Optical coherence tomography is associated with cognitive and physical disability in multiple sclerosis independently of other biomarkers.
Nuria Cerdá Fuertes (Basel | CH)
We aimed at evaluating the relative role of Optical coherence tomography (OCT) next to serum neurofilament light chain (sNfL) and magnetic resonance imaging (MRI), for assessing cognitive and physical disability in multiple sclerosis (MS).
Cross-sectional study with 100 MS patients (63 female, age: 50.4±11.5 years(y); disease duration: 18.7± 9.8y; education: 14.1±3.3y, 80% with relapsing remitting MS) and 52 matched healthy controls (HC; 34 female, age: 51.4±13.7y; education: 16.0±3.3y). All subjects underwent an OCT to assess the mean peripapillary retinal nerve fiber layer (pRNFL) thickness, and the volume of the ganglion cell-inner plexiform- (GCIPL) and inner nuclear layers (INL). For patients with prior optic neuritis, we included only the non-affected eye and for the rest, we took the average OCT measures of both eyes. Brief International Cognitive Assessment for Multiple Sclerosis and the Expanded Disability Status Scale (EDSS) were used to quantify cognitive and physical disability. sNfl levels were measured and T2 lesion volume (T2LV) and brain parenchymal fraction (BPF) were assessed on MRI, using GruSEG and FreeSurfer respectively.
Compared to HC, patients had lower mean pRNFL thickness (p< 0.001) and GCIPL volume (p< 0.001), but INL volume did not differ (p= 0.093).
After correction for age, vision and education, pRNFL thickness was associated with the symbol digit modalities test (SDMT) in patients (β= 0.2, p= 0.030). In a multivariate analysis including sNfL, BPF and T2LV, pRNFL (β= 0.19, p= 0.044) and T2LV (β= -0.24, p= 0.023) were the only predictors that remained associated with the SDMT.
Mean pRNFL thickness and GCIPL volume showed associations with the EDSS (β= -0.37, p< 0.001 and β= -0.46, p< 0.001). In a multivariate analysis including sNfL, BPF, and T2LV, GCIPL volume was the strongest predictor of the EDSS (β= -0.32, p< 0.001), followed by sNfL (β= 0.18, p= 0.024).
OCT measures, as markers of neuroaxonal loss, are associated with cognitive and physical disability in MS patients independently of serum- (sNfL) and MRI- (BPF, T2LV) markers. Furthermore, GCIPL was the strongest predictor of physical disability. With the advantage of being a quick, patient-friendly examination, needing only minimal post-processing, OCT can play a major role in the stratification of MS patients at risk of higher cognitive and physical disability.
Therapeutic burst-suppression for refractory status epilepticus – a relevant treatment goal? A single-center 9-years cohort study.
Urs Fisch (Basel | CH)
Current guidelines recommend to treat refractory status epilepticus (RSE) with continuous intravenous anesthetic drugs (IVAD) to achieve a electroencephalographic (EEG) burst attenuation/suppression pattern (BS). However, the evidence for the benefit of BS and its appropriate extent and duration is scarce. This study investigated the frequency of therapeutically induced BS and its association with clinical outcome in adult RSE patients receiving IVAD as antiseizure treatment.
Retrospective analysis of all adult patients treated for RSE with continuous IVAD in an intensive care unit of a Swiss academic tertiary medical center between 2011 and 2019. BS was visually assessed during the first two minutes of each one-hour epoch of EEG monitoring. BS with ≥ 50 % suppression percent was defined according to the American Clinical Neurophysiology Society’s (ACNS) Standardized Critical Care EEG Terminology 2021, whereas a BS with a suppression percent between 20 – 49 % was defined as incomplete BS. The primary outcome was the frequency of induced EEG burst-suppression during IVAD treatment. Secondary outcomes were the association of clinical courses and outcomes of RSE patients with the presence of BS or incomplete BS. Logistic regression was performed for outcome analysis.
Of 526 adult patients with status epilepticus (SE) between 2011 and 2019, 147 RSE patients with IVAD as antiseizure treatment were identified (median 63 years, 44 % female). Thereof, 85 (58 %) patients had presumed fatal etiology. Among RSE patients with IVAD, 34 (23 %) attained BS and 25 (17 %) incomplete BS at least at one time point during EEG monitoring. The univariable comparison between patients with and without persistent termination of RSE did not show an association with the presence of BS (p = 0.13), incomplete BS (p = 0.41) or absence of any BS (p = 0.43). Likewise, the univariable comparison between surviving and non-surviving patients did not show any association with BS (p = 0.83), incomplete BS (p = 0.47) or absence of BS (p = 0.71). In contrast, presumed fatal etiology was significantly associated with absence of RSE termination (p = 0.006) and death (p = 0.001).
