alice in wonderland syndrome - neurology:cp · table 1 conditions in which alice in wonderland...

Neurologyreg Clinical Practice Review

Alice in Wonderland syndromeA systematic reviewJan Dirk Blom MD PhD

AbstractPurpose of review To summarize the literature onAlice in Wonderland syndrome (AIWS) a disordercharacterized by distortions of visual perceptionthe body schema and the experience of time Recentfindings On the basis of 169 published casedescriptions the etiology of AIWS is divided into 8main groups with neurologic disorders affectingmostly adults and elderly patients and encephalitidesaffecting mostly patients aged 18 years Symp-toms of AIWS are also experienced in the generalpopulation with up to 30 of adolescents reportingnonclinical symptoms Summary In clinical cases ofAIWS auxiliary investigations (including blood testsEEG and brain MRI) are strongly advised Treatmentshould be directed at the suspected underlying con-dition although reassurance that the symptomsthemselves are not harmful seems to suffice in about50 of the cases International classifications suchas the DSM and ICD should consider placing the syn-drome on their research agenda Neurol Clin Pract

20166259ndash270

First described in 1955 Alice in Wonderland syndrome (AIWS) is a perceptualdisorder characterized by distortions of visual perception (metamorphopsias)the body schema and the experience of time The name refers to Lewis Carrollrsquoswell-known childrenrsquos book Alicersquos Adventures in Wonderland1 in which Alice

feels (among other things) her body growing both larger and smaller (figures 1 and 2)After 60 years of relative obscurity AIWS has begun to receive scientific attention Thisrenewed interest is in part because of the current possibility to explore the brainrsquosnetworks responsible for mediating its symptoms with the aid of functional imagingtechniques2ndash6 AIWS symptoms have both diagnostic and therapeutic consequencesthat differ substantially from those in schizophrenia spectrum disorders and other

Parnassia Psychiatric Institute The Hague Leiden University Leiden and Department of Psychiatry University ofGroningen Groningen the Netherlands

Funding information and disclosures are provided at the end of the article Full disclosure form informationprovided by the author is available with the full text of this article at Neurologyorgcp The Article ProcessingCharge was paid by the author

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 40 (CC BY-NC-ND) which permits downloading and sharing the work provided it isproperly cited The work cannot be changed in any way or used commercially

Correspondence to jdblomparnassianl

Neurology Clinical Practice |||||||||||| June 2016 Neurologyorgcp 259

hallucinatory syndromes This article presents an overview of the literature on AIWSpublished over the past 60 years and summarizes its implications for clinical practice andresearch

METHODSA systematic literature search was carried out in PubMed (until June 2015) using thesearch terms ldquoAlice in Wonderland syndromerdquo ldquosyndrome of Alice in Wonderlandrdquoand variants thereof Included were articles in the English Dutch German FrenchSpanish and Italian languages All cross-references were checked systematically In this

Figure 1 Alice experiences total-body macrosomatognosia Illustration by John Tenniel(1865)

Figure 2 (A) Alice experiences partial macrosomatognosia and (B) Alice experiences total-body microsomatognosia Illustrations by John Tenniel (1890)

260 copy 2016 American Academy of Neurology

Jan Dirk Blom

Table 1 Conditions in which Alice in Wonderland syndrome has been described in the literature with the numbers of casedescriptions per age group

ConditionNo of case reports () intotal group (N 5 166)

No of case reports () inpatients aged pound18 y

No of case reports ()in patients aged gt18 y

Infectious diseases 38 (229) 36 (217) 2 (12)

Coxsackie B1 virus encephalitis 2 (12) 2 (12) mdash

Cytomegalovirus 1 (06) 1 (06) mdash

Epstein-Barr virus encephalitis(mononucleosis infectiosa)

26 (157) 24 (145) 2 (12)

Influenza A virus encephalitis 3 (18) 3 (18) mdash

Lyme neuroborreliosis 1 (06) 1 (06) mdash

Scarlet fever 1 (06) 1 (06) mdash

Typhoid encephalopathy 1 (06) 1 (06) mdash

Varicella-zoster encephalitis 3 (18) 3 (18) mdash

CNS lesions 13 (78) 3 (18) 10 (60)

Acute disseminated encephalomyelitis 1 (06) mdash 1 (06)

Cavernous angioma 1 (06) mdash 1 (06)

Cerebral arteriosclerosis 1 (06) mdash 1 (06)

Cerebral thrombosis 1 (06) mdash 1 (06)

Cerebral hemorrhage 1 (06) mdash 1 (06)

Cerebral infarction 1 (06) mdash 1 (06)

Brain tumor 1 (06) mdash 1 (06)

Microembolization after open heartsurgery

1 (06) mdash 1 (06)

Robin Hood syndrome 1 (06) mdash 1 (06)

Traumatic encephalopathy 3 (18) 3 (18) mdash

Wallenberg syndrome 1 (06) mdash 1 (06)

PNS lesions 2 (12) mdash 2 (12)

Eye disease 1 (06) mdash 1 (06)

Middle-ear disease 1 (06) mdash 1 (06)

