A 53-year-old woman presented with a 5-year to 6-year history of personality and behavioral changes (). She initially appeared disengaged with decreased appetite, and was treated for depression with little response. Soon after, the patient began to have daydreams about having relationships with famous actors. She typically reported that she was either friendly with or married to these celebrities, and at least once mentioned having children with George Clooney. She spent significant amounts of time conversing with her imaginary husbands. When asked about her real husband, she replied that in her imaginary world, he had gotten lost while hiking, and so she was free to have these other relationships. However, when pressed on the nature of these relationships, she submitted that they were not real and that she was married to her husband. Regarding her behavior, she stated that “thinking (was) as good as doing.” These fantastic relationships remained present throughout the course of her illness.
Time course of patient’s disease progression.
Approximately 4 years before presenting to the Frontotemporal Dementia Clinic at the University of California, Los Angeles, the patient became even more withdrawn from social interactions and activities. She demonstrated decreased motivation to perform daily household tasks, where previously she had been quite meticulous (eg, vacuuming the house every day). One year before presentation, she began to have more difficulty performing instrumental activities of daily living and experienced a decline in self-care. In particular, she began to struggle with simple tasks such as turning on the shower or putting a key in the car ignition. She began to make inappropriate comments or ask silly questions to strangers, and her behavior was puerile. She was more impulsive and she developed an increasing appetite for sweets. She exhibited compulsive and repetitive behaviors: counting, avoiding stepping on cracks on sidewalks, picking at her fingers, pinching her lip, rubbing her right knee or right face, and swaying back and forth when standing. Around the time of initial presentation, the patient’s eldest daughter, who was brain damaged from a near-drowning accident at the age of 5 years, had recently been placed into a nursing home. Though our patient had been her daughter’s primary caregiver, she seemed oblivious to this event.
On initial examination, the patient exhibited a fixed smile and frequent staring. She scored a 30/30 on the Mini-Mental State Examination. Further neurobehavioral assessment showed decreased reverse digit span, decreased phonemic and categorical verbal fluency, poor verbal recall but intact verbal recognition memory, intact visuoconstructional ability, and decreased performance on go-no-go, antisaccade, and judgment testing.
Magnetic resonance imaging revealed global cerebral atrophy, which was particularly pronounced in the frontal lobes. Single photon emission computed tomography imaging revealed hypoperfusion that was most prominent in the right anterior prefrontal, lateral, and orbitofrontal lobes, the right anterior portion of the interhemispheric fissure, the right anterior temporal lobe, and the anterior portion of the cingulate gyrus. Hypoperfusion was present to a lesser degree in the left cerebral hemisphere (). Taken together, her clinical presentation and neuroimaging findings were consistent with a diagnosis of bvFTD.
FIGURE 2 A, Axial SPECT scan showing frontal and temporal hypoperfusion, right greater than left. B, Brain at autopsy showing marked atrophy of the frontal and anterior temporal lobes. C, Coronal section showing temporal lobe atrophy with relative sparing of bilateral (more ...)
One year after initial presentation, she began to exhibit increasingly inappropriate behaviors. In particular, she would confront young strangers and ask them about their sexual orientation, or she would directly ask smokers why they did not quit smoking. Her imaginary world became more involved, and she started imagining sexual acts with movie stars. She told her family that she was thinking about becoming gay. Despite being treated with sertraline, her repetitive acts, such as counting, disrupted her daily routine. She was started on a low dose of quetiapine and became somewhat less impulsive and compulsive.
The patient’s fantastic thinking continued to focus on celebrities. Two years after presentation, she reported active fantasies about Kevin Costner, and made comments about this relationship in public. She was still engaging in repetitive acts, and was becoming more environmentally dependent and distractible. By 2.5 years after presentation, she was very compliant and displayed fewer behavioral problems although she continued to make inappropriate comments regarding the sexual orientation of women strangers she saw in public. She developed bruxism. Three years after initial presentation, the patient began to make obscene gestures to passersby when riding in the car and started to refuse liquids. She still had vivid fantasies, claiming that she was married to George Clooney and had had 2 children with him.
Soon after, the patient began to deteriorate. She developed postural myoclonus and was started on clonazepam. Almost 4 years after initial presentation, she had 2 seizures, and was started on levetiracetam. Her disinhibited behaviors decreased and she was increasingly less responsive to questions. She developed a visual grasp, increased neck tone, and poor balance. Soon after, the patient became mute and refused to open her mouth for food or liquids. She followed commands intermittently and displayed motor impersistence. Her myoclonus had increased, and she had become increasingly rigid, especially in the axial plane. She could still walk, though with a list and very poor balance. The patient died 6 months later, 11 years from the onset of her illness.
Autopsy revealed the presence of Pick disease. On gross examination, the 1040 g (unfixed weight) brain demonstrated diffuse cerebral cortical atrophy in the frontal and temporal lobes, with a slight left hemisphere predominance and relative sparing of the parietal and occipital cortices (). Microscopic examination included routine hematoxylin and eosin staining and immunohistochemistry incorporating primary antibodies to β-amyloid 1 to 40 and 1 to 42, τ, and α-synuclein. There was severe neuronal loss, gliosis, and spongiosis of the deep cortical layers of the bilateral frontal and temporal lobes, which was more pronounced on the right (). There was also moderate neuronal loss and gliosis of the striatum and substantia nigra. Cortical tissue from the parietal and occipital lobes was relatively less affected. Immunostaining revealed abundant τ-positive Pick bodies within the remaining neurons in the frontal and temporal cortices, and the pyramidal and granule neurons within the hippocampus. Rare Pick bodies were also seen in the parietal and occipital cortex and striatum ().
FIGURE 3 Histologic sections. A, H&E staining. A1, Frontal cortex demonstrating spongiosis of the deep cortical layers (40 ×). A2, Highlights marked gliosis, neuron loss and Pick bodies (arrow) (400 ×). A3, Details of Pick bodies (arrows) (more ...)