ArticlePDF Available

An Overview of the Symptoms and Typical Disorders Associated with Alice in Wonderland Syndrome

Authors:

Abstract and Figures

The Alice in Wonderland syndrome refers to a set of symptoms characterized by perceptual distortions, such as visual distortions (i.e., metamorphopsia), body image and time distortions. The Alice in Wonderland syndrome has been described consistently over the past five decades in various cultural settings. Migraine headaches and epilepsy were the etiologies first described and most frequently reported in the literature; however, infectious, neurological, toxic and psychiatric causes have also been reported. Although little is known regarding the specific pathophysiological pathways, dysfunctions of the NMDA neurotransmission and inflammations, as well as edemas of cerebral regions close to the visual pathways may be implicated.
Content may be subject to copyright.
part of
281
ISSN 1758-2008
10.2217/NPY.12.37 © 2012 Future Medicine Ltd Neuropsychiatr y (2012) 2(4), 281–289
SUMMARY The Alice in Wonderland syndrome refers to a set of symptoms characterized
by perceptual distortions, such as visual distortions (i.e., metamorphopsia), body image
and time distortions. The Alice in Wonderland syndrome has been described consistently
over the past ve decades in various cultural settings. Migraine headaches and epilepsy
were the etiologies rst described and most frequently reported in the literature; however,
infectious, neurological, toxic and psychiatric causes have also been reported. Although little
is known regarding the specic pathophysiological pathways, dysfunctions of the NMDA
neurotransmission and inammations, as well as edemas of cerebral regions close to the
visual pathways may be implicated.
1CHU de Toulouse & Universite de Toulouse, Toulouse, France
2Center for Anxiet y & Traumatic Stress Disorders, Massachusetts G eneral Hospital & Harvard Medical Sc hool, One Bowdoin Square,
6thFloor, Suite 650, Boston, MA02114, USA
*Author for correspond ence: tebui@partners .org
SPECIAL REPORT
Francois Montastruc1, Noah Schwarz2, Laurent Schmitt1 & Eric Bui*1,2
An overview of the symptoms
andtypical disorders associated with Alice in
Wonderland syndrome
Practice points
Alice in Wonderland syndrome is characterized by the sudden onset of distorted visual perceptions, such as
metamorphopsia, allesthesia and teliopsia, unexplained by a ophthalmological pathology.
Most frequent etiologies are migraine headaches and epilepsy.
Patients are often aware of their own distortions, dierentiating this condition from psychoses in which insight
is usually impaired.
Symptoms typically resolve with treatment of accompanying pathology.
In Lewis Carroll’s Alice in Wonderland’s open-
ing scene [1], A lice drank from a bottle that
caused her to shrink: “What a curious feeling!
said Alice; “I must be shutting up like a telescope.”
Later, eating a piece of cake made her grow:
Curiouser and curiouser” cried Alice. “Now, I
am opening out like the largest telescope that ever
was! Goodbye feet !
Although Lippman published the first clini-
cal reports of a syndrome, including symptoms
resembling these unusual body image distor-
tions, in a paper reporting on seven migraine
patients [2], it was not until 1955 that another
author, Todd, named the syndrome after Lewis
Carroll’s novel [3]. In his publication, Todd
proposed grouping the symptoms experienced
For reprint orders, please contact: reprints@futuremedicine.com
Neuropsychiatry (2012) 2(4) future science group
282
SpeciAl RepoRt Montastruc, Schwarz, Schmitt & Bui
by Alice (“hyperschematia, hyposchematia,
de realization, depersonalization and somato-
psychic duality) together with other symptoms
that often accompany them such as “illusory
changes in the size, distance, or position of sta-
tionary objects in the subject’s visual field, illu-
sory feelings of levitation; and illusory alterations
in the sense of the passage of time” [3]. Todd also
noted that patients are often aware of their own
distortions, differentiating this condition from
psychoses in which insight is usually impaired.
To date, visual distortions or metamorphopsia
are still the hallmarks of Alice in Wonderland
syndrome (A IWS); however, other symptoms
frequently accompany them. These include:
an inability to recognize faces (prosopag nosia),
illusions in which objects appear to be smaller
(micropsia) or larger (macropsia) or in which
people appear to be miniscule (lilliputianism)
and objects transposed from one point of view to
another (allesthesia). Finally, in some cases, symp-
toms of dissociation, such as de personalization
(the feeling of watching oneself act, while having
no control over a situation) and derealization (the
alteration in the perception or experience of the
external world so that it seems unreal), occur
concurrently with the classic visual distortions.
While the first cases of AIWS were described
in patients with migraine headaches or epi-
lepsy (in his description of the syndrome, Todd
reported six cases of AIWS associated with
migraine and epilepsy), in the five decades fol-
lowing Lippman and Todd’s descriptions, cases
of AIWS involving other etiologies have been
regularly reported in the literature. The present
article aims to review the literature available on
the etiologies of AIWS.
Search method & characteristics of the
reported cases
A search was conducted on MEDLINE using the
key words ‘Alice in Wonderland Syndrome’ and
Alice in Wonderland’. Further publications were
identified from the reference list of publications
selected, while review papers were excluded from
our study [4–6] . Including Lippman and Todd’s
papers, the search yielded a total of 33 publica-
tions examining AIWS. All publications were
either single case reports (n = 21) or case series
(n = 10).
In total, from 1952 to 2012, 86 cases of AIWS
were reported in the literature. The youngest
patients were 4 years old [7,8] , and the oldest
was 74 years of age [9]. The cases reported reveal
no gender imbalance (n = 47; females: 55%).
The shortest duration was a few days [10], while
the longest syndrome described lasted several
years [11].
The vast majority of descriptions had either
a neurological or an infectious etiology (n = 31;
36% and n = 35; 41%, respectively); only three
papers described patients with a psychiatric dis-
order [9,12,13]. Interestingly, publications emanated
from 12 different countries belonging to four
different continents (Africa, America, Asia and
Europe). All the relevant studies are reported in
Table1.