Paroxysmal neurologic disorders 51 (307) 33 (199) 18 (108)

Epilepsy 5 (30) 4 (24) 1 (06)

Headache with neurologic deficits andCSF lymphocytosis

1 (06) mdash 1 (06)

Migraine 45 (271) 29 (175) 16 (96)

Psychiatric disorders 6 (36) mdash 6 (36)

Depressive disorder 2 (12) mdash 2 (12)

Derealizationdepersonalization disorder 1 (06) mdash 1 (06)

Misidentification syndrome 1 (06) mdash 1 (06)

Schizophrenia 1 (06) mdash 1 (06)

Schizoaffective disorder 1 (06) mdash 1 (06)

Medication 10 (60) 4 (24) 6 (36)

5-HT2 antagonist 1 (06) mdash 1 (06)

Dextromethorphan 1 (06) 1 (06) mdash

Continued


Alice in Wonderland syndrome

article symptoms of AIWS experienced by patients diagnosed with a neurologic psy-chiatric or other medical condition are referred to as ldquoclinicalrdquo and symptoms of AIWSexperienced by individuals in the general population who have not sought medical at-tention are referred to as ldquononclinicalrdquo

RESULTSThe search terms yielded 130 hits in PubMed Of these 59 articles had AIWS as theirmain subject Via cross-references an additional 11 articles were found yielding a totalof 70 articles Of these more than 50 were published during the prior decade A totalof 170 patients were described 20 from one case series7 and 48 from another case series8

The majority of the remaining articles consisted of individual case descriptions Becauseone patient was described twice910 the total number of original case descriptions was169 Patient sex was mentioned for 162 patients 556 of them were male Agewas mentioned in 166 patients mean age was 155 years A total of 132 patients were18 years with a mean age of 9 years and 34 patients were 19 years and older with amean age of 40 years Table 1 presents an overview of the many disorders intoxicationsand other conditions that have been described in the context of AIWS Among youthsthe most frequently described condition was encephalitis (217 vs 12 among adults

Table 1 Continued




Cough syrup (containing dihydrocodeineand DL-methylephedrine)

1 (06) mdash 1 (06)

Montelukast 1 (06) 1 (06) mdash

Oseltamivir 1 (06) 1 (06) mdash

Risperidone 1 (06) mdash 1 (06)

Topiramate 4 (24) 1 (06) 3 (18)

Substance-induced (HPPD) 10 (60) 1 (06) 9 (54)

Amanita muscaria 1 (06) mdash 1 (06)

Amphetamines 1 (06) mdash 1 (06)

Ayahuasca 1 (06) mdash 1 (06)

Cannabis 1 (06) 1 (06) mdash

Cocaine 1 (06) mdash 1 (06)

LSD 1 (06) mdash 1 (06)

MDMA 1 (06) mdash 1 (06)

Mescaline 1 (06) mdash 1 (06)

Toluene-containing solvent 1 (06) mdash 1 (06)

Trichlorethylene 1 (06) mdash 1 (06)

Miscellaneous 5 (30) mdash 5 (30)

Hypnagogic state 1 (06) mdash 1 (06)

Hypnopompic state 1 (06) mdash 1 (06)

Hypnotherapy 1 (06) mdash 1 (06)

Hyperpyrexia 1 (06) mdash 1 (06)

Sensory deprivation 1 (06) mdash 1 (06)

Abbreviations HPPD 5 hallucinogen persisting perception disorder PNS 5 peripheral nervous system


Jan Dirk Blom

and elderly patients) with the Epstein-Barr virus being the most frequently reportedpathogen (684 of all cases of encephalitis) Among the group of adults and elderlypatients neurologic disorders were most frequently described (168) of all these dis-orders migraine was the most prevalent condition (96) The course and outcome weredescribed in 150 patients In 54 patients (360) the treatment regimen was also spec-ified this mostly involved pharmacologic treatment aimed at alleviating the underlyingcondition One patient received electroconvulsive treatment11 and another patient re-ceived repetitive transcranial magnetic stimulation2 both treatments were successful Theremaining patients received no treatment or it was unspecified Full remission wasobtained in 467 of all patients and partial or temporary remission in 113In chronic conditions such as epilepsy and migraine full remission was obtained onlyrarely

DISCUSSION

Historical perspectiveThe term Alice in Wonderland syndrome was introduced in 1955 by the British psychiatristJohn Todd (1914ndash1987) to cover a group of symptoms ldquo intimately associated with mi-graine and epilepsy although not confined to these disordersrdquo12 As envisioned by Todd12 thegroup comprised derealization depersonalization hyperschematia hyposchematia and soma-topsychic duality as well as illusory changes in the size distance or position of stationaryobjects in the visual field illusory feelings of levitation and illusory alterations in the sense ofthe passage of time Incidentally Todd was well aware that he was not the first to describethose individual symptoms Many of them had appeared before in the literature on hysteria13

