Simon D Thompson

Artemin-GFRα3 interactions partially contribute to acute inflammatory hypersensitivity.

The expression of artemin (ARTN), a glial cell line-derived neurotrophic factor (GDNF) family ligand, increases in pre-clinical models of nociception and recent evidence suggests this growth factor may play a causative role in inflammatory pain mechanisms. The aim of this study was to demonstrate functional inhibition of ARTN with monoclonal antibodies and to determine whether ARTN neutralisation could reverse inflammatory pain in mice. We show that monoclonal antibodies with high affinity to ARTN, completely inhibit ARTN-induced Ret and ERK activation in a human neuroblastoma cell line, and block capsaicin-induced CGRP secretion from primary rat DRG cultures. In addition, administration of anti-ARTN antibodies to mice provides a transient, partial reversal (41%) of FCA-induced mechanical hypersensitivity. Anti-ARTN antibodies had no effect on hypersensitivity in response to partial nerve ligation in mice. These data suggest that ARTN-GFRα3 interactions partially mediate early stage nociceptive signalling following an inflammatory insult.

DESH negative normal pressure hydrocephalus: can patients still benefit from shunt insertion?

Selecting probable idiopathic normal pressure hydrocephalus (INPH) patients for shunt insertion presents a challenge because of coexisting comorbidities and other conditions that could mimic NPH. The characteristic appearance of DESH (Disproportionately Enlarged Subarachnoid Space Hydrocephalus) on brain imaging has been shown to have a high positive predictive value in identifying shunt responsive INPH patients (SINPHONI trial). However, the negative predictive value of this radiological sign was not clearly demonstrated.

Three-hundred cases of Spiegelberg ICP monitoring for hydrocephalus and CSF disorders: the Queen Square experience

Results ICPM was undertaken for a number of different conditions including undiagnosed headache (20.4%), IIH (28.7%), NPH (5.3%), high-pressure hydrocephalus (eg congenital/ post-traumatic/post-SAH) (17.2%) and Chiari malformations/syringomyelia (13.6%). Indications for ICPM included headache (74.0%), visual disturbance (6.2%), gait disturbance (6.2%) and cognitive disturbance (5.0%). Mean monitoring time was 37.3 hrs (range 12-154 hrs). Monitoring was conducted in the presence of a CSF shunt (50.6%), venous stent (3.7%) and previous cranial decompression (6.5%). Dynamic monitoring (eg with different shunt settings or pre/post venous stent insertion) was undertaken in 12.4%. Outcomes from ICPM included insertion of new CSF shunt (21.0%), revision of CSF shunt (13.0%), insertion of venous stent (6.5%), insertion of and lumbar drains for infusion studies (3.6%); importantly, non-operative treatment was pursued in a number of cases including shunt valve adjustment (7.7%) and conservative management (29.9%). Complications included superficial infection (4 patients, 1.2%), symptomatic intracerebral haematoma (1 patient, 0.3%) and misplacement (3 patients, 0.9%); importantly, there were no cases of deep intracranial infection and the only case of seizures was in the patient with the intracerebral haematoma. Conclusion This is the largest known series of ICPM for CSF disorders. It shows that ICP monitoring is a safe procedure and may be undertaken as part of routine protocol in the management of complex hydrocephalus patients. The number of cases that were subsequently managed conservatively or with a simple valve adjustment (37.6%) indicates the utility in terms of reducing operative interventions. Further evaluation of positive and negative predictive values based on the results of ICP monitoring and health-economic analyses will push the case for routine ICP monitoring prior to definitive management of all hydrocephalus patients.

Venous sinus stenting immediately reduces intracranial pressure in Idiopathic Intracranial Hypertension patients with venous sinus stenosis

Idiopathic Intracranial Hypertension (IIH) is characterised by an increased intracranial pressure (ICP) in the absence of any central nervous system disease or structural abnormality, and normal CSF composition. Management becomes complicated once surgical intervention is required. Venous sinus stenosis has been suggested as a possible aetiology for IIH. Venous sinus stenting has emerged as a possible interventional option. Evidence for venous sinus stenting is based on elimination of the venous pressure gradient and clinical response. There have been no studies demonstrating the immediate effect of venous stenting on ICP.

