Persistent Migraine Aura: New Cases, a Literature Review, and Ideas About Pathophysiology

Sam Thissen, MD; Iris G. Vos, MD; Tobien H. Schreuder, MD; Wendy M.J. Schreurs, MD; Linda A. Postma, PhD; Peter J. Koehler, PhD

Disclosures

Headache. 2014;54(8):1290-1309. 

In This Article

Results

New Cases

Case 1. A 66-year-old man without a history of migraine was referred to our outpatient clinic by an ophthalmologist because of seeing white dots in front of both eyes since June 2011. He described this as "snow" in both visual fields as in "television static." Another comparison he used was like "rain on a window." At first these symptoms occurred intermittently until they persisted. Besides these symptoms, he complained of paroxysmal vertigo and continuous headache. The pain was of a pressing, tightening (non-pulsating) nature, with mild intensity. It was located bilaterally and not accompanied by other symptoms. At first, the headache was paroxysmal and later sustained. Physical, neurological, and ophthalmological examinations (including electroretinogram [ERG] and electrooculography [EOG]) were normal. Laboratory work-up, including paraneoplastic antibodies and lumbar puncture, did not show any abnormalities. Visual evoked potentials (VEP), Transcranial and extracranial Dopplers were normal, as well as FDG-PET. Cerebral computed tomography (CT; magnetic resonance imaging [MRI] was contraindicated) did not show occipital abnormalities (there was some doubt about a cortical infarction on the left; however, he had never had complaints associated with this). He was diagnosed with PMA-PPVD. Treatment with sodium valproate showed no effect, after which he started with lamotrigine. The aura is still present today.

Case 2. A 41-year-old woman had a history of MA since the age of 16. Her attacks began with right-sided visual disturbances, rarely left-sided. This was sometimes accompanied by tingling of the right hand and arm. She once experienced left-sided symptoms, consisting of tingling of the mouth, tongue, and speech arrest. Afterwards she always developed a stabbing headache without nausea or vomiting. She was using frovatriptan and sodium valproate. Since October 2011, she developed a persistent aura that consisted of a blurred rim on the periphery of the left visual field. Physical, neurological, and ophthalmological examinations were normal. Laboratory work-up showed no abnormalities. Cerebral MR, including perfusion MR, was normal. FDG-PET showed no asymmetry. She was diagnosed with PMA-TA, and valproate was replaced by aspirin because of weight gain. The aura attacks disappeared, but the persistent aura in the left hemifield did not. Acetozolamide did not have any effect on the aura symptoms. Treatment with lamotrigine (2 × 75 mg) completely resolved the persistent aura after 3 months.

Case 3. A 59-year-old woman visited our outpatient clinic with episodes of visual disturbances in the right visual field, usually lasting several minutes. She described these as confluent, scintillating dots. Since January 2011, she experienced a white, light rim around the periphery of the right visual field. These symptoms were accompanied by a constant oppressive headache, without nausea and vomiting. Physical and neurological examinations were normal. Laboratory work-up did not show any abnormalities. Cerebral MRI was normal. She was diagnosed with PMA-TA. The aura is still present until today. So far she does not wish further treatment or further analysis (FDG-PET).

Case 4. A 20-year-old man experienced continuous flickering in the complete visual field for 3–4 years. In the past he experienced the same visual aura, but intermittently. These complaints worsened when looking at a white or blue background. His general practitioner prescribed topiramate (2 × 25 mg) without any effect. The auras were not accompanied by headache, nausea, or other symptoms. Previous ophthalmological examination was normal. MRI of the brain was normal. He was diagnosed with PMA-PPVD. Lamotrigine (2 × 50 mg) was started recently.

In summary, the age of these four patients ranges between 20 and 66 years. Duration of symptoms ranges from 1.5 to 4 years. Three patients had a normal MRI of the brain. In one case, MRI was contraindicated. In this case, the cerebral CT showed no occipital abnormalities. So far, two of our patients underwent an FDG-PET, with normal results. Only one patient had beneficial effect from medication, notably lamotrigine. Two patients are still treated with lamotrigine, without effect at present.

A fifth patient was excluded because of a small infarction, but as the complaints were similar as in other patients, we wish to present the case. A 74-year-old woman suffered from MA for many years. She experienced episodes of unilateral throbbing headache with left-sided visual aura, usually during menstruation. The auras consisted of lightning flashes and colored dots. The last few years the migraine attacks had become rare. In April 2011 she attended our outpatient clinic with complaints of visual disturbances. She had suddenly experienced zigzag lines and lightning flashes in her left visual field that were sometimes accompanied by flickering stars. These visual disturbances persisted already for 2 months. She recognized the symptoms as her typical left-sided visual migraine aura. She did not suffer from headache, nausea, or other complaints.

Physical, neurological, and ophthalmological examinations were normal, as was basic laboratory work-up. Electroencephalography (EEG) was normal; cerebral MRI demonstrated a small occipital paramedian infarction on the right side that was better visible in a second MRI, during which session perfusion MRI was included. Global perfusion in that area was diminished. FDG-PET showed hypoactivity in the right occipital lobe.

She was diagnosed with migrainous infarction. The patient was prescribed aspirin (100 mg daily), acetozolamide (250 mg daily), sodium valproate (1000 mg daily), and nimodipine (240 mg daily) consecutively, without any effect. The symptoms still persist.

