Conjoint FTLD‐FUS of the neuronal intermediate filament inclusion disease type, progressive supranuclear palsy and Alzheimer's pathology presenting as parkinsonism with early falls and late hallucinations, psychosis and dementia

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Progressive supranuclear palsy (PSP) is a low‐prevalence atypical parkinsonism with underlying 4R tauopathy and a growing number of clinical phenotypes, making its differential diagnosis from other conditions such as Parkinson's disease (PD) and corticobasal degeneration particularly challenging 1. Neuronal intermediate filament inclusion disease (NIFID), a sporadic alpha‐internexin and fused in sarcoma (FUS) proteinopathy, is an even rarer condition with few cases published worldwide. It is most often diagnosed at autopsy, again due to a remarkable clinical heterogeneity ranging from young‐onset frontotemporal dementia to PSP look‐alike parkinsonism, among other phenotypes 3. Here, we report a new NIFID case, which, besides adding to the few previous reports, is unique as it constitutes the first description of its co‐occurrence with PSP pathology.
A 76‐year‐old man was referred to our clinic due to a 4‐year history of left upper limb tremor, both during action (feeding, carrying a bag) and at rest, to which loss of balance and falling backwards were added 2 years before referral. His previous personal history was remarkable for poorly controlled diabetes mellitus, obesity, a myocardial infarction in 1998 (at age 67), lumbosacral radiculopathy and sleep apnoea syndrome treated with continuous positive airway pressure. Abnormal behaviours during sleep, constipation and erectile dysfunction were other complaints that had been attributed to his comorbidities (sleep apnoea and diabetes mellitus). His sense of smell had always been poor. Family history was negative for known neurodegenerative or psychiatric diseases.
Upon the first neurological examination bilateral bradykinesia and left upper limb postural and rest tremor were noted, along with reduced blinking, albeit without clear‐cut supranuclear gaze abnormalities. Falling backwards on pull test was also observed. PSP was suspected. A brain MRI showed a hint of flattening of the mid‐brain tectum (Figure 1A) as well as scattered lacunar lesions in the subcortical white matter sparing the basal ganglia (Figure 1B). Dopamine‐transporter imaging showed presynaptic nigrostriatal denervation mostly in the right putamen (Figure 1C).
In the ensuing 2 years, introduction of levodopa up to 300 mg t.i.d. did not result in any clinical improvement. Three years after first assessment the patient was experiencing daily falls, with persistence of the rest and postural tremor of his left hand, frequent vocalizations, dysphagia (coughing and occasional choking with liquids) and dysarthria, without aphasic traits, along with broken saccades upwards and a need to bend the neck in order to look downwards (but with normal pursuit), as well as reflex blepharospasm. Thus, the clinical suspicion was that of parkinsonian variant of PSP, after the onset with asymmetrical rest tremor, the hint of supranuclear oculomotor involvement and the early falls. By then, the patient had purchased a motorized wheel chair, but shortly afterwards his relatives had to persuade him to use a conventional one, after he had almost driven over a couple of pedestrians, due to a euphoric state while driving. In this setting, the patient began to experience delusional jealousy (he was convinced that his wife was having affairs behind his back, to the point that he followed her several times while he was still able to get around, resulting once in a fall with a head injury, which needed a few stitches), well‐formed visual hallucinations (a football player in his bedroom), sexual disinhibition and fluctuating alertness. Systemic explanations such as infections were ruled out and a brain CT also excluded chronic subdural haematoma. Levodopa was withdrawn and quetiapine started, with good control of psychotic symptoms, but worsening of motor symptoms. Psychiatric stabilization allowed for the reintroduction of low‐dose levodopa, which was followed by conspicuous motor improvement, with the patient even managing to resume assisted walking over short distances.

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