"Benign" tremor? A serial case report of 2.5 year progression from mild cognitive impairment to amnestic dementia following deep brain stimulator placement for essential tremor.

Essential tremor (ET) is a prevalent neurological disorder with associated neuropsychological sequalae. Although cognitive deficits associated with ET are traditionally conceptualized as attention, processing speed, and executive impairments attributed to underlying frontal-subcortical dysfunction, emerging literature highlights the elevated frequency of progressive amnestic memory impairments in patients with ET. This case study centers around a 75-year-old woman with a 15-year history of ET who underwent deep brain stimulation (DBS) as well as three neuropsychological evaluations, one pre-surgically and two post-surgically at one and two-years post successful DBS surgery. Neuropsychological evaluation results revealed circumscribed mild and variable memory deficits pre-surgically and one-year post-surgically, However, two-years post-DBS, reliable change indices revealed significant declines in verbal/visual memory, consistent with an amnestic presentation, in addition to executive functions, aspects of higher-level language abilities, and overall IQ. This case study adds to a growing literature identifying a subset of ET patients with a neurodegenerative cognitive trajectory characterized by progressive, amnestic memory impairment. The case also highlights the importance of serial monitoring of cognition beyond the pre-surgical DBS workup to monitor for clinically significant decline(s).

Demoralization in essential tremor: prevalence, clinical correlates, and dissociation from tremor severity.

OBJECTIVE: Essential tremor (ET) is associated with psychological difficulties, including anxiety and depression. Demoralization (feelings of helplessness, hopelessness, inability to cope), another manifestation of psychological distress, has yet to be investigated in ET. Our objectives are to (1) estimate the prevalence of demoralization in ET, (2) assess its clinical correlates, and (3) determine whether demoralization correlates with tremor severity. METHODS: We administered the Kissane Demoralization Scale (KDS-II) and several psychosocial evaluations (ie, scales assessing subjective incompetence, resilience, and depression [eg, Geriatric Depression Scale]) to 60 ET subjects. Tremor was assessed with a disability score and total tremor score. KDS-II >8 indicated demoralization. RESULTS: Among 60 ET subjects (mean age = 70.2 ± 6.8 years), the prevalence of demoralization was 13.3%, 95% confidence interval = 6.9-24.2%. Although there was overlap between demoralization and depression (10% of the sample meeting criteria for both), 54% of depressed subjects were not demoralized, and 25% of demoralized subjects were not depressed. Demoralization correlated with psychological factors, but demoralized subjects did not have significantly higher total tremor scores, tremor disability scores, or years with tremor. CONCLUSIONS: Demoralization has a prevalence of 13.3% in ET, similar to that in other chronic or terminal illnesses (eg, cancer 13-18%, Parkinson's disease 18.1%, coronary heart disease 20%). Demoralization was not a function of increased tremor severity, suggesting that it is a separable construct, which could dictate how a patient copes with his/her disease. These data further our understanding of the psychological and psychosocial correlates of ET.

Unilateral Thalamic Deep Brain Stimulation Versus Focused Ultrasound Thalamotomy for Essential Tremor.

BACKGROUND: The predominant neurosurgical approach to medication-refractory essential tremor is thalamic deep brain stimulation (DBS). The emergence of magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy has reawakened the debate surrounding the use of DBS versus thalamotomy for this indication. Herein, we aimed to provide a contemporary comparison between DBS and MRgFUS. METHODS: Two controlled trials that evaluated DBS and MRgFUS for the unilateral treatment of refractory essential tremor were compared. Clinical outcomes extracted included postural tremor score in the treated upper extremity, quality of life (QoL), and incidence of adverse events (AE). RESULTS: Baseline patient characteristics were comparable in the 2 studies, except that DBS patients were younger and had more severe baseline tremor. Both DBS- and MRgFUS-treated patients had significant tremor improvement that was sustained for 1-year posttreatment, and significant improvement in QoL. The MRgFUS cohort had higher rates of persistent neurologic AE, whereas the DBS group had higher rates of surgery- and hardware-related AEs, including intracranial hemorrhage. CONCLUSIONS: In context of prior literature, both DBS and MRgFUS significantly improve tremor control and QoL. The 2 approaches are predominantly differentiated by their AE-profile. Additional head-to-head comparison on matched clinical populations are required to more accurately compare clinical efficacy and long-term outcomes.

