Is there cerebellar pathology in essential tremor?

The neuropathology of essential tremor (ET), in particular, cerebellar pathology, is a matter of controversy. In recent issues, two clinicopathologic studies of ET patients reported deviating results concerning cerebellar pathology. One study (study I) comparing 32 ET patients (mean age: 86 6 6.1 years; duration of tremor not given) and 16 age-matched controls (including 8 brains [15.6%] from an earlier report), using free-floating parasagittal cerebellar hemispheric sections (100 mm thick) stained for calbindin, without random unbiased stereological methods, demonstrated an 18% reduction of Purkinje cell (PC) linear density, compared to controls (P 5 0.007), and inverse association of PC density with torpedo count and significantly increased Basket cell axonal plexus density indicating greater PC axonal remodeling. The study confirms the results of earlier studies of the same group, including 14 and 33 ET cases with mean tremor duration of 27.9 and 32.5 years, using different patient cohorts and histologic methods (hematoxylin and eosin and alpha-synuclein [a-Syn] stains of 7mm-thick parasagittal sections of neocerebellum). The other study (study II) comparing 56 ET patients (including 10 with asymptomatic Lewy bodies [incidental Lewy body disease; ILBD] and 2 with PSP; mean age: 89 6 5.6 years; duration of tremor: 10.3 6 12.6 years), using 5-mm-thick paraffin sections of cerebellar hemisphere stained with routine, silver, and a-Syn stains, demonstrated no changes in PC linear density between ET cases and controls and no relationship between age, duration of tremor, and PC density. However, in an earlier study of 11 ET cases with duration of tremor between 4 and 58 years, the same group reported some cerebellar pathology in 7 ET subjects (superior vermian atrophy and proliferation of Bergman glia in 3 each), however without mentioning loss of PCs or occurrence of torpedoes. These data confirmed other studies of ET patients (similar age; mean duration of tremor: 32-34 years) reporting no essential cerebellar PC loss. The deviating results of the various neuropathologic studies in ET are difficult to explain. They may be related to three possibilites: (1) patient selection biases (specific group of clinically well-characterized ET patients [study I] vs. largely community-based sample of partly undiagnosed and untreated ET cases, including some ILBD and PSP cases [study II]) and, probably, different duration of tremor; (2) different methodologies and counting methods (100-mm-thick floating sections stained with calbindin [study I] vs. 5-mm-thick sections with routine stains [study II], the latter probably demonstrating more details resulting from greater volume effect than thinner sections, although previous studies using 7-mm-thick sections showed similar significant PC loss. This suggests that differences in technique may not definitely explain devianting results; and (3) differences in field sizes and lack of standardization across studies, restricting microscopy to linear segments. This latter possibility has to be controlled in further standardized studies. The pathophysiology of ET remains not fully understood. Standard neuropathologic studies have reported no consistent changes, but some detailed studies found neurodegenerative changes in most ET cases: 24% demonstrated lower brainstem LBs and 76% experienced loss of PCs and its sequelae, whereas a recent study, using different histological techniques, revealed a modest (18%), but significant, reduction of PCs with different, but overlapping, distribution curves of PC loss. Unfortunately, reduced PC counts in ET cases, compared to controls, could not be replicated by others. There are no consistent data on the dentate nucleus in ET; a reduced number of dentate neurons was observed in 6% to 12.5% of ET cases. Of note is that all of these studies were based on clinical diagnosis of ET, without focusing on genetic bases of the disorder. Hence, there should be future prospective clinicopathologic studies on ET patients (sporadic and familial ones) that should be classified based on both genotyping and clinical profiles, as well as use comparable methodologies in neuropathologic workup of both ET patients and controls. -----------------------------------------------------------*Correspondence to: Kurt A. Jellinger, Institute of Clinical Neurobiology, Kenyongasse 18, A-1070 Vienna, Austria; kurt.jellinger@univie.ac. at