Locating the ventral intermediate thalamic nucleus for deep brain stimulation surgery: analysis of a case series comparing CT and MR targeting.

BACKGROUND: Deep brain stimulation (DBS) surgery targeting the ventral intermediate thalamic nucleus (Vim) has proven efficacy in the treatment of tremor. AIMS: The primary aim is to investigate whether there is a statistically significant difference in patient outcomes when CT-guided targeting of the Vim is compared with MRI-guided targeting. METHODS: This is a retrospective study concerning patients undergoing Vim-targeted DBS at the Department of Neurosurgery, Royal Victoria Infirmary in Newcastle (9th August 2012 to 4th January 2019). Fahn-Tolosa-Marin Tremor Scale (FTM TS) and EQ-5D scores were collected from patient notes. Statistical analysis was performed using IBM® SPSS® Statistics Version 24. Independent samples t-tests were used to compare means. RESULTS: Independent samples t-test did not reveal a statistically significant difference between CT (n = 10; FTM TS mean = 65.40, SD = 11.40; EQ-5D mean = 39.50, SD = 17.87) and MR (n = 7; FTM TS mean = 60.57, SD = 7.50; EQ-5D mean = 32.14, SD = 9.94) groups in pre-surgery FTM TS (t(15) = 0.977, p = 0.344) and EQ-5D (t(15) = 0.982, p = 0.342) scores. No statistically significant difference between the CT (FTM TS mean = 24.12, SD = 20.47; EQ-5D mean = 75.56, SD = 15.63) and MR (FTM TS mean = 22.86, SD = 6.72; EQ-5D mean = 70.43, SD = 15.48) groups was revealed at 1 year assessment of FTM TS (t(14) = 0.155, p = 0.879) and EQ-5D (t(14) = 0.654, p = 0.524). The median difference between pre- and post-surgery FTM TS and EQ-5D scores in the CT group at 1 year was 43.00 and 35.00, respectively. The MR patient group median difference in pre- and post-surgery at 1 year was 35.00 and 35.00 respectively. CONCLUSION: No statistically significant difference between CT and MR image-guided targeting patient groups was detected.

Patient selection and outcome of deep brain stimulation for multiple sclerosis-associated tremor.

INTRODUCTION: Tremor is a disabling symptom of multiple sclerosis (MS), with limited treatment modalities. Thalamic ventral-intermediate-nucleus (VIM) deep brain stimulation (DBS) is a method of neuromodulation. We describe the long-term outcomes of our carefully selected patients who underwent VIM DBS for their MS-associated tremor. METHODS: Patients were referred from the regional neurology units. Pre-operative assessments included suitability for anesthesia, tremor quantification by the Fahn-Tolosa-Marin scores, and quality-of-life (EQ5D) measures. Exclusion criteria included prominent cerebellar symptoms such as ataxia and dysmetria, intracranial pathology such as ventriculomegaly, cerebellar plaques and thalamic abnormality, and comorbid psychiatric symptoms. Seven patients (3M:4F) underwent DBS for MS-associated tremor between September 2013 and February 2019. Mean age was 42 years (±SD 8 years). DBS was performed at a mean of 13 years (±SD 9 years) after diagnosis of MS. RESULTS: There were no postoperative surgical complications. All patients showed improvement in FTM tremor scores, by up to 61% at 6 months postoperatively. There was an improvement of 30-175% in quality-of-life scores at 6 months. Improvement of tremor and quality of life, over baseline, was sustained over a long period of follow-up (mean 26.6 months ± SD 20.7 months), including our longest duration at 72 months. CONCLUSION: With careful selection, DBS is a safe, efficacious intervention for MS-tremor and can positively impact on tremor and quality of life, with effects over a long period. As patients live longer with MS and the advent of new therapies, DBS should be considered for selected patients.

DBS in tremor with dystonia: VIM, GPi or both? A review of the literature and considerations from a single-center experience.

