Clinical Study Stereotact Funct Neurosurg 2015;93:127–132 DOI: 10.1159/000368438
Received: December 31, 2013 Accepted after revision: September 18, 2014 Published online: February 19, 2015
Effects of Cerebellothalamic Tractotomy on Cognitive and Emotional Functioning in Essential Tremor: A Preliminary Study in 5 Essential Tremor Patients Katharina Ledermann a Daniel Jeanmonod b Salome McAleese d Christoph Aufenberg f Klaus Opwis c Chantal Martin-Soelch e
a Department of Psychiatry and Psychotherapy and b Neurosurgical Clinic, Functional Neurosurgery, University Hospital Zurich, Zurich, c Department of Psychology, Center for Cognitive Psychology and Methodology, University of Basel, and d Hoffmann-La Roche, Basel, and e Department of Psychology, Division of Clinical Psychology, University of Fribourg, Fribourg, Switzerland; f Klinik für Neurologie mit Klinischer Neurophysiologie, Herz-Jesu-Krankenhaus, Akademisches Lehrkrankenhaus der Westfälischen-Wilhelms-Universität Münster, Münster, Germany
Abstract Background: Subthalamic stereotactic interventions have recently caught renewed interest as a treatment for essential tremor (ET). However, it is not clear whether these interventions are associated with neurocognitive, mood or personality changes. Objective: To investigate neurocognition, neuropsychiatric functions and personality variables in patients with ET and to explore the neurocognitive and neuropsychiatric effects of cerebellothalamic tractotomy (CTT), a form of subthalamotomy. Methods: In our study, we investigated cognitive functions, frontal functions, mood and personality variables in 5 patients with intractable ET. Patients were tested before and 3 months after surgery using neuropsychological tests, clinical scales for depression, anxiety, anger regulation and a personality test. Results: Before surgery, ET patients showed normal neurocognitive function, a slightly elevated frontal lobe score in the dimensions mental control
© 2015 S. Karger AG, Basel 1011–6125/15/0932–0127$39.50/0 E-Mail [email protected] www.karger.com/sfn
and memory, without being indicative of a frontal lesion, and no elevated depression or anxiety scores compared to norm values. After surgery, there was no change in neurocognitive function and no increase in depression or anxiety scores. Conclusion: In this exploratory study on 5 ET patients, CTT was not associated with alterations of mood or neurocognitive functions. © 2015 S. Karger AG, Basel
Introduction
Essential tremor (ET) is one of the most common movement disorders [1, 2]. The prevalence of ET has been estimated to be between 4 and 5.6% among individuals aged 40 years and above [3], and its prevalence continues to rise with age, prevalence estimates being up to 21.7% among persons aged 95 and older [4]. It is characterized not only by kinetic or postural tremor, but, as recent literature suggests, also by a broader tremor phenomenology with other motor manifestations and cognitive and psychiatric nonmotor features [5, 6]. CogniKatharina Ledermann, PhD Department of Psychiatry and Psychotherapy University Hospital Zurich Haldenbach 16/18, CH–8091 Zürich (Switzerland) E-Mail Katharina.ledermann @ usz.ch
Downloaded by: University of Pittsburgh 198.143.32.65 - 1/27/2016 9:32:29 PM
Key Words Essential tremor · Stereotactic surgery · Neurocognition · Neuropsychiatry
128
Stereotact Funct Neurosurg 2015;93:127–132 DOI: 10.1159/000368438
ment. There are only few [24] controlled studies on the effect of the thalamic target on neurocognitive function, frontal functions, personality and mood in ET and as far as we know none on the subthalamic target. Subthalamic interventions leave thalamic cells intact, which might correlate with a lower incidence of cognitive/emotional impairments. The first aim of this explorative study was to investigate neurocognitive functions, mood and personality variables in patients with ET before and after CTT. We hypothesized that (1) ET patients would show preoperative cognitive impairments, increased depression scores and, on the personality inventory, higher levels of inhibitedness and anger ‘out’ scores and that (2) the CTT would not worsen cognitive functioning and might be associated with improvement in mood.
