Deep brain stimulation for Alzheimer disease: a decision and cost-effectiveness analysis.

Alzheimer disease (AD) is characterized by impairments in memory function. Standard AD treatment provides marginal improvements in this domain. Recent reports, however, suggested that deep brain stimulation (DBS) may result in improved memory. Given significant equipment costs and health expenses required for DBS surgery, we determine clinical and economic thresholds required for it to be as effective as standard AD treatment. Literature review yielded annual AD progression probabilities, health-related quality of life (QoL), and costs by AD stage. Our 5-year decision analysis model compared cumulative QoL in quality-adjusted life years (QALYs) and costs of standard therapy to theoretical DBS treatment of various success rates, using known complication rates and QoL data. The base case was a patient with mild-stage AD. DBS success was defined as regression to and maintenance of minimal stage AD, which was defined as midway between mild and no dementia, for the first year, and continuation of the natural course of AD for the remaining 4 years. Compared to standard treatment alone, DBS for mild-stage AD requires a success rate of 3% to overcome effects of possible surgical complications on QoL. If DBS can be delivered with success rates above 20% ($200 K/QALY) or 74% ($50 K/QALY) for mild AD, it can be considered cost-effective. Above a success rate of 80%, DBS treatment is both clinically more effective and more cost-effective than standard treatment. Our findings demonstrate that clinical and economic thresholds required for DBS to be cost-effective for AD are relatively low.

Red Blood Cell Distribution Width is Associated with Poor Clinical Outcome After Subarachnoid Hemorrhage: A Pilot Study.

INTRODUCTION: The red cell distribution width (RDW) is a biomarker strongly associated with poor outcome in inflammatory and thrombotic diseases. Subarachnoid hemorrhage (SAH) is both an inflammatory and thrombotic state in which many biomarkers have been studied. In this exploratory pilot study, we sought to determine whether RDW predicts poor outcome in patients with SAH. METHODS: Patients with moderate-to-severe SAH were prospectively enrolled in an observational study of biomarkers and outcome. CBC, ESR, high sensitivity CRP, D-dimer, and fibrinogen were obtained on post-bleed days (PBD) 1, 3, 5, 7, and 10. Poor outcome was defined as a modified Rankin score of 3-6 at 90-days. RESULTS: Of 40 patients, 5 (12.5%) died and 19 (47.5%) had a poor outcome. RDW (p = 0.046) when measured serially over the study period, was significantly higher among patients with poor outcome. Maximum RDW (OR 2.3 95% CI 1.2-3.6; p = 0.014) and maximum WBC count (OR 1.29 95% CI 1.04-1.60; p = 0.018) were associated with poor outcome. Stepwise addition of maximum ESR, CRP, D-dimer, and fibrinogen yielded a model with RDW (OR 2.54 95% CI 1.21-5.35; p = 0.014) and fibrinogen (OR 1.01 95% CI 1.002-1.01; p = 0.004) predicting outcome. With addition of age and Hunt and Hess grade, RDW, fibrinogen, and high-grade status remained significantly associated with poor outcome. Use of PBD1 RDW in lieu of maximum RDW, resulted in a similar model. CONCLUSIONS: An elevated RDW is associated with poor outcome in SAH patients. RDW may be a useful predictor of outcomes after SAH.

Observational approach to subjects with mild-to-moderate head injury and initial non-neurosurgical lesions.

BACKGROUND: The model of care for patients with mild-to-moderate head injury and CT-detected lesions that do not require an immediate intervention is a matter of debate. This study compared the effects on outcome of a model based either on observation in a neurosurgical unit (NSU) or in a peripheral hospital (PH), making use of neurosurgical expertise via a teleradiology system. PATIENTS AND METHODS: The investigation reviewed the data that was prospectively collected in 865 cases with mild-to-moderate head injury and positive CT scan, not needing immediate neurosurgical evacuation. Outcome was determined at 6 months. The predictive value of location of observation on outcome was evaluated by logistic regression, after adjustment for the propensity score to the type of observation (calculated on main entry variables). FINDINGS: 700 subjects had a mild head injury, 105 had a moderate injury with GCS 13-11 and 60 with Glasgow Coma Scale (GCS) 10-9. Only 152/865 subjects (17.6%) were admitted to a NSU. During observation, neurosurgery was necessary in 117 cases (13.5%), 74/152 (48.7%) NSU-observed patients and 43/713 (6.0%; p<0.001) PH-observed cases. The outcome was unfavourable in 18% of the NSU cases versus 10% of the PH cases (p = 0.143). After correction for propensity, no significant differences were found between models of observation (NSU vs. PH; odds ratio, 0.92; 95% confidence interval, 0.49 to 1.75). INTERPRETATION: A model of care based on observation in PH with neurosurgical consult by teleradiology system, repeat CT scanning and transfer time 30-60 min to a NSU is not detrimental for subjects with initial non-neurosurgical lesions after mild-to-moderate head injury.

