ISSN 0017-8748 doi: 10.1111/head.12392 Published by Wiley Periodicals, Inc.

Headache © 2014 American Headache Society

Review Article 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 Koehler, PhD

Background.—Persistent migraine aura without infarction (PMA) is a rare condition that is defined as an aura that lasts longer than 1 week in absence of infarction. Two types of PMA have been distinguished, notably persistent primary visual disturbance (PPVD) and typical aura (TA). Objectives.—This case-based review article describes four new cases of PMA as well as reviews all cases reported, trying to identify relevant associations, in particular with respect to functional investigations. Methods.—We performed a systematic literature search, extending from the period when it was first described (1991) to March 2014. We included all case descriptions of which criteria for PMA formulated in the International Classification of Headache Disorders, second edition, were met. In addition, we described four new cases. Results.—We identified 47 cases of PMA, 27 PMA-PPVD and 19 PMA-TA. In one case, there was not enough information to define the type of PMA. The mean age of onset was 30 years, varying from 7 to 74 years. The duration of symptoms varied from 9 days to 28 years. Besides a longer duration in symptoms in the PMA-PPVD group, we could not identify any differences between these groups. Some authors report occipital hypoactivity on Tc99m-hexamethylpropylene amine oxime -single-photon emission computed tomography (Tc99m-HMPAO-SPECT) or fluorodeoxyglucose-positron emission tomography (FDG-PET) in PMA cases, but data are inconsistent. Multiple drugs have been used for the treatment of PMA, usually with little effect. Lamotrigine seems to be the most effective drug. Conclusion.—Despite the fact that 47 cases of PMA have been reviewed in this paper, many questions remain. The cases that have been described so far show inconsistent data with respect to the results of functional studies as well as treatment effects. The pathophysiology of PMA is still largely a matter of conjecture. Key words: migraine with aura, persistent migraine aura, persistent primary visual disturbance, Tc99m-HMPAO-SPECT, FDG-PET, treatment Abbreviations: CSD cortical spreading depression, CSF cerebrospinal fluid analysis, DWI diffusion-weighted imaging, EEG electroencephalography, EOG electrooculography, ERG electroretinogram, MA migraine with aura, MTT mean transit time, PMA persistent migraine aura without infarction, PPVD persistent primary visual disturbance, rCBF regional cerebral blood flow, TA Typical Aura, TCD transcranial Doppler, VEP visual evoked potentials (Headache 2014;••:••-••)

From the Department of Neurology, Atrium Medical Centre, Heerlen, The Netherlands (S. Thissen, I.G. Vos, A.H.C.M.L. Schreuder, and P.J. Koehler); Department of Nuclear Medicine, Atrium Medical Centre, Heerlen, The Netherlands (W.M.J. Schreurs); Department of Neuroradiology, Maastricht University Medical Centre, Maastricht, The Netherlands (A.A. Postma). Address all correspondence to S. Thissen, P.O. Box 4446, Heerlen 6401 CX, The Netherlands. Accepted for publication April 5, 2014. Conflict of Interest: None.

1

2 Migraine is a common and disabling disorder. In migraine with aura (MA), the aura is a most interesting phenomenon that is thought to be associated with Leao’s cortical spreading depression. About 20% of migraineurs experience MA, of which 99% is visual.1 Migraine auras are recurrent attacks of reversible focal neurological symptoms that typically spread in 5–20 minutes, and each symptom does not last more than 60 minutes. If these symptoms last longer, between 60 minutes and 1 week, they are called prolonged aura. MA is a risk factor for cardiovascular disease.2 Persistent migraine aura without infarction (PMA) is a condition in which auras last longer than 1 week, in absence of radiological evidence of infarction.3 Luda et al were the first to report PMA in, a 65-year-old patient with a history of migraine. She experienced a sustained visual aura for over 12 months, following a typical MA attack.4 Cases of PMA seem to be an extreme of the spectrum. Lance and Goadsby distinguished two types of PMA. First is PMA with typical aura (PMA-TA), in which patients experience a persistent typical migraine aura with oscillation, scotoma, and fortification in one hemifield. The second type is called persistent primary visual disturbance (PMA-PPVD). These patients describe “visual snow” or “television static” in the whole visual field of both eyes, in addition to intermittent scotoma or oscillating lights.5 A number of PMA cases have been reported previously with inconsistent data with respect to diagnostic tools and treatment.

