Neurogenic inflammation after traumatic brain injury and its potentiation of classical inflammation

Background: The neuroinflammatory response following traumatic brain injury (TBI) is known to be a key secondary injury factor that can drive ongoing neuronal injury. Despite this, treatments that have targeted aspects of the inflammatory pathway have not shown significant efficacy in clinical trials. Main body: We suggest that this may be because classical inflammation only represents part of the story, with activation of neurogenic inflammation potentially one of the key initiating inflammatory events following TBI. Indeed, evidence suggests that the transient receptor potential cation channels (TRP channels), TRPV1 and TRPA1, are polymodal receptors that are activated by a variety of stimuli associated with TBI, including mechanical shear stress, leading to the release of neuropeptides such as substance P (SP). SP augments many aspects of the classical inflammatory response via activation of microglia and astrocytes, degranulation of mast cells, and promoting leukocyte migration. Furthermore, SP may initiate the earliest changes seen in blood-brain barrier (BBB) permeability, namely the increased transcellular transport of plasma proteins via activation of caveolae. This is in line with reports that alterations in transcellular transport are seen first following TBI, prior to decreases in expression of tight-junction proteins such as claudin-5 and occludin. Indeed, the receptor for SP, the tachykinin NK1 receptor, is found in caveolae and its activation following TBI may allow influx of albumin and other plasma proteins which directly augment the inflammatory response by activating astrocytes and microglia. Conclusions: As such, the neurogenic inflammatory response can exacerbate classical inflammation via a positive feedback loop, with classical inflammatory mediators such as bradykinin and prostaglandins then further stimulating TRP receptors. Accordingly, complete inhibition of neuroinflammation following TBI may require the inhibition of both classical and neurogenic inflammatory pathways.Frances Corrigan, Kimberley A. Mander, Anna V. Leonard and Robert Vin

Hearing preservation after low dose linac radiosurgery for acoustic neuroma depends on initial hearing and time

PurposeTo assess long term outcomes and factors determining hearing preservation after low dose linac stereotactic radiosurgery (SRS) for acoustic neuroma (AN) at the Royal Adelaide Hospital using prospectively collected data.Material and methodsBetween 1994 and 2010, 102 patients had SRS for AN. Five patients had neurofibromatosis type 2, six sporadic cases had relapsed after surgery, and the remaining 91 sporadic cases had primary SRS. Dose was 12 or 14 Gy. Sustained changes ≥ 2 mm in any diameter were deemed significant, and useful hearing was defined as inter-aural pure tone average (PTA) ≤ 50 dB. Possible prognostic factors for hearing retention were tested by dividing the patients at pre-specified cutpoints: age (60 years), maximum tumour diameter (20mm), initial PTA (20 dB) and dose (12 vs 14 Gy).ResultsEighty-four of the 91 sporadic primary SRS cases were evaluable for tumour control with at least one post-treatment MRI. Their median follow-up was 65 mo (range 10-184 mo). Eighty-two (97.6%) were controlled, the remaining two requiring salvage surgery for progression at 5.75 and 9.75 years. Also, one of the post-operative cases required surgery at 2.1 years after SRS. For the 50 sporadic primary SRS patients with initially useful hearing, median age was 56 (range 21-76), median initial PTA 16 dB (range -11 to +45 dB) and median tumour diameter 21 mm (range 10-33 mm). Four received 14 Gy, the rest 12 Gy. After SRS, 19 patients (38%) retained useful hearing. The Kaplan-Meier estimated preservation rate at 5 years was 50% (95% CI 36-64%) but by 10 years, this had fallen to 23% (95% CI 12-41%). On univariate analysis, the only significant factor was initial PTA (P ConclusionsTumour control was excellent (99/102=97% freedom from surgical salvage). Hearing preservation was strongly dependent on initial PTA, but there was a steady fall-off in hearing out to at least 10 years.Daniel E. Roos, Andrew E. Potter and Andrew C. Zacesthttp://www.elsevier.com/wps/find/journaldescription.cws_home/506042/description#descriptio

Recurrent haemorrhage from a malignant brain stem glioma: a review of the mechanisms of tumoural haemorrhage

The authors report a 23-year-old man who was diagnosed with a brain stem malignant glioma following his first episode of generalised seizure. This was subsequently complicated by three separate documented episodes of intracranial haemorrhage. The literature is reviewed and the pathophysiological mechanisms of tumoural haemorrhage are discussed. It is speculated that significant intratumoural arteriovenous shunting may lead to recurrent haemorrhages.G. Lee, A. C. Zacest and P. L. Reill

