Abstract

Glioblastoma multiforme is an aggressive, disabling, and deadly disease of the central nervous system. Early detection and treatment improve the prognosis for adults with glioblastoma. Advanced practice nurses can help identify patients with glioblastoma multiforme early in the disease process and provide these patients with comprehensive nursing care. This article describes the clinical presentation, diagnosis, postoperative care, treatments, symptom management, health promotion, and psychosocial care for patients with glioblastoma multiforme.

Introduction to Glioblastoma Multiforme

Glioblastoma multiforme (GBM) is the most common primary malignant tumor of the central nervous system. GBM advances rapidly and tends to recur after treatment, resulting in severe disability and death. The 1-year and 2-year relative survival rates for GBM are 29.6% and 9.0%, respectively. Only 3.4% of patients with a GBM diagnosis survive more than 5 years,[1,2] but life expectancy for GBM in the United States has been increasing. Early identification of the tumor, surgical resection, radiation therapy, and chemotherapy improve the prognosis for GBM.[3]

The incidence of GBM increases with age; most patients are 65 years or older at the time of diagnosis.[1,2] This incidence is expected to increase when the first baby boomers -- individuals born between 1946 and 1964 -- reach the age of 65 in 2011. By 2030 the number of Americans over age 65 will double, reaching 71 million or roughly 20% of the U.S. population.[4] Consequently, advanced practice nurses (APNs) working in oncology, primary care, acute care, long-term care, psychiatry, palliative care, and other specialties may encounter patients with GBM more frequently than ever before.

APNs may be able to identify patients with GBM early in the course of disease and, as members of a multidisciplinary team, provide postoperative care, initiate and monitor treatments, and manage symptoms.[5] Moreover, the Institute of Medicine recently explored the delivery of psychosocial services to patients with cancer and their families, and found that the psychosocial needs of these patients in the United States are often neglected.[6] APNs, educated in holistic care, are prepared to address the extremely important social and emotional issues precipitated by a diagnosis of GBM.

Clinical Presentation and Evaluation of GBM

Presenting symptoms and signs depend on the location, size, rate of growth, and substances secreted by a tumor.[7] Symptoms and signs of GBM can be focal or generalized. The most common problems on initial presentation, in order of frequency, are: headache, memory loss, cognitive changes, motor weakness, language deficit, personality changes, seizures, disturbance of vision, change in level of consciousness, nausea and vomiting, and altered sensation.[8]

Diagnostic Evaluation

In addition to a thorough history and neurologic examination, the patient presenting with symptoms or signs of brain tumor requires radiographic imaging. Magnetic resonance imaging (MRI) with and without intravenous contrast is the gold standard for diagnostic imaging of the brain. High-grade (stage III/IV) brain tumors such as GBM enhance with intravenous administration of a contrast agent. The patient with a contrast-enhancing lesion on MRI of the brain should be referred for neurosurgical consultation.[7,9]

The neurosurgical plan of care will vary, depending on the location and number of discrete areas of contrast enhancement. Stereotactic needle biopsy may be indicated if the lesion is in an area of the brain where resection carries a high risk for disability. Needle biopsy may also be preferred if a contrast-enhancing lesion is in a surgically inaccessible area of the brain or if there are multiple lesions. During surgery, a sample of tissue from the lesion(s) is sent from the operating room directly to pathology for preliminary testing. A smear or frozen section is sufficient to provide the surgeon with a working diagnosis. When this preliminary testing is consistent with a high-grade glioma, the surgeon will remove as much macroscopic tumor as possible.[7]

Although preliminary testing may suggest a high-grade glioma, a definitive diagnosis of GBM requires formal histologic analysis of the tumor specimen. Permanent tissue slides are examined by the pathologist using immunohistochemical staining, molecular analysis, and other tests. Tissue consistent with GBM tests positive for glial fibrillary acidic protein, and demonstrates glomeruloid microvascular proliferation and pseudopalisading necrosis.[10,11]

Postoperative Care of GBM

Neurosurgical services often prescribe an antiepileptic drug (AED) for patients with brain tumor after surgery, even those with no history of seizures. This is a common practice, although AEDs are not effective at preventing the first seizure associated with brain tumors,[12] and the risk for postcraniotomy seizures is low.[13]