OBJECTIVE In this article, we describe four new cases of PMA in our own practice. All patients provided informed consent. In addition, we review all cases reported in literature and try to identify relevant associations, in particular with respect to functional investigations. PATIENTS AND METHODS We describe four new cases in our own practice and performed a systematic literature search identifying articles that report persistent or sustained visual aura symptoms. Data were obtained from a search in PubMed from their first availability up to March

2014. Search terms included “migraine” OR “visual” in combination with “aura”, AND “persistent” OR “sustained.” Furthermore, we conducted an additional search with the terms: “visual disturbance”, “visual snow” in combination with “persistent” OR “sustained.” There were no search limits considering language. This search led to 26 results. We also searched the reference lists of individual articles. Titles and abstracts of all studies retrieved were examined. We included all case descriptions in which criteria for PMA formulated in the International Classification of Headache Disorders, second edition, were met.6 For statistical analysis we used chi-square test for normal distributed data and Mann–Whitney U-test for non-normal distributed data. We used SPSS statistical software package 17.0 (IBM Corporation, Armonk, NY, USA).

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

Headache 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 rightsided 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 PMATA, 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)

3 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-yearold 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)

4 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 (Tables 1 and 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

Age

65

32

26

29

9

67

Patient/ Ref. no

14

27

37

47

57

67

F

F

F

M

F

F

Sex

67

9

29

26

28

64

Age of Onset

4 months

2 months

5 months

2 months

4 years

1 year

Duration

Black cracks and lines in entire visual fields. Colored dots of light. Bounced like neon lights, with eyelids open or closed.

Constant blobs of white and gray squiggles, clouds, comets, bubbles “lines of ants” and “a million dots.” Worse at night. Blue squares and people’s heads.

Persistent constant flashing lights and circles (stars filling both visual fields).

Accumulation of photopsias, eventually the entire visual fields. Floating in space, with a flickering quality. Occasionally purple-andgold or rust-colored waves with eyes closed. Lights throughout visual fields, bilateral.

Scintillating scotomas in right visual hemifields. Disturbed vision. Geometrical figures (rings of chains), especially upper right quadrants.

Type of Aura

0

0

0

0

0

1*

PMATA

1

1

1

1

1

0

PMAPPVD

Headache. History of migraine.

Daily headache. History of migraine.

Daily headache. Onset after trauma. No history of migraine. Diffuse, non-pulsating headache. History of migraine.

Episodic headache. History of migraine

No headache. History of migraine

Additional Features

MRI: small right parietal white matter lesion, most likely a venous angioma. EEG, ERG, VEP. SPECT: bilateral decreased parietal activity.

MRI, EEG, ERG, CSF, SPECT: decreased left temporal lobe activity. MRI, EEG, CSF, Duplex, TCD. SPECT: asymmetric activity in the visual association cortex, right > left. MRI, EEG

EEG, Doppler, CT, MRI, VEP normal. SPECT: decreased blood supply left hemisphere. MRI, EEG.

Investigation(s)

Table 1.—Persistent Migraine Aura (PMA): 47 Cases From Literature and Four New Cases

Phenobarbital and amitriptyline decreased frequency of headaches and reduced but not resolved visual images. Amitriptyline and ibuprofen.

Phenytoin, carbamazepine, verapamil and nifedipine little effect.

Amitriptyline, carbamazepine > no effect

Carbamazepine, diazepam, flunarizine, nimodipine and citicoline without effect. Verapamil, acetylsalicylic acid, fluoxetine, baclofen and buspirone – no effect

Medication

Headache 5

Age

37

20

30

23

Patient/ Ref. no

77

87

97

107

F

M

F

M

Sex

19

30

18

37

Age of Onset

3.5 years

8 months

2 years

6 months

Duration

Blurry, gray vision in left lower quadrant of both eyes, lasting several weeks. Next 6 months persistent television set “snow” and grainy vision throughout all fields. Later energized sparkle to the snow. Worsened in dim illumination. Constant white and black dots, “snow” and “TV static” over entire visual field. Later persistence of visual images (palinopsia) developed. “Snow” and “flickering” similar to what was “between TV channels.” Initially only in dark illumination. “Rain-like” pattern in front of both eyes, at times appearing like a carpet background. “Heat waves” with flickering lights. Five episodes of visual “black-out” and bright “daggers and spots” lasting 40 seconds.

Type of Aura

0

0

0

0

PMATA

1

1

1

1

PMAPPVD

Table 1.—Continued

Headache not mentioned. History of migraine.

Without headaches. History of migraine.

Headache not mentioned. Onset after trauma. History of migraine.

Periodic bilateral retrobulbar headaches. History of migraine.

Additional Features

MRI: small biparietal-occipital white matter lesions. EEG, ERG and SPECT normal.

MRI. SPECT: bilaterally, hypoperfusion, parieto-occipital

MRI, EEG. SPECT: bilaterally, hypoperfusion.

MRI, EEG.

Investigation(s)

Verapamil, clonazepam and acetylsalicylic acid only modest effect.

Nortriptyline and carbamazepine resolved only palinopsia. The other visual disturbances persisted for 2 years. Nifedipine unhelpful, sertraline reduced visual phenomena by 50%.