Early predictors of unfavourable outcome in subjects with moderate head injury in the emergency department.

BACKGROUND: Subjects with moderate head injury are a particular challenge for the emergency physician. They represent a heterogeneous population of subjects with large variability in injury severity, clinical course and outcome. We aimed to determine the early predictors of outcome of subjects with moderate head injury admitted to an Emergency Department (ED) of a general hospital linked via telemedicine to the Regional Neurosurgical Centre. PATIENTS AND METHODS: We reviewed, prospectively, 12,675 subjects attending the ED of a General Hospital between 1999 and 2005 for head injury. A total of 309 cases (2.4%) with an admission Glasgow Coma Scale (GCS) 9-13 were identified as having moderate head injury. The main outcome measure was an unfavourable outcome at 6 months after injury. The predictive value of a model based on main entry variables was evaluated by logistic regression analysis. FINDINGS: 64.7% of subjects had a computed tomographic scan that was positive for intracranial injury, 16.5% needed a neurosurgical intervention, 14.6% had an unfavourable outcome at 6 months (death, permanent vegetative state, permanent severe disability). Six variables (basal skull fracture, subarachnoid haemorrhage, coagulopathy, subdural haematoma, modified Marshall category and GCS) predicted an unfavourable outcome at 6 months. This combination of variables predicts the 6-month outcome with high sensitivity (95.6%) and specificity (86.0%). INTERPRETATION: A group of selected variables proves highly accurate in the prediction of unfavourable outcome at 6 months, when applied to subjects admitted to an ED of a General Hospital with moderate head injury.

Brief history of surgical timing: surgery for ruptured intracranial aneurysms.

The neurosurgical profession has taken a circuitous route to attain its current knowledge about timing for aneurysm surgery. While addressing the timing issue, neurosurgeons were beset by many pressures simultaneously. They were forced to justify not only optimal surgical techniques but the need for surgery at all in the treatment of ruptured aneurysms. The beliefs of surgeons with strong personalities, in addition to intuitive guesses, often served to guide surgery in the absence of scientific evidence. That any progress could be made against a background of desperately ill patients and frustrating early results is remarkable. The author briefly outlines the controversies and misdirection that accompanied this progress toward understanding surgical timing in the treatment of ruptured aneurysms.

Characterization of the role of AMP-activated protein kinase in the regulation of glucose-activated gene expression using constitutively active and dominant negative forms of the kinase.

In the liver, glucose induces the expression of a number of genes involved in glucose and lipid metabolism, e.g., those encoding L-type pyruvate kinase and fatty acid synthase. Recent evidence has indicated a role for the AMP-activated protein kinase (AMPK) in the inhibition of glucose-activated gene expression in hepatocytes. It remains unclear, however, whether AMPK is involved in the glucose induction of these genes. In order to study further the role of AMPK in regulating gene expression, we have generated two mutant forms of AMPK. One of these (alpha1(312)) acts as a constitutively active kinase, while the other (alpha1DN) acts as a dominant negative inhibitor of endogenous AMPK. We have used adenovirus-mediated gene transfer to express these mutants in primary rat hepatocytes in culture in order to determine their effect on AMPK activity and the transcription of glucose-activated genes. Expression of alpha1(312) increased AMPK activity in hepatocytes and blocked completely the induction of a number of glucose-activated genes in response to 25 mM glucose. This effect is similar to that observed following activation of AMPK by 5-amino-imidazolecarboxamide riboside. Expression of alpha1DN markedly inhibited both basal and stimulated activity of endogenous AMPK but had no effect on the transcription of glucose-activated genes. Our results suggest that AMPK is involved in the inhibition of glucose-activated gene expression but not in the induction pathway. This study demonstrates that the two mutants we have described will provide valuable tools for studying the wider physiological role of AMPK.

