Administration off label of recombinant factor-VIIa (rFVIIa) to patients with blunt or penetrating brain injury without coagulopathy.

Traumatic brain contusions may increase in size over time or may develop at a delay after injury. This may lead to neurological deterioration, long term morbidity or even death. Coagulation disorders after injury can contribute to progression of haemorrhage. Recombinant activated factor VII (rFVIIa) was used in 12 patients with a severe head injury who had no systemic coagulopathy but who were considered to be at risk of progression of their intracranial lesion. Twelve consecutive patients suffering from life-threatening acute head injuries from blunt (3 cases) and penetrating mechanisms were given with rFVIIa, either to prevent the expected development of brain contusion or to assist in bleeding control during surgery. In 11 patients, rFVIIa was given by the attending neurosurgeon. Two of the patients died of their severe penetrating injuries one of whom had severe vasospasm 2 days after administration of rFVIIa. The other 11 patients did not appear to suffer any treatment-related adverse effects. When the drug was given prophylactically to prevent brain resection (6 cases) or to limit the need for widening resection (5 cases), marked control was achieved in seven cases, and a lesser effect was observed in the other 4 cases. We conclude that, in a small and highly individually selected series of patients with severe head injury, the administration of rFVIIa did not lead to adverse effects. Although the majority of patients were considered to be at high risk of progression of their lesions, this occurred in only one. The early use of rFVIIa in head injured patients without systemic coagulopathy may reduce the occurrence of enlargement of contusions, the requirement of further operation, and adverse outcome. Prospective randomised controlled studies are required to investigate this.

Intrathecal or intraventricular therapy for post-neurosurgical Gram-negative meningitis: matched cohort study.

Gram-negative post-operative meningitis due to carbapenem-resistant bacteria (CR-GNPOM) is a dire complication of neurosurgical procedures. We performed a nested propensity-matched historical cohort study aimed at examining the possible benefit of intrathecal or intraventricular (IT/IV) antibiotic treatment for CR-GNPOM. We included consecutive adults with GNPOM in two centres between 2005 and 2014. Patients receiving combined systemic and IT/IV treatment were matched to patients receiving systemic treatment only. Matching was done based on the propensity of the patients to receive IT/IV treatment. We compared patient groups with 30-day mortality defined as the primary outcome. The cohort included 95 patients with GNPOM. Of them, 37 received IT/IV therapy in addition to systemic treatment (22 with colistin and 15 with amikacin), mostly as initial therapy, through indwelling cerebrospinal fluid drains. Variables associated with IT/IV therapy in the propensity score included no previous neurosurgery, time from admission to meningitis, presence of a urinary catheter and GNPOM caused by carbapenem-resistant Gram-negative bacteria. Following propensity matching, 23 patients given IT/IV therapy and 27 controls were analysed. Mortality was significantly lower with IT/IV therapy: 2/23 (8.7%) versus 9/27 (33.3%), propensity-adjusted OR 0.19, 95% CI 0.04-0.99. Death or neurological deterioration at 30 days, 14-day and in-hospital mortality were lower with IT/IV therapy (OR <0.4 for all) without statistically significant differences. Among patients discharged alive, those receiving IT/IV therapy did not experience more neurological deterioration. Serious adverse events with IT/IV therapy were not documented. Our results support the early use of IT antibiotic treatment for CR-GNPOM when a delivery method is available.

Risk factors associated with death or neurological deterioration among patients with Gram-negative postneurosurgical meningitis.

In a retrospective cohort of 115 patients with Gram-negative postneurosurgical meningitis, factors associated with 30-day mortality or neurological deterioration on multivariate analysis included days from admission to meningitis (OR 1.05 per day, 95% CI 1.02-1.09), decreased level of consciousness (OR 2.69, 95% CI 0.99-7.31), blood glucose level >180 mg/dL (OR 3.70, 95% CI 1.27-10.77), higher creatinine level (OR 4.07 per 1 mg/dL, 95% CI 1.50-11.08), and cerebrospinal fluid glucose <50 mg/dL (OR 5.02, 95% CI 1.71-14.77) at diagnosis. A predictive score triaged patients into three groups with low (4/44, 9.1%), intermediate (16/38, 42.1%) and high (22/33, 66.7%) unfavourable outcome rates. Validation on a different group of 36 patients with Gram-negative postneurosurgical meningitis was acceptable.