Abduction strength following intramedullary nailing of the femur

Objectives: To assess hip abductor function, strength and complaints following insertion of a femoral intramedullary nail. Design: Retrospective clinical review. Setting: Department of Orthopaedics, Adelaide Women's and Children's Hospital, Adelaide. Department of Orthopaedic Surgery and Trauma, Royal Adelaide Hospital, Adelaide, South Australia, Australia. Patients: 1. 32 of 37 patients who had an intramedullary nail inserted for an isolated femoral shaft fracture at the Royal Adelaide Hospital between 1987 and 1990. 2. 14 of 18 patients who had closed femoral shortening for leg length discrepancy, at the Adelaide Women's and Children's Hospital between 1985 and 1987. Patients with pathology involving the abductor mechanism were excluded. 3. 40 asymptomatic controls. Intervention: Intramedullary fixation for femoral shaft fractures or as part of closed femoral shortening. All procedures were performed on a traction table via a gluteal splitting approach with reamed nails. Main Outcome Measurements: Complaints included, pain, stiffness, limp and diminished walking distance. Examination of abductor function and measurement of abductor strength. Radiological assessment at followup. Results: Complaints included trochanteric pain (40%, 40%), thigh pain (10%, 8%) and limp (13%, 42%) in the femoral fracture and closed femoral shortening groups respectively. There was significant difference in the abduction strength (p<0.01) and abduction ratio (p<0.01) between the control and each treatment group. Abductor weakness correlated (r=0.30) with the incidence of complaints. Conclusion: Pain, limp and weakness are common following insertion of a femoral intramedullary nail. Agluteal retracting approach may minimize abductor weakness.G. I. Bain, A. C. Zacest, D. C. Paterson, J. Middleton, A. P. Poh

LINAC radiosurgery for cerebral arteriovenous malformations: a single centre prospective analysis and review of the literature

Abstract not availableAndrew C. Zacest, Julianna Caon, Daniel E. Roos, Andrew E. Potter, Thomas Sulliva

Substance P immunoreactivity increases following human traumatic brain injury

Recent experimental evidence suggests that neuropeptides, and in particular substance P (SP), are released following traumatic brain injury (TBI) and may play a significant role in the aetiology of cerebral edema and increased intracranial pressure. Whether SP may play a similar role in clinical TBI remains unknown and was investigated in the current study. Archival post-mortem material was selected from patients who had sustained TBI, had died and had undergone post-mortem and detailed neuropathological examination (n = 13). A second cohort of patients who had died, but who showed no neuropathological abnormality (n = 10), served as case controls. Changes in SP immunoreactivity were examined in the cerebral cortex directly beneath the subdural haematoma in 7 TBI cases and in proximity to contusions in the other 6 cases. Increased SP perivascular immunoreactivity was observed after TBI in 10/13 cases, cortical neurones in 12/13 and astrocytes in 10/13 cases. Perivascular axonal injury was observed by amyloid precursor protein (APP) immunoreactivity in 6/13 TBI cases. Co-localization of SP and APP in a small subset of perivascular fibres suggests perivascular axonal injury could be a mechanism of release of this neuropeptide. The abundance of SP fibres around the human cerebral microvasculature, particularly post capillary venules, together with the changes observed following TBI in perivascular axons, cortical neurones and astrocytes suggest a potentially important role for substance P in neurogenic inflammation following human TBI.Andrew C. Zacest, Robert Vink, Jim Manavis, Ghafar T. Sarvestani, and Peter C. Blumberg

Enhanced intrinsic radiosensitivity after treatment with stereotactic radiosurgery for an acoustic neuroma

Enhanced radiosensitivity is an uncommon phenomenon attributable to deficient DNA repair after radiotherapy which can be assessed with the γ-H2AX assay. Reports of radiosensitivity after stereotactic radiosurgery (SRS) are uncommon. We describe a case where the clinical, radiological and laboratory findings suggest enhanced radiosensitivity after SRS for an acoustic neuroma.Gerard Adams, Olga A. Martin, Daniel E. Roos, Pavel N. Lobachevsky, Andrew E. Potter, Andrew C. Zacest, Eva Bezak, William M. Bonner, Roger F. Martin, Trevor Leon