Recurrent steroid-responsive cerebral vasogenic edema in status migrainosus and persistent aura

Abstract

Background

Status migrainosus (SM) and persistent aura (PA) without infarction are complications of migraine. Although several patients have been reported to have reversible brain lesions associated with complications of migraine, their nature and pathophysiology remain unclear.

Case

We report on a 38-year-old male who presented with nine episodes of SM and PA over eight years. Serial neuroimaging studies including brain magnetic resonance imaging (MRI), blood flow single photon emission tomography (SPECT),¹⁸ F-fluorodeoxyglucose positron emission tomography (FDG-PET) and¹¹ C-flumazenil PET (FMZ-PET) demonstrated cerebral vasogenic edema (CVE) with hypoperfusion and hypometabolism in the area, anatomically corresponding to the area with PA. SM and PA were effectively controlled by corticosteroid therapy. Follow-up MRI revealed complete reversibility of the CVE, which was supported by normal FMZ-PET and FDG-PET findings.

Conclusion

We have described a patient with transient brain lesions associated with complications of migraine who was diagnosed with fully reversible and steroid responsive CVE.

Introduction

Status migrainosus (SM) is defined as a debilitating migraine headache lasting >72 hours, and persistent aura (PA) without infarction is defined as aura symptoms persisting one week or more without evidence of infarction (1). Unlike migrainous infarction, which is characterized by migraine with aura and ischemic infarction in a relevant area, reversible brain lesions associated with cerebral vasogenic edema (CVE) are rarely reported in patients with SM (2) or PA (3,4). However, the mechanism of CVE in migraine remains unclear. We describe a patient with SM and PA, classified as complications of migraine (1.4.1) in the International Classification of Headache Disorders, third edition beta (ICHD-3 beta) (1), who presented with recurrent episodes of reversible CVE.

Case report

A 38-year-old male with migraine presented with recurrent SM and PA, experiencing nine episodes from June 2006 to January 2013. His migraines were triggered by stress, smoking and drinking alcohol. There was no family history of migraine.

Beginning at 31 years of age, this patient began to experience migraines with visual aura. Aura usually presented as positive features, including achromatic, flickering, flashing lights or achromatic circles, in the unilateral homonymous visual field. The aura was followed by headaches, most of which were unilateral, pulsating, and of moderate to severe severity, with nausea, vomiting and photophobia. In addition to the usual migraine with aura, he also experienced nine episodes of negative visual symptoms, such as homonymous hemianopsia. Visual field defect and headache usually lasted for more than 10 to 14 days with common therapies for migraine. The vital signs and neurological examinations were normal except for visual field defect.

During the attack phase of migraine, magnetic resonance imaging (MRI) in this patient showed reversible unilateral occipito-temporo-parietal, cortical and adjacent subcortical white matter lesions, visible as hyperintense signals on fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted images (DWI), with an elevated apparent diffusion coefficient (ADC), consistent with CVE. Brain blood flow single photon emission tomography (SPECT) using Tc99m-ethyl cysteinate dimer (Tc99m-ECD) showed hypoperfusion of the involved visual cortex with increased surrounding perfusion.¹⁸ F-fluorodeoxyglucose positron emission tomography (FDG-PET) showed hypometabolism in the occipital-temporal cortex, probably related to vasogenic edema.¹¹ C-flumazenil PET (FMZ-PET) showed decreased flumazenil receptor binding in the involved occipital cortex. MR spectroscopy revealed a prominent lactate peak in the lesion. Following each episode, these lesions completely disappeared on brain MRIs, with recovery of FMZ receptor binding capacity on FMZ-PET (Figure 1). Angiography and laboratory tests of cerebrospinal fluid and serum lactic and pyruvic acids were normal. The patient was negative for mutations associated with mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS), as well as being negative for antinuclear antibody, antineutrophil cytoplasmic antibody, lupus anticoagulant, anticardiolipin antibody, coagulation factor and paraneoplastic antibody (Supplemental data 1).

Figure 1.

