Primary dystonia

Primary dystonia

Primary dystonia is a neurological disease with the characteristics of abnormal, involuntary twisting and turning movements, which greatly affects life quality of patients.

Primary dystonia is suspected when the dystonia is the only sign and there is no identifiable cause or structural abnormality in the central nervous system.

Primary Dystonia Etiology.

The dystonia pathophysiology is poorly understood. As opposed to secondary forms of dystoniaprimary dystonia has long been believed to lack any neuroanatomical substrate. During trajectory planning for DBS, however, conspicuous T2-hyperintense signal alterations (SA) were registered within the target region, even in young patients, where ischemia is rare.

Fifty MRIs of primary dystonia patients scheduled for DBS were analyzed. Total basal ganglia (BG) volumes, as well as proportionate SA volumes, were measured and compared to 50 age-matched control patients.

There was a 10-fold preponderance of percentaged SA within the globus pallidus (GP) in dystonia patients. The greatest disparity was in young patients <25 years. Also, total BG volume differences were observed with larger GP and markedly smaller putamen and caudate in the dystonia group.

BG morphology in primary dystonia differed from a control population. Volume reductions of the putamen and caudate may reflect functional degeneration, while volume increases of the GP may indicate overactivity. T2-hyperintensive SA in the GP of young primary dystonia patients, where microvascular lesions are highly unlikely, are striking. Their pathogenic role remains unclear 1).

Pallidal Deep Brain Stimulation is the primary surgical treatment for dystonia 2). The response is better for primary dystonias, e.g. tardive dystonias than for secondary dystonias such as postanoxic, postencephalitic, perinatal, and post-stroke dystonia 3) (other targets need to be assessed). For primary dystonias, the globus pallidus internus (GPi) is the most common primary target. Good results have also been reported with STN DBS. Dyskinetic cerebral palsy in children may also be treated with pallidal stimulation 4).


Treatments for dystonia consist of oral medications, botulinum neurotoxin injections, physical therapy and surgeries. For medication-refractory dystonia, surgeries, especially deep brain stimulation (DBS), are the optimal option.

Treatment response is better for primary dystonias than for secondary dystonias. 5).

A strategy based on targeted gene panel sequencing identifies possibly pathogenic variants in fewer than 20% of cases in the early-onset and familial form of dystonia. By using Whole Exome Sequencing (WES), Wirth et al. aimed to identify the missing genetic causes in dystonic patients without a diagnosis despite gene panel sequencing.

WES was applied to DNA samples from 32 patients with early-onset or familial dystonia investigated by sequencing of a 127 movement disorders-associated gene panel. Dystonia was described according to the familial history, body distribution, evolution pattern, age of onset, associated symptoms and associated movement disorders. Rate of diagnoses was evaluated for each clinical feature.

They identified causative variants for 11 patients from 9 families in CTNNB1, SUCLG1, NUS1, CNTNAP1, KCNB1, RELN, GNAO1, HIBCH, ADCK3 genes, yielding an overall diagnostic rate of 34.4%. Diagnostic yield was higher in complex dystonia compared to non-complex dystonia (66.7%-5.9%; p < 0.002), especially in patients showing intellectual disability compared to the patients without intellectual disability (87.5%-16.7%; p < 0.002).

This approach suggests WES as an efficient tool to improve the diagnostic yield after gene panel sequencing in dystonia. Larger study are warranted to confirm a potential genetic overlap between neurodevelopmental diseases and dystonia 6).

A 13-year-old boy suffering from extremely severe primary dystonia, with a BFMDRS-M score of 118 and a TWSTRS-S score of 29. The examination of 173 genes including DYT failed to identify any abnormality. He responded ineffectively to medications. After both bilateral subthalamic nucleus DBS and unilateral Vim-Vo thalamotomy (combined thalamic lesion in ventralis intermedius nucleus and ventralis oralis nucleus), his movement disorder improved dramatically. Four months and seven months after the operation, the scores of two rating scales sharply decreased. And potential brain structural changes were reflected in sensorimotor-related cortical thickness, surface area and gray matter volume from MRI, which revealed a valid method to evaluate surgical effect on the brain with enough patients.

DBS and thalamotomy is potentially an effective combination of treatments for severe medication-refractory dystonia 7).