Etiologies
Neurological etiologies
Migraine headaches
Migraine was the rst etiology identified for
AIWS, as reported above [2,3]. In line with these
two first publications, Golden reported the case
of two children with recurrent episodes marked
by an impaired sense of time, altered body image
and visual hallucinations [14]. Both children had
family and personal histories of migraine. Kew
et al. also reported the case of a patient with a
long history of migraine [15]. The patient expe-
rienced somesthetic auras with and without
headaches. The aura was of her body shrinking
(microsomatognosia) and a gross magnification
of both hands: “I suddenly get a feeling that my
hands are huge and I mean huge: ginormous”
[15]. The authors observed that in general patients
were reluctant to discuss these symptoms, as con-
trary to visual hallucinations, they were usually
aware that the distortions of AIWS were not real.
A fifth report detailed the case of a migraine
patient with abdominal colic and AIWS [16].
The patient irregularly experienced attacks of
abdominal colic associated with autonomic
manifestations (e.g., nausea, abdominal flushing,
pallor, tachycardia and diarrhea) and experiences
of distorted shape, size and position of objects
or subjects. The author highlighted that in two
cases the migraine phenomena disappeared after
antiepileptic treatment (valproic acid) and may
have resulted from the same neurophysiological
process as the migraine headache.
Epilepsy
Epilepsy has also been identif ied as an eti-
ology of AIWS. In his landmark publication,
Todd diagnosed AIWS in association with
migraine–epilepsy in two cases [3]. The two
patients (two women, 17 and 32 years of age),
Symptoms & typical disorders associated with Alice in Wonderland syndrome SpeciAl RepoRt
future science group www.futuremedicine.com 283
Table 1. Summary of the studies examining Alice in Wonderland Syndrome between 1952 and 2012.
Study
(year)
Country Patients (n;
population)
Type of
publication
Symptom(s) Etiology Symptoms
duration
Ref.
Lippman
(1952)
USA n=7 (six women,
one man, aged
23–64years)
Case series Micropsia and macropsia Migraine [2]
Todd (1955) UK n=6 (ve women,
one man, aged
17–43years)
Case series Micropsia, macropsia, teliopsia,
peliopsia, giddiness, sensation
of being ‘split’, derealization,
depersonalization, sense of
time slowing down, paresthesia,
headaches and palpitations
Onecase unknown,
threecases of
migraine, twocases
of migraine–epilepsy
[3]
Copperman
(1977)
USA n=3 (one boy,
aged9.5years,
twogirls, aged 17
and 18years)
Case series Derealization, macropsia,
micropsia, hyperacusis, tinnitus
and blurring of vision
Mononucleosis
infection
Intermittent
symptoms for
2months
[18]
Golden
(1979)
USA n=2 (onegirl,
aged11years, one
boy, aged1year)
Case series Metamorphopsia, attacks of
impairment of time sense, body
image and visual analysis of the
environment
Juvenile migraine [14]
Sanguineti
etal. (1983)
Italy n=1 (32‑year‑old
male)
Case report Metamorphopsia, perception
of objects rapidly moving
backwards and forwards,
derealization, miscalculation
of the position of objects and
blurring of vision
Mononucleosis
infection
[19]
Lahat etal.
(1990)
Israel n=1 (6‑year‑old
girl)
Case report Metamorphopsia, headaches
and anxiety
Mononucleosis
infection
6 weeks [20]
Liaw and
Shen (1991)
China n=4 (twogirls,
two boys, aged
4–9years)
Case series Micropsia, macropsia,
lilliputianism and allesthesia
Mononucleosis
infection
1 week–
3months
[38]
Cinbis
and Aysun
(1992)
Turkey n=1 (7‑year‑old
girl)
Case report Micropsia Mononucleosis
infection
6months [39]
Wang etal.
(1996)
Taiwan n=1 (4‑year‑old
boy)
Case report Metamorphopsia, micropsia,
macropsia and illusional
symptoms (e.g., interpretation of
a wire for a snake)
Coxsackievirus B1
infection
1year [7]
Mizuno
etal. (1998)
Japan n=1 (54‑year‑old
male)
Case report Metamorphopsia and
lengthening and shortening of
time experience
Major depressive
disorder
3months [12]
Kew etal.
(1998)
UK n=1 (52‑year‑old
woman)
Case report Headaches with somesthetic
auras, micropsia and macropsia
Migraine Several years [15]
Kuo etal.
(1998)
Taiwan n=4 (threegirls,
one boy, aged
3–8years)
Case series Metamorphopsia and visual
hallucinations
Twocases of
mononucleosis
infection, onecase
with abnormal EEG,
onecase unknown
5–13days [10]
Takaoka
and Takata
(1999)
Japan n=1 (46‑year‑old
male)
Case report Side eects of
syrup containing
dihydrocodein
phosphate and
dimethylphedrine
hydrochloride
More than
3years
[11]
–: Not applicab le.
Neuropsychiatry (2012) 2(4) future science group
284
SpeciAl RepoRt Montastruc, Schwarz, Schmitt & Bui
Table 1. Summary of the studies examining Alice in Wonderland Syndrome between 1952 and 2012 (cont.).
Study (year) Country Patients (n;
population)
Type of
publication
Symptom(s) Etiology Symptoms
duration
Ref.
Lahat etal.
(1999)
Israel n=5
(threegirls,
two boys,
aged
10–13years)
Case series Micropsia, macropsia,
erythropsia and polyopia
Mononucleosis
infection
4 or 6 weeks [21]
Perez‑Mendez
etal. (2001)
Spain n=1 (6‑year‑
old boy)
Case report Macropsia Mononucleosis
infection
2days [40]
Takaoka etal.
