Focused ultrasound therapy in movement disorders: management roadmap toward optimal pathway organization.

MRI-guided focused ultrasound (MRgFUS) lesioning is an innovative, safe and effective treatment which provides an innovative development in the field of minimally invasive stereotactic neurosurgery. Based on the application of focused ultrasound energy under full MR planning and thermal imaging control, unilateral lesioning of the thalamus, subthalamic nucleus, and globus pallidus is indicated for the treatment of movement disorders, including essential tremor, Parkinson's disease, and dystonia. We started to apply this technique in February 2019 for the treatment of patients with movement disorders. The authors developed a diagnostic therapeutic care pathway, which is herewith proposed and applied as an explication of standard clinical practice in use. The project was the result of the application of different methods such as Health Technology Assessment (HTA), Strengths, Weaknesses, Opportunities and Threats analysis (SWOT) and Demin -Plan, Do, Check, Act (PDCA) cycle. The aim of this project was to standardize the MRgFUS diagnostic-therapeutic pathway (DTP), describe its application and the appropriateness of different phases (patient selection, intervention phase and follow-up). Here, we described in detail our experience in the DTP application from 2019 up to now in 610 patients with movement disorders.

The Optimal Targeting for Focused Ultrasound Thalamotomy Differs between Dystonic and Essential Tremor: A 12-Month Prospective Pilot Study.

BACKGROUND: Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy is increasingly used to treat drug-resistant essential tremor (ET). Data on MRgFUS thalamotomy in dystonic tremor (DT) are anecdotal. OBJECTIVES: To investigate efficacy, safety, and differences in target coordinates of MRgFUS thalamotomy in DT versus ET. METHODS: Ten patients with DT and 35 with ET who consecutively underwent MRgFUS thalamotomy were followed for 12 months. Although in both groups the initial surgical planning coordinates corresponded to the ventralis intermediate (Vim), the final target could be modified intraoperatively based on clinical response. RESULTS: Tremor significantly improved in both groups. The thalamic lesion was significantly more anterior in DT than ET. Considering both ET and DT groups, the more anterior the lesion, the lower the odds ratio for adverse events. CONCLUSIONS: MRgFUS thalamotomy is safe and effective in DT and ET. Compared to classical Vim coordinates used for ET, more anterior targeting should be considered for DT.

Unraveling Autonomic Dysfunction in GBA-Related Parkinson's Disease.

Background: Patients with Parkinson's disease (PD) and GBA gene mutations (GBA-PD) develop nonmotor complications more frequently than noncarriers. However, an objective characterization of both cardiovascular and sudomotor autonomic dysfunction using extensive clinical and instrumental measures has never been provided so far. Survival is reduced in GBA-PD regardless of age and dementia, suggesting that other hitherto unrecognized factors are involved. Objectives: To provide instrumental measures of pattern and severity of autonomic dysfunction in GBA-PD and explore their correlation with other non-motor symptoms and implications for clinical practice. Methods: In this cross-sectional study, 21 GBA-PD and 24 matched PD noncarriers underwent extensive assessment of motor and non-motor features, including neuropsychological testing. Cardiovascular autonomic function was explored through a comprehensive battery of indexes, including power spectral analysis of the R-R intervals and blood pressure short-term variability during resting state and active maneuvers. Dynamic Sweat Test was used to assess post-ganglionic sudomotor dysfunction. Results: Despite minimal or absent clinical correlates, cardiovagal and sympathetic indexes, heart rate variability parameters and sudomotor postganglionic function were more severely impaired in GBA-PD than noncarriers (overcoming relatively preserved compensatory peripheral sympathetic function), suggesting more prominent cardiac sympatho-vagal demodulation, efferent baroreflex failure and peripheral sympathetic dysfunction in GBA-PD. Cardiovascular dysautonomia showed marginal correlations with cognitive impairment. Conclusions: Compared to PD noncarriers, GBA-PD display more severe instrumental autonomic abnormalities, which may be underestimated by purely clinical measures, despite their relevance on morbidity and mortality. This supports the necessity of implementing instrumental autonomic assessment in all GBA-PD, regardless of clinically overt symptoms.

Ambroxol as a disease-modifying treatment to reduce the risk of cognitive impairment in GBA-associated Parkinson's disease: a multicentre, randomised, double-blind, placebo-controlled, phase II trial. The AMBITIOUS study protocol.