Our results underscore the challenges of achieving EEG BS as recommended during IVAD treatment in patients with RSE. Furthermore, in contrast to SE etiology, our analysis did not find evidence that achievement of BS influences persistent RSE termination or survival.
Receptor clustering and pathogenic complement activation in myasthenia gravis depend on synergy between antibodies with multiple subunit specificities
Tobias Derfuss (Basel | CH)
Myasthenia gravis is an autoimmune disorder defined by muscle weakness and fatigability associated with antibodies against proteins of the neuromuscular junction (NMJ). The most common autoantibody target is the acetylcholine receptor (AChR). Three mechanisms have been postulated by which autoantibodies might interfere with neurotransmission: direct blockade of acetylcholine binding to receptor, complement-mediated damage of the postsynaptic membrane, and enhanced internalization of the receptor. It is very likely that more than one of these mechanisms operate in parallel, and therefore dissecting the mechanisms of autoantibody-mediated pathology requires patient-derived, monoclonal antibodies.
Using membrane antigen capture activated cell sorting (MACACS) we isolated AChR-specific B cells from patients with myasthenia gravis, and produced and studied recombinant antibodies. All six cloned AChR-antibodies were hypermutated, but of varying isotypes (IgG1, IgG3, IgG4) and recognizing the four different chains of the AChR. Despite strong binding to the receptor, none of the individual antibodies had a strong influence on neuromuscular signal transmission as measured in an in vitro neuromuscular synapse model. They also did not activate complement or induce myasthenic signs in vivo. However, combinations of antibodies induced strong complement activation in vitro, and severe muscle weakness in a passive transfer myasthenia gravis rat model, associated with NMJ destruction and complement activation in muscle. The strongest complement activation was mediated by combinations of antibodies targeting disparate subunits of the AChR, and such combinations also induced the formation of large clusters of AChR on the surface of live cells in vitro. We propose that this synergy between antibodies of different epitope specificities is a fundamental feature of the disease, that can explain the well-known discrepancy between serum anti-AChR titers and clinical severity. This model also has implications for therapeutic strategies currently under investigation.
MRI-based small vessel disease classification of intracerebral haemorrhage
Martina Goeldlin (Bern | CH)
Background: Cerebral small vessel disease (SVD) is the major cause of intracerebral hemorrhage (ICH), but there is no comprehensive classification of ICH subtypes according to different SVD phaenotypes. We aimed to develop an MRI-based classification for SVD-related ICH and assess association with outcomes.
Methods: We performed a retrospective study of prospectively collected data of patients enrolled in the national, multicenter Swiss Stroke Registry from 2013-2019. We included consecutive patients with non-traumatic, SVD-related ICH and available MRI. Patients were classified according to a novel MRI-based classification using haemorrhagic (microbleeds, cortical siderosis) and non-haemorrhagic (white matter hyperintensities, lacunes, perivascular spaces) MRI markers and haematoma location as cerebral amyloid angiopathy (CAA), deep perforator arteriopathy (DPA), mixed SVD or undetermined SVD. The primary clinical outcomes were recurrent ICH or ischemic stroke at 3 months. We performed a Firth penalized logistic regression and competing risk analysis according to Fine and Gray.
Results: We enrolled 1180 patients (age (IQR) 73 (62-80) years, baseline NIHSS 6 (2-12), 538/1180 (45.6%) lobar hematoma location, systolic blood pressure on admission 166 (145-185) mmHg). During follow-up 57 patients had 58 events (29 ICH, 29 ischemic strokes, event rate 4.8%). The rate of recurrent ICH and ischaemic stroke at 3 months was 4%/1% for CAA, 0.7%/2.6% for DPA, 2.7%/2.9% for mixed SVD and 3.8%/3.4% for undetermined SVD, respectively, without a statistically significant difference between groups.
Discussion: This new MRI-based SVD-ICH phaenotype classification based on objective radiological markers is feasible and may improve classification and reporting of ICH subtypes in clinical practice and research.
Omicron breakthrough disease activity in the Swiss Multiple Sclerosis Cohort Study
Varenka Epple (Basel | CH)
In patients with Multiple Sclerosis (pwMS), specific disease modifying treatments (DMTs) may compromise immune response following SARS-CoV-2 vaccination. Limited information is available, whether levels of anti-SARS-CoV-2 antibodies are linked to the risk of breakthrough infections in pwMS.