Rand-Stein analgesia protocol for cataract surgery.

OBJECTIVE: To describe the safety and efficacy of an analgesia protocol that enables the surgeon to maintain control over an alert patient experiencing seemingly painless ambulatory cataract surgery, while eliminating the risks and side effects associated with general, local, topical, and intracameral anesthesia. DESIGN: Noncomparative, interventional case series. PARTICIPANTS: Five thousand one hundred sixty-eight consecutive cataract surgery cases operated on by the same surgeon from April 1, 1993 through June 1, 1998. METHODS: This technique produces profound ocular analgesia, avoiding any undesired sedative effects, using very low-dose, titrated, intravenous alfentanil. Complete control of the uncooperative patient, including lid squeezing and ocular and general body movements, is obtainable whenever necessary using very low-dose, titrated, intravenous methohexital. MAIN OUTCOME MEASURES: Success was defined as surgery completed in a controlled manner without the need to convert to general, local, topical, or intracameral anesthesia and the patient's experience being perceived as pain free. RESULTS: One hundred percent of the cases were successful without ever deviating from the protocol. CONCLUSIONS: This analgesia protocol offers advantages for cataract surgery. It virtually eliminates the morbidity of cataract surgery associated with other anesthesia techniques while providing excellent and reliable control. It allows for an immediate postoperative recovery with instantaneous vision restoration. These patients are generally awake, alert, and retain their protective reflexes.

The regulation of AMP-activated protein kinase by phosphorylation.

The AMP-activated protein kinase (AMPK) cascade is activated by an increase in the AMP/ATP ratio within the cell. AMPK is regulated allosterically by AMP and by reversible phosphorylation. Threonine-172 within the catalytic subunit (alpha) of AMPK (Thr(172)) was identified as the major site phosphorylated by the AMP-activated protein kinase kinase (AMPKK) in vitro. We have used site-directed mutagenesis to study the role of phosphorylation of Thr(172) on AMPK activity. Mutation of Thr(172) to an aspartic acid residue (T172D) in either alpha1 or alpha2 resulted in a kinase complex with approx. 50% the activity of the corresponding wild-type complex. The activity of wild-type AMPK decreased by greater than 90% following treatment with protein phosphatases, whereas the activity of the T172D mutant complex fell by only 10-15%. Mutation of Thr(172) to an alanine residue (T172A) almost completely abolished kinase activity. These results indicate that phosphorylation of Thr(172) accounts for most of the activation by AMPKK, but that other sites are involved. In support of this we have shown that AMPKK phosphorylates at least two other sites on the alpha subunit and one site on the beta subunit. Furthermore, we provide evidence that phosphorylation of Thr(172) may be involved in the sensitivity of the AMPK complex to AMP.

Laminectomy compared with laparoscopic diskectomy and outpatient laparoscopic diskectomy for herniated L5-S1 intervertebral disks.

The objective of this study was to evaluate the clinical efficacy and cost effectiveness of inpatient and outpatient laparoscopic lumbar diskectomy (LLD) compared with laminectomy (LAM) in the surgical treatment of disabling L5-S1 disk herniation. Sixty-two adults underwent surgery for herniated L5-S1 intervertebral disks (31 LLD and 31 LAM). Operative blood loss (EBL) (milliliters), operative time (ORT) (minutes), hospital stay (LOS), and rehabilitation time to normal activity (REHAB) (days), recurrent symptoms, postoperative morbidity, percent pain free, and hospital patient charges were calculated. Thirty LLD patients (97%) had immediate relief of disk pain. Morbidity after LLD included transient urinary retention (one) and rectus hematoma (one). One LAM patient had a pseudomeningocele. Among patients observed for > or =6 months, with a median follow up time of 34 months, 22 of 25 LLD patients (88%) returned to normal activity, while 12 of the LAM group (52%) were disabled (p = 0.004). Functional outcome was improved by LLD for workers compensation patients followed > or =6 months, with 86% LAM disabled, vs. 10% LLD (p = 0.001). Sixteen LLD patients (52%) and 18 (58%) of the LAM group needed postoperative physical therapy. Four LLD patients recurred; three required reoperation. Four LAM patients had surgery for recurrent disk herniation. ORT was longer for LLD than LAM (210 vs. 158 minutes, median, p < 0.05). EBL and REHAB time were significantly reduced with LLD, vs. LAM. With a median follow-up of 34 months, 58% of LLD and 39% of LAM patients followed > or =6 months were pain free. Outpatient LLD (n = 9) reduced LOS (1 day vs. 2 days and 4 days, p < 0.01) and lowered patient charges ($4,405 vs. $5,723 and $7,192, p < 0.01) compared with inpatient LLD (n = 23) and LAM, respectively. LLD is a safe, cost-effective, minimally invasive alternative to LAM for treating herniated L5-S1 disks. Compared with LAM, LLD reduces EBL, LOS, REHAB time, and patient charges, improves function, and increases long-term pain relief. Cost effectiveness is optimized when LLD is performed as outpatient surgery.