In children, use of the AED is often discontinued a month after surgery because long-term use of AEDs for postsurgery seizure prophylaxis is not indicated.[14] In 1 study, only 5.4% of postcraniotomy patients followed for a mean of 2.4 years had seizures.[15] The incidence of side effects associated with AEDs warranting discontinuation of therapy with the drug in postcraniotomy patients is 12.9%, making the risk for an adverse reaction to seizure prophylaxis even greater than the risk for seizures in this population.[16] Moreover, if AEDs are given during cranial radiation, there is an increased risk for a severe skin reaction.[17] Although there is significant evidence against the practice, AEDs are still routinely prescribed after craniotomy to patients with GBM who have no history of seizures. Antiepileptic agents should be tapered and discontinued starting the first week after craniotomy.[12]

Corticosteroids are routinely given after craniotomy to help control brain edema and its related symptoms and signs (eg, headache, nausea, vomiting, and drowsiness). Corticosteroids also reduce acute radiation toxicity and help prevent chemotherapy-induced nausea and vomiting.[7] To prevent or limit adverse effects from radiation and chemotherapy, APNs responsible for symptom management may wish to continue corticosteroids during the early stages of the patient's radiation and chemotherapy. A few weeks into radiation and chemotherapy, corticosteroids can be tapered and discontinued in asymptomatic patients.[7] Patients receiving corticosteroids should also be taking a medication to protect the gastrointestinal tract. Histamine-2 blockers or proton-pump inhibitors decrease the risk for corticosteroid-associated peptic ulcers, ulcerative esophagitis, gastrointestinal hemorrhage, and gastrointestinal perforation.[18,19]

A MRI of the brain with and without intravenous contrast agent is obtained 24-72 hours after craniotomy, at the completion of radiation therapy, and then at least every 2 months. Recurrence of GBM is most often diagnosed by an increase in the size of an old area of contrast enhancement or when there is a new area of contrast enhancement on MRI.[7,9] Radiation necrosis, however, may also cause contrast enhancement on MRI of the brain. Positron-emission tomography of the brain with fluorodeoxyglucose contrast can distinguish radiation necrosis from tumor recurrence.[20-22] Radiation and chemotherapy should begin as soon as possible after histologic confirmation of GBM.[7]

Newly Diagnosed GBM

Fractionated irradiation is standard therapy for patients with newly diagnosed GBM. The site of the tumor, plus a 2- to 3-cm margin surrounding the tumor, is the focus of radiation. Radiation treatments are given once a day, Monday through Friday, for 6 weeks, for a total of 30 treatments. Radiation therapy may cause headache, vomiting, cerebral edema, hydrocephalus, necrosis, increased intracranial pressure, demyelination, dementia, gait ataxia, focal neurologic signs, seizures, incontinence, brain atrophy, alopecia, and leukoencephalopathy.[7]

Radiation therapy plus concomitant and adjuvant temozolomide (Temodar®) for newly diagnosed glioblastoma, when compared with radiation therapy alone, resulted in a 2.5-month increase in median survival and a 16.1% improvement in the 2-year survival rate. Temozolomide, 75 mg/m2 per day, is started the day before, or the day of, the first radiation treatment (Table 1). Unlike radiation therapy, temozolomide is given 7 days a week, for 42 consecutive days (6 weeks). Nausea, fatigue, neutropenia, thrombocytopenia, and opportunistic infections are potential adverse effects of temozolomide.[3] Nausea may be lessened by having patients take temozolomide on an empty stomach -- at least 2 hours after a meal. An antiemetic taken 30-60 minutes before temozolomide may also prevent nausea. Patients who experience fatigue should take temozolomide at bedtime.

Complete blood counts should be obtained weekly to monitor for neutropenia and thrombocytopenia. Serum chemistries, including electrolytes, blood urea nitrogen, creatinine, total bilirubin, and liver enzymes should be monitored every 28 days.[7] Temozolomide has been associated with the opportunistic infection Pneumocystis jiroveci pneumonia. [23] (Originally called P carinii pneumonia [PCP], the condition is still commonly called PCP even though the causative organism has been renamed P jiroveci.) PCP can be prevented with 1 tablet of trimethoprim-sulfamethoxazole double strength (Bactrim DS®), taken 3 times a week.[24-26]

After the completion of radiation therapy and 42 days of temozolomide, the patient is given a 28-day (4-week) break from treatment. If the patient has not experienced significant adverse effects from temozolomide, the dose is increased to 150 mg/m2 per day, given for 5 consecutive days, followed by another 28-day break. If there are no significant adverse effects with the increased dose of temozolomide, treatment is continued and the dose is increased again to 200 mg/m2 per day, for 5 consecutive days every 28 days.[3]