Methods Study Design This is a case study with a pre/post design. We performed a testing session before surgery (baseline) and a follow-up session 3 months after surgery. The time period during which these cases were studied was from the beginning of 2003 to the end of 2004. Study Setting Participants were tested before and after surgery at the Neurosurgical Clinic of the University Hospital Zurich, in an outpatient setting when coming for the regular medical visits. Participants We included 5 patients (4 men) with ET who were treated by CTT at the Department of Functional Neurosurgery at the University Hospital Zurich. Tremor relief, rated between 0 and 4, was examined using classical neurological tests, i.e. drinking and pouring, writing by hand and drawing spirals, by a medical intern specialized in neurosurgery. Neurosurgical Procedure Reversibility is often cited as an important advantage of the DBS technology. However, and also most significantly, radiofrequency lesioning has, in contrast to DBS, no ongoing long-term technical complications. These were shown to amount to 8.4% per electrode-year [37]. Having the possibility to use a subthalamic target, thus leaving the thalamus intact and sparing the thalamocortical functions, we opted for the radiofrequency lesioning CTT. The center of the CTT target is located 5 mm posterior to the midcommissural point, 3 mm below the intercommissural line and 8 mm lateral to the thalamoventricular border. It was reached using an anteroposterior angle of 55° and a mediolateral angle of 20°. Physiological confirmation was performed using microelectrode recordings and macrostimulation. The active radiofrequency electrode tip was 1.1/2 mm, and the dimensions of the radiofrequency thermolesion ellipsoid were 4 over 5 mm. The target tissue was heated to temperatures between 85 and 90 ° C; more details about the surgical procedure can be found in Magnin et al.
Ledermann/Jeanmonod/McAleese/ Aufenberg/Opwis/Martin-Soelch
Downloaded by: University of Pittsburgh 198.143.32.65 - 1/27/2016 9:32:29 PM
tive abnormalities characterized by mild frontal dysfunction have been investigated in these patients [for a review, see 7]. Some studies reported considerable proportions of depressive symptoms in ET patients [6, 8, 9; for a review, see 10, 11]. Although only few studies (e.g. Chatterjee et al. [12]) have investigated personality traits in ET so far, a higher prevalence of anxiety and an anxious personality type were reported in ET patients [for a review, see 10, 11]. In other movement disorders, such as Parkinson’s disease, lower levels of external expression of anger and higher levels of anger control have been reported [13]. The pathophysiology of ET still engenders debate. Several lines of evidence relate tremor genesis to anomalies of the cerebellothalamic pathway [14, 15]. In humans, hyperactivity of the cerebellum is thought to trigger a dysfunction of the cerebellothalamic tract [16]. The involvement of the thalamus in tremor genesis is supported by, among other findings, the elimination or diminution of tremor by thalamotomy and thalamic deep brain stimulation (DBS) of the cerebellarrecipient thalamic nucleus [for a review, see 14]. Medications are often considered to be effective in only 50% of patients [2]. When the disorder becomes resistant to medication, surgical options for such patients are either ablative procedures such as thalamotomy [17, 18] or DBS [19]. Although thalamic DBS has been shown to be a safe and effective therapy in ET patients followed for up to 13 years [20], ET cases exist where DBS failed to produce symptomatic or functional improvement. Thalamotomy has been shown to provide improvement in function for these patients [21]. Stereotactic surgery of the cerebellar-recipient ventral lateral posterior (or ventral intermedius) thalamic nucleus and of the subthalamic area below it can be effective with an estimated average rate of success of at least 70–80% of cases [15, 22–29]. There is strong clinical and neuroanatomical evidence [30] that the interventions performed in the part of the subthalamus situated below the cerebellar-recipient thalamic nucleus, which has received different names (posterior subthalamic area, prelemniscal radiation, caudal zona incerta), interrupt the cerebellothalamic tract on its way to the ventral lateral posterior nucleus. We have thus chosen to call it cerebellothalamic tractotomy (CTT) [31]. It is to be noted that subthalamic targets have been proposed early in the history of stereotactic neurosurgery [32–34]. There is some recent evidence that the subthalamic target is more efficient in ET than the thalamic one [25, 35, 36]. It presents the additional advantage of a small target, optimal to be covered by stimulation or to receive thermocoagulation treat-
Patient Sex Age, Duration, Surgical years years target
Medicated Long-term in both relief, % testing sessions
P1 P2 P3 P4 P5
yes yes yes yes yes
M M M M F
42 68 77 67 65
25 10 15 20 23
CTT left CTT left CTT left CTT right CTT left
100 100 100 100 100
Duration corresponds to the time since diagnosis. The patient’s estimation of the long-term postoperative relief, expressed as percentage of the preoperative value, was determined based on the physician’s evaluation.