Serial neuroimaging findings. (a–e) Chronological arrangement of fluid-attenuated inversion recovery (FLAIR) images between migraine attacks. During each attack, newly developed high-signal intensity lesions were observed in the unilateral occipital lobe. These lesions were resolved on follow-up images. (f–h) Functional neuroimages from August to September 2009. The lesion in the right occipital lobe (arrow) showed hypoperfusion on SPECT using Tc99m-ECD (f), decreased flumazenil receptor binding on PET using¹¹ C-flumazenil (FMZ-PET) (g), and hypometabolism on PET using¹⁸ F-fluorodeoxyglucose (FDG-PET) (h). The left occipital lobe (asterisk), in which the previous lesion (b) had been located, showed normal findings on SPECT, FMZ-PET and FDG-PET, indicating that the CVE in this patient was completely reversible.

SM and PA did not respond to common therapies such as triptan and nonsteroidal anti-inflammatory drugs. The patient’s last two episodes were accompanied by seizure. He became somewhat confused, and electroencephalography showed 1.5–2 Hz rhythmic spikes and wave arising from the occipital area. Antiepileptic drugs were ineffective for this patient’s migraines, but both his migraines and visual field defects effectively ceased just after initiation of corticosteroid therapy. We prescribed intravenous methylprednisolone 500 mg/day for three days followed by oral prednisolone 60 mg/day for one week. The patient’s dose of oral prednisolone was slowly tapered over three weeks to 5 mg/day, and was maintained at that level thereafter. His migraine and visual field defect began to improve within one day after initiation of corticosteroid therapy. The patient felt that the defective area became brighter than before. The improvement of the visual field defect was confirmed by a confrontation test. Visual analog scale of headache severity improved from 7–8 to 1–2 within one day. The time required for complete resolution of his visual field defects for each episode varied from two days to two weeks.

Discussion

This patient presented with nine episodes of SM and PA over eight years. Serial neuroimaging studies revealed reversible CVE, which responded to steroid therapy. Extensive evaluation successfully excluded the possibility of other potential causes, such as migrainous infarction, posterior reversible encephalopathy syndrome (PRES), MELAS, vasculitis, tumor, and inflammatory disease, all of which also cause recurrent neurologic deficits with CVE. However, these diseases usually result in neuronal damage and cortical atrophy. PRES, also known as hypertensive encephalopathy, usually presents with symmetric vasogenic edema within the parieto-occipital area. This patient was normotensive during the attack and unilateral vasogenic edema is uncommon for PRES. We did not perform gene testing for POLG1, which can result in mitochondrial encephalopathy.

By contrast, several patients including ours have been reported with transient brain abnormalities accompanied by complications of migraine, such as hemiplegic migraine and persistent aura (Table 1). Unlike migrainous infarction, which occurs in a patient with migraine with aura and accompanies ischemic infarction in relevant areas, these lesions were reversible. On MRI, familial and sporadic hemiplegic migraines appeared as cortical edema contralateral to the hemiparesis. The lesions showed hypometabolism on FDG-PET, as well as hyper- or hypoperfusion, depending on the individual patient. There were several differences between this patient and patients with familial hemiplegic migraine. Our patient showed no evidence of motor weakness or family history of migraine. In addition, patients with familial hemiplegic migraine have not been reported to respond to steroid therapy. However, some imaging findings were similar, suggesting that the pathomechanism of transient brain lesion in our patient may be similar to that of familial hemiplegic migraine, which is usually explained by cortical spreading depression (CSD). Transient brain lesions in most patients with prolonged aura also manifested as CVE with enhancement. During PA, MRI showed ADC restriction and FDG-PET showed hypometabolism. Transient brain abnormalities accompanying an uncomplicated aura are very rare, presenting as reversible white matter or cortical hyperintense lesions on FLAIR images.

Table 1.

Review of the cases that showed transient brain abnormalities associated with migraine described in the literature.

