral involvement is rare; it is also often associated with intracranial organic lesions, so it was excluded in this case [11]. Although epilepsy and migraine often coexist and share overlapping symptoms, the aura in epilepsy usually lasts for a shorter duration (< 5 minutes) and is commonly accompanied by limb convulsions, involuntary movements, urinary incontinence, and consciousness disturbances [12]. We performed comprehensive ictal monitoring via sleep EEG without detecting epileptiform discharges, but simultaneously conducted MEG to refine the differential diagnosis. MEG detects nanotesla-scale magnetic fields from synchronized neuronal activity noninvasively, providing both millisecond temporal resolution and millimeter-scale spatial localization. Limited by patient compliance, we only obtained interictal MEG data. Characteristic analyses demonstrated that epilepsy patients during interictal periods typically show focal spike/sharp wave discharges, prolonged somatosensory evoked field latency, and enhanced auditory evoked field amplitudes. In this case, systematic MEG evaluation including both resting-state and evoked responses revealed neither epileptiform discharges nor these characteristic pathological patterns, allowing us to definitively exclude epileptic seizures when combined with clinical manifestations. Based on the patient’s medical history, her headache characteristics met the criteria for migraine. After excluding other potential causes of persistent bilateral photopsia and ophthalmoplegia, we considered that the patient was most likely to be diagnosed with migraine with aura. Photopsia is a positive visual aura symptom, while ophthalmoplegia is one of the brainstem aura manifestations. According to the ICHD-3 criteria, the diagnosis of migraine with brainstem aura (ICHD-3 1.2.2) requires the presence of at least two brainstem symptoms (such as vertigo, diplopia, tinnitus, or ataxia). Throughout the clinical course, the patient experienced only 2–3 episodes of tinnitus, each lasting more than 5 min, but these were easily overlooked due to their low frequency and lack of significant concern from the patient. During ictal periods, the patient developed impaired ocular motility in all directions with visual acuity reduced to hand motion perception only, which explains the absence of reported diplopia. Ophthalmologic examination confirmed bilateral oculomotor, trochlear, and abducens nerve palsies during attacks. Combined with intermittent tinnitus, these findings meet the diagnostic criteria for migraine with brainstem aura. The patient was unable to complete Doll’s eye reflex testing during acute attacks due to severe headache, precluding precise localization of the ophthalmoplegia. However, the completely normal neurological examination during interictal periods, along with normal pupillary size but sluggish light reflexes, suggests that the ocular motility disorder is more likely attributable to central regulatory dysfunction (supranuclear origin). Previous studies have established that cortical spreading depression (CSD), the core pathophysiological mechanism of migraine aura, typically originates in the occipital cortex before propagating to other cortical areas and the brainstem, providing further support for this diagnosis.

Migraine auras can present as various focal neurological deficits. Although typical auras usually last less than one hour, some studies have reported that auras can last longer. The first edition of the ICHD defined migraine with aura lasting longer than 60 min but less than a week as migraine with prolonged aura [13]. However, this definition was removed in the second and third editions of the ICHD [6, 14]. According to the ICHD-3 criteria, non-hemiplegic auras lasting more than a week are classified as persistent aura without infarction, while those lasting 60 min to 7 days are classified as possible migraine with aura (prolonged aura) [6]. In this case, the patient initially experienced persistent aura lasting approximately one month. Brain MRI performed at a local hospital showed no evidence of infarction, consistent with persistent aura without infarction (ICHD-3 1.4.2) [6]. When the symptoms recurred, exhibiting features of migraine with prolonged aura. Prior to admission to our hospital, the headache frequency was daily, with more than 8 days per month meeting criteria for migraine headache, fulfilling the diagnostic criteria for CM (ICHD-3 1.3) [6].