Amitriptyline and acetylsalicylic acid unhelpful.

Medication

6

36

51

55

61

53

117

128

139

1410

1510

F

F

F

M

M

51

61

55

50

31

2 years

2 months

10 days

10 months

5 years

Bright flashing dots of light, zigzags, blind spots, sparkles in all visual fields. Pulsating.

Left of center in both eyes, scintillations and jagged zigzags . . . like crushed, broken glass at the periphery of the scotoma. Fluctuating in size. (Typical migraine aura she experienced before).

Constant flickering “like a fluorescent bulb that is about to go out” at the edges of the visual field of both eyes. Persisted for 5 years. Bright objects in the temporal fields (left > right eye) persisted as bright lines for up to 15 seconds when looking away, and after looking at a brightly lit wall and moving his head or eyes quickly, the temporal portion of his visual field “glowed with a rim of brightness.” Binocular, bilateral visual distortion, “Jagged lines,” white lights, “Picasso faces,” “holes in my vision.” Increased with work activity and exposure to bright light. Visual field defect bilateral left inferior. Shimmering, zigzag patterns of sparkling light in left visual field.

0

2

1

0

2

1

0

0

2

0

MRI/MRA, EEG all normal.

MRI.

Throbbing CT normal. unilateral headaches. New-onset symptoms (no history of migraine). Episodic MRI, EEG. headaches typical to previous migraine attacks. Persistent, fluctuating, tingling left face and lips. History of migraine. Episodic MRI, EEG headaches and tingling face. Constant low-intensity headaches. History of migraine.

Mild headaches twice monthly. History of migraine.

Headache not mentioned. History of migraine.

Propranolol, naproxen, amitriptyline, verapamil, metoprolol and sumatriptan not effective. Divalproex sodium – headache and aura ceased.

Propranolol – no effect Divalproex sodium – visual symptoms ceased entirely.

None.

Verapamil, propranolol, valproic acid sertraline all poorly tolerated.

None

Headache 7

Age

34

45

24

39

46

Patient/ Ref. no

1611

1712

1812

1913

2013

F

F

F

F

F

Sex

42

11

21

45

34

Age of Onset

4 years

28 years

3 years

3 months

10 days

Duration

Blotches in central vision, colored at times, more visible with eyes closed. Fluctuates, worse every other week.

Numerous stars, persistently flickering in her right hemifield for 3 years. Uncolored stars, kept moving eccentrically, and sometimes confluent. Persistent flashing lights. Thousands of small yellow, white, or silvery dots over whole of both visual fields. Seen with eyes closed. Episodically bigger flashing lights.

Coin-sized white spot with occasional flickering in the left hemifield. Persisted, regardless eyes open or closed.

Persistent right-sided visual field loss. Grayed or blacked out.

Type of Aura

0

0

1

1

1

PMATA

2

1

0

0

0

PMAPPVD

Table 1.—Continued

Weekly throbbing headache. Vomiting, photophobia, phonophobia and vertigo. 24–72 hours. History of migraine. Persistent headache. History of migraine.

Mild daily headache. History of migraine.

Headache left temporal. Daily. History of migraine.

Severe migraine headache. History of migraine.

Additional Features

MRI

MRI, EEG, VEP normal. SPECT: disclosed decreased blood. SPECT perfusion in the right occipital region. SPECT after remission showed no hypoperfusion. MRI, EEG, VEP normal. SPECT: hypoperfusion left occipital region. After remission, no hypoperfusion. MRI, EEG, ERG, VEP all normal

MRI/MRA,

Investigation(s)

Pizotifen, sodium valproate, flunarizine, topiramate and dothiepin – no effect.

Acetazolamide, amitriptyline, pizotifen, propranolol and intranasal ketamine – no effect.

Flunarizine, atenolol and propranolol ineffective. Lamotrigine 50 mg/ day effective

Prochlorperazine, methylprednisolone, divalproex sodium, without effect. Furosemide resolved symptoms. Lamotrigine 50–100 mg/day. Symptoms resolved

Medication

8

27

33

43

28

41 26

37

2113

2213

2314

2415

2516 2617

2717

M

F F

F

F

F

F

32

41 16

28

42

30

23

5 years

TV static/noise

Visual aura TV static (countless tiny black and white dots scattered throughout the entire visual field)

>7 days 10 years

Right hemifield, bright halo on right edge of objects and a scintillating scotoma with grey and white squares. Like a chessboard.

Scintillating bilateral scotomas as well as photopsias and amaurosis

months

Looking at a bright light over the right hemifield with superimposed flashes of light every few minutes

Persistent shimmering over the entire visual field bilaterally. (looking to a road on a very hot day). Periodically tiny pinpoints of bright light lasting 30 seconds.

35 days

18

3 years

4 years

0

3 0

0

1

1

0

1

3 1

2

0

0

1

Headache not specifically described. History of migraine.