Dosing modifications must be made to metronomic (low, nontoxic doses on a frequent schedule without long interruptions) temozolomide if significant neutropenia or thrombocytopenia occurs. For an absolute neutrophil count (ANC) of 1000-1500 cells/µL or platelet count of 50,000-100,000 cells/µL, temozolomide should be held until the ANC is >1500 cells/µL and the platelet count is > 100,000 cells/µL. When the neutropenia or thrombocytopenia is resolved, temozolomide is resumed at the same dose. For an ANC< 1000 cells/µL or a platelet count <50,000 cells/µL, temozolomide should be held until the ANC is >1500 cells/µL and the platelet count is >100,000 cells/µL. Temozolomide may be continued once the ANC and platelets have recovered, but the dose should be decreased by 50 mg/m2 per day.[27]

The appropriate duration of metronomic temozolomide therapy is somewhat controversial.[28] Stupp and colleagues[3] gave their patients with GBM (high-grade glioma) radiation therapy plus concomitant temozolomide, and then 6 cycles of metronomic temozolomide. For low-grade gliomas (eg, oligodendrogliomas), metronomic temozolomide is prescribed at 200 mg/m2 per day for 12-24 months.[29] In the absence of GBM recurrence and significant toxicity, clinicians may prefer to continue metronomic temozolomide beyond 6 cycles. However, prolonged use of alkylating agents such as temozolomide has been associated with myelodysplasia and leukemia.[29-32] Thus, the decision to continue metronomic temozolomide beyond 6 cycles must be made with the awareness that as the cumulative temozolomide dose increases, the patient's risk of developing a secondary cancer also increases.

Recurrent GBM

Bevacizumab (Avastin®) and irinotecan (Camptosar®/CPT-11) may be used to treat recurrent malignant glioma (Table 1). In phase 2 trials, Vrendenburgh and colleagues[33] achieved radiographic responses in 63% of patients, with 6-month median progression-free and survival probabilities of 38% and 72%, respectively. The medications are given by intravenous infusion every 2 weeks. The dose of bevacizumab is 10 mg/kg. For irinotecan, the dose is 125 mg/m2 for patients who are not taking an enzyme-inducing antiepileptic drug (EIAED), and for patients who are taking an EIAED the dose is 340 mg/m2.[33]

Adverse reactions to bevacizumab include hypertension, deep-vein thrombosis, arterial thrombosis, intra-abdominal venous thrombosis, myocardial infarction, ischemic cardiovascular accident, gastrointestinal perforation, and intra-abdominal abscess. In Vrendenburgh and colleagues' study, 3 of 32 patients developed deep-vein thrombus or pulmonary embolus. The most common and significant adverse effect of irinotecan is diarrhea.[33]

Imatinib mesylate (Gleevec®) and hydroxyurea (Hydrox®) are also used to treat recurrent GBM. This drug combination has produced a median progression-free survival of 14.4 weeks, a median overall survival of 48.9 weeks, and a 6-month progression-free survival rate of 27%. Imatinib mesylate and hydroxyurea are given, without interruption, in daily oral doses. The dosage of imatinib mesylate is 500 mg twice a day for those receiving an EIAED, and 400 mg once a day for those who are not taking an EIAED. The dosage for hydroxyurea is 500 mg twice each day (Table 1). Adverse effects encountered most often for imatinib mesylate and hydroxyurea are neutropenia, thrombocytopenia, and edema.[33,34]

Carboplatin (Paraplatin®) and erlotinib (Tarceva®) have shown success in treating recurrent GBM. With these drugs, the median progression-free survival was 9 weeks, the median overall survival was 30 weeks, and the 6-month progression-free survival rate was 14%. Carboplatin is administered intravenously every 28 days. The formula to determine the dose of carboplatin is as follows:

6 mg/mL x (creatinine clearance + 25) = dose of carboplatin in milligrams.