BACKGROUND: Deep brain stimulation (DBS) is an established treatment for dystonia and tremor. However, there is no consensus about the best surgical targeting strategy in patients with concomitant tremor and dystonia. Both the thalamic ventral intermediate nucleus (VIM) and the globus pallidus pars interna (GPi) have been proposed as targets. Few cases using them together in a double-target approach have also been reported. METHODS: We reviewed the literature on this topic, summarizing results of different target choices. Additionally, we retrospectively report a case series of nine patients with sporadic dystonia and severe tremor treated with a double-target strategy at our center. Outcome measures were the Burke-Fahn-Marsden Dystonia Rating Scale (BFM) and Eq-5d scale. RESULTS: In published studies of patients with dystonia and tremor, VIM-DBS is highly effective on tremor but raise some concerns about dystonia's control, while GPi-DBS is more effective on dystonia but does not always relieve tremor. GPi + VIM-DBS shows good efficacy but is rarely reported and reserved for selected patients. In our patients, the double-target strategy obtained a significant and durable improvement in tremor, dystonia, and quality of life. Additionally, compared with a cohort of patients with tremor treated with VIM-DBS only, significantly lower frequency and intensity of VIM stimulation were required to control tremor. CONCLUSION: Our findings and published evidence seem to support the double-targeting approach as a safe and effective option in selected patients with tremor-dominant dystonia. This strategy appears to provide a more extensive control of either dystonia or tremor and may have a potential for limiting stimulation-related side effects.

The AMPA receptor antagonist perampanel suppresses epileptic activity in human focal cortical dysplasia.

Focal cortical dysplasia (FCD) is one of the most common malformations causing refractory epilepsy. Dysregulation of glutamatergic systems plays a critical role in the hyperexcitability of dysplastic neurons in FCD lesions. The pharmacoresistant nature of epilepsy associated with FCD may be due to a lack of well-tolerated and precise antiepileptic drugs that can target glutamate receptors. Here, for the first time in human FCD brain slices, we show that the established, noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, perampanel has potent antiepileptic action. Moreover, we demonstrate that this effect is due to a reduction in burst firing behavior in human FCD microcircuits. These data support a potential role for the treatment of refractory epilepsy associated with FCD in human patients.

Population data for 23 autosomal STR loci in White British population.

We report allele frequencies and standard population genetics parameters for 23 forensic autosomal STR loci tested among White British population. In addition, we use generated allele frequency data to compare the extent of genetic variation with 19 other European populations.

CT scan exposure in children with ventriculo-peritoneal shunts: single centre experience and review of the literature.

PURPOSE: A computed tomography (CT) scan in childhood is associated with a greater incidence of brain cancer. CT scans are used in patients with ventriculo-peritoneal (VP) shunts in whom shunt dysfunction is suspected. We wanted to assess the CT scan exposure in a cohort of children with VP shunts and attempt to quantify their radiation exposure. METHODS: A single-centre retrospective analysis was performed recording CT head scans in children younger than 18 years with VP shunts. Hospital coding data was cross-referenced with electronic records and radiology databases both in our neurosurgery unit and in hospitals referring to it. RESULTS: One hundred and fifty-two children with VP shunts were identified. The mean time with shunt in situ was 5.4 years (± 4.61). A mean of 3.33 CT scans (range 0-20) were performed on each child, amounting to 0.65 (± 0.87) CTs per shunt year. Based on 2 msv of radiation per scan, this equates to an average exposure of 1.31 msv per child per shunt year. CONCLUSION: Children who have multiple CT head scans for investigation of possible shunt dysfunction are at a greater risk of developing cancer. We discuss the implications of this increased risk and discuss strategies to limit radiation exposure in children with VP shunts.

The role of astrocytes in seizure generation: insights from a novel in vitro seizure model based on mitochondrial dysfunction.

Approximately one-quarter of patients with mitochondrial disease experience epilepsy. Their epilepsy is often severe and resistant towards conventional antiepileptic drugs. Despite the severity of this epilepsy, there are currently no animal models available to provide a mechanistic understanding of mitochondrial epilepsy. We conducted neuropathological studies on patients with mitochondrial epilepsy and found the involvement of the astrocytic compartment. As a proof of concept, we developed a novel brain slice model of mitochondrial epilepsy by the application of an astrocytic-specific aconitase inhibitor, fluorocitrate, concomitant with mitochondrial respiratory inhibitors, rotenone and potassium cyanide. The model was robust and exhibited both face and predictive validity. We then used the model to assess the role that astrocytes play in seizure generation and demonstrated the involvement of the GABA-glutamate-glutamine cycle. Notably, glutamine appears to be an important intermediary molecule between the neuronal and astrocytic compartment in the regulation of GABAergic inhibitory tone. Finally, we found that a deficiency in glutamine synthetase is an important pathogenic process for seizure generation in both the brain slice model and the human neuropathological study. Our study describes the first model for mitochondrial epilepsy and provides a mechanistic insight into how astrocytes drive seizure generation in mitochondrial epilepsy.

