DÄ internationalArchive39/2021Visual Phenomena Associated With Migraine and Their Differential Diagnosis

Review article

Visual Phenomena Associated With Migraine and Their Differential Diagnosis

Dtsch Arztebl Int 2021; 118: 647-53. DOI: 10.3238/arztebl.m2021.0287

Eren, O E; Wilhelm, H; Schankin, C J; Straube, A

Background: Visual phenomena are of many different kinds; their differential diagnosis is usually possible with directed history-taking. In this review, we describe common visual phenomena that must be distinguished from a migraine aura.

Methods: This review is based on publications retrieved by a selective search in PubMed and the Web of Knowledge/Science, with special attention to the current classification of the International Headache Society and the recommendations of the German Migraine and Headache Society. The following search terms were used: “visual phenomena/phenomenon,” “migraine aura,” and “persistent/complication/long-lasting/ongoing.”

Results: The most helpful questions for differential diagnosis are whether the symptoms are present in one eye only or in both, whether their onset was sudden or over minutes or days, and whether the phenomenon has occurred only once or repeatedly, or is persistently present. A visual aura associated with migraine must be distinguished, in rare cases, from an isolated epileptic aura, from cerebral/retinal ischemia, or from visual snow. Further differential diagnoses include a persisting perceptual disturbance after hallucinogen use (HPPD, “hallucinogen persisting perception disorder”) and the Charles Bonnet syndrome (CBS); the latter arises as a consequence of severely impaired vision. Posterior reversible encephalopathy syndrome (PRES) is rare and generally reveals itself over its further course through the appearance of additional clinical manifestations. Primary ophthalmological causes can usually be readily identified and classified by ophthalmological examination.

Conclusion: Patients with visual phenomena typically consult physicians from various medical specialties. A correct differential diagnosis can be made based on the history if the physician views the symptoms in their overall context to determine the particular disease entity that is responsible.

LNSLNS

All physicians commonly encounter patients whose symptoms are not confined to a single medical discipline. This is especially true of visual disorders, where identification of the cause may require ophthalmological, neurological, and even psychiatric expertise. Particularly close attention has to be paid to the patient’s subjective account (Table 1), which provides important pointers to further interrogation about the medical history, the diagnostic work-up, classification of the disorder, and perhaps even the appropriate treatment.

A selection of commonly occurring visual symptoms, with their clinical manifestations and patients’ subjective descriptions*
Table 1
A selection of commonly occurring visual symptoms, with their clinical manifestations and patients’ subjective descriptions*

The aim of this review is to describe the visual phenomena that occur in connection with migraine and their potential differential diagnoses. It is clinically significant whether the reported visual disorder is found in both eyes (binocular) or only in one eye (monocular). If the visual symptoms remain present when each eye is covered in turn, a binocular problem can be assumed, originating somewhere posterior to the optic chiasm in the central nervous system. It is also helpful to distinguish between recurrent and persistent visual phenomena.

Transient binocular visual phenomena

Migraine aura

The aura experienced by some migraine sufferers is the classic example of a recurring, self-limiting, primarily visual phenomenon. In a third of cases there are also sensory symptoms (somatosensory aura); a quarter of sufferers have speech or language problems (dysphasic/aphasic aura); and ±6% experience motor deficits (motor/hemiplegic aura) (1). Less common is brainstem aura, whose manifestations include the following (2):

  • Slurred speech (dysarthria)
  • Double vision (diplopia)
  • Vertigo (rotational/postural)
  • Noises in the ears (tinnitus) with hearing impairment (hypacusis)
  • Coordination disorders (ataxia)
  • Alterations of consciousness

Overall, it is estimated that around 30% of migraine patients have auras, meaning that migraine auras can be assumed in about 3.5–8% of the population (1, 3, 4). Characteristic of the typical visual aura is that it begins with development of a paracentral scotoma or of fortification figures (blinking diamond/kaleidoscope), followed by extension to the peripheral visual field. Typical is the parallel or successive manifestation of irritative phenomena (“bright blinking lights”) and a visual field defect (“black hole”), as well as migration from central to peripheral. By the time the flickering has reached the periphery, it is usually no longer present centrally. Although this form of visual aura is binocular, patients often do not realize it, frequently perceiving their vision as a 50/50 “screen” with the left half supplied by the left eye and the right half by the right eye. Much rarer are visual auras in the form of altered object perception, with magnification or diminution (macropsia/micropsia) as in Alice in Wonderland syndrome (lifetime prevalence in patients with migraine: 15–19%) (5, 6).