Migraine headache. History of migraine. Unknown. Everyday headache with exacerbations. History of migraine.

Background, featureless headache once a week/month. Migraine once every few months. History of migraine. Exacerbations for 20–60 minutes every 3–6 months. Left-sided throbbing headaches of moderate intensity twice a week with photophobia and phonophobia. History of migraine. Pulsating headache (left temporoorbital, severe to moderate). History of migraine. Unknown.

Unknown.

EEG, VEP, Doppler, Lamotrigine. CT, MRI. SPECT: decreased left fronto-parieto-occipital and right occipital blood perfusion pMRI decreased 18–25% left – right hemisphere CT, EEG, VEP, Topiramate, MRI, MRA, sumatriptan – no MRV, pMRI, effect. Nimodipine fMRI. probably effective. MRI. Unknown. Blood tests, MRI, Propranolol, EEG. amitriptyline, sumatriptan, flubiprofen, lamotrigine – no effect. Blood tests, MRI, Topiramate, flunarizine, EEG. duloxetine and lamotrigine.

MRI, VEP

MRI, VEP

Headache 9

Age

56

41

51

27

58

25

11

Patient/ Ref. no

2817

2917

3017

3117

3218

3319

3420

F

F

M

M

F

F

F

Sex

11

25

58

25

50

40

36

Age of Onset

Lightning flashes, inferior visual field disturbance. Persistent negative phenomenon (“shadow” in the eyes). Transient bright zigzag lines in her temporal visual fields.

>4 months

Persistent hemianopia right visual field.

One white or silver light bar (sometimes two) in left lower quadrant.

One flashing bright oval spot, about half of a fingerprint in size, staying at the corner of right eye; became bilateral several months after cessation of prophylactic medication Bitemporal bright spots, one on each side, like afterimages of strong lights.

Sapphire or yellowish thumbnail-sized nonscintillating comets moving forward from behind

Type of Aura

4 months

8 weeks

2 years

1 year

1 year

20 years

Duration

2

2

1

2

1

2

0

PMATA

0

0

0

0

0

0

2

PMAPPVD

Table 1.—Continued

Headache. History of migraine.

Headache. History of migraine

Headache not specifically described. History of migraine. Throbbing headache, vomiting. History of migraine.

Migraine headache. History of migraine.

Exacerbations of headache. History of migraine.

Daily headache with exacerbations. History of migraine.

Additional Features

MRI.

CT, MRI, PET, TCD, EEG. FSE left occipital cortex, DWI detected a lesion in the same cortical location. VEP, MRI/MRA TCD, EEG.

Blood tests, MRI, EEG.

Blood tests, MRI, EEG.

Blood tests, MRI, EEG.

Blood tests, MRI, EEG.

Investigation(s)

Sodium valproate, propranolol without effect. Atenolol no effect. Furosemide 40 mg p.o. daily.

Unknown.

Sumatriptan, diclofenac, naproxen, ergotamine, acetaminophen, flunarizine, propranolol, sodium valproate. Propranolol, verapamil, lamotrigine and indomethacin.

Propranolol, topiramate and lamotrigine – decrease in headache and aura but still present. Propranolol, flunarizine – no effect. Topiramate and lamotrigine – some effect, but still present.

Medication

10

41

14

74

25

39

36

3521

3622

371

381

391

401

F

M

F

F

F

F

15

34

7

74

14

41

21 years

>5 years

18 years

>8 weeks

1 month

9 days

Circles of light in the center of vision, bluish intermittently without scotoma, lasting. After-images or tracers. Little bugs, television snow constantly.

Sudden change in color perception; “seeing through a dark red lens,” in lower visual fields of both eyes. Squiggles in her left field, both eyes, inferior more than superior. With eyes closed, kaleidoscope-type letters with a colored background. Television static, tiny air molecules, rain on a window, most noticeable if she is looking at the sky or a white background. Both eyes, also with eyes closed. Small fuzzy holes. Slowly the holes became larger over several minutes, half of visual field. Faint squiggly lines and a slight haze in entire visual field. Worsened to “snow vision.” Sparks, shooting stars, and floaters.

White, bright particles falling in both visual fields (visual snow).

0

0

0

1

0

0

1

1

1

0

2

1

Intermittently headache, vomiting, nausea. History of migraine.

Severe headache with vomiting and nausea. New onset. No prior history of migraine. Mother with migraine.

Daily headache. History of migraine.

Recurring headaches. History of migraine.

Bilateral parenthesia in the extremities. Headache. History of (basilar) migraine. No headache. History of migraine.

MRI/MRA.

Unknown.

MRI.

MRI/MRA.

MRI, TCD, EEG all normal.

MRI, MRA, TCD, ADC/DWI left occipital signal disturbance.

