Understanding the role of surgical intervention for patients with concomitant degenerative spinal disease without deformity and Parkinson's disease: a meta-analysis.

INTRODUCTION: Parkinson's disease is a common neurodegenerative disease. With an aging population, co-existent degenerative diseases of the spine in these patients will become more prevalent. RESEARCH QUESTION: This systematic review and meta-analysis aims to establish the incidence and risk of adverse outcomes following spinal surgery in patients with Parkinson's disease. Material and Methods A literature review was carried out in order to identify studies assessing the outcomes of adult patients with Parkinson's disease undergoing spinal surgery for degenerative conditions. Studies with less than ten subjects or those assessing surgery for spinal deformity or trauma were excluded. RESULTS: Of 74 studies identified, seven were included for meta-analysis. In the 689,578 participants, there was a significantly higher incidence, but not higher risk, of complications (0.54 95% CI [0.19-0.85] vs 0.07 95% CI [0.01-0.41]; p = 0.048) and revision surgery (0.6 95% CI [0.25-0.88] vs 0.1 95% CI [0.05-0.19]; p = 0.003) amongst patients with Parkinson's disease compared to controls. We also demonstrated a significantly lower incidence but not lower risk of clinical improvement (0.27 95% CI [0.16-0.41] vs 0.57 95% CI [0.36-0.76]; p = 0.02) after surgery in patients with Parkinson's disease. There was no difference in the incidence or risk of death following surgery. DISCUSSION AND CONCLUSION: Spinal surgery for concomitant degenerative diseases in patients with Parkinson's disease is associated with a lower incidence of clinical improvement and a higher incidence of complications. Medical management should be optimised before an individually tailored and well-considered surgical intervention is implemented.

A systematic review identifying outcome measures used in evaluating adults sustaining cervical spine fractures.

OBJECTIVE: To assess the outcome measures used in studies investigating cervical spine fractures in adults, with or without associated spinal cord injury, to inform development of a core outcome set. METHODS: Medline, Embase and Scopus were searched for relevant studies until May 28, 2022, without a historic limit on study date. Study characteristics, population characteristics and outcomes reported were extracted and analyzed. RESULTS: Our literature search identified 536 studies that met criteria for inclusion, involving 393,266 patients. Most studies were single center (87.3%), retrospective studies (88.9%) and involved a median of 40 patients (range 6-167,278). Treatments assessed included: surgery (55.2%), conservative (6.2%), halo immobilization (4.9%), or a mixture (33.2%). Median study duration was 84 months (range 3-564 months); the timing of clinical and/or radiological follow-up assessment after injury was reported in 56.7%. There was significant heterogeneity in outcomes used, with 79 different reported outcomes measures. Differences in use were identified between smaller/larger, retro-/prospective and single/multicenter cohorts. Over time, the use of radiological outcomes has declined with greater emphasis on patient-reported outcome measures (PROMs). Studies of conservative management were more likely to detail PROMs and mortality, whereas surgical studies reported Frankel/ASIA grade, radiological fusion, complication rates, duration of hospital stay and re-operation rates more frequently. In studies assessing the elderly population (> 65 years), use of PROMs, mortality, hospital stay and discharge destination were more common, whereas fusion was reported less often. Response rates for outcome assessments were lower in studies assessing elderly patients, and studies using PROMs. CONCLUSIONS: We have classified the various outcome measures used for patients with cervical spine fractures based on the COMET outcome taxonomy. We also described the contexts in which different outcomes are more commonly employed to help guide decision-making when designing future research endeavors.

Are PARKIN patients ideal candidates for dopaminergic cell replacement therapies?