The neurophysiological correlate is cortical spreading depression (CSD), first described by Leão, in an animal experiment carried out in 1944, as a slow diffusion of stimuli over the cortex (7). Indirect confirmation of this concept was later provided by functional magnetic resonance imaging during spontaneous/triggered visual auras, showing changes in cerebral perfusion parallel to the diffusion of the visual aura in the field of vision (8). The blood oxygenation level-dependent (BOLD) signal migrated over the extrastriatal cortex at a rate of circa 3.5 mm/min, corresponding approximately to the speed calculated by Lashley in 1941 on the basis of observations of his own visual auras (9). Auras typically last for 5–60 min. Complex auras, e.g., successive visual and somatosensory auras, may last longer, but each individual modality should then last less than an hour.

Migraine auras are usually self-limiting. To date, there is no reliably effective treatment. In patients who experience auras very frequently and are bothered by them, preventive treatment with flunarizine or lamotrigine can be tried (10). Moreover, aspirin 80 mg proved highly effective in a case series of 49 patients with frequent (10.2×/month) migraine aura (reduction in 93%, including 20% with complete resolution) (11). No controlled trials have been conducted.

Possible trigger factors are often mentioned, such as increased physical activity/stress, sensory influences, or a disturbed day/night rhythm (12). Although these are extremely difficult to demonstrate under experimental conditions (13, 14), the person affected can try to avoid subjective trigger factors.

In most cases the aura is followed by the well-known headache, although the latter may not occur, or may begin before or during the aura (1, 15). It is common to encounter patients who report isolated auras. In combination with somatosensory or aphasic auras, these cases must be distinguished from acute stroke (16, 17).

Transient ischemic attack

A transient ischemic attack (TIA) represents a brief interruption of cerebral perfusion, with the clinical deficits depending on the vessels affected. By definition, a TIA lasts no longer than 24 h; however, it often resolves completely within 60 min. The occurrence of a TIA should be seen as a “warning shot,” because one fourth of those affected go on to have a stroke (18). The migraine aura is a predestined “stroke mimic” (17). However, the potential initiation of systemic lysis in the acute phase, together with lifelong secondary prophylaxis, render clinical differentiation highly important. A classification such as that shown in Table 2 permits distinction of TIA from migraine aura with sensitivity of 99% and specificity of 95% (19).

Differentiation between transient ischemic attacks and migraine aura (from [19])
Table 2
Differentiation between transient ischemic attacks and migraine aura (from [19])

It should also be mentioned that the incidence of TIA rises sharply with age (0.52–2.37% in 55- to 64-year-olds vs. 2.18–6.06% in 75- to 84-year-olds) (20), while the prevalence of migraine peaks between the ages of 20 and 50 years (21).

Epilepsy aura

A differential diagnosis seen particularly in children, very occasionally also in adults, is the visual aura that may occur in cases of epilepsy, especially in focal occipital seizures. These sometimes also feature episodes of unilateral myoclonus or disturbance of consciousness, which simplify the differentiation from migraine aura and point clearly to epilepsy. However, there are also cases in which the visual aura is the sole symptom. In a study published in 2017 (27 patients with epilepsy vs. 27 with migraine), the principal distinguishing characteristic was how long the visual phenomenon lasted. Duration of more than 5 min excluded epilepsy aura (median 56 s) in favor of migraine aura, with sensitivity of 100% and specificity of 92%. Moreover, none of the epilepsy patients reported sensitivity to light/noise or occurrence of nausea/vomiting, against well over half of the migraine patients. Clinically, abrupt onset and fixed lateralization in the visual field indicated epilepsy (22).

Headaches are also observed after epileptic seizures and therefore do not constitute an exclusion criterion (23). Although an isolated visual aura is uncommonly encountered in epilepsy, given the overall 0.34–0.93% prevalence of epilepsy it represents an important differential diagnosis (24).

