Benign tremulous parkinsonism: A clinicopathological study

Resting tremor (RT), bradykinesia, and rigidity are three main features of Parkinson’s disease (PD). Conventionally, combination of two of these three is used for clinical diagnosis of PD. PD patients with predominant bradykinesia and rigidity are known as akinetic-rigid (A/R), and those with predominant tremor are classified as tremor dominant (TD). Although RT is characteristic of PD and action (postural or kinetic) tremor (AT) is typical of essential tremor (ET), most PD cases also manifest AT1 and nearly one-third of ET cases have RT.2 The diagnosis of PD and ET each is based on clinical assessment, as no reliable biological markers are available. While in PD there is marked loss of substantia nigra dopaminergic neurons and Lewy body inclusions there are no pathological findings diagnostic of ET. Most ET cases have normal brain histology.2 Longitudinal clinical observations, medical imaging, and autopsy studies indicate that clinical diagnoses of ET and PD are inaccurate in some cases.3-5 Benign tremulous Parkinsonism (BTP) is a rare clinical entity characterized by tremor onset, clinical diagnosis of Parkinsonism, continued prominent tremor but little or no other motor features of PD, slow progression, poor responsive to levodopa (LD), and unknown pathology.6 We report clinical–pathological study of one BTP patient. At age 52, she developed right thumb RT and 1 year later left thumb RT. The tremor improved with activity. Examination at age 54 revealed bilateral pill-rolling tremor and mild rigidity and bradykinesia. Diagnosis of PD was made, and she was started on an anticholinergic agent. Eight months later, she was evaluated at Movement Disorder Clinic Saskatoon (MDCS). The findings were similar to those noted earlier. Diagnosis of PD was made and she was started on LD. Her mother, brother, and sister had tremor, but neither was evaluated at the MDCS. During the next 23 years while on LD, she was evaluated 19 times at the MDCS. At age 60, she developed slowly progressive AT in both upper limbs. Tremor remained the prominent feature but there was little or no bradykinesia or rigidity and the gait and posture remained normal for her age. There was no symptomatic benefit on LD, and no motor-response fluctuations or dyskinesia were observed. At age 77, the LD was discontinued. She reported feeling better but there was no change in the motor symptoms. During the next 11 years while off LD, she was assessed 15 times at the MDCS. The upperlimb tremor became progressively disabling, but there was no bradykinesia or rigidity. Her hand writing deteriorated and by age 82 she could not write legibly. At age 83, she had onset of progressive decline in cognitive function and for the last 3 years of life she required nursing home care. A video was made at age 83 (Video segment 1). It shows moderate amplitude AT and RT in the upper limbs, right more than left, normal posture, and no bradykinesia. She died at age 88. Autopsy revealed Alzheimer’s disease (AD) pathology. We concluded that the AD did not contribute to her tremor which had onset at age 52 years. The final diagnosis was ET plus RT and unrelated AD. Our patient had all the clinical features of BTP.6 Review of literature indicates that some patients with features similar to BTP6 have been described under ET. One report of 10 cases with prominent tremor and clinical diagnosis of PD, made by UK brain bank criteria, had no worsening of symptoms after LD withdrawal and normal presynaptic dopaminergic index on SPECT studies.4 Therefore, the diagnosis was changed to ET in some of these cases. In one tremor-dominant case, PD diagnosis was changed to ET based on long follow-up and normal brain histology.5 We reported one autopsy case with clinical features of BTP where the final diagnosis was ET plus RT7 (Case 5). Progression of PD with TD profile is slower than in A/R cases.8 The most likely explanation is a more widespread pathology in A/R than in the TD cases.9 Cumulative scientific information is critical in understanding the pathophysiology of clinical entities resembling PD. Substantia nigra pathology as the basis of PD was established more than 100 years after the clinical description by James Parkinson, and Progressive Supranuclear Palsy and Multiple System Atrophy pathological findings were recognized more than 40 years later. We conclude that some cases diagnosed as BTP suffer from ET. Further studies are needed to define the full spectrum of BTP.