Erlotinib is taken orally once a day throughout a 28-day cycle. The starting dosage is 150 mg/d, and the dose is increased as tolerated in 25-mg increments every 28 days to a maximum of 200 mg (Table 1). Carboplatin and erlotinib are given until GBM progresses or significant toxicity develops. The most common grade 3 toxicities are lymphocytopenia (40%), neutropenia (30%), thrombocytopenia (28%), fatigue (21%), and pruritus/rash (12%).[35]

Erlotinib is frequently associated with significant adverse dermatologic effects, the most common of which is a rash with sterile pustules. Antihistamines may be helpful for pruritus. Minocycline (Minocin®), 100 mg, taken orally twice a day may be prescribed for a rash-related secondary bacterial skin infection.[36]

Future Therapies for GBM

As of September 2008, 182 active clinical trials worldwide involved interventions for GBM. Many of these trials involve the chemotherapy agents discussed above, but with different combinations of agents (eg, bevacizumab plus temozolomide for newly diagnosed GBM), or higher doses (eg, dose-intense temozolomide for recurrent GBM).[37] There are new drugs, and a vaccine, under investigation.

Epidermal growth factor receptor variant III is a gene mutation that occurs in GBM. A vaccination against this mutation for patients with newly diagnosed GBM is being studied. After craniotomy, GBM tumor cells often remain in the surgical cavity and other parts of the brain. The goal for the vaccine is to enable the body to mount an effective immune response to these residual tumor cells.[38]

Role of the APN in Symptom Management in GBM

The APN can improve the quality of life for patients with GBM by monitoring the adverse effects of the disease or treatment and by formulating a plan with the patient to manage and reduce uncomfortable symptoms and associated distress. The APN can also help to keep patients undergoing radiation and chemotherapy healthy, and perhaps avoid hospitalizations for symptom management.

Pain

Headache is a common presenting symptom for GBM; patients may have headaches both after craniotomy and during treatment. Headaches are usually the result of increased intracranial pressure, a consequence of cerebral edema, tumor growth, or intracranial hemorrhage. Patients who have recently undergone craniotomy or radiation therapy will often have some degree of cerebral edema and related symptoms such as headache.

Corticosteroids may be prescribed or the dose increased to help decrease cerebral edema and relieve headache. Patients experiencing a sudden change in the character or intensity of their headaches, and other symptoms or signs of greatly increased intracranial pressure, should have imaging studies of their brain to assess for intracranial hemorrhage or other abnormality.[7,8,39]

Nausea

GBM and its treatment frequently cause nausea requiring the administration of antiemetics. 5-Hydroxytryptamine-3 (5-HT3) serotonin receptor antagonists are less likely to cause significant adverse effects than older antiemetics, and each drug in this class appears to be equally effective.[40] A 5-HT3 serotonin receptor antagonist given 30-60 minutes before chemotherapy can help prevent nausea, and the antiemetic can be repeated as needed.[3]

A corticosteroid may be added if a 5-HT3 alone is not effective in preventing nausea. Of the corticosteroids, dexamethasone (Decadron®) has demonstrated the greatest effectiveness in the prevention and treatment of nausea and vomiting. Aprepitant (Emend®), a neurokinin-1 receptor antagonist, may also be added to the regimen to control nausea.[40] Lorazepam (Ativan®), alprazolam (Xanax®), or diphenhydramine (Benadryl®) may be used if the first 3 agents do not control nausea or if acute emesis occurs (Table 2).[40-43]

Fatigue

Cancer-related fatigue is persistent tiredness or exhaustion, out of proportion to recent activities, that is caused by cancer or cancer treatment.[44] Patients with cancer may experience fatigue before, during, and after treatment. Fatigue can even occur in patients with cancer who have achieved "disease-free" status after treatment. Management of cancer-related fatigue should begin with the identification and treatment of comorbid conditions, such as anemia or hypothyroidism, which contribute to fatigue.[45]

Randomized controlled trials investigating the effects of exercise on cancer-related fatigue have demonstrated that exercise significantly alleviates fatigue. It is unclear, however, what type, duration, frequency, and intensity of exercise is best for managing cancer-related fatigue.[46] Corticosteroids have been shown to reduce fatigue in patients with metastatic cancer. Bupropion (Wellbutrin®), methylphenidate (Ritalin®), modafinil (Provigil®), and donepezil (Aricept®) have all shown promise for treating cancer-related fatigue in open-label studies, but have not yet demonstrated benefits in randomized placebo-controlled trials.[47-49] In a randomized placebo-controlled trial, dexmethylphenidate (Focalin®) significantly lessened cancer-related fatigue in nonanemic patients with cancer who had completed chemotherapy.[47,50]

