Non-cytotoxic radiosensitizers in brain radiotherapy: journey till the first decade of this millennium.

Brain tumors, primary and metastatic, are a cause of significant mortality and morbidity. Radiotherapy (RT) forms an integral part of the treatment of brain tumors. Intrinsic relative tumor radio-resistance, normal tissue tolerance and impact on neurocognitive function, all limit the efficacy of RT. Radiosensitizers can potentially increase efficacy on tumors while maintaining normal tissue toxicity, with or without inherent cytotoxicity. This article reviews the evolution of evidence with use of non-cytotoxic radiosensitizers in brain radiotherapy and their status at the end of the first decade of this millennium. Considering, the era of development and mechanism of action, these agents are classified as first, second and third-generation non-cytotoxic radiosensitizers. The last millennium involved elaboration of first-generation compounds including halogenated pyrimidines, hypoxic cell sensitizers (e.g. imidazoles) and glycolytic inhibitors (e.g. lonidamine). The first decade of this millennium has highlighted redox modulators like motexafin gadolinium and newer hypoxic cell sensitizers like efaproxiral, which have shown promise. However, phase III trials and meta-analyses have not identified a clear winner though the second-generation has shown some rays of hope. Recent research has focused on expanding the horizon by studying modulation of newer molecular pathways like DNA repair, microtubule stabilization, cytokine function and nuclear factor-kappa beta (NF-KB) in order to increase RT efficacy. The review concludes by summarizing the class of evidence and the level of recommendation available for use of non-cytotoxic radiosensitizers in brain RT.

Trimodal nanoelectrode array for precise deep brain stimulation: prospects of a new technology based on carbon nanofiber arrays.

Although deep brain stimulation (DBS) has recently been shown to be effective for neurological disorders such as Parkinson's disease, there are many limitations of the current technology: the large size of current microelectrodes (approximately 1 mm diameter); the lack of monitoring of local brain electrical activity and neurotransmitters (e.g. dopamine in Parkinson's disease); the open-loop nature of the stimulation (i.e. not guided by brain electrochemical activity). Reducing the size of the monitoring and stimulating electrodes by orders of magnitude (to the size of neural elements) allows remarkable improvements in both monitoring (spatial resolution, temporal resolution, and sensitivity) and stimulation. Carbon nanofiber nanoelectrode technology offers the possibility of trimodal arrays (monitoring electrical activity, monitoring neurotransmitter levels, precise stimulation). DBS can then be guided by changes in brain electrical activity and/or neurotransmitter levels (i.e. closed-loop DBS). Here, we describe the basic manufacture and electrical characteristics of a prototype nanoelectrode array for DBS, as well as preliminary studies with electroconductive polymers necessary to optimize DBS in vivo. An approach such as the nanoelectrode array described here may offer a generic electrical-neural interface for use in various neural prostheses.

Monitoring for neuroprotection. New technologies for the new millennium.

Monitoring for neuroprotection, like surgery, has placed on emphasis on minimal or non-invasiveness. Monitoring of parameters that truly reflect the degree of injury to the nervous system is another goal. Thus, two themes for the coming decade in neuromonitoring will be: (1) less-invasive monitoring; and (2) parameters that more closely reflect the etiological factors in ischemic or other neuroinjury. In this paper, we review neuromonitoring techniques and devices that can be used readily in the operating room or intensive care unit setting. Those that require transport of the patient to a special facility (e.g., for computed tomography or magnetic resonance imaging/spectroscopy) and those that have been in standard practice for neuromonitoring (e.g., electrophysiological monitoring--EEG, evoked potentials) are not considered. The two techniques considered in detail are (1) continuous multiparameter local brain tissue monitoring with microprobes, and (2) non-invasive continuous local brain tissue oxygenation monitoring by near infrared spectroscopy. Both techniques have been cleared by the Food and Drug Administration (FDA) for clinical use. The rationale for their use, the nature of the devices, and clinical results to date are reviewed. It is expected that both techniques will gain wide acceptance during the coming decade; further advances in neuromonitoring that can be expected further into the twenty-first century are also discussed.