Butalbital, propranolol, verapamil resolved headache. Divalproex sodium, lamotriginem gabapentin, acetazolamide, sertraline, carbamazepine and topiramate. The only medication that produced improvement was baclofen. Propranolol, divalproex sodium, topiramate no effect.

Divalproex sodium, prednisone, topiramate, valproic acid, furosemide, promethazine with only slight decrease. Unknown.

Methylphenidate, acetylsalicylic acid, topiramate.

Unknown.

Headache 11

14

12

21

66

41

59

20

4123

4224

4325

44

45

46

47

M

F

F

M

F

F

F

Sex

17

57

39

64

21

10

14

Age of Onset

3–4 years

2 years

1.5 years

2 years

6 months

3 years

6 weeks

Duration

1

0

0

PMATA

0

1

1

0

New Cases

Confluating, scintillating dots. White rim around periphery of the right visual field. Continuous flickering light, bilateral. Increasing when looking to blue/white background.

Blurred rim on the periphery of the left visual field.

White dots in front of both eyes. “Television static.” “Like rain on a window.”

Right side of field of vision going dark.

Bright, jagged spots and black and white flashes with sparkles and dots. Blurred vision. Photophobia.

“Falling rain” with flickering white lights in both eyes. Diffuse scintillating white lights.

Type of Aura

1

0

0

1

0

1

1

PMAPPVD

Throbbing headache. History of migraine. Intermittent headaches. No history of migraine (first onset).

None. History of migraine.

Headache. History of migraine.

No headache. History of migraine.

Throbbing headache. History of migraine.

Headache, lightheadedness. History of migraine.

Additional Features

MRI normal.

MRI.

ERG, EOG, CT (contra-indication MRI), VEP, TCD and PET all normal. MRI, PET normal.

MRI, MRA, TCD, SPECT.

MRI, EEG, ERG, EOG normal. PET: mild hypermetabolic activity, occipital. MRI, VEP.

Investigation(s)

Topiramate, no effect. Lamotrigine.

Acetozolamide no effect. Lamotrigine 150 mg/day, completely resolved aura. None.

Sodium valproate. Lamotrigine.

Sumatriptan, topiramate, riboflavin, flunarizine, acetazolamide. Acetaminophen, lamotrigine, furosemide.

None.

Medication

ADC = apparent diffusion coefficient; CSF = cerebrospinal fluid; CT = computed tomography; DWI = diffusion-weighted imaging; EEG = electroencephalography; EOG = electrooculography; ERG = electroretinography; fMRI = functional MRI; MRA = magnetic resonance angiography; MRI = magnetic resonance imaging; PET = positron emission tomography; pMRI = perfusion-weighted magnetic resonance imaging; PPVD = primary persistent visual disturbance; SPECT = single-photon emission computed tomography; TA = typical aura; TCD = transcranial Doppler; VEP = visual evoked potential. *PMA-TA and PMA-PPVD: 1 = definitely; 2 = doubtful; 3 = classification not possible.

Age

Patient/ Ref. no

Table 1.—Continued

12

70

18

34

33

37

34

46

126

226

39

427

511

628

729

F

F

F

F

F

M

M

Sex

46

34

37

33

34

18

70

Age of Onset

4 years

2 days

5 days

>5 days

1 month

2 weeks

5 weeks

Duration

In the middle of catheter ablation, visual disturbances such as phosphenes, double vision, and visual perseverations. Dazzling spots in the air, similar to the reflection of the water. After-images, in inverted color.

Zigzag lines at the center of her visual field that moved slowly to the periphery and then dissipated (as in typical aura). Small bright flashes of light, zigzag lines, and fortification spectra in both visual fields. Flashing lights in left visual field.

Slowly undulating thick, gray lines. “Pinwheel” bright whirling color mainly yellow and red, in left visual field of both eyes. Bursts into his vision form of concentric gray circles like ripples in a pond. Visual field defect left eye. “Spider web-shaped.” Several minutes flashing colored light. No visual complaints.

Type of Aura

Severe headache. Psychomotor slowness, confusion, difficulty in speech, left lateral hemianopia, and paresthesias on the left side of the face and upper limb. Strong headache.

Numbness in left cheek, left side of her mouth, and tingling of her left hand without headache. –

None

–

–

Additional Features

MRI, SPECT, EEG, VEP.

MRI: white matter increased signal intensity periventricular and subcortical. Duplex, MRA, EEG normal. PA: CADASIL.

MRI/MRA

MRI/MRA

CT normal

Unknown

Unknown

Investigation(s)

Phenobarbital, sodium valproate, clonazepam, carbamazepine, phenytoin, zonisamide, primidone, acetozolamide, clobazam, loxoprofensodium, sumatriptan, imipramine hydrochloride, fluvoxamine maleate, paroxetine hydrochloride hydrate, sulpiride, fluphenazine maleate, tofisopam, arotinololhydrochloride, lomerizine hydrochloride, difenidol hydrochloride and rebamipide.