Diarrhea

Diarrhea is a frequent problem for patients receiving chemotherapy for GBM, particularly those taking irinotecan.[33] Acute diarrhea should be managed with a 4-mg starting dose of loperamide (Imodium®), followed by 2 mg every 4 hours. If diarrhea continues for more than 12 hours, loperamide may be increased to every 2 hours. Patients experiencing diarrhea for more than 24 hours should be given a 7-day prescription for a fluoroquinolone. If diarrhea persists with use of loperamide for more than 48 hours, the loperamide should be discontinued and the patient should be admitted to the hospital for the administration of intravenous fluids and octreotide (Sandostatin®) (Table 3).[51]

Health Promotion for Patients With GBM

Chemotherapy, radiation therapy, and corticosteroids are all forms of immunotherapy that suppress the immune system, making patients with cancer more susceptible to infection. Patients with GBM should continue to receive dental care, but to decrease the risk for infection, these patients should avoid scheduling a dental or invasive medical procedure during chemotherapy. If a patient is taking metronomic temozolomide, for example, he or she should avoid having a dental or medical procedure during the 5-day chemotherapy cycle.

Immunotherapy for GBM may also decrease the patient's ability to respond to vaccinations. Patients with a solid tumor such as GBM may be more capable of mounting an antibody response to vaccinations than patients with a hematologic malignancy such as leukemia. It is recommended that all patients with cancer receive the influenza vaccine annually. The vaccine should be given more than 2 weeks before initiating chemotherapy, or between cycles of chemotherapy. Pneumococcal polysaccharide vaccine (Pneumovax®) is also recommended. Patients should receive the vaccine at least 10 days before starting, or 3 months after, chemotherapy.[52]

Psychosocial Care

GBM and its treatment create a variety of problems for patients, their families, and loved ones. Disabilities, adverse treatment reactions, and prognosis are substantial burdens and increase the risk for anxiety, depression, and other mental health problems. If unchecked, psychological and behavioral problems can affect a patient's memory, decision making, and participation in the plan of care.[6]

Transportation can be a problem for some patients. Seizures are common in the brain tumor population, and in many states, a patient must be seizure-free for months before resuming driving. Patients with GBM who have seizures or other disabilities may be unable to transport themselves to medical appointments.

Patients and their families may also have a difficult time paying for medications, even if the patient has health insurance. Temozolomide and bevacizumab are expensive medications. Imagine a male patient who is 5'9" and 155 pounds (a body surface area of 1.85 m2) who has just been given a GBM diagnosis and needs to start temozolomide. He will need to take 140 mg of temozolomide (75 mg/m2 per day) for 42 consecutive days. Each 140-mg capsule of temozolomide costs $283.32 ($1416.59 for 5 capsules) and the total for 42 capsules is $11,899.44. For the first cycle of metronomic temozolomide (5 days at 150 mg/m2 per day), the patient will need to take 2 of the 140-mg capsules daily for a total cost of $2833.20. For subsequent cycles of metronomic temozolomide (200 mg/m2 per day), the patient will need to take one 250-mg capsule, one 100-mg capsule, and one 20-mg capsule each day for 5 days. The prices for 5 each of the 250-mg, 100-mg, and 20-mg capsules, respectively, are $2334.29, $933.70, and $186.71. The total cost for each 5-day cycle of metronomic temozolomide at 200 mg/m2 per day is therefore $3454.70.[53]

If the same patient experiences GBM recurrence, his chemotherapy may be changed to bevacizumab and irinotecan. He will need 10 mg/kg of bevacizumab every 2 weeks. At 155 pounds, he is roughly 70 kg, so he will need 700 mg of bevacizumab. The cost of bevacizumab is $687.50 per 100 mg, so the cost of each infusion will be $4812.50.[54,55]

The costs described above do not include the expense of antiemetics and other medications that may be required along with temozolomide or bevacizumab. Many patients with GBM have health insurance, but instead of a flat-rate copay, they may pay a percentage of the cost of their medications. The higher the cost of their medications, the more they have to pay. Other GBM patients have health insurance that limits the total coverage of their medications (eg, $10,000 per year), and medication expenses exceeding this amount must be paid out-of-pocket.

Although there are many potential psychosocial issues for patients with GBM, many resources are available for addressing these problems. The Institute of Medicine's Cancer Care for the Whole Patient: Meeting Psychosocial Health Needs[6]lists resources for counseling, decision support, education, emotional support, financial assistance, financial counseling, housing, legal advice, legal assistance, transportation, caregiver support, logistical support, and wigs and prosthetics. The Brain Tumor Society provides patients with GBM and their families with education, emotional support, and financial assistance.[6]

Conclusion

GBM is the most common malignant neoplasm of the central nervous system. APNs can help recognize GBM early in the disease and initiate the diagnostic process. As part of a multidisciplinary team, APNs can provide postoperative care, initiate and manage chemotherapy, manage disease and treatment-related symptoms, promote health, provide psychosocial care, and improve the quality of life for patients with GBM.

