Essential tremor: what is beyond the oscillatory monosymptomatic illness?

Essential tremor (ET) is now considered as a slowly progressive neurodegenerative disorder with a variety of motor and non-motor manifestations. The objectives of this work were to study the existence of cognitive, mood, olfactory, and balance dysfunctions in ET patients and their relation to tremor severity as well as patients’ activity of daily livings. This study was performed on 36 ET patients and 24 healthy controls subjects (HCS) submitted to The Essential Tremor Rating Assessment Scale (TETRAS), advanced activity of daily living scale (AADLs), Montreal cognitive assessment scale (MoCA), Montgomery–Åsberg Depression Rating Scale (MADRS), auditory mismatch negativity (MMN), Sniffin’ Sticks test (SST), computerized dynamic posturography (CDP), and brain MRI diffusion tensor tractography (DTT). ET patients showed significant decrease in AADLs, MoCA, SST (threshold, identification, and discrimination subscales) as well as visual and vestibular ratios of CDP compared to HCS. Auditory MMN showed significant reduction in the amplitude and prolongation of latencies while corticospinal tracts, thalamo-cortical connectivity, and middle cerebellar peduncles DTT revealed reduced fractional anisotropy in ET patients with normal tracts densities. ET patients exhibit a wide variety of non-motor manifestations including cognitive impairment, depressive symptoms, hyposmia, and increased risk of falls with consecutive reduced activity of daily living beyond the deleterious effects of the kinetic tremor.


Introduction
Essential tremor (ET) is the most common adult onset movements' disorders affecting 1% of the general population and > 5% of those above the age of 65 years [1]. The traditional descriptions of ET as a benign monosymptomatic illness with postural and/or kinetic tremors had been given way while the disorder is now considered as a slowly progressive neurodegenerative movement disorder which is highly heterogenous in its hereditability, affected body parts, response to treatment, rate of progression, and possible existence of non-motor manifestations [2].
In 2018, The International Parkinson and Movement Disorder Society (MDS) had introduced the term ETplus to describe patients with additional neurological signs of uncertain significance that are not enough for the assumption of comorbidity or additional diagnosis. However, the permissible spectrums and severities of these non-motor manifestations are poorly defined in objective assessments [3,4]. These non-tremorgenic manifestations include subtle cerebellar dysfunctions, balance and gait impairments, oculomotor disturbances, cognitive decline, psychiatric abnormalities, hearing and olfactory problems, and upper airways dysfunctions and sleep disturbances [5].

Aim of the work
The aim of the work was to study the cognitive, mood, olfactory, and balance dysfunctions in ET patients and their relation to tremor severity as well as patients' activity of daily livings (ADLs).