(2001)
Japan n=1 (22‑year‑
old woman)
Case report Déjà vu, delusional
misidentication syndromes,
micropsia, macropsia,
allesthesia and hallucination
Abuse of toluene
based solvent
1year [26]
Zwijnenburg
(2002)
The
Netherlands
n=1 (9‑year‑
old girl)
Case report Micropsia, macropsia and
headaches
Epilepsy 2days [17]
Häusler etal.
(2002)
Germany 3/48 (unclear
from article)
2‑year
prospective
study
Metamorphopsia Reactived
mononucleosis
infection
6months [41]
Evans (2006)
and Evans and
Rolak (2004)
USA n=2 (women
aged 27 and
31years)
Case series Micropsia, macropsia,
derealization and headaches
Onecase of migraine,
onecase of side eect
with topiramate
[28,29]
Gencoglu
etal. (2005)
Turkey n=1 (7‑year‑
old girl)
Case report Micropsia and macropsia Viral infection other
than Epstein–Barr virus
[32]
Corral‑
Caramés etal.
(2009)
Spain n=1 (8‑year‑
old girl)
Case report Micropsia Migraine 3 weeks [42]
Hamed (2010) Egypt n=1 (20‑year‑
old male)
Case report Micropsia, teliopsia,
associated with abdominal
colic and headaches
Migraine variant with
abdominal colic
[16]
Brumm etal.
(2010)
USA n=1 (12‑year‑
old boy)
Case report Teliopsia, micropsia,
with phonophobia and
photophobia
Migraine – [31]
Bui etal.
(2010)
France n=1 (74‑year‑
old male)
Case report Micropsia Major depressive
disorder
45days [9]
Jürgens etal.
(2011)
Germany n=1 (17‑year‑
old girl)
Case report Nocturnal macropsia Adverse drug reaction
of topiramate
3months [27]
Augarten and
Aderka (2011)
Israel n=1 (11‑year‑
old girl)
Case report Micropsia, macropsia, sense
of time slowing down and
teliopsia
H1N1 viral infection 3days [23]
Weidenfeld
and Borusiak
(2011)
Germany n=9 (boys
aged
6–11years)
Case series Micropsia, macropsia,
diplopic images and panic or
agitation
Twocases with
reappearance
of symptoms
after >1year
[43]
Nakaya etal.
(2011)
Japan n = 1 (5‑year‑
old girl)
Case report Micropsia and macropsia H1N1 viral infection 2months [22]
Losada‑Del
Pozo etal.
(2011)
Spain n=20 (boys
and girls aged
4–16years)
Retrospective
study
Micropsia, macropsia,
derealization and
acceleration of the time
Ninecases of viral
infections (ve
mononucleosis
infections), eightcases
of migraine, onecase
of epilepsy, onecase
with dextrometrophan
and onecase with
cannabis
[8]
–: Not applicab le.
Symptoms & typical disorders associated with Alice in Wonderland syndrome SpeciAl RepoRt
future science group www.futuremedicine.com 285
had a history of migraine associated with meta-
morphopsia. EEG data showed a paroxysmal
dysrhythmia, especially in the temporal lobes.
More recently, Zwijnenburg et al. also reported
a case of AIWS in a 9-year-old girl resulting
from frontal cortex epilepsy [17]. Over 4 days, the
patient presented with short attacks consisting
of headaches, anxiety and symptoms of AIWS.
Treatment with propranolol for migraine did not
improve her condition. Two intericteral EEGs
revealed intermittent abnormalities (low-voltage
spikes and spikewave complexes) exclusively at
the right-frontopolar electrode. The seizures dis-
appeared after treatment with the anticonvulsant,
valproic acid. A similar case was later described
in which a 14-year-old girl experienced derealiza-
tion, micropsia and macropsia associated with
headaches [8]. EEG recordings showed posterior
slow waves in the left hemisphere and further
investigation identified a left temporal posterior
foci. Both clinical symptoms and EEG abnor-
malities subsided with anticonvulsive medica-
tion. These findings suggest the implications of
epilepsy in AIWS, however, because of similari-
ties between migraine headaches and epilepsy, a
migraine etiology cannot be ruled out.
Although to date, no other neurological eti-
ologies have been reported in the literature, some
authors have argued that in patients presenting
with hallucinations or metamorphopsia, the pres-
ence of an organic etiology such as cerebral tumor,
central nervous infection, traumatic brain injury
or cerebral aneurisms should be investigated [3,17].
Viral etiologies
The association between AIWS and Epstein–Barr
infection was first published by Copperman
in 1977 [18]. He described three patients, one
preadolescent male and two adolescent females,
with classical symptoms of mononucleosis infec-
tion with asthenia, enlargement of the lymph
nodes or spleen and biologic abnorma lities
(increase in lymphocyte concentration and a
positive test for mononucleosis infection), fol-
lowed by perceptual defects concerning the size,
position and distance of objects. After examin-
ing a similar case, Sanguineti et al. suggested
that patients be tested for infection prior to
psychiatric diagnosis [19]. Moreover, Lahat et al.
noted that metamorphopsia may appear before
the onset or after the resolution of all mono-
nucleosis infection symptoms [20] , the duration
of the visual illusions ranged from 2 weeks to
7 months.
In support of a viral etiology, Losada-Del Pozo
et al. recently found that five out of 20 cases of
AIWS were associated with the Epstein–Barr
virus [8]. In these viral etiologies, patients most
frequently experienced micropsia or macropsia.
In another study, Lahat found that children
with AIWS and infectious mononucleosis dis-
played visual evoked potentials of amplitudes
similar to those of migraine patients, suggest-
ing that mononucleosis infection and migraine
may share a common physiopathologic pathway
with AIWS [21].