1)

Bai X, Vajkoczy P, Faust K. Morphological Abnormalities in the Basal Ganglia of Dystonia Patients. Stereotact Funct Neurosurg. 2021 Jan 20:1-12. doi: 10.1159/000512599. Epub ahead of print. PMID: 33472209.
2) , 3)

Awan NR, Lozano A, Hamani C. Deep brain stimulation: current and future perspectives. Neurosurg Focus. 2009; 27. DOI: 10.3171/2009.4.FOCUS0982
4)

Keen JR, Przekop A, Olaya JE, et al. Deep brain sti- mulation for the treatment of childhood dystonic cerebral palsy. J Neurosurg Pediatr. 2014; 14: 585–593
5)

Awan NR, Lozano A, Hamani C. Deep brain stimulation: current and future perspectives. Neurosurg Focus. 2009 Jul;27(1):E2. doi: 10.3171/2009.4.FOCUS0982. Review. PubMed PMID: 19569890.
6)

Wirth T, Tranchant C, Drouot N, Keren B, Mignot C, Cif L, Lefaucheur R, Lion-François L, Méneret A, Gras D, Roze E, Laroche C, Burbaud P, Bannier S, Lagha-Boukbiza O, Spitz MA, Laugel V, Bereau M, Ollivier E, Nitschke P, Doummar D, Rudolf G, Anheim M, Chelly J. Increased diagnostic yield in complex dystonia through exome sequencing. Parkinsonism Relat Disord. 2020 Apr 20;74:50-56. doi: 10.1016/j.parkreldis.2020.04.003. [Epub ahead of print] PubMed PMID: 32334381.
7)

Lin H, Cai XD, Zhang DD, Liu JL, Li WP. Both DBS and Thalamotomy in a 13-year-old Patient with Primary Dystonia: A Case Report. World Neurosurg. 2018 Jun 8. pii: S1878-8750(18)31202-6. doi: 10.1016/j.wneu.2018.05.248. [Epub ahead of print] PubMed PMID: 29890276.

Intraoperative microelectrode recording

Intraoperative microelectrode recording

Microelectrode recording (MER) is used to confirm targeting accuracy during deep brain stimulation (DBS) surgery.


While the efficacy of deep brain stimulation (DBS) to treat various neurological disorders is undisputed, the surgical methods differ widely and the importance of intraoperative microelectrode recording (MER) or macrostimulation (MS) remains controversially debated 1).


At many centers around the world that treat movement disorders, the gold standard for optimally targeting the sensorimotor area of the STN currently relies on microelectrode recording (MER) of single and multi-neuron activity traversing the planned surgical trajectories.

see HaGuide Tool.

When extracellular microelectrodes (tens of microns in diameter) are placed within the brain, they record the extracellular electric field generated by multiple nearby spiking neurons. This is the basis of the microelectrode recording technique used daily by many functional neurosurgeons, and is core to the development of various brain computer interfaces.


The functional regions clustering through microelectrode recording (MER) is a critical step in deep brain stimulation (DBS) surgery. The localization of the optimal target highly relies on the neurosurgeon’s empirical assessment of the neurophysiological signal. This work presents an unsupervised clustering algorithm to get the optimal cluster result of the functional regions along the electrode trajectory.

The dataset consists of the MERs obtained from the routine bilateral DBS for PD patients. Several features have been extracted from MER and divided into groups based on the type of neurophysiological signal. We selected single feature groups rather than all features as the input samples of each division of the divisive hierarchical clustering (DHC) algorithm. And the optimal cluster result has been achieved through a feature group combination selection (FGS) method based on genetic algorithm (GA). To measure the performance of this method, we compared the accuracy and validation indexes of three methods, including DHC only, DHC with GA-based FGS and DHC with GA-based feature selection (FS) in other studies, on the universal and DBS datasets.

Results show that the DHC with GA-based FGS achieved the optimal cluster result compared with other methods. The three borders of the STN can be identified from the cluster result. The dorsoventral sizes of the STN and dorsal STN are 4.45 mm and 2.02 mm. In addition, the features extracted from the multiunit activity, background unit activity and local field potential are found to be the most representative feature groups to identify the dorsal, d-v and ventral borders of the STN, respectively.

The clustering algorithm showed a reliable performance of the automatic identification of functional regions in DBS. The findings can provide valuable assistance for both neurosurgeons and stereotactic surgical robots in DBS surgery 2).


It is unclear which magnetic resonance imaging (MRI) sequence most accurately corresponds with the electrophysiological subthalamic nucleus (STN) obtained during microelectrode recording (MER, MER-STN). CT/MRI fusion allows for comparison between MER-STN and the STN visualized on preoperative MRI (MRI-STN).

