Cortical tremor: a tantalizing conundrum between cortex and cerebellum Free

We read with interest the recent ‘Update’ (Latorre et al., 2020) providing a detailed analysis of the mechanisms defining cortical tremor, the leading symptom in familial cortical myoclonic tremor and epilepsy (FCMTE) or familial adult myoclonic epilepsy (FAME).

Tremor and myoclonus are common hyperkinetic movement disorders and their correct classification on clinical and electrophysiological features enables the search for aetiological diagnosis and guides tailored treatment (Zutt et al., 2019).

We agree that cortical tremor should be included within the ‘spectrum of cortical myoclonus’, originating from an abnormal sensorimotor cortical excitability and resulting in rhythmic cortical myoclonus. This view is supported by the electrophysiological findings in these patients, namely (i) an electromyographic pattern consistent with irregular, arrhythmic (or semi-rhythmic) and high-frequency (∼10/s) myoclonic jerks occurring in busts lasting ∼50 ms, synchronous between agonist and antagonist muscles (versus the regular agonist/antagonist alternate pattern observed in tremor); (ii) jerk-locked averaging analysis demonstrating a positive-negative, biphasic, pre-myoclonic spike (or less frequently a complex pattern of wavelets) related to myoclonus on the contralateral sensorimotor regions; (iii) enhanced somatosensory-evoked potentials (P25-N33 amplitude > 8.5 µV); (iv) increased long-loop reflex I (C-reflex) response evoked by stimulation of the peripheral nerve; and (v) strong cortical and intermuscular coherence in an 8–30-Hz range (Striano et al., 2005; Uyama et al., 2005).

We also agree that cortical hyperexcitability can result from a decreased cortical inhibition by the cerebellum via the cerebellar-thalamocortical projections, in line with rare post-mortem studies showing cerebellar pathology (Uyama et al., 2005), and MRI spectroscopy data showing elevated choline/creatine ratio in the cerebellum cortex of patients (Striano et al., 2009) as well as brain magnetic resonance diffusion tensor imaging evidence for decreased mean fractional anisotropy (i.e. microstructural damage of the cerebellar white matter) in FCTME compared with essential tremor patients (Buijink et al., 2013).

Regarding the treatment, cortical tremor is not responsive to alcohol or levodopa but improves with antiseizure medications, especially if combining both anti-epileptic and antimyoclonic activity, e.g. valproate, levetiracetam, and benzodiazepines (Striano et al., 2005; Uyama et al., 2005; Coppola et al., 2011) whereas some drugs, such as gabapentin, may precipitate a severe myoclonic status (Striano et al., 2007).

Cerebellum receives information from the motor cortex and that cerebellar output influences different neuronal populations in the motor cortex (Striano et al., 2013). However, it remains to be elucidated whether the excessive excitability is due to the enhanced intrinsic rhythmic activity of cortical generators or the abnormal reciprocal interactions with subcortical structures. Alternatively, decreased cortical inhibition may be caused by dysfunction of the cerebellar-thalamocortical loop secondary to primary cerebellar pathology, especially at the level of the cerebellar cortex. Moreover, clinical observations suggest a correlation between clinical severity and patients' ages, indicating that the clinically evident progression of the disease reflects—at least in part—the effect of physiological ageing (Coppola et al., 2011).

The recent discovery that this condition is caused by intronic pentameric expansions with a high somatic instability in distinct genes (SAMD12, STARD7, MARCH6), highly expressed in the cerebellum, suggests the formation of repeat-containing RNA structures that aggregate in the nucleus of cells (RNA foci), trapping numerous proteins that are unable to function properly (Lagorio et al., 2019). This finding shed new light on the pathophysiology of the disease and offers hope of preventive or curative options, such as RNA-targeting treatments. Further studies are needed to explore the cerebellar-cortical connectivity and the sensory-motor cortical hyperexcitability in this disease.

Data availability

The dataset supporting the conclusions of this article are included within the article.

Acknowledgements

This work was developed within the framework of the DINOGMI Department of Excellence of MIUR 2018-2022 (legge 232 del 2016). The ‘Beyond Epilepsy’ project is supported by BioMarin Pharmaceutical Inc.

Funding

No funding was received towards this work.

Competing interests

P.S. has received speaker fees and participated at advisory boards for BioMarin, Zogenyx, GW Pharmaceuticals, and has received research funding by ENECTA BV, GW Pharmaceuticals, Kolfarma srl., Eisai. All other authors report no competing interests.

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