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.

Functional localization and visualization of the subthalamic nucleus from microelectrode recordings acquired during DBS surgery with unsupervised machine learning.

Microelectrode recordings are a useful adjunctive method for subthalamic nucleus localization during deep brain stimulation surgery for Parkinson's disease. Attempts to quantitate and standardize this process, using single computational measures of neural activity, have been limited by variability in patient neurophysiology and recording conditions. Investigators have suggested that a multi-feature approach may be necessary for automated approaches to perform within acceptable clinical standards. We present a novel data visualization algorithm and several unique features that address these shortcomings. The algorithm extracts multiple computational features from the microelectrode neurophysiology and integrates them with tools from unsupervised machine learning. The resulting colour-coded map of neural activity reveals activity transitions that correspond to the anatomic boundaries of subcortical structures. Using these maps, a non-neurophysiologist is able to achieve sensitivities of 90% and 95% for STN entry and exit, respectively, to within 0.5 mm accuracy of the current gold standard. The accuracy of this technique is attributed to the multi-feature approach. This activity map can simplify and standardize the process of localizing the subthalamic nucleus (STN) for neurostimulation. Because this method does not require a stationary electrode for careful recording of unit activity for spike sorting, the length of the operation may be shortened.

High-frequency oscillations (>200 Hz) in the human non-parkinsonian subthalamic nucleus.

The human basal ganglia, and in particular the subthalamic nucleus (STN), can oscillate at surprisingly high frequencies, around 300 Hz [G. Foffani, A. Priori, M. Egidi, P. Rampini, F. Tamma, E. Caputo, K.A. Moxon, S. Cerutti, S. Barbieri, 300-Hz subthalamic oscillations in Parkinson's disease, Brain 126 (2003) 2153-2163]. It has been proposed that these oscillations could contribute to the mechanisms of action of deep brain stimulation (DBS) [G. Foffani, A. Priori, Deep brain stimulation in Parkinson's disease can mimic the 300 Hz subthalamic rhythm, Brain 129 (2006) E59]. However, the physiological role of high-frequency STN oscillations is questionable, because they have been observed only in patients with advanced Parkinson's disease and could therefore be secondary to the dopamine-depleted parkinsonian state. Here, we report high-frequency STN oscillations in the range of the 300-Hz rhythm during intraoperative microrecordings for DBS in an awake patient with focal dystonia as well as in a patient with essential tremor (ET). High-frequency STN oscillations are therefore not exclusively related to parkinsonian pathophysiology, but may represent a broader feature of human STN function.

Anterior thalamic nucleus stimulation for epilepsy.

One option for treatment of medically refractory debilitating epilepsy is stimulation of the anterior thalamic nucleus, which projects via the cingulate gyrus to limbic structures and neocortex. In this chapter we describe the technique for anterior thalamic deep brain stimulation and report outcomes of early series of patients. The prospective double-blind randomized Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy (SANTE) trial will evaluate the efficacy of this technique for epilepsy treatment.

Emergence of complex, involuntary movements after gamma knife radiosurgery for essential tremor.

Gamma knife radiosurgery is generally considered a safer alternative to traditional pallidotomy or thalamotomy. We report the case of a 59-year-old patient with essential tremor who developed a complex, disabling movement disorder following gamma knife thalamotomy. This case illustrates the need for long-term follow-up to fully evaluate the potential for complications following radiosurgery.

Revision of deep brain stimulator for tremor. Technical note.

The treatment of essential tremor with thalamic deep brain stimulation (DBS) is considered to be more effective and to cause less morbidity than treatment with thalamotomy. Nonetheless, implantation of an indwelling electrode, connectors, and a generator is associated with specific types of morbidity. The authors describe three patients who required revision of their DBS systems due to lead breakage. The connector between the DBS electrode and the extension wire, which connects to the subclavicular pulse generator, was originally placed subcutaneously in the cervical region to decrease the risk of erosion through the scalp and to improve cosmesis. Three patients presented with fractured DBS electrodes that were located in the cervical region near the connector, necessitating reoperation with stereotactic retargeting and placement of a new intracranial electrode. At reoperation, the connectors were placed subgaleally over the parietal region. Management of these cases has led to modifications in the operative procedure designed to improve the durability of DBS systems. The authors recommend that surgeons avoid placing the connection between the DBS electrode and the extension wire in the cervical region because patient movement can cause microfractures in the electrode. Such microfractures require intracranial revision, which may be associated with a higher risk of morbidity than the initial operation. The authors also recommend considering prophylactic relocation of the connectors from the cervical area to the subgaleal parietal region to decrease the risk of future DBS electrode fracture, which would necessitate a more lengthy procedure to revise the intracranial electrode.