Kochanski et al. describe a technique using intraoperative computed tomography (CT) extrapolation (iCTE) to predetermine and adjust the trajectory of the guide tube to improve microelectrode targeting accuracy. They hypothesized that this technique would decrease the number of MER tracks and operative time, while increasing the recorded length of the subthalamic nucleus (STN) 3).

Case series

Krauss et al. included 101 patients who underwent awake bilateral implantation of electrodes in the subthalamic nucleus with microelectrode recording (MER) and macrostimulation (MS) for Parkinson’s disease from 2009 to 2017 in a retrospective observational study. They analyzed intraoperative motor outcomes between anatomically planned stimulation point (PSP) and definite stimulation point (DSP), lead adjustments, and Unified Parkinson’s Disease Rating Scale Item III (UPDRS-III), levodopa equivalent daily dose (LEDD), and adverse events (AE) after 6 months.

They adjusted 65/202 leads in 47/101 patients. In adjusted leads, MS results improved significantly when comparing PSP and DSP (p < 0.001), resulting in a number needed to treat of 9.6. After DBS, UPDRS-III and LEDD improved significantly after 6 months in adjusted and nonadjusted patients (p < 0.001). In 87% of leads, the active contact at 6 months still covered the optimal stimulation point during surgery. In total, 15 AE occurred.

MER and MS have a relevant impact on the intraoperative decision of final lead placement and prevent a substantial rate of poor stimulation outcome. The optimal stimulation points during surgery and chronic stimulation strongly overlap. Follow-up UPDRS-III results, LEDD reductions, and DBS-related AE correspond well to previously published data 4).


The precision and accuracy of direct targeting with quantitative susceptibility mapping (QSM) was examined in a total of 25 Parkinson’s disease patients between 2013 and 2015 at the Department of Neurosurgery, Mount Sinai Health System, New York. QSM was utilized as the primary magnetic resonance imaging (MRI) method to perform direct STN targeting on a stereotactic planning station utilizing computed tomography/MR fusion. Intraoperative microelectrode recordings (MER) were obtained to confirm appropriate trajectory through the sensorimotor STN.

Estimations of STN thickness between the MER and QSM methods appeared to be correlated. Mean STN thickness was 5.3 mm. Kinesthetic responsive cells were found in > 90% of electrode runs. The mean radial error (±SEM) was 0.54 ± 0.1 mm. Satisfactory clinical response as determined by Unified Parkinson’s Disease Rating Scale (UPDRS III) was seen at 12 mo after surgery.

Direct targeting of the sensorimotor STN using QSM demonstrates MER correlation and can be safely used for deep brain stimulation lead placement with satisfactory clinical response. These results imply that targeting based on QSM signaling alone is sufficient to obtain reliable and reproducible outcomes in the absence of physiological recordings 5).

In their analysis, Rasouli et al accept that the raw measurements they derived by the 2 methods (microelectrode recording [MER] vs quantitaive susceptibility mapping [QSM]) do not exhibit a high degree of correlation. They offer several reasons for this (differences in resolution, standard deviations, and narrow range of measurements), thereby justifying the use of normalized data and the Bland–Altman analysis. In contrast to the Bland–Altman analysis, which suggests agreement, the intra-correlation coefficient (ICC) = 0.12 implies that there is high variability between QSM and MER measurements within an individual (ie, they are not in good agreement). More useful in our view would be to see how well the actual measurements made with the 2 methods agree on a case by case basis. How often do the measurements agree within 0.1, 0.5, 1, 2 mm, etc.? Such valuable information would allow the readers to decide for themselves whether a measured subthalamic nucleus (STN) span on QSM is a legitimate proxy for the gold standard of measuring the STN with MER and we urge the authors to publish this data in a subsequent letter 6).

References

1) , 4)

Krauss P, Oertel MF, Baumann-Vogel H, Imbach L, Baumann CR, Sarnthein J, Regli L, Stieglitz LH. Intraoperative Neurophysiologic Assessment in Deep Brain Stimulation Surgery and its Impact on Lead Placement. J Neurol Surg A Cent Eur Neurosurg. 2020 Oct 13. doi: 10.1055/s-0040-1716329. Epub ahead of print. PMID: 33049794.
2)

Cao L, Jie L, Zhou Y, Liu Y, Liu H. Automatic feature group combination selection method based on GA for the functional regions clustering in DBS. Comput Methods Programs Biomed. 2019 Sep 23;183:105091. doi: 10.1016/j.cmpb.2019.105091. [Epub ahead of print] PubMed PMID: 31590098.
3)