Independent validation of the Quality of Life in Essential Tremor Questionnaire (QUEST).

BACKGROUND AND PURPOSE: Quality of Life in Essential Tremor Questionnaire (QUEST) was specially developed for essential tremor population to measure the health-related quality of life. Besides the development of the Hungarian version, we performed an independent testing of the scale adding further information on its clinimetric properties. METHODS: In this study 133 ET patients treated at University of Pécs, Hungary, were enrolled. Besides QUEST, we assessed Patient's Global Impression-Severity (PGI-S) and Fahn-Tolosa-Marin Tremor Rating Scales. After the independent validation in accordance to the Classic Theory of Tests, we evaluated cut-off values for detecting clinically meaningful ET-related disabilities based on receiver operating characteristics analysis. RESULTS: Cronbach's a was 0.897. QUEST demonstrated high convergent validity with PGI and divergent validity with disease-duration, positive family history, need for deep brain stimulation surgery, and the presence of depression and anxiety. Presence of moderate ET-related disabilities was identified by scores > 11.25 points on QUEST-SI (sensitivity: 77.4%, specificity: 83.3%); whereas scores > 20.35 points indicated severe ET-related disabilities (sensitivity: 83.3%, specificity: 59.1%). CONCLUSION: We demonstrated that the fundamental clinimetric properties of the QUEST are satisfactory.

Patients with essential tremor can have manual dexterity and attention deficits with no impairments in other cognitive functions / Pacientes com tremor essencial podem apresentar prejuízo na destreza manual e déficit de atenção sem prejuízo em outras áreas da cognição

ABSTRACT Essential tremor (ET) was long believed to be a monosymptomatic disorder. However, studies have evidenced structural changes and attention is now being focused on non-motor symptoms. The objective of the study is to describe and compare ET patients with control groups according to their cognitive functions, and secondarily, to compare their sociodemographic characteristics and other clinical features. All participants were assessed using the Fahn-Tolosa-Marin Tremor Rating Scale for the severity of tremor; a neuropsychological assessment battery and a screening questionnaire for mood and anxiety symptoms. There were no significant age and gender differences between all groups. As for neuropsychological assessment results, a significant difference was found only in the Pegboard test. We also found a significant negative correlation between a poorer cognitive test results and disease severity and a significant differences regarding depression or anxiety symptoms in patients with ET. The study results suggest that patients with ET have impaired manual dexterity and attention.

RESUMO O tremor essencial (TE) era considerado como um transtorno monossintomático. Contudo estudos tem demonstrado alterações anatômicas despertando o interesse para sintomas não-motores.O objetivo do estudo é descrever e comparar pacientes com grupos controles segundo suas funções cognitivas, e secundariamente, comparar suas características demográficas e outros sintomas clínicos. Todos os participantes foram submetidos à escala de Fahn, Tolosa e Marin para avaliação da intensidade do tremor, a uma bateria neuropsicológica e a um questionário para detecção de transtorno de humor e ansiedade. Não houve diferença significativa na idade e gênero entre todos os grupos. Quanto ao resultado da avaliação neuropsicológica, foi encontrado uma diferença significativa apenas no Test Pegboard. Nós também encontramos uma correlação negativa no desempenho dos testes cognitivos e intensidade do tremor, presença de sintomas depressivos e ansiosos. Os resultados deste trabalho sugerem que pacientes com TE apresentem alteração na destreza manual e na atenção.

Long-term follow-up of thalamic deep brain stimulation for essential tremor - patient satisfaction and mortality.