on general neurology14ndash17 and on soldiers with occipital wounds after World Wars I andII1819 Moreover in 1933 and 1952 Coleman20 and Lippman21 respectively had alreadydrawn comparisons between those symptoms and the experiences of Alice in Wonderlandalbeit without turning the name into an eponym Lippman21 was also the first to suggest thatthe bodily changes experienced by Alice might well be inspired by body schema illusionsLewis Carroll had experienced himself Carroll (pseudonym of the British mathematicianCharles Lutwidge Dodgson 1832ndash1898) had migraines and his diaries indicate that hisattacks were sometimes preceded by aural phenomena22 However historians consider Lipp-manrsquos hypothesis inconclusive as the diaries fail to demonstrate that Dodgson experiencedany aural phenomena before he wrote his book23 An alternative hypothesis is that Dodgsonhad knowledge ofmdashor perhaps had experimented withmdashthe hallucinogenic mushroomAmanita muscaria24 Whatever the exact course of events may have been with Alice inWonderland Dodgson created a character that appealed as much to physicians as it did tothe bookrsquos intended audience And Todd by adopting the name chose a memorable monikerfor a group of symptoms hitherto described in isolation of each other

PhenomenologyOver 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 incommon with each other is that they constitute distortions of sensory perception rather thanhallucinations or illusions25 Hallucinations are percepts experienced in the absence of anappropriate stimulus from the outside world such as a voice heard in the absence of sound

The differential diagnosis of AIWS and itsindividual symptoms is complex as it involvesat least 3 levels of conceptualization



Table 2 Visual distortions (metamorphopsias) that may be experienced in the context of Alice in Wonderland syndrome

Type of metamorphopsia CharacterizationNo of times () describedin the literature (N 5 169)

Achromatopsia The inability or strongly diminished ability to perceive color 9 (53)

Akinetopsia The inability to perceive motion mdash

Arugopsia Seeing wrinkled surfaces as smooth 1 (06)

Chloropsia Green vision mdash

Chromatopsia Seeing things in a single hue (as in chloropsia cyanopsiaerythropsia ianothinopsia and xanthopsia)

1 (06)

Corona phenomenon An extra contour around objects mdash

Cyanopsia Blue vision mdash

Dyschromatopsia Color confusion 3 (18)

Dysmegalopsia A diminished ability to appreciate the size of objects mdash

Dysmetropsia A change in the apparent size and distance of objects mdash

Dysmorphopsia Lines and contours appearing to be wavy 34 (201)

Dysplatopsia Objects appearing flattened and elongated mdash

Enhanced stereoscopic vision An exaggeration of the depth and detail of visually perceivedobjects

2 (12)

Entomopia Seeing multiple images as if perceived through an insectrsquoseye

mdash

Erythropsia Red vision 3 (18)

Gyropsia Seeing an illusory circular movement mdash

Hemimetamorphopsia A visual distortion of only one half of an object mdash

Hyperchromatopsia Seeing colors as exceptionally bright 4 (24)

Ianothinopsia Purple vision 1 (06)

Illusory splitting An illusory vertical splitting of objects 1 (06)

Illusory visual spread A perceived extension expansion or prolongation of objects mdash

Inverted vision Objects appearing rotated (usually in the coronal plane over90deg or 180deg)

1 (06)

Kinetopsia Illusory movement 15 (89)

Loss of stereoscopic vision Objects appearing 2-dimensional or ldquoflatrdquo mdash

Macroproxiopia Objects appearing larger and closer by than they are 2 (12)

Macropsia Seeing things larger than they are 76 (450)

Micropsia Seeing things smaller than they are 99 (586)

Microtelepsia Objects appearing smaller and farther away than they are 7 (41)

Monocular metamorphopsia Metamorphopsia for one eye mdash

Mosaic vision A fragmentation of perceived objects into irregularcrystalline polygonal facets interlaced as in a mosaic

mdash

Palinopsia Illusory recurrence of visual percepts (as in polyopia illusoryvisual spread and the trailing phenomenon)

3 (18)

Pelopsia Objects appearing closer by than they are 11 (65)

Plagiopsia Objects appearing as if tilted mdash

Polyopia Seeing multiple identical copies of a single image 1 (06)

Porropsia Stationary objects appearing to move away 3 (18)

Prosopometamorphopsia Apparent distortion of faces 3 (18)

Continued


Jan Dirk Blom

production or a cat seen that is not there Illusions do have a source in the outside worldalbeit one that is (often fleetingly) misperceived or misinterpreted Thus music may beheard in the drone of passing traffic and a curtain moving in the wind may be mistakenfor an intruder Like illusions distortions are based on sensory impressions but theyfeature highly specific changes in highly specific aspects of the sensory input picture Forexample all straight lines may be perceived as wavy (dysmorphopsia) all vertical lines asslanted (plagiopsia) all stationary objects as moving (kinetopsia) or all eyes as unnatu-rally big (prosopometamorphopsia) Tables 2 and 3 describe the many possible variantsand also how often they have been described in case reports of AIWS Strikingly mi-cropsia and macropsia have been described most frequently in the literature (in 586and 450 of all patients respectively) which might indicate that they are the mostprevalent types of distortion but also that they are the best known and therefore studiedmost frequently