Ibuprofen, ketorolac, lorazepam, mannitol

Droperidal, magnesium, methylprednisolone no effect. Furosemide resolved problems.

Acetylsalicylic acid. Furosemide, verapamil

Acetaminophen with codeine

Unknown

Acetylsalicylic acid, cyproheptadine

Medication

Induced by ablation

Duration of symptoms < 7 days

Duration of symptoms < 7 days

No visual aura

Intermittent aura

Intermittent aura

Intermittent aura

Reason of Exclusion

CADASIL = cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CT = computed tomography; EEG = electroencephalography; MRA = magnetic resonance angiography; MRI = magnetic resonance imaging; SPECT = single-photon emission computed tomography; VEP = visual evoked potential.

Age

Patient/ Ref. No.

Table 2.—Excluded Cases

Headache 13

14 Table 3.—Distinction Between PMA-Persistent Primary Visual Disturbance (PPVD) and PMA-Typical Aura (TA)†

PMA-TA PMA-PPVD P*

Cases

Age of Onset (Years)

Duration (Days)

M:F

19 27 –

41.2 28.4 .07

757.6 1884.9 .007

4 : 15 8 : 19 .51

Headache

14 22 .52

*P values were calculated using Χ2 test for normal distributed data and Mann–Whitney U-test for non-normal distributed data. †Case numbers TA: 1,4,7,9,10–14,17–20, 25; Case numbers PPVD: 1,7,8,10,13,15,17, 21–24. F = female; M = male; PMA = persistent migraine aura.

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 frontoparieto-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

DISCUSSION We reviewed data of 47 patients with PMA and with this number attempted to discern any patterns within this remarkable phenomenon. There is a broad

Table 4.—Cases Studied by Tc99m-HMPAO-SPECT, FDG-PET, and MR-PWI

Cases†

Imaging SPECT PET MR-PWI TA : PPVD

1 =↓‡ – – TA

3 =↓ – – P

4 ↓↓ – – P

6 ↓↓ – – P

8 ↓↓ – – P

9 ↓↓ – – P

10 == – – P

17 ↓= – – TA

18 ↓= – – TA

23 ↓↓ – ↓↓ TA

24 – – == P

32 – == – TA

41 – ↑↑ – P

43 == – – TA

44 – == – P

45 – == – TA

†The numbers represent the cases described in Table 1. ‡The first icon indicates the right hemisphere, and the second the left hemisphere. – = no investigation; = = normal; ↑ = increased; ↓ = decreased; Tc99m-HMPAO-SPECT = Tc99m-hexamethylpropylene amine oxime -single-photon emission computed tomography; FDG-PET = fluorodeoxyglucose-positron emission tomography; MR-PWI = magnetic resonance perfusion-weighted imaging; P = primary persistent visual disturbance; TA = typical aura.

Headache

15 Table 5.—Medication Options Described in Literature and Their Effectiveness

Group

Antiepileptics

Benzodiazepine Beta-blockers

Calcium-antagonist

Diuretics NSAIDs

SSRI TCAs

Various

Drug

Cases

Effect

Carbamazepine Divalproex sodium

1,3,4,8,39 14,15,16,37,39,40

Gabapentin Lamotrigine

Nifedipine Nimodipine Verapamil Furosemide

39 17,18,23,26,27,28,29,31,39,43,44, 45,47 5 4 20,24,27,28,29,36,37,39,40,42,47 12,20,30,33,37,44 10 1 18,34 27 12,14,15,18,19,26,28,29,30,31, 33,39,40 4,9 1,24,42 2,4,10,12,15,31,39 16,34,37,43

Diclofenac Flubiprofen Ibuprofen Indometacine Naproxen Fluoxetine Sertraline Amitriptyline

30 26 6 31 15,30 2 9,12,39 3,5,6,7,15,19,26

4 partial 24 partial None 16,34 complete, partial 43 None None None None None None 9 partial None

Nortriptyline Acetaminophen Acetazolamide Acetylsalicylic acid Baclofen Buspirone Butalbital Citicoline Codeine Duloxetine Ergotamine Flunarizine Ketamine Methylphenidate Methylprednisolone Pizotifen Prochlorperazine Promethazine Sumatriptan

8 30,43 19,39,42,45 2,7,10,36 2,39 2 39 1 3 27 30 1,18,20,27,29,30,42 19 36 16 19,20 16 37 15,24,30, 42

None None None 10 partial 39 partial None None None None None None None None None None None None None None

Phenobarbital Phenytoin Topiramate Valproic acid Clonazepam Diazepam Atenolol Metoprolol Propranolol

None 14 complete + 15 partial None 17,18,45 complete + 28,29,43 partial None None None None None None None None None

Other

50–150 mg/day

40 mg/day

Decreased headache

NSAID = non-steroidal anti-inflammatory drugs; SSRI = selective serotonin re-uptake inhibitor; TCA = tricyclic antidepressant.