Neuroprotection for the new millennium. Matchmaking pharmacology and technology.

A major theme of the 1990s in the pathophysiology of nervous system injury has been the multifactorial etiology of irreversible injury. Multiple causes imply multiple opportunities for therapeutic intervention--hence the abandonment of the "magic bullet" single pharmacologic agent for neuroprotection in favor of pharmacologic "cocktails". A second theme of the 1990s has been the progress in technology for neuroprotection, minimally- or non-invasive monitoring as well as treatment. Cardiac stenting has eliminated the need, in many cases, for open heart surgery; deep brain stimulation for Parkinson's disease has offered significant improvement in quality of life for many who had exhausted cocktail drug treatment for their disease. Deep brain stimulation of the subthalamic nucleus offers a novel treatment for Parkinson's disease where a technological advance may actually be an intervention with effects that are normally expected from pharmacologic agents. Rather than merely "jamming" the nervous system circuits involved in Parkinson's disease, deep brain stimulation of the subthalamic nucleus appears to improve the neurotransmitter imbalance that lies at the heart of Parkinson's disease. It may also slow the progression of the disease. Given the example of deep brain stimulation of the subthalamic nucleus for Parkinson's disease, in future one may expect other technological or "hardware" interventions to influence the programming or "software" of the nervous system's physiologic response in certain disease states.

Combined buccal mucosa island and sternohyoid flaps: a new technique of hemilaryngeal reconstruction studied in a canine model.

No single method of reconstruction has proven ideal for all patients with defects following vertical hemilaryngectomy. In this report, we detail a new technique for hemilaryngeal reconstruction involving the use of a pedicled buccal mucosa island flap supplied by the facial artery and vein. The buccal flap was used to resurface a transversely oriented sternohyoid myofascial flap. The reconstructive outcome was analyzed in 4 animals, 3 of which survived the early postoperative period. Videoendoscopy and stroboscopy were performed to analyze the laryngeal configuration and vibration. Each subject was decannulated and had a competent airway free of aspiration. After sacrifice of the animals, whole organ axial sections were made at multiple levels. Endoscopic and histologic findings documented that this technique produced an appropriate neocord position. Laryngeal stroboscopy in each animal showed bilateral mucosal traveling waves, with entrainment of the reconstructed neocord mucosa and native vocal cord mucosa. We conclude that the layered reconstructive technique described, compared to traditional methods of reconstruction, more closely replicates the structure of the excised tissue in hemilaryngeal reconstruction, potentially resulting in an improved voice outcome.

Encephalitis due to a free-living amoeba (Balamuthia mandrillaris): case report with literature review.

BACKGROUND: Amebic infections can spread to the central nervous system with a lengthy but usually fatal course. A typical case is presented to raise awareness of this increasingly reported infectious process that may have a more favorable outcome if diagnosed in its early stages. CASE DESCRIPTION: A 38-year-old male presented with an ulcerating 10 x 8 cm mass on his thigh and smaller skin nodules. In less than 6 months seizures developed due to granulomatous lesions of the brain. Biopsies/excisions of the thigh lesion, a subcutaneous nodule, and a brain lesion were performed. He failed to respond to broad spectrum antibiotics and antineoplastic agents, and died within 6 weeks of the initial MRI scan of the brain. Rare amebic trophozoites were appreciated in the biopsy specimens on post-mortem review, and Balamuthia mandrillaris confirmed as the infecting agent on immunofluorescence studies. CONCLUSIONS: Granulomatous amebic encephalitis is a parasitic infection with a lengthy clinical course before rapid deterioration due to extensive brain lesions is noted. Either early treatment with antimicrobials or-in rare cases-excision of the brain lesion(s) may offer the chance of a cure.

Hemilaryngeal transplantation in the canine model: technique and implications.

