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.

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.

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.

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.

Morphological study of the spinal canal content for subarachnoid endoscopy.

STUDY DESIGN AND OBJECTIVE: This study was designed to examine the morphology of the spinal dural sac and contents, using magnetic resonance imaging in order to define the inner geometrical dimensions that confine the manoeuvre of an endoscope inserted in the lumbar region and along the thoracic and cervical spine. BACKGROUND: The morphology of the spine has been studied since the development of myelography. However, most studies have measured the diameters of the spinal cord only, not the size of the subarachnoid space. In addition, the few studies available on the subarachnoid space have focused on the cervical spine, leaving a near-complete dearth of data on the subarachnoid space dimensions along the thoracic spine. METHODS: Based on MRI images of the spine from 42 patients, the dimensions of the spinal cord, dural sac, and subarachnoid space were measured at mid-vertebral and inter-vertebral disc levels. RESULTS: It was found that at each selected transverse level, the subarachnoid space tends to be symmetrical on the right and left sides of the cord, and measures 2.5 mm on average. However, the posterior and anterior segments, measured on the mid-sagittal plane, are generally asymmetrical and vary widely in size, ranging from 1 to 5 mm. These measurements match those found in previous studies, where these are available. The coefficient of variance for the dimensions of the subarachnoid space is as high as 42.4%, while that for the dimensions of the spinal cord is 10-15%. CONCLUSIONS: The findings presented here expand our knowledge of the spinal canal's morphology, and show that an endoscope designed to travel within the subarachnoid space must be smaller than 2.5 mm in diameter.

Comparison of moderate hyperventilation and mannitol for control of intracranial pressure control in patients with severe traumatic brain injury--a study of cerebral blood flow and metabolism.

OBJECTIVE: To compare the respective effects of established measures used for management of traumatic brain injury (TBI) patients on cerebral blood flow (CBF) and cerebral metabolic rates of oxygen (CMRO2), glucose (CMRGlc) and lactate (CMRLct). METHODS: Thirty-six patients suffering from severe traumatic brain injury (TBI) were prospectively evaluated. In all patients baseline assessments were compared with that following moderate hyperventilation (reducing PaCO2 from 36 +/- 4 to 32 +/- 4 mmHg) and with that produced by administration of 0.5 gr/kg mannitol 20% intravenously. Intracranial and cerebral perfusion pressure (ICP, CPP), CBF and arterial jugular differences in oxygen, glucose and lactate contents were measured for calculation of CMRO2, CMRGlc and CMRLct. RESULTS: Following hyperventilation, CBF was significantly reduced (P < 0.0001). CBF remained most often above the ischemic range although values less than 30 ml x 100 gr(-1) x min(-1) were found in 27.8% of patients. CBF reduction was associated with concurrent decrease in CMRO2, anaerobic hyperglycolysis and subsequent lactate production. In contrast, mannitol resulted in significant albeit moderate improvement of cerebral perfusion. However, administration of mannitol had no ostensible effect either on oxidative or glucose metabolism and lactate balance remained mostly unaffected. CONCLUSIONS: Moderate hyperventilation may exacerbate pre-existing impairment of cerebral blood flow and metabolism in TBI patients and should be therefore carefully used under appropriate monitoring. Our findings rather support the use of mannitol for ICP control.

Alteration in brain natriuretic peptide (BNP) plasma concentration following severe traumatic brain injury.

BACKGROUND: Brain natriuretic peptide (BNP) is a potent natriuretic and vasodilator factor which, by its systemic effects, can decrease cerebral blood flow (CBF). In aneurysmal subarchnoid hemorrhage (aSAH), BNP plasma concentrations were found to be associated with hyponatremia and were progressively elevated in patients who eventually developed delayed ischemic deficit secondary to vasospasm. The purpose of the present study was to evaluate trends in BNP plasma concentrations during the acute phase following severe (traumatic brain injury) TBI. METHODS: BNP plasma concentration was evaluated in 30 patients with severe isolated head injury (GCS<8 on admission) in four time periods after the injury (period 1: days 1-2; period 2: days 4-5; period 3: days 7-8; period 4: days 10-11). All patients were monitored for ICP during the first week after the injury. FINDINGS: The initial BNP plasma concentrations (42+/-36.9 pg/ml) were 7.3 fold (p<0.01) higher in TBI patients as compared to the control group (5.78+/-1.90 pg/ml). BNP plasma concentrations were progressively elevated through days 7-8 after the injury in patients with diffused SAH as compared to patients with mild or no SAH (p<0.001) and in patients with elevated ICP as compared to patients without elevated ICP (p<0.001). Furthermore, trends in BNP plasma concentrations were significantly and positively associated with poor outcome. INTERPRETATION: BNP plasma concentrations are elevated shortly after head injury and are continuously elevated during the acute phase in patients with more extensive SAH and in those with elevated ICP, and correlate with poor outcomes. Further studies should be undertaken to evaluate the role of BNP in TBI pathophysiology.