Influence of task-related ipsilateral hand movement on motor cortex excitability.

OBJECTIVE: The time course of the right motor cortex excitability in relation to a task-related voluntary right thumb twitch was studied using sub-threshold transcranial magnetic stimulation (TMS) to the right motor cortex. METHODS: Motor excitability was studied in 8 adult subjects who made a brief right thumb twitch to the predictable omission of every fifth tone in a series of tones 2.5 s apart. This paradigm avoided an overt sensory cue, while allowing experimental control of TMS timing relative to both movement and the cue to move. Motor excitability was characterized by several measures of motor evoked potentials (MEPs) recorded from the left thenar eminence in response to TMS over the right scalp with a 9 cm coil: probability of eliciting MEPs, incidence of MEPs and amplitude of MEPs. RESULTS: All subjects showed suppression of motor excitability immediately following a voluntary right thumb twitch (ipsilateral response), and up to 1 s after it. However, two distinctly different effects on motor excitability were observed before the response: two subjects showed excitation, beginning about 500 ms before response until 300 ms after it, followed by the post-movement suppression; 6 subjects displayed pre-movement suppression, beginning about 600 ms before the response and persisting for the duration. CONCLUSIONS: The net effect of an ipsilateral response on motor cortex can be either inhibitory or excitatory, changing with time relative to the response. These findings are compatible with two separate processes, inhibitory and excitatory, which interact to determine motor excitability ipsilateral to the responding hand.

Novel magnetic technology for intraoperative intracranial frameless navigation: in vivo and in vitro results.

OBJECTIVE: To characterize the accuracy of the Magellan electromagnetic navigation system (Biosense Webster, Tirat HaCarmel, Israel) and to demonstrate the feasibility of its use in image-guided neurosurgical applications. DESCRIPTION OF INSTRUMENTATION: The Magellan system was developed to provide real-time tracking of the distal tips of flexible catheters, steerable endoscopes, and other surgical instruments, using ultra-low electromagnetic fields and a novel miniature position sensor for image-correlated intraoperative navigation and mapping applications. METHODS: An image registration procedure was performed, and static and qualitative accuracies were assessed in a series of phantom, animal, and human neurosurgical studies. EXPERIENCE AND RESULTS: During the human study phase, an accuracy error of up to 5 mm was deemed acceptable. Results demonstrated that this degree of accuracy was maintained throughout all procedures. All anatomic landmarks were reached with precision and were accurately viewed on the display screen. Navigation that relied on the system was also successful. No interference with operating room equipment was noted. The accuracy of the system was maintained during regular surgical procedures, using standard surgical tools. CONCLUSION: The system provides precise lesion localization without limiting the line of vision, the mobility of the surgeon, or the flexibility of instruments. Electromagnetic navigation promises new advances in neuronavigation and frameless stereotactic surgery.

Primary cutaneous extravertebral meningioma. Case report.

A case of cutaneous extravertebral meningioma is presented. It was diagnosed in infancy as a lumbar meningocele. Operation was initially refused but was subsequently demanded for cosmetic reasons. The findings were a very thick corrugated skin and a cutaneous meningioma connected by a fibrous tract to the dura mater. The presence of a fibrous stalk linking the tumor to the dura mater might have been the pathogenetic connection between the meningocele and cutaneous meningioma.

Recurrence of intracranial meningiomas: the role played by regional multicentricity. Part 2: Clinical and radiological aspects.

Globular single meningiomas are generally regarded as benign tumors that can be completely removed. Nevertheless, after a total macroscopic resection including the insertion zone (Grade 1 operation according to Simpson's classification), the incidence of recurrence ranged from 9% to 14% at the 5-year follow-up review. The authors have shown that single meningiomas represent only the visible predominant growth in the midst of a wide neoplastic field in the dura mater. Regional multiplicity in meningiomas would thus seem to be the rule. With this in mind, the authors propose to divide recurrences after Grade 1 operations into true local and false regional. A local recurrence is defined as a regrowth within the limits of the previous dural flap. Regional recurrence is when new growth develops outside the previous craniotomy site; this should not be considered as a recurrence but as a new primary site. These regional recurrences might explain some unexpected late tumor growth occurring after a Grade 1 operation. Five illustrative cases in which regional recurrence was detected by computerized tomography are presented. The authors also propose to add a supplementary grade to Simpson's surgical grading: Grade 0. This operation would entail a wide resection of the dura around the attachment zone of the meningioma. The authors hope that with a Grade 0 operation the incidence of recurrence might be reduced.

