EDITORIAL
A Normal Inferior Olive in Essential Tremor— Peacemaker or Pacemaker? Tabish A. Saifee, MRCP and Mark J. Edwards, PhD* Sobell Department for Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, United Kingdom
The cause and mechanism of essential tremor (ET) have been difficult to pin down, with recent vociferous debate regarding clinical case definition and the presence, absence and meaning of putative neurodegenerative findings in the cerebellum of patients. The recent finding of a causative but infrequent mutation in ET underlines the issue of heterogeneity.1 This heralds, at least for now, a triumph for the disease “splitters” over the “lumpers” in the march to progress.2 Nevertheless, some assertions are crystallizing. A variety of methodological approaches—from functional imaging,3 spectroscopy,4 volumetry,5 and simple associative conditioning6,7 to eye movement,8 and gait analysis9— implicate the cerebellum as key to the syndrome, but in what way, the jury is out. However, this is a “networkopathy,” and other areas such as the motor cortex and thalamus seem bound in a dynamic network that is entrained at tremor frequency. On the basis of 3 lines of evidence, the inferior olivary nucleus (ION) has been suggested as a node in this pathological network and even as a main player. First, the harmaline animal model of ET unequivocally represents oscillatory output from the ION. Second, there is a physiological rationale that the ION could play a role in tremor generation given the calcium-dependent neuronal synchrony of the ION sufficient to drive the cerebellothalamocortical circuit to produce tremor.10 Third, a functional imaging study11 has suggested abnormal activation of the ION in ET. The actual story, however, seems less clear-cut, with a lack of evidence of ION involvement in the majority of ET patients studied with functional imaging3,12,13 and, less specifically, medullary activation in just 1 study.14
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*Correspondence to: Dr. Mark Edwards, Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK;
[email protected]
Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. Received: 13 February 2013; Revised: 12 March 2013; Accepted: 1 April 2013 Published online 31 May 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.25485
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In this issue of Movement Disorders, Louis and others address the important issue of whether the ION is involved in ET from a neuropathological point of view.15 They report a case–control series of 14 ET cases and 15 controls. Of note, none of their patients had Lewy bodies in regions normally examined in their assessment, despite previous reports from the same group of a Lewy body subtype of ET. By the authors’ rationale, all the ET cases in this study would thus be expected to fall within the “cerebellar” subtype coined by the group. The bottom line of the study is that there were no identifiable pathological changes in the IONs in these patients compared with controls.15 This is certainly fresh and interesting evidence. So where does a structurally normal ION in ET leave us? Well, this study by itself certainly does not completely answer the question of whether the ION is involved in ET, as the lack of degenerative change does not exclude a role for functional disturbance within the ION in the generation of ET. However, in contrast to the key role of the ION in harmaline tremor and oculopalatal tremor, available evidence for functional disturbance is sparse. One study11 demonstrated alcohol-associated increases of regional blood flow in the IONs of patients with ET but not controls, perhaps via cerebellar projections to the ION. In a study by Bucher et al,13 2 of 12 patients with ET demonstrated ION activation. Notably, the excitatory cerebellar nuclei neurons that project to the thalamus and the inhibitory nuclei neurons that provide feedback to the olive are innervated by the same Purkinje cell axons,16 although they take part in tonic and phasic control, respectively.17 So, different cerebellar rhythms may coexist, and their underlying networks can still, at least partly, be shared. The variable involvement of the ION in functional imaging studies in ET11–14 could relate to the nonlinear dynamics of the network,18 the signal-to-noise ratio required for detection of activity, or the ever-present issue of case heterogeneity. We therefore still need categorical evidence for or against the functional involvement of ION in ET. If the ION is involved in the oscillatory network, this study is of importance because it would suggest that effects of abnormal synchrony are not
