Clinical Reasoning: A 65-Year-Old Woman With Tremor

Section 1

A 65-year-old woman was referred to our hospital for the evaluation of tremor, which had initially appeared in her right upper limb 3 years previously and progressed to her left upper limb and head 2 years previously. The tremor was most prominent during movement, but also occurred during rest. The patient felt unsteady when walking, although she denied falling and slowness of movement and symptoms of dysautonomia (e.g., positional lightheadedness, urinary dysfunction). She reported that her short-term memory had worsened and that the tremor intruded on her activities of daily living. The patient reported no medical history or previous trauma, hypoxic insult, or neurotoxic exposure, and no drug or alcohol use. There was no family history of tremor.

Neurologic examination revealed distal asymmetric medium-amplitude tremors in both upper limbs (more pronounced on the right) at rest and with movement (postural and kinetic). The head tremor manifested as the “yes-yes” type. The tremors were more prominent with movement and had an intention component and low frequency. They were exacerbated with cognitive activity. The patient had no proximal wing-beating tremor or dystonic posturing in the hands or neck. Bradykinesia and rigidity were absent. Her gait was slightly unsteady, but not ataxic. Finger-to-nose testing revealed subtle dysmetria in the right arm. All other findings of neurologic examination, including the assessment of rapid alternating movements, muscle tone, and reflexes, were normal. The patient's Mini-Mental State Examination score was 28 and her Montreal Cognitive Assessment score was 20, which were expected given that she had 6 years of schooling.

Section 2

Tremor phenomenology aids the establishment of a diagnosis. Key aspects of tremor include its location and anatomic distribution, axis, frequency, amplitude, positionality, and setting (i.e., occurring at rest or with movement, with posture). In the present case, the patient presented with chronic progressive tremors occurring at rest and with movement, but more prominent with movement and having an intention component. She also had cognitive and balance complaints. The differential diagnosis is limited, including essential tremor plus, other tremor types (e.g., dystonic and Holmes), tremor secondary to medication use or underlying medical condition (i.e., Wilson disease), tremor caused by a structural lesion (i.e., tumor, multiple sclerosis lesion, cerebral infarction in the midbrain or thalamus), and psychogenic tremor.

The initial workup included blood cell counts; assessment of liver, kidney, and thyroid function; measurement of electrolytes, glucose, ammonia, and serum ceruloplasmin; CSF analysis; EMG; and cranial MRI. All findings were normal, except that the T2-weighted fluid-attenuated inversion recovery (FLAIR) MRI sequence showed hyperintensity in the bilateral middle cerebellar peduncles (MCPs) and periventricular white matter (Figure, A).

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Figure Radiologic Imaging and Skin Biopsy Findings

Brain MRI showed hyperintensity in the bilateral middle cerebellar peduncles on fluid-attenuated inversion recovery sequences (A, asterisks) and hyperintensity in the corticomedullary junction and corpus callosum on diffusion-weighted sequences (B, arrows). (C) Skin biopsy revealed intranuclear inclusions in the sweat gland cells (arrow).

Section 3

According to the clinical presentation of tremor and radiologic features (bilateral MCP signs), fragile X-associated tremor/ataxia syndrome (FXTAS) was initially suspected. However, the patient was female and had no family history, which is not characteristic for FXTAS. Additionally, genetic testing for FMR1 was negative. Other potential entities with bilateral MCP signs were excluded; the key points are summarized in the table.

To better characterize these abnormalities, magnetic resonance angiography (MRA), diffusion-weighted imaging (DWI), apparent diffusion coefficient (ADC) mapping, and contrast-enhanced T1-weighted imaging (T1WI) were performed. Brain MRA and contrast-enhanced T1WI findings were unremarkable. DWI showed hyperintensity and ADC mapping showed isointensity in the bilateral MCPs. In addition, DWI and ADC mapping showed hyperintensity in the corticomedullary junction and corpus callosum (Figure, B).

Section 4

Although hyperintensity in the corticomedullary junction on DWI is occasionally observed in patients with FXTAS, oculopharyngeal myopathy with leukoencephalopathy, and cystathionine β-synthase deficiency,^1,2 it is also an important clue in the diagnosis of adult-onset neuronal intranuclear inclusion disease (NIID).³ To confirm this diagnosis, skin biopsy was performed; electron microscopic analysis revealed intranuclear inclusions in the sweat gland cells (Figure, C). Ultimately, adult-onset NIID was diagnosed. Further genetic testing for NOTCH2NLC was negative. As NIID has no known cure, the patient was started on symptomatic treatment (levodopa/benserazide, 125 mg 3 times a day), but she did not respond. Thus, the treatment was changed to propranolol (10 mg orally 3 times a day), and the patient's tremor symptoms improved.