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A overview of the symptoms ad typical disorders associated with Alice i Woderlad sydrome Fracois Motastruc1, Noah Schwarz2, Lauret Schmitt1 & Eric Bui*1,2 Practice poits Alice i Woderlad sydrome is characterized
A overview of the symptoms ad typical disorders associated with Alice i Woderlad sydrome Fracois Motastruc1, Noah Schwarz2, Lauret Schmitt1 & Eric Bui*1,2 Practice poits Alice i Woderlad sydrome is characterized by the sudde oset of distorted visual perceptios, such as metamorphopsia, allesthesia ad teliopsia, uexplaied by a ophthalmological pathology. Most frequet etiologies are migraie headaches ad epilepsy. Patiets are ofte aware of their ow distortios, differetiatig this coditio from psychoses i which isight is usually impaired. Symptoms typically resolve with treatmet of accompayig pathology. Summary The Alice i Woderlad sydrome refers to a set of symptoms characterized by perceptual distortios, such as visual distortios (i.e., metamorphopsia), body image ad time distortios. The Alice i Woderlad sydrome has bee described cosistetly over the past five decades i various cultural settigs. Migraie headaches ad epilepsy were the etiologies first described ad most frequetly reported i the literature; however, ifectious, eurological, toxic ad psychiatric causes have also bee reported. Although little is kow regardig the specific pathophysiological pathways, dysfuctios of the NMDA eurotrasmissio ad iflammatios, as well as edemas of cerebral regios close to the visual pathways may be implicated. I Lewis Carroll s Alice i Woderlad s ope ig scee [1], Alice drak from a bottle that caused her to shrik: What a curious feelig! said Alice; I must be shuttig up like a telescope. Later, eatig a piece of cake made her grow: Curiouser ad curiouser cried Alice. Now, I am opeig out like the largest telescope that ever was! Goodbye feet! Although Lippma published the first clii cal reports of a sydrome, icludig symptoms resemblig these uusual body image distor tios, i a paper reportig o seve migraie patiets [2], it was ot util 1955 that aother author, Todd, amed the sydrome after Lewis Carroll s ovel [3]. I his publicatio, Todd proposed groupig the symptoms experieced CHU de Toulouse & Uiversite de Toulouse, Toulouse, Frace Ceter for Axiety & Traumatic Stress Disorders, Massachusetts Geeral Hospital & Harvard Medical School, Oe Bowdoi Square, 6th Floor, Suite 650, Bosto, MA 02114, *Author for correspodece: /NPY Future Medicie Ltd Neuropsychiatry (2012) 2(4), part of ISSN Motastruc, Schwarz, Schmitt & Bui by Alice ( hyperschematia, hyposchematia, de realizatio, depersoalizatio ad somatopsychic duality ) together with other symptoms that ofte accompay them such as illusory chages i the size, distace, or positio of statioary objects i the subject s visual field, illusory feeligs of levitatio; ad illusory alteratios i the sese of the passage of time [3]. Todd also oted that patiets are ofte aware of their ow distortios, differetiatig this coditio from psychoses i which isight is usually impaired. To date, visual distortios or metamorphopsia are still the hallmarks of Alice i Woderlad sydrome (AIWS); however, other symptoms frequetly accompay them. These iclude: a iability to recogize faces (prosopag osia), illusios i which objects appear to be smaller (micropsia) or larger (macropsia) or i which people appear to be miiscule (lilliputiaism) ad objects trasposed from oe poit of view to aother (allesthesia). Fially, i some cases, symptoms of dissociatio, such as de persoalizatio (the feelig of watchig oeself act, while havig o cotrol over a situatio) ad derealizatio (the alteratio i the perceptio or experiece of the exteral world so that it seems ureal), occur cocurretly with the classic visual distortios. While the first cases of AIWS were described i patiets with migraie headaches or epilepsy (i his descriptio of the sydrome, Todd reported six cases of AIWS associated with migraie ad epilepsy), i the five decades followig Lippma ad Todd s descriptios, cases