Neurturin and a Glp-1 Analogue Act Synergistically to Alleviate Diabetes in Zucker Diabetic Fatty Rats

Neurturin (NRTN), a member of the glial-derived neurotrophic factor family, was identified from an embryonic chicken pancreatic cDNA library in a screen for secreted factors. In this study, we assessed the potential antidiabetic activities of NRTN relative to liraglutide, a glucagon-like peptide 1 receptor agonist, in Zucker diabetic fatty (ZDF) rats. Subcutaneous administration of NRTN to 8-week-old male ZDF rats prevented the development of hyperglycemia and improved metabolic parameters similar to liraglutide. NRTN treatment increased pancreatic insulin content and β-cell mass and prevented deterioration of islet organization. However, unlike liraglutide-treated rats, NRTN-mediated improvements were not associated with reduced body weight or food intake. Acute NRTN treatment did not activate c-Fos expression in key feeding behavior and metabolic centers in ZDF rat brain or directly enhance glucose-stimulated insulin secretion from pancreatic β-cells. Treating 10-week-old ZDF rats with sustained hyperglycemia with liraglutide resulted in some alleviation of hyperglycemia, whereas NRTN was not as effective despite improving plasma lipids and fasting glucose levels. Interestingly, coadministration of NRTN and liraglutide normalized hyperglycemia and other metabolic parameters, demonstrating that combining therapies with distinct mechanism(s) can alleviate advanced diabetes. This emphasizes that therapeutic combinations can be more effective to manage diabetes in individuals with uncontrolled hyperglycemia.

Comorbidites in NPH - local introspective - ‘Shunt them all’!.

In response to the 2013 ISH-CSF task force review on comorbidities in NPH we assessed 73 patients who were diagnosed with NPH and underwent shunt surgery at our tertiary neurosurgical unit between August 2008 and August 2012.

Intracranial pressure and venous sinus pressure gradients: what happens 3 months after stenting?

Benign Intracranial hypertension (BIH) is commonly associated with venous sinus stenosis. Increasingly, this is treated endovascularly with stent insertion. However, this treatment modality is still controversial. Clinical improvement post stent insertion has been described. Little is known about long-term control of intracranial pressure (ICP). In our unit, catheter cerebral venogram with pressure measurements is routinely performed 3 months post stent insertion in BIH patients. We aim to quantify the degree of venous pressure changes in stenosis patients treated with sinus stenting and how the changes correlate with radiographic improvements.

Superficial and Deep Skin Preparation with Povidone-Iodine for Ventriculoperitoneal Shunt Surgery : A Technical Note

Objective Ventriculoperitoneal (VP) shunt surgery is a common and effective treatment for hydrocephalus and cerebrospinal fluid disorders. Infection remains a major cause of morbidity and mortality after a VP shunt. There is evidence that a deep skin flora microbiome may have a role to play in post-operative infections. In this technical note, we present a skin preparation technique that addresses the issue of the skin flora beyond the initial incision. Methods The patient is initially prepped, as standard, with. a single layer of 2% CHG+70% isopropyl alcohol. The novel stage is the ‘double incision’ whereby an initial superficial incision receives a further application of povidone-iodine prior to completing the full depth incision. Results Of the 84 shunts inserted using the double-incision method (September 2015 to September 2016), only one developed a shunt infection. Conclusion The double incision approach to skin preparation is a unique operative stage in VP shunt surgery that may have a role to play in reducing acute shunt infection.

Intracranial pressure in patients with papilloedema

Papilloedema is a clinical manifestation of chronically raised intracranial pressure (ICP), often seen in idiopathic intracranial hypertension (IIH). However, the extent of intracranial hypertension required to produce papilloedema is not known. We compare ICP values in IIH patients who developed papilloedema and those who did not. We aim to identify a pathological ICP threshold predictive of the development of papilloedema in IIH patients.

Transtentorial Distortion Syndrome: Consistent Complication Following Lateral and Fourth Ventricular Shunting in Adults

BACKGROUND Complex hydrocephalus affecting lateral and fourth ventricles separately is occasionally managed with cerebrospinal fluid diversion via supratentorial and infratentorial ventricular catheters. The optimal configuration to reduce complications is currently unknown in adults. We describe a consistently similar clinical presentation of patients with complex hydrocephalus and a fourth ventricle separately drained by infratentorial shunt insertion. METHODS This was a retrospective single-center case series. Medical notes were reviewed for clinical presentation, brain imaging, and neurophysiologic tests results. All patients underwent intracranial pressure monitoring (ICPM). Outcomes were determined by ventricular appearance on brain imaging computed tomography and symptomatic improvements postoperatively. RESULTS Five adult patients referred to the hydrocephalus service had separate infratentorial and supratentorial shunt systems. A common clinical presentation was observed, including lower motor neuron facial palsy (confirmed with electrophysiology), ophthalmoplegia, dysarthria, impaired gait headache, and nausea. We refer to this as transtentorial distortion syndrome. Twenty-four-hour ICPM demonstrated clear low pressures. All patients underwent shunt revision connecting the transtentorial shunts via a Y-connector and the addition of a distal valve. All subjects had improved ventricular appearance on computed tomography scans post revision, and normalization of ICPM was observed. In the follow-up period of 6 months, no patient required further shunt revision. CONCLUSION To prevent transtentorial distortion syndrome, supratentorial and infratentorial shunt constructs in adults with encysted fourth ventricles should be similar to the shunt systems widely known in the pediatric population with Dandy-Walker syndrome (i.e., joint output to a single valve distal to the connection of the 2 proximal drainage catheters).