BACKGROUND: Ventral intermediate thalamic nucleus (VIM) deep brain stimulation (DBS) is an effective treatment for tremor, but there is limited data on long-term efficacy and mortality after VIM-DBS. Here we report the analysis of patient satisfaction and mortality in all patients treated in our center 1996-2010 with VIM-DBS for essential tremor (ET). METHODS: Forty-six consecutive patients were included in this study. Medical records were reviewed, and a follow-up questionnaire was sent to all surviving patients. RESULTS: Seventy percent of all possible participants (26 patients) answered the questionnaire. Follow-up time for the responding patients was median 6.0 years (2-16). Median self-reported score on visual analogue scale of the initial postoperative effect on tremor was 8.5 (0.1-10), with a significant reduction to 7.4 (0-10) at follow-up (p = 0.001). Patients reported a median score of 10 (0-10) for overall patient satisfaction with VIM-DBS treatment. Eight patients (17%) died after median 8.9 years (0.6-15) after surgery, at median age 77.4 years (70-89). One patient (2%) committed suicide seven months after the operation. Calculated standard mortality ratio among ET patients was 1.3 (CI 0.6-2.6), similar to the general population. CONCLUSION: We found no significant increase in mortality in this cohort of VIM-DBS operated ET patients compared to the general population in Norway. The patients reported high long-term satisfaction and continuing effect of VIM-DBS on tremor even after many years. VIM-DBS therefore seems to be an effective symptomatic long-term treatment of ET. However, one patient committed suicide. Only one other suicide has previously been reported after VIM-DBS. It is therefore still unclear whether VIM-DBS increases suicide risk.

Cognitive effects of deep brain stimulation for essential tremor: evaluation at 1 and 6 years.

Only a few studies have explored cognitive changes with deep brain stimulation (DBS) in patients with essential tremor (ET). Furthermore, the cognitive effects after years of electrical stimulation are unknown. Assessing the impact of stereotactic electrode implantation and the actual electrical stimulation on cognition in patients with ET in the short and long term is of interest, because DBS is increasingly applied and can offer deeper insight into human brain functions. We examined nine ET patients before surgery (PRE-SURGERY), and 1 and 6 years thereafter with DBS switched on (DBS-ON) and off (DBS-OFF). Standardized neuropsychological tests and reaction time tests were applied. There were no differences in tasks of verbal fluency, memory, and executive and intellectual functions comparing PRE-SURGERY, DBS-ON, and DBS-OFF at 1 and 6 years post-surgery. Imaging data revealed that the dorsolateral prefrontal cortex and mamillo-thalamic tracts crucial for cognitive functioning were spared by electrode implantation. Additionally, with electrodes targeting the thalamus and adjacent subthalamic area, the actual electrical stimulation did not affect neuropsychological functioning. However, lesions caused by electrode implantation led to an increase in simple reaction time, while the actual electrical stimulation restored impaired reaction time. This is the second largest study of neuropsychological functioning in patients with ET treated with DBS, and the first covering a neuropsychological long-term follow-up over 6 years. Neither stereotactic surgery nor electrical stimulation affected higher cognitive processes. This study proposes that cerebello-thalamo-cortical pathways in humans are involved in tasks of simple reaction time.

Personality profile in essential tremor: a case-control study.

BACKGROUND: Neuropsychiatric findings described in essential tremor (ET) include depression and anxiety. There may be personality features as well; in 2004, we demonstrated higher harm avoidance (HA) scores in ET patients than controls. We now (1) determined whether this finding could be replicated in a new sample of cases and controls, and (2) analyzed HA sub-scores (HA1-HA4) to further understand case-control differences. DESIGN/METHODS: 60 ET cases and 35 controls were evaluated using the Tridimensional Personality Questionnaire (TPQ), which assesses three domains of personality: HA, novelty seeking (NS), and reward dependence (RD). RESULTS: Total HA and total NS scores were marginally higher in cases than controls (14.8 ± 7.6 vs. 12.4 ± 5.3, p = 0.09) and (13.8 ± 5.4 vs. 11.8 ± 4.9, p = 0.09), respectively. When adjusted for age and gender, cases and controls differed with respect to total HA score (p = 0.03) but not total NS score (p = 0.10). Further analysis of HA sub-scores demonstrated that HA1 (anticipatory worry and pessimism) and HA4 (fatigability and asthenia) were most robustly elevated in cases vs. controls (p = 0.04 and p = 0.01, respectively). CONCLUSIONS: This study suggests that ET cases have a personality profile characterized by a greater HA, with certain domains of HA most affected. It is unclear whether this personality profile is pre-morbid or is a co-morbid feature of the illness, nor it is known whether the greater tendency towards HA in ET lessens receptivity to deep brain stimulation surgery and other therapies.