The duration of symptoms of AIWS tends to be short mostly on the order of minutes todays26 however symptoms may also persist for years2 or even be lifelong27 A salient detailis that after visual fixation on an object metamorphopsias may sometimes arise after aninterval of seconds to minutes2728 After that temporal delay objects are perceived in adistorted manner but during the delay the perceptual process is undisturbed In the historicalliterature this phenomenon has been explained as a sign of cerebral asthenopia2829 (ie anunusual fatigability of the perceptual system)

EpidemiologyNo epidemiologic data on AIWS in the population at large are available Although it is gener-ally assumed that the syndrome is rare clinical studies among patients with migraine indicatethat the prevalence rate in this group may be around 152330 Moreover some studies indicatethat individual symptoms of AIWS are not rare in the general population A cross-sectionalstudy of 1480 adolescents31 found a lifetime prevalence of micropsia andor macropsia of56 for males and 62 for females A second cross-sectional study of 3224 high schoolstudents32 found 6-month prevalence rates of 38 for micropsia 39 for macropsia 25for protracted duration and 13 for the quick-motion phenomenon A third cross-sectionalstudy33 of 297 individuals with a median age of 257 years found lifetime prevalence rates of303 for teleopsia 185 for dysmorphopsia 151 for macropsia and 141 for mi-cropsia This study also showed that 389 of the affected individuals experienced a singlesymptom 336 experienced 2 106 experienced 3 and 168 experienced 4 Thisbuildup might indicate a common underlying etiologic process responsible for the mediationof all 4 symptoms or a stochastic process in which the presence of one symptom lowers thethreshold for another one to join in

Table 2 Continued


Teleopsia Objects appearing to be farther away than they are 39 (231)

Trailing phenomenon A series of discontinuous stationary images trailing behind amoving object

mdash

Visual allachesthesia Objects appearing dislocated into the opposite visual field 4 (24)

Visual perseveration An illusory recurrence of visual percepts after an object hasmoved out of focus

mdash

Xanthopsia Yellow vision mdash

Zoom vision Vision fluctuating between micropsia and macropsia or betweenmicrotelepsia and macroproxiopia

4 (24)



PathophysiologyThe symptoms of AIWS are attributed to functional and structural aberrations of the per-ceptual system34 On the whole central pathology is considered the most prevalent causehowever dysmorphopsia for example is also experienced in the context of retinal ab-lation and some other types of eye disease and plagiopsia (visual tilt) is also experiencedin the context of labyrinthine disease35 Nevertheless most symptoms of AIWS areattributed to centrally located neuron populations and even cell columns that respondselectively to specific types of sensory input (for vision notably cortical areas V1ndashV5)Area V4 of the extrastriate visual cortex for example responds selectively to colorwhereas area V5 responds to movement Both areas also respond to shape and depthbut 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 inabilityto visually perceive vertical lines (plagiopsia) or lines under a different angle is attributedto loss of function of orientation columns that are grouped together throughout thehorizontal layers of visual cortex Similarly various neuron populations have been iden-tified as being responsible for mediating different types of metamorphopsia and for othermetamorphopsias educated guesses have been made36 Sometimes this involves higher-order mismatches between larger components of the visual network which can varyinterindividually An example of the latter situation can be found in complex types ofprosopometamorphopsia in which human faces may be perceived consistently as animalfaces27 and even in an apparently straightforward symptom such as micropsia which wasfound to be associated with a consistent pattern of occipital hypoactivation and parietalhyperactivation in an fMRI study6

Table 3 Somesthetic and other nonvisual distortions that may be experienced in the context of Alice in Wonderlandsyndrome

Type of distortion CharacterizationNo of times () describedin the literature (N 5 169)

Aschematia Inadequate representation of the space occupied by some partof the body

1 (06)

Derealization Experiencing the world as unreal 17 (100)

Depersonalization Experiencing oneself as unreal 7 (41)

Hyperschematia Overrepresentation of the space occupied by some part ofthe body

1 (06)

Hyposchematia Underrepresentation of the space occupied by some part ofthe body

mdash

Illusory feeling of levitation Sensation of floating in the air 4 (24)

Palisomesthesia Illusory recurrence of somesthetic percepts mdash

Paraschematia Inappropriate representation of the space occupied by somepart of the body

mdash

Partial macrosomatognosia Experiencing a part of the body as larger than it is 12 (71)

Partial microsomatognosia Experiencing a part of the body as smaller than it is 13 (77)

Protracted duration Deceleration of psychological time 6 (36)

Quick-motion phenomenon Acceleration of psychological time 22 (130)

Splitting of the body image Sensation of onersquos own body being split in 2 usually downthe middle

1 (06)

Time distortion Altered experience of psychological time 3 (18)

Total-body macrosomatognosia Experiencing the whole body as larger than it is 15 (89)

Total-body microsomatognosia Experiencing the whole body as smaller than it is 14 (83)