Laparoscopic L5-S1 diskectomy: a cost-effective, minimally invasive general surgery--neurosurgery team alternative to laminectomy.

Laparoscopic L5-S1 diskectomy (LLD) is a promising new technique for managing disabling pain from herniated lumbar disks. It is unknown, however, whether the clinical results of LLD are superior to those of traditional laminectomy (LAM). This study was undertaken, therefore, in order to compare LLD and LAM in the management of L5-S1 disk herniation unresponsive to conservative treatment measures. Clinical records of 22 patients who underwent 23 LLD procedures and of 23 LAM patients were reviewed with respect to demographics and median age, operative blood loss, operative time, hospital stay, and time of rehabilitation to work/normal activity, as well as postoperative morbidity, recurrent symptoms, long-term functional status, and inhospital patient charges. Two LLD patients had undergone LAM previously, and one had a percutaneous microdiskectomy. All LLD patients had relief of disk pain immediately after surgery. Morbidity after LLD included transient brachial plexus neuropraxia (1), urinary retention (1), and rectus hematoma (1). No LAM complications were reported. Among LLD patients, compared with LAM, median age (34.5 years versus 40 years), estimated blood loss (12 mL versus 68 mL), hospital length of stay (1 day versus 3 days), time to normal activity (17 days versus 79 days) and mean inhospital patient charges ($5,737 +/- 283 versus $7,762 +/- 662) were reduced significantly (P < 0.05). LLD operating time was significantly longer than LAM (210 versus 160 minutes median, P < 0.01). With a median follow-up time of 11.0 months (range, 2 to 23 months) all LLD patients had returned to normal activity, whereas 7 of the LAM group (30%) remained disabled (P < 0.01). Sixty-eight per cent of LLD patients were pain-free during follow-up, compared with 39 per cent of the LAM group (P < 0.05). Sixty-four per cent of LLD patients and 57 per cent of the LAM group needed postoperatively physical therapy. One LLD and 4 LAM patients required reoperation, by LLD and LAM, respectively, for recurrent disk herniation. LLD is a safe, cost-effective, minimally invasive operation for managing disabling L5-S1 disk herniation. Compared with LAM, LLD reduces blood loss, length of stay, rehabilitation time, and patient charges, and improves long-term functional and pain-free status. LLD should be considered as an alternative to LAM for patients with herniated L5-S1 intervertebral disks unresponsive to conservative management.

Laparoscopic lumbar diskectomy: preliminary report of a minimally invasive anterior approach to the herniated L5-S1 disk.

Approximately 300,000 patients each year in the United States undergo laminectomy for disabling lumbar disk herniation. Postlaminectomy hospitalization is 3-7 days and convalescence may be prolonged. As an alternative to laminectomy, we have developed a technique for performing L5-S1 lumbar diskectomy laparoscopically. Using an anterior approach, the intervertebral disk space is opened and the diskectomy is performed under direct videolaparoscopic imaging. After pneumoperitoneum is established, the patient is placed in a steep Trendelenburg position. The small bowel is retracted cephalad and the colon moved to the left. The iliac vessels are identified visually and by Doppler probe. Then the presacral space is dissected in the midline to expose the L5-S1 disk. The disk annulus is opened with the Nd:YAG contact laser (four cases) or the harmonic scalpel (three cases). Diskectomy is performed under direct videolaparoscopic vision using standard neurosurgical instruments modified for laparoscopy. The posterior longitudinal ligament can be visualized directly to define the posterior limits of the completed diskectomy. Laparoscopy lumbar diskectomy has been performed on seven patients (five male, two female). No perioperative complications occurred. All seven patients had immediate relief of back pain after laparoscopic lumbar diskectomy. Five patients were discharged the next day and two on the second postoperative day. L5-S1 laparoscopic lumbar diskectomy is feasible and safe. It may be an effective minimally invasive alternative to laminectomy.