Long-term benefits in quality of life after unilateral thalamic deep brain stimulation for essential tremor.

OBJECT: The goal of this study was to evaluate short- and long-term benefits in quality of life (QOL) after unilateral deep brain stimulation (DBS) for essential tremor (ET). METHODS: Patients who received unilateral DBS of the ventral intermediate nucleus of the thalamus between 1997 and 2010 and who had at least 1 follow-up evaluation at least 1 year after surgery were included. Their QOL was assessed with the Parkinson Disease Questionnaire-39 (PDQ-39), and ET was measured with the Fahn-Tolosa-Marin tremor rating scale (TRS) prior to surgery and then postoperatively with the stimulation in the on mode. RESULTS: Ninety-one patients (78 at 1 year; 42 at 2-7 years [mean 4 years]; and 22 at >7-12 years [mean 9 years]) were included in the analysis. The TRS total, targeted tremor, and activities of daily living (ADL) scores were significantly improved compared with presurgical scores up to 12 years. The PDQ-39 ADL, emotional well-being, stigma, and total scores were significantly improved up to 7 years after surgery compared with presurgical scores. At the longest follow-up, only the PDQ-39 stigma score was significantly improved, and the PDQ-39 mobility score was significantly worsened. CONCLUSIONS: Unilateral thalamic stimulation significantly reduces ET and improves ADL scores for up to 12 years after surgery, as measured by the TRS. The PDQ-39 total score and the domains of ADL, emotional well-being, and stigma were significantly improved up to 7 years. Although scores were improved compared with presurgery, other than stigma, these benefits did not remain significant at the longest (up to 12 years) follow-up, probably related in part to changes due to aging and comorbidities.

Factors associated with receptivity to deep brain stimulation surgery among essential tremor cases.

BACKGROUND: A sizable proportion of essential tremor (ET) patients suffer from medically-refractory ET. Although deep brain stimulation (DBS) surgery is a safe and highly effective treatment, it may be under-utilized. We are unaware of studies that assess ET patients' attitudes toward DBS surgery and the factors that motivate them toward or away from such surgery. METHODS: ET cases, enrolled in an ongoing clinical-pathological study, underwent an in-person evaluation. They were asked "What is the likelihood that you would allow yourself to have DBS surgery?", thus rating their 'surgical receptivity' from 0 to 100. RESULTS: One-third (47/146, 32.2%) of ET cases reported that they would consider DBS surgery. In univariate analyses, younger age (p = 0.017), self-reported embarrassment (p = 0.001), more depressive symptoms (p = 0.008), more dysthymia (p = 0.029), higher total tremor score (marginal p = 0.13) and lower burden of medical comorbidity (marginal p = 0.16) were associated with greater surgical receptivity. In multivariate logistic regression models, only self-reported embarrassment (p = 0.006) and, marginally, younger age (p = 0.059) were independently associated with surgical receptivity. CONCLUSIONS: We identified a number of factors that were associated with increased receptivity to DBS surgery. Interestingly, psychosocial variables (dysthymia, depressive symptoms, self-reported embarrassment) featured prominently among these factors; indeed, self-reported embarrassment was the most robust factor. Tremor severity, though associated in univariate analyses with increased surgical receptivity, was not as robust of a predictor as was self-reported embarrassment. Future studies, which are community-based as well as those which also assess the patient's level of understanding about DBS will further add to the literature on this topic.

Elderly-onset essential tremor and mild cognitive impairment: a population-based study (NEDICES).