Parkinson's is a heterogeneous, complex condition. Stratification of Parkinson's subtypes will be essential to identify those that will benefit most from a cell replacement therapy. Foetal mesencephalic grafts can alleviate motor symptoms in some Parkinson's patients. However, on-going synucleinopathy results in the grafts eventually developing Lewy bodies, and they begin to fail. We propose that Parkinson's patients with PARKIN mutations may benefit most from a cell replacement therapy because (a) they often lack synucleinopathy, and (b) their neurodegeneration is often confined to the nigrostriatal pathway. While patients with PARKIN mutations exhibit clinical signs of Parkinson's, post-mortem studies to date indicate the majority lack Lewy bodies suggesting the nigral dopaminergic neurons are lost in a cell autonomous manner independent of α-synuclein mechanisms. Furthermore, these patients are usually younger, slow progressing and typically do not suffer from complex non-nigral symptoms that are unlikely to be ameliorated by a cell replacement therapy. Transplantation of dopaminergic cells into the putamen of these patients will provide neurons with wild-type PARKIN expression to re-innervate the striatum. The focal nature of PARKIN-mediated neurodegeneration and lack of active synucleinopathy in most young-onset cases makes these patients ideal candidates for a dopaminergic cell replacement therapy. Strategies to improve the outcome of cell replacement therapies for sporadic Parkinson's include the use of adjunct therapeutics that target α-synuclein spreading and the use of genetically engineered grafts that are resistant to synucleinopathy.

Long-term effectiveness and tolerability of vagal nerve stimulation in adults with intractable epilepsy: a retrospective analysis of 100 patients.

Data for 100 vagal nerve stimulation (VNS) patients were collected and analysed retrospectively. The mean seizure reduction was 17.86% (n = 67) at 6 months, 26.21% (n = 63) at 1 year, 30.43% (n = 53) at 2 years, 48.10% (n = 40) at 3 years, 49.44% (n = 32) at 4 years, 50.52% (n = 35) at 5 years, 45.85% (n = 31) at 6 years, 62.68% (n = 25) at 8 years, 76.41% (n = 9) at 10 years, 82.90% (n = 4) at 12 years. Evidence of statistical significance for mean seizure reduction over time was strong with all p values less than 0.05 except at 12 years (p = 0.125) where the sample size was small (n = 4). Mean seizure reduction was 49.04% and 51 (51%) patients were considered responders, defined as a 50% or more reduction in seizure frequency. Twenty-one (21%) patients suffered surgical complications. Of these 15 patients were self-limiting and 6 patients were irreversible or required a device revision. Fifty patients (50%) suffered from side-effects, while vagal stimulation cycled on (VNS on) post-operatively. However, of these, only one patient suffered from intolerable side effects requiring the device to be switched off temporarily. This study demonstrates the long-term efficacy in seizure reduction with the use of VNS. Complication rates and tolerability did not deviate greatly from that previously reported, indicating that VNS is a safe and effective treatment for seizure reduction in intractable epilepsy.

Clinical outcomes from bilateral versus unilateral stimulation of the pedunculopontine nucleus with and without concomitant caudal zona incerta region stimulation in Parkinson's disease.

INTRODUCTION: The Pedunculopontine nucleus is a novel target for deep brain stimulation and this may improve postural instability and gait dysfunction in Parkinson's disease. If unilateral Pedunculopontine nucleus stimulation is as efficacious as bilateral stimulation this would lead to less surgical risk. METHODS: 5 Parkinson's disease patients with bilateral caudal Zona Incerta region and Pedunculopontine nucleus electrodes were assessed using the motor component of the Unified Parkinson's Disease Rating Scale. Patients were assessed in the on-medication state to determine the optimal combination of stimulation setting for axial symptom control. RESULTS: The on-medication composite axial-subscore only showed a statistically significant improvement when bilateral Pedunculopontine nucleus and caudal Zona Incerta region stimulation was used. CONCLUSIONS: In the on-medication state bilateral Pedunculopontine nucleus and caudal Zona Incerta region stimulation is required in order to produce a significant change in the motor Unified Parkinson's Disease Rating Scale axial-subscore from baseline.

Duration of External Neck Stabilisation (DENS) following odontoid fracture in older or frail adults: protocol for a randomised controlled trial of collar versus no collar.