Subjects and methods
The study was a cross-sectional case-control study conducted on 36 ET patients and 24 age, sex, and educational level matched healthy control subjects (HCS). Inclusion criteria consisted of consecutive ET patients aged 50-65 years (to avoid the aging effect on the studied parameters) and diagnosed according to The Consensus Statement on the Classification of Tremors of the MDS [6]. Patients were recruited from the movement disorder clinic, Center of Neurology and Psychiatry, Tanta University Hospitals, in the period from 1 October 2017 to the end of December 2019.
Exclusion criteria encompassed ET patients with comorbid endocrinal, renal, or hepatic diseases as well as middle ear dysfunctions or MRI contraindications. The study protocol was approved by the Research Ethics Committee and Quality Assurance Unit, Faculty of Medicine, Tanta University; the participation was voluntary and informed consents were obtained before engagement in the study.
Included patients were subjected to tremor severity assessment using The Essential Tremor Rating Assessment Scale (TETRAS) [7] as well as history taking stressing on family history of ET, disease duration and response to propranolol (ET was considered propranolol responsive if the TETRAS improved by ≥ 50% from the baseline). Included subjects were also submitted to the Montreal Cognitive Assessment Scale (MoCA) Arabic Version, the advanced activities of daily living scale (AADLs) [8], and Montgomery-Åsberg Depression Rating Scale (MADRS) [9].
Studied subjects were also submitted to auditory mismatch negativity (MMN) test which used the oddball paradigm for speech stimuli, da/ga sounds as standard/deviant stimuli, presented at 1/s repetition rate, 15% deviant probability, and 50 dB sound level. MMN was calculated in the difference waveform according to manual specification of Smart Evoke Potential, Home Intelligence Service (HIS), USA (Additional file 1).
Statistical analysis was conducted using SPSS Prism, version 20, 2013 created by IBM, Chicago, IL, USA. Statistical differences were tested using chi-square for categorical variables and Student's t test for numerical ones. For bilaterally assessed parameters, all included subjects were represented by the mean measure of both sides. Correlation analysis was performed using Pearson's correlation test. p value < 0.05 was considered statistically significant.
The results of the present study showed highly significant decrease of MoCA scale in ET patients compared to that in HCS with p < 0.001. Regarding the speech MMN, 10 (27.8%) of ET patients had absent evoked potential compared to none of the HCS. Patients with evoked responses showed highly significant prolongation of the latencies and reduction of the amplitude compared to HCS with p values < 0.001. Absent responses and higher MMN abnormalities were present among those with older ages, longer disease duration, and increased TETRAS ( Table 1).
Regarding the results of CDP, there were significant decreases in VIS and VEST ratios of ET patients compared to HCS (p values < 0.001) while SOM ratio showed non-significant difference (p value = 0.149) ( Table 1, Fig. 1).
The present study showed significant reduction in each of TSST, ISST, DSST, and TDI in ET patients compared to HCS with p values 0.001, 0.001, 0.004, and 0.001, respectively. Regarding the results of TDI sum score, 9 (25%) ET patients had normal smelling performance and 27 (75%) were hyposmic compared to 17 (70.8%) and 7 (29.2%) for HCS, respectively. None of the included subjects had functional anosmia with TDI ≤ 15 points (Table 1).
Regarding the DTT data, the results revealed highly significant reductions in mean FA for CST, TCC, and MCP of ET patients compared to HCS with p values < 0.001. On the other hand, the studied tract densities showed non-significant differences between ET patients and HCS with p values > 0.05 (Table 1, Fig. 2).
The VIS and VEST, CDP as well as examined tracts FA were lower in patients with positive family history of ET, propranolol response, and/or those with additional head, voice, or lower limb tremors. In contrast, MoCA scale, auditory MMN, and SST had no relations to such variables.
Correlation analysis data revealed that MoCA as well as VEST were negatively correlated with disease duration and TETRAS, but positively correlated with AADLs ( Fig. 3). At the same time, MADRS as well as MMN latency showed positive correlation with disease    Table 2).