Recent publications report additional cases
of AIWS caused by viral infection, including
the Coxsackie B1 enterovirus and H1N1 influ-
enza virus [7]. Wang et al. reported the case of
a 4-year-old boy with intermittent fever, cough,
abdominal pain, watery diarrhea and hepato-
splenomegaly associated with visual aberrations
(perception of the wall moving backward and
forward rapidly and change of his parents’ body
image in size) [7] . Biologic and serologic tests
Table 1. Summary of the studies examining Alice in Wonderland Syndrome between 1952 and 2012 (cont.).
Study (year) Country Patients (n;
population)
Type of
publication
Symptom(s) Etiology Symptoms
duration
Ref.
Blom etal.
(2011)
The
Netherlands
n = 1 (36‑year‑
old woman)
Case report Micropsia, macropsia,
allesthesia, verbal
auditory hallucinations,
déjà vu experiences,
time distorsions and
intuitive feeling of a
‘presence’
Schizoaective
disorder
1year [13]
Binalsheikh
etal. (2012)
USA n = 1 (7‑year‑
old boy)
Case report Metamorphopsia and
auditory hallucination
Lyme disease 3 weeks [24]
Bayen etal.
(2012)
France n = 1 (37‑year‑
old woman)
Case report Teliopsia and macropsia
with headaches
Migraine – [44]
–: Not applicab le.
Neuropsychiatry (2012) 2(4) future science group
286
SpeciAl RepoRt Montastruc, Schwarz, Schmitt & Bui
identified Coxsackie virus B1 in cerebro spinal
fluid and rectal swab cultures. The authors
noted that Coxsackie B1 infection was most
often asymptomatic, but that neurologic al
symptoms, when they did occur, more often
included aseptic meningitis, encephalitis, paraly-
sis, Guillain–Barré syndrome, transverse myeli-
tis, cerebellar ataxia or peripheral neuritis than
AIWS did.
Recent case reports suggest the possibil-
ity of other viral etiologies. Two publications
have reported cases of AIWS associated with
the H1N1 virus in both a 5 and 11-year-old
girl [22, 23]. The two girls presented both meta-
morphopsia and influenza symptoms, which
disappeared spontaneously after a few months.
Similarly, Losada-Del Pozo et al. identified sev-
eral cases in which cytomegalovirus and varicella
zoster virus were involved in separate, similar
cases of AIWS [8].
Bacterial infection may also cause AIWS.
Until recently, Lyme neuroborreliosis was
known to induce headache, emotional lability
and disturbances in sleep, concentration and
memory, although not AIWS. In a recent publi-
cation, Binalsheikh et al. reported a case of Lyme
disease presenting with micropsia, macropsia
and auditory hallucinations without headaches,
suggesting the presence of AIWS [24].
Psychiatric etiologies
Depressive disorders have also been described
in conjunction with AIWS in two publications
[9,12]. The first was a case report of a 54-year-old
patient with time and body-image distortions,
metamorphopsia and a depressive disorder [12].
In the second publication, Bui et al. reported
the case of a man with major depressive disor-
der who, 10 days after admission, complained
of body distortions [9] . The patient achieved
remission of AIWS and depressive symptoms
after five electroconvulsive therapy sessions.
Cotard’s syndrome, which includes delusions
ranging from the belief that one has lost organs
to the conviction that one is dead, is usually asso-
ciated with severe depression [25]. It has there-
fore been suggested that AIWS in the context
of depressive disorders may be a variant of this
syndrome [9]. More generally, it could be argued
that AIWS occurring during a major depressive
episode may actually represent psychotic features
accompanying the mood disorder.
Psychotic symptoms include disturbances of
thought, visual perception, feeling and behavior,
and may occur alongside metamorphopsia [17].
Consequently, it has been suggested that schizo-
phrenia may be a cause of AIWS [3]. The litera-
ture review by the authors of this article found
only one case of a patient with AIWS who was
diagnosed with schizoaffective disorder [13].
Potential explanations for this relative lack of evi-
dence may include either the under-reporting of
AIWS symptoms in patients with psychosis (e.g.,
because of disorganized behaviors or thoughts)
or the tendency for psychiatrists to treat AIWS
symptoms as symptoms of schizophrenia.
Although it may be difficult to differentiate
AIWS from psychosis, compared with coenes-
thesias of psychosis, AIWS is usually character-
ized by intact insight, short-lived symptoms and
an identified neurological etiology.
Toxic & pharmacological etiologies
Illicit drugs, such as lysergic acid diethylam-
ide, 3,4 -methylenediox ymetha mphetam ine
(‘ecstasy’), mescaline and inhalants may pro-
duce hallucinations and metamorphopsia and
unsurprisingly, have also been reported to induce
phenomena such as AIWS. In a case report of
a 15-year-old boy with no medical history who
presented with acute symptoms of derealiza-
tion, micropsia, macropsia and a sense of accel-
erated time over the course of 24 h, AIWS was
attributed to cannabis use [8].
Takaoka et al. reported a case of toluene-based
solvent abuse resulting in symptoms of AIWS
[26]. After several years of abuse, the 22-year-old
woman developed a distorted perception of her
body, colors and time.
Much like illicit drugs, certain medications
can induce visual hallucinations. To date, two
cases of AIWS induced by the anticonvulsant
topiramate have been published [27,28]. Evans and
Rolak described a 31-year-old patient who devel-
oped AIWS 1 week after starting topiramate [29].
After 2 and a half months of intermittent AIWS
episodes, topiramate was discontinued and the
syndrome resolved gradually within 1 month.
In the other case report, Jürgens et al. presented
the case of a 17-year-old girl with a past history
of migraine headaches without aura [27]. The
patient complained of intermittent, nocturnal
distortions of her body image, both macropsia
and micropsia, with a dose above 75 mg/day.
Approximately 2 weeks after topirimate was
tapered off to 50 mg/day, the nocturnal phenom-
ena ceased. Returning the dose to 75 mg/day
again resulted in metamorphopsia.