Case	Migraine type	Sex/age at onset	Clinical features (significant clinical findings unrelated to migraine attack)	Imaging findings
1 (Neurology, 20065)	Migraine with aura	M/56	Typical visual aura and migraine followed by blurred vision.	MRI: reversible high-signal intensity on FLAIR in Rt. parieto-occipital cortex, DWI and low value on ADC mapping.
2 (Neurol India, 20086)	Migraine with aura	F/35	Visual aura along with loss of vision and migraine.	MRI: reversible white matter hyperintense lesion on FLAIR. Normal DWI, T2WI and T1WI. Normal MRA.
3 (Headache, 20087)	Migraine without aura	M/18	Migraine.	CT: Lt. temporo-parieto-occipital low attenuation. MRI after five days: no lesion.
4 (Neurology, 20028)	Migraine with prolonged aura	F/66	Visual scotoma followed by nausea, vomiting, global aphasia, Rt.-sided neglect and pronator drift over days.	CT, MRA: unremarkable. MRI: delayed enhanced T1W image showed leakage of contrast in the Lt. anterior and temporal lobe. Increased cerebral blood flow and volume.
5 (Headache, 20079)	Migraine with prolonged aura	M/33	Intractable headache with prolonged aura, seizure (Sturge-Weber syndrome)	MRI: Focal hyperemia in the Rt. occipital cortex, Gd enhancement along the sulci and retention of the contrast material in the vessels in the Rt. occipital cortex (vasogenic leakage) in the acute stage. All features resolved in the convalescent stage except Rt. occipital hypoperfusion.
6 (Cephalalgia, 200810)	Persistent visual migraine aura	M/58	Migraine and Rt.-sided visual field defect lasting for 15 days.	MRI: Reversibly restricted water diffusion and decreased ADC from the Lt. occipital to the temporo-parietal cortex. FDG-PET: decreased metabolism. TCD: normal blood flow velocity of PCA.
7 (Headache, 201011)	Basilar migraine, persistent visual aura	F/41	Persistent visual aura, bilateral paresthesias in the extremities.	MRI: no lesions in T1WI, T2WI, FLAIR and DWI, but an abnormal signal appeared in the Lt. occipital lobe in ADC. Normal MRA.
8 (J Neuroimmunol, 199712)	Migrainosus status, prolonged aura	F/67	Migraine with aphasia, Rt. hemianopsia, lasting four days.	MRI: increased perfusion and leakage of contrast into subarachnoid space.
9 (Cephalagia, 20092)	Recurrent status migrainosus	F/18	Status migrainosus.	MRI: increased diffusion, elevated ADC (Recurrent vasogenic cerebral edema). FDG-PET: hypometabolism.
10 (AJNR Am J Neuroradiol, 199813)	Basilar artery migraine	M/17	Lt.-sided headache followed by Rt. visual field defect, vertigo, unsteadiness, dysarthria, numbness of perioral area and over the tips of his fingers (two episodes of nocturnal seizure).	CT: low attenuation over the left medial occipital cortex MRI: focal area of low signal intensity over the same area on T1WI, which became hyperintense on the proton density and T2WI. No contrast enhancement was seen. Hyperintense T2 lesion resolved in follow-up MRI. Normal MRA.
11 (Neurology, 200014)	Hemiplegic migraine	F/33	Rt. hemiplegia, fever, confusion, headache and mutism.	MRI: normal T1WI, T2WI and reversible reduction of water diffusion contralateral to the hemiplegic side.
12 (AJNR Am J Neuroradiol, 200115)	Hemiplegic migraine	F/8	Headache, Lt.-sided hemiplegia.	MRI: normal T1WI, T2WI, FLAIR. MRA: unilateral dilation of branches of both the middle and posterior cerebral arteries. Perfusion MRI: hyperperfusion of the ipsilateral hemisphere.
13 (Neurosci Lett, 200216)	Familial hemiplegic migraine	M/16	Rt.-sided hemiparesis, aphasia.	FDG-PET: hypometabolism in left hemisphere’s fronto-basal cortex, caudate nucleus and thalamus. MRI including perfusion and DWI: normal.
14 (Cephalalgia, 200417)	Familial hemiplegic migraine	M/21	Somnolent with Rt.-sided hemiplegia.	MRI: normal findings in DWI. Perfusion MRI, HMPAO-SPECT: hyperperfusion