Gap junction networks can generate both ripple-like and fast ripple-like oscillations.

Fast ripples (FRs) are network oscillations, defined variously as having frequencies of > 150 to > 250 Hz, with a controversial mechanism. FRs appear to indicate a propensity of cortical tissue to originate seizures. Here, we demonstrate field oscillations, at up to 400 Hz, in spontaneously epileptic human cortical tissue in vitro, and present a network model that could explain FRs themselves, and their relation to 'ordinary' (slower) ripples. We performed network simulations with model pyramidal neurons, having axons electrically coupled. Ripples (< 250 Hz) were favored when conduction of action potentials, axon to axon, was reliable. Whereas ripple population activity was periodic, firing of individual axons varied in relative phase. A switch from ripples to FRs took place when an ectopic spike occurred in a cell coupled to another cell, itself multiply coupled to others. Propagation could then start in one direction only, a condition suitable for re-entry. The resulting oscillations were > 250 Hz, were sustained or interrupted, and had little jitter in the firing of individual axons. The form of model FR was similar to spontaneously occurring FRs in excised human epileptic tissue. In vitro, FRs were suppressed by a gap junction blocker. Our data suggest that a given network can produce ripples, FRs, or both, via gap junctions, and that FRs are favored by clusters of axonal gap junctions. If axonal gap junctions indeed occur in epileptic tissue, and are mediated by connexin 26 (recently shown to mediate coupling between immature neocortical pyramidal cells), then this prediction is testable.

Spinal cord stimulation for visceral pain related to chronic pancreatitis: report of 2 cases.

OBJECTIVE: To report our experience related to the use of spinal cord stimulation (SCS) for relief of chronic pancreatitis-related neuropathic visceral pain. METHODS: Two patients, 50 years old and 39 years old, presented with intractable visceral pain related to chronic pancreatitis. A quadripolar electrode for SCS was inserted at the T8-10 level using a percutaneous technique. After a successful trial, a permanent stimulator was inserted. RESULTS: At a mean follow-up of 7 years, both patients showed a marked improvement, with 80% and 90% decrease of pain, respectively, as assessed by Visual Analogue Scale. Pain medications were discontinued in both cases. CONCLUSIONS: SCS appears to be an effective long-term treatment for neuropathic visceral pain related to chronic pancreatitis.

Glissandi: transient fast electrocorticographic oscillations of steadily increasing frequency, explained by temporally increasing gap junction conductance.

PURPOSE: We describe a form of very fast oscillation (VFO) in patient electrocorticography (ECoG) recordings, that can occur prior to ictal events, in which the frequency increases steadily from ≈ 30-40 to >120 Hz, over a period of seconds. We dub these events "glissandi" and describe a possible model for them. METHODS: Four patients with epilepsy had presurgical evaluations (with ECoG obtained in two of them), and excised tissue was studied in vitro, from three of the patients. Glissandi were seen spontaneously in vitro, associated with ictal events-using acute slices of rat neocortex-and they were simulated using a network model of 15,000 detailed layer V pyramidal neurons, coupled by gap junctions. KEY FINDINGS: Glissandi were observed to arise from human temporal neocortex. In vitro, they lasted 0.2-4.1 s, prior to ictal onset. Similar events were observed in the rat in vitro in layer V of frontal neocortex when alkaline solution was pressure-ejected; glissandi persisted when γ-aminobutyric acid A (GABA(A)), GABA(B), and N-methyl-d-aspartate (NMDA), and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors were blocked. Nonalkaline conditions prevented glissando generation. In network simulations it was found that steadily increasing gap junction conductance would lead to the observed steady increase in VFO field frequency. This occurred because increasing gap junction conductance shortened the time required for an action potential to cross from cell to cell. SIGNIFICANCE: The in vitro and modeling data are consistent with the hypothesis that glissandi arise when pyramidal cell gap junction conductances rise over time, possibly as a result of an alkaline fluctuation in brain pH.