of AIWS ivolvig other etiologies have bee regularly reported i the literature. The preset article aims to review the literature available o the etiologies of AIWS. Search method & characteristics of the reported cases A search was coducted o MEDLINE usig the key words Alice i Woderlad Sydrome ad Alice i Woderlad. Further publicatios were idetified from the referece list of publicatios selected, while review papers were excluded from our study [4 6]. Icludig Lippma ad Todd s papers, the search yielded a total of 33 publicatios examiig AIWS. All publicatios were either sigle case reports ( = 21) or case series ( = 10). I total, from 1952 to 2012, 86 cases of AIWS were reported i the literature. The yougest patiets were 4 years old [7,8], ad the oldest was 74 years of age [9]. The cases reported reveal o geder imbalace ( = 47; females: 55%). The shortest duratio was a few days [10], while the logest sydrome described lasted several years [11]. The vast majority of descriptios had either a eurological or a ifectious etiology ( = 31; 36% ad = 35; 41%, respectively); oly three papers described patiets with a psychiatric disorder [9,12,13]. Iterestigly, publicatios emaated from 12 differet coutries belogig to four differet cotiets (Africa, America, Asia ad Europe). All the relevat studies are reported i Table 1. Etiologies Neurological etiologies Migraie headaches Migraie was the first etiology idetified for AIWS, as reported above [2,3]. I lie with these two first publicatios, Golde reported the case of two childre with recurret episodes marked by a impaired sese of time, altered body image ad visual halluciatios [14]. Both childre had family ad persoal histories of migraie. Kew et al. also reported the case of a patiet with a log history of migraie [15]. The patiet experieced somesthetic auras with ad without headaches. The aura was of her body shrikig (microsomatogosia) ad a gross magificatio of both hads: I suddely get a feelig that my hads are huge ad I mea huge: giormous [15]. The authors observed that i geeral patiets were reluctat to discuss these symptoms, as cotrary to visual halluciatios, they were usually aware that the distortios of AIWS were ot real. A fifth report detailed the case of a migraie patiet with abdomial colic ad AIWS [16]. The patiet irregularly experieced attacks of abdomial colic associated with autoomic maifestatios (e.g., ausea, abdomial flushig, pallor, tachycardia ad diarrhea) ad experieces of distorted shape, size ad positio of objects or subjects. The author highlighted that i two cases the migraie pheomea disappeared after atiepileptic treatmet (valproic acid) ad may have resulted from the same europhysiological process as the migraie headache. Epilepsy Epilepsy has also bee idetified as a etiology of AIWS. I his ladmark publicatio, Todd diagosed AIWS i associatio with migraie epilepsy i two cases [3]. The two patiets (two wome, 17 ad 32 years of age), 282 Neuropsychiatry (2012) 2(4) future sciece group Symptoms & typical disorders associated with Alice i Woderlad sydrome Table 1. Summary of the studies examiig Alice i Woderlad Sydrome betwee 1952 ad Study (year) Lippma (1952) Coutry Patiets (; populatio) = 7 (six wome, oe ma, aged years) Todd (1955) UK = 6 (five wome, oe ma, aged years) Copperma (1977) Golde (1979) Saguieti et al. (1983) Lahat et al. (1990) Liaw ad She (1991) Cibis ad Aysu (1992) Wag et al. (1996) Mizuo et al. (1998) Kew et al. (1998) Kuo et al. (1998) Takaoka ad Takata (1999) : Not applicable. Italy Israel Chia Turkey Taiwa Japa UK Taiwa Japa = 3 (oe boy, aged 9.5 years, two girls, aged 17 ad 18 years) = 2 (oe girl, aged 11 years, oe boy, aged 1 year) = 1 (32 year-old = 1 (6 year-old = 4 (two girls, two boys, aged 4 9 years) = 1 (7 year-old = 1 (4 year-old boy) = 1 (54 year-old = 1 (52 year-old woma) = 4 (three girls, oe boy, aged 3 8 years) = 1 (46 year-old Type of publicatio Symptom(s) Etiology Symptoms duratio Micropsia ad macropsia Migraie [2] teliopsia, peliopsia, giddiess, sesatio of beig split, derealizatio, depersoalizatio, sese