Literature Review Including the Four New Cases

We identified 50 possible cases, presented in 22 articles, published between 1991 and 2014 (Table 1).[1,4,7–25] We added the data of our four new cases of PMA. We excluded seven cases (Table 2). Six, because the authors did not mention visual aura symptoms or the duration of (persistent) symptoms was less than 7 days.[9,11,26–29] Furthermore, we decided to exclude a case of PMA, described by Koyama et al,[29] because it was induced by catheter ablation. Ultimately, this leaves 47 cases of which four are newly presented.

The mean age of onset was 30 years, varying from 7 to 74 years. As was previously mentioned in the literature, PMA seems to have a predominance in women (75%).[7,17] The duration of symptoms varied from 9 days to 28 years (median 365 days). Forty-two patients had a known history of migraine. Thirty-six (76%) patients reported some form of headache accompanying the episode of persistent visual aura. (Table 1)

PMA-TA vs PMA-PPVD

The specific aura was described accurately in most case reports. Positive visual phenomena were described as colored dots; scintillating scotomas; disturbed, blurry vision; geometrical figures, circles or rims; flickering or flashing lights; blobs of white and gray; black cracks of lines; television snow; rain-like patterns; micropsia; palinopsia; squiggles; zigzag patterns; and blind spots.[1,4,7–25] In an attempt to classify these 47 PMA patients into TA and PPVD (see above), we found 19 patients with PMA-TA and 27 with PMA-PPVD (Table 1, Table 2 and Table 3). In one case, there was not enough information to classify the aura into these categories.[16]

The PMA-TA group was older (41 vs 28, P = .07) and had a significantly, much shorter duration of symptoms (757 vs 1885 days, P = .007). However, in the PMA-PPVD group there were more outliers in the extreme. The percentage of male patients was 21% and 29% in the PMA-TA and PMA-PPVD groups. There was no significant difference in the prevalence of headache between these groups (73.6% vs 81.4%, P = .52).

Structural and Functional Investigations

Structural imaging techniques and neurophysiological investigations were utilized to exclude underlying pathology other than migraine. Furthermore, functional investigations were conducted to get more inside in the underlying pathophysiology of PMA. Techniques that have been applied include MRI, Tc99m-HMPAO-SPECT, FDG-PET, MR angiography, MR perfusion, CT, EEG, VEP, ERG, EOG, Doppler, transcranial Doppler, and cerebrospinal fluid analysis.[1,4,7–25] It was not always clear what these investigations were based on, but probably they were done to exclude other pathology or provide possible insight into the pathophysiology.

The majority of patients (94%) underwent MR scanning of the brain to exclude infarction. In one case the authors do not mention whether the patient underwent an MR scan.[1] In two cases only a CT was conducted, one patient had a pacemaker and therefore a contraindication for MRI.[9] In most cases the MR was normal. Bereczki et al found changes in fast spin echo and diffusion-weighted imaging, interpreted as mild edema, in a patient with PMA. These changes resolved over the course of time at follow up, when the patient was symptom-free.[18] Belvís et al described a disturbance in the left occipital lobe in a PMA patient, shown on apparent diffusion coefficient (ADC) and in regional apparent diffusion coefficient ((r)ADC) maps. The changes disappeared after the symptoms resolved.[21] These findings could not be confirmed in other cases.[13]

Tc99m-HMPAO-SPECT and FDG-PET scanning was carried out in 11 and four cases respectively (Table 4).[4,7,12,14,18,23,25] There are inconsistent reports about SPECT in PMA. Luda et al were the first to describe hypoperfusion in the parieto-occipital region during symptoms.[4] This phenomenon was previously described in MA by Lauritzen and Olesen.[30] Liu et al stated that the inconsistent localization of the SPECT abnormalities and the subjectivity of SPECT interpretations, without normative data, did not allow them to draw any definite conclusions in their cases.[7] Chen et al also presented two cases of patients with PMA, with decreased blood perfusion on SPECT on the affected side of the brain. They demonstrated a resolution of the occipital hypoperfusion after resolution of symptoms on follow-up SPECT.[12] Relja et al found bilateral decreased perfusion in one case, particularly in the occipital region.[14]

Jäger et al tried to identify such hypoperfusion by using perfusion MRI. They did not find any changes in relative cerebral blood volume or mean transit time (MTT).[13] The patient of San Juan et al had a normal perfusion MRI.[15] Applying SPECT, Relja et al demonstrated decreased blood perfusion in the fronto-parieto-occipital region of the affected side, but in addition, hypoperfusion in the unaffected side. Perfusion MRI confirmed this hypoperfusion pattern that resolved at follow up, as did the clinical symptoms.[14]

Treatment

A broad range of medication is mentioned in the literature, including acetaminophen, acetazolamide, amitriptyline, atenolol, buspirone, butalbital, carbamazepine, citicoline, clonazepam, codeine, cyproheptadine, diazepam, diclofenac, dothiepin, duloxetine, ergotamine, flubiprofen, flunarizine, fluoxetine, gabapentin, ibuprofen, indometacin, ketamine, methylphenidate, methylprednisolone, metoprolol, naproxen, nortriptyline, phenobarbital, phenytoin, pizotifen, prochlorperazine, promethazine, propranolol, sertraline, sumatriptan, topiramate, valproic acid, and verapamil. Most drugs seemed to have little effect.[1,4,7,8,10–13,15,17,19,20,22] Acetylsalicylic acid, baclofen, divalproex sodium, furosemide, lamotrigine, nifedipine, nimodipine and sertraline seemed to have some effect, completely resolving the symptoms in some cases, of which lamotrigine seems the most effective, as was also shown in one of our patients, who experienced efficacy at a dosage of 75 mg b.i.d. (Table 5).[1,7,10–12,15,17,20,25]

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