16 variation in age of onset, with an average age of 30. The majority of the patients were women. Both age and female preponderance may be explained by the prevalence of MA in the general population and not be a characteristic of PMA itself.31 The wide variation in duration of symptoms makes it difficult to predict the prognosis and outcome of these symptoms. Accurate history taking is the most important diagnostic tool. A normal neurologic, as well as ophthalmologic examination, is required to diagnose PMA, although visual field exam could be abnormal because of negative symptoms (ie, scotoma) as part of the aura. Obtaining an MR of the brain is necessary to exclude infarction and other pathology.6 This was the case in 44 (94%) patients. Therefore, we cannot be completely certain of the diagnosis PMA in three cases. In one case there was a CT scan without signs of infarction. In one case no information about imaging studies was provided. In our first case there was some doubt about a cortical infarction on the left. However, this possible lesion could not explain the patient’s symptoms and was therefore considered an incidental finding. The fifth patient that we presented above, and who was excluded from the series, is illustrative in a way that typical PMA-TA may be present with a small infarction and therefore demonstrating that MR is necessary and should be studied carefully. This kind of lesions could easily escape detection on CT and we wondered whether more powerful MR scan would enable detection of lesions in the other patients. Lance and Goadsby made a distinction between PMA-TA and PMA-PPVD.5 There were more PPVD (27) cases than TA (19) in our review. The precise significance of this distinction is unknown, but there may be a difference in underlying pathophysiology and treatment efficacy. Besides a significant difference in duration of symptoms, we have been unable to find any differences between these groups in the present review (Table 3). Previously, Lashley’s experience of his own visual aura led to his proposal that the aura was due to a spreading abnormality that migrated over the visual cortex at a rate of 3–5 mm per minute.32 Presently, visual aura is thought to be associated with the phenomenon of cortical spreading depression (CSD)

usually starting in the occipital cortex as described by Leao. CSD is a neuronal depolarization wave with subsequent suppression of electrical activity that moves across contiguous cortical areas at a rate of about 2–5 mm per minute after mechanical or chemical perturbation of the cortex in experimental animals.33 CSD is followed by changes of the regional cerebral blood flow (rCBF). During the aura phase, patients develop rCBF reduction (oligemia), which does not reach critical values (ischemia). Oligemia gradually spreads anteriorly in the course of 15–45 minutes.34 Studies during attacks showed alterations in relative cerebral blood flow, cerebral blood volume, as well as tissue MTT in the grey matter of the occipital cortex contralateral to the affected visual hemifield and, more rarely, hypoperfusion of the whole hemisphere.35 Hadjikhani et al reported a case of spontaneous migraine studied with functional MRI techniques, revealing a slow neuronal change in the occipital cortex, moving forward at a rate of 3–6 mm per minute, during the aura phase.36 These data might create expectations with respect to functional studies in PMA. Although the specific pathophysiology of PMA without infarction is still unknown,17 several theories on the underlying pathophysiological mechanism have been proposed. These include abnormal energy metabolism in the brain, brain magnesium levels being significantly lower than that of nonmigraineurs, greater reactivity of N-methyl-Daspartate receptors to glutamate, a lowered threshold to CSD, and loss of inhibitory GABA-ergic interneurons; they may combine to cause sustained visual aura.14 Other authors oppose a sustained hyperexcitability of the visual cortex without significant dynamic modulation.This study also suggests a pathophysiologic link to sustained excitatory links possibly related to reverberating CSD.37 Several studies have been undertaken to investigate these underlying pathophysiological hypotheses in PMA by using Tc99m-HMPAO-SPECT, FDG-PET and MR–perfusion-weighted imaging (PWI).4,13-15,18,21,38 As reviewed above, these investigations show conflicting data. Eleven PMA cases have been studied with Tc99m-HMPAO-SPECT; they show inconsistent

