Vasogenic Leakage and the Mechanism of Migraine with Prolonged Aura in Sturge-Weber Syndrome

Sturge–Weber syndrome (SWS) is a neurocutaneous disorder, characterized by unilateral facial nevus flammeus in the territory of the first division of the trigeminal nerve ipsilateral to the leptomeningeal angiomatosis (1). While epilepsy and mental retardation are the most common symptoms, migraine-like headache has been recognized as an important phenotypical spectrum of SWS (2–6). We report a case of SWS, who had a 19-year history of recurrent attacks mimicking migraine with prolonged aura. Based on clinical and neuroimaging data we demonstrate the mechanism of migrainous attacks in SWS and speculate possible implication for the pathophysiology of prolonged aura in migraine.

Case report

A 33-year-old man was admitted to our hospital with intractable headache with prolonged aura. He developed epileptic seizure at the age of 3 years, then being prescribed antiepileptic drug for a couple of years but he stopped taking medication because of the absence of seizure. At the age of 14 years he began to suffer from migraine-like attacks episodically, characterized by pulsating, predominantly unilateral, and moderate or severe headache aggravated by routine physical activity, and associated symptoms such as photophobia, nausea and vomiting. Similar bouts of headache in the right fronto-parietal region occurred at the age of 15, 16 and 23 years, and were always preceded by sudden onset of visual aura such as prism-like bright scintillation followed by foggy visual blurring, which usually started within 30 min prior to headache and persisted a week even after headache subsided. Since the age of 23, he developed mild attacks of headache preceded by visual scintillation once or twice a year. No seizure or altered consciousness was experienced. A family history including migraine or epilepsy was negative.

Three days before admission he began to see prism-like scintillation, followed by visual blurring more marked in the left visual field than in the right. Thirty minutes after the onset of visual symptoms he developed moderated throbbing pain in the right fronto-parietal region, which was aggravated by daily physical activity. Visual scintillation included various forms of photopsias such as white small sparks, wavy lines or simple geometric forms, which often arose from the central portion of the vision, but they did not increase in size or spread to the periphery of the vision with time. Visual scintillation tended to subside at rest but was often provoked by physical activity while foggy left visual blurring persisted with some fluctuation. He suffered from intractable migrainous headache for the consecutive three days. He was finally admitted to our hospital with persistent headache with visual blurring.

On admission he had facial nevus flammeus in the territories of the first and second division of the right trigeminal nerves. On neurological examination, he had the left visual field defect on confrontation test, but otherwise normal. Mini-mental status examination score was 30. Goldmann perimetry confirmed the presence of the left homonymous hemianopsia with macular sparing (Fig. 1a). Routine blood tests were normal. A lumber puncture showed acellular cerebrospinal fluid (CSF) and mild elevation in protein content (54 mg/dl) and normal lactate level (17.4 mg/dl). EEG showed asymmetrical low voltage activities in the right occipital region without epileptiform discharges. On day 4 when visual symptoms and headache were still prominent, diffusion-weighted MRI (DWI) of the brain was unremarkable. Brain blood flow single photon emission computed tomography (SPECT) studied on the same day using ¹²³I-iodoamphetamine (IMP) 167 MBq as a tracer showed focal hyperaemia in the right occipital cortex (Fig. 1b). Brain CT scan showed calcification in the right occipital cortex and the trigone of the right lateral ventricle. Enhanced MRI with gadolinium-DTPA showed homogenously enhanced right choroid plexus and marked enhancement in the sulci of the right medial occipital cortex, suggesting the presence of leptomeningeal angiomatosis compatible with SWS (7, 8) (Fig. 1c). CT angiography showed retention of the contrast material in the right medial occipital cortex (Fig. 1d). Conventional angiography showed indistinct staining in the right occipital lobe during the capillary phase, but no obvious venous malformations were found. A diagnosis of SWS was made based on the unilateral facial port-wine naevus and associated MRI findings.

Figure 1

The combination of the results of studies obtained during the acute (a–d) and convalescent stage (e–h), including Goldmann perimetry (a, e), flow SPECT study using ¹²³I-iodoamphetamine (b, f), brain MRI with gadolinium enhancement (c, g), and CT angiography (d, h). (a, b) were obtained on day 4, (c, d) were on day 5, (e, f) were on day 17, (g, h) were obtained 10 weeks later following the first scans. The right side of the brain was displayed on the left on each brain image (b, c, d, f, g, h). During the acute stage of migrainous headache and visual symptoms, there are focal hyperaemia in the right occipital cortex (b), gadolinium enhancement along the sulci of the right medial occipital cortex (c), and retention of the contrast material in the vessels in the right occipital cortex (d) corresponding to the left homonymous hemianopsia with macular sparing (a). During the convalescent stage, the left visual field defect, focal hyperaemia, and retention of the contrast material resolved (e, f, h), but an area of hypoperfusion was seen in the right occipital cortex (f). Marked enhancement in the sulci of the right occipital cortex on the first MRI (c) compared with that on the second one (g) suggests augmented vasogenic leakage from the occipital leptomeningeal angiomatosis during the migrainous attack with prolonged visual aura.