Unplanned reoperation rates in pediatric neurosurgery: a single center experience and proposed use as a quality indicator.

OBJECT: The pediatric neurosurgery practice over 2 years was reviewed at a tertiary neurosciences center. The intention was to establish the frequency of unplanned reoperations at the center, investigate the factors responsible, and consider using unplanned reoperations as a quality indicator. METHODS: All pediatric neurosurgical operations done between January 2008 and January 2010 were reviewed using data from operation theater logs and hospital records. Data were recorded as per the standard requirements of the Society of British Neurological Surgeons for incorporation into the national database. "Unplanned reoperation" was defined as any unscheduled secondary procedure required for a complication resulting directly or indirectly from the index operation or as an unscheduled return to the operating theater for the same condition. Operations were defined as "urgent" if they had to be performed out of hours (that is, outside the hours of 8:00 a.m. to 5:00 p.m.), "emergency elective" if they were included on the emergency list but within working hours, and "routine elective" if they were on the scheduled operations list. Both overall and 30-day unplanned reoperation rates were considered. Factors influencing unplanned reoperations were explored using a logistic regression model. RESULTS: Four hundred ten operations were analyzed. The overall unplanned reoperation rate was 28%. The median time to an unplanned reoperation was 9 days. Risk factors for unplanned reoperations included a CSF diversion procedure (OR 7, p < 0.0001) and an urgent procedure (OR 2.5, p = 0.02, higher unplanned reoperations for urgent procedures relative to routine electives). The 30-day unplanned reoperation rate was 17%. Urgent cases composed 32% of all operations. Trainees performed 52% of the urgent operations. Forty-four percent of all operations were related to CSF diversion. Sixty-four percent of patients had reoperations during the course of the study period, and 44% of these reoperations were unplanned. CONCLUSIONS: An unplanned return to the operation theater is common in the authors' pediatric neurosurgical practice and is procedure specific. Unplanned reoperation rates may be useful for monitoring quality across hospitals and identifying opportunities for quality improvement. The authors propose the use of this index as a quality indicator and advocate its validation in a prospective multicenter study.

A prospective pilot study of two-session Gamma Knife surgery for large metastatic brain tumors.

The purpose of this prospective study is to evaluate the efficacy and limitations of two-session Gamma Knife radiosurgery (GKS) alone for large metastatic brain tumors. Inclusion criteria were as follows: (i) patients with large metastatic brain tumors (volume >15 cm(3) in the supratentorial region or >10 cm(3) in the infratentorial region), and (ii) tumors not causing clinical signs of impending cerebral herniation. Twenty-eight lesions in 27 consecutive patients (18 men and 9 women, age range 32 to 88 years, median age 65 years) were included in this study. The radiosurgical protocol was as follows: 20-30 Gy given in two fractions 3-4 weeks apart. The local tumor control rate and the overall survival rate were calculated by using the Kaplan-Meier method. Median tumor volumes were 17.8 cm(3) at first GKS and 9.7 cm(3) at second GKS. Median follow-up time was 8.9 months. The local control rate was 85 % at 6 months and 61 % at 12 months. The overall survival rate after GKS was 63 % at 6 months and 45 % at 12 months. The 1-year rate of prevention of neurological death was maintained at 78 %. Mean Karnofsky performance status (KPS) improved from 61 [95 % confidence interval (CI), 57-71] at first GKS to 80 (95 % CI, 74-85) at second GKS; the best follow-up mean KPS was 85 (95 % CI, 78-91) (p < 0.001). Local tumor recurrence necessitated craniotomy in two patients and repeat GKS in three patients. Seventeen patients died, and the causes of death were as follows: 3 from local progression, 2 from meningeal carcinomatosis, and 12 from progression of the primary tumor. Delayed symptomatic perilesional edema developed in one patient and eventually resolved with conservative treatment. Two-session GKS for large brain metastases appears to be an effective treatment in terms of both local tumor control and neurological palliation with minimal treatment-related morbidity. These data suggest that two-session GKS could be used as an alternative to surgical resection of large tumors in patients with significant comorbidity and/or at an advanced age. The optimum regimen for dose and fraction schedule remains to be established.