PURPOSE: There is no ideal method for reconstruction of hemilaryngeal defects because there is no autologous flap or graft that can reproduce the unique structural properties of the larynx. In this article, the technique, potential research, and clinical applications of hemilaryngeal transplantation are addressed. MATERIALS AND METHODS: In a canine model, transplantation of a hemilarynx was performed. The thyroarytenoid muscle was reinnervated, and an arytenoid adduction was performed to ensure a competent larynx during the early postoperative period. RESULTS: The canine tolerated the procedure well and the transplanted larynx remained healthy and well vascularized during the postoperative period. Electromyography of the transplanted thyroarytenoid muscle verified reinnervation 2 months after the procedure. During induced phonation, vibration was symmetrical with a normal-appearing laryngeal geometry. CONCLUSIONS: Preliminary experience indicates that this technique has unique advantages compared with other available techniques for laryngeal reconstruction. Only with additional progress in transplantation medicine could this procedure be considered an option for reconstruction of human partial laryngeal defects.

Comparison of nerve banking techniques in delayed laryngeal reinnervation.

Successful laryngeal transplantation will require adequate reinnervation of the larynx to allow phonation, coordinated swallowing, and respiration. A delay between laryngectomy and transplantation would be necessary in oncology patients because of the need for immunosuppression. In these patients, reinnervation of the donor organ would require "banking" and recovery of dormant recipient recurrent laryngeal nerves (RLNs). This pilot study was undertaken to compare the effectiveness of RLN storage using 1 of 2 techniques: 1) inserting the nerve into a muscle pocket or 2) anastomosing the proximal RLN stump to the ansa cervicalis. Six months following nerve transection and "banking," the proximal anterior branch of the RLN was reanastomosed to the distal anterior segment and the posterior branch was anastomosed directly to the posterior cricoarytenoid muscle. Tensionometry, image analysis, and electromyographic data were collected 1 year later. Results show reinnervation of adductors and abductors with both techniques. Banking of the RLN branches during total laryngectomy is effective and should permit delayed physiological reinnervation following laryngeal transplantation.

Neuroprotective "agents" in surgery. Secret "agent" man, or common "agent" machine?

The search for clinically-effective neuroprotective agents has received enormous support in recent years--an estimated $200 million by pharmaceutical companies on clinical trials for traumatic brain injury alone. At the same time, the pathophysiology of brain injury has proved increasingly complex, rendering the likelihood of a single agent "magic bullet" even more remote. On the other hand, great progress continues with technology that makes surgery less invasive and less risky. One example is the application of endovascular techniques to treat coronary artery stenosis, where both the invasiveness of sternotomy and the significant neurological complication rate (due to microemboli showering the cerebral vasculature) can be eliminated. In this paper we review aspects of intraoperative neuroprotection both present and future. Explanations for the slow progress on pharmacologic neuroprotection during surgery are presented. Examples of technical advances that have had great impact on neuroprotection during surgery are given both from coronary artery stenosis surgery and from surgery for Parkinson's disease. To date, the progress in neuroprotection resulting from such technical advances is an order of magnitude greater than that resulting from pharmacologic agents used during surgery. The progress over the last 20 years in guidance during surgery (CT and MRI image-guidance) and in surgical access (endoscopic and endovascular techniques) will soon be complemented by advances in our ability to evaluate biological tissue intraoperatively in real-time. As an example of such technology, the NASA Smart Probe project is considered. In the long run (i.e., in 10 years or more), pharmacologic "agents" aimed at the complex pathophysiology of nervous system injury in man will be the key to true intraoperative neuroprotection. In the near term, however, it is more likely that mundane "agents" based on computers, microsensors, and microeffectors will be the major impetus to improved intraoperative neuroprotection.

Vocal function following vertical hemilaryngectomy: comparison of four reconstruction techniques in the canine.

