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."