To determine the rate of Omicron breakthrough infection and severity of COVID-19 in a cohort of MS patients treated with different DMTs and to estimate the impact of SARS-CoV-2-specific antibody levels on breakthrough infection risk.
This study is nested within the Swiss MS Cohort, a nationwide multicenter study that has recruited 1585 pwMS. Patients who received two doses of SARS-CoV-2 vaccines before Omicron became the dominant variant in Switzerland on Dec-15, 2021 and had a follow-up thereafter were included. Data on SARS-CoV-2 infections, severity of COVID-19 according to the WHO scale and SARS-CoV-2 vaccines were collected by questionnaires. Anti-SARS-CoV-2-S antibody levels were measured after the second vaccine dose. Incidence of infections grouped by antibody level after second vaccination was visualized using Kaplan-Meier curves. Cox regression models were used to estimate the impact of antibody levels on the hazard of breakthrough infection during follow-up.
242 pwMS (median age 49 years, 162 (67 %) female, 36 (15 %) with progressive disease, median EDSS 2.5) were included. 22 (9 %) had SARS-CoV-2 infection and 137 (57 %) at least one additional vaccine dose prior to Omicron start. Since then, 57 breakthrough infections were reported. Severity of breakthrough disease on WHO scale ranged from 1-10. 7 were asymptomatic, 46 were symptomatic as outpatients, 3 were hospitalized and 1 died. Patients with antibody levels > 150 U/ml (n = 95) after second vaccination had a 64 % reduced risk for Omicron breakthrough-infection compared to patients with antibody levels < 0.7 U/ml (n = 81) (HR 0.36, 95 % CI = 0.18-0.71, p < 0.01). This effect was maintained after adjustment for DMT at vaccination and time since second vaccination.
Humoral immune response after second SARS-CoV-2 vaccination is associated with Omicron breakthrough infection rate, a finding contrasting general populations, where antibody levels seem to have little impact on protecting from Omicron infection. Most breakthrough infections in our cohort were mild. Analyses on the effect of booster vaccinations on serology and infection rates will follow.
The Spinal Cord Lateral Tract Sign as an rAMIRA-based MRI sign for Upper Motor Neuron Involvement in Amyotrophic Lateral Sclerosis in a Clinical Setting
Maria Janina Wendebourg (Basel | CH)
Background/Aims: Signs of upper motor neurons (UMN) dysfunction can be elusive and difficult to identify in amyotrophic lateral sclerosis (ALS) (1), but are important for timely diagnosis (2). One of the core macro-pathological features of ALS, the spinal cord lateral tract (SCLT) sclerosis, was described by Charcot and shaped the name of the disease (3). Histopathologically, these areas are characterized by axonal loss and diffuse astrocytic gliosis (4, 5). Averaged Magnetization Inversion Recovery Acquisitions (rAMIRA) is a novel MRI approach enabling spinal cord (SC) gray and white matter (WM) imaging with high contrast in clinically feasible acquisition times at 3 Tesla (T) (6, 7). The aims of the study were to define and validate the SCLT sign and to investigate its sensitivity and specificity in patients with ALS, other lower-motor neuron (LMN) diseases, and healthy controls (HC).
Methods: 38 patients with an established diagnosis of ALS (Gold Coast criteria), 60 HC, 25 patients with post-polio syndrome (PPS, March of Dimes criteria), and 10 patients with 5q-spinal muscular atrophy (SMA) were investigated by axial 2D rAMIRA imaging at the intervertebral disc levels C2/C3 - C5/C6 (3T-PRISMA, Siemens). Clinical and demographic data of all participants were obtained. The SCLT sign was defined and validated in a multi-step process by 4 independent raters in subsets of participants and its sensitivity and specificity in detecting ALS were calculated.
Results: The SCLT sign, defined as evenly spread, uni-or bilateral hyperintensities in the SC WM dorsolaterally to the anterior horns, was present in ALS patients in 50 %, 49 %, 54 % and 46 % at the respective levels C2/C3-C5/C6, and in up to 89 % of ALS patients with UMN predominance. In the HC, PPS and SMA groups, the sign was present in 3 %, 8 %, and 0 %, respectively, thus rendering a sensitivity of 58 % and specificity of 98 % at C3/C4 to identify ALS cases. The sign was detectable irrespective of disease duration and persisted on serial imaging over 2 years.
