Adverse motor effects of progressive supranuclear palsy with frontal lobe signs: A case report

Abstract

Dear Editor, Progressive supranuclear palsy (PSP) is an atypical parkinsonian syndrome, characterized by supranuclear gaze palsy, frequent falls and dementia. Although postural instability and oculomotor dysfunction are the hallmark features of PSP, approximately 20% of patients present with cognitive dysfunction and behavioral changes within the first 2 years. Initial atypical presentations can sometimes lead to misdiagnosis, resulting in prescription of inappropriate medication, which could have adverse effects and impair the activities of daily living (ADL). A 63-year-old woman presented with impaired memory and disorientation. Her husband noticed increasing apathy and stereotypical behaviors 10 months before the first presentation to Tohoku University Hospital, Sendai, Japan. She had trouble carrying out housekeeping tasks and communicating with her friends, she would eat the same meal repeatedly and visit a health club at the same time every day. On initial examination, the Mini-Mental State Examination score was 27 points for the serial sevens, and 24 points on backward spelling items. The Frontal Assessment Battery score was 12 points, and the Neuropsychiatric Inventory Questionnaire score was 2 points, suggestive of declining frontal lobe function and fewer psychological symptoms. Neurological examination showed no significant abnormalities, such as muscle tonus, eye movement, tendon reflexes or postural reflexes, with the exception of slowed verbal responses. Mild atrophy was observed in the hippocampus and frontal lobe on brain magnetic resonance imaging. Iofetamine I-123 single-photon emission computed tomography showed significantly decreased blood flow to the frontal and parietal lobes, posterior cingulate cortex, and precuneus (Fig. 1a). The frontal variant of Alzheimer’s disease was suspected, and the patient was prescribed donepezil. After the first presentation, the patient showed a significant reduction in the ability to carry out ADL, and experienced repeated unprovoked falls and aspontaneity. Neurological examination carried out 9 months after the first presentation showed vertical supranuclear gaze palsy, gait freezing and akinetic–rigid syndrome. There were no signs of apraxia or myoclonus. No amyloid pathology (amyloid β [1–42]: 1124 pg./mL) or tau burden (ttau: 717 pg/mL, p-tau: 67.8 pg/mL) were found on cerebrospinal fluid testing. Magnetic resonance imaging showed atrophy predominantly in the midbrain (Fig. 1b). Dopamine transporter imaging using single-photon emission computed tomography with an I-123 ioflupane tracer showed striatal dopaminergic degeneration (Fig. 1c). Thus, the patient had all the core features and imaging findings of PSP with Richardson syndrome. We stopped donepezil and started treatment with levodopa after the diagnosis of PSP. Although the patient could barely walk without intense support earlier, she was able to walk with slight assistance after the change in medication. Subsequently, we carefully decreased the dose of levodopa. Although she continued to show severe frontal lobe dysfunction, her motor function has remained stable during the follow-up period. An earlier study showed that donepezil adversely affected mobility and the ability to carry out ADL because of the cholinergic effects on the frontosubcortical motor and cognitive circuits in patients with PSP. We were unable to accurately determine the intensity of the adverse effects in the present patient, because we changed her medication simultaneously. However, tapering the dose of levodopa did not affect the motor function significantly. Therefore, the adverse effect of cholinergic agents seemed to uncover the impairment in the motor circuits. During the initial presentation, the patient was probably in the prodromal stage and showed no motor dysfunction, except for the frontal lobe signs, and failed to fulfill the diagnostic criteria. Although stereotypy is widely recognized as a symptom of frontotemporal dementia, studies have shown that it can also be caused by PSP, frontal dysfunction and hypoperfusion. They are the sequela of deafferentation, and can appear even when the pathological changes are limited. Retrospective voxel-based morphometry analysis showed predominant midbrain atrophy, especially in the cerebral peduncle, which is an indicator of PSP (Fig. 1d). After 9 months, she was diagnosed with PSP with Richardson syndrome, due to vertical supranuclear gaze palsy and repeated unprovoked falls, based on the Movement Disorder Society criteria. As the initial presentation and predominant type can be variable, PSP is frequently misdiagnosed. Just 26.2% of autopsy-confirmed PSP cases were properly diagnosed at the first presentation, and it takes an average of 4.9 years to diagnose PSP. We diagnosed this rare type of PSP with Richardson syndrome that started with stereotypical behavior. As the motor side-effects of the cholinergic agent rendered the vulnerability of the frontosubcortical circuits prominent, a review of the diagnosis with neuroimaging enabled a relatively early diagnosis of PSP. The ready administration of cholinergic drugs to patients with dementia can cause severe deterioration in their motor functions and ADL if these drugs are not appropriate for their specific underlying pathology. Therefore, meticulous diagnosis and follow up are mandatory for dementia care in an aging society.