The goals of laryngeal reconstruction have been prevention of aspiration, production of a functional voice, and maintenance of an adequate airway for decannulation. A number of procedures for partial laryngeal reconstruction have accomplished these objectives. However, few studies have attempted to compare patients' vocal characteristics following different reconstruction procedures. In this study, an in vivo canine model was used to compare acoustic and aerodynamic measures of vocal function for the following vertical hemilaryngectomy reconstruction techniques: 1) a superiorly based sternohyoid muscle flap, 2) a modified epiglottic laryngoplasty, 3) a new procedure using a layered vascularized buccal mucosal flap and a transversely oriented sternohyoid muscle flap, and 4) hemilaryngeal transplantation combined with arytenoid adduction. Hemitransplantation provided the most efficient phonation of the four techniques. The vascularized buccal mucosa flap produced the best phonation of the autologous tissue techniques examined. Both vascularized buccal mucosa flap and hemilaryngeal transplantation subjects demonstrated a mucosal wave on stroboscopy. The results indicate that vocal function will improve as the layered structure of the vocal fold is more accurately replicated in a reconstructed hemilarynx. Endoscopic findings and whole organ sections are presented.

Surgical resection of brain metastases from lung cancer.

The role of surgical resection for brain metastases is evolving. The most common primary for brain metastases is lung; in the US in 1992, for example, there were nearly 40,000 deaths with symptomatic brain metastases from lung cancer. We reviewed a series of 25 consecutive patients with non small cell lung cancer (NSCLC) undergoing open resection of one or more symptomatic brain metastases to consider the role of open resection. Twenty-three of the 28 resected lesions were 3 cm or greater in diameter; 19 were solid and nine cystic. Surgical adjuncts included (where indicated): stereotactic biopsy, cyst drainage, and craniotomy; intra-operative ultrasound; and intra-operative evoked potential mapping of the sensorimotor area. Six patients underwent thoracotomy for resection of the lung primary (in all but one case, prior to craniotomy). Except for two patients who had whole brain radiation therapy (WBXRT) prior to referral to Neurosurgery, all patients underwent WBXRT (30 to 60 Gy) postoperatively. The mean survival from date of craniotomy was 13.1 months, with two patients still alive at ten and seventeen months post-craniotomy. Survival comparisons which were significantly different included (1) lung surgery versus no lung surgery (25.7 months versus 9.1 months, P < 0.001), and (2) metachronous presentation of the lung primary and brain metastasis versus synchronous presentation (17.6 months versus 9.5 months, P = 0.025). Survival comparisons which were not significantly different included single versus multiple metastases, complete versus incomplete resection, adenocarcinoma versus large or squamous or cell histology, supratentorial versus infratentorial location, solid versus cystic metastasis, and age < or = 60 years versus > 60 years. These results, when compared with the literature on brain metastases, suggest that aggressive resection of symptomatic metastases from lung cancer (even if multiple) can improve functional survival over conservative management, and that small, asymptomatic lesions are well-controlled by WBXRT. They also confirm the previous finding that surgical treatment of both the lung primary and the brain metastases may afford the greatest period of functional survival for these patients.

Cerebrospinal fluid pH and PCO2 rapidly follow arterial blood pH and PCO2 with changes in ventilation.

Changes in ventilatory rate affect arterial blood pH and PCO2 within seconds to minutes, but the corresponding acute changes for cerebrospinal fluid (CSF) pH and PCO2 have been as well documented. Using our previously-described swine model of brain retraction ischemia, we examined changes in arterial and CSF pH and PCO2 with acute changes in ventilation in four animals. Newly developed fluorescent dye technology permitted near-instantaneous recording of CSF pH and PCO2 during acute hyperventilation (end-tidal PCO2 of 20 mm Hg) and acute hypoventilation (end-tidal PCO2 of 50 mm Hg). The Puritan-Bennett 3300 Intra-Arterial Blood Gas Monitor (PB3300) was used with the sensor placed in the CSF in the interhemispheric fissure posterior to the corpus callosum. The following data were gathered at 5, 15, 30, and 60 minutes after the ventilatory change: arterial pH and PCO2, end-tidal CO2, laser-Doppler cerebral blood flow, and CSF pH and PCO2. The baseline (normoventilation) values for arterial and CSF pH and PCO2 in swine were comparable to those in humans: arterial pH 7.44 and PCO2 43 mm Hg; CSF pH 7.31 and PCO2 55 mm Hg. Changes in pH and PCO2 with hyperventilation and hypoventilation occurred rapidly in both arterial blood and CSF. Steady-state values were reached within 15 minutes for hypoventilation, and 30 minutes for hyperventilation. The correlation between arterial and CSF values for both pH and PCO2 at 5, 15, 30, and 60 minutes were all very highly significant (P < 0.001) except for arterial and CSF PCO2 at 5 minutes (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