Mild cognitive impairment (MCI) is often considered to be a transitional stage between normal aging and dementia. Frontal-executive dysfunction, memory impairments, and dementia have been associated with essential tremor (ET). Yet the association between MCI and ET has only been examined in one prior study. We determined whether ET is associated with MCI. We identified all persons with MCI and ET in a dementia-free, population-based study in central Spain (NEDICES). MCI was diagnosed using consensus criteria of the International Working Group on MCI. Forty-two (20.3%) of 207 ET cases had MCI versus 399 (16.1%) of 2,472 non-ET subjects (controls) (odds ratio [OR] = 1.32, 95% Confidence Interval [CI] = 0.93 to 1.89, p = 0.12). In a model that adjusted for age, gender, educational level, smoking, hearing impairment, depressive symptoms or antidepressant use, and use of a medication that could potentially affect cognitive function, the OR was 1.28, 95% CI = 0.88 to 1.84, p = 0.19. In an adjusted model, ET cases with tremor onset after age 65 were 57% more likely to have MCI than controls (OR = 1.57, 95% CI = 1.03 to 2.38, p = 0.03), whereas ET cases with tremor onset prior to age 65 and controls were equally likely to have MCI (OR = 0.73, 95% CI = 0.34 to 1.57, p = 0.43). In this study, older-onset ET was associated with MCI. This finding supports the hypothesis that cognitive disturbances are one of the core non-motor symptoms of ET.

Do patient's get angrier following STN, GPi, and thalamic deep brain stimulation.

OBJECTIVE: The objective of the study was to examine whether deep brain stimulation (DBS) of the subthalamic nucleus (STN), the globus pallidus internus (GPi), and/or the ventralis intermedius thalamic nucleus (Vim) was associated with making patients angrier pre to post-surgical intervention. BACKGROUND: Secondary outcome analysis of the NIH COMPARE Parkinson's Disease DBS trial revealed that participants were angrier and had more mood and cognitive side effects following DBS. Additionally blinded on/off analysis did not change anger scores. The sample size was small but suggested that STN DBS may have been worse than GPi in provoking anger. We endeavored to examine this question utilizing a larger dataset (the UF INFORM database), and also we included a third surgical target (Vim), which has been utilized for a different disease, essential tremor. METHODS: Consecutive patients from the University of Florida Movement Disorders Center who were implanted with unilateral DBS for Parkinson's disease (STN or GPi) or essential tremor (Vim) were included. Patients originally implanted at outside institutions were excluded. Pre-operative and 4- to 6-month post-operative Visual Analog Mood Scale (VAMS) scores for all three groups were compared; additionally, pre-operative and 1- to 3-month scores were compared for STN and GPi patients. A linear regression model was utilized to analyze the relationship between the VAMS anger score and the independent variables of age, years with symptoms, Mini-Mental Status Examination (MMSE) score, handedness, ethnicity, gender, side of surgery, target of surgery, baseline Dementia Rating Scale (DRS) total score, baseline Beck Depression Index (BDI) score, micro- and macroelectrode passes, and years of education. Levodopa equivalent dosages and dopamine agonist use were analyzed for a potential impact on anger scores. RESULTS: A total of 322 unilateral DBS procedures were analyzed, with STN (n=195), Vim (n=71), and GPi (n=56) making up the cohort. An ANOVA was used to detect significant differences among the three targets in the changes pre- to post-operatively. Similar to the COMPARE dataset, at 4 months, the only subscore of VAMS to reveal a significant difference between the three targets was the angry subscore, with GPi revealing a mean (standard) change of 2.38 (9.53); STN, 4.82 (14.52); and Vim, -1.17 (11.51) (p=0.012). At 1-3 months post-operation, both STN and GPi groups were significantly angrier (p=0.004), but there was no significant difference between the two groups. However, GPi patients were significantly more confused as compared to STN patients (p=0.016). The linear regression model which sought independent explanatory variables revealed a relationship between the VAMS anger score and the surgical target and the disease duration. The mean changes for STN and GPi DBS pre- to post-operation were 11.67 (p=0.001) and 8.21 (p=0.022) units more than those with Vim, respectively. For every year added of disease duration, the VAMS anger score increased by 0.24 (p=0.022). For the GPi and STN groups, number of microelectrode passes was significantly associated with angry score changes (p=0.014), with the anger score increasing 2.29 units per microelectrode pass. Independent variables not associated with the VAMS anger score included the surgery side, handedness, gender, ethnicity, education, age at surgery, MMSE, DRS, and BDI scores. Although the STN group significantly decreased in LED when compared to GPi, there was no relationship to anger scores. Similarly, dopamine agonist use was not different between STN and GPi groups and did not correlate with the VAMS anger score changes. CONCLUSIONS: STN and GPi DBS for Parkinson's disease were associated with significantly higher anger scores pre- to post-DBS as compared to Vim for essential tremor. Anger score changes in STN and GPi patients seem to be associated with microelectrode passes, suggesting that it may be a lesional effect. PD patients with longer disease duration may be particularly susceptible, and this should be kept in mind when discussing the potential of DBS surgery for an individual patient. Essential tremor patients who on average have much longer disease durations did not get angrier. The changes in anger scores were not related to LED change or dopamine agonist use. Whether the induction of anger is disease-specific or target-specific is not currently known; however, our data would suggest that PD patients implanted in STN or GPi are at a potential risk. Finally, on closer inspection of the COMPARE DBS data, VAMS anger scores did not change on or off DBS, suggesting that anger changes may be more of a lesional effect rather than a stimulation induced one (Okun et al., 2009).