INTRODUCTION: Fractures of the odontoid process frequently result from low impact falls in frail or older adults. These are increasing in incidence and importance as the population ages. In the UK, odontoid fractures in older adults are usually managed in hard collars to immobilise the fracture and promote bony healing. However, bony healing does not always occur in older adults, and bony healing is not associated with quality of life, functional, or pain outcomes. Further, hard collars can cause complications such as skin pressure ulcers, swallowing difficulties and difficulties with personal care. We hypothesise that management with no immobilisation may be superior to management in a hard collar for older or frail adults with odontoid fractures. METHODS AND ANALYSES: This is the protocol for the Duration of External Neck Stabilisation (DENS) trial-a non-blinded randomised controlled trial comparing management in a hard collar with management without a collar for older (≥65 years) or frail (Rockwood Clinical Frailty Scale ≥5) adults with a new odontoid fracture. 887 neurologically intact participants with any odontoid process fracture type will be randomised to continuing with a hard collar (standard care) or removal of the collar (intervention). The primary outcome is quality of life measured using the EQ-5D-5L at 12 weeks. Secondary outcomes include pain scores, neck disability index, health and social care use and costs, and mortality. ETHICS AND DISSEMINATION: Informed consent for participation will be sought from those able to provide it. We will also include those who lack capacity to ensure representativeness of frail and acutely unwell older adults. Results will be disseminated via scientific publication, lay summary, and visual abstract. The DENS trial received a favourable ethical opinion from the Scotland A Research Ethics Committee (21/SS/0036) and the Leeds West Research Ethics Committee (21/YH/0141). TRIAL REGISTRATION NUMBER: NCT04895644.

Bilateral caudal zona incerta nucleus stimulation for essential tremor: outcome and quality of life.

BACKGROUND: Over the past few years, bilateral stimulation of the caudal or motor part of the zona incerta nucleus (cZI) has been performed by the authors in patients with essential tremor (ET). Outcomes including quality of life data in 15 patients with a follow-up period of up to 84 months (mean 31.7 ± 28.6 months) are presented. METHODS: 15 consecutive ET patients underwent MRI guided bilateral cZI deep brain stimulation implantation. Patients were assessed by applying the Fahn-Tolosa-Marin Tremor Rating Scale and the Short Form Health Survey-36 (SF-36) to assess quality of life. RESULTS: The total tremor score improved by 73.8% (p<0.0001). The part A score (items 1-9) improved by 86.6% (p<0.0001). Postural tremor improved by 88.2% (p<0.0001) and action tremor by 82.2% (p<0.0001). The part B score, which evaluates the functional activities of the upper limbs, improved by 60.1% (p<0.0001). Part C score, which evaluates the activities of daily living, improved by 80.0% (p<0.0001). The SF-36 physical component score improved by 23.7% (p<0.0001) and the mental component score by 22.4% (p<0.0001). There was one wound infection and three patients developed stimulation related transient dysarthria. None developed any disequilibrium or tolerance to stimulation. CONCLUSION: Bilateral cZI stimulation is safe and effective in suppressing the postural and action component of ET. It is associated with a low incidence of stimulation related complications and patients do not develop tolerance to stimulation with maintained clinical benefit over a follow-up period of up to 7 years.

Outcomes from stimulation of the caudal zona incerta and pedunculopontine nucleus in patients with Parkinson's disease.

INTRODUCTION: Axial symptoms including postural instability, falls and failure of gait initiation are some of the most disabling motor symptoms of Parkinson's disease (PD). We performed bilateral deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) in combination with the caudal zona incerta (cZi) in order to determine their efficacy in alleviating these symptoms. METHODS: Seven patients with predominant axial symptoms in both the 'on' and 'off' medication states underwent bilateral cZi and PPN DBS. Motor outcomes were assessed using the motor component of the Unified Parkinson's Disease Rating Scale (UPDRS 3) and a composite axial subscore was derived from items 27, 28, 29 and 30 (arising from chair, posture, gait and postural stability). Quality of life was measured using the PDQ39. Comparisons were made between scores obtained at baseline and those at a mean follow-up of 12 months. RESULTS: In both the off and on medication states, a statistically significant improvement in the UPDRS part 3 score was achieved by stimulation of the PPN, cZi and both in combination. In the off medication state, our composite axial subscore of the UPDRS part 3 improved with stimulation of the PPN, cZi and both in combination. The composite axial subscore, in the 'on' medication state, however, only showed a statistically significant improvement when a combination of cZi and PPN stimulation was used. CONCLUSIONS: This study provides evidence that a combination of PPN and cZi stimulation can achieve a significant improvement in the hitherto untreatable 'on' medication axial symptoms of PD.

