Late onset aura may herald cerebral amyloid angiopathy: A case report

Abstract

Background

Although migraine usually begins in the early decades of life, late onset of migraine with aura is occasionally observed and can occur without headache, causing confusion in the differential diagnosis.

Case report

A 72-year-old man presented with recurrent episodes of visual aura lasting for 20 minutes. These episodes had started at 57 years of age and were only once accompanied by a severe headache. Magnetic resonance imaging revealed changes in the periventricular white matter, left occipital haemorrhage and subcortical haemosiderin deposits, compatible with cerebral amyloid angiopathy. Previous treatment with antiplatelet drugs was discontinued. His episodes of visual aura stopped on treatment with lamotrigine and add-on treatment with verapamil.

Conclusion

In patients with a late onset of migraine aura, doctors must consider other under-recognized causes of transient neurological symptoms, such as cerebral amyloid angiopathy. Blood-sensitive magnetic resonance imaging sequences are the best tool for the early detection of an underlying pathology and therefore treatment with antiplatelet/anticoagulant drugs should be avoided as this may increase the risk of haemorrhage.

Introduction

Fisher first described ‘late life migraine accompaniments’ in patients with aura that began after 45 years of age (1). Late onset aura (LOA) are usually considered benign (2), but their presence raises diagnostic doubts because patients with aura tend to have transient ischaemic attacks, seizures and other neurological disorders. Cerebral amyloid angiopathy (CAA) is one of the diseases causing LOA, but it is under-recognized, even by experienced doctors. It is also a risk factor for spontaneous lobar intracerebral haemorrhage and anticoagulant-related bleeding. It usually presents with cognitive decline or transient focal neurological episodes (TFNEs), called ‘amyloid spells’, in elderly patients.

We describe here an elderly patient misdiagnosed with migraine with aura after presenting with recurrent visual phenomena. He was later diagnosed as having probable CAA according to the Boston criteria (3) and responded to treatment with lamotrigine and verapamil.

Case report

A 72-year-old man was admitted to our clinic with visual symptoms that started after the age of 57 years. These symptoms were only once accompanied by headache. He reported light beams and cube-shaped light flashes in the right visual field and right hemianopia while reading that lasted about 20–30 minutes and was repeated three to four times a year. These episodes were diagnosed as migraine with aura by an experienced neurologist. He had an episode of throbbing headache on the top of his head, which increased with coughing, accompanied by photophobia, phonophobia and osmophobia, after similar visual episodes that lasted for 25–30 minutes 10 days prior to admission. His pain had lasted for one night and he reported difficulties in finding the path to his home during the episode of pain.

The patient had a past history of hyperlipidaemia, benign prostatic hyperplasia, gastritis and allergic rhinitis. His family history revealed the sudden death of his father from heart disease. The patient was receiving propranolol and clopidogrel treatment on admission to our clinic; he had no significant benefit from these and had previously been treated with levetiracetam.

A systemic examination of the patient was normal and the neurological examination was unremarkable except for right superior homonymous quadrantanopia. Blood tests were within normal limits. Cranial magnetic resonance imaging (MRI) performed two years previously to investigate his visual symptoms revealed bilateral periventricular and subcortical diffuse ischaemic gliotic signal changes on the FLAIR and T2 sequences, together with subcortical haemosiderin deposits in the left occipital and cerebellar hemisphere on blood-sensitive MRI sequences (Figure 1). Intracranial and extracranial MRI angiography examinations were unremarkable. Sleeping and waking electroencephalograms from the same time period were unremarkable and neuropsychological testing was normal except for mild difficulties in sustaining attention. The cranial MRI examination repeated after the last episode of aura, which was accompanied by headache, revealed a 31 × 18 mm haemorrhage in the left occipital lobe and multiple subcortical millimetre-sized haemorrhage foci consistent with amyloid angiopathy on the gradient echo sequence (Figure 2). Right superior homonymous quadrantanopia was present in the visual field testing. A Sniffin’ Sticks Odor Test (Heinrich Burghart GmbH, Wedel, Germany) was performed and the threshold of the patient was decreased compared with the normal values for his age group.

Figure 1.

(a) Bilateral periventricular and subcortical ischaemic gliotic white matter changes on FLAIR sequence and (b) subcortical haemosiderin deposit (micro-haemorrhage foci) in left occipital lobe on gradient echo sequences.

Figure 2.

(a) Bilateral periventricular and subcortical ischaemic gliotic white matter changes on FLAIR sequence and (b, c) bilateral subcortical haemosiderin deposits (micro-haemorrhage foci) and intracerebral haemorrhage in the left occipital lobe on gradient echo sequences. This scan was performed two years after the first as a result of the headache attack.

The patient's previous visual episodes were thought to be caused by amyloid angiopathy foci and were diagnosed as TFNEs rather than LOA of migraine. Treatment with clopidogrel and propranolol was discontinued. The frequency of TFNEs had markedly increased to daily occurrence after the headache episode and the patient’s quality of life was impaired. Lamotrigine treatment was started and the dose was increased to 150 mg/day. The frequency of TFNEs decreased by 50% on treatment with lamotrigine, but did not stop; an add-on of 120 mg/day verapamil, which was the highest dose allowed by his cardiologist, resulted in the remission of TFNEs at the six-month follow-up.