Headache data.4,7,12,14,25 In five cases there was bilateral hypoactivity, and in four cases hemi-hypoperfusion. Only in two cases the SPECT showed normal activity of the bilateral occipital cortex. Occipital hypoperfusion on SPECT might be due to reduced neuronal activity and metabolism during the supposed reverberating waves of spreading depression. Focal hypoperfusion might not be the true pathogenetic origin.17 Nevertheless, this indicates that the occipital cortex is involved in the pathogenesis of persistent visual auras. The inconsistency of the data presented might be explained by the difference in clinical symptoms. One could think that a typical aura in one hemifield would show hypoperfusion on the contralateral side, whereas symptoms in both visual fields may be correlated with bilateral hypoperfusion. However, we could not identify such an association. Despite these findings, this still does not exclude such an association. Findings with SPECT seem subjective and difficult to interpret with a lack of standardization. This makes it difficult to interpret the presented results. Four cases have been studied with FDG-PET.18,23 Three showed normal results. In one case there was bilateral hyperactivity. Mathew et al found hyperactivity in the occipital region, indicating hypermetabolism of the contralateral cortex in patients with migraine aura.38 Only one study, using MR-PWI, could identify hypoperfusion during PMA.14 However, no conclusions can be drawn from these conflicting data. Revision and standardization of the imaging protocols could possibly lead to other results. Therefore, further studies are needed to establish the role of Tc99m-HMPAO-SPECT and FDG-PET in migraine aura and PMA. This could lead to a better understanding of its underlying pathophysiology (Table 4). Thinking of the one patient, described above, with a subtle occipital cortical infarction and hypoperfusion on the PET scan, one may wonder whether CT scans done in some of the patients were sufficient to detect small lesions. Moreover, it may be questioned whether MR scans presently used for routine clinical purposes (usually 1.5 Tesla with variable slice thickness) are sensitive enough to pick up small cortical lesions. Lesions found in migraineurs (mainly those

17 with aura) in the Cerebral Abnormalities in Migraine, an Epidemiological Risk Analysis (CAMERA) study were largely found in the cerebellum, but patients with PMA were not included. Could small (without causing hemianopia) cortical infarctions in the occipital cortex be responsible for PMA by causing loss of inhibitory GABA-ergic interneurons resulting in an imbalance in local networks leading to reverberating CSDs?39,40 The treatment of PMA is purely based on case reports and expert opinion. As could be expected in such a rare phenomenon, there are no double-blind, placebo-controlled studies. Only a few drugs have been described to be effective: Acetylsalicylic acid,10 baclofen,1 divalproex sodium,10 furosemide,11,20,25 lamotrigine,12,17,25 nifedipine,15 nimodipine,15 and sertraline.7 Basically, treatment is based upon the theory of hyperexcitability.1 In our cases only lamotrigine was effective, with resolution of symptoms in one case. In literature, lamotrigine also seems the most described effective treatment (Table 5). Wang et al tried to find a prediction model for the prognosis of PMA. The analysis involved 29 patients. They concluded that PPVD had a poorer prognosis, and higher Visual Aura Rating Scale scores, which are more typical of migraine visual aura, predicted a better outcome. For those with a potential for complete resolution, improvement would occur early in the course.17 We have been unable to reproduce these figures mainly because of incomplete data in these 47 cases. Recently Schankin et al described the phenomenon “visual snow” or “positive persistent visual disturbance” as a distinct disease entity from MA. They describe 120 patients with this unique clinical syndrome. The criteria they formulated include visual snow during daytime or at night plus at least one of the following: floaters, persistent after-images, “hard time seeing at night,” “little cells that travel on a wiggly path,” photophobia, “moving objects leave trails,” flashes and “swirls with eyes closed.” The etiology is currently unknown.41,42

CONCLUSION Despite the fact that 47 cases of PMA have been reviewed in this paper, many questions remain. The

18 cases that have been described so far show inconsistent data with respect to the results of functional studies and treatment. The pathophysiology of PMA is still largely a matter of conjecture. As we suppose that PMA is more frequent than reported up to the present, it would be useful to report more series including results of functional studies that may lead to more insight into the pathophysiology of the condition. Although the data on physiological studies were inconsistent, there may be a preponderance with respect to hypoperfusion SPECT studies. PMA should be considered in patients who complain of persistent visual phenomena even without a history of migraine. Diagnostic studies, at least a neurologic and neuro-ophthalmologic examination, as well as a high-resolution MR scan with thin slices, should be considered to exclude other pathology. The variability of the data is too large to provide a prognosis for individual patients. Symptoms may persist for up to 28 years. Lamotrigine may be the most effective treatment. Further studies are needed to identify the underlying pathophysiology.

STATEMENT OF AUTHORSHIP Category 1 (a) Conception and Design Sam Thissen, Peter Koehler (b) Acquisition of Data Sam Thissen, Iris Vos, Tobien Schreuder, Peter Koehler (c) Analysis and Interpretation of Data Sam Thissen, Iris Vos, Tobien Schreuder, Wendy Schreurs, Linda Postma, Peter Koehler Category 2 (a) Drafting the Manuscript Sam Thissen, Peter Koehler (b) Revising It for Intellectual Content Sam Thissen, Iris Vos, Tobien Schreuder, Wendy Schreurs, Linda Postma, Peter Koehler Category 3 (a) Final Approval of the Completed Manuscript Sam Thissen, Iris Vos, Tobien Schreuder, Wendy Schreurs, Linda Postma, Peter Koehler

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