Treatment and follow-up

The patient received a preventive combination treatment for migraines, which included 500 mg of valproate sodium taken nightly, 25 mg of topiramate taken twice daily, 75 mg of pregabalin taken daily, and 75 mg of venlafaxine taken daily. By the fifth day, the patient’s aura symptoms had completely disappeared, leaving only mild headache. After discharge, the patient adhered to the prescribed medication regimen. One year later, during a follow-up phone call, the patient reported no recurrence of aura symptoms, only occasional mild to moderate headaches.

Discussion

The significant feature of this case is the simultaneous and persistent presence of both visual and brainstem auras, with the longest duration lasting up to 1 month. Although cases of migraine with persistent auras are not uncommon, the simultaneous persistence of multiple aura symptoms is still relatively rare. We conducted a PubMed search for literature published between 1874 and October 2024 using the search terms “migraine” or “aura,” “persistent” or “extended” (without language restrictions), identifying 39 relevant studies (Table 1) [15–51]. These studies reported a total of 137 patients, including 64 with persistent migraine auras without infarction (PMA), 70 with migraine accompanied by prolonged auras, and 3 who experienced one episode of migraine with aura and one episode of migraine with prolonged aura. Among these patients, 25 exhibited multiple persistent or prolonged aura symptoms. We performed a statistical analysis of these patients, which revealed an average age of 36.4 years, with a higher female prevalence (male-to-female ratio of 1:3). Visual symptoms were the most common aura, and among patients with multiple aura symptoms, the vast majority had a combination of visual and sensory auras. Our statistical findings are consistent with a review study that examined PMA literature from 1991 to 2014, including 47 patients. The study found that visual auras were the most common persistent aura symptoms and more frequently occurred in females. It also reported that the average age of onset for PMA was 30 years, with aura durations ranging from 9 days to 28 years, and most patients had a known history of migraines[44]. It is noteworthy that this patient progressively developed CM from recurrent migraine with prolonged aura. Although the first edition of ICHD explicitly classified aura duration exceeding 60 min as “migraine with prolonged aura,” this classification was removed in ICHD-II and subsequent versions, likely due to its low clinical incidence and insufficient research evidence. In fact, current clinical data suggest that prolonged aura phenomena are not uncommon in clinical practice. A prospective study using electronic diaries to document symptoms during three consecutive aura episodes in 54 patients revealed that 26% of participants experienced at least one aura episode lasting over 1 hour. The most frequently recorded aura symptoms were visual disturbances, sensory abnormalities, and speech impairments [52]. Based on this patient’s clinical characteristics, we propose that recording migraine aura duration and type is clinically valuable, even without atypical features. This approach not only facilitates precise staging of attacks but also reduces diagnostic uncertainty. Moreover, the disease progression observed in this case due to delayed preventive treatment underscores the importance of establishing clear initiation criteria for preventive therapy in patients with a history of prolonged aura. These clinical observations may provide substantial empirical evidence for future revisions of the ICHD diagnostic criteria. Recently, a study reported a 24-year-old male patient from India who experienced diplopia and bilateral ophthalmoplegia lasting for 4 weeks. The patient had a clear history of visual and sensory auras during childhood. After extensive examination, he was diagnosed with PMA [49]. Our case is similar to this report, but differs in that our patient had no history of migraines and presented with persistent bilateral visual brightness and ophthalmoplegia at onset, which made the diagnosis more challenging and may have been confused with other neurological conditions.

Table 1.