Background: Heterozygous mutations in the GBA gene, encoding the lysosomal enzyme ß-glucocerebrosidase (GCase), are the most frequent genetic risk factor for Parkinson's disease (PD). GBA-related PD (GBA-PD) patients have higher risk of dementia and reduced survival than non-carriers. Preclinical studies and one open-label trial in humans demonstrated that the chaperone ambroxol (ABX) increases GCase levels and modulates α-synuclein levels in the blood and cerebrospinal fluid (CSF). Methods and analysis: In this multicentre, double-blind, placebo-controlled, phase II clinical trial, we randomise patients with GBA-PD in a 1:1 ratio to either oral ABX 1.2 g/day or placebo. The duration of treatment is 52 weeks. Each participant is assessed at baseline and weeks 12, 26, 38, 52 and 78. Changes in the Montreal Cognitive Assessment score and the frequency of mild cognitive impairment and dementia between baseline and weeks 52 are the primary outcome measures. Secondary outcome measures include changes in validated scales/questionnaires assessing motor and non-motor symptoms. Neuroimaging features and CSF neurodegeneration markers are used as surrogate markers of disease progression. GCase activity, ABX and α-synuclein levels are also analysed in blood and CSF. A repeated-measures analysis of variance will be used for elaborating results. The primary analysis will be by intention to treat. Ethics and dissemination: The study and protocols have been approved by the ethics committee of centres. The study is conducted according to good clinical practice and the Declaration of Helsinki. The trial findings will be published in peer-reviewed journals and presented at conferences. Trial registration numbers: NCT05287503, EudraCT 2021-004565-13.

A Brief Explanation on Surgical Approaches for Treatment of Different Brain Tumors.

The main goal of brain tumor surgery is to achieve gross total tumor resection without postoperative complications and permanent new deficits. However, when the lesion is located close or within eloquent brain areas, cranial nerves, and/or major brain vessels, it is imperative to balance the extent of resection with the risk of harming the patient, by following a so-called maximal safe resection philosophy. This view implies a shift from an approach-guided attitude, in which few standard surgical approaches are used to treat almost all intracranial tumors, to a pathology-guided one, with surgical approaches actually tailored to the specific tumor that has to be treated with specific dedicated pre- and intraoperative tools and techniques. In this chapter, the basic principles of the most commonly used neurosurgical approaches in brain tumors surgery are presented and discussed along with an overview on all available modern tools able to improve intraoperative visualization, extent of resection, and postoperative clinical outcome.

Corrigendum: PMCA-based detection of prions in the olfactory mucosa of patients with sporadic Creutzfeldt-Jakob disease.

[This corrects the article DOI: 10.3389/fnagi.2022.848991.].

Intraoperative Neurophysiologic and Angiographic Techniques to Identify the Posterior Median Sulcus for Midline Myelotomy.

Accurate midline myelotomy through the posterior median sulcus (PMS) is the key step to minimize surgical morbidity during intramedullary tumor removal.1,2 When an intramedullary mass is present, the cord is usually rotated and it may be difficult to distinguish its sulci.2-4 Inadvertent dissection through the dorsal columns exposes the patient to disabling postoperative deficits.5 In recent years, together with the well-established neurophysiologic phase-reversal method, newer intraoperative angiographic techniques have been developed to identify the PMS.1-4 In order to illustrate the combination of the 2, we present the case of a 31-year-old man with a right claw hand syndrome who underwent surgical excision of a C6-D1 ependymoma (Video 1).6,7 After localizing the tumor with ultrasound, somatosensory evoked potentials (obtained by stimulating the dorsal columns with the use of a bipolar handheld neurostimulator) were employed to identify the PMS by means of the phase reversal technique, which uncovered the silent central line corresponding to the PMS. Use of indocyanine green fluorescence (ICG) later confirmed with certainty the location of the spinal cord's midline by enabling identification of the dorsal medullary veins exiting the PMS. As expected, the midline was significantly laterally displaced by the tumor. After penetrating the PMS, gentle dissection between the 2 posterior chordae enabled the surgeon to reach and enucleate the tumor in a minimally traumatic fashion. No postoperative deficits were reported. This method represents a direct and effective way to reduce morbidity resulting from this type of surgery.

Phosphorylated α-synuclein in skin Schwann cells: a new biomarker for multiple system atrophy.