Jan Dirk Blom

Mutatis mutandis the same would seem to hold true for somesthetic distortions in thesense that functional andor structural aberrations of specific neuron populations in somato-sensory cortical areas are responsible for mediating body schema illusions such as microsoma-tognosia palisomesthesia aschematia etc In these cases parts of the network located aroundthe parieto-temporo-occipital junction are responsible37 although here too a mismatch be-tween higher-order components of the network as a whole may be at play as in ischemia ofdistal parts of the anterior cerebral arteries that supply parts of the perceptual network re-sponsible for integrating composite sensory data for awareness of the body schema38 Whethersimilar mechanisms are responsible for mediating time distortions is as yet unknown

EtiologyThe conditions responsible for mediating the symptoms of AIWS are legion Table 1 presentsthose described so far in the literature classified into 8 main groups One of those groups isldquosubstance-inducedrdquo also known as hallucinogen persisting perception disorder (HPPD)39 anosologic construct featured in the DSM-540 and other classifications as a separate diagnosticcategory that covers perceptual symptoms that arise during (or after the cessation of) the useof illicit substances The list of conditions associated with AIWS is long and is expected togrow even longer when more cases and case series are published

Diagnosis and differential diagnosisAIWS does not feature in major classifications such as the ICD-1041 and the DSM-540 As aconsequence in clinical practice the diagnosis of AIWS stands and falls with proper history-taking a thorough physical (including neurologic and often otologic andor ophthalmic)examination and sound knowledge of the many and varying symptoms characteristic ofAIWS and their possible causes Cases with a suspected central origin should prompt auxiliaryinvestigations including blood tests EEG and brain MRI scan even though the chances offinding any demonstrable lesions are generally considered to be low8

The differential diagnosis of AIWS and its individual symptoms is complex as it involves atleast 3 levels of conceptualization First the symptoms need to be distinguished from other pos-itive disorders of perception such as hallucinations and illusions with which they may be easilyconfused Second their most likely cause needs to be established As table 1 indicates manydiagnoses are possible Therefore third whether the diagnosed condition may be responsiblefor mediating the symptoms must be established Because metamorphopsias and other dis-tortions are also experienced by individuals in the general population situations may arise inwhich the disorder diagnosed is not causally connected with the symptoms at hand or inwhich a therapeutic intervention turns out to be the actual cause

Treatment and prognosisMost nonclinical and clinical cases of AIWS are considered benign in the sense that full remis-sion of the symptoms can often be obtained sometimes spontaneously and in other cases afterproper treatment However in clinical cases with an underlying chronic condition (such as mi-graine and epilepsy) symptoms tend to recur in concordance with active phases of the diseaseand in cases of encephalitis the prognosis may also vary As a consequence the need to treatrequires careful assessment proper knowledge of the natural course of the various underlyingconditions that are possible and a careful explanation to the patient of what to expect fromwhich therapeutics under which circumstances In many cases reassurance will suffice When-ever treatment is considered useful and necessary it needs to be aimed at the suspected

Whenever treatment is considered useful andnecessary it needs to be aimed at thesuspected underlying condition



underlying condition In clinical practice this mostly involves theprescription of antiepileptics migraine prophylaxes antiviralagents or antibiotics The literature indicates that antipsychoticsare rarely prescribed7 and that in most cases their effectiveness isconsidered marginal Moreover when distortions are experi-enced as comorbid symptoms in patients with psychosis it isimportant to take into account the possibility that they cansometimes be induced or aggravated by antipsychotics becauseof their potential to lower the threshold for epileptic activity (ashas been described for risperidone)42

LimitationsThe number of case descriptions of AIWS is small especiallyconsidering the fact that the syndrome appears to be seriouslyunderdiagnosed and that individual symptoms may be system-atically neglected This may be at least partly because interna-tional diagnostic classifications have so far refrained fromincluding the syndrome The operational definition of AIWSand its diagnostic criteria are in need of further developmentMore specifically the question remains whether distortions inthe olfactory gustatory auditory sexual coenesthetic kines-thetic proprioceptive algesic vestibular and thermic modali-ties should be added to the list of possible symptoms ofAIWS More importantly however the validity of AIWS as

an independent nosologic construct needs to be assessed as well as its overlap with relatedsyndromes such as HPPD (which is also referred to in the literature as ldquoLSD-induced Alicein Wonderland syndromerdquo43) Other limitations are the lack of systematic epidemiologicdata and our limited insight into the many etiologic and pathophysiologic mechanismspossible in this context Functional imaging techniques such as SPECT and fMRI have thepotential to aid in localizing the network structures involved in mediating the symptoms ofAIWS however so far only 5 case reports have been published2ndash6 probably becausepatients with longer-lasting distortions are hard to find and contrast signals in individualpatients may be weak