Migraine with persistent or prolonged aura: 137 cases from literature

Authors (years)	n	Age of patient	F/M	Type of aura	Duration of aura	Investigation(s)	Medication and effects
Haas et al. (1982)[15]	2	18, 70	0/2	Visual; Visual and sensory	7 mo; 5 wk	CT/EEG: normal	Aspirin - ineffective; Cyproheptadine - effective
Luda et al. (1991)[16]	1	65	1/0	Visual	> 12 mo	CT/MRI: normal; SPECT: hypoperfusion in the left hemisphere	Carbamazepine, diazepam, flunarizine, nimodipine and citicoline - all ineffective
Liu et al. (1995)[17]	10	32, 26, 29, 9, 67, 37, 20, 30, 23, 36	6/4	Visual	> 1 mo; >1 yr	MRI/SPECT: abnormal	Verapamil, acetylsalicylic acid, amitriptyline, carbamazepine; fluoxetine, baclofen, buspirone, phenytoin, verapamil, nifedipine, phenobarbital, ibuprofen, nortriptyline, nifedipine
Renzi et al. (1997)[18]	1	27	1/0	Brainstem	> 1 wk	EEG: normal	Sandomigran
Rothrock et al. (1997)[19]	2	53, 61	2/0	Visual and sensory	> 2 mo; >4 yr	MRI/EEG: normal	Divalproex sodium - effective for one patient, partially effective for another
Kowacs et al. (1999)[20]	1	42	1/0	Visual.	1.5 h	MRI: normal	Sumatriptan - partially effective
Bento et al. (2000)[21]	1	30	0/1	Visual	6 d	EEG/CT: normal	Propanolol - effective
Rozen et al. (2001)[22]	2	34, 37	2/0	Visual; Visual, sensory and motor	Visual: >2 d; Visual: 24 h, sensory: 3 h, and motor: 5 h	MRI/MRA: normal	Furosemide - effective for one patient, partially effective for another; Prochlorperazine, methylprednisolone, divalproex sodium, magnesium, droperidol - all ineffective to aura
Evans et al. (2000)[23]	1	33	1/0	Sensory	> 11 d	MRI/MRA: normal	Furosemide and verapamil - effective
Chen et al. (2001)[24]	2	24, 45	2/0	Visual	> 3 mo; >3 yr	MRI/EEG/VEP: normal; SPECT: occipital hypoperfusion	Lamotrigine - effective
Smith et al. (2002)[25]	1	66	1/0	Visual, speech and motor	1 h − 1 wk	EEG: intermittent, irregular focal δ/θ slowing; T1WI: contrast leakage in the left anterior and temporal lobes; MRA: normal	Steroids and divalproe - effective
Rozen et al. (2003)[26]	2	27, 28	2/0	Visual; Brainstem, motor and sensory	1 h -1 wk	MRI/MRA/MRV: normal; MRI/MRA: an old right frontal cortical infarct, multiple areas of intracerebral arterial stenosis	Prochlorperazine and magnesium sulfate - effective for one patient, recurrent for another
Relja et al. (2005)[27]	1	43	1/0	Visual	> 1 wk	SPECT/PWI: decreased left fronto-parieto -occipital and right occipital blood perfusion	Lamotrigine
Jäger et al. (2005)[28]	4	39, 46, 27, 32	4/0	Visual	> 1 wk	MRI: normal	Acetazolamide, amitriptyline, pizotifen and propranolol and acute treatment with intranasal ketamine, sodium valproate, flunarizine, topiramate, and dothiepin - all ineffective
Resnick et al. (2006)[29]	1	56	0/1	Visual	18 h	MRA: normal; FLAIR: increased signal along the parieto-occipital cortex associated with gyral effacement; DWI: high confluent signal	Valproic acid - effective
Schulz et al. (2007)[30]	4	32, 30, 58, 41	4/0	Visual; Visual and sensory; Visual, sensory and speech.	1–24 h; > 1 week	1 H-MRS: the PCr/Pi ratio decreased significantly	-
San-Juan et al. (2007)[31]	1	28	1/0	Visual	35 d	fMRI: left occipital activation; PWI: decreased transit mean time in right frontal region	Nimodipine - probably effective
Koyama et al. (2007)[32]	1	46	1/0	Visual	4 yr	MRI/SPECT/EEG/VEP: normal	Antiepileptics, antiheadache drugs, antidepressants, antipsychotics and other drugs - all ineffective
