Possible Association Between Alice In Wonderland Syndrome And Influenza A Infection

The patient was diagnosed with influenza A because of flu-like symptoms, with fever and a positive result for influenza diagnostic test by immunofluorescence assay (IFA). She improved after treatment with oseltamivir (120 mg/day) for 5 days. About 1 week later, she complained of recurrent abnormal visual phenomena, including perceptions of walls or window blinds moving rapidly up and down, changes in the sizes, shapes, and distances of objects, and of worms moving under her blanket. The frequency of these episodes, which lasted for 10–20 minutes, increased within 1 month, from once every 2–3 days to 2–3 times per day. She felt so frightened that she required the presence of her family to go to sleep, especially at nighttime. She was then referred to our psychiatric outpatient department and consulted a pediatric neurologist. The results of a neurological examination were normal. She had no previous history of trauma, drug ingestion, migraine, epilepsy, or other central nervous system or psychiatric disorders. The results of psychological testing showed a high-to-average intelligence quotient (full IQ: 116; verbal IQ: 112, performance IQ: 119) and intact cognitive functioning. The results of an electroencephalogram, cranial magnetic resonance imaging, and biochemical tests were unremarkable. Serological studies demonstrated an Epstein–Barr virus (EBV) immunoglobulin M (IgM) titer of 1:10 (negative) and an EBV IgG titer of 1:160 (positive), which failed to support acute EBV infection.³ The patient and her parents were reassured after we explained the unique but usual nature of the syndrome. The frequency and duration of her AIWS episodes diminished gradually, and she had recovered completely by the first 2-month follow-up and did not experience recurrence during the subsequent year.

The causes of AIWS include epilepsy, migraine, adverse drug reaction or intoxication,^1,2 and infectious mononucleosis.⁴ An association with viral infections, most commonly EBV infection,^5,6 and, infrequently Coxsackie virus, or chickenpox,⁷ has also been reported. In our patient’s case, the negative results of viral serological tests, neuroimaging, and neurophysiological assessments excluded acute EBV infection or other etiologies. Therefore, the neuropsychiatric manifestations of influenza A viral infection and the adverse neuropsychiatric effects of oseltamivir were considered relevant to our patient.

Neuropsychiatric symptoms during influenza infection have been reported during epidemics and are often associated with serious sequelae or death. A rising incidence of influenza-related encephalitis/encephalopathy in Japan, predominantly in children, has been described.⁸ Various other clinical central nervous system manifestations, such as Reye’s syndrome, acute necrotizing encephalopathy, myelitis, and Guillain–Barré syndrome, may occur during the course of influenza infections.⁸ We are unaware of any other reports of an association between AIWS and influenza infection. Although adverse neuropsychiatric events were reported by the U.S. Food and Drug Administration in 103 children taking oseltamivir, including delirium, behavioral disorders, hallucinations, convulsions, and confusion, none was related to AIWS. However, several retrospective studies found no evidence that oseltamivir treatment for influenza increased the risk of adverse neuropsychiatric outcomes,^9,10 suggesting that these neuropsychiatric events might actually have been the result of the viral illness.

To the best of our knowledge, this is the first case report of an association between AIWS and influenza A infection. The clinical course of this patient suggests a benign or self-limited outcome. Other reports have described patients^1,2,4,7 with similar complete recoveries after several weeks-to-months, with no neurological sequelae. Therefore, reassurance and health education can lessen the anxiety and fear of the patient and his/her family. Although areas of reduced cerebral perfusion near the visual tract and visual cortex,^5,6 and high amplitudes of P100-N145 in the visual evoked potential⁴ have been reported in children with AIWS, the underlying pathogenesis is still unclear. More detailed clinical observations are required to assess whether either influenza A infection or the use of oseltamivir or both are precipitating factors in AIWS.