Symptoms & typical disorders associated with Alice in Wonderland syndrome SpeciAl RepoRt
future science group www.futuremedicine.com 287
Dextromethorphan, an NMDA antagonist,
may also be involved in AIWS. The case of
a 4-year-old girl developing AIWS (microp-
sia) within 36 h of administration of dex-
tromethorphan, which remitted after drug
discontinuation, was reported in the literature [8].
Finally, oseltamivir, a neuraminidase inhibi-
tor prescribed in the treatment of flu symptoms
has been reported to possibly induce neuro-
psychiatric symptoms, such as hallucinations
[30]. In the two case reports of AIWS associated
with the H1N1 infection [22 ,23] , this drug was
prescribed and its role in the onset of AIWS
cannot be ruled out.
Potential pathophysiological pathways
The broader pathophysiology of AIWS is largely
unknown and the multiple etiologies suggest
many neurobiological mechanisms. Radiology
(cranial computed tomography or MRI) has
failed to demonstrate the involvement of any
specific brain areas [31] and EEG data has only
shown nonspecific electrophysiological abnor-
malities [3,17]. Results from a few neuroim-
aging studies, however, suggest the possible
involvement of visual pathways [10,31–33]. Kuo
et al. reported a hypoperfusion in the temporal
lobe, occipital lobe and perisylvian area in four
patients with AIWS using single-photon emis-
sion computed tomography brain scan [10]. The
authors suggested that, independently from the
etiology, AIWS may result from a focal brain
parenchymal edema and a decrease in regional
cerebral blood flow in the regions located close
to the visual pathway and the associated visual
cortex. Gencoglu et al. examined cerebral per-
fusion using single-photon emission computed
tomography imaging in a 7-year-old girl present-
ing with AIWS occurring 15 days after an upper
respiratory tract infection with tonsillitis and also
found hypoperfusion near the visual pathway (in
this case, in the right frontal and the right fron-
toparietal regions) [32]. Finally, a recent publica-
tion using functional MRI reported increased
activation in both auditory and visual cortices
in a patient with verbal auditory hallucinations
and AIWS [13].
Another etiological pathway to AIWS may
be a dysfunction in the NMDA neurotrans-
mitter system. The pharmacological profile
of topiramate includes the potentialization of
GABA-A receptors and blockade of excitatory
NMDA transmission; similarly, dextrometho-
rphan has been shown to antagonize NMDA
neurotransmission. The fact that both of these
NMDA inhibitors may induce AIWS suggests
that the syndrome’s pathophysiological pathway
may perhaps involve dysfunction in the NMDA
neurotransmission system. NMDA inhibitors,
such as ketamine, amantadine or memantine,
have been known to induce hallucination, dere-
alization and depersonalization similar to those
associated with AIWS [31,34, 35].
While there is minimal evidence on the
pathophysiology of AIWS, more specific evi-
dence exists on the pathophysiolog y of its
distinct visual distortions. In a review of the
neuro physiological and anatomical correlates of
‘positive’ visual pathologies, Ffytche et al. sug-
gest that micropsia and macropsia are the result
of mechanisms in the visual cortices failing to
account for the extent of an object’s retinal pro-
jection [36]. The authors propose that allesthesia,
the transposition of objects in the visual field,
may be due to disturbances in the integration
of vestibular and visual inputs, possibly in the
anterior parietal lobe [36] .
Conclusion & future perspective
The AIWS is a clinical entity that has been
described consistently over the past five decades
in various cultural settings. While migraines
headaches and epilepsy were the first and most
frequent etiologies reported in the literature,
a number of different infectious, neurologi-
cal, toxic and psychiatric conditions have been
found to possibly be accompanied by AIWS-like
symptoms. To date, little is known regarding the
specific pathophysiological pathways involved in
this condition, but the available evidence points
to the possible implication of the dysfunction of
NMDA neurotransmission and/or inflamma-
tion and edema of cerebral regions close to the
visual pathways.
In conclusion, it is probable that what is cur-
rently referred to as AIWS actually includes a
number of very heterogeneous conditions. In the
future, further research aiming to better define
the criteria of this syndrome are warranted,
particularly in view of the possible overlap with
other rare syndromes that involve distortions in
the perception of body parts such as Cotard’s
syndrome [25] or Koro syndrome (illusion of a
shrinking penis) [37]. Future advances in the
understanding of the neurobiology underlying
‘positive’ visual distortions will help inform
whether or not AIWS should be considered a
distinct condition.
Neuropsychiatry (2012) 2(4) future science group
288
SpeciAl RepoRt Montastruc, Schwarz, Schmitt & Bui
Financial & competing interests disclosure
The authors have no relevant affiliations or financial
involvement with any organization or entity with a finan-
cial interest in or financial conflict with the subject matter
or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or
options, expert t estimony, grants or patents received or
pending, or royalties.
No writing assistance was utilized in the production of
this manuscript.
References
Papers of special note have been highlighted as :
 of interest
1 Carroll L . Alice’s Adventures in Wonderland.
Macmillan and Co., London, UK (1865).
 Carroll’s novel provided Todd (1955)
with both the name and prototypical case
for coining A lice in Wonderland
syndrome (AIWS).
2 Lippman CW. Certain hallucinations
peculiar to migraine. J. Nerv. Ment. Dis.
116(4), 346 –351 (1952).
3 Todd J. The syndrome of A lice in
Wonderland. Can. Med. Assoc. J. 73 (9),
701–704 (1955).
 Todd’s is the first published account of cases
classified as AI WS.
4 Cau C. The A lice in Wonderland syndrome.
Minerva Med. 90(10), 397–401 (1999).
5 Podoll K, Ebel H, Robinson D, Nicola U.
Obligatory and facultative symptoms of the
Alice in Wonderland syndrome. Minerva
Med. 93 (4), 287–293 (2002).
6 Gaul C, Kraya T, Holle D, Benkel-
Herrenbruck I, Schara U, Ebinger F.