Departments of Neurology and Radiology, Massachusetts General Hospital, and Neuroscience Program, Harvard Medical School, 149 13th Street, Charlestown, MA02129, USA.

Glioblastoma tumour cells release microvesicles (exosomes) containing mRNA, miRNA and angiogenic proteins. These microvesicles are taken up by normal host cells, such as brain microvascular endothelial cells. By incorporating an mRNA for a reporter protein into these microvesicles, we demonstrate that messages delivered by microvesicles are translated by recipient cells. These microvesicles are also enriched in angiogenic proteins and stimulate tubule formation by endothelial cells. Tumour-derived microvesicles therefore serve as a means of delivering genetic information and proteins to recipient cells in the tumour environment. Glioblastoma microvesicles also stimulated proliferation of a human glioma cell line, indicating a self-promoting aspect. Messenger RNA mutant/variants and miRNAs characteristic of gliomas could be detected in serum microvesicles of glioblastoma patients. The tumour-specific EGFRvIII was detected in serum microvesicles from 7 out of 25 glioblastoma patients. Thus, tumour-derived microvesicles may provide diagnostic information and aid in therapeutic decisions for cancer patients through a blood test.

Houston -- Amyotrophic lateral sclerosis (ALS) researchers at - The Methodist Hospital in Houston have shown that transplanted bone marrow stem cells can attach themselves to injured areas in the brain or spinal cord, possibly providing a way to deliver future gene therapy.

According to Dr. Stanley H. Appel's study published in the Oct. 14, 2008, issue of Neurology®, the medical journal of the American Academy of Neurology, these "Trojan horse" cells may improve the ability to deliver gene therapy to the brain and spinal cord.

The original intent of this study focused on whether transplanted bone marrow stem cells in six patients with sporadic ALS would suppress neuroinflammation and improve the patients' clinical outcomes, said Appel, co-founder and co-director of the Methodist Neurological Institute at The Methodist Hospital. While the results showed no benefit in fighting the disease, Appel's research team found that transplanting bone marrow stem cells that are closely matched to the patients' own bone marrow allowed for a significant percentage of those cells to travel to and reside in the brain or spinal cord. However, it is clear from the study that unless the bone marrow stem cells are engineered to secrete neuroprotective factors, such transplants are not likely to be beneficial in human ALS.

Despite improved pharmacological options, about 20% of patients with primary generalized epilepsy and 35% of partial epilepsies remain medically refractory. Difficult to control seizures affect the patient's ability to live a normal life and have enormous psychosocial, behavioral, and cognitive effects. Refractory epilepsy also decreases life expectancy. Patients with uncontrolled seizures are at greater risk for sudden unexplained death (SUDEP), which accounts for about 50% of deaths in refractory epilepsy. Surgery is one alternative option, neurostimulation another.
Several electronic methods of neurostimulation are gaining adherents and others are still under clinical investigation, according to a recent press conference held by the American Medical Association which defined new and emerging methods of neuromodulation.

1) Vagus nerve stimulation (VNS) is . VNS Therapy™ was first approved in 1997 as adjunctive therapy for partial onset seizures refractory to AEDs in patients over 12 years of age. This indication is based on outcomes of five controlled, clinical trials which showed median reductions in seizures of 31.% to 41% at 1 to 3 years, and a favorable side effect profile.

2) Deep brain stimulation (DBS) is FDA-approved for movement disorders such as Parkinson's disease, but it is still under investigation in refractory epilepsy. Studies have successfully targeted deep brain sites such as the hippocampus, mammillary bodies, and cingulate gyrus for DBS seizure inhibition, according to and Hans Luders of Cleveland Clinic Foundation. A frequent target appears to be the thalamus, but it is still not clear which brain region exhibits the most effective seizure control when stimulated. Andres Lozano of the University of Toronto reported on five patients with generalized or complex partial seizures who received anterior thalamic stimulation and had a 93% seizure reduction. Mexico's Francisco Velasco and colleagues implanted bilateral electrodes in both centromedial thalamic nuclei in patients with generalized seizures, using intermittent, alternating, bilateral stimulation. Best results were obtained in Lennox-Gastaut patients. Velasco also administered continuous stimulation of the epileptic focus in another group of 10 patients scheduled for temporal lobectomy, with a resultant significant decrease in clinical seizures and interictal spikes. At the 2002 American Epilepsy Society meeting, Vonck et al reported on the use of central, localized, chronic stimulation of medial temporal lobe structures in uncontrolled epilepsy, with a 50% to 90% seizure reduction and no significant side effects during 3 to 6 months