Multiple system atrophy (MSA) is characterized by accumulation of phosphorylated α-synuclein (p-syn) as glial cytoplasmic inclusions in the brain and a specific biomarker for this disorder is urgently needed. We aimed at investigating if p-syn can also be detected in skin Remak non-myelinating Schwann cells (RSCs) as Schwann cell cytoplasmic inclusions (SCCi) and may represent a reliable clinical biomarker for MSA. This cross-sectional diagnostic study evaluated skin p-syn in 96 patients: 46 with probable MSA (29 with parkinsonism type MSA and 17 with cerebellar type MSA), 34 with Parkinson's disease (PD) and 16 with dementia with Lewy bodies (DLB). We also included 50 healthy control subjects. Patients were recruited from five different medical centres. P-syn aggregates in skin sections were stained by immunofluorescence, followed by analyses with confocal microscopy and immuno-electron microscopy. All analyses were performed in a blinded fashion. Overall, p-syn aggregates were found in 78% of MSA patients and 100% of patients with PD/DLB, whereas they could not be detected in controls. As for neuronal aggregates 78% of MSA patients were positive for p-syn in somatic neurons, whereas all PD/DLB patients were positive in autonomic neurons. When analysing the presence of p-syn in RSCs, 74% of MSA patients were positive, whereas no such SCCi could be observed in PD/DLB patients. Analyses by immuno-electron microscopy confirmed that SCCi were only found in cases with MSA and thus absent in those with PD/DLB. In conclusion, our findings demonstrate that (i) fibrillar p-syn in RSCs is a pathological hallmark of MSA and may be used as a specific and sensitive disease biomarker; (ii) in Lewy body synucleinopathies (PD/DLB) only neurons contain p-syn deposits; and (iii) the cell-specific deposition of p-syn in the skin thus mirrors that of the brain in many aspects and suggests that non-myelinated glial cells are also involved in the MSA pathogenesis.

MRI-guided focused-ultrasound thalamotomy in essential tremor: Immediate and delayed changes in cortico-muscular coherence and cortico-cortical out-strength.

OBJECTIVE: Drug-resistant essential tremor (ET) can be treated by Magnetic-Resonance-guided Focused-Ultrasound (MRgFUS) targeted to thalamic ventralis-intermediate nucleus (ViM). We are presenting the results obtained in ET patients by evaluating the cortico-muscular coherence (CMC) and the out-strength among cortical areas. METHODS: We recorded MEG-EMG signals in 16 patients with predominant tremor on the right upper limb. The examination was performed the day before MRgFUS (T0) treatment, 24 hours (T1), and 3-months (T2) after lesioning the left ViM. Normalized CMC (nCMC) and cortico-cortical out-strength among cortical areas were assessed during isometric extension of the right hand. RESULTS: According to the Essential Tremor Rating Assessment Scale, 13 of 16 patients were considered responders. At T1, in the beta-band, nCMC increased in the left hemisphere, namely in the areas directly involved in motor functions. At T2, the nCMC in non-motor areas decreased and the out-strength from other examined cortical areas toward the left motor-area decreased. CONCLUSIONS: In patients positively responding to MRgFUS, the CMC increased in the motor-area of the treated hemisphere immediately after the treatment, while the reorganization of CMC and cortico-cortical out-strength toward the cortical motor area occurred with a delay. SIGNIFICANCE: The effective treatment with MRgFUS corresponds with a readjustment of the CMC and of the communication between cortical areas.

Magnetic Resonance-Guided Focused Ultrasound Thalamotomy May Spare Dopaminergic Therapy in Early-Stage Tremor-Dominant Parkinson's Disease: A Pilot Study.

BACKGROUND: Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy is a safe and effective procedure for drug-resistant tremor in Parkinson's disease (PD). OBJECTIVE: The aim of this study was to demonstrate that MRgFUS ventralis intermedius thalamotomy in early-stage tremor-dominant PD may prevent an increase in dopaminergic medication 6 months after treatment compared with matched PD control subjects on standard medical therapy. METHODS: We prospectively enrolled patients with early-stage PD who underwent MRgFUS ventralis intermedius thalamotomy (PD-FUS) and patients treated with oral dopaminergic therapy (PD-ODT) with a 1:2 ratio. We collected demographic and clinical data at baseline and 6 and 12 months after thalamotomy. RESULTS: We included 10 patients in the PD-FUS group and 20 patients in the PD-ODT group. We found a significant increase in total levodopa equivalent daily dose and levodopa plus monoamine oxidase B inhibitors dose in the PD-ODT group 6 months after thalamotomy. CONCLUSIONS: In early-stage tremor-dominant PD, MRgFUS thalamotomy may be useful to reduce tremor and avoid the need to increase dopaminergic medications. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Significance and clinical suggestions for the somatosensory evoked potentials increased in amplitude revealed by a large sample of neurological patients.