CONCLUSIONSSince 1955 no more than 169 case descriptions of AIWS have been published The literatureindicates that this may be only the tip of the iceberg with many individual symptoms of AIWSbeing experienced (albeit occasionally and only fleetingly) by up to 30 of adolescents in thegeneral population Although reassurance seems to suffice in roughly half of the clinical casesthe suspicion of a central origin of the symptoms should prompt auxiliary investigations in theform of blood tests EEG and brain MRI Although firm evidence to justify these auxiliaryinvestigations is lacking I recommend them on clinical grounds because of the spectrum ofknown etiologies and the prospect of improved outcome in a substantial number of cases afteradequate treatment Treatment if necessary needs to be directed at the suspected underlyingcause Regarding research much larger patient sample sizes are needed to allow for sufficientstatistical power of empirical studies of AIWS and its individual symptoms In addition epide-miologic surveys in the population at large are needed to establish sound prevalence data As analternative or an adjuvant strategy one might consider creating an international database forcases of AIWS with special attention paid to phenomenological characteristics diagnostic find-ings (including substance abuse) natural course and treatment results For such a database tobe effective all new cases of AIWS should be subjected to a systematic assessment includingproper history-taking neurologic and other physical examinations and auxiliary investigations

Take-home pointsbull AIWS is characterized by perceptual

distortions rather than hallucinations orillusions and therefore needs to bedistinguished from schizophrenia spectrumand other psychotic disorders

bull When symptoms of AIWS are transient andnot associated with any other pathologyreassurance that the symptoms themselvesare not harmful may suffice

bull Based on the large spectrum of knownetiologies and the prospect of improvedoutcome I recommend auxiliaryinvestigations to address symptomreoccurrence causing major distress ordysfunction with or without otherpathology

bull In clinical cases treatment needs to bedirected at underlying conditions


Jan Dirk Blom

In chronic cases functional imaging techniques may be helpful in establishing specific neuro-biological correlates of individual symptoms (although there are often various practicalobstacles to be overcome) AIWS is in need of proper representation in international diagnosticclassifications such as the ICD (for example under the heading of ldquoDiseases of the NervousSystem Episodic and Paroxysmal Disordersrdquo or ldquoOther Disorders of the Nervous Systemrdquo)and the DSM (preferably under a new heading called ldquoPerceptual Disordersrdquo which in futureeditions might also include other nonpsychotic perceptual disorders such as the CharlesBonnet syndrome exploding head syndrome and cenesthesiopathy) Last but not leastour insight into the nature of AIWS might be enhanced by network analyses of the mutualrelationships of individual symptoms as well as their relationships with the perceptual net-works underlying them In the meantime however it is possible to carry out a carefuldiagnostic procedure to help this partly hidden group of patients obtain a proper diagnosisand if possible adequate reassurance and if necessary appropriate treatment

REFERENCES1 Carroll L Alicersquos Adventures in Wonderland London MacMillan and Co 18652 Blom JD Looijestijn J Goekoop R et al Treatment of Alice in Wonderland syndrome and verbal

auditory hallucinations using repetitive transcranial magnetic stimulation A case report with fMRIfindings Psychopathology 201144337ndash344

3 Morland D Wolff V Dietemann JL et al Robin Hood caught in Wonderland brain SPECTfindings Clin Nucl Med 201338979ndash981

4 Kuo YT Chiu NC Shen EY Ho CS Wu MC Cerebral perfusion in children with Alice in Won-derland syndrome Pediatr Neurol 199819105ndash108

5 Gencoglu EA Alehan F Erol I Koyuncu A Aras M Brain SPECT findings in a patient with Alice inWonderland syndrome Clin Nucl Med 200530758ndash759

6 Brumm K Walenski M Haist F Robbins SL Granet DB Love T Functional magnetic resonance imagingof a child with Alice in Wonderland syndrome during an episode of micropsia J AAPOS 201014317ndash322

7 Losada-Del Pozo R Cantariacuten-Extremera V Garciacutea-Pentildeas JJ et al Caracteristiacutecas y evolucioacutende los pacientes con siacutendrome de Alicia en el Paiacutes de las Maravillas Rev Neurol 201153641ndash648

8 Liu AM Liu JG Liu GW Liu GT ldquoAlice in Wonderlandrdquo syndrome presenting and follow-upcharacteristics Pediatr Neurol 201451317ndash320

9 Eshel GM Eyov A Lahat E Brauman A Alice in Wonderland syndrome a manifestation of acuteEpstein-Barr virus infection Pediatr Infect Dis J 1987668

10 Lahat E Eshel G Arlazoroff A ldquoAlice in Wonderlandrdquo syndrome a manifestation of infectiousmononucleosis in children Behav Neurol 19914163ndash166

11 Bui E Chatagner A Schmitt L Alice in Wonderland syndrome in major depressive disorderJ Neuropsychiatry Clin Neurosci 201022352

12 Todd J The syndrome of Alice in Wonderland Can Med Assoc J 195573701ndash70413 Charcot JM Leccedilons du Mardi agrave La Salpecirctriegravere Policlinique 1888ndash1889 Paris E Lecrosnier amp Babeacute 188914 Veraguth O Ueber Mikropsie und Makropsie Dtsch Z Nervenheilkd 190324453ndash46415 Bonnier P Lrsquoascheacutematie Rev Neurol 190513605ndash60916 Wilson SAK Dysmetropsia and its pathogenesis Trans Ophthalmol Soc U K 191636412ndash44417 Poumltzl O Uumlber Anfaumllle vom Thalamustypus Z Gesamte Neurol Psychiatr 1943176793ndash80018 Gelb A Goldstein K Zur Psychologie des optischen Wahrnehmungs- und Erkennungsvorganges