Migra ine va riants and unusual types of
migraine in childhood. Schmerz 25(2),
148–156 (2011).
7 Wang SM, Liu CC, Chen YJ, Chang YC,
Huang CC. Alice in Wonderland syndrome
caused by coxsackievirus B1. Pediatr. Infect.
Dis. J. 15(5), 470–471 (1996).
8 Losada-Del Pozo R, Canta rin-Extremera V,
Garcia-Penas JJ et al. Characteristics and
evolution of patients with A lice in
Wonderland syndrome. Rev. Neurol. 53(11),
641–648 (2011).
9 Bui E, Chatagner A, Schmitt L . Alice in
Wonderland syndrome in major depressive
disorder. J. Neuropsychiatr. Clin. Neurosci.
22(3), 352J, e316–e352.e16 (2010).
 Discusses differential diagnosis of AIWS
and psychosis, specifica lly Cotard’s delusion,
in the c ase of major depressive disorder.
10 Kuo YT, Chiu NC, Shen EY, Ho CS, Wu
MC. Cerebral perfusion in children with
Alice in Wonderland syndrome. Pediatr.
Neurol. 19(2), 105–108 (1998).
11 Takaoka K, Takata T. ‘Alice in Wonderla nd’
syndrome and lilliputian hallucinations in a
patient with a substance-related disorder.
Psychopathology 32(1), 47–49 (1999).
12 Mizuno M, Kashima H, Chiba H, Murakami
M, Asai M. ‘Alice in Wonderland’ syndrome
as a precursor of depressive disorder.
Psychopathology 31(2), 85–89 (1998).
13 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 f MRI findings.
Psychopathology 44(5), 337–344 (2011).
14 Golden GS. The Alice in Wonderland
syndrome in juvenile migraine. Pediatrics
63(4), 517–519 (1979).
15 Kew J, Wright A, Halligan PW. Somesthetic
aura: the experience of ‘Alice in Wonderland’.
Lancet 351(9120), 1934 (1998).
16 Hamed SA. A migraine variant with
abdominal colic and A lice in Wonderland
syndrome : a case report and review. BMC
Neurol. 10, 2 (2010).
 Details an uncommon AIWS comorbidity
and chronic abdominal distress, in order to
deduce overlapping CNS mechanisms.
17 Zwijnenburg PJ, Wennink JM, Laman DM,
Linssen WH. Alice in Wonderland syndrome:
a clinical presentation of frontal lobe epilepsy.
Neuropediatrics 33(1), 53–55 (2002).
18 Copperman SM. ‘Alice in Wonderland
syndrome as a presenting symptom of
infectious mononucleosis in children:
a description of three affected young people.
Clin. Pediatr. (Phila .). 16(2), 143–146 (1977).
19 Sanguineti G, Crovato F, De Marchi R,
Desirello G. ‘Alice in Wonderland’ syndrome
in a patient with infectious mononucleosis.
J. Infect. Dis. 147(4), 782 (1983).
20 Lahat E, Eshel G, Arlazoroff A. ‘Alice in
Wonderland’ syndrome and infectious
mononucleosis in children. J. Neurol.
Neurosurg. Psychiatr. 53(12), 1104 (1990).
21 Lahat E, Berkovitch M, Barr J, Paret G,
Barzilai A. Abnormal visual evoked potentia ls
in children with ‘Alice in Wonderland
syndrome due to infectious mononucleosis.
J. Child. Neurol. 14(11), 732–735 (1999).
22 Nakaya H, Yamamoto T, Takano M et al.
Alice in Wonderland syndrome caused by the
2009 pandemic H1N1 influenza A virus.
Pediatr. Infect. Dis. J. 30 (8), 725–726 (2011).
23 Augarten A, Aderka D. Alice in Wonderland
syndrome in H1N1 influenza : case report.
Pediatr. Emerg. Care 27(2), 120 (2011).
24 Binalsheik h IM, Griesemer D, Wang S,
Alvarez-A ltalef R. Lyme neuroborreliosis
presenting as Alice in Wonderland syndrome.
Pediatr. Neurol. 46(3), 185–186 (2012).
25 Debruyne H, Portzky M, Van Den Eynde F,
Audenaert K. Cotard’s syndrome : a review.
Curr. Psychiatr. Rep. 11(3), 197–202 (2009).
26 Takaoka NI, Nobuya Niwa K. ‘Alice in
Wonderland’ syndrome as a precursor of
delusional misidentification syndromes. Int.
J. Psychiatr. Clin. Prac. 5(2), 149–151 (2001).
27 Jürgens TP, Ihle K, Stork JH, May A. ‘Alice in
Wonderland syndrome’ associated with
topiramate for migraine prevention. J. Neurol.
Neurosurg. Psychiatry 82(2), 228–229 (2011).
28 Evans RW. Reversible palinopsia and the
Alice in Wonderland syndrome associated
with topiramate use in migraineurs. Headache
46(5), 815–818 (2006).
29 Evans RW, Rolak L A. The Alice in
Wonderland syndrome. Headache 44(6),
624– 625 (2004).
30 Jefferson T, Jones M, Doshi P, Del Mar C.
Possible harms of oselta mivir – a call for
urgent action. Lancet 374(9698), 1312–1313
(2009).
31 Brumm K, Walensk i M, Haist F, Robbins SL,
Granet DB, L ove T. Functional magnetic
resonance imaging of a child with Alice in
Wonderland syndrome during an episode of
micropsia . J. AAPOS 14(4), 317–322 (2010).
32 Gencoglu EA, Alehan F, Erol I, Koyuncu A,
Aras M. Brain SPECT findings in a patient
with Alice in Wonderland syndrome. Clin.
Nucl. Med. 30(11), 758–759 (2005).
 Reports an illustrative single-photon
emission computed tomography in which a
patient ex hibits hypofusion surrounding the
visua l pathway.