of time slowig dow, paresthesia, headaches ad palpitatios Derealizatio, macropsia, micropsia, hyperacusis, tiitus ad blurrig of visio Metamorphopsia, attacks of impairmet of time sese, body image ad visual aalysis of the eviromet Metamorphopsia, perceptio of objects rapidly movig backwards ad forwards, derealizatio, miscalculatio of the positio of objects ad blurrig of visio Metamorphopsia, headaches ad axiety lilliputiaism ad allesthesia Oe case ukow, three cases of migraie, two cases of migraie epilepsy Mooucleosis Ref. [3] Itermittet symptoms for 2 moths [18] Juveile migraie [14] Mooucleosis Mooucleosis Mooucleosis Micropsia Mooucleosis Metamorphopsia, micropsia, macropsia ad illusioal symptoms (e.g., iterpretatio of a wire for a sake) Metamorphopsia ad legtheig ad shorteig of time experiece Headaches with somesthetic auras, micropsia ad macropsia Metamorphopsia ad visual halluciatios Coxsackievirus B1 Major depressive disorder [19] 6 weeks [20] 1 week 3 moths [38] 6 moths [39] 1 year [7] 3 moths [12] Migraie Several years [15] Two cases of mooucleosis, oe case with abormal EEG, oe case ukow Side effects of syrup cotaiig dihydrocodei phosphate ad dimethylphedrie hydrochloride 5 13 days [10] More tha 3 years [11] future sciece group 283 Motastruc, Schwarz, Schmitt & Bui Table 1. Summary of the studies examiig Alice i Woderlad Sydrome betwee 1952 ad 2012 (cot.). Study (year) Coutry Patiets (; populatio) Lahat et al. (1999) Perez-Medez et al. (2001) Takaoka et al. (2001) Zwijeburg (2002) Häusler et al. (2002) Evas (2006) ad Evas ad Rolak (2004) Gecoglu et al. (2005) Corral- Caramés et al. (2009) Israel = 5 (three girls, two boys, aged years) Spai = 1 (6 yearold boy) Japa The Netherlads Germay Turkey Spai = 1 (22 yearold woma) = 1 (9 yearold 3/48 (uclear from article) = 2 (wome aged 27 ad 31 years) = 1 (7 yearold = 1 (8 yearold Hamed (2010) Egypt = 1 (20 yearold Brumm et al. (2010) Bui et al. (2010) Jürges et al. Augarte ad Aderka Weidefeld ad Borusiak Nakaya et al. Losada-Del Pozo et al. : Not applicable. Frace Germay Israel Germay Japa Spai = 1 (12 yearold boy) = 1 (74 yearold = 1 (17 yearold = 1 (11 yearold = 9 (boys aged 6 11 years) = 1 (5 yearold = 20 (boys ad girls aged 4 16 years) Type of publicatio Symptom(s) Etiology Symptoms duratio erythropsia ad polyopia Mooucleosis Macropsia Mooucleosis 2 year prospective study Déjà vu, delusioal misidetificatio sydromes, micropsia, macropsia, allesthesia ad halluciatio Micropsia, macropsia ad headaches Metamorphopsia derealizatio ad headaches Abuse of tolueebased solvet Ref. 4 or 6 weeks [21] 2 days [40] 1 year [26] Epilepsy 2 days [17] Reactived mooucleosis Oe case of migraie, oe case of side effect with topiramate 6 moths [41] [28,29] Micropsia ad macropsia Viral other [32] tha Epstei Barr virus Micropsia Migraie 3 weeks [42] Micropsia, teliopsia, associated with abdomial colic ad headaches Teliopsia, micropsia, with phoophobia ad photophobia Migraie variat with abdomial colic [16] Migraie [31] Micropsia Major depressive disorder 45 days [9] Noctural macropsia Adverse drug reactio 3 moths [27] of topiramate sese H1N1 viral 3 days [23] of time slowig dow ad teliopsia diplopic images ad paic or agitatio Two cases with reappearace of symptoms after 1 year Micropsia ad macropsia H1N1 viral 2 moths [22] Retrospective study derealizatio ad acceleratio of the time Nie cases of viral s (five mooucleosis s), eight cases of migraie, oe case of epilepsy, oe case with dextrometropha ad oe case with caabis [43] [8] 284 Neuropsychiatry (2012) 2(4) future sciece group Symptoms & typical disorders associated with Alice i Woderlad sydrome Table 1. Summary of the studies examiig Alice i Woderlad Sydrome betwee 1952 ad 2012 (cot.). Study (year) Coutry Patiets (; populatio) Blom et al. Bialsheikh et al. (2012) Baye et al. (2012) : Not applicable. The Netherlads Frace = 1 (36-yearold woma) = 1 (7 yearold boy) = 1 (37 yearold woma) Type of publicatio Symptom(s) Etiology Symptoms duratio allesthesia, verbal auditory halluciatios, déjà vu experieces, time