Posterior reversible encephalopathy syndrome

Long-lasting binocular visual disorders can also be observed in cases of posterior reversible encephalopathy syndrome (PRES), although they are then accompanied by further symptoms such as headache, epileptic seizures, and disturbances of consciousness (25). Cranial imaging shows vasogenic edema, usually parieto-occipital in location, hence the name of the syndrome. The prevalence/incidence is unknown (26), and the pathophysiology has not been fully elucidated. The following possible reasons for development of edema have been postulated (25, 26):

  • Disturbance of vasogenic autoregulation by cerebral hyperperfusion in the context of elevated arterial blood pressure (hypertensive crisis, renal disease)
  • Endothelial malfunction caused by cytotoxins (immunosuppressants, chemotherapeutics) in the context of sepsis
  • (Pre-)eclampsia
  • Autoimmune diseases

The treatment is symptomatic, accompanied by monitoring of blood pressure, with the principal aim of eliminating the underlying cause.

Persistent binocular visual phenomena

Persistent visual aura with no evidence of cerebral infarction

If the symptoms continue for more than a week and the phenomena correspond to a typical visual migraine aura, the International Classification of Headache Disorders (ICHD) includes “persistent aura without infarction” under the complications of migraine (ICHD-3 1.4.2) (27). For this diagnosis to be assigned, the patient has to have had a recent episode of migraine with visual aura. Typically, the existing aura symptoms continue, although they may fluctuate in intensity. Overall, not many cases have been described but they are well documented (28).

As early as 1995, Liu et al. reported refractory visual phenomena following a migraine attack in a case series of 10 patients (29). These phenomena met most of the criteria listed in Table 3, however, and in view of the symptoms described, featuring a constant flickering over the whole field of vision that resembled snow or television static, they would nowadays be classified as visual snow.

Visual snow and visual snow syndrome: diagnostic criteria
Table 3
Visual snow and visual snow syndrome: diagnostic criteria

Visual snow and visual snow syndrome

While visual phenomena are often viewed merely as accompanying symptoms, in the case of visual snow (VS) they give the disease its name. The affected patients suffer constant flickering vision, persisting in some cases for years, which resembles the above-mentioned static on the screen of a television with a poorly adjusted analog signal.

Classically, the patients see bright dots on a dark background and dark dots on a light-colored background, although multicolored, transparent, or shimmering dots have been described. This is accompanied by other visual phenomena (Table 3) and also by non-visual symptoms such as tinnitus, lethargy, and impairment of concentration (30). The prevalence of VS is unknown.

The pathophysiology has not been completely elucidated. Imaging studies and electrophysiological data point to a dysfunction of the visual association cortex (31, 32), but functional involvements of thalamocortical pathways and the primary visual cortex have been discussed (33, 34). In light of the frequent occurrence of non-visual symptoms such as tinnitus (35), non-visual areas also seem to be involved (31, 36).

No effective medication is yet known. Reports of improvement in individual cases have been published for, among other substances, the anticonvulsants lamotrigine and topiramate (37, 38).

In most cases, patients with visual snow syndrome (VSS) are unable to identify a triggering factor. However, similar symptoms have been reported in connection with the intake of hallucinogenic drugs.

Hallucinogen persisting perception disorder

The current thinking is that persistently disturbed perception after use of hallucinogens (hallucinogen persisting perception disorder, HPPD; DSM-5 292.89) is differentiated from VSS by its temporal association with intake of hallucinogenic drugs (primarily lysergic acid diethylamide [LSD], cannabis, and 3,4-methylenedioxy-N-methylamphetamine [MDMA]) (39). Two types of HPPD are distinguished:

  • Type 1 is characterized by brief, self-limiting flashbacks (visual phenomena as in the initial state of intoxication).
  • Type 2 describes persistent symptoms.