Discussion

The clinical description of aura by our patient definitely resembled migraine aura. However, migraine attacks usually begin in the first three decades of life (4), although a late life onset of migraine with aura is not rare and can occur without headache (2). The International Headache Society classify typical aura occurring in the absence of any headache as ‘Typical aura without headache’ (5). Therefore our patient was diagnosed with LOA by an experienced neurologist. In Fisher’s first series of 120 patients, 35 presented with transient episodes that resembled the neurological accompaniments of migraine; headaches occurred in 50% of patients. In a population-based study from the Framingham cohort, 26 of 186 patients with a first sudden visual defect (14%) were evaluated as having visual aura related to migraine. The age of onset was older than 50 years in 77% of patients. Fifty-eight per cent of patients with visual symptoms never had headache and forty-two per cent had no history of recurrent headache. The overall prevalence of migrainous visual symptoms without headache was 0.71% (2). In a prospective study, migraine with aura was reported in 26% of patients. Of these, 6% were aged 50 years and older. About 30% of patients experienced migraine aura for the first time after the age of 50 years. The prevalence of first-time migraine aura after the age of 50 years was 1.8%. Typical aura without headache was reported by 61% (11/18) of patients (6).

Although mostly benign, LOA must be differentiated from secondary causes. In a review of differential diagnosis in LOA, it was stated that TIAs, seizures, subarachnoid haemorrhage, arteriovenous malformation, dural arteriovenous fistula, patent foramen ovale, posterior circulation embolism, internal carotid artery dissection, vertebral artery dissection, carotid artery stenosis, moyamoya disease, brain tumours and other rare disorders can also mimic migraine aura, in addition to the CAA seen in our patient (7). Therefore the diagnosis of late life migraine accompaniments should be made by exclusion with appropriate investigations. Blood-sensitive MRI is especially important to properly exclude CAA, as evidenced by patient.

TFNEs have recently been recognized as one of the clinical manifestations of CAA. In a multicentre retrospective cohort study of 172 patients with CAA by Charidimou et al. (8), 25 patients (14.5%) were found to have TFNE. The most common positive symptom was the gradual spread of transient paraesthesia affecting the mouth and hand that lasted less than 30 minutes in most patients. Only four of the 25 patients (16%) had episodes of visual disturbances similar to migraine aura involving monocular blurred vision, flickering or flashing lights, transient ‘zig-zags’ (teichopsia) or visual loss, thus making our patient of note. Charidimou et al. (8) also found a higher risk of superficial cortical siderosis/convexity subarachnoid haemorrhage in patients with CAA and TFNE compared with those without TFNE (50 versus 19%).

The mechanisms of CAA-related TFNE remain uncertain, but one hypothesis includes cortical spreading depression (8). However, the role of ischaemia in some episodes cannot be ruled out, such as small vessel occlusions or focal vasospasm due to an acute convexity subarachnoid haemorrhage or vascular amyloid β deposition; the pathophysiology of CAA-related TFNE could be explained with some of the transient focal symptoms seen in reversible segmental cerebral vasoconstriction syndromes with acute convexity subarachnoid haemorrhage (9). We think that TFNEs in patients with CAA markedly resemble visual or somatosensory LOA and that these two episodic phenomena may share some common mechanisms such as cortical spreading depression, causing symptomatic (CAA-related) LOA. Alternatively, TFNEs may have entirely different vascular or other mechanisms, which make a distinction more valuable with regard to treatment options.

Our patient did not report any symptoms related to cognitive dysfunction and his neuropsychological test results were within normal limits. We also performed the Sniffin’ Sticks Odor Test (odour threshold, discrimination, identification) and the results were unremarkable except for the odour threshold, which was lower than the normative values for the Turkish population (2.5 versus 3.3) (10). Although a decrease in olfaction is expected with advanced age, the further decrease in our patient may be related to the involvement of small cerebral vessels, probably of the cortical olfactory region. However, this needs further investigation.

Intracerebral haemorrhage was detected in this patient with late onset recurrent visual aura in an episode with accompanying headache. Subcortical haemosiderin deposits consistent with CAA were detected on blood-sensitive MRI sequences and antiplatelet treatment was therefore stopped. This finding emphasized that blood-sensitive MRI sequences should not be avoided in LOA. There is no published evidence for the treatment of the TFNEs of CAA except for a few anecdotal papers reporting the beneficial effect of topiramate and verapamil (11). The TFNEs in our patient responded well to a combination of lamotrigine and verapamil and these options could be considered in similar patients.

Conclusion

Appropriate investigations may be needed to exclude secondary causes before the diagnosis of late life migraine accompaniments. CAA is a neglected differential diagnosis of LOA. Blood-sensitive MRI and avoidance of anticoagulant and antiplatelet drugs are important in these patients.

Clinical implications

In patients with late onset migraine aura, doctors must consider other under-recognized causes of transient neurological symptoms, such as cerebral amyloid angiopathy.

Blood-sensitive MRI sequences are the best tool for the early detection of cerebral amyloid angiopathy.