Postischemic delayed Holmes' tremor responding to low‐dose cabergoline

Holmes’ tremor is an unusual combination of rest, postural, and kinetic tremor of extremities. It is usually caused by a focal neurological disease of midbrain.1 In general, tremor disorders affect quality of life by impending simple motor tasks and activities of daily living. Unfortunately, symptomatic medical treatment of Holmes’ tremor is often unsuccessful. The use of levodopa, clonazepam, a combination of propranolol and valproate, glutethimide, benztropine, bromocriptine, and amantadine has occasionally led to satisfactory clinical benefits.2 Here we report on a case with postischemic delayed Holmes’ tremor dramatically responding to low dose cabergoline treatment. A 57-year-old man with history of hypertension and smoking suddenly developed unsteadiness and dropping of right upper eyelid. Neurological examination revealed dysarthria, a total right occulomotor nerve paralysis, and leftsided mild hemiparesis. Magnetic resonance imaging (MRI) showed an acute midbrain infarction involving right red nucleus and substantia nigra regions (Fig. 1). During follow-up extending to 4 years, right occulomotor nerve involvement only slightly improved and left-sided spasticity developed. Five years after the ischemic episode, the patient was referred again because of a tremor affecting left extremities. On examination, a severe-intensity, slow, large-amplitude resting tremor was observed on the left side. Tremor was also present during posture and action and was worsened by emotional distress and attempts to inhibit the tremor. There was no associated rigidity. Gait was almost impossible because of leg action tremor and the patient could not perform activities of daily living without assistance. MRI demonstrated no other pathology except chronic midbrain infarction. He was started on levodopa– carbidopa 250/25 mg three times a day and no response was observed during 1 month. Then, he was given cabergoline 1 mg/day. At the end of 1 month, he was able to walk independently and carry out most of daily activities by himself. However, the improvement of tremor was not satisfactory and cabergoline dose was increased to 2 mg/day. One month later, improvement of tremor was dramatic with complete alleviation of all components. Holmes’ tremor is a symptomatic tremor occurring after different lesions centered to the brain stem with damage to the neighboring cerebellothalamic and nigrostriatal fiber tracts. Involvement of these two systems accounts for static, postural, and kinetic features of Holmes’ tremor.1 Remy and colleagues3 demonstrated that fluorodopa uptake of the striatum of patients with Holmes’ tremor was too low ipsilateral to the midbrain lesion. MRI location of the midbrain lesion in our case indicates that substantia nigra, nigrostriatal dopaminergic fibers, or both are involved. The pathophysiology of Holmes’ tremor probably involves compensatory changes in nervous system function.1 Resultant symptomatology of Holmes’ tremor is a combination of dopaminergic and nondopaminergic components of tremor. Two main systems, the dopaminergic nigrostriatal system and the cerebellothalamic system, may be involved disproportionally among different patients and, furthermore, compensatory changes over time may go against the nigrostriatal dopaminergic system as in our case. This hypothesis may account for the response variability of Holmes’ tremor to pharmacotherapy. Interestingly, our case displays a contrast between a dramatic response to cabergoline and lacking response to levodopa. In some cases of Holmes’ tremor, the dopaminergic neurons in the substantia nigra might be destroyed to such an extent that the presynaptic part of the dopaminergic connections in the striatum are hardly present anymore. This would be in contrast to the degenerative disease and could be an explanation for the lack of response to levodopa. D2 dopamine receptors are mainly distributed in striatum.4 Cabergoline is a highly selective D2 receptor agonist5 and it has been shown that it has a higher efficacy and safety than other dopamine agonists.6,7 Our patient is the first case in literature showing dramatic response to low-dose cabergoline treatment. Although treatment of Holmes’ tremor has been disappointing, cabergoline may be an effective treatment choice with its higher dopaminergic selectivity.