[31]. Postoperative MRI and an atlas drawing displaying the CTT target are provided in the supplementary material (online suppl. fig. 1 [57]; for all online suppl. material, see www.karger.com/ doi/10.1159/000368438). All patients gave written informed consent for neuropsychological testing. Patient 1 had a thalamic stimulator implanted for 2 years, which was extracted before baseline testing and stereotactic surgery in the cerebellothalamic tract. The other patients had no history of surgical treatment of the tremor. The patients’ characteristics and the stereotactic targets are documented in table 1. All patients remained under their personal medication throughout our testing sessions (including antihypertensives, antidepressants, tranquilizers, β-blockers, glucocorticoids, antiepileptics and analgetics). Variables The main outcome variables were tremor relief, neurocognitive functioning, neuropsychiatric state and personality characteristics in ET patients (before and after surgery). The main confounder variable was the medication.
ry as evaluated by a word list learning test. The neuropsychiatric state was assessed using the Beck Depression Inventory [44] for depression, the State-Trait Anxiety Inventory [45] for anxiety and the State-Trait Anger Inventory [46] for anger regulation. We used the Freiburg Personality Inventory (FPI) to assess personality variables. The FPI is a list of 138 descriptions of personal characteristics which have to be answered with ‘true’ or ‘false’, measuring the following personality variables: life satisfaction, social orientation, achievement orientation, inhibitedness, excitability, aggressiveness, strain, somatic complaints, health concerns, frankness, extraversion and emotionality [47]. The scores of these subscales are expressed as age- and sex-matched standard stanine scores. Neuropsychological testing sessions were scheduled a few days before surgery (baseline) and 3 months after surgery (follow-up). Testing sessions took place at the University Hospital Zurich. Data Analyses For each dependent measure, raw test scores were converted to demographically adjusted standard scores using published normative data [47–50]. ET patients were compared at baseline with the standard norms of the neuropsychological tests. Follow-up test scores were compared with the norm values and the baseline scores. The statistical significance of the observed difference was corrected for multiple comparisons for each independent measure (3 comparisons for the group of ET patients: with the norm and with the postsurgical results). We used 1-sample t tests for the comparison with the norm value, i.e. the Bonferroni-corrected level of significance (BF) of p < 0.05/3 = 0.016. We used paired t tests for pre/post surgery comparisons (BF of p < 0.05/3 = 0.016). Unless otherwise specified, p values are 2-tailed, and the statistical significance threshold is at p < 0.05. The size of the observed effects in the 3 comparisons was calculated using Cohen’s d (0.2 < d < 0.4: small effect; 0.5 < d < 0.7: medium effect; d > 0.8: large effect). To check whether our nonsignificant results were due to a lack of statistical power, we conducted post hoc power analyses using GPower [51]. The data were analyzed using the Statistical Package for the Social Sciences software (version 20.0, IBM, Chicago, Ill., USA).