Delayed onset of traumatic extradural hematoma.

During a 4 1/2-year period, seven patients with delayed onset of an extradural hematoma were seen among 80 consecutively treated cases of extradural hematoma for a frequency of 8.75%. The hematomas were insignificant or not present on initial computerized tomography (CT) scanning. Repeat CT scans within 24 hours of admission showed sizeable hemorrhages. Six hematomas were evacuated, and one was reabsorbed spontaneously. In only one patient did neurological deterioration herald the onset of the extradural hematoma, four patients remained unchanged, and two improved before diagnosis. Intracranial pressure (ICP) was monitored in five patients, four of whom showed intermittent rise in pressure despite preventive treatment. Intracranial hypotension and rapid recovery from peripheral vascular collapse seemed to be contributory factors in the delayed onset of an extradural hematoma. Awareness of this entity, a high degree of vigilance, ICP monitoring, and repeat CT scanning within 24 hours of injury are strongly recommended in these cases, especially after decompression by either surgical or medical means, recovery from shock, or whenever there is evidence of even minimal bleeding under a skull fracture on the initial CT scan.

Eighth nerve contributions to cat auditory brainstem responses (ABR).

There is a temporal correspondence between some of the early components of the auditory brainstem potentials in cat and the negative peak of the triphasic nerve action potential recorded from selected points along the VIII cranial nerve. The intracranial portion of the VIII nerve in cat has a conduction velocity of 10 meters/s. The initial peak of the ABR, P1a, is coincident with the negative portion of the triphasic VIII nerve action potential within the cochlea as recorded from the round window. The next peak (P1b) of the ABR occurs 400 microseconds later and is coincident with the negative portion of the triphasic VIII nerve action potential recorded from just within the lateral border of the cochlear nucleus. These results are similar to studies of the human ABR that show waves I and II are correlated with activity of the VIII nerve. It is likely that waves P1a and P1b in cat are homologous to waves I and II in human. In cat, these first two peaks of the ABR can be distinguished in vertex to neck recordings but not in vertex to ipsilateral mastoid derivations.

Effects of myelin or cell body brainstem lesions on 3-channel Lissajous' trajectories of feline auditory brainstem evoked potentials.

Auditory brainstem evoked potentials (ABEP) were recorded from 16 awake cats to obtain 3-Channel Lissajous' Trajectories (3CLTs) using three orthogonal differential electrode configurations (nasion-midline nuchal ridge, left-right mastoids, vertex-midline under the mandible). Potentials, evoked by monaural 80 dBnHL (re, human threshold) clicks, were studied before, and up to 7 weeks after inducing neuronal lesions localized to the cochlear nucleus (CN) or the superior olivary complex (SOC), or myelin lesions localized to the fibers of the trapezoid body connecting these two structures. Neuronal lesions were induced by injection of kainic acid (KA), while myelin lesions were induced by injection of L-alpha-lysophosphatidylcholine (LPC). With CN neuronal lesions the major changes in 3CLT were in the time domain of 'b', 'c' and 'd' (components P2, P3 and P4 of single-channel ABEP). With SOC neuronal lesions the major changes were in 'c' and 'd' of 3CLT (P3 and P4 of ABEP). With trapezoid body lesions the major change was in 'c' (P3 of ABEP). The results are compatible with the peripheral generation of the first ABEP components (P1a and P1b). The second component (P2) is generated by ipsilateral CN neurones and their outputs. The third component (P3) is generated primarily by ipsilateral SOC neurones and their outputs, with the ipsilateral CN providing input. The The fourth component (P4) is generated bilaterally by the SOC neurones and their outputs, receiving their inputs from ipsilateral CN. The fifth ABEP component (P5) is generated by structures central to the SOCs and their immediate outputs. Neither focal neuronal nor myelin lesions were sufficient to produce obliteration of any component, consistent with a set of generators for each of the ABEP components, consisting of both cell bodies and their output fibers, that is distributed spatially in the brainstem.