Kochanski RB, Bus S, Pal G, Metman LV, Sani S. Optimization of Microelectrode Recording in Deep Brain Stimulation Surgery Using Intraoperative Computed Tomography. World Neurosurg. 2017 Jul;103:168-173. doi: 10.1016/j.wneu.2017.04.003. Epub 2017 Apr 10. PubMed PMID: 28408262.
5)

Rasouli J, Ramdhani R, Panov FE, Dimov A, Zhang Y, Cho C, Wang Y, Kopell BH. Utilization of Quantitative Susceptibility Mapping for Direct Targeting of the Subthalamic Nucleus During Deep Brain Stimulation Surgery. Oper Neurosurg (Hagerstown). 2018 Apr 1;14(4):412-419. doi: 10.1093/ons/opx131. PubMed PMID: 28531270.
6)

Alterman RL, Fleishman A, Ngo L. In Reply: Commentary: Utilization of Quantitative Susceptibility Mapping for Direct Targeting of the Subthalamic Nucleus During Deep Brain Stimulation Surgery. Oper Neurosurg (Hagerstown). 2018 Jul 13. doi: 10.1093/ons/opy139. [Epub ahead of print] PubMed PMID: 30011048.

Asleep subthalamic deep brain stimulation for Parkinson’s disease

Asleep subthalamic deep brain stimulation for Parkinson’s disease

Recent advances in methods used for deep brain stimulation (DBS) include subthalamic nucleus electrode implantation in the “asleep” patient without the traditional use of microelectrode recordings or intraoperative test stimulation.

Meta-Analysis

2019

Liu et al. systematically reviewed the literature to compare the efficacy and safety of awake and asleep deep brain stimulation surgery. They identified cohort studies from the Cochrane libraryMEDLINE, and EMBASE (January 1970 to August 2019) by using Review Manager 5.3 software to conduct a meta-analysis following the PRISMA guidelines. Fourteen cohort studies involving 1,523 patients were included. The meta-analysis results showed that there were no significant differences between the GA and LA groups in UPDRSIII score improvement (standard mean difference [SMD] 0.06; 95% CI -0.16 to 0.28; p = 0.60), postoperative LEDD requirement (SMD -0.17; 95% CI -0.44 to 0.12; p = 0.23), or operation time (SMD 0.18; 95% CI -0.31 to 0.67; p = 0.47). Additionally, there was no significant difference in the incidence of adverse events (OR 0.98; 95% CI 0.53-1.80; p = 0.94), including postoperative speech disturbance and intracranial hemorrhage. However, the volume of intracranial air was significantly lower in the GA group than that in the LA group. In a subgroup analysis, there was no significant difference in clinical efficacy between the microelectrode recording (MER) and non-MER groups. We demonstrated equivalent clinical outcomes of DBS surgery between GA and LA in terms of improvement of symptoms and the incidence of adverse events. Key Messages: MER might not be necessary for DBS implantation. For patients who cannot tolerate DBS surgery while being awake, GA should be an appropriate alternative 1).

Case series

A retrospective review of clinical outcomes of 152 consecutive patients. Their outcomes at 1 yr postimplantation are reported; these include Unified Parkinson’s Disease Rating Scale (UPDRS) assessment, Mobility Tinetti TestPDQ-39 quality of life assessment, Mattis Dementia Rating ScaleBeck Depression Inventory, and Beck Anxiety Inventory. They also report on a new parietal trajectory for electrode implantation.

UPDRS III improved from 39 to 20.5 (47%, P < .001). The total UPDRS score improved from 67.6 to 36.4 (46%, P < .001). UPDRS II scores improved from 18.9 to 10.5 (44%, P < .001) and UPDRS IV scores improved from 7.1 to 3.6 (49%, P < .001). There was a significant reduction in levodopa equivalent daily dose after surgery (mean: 35%, P < .001). PDQ-39 summary index improved by a mean of 7.1 points. There was no significant difference found in clinical outcomes between the frontal and parietal approaches.

“Asleep” robot-assisted DBS of the subthalamic nucleus demonstrates comparable outcomes with traditional techniques in the treatment of Parkinson’s disease. 2).


The objective of a study of Senemmar et al. was to investigate whether asleep deep brain stimulation surgery of the subthalamic nucleus (STN) improves therapeutic window (TW) for both directional (dDBS) and omnidirectional (oDBS) stimulation in a large single-center population.