Results
Measures Neurocognitive functioning was assessed using the Mini Mental State Examination (MMSE) combined with clock drawing (MMS comb.) to screen for general cognitive functioning. Clock drawing has been shown to be a useful tool for examining spatial and constructive abilities, neglect or perseverance tendencies [38]. For the MMSE, a score
Received: December 31, 2013 Accepted after revision: September 18, 2014 Published online: February 19, 2015
Effects of Cerebellothalamic Tractotomy on Cognitive and Emotional Functioning in Essential Tremor: A Preliminary Study in 5 Essential Tremor Patients Katharina Ledermann a Daniel Jeanmonod b Salome McAleese d Christoph Aufenberg f Klaus Opwis c Chantal Martin-Soelch e
a Department of Psychiatry and Psychotherapy and b Neurosurgical Clinic, Functional Neurosurgery, University Hospital Zurich, Zurich, c Department of Psychology, Center for Cognitive Psychology and Methodology, University of Basel, and d Hoffmann-La Roche, Basel, and e Department of Psychology, Division of Clinical Psychology, University of Fribourg, Fribourg, Switzerland; f Klinik für Neurologie mit Klinischer Neurophysiologie, Herz-Jesu-Krankenhaus, Akademisches Lehrkrankenhaus der Westfälischen-Wilhelms-Universität Münster, Münster, Germany
Abstract Background: Subthalamic stereotactic interventions have recently caught renewed interest as a treatment for essential tremor (ET). However, it is not clear whether these interventions are associated with neurocognitive, mood or personality changes. Objective: To investigate neurocognition, neuropsychiatric functions and personality variables in patients with ET and to explore the neurocognitive and neuropsychiatric effects of cerebellothalamic tractotomy (CTT), a form of subthalamotomy. Methods: In our study, we investigated cognitive functions, frontal functions, mood and personality variables in 5 patients with intractable ET. Patients were tested before and 3 months after surgery using neuropsychological tests, clinical scales for depression, anxiety, anger regulation and a personality test. Results: Before surgery, ET patients showed normal neurocognitive function, a slightly elevated frontal lobe score in the dimensions mental control
© 2015 S. Karger AG, Basel 1011–6125/15/0932–0127$39.50/0 E-Mail [email protected] www.karger.com/sfn
and memory, without being indicative of a frontal lesion, and no elevated depression or anxiety scores compared to norm values. After surgery, there was no change in neurocognitive function and no increase in depression or anxiety scores. Conclusion: In this exploratory study on 5 ET patients, CTT was not associated with alterations of mood or neurocognitive functions. © 2015 S. Karger AG, Basel
Introduction
Essential tremor (ET) is one of the most common movement disorders [1, 2]. The prevalence of ET has been estimated to be between 4 and 5.6% among individuals aged 40 years and above [3], and its prevalence continues to rise with age, prevalence estimates being up to 21.7% among persons aged 95 and older [4]. It is characterized not only by kinetic or postural tremor, but, as recent literature suggests, also by a broader tremor phenomenology with other motor manifestations and cognitive and psychiatric nonmotor features [5, 6]. CogniKatharina Ledermann, PhD Department of Psychiatry and Psychotherapy University Hospital Zurich Haldenbach 16/18, CH–8091 Zürich (Switzerland) E-Mail Katharina.ledermann @ usz.ch
Downloaded by: University of Pittsburgh 198.143.32.65 - 1/27/2016 9:32:29 PM
Key Words Essential tremor · Stereotactic surgery · Neurocognition · Neuropsychiatry
128
Stereotact Funct Neurosurg 2015;93:127–132 DOI: 10.1159/000368438
ment. There are only few [24] controlled studies on the effect of the thalamic target on neurocognitive function, frontal functions, personality and mood in ET and as far as we know none on the subthalamic target. Subthalamic interventions leave thalamic cells intact, which might correlate with a lower incidence of cognitive/emotional impairments. The first aim of this explorative study was to investigate neurocognitive functions, mood and personality variables in patients with ET before and after CTT. We hypothesized that (1) ET patients would show preoperative cognitive impairments, increased depression scores and, on the personality inventory, higher levels of inhibitedness and anger ‘out’ scores and that (2) the CTT would not worsen cognitive functioning and might be associated with improvement in mood.