distorsios ad ituitive feelig of a presece Metamorphopsia ad auditory halluciatio Teliopsia ad macropsia with headaches Schizoaffective disorder Ref. 1 year [13] Lyme disease 3 weeks [24] Migraie [44] had a history of migraie associated with metamorphopsia. EEG data showed a paroxysmal dysrhythmia, especially i the temporal lobes. More recetly, Zwijeburg et al. also reported a case of AIWS i a 9-year-old girl resultig from frotal cortex epilepsy [17]. Over 4 days, the patiet preseted with short attacks cosistig of headaches, axiety ad symptoms of AIWS. Treatmet with propraolol for migraie did ot improve her coditio. Two itericteral EEGs revealed itermittet abormalities (low-voltage spikes ad spikewave complexes) exclusively at the right-frotopolar electrode. The seizures disappeared after treatmet with the aticovulsat, valproic acid. A similar case was later described i which a 14-year-old girl experieced derealizatio, micropsia ad macropsia associated with headaches [8]. EEG recordigs showed posterior slow waves i the left hemisphere ad further ivestigatio idetified a left temporal posterior foci. Both cliical symptoms ad EEG abormalities subsided with aticovulsive medicatio. These fidigs suggest the implicatios of epilepsy i AIWS, however, because of similarities betwee migraie headaches ad epilepsy, a migraie etiology caot be ruled out. Although to date, o other eurological etiologies have bee reported i the literature, some authors have argued that i patiets presetig with halluciatios or metamorphopsia, the presece of a orgaic etiology such as cerebral tumor, cetral ervous, traumatic brai ijury or cerebral aeurisms should be ivestigated [3,17]. Viral etiologies The associatio betwee AIWS ad Epstei Barr was first published by Copperma i 1977 [18]. He described three patiets, oe preadolescet male ad two adolescet females, with classical symptoms of mooucleosis with astheia, elargemet of the lymph odes or splee ad biologic abormalities (icrease i lymphocyte cocetratio ad a positive test for mooucleosis ), followed by perceptual defects cocerig the size, positio ad distace of objects. After examiig a similar case, Saguieti et al. suggested that patiets be tested for prior to psychiatric diagosis [19]. Moreover, Lahat et al. oted that metamorphopsia may appear before the oset or after the resolutio of all mooucleosis symptoms [20], the duratio of the visual illusios raged from 2 weeks to 7 moths. I support of a viral etiology, Losada-Del Pozo et al. recetly foud that five out of 20 cases of AIWS were associated with the Epstei Barr virus [8]. I these viral etiologies, patiets most frequetly experieced micropsia or macropsia. I aother study, Lahat foud that childre with AIWS ad ifectious mooucleosis displayed visual evoked potetials of amplitudes similar to those of migraie patiets, suggestig that mooucleosis ad migraie may share a commo physiopathologic pathway with AIWS [21]. Recet publicatios report additioal cases of AIWS caused by viral, icludig the Coxsackie B1 eterovirus ad H1N1 iflueza virus [7]. Wag et al. reported the case of a 4 year-old boy with itermittet fever, cough, abdomial pai, watery diarrhea ad hepatospleomegaly associated with visual aberratios (perceptio of the wall movig backward ad forward rapidly ad chage of his parets body image i size) [7]. Biologic ad serologic tests future sciece group 285 Motastruc, Schwarz, Schmitt & Bui idetified Coxsackie virus B1 i cerebro spial fluid ad rectal swab cultures. The authors oted that Coxsackie B1 was most ofte asymptomatic, but that eurological symptoms, whe they did occur, more ofte icluded aseptic meigitis, ecephalitis, paralysis, Guillai Barré sydrome, trasverse myelitis, cerebellar ataxia or peripheral euritis tha AIWS did. Recet case reports suggest the possibility of other viral etiologies. Two publicatios have reported cases of AIWS associated with the H1N1 virus i both a 5 ad 11-year-old girl [22,23]. The two girls preseted both metamorphopsia ad iflueza symptoms, which disappeared spotaeously after a few