Efficacy of unilateral deep brain stimulation of the thalamic ventralis intermedius nucleus in a patient with bipolar disorder associated with Klinefelter syndrome and essential tremor. Case report.

Deep brain stimulation (DBS) of the ventralis intermedius nucleus (Vim) is a safe and effective treatment for essential tremor. Bipolar disorder and essential tremor had each been reported to occur in association with Klinefelter syndrome but the three diseases have been reported to occur together in only one patient. The genetic basis and natural history of these disorders are not completely understood and may be related rather than coincidental. The authors report on a 23-year-old man with Klinefelter syndrome (47,XXY) and bipolar disorder who was treated successfully with unilateral DBS of the thalamic Vim for essential tremor.

Long-term deep brain stimulation in a patient with essential tremor: clinical response and postmortem correlation with stimulator termination sites in ventral thalamus. Case report.

Essential tremor can be suppressed with chronic, bilateral deep brain stimulation (DBS) of the ventralis intermedius nucleus (Vim), the cerebellar receiving area of the motor thalamus. The goal in this study was to correlate the location of the electrodes with the clinical efficacy of DBS in a patient with essential tremor. The authors report on a woman with essential tremor in whom chronic bilateral DBS directed to the ventral thalamus produced adequate tremor suppression until her death from unrelated causes 16 months after placement of the electrodes. Neuropathological postmortem studies of the brain in this patient demonstrated that both stimulators terminated in the Vim region of the thalamus, and that chronic DBS elicited minor reactive changes confined to the immediate vicinity of the electrode tracks. Although the authors could not identify neuropathological abnormalities specific to essential tremor, they believe that suppression of essential tremor by chronic DBS correlates with bilateral termination of the stimulators in the Vim region of the thalamus.

Ventricular asystole during vagus nerve stimulation for epilepsy in humans.

Electrical stimulation of the vagus nerve, a recently available option for patients with refractory epilepsy, has demonstrated safety and efficacy. We report four patients with refractory epilepsy who experienced ventricular asystole intraoperatively during initial testing for implantation of the vagus nerve stimulator. Acute intraoperative vagus nerve stimulation may create ventricular asystole in humans. Extracorporeal cervical vagus nerve stimulation testing with continuous EKG monitoring intraoperatively before generator implantation is warranted.

Magnetic resonance imaging and temporal lobe epilepsy.

Surgical treatment is a well established option for patients with medically refractory temporal lobe epilepsy. Magnetic resonance imaging (MRI) has revolutionized the evaluation of these patients. New techniques can identify structural, metabolic and functional abnormalities associated with the epileptogenic zone. Mesial temporal sclerosis is the most common pathological finding and presents as hippocampal atrophy, which can be detected by visual inspection in most cases. Volumetric analysis of medial temporal structures offers the advantage of detecting bilateral abnormalities. Magnetic resonance spectroscopy can detect metabolic abnormalities associated with the epileptogenic focus. Functional MRI allows for the non-invasive evaluation of cognitive function, allowing for the localization of the neuroanatomic substrate of motor, sensory and cognitive functions. Intraoperative MRI-based image guided systems are a useful adjunct in the surgical treatment of this epileptic syndrome.

Apoptosis is induced in glioma cells by antisense oligonucleotides to protein kinase C alpha and is enhanced by cycloheximide.

The protein kinase C (PKC) activity of human glioma cells correlates with their rate of proliferation. We report here that the down-regulation of the predominant PKC isoform of glioma cells, alpha, by antisense phosphorothioate oligonucleotides (AS PTO) significantly reduced the rate of proliferation of three human glioma cell lines. This reduction in growth rate was attributed to apoptosis, as assessed by terminal deoxynucleotidyl transferase (TdT) assay. Unexpectedly, when low concentrations of the protein synthesis inhibitor cycloheximide (CHX) were administered to A172 cells immediately prior to AS PTO treatment, a marked enhancement in the number of apoptotic cells was observed. These findings suggest that PKC alpha plays a pivotal role in the ability of gliomas to avoid apoptotic cell death.

Signal transduction for proliferation of glioma cells in vitro occurs predominantly through a protein kinase C-mediated pathway.