A total of 104 consecutive patients with Parkinson’s disease (PD) undergoing STN-DBS surgery (80 asleep and 24 awake) were compared regarding TW, therapeutic thresholdside effect threshold, improvement of Unified PD Rating Scale motor score (UPDRS-III) and degree of levodopa equivalent daily dose (LEDD) reduction.

Asleep DBS surgery led to significantly wider TW compared to awake surgery for both dDBS and oDBS. However, dDBS further increased TW compared to oDBS in the asleep group only and not in the awake group. Clinical efficacy in terms of UPDRS-III improvement and LEDD reduction did not differ between groups.

The study provides first evidence for improvement of therapeutic window by asleep surgery compared to awake surgery, which can be strengthened further by dDBS. These results support the notion of preferring asleep over awake surgery but needs to be confirmed by prospective trial3).


Clinical outcome studies have shown that “asleep” DBS lead placement, performed using intraoperative imaging with stereotactic accuracy as the surgical endpoint, has motor outcomes comparable to traditional “awake” DBS using microelectrode recording (MER), but with shorter case times and improved speech fluency 4).


Ninety-six patients were retrospectively matched pairwise (48 asleep and 48 awake) and compared regarding improvement of Unified PD Rating Scale Motor Score (UPDRS-III), cognitive function, Levodopa-equivalent-daily-dose (LEDD), stimulation amplitudes, side effects, surgery duration, and complication rates. Routine testing took place at three months and one year postoperatively.

Results: Chronic DBS effects (UPDRS-III without medication and with stimulation on [OFF/ON]) significantly improved UPDRS-III only after awake surgery at three months and in both groups one year postoperatively. Acute effects (percentage UPDRS-III reduction after activation of stimulation) were also significantly better after awake surgery at three months but not at one year compared to asleep surgery. UPDRS-III subitems “freezing” and “speech” were significantly worse after asleep surgery at three months and one year, respectively. LEDD was significantly lower after awake surgery only one week postoperatively. The other measures did not differ between groups.

Overall motor function improved faster in the awake surgery group, but the difference ceased after one year. However, axial subitems were worse in the asleep surgery group suggesting that worsening of axial symptoms was risked improving overall motor function. Awake surgery still seems advantageous for STN-DBS in PD, although asleep surgery may be considered with lower threshold in patients not suitable for awake surgery 5).

References

1)

Liu Z, He S, Li L. General Anesthesia versus Local Anesthesia for Deep Brain Stimulation in Parkinson’s Disease: A Meta-Analysis. Stereotact Funct Neurosurg. 2019;97(5-6):381-390. doi:10.1159/000505079
2)

Moran CH, Pietrzyk M, Sarangmat N, Gerard CS, Barua N, Ashida R, Whone A, Szewczyk-Krolikowski K, Mooney L, Gill SS. Clinical Outcome of “Asleep” Deep Brain Stimulation for Parkinson Disease Using Robot-Assisted Delivery and Anatomic Targeting of the Subthalamic Nucleus: A Series of 152 Patients. Neurosurgery. 2020 Sep 28:nyaa367. doi: 10.1093/neuros/nyaa367. Epub ahead of print. PMID: 32985669.
3)

Senemmar F, Hartmann CJ, Slotty PJ, Vesper J, Schnitzler A, Groiss SJ. Asleep Surgery May Improve the Therapeutic Window for Deep Brain Stimulation of the Subthalamic Nucleus [published online ahead of print, 2020 Jul 13]. Neuromodulation. 2020;10.1111/ner.13237. doi:10.1111/ner.13237
4)

Mirzadeh Z, Chen T, Chapple KM, Lambert M, Karis JP, Dhall R, Ponce FA. Procedural Variables Influencing Stereotactic Accuracy and Efficiency in Deep Brain Stimulation Surgery. Oper Neurosurg (Hagerstown). 2018 Oct 18. doi: 10.1093/ons/opy291. [Epub ahead of print] PubMed PMID: 30339204.
5)

Blasberg F, Wojtecki L, Elben S, Slotty PJ, Vesper J, Schnitzler A, Groiss SJ. Comparison of Awake vs. Asleep Surgery for Subthalamic Deep Brain Stimulation in Parkinson’s Disease. Neuromodulation. 2018 Aug;21(6):541-547. doi: 10.1111/ner.12766. Epub 2018 Mar 13. PubMed PMID: 29532
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