The Head Injury Severity Scale (HISS): a practical classification of closed-head injury.

The authors introduce a two-dimensional scale for rating closed-head injury, the Head Injury Severity Scale (HISS). This system is based on a five-interval severity classification (minimal through critical), determined primarily by the initial post-resuscitation Glasgow Coma Scale score. The second dimension is predicated on the presence or absence of complications, appropriate for each severity interval. The outcomes of almost 25,000 patients with head injury encountered at our institution over a 7-year period were evaluated. We discovered that adding a complication dimension to each severity category resulted in significant outcome differences and effectively divided patients into groups with very different risks, prognosis and treatment requirements. The HISS is proposed as a framework on which further research can be done to guide care to predict outcome and to perform audits on head-injured patients.

Laparoscopic laser lumbar diskectomy. Operative technique and case report.

Approximately 300,000 patients each year in the United States undergo laminectomy for disabling lumbar disc herniation. Post-laminectomy hospitalization is 3-7 days and convalescence may be prolonged. As an alternative to laminectomy, we have developed a technique for performing L5-S1 lumbar diskectomy laparoscopically. Using an anterior approach, the intervertebral disc space is opened and the diskectomy is performed under direct videolaparoscopic imaging. After pneumoperitoneum is established, the patient is placed in a steep Trendelenburg position. The small bowel is retracted cephalad and the colon is moved to the left. The iliac vessels are identified visually and by Doppler probe, and the presacral space is dissected in the midline to expose the L5-S1 disc. In the case presented, the disc annulus was opened with the Nd:YAG contact laser, and diskectomy was performed under direct videolaparoscopic vision using standard neurosurgical instruments modified for laparoscopy. The posterior longitudinal ligament can be visualized directly to define the posterior limits of the completed diskectomy. In the case described, pain relief was confirmed immediately after the procedure. The patient was discharged after 2 hospital days, and returned to normal activity in 8 days.

Delayed and progressive brain injury in children and adolescents with head trauma.

We performed serial CT scans on 351 children and adolescents with serious closed-head injury. Delayed or progressive lesions were encountered in 145 (41%). The occurrence of such delayed cerebral injuries correlated with the severity of the initial head trauma, with the presence of major extracranial injury and with studies of coagulopathy on admission. The presence of delayed cerebral injury had a profound influence on survival and recovery from head trauma, especially when the initial severity of the head injury was taken into account. We conclude that serial CT scans provide a reliable means of diagnosing and following the progress of delayed cerebral injury in the pediatric population.

Limitations of neurological assessment in mild head injury.

The authors have investigated two commonly used methods of assessing neurological status in patients with mild head injury to determine whether they can predict intracranial damage. Of 686 such patients with cranial computed tomography (CT) scans, scan results were recorded, along with total and motor components of the Glasgow Coma Scale (GCS) and the Reaction Level Scale (RLS85). Despite relatively normal admission neurological examinations, 127 of the 689 patients (18.4%) had intracranial lesions, and 38 (5.5%) required surgery. There was no significant difference in distribution of the GCS in patients with and without intracranial lesions. The RLS85 was superior to the GCS in predicting intracranial pathology, and a significant association between RLS85 and lesions on CT scanning was noted. However, even this test was normal in 19 patients found to have intracranial pathology, including nine who required surgery. The authors conclude that a normal or near-normal mental status examination in a head-injured patient on arrival at the emergency room is inadequate to exclude a potentially serious intracranial lesion. It is unlikely that further refinements in the clinical evaluation will result in diagnostic accuracy comparable with that of CT scanning. Accordingly, we recommend that any patient who has suffered a loss of consciousness or amnesia following head injury have an urgent cranial CT scan.