Previous work has demonstrated that glioma cells have very high protein kinase C (PKC) enzyme activity when compared to non-malignant glia, and that their PKC activity correlates with their proliferation rate. The purpose of this study was to determine whether the elevated PKC activity in glioma is secondary to an autonomously active PKC isoform implying oncogenic transformation, or whether this activity is driven by upstream ligand-receptor tyrosine kinase interactions. We treated established human glioma cell lines A172, U563 or U251 with either the highly selective PKC inhibitor CGP 41 251, or with genistein, a tyrosine kinase inhibitor. The proliferation rate and PKC activity of all the glioma lines was reduced by CGP 41 251; the IC50 values for inhibiting cell proliferation corresponded to the IC50v values for inhibition of PKC activity. Genistein also inhibited cell proliferation, with IC50 proliferation values approximating those for inhibition of tyrosine kinase activity in cell free protein extracts. Importantly, in genistein-treated cells, downstream PKC enzyme activity was dose dependently reduced such that the correlation coefficient for effects of genistein on proliferation rate and PKC activity was 0.92. These findings suggest that upstream tyrosine kinase linked events, rather than an autonomously functioning PKC, result in the high PKC activity observed in glioma. Finally, fetal calf serum (FCS) evoked a strong mitogenic effect on glioma cell lines. This mitogenic activity was completely blocked by CGP 41 251, suggesting that although the many mitogens in FCS for glioma cells signal initially through genistein-inhibitable tyrosine kinases, they ultimately channel through a PKC-dependent pathway. We conclude that proliferative signal transduction in glioma cells occurs through a predominantly PKC-dependent pathway and that selectively targeting this enzyme provides an approach to glioma therapy.

Protein kinase C and growth regulation of malignant gliomas.

This article reviews the role of the signal transduction enzyme protein kinase C in the regulation of growth of malignant gliomas, and describes how targetting this enzyme clinically can provide a novel approach to glioma therapy.

Protein kinase C isoform alpha overexpression in C6 glioma cells and its role in cell proliferation.

Previous studies from this laboratory have demonstrated that protein kinase C (PKC) enzyme activity is highly correlated with the proliferation rate of glioma cells, and that glioma cells of both human and rat origin have very high PKC enzyme activity when compared to non-malignant glia including astrocytes, the antecedents of most gliomas. In the present study, by contrasting the rat C6 glioma cells with non-malignant rat astrocytes, we have sought to determine whether the high PKC enzyme activity of glioma cells was due to the overexpression of a specific isoform of PKC. By Western blot analyses, both C6 glioma cells and astrocytes were found to express PKC alpha, beta, delta, epsilon and zeta, but not gamma. Enzyme activity measurements revealed that the elevated PKC activity of glioma cells compared to glia was calcium-dependent, thereby implicating abnormal activity of the alpha or beta isoforms. On Western blots, when compared to astrocytes, glioma cells were determined to overexpress PKC alpha but not beta. An antisense oligonucleotide to PKC alpha, directed at the site of initiation of translation, inhibited the proliferation rate of glioma cells when compared to cells treated with control oligonucleotides; PKC enzyme activity and PKC alpha protein expression were significantly reduced by the antisense treatment. These results suggest that the high PKC enzyme activity of glioma cells, and its correspondence with proliferation rate, is the result of overexpression of isozyme alpha. Targetting PKC alpha in glioma cells may provide a refinement of therapy of glioma patients, some of which are already showing clinical stabilization when treated with drugs with PKC-inhibitory effects.

T cell-mediated cytotoxicity of human gliomas: a tumor necrosis factor-independent mechanism.

Cellular immune effector mechanisms are implicated as potential therapies for malignant gliomas. We have examined the potential for anti-CD3-activated human peripheral blood-derived CD4+ and CD8+ T cells to induce lysis of human glioma cell lines in vitro, the mechanism of action of these cells, and the capacity of the glioma to inhibit the effect. We found that activated CD4+ and CD8+ T cell preparations containing less than 5% natural killer cells could induce significant lysis of the glioma cell line U251, as measured by an 18-hour, but not 5-hour, chromium-51 or lactate dehydrogenase release assay. This effect was not reproduced using recombinant tumor necrosis factor or inhibited with antitumor necrosis factor antibody. Anti-lymphocyte functional antigen-1 and anti-intercellular adhesion molecule antibodies also did not inhibit the effect. Glioma-derived supernatant could inhibit the proliferation of the T cells but not the cytotoxic effect. Human fetal astrocytes were also susceptible to the cytotoxic effect of the activated T cells. These results indicate that activated T cells can induce glioma cytotoxicity via a mechanism independent of tumor necrosis factor. The therapeutic potential of this effector mechanism will depend on its capacity to deliver these cells or their specific effector molecules to the tumor site or to augment the activity of such cells, which accumulate naturally in gliomas.