Primary osteogenic sarcoma arising from the dura mater: case report.

A 42-year-old woman who sought treatment for left drop foot was found to have a right frontoparietal parasagittal mass. Gross total resection of the tumor was performed and pathologic analysis revealed high grade osteoblastic osteosarcoma. The patient received adjuvant chemotherapy and continues to do well with no evidence of metastases or local recurrence 3 years after initial presentation.

Time course of motor excitability before and after a task-related movement.

AIMS OF THE STUDY: The time course of motor excitability during a task-related unilateral right thumb movement was studied using sub-threshold transcranial magnetic stimulation (TMS) to the contralateral left motor cortex. The level of stimulation evoked a motor evoked potential (MEP) in the thumb when the subject was at rest in approximately 10% of the trials. METHODS: Subjects made a brief right thumb movement to the predictable omission of regularly presented tone bursts allowing experimental definition of TMS relative to the cue to move. Motor cortical excitability was characterized by amplitude and/or probability of eliciting MEPs. RESULTS: There were four periods of altered motor excitability during task performance compared to a control resting state: a first period of weak facilitation before movement between -500 to -200 ms, a second period without increased excitability approximately 150 ms before movement onset when MEPs amplitude was below that seen in rest, a third period of strong facilitation between -100 ms before movement and +200 ms after facilitation and a fourth period of weak facilitation between +200 to +500 ms. CONCLUSION: These results show that during performance of a task requiring a motor response, motor cortical excitability is increased above resting for hundreds of millisecond before and after the response, except for a transient period between 75 and 150 ms prior to movement onset. The temporal pattern of these excitability changes is compatible with multiple excitatory and inhibitory inputs interacting on motor cortex.

Spinal cord compression in Paget's disease of bone with reference to sarcomatous degeneration and calcitonin treatment.

Four cases of spinal cord compression stemming from Paget's disease of bone tissue are reported. Sarcomatous degeneration was proved in one case and in another one malignancy was deduced by computed tomography (CT) scanning. Clinical and radiologic manifestations as well as surgical management are discussed. The value of CT scanning of the spine as an aid in the evaluation of structural changes and the size of the soft tissue mass in sarcomatous degeneration of the lesion is stressed. After calcitonin administration, alleviation of pain and improvement in neurological status have occurred in two treated patients.

Penetrating head injuries caused by a new weapon, the side dome.

The "side dome" is a mix of high and low explosives with a multitude of small metal balls molded within a specially designed half-sphere that directs the explosion wave and the projectiles in one direction to augment the harm. This weapon, originally designed by guerrilla and terrorist groups, is now used by regular armies. This report presents one craniocervical and eight cranial injuries caused by this new weapon and discusses the cases' various clinical features, the paucity of intracerebral cavitation damage along the missile track, the need for only minimally aggressive surgery, and the relatively favorable outcome. In all cases, the helmet offered good protection and the entry of the projectiles was just below its rim in an upward direction.

Effects of myelin or cell body brainstem lesions on 3-channel Lissajous' trajectories of fast and slow components of feline auditory brainstem evoked potentials.

Auditory brainstem evoked potentials (ABEP) were recorded from 16 awake cats using three orthogonal differential electrode pairs before and during a week after inducing neuronal lesions localized to the cochlear nucleus (CN) or the superior olivary complex (SOC), or myelin lesions localized to the fibers of the trapezoid body. ABEPs were digitally filtered to include only the slow ('pedestal') component, or only the faster first to fifth components, and three-channel Lissajous' trajectories (3CLTs) of these fast and slow components of ABEP were obtained. Cell body lesions and myelin lesions induced effects on 3CLT measures of both fast and slow components of ABEP. The results suggest a primary contribution of cell body activity to the slow component, and a primary fiber tract contribution to the fast components. However, the results do not support exclusive generation of the pedestal by cell body and dendritic post-synaptic potentials and of the faster components by action potentials along fibers. The results are consistent with a set of generators for each of the slow and fast components of ABEP, consisting of both cell bodies and their output fibers, that are spatially distributed in the brainstem.