A review of brain retraction and recommendations for minimizing intraoperative brain injury.

Brain retraction is required for adequate exposure during many intracranial procedures. The incidence of contusion or infarction from overzealous brain retraction is probably 10% in cranial base procedures and 5% in intracranial aneurysm procedures. The literature on brain retraction injury is reviewed, with particular attention to the use of intermittent retraction. Intraoperative monitoring techniques--brain electrical activity, cerebral blood flow, and brain retraction pressure--are evaluated. Various intraoperative interventions--anesthetic agents, positioning, cerebrospinal fluid drainage, operative approaches involving bone resection or osteotomy, hyperventilation, induced hypotension, induced hypertension, mannitol, and nimodipine--are assessed with regard to their effects on brain retraction. Because brain retraction injury, like other forms of focal cerebral ischemia, is multifactorial in its origins, a multifaceted approach probably will be most advantageous in minimizing retraction injury. Recommendations for operative management of cases involving significant brain retraction are made. These recommendations optimize the following goals: anesthesia and metabolic depression, improvement in cerebral blood flow and calcium channel blockade, intraoperative monitoring, and operative exposure and retraction efficacy. Through a combination of judicious retraction, appropriate anesthetic and pharmacological management, and aggressive intraoperative monitoring, brain retraction should become a much less common source of morbidity in the future.

Corpus callosotomy effects on cerebral blood flow and evoked potentials (transcallosal diaschisis).

The role of the corpus callosum in diaschisis was examined through the acute effects of stereotactic corpus callosum section on cerebral blood flow and somatosensory or auditory evoked potentials bilaterally during unilateral brain retraction ischemia, using a previously reported swine model. Cerebral blood flow and evoked potential amplitude contralateral to retraction increased during retraction with the corpus callosum intact, compared with post-callosal section values. With retraction following callosal section, there was no increase in cerebral blood flow or evoked potential amplitude contralateral to retraction. Diaschisis during the early stages of a focal, unilateral injury takes the form of a contralateral disinhibition (as measured by cerebral blood flow and evoked potentials), an effect which is lost following callosal section.

Effects of mannitol on cerebral blood flow, blood pressure, blood viscosity, hematocrit, sodium, and potassium.

In our miniature swine model of brain retraction ischemia under conditions simulating the neurosurgical operating room, we studied the effects of bolus mannitol (2 g/kg) administration on cerebral blood flow, blood pressure, blood viscosity, hematocrit, sodium, and potassium serially for 4 hours following administration, at which time a second bolus was administered. Both viscosity and hematocrit were significantly decreased transiently following both the first and second boluses. Sodium was decreased for 30 minutes following the first bolus, 15 minutes following the second bolus, and increased at 150 minutes and later following the second bolus. There was a mild decrease in blood pressure and a mild increase in cerebral blood flow following mannitol, but little difference between the first hour following a bolus (when the viscosity and hematocrit were decreased) and hours 2-4 (when they were near baseline). Mannitol's effects on blood pressure and cerebral blood flow probably depend on factors in addition to its effects on blood viscosity and hematocrit. The results are discussed in light of previous findings that bolus mannitol administration may improve cerebral blood flow in ischemia, but does not appear to benefit the preservation of brain electrical activity.

Retraction brain ischaemia: cerebral blood flow, evoked potentials, hypotension and hyperventilation in a new animal model.