Methods Study Design This is a case study with a pre/post design. We performed a testing session before surgery (baseline) and a follow-up session 3 months after surgery. The time period during which these cases were studied was from the beginning of 2003 to the end of 2004. Study Setting Participants were tested before and after surgery at the Neurosurgical Clinic of the University Hospital Zurich, in an outpatient setting when coming for the regular medical visits. Participants We included 5 patients (4 men) with ET who were treated by CTT at the Department of Functional Neurosurgery at the University Hospital Zurich. Tremor relief, rated between 0 and 4, was examined using classical neurological tests, i.e. drinking and pouring, writing by hand and drawing spirals, by a medical intern specialized in neurosurgery. Neurosurgical Procedure Reversibility is often cited as an important advantage of the DBS technology. However, and also most significantly, radiofrequency lesioning has, in contrast to DBS, no ongoing long-term technical complications. These were shown to amount to 8.4% per electrode-year [37]. Having the possibility to use a subthalamic target, thus leaving the thalamus intact and sparing the thalamocortical functions, we opted for the radiofrequency lesioning CTT. The center of the CTT target is located 5 mm posterior to the midcommissural point, 3 mm below the intercommissural line and 8 mm lateral to the thalamoventricular border. It was reached using an anteroposterior angle of 55° and a mediolateral angle of 20°. Physiological confirmation was performed using microelectrode recordings and macrostimulation. The active radiofrequency electrode tip was 1.1/2 mm, and the dimensions of the radiofrequency thermolesion ellipsoid were 4 over 5 mm. The target tissue was heated to temperatures between 85 and 90 ° C; more details about the surgical procedure can be found in Magnin et al.
Ledermann/Jeanmonod/McAleese/ Aufenberg/Opwis/Martin-Soelch
Downloaded by: University of Pittsburgh 198.143.32.65 - 1/27/2016 9:32:29 PM
tive abnormalities characterized by mild frontal dysfunction have been investigated in these patients [for a review, see 7]. Some studies reported considerable proportions of depressive symptoms in ET patients [6, 8, 9; for a review, see 10, 11]. Although only few studies (e.g. Chatterjee et al. [12]) have investigated personality traits in ET so far, a higher prevalence of anxiety and an anxious personality type were reported in ET patients [for a review, see 10, 11]. In other movement disorders, such as Parkinson’s disease, lower levels of external expression of anger and higher levels of anger control have been reported [13]. The pathophysiology of ET still engenders debate. Several lines of evidence relate tremor genesis to anomalies of the cerebellothalamic pathway [14, 15]. In humans, hyperactivity of the cerebellum is thought to trigger a dysfunction of the cerebellothalamic tract [16]. The involvement of the thalamus in tremor genesis is supported by, among other findings, the elimination or diminution of tremor by thalamotomy and thalamic deep brain stimulation (DBS) of the cerebellarrecipient thalamic nucleus [for a review, see 14]. Medications are often considered to be effective in only 50% of patients [2]. When the disorder becomes resistant to medication, surgical options for such patients are either ablative procedures such as thalamotomy [17, 18] or DBS [19]. Although thalamic DBS has been shown to be a safe and effective therapy in ET patients followed for up to 13 years [20], ET cases exist where DBS failed to produce symptomatic or functional improvement. Thalamotomy has been shown to provide improvement in function for these patients [21]. Stereotactic surgery of the cerebellar-recipient ventral lateral posterior (or ventral intermedius) thalamic nucleus and of the subthalamic area below it can be effective with an estimated average rate of success of at least 70–80% of cases [15, 22–29]. There is strong clinical and neuroanatomical evidence [30] that the interventions performed in the part of the subthalamus situated below the cerebellar-recipient thalamic nucleus, which has received different names (posterior subthalamic area, prelemniscal radiation, caudal zona incerta), interrupt the cerebellothalamic tract on its way to the ventral lateral posterior nucleus. We have thus chosen to call it cerebellothalamic tractotomy (CTT) [31]. It is to be noted that subthalamic targets have been proposed early in the history of stereotactic neurosurgery [32–34]. There is some recent evidence that the subthalamic target is more efficient in ET than the thalamic one [25, 35, 36]. It presents the additional advantage of a small target, optimal to be covered by stimulation or to receive thermocoagulation treat-
Patient Sex Age, Duration, Surgical years years target
Medicated Long-term in both relief, % testing sessions
P1 P2 P3 P4 P5
yes yes yes yes yes
M M M M F
42 68 77 67 65
25 10 15 20 23
CTT left CTT left CTT left CTT right CTT left
100 100 100 100 100
Duration corresponds to the time since diagnosis. The patient’s estimation of the long-term postoperative relief, expressed as percentage of the preoperative value, was determined based on the physician’s evaluation.