Conclusion: The SCLT sign shows a high specificity in distinguishing patients with ALS from HC and patients with other LMN disorders. Further investigations of patients early in the disease course, particularly those without clinical signs of UMN dysfunction, and of patients with other UMN disorders are necessary next steps to estimate the potential of this novel imaging marker to improve the ALS diagnostic process.
Atrophy of the Cervical Spinal Cord Gray Matter: a new surrogate marker in Amyotrophic Lateral Sclerosis
Eva Maria Kesenheimer (Basel | CH)
Background: There is an urgent need for valid and reliable imaging biomarkers to reduce the diagnostic delay, to monitor the disease course, and to evaluate drug efficacy in upcoming trials in amyotrophic lateral sclerosis (ALS). The novel AMIRA (Averaged Magnetization Inversion Recovery Acquisitions) method enables high resolution MR-imaging with improved contrast of spinal cord (SC) gray matter (GM) and white matter in clinically feasible acquisition times at 3 Tesla.(1,2)
The aims of this study were to compare cervical SC GM areas between patients with a diagnosis of ALS and healthy, age- and sex-matched control subjects (HC) and to assess the association of cervical SC GM area and established measures of clinical disability, the revised ALS functional rating scale and of respiratory impairment, the sniff nasal inspiratory pressure (SNIP) in ALS.
Methods: Using axial 2D radial (r)AMIRA imaging(1) at the cervical intervertebral disc level C3/C4 acquired at a 3T PRISMA scanner (Siemens healthineers) and a semi-automated segmentation approach (JIM7, www.xinapse.com), we compared SC GM areas of 36 patients diagnosed with ALS according to the Gold Coast criteria(3) (mean age 61.7 yrs, 14 women, with bulbar and spinal onset, mean disease duration 32.9 months) and 36 age- and sex-matched HC. The associations between SC GM area and disability metrics (ALSFRS-R(4) and SNIP(5)) were assessed by multivariable regression analyses with adjustment for age and sex.
Results: SC GM area at the level C3/C4 was significantly reduced in patients with ALS compared to HC (mean GM area in mm2 (SD): ALS 16.6 (2.3); HC 19.65 (2.7); relative reduction 15.4%, p < 0.0001). In multivariable regression analyses adjusting for age and sex, GM area at C3/C4 explained 36.1% of ALSFRS-R variance (p = 0.0001) and 32.2% of SNIP variance in patients with ALS, respectively.
Conclusions: Cervical SC GM area in ALS patients shows significant atrophy compared to HC and correlates with established measures of clinical disability and respiratory impairment, namely ALSFRS-R and SNIP. Further longitudinal investigations, particularly of patients early in the disease course, are necessary next steps to evaluate the potential of this novel and easy to assess imaging marker for monitoring and predicting the disease course, and its potential as a surrogate in upcoming drug trials.
Herpes Zoster Burden of Disease: An Analysis of The Placebo Group Data from Three Randomized Phase III Studies
Desmond Curran (Wavre | BE)
The risk of herpes zoster (HZ) is associated with a decline in the immune system function, linked to aging and/or in individuals who are immunocompromised or immunosuppressed due to disease or therapy. In this post-hoc analysis, we describe the incidence and burden of HZ pain in immunocompetent patients ≥ 50 years of age (YOA) and in hematopoietic stem cell transplantation (HSCT) recipients aged ≥ 18 YOA.
ZOE-50 (NCT01165177), ZOE-70 (NCT01165229) and ZOE-HSCT (NCT01610414) were phase III, observer-blind, placebo-controlled, randomized studies conducted in immunocompetent adults ≥ 50 YOA (ZOE-50) and ≥ 70 YOA (ZOE-70); and in HSCT recipients aged ≥ 18 YOA, respectively. Studies were conducted between August 2010 and July 2015, and between July 2012 and February 2017 for the ZOE-50/ZOE-70 and ZOE-HSCT studies, respectively. The participants received 1 or 2 doses of the adjuvanted recombinant zoster vaccine or placebo, 1 to 2 months apart. The analysis was performed on unvaccinated/placebo subjects who had a confirmed HZ episode during the original studies. HZ pain and interference with activities of daily living was assessed by the Zoster Brief Pain Inventory instrument.