15 (Neuroradiology, 200318)	Familial hemiplegic migraine	M/13	Hemiparesis. Headache, confusion, seizure.	MRI: unilateral cortical swelling, vascular dilatation and decreased water diffusion contralateral to the hemiparesis.
16 (Headache, 200419)	Migraine-associated seizure	F/33	Migraine with aura followed by seizure.	MRI: recurrent reversible brain lesion, which is decreased signal intensity on T1WI, increased signal intensity on FLAIR and T2WI.
17 (Cephalalgia 20054)	Sporadic hemiplegic migraine	F/35	Headache followed by Rt. arm weakness, Rt. visual field defect, aphasia and confusion that persisted for one week.	MRI: Focal hyperemia in the Lt. cerebral hemisphere and augmented vasogenic leakage was demonstrated on the delayed enhanced FLAIR in acute stage. Dilatation of the left MCA in MRA. All features resolved during convalescent stage.
18 (Cephalalgia, 200620)	Sporadic hemiplegic migraine	F/33	Hemiparesis, headache.	MRI: diffusion restriction on DWI, hyperintensity and swelling of the gray matter on T2WI, and gyral enhancement in the right hemisphere. MRA: normal. Perfusion MRI: increased vascularity in the gray matter of the right temporoparietal region. MRS: reduced neuronal activity.
19 (Cephalalgia, 200621)	Familial hemiplegic migraine	M/48	Migraine with aura, visual loss, Lt.-sided hemisensory and motor dysfunction.	MRI: right posterior gyral enhancement with edema. MRA: dilated right MCA and distal PCA. FDG-PET: increased in activity contralateral to the hemiplegic side.
20 (Headache, 200922)	Familial hemiplegic migraine	F/12	Confusion, global aphasia, Rt.-sided hemiparesis and headache.	MRI: increased signal on the T2WI and FLAIR with decreased signal on T1WI. MRA: increased flow involving left distal PCA and MCA FDG-PET: hypometabolism in the affected hemisphere. SPECT: normal.
21 (Case Rep Neurol Med, 201123)	Sporadic hemiplegic migraine	F/24	Headache, blurred vision, Rt.-sided hemiparesis, aphasia and right focal motor seizure.	MRI: cortical hyperintensity and edema on T2WI and FLAIR with no restriction pattern on DWI.
22 (J Korean Med Sci, 201224)	Familial hemiplegic migraine type 1	M/43	Rt. hemianopsia, aphasia, followed by coma.	MRI: cerebellar atrophy. CT angiography: increased vascularity in the left hemisphere and elevated cerebral blood flow in perfusion weighted image.
23 (J Neurol Neurosurg Psychiatry, 201225)	Familial hemiplegic migraine type II	F/39, F/42, F/69	Hemiplegic migraine, eighth attacks.	MRI: augmented vasogenic leakage with cortical edema in one attack. MRA: MCA vasodilation in five attacks. SPECT: hyperperfusion in the affected hemisphere contralateral to hemiplegia in five attacks, hypoperfusion in three attacks.
24 (Pediatr Neurol, 201226)	Familial hemiplegic migraine	F/13, M/8, M/15	Rt.-sided weakness, speech difficulty, altered mental status and gait abnormalities.	MRI: cortical edema restricted to the left cerebral hemisphere.
25 (Headache, 201227)	Hemiplegic migraine	F/9, F/9	Headache, hemiparesis, sensory changes, altered mental status, and aphasia.	MRI: subtle restricted diffusion on DWI with correlating ADC parietal cortex. Subtle swelling and cortical hyperintensity on FLAIR.
26 (J Neurol, 201328)	Hemiplegic migraine	M/29, F/33	Hemiparesis, headache.	MRI: diffuse cortical swelling and abnormal cortical diffusion in DWI and meningeal enhancement contralateral to the side of paresis. MRA: string and beads appearance of proximal cerebral arteries.
27 (Cephalalgia, 201429)	Pediatric hemiplegic migraine	F/13	Rt.-sided hemiplegia, deterioration of vigilance and paraphasia.	MRI: normal diffusion tensor image sequences, large area of hypoperfusion within the left cerebral hemisphere and SWI demonstrated a matching area with prominent, hypointense draining sulcal veins. MRA: subtle narrowing of the left MCA.

