Introduction

Alice in Wonderland Syndrome (AIWS) is a condition that manifests distorted visual or somatosensory perceptions or both. Distortions include objects in the visual field appearing smaller (micropsia) and farther away (teleopsia) or larger (macropsia) and nearer (pelopsia) than they are or one’s own body appearing smaller (microsomatognosia) or larger (macrosomatognosia) than it is. Hécaen and De Ajuriaguerra¹ reported these symptoms in a patient with epilepsy, and Lippman² reported these symptoms in patients with migraine, both in 1952. The term AIWS was coined by the English psychiatrist John Todd³ in 1955 in a report that included 6 patients with anxiety disorders and personal or family histories of migraine or epilepsy. Of note, 5 of 6 patients in the series by Todd³ experienced migraine headaches with vertigo or balance symptoms, which presaged a report by Beh et al,⁴ of 17 patients with vestibular migraine who experienced AIWS. Of these patients, 13 had perceptual distortions during vestibular migraine attacks. Matsudaira and colleagues⁵ reported a case of AIWS coinciding with electroencephalogram (EEG) changes in an 82-year-old female with focal epilepsy. Meanwhile, Shah and co-authors⁶ described decreased EEG activity in the temporo-occipital region of an 8-year-old male suspected of having AIWS, presenting with micropsia, teleopsia, and dysmorphopsia. The AIWS is sometimes characterized as rare; however, studies with large cohorts assessing the prevalence are lacking. One study, consisting of more than 800 individuals with migraines estimated a prevalence of around 16.5%, congruent with other reports of around 15%.^7,8 While migraines may be the most common condition associated with AIWS, other neurologic and infectious etiologies, including epilepsy, brain lesions, and Epstein-Barr virus have been reported.⁹

Apart from certain medical conditions, AIWS has been reported with intoxicants and medications.¹⁰ Vilela and colleagues¹¹ reported a case of AIWS in a 67-year-old female who experienced symptoms of body image distortions within weeks of reinitiating sertraline for the treatment of major depressive disorder. Dugauquier and Bidgoli¹² described a case of methylphenidate-associated AIWS symptoms of micro- and macropsia in a 12-year-old male with attention-deficit/hyperactivity disorder. Symptoms began in the second year of methylphenidate use after a change in treatment regimen, resolved with methylphenidate discontinuation, and recurred when the medication was rechallenged. Cases of topiramate-associated AIWS have also been reported, which are described within this report. The following case report describes the onset, progression, and resolution of potential topiramate-induced AIWS in a patient with vestibular migraines.

Case Report

A 40-year-old woman was admitted to a 3-week intensive outpatient program at a pain rehabilitation center (PRC) to address functional decrements related to chronic migraine headaches. Other medical history included Sjogren’s syndrome, persistent postural-perceptual dizziness, and generalized anxiety disorder. The patient reported an approximate 25-year history of migraine headaches at a frequency of 6 to 7 days per month. Symptoms associated with migraine attacks included photophobia, phonophobia, and visual aura. Vestibular symptoms began approximately 10 years before the PRC admission, including spinning vertigo, rocking unsteadiness, and nonvertiginous dizziness. Vertigo was described as intermittent, lasting for about a minute and occurring multiple times on days when it was present. It was often but not always associated with headaches, which fulfilled the diagnostic criteria for vestibular migraine.¹³ Unsteadiness and dizziness settled into the daily pattern of persistent postural-perceptual dizziness.¹⁴ Along with vestibular symptoms that emerged, the patient concomitantly experienced persistent positive visual phenomena of migraine (ie, visual snow). A work-up at the time included clinical otologic and neuro-ophthalmic examinations, audiometric and vestibular laboratory testing, and magnetic resonance imaging of the brain and computed tomography of the temporal bone, which were described as unremarkable.

Six years before participation in PRC, the patient was prescribed nortriptyline, titrated to 125 mg/d, which improved her attacks of vertigo. Topiramate was also initiated and titrated to 100 mg/d, which partially reduced her rocking sensations and migraine frequency but was associated with fatigue, mild word-finding difficulties, and paresthesias. Around this time, onabotulinumtoxin A, every 3-months, was initiated along with naratriptan as an abortive agent. During the following 2 years, topiramate was titrated to 150 mg/d with documentation of further improvement of migraine frequency and vestibular symptoms with similar reported adverse effects. In the year after, topiramate would be increased to 200 mg/d, with documented unclear benefits, leading to a further increase of 250 mg/d. This increase was only brief, as it was associated with significantly worsening fatigue, visual snow, word-finding difficulties, and other cognitive adverse effects. Thus, topiramate was reduced back to 200 mg/d for approximately another year. Six months before the PRC admission, due to ongoing adverse effects and the history that topiramate 200 mg/d provided no additional benefit over 150 mg/d, the dose was lowered again to 150 mg/d. Around this time, it was believed nortriptyline was contributing to orthostasis, and it was changed to venlafaxine with atogepant changed as an abortive therapy. Eventually, there was a decision to taper topiramate due to fatigue, word-finding difficulties, and the patient’s newly reported perception of inefficacy. Four weeks before PRC program admission, the topiramate dose had been reduced to 50 mg/d.