Overall, 280 HZ confirmed patients aged ≥ 50 YOA, 240 HZ patients aged ≥ 70 YOA, and 172 HZ patients aged ≥ 18 YOA were included in the placebo groups for the ZOE-50, ZOE-70 and ZOE-HSCT studies, respectively. The incidence of HZ was 9.1/1000 person years in both the ZOE-50 and ZOE-70 placebo groups and 95.6/1000 person years in the ZOE-HSCT study placebo group. In the 3 studies, the majority of individuals with HZ experienced severe pain, with approximately 90% of individuals reporting clinically significant pain. Descriptive statistics on the location of the rash, number of dermatomes involved, the presence of pain and pain intensity will be presented by study group.
Our assessments show that the incidence and burden of HZ is high in immunocompetent adults aged ≥ 50 YOA and even more so in HSCT recipients aged ≥ 18 YOA.
Long-term Blood Pressure Variability is Associated with White Matter Integrity and Cognitive Decline in Patients with Mild Cognitive Symptoms and Cerebral Amyloid Angiopathy
Lukas Sveikata (Genève | CH)
Background: Emerging evidence suggests that long-term blood pressure variability (BPV) may contribute to cerebral small vessel disease progression and cognitive impairment beyond the deleterious effects of elevated blood pressure. (1,2) We investigated whether BPV is associated with white matter (WM) microstructural integrity and cognitive decline in elderly individuals with cerebral amyloid angiopathy (CAA), a well-characterized cerebral small vessel disease.
Methods: We recruited 131 non-demented individuals (73.3 ± 7.0 y, 33/101 female/male, MMSE 27.5 ± 2.0) from the Massachusetts General Hospital memory-clinic cohort with and without CAA (24/50 possible/probable CAA) according to modified Boston criteria. Participants underwent detailed neuropsychological testing and a 3 T research MRI. Visit-to-visit BPV was assessed using the coefficient of variation derived from serial BP measures during a 5-year interval. A novel diffusion tensor imaging marker – peak width of skeletonized mean diffusivity (PSMD) – was used to evaluate the WM integrity. (3) We used linear regression models to assess the association between BPV with PSMD and domain-specific cognitive decline. Models were adjusted for mean BP, age, sex, hypertension, antihypertensive medication, diabetes, smoking, and body mass index.
Results: We found a strong association between loss of WM integrity and high systolic BPV (β = 0.43, P < 0.001). The association remained significant in the adjusted regression model (β = 0.41, P < 0.001). Furthermore, the association of BPV with WM integrity was stronger when CAA was present (β = 9.33, P for interaction < 0.023). Higher BPV was associated with decline in global cognition (β = -0.24, P = 0.035) and processing speed (β = -0.30, P = 0.022). BPV also had a weak association with decline in executive function (β = -0.19, P = 0.106), and memory (β = -0.19, P = 0.095).
Conclusions: Our findings show that long-term BPV is associated with microstructural vascular white matter injury that may contribute to domain-specific cognitive decline in older adults. The association between BPV and white matter integrity may in part be driven by CAA-related vascular dysfunction. Better control of BPV could be a novel therapeutic target to slow cognitive decline over time. As a next step, we will use BP telemonitoring technologies to evaluate whether real-world BP fluctuations contribute to vascular brain injury and vascular cognitive impairment.
Neurostatus-SMARTCARE in comparison to standard Neurostatus-EDSS® – a prospective Swiss multicenter randomized cross-over study
Giulia Mallucci (Basel | CH)
BACKGROUND: Multiple sclerosis (MS) is a chronic neurological disease and patients present with symptoms, which can occur as relapses or as progressive neurological deterioration. Comprehensive, standardized clinical neurological assessment is the gold standard to evaluate activity and to track disability over time. The Neurostatus-eEDSS® is the standard assessment deployed in MS randomized clinical trials (RCT), typically serving as the primary endpoint. COVID-19 pandemic has impacted conduct clinical studies. This opened opportunities to adapt the data capture systems in clinical trials i.e. conducting neurological assessments on phone or video. We have developed a new version of Neurostatus-eEDSS® for trained non-neurologist healthcare professionals (HCP) to perform these assessments. . This Neurostatus-SMARTCARE (“smartly modernized assessment: recorded, telemedical, care professional-assisted, remotely evaluated”) assessment is video recorded, allowing neurologists to review and re-assess the ratings for quality control as needed.
AIM: to assess the concordance between Neurostatus-SMARTCARE, performed by HCPs, and Neurostatus-EDSS®, performed by neurologists.