Wang et al. (2008)[33]	6	26, 37, 56, 41, 51, 27	4/2	Visual	10 year; 5 year; 20 + yr; nearly 1 year; 1 year; 2yr	-	Propranolol, sumatriptan, lamotrigine, topiramate, flunarizine and amitriptyline, duloxetine, valproic acid, verapamil, flurbiprofen, diclofenac, naproxen, ergotamine/caffeine, paracetamol, indomethacin
Go´mez-Choco et al. (2008)[34]	1	22	1/0	Sensory	> 1 h	CT/MRA: normal; FLAIR: sulcal hyperintensity surrounding the left temporal lobe in several slices all the way up to the convexity	-
Bereczki et al. (2008)[35]	1	58	0/1	Visual	15 d	FSE: mild edema in left occipital cortex; DWI: lesion at same location; EEG: reduced alpha activity	-
Almeida et al. (2009)[36]	1	11	1/0	Visual	4 mo	MRI: normal	Atenolol - partially effective; Furosemide - effective
Razeghinejad et al. (2009)[37]	1	25	1/0	Visual	4 mo	MRI/MRA/TCD/EEG: normal	Sodium valproate and propranolol-ineffective
Belvís et al. (2010)[38]	1	41	1/0	Visual and sensory	9 d	MRA/T1/T2/FLAIR/ DWI: normal; ADC: signal disturbance in left occipital lobe	Rizatriptan and ibuprofen - partially effective
Chen et al. (2011)[39]	6	25, 36, 55, 40, 50, 26	4/2	Visual	> 1 wk	MEG: persistent hyperexcitability of the visual cortex without interictal-ictal variation	-
Sethi et al. (2012)[40]	1	14	1/0	Visual	One episode: 5d; another episode: 4.5 wk	MRI/MRA/TCD/EEG: normal	Methylphenidate and topiramate - ineffective; Aspirin - effective
Simpson et al. (2013)[41]	1	12	1/0	Visual	3 yr	MRI: a small arachnoid cyst in the medial left temporal fossa; VEP/EEG: normal	Sumatriptan, riboflavin, flunarizine, occipital nerve injections, acetazolamide -ineffective Topiramate - partially effective
Bruen et al. (2013)[42]	1	14	1/0	Visual	6 wk	EEG: mild right hemispheric wave slowing; PET: mild occipital hypermetabolism, cuneus hypometabolism; MRI: normal	-
Lim et al. (2014)[43]	1	21	1/0	Visual	6 mo	MRI/MRA/TCD/SPECT: normal	Lamotrigine and furosemide - effective
Thissen et al. (2014)[44]	4	66,41,59,20	2/2	Visual	> 1 yr	MRI/PET/CT: normal	Lamotrigine - effective for one patient, ineffective for two patients; Sodium valproate, acetazolamide, topiramate - all ineffective
Kim et al. (2015)[45]	1	38	0/1	Visual	10 d − 14d	MRI/SPECT/FDG-PET/FMZ-PET: CVE with hypoperfusion and hypometabolism	Corticosteroid - effective
Cuadrado et al. (2017)[46]	18	40, 56, 52, 20, 61, 48, 36, 42, 27, 57, 43, 44, 45, 42, 46, 35, 43, 48	16/2	Visual; Sensory; Visual and sensory	> 1 wk; 1 h -7 d	-	Bilateral GON block - effective in 11 patients, recurrent in 2 patients, partially effective in 6 patients
Viana et al. (2018)[47]	38	-	-	Visual; Sensory; Speech	1 h -7 d	-	-
Viola et al. (2018)[48]	8	-	5/3	Visual; Speech; Sensory; Motor and sensory	2–8 h	CT/MRI/EEG: normal. TCD: increased resistance in microcirculation of occipital, temporal, parietal, and frontal areas contralateral to aura symptoms	-
Prakash et al. (2021)[49]	1	24	0/1	Brainstem	Tinnitus and vertigo: 30 min, diplopia and ophthalmoplegia: 4 wk	MRI: normal	Sodium valproate and Lamotrigine - effective
Kaltseis et al. (2021)[50]	1	16	1/0	Visual and sensory	> 2 yr	MRI/MRA: normal EEG: the left parieto - occipital slowing.	Zonisamide - effective
Liu et al. (2021)[51]	1	35	1/0	Visual	10 d	T2 MRI: right occipital parenchymal edema; MRA: small high-flow vessels noted; EEG: focal nonepileptic theta waves over right occipital area	Lamotrigine - effective