33 Hung KL, Liao HT, Tsai ML. Epstein–Barr
virus encephalitis in children. Acta Paediatr.
Taiwan 41(3), 140–146 (2000).
34 MacLennan FM. Ketamine tolerance and
hallucinations in children. Anaesthesia 37(12),
1214–1215 (1982).
35 Jarvis B, Figgitt DP. Memantine. Drugs Aging
20(6), 465–476; discussion 477–468 (2003).
future science group www.futuremedicine.com 289
Symptoms & typical disorders associated with Alice in Wonderland syndrome SpeciAl RepoRt
36 Ffytche DH, Blom JD, Catani M. Disorders
of visual perception. J. Neurol . Neurosurg.
Psychiatr. 81(11), 1280–1287 (2010).
37 Mattelaer JJ, Jilek W. Koro – the
psychological disappeara nce of the penis.
J. Sex Med. 4(5), 1509–1515 (2007).
38 Liaw SB, Shen EY. A lice in Wonderland
synd rome a s a presenting symptom of EBV
infection. Pediatr. Neurol. 7(6), 464466
(1991).
39 Cinbis M, Aysun S . Alice in Wonderland
synd rome a s an initial manifestation of
Epstein–Barr virus infection.
Br. J. Ophthalmol. 76(5), 316 (1992).
40 Perez Mendez C, Martin Mardomingo M,
Otero Martinez B, Lagunilla Herrero L,
Fernandez Zurita C. A lice in Wonderland
syndrome due to Epstein–Barr virus infection.
An. Esp. Pediatr. 54(6), 601–602 (2001).
41 Häusler M, Ramaekers VT, Doenges M,
Schweizer K, Ritter K, Schaade L.
Neurological complications of acute and
persistent Epstein–Barr virus infection in
paediatric patients. J. Med. Virol . 68(2),
253–263 (2002).
42 Corral-Caramés MJ, Gonzalez-Lopez MT,
Lopez-Abel B, Taboas-Pereira M A, Francisco-
Morais MC. A lice in Wonderland syndrome
as persistent aura of migraine and migraine
disease starting. Rev. Neurol. 48(10), 520–522
(2009).
43 Weidenfeld A, Borusiak P. Alice-in-
Wonderland syndrome – a case-based update
and long-term outcome in nine children.
Childs Nerv. Syst. 27(6), 893– 896 (2011).
 Conducts a relatively long-term follow-up of
AIWS patients, illustrating the syndrome’s
benign, transient nature.
44 Bayen E, Cleret De Langavant L, Fenelon G.
[The Alice in Wonderland syndrome: an
unusual aura in migraine]. Rev. Neurol . (Paris)
168(5), 457–459 (2012).
... Treatment usually involves reassurance and management of underlying conditions. AIWS can be distinguished from schizophrenia on the characteristic nature of perceptual disturbances, absence of thought disorder and delusions, good insight and age of onset usually in childhood (Montastruc et al., 2012). This is important in providing patients an accurate diagnosis, prognosis, reassurance and avoiding antipsychotics, which are ineffective. ...
Chapter
Originally, rare diseases and orphan diseases were not synonyms. Rare diseases became known as orphan diseases because pharmaceutical companies were not interested in developing treatments for them. The Orphan Drug Act (USA) used financial incentives for orphan drug development. Herewith, a definition for rare disease was also established. This differs slightly across countries. Some rare diseases respond to drugs that are not orphan drugs. Orphan diseases refer to neglected diseases and even common disorders as endometrial cancer and infantile diabetes. Nonetheless, nowadays very often rare and orphan are used as synonyms. The causes for rare diseases are very diverse. The majority are thought to be genetic. Most lack proper diagnosis, treatment, or known therapeutic targets. However, rare disease patients account for a huge proportion of the health burden. This chapter discusses rare (and orphan) diseases, what has been reported about them, and how they appear to the general public. The different categories of rare diseases are introduced.
Article
Full-text available
The aim of this article is to present a summarizing overview on ethnomedical aspects of koro (in Chinese called suo-yang), the panic anxiety state in which affected males believe that the penis is shrinking and/or retracting, and perhaps disappearing. While reduction of penile volume occurs physiologically due to vasoconstriction in cold temperature and intense anxiety, it is believed in certain cultures that genital shrinking leads to impotence and sterility, and eventually to death. Traditional Chinese medicine treats suo-yang, the reduction of the male principle yang, as a dangerous disturbance of the life-sustaining yin-yang equilibrium of the organism. Koro has therefore been held to be a Chinese “culture-bound” condition. However , the koro phenomenon is also known among diverse ethnic and religious groups in Asia and Africa, typically in cultures in which reproductive ability is a major determinant of a young person's worth. Koro epidemics of panic anxiety due to widespread fears of losing one's genitals, procreative ability, and even one's life, are triggered by rumors of genital disappearance supposedly caused in China by female fox spirits, in Singapore and Thailand by mass poisoning, and in Africa by sorcery, usually in the context of socioeconomic or political tension. Today, in contemporary Western societies, ideas of genital disappearance are not culturally endorsed. But historically, it should be remembered that in the late Middle Ages in Europe, a man could lose his membrum virile through magical attacks by witches. Mattelaer JJ, and Jilek W. Koro—The psychological disappearance of the penis. J Sex Med 2007;4:1509–1515 The conclusion is that the psychological disappearance of the penis is a universal syndrome that was described recently in Asia and Africa and already in Medieval Europe.