3) Transcranial magnetic stimulation (TMS) is currently used to treat conditions ranging from depression to cerebral ischemia, and is now being studied for refractory epilepsies. The National Institutes of Health is still recruiting medically refractory patients between 5 and 65 years of age whose seizures originate from a neocortical focus near the surface of the brain. TMS produces a brief, high-current pulse in a circular magnetic coil to produce a magnetic field with lines of flux passing perpendicularly to the coil. The magnetic field is then conducted through the skull and converted to an electrical current when it reaches the brain. Some studies looked at single pulses, others at repetitive pulses. At the 2002 AES meeting, Tergau et al from Germany, gave an interim analysis of an ongoing placebo-controlled multicenter trial which suggested that low-frequency TMS using 0.3 Hz over a 4 week period achieved significant seizure reduction compared with 1.0Hz and placebo stimulation. According to Mark Hallett of the National Institute of Neurological Disorders and Stroke, TMS has limited use because it affects only the superficial cortex, but Hallett remains hopeful that coils can be developed that will stimulate at greater depth.

4) Arguably the most interesting and technically challenging emerging technology is the closed-loop system developed by NeuroPace, Inc. (NP) (Sunnyvale, CA). The device is inserted in the skull, and electrodes are implanted directly at the site of seizure onset to deliver impulses that terminate seizures before they develop. Obviously locating the site of the seizure requires accurate and sensitive imaging methodology. Once identified, ictal patterns are programmed into the device and the computer recognizes the pattern and delivers an electrical stimulation to stop progression. Michael Smith, director of the Epilepsy Center at Rush-Presbyterian St. Luke's Medical Center in Chicago, is an investigator in an ongoing FDA clinical study of NP Model 300 which is still recruiting patients. He uses several imaging and computer assisted physiology methods such as high resolution MRI, subtracted interictal/ictal SPECT co-registered to MRI (SISCOM), and magnetoencephalography (MEG) to locate the seizure focus. Early studies by Esteller et al at the University of Pennsylvania used NP in mesial or neocortical partial seizures and reported a sensitivity of 92%.

	VNS Therapy™ - Cyberonics, Inc. Since 1997, VNS Therapy™ has been approved for use as an adjunctive therapy in reducing the frequency of seizures in adults and adolescents over 12 years of age with partial onset seizures that are refractory to antiepileptic medications. This indication is based on outcomes from 5 controlled, clinical trials. Efficacy, measured as median seizure reduction, was observed in these clinical trials and other study populations. VNS Therapy resulted in median reductions in seizures of 31.3%, 40.7%, and 40.4% at 1, 2, and 3 years, respectively. Moreover, VNS Therapy offers a unique and favorable side effect profile that avoids cerebral toxicity.
	Model 200² - Magstim Company US LLC Based upon the original Magstim design the new Magstim 200² monophasic transcranial stimulator draws upon the years of knowledge and expertise gathered in both the clinical and research environments. Resulting in an innovative design that will help further establish the new Magstim range as the system of preferred choice. Ergonomic modular approach to design to complement any operating environment and facilitate simple upgradeability to future Magstim systems. Total compatibility and flexibility through additional intelligent hardware, the Magstim 200² is fully compatible with all existing Magstim coils (remote control operation requires new coils). New Microprocessor controlled system hardware for added system safety whilst also enabling remote software upgrades and PC interfacing capabilities via standard internal serial port.
	Activa® Therapy System - Medtronic Inc. Activa Parkinson's Control Therapy uses electrical stimulation to safely and effectively treat some of the most disabling motor symptoms of Parkinson's disease. Activa Parkinson's Control Therapy is a safe and effective adjunctive treatment option for many Parkinson's patients. Activa Therapy controls rigidity, bradykinesia/akinesia and/or tremor while reducing the duration of dyskinesia related to antiparkinsonian medication.

OBJECTIVE: The reasons for neuropsychological deficits after subarachnoid hemorrhage (SAH) are fairly unknown. Cholinergic basal forebrain (BFB) neurons are essential for attention, memory, and emotion. We investigated possible changes in the cholinergic BFB and its hippocampal and neocortical terminals after experimental SAH.