Z Gesamte Neurol Psychiatr 1918411ndash14119 Seitelberger F Uumlber Phantomerscheinungen bei Thalamuserkrankungen Wien Z Nervenheilkd

Grenzgeb 19524259ndash26520 Coleman SM Misidentification and non-recognition J Ment Sci 19337942ndash5121 Lippman CW Certain hallucinations peculiar to migraine J Nerv Ment Dis 1952116346ndash35122 Podoll K Robinson D Lewis Carrollrsquos migraine experiences Lancet 1999353136623 Restak RM Alice in migraineland Headache 200646306ndash31124 Carmichael C Wonderland revisited London Miscellany 19962819ndash2825 Blom JD A Dictionary of Hallucinations New York NY Springer 201026 Lanska JR Lanska DJ Alice in Wonderland syndrome somesthetic vs visual perceptual disturbance

Neurology 2013801262ndash126427 Blom JD Sommer IEC Koops S Sacks OW Prosopometamorphopsia and facial hallucinations

Lancet 20143841998

Neurologyorgcp



28 Willanger R Klee A Metamorphopsia and other visual disturbances with latency occurring in patientswith diffuse cerebral lesions Acta Neurol Scand 1966421ndash18

29 Poumltzl O Die Optisch-Agnostische Stoumlrungen Leipzig F Deuticke 192830 Smith RA Wright B Bennett S Hallucinations and illusions in migraine in children and the Alice in

Wonderland syndrome Arch Dis Child 2015100296ndash29831 Abe K Suzuki T Prevalence of some symptoms in adolescence and maturity social phobias anxiety

symptoms episodic illusions and idea of reference Psychopathology 198619200ndash20532 Abe K Oda N Araki R Igata M Macropsia micropsia and episodic illusions in Japanese adolescents

J Am Acad Child Adolesc Psychiatry 198928493ndash49633 Lipsanen T Lauerma H Peltola P Kallio S Visual distortions and dissociation J Nerv Ment Dis

1999187109ndash11234 ffytche DH Howard RJ The perceptual consequences of visual loss ldquopositiverdquo pathologies of vision

Brain 19991221247ndash126035 Deecke L Mergner T Plester D Tullio phenomenon with torsion of the eyes and subjective tilt of

the visual surround Ann NY Acad Sci 1981374650ndash65536 ffytche DH Blom JD Catani M Disorders of visual perception J Neurol Neurosurg Psychiatry

2010811280ndash128737 Ceriani F Gentileschi V Muggia S et al Seeing objects smaller than they are micropsia following

right temporo-parietal infarction Cortex 199834131ndash13838 Kew J Wright A Halligan PW Somesthetic aura the experience of ldquoAlice in Wonderlandrdquo Lancet

1998351193439 Litjens RP Brunt TM Alderliefste GJ et al Hallucinogen persisting perception disorder and the

serotonergic system a comprehensive review including new MDMA-related clinical cases Eur Neuro-psychopharmacol 2014241309ndash1323

40 American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders 5th edWashington DC American Psychiatric Association 2013

41 World Health Organization The International Classification of Diseases 10th Revision GenevaWorld Health Organization 1992

42 Morehead DB Exacerbation of hallucinogen-persisting perception disorder with risperidone J ClinPsychopharmacol 199717327ndash328

43 Lerner AG Lev Ran S LSD-associated ldquoAlice in Wonderland syndromerdquo (AIWS) a hallucinogenpersisting perception disorder (HPPD) case report Isr J Psychiatry Relat Sci 20155267ndash69

Received October 11 2015 Accepted in final form January 12 2016

AUTHOR CONTRIBUTIONSDraftingrevising the manuscript study concept or design and analysis or interpretation of data

STUDY FUNDINGNo targeted funding reported

DISCLOSURESJD Blom received publishing royalties for Katatonie en Dissociatie (AccreDidactPrelum 2014) VisueleHallucinaties en Andere Positieve Visuele Waarnemingsstoornissen (AccreDidactPrelum 2013) Halluci-nations Research and Practice (Springer 2012) and A Dictionary of Hallucinations (Springer 2010)Full disclosure form information provided by the author is available with the full text of this article atNeurologyorgcp

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Migraine trait symptoms in migraine with and without auraApril 22 2014821416ndash1424

Alice in Wonderland Syndrome Somesthetic vs visual perceptual disturbanceMarch 26 2013801262ndash1264


Jan Dirk Blom

DOI 101212CPJ000000000000025120166259-270 Published Online before print April 8 2016Neurol Clin Pract

Jan Dirk BlomAlice in Wonderland syndrome A systematic review

This information is current as of April 8 2016

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Neurology All rights reserved Print ISSN 2163-0402 Online ISSN 2163-0933since 2011 it is now a bimonthly with 6 issues per year Copyright copy 2016 American Academy of

is an official journal of the American Academy of Neurology Published continuouslyNeurol Clin Pract

hallucinatory syndromes This article presents an overview of the literature on AIWSpublished over the past 60 years and summarizes its implications for clinical practice andresearch