F female, M male, hr hour, d day, wk week, mo month, yr year, CT computed tomography, EEG electroencephalogram, MRI magnetic resonance imaging, SPECT single photon emission computed tomography, MRA magnetic resonance angiography, VEP visual evoked potential, T1WI T1-weighted imaging, PWI perfusion-weighted imaging, FLAIR fluid-attenuated inversion recovery, DWI diffusion-weighted imaging, 1 H-MRS proton spectroscopy, PCr/Pi phosphocreatine/phosphate PCr/Pi, fMRI functional magnetic resonance imaging, FSE fast spin echo, TCD transcranial Doppler, ADC apparent diffusion coefficient, PET positron emission tomography, 18 F-FDG PET 18 F-fluorodeoxyglucose PET, 11 C-FMZ PET 11 C-flumazenil PET, CVE cerebral vasogenic edema, GON greater occipital nerve

The incidence of brainstem auras is much lower than that of typical visual, sensory, and speech aura symptoms. Brainstem aura symptoms include dysarthria, dizziness, tinnitus, hearing loss, diplopia, ataxia, and altered consciousness. Previous studies have found that diplopia accompanied by ophthalmoplegia is the most common brainstem aura symptom, followed by dizziness and tinnitus [53]. A large-scale observational study of 362 migraine patients with typical auras found that 10% (38/362) had migraine with brainstem aura, confirming that brainstem auras can occur in any migraine patient with typical aura symptoms [54]. This is the first report of PMA in the Chinese population. Our goal is to remind neurologists that migraine aura symptoms are complex and diverse. When encountering sudden, unexplained, persistent neurological symptoms, attention should be paid to whether the patient experiences headache symptoms. If necessary, further inquiry should be made into whether the headache characteristics align with those of a migraine, and the possibility of PMA should not be overlooked. Additionally, necessary examinations should be conducted to exclude secondary causes.

The pathogenesis of migraine with persistent or prolonged aura remains unclear. Magnetic resonance spectroscopy studies suggest that potential pathological mechanisms include abnormalities in brain energy metabolism, reduced brain magnesium levels, enhanced NMDA receptor responsiveness to glutamate, lowered CSD thresholds, and the loss of inhibitory GABAergic interneurons. These factors may interact to cause persistent aura [55]. A study found that prolonged migraine auras may be related to microvascular spasm. The study used transcranial Doppler ultrasound and confirmed increased microcirculatory resistance in cortical areas corresponding to the aura distribution. These microvascular spasms were associated with reduced cortical blood flow, suggesting that endothelial dysfunction in microvessels could be a potential pathological mechanism for persistent auras [56]. Furthermore, neuroimaging studies have shown that during the aura phase, migraine patients exhibit reduced relative cerebral blood flow (rCBF), indicating a hypoperfused state, but not reaching ischemic thresholds [57]. This suggests that migraine auras are not caused by ischemia, but rather by abnormal neuronal and cellular discharges, with vascular changes being a secondary manifestation of neuronal activity fluctuations [58]. CSD is widely regarded as the key mechanism underlying the development of migraine auras, causing pain by activating the nociceptors of the trigeminal nerve. Previous studies have shown that CSD in the occipital cortex explains the spatial and temporal characteristics of visual migraine auras. CSD initially manifests as hyperemia, lasting 3 to 4.5 minutes, followed by mild hypoperfusion lasting 1 to 2 hours, which corresponds to changes observed in the occipital cortex after the onset of visual auras [57, 59]. A MEG study further observed that migraine patients with persistent visual auras exhibited cortical hyperexcitability during both the interictal and ictal phases. Researchers speculated that persistent CSD reverberations might be the primary cause of persistent visual aura, explaining the phenomenon from two perspectives: first, the exacerbation of persistent visual aura could lead to neuronal overactivation, the accumulation of metabolic products like lactate and protons, and the induction of repetitive CSD. Due to the brain’s protective mechanisms, continuous exacerbation might also lead to sensory overload and energy depletion, eventually triggering CSD. Second, the propagation of excitatory waves and the impact of CSD on cortical inhibition could increase brain excitability, thereby increasing susceptibility to CSD [39]. A PET study supports this hypothesis, showing continuous metabolic activation of the medial occipital cortex during persistent visual auras, which was not observed during typical migraine auras [60]. However, the exact triggering mechanism of CSD and how it induces migraines and auras remains incompletely understood and requires further verification through animal experiments and clinical studies. Previous hypotheses suggested that CSD could originate from any brain area, and the simultaneous presence of visual and brainstem auras in this case seems to support this view.