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.

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.

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.

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.

Severe head injury in children--analyzing the better outcome over a decade and the role of major improvements in intensive care.

We suggest a few possible explanations, including improvement of intensive care, as the main cause, for the improved outcome after severe head injury in children and present the predictors of outcome observed in a contemporary series. From January 1984 to June 1988 we saw 117 children (ages 0-14) with postresuscitation GCS (Glasgow Come Scale) scores of 3-8. The more recent cohort of children seen in 1994-1996 was made up of 152 patients. Apart from standard statistics we used a segmentation method called CHAID (SSPS software). Previously known predictors of outcome are found still to apply in our series. Although in the recent period there was a lower proportion of patients with GCS 3-4 (11% versus 32%), a higher percentage had suffered multiple trauma (56% versus 33%). The rates of craniotomy and of ICP monitoring were similar (66% and 61%). Comparison of the two cohorts for outcome at discharge and through 1 year shows that mortality fell from 33% to 10% and the proportion achieving improvement of neurological status increased from 24% to 56%. CHAID analysis showed that the mortality rates of patients within specific groups declined significantly over the two periods: (1) a significant reduction in mortality was seen in patients with GCS 5-7, especially those with diffuse axonal injury (DAI) (17.3% to 0%); (2) no child admitted in shock survived in the earlier period, whereas 7 with GCS 4-6 survived during the recent period. The best model for mortality prediction includes GCS, and in the GCS 4-7 subgroup, the presence of subdural hematoma. It seems that the trend toward better immediate outcome is continuous, and this is the more striking when the severity of injury is taken into consideration. Our belief is that the modern medical and surgical techniques, although incurring higher costs and necessitating ongoing intensity, are well worth the effort.

Profuse hemorrhage from cerebral vessels in tangential missile injuries.

Tangential missile injuries are recognized as a cause of cerebral damage by in driven bone fragments, parenchymal lacerations and intracerebral haematomas. Severe blood loss from this type of injury was not reported. Four patients are described in whom high kinetic energy missiles caused severe tangential craniocerebral injuries. Their condition was aggravated by life threatening haemorrhage. The bleeding vessels were cerebral arteries or major veins entrapped in the fracture line and bleeding extracranially. This blood loss cannot be controlled by dressing and salvage could be achieved only by immediate resuscitation, vigorous fluid replacement and very rapid evacuation to a neurosurgical center.

Motor evoked potentials in the preoperative and postoperative assessment of normal pressure hydrocephalus.

Motor evoked potentials and central motor conduction time (CMCT) were examined from both upper and lower limbs in patients with normal pressure hydrocephalus to find a predictor for the success of shunting procedures. The hypotheses that walking disturbances are due to pyramidal tract compression as well as the possibility that the upper limbs are affected subclinically in these patients were also studied. The study suggests that the walking disturbances are not the result of a major pyramidal tract dysfunction but probably involve the sensorimotor integration leading to normal gait. Furthermore, CMCT measured with electromagnetic motor stimulation can help in selecting the patients that will benefit from shunting. The study does not provide electrophysiological evidence of upper limb involvement in normal pressure hydrocephalus.

[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.

Experimental facial myokymia in cat.

INTRODUCTION: The objective of this study was to describe facial myokymia in experimental animals accompanying kainic acid affects on facial motor neurons. MATERIAL & METHODS: Anesthetized cats were injected with kainic acid into the pons adjacent to the facial nucleus. Facial movements appeared shortly after the injections and facial electromyographic potentials were recorded. Cats were killed up to 4 weeks later, the brainstems were processed histologically, and the number of neurons in the facial nucleus counted. RESULTS: Cats receiving injection of kainic acid adjacent to facial nucleus all developed spontaneous writhing movements of the face ipsilateral to the injection site, clinically resembling facial myokymia in humans. Transient facial paresis, lasting several weeks, appeared in some of the cats. Facial myokymia occurred independent of histological evidence of neuronal loss in facial nucleus, whereas facial paresis occurred in all but one of the animals with significant neuronal loss in the facial nucleus. Placing a needle into the superior olive without injecting kainic acid or injections of kainic acid into cochlear nucleus was not accompanied by facial myokymia or subsequent facial paresis. CONCLUSION: Facial movements in cats similar to myokymia in humans accompanies kainic acid injections adjacent to the nucleus of the facial nerve.