moths. Similarly, Losada-Del Pozo et al. idetified several cases i which cytomegalovirus ad varicella zoster virus were ivolved i separate, similar cases of AIWS [8]. Bacterial may also cause AIWS. Util recetly, Lyme euroborreliosis was kow to iduce headache, emotioal lability ad disturbaces i sleep, cocetratio ad memory, although ot AIWS. I a recet publicatio, Bialsheikh et al. reported a case of Lyme disease presetig with micropsia, macropsia ad auditory halluciatios without headaches, suggestig the presece of AIWS [24]. Psychiatric etiologies Depressive disorders have also bee described i cojuctio with AIWS i two publicatios [9,12]. The first was a case report of a 54-year-old patiet with time ad body-image distortios, metamorphopsia ad a depressive disorder [12]. I the secod publicatio, Bui et al. reported the case of a ma with major depressive disorder who, 10 days after admissio, complaied of body distortios [9]. The patiet achieved remissio of AIWS ad depressive symptoms after five electrocovulsive therapy sessios. Cotard s sydrome, which icludes delusios ragig from the belief that oe has lost orgas to the covictio that oe is dead, is usually associated with severe depressio [25]. It has therefore bee suggested that AIWS i the cotext of depressive disorders may be a variat of this sydrome [9]. More geerally, it could be argued that AIWS occurrig durig a major depressive episode may actually represet psychotic features accompayig the mood disorder. Psychotic symptoms iclude disturbaces of thought, visual perceptio, feelig ad behavior, ad may occur alogside metamorphopsia [17]. Cosequetly, it has bee suggested that schizophreia may be a cause of AIWS [3]. The literature review by the authors of this article foud oly oe case of a patiet with AIWS who was diagosed with schizoaffective disorder [13]. Potetial explaatios for this relative lack of evidece may iclude either the uder-reportig of AIWS symptoms i patiets with psychosis (e.g., because of disorgaized behaviors or thoughts) or the tedecy for psychiatrists to treat AIWS symptoms as symptoms of schizophreia. Although it may be difficult to differetiate AIWS from psychosis, compared with coeesthesias of psychosis, AIWS is usually characterized by itact isight, short-lived symptoms ad a idetified eurological etiology. Toxic & pharmacological etiologies Illicit drugs, such as lysergic acid diethylamide, 3,4-methyleedioxymethamphetamie ( ecstasy ), mescalie ad ihalats may produce halluciatios ad metamorphopsia ad usurprisigly, have also bee reported to iduce pheomea such as AIWS. I a case report of a 15 year-old boy with o medical history who preseted with acute symptoms of derealizatio, micropsia, macropsia ad a sese of accelerated time over the course of 24 h, AIWS was attributed to caabis use [8]. Takaoka et al. reported a case of toluee-based solvet abuse resultig i symptoms of AIWS [26]. After several years of abuse, the 22 year-old woma developed a distorted perceptio of her body, colors ad time. Much like illicit drugs, certai medicatios ca iduce visual halluciatios. To date, two cases of AIWS iduced by the aticovulsat topiramate have bee published [27,28]. Evas ad Rolak described a 31 year-old patiet who developed AIWS 1 week after startig topiramate [29]. After 2 ad a half moths of itermittet AIWS episodes, topiramate was discotiued ad the sydrome resolved gradually withi 1 moth. I the other case report, Jürges et al. preseted the case of a 17-year-old girl with a past history of migraie headaches without aura [27]. The patiet complaied of itermittet, octural distortios of her body image, both macropsia ad micropsia, with a dose above 75 mg/day. Approximately 2 weeks after topirimate was tapered off to 50 mg/day, the octural pheomea ceased. Returig the dose to 75 mg/day agai resulted i metamorphopsia. 286 Neuropsychiatry (2012) 2(4) future sciece group Symptoms & typical disorders associated with Alice i Woderlad sydrome Dextromethorpha, a NMDA atagoist, may also be ivolved i AIWS.
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