Philadelphia Geriatric Morale Scale in essential tremor: a population-based study in three Spanish communities.

Essential tremor (ET) is associated with both functional disability and depression. Each could contribute to a poor sense of well-being and low morale. We hypothesized that morale would be lower in ET cases than controls. Using a population-based, cross-sectional design, morale was assessed in 187 ET cases and 561 matched controls living in three communities in central Spain using the Philadelphia Geriatric Center Morale Scale (PGCMS) (range = 0 [low morale]-17), which included three-dimensions of psychological well-being: agitation, lonely dissatisfaction, and attitude toward own aging. The PGCMS score was lower in ET cases than controls (9.41 +/- 3.21 vs. 10.39 +/- 2.92, P < 0.001), as were the Agitation subscore (3.17 +/- 1.71 vs. 3.78 +/- 1.67, P< 0.001) and Lonely Dissatisfaction subscore (3.75 +/- 1.34 vs. 4.02 +/- 1.24, P < 0.05). Nearly one-half of the ET cases were classified as having low morale compared with only one-third of controls (P = 0.006). In a linear regression analysis adjusting for demographic factors and multiple comorbid conditions, ET cases had a lower log PGCMS score than controls (P < 0.001). Exclusion of participants on antidepressant medication did not change the results. Our results indicate that morale is significantly lower in community-dwelling ET cases than in matched controls. This lower morale could in part be a proxy for mild, untreated depression. It therefore seems important to detect and then possibly treat this problem to improve the psychological well-being of patients with this disease.

Stimulation of the motor cortex for disabling essential tremor.

OBJECTIVE: To examine the safety and efficacy of targeted stimulation of the motor cortex as a treatment for essential tremor (ET). PATIENTS AND METHODS: At the University of Kansas Medical Center, two patients with essential tremor received stimulation of the (contralateral) motor cortex using an investigational implantable pulse generator (IPG). Patients were evaluated with the Fahn Tolosa Marin tremor rating scale (TRS) at baseline, 1 week and 4 weeks after surgery, both with stimulation turned on and turned off. Both patients also received neuropsychological assessments at baseline and again after surgery. RESULTS: Patient 1 was a 75-year-old male with tremor for 20 years. His baseline total TRS score was 61 and his TRS 1 month after surgery was 57. His IPG was set at 30 Hz, 3 mA and 250 micros pulse width. Patient 2 was a 60-year-old male with tremor for over 10 years. His baseline total TRS was 47 and it was 43, 1 month after surgery. His IPG was set at 50 Hz, 5 mA and 250 micros pulse width. There were no adverse effects. CONCLUSION: Cortical stimulation of the primary hand motor cortex contralateral to the dominant hand was ineffective for the treatment of ET with the stimulation parameters used in this study. Future research examining other stimulation parameters is necessary to determine if there is a role for cortical stimulation in the treatment of ET.