[Temporal hemianopia and diabetes insipidus following head injury].

Bitemporal hemianopia and diabetes insipidus following head injury are caused by a lesion in the center of the optic chiasm, together with injury to the adjacent pituitary stalk or the hypothalamus. This combination was thought to be a rare complication of severe head injury. The case of a 16-year-old male is presented, which together with recent reports suggests that this relatively under-recognized syndrome is not infrequent, that it may follow even minor head injury, and that magnetic resonance imaging can demonstrate the chiasmal lesion.

[Head injury in the elderly].

We report 281 consecutive admissions of head-injured patients over 65 years of age. 2/3 were males, as in younger age groups, despite the decreased activity and increased proportion of females among the elderly. The main causes of injury were falls (71.8%; mostly at home) and pedestrian accidents (20.6%). There was a high incidence of cardiovascular disease among the men. The unique set of causes and types of head injuries in this age group (1/3 chronic subdural hematomas, 1/3 cerebral contusions and 1/5 acute subdural hematomas), as well as the grim outcome, justify regarding head injury in the elderly as a special clinical entity. Its special medical, surgical, organizational and ethical aspects should be considered.

The 18 kDa mitochondrial translocator protein (TSPO) prevents accumulation of protoporphyrin IX. Involvement of reactive oxygen species (ROS).

By exposing cells of the U118MG glioblastoma cell line to protoporphyrin IX (PPIX) in culture, we found that the 18 kDa mitochondrial translocator protein (TSPO) prevents intracellular accumulation of PPIX. In particular, TSPO knockdown by stable transfection of TSPO silencing siRNA vectors into U118MG cells leads to mitochondrial PPIX accumulation. In combination with light exposure, the PPIX accumulation led to cell death of the TSPO knockdown cells. In the sham control cells (stable transfection of scrambled siRNA vectors), TSPO expression remained high and no PPIX accumulation was observed. The prevention of PPIX accumulation by TSPO was not due to conversion of PPIX to heme in the sham control cells. Similar to TSPO knockdown, the reactive oxygen species (ROS) scavenger glutathione (GSH) also enhanced PPIX accumulation. This suggests that that ROS generation as modulated by TSPO activation may present a mechanism to prevent accumulation of PPIX.

Targeted therapy for high-grade glioma with the TGF-ß2 inhibitor trabedersen: results of a randomized and controlled phase IIb study.

This randomized, open-label, active-controlled, dose-finding phase IIb study evaluated the efficacy and safety of trabedersen (AP 12009) administered intratumorally by convection-enhanced delivery compared with standard chemotherapy in patients with recurrent/refractory high-grade glioma. One hundred and forty-five patients with central reference histopathology of recurrent/refractory glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA) were randomly assigned to receive trabedersen at doses of 10 or 80 µM or standard chemotherapy (temozolomide or procarbazine/lomustine/vincristine). Primary endpoint was 6-month tumor control rate, and secondary endpoints included response at further timepoints, survival, and safety. Six-month tumor control rates were not significantly different in the entire study population (AA and GBM). Prespecified AA subgroup analysis showed a significant benefit regarding the 14-month tumor control rate for 10 µM trabedersen vs chemotherapy (p= .0032). The 2-year survival rate had a trend for superiority for 10 µM trabedersen vs chemotherapy (p = .10). Median survival for 10 µM trabedersen was 39.1 months compared with 35.2 months for 80 µM trabedersen and 21.7 months for chemotherapy (not significant). In GBM patients, response and survival results were comparable among the 3 arms. Exploratory analysis on GBM patients aged ≤55 years with Karnofsky performance status >80% at baseline indicated a 3-fold survival at 2 and 3 years for 10 µM trabedersen vs chemotherapy. The frequency of patients with related or possibly drug-related adverse events was higher with standard chemotherapy (64%) than with 80 µM trabedersen (43%) and 10 µM trabedersen (27%). Superior efficacy and safety for 10 µM trabedersen over 80 µM trabedersen and chemotherapy and positive risk-benefit assessment suggest it as the optimal dose for further clinical development in high-grade glioma.