Alice in Wonderland syndrome

Historical perspective

The term Alice in Wonderland syndrome was introduced in 1955 by the British psychiatrist John Todd (1914–1987) to cover a group of symptoms “… intimately associated with migraine and epilepsy, although not confined to these disorders.”¹² As envisioned by Todd,¹² the group comprised derealization, depersonalization, hyperschematia, hyposchematia, and somatopsychic duality, as well as illusory changes in the size, distance, or position of stationary objects in the visual field; illusory feelings of levitation; and illusory alterations in the sense of the passage of time. Incidentally, Todd was well aware that he was not the first to describe those individual symptoms. Many of them had appeared before in the literature on hysteria,¹³ on general neurology,^14,–,17 and on soldiers with occipital wounds after World Wars I and II.^18,19 Moreover, in 1933 and 1952, Coleman²⁰ and Lippman,²¹ respectively, had already drawn comparisons between those symptoms and the experiences of Alice in Wonderland, albeit without turning the name into an eponym. Lippman²¹ was also the first to suggest that the bodily changes experienced by Alice might well be inspired by body schema illusions Lewis Carroll had experienced himself. Carroll (pseudonym of the British mathematician Charles Lutwidge Dodgson, 1832–1898) had migraines, and his diaries indicate that his attacks were sometimes preceded by aural phenomena.²² However, historians consider Lippman's hypothesis inconclusive, as the diaries fail to demonstrate that Dodgson experienced any aural phenomena before he wrote his book.²³ An alternative hypothesis is that Dodgson had knowledge of—or perhaps had experimented with—the hallucinogenic mushroom Amanita muscaria.²⁴ Whatever the exact course of events may have been, with Alice in Wonderland, Dodgson created a character that appealed as much to physicians as it did to the book's intended audience. And Todd, by adopting the name, chose a memorable moniker for a group of symptoms hitherto described in isolation of each other.

Phenomenology

Over the past 60 years, AIWS symptoms have come to include 42 visual symptoms (table 2) and 16 somesthetic and other nonvisual symptoms (table 3). What these symptoms have in common with each other is that they constitute distortions of sensory perception rather than hallucinations or illusions.²⁵ Hallucinations are percepts experienced in the absence of an appropriate stimulus from the outside world, such as a voice heard in the absence of sound production or a cat seen that is not there. Illusions do have a source in the outside world, albeit one that is (often fleetingly) misperceived or misinterpreted. Thus music may be heard in the drone of passing traffic and a curtain moving in the wind may be mistaken for an intruder. Like illusions, distortions are based on sensory impressions, but they feature highly specific changes in highly specific aspects of the sensory input picture. For example, all straight lines may be perceived as wavy (dysmorphopsia), all vertical lines as slanted (plagiopsia), all stationary objects as moving (kinetopsia), or all eyes as unnaturally big (prosopometamorphopsia). Tables 2 and 3 describe the many possible variants and also how often they have been described in case reports of AIWS. Strikingly, micropsia and macropsia have been described most frequently in the literature (in 58.6% and 45.0% of all patients, respectively), which might indicate that they are the most prevalent types of distortion but also that they are the best known and therefore studied most frequently.

The duration of symptoms of AIWS tends to be short, mostly on the order of minutes to days²⁶; however, symptoms may also persist for years² or even be lifelong.²⁷ A salient detail is that after visual fixation on an object, metamorphopsias may sometimes arise after an interval of seconds to minutes.^27,28 After that temporal delay, objects are perceived in a distorted manner, but during the delay the perceptual process is undisturbed. In the historical literature this phenomenon has been explained as a sign of cerebral asthenopia^28,29 (i.e., an unusual fatigability of the perceptual system).

Epidemiology

No epidemiologic data on AIWS in the population at large are available. Although it is generally assumed that the syndrome is rare, clinical studies among patients with migraine indicate that the prevalence rate in this group may be around 15%.^23,30 Moreover, some studies indicate that individual symptoms of AIWS are not rare in the general population. A cross-sectional study of 1,480 adolescents³¹ found a lifetime prevalence of micropsia and/or macropsia of 5.6% for males and 6.2% for females. A second cross-sectional study of 3,224 high school students³² found 6-month prevalence rates of 3.8% for micropsia, 3.9% for macropsia, 2.5% for protracted duration, and 1.3% for the quick-motion phenomenon. A third cross-sectional study³³ of 297 individuals with a median age of 25.7 years found lifetime prevalence rates of 30.3% for teleopsia, 18.5% for dysmorphopsia, 15.1% for macropsia, and 14.1% for micropsia. This study also showed that 38.9% of the affected individuals experienced a single symptom, 33.6% experienced 2, 10.6% experienced 3, and 16.8% experienced 4. This buildup might indicate a common underlying etiologic process responsible for the mediation of all 4 symptoms or a stochastic process in which the presence of one symptom lowers the threshold for another one to join in.