METHODSA systematic literature search was carried out in PubMed (until June 2015) using thesearch terms ldquoAlice in Wonderland syndromerdquo ldquosyndrome of Alice in Wonderlandrdquoand variants thereof Included were articles in the English Dutch German FrenchSpanish and Italian languages All cross-references were checked systematically In this

Figure 1 Alice experiences total-body macrosomatognosia Illustration by John Tenniel(1865)

Figure 2 (A) Alice experiences partial macrosomatognosia and (B) Alice experiences total-body microsomatognosia Illustrations by John Tenniel (1890)


Jan Dirk Blom









26 (157) 24 (145) 2 (12)






CNS lesions 13 (78) 3 (18) 10 (60)









1 (06) mdash 1 (06)








Epilepsy 5 (30) 4 (24) 1 (06)


1 (06) mdash 1 (06)

Migraine 45 (271) 29 (175) 16 (96)







Medication 10 (60) 4 (24) 6 (36)



Continued






Table 1 Continued





1 (06) mdash 1 (06)




Topiramate 4 (24) 1 (06) 3 (18)







LSD 1 (06) mdash 1 (06)

MDMA 1 (06) mdash 1 (06)












Jan Dirk Blom


DISCUSSION














1 (06)









2 (12)


mdash









1 (06)









mdash


3 (18)






Continued


Jan Dirk Blom




Table 2 Continued




mdash



mdash



4 (24)







1 (06)




1 (06)


mdash




mdash






1 (06)





Jan Dirk Blom



















Jan Dirk Blom

















Lancet 20143841998

Neurologyorgcp




























Jan Dirk Blom



















Reprints












26 (157) 24 (145) 2 (12)






CNS lesions 13 (78) 3 (18) 10 (60)









1 (06) mdash 1 (06)








Epilepsy 5 (30) 4 (24) 1 (06)


1 (06) mdash 1 (06)

Migraine 45 (271) 29 (175) 16 (96)







Medication 10 (60) 4 (24) 6 (36)



Continued






Table 1 Continued





1 (06) mdash 1 (06)




Topiramate 4 (24) 1 (06) 3 (18)







LSD 1 (06) mdash 1 (06)

MDMA 1 (06) mdash 1 (06)












Jan Dirk Blom


DISCUSSION














1 (06)









2 (12)


mdash









1 (06)









mdash


3 (18)






Continued


Jan Dirk Blom




Table 2 Continued




mdash



mdash



4 (24)







1 (06)




1 (06)


mdash




mdash






1 (06)





Jan Dirk Blom



















Jan Dirk Blom

















Lancet 20143841998

Neurologyorgcp




























Jan Dirk Blom



















Reprints







Table 1 Continued





1 (06) mdash 1 (06)




Topiramate 4 (24) 1 (06) 3 (18)







LSD 1 (06) mdash 1 (06)

MDMA 1 (06) mdash 1 (06)












Jan Dirk Blom


DISCUSSION














1 (06)









2 (12)


mdash









1 (06)









mdash


3 (18)






Continued


Jan Dirk Blom




Table 2 Continued




mdash



mdash



4 (24)







1 (06)




1 (06)


mdash




mdash






1 (06)





Jan Dirk Blom



















Jan Dirk Blom

















Lancet 20143841998

Neurologyorgcp




























Jan Dirk Blom



















Reprints





DISCUSSION














1 (06)









2 (12)


mdash









1 (06)









mdash


3 (18)






Continued


Jan Dirk Blom




Table 2 Continued




mdash



mdash



4 (24)







1 (06)




1 (06)


mdash




mdash






1 (06)





Jan Dirk Blom



















Jan Dirk Blom

















Lancet 20143841998

Neurologyorgcp




























Jan Dirk Blom



















Reprints











1 (06)









2 (12)


mdash









1 (06)









mdash


3 (18)






Continued


Jan Dirk Blom




Table 2 Continued




mdash



mdash



4 (24)







1 (06)




1 (06)


mdash




mdash






1 (06)





Jan Dirk Blom



















Jan Dirk Blom

















Lancet 20143841998

Neurologyorgcp




























Jan Dirk Blom



















Reprints







Table 2 Continued




mdash



mdash



4 (24)







1 (06)




1 (06)


mdash




mdash






1 (06)





Jan Dirk Blom



















Jan Dirk Blom

















Lancet 20143841998

Neurologyorgcp




























Jan Dirk Blom



















Reprints








1 (06)




1 (06)


mdash




mdash






1 (06)





Jan Dirk Blom



















Jan Dirk Blom

















Lancet 20143841998

Neurologyorgcp




























Jan Dirk Blom



















Reprints






















Jan Dirk Blom

















Lancet 20143841998

Neurologyorgcp




























Jan Dirk Blom



















Reprints




















Lancet 20143841998

Neurologyorgcp




























Jan Dirk Blom



















Reprints





























Jan Dirk Blom



















Reprints






















Reprints




alice in wonderland syndrome - neurology:cp · table 1 conditions in which alice in wonderland...

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