Undue intraoperative brain retraction can cause significant neurosurgical morbidity. By combining brain retractor blade pressure measurement with monitoring of brain electrical activity, one can determine the limits of safe brain retraction and then test systematically various therapeutic interventions. Cortical evoked potential (EP) mapping and laser-Doppler cerebral blood flow (CBF) measurement were undertaken during brain retraction in the miniature swine (Sus scrofa). Forelimb somatosensory EP recording during subtemporal retraction simulated the pterional and subtemporal approaches, respectively. Retraction pressure of 30 mmHg usually resulted in a 50% decrement in EP amplitude after 10 to 20 minutes in normotensive, normocapnic adult animals. Recovery of EP occurred within 5 to 10 minutes of retraction release. The effects of animal age, induced hypotension (nitroprusside, MAP approximately 40), and induced hypocapnia (hyperventilation, PaCO2 approximately 28) on EP preservation during retraction were then investigated, with data reported here from 23 animals (8 to 35 kg). By Spearman rank correlation coefficients, early loss of EP was associated with the following: lower MAP (p approximately 0.0001), lower CBF (p approximately 0.0005), lower PaCO2 (p less than 0.001), and older age (p approximately 0.01). These results indicate (1) retractors should be relaxed every 10-15 minutes whenever possible (for at least 5 minutes), and (2) hypotension, in particular, but also hypocapnia (hyperventilation) should not be used indiscriminately. Details of this new model of retraction ischaemia are presented.

Retraction brain ischaemia: mannitol plus nimodipine preserves both cerebral blood flow and evoked potentials during normoventilation and hyperventilation.

In our miniature swine model simulating operating room brain retraction, we investigated the effects of mannitol plus nimodipine on cerebral blood flow (CBF) and evoked potentials (EP) ipsilateral and contralateral to retraction, in comparison with either agent alone, during both normoventilation and hyperventilation. We here report results in 27 animals with intravenous mannitol (2 g kg-1 over 15 min) and/or nimodipine (1 microgram kg-1 min-1 constant infusion). Mannitol plus nimodipine was superior both to controls and to either mannitol alone or nimodipine alone in preserving EP amplitude ipsilateral to retraction during both normoventilation and hyperventilation. Mannitol alone was effective in normoventilation at preserving EP, while nimodipine alone was effective in hyperventilation. No significant asymmetries in CBF or EP were seen with mannitol plus nimodipine in either normoventilation or hyperventilation. By five minutes postretraction CBF had returned to preretraction values for all groups, and EP amplitude had returned also except for hyperventilated controls. In this model of brain retraction, mannitol plus nimodipine is superior to either agent alone in maintaining both CBF and EP when normoventilation and hyperventilation are employed. The results are discussed in terms of the possible mechanisms for the different and complementary effects of mannitol and nimodipine.

Transhemispheric diaschisis. A review and comment.

We review here the literature in both animal models and humans concerning electrical activity, blood flow, and metabolism in the hemisphere contralateral to unilateral cerebral ischemia. We analyze the data by periods based on the time from initial injury to emphasize the time course of transhemispheric diaschisis. Contralateral electrical activity, such as evoked potential amplitude, is increased in the late stages after unilateral infarction, with the data from the more acute periods being inconclusive. Contralateral blood flow changes probably depend on the magnitude of the ischemic injury, with a larger insult resulting in a decrease not seen with smaller insults. Some studies have shown a decrease in contralateral blood flow over the first week followed by a gradual return toward baseline. Most measures of contralateral metabolism show a time course similar to blood flow, that is, a decrease followed by gradual recovery. The effects of corpus callosum section on transhemispheric diaschisis are not yet established. We provide examples to show that under certain conditions, diaschisis may represent a loss of remote inhibition rather than a loss of remote facilitation, as von Monakow originally suggested. By following the contralateral changes over time, particularly during the first minutes and hours of ischemia, insight will be gained into the brain's responses remote from the focus of ischemic injury. These responses should bear a relation to the brain's defense mechanisms ipsilaterally to the region of ischemia.