METHODS: A multicentre randomized cross-over study in Switzerland with 100 MS patients that have consented to participate are randomized 1:1 to group A or group B. Group A undergoes first Neurostatus-EDSS® and afterwards Neurostatus-SMARTCARE - group B starts with Neurostatus-SMARTCARE and finishes with Neurostatus-EDSS®. At the next regular visit –i.e. 6 or12 months- the reverese order is applied. The HCP and neurologist performing the evaluations are blinded to each others findings and assessment scores. . All examinations are entered into an electronical case report form and video recorded.
CONCLUSION: The combination of a video recorded system and an expert assessment presents a unique opportunity for innovation in MS RCTs. In addition, Neurostatus-SMARTCARE may be extended to clinical care settings by allowing home based assessment by MS HCPs, thereby reducing the burden on patients and caregivers. Furthermore it offers the potential for more frequent remote assessments and reducing the costs.
Brain fog in neuropathic postural tachycardia syndrome: associated with autonomic hyperarousal?
Belén Rodriguez (Bern | CH)
Background: Brain fog is a common and highly disturbing symptom for patients with neuropathic postural tachycardia syndrome (POTS). Cognitive deficits have been measured exclusively in the upright body position and mainly comprised impairments of higher cognitive functions. The cause of brain fog is still unclear today. This study aimed to investigate whether increased autonomic activation might be an underlying mechanism for the occurrence of brain fog in neuropathic POTS. We therefore investigated cognitive function in patients with neuropathic POTS and a healthy control group depending on body position and in relation to norepinephrine release as a sensitive indicator of acute stress. The second aim was to test the effect of water intake on cardiovascular regulation, orthostatic symptoms, cognitive function and norepinephrine release.
Methods: Thirteen patients with neuropathic POTS and 15 healthy control subjects were included. All participants completed a total of four rounds of cognitive testing: two before and two after the intake of 500 ml still water, each first in the supine position and then during head-up tilt. At the end of each cognitive test, a blood sample was collected for determination of plasma norepinephrine. After each head-up tilt phase participants were asked to rate their current symptoms on a visual analogue scale.
Results: Working memory performance in the upright body position was impaired in patients, which was associated with self-reported symptom severity. Patients had elevated plasma norepinephrine independent of body position and water intake that increased excessively in the upright body position. The excessive increase of plasma norepinephrine was related to heart rate and symptom severity. Water intake in patients decreased norepinephrine levels and heart rate, and improved symptoms as well as cognitive performance.
Conclusion: Brain fog and symptom severity in neuropathic POTS are paralleled by an excessive norepinephrine secretion. Bolus water drinking down regulates norepinephrine secretion and improves general symptom severity including brain fog.
Frequency dependent interindividual variability of the deep brain stimulation effect on upper-limb bradykinesia
Patrick Dorin (St. Gallen | CH)
To demonstrate that there are interindividual differences in the response of upper limb bradykinesia to subthalamic deep brain stimulation (STN-DBS) in patients with Parkinson’s disease (PD) depending on the stimulation frequency used.
There is evidence that increasing stimulation frequency of STN-DBS beyond the standard settings of 130 Hz may improve tremor, whereas lower frequencies "< 100 Hz" are more beneficial for axial motor symptoms. There are also indications that the improvement of upper limb motor symptoms varies between patients depending on the frequency used.
A kinematic analysis of a finger-tapping train for 20 sec. was assessed in 13 PD patients (median: 63 ears; range 56-71 years) with chronic ("> 3" months) bilateral STN-DBS after overnight PD drug withdrawal. Frequencies were varied in intervals of 10 Hz from 60-180 Hz (randomized sequence), while the TEED was kept stable. Every train of finger-tapping was performed twice for each frequency five minutes after the frequency had been changed. The decrement of the amplitude of the finger taps (i.e. distance between index finger and thumb) was measured by means of a kinematic system and estimated by fitting a regression line to the amplitude values. The regression coefficients were compared statistically.
As expected the amplitude decrement of finger taps improved under DBS compared to the state off DBS ("p < 0.001"). The optimal stimulation frequency with the least decrement varied from patient to patient. There was no consistent peak frequency across patients. Similar observations were made for the worst stimulation frequencies which in a few patients resulted in an even worse motor performance than off DBS
Our results indicate that the effect of DBS on upper limb bradykinesia varies across individuals depending on the frequency used. The standard frequency of 130 Hz may not yield the best motor response to DBS in all individuals. We propose that evaluating different stimulation frequencies may contribute to an optimisation of the DBS effect, whereas the concept of “one frequency fits all” should be abolished.