On admission he was advised to keep a headache diary and take analgesics when headache exceeded 80% of the maximum intensity on the headache scale. Although simple analgesics was temporarily effective for headache, headache returned on the following day while the left visual field defect remained unchanged throughout four days after admission. Foggy visual filed defect was not affected by changes in headache intensity or use of simple analgesics, but the occurrence of visual scintillation decreased after admission. The bout of headache ceased completely three hours after taking simple analgesics on day 7, no headache came again on the following day. Visual field defect also gradually improved on day 9 and no visual filed defect was detected on day 10. Goldmann perimetry confirmed the complete resolution of visual field defect on day 17 (Fig. 1e). The second IMP-SPECT study performed on the same day showed mild focal reduction in flow in the right occipital cortex (Fig. 1f). Enhanced MRI obtained 10 weeks later showed lesser degree of enhancement in the sulci of the corresponding cortex compared with that during the acute stage, suggesting augmented gadolinium leakage from the occipital leptomeningeal angiomatosis during the acute stage of symptoms (Fig. 1g). The second CT angiography obtained 10 weeks later also showed resolution of the retention of the contrast material in the right occipital cortex. (Fig. 1h).

Discussion

This case showed three important findings. First, migraine-like headache with prolonged aura can be the sole manifestation of patients with SWS. Second, focal hyperaemia associated with vasogenic leakage was seen in the brain region corresponding to the prolonged aura and possibly headache. Third, occipital leptomeningeal angiomatosis could be the underlying disorder causing both prolonged visual aura and headache.

Migraine-like headache has been recognized as an important manifestation of SWS (2–6). Twenty-eight per cent of patients with SWS (2) may experience headache having clinical characteristics of migraine criteria by International Headache Society (IHS) (9). Sporadic hemiplegic migraine is also reported (3). To the best of our knowledge, there is, however, no report of a case presenting with attacks mimicking migraine with prolonged aura.

Although this patient's clinical features fulfil the IHS criteria for the symptomatology of migraine, it would be appropriate to classify this headache into the category of secondary headache associated with vascular disorders until pathophysiological mechanism of migraine with aura in SWS is elucidated. In addition, it is likely that visual symptoms are attributed to neuronal dysfunction of the brain regions covered by occipital leptomeningeal angiomatosis.

The mechanism of recurrent headache with prolonged visual symptoms remains speculative. A variety of possible causes include recurrent small leaks from leptomeningeal angiomatosis, venous anomalies, occipital lobe seizure, reperfusion hyperaemia, focal encephalitis, and the activation of the trigeminovasular system. The activation of the trigeminovascular system is worth considering in detail because of obvious involvement of trigeminal nerves in this disease, while all the other causes seem unlikely to explain the clinical and imaging data in this patient.

Leptomeningeal angiomatosis is known to consist of abnormal pial vessels with increased permeability of the altered vessel walls (10). Enhanced MRI findings suggested the presence of augmented gadolinium leakage during the acute stage of symptoms from the occipital leptomeningeal angiomatosis into the subarachnoid space. Hence, it is speculated that once the trigemonovascular system is activated by unknown trigger as in migraine, augmented reaction should develop particularly in the area of leptomeningeal angiomatosis and increase vasogenic leakage of plasma and neuropeptides into the subaracnoid space. Neuropeptides further activate (11) or sensitize (12) the peripheral trigeminovascular fibers, causing migraine features and vasodilatation in the corresponding cortex. Recently, we have reported as similar phenomenon in mitochondrial angiopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), in which activation of peripheral trigeminovascular fibers in the surroundings of the stroke-like lesions may be involved in the mechanism of episodic headache in MELAS based on the dramatic response of headache to sumatriptan, 5-HT_1B/1D agonist, and associated DWI findings probably attributed to mitochondrial dysfunction in the capillary endothelium with increased permeability (13, 14). Progressive spread of the stroke-like lesions with concomitant vasogenic oedema is also a characteristic feature of the acute brain lesions in MELAS (15), suggesting involvement of the endothelial cells of the intraparenchymal small blood vessels. While in patients with SWS, a maldevelopmental event primarily involves the leptomeningeal pial vessels overlying the cerebral cortex, not usually involving the intraparenchymal blood vessels therefore vasogenic oedema in the brain region corresponding to prolonged visual aura may not be evident on or be absent from a brain MRI scan unless cerebral venous anomalies cause venous congestion in the brain.

It is also very important that focal hyperaemia with augmented vasogenic leakage was seen in the brain region corresponding to the prolonged visual aura. It is now believed that the migraine aura is due to neuronal dysfunction, not primary ischaemia. Migraine aura is usually accompanied by hypoperfusion in the brain region corresponding to the aura, which should be secondary to neuronal suppression. However, the pathophysiological mechanism of prolonged aura remains to be elucidative, and associated cerebral blood flow changes should further be investigated. As recently reported in a single case of migraine with prolonged aura (16), augmented vasogenic leakage, which is presumably caused by trigeminovascular activation, may play a role in the mechanism of prolonged aura and probably migraine. It remains to be determined whether it may prolong the duration of neuronal suppression or delay the spontaneous recovery of neuronal suppression.