The impact of low-frequency stimulation of the pedunculopontine nucleus region on reaction time in parkinsonism.

OBJECTIVES: Attentional augmentation and enhanced motor function are potential mechanisms by which stimulation of the region of the pedunculopontine nucleus (PPN) may improve gait in parkinsonism. Here, the authors assess the impact of stimulation of this region on attentional and motor aspects of reaction task performance in patients with parkinsonism. METHODS: Eleven patients implanted with PPN stimulators underwent computerised assessment of simple, choice and digit vigilance reaction tasks. Patients were assessed 'off medication' during stimulation at different frequencies (0 Hz, 5 Hz, 10 Hz and 'therapeutic' 20-35 Hz). There were two primary endpoints: 'Speed of Reaction' (sum of the mean task reaction times) and 'Accuracy of Reaction' (reflecting omissions and percentage of correct responses). Baseline performance was compared with age- and sex-matched healthy controls. Clinical effects of stimulation were assessed using the Unified Parkinson's Disease Rating Scale and a falls frequency scale. RESULTS: Compared with healthy controls, subjects had significant deficits in 'Speed of Reaction' and in all mean task reaction times. 'Accuracy of Reaction' was not different from healthy controls and did not improve with stimulation. 'Speed of Reaction' significantly improved with stimulation at therapeutic frequencies (20-35 Hz). Of the individual tasks, only simple reaction time improved significantly. Simple reaction time distribution analysis revealed a general speeding of responses rather than a selective reduction in outliers. Acute PPN stimulation improved gait and balance but not akinesia scores. Chronic PPN stimulation significantly improved falls frequency. Falls score improvement significantly correlated with changes to simple reaction time with therapeutic stimulation. CONCLUSION: The pattern of reaction time improvement with stimulation of the PPN area suggests a benefit on motor performance, rather than augmentation of attention.

Neuralgia of the glossopharyngeal and vagal nerves: long-term outcome following surgical treatment and literature review.

This study describes our experience in the surgical treatment of neuralgia of the glossopharyngeal and vagal nerves. Over the last 19 years, 21 patients underwent surgery. Their case notes were reviewed to obtain demographic information, clinical presentation, surgical findings and early results. All patients were then contacted by telephone for long-term results and complications. Independent analysis of results was carried out by a Neurology team. Ten patients had microvascular decompression (MVD). Four patients had MVD and nerve section. In the remaining seven patients, the glossopharyngeal and first two rootlets of the vagal nerve were sectioned. Nineteen (90%) of 21 patients experienced complete relief of pain immediately after surgery. The remaining patients reported an improvement in their symptoms. There were no mortalities. Four patients experienced short-term complications, which resolved. Two patients were left with a persistent hoarse voice. At follow-up (mean duration of 4 years), there was no recurrence in symptoms. In our experience, surgery is safe and effective for the treatment of vago-glossopharyngeal neuralgia.

High frequency stimulation of the mamillothalamic tract for the treatment of resistant seizures associated with hypothalamic hamartoma.

We investigate the clinical outcome from stimulation of the mamillothalamic tract in two patients with intractable epilepsy secondary to hypothalamic hamartomas. One patient has a left-sided and the other a right-sided tumor. Both patients presented with a history of gelastic and complex partial seizures resistant to multiple antiepileptic drugs. Both patients underwent insertion of a single deep brain-stimulating electrode ipsilateral to the site of the tumor, lying adjacent to the mamillothalamic tract. Postoperatively they both had a significant reduction in seizure frequency, with one patient being seizure free for the last 10 months. An improvement in mood was reported by the patient's primary carers and demonstrated on quality of life questionnaires.

Local field potential recordings from the pedunculopontine nucleus in a Parkinsonian patient.