Discussion
The present study showed that ET patients exhibit a variety of cognitive, mood, olfactory, and balance impairments exceeding their age-and sex-matched counterparts pointing to the multi-systemic neurological nature of the disorder which affects a wide range of brain areas. This result is passing with the works of Louis, 2019 [13] as well as Soto and Fasano, 2020 [14] who stated that ET is no longer considered as a benign monosymptomatic illness with isolated postural tremor but a slowly progressive neurodegenerative disorder with a variety of motor and non-motor manifestations due to enhanced brain biological aging.
The results revealed that the most common nonmotor symptoms of ET patients were subjective cognitive decline and mild depressive symptoms while most patients were not aware of their olfactory or balance problems except after objective assessment. Lack of awareness to the existence of non-tremorgenic dysfunctions is most probably related to their very slow rate of progression as well as cultural believes that these manifestations were attributed to the effect of physiological brain aging. These results are in harmony with the study of Azar and colleagues, 2017 [15] who stated that, despite the great negative impacts of ET non-motor manifestations on the quality of life, many patients are unaware of their existence.
The study showed higher incidence of mild cognitive impairment among ET patients than their age-and sexmatched peers. At the same time, the abnormal auditory MMN-evoked response reflects impaired working memory, attentional switch as well as automatic pre-attentive discrimination of acoustic changes. These results are passing with the work of Meyers and colleagues, 2019 [16] as well as Novellino and colleagues, 2020 [17] who demonstrated greater cognitive decline not only among ET patients but also their 1st degree relatives. They also identified hippocampal microstructural damage correlated with the ET-associated cognitive impairment and make it as a risk for dementia. On the other hand, Medeiros and colleagues, 2016 [18] found non-significant diminution of the global cognitive functions in ET patients compared to healthy control possibly due to the wide age range of their included patients beside recruitment of young ET patients with short disease duration.
The present work revealed that a great proportion of ET patients experienced depressive symptoms with feeling of sadness, helplessness, and hopelessness. These mood disturbances had very mild positive correlation with the tremor severity but greatly impair patients' ADLs. These data are in accordance with the study of Cersonsky and colleagues, 2019 [19] who demonstrated high demoralization feelings and psychological distress in ET patients even in those with mild tremor disability scores.
Regarding olfactory performance, the results showed mild hyposmia in some ET patients greater than expected for age which was not correlated with the disease duration and/or severity. This finding is passing with the work of Giorelli and colleague, 2014 [20] who identified mild olfactory dysfunction in their included ET patients higher than control. On the other hand, Wu and colleague, 2016 [21] revealed non-significant difference regarding olfactory performance in ET patients compared to healthy control. This discrepancy is possibly related to their inclusion of older age group subjects, use different methods of olfactory assessment, and the racial difference in smelling performance.
The results of the present work showed impaired static and dynamic balance control in ET patients evidenced by decreased VIS and VEST, CDP ratio. On the other hand, the SOM ratio was not significantly impaired. Moreover, VEST ratio was negatively correlated with the disease duration and severity while VIS ratio had no such association. All these data point to the increased risk of falls in ET patients and the different pathogenic effect induced by ET on the three sensory components of balance. These results are in accordance with that of Prasad and colleagues, 2018 [22] who concluded that CDP reveals significant balance impairment in ET patients which adds to the growing body evidence of cerebellar involvement in ET.
The study revealed reduces FA in each of CST, MCP, and TCC, DTT of ET patients while tracts density was non-significantly affected pointing to the microstructural connectivity changes induced by ET. These changes include increased heterogenicity of axon FA (myelination) with preserved tract density (fiber number) which results in decreased synchrony of impulses transduction. These results are passing with that of Chung and colleagues, 2013 [23] who identified that ET induces heterogeneous cortical thinning and white matter alteration with a resultant alteration in the rate of disease progression as well as clinical response to propranolol.
The results also showed positive correlation between brain network changes (DTT, mean FA) and each of tremor severity (TETRAS) as well as cognitive impairment (MoCA) while such association was absent with other examined parameters including olfactory, mood, and balance dysfunctions. This information suggests that ET-associated kinetic tremor and cognitive decline may share the same neuroanatomical basis. At the same time, neuropeptides and neuro-circuits involved in olfactory, mood, and balance changes are different. The net result hypothesizes that ET is a multisystem, multipeptide, and multi-networks brain disorder with each manifestation; either motor or non-motor has its own route of progression. These data may open a small window in solving the mystery of ET heterogenicity which could improve the treatment results. These data are in harmony with that of Tian and colleagues, 2018 [24] as well as Akram colleagues, 2018 [25] who demonstrated an association between brain microstructural and cognitive impairment in ET. They also stated that good assessment of such matrices changes allows for better selective targeting of disrupted networks during deep brain stimulation as well as MRI-guided focused thalamotomy. On the other hand, Sengul and colleagues, 2019 [26] revealed significant correlation between depression severity and DTT parameters including FA. This discrepancy is possibly due to different patients' demography with enrollment of higher number of female genders, the use of a different depression scale, and DTT measurements in other regions of interest (ROI) including the prefrontal cortex, paralimbic, and limbic structures.

Conclusion
Essential tremor patients exhibit a wide variety of nontremorgenic manifestations including mood disturbances, cognitive impairment, olfactory dysfunctions, and increased liability to fall which have great negative impacts on the patients' ADLs beyond that is caused by the postural tremor itself.