M: male; F: female; Rt.: right; Lt.: left; CT: computed tomography; MRI: magnetic resonance imaging; MRA: magnetic resonance angiography; T1WI: T1-weighted image; T2WI: T2-weighted image; Gd: gadolinium; DWI: diffusion-weighted image; ADC: apparent diffusion coefficient; FDG-PET:¹⁸ F-fluorodeoxyglucose positron emission tomography; TCD: transcranial Doppler; HMPAO-SPECT: [99mTc] hexamethyl-propyleneamine-oxime-single photon emission tomography; FLAIR: fluid-attenuated inversion recovery; MCA: middle cerebral artery; PCA: posterior cerebral artery; MRS: magnetic resonance spectroscopy; SWI: susceptibility weighted imaging.

In this patient, the CVE lesions were evaluated by functional neuroimaging modalities. Hypoperfusion of the visual cortex with increased surrounding perfusion in SPECT may represent a cerebral blood flow state of CSD (30). Hypometabolism on FDG-PET may be responsible for PA, which presented as a visual field defect. In contrast to findings in a previous patient, showing that PA was associated with hyperemia and augmented vasogenic leakage (4), the results in our patient suggest that hypoperfusion and hypometabolism may underlie the mechanism for PA and CVE in CSD. Although a prominent lactate peak and decreased FMZ receptor binding of CVE suggest a possible ischemic insult and disruption of the neuronal integrity of the lesion, the CVE and migraine were dramatically improved in our patient by corticosteroid therapy. Complete reversibility was supported not only by follow-up MRI, but also by normal FMZ-PET and FDG-PET findings in the contralateral occipital lobe, which had been previously damaged.

CSD has been shown to upregulate matrix metallopeptidase-9 (MMP-9) in the brains of rats and mice, altering the permeability of the blood-brain barrier (BBB) (31), and post-headache MMP-9 concentrations were significantly higher in migraine than in non-migraine patients (9,32). Because MMPs are endopeptidases that target the extracellular matrix, they can loosen the intercellular tight junctions of the BBB (33), leading to CVE.

Migraine aura-triggered seizure is another complication of migraine (1). The last two episodes in our patient were accompanied by seizure. Although diagnosis of migraine aura-triggered seizure is often confusing because occipital seizure can mimic migraine with aura, the findings in our patient were closer to migraine aura-triggered symptomatic seizure resulting from CVE than to epilepsy-related headache for several reasons. First, several electroencephalograms during the attack phase of SM and PA were normal before the eighth episode. Second, antiepileptic drugs were ineffective in treating this patient’s SM and PA. Finally, the CVE lesion showed hypometabolism on FDG-PET and hypoperfusion on SPECT. Because ictal FDG-PET and SPECT usually show hypermetabolism and hyperperfusion, the SM and PA in our patient cannot be explained by seizure.

In conclusion, we have described a patient with transient brain lesions associated with complications of migraine who was diagnosed with fully reversible and steroid-responsive CVE. Further studies are needed to elucidate the pathophysiological mechanisms of CVE in patients with complicated migraine.

Clinical implications

Reversible brain lesions associated with complications of migraine, such as status migrainosus (SM) and persistent aura (PA) without infarction, have been reported in limited numbers of patients.

We describe a 38-year-old male who presented with SM and PA. Serial neuroimaging studies revealed cerebral vasogenic edema, which was steroid responsive and completely reversible.