The pedunculopontine nucleus has recently been introduced as a new therapeutic target for deep brain stimulation in patients suffering from Parkinson's disease, particularly those with severe gait and postural impairment. Stimulation at this site is typically delivered at low frequencies in contrast to the high frequency stimulation required for therapeutic benefit in the subthalamic nucleus. Therefore, we looked for and demonstrated evidence of low frequency synchronization of activity in the pedunculopontine nucleus of a patient with Parkinson's disease that increased after treatment with dopamine and which might be mimicked by local deep brain stimulation at low frequency.

Comparison of atlas- and magnetic-resonance-imaging-based stereotactic targeting of the subthalamic nucleus in the surgical treatment of Parkinson's disease.

AIMS: To assess the variability of the subthalamic nucleus (STN) size, orientation and target coordinates from direct visualization on high-resolution magnetic resonance (MR) images in patients undergoing surgical intervention for Parkinson's disease. METHODS: Sixty-six patients with Parkinson's disease were included in this study. The STN was visualized directly on high-resolution MR images, the size and orientation in both coronal and axial planes were recorded, as were the coordinates of the dorsolateral STN target in relation to the anterior-posterior commissural (AC-PC) line. The same STN target was defined in the Schaltenbrand atlas and atlas-based coordinates in proportion to the patient's AC-PC dimension were calculated. MR-imaging-based STN target coordinates were compared with the corresponding atlas-based coordinates. RESULTS: Marked variation of STN size and orientation was observed. A significant difference was demonstrated on comparing left- and right-sided x and y coordinates. The comparison between MR-imaging-based and atlas-derived target coordinates demonstrated a significant difference in all directions except the left y coordinate. CONCLUSIONS: This study demonstrates the substantial individual variability of STN size, orientation and target coordinates and a significant difference between target coordinates obtained by direct visual targeting on MR images and those obtained by indirect targeting based on atlases.

Subcortical evoked activity and motor enhancement in Parkinson's disease.

Enhancements in motor performance have been demonstrated in response to intense stimuli both in healthy subjects and in the form of 'paradoxical kinesis' in patients with Parkinson's disease. Here we identify a mid-latency evoked potential in local field potential recordings from the region of the subthalamic nucleus, which scales in amplitude with both the intensity of the stimulus delivered and corresponding enhancements in biomechanical measures of maximal handgrips, independent of the dopaminergic state of our subjects with Parkinson's disease. Recordings of a similar evoked potential in the related pedunculopontine nucleus - a key component of the reticular activating system - provide support for this neural signature in the subthalmic nucleus being a novel correlate of ascending arousal, propagated from the reticular activating system to exert an 'energizing' influence on motor circuitry. Future manipulation of this system linking arousal and motor performance may provide a novel approach for the non-dopaminergic enhancement of motor performance in patients with hypokinetic disorders such as Parkinson's disease.

A magnetic resonance imaging-directed method for transventricular targeting of midline structures for deep brain stimulation using implantable guide tubes.

OBJECTIVE: The periventricular gray/periaqueductal gray (PVG/PAG) is a target site for deep brain stimulation for chronic pain. The pedunculopontine nucleus (PPN) is a target for the treatment of axial disturbance in Parkinson's disease. Conventionally, a trajectory lateral to the ventricle is used in targeting deep subcortical structures; however, this limits the number of active contacts that can be placed in these midline targets. To maximize the number of contacts within these targets, a trajectory traversing the ventricles may be used; however, this is avoided because lead placement remains unpredictable with problems including ventricular lead migration and hemorrhage. We describe a novel method for accurate and safe transventricular targeting. METHODS: Magnetic resonance imaging is used for visualizing the target structure. A trajectory traversing the lateral ventricle is planned, avoiding blood vessels. The guide tube is inserted through the ventricle to a position short of the target site and its proximal end is fixed. A stylet is inserted in the guide tube with its distal end at the target site. After intraoperative radiological confirmation of placement, the indwelling stylet is removed and the guide tube acts as a port for delivering the stimulating electrode. RESULTS: The PVG/PAG matter and the PPN were targeted, taking a transventricular trajectory. We implanted unilateral PVG/PAG matter electrodes in 10 patients and bilateral PPN electrodes in 3 patients. All electrodes were implanted accurately within the desired target with no complications. CONCLUSION: The use of an implanted guide tube enables the safe and accurate transventricular targeting of the PVG/PAG matter and the PPN.