Conclusion

Migraine with two different types of persistent auras is considered a rare condition, but the number of reported cases has gradually increased in recent years. The present case involved a patient with the rare occurrence of persistent visual and brainstem auras, which increased the difficulty of diagnosis. Migraine is a common and highly disabling disease. When patients present with persistent neurological symptoms of unknown cause, the possibility of migraine with persistent auras should be considered. Early diagnosis can help improve prognosis.

Abbreviations

GBD

Global burden of disease

ICHD-3

The international classification of headache disorders, third edition

EM

Episodic migraine

CM

Chronic migraine

MwoA

Migraine without aura

MwA

Migraine with aura

MRI

Magnetic resonance imaging

VAS

Visual Analog Scale

VEP

Visual evoked potential

CSF

Cerebrospinal fluid

EEG

Electroencephalogram

MEG

Magnetoencephalography

PET

Positron emission tomography

FLAIR

Fluid attenuated inversion recovery

DWI

Diffusion weighted imaging

ASL

Arterial spin labeling

MRA

Magnetic resonance angiography

MRV

Magnetic resonance venography

TIA

Transient ischemic attack

RPON

Recurrent painful ocular myopathy

PMA

Persistent migraine auras without infarction

CSD

Cortical spreading depression

rCBF

Relative cerebral blood flow

F

Female

M

Male

hr

Hour

d

Day

wk

Week

mo

Month

yr

Year

CT

Computed tomography

SPECT

Single photon emission computed tomography

T1WI

T1-weighted imaging

PWI

Perfusion-weighted imaging

1H-MRS

Proton spectroscopy

PCr/Pi

Phosphocreatine/phosphate PCr/Pi

fMRI

Functional magnetic resonance imaging

FSE

Fast spin echo

TCD

Transcranial Doppler

ADC

Apparent diffusion coefficient

18F-FDG PET

18 F-fluorodeoxyglucose PET

11C-FMZ PET

11 C-flumazenil PET

CVE

Cerebral vasogenic edema

GON

Greater occipital nerve

Authors’ contributions

The case was conceptualized, data organized by XSL. All authors collaborated in the collection process of clinical information and MRI data. XSL initially drafted the manuscript, which underwent rigorous review and revision by all authors, ultimately reaching a consensus on the final version.

Funding

National Key R&D Program of China【2024YFC2510100】.

Joint Funds of the National Natural Science Foundation of China【U24A20683】.

Beijing Natural Science Foundation【Z200024】.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

This study was approved by the institutional review board of Beijing Tiantan Hospital, Capital Medical University (no. KY2022-044). The patient gave written informed consent for the use of their personal or clinical details, as well as any identifying images published in this study. All investigations were conducted in accordance with the principles of the Declaration of Helsinki.

Consent for publication

The patient has provided written informed consent for the use of their personal or clinical details, as well as any identifiable images published in this study. Simultaneously, all authors consent for the publication.

Competing interests

The authors declare no competing interests.