Alice in Wonderland Syndrome: What Can It Reveal?

Roxana Tabakman

November 11, 2019

Alice in Wonderland Syndrome (AIWS) is a paroxysmal, hallucinatory disorder with typical visual perceptual features. With fewer than 200 reported cases in the world, the syndrome is named after Lewis Carroll's famous book because, like Alice, patients with AIWS experience changes in the perception of their body dimensions, experiencing macro or microsomatognosia — the feeling of being bigger or smaller in relation to their environment.

The change is transient, lasting from a few minutes to more than a day. Its precise pathophysiology and anatomical correlation have not yet been established. However, recent reports suggest that the syndrome may be related to stroke and Zika.

Elderly Woman Worried About Her Son

At the end of last year, in Santos, São Paulo, Brazil, an 80-year-old woman, worriedly asked her son what was happening to his arm. She said she saw his arm grow progressively, and his hand got smaller. The woman was admitted to the hospital shortly after this episode, which had already passed, but assured doctors that she had seen her son's arm "getting increasingly bigger".

The medical history revealed homonymous hemianopia after aura, moderate holocranial (bifrontal) pain, and light sensitivity.

"The patient was 80-years-old and had a history of migraines. In the care setting, they could have thought simply that the AIWS was due to migraine, which is the usual cause, but in this case, it was not. Depending on the age range, the auras are a red flag," said Dr Yara Dadalti Fragoso, neurologist, and professor at the Faculdade de Medicina da Universidade Metropolitana de Santos (Unimes), and co-author of the case report published in September in the journal Arquivos de Neuro-Psiquiatria .

Among the reports published to date, the most common cause of AIWS was migraine (27.1%), followed by infection (22.9%) - mainly Epstein-Barr virus (15.7%). In decreasing order, the other aetiologies were: brain lesions (7.8%), medical drugs (6%), recreational drugs (6%), psychiatric disorders (3.6%), epilepsy (3%), peripheral nervous system disease (1.2%), and others (3%). In approximately 20% of patients, no cause was found.

In the case of the Santos patient, a few hours after the episode, magnetic resonance imaging (MRI) revealed a right occipital lobe haemorrhage. Further investigation confirmed the diagnosis of amyloid angiopathy. With complete remission of the bleeding, the patient no longer had visual hallucinations.

Few case reports with images describe stroke in AIWS.

Dr Fragoso said: "We cannot find a brain area responsible for the syndrome. In some cases, it is the right side, in others the left, in some the occipital area, in others the parietal. But we must consider that they only appear when the cause is a tumour or vascular; when the cause of AIWS is migraine, no injury occurs. That's why we wrote the paper."

In practical terms, Dr Fragoso stressed the importance of alerting practitioners, especially primary care physicians, to the need not to consider these symptoms merely as a hallucinatory psychiatric illness. She added: "If it is sudden in adulthood, one should think of vascular or tumoral causes. When AIWS is due to migraine, adults usually have had episodes as a child or adolescent. It is unusual for the first time to happen in adults."

"What makes this case interesting is that MRI shows a vascular change, ischaemic lack of oxygenation, which is a very rare cause," evaluated Dr Marcus Vinicius Magno Gonçalves, adjunct professor of neurology at the Universidade da Região de Joinville (Univille), who did not take part in the research.

"AIWS was initially described by a psychiatrist, and often the doctor may think that (s)he is facing a psychiatric case and that there is no need to investigate other causes further," the professor said.

Is it Related to Zika?

"The patient came to the clinic stating that 'she felt bewitched'", Venezuelan physician Dr Alberto Paniz Mondolfi told Medscape. She was a 15-year-old girl saying that she had "an enormous head and hands compared to the trunk, and complaining that she couldn't even drink water because she saw the glass either too close or too far from her mouth.

"Visual hallucinations were not restricted to the patient's body, they extended to family members and those around them. The teenager also presented with telopsia, when objects appear to be more distant than they actually are. She suffered numerous episodes throughout the day, and asymptomatic moments generated anxiety attacks," said the doctor.

With this combination of symptoms, the patient from the city of Barquisimeto, Venezuela, contacted the Department of Infectious Diseases and Tropical Medicine at the Barquisimeto Diagnostic Institute (BDI) where Dr Mondolfi works, because the visual hallucinations began 10 days after the young woman had symptoms corresponding to an acute Zika virus infection: fever of 39ºC (102.2°F), rash, distal arthralgia of the small joints, and dry conjunctivitis. After 3 days with symptoms and signs of Zika infection, the patient remained asymptomatic for 7 days, and only then developed the AIWS symptoms.