OBJECTIVES: To investigate the relationship between N20-P25 peak-to-peak amplitude (N20p-P25p) of somatosensory evoked potentials (SEPs) and the occurrence of abnormalities of the peripheral and/or central sensory pathways and of myoclonus/epilepsy, in 308 patients with increased SEPs amplitude from upper limb stimulation. METHODS: We compared cortical response (N20p-P25p) in different groups of patients identified by demographic, clinical, and neurophysiological factors and performed a cluster analysis for classifying the natural occurrence of subgroups of patients. RESULTS: No significant differences of N20p-P25p were found among different age-dependent groups, and in patients with or without PNS/CNS abnormalities of sensory pathways, while myoclonic/epileptic patients showed higher N20p-P25p than other groups. Cluster analysis identified four clusters of patients including myoclonus/epilepsy, central sensory abnormalities, peripheral sensory abnormalities, and absence of myoclonus and sensory abnormalities. CONCLUSIONS: Increased N20p-P25p prompts different possible pathophysiological substrates: larger N20p-P25p in patients with cortical myoclonus and/or epilepsy is likely sustained by strong cortical hyperexcitability, while milder increase of N20p-P25p could be underpinned by plastic cortical changes following abnormalities of sensory pathways, or degenerative process involving the cortex. SEPs increased in amplitude cannot be considered an exclusive hallmark of myoclonus/epilepsy. Indeed, in several neurological disorders, it may represent a sign of adaptive, plastic, and/or degenerative cortical changes.

PMCA-Based Detection of Prions in the Olfactory Mucosa of Patients With Sporadic Creutzfeldt-Jakob Disease.

Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare neurodegenerative disorder caused by the conformational conversion of the prion protein (PrPC) into an abnormally folded form, named prion (or PrPSc). The combination of the polymorphism at codon 129 of the PrP gene (coding either methionine or valine) with the biochemical feature of the proteinase-K resistant PrP (generating either PrPSc type 1 or 2) gives rise to different PrPSc strains, which cause variable phenotypes of sCJD. The definitive diagnosis of sCJD and its classification can be achieved only post-mortem after PrPSc identification and characterization in the brain. By exploiting the Real-Time Quaking-Induced Conversion (RT-QuIC) assay, traces of PrPSc were found in the olfactory mucosa (OM) of sCJD patients, thus demonstrating that PrPSc is not confined to the brain. Here, we have optimized another technique, named protein misfolding cyclic amplification (PMCA) for detecting PrPSc in OM samples of sCJD patients. OM samples were collected from 27 sCJD and 2 genetic CJD patients (E200K). Samples from 34 patients with other neurodegenerative disorders were included as controls. Brains were collected from 26 sCJD patients and 16 of them underwent OM collection. Brain and OM samples were subjected to PMCA using the brains of transgenic mice expressing human PrPC with methionine at codon 129 as reaction substrates. The amplified products were analyzed by Western blot after proteinase K digestion. Quantitative PMCA was performed to estimate PrPSc concentration in OM. PMCA enabled the detection of prions in OM samples with 79.3% sensitivity and 100% specificity. Except for a few cases, a predominant type 1 PrPSc was generated, regardless of the tissues analyzed. Notably, all amplified PrPSc were less resistant to PK compared to the original strain. In conclusion, although the optimized PMCA did not consent to recognize sCJD subtypes from the analysis of OM collected from living patients, it enabled us to estimate for the first time the amount of prions accumulating in this biological tissue. Further assay optimizations are needed to faithfully amplify peripheral prions whose recognition could lead to a better diagnosis and selection of patients for future clinical trials.

Minimally Invasive Carpal Tunnel Release: A Technical Note and a 20-Year Retrospective Series.