Pathophysiology

The symptoms of AIWS are attributed to functional and structural aberrations of the perceptual system.³⁴ On the whole, central pathology is considered the most prevalent cause; however, dysmorphopsia, for example, is also experienced in the context of retinal ablation and some other types of eye disease, and plagiopsia (visual tilt) is also experienced in the context of labyrinthine disease.³⁵ Nevertheless, most symptoms of AIWS are attributed to centrally located neuron populations and even cell columns that respond selectively to specific types of sensory input (for vision, notably cortical areas V1–V5). Area V4 of the extrastriate visual cortex, for example, responds selectively to color, whereas area V5 responds to movement. Both areas also respond to shape and depth, but bilateral loss of function of V4 results in achromatopsia (the inability to see color) and bilateral loss of V5 results in akinetopsia (the inability to see motion). The inability to visually perceive vertical lines (plagiopsia) or lines under a different angle is attributed to loss of function of orientation columns that are grouped together throughout the horizontal layers of visual cortex. Similarly, various neuron populations have been identified as being responsible for mediating different types of metamorphopsia, and for other metamorphopsias educated guesses have been made.³⁶ Sometimes this involves higher-order mismatches between larger components of the visual network, which can vary interindividually. An example of the latter situation can be found in complex types of prosopometamorphopsia, in which human faces may be perceived consistently as animal faces,²⁷ and even in an apparently straightforward symptom such as micropsia, which was found to be associated with a consistent pattern of occipital hypoactivation and parietal hyperactivation in an fMRI study.⁶

Mutatis mutandis, the same would seem to hold true for somesthetic distortions, in the sense that functional and/or structural aberrations of specific neuron populations in somatosensory cortical areas are responsible for mediating body schema illusions such as microsomatognosia, palisomesthesia, aschematia, etc. In these cases, parts of the network located around the parieto-temporo-occipital junction are responsible,³⁷ although here too a mismatch between higher-order components of the network as a whole may be at play, as in ischemia of distal parts of the anterior cerebral arteries that supply parts of the perceptual network responsible for integrating composite sensory data for awareness of the body schema.³⁸ Whether similar mechanisms are responsible for mediating time distortions is as yet unknown.

Etiology

The conditions responsible for mediating the symptoms of AIWS are legion. Table 1 presents those described so far in the literature, classified into 8 main groups. One of those groups is “substance-induced,” also known as hallucinogen persisting perception disorder (HPPD),³⁹ a nosologic construct featured in the DSM-5⁴⁰ and other classifications as a separate diagnostic category that covers perceptual symptoms that arise during (or after the cessation of) the use of illicit substances. The list of conditions associated with AIWS is long and is expected to grow even longer when more cases and case series are published.

Diagnosis and differential diagnosis

AIWS does not feature in major classifications such as the ICD-10⁴¹ and the DSM-5.⁴⁰ As a consequence, in clinical practice the diagnosis of AIWS stands and falls with proper history-taking, a thorough physical (including neurologic and often otologic and/or ophthalmic) examination, and sound knowledge of the many and varying symptoms characteristic of AIWS and their possible causes. Cases with a suspected central origin should prompt auxiliary investigations including blood tests, EEG, and brain MRI scan, even though the chances of finding any demonstrable lesions are generally considered to be low.⁸

The differential diagnosis of AIWS and its individual symptoms is complex, as it involves at least 3 levels of conceptualization. First, the symptoms need to be distinguished from other positive disorders of perception such as hallucinations and illusions, with which they may be easily confused. Second, their most likely cause needs to be established. As table 1 indicates, many diagnoses are possible. Therefore, third, whether the diagnosed condition may be responsible for mediating the symptoms must be established. Because metamorphopsias and other distortions are also experienced by individuals in the general population, situations may arise in which the disorder diagnosed is not causally connected with the symptoms at hand or in which a therapeutic intervention turns out to be the actual cause.

Treatment and prognosis

Most nonclinical and clinical cases of AIWS are considered benign, in the sense that full remission of the symptoms can often be obtained, sometimes spontaneously and in other cases after proper treatment. However, in clinical cases with an underlying chronic condition (such as migraine and epilepsy), symptoms tend to recur in concordance with active phases of the disease, and in cases of encephalitis the prognosis may also vary. As a consequence, the need to treat requires careful assessment, proper knowledge of the natural course of the various underlying conditions that are possible, and a careful explanation to the patient of what to expect from which therapeutics under which circumstances. In many cases reassurance will suffice. Whenever treatment is considered useful and necessary, it needs to be aimed at the suspected underlying condition. In clinical practice this mostly involves the prescription of antiepileptics, migraine prophylaxes, antiviral agents, or antibiotics. The literature indicates that antipsychotics are rarely prescribed⁷ and that in most cases their effectiveness is considered marginal. Moreover, when distortions are experienced as comorbid symptoms in patients with psychosis, it is important to take into account the possibility that they can sometimes be induced or aggravated by antipsychotics because of their potential to lower the threshold for epileptic activity (as has been described for risperidone).⁴²

Limitations

The number of case descriptions of AIWS is small, especially considering the fact that the syndrome appears to be seriously underdiagnosed and that individual symptoms may be systematically neglected. This may be at least partly because international diagnostic classifications have so far refrained from including the syndrome. The operational definition of AIWS and its diagnostic criteria are in need of further development. More specifically, the question remains whether distortions in the olfactory, gustatory, auditory, sexual, coenesthetic, kinesthetic, proprioceptive, algesic, vestibular, and thermic modalities should be added to the list of possible symptoms of AIWS. More importantly, however, the validity of AIWS as an independent nosologic construct needs to be assessed, as well as its overlap with related syndromes such as HPPD (which is also referred to in the literature as “LSD-induced Alice in Wonderland syndrome”⁴³). Other limitations are the lack of systematic epidemiologic data and our limited insight into the many etiologic and pathophysiologic mechanisms possible in this context. Functional imaging techniques such as SPECT and fMRI have the potential to aid in localizing the network structures involved in mediating the symptoms of AIWS; however, so far, only 5 case reports have been published,^2,–,6 probably because patients with longer-lasting distortions are hard to find and contrast signals in individual patients may be weak.