METHODS: SAH was induced in 19 male Wistar rats by stereotactic injection of 150 microL of autologous blood into the prechiasmatic cistern. Five control animals received 150 microL of saline. Continuous monitoring of brain tissue oxygen tension, intracranial pressure, and cerebral perfusion pressure was performed. After 4 and 14 days, the BFB was analyzed for cholinergic and gamma-aminobutyric acid-ergic cell counts. The number of cholinergic terminals in the hippocampus and neocortex was calculated by optical densitometry.

RESULTS: SAH resulted in a 20 to 30% decrease in cholinergic BFB neurons in the medial septum and diagonal band at 4 and 14 days. A similar decline in the density of hippocampal and neocortical cholinergic terminals was demonstrated. Animals treated with saline did not exhibit significant cholinergic cell loss, and gamma-aminobutyric acid-ergic neurons appeared unaffected by the SAH. Courses of intracranial pressure and cerebral perfusion pressure did not differ between animals injected with blood and saline, but brain tissue oxygen tension decreased considerably and continued to stay below baseline in SAH, although it returned to normal values after saline injection.

CONCLUSION: The present study provides evidence for a decrease of cholinergic BFB neurons after SAH. The direct effect of blood in the basal cisterns seemed to result in an enduring tissue hypoxia as a significant mechanism for cholinergic degeneration.

ABSTRACT

Background: Hypothermia therapy improves survival and the neurologic outcome in animal models of traumatic brain injury. However, the effect of hypothermia therapy on the neurologic outcome and mortality among children who have severe traumatic brain injury is unknown.

Methods: In a multicenter, international trial, we randomly assigned children with severe traumatic brain injury to either hypothermia therapy (32.5°C for 24 hours) initiated within 8 hours after injury or to normothermia (37.0°C). The primary outcome was the proportion of children who had an unfavorable outcome (i.e., severe disability, persistent vegetative state, or death), as assessed on the basis of the Pediatric Cerebral Performance Category score at 6 months.

Results: A total of 225 children were randomly assigned to the hypothermia group or the normothermia group; the mean temperatures achieved in the two groups were 33.1±1.2°C and 36.9±0.5°C, respectively. At 6 months, 31% of the patients in the hypothermia group, as compared with 22% of the patients in the normothermia group, had an unfavorable outcome (relative risk, 1.41; 95% confidence interval [CI], 0.89 to 2.22; P=0.14). There were 23 deaths (21%) in the hypothermia group and 14 deaths (12%) in the normothermia group (relative risk, 1.40; 95% CI, 0.90 to 2.27; P=0.06). There was more hypotension (P=0.047) and more vasoactive agents were administered (P<0.001) in the hypothermia group during the rewarming period than in the normothermia group. Lengths of stay in the intensive care unit and in the hospital and other adverse events were similar in the two groups.

Conclusions: In children with severe traumatic brain injury, hypothermia therapy that is initiated within 8 hours after injury and continued for 24 hours does not improve the neurologic outcome and may increase mortality.

Better Backs by Better Beds?
Bergholdt, Spine. 33(7):703-708, April 1, 2008.

Study Design. A "randomized"/stratified, single-blinded, parallel-group study.

This is an elegant study from Tom Bendix in Denmark. They evaluated 3 structurally different mattresses relative influence on patients with chronic low back pain (CLBP). You know the patient that asks 'should I buy an orthopaedic mattress? This helps you answer them.

In several advertisements, it is proclaimed that certain mattresses have a positive effect on LBP, and especially a hard mattress is commonly believed to have a positive effect. One hundred sixty CLBP patients were randomized to 1 of 3 groups, having a mattress/bed mounted in their sleeping room for 1 month. The beds were: (1) waterbed (Akva), (2) body-conforming foam mattress (Tempur), and (3) a hard mattress (Innovation Futon).

There was a high 'drop-out' rate despite astonishing efforts by the research group to provide the double beds where requested. The analyses were performed on 141 patients. During the 1-month trial period another 27 patients stopped ahead of time, which were accounted for by "worse case" as well as "no-change" analyses. Both the waterbed and the foam mattress seemed superior to the hard mattress, especially when using the probably most relevant "worst case"

They conclude that the Waterbed and foam mattress' did influence back symptoms, function and sleep more positively as apposed to the hard mattress, but the differences were small.

The discussion is really interesting regarding possible reasons for this. The soft beds maybe cause more movement and so less stiffness. Staying active again.