[31]. Postoperative MRI and an atlas drawing displaying the CTT target are provided in the supplementary material (online suppl. fig. 1 [57]; for all online suppl. material, see www.karger.com/ doi/10.1159/000368438). All patients gave written informed consent for neuropsychological testing. Patient 1 had a thalamic stimulator implanted for 2 years, which was extracted before baseline testing and stereotactic surgery in the cerebellothalamic tract. The other patients had no history of surgical treatment of the tremor. The patients’ characteristics and the stereotactic targets are documented in table 1. All patients remained under their personal medication throughout our testing sessions (including antihypertensives, antidepressants, tranquilizers, β-blockers, glucocorticoids, antiepileptics and analgetics). Variables The main outcome variables were tremor relief, neurocognitive functioning, neuropsychiatric state and personality characteristics in ET patients (before and after surgery). The main confounder variable was the medication.
ry as evaluated by a word list learning test. The neuropsychiatric state was assessed using the Beck Depression Inventory [44] for depression, the State-Trait Anxiety Inventory [45] for anxiety and the State-Trait Anger Inventory [46] for anger regulation. We used the Freiburg Personality Inventory (FPI) to assess personality variables. The FPI is a list of 138 descriptions of personal characteristics which have to be answered with ‘true’ or ‘false’, measuring the following personality variables: life satisfaction, social orientation, achievement orientation, inhibitedness, excitability, aggressiveness, strain, somatic complaints, health concerns, frankness, extraversion and emotionality [47]. The scores of these subscales are expressed as age- and sex-matched standard stanine scores. Neuropsychological testing sessions were scheduled a few days before surgery (baseline) and 3 months after surgery (follow-up). Testing sessions took place at the University Hospital Zurich. Data Analyses For each dependent measure, raw test scores were converted to demographically adjusted standard scores using published normative data [47–50]. ET patients were compared at baseline with the standard norms of the neuropsychological tests. Follow-up test scores were compared with the norm values and the baseline scores. The statistical significance of the observed difference was corrected for multiple comparisons for each independent measure (3 comparisons for the group of ET patients: with the norm and with the postsurgical results). We used 1-sample t tests for the comparison with the norm value, i.e. the Bonferroni-corrected level of significance (BF) of p < 0.05/3 = 0.016. We used paired t tests for pre/post surgery comparisons (BF of p < 0.05/3 = 0.016). Unless otherwise specified, p values are 2-tailed, and the statistical significance threshold is at p < 0.05. The size of the observed effects in the 3 comparisons was calculated using Cohen’s d (0.2 < d < 0.4: small effect; 0.5 < d < 0.7: medium effect; d > 0.8: large effect). To check whether our nonsignificant results were due to a lack of statistical power, we conducted post hoc power analyses using GPower [51]. The data were analyzed using the Statistical Package for the Social Sciences software (version 20.0, IBM, Chicago, Ill., USA).
Results
Measures Neurocognitive functioning was assessed using the Mini Mental State Examination (MMSE) combined with clock drawing (MMS comb.) to screen for general cognitive functioning. Clock drawing has been shown to be a useful tool for examining spatial and constructive abilities, neglect or perseverance tendencies [38]. For the MMSE, a score