According to the literature, 65% of AIWS cases occur in children under 18 years. Among adults, it is more common that the syndrome is caused by migraine, while in children, the most common cause is an infection. AIWS has already been linked to several infections, including H1N1 influenza.

"In this case, we studied extensively all viruses that can manifest in the central nervous system (CNS). The results were negative for Epstein-Barr virus, herpes, varicella-zoster virus, enteroviruses, parasites, and all arboviruses, except Zika. The serologic test was positive, as well as the molecular confirmation in urine," replied Dr Mondolfi, who is also an assistant professor of microbiology at Icahn School of Medicine at Mount Sinai, in the United States.

As reported in the  Journal of NeuroVirology , this patient had neither relevant past medical history, nor history of migraine, epilepsy, neurological disorders, use of medication or recreational drugs. During the periods of symptom remission, neurological, neuro-ophthalmic, electroencephalogram (EEG), computed tomography (CT), toxicological, and metabolic profile panel tests were performed.

"Everything was normal. This is the first case of Zika virus-associated metamorphopsia. It is a clinical manifestation of the Zika virus that had not been described before," said Dr Mondolfi.

Fearing it was an undetected herpes virus infection, doctors prescribed aciclovir for the patient. And, even without evidence in this regard, but fearing that the adolescent might develop Guillain-Barré Syndrome, she also received intravenous immunoglobulin.

"Zika is a neurotropic virus, but the patient had already passed the acute period, and there was no evidence of further inflammation. As she was a teenager, I remembered a very rare disease, N-methyl-D-aspartate anti-receptor (NMDA) encephalitis, which is more common in women and has a combination of neurological symptoms caused by a benign ovarian tumour. But the antibody panel also turned out negative. That left us with no possibilities," said Dr Mondolfi. "The only thing left to think was that it could share the substrate with the NMDA encephalitis and that we were facing a case of molecular mimicry."

The team hypothesised that the Zika virus caused an injury, exposing the antigens, and that the antibodies, by molecular mimicry, joined the neurons of the somatosensory areas.

"We were the first to suggest the hypothesis of molecular mimicry," said Dr Mondolfi.

It was then that the team decided to treat the event as an NMDA anti-receptor encephalitis. "What we do in these cases is give steroids or filter the blood by plasmapheresis," he explained.

"The patient was treated with steroids and in the first week had a partial response, with a reduction in the number of episodes. This gave impetus to the idea of a possible explanation of autoantibodies and molecular mimicry. So, we decided to do plasmapheresis. In the second week, the patient had a complete recovery."

Dr Mondolfi acknowledges that he has no way of knowing what would have happened had he not given this treatment, "but anti-NMDA encephalitis rarely resolves spontaneously".

More Hidden Alices?

Dr Fragoso believes that the Alice in Wonderland syndrome may be much more frequent than imagined.

People may not mention these occurrences to their doctors, she said, "because they think it is spiritual". She continued: "So, when the results of the tests show nothing unusual, they leave the clinic without any explanation."

She tells how she experienced episodes herself, as a child: "My hand grew and grew, and I looked at people, but no one found it strange. So, I'd put them in my pocket so no one could see, but I thought that my hand did not fit inside," she said.

The important thing here, argues Dr Fragoso, is for doctors to be alert: "When a patient with such a complaint turns up, think that it may be a case of Alice in Wonderland Syndrome. So you need to be very thorough in history taking and evaluation, so that the patient knows (s)he can talk to the doctor, that (s)he will be given due attention."

Dr Yara Dadalti Fragoso, and Dr Alberto Paniz Mondolfi reported no relevant conflicts of interest.

Translated and adapted from Medscape's Portuguese Edition .

Fonte Brooks, Joseph Bruno Bidin, Prosdocimi, Fabio César, Rosa, Pedro Banho da, & Fragoso, Yara Dadalti. (2019). Alice in Wonderland syndrome: “Who in the world am I?”. Arquivos de Neuro-Psiquiatria, 77(9), 672-674. Epub September 23, 2019.

Mastria G, Mancini V, Viganò A, Di Piero V. Alice in Wonderland Syndrome: A Clinical and Pathophysiological Review. Biomed Res Int. 2016;2016:8243145. doi:10.1155/2016/8243145

Paniz-Mondolfi AE, Giraldo J, Rodríguez-Morales AJ, Pacheco O, Lombó-Lucero GY, Plaza JD, et al. Alice in Wonderland syndrome: a novel neurological presentation of Zika virus infection. J Neurovirol. 2018 Oct;24(5):660-3.


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