During her admission interview at the PRC, the patient divulged the ongoing perception that her upper extremities were very large. In exploring with the patient further, she retrospectively identified a correlation between the start of the macrosomatognosia symptom and the initial titration of topiramate to 100 mg/d and then a worsening at 150 mg/d. She stated that macrosomatognosia could occur independently from prodromal symptoms of migraine or migraine attacks themselves and were continuing to occur by the time she arrived at the PRC. During the review of available outside records, no specific details related to macrosomatognosia or perceptual disturbances were documented. Given the possible temporal link between topiramate and the onset of macrosomatognosia, along with associated complaints of fatigue, topiramate was further reduced to 25 mg/d for 3 days and then discontinued. Over the next 5 days, the patient reported resolution of macrosomatognosia and improvement of fatigue, which remained absent for the remaining 11 days of the PRC program. There were no reports of increased migraine intensity or frequency following the discontinuation. Using the Naranjo ADR Probability Scale,¹⁵ it was determined there was a possible (score: 4, where > 9 = highly probable, 5–8 = probable, 1–4 = possible and ≤0 = doubtful) association between topiramate and macrosomatognosia.

Discussion

The AIWS is found in both children and adults, with most reported cases associated with migraine but, as previously noted, is also associated with a range of other neurologic or infectious illnesses.⁸ More than 50 variations of visual and somatosensory symptoms have been described with AIWS, with more commonly reported symptoms including micropsia, macropsia, teleopsia, dysmorphopsia, microsomatognosia, and macrosomatognosia.^8,16 The pathophysiologic mechanisms underlying AIWS are unclear; however, one proposed process is dysfunction within networks through the temporo-parieto-occipital junction that integrate visual and somatosensory stimuli and potentially pathways into the thalamus and visual cortical areas V4 and V5, which process color, shapes, movement, and depth perception.^8,9 A “hyperconnectivity” between V3 and the posterior superior temporal sulcus has also been reported in patients with migraine and AIWS but not in those who only present with typical aura or in healthy controls, suggesting another potential pathophysiologic mechanism.⁹ AIWS symptoms are usually transient, lasting from minutes to days, but in rare cases can last years.⁸ AIWS is not a defined diagnostic entity within standardized nomenclature such as the International Classification of Diseases, 10^th Revision,¹⁷ International Classification of Headache Disorders, 3^rd edition,¹⁸ or Diagnostic and Statistical Manual of Mental Disorders, 5^th Edition – Text Revision.¹⁹ Therefore, there are no established diagnostic criteria, which might contribute to its under-recognition. That said, attempts at classification and characterizing this syndrome have been suggested.^9,20

Topiramate is an antiseizure medication used in the management of seizures and migraine. While topiramate’s specific mechanism of action is not fully understood, there are many postulated, including the following: sodium channel blocker, L-type calcium channel blocker, enhancement of gamma-aminobutyric acid inhibition, and decreased ionotropic glutamate receptor (AMPA and kainate) activation.^21,22 It is not known how topiramate might influence perceptual changes associated with AIWS, but it may impact the visual system in some way.²³ Topiramate is associated with other ophthalmic adverse reactions such as diplopia, acute myopia with secondary angle–closure glaucoma, and visual field defects.^16,24 These ocular changes have been attributed to the ciliary body and choroid edema,²⁵ which does not necessarily explain topiramate-induced visual distortions or perceptions such as those encountered in AIWS. Other visual disturbances have also been reported with topiramate, including isolated palinopsia (ie, recurrence or persistence of a visual image after removal of the stimulus).^16,26 While palinopsia may be a symptom associated with AIWS, the occurrence of palinopsia alone without perceived body distortions is not congruent with definitions that have been set forth to characterize AIWS.²⁷

To date, only a few case reports have outlined a potential relationship between topiramate and AIWS. In the extant literature (Table), cases of AIWS and other visual phenomena were either reversed once topiramate was discontinued, decreased in severity following dose reduction(s), or worsened with rechallenge, suggesting a direct association between the medication and these clinical manifestations. These reported cases of topiramate-associated AIWS or other visual phenomena resolved within 4 to 23 days of medication discontinuation, placing this case within the range of those previously described.

TABLEReports of visual phenomena associated with topiramate

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Several key takeaways from this case can be highlighted. (1) AIWS has a long-standing association with migraine and epilepsy, with early descriptions dating back to 1952, and a recent series suggests a particular association with vestibular migraine, which affected the patient in this report.^1,2,4 (2) Medications may be associated with AIWS, including ones like topiramate, which are established treatments for migraine and epilepsy. Thus, both illnesses and medications should be carefully considered when determining the differential diagnosis of AIWS. (3) Optimal management of AIWS may require more aggressive treatment of causal illnesses or, conversely, discontinuation of potentially offending medication. The choice between these therapeutic options requires careful examination of the historical timeline.

Limitations of this case should be acknowledged, such as the use of available outside records, as well as potential inaccuracies in the patient’s identification of the temporal relation between treatment with topiramate and appearance of AIWS symptoms. Importantly, preexisting vestibular migraine also serves as a confounder. Also, the patient’s multiple comorbidities and numerous medication treatment trials are confounders. However, no evidence was found in the review linking Sjogren’s syndrome to AIWS and similarly with persistent postural-perceptual dizziness. Given the exposure to antidepressants for migraines and generalized anxiety disorder, it may be plausible that these treatments contributed to the patient’s presentation. However, the current body of literature linking antidepressants and AIWS seems limited to a single case report. The prospective observation of the patient’s macrosomatognosia resolution in the setting of topiramate discontinuation, however, reinforces the possible association between topiramate and AIWS in a patient with an illness capable of causing the syndrome. Additionally, as topiramate titrated to 100 mg, there was documentation of reduced migraines, and, in theory, symptoms of AIWS might have been expected to lessen, not been exacerbated—again pointing to this possible iatrogenic association.

Conclusion

The AIWS, although not widely identified, has been described in the medical literature for nearly 75 years. It was first linked to epilepsy and migraine, later to other neurologic illnesses, and to various central nervous system–active medications. The present case adds to the existing literature of previous reports describing the potential for topiramate to be associated with AIWS and highlights the need to consider both neurologic illnesses and neuropsychiatric medications in the differential diagnosis of this unusual syndrome.