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necessarily toxic to cells leading to degenerative change as speculated.19 The idea that tremor itself could produce cellular changes may turn one’s attention to epilepsy as a paradigm of abnormal synchronous output. The process of kindling, a model for seizures, has been shown to induce many changes, for example, in the GABA receptor,20 which may then predispose to future synchrony.21 Could an analogous mechanism explain the slow progression of essential tremor with subtle cellular changes including those associated with the GABA receptor?22 Although a tempting idea, the supporting data for epilepsy are not always consistent.23 Beyond this, the data provide some additional pieces of information to guide the current disparate debate about the “true” origins of ET. From the sidelines, claims and counterclaims about ET being a neurodegenerative disorder may seem to be far removed from our patients with tremor, but they are not. With the array of potential targets for DBS in tremor and treatment trials being informed by perceived disease mechanism, it is essential to have a good understanding of the pathology and network dynamics underlying this condition. It is of great importance to differentiate between a neurodegenerative disorder in which the ultimate goal for treatment would be disease modification via neuroprotection versus a nondegenerative disorder of abnormal network activation in which the ultimate goal would be symptomatic treatment, perhaps through membrane stabilization or neurotransmitter modulation. These issues are important, as considerable resources are being and will be spent, and many patients are waiting for answers. So do these data provide any further insight into the argument of ET being a degenerative or nondegenerative condition? The torpedo count, a nonspecific marker of degeneration but reported to be particularly high in ET by the same lead author,24 is given in this article as a median, which rather begs the question of whether the means were not significantly different, perhaps because of outlying results. In which direction these outliers lie and in which groups would be of interest. Although the Purkinje cell counts are significantly different (6.4 6 2.2 versus 8.8 6 2.2), the effect size appears small, not perhaps what one might expect to see in a neurodegenerative process thought to occur over decades. Further, the basket cell axonal cell density is not significantly different, although this has been reported by the same group to be indicative of cerebellar degeneration in ET.25 It is also important for us to ask that if ET was a neurodegenerative disease, would we not expect to see changes in the ION (and indeed other brain structures) after a long duration of disease? It would be rather unusual for a degenerative condition of the nervous system to not have spread to other brain areas after many decades of symptoms.
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It is not satisfactory, as the authors of this article do, to dismiss reports from other groups of lack of degenerative change in patients with ET as a result of inadequate powering of studies. Neuropathological characterization of a disease is not all about group data; individual patients matter. If there are cases fulfilling strict clinical criteria for ET who do not have pathological changes within the cerebellum then there are only a small number of logical explanations. Either the neuropathology has not been performed correctly, the clinical characterization has not been performed correctly,26 or the thing we define as ET according to current clinical criteria can occur without neurodegenerative changes. Arguments about powering of studies do not enter into this discussion. This supersedes more complex (albeit important) arguments about the true meaning of the neuropathological changes revealed in some cases of ET and gets to the heart of the problem we all now have with this common movement disorder. So where next for ET? Maybe it comes back to the clinic and to clinical characterization. In movement disorders we are used to taking a collection of historical and examination findings, some of which may be subtle, and using them to fit a patient within a diagnostic category. Perhaps one of the problems with tremor in general is that our diagnostic categories are very few, and for primary tremor syndromes, those in common usage in the clinic are inadequate. What else, after all, can we reasonably call a patient with slowly progressive primary action tremor apart from ET? But, and here comes the problem, what if the tremor is relatively asymmetric? What if there is some subtle “dinner-forking” of the fingers of one hand? What if there is a prominent rest component? We have heard the debates about dystonic tremor and ET before, and these are important, but overcalling dystonia is as great a risk as ignoring it when it is there. We all know there are patients out there with primary tremor who do not fit strict criteria for ET but do not clearly fit anywhere else, something recognized in previous tremor categorizations; but in regular clinical practice, how can we stop these people ending up in the ET “box”? Furthermore, how can we improve our clinical criteria so that patients who can be clearly diagnosed as ET under current criteria can be successfully divided according to the pathophysiological heterogeneity we know is there? The onus is now on those with specialist interest and knowledge of tremor to resolve this important, “essential” issue. Consensus is the only obvious way forward, and the starting point is clearly to embrace the heterogeneity. From this point, multimodal clinical and experimental assessment of patients with tremor with rigorous unbiased correlation between experimental data and clinical phenotype may begin to show us the way through to a pathophysiologically based
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classification of tremor. After all, the olive branch is peacemaker, not pacemaker.
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