A case of recurrent depressive disorder presenting with Alice in Wonderland syndrome: psychopathology and pre- and post-treatment FDG-PET findings

Alice in Wonderland syndrome (AIWS) is a rare neuropsychiatric syndrome, which Todd [1] named after the character created by Lewis Carroll. Collective manifestations of AIWS include distortion of extrapersonal visual image (micropsia, macropsia, metamorphopsia, teleopsia, and pelopsia), altered perception of one’s body image, and a disturbed sense of the passage of distance and time [2].

Many conditions have been reported to contribute to AIWS, and Lanska et al. [2] indicates that viral infection and migraine are the two most commonly identified causes, occurring preferentially in young individuals. To the best of our knowledge, only two reports to date have associated AIWS with a depressive disorder [3, 4], neither of which clearly showed the concurrent nature of major depressive episodes and AIWS.

Evidence from a number of studies using fluorodeoxyglucose positron emission tomography (FDG-PET) indicates that specific cortical regions, primarily in the frontal cortex, are related to mood disorders. However, the results from imaging studies have not yielded a clear story, and many conflict with each other [5‐7]. One of the more consistent findings with regard to depression, is that hypometabolism in the frontal cortex is characteristic in patients with depressive episodes, and can be partially reversed by successful treatment. In contrast, the biological basis of AIWS is even less clear, although a few studies have made attempts studying it using functional brain imaging [8‐11].

Here, we present a case of an older patient whose recurrent depressive episodes and AIWS emerged and remitted simultaneously with successful treatment with antidepressants, antipsychotics, and electroconvulsive therapy (ECT). This is the first report showing the concurrent and recurrent nature of, depressive episodes and AIWS, and the strong association between the two. The clinical manifestations and pre- and post-treatment FDG-PET images provide insights into the psychopathological and biological basis of AIWS.

Here, we report the case of a 63-year-old Japanese man with no medical or psychiatric history, except for type-2 diabetes mellitus and essential hypertension. He had no previous history of psychotropic drug use, including antidepressants and antipsychotics. Additionally, he had no developmental abnormalities or neurodevelopmental disorders. He held a steady job from college graduation until retirement age, and his wife described his premorbid personality as dependable, sociable, and patient. He had no family history of psychiatric disorders, migraine, or epilepsy.

One year before his first admission to an inpatient psychiatric unit, he started experiencing mild depressive moods and fatigue that did not disrupt his day-to-day functioning. Two months before the first hospital admission, he began complaining about typical AIWS symptoms, including micropsia, altered perception of his body image, and a disturbed sense of the passage of distance and time. All sorts of objects in his environment, such as buildings and cars, looked extremely small to him. He gave up driving because cars looked so small that he lost his sense of speed and distance in relation to the cars around him. Nearby objects also looked very small, with the single exception of pill strips that he had difficulty opening. Moreover, even though he knew it was not possible, he felt as if he could ‘step over’ long distances in a flash, such as the 50 km from his suburban town to the center of Tokyo. Additionally, he felt that days passed extremely quickly, as if in a single moment. He also sometimes felt his body was slightly enlarged or shrunken compared with normal. These AIWS symptoms persisted all day long during the depressive episodes.

In addition to the typical AIWS symptoms described above, he also complained of disturbances in high-order cognition. For instance, he said, “I cannot sense how important the news is. For example, when I see news about a serial murder on television, I can understand intellectually how sad it is, but I cannot realize it emotionally”. Similarly, he said, “I cannot appreciate the value of money. Even if there were a ¥10,000 bill in front of me, I wouldn’t care about it because I can’t realize how much value it would have”. Although his bowel movements and urination were normal, he complained of a decreased urge to defecate and urinate.

The depressed mood, loss of interest and pleasure, psychomotor retardation, fatigue, and reduced concentration gradually worsened. He was referred to a neurologist. Organic causes were ruled out as follows: his blood-sugar level and blood pressure were well controlled with insulin injections and oral medications; he was a non-drinker, had no history of head trauma, and took no medications associated with adverse reactions that could mimic depression, such as beta-blockers and cimetidine. Neurological examinations and laboratory tests including endocrine evaluations and an HIV test, electroencephalography, and brain magnetic resonance imaging (MRI) detected no abnormalities. He was then referred to a psychiatrist. After confirming that he was not experiencing a manic episode, was not using illicit drugs, and had not experienced any recent stressful life events, he was diagnosed as having a severe depressive episode with AIWS. His condition worsened to the degree that he could not continue working despite taking paroxetine, and he was hospitalized for the first time.

At this first admission, he was bed-ridden all day because of severe depressive symptoms. Administration of amitriptyline (75 mg/day) and perphenazine (6 mg/day) induced gradual improvement of depressive and AIWS symptoms. He was discharged on day 47 after he had remitted almost completely from the depressive episode, with the exception of easily becoming fatigued and waking at night. At that time, he was also completely remitted from AIWS. His day-to-day functioning returned to normal, and his work and life continued as they had before the episode began.

Three years after discharge, he relapsed into another major depressive episode, again simultaneously presenting with AIWS. The symptoms worsened despite the use of amitriptyline (50 mg/day) and aripiprazole (6 mg/day) in the outpatient clinic. The Visual Perception Test for Agnosia detected nothing abnormal. His thoughts became stunted and he became very inactive, lying in bed all day. He continuously refused inpatient treatment because he delusionally believed he was too poor. Upon the strong recommendation from his family, 8 months after this recurrence, he was admitted to the hospital with recurrent severe depressive symptoms and AIWS at the age of 67 years.

At this second admission, he was alert and oriented, but had prolonged speech latency and spoke in a slow and quiet manner without making eye contact. His face was unshaven and he did not smile. Dementia was ruled out as a plausible cause of his symptoms for the following reasons: 1) his Mini-Mental State Examination (MMSE) score was 28/30 during this depressive episode, 2) he made a complete recovery from the observed reduction in concentration and processing speed after treatment of the first episode, 3) he exhibited no other signs of recognizable cognitive decline such as impaired executive function, learning, memory, language, or social recognition, and 4) he did not exhibit any typical symptoms of common dementia subtypes, such as amnesia, fluctuating cognition, visual hallucinations, extrapyramidal symptoms, or behavioral symptoms. Evidence of depressive symptoms and AIWS was comparable between the first and second episodes. He scored 30/63 on the Beck Depression Inventory-II (BDI-II), indicating severe depression. An ophthalmologist confirmed no eye/visual abnormalities with the exception of bilateral cataracts. Pre-therapy FDG-PET was performed as described below. After 2 weeks of maprotiline (75 mg/day) had no effect, twice-weekly ECT, duloxetine (60 mg/day) and mirtazapine (45 mg/day) were administered. He remitted completely from AIWS and almost completely from the depressive episode after 12 ECT sessions, except for a mild reduction in concentration. He scored 12/63 on the BDI-II, which also indicated significant recovery from depression. He was discharged after 75 days, just after post-therapeutic FDG-PET was performed.

We present the first case demonstrating a clear relationship between recurrent depressive disorder and AIWS. The co-occurrence and similarities in clinical manifestations between AIWS and psychotic depression imply a common psychopathological basis. The metabolic abnormalities seen in high-order brain regions on FDG-PET images suggest a biological basis of AIWS and psychotic symptoms of depression. Careful analysis of psychiatric symptoms comparing with metabolic changes using FDG-PET provides new insights into higher-order involvements, not only primary visual perception, in AIWS and psychotic depression.