Introduction The surgical treatment of carpal tunnel syndrome (CTS) has been enriched, during the last years, by different minimally invasive techniques to decompress the median nerve at the wrist as the endoscopic approaches or modified open technique. However, controversy remains about their safety and complication rate. We present the results of our minimally-invasive technique to median nerve release at the wrist. We will discuss the instrumental preoperative assessment, surgical steps, post-operative management, and complications. Methods We retrospectively reviewed clinical and neurophysiological data of all patients admitted at our institution between January 2001 and December 2020 for CTS surgery. The technique, performed under local anesthesia, is based on a single, small, linear transverse incision proximal to the wrist fold. After unsharpened dissection of subcutaneous tissues, a grooved guide is inserted in a slightly medial direction towards the fourth finger; this strategy prevents possible damages of nerve branches that could originate at this level. A second small incision over the guide's tip allows a wide corridor in the context of the ligament. The carpalotome is then inserted into the guide; the two minor wounds are closed with 5-0 prolene sutures. The final result is a wide release of the nerve. Results A total of 1568 operations on 1371 patients were performed using the described technique at our institution. The patients' cohort showed a higher prevalence of women (68%), with a mean age of 56.4 years (range 24-88 years). Paresthesia and numbness of the first three fingers were the most frequent signs and symptoms. All patients were submitted to a preoperative electrophysiological evaluation, which revealed the typical signs of CTS in most patients. The US evaluation of the median nerve at the wrist was a more recent introduction, dating from 2018. In 47 patients, despite an electromyography (EMG) not showing marked neurophysiological signs of severe CTS, the ultrasonographic evaluation was strongly consistent with the clinical diagnosis. In such patients, carpal tunnel release determined the resolution of symptoms. In 99.8% of total cases, we obtained a complete symptoms remission, with the disappearance of acroparesthesia and numbness. Conclusion The use of this technique has become widespread at our institution due to fewer local complications, a very low rate of recurrence, faster functional recovery, and reduced surgical time if compared to traditional open surgery and to endoscopic release too.

Short- and long-term motor outcome of STN-DBS in Parkinson's Disease: focus on sex differences.

INTRODUCTION: Subthalamic nucleus deep brain stimulation (STN-DBS) is an established treatment for patients with Parkinson's disease (PD) with motor complications; the contribution of sex in determining the outcome is still not understood. METHODS: We included 107 patients (71 males) with PD consecutively implanted with STN-DBS at our center. We reviewed patient charts from our database and retrospectively collected demographical and clinical data at baseline and at three follow-up visits (1, 5 and 10 years). RESULTS: We found a long-lasting effect of DBS on motor complications, despite a progressive worsening of motor performances in the ON medication condition. Bradykinesia and non-dopaminergic features seem to be the major determinant of this progression. Conversely to males, females showed a trend towards worsening in bradykinesia already at 1-year follow-up and poorer scores in non-dopaminergic features at 10-year follow-up. Levodopa Equivalent Daily Dose (LEDD) was significantly reduced after surgery compared to baseline values; however, while in males LEDD remained significantly lower than baseline even 10 years after surgery, in females LEDD returned at baseline values. Males showed a sustained effect on dyskinesias, but this benefit was less clear in females; the total electrical energy delivered was consistently lower in females compared to males. The profile of adverse events did not appear to be influenced by sex. CONCLUSION: Our data suggest that there are no major differences on the motor effect of STN-DBS between males and females. However, there may be some slight differences that should be specifically investigated in the future and that may influence therapeutic decisions in the chronic follow-up.

Progressive brachial plexus enlargement in hereditary transthyretin amyloidosis.

Axonal polyneuropathy is the main feature of hereditary transthyretin amyloidosis (ATTRv). Nerve morphological abnormalities have been reported, but longitudinal changes have never been assessed. We performed a prospective widespread nerve ultrasound evaluation and nerve cross-sectional area (CSA) was compared with baseline data in both ATTRv patients and pre-symptomatic carriers. Thirty-eight subjects were evaluated (mean follow-up 17.1 months), among them 21 had polyneuropathy while 17 were pre-symptomatic carriers. CSA significantly increased at brachial plexus in both groups (p = 0.008 and p = 0.012) pointing to progressive brachial plexus enlargement as a longitudinal biomarker of both disease progression and disease occurrence in pre-symptomatic carriers.