Ganglioglioma presenting as a vascular lesion in a 10-year-old boy. Case report.

The authors present the case of a 10-year-old boy admitted for evaluation of a generalized seizure and a history of headaches. Computerized tomography (CT) and gadolinium-enhanced magnetic resonance (MR) imaging demonstrated a large nonhomogeneous contrast-enhancing mass of the left frontal lobe, with a large cystic component. Cerebral angiography revealed the lesion to be highly vascular and fed entirely by the internal carotid artery system. The patient underwent craniotomy and the lesion was completely removed. Neuropathological study revealed that the tumor was a ganglioglioma. On review of the literature, it was found that gangliogliomas often present in the second and third decade, are known to have cystic components, and are contrast-enhancing on CT and MR imaging; however, they are classically known to be avascular on angiography. This case of a markedly vascular ganglioglioma emphasizes that these tumors should be included in the differential diagnosis of vascular supratentorial lesions.

Protein kinase C inhibitors suppress cell growth in established and low-passage glioma cell lines. A comparison between staurosporine and tamoxifen.

We have previously demonstrated that the proliferation of established human glioma cell lines correlated with protein kinase C (PKC) activity and that a relatively selective PKC inhibitor, staurosporine, inhibits glioma cell proliferation. The purpose of this study was to determine whether low-passage glioma cell lines were also sensitive to staurosporine and to compare the antimitotic effects of staurosporine with tamoxifen, an antiestrogen with a known PKC inhibitory effect presently being investigated in the treatment of recurrent glioma. We measured the effects of treatment with staurosporine or tamoxifen on the proliferation rate of five established glioma cell lines (A172, U251, U87, U373, U563) and four low-passage glioma cell lines. The proliferation of all cell lines was inhibited by staurosporine, at an IC50 value (concentration at which activity is 50% inhibited) of approximately 2 nmol/L. All established lines, but only one low-passage line, were susceptible to tamoxifen, with an IC50 value of 10 mumol/L. Three of the four low-passage lines were poorly inhibited by tamoxifen. The IC50 values for the inhibition of cellular proliferation by staurosporine and tamoxifen closely corresponds to the IC50 data for the inhibition of particulate PKC activity in gliomas. We conclude that staurosporine is more effective in the inhibition of glioma proliferation than tamoxifen and that staurosporine is potentially useful in the adjuvant treatment of gliomas. The correspondence in IC50 results for proliferation and PKC activity further strengthens the hypothesis that an aberrant PKC system in gliomas drives their hyperproliferative state.

Staurosporine differentially inhibits glioma versus non-glioma cell lines.

We have previously demonstrated that the protein kinase C (PKC) activity of human glioma cell lines was significantly elevated (by 3 orders of magnitude) when compared to non-malignant adult human glia, and that the proliferation rate of several established human glioma cell lines correlated with the measured protein kinase C activity. The purpose of this study was to determine whether 1) elevated PKC activity was also a characteristic of fast growing cell lines of non-glial origin, 2) the proliferation rate of non-glioma cell lines correlated with their PKC activity and 3) the proliferation of non-glioma cell lines could be inhibited by staurosporine, a relatively selective PKC inhibitor, which significantly attenuates the growth of glioma cells. Eight established human non-glioma cell lines (bladder, colorectal, rhabdomyosarcoma-oligodendrocyte hybrid, melanoma, cervix, and fibroblast) were compared to the highly proliferative A172 glioma cell line. PKC activity was significantly higher in the glioma cell lines even though 3 of 8 of the non-glioma lines had higher proliferation rates than A172. In non-glioma cell lines, no correlation was found between the PKC activity and proliferation rates. Staurosporine was more effective in decreasing the proliferation of three glioma cell lines compared to the non-glioma cell lines. We conclude that PKC activity is differentially increased in glioma cell lines and that their proliferation rate is more sensitive to inhibition by staurosporine. Targetting the PKC system may prove to be of therapeutic benefit to patients with malignant gliomas.