Article
Full-text available
Die Migräne ist eine häufige primäre Kopfschmerzerkrankung, die sich im Kindes- und Jugendalter manifestieren kann. Neben der klassischen Form einer kindlichen Migräne treten die seltenen periodischen Vorläufersyndrome, Migränevarianten und ungewöhnliche Manifestationen der Migräne im Kindes- und Jugendalter auf. Hierzu zählen das zyklische Erbrechen, die abdominelle Migräne, der gutartige paroxysmale Schwindel in der Kindheit, der gutartige Tortikollis im Kleinkindalter, die alternierende Hemiplegie des Kindesalters, die akute konfusionelle Migräne (ACM) und das Alice-im-Wunderland-Syndrom. Migraine is a frequent primary headache disorder in children and adolescents. Most of the young sufferers of migraine describe typical migraine symptoms but sometimes rare forms of migraine variants and unusual types of migraine occur in children and adolescents. These childhood periodic syndromes are common precursors of migraine. Phenotypes are alternating hemiplegia of childhood, benign paroxysmal torticollis, benign paroxysmal vertigo of childhood, alternating hemiplegia in childhood, Alice in Wonderland syndrome, cyclic vomiting syndrome, acute confusional migraine and abdominal migraine. SchlüsselwörterMigränevariante–Erbrechen–Abdominelle Migräne–Alternierende Hemiplegie des Kindesalters–Tortikollis KeywordsMigraine variant–Vomiting–Abdominal migraine–Alternating hemiplegia of childhood–Torticollis
Article
The Alice in Wonderland syndrome is a term applied to altered bizarre perceptions of size and shapes of a patient's body and illusions of changes in the forms, dimensions, and motions of objects that a patient with this syndrome encounters. These metamorphopsias arise during complex partial seizures, migraine headaches, infections, and intoxications. The illusions and hallucinations resemble the strange phenomena that Alice experienced in Lewis Carroll's Alice's Adventures in Wonderland. Charles Lutwidge Dodgson, whose nom de plume was Lewis Carroll, experienced metamorphopsias. He described them in the story that he wrote for Alice Liddell and her two sisters after he spun a tale about a long and strange dream that the fictional Alice had on a warm summer day. The author of this chapter suggests that Dodgson suffered from migraine headaches and used these experiences to weave an amusing tale for Alice Liddell. The chapter also discusses the neurology of mercury poisoning affecting the behavior of Mad Hatter character. The author suggests that the ever-somnolent Dormouse suffered from excessive daytime sleepiness due to obstructive sleep apnea.
Article
The present paper describes a case of abuse of toluene-based solvent in which features of both 'Alice in Wonderland' (AIW) syndrome with déjá vu , and delusional misidentification syndromes (DMS), were exhibited. Toluene-induced brain dysfunction was the basis of the weak ties between percepts and sensory information, which in turn led to the misperceptions. Once misperceptions fed back into the cycle comprised of misperceptions, false beliefs and erroneous expectations, DMS were induced. AIW syndrome with déjá vu is a precursor and forms the basis of DMS.
Article
New daily persistent headache is a rare chronic daily headache of long duration characterized by the abrupt onset of persistent headache that generally develops over less than 3 days and does not remit. While it was initially thought to be a benign, self-limiting disorder, further research has shown that a significant percentage of patients continue to suffer for many years, often experiencing pain that is refractory to treatment. This article reviews the symptoms, pathophysiology, diagnostic criteria, diagnostic testing, treatment, and prognosis.
Article
Neurological complications of Epstein-Barr virus (EBV) have been reported almost exclusively in the course of acute primary infections. The role of EBV in paediatric neurological disease was investigated prospectively over a 2-year period, searching for acute primary, chronic, and reactivated EBV infections. Active EBV infections were diagnosed in 10/48 patients, including two with acute primary EBV infections (cranial neuritis and cerebellitis), one with chronic active infection (T/NK cell lymphoma with cranial neuritis), and seven with reactivated infections. Among these seven patients, three showed “Alice in Wonderland” syndrome, one facial nerve palsy, one progressive macrocephaly, and two prolonged encephalitic illness. The prognosis was good except for the patient with lethal T/NK cell lymphoma and the two girls with encephalitic illness. Despite steroid treatment, these girls suffered prolonged cognitive impairment and epileptic seizures. Both developed left-sided hippocampal atrophy, and one of them hippocampal sclerosis. Like primary infections, reactivated EBV infections cause neurological complications in a considerable number of paediatric patients, lead to serious long-term complications, and may contribute to the pathogenesis of hippocampal lesions. J. Med. Virol. 68: 253–263, 2002. © 2002 Wiley-Liss, Inc.
Article
Cotard’s syndrome is a rare disorder in which nihilistic delusions concerning one’s own body are the central feature. It is not listed as a specific disorder in the DSM-IV, as it is typically viewed as a part of other underlying disorders. However, it remains important to recognize the syndrome because specific underlying mechanisms are present, and prognostic and therapeutic consequences have to be taken into account. This review presents an up-to-date overview of Cotard’s syndrome, which was initially described more than a century ago.
Article
We describe a 7-year-old boy with Alice in Wonderland syndrome associated with Lyme disease. He presented with metamorphopsia and auditory hallucinations in the absence of previous tick bites or other signs of Lyme disease. The boy never developed clinical seizures, and electroencephalograms during these spells indicated no epileptic activity. There was no history of migraine. Cranial magnetic resonance imaging produced normal results. Lyme serology tested positive in both serum and cerebrospinal fluid. He was treated with intravenous ceftriaxone for 3 weeks, with complete resolution of signs. This case report is the first, to our knowledge, of neuroborreliosis presenting as Alice in Wonderland syndrome with complete resolution of findings after intravenous antibiotic treatment.
Article
The Alice in Wonderland syndrome consists in a perceptual distortion of one's body size and shape. It is rarely encountered in adults, where it is mainly associated with migraine with aura and epilepsy. A 37-year-old woman had had a migraine without aura since puberty. In the months following a parturition, she experienced several epidodes of unusual auras preceding typical migrainous headache. The aura lasted about 30min and consisted in the feeling of lengthening of the trunk and of the four limbs, associated with a sensation of well-being. Epileptologic and experimental data suggest that the Alice in Wonderland syndrome is associated with a transient dysfunction of associative somatosensory areas in the parietal cortex.