Visual phenomena whose symptoms fulfill the criteria of VSS also occur in type 2, although the spectrum of visual manifestations can be much wider (e.g., complex figures or objects) (40, e1). The prevalence of HPPD is unknown, and the pathophysiology is not understood. The possible causes that have been discussed include the death of serotonergic inhibitory interneurons and also the involvement of areas as postulated for VSS (36, e1, e2). Correspondingly, a study of 1100 patients who suffered from VSS also included 70 patients with abuse of hallucinogenic drugs who were otherwise clinically identical (35). Another thing the two diseases have in common is the lack of effective treatment. In the case of HPPD type 2, there are individual case reports showing a degree of efficacy for benzodiazepines, neuroleptics, and anticonvulsants (e1).

Charles Bonnet syndrome

Patients with Charles Bonnet syndrome (CBS) may initially consult an ophthalmologist, but are just as likely to turn to a neurologist or a psychiatrist. The primary deciding factor is the cardinal visual symptom, which may range from simple phosphenes to (pseudo)hallucinations (e3). The underlying condition in CBS is a high-grade loss of visual capacity that may be localized at any site involved in visual perception (eye, optic tract, visual cortex) (e4). Patients may report both the clinical picture of persistent migraine aura and complex compositions such as fields of roses in bloom, for example. People are frequently seen, often exotically dressed and with distorted features, and sometimes animals, real or fantastic. The persons and animals have no relation to the patient’s real life, and the colors are often intense. The scenes are like a silent film, with no noises perceived. The patients are always aware that what they are experiencing is hallucinatory, and the hallucinations are exclusively visual, with no involvement of other senses and certainly no delusions.

The prevalence of CBS in elderly sight-impaired patients is 2.8–20% (e5); this collective is not representative, however, as the prevalence was determined in dependency on disease severity. Three fourths of patients do not mention their visual hallucinations spontaneously for fear of being thought mad (e6). The most important element of the treatment is to explain that the hallucinations are not a sign of psychosis or incipient dementia. Physicians should therefore always ask their elderly patients, particularly those with macular degeneration, whether they are having any hallucinations. Patients who answer in the affirmative can be offered neuroleptics or anticonvulsants (e4).

Monocular visual phenomena

Monocular visual symptoms primarily indicate a disorder affecting the eye or optic nerve (Table 4).

The principal differential diagnoses of migraine aura and visual phenomena
Table 4
The principal differential diagnoses of migraine aura and visual phenomena

The vitreous body shrinks over the course of life and often becomes detached, particularly in old age. Detachment is initially followed by phosphenes (flashes of light). If a small blood vessel is ruptured, the resulting bleeding is perceived as rising smoke or many black dots. In this situation the retina can tear and eventually become detached (incidence 10/100 000) (e8). This is then perceived as a falling curtain or rising wall.

Lesions of the optic nerve or the retinal nerve fibers (e.g., in glaucoma: prevalence 2.79% in patients > 50 years) (e9) usually lead to scotomas. If these are only small, they often remain unnoticed. An acute ischemic infarction of the central retinal artery (incidence 0.85/100 000) (e10) results in an acute monocular central scotoma. In cases of inflammatory origin (optic neuritis, incidence 5/100 000) (e11) the first symptom observed is usually color desaturation, but here too, flashes of light may occur in the early stage (e12).

An extremely rare phenomenon that is often difficult to diagnose is retinal migraine (prevalence unknown). Clinically, there are recurring episodes of strictly monocular visual phenomena such as flickering, scotomas, or blindness in association with typical migraine headaches (27). In most cases the same eye is affected every time. Retinal migraine may be falsely diagnosed in a patient with a visual aura whose headache has a pronounced ocular component. Particularly if the visual impairment persists for more than 60 min or headache is absent, the diagnosis should be reconsidered (e13, e14).

Instrument-based diagnosis

Only in rare cases is a diagnosis positively assisted by instrument-based techniques (Table 5). The best opportunity is enjoyed by the ophthalmologist, who can swiftly detect pathologies of the vitreous body, retina, or optic nerve on the basis of isolated symptoms, e.g., floaters and monocular color/vision/ visual field defects.

Diagnostic modalities and their role in diseases of the visual system
Table 5
Diagnostic modalities and their role in diseases of the visual system

Electroencephalography (EEG), ideally in the form of inpatient monitoring, can be used to distinguish a visual epilepsy aura from a migraine aura: the former may manifest a seizure pattern (in 88.9% of cases during first aura) (22). Routinely performed cranial magnetic resonance imaging (cMRI) usually shows no abnormality—except in the case of epilepsy aura or CBS—but may be necessary in order to provide the patient with adequate information and reassurance.