Preoperative MRI/MRA for microvascular decompression in trigeminal neuralgia: consecutive series of 67 patients.

BACKGROUND: Microvascular decompression is an accepted treatment for primary trigeminal neuralgia. In recent years, efforts have been made to investigate the role of preoperative MRI/MRA in selecting patients with neurovascular compression. METHODS: Ninety-two consecutive patients underwent a standard retrosigmoid craniotomy for microvascular decompression between 2005 and 2009, of whom 67 had a preoperative MRI and MRA according to the protocol of our department. Operative findings were accurately recorded and compared to MRI/MRA results. Follow-up was in the form of telephone interview. RESULTS: Preoperative MRI sensitivity was 96%, while specificity was 75% (1 false positive among 4 patients with negative intra-operative findings). The predictive value of a positive MRI/MRA was 98%, while the predictive value of a negative MRI/MRA was 50%. Fifty-four patients were available for outcome assessment at a mean follow-up of 3.8 years (range 1-5). Seventy-two percent of patients were pain-free, 9.5% had mild residual pain, while 18.5% had a poor outcome (moderate to severe residual pain). The correlation between preoperative MRI/MRA and outcome was not statistically significant (P = 0.570). CONCLUSIONS: Preoperative MRI has both good sensitivity and positive predictive value. Specificity and negative predicitve value were limited in this series. No correlation was found between preoperative imaging and outcome. Both radiological and clinical criteria are important for patient selection.

Tethering of the cervico-medullary junction with central cord oedema after foramen magnum decompression for Chiari malformation.

An unusual complication following foramen magnum decompression for Chiari malformation is described: adhesive tethering of the cervico-medullary junction with oedema of the upper spinal cord and lower medulla. Further surgery was required to correct this condition.

A nonsynaptic mechanism underlying interictal discharges in human epileptic neocortex.

Very fast oscillations (VFOs, >80 Hz) are important for physiological brain processes and, in excess, with certain epilepsies. Putative mechanisms for VFO include interneuron spiking and network activity in coupled pyramidal cell axons. It is not known whether either, or both, of these apply in pathophysiological conditions. Spontaneously occurring interictal discharges occur in human tissue in vitro, resected from neocortical epileptic foci. VFO associated with these discharges was manifest in both field potential and, with phase delay, in excitatory synaptic inputs to fast spiking interneurons. Recruitment of somatic pyramidal cell and interneuron spiking was low, with no correlation between VFO power and synaptic inputs to principal cells. Reducing synaptic inhibition failed to affect VFO occurrence, but they were abolished by reduced gap junction conductance. These data suggest a lack of a causal role for interneurons, and favor a nonsynaptic pyramidal cell network origin for VFO in epileptic human neocortex.

Factors predicting improvement in primary generalized dystonia treated by pallidal deep brain stimulation.

Despite the beneficial effects of Globus Pallidus internus (GPi) deep brain stimulation (DBS) in patients with primary generalized dystonia (PGD), the degree of improvement varies from one patient to another. The objective of this study was to examine the effects of clinical, anatomical (volume of the GPi), and electrical variables on the postoperative Burke-Fahn-Marsden Dystonia rating scale (BFMDRS) motor score to identify which factors may be predictive of the degree of improvement. We reviewed retrospectively the clinical records of 40 steady-state patients with PGD who had been treated by bilateral GPi lead implantation. The follow-up period was 2 to 8 years. The correlation between the electrical parameters (voltage, impedance, and current) and the clinical outcome was studied. An analysis of covariance was performed to identify factors predictive of the magnitude of improvement. The most influential factors according to the model are as follows: the preoperative BFMDRS score (P < 0.0001); age at surgery (P < 0.0001); the right GPi volume (P = 0.002); the left stimulated GPi volume (P = 0.005). No significant correlation was found between the electrical parameters used and the mean motor scores in steady state.