Excessive neural synchrony in Machado‐Joseph disease responsive to subthalamic nucleus stimulation

Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is one of the polyglutamine repeat neurodegenerative disorders and the most common form of SCA worldwide. Yet, its neural basis remains enigmatic and its management symptomatic and palliative. We report on a medication-refractory parkinsonian subtype of MJD/SCA3 complicated by a large amplitude re-emergent postural tremor, dramatically arrested by DBS of the STN (see Video). STN local field potential (LFP) recordings further afforded novel insights into pathological neuronal firing in MJD/SCA3. A 48-year-old man with a genetic diagnosis of MJD/SCA3 presented with a 7-year progressive history of global bradykinesia, coarse 4to 7-Hz resting tremor, severely debilitating “flapping” re-emergent postural tremor (believed to share a common pathophysiology, distinct from that of essential tremor), cogwheeling of the wrists, reduced arm swing, and narrow gait. Brain MRI was normal, but single-photon emission computed tomography with DaTscan contrast showed significant loss of signal uptake in both the caudate and putamen. On 200-mg levodopa challenge, there was a 17% improvement in UPDRS, but the tremor was unresponsive. The patient reported intolerance to all antiparkinsonian medications trialed. DBS is the surgical intervention of choice for parkinsonism; in the absence of signs suggestive of cerebellar or thalamic pathology, the STN was selected as the sole target nucleus (techniques previously described). LFPs, believed to provide a measure of population neuronal activity in the vicinity of the electrode, were recorded 3 days later (5-minute period; patient sitting upright with hands on knees)—preceding connection of the electrodes to a pulse generator. Power spectra derived from bipolar STN-LFP recordings revealed peaks of activity centered at 4 and 7 Hz. Such activity has previously been related to tremor and may suggest coexistence of tremors of two different frequencies. Furthermore, more focal peaks of activity were observed across a 13to 30-Hz frequency range, drawing a striking parallel to neuronal firing patterns commonly described in Parkinson’s disease (Fig. 1). Bilateral STN DBS led to an immediate arrest of tremor and amelioration in bradykinesia and rigidity. At 6 months postop, a 43% improvement in motor UPDRS (from 44 to 25) was achieved with the following stimulation parameters: active contacts 0 (4.6 V) and 5 (3.8 V); 130 Hz; and 90-ms pulse width. Concomitant improvements in activities of daily living were reported and persist 3 years postop, including: 80% improvement in ability to drink from a cup (returning to 10/10 function) and showering standing, with 90% improvement in pouring a drink and using a knife and fork. Marked variation in polyglutamine repeat length and the capricious locations of resulting intranuclear inclusions, account for the remarkable heterogeneity of MJD/SCA3’s presentation. In our patient, excessive 4to 8-Hz and 13to 30-Hz STN neuronal synchrony, likely secondary to microscopic MJD/SCA3 pathology, may have contributed to some of the symptomatology. Whilst a possible role of stimulation of neighboring tracts cannot be ruled out, STN DBS likely acted to disrupt pathological neuronal firing.