Outlook

Migraine aura is a commonly occurring phenomenon with a broad spectrum of clinical presentations. Moreover, a number of other diseases are associated with visual disorders. With increasing age, migraine aura occurs less often and other disorders assume prominence. Careful history taking is a crucial element in the diagnostic process.

Experience shows that swift classification of visual phenomena coupled with description of specific symptoms may lead to reduction of the disease burden and improvement in the patient’s acceptance of the illness, although many visual phenomena are currently not amenable to successful treatment in most cases (HPPD, VSS, CBS). It is important to explain that, in the absence of a secondary cause, there is no danger of deterioration or blindness. Nevertheless, one must take care not to overlook treatable, perhaps time-critical entities such as retinal detachment or cerebral ischemia. Especially in the case of the latter, new criteria seem to facilitate the previously difficult differentiation from migraine aura.

It remains to be hoped that specific tests will be developed to clarify the pathophysiology of the persistent symptoms in particular, opening the way to targeted treatment.

Conflict of interest statement
Prof. Straube has received lecture fees or consultancy payments from Allergan, Novartis, Lilly, Sanofi, and TEVA, as well as third-party study funding from Novartis.

Prof. Schankin has received consultancy payments from Novartis, Eli Lilly, TEVA Pharmaceuticals, Lundbeck, Allergan, Almirall, Amgen, MindMed, and Grünenthal, as well as third-party study funding from the German Migraine and Headache Society (Deutsche Migräne- und Kopfschmerzgesellschaft), the Eye on Vision Foundation, and the Baasch–Medicus Foundation. He is a part-time employee of Zynnon AG.

Dr. Eren has received lecture fees or consultancy payments from Novartis and Lilly, as well as third-party study funding from the German Migraine and Headache Society (Deutsche Migräne- und Kopfschmerzgesellschaft) und the Eye on Vision Foundation.

Prof. Wilhelm declares that no conflict of interest exists.

Manuscript received on 29 April 2021, revised version accepted on 29 June 2021

Translated from the original German by David Roseveare

Corresponding author
Dr. med. Ozan E. Eren
Neurologische Klinik
LMU Klinikum – Campus Großhadern
Marchioninistr. 15
81377 München, Germany
ozan.eren@med.uni-muenchen.de

Cite this as:
Eren OE, Wilhelm H, Schankin CJ, Straube A: Visual phenomena associated with migraine and their differential diagnosis. Dtsch Arztebl Int 2021; 118: 647–53. DOI: 10.3238/arztebl.m2021.0287

Supplementary material
eReferences
www.aerzteblatt-international.de/m2021.0287

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This article has been certified by the North Rhine Academy for Continuing Medical Education. Participation in the CME certification program is possible only over the internet: cme.aerzteblatt.de. The deadline for submission is 30 September 2022.

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Department of Neurology, University Hospital, LMU Munich, Munich, Germany: Dr. med. Ozan E. Eren, MD, Prof. Dr. med. Andreas Straube, MD
Department of Neurology, Inselspital, University Hospital Bern, Switzerland:
Prof. Dr. med. Christoph J. Schankin, MD
Department of Ophthalmology, University of Tübingen: Prof. Dr. med. Helmut Wilhelm, MD
A selection of commonly occurring visual symptoms, with their clinical manifestations and patients’ subjective descriptions*
Table 1
A selection of commonly occurring visual symptoms, with their clinical manifestations and patients’ subjective descriptions*
Differentiation between transient ischemic attacks and migraine aura (from [19])
Table 2
Differentiation between transient ischemic attacks and migraine aura (from [19])
Visual snow and visual snow syndrome: diagnostic criteria
Table 3
Visual snow and visual snow syndrome: diagnostic criteria
The principal differential diagnoses of migraine aura and visual phenomena
Table 4
The principal differential diagnoses of migraine aura and visual phenomena
Diagnostic modalities and their role in diseases of the visual system
Table 5
Diagnostic modalities and their role in diseases of the visual system
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