Vagus nerve stimulation therapy for patients with persistent seizures after epilepsy surgery

BACKGROUND: This study reports the effectiveness of vagus nerve stimulation (VNS) among patients who failed cranial surgery for intractable epilepsy. METHODS: Data were obtained from the Cyberonics VNS therapy patient outcome registry. The integrity of the systems for collecting and processing registry data was authenticated by an independent auditing agency. RESULTS: Two nonconsecutive cohorts were compared: patients who had had prior cranial surgery (CS group, n = 921) and those who had not (non-CS group, n = 3,822). For the CS group, the median reduction in seizure frequency was 42.5% after 3 months of VNS therapy, 42.9% at 6 months, 45.7% at 12 months, 52.0% at 18 months and 50.5% at 24 months. For the non-CS group, analogous rates were 47.0, 52.9, 60.0, 62.7 and 66.7%, respectively. CONCLUSION: The effectiveness of VNS is maintained during prolonged stimulation. Patients who failed prior cranial surgery did not respond quite as favorably as all other patients receiving VNS therapy.     

Vagus nerve stimulation therapy for seizures

Of the 3 million patients with seizures in North America approximately 70% have effective seizure control with medications. In the group refractory to medical treatment only a minority fit the criteria for surgical therapy. Vagus nerve stimulation therapy seems to be a suitable nonpharmacologic therapy for reducing seizure frequency in these cases. It is a simple device with 2 electrodes and an anchor loop implanted on the midcervical portion of left vagus nerve and the impulse generator is implanted subcutaneously in the left infraclavicular region. The left vagus is the preferred site as the right vagus innervates the sinoatrial node and influences the heart rate. Data from laboratory studies suggest that it most probably works by increasing the release of norepinephrine in the locus ceruleus, which in turn increases the seizure threshold. More than 32,000 devices have been implanted since it was approved in 1997. There is class I evidence that vagus nerve stimulator reduces the frequency of seizures. In addition it also elevates the patients' mood-independent of seizure control. In one of the studies 50% reduction in seizure frequency was 37% in the first year and 44% in the second and third year. The side effects commonly reported are constriction in the throat, change in voice, and throat pain which most patients are able to tolerate and continue the use of the device. In conclusion VNS seems to be an effective nonpharmacologic therapy for medically refractory partial onset seizures.     

Efficacy of vagal nerve stimulation in children with medically refractory epilepsy

OBJECTIVE: The effects of vagal nerve stimulation (VNS) on seizure frequency and quality of life were analyzed retrospectively in children with medically refractory epilepsy. METHODS: Thirty-eight children aged 11 months to 16 years underwent implantation of vagal nerve stimulators. Age of seizure onset, duration of epilepsy, and seizure type and frequency were recorded preoperatively. Age at implantation, length of follow-up, seizure type and frequency, and change in quality of life (QOL) were recorded postoperatively. Changes in QOL were assigned a QOL score by the caretakers on a visual analog scale of -1 (much worse) to +1 (much improved). RESULTS: The median follow-up period was 12 months (range, 10-18 mo). Eleven (29%), 15 (39%), 5 (13%), and 7 (18%) children had greater than 90% reduction, 50 to 90% reduction, less than 50% reduction, and no reduction in seizure frequency, respectively. For all children, seizure reduction by seizure type was as follows: atonic (80%), absence (65%), complex partial (48%), and generalized tonicoclonic (45%). The mean change in QOL score was 0.61. Eighty-six percent of the children had QOL scores of 0.5 (improved) or higher. Follow-up of at least 6 months was associated with greater seizure reduction (P = 0.05) and higher QOL score (P < 0.01). Seizure reduction was greater in children with onset of epilepsy after 1 year of age (P < 0.05). The age of the child and duration of epilepsy were not associated with greater or lesser degrees of seizure reduction. CONCLUSION: VNS provided improvements in seizure control for the majority of children regardless of age. QOL was improved in the majority of children with VNS. VNS should be considered for children with medically refractory epilepsy who have no surgically resectable focus.     

Vagus Nerve Stimulation for Medically Refractory Epilepsy; Efficacy and Cost-Benefit Analysis

Summary  Introduction. Vagus nerve stimulation is a novel treatment for patients with medically refractory epilepsy, who are not candidates for conventional epilepsy surgery, or who have had such surgery without optimal outcome. To date only studies with relatively short follow-up are available. In these studies efficacy increased with time and reached a maximum after a period of 6 to 12 months. Implantation of a vagus nerve stimulator requires an important financial investment but a cost-benefit analysis has not been published.  Patients and Methods. Our own experience with VNS in Gent comprises 15 patients with mean age of 29 years (range: 17–44 years) and mean duration of epilepsy of 18 years (range: 4–32 years). All patients underwent a comprehensive presurgical evaluation and were found not to be suitable candidates for resective epilepsy surgery. Mean post-implantation follow-up is 24 months (range: 7–43 months). In patients with follow-up of at least one year, efficacy of treatment in terms of seizure control and seizure severity was assessed one year before and after the implantation of a vagus nerve stimulator. Epilepsy-related direct medical costs (ERDMC) before and after the implantation were also compared.  Results. A mean reduction of seizure frequency from 14 seizures/month (range: 2–40/month) to 8 seizures/month (range: 0–30/month) was achieved (Wilcoxon signed rank test n=14; p=0.0016). Five patients showed a marked seizure reduction of ≥50%; 6 became free of complex partial seizures, 3 of whom became entirely seizure free for more than 12 months; 2 patients had a worthwhile reduction of seizure frequency between 30–50%; in 2 patients seizure frequency reduction has remained practically unchanged. Seizure freedom or ≥50% seizure reduction was achieved within the first 4 months after implantation in 6/11 patients. Before the implantation, the mean yearly epilepsy-related direct medical costs per patient were estimated to be 8830US$ (n=13; range: 1879–31129US$; sd=7667); the average number of hospital admission days per year was 21 (range: 4–100; sd=25.7). In the 12 months after implantation, ERDMC had decreased to 4215US$ (range: 615–11794US$; sd=3558) (Wilcoxon signed rank test n=13; p=0.018) and the average number of admission days to 8 (range: 0–35) (Wilcoxon signed rank test n=13; p=0.023).  Conclusion. VNS is an effective treatment of refractory epilepsy and remains effective during long-term follow-up. Cost-benefit analysis suggests that the cost of VNS is saved within two years following implantation.     

Long-term multicenter experience with vagus nerve stimulation for intractable partial seizures: results of the XE5 trial

OBJECTIVE: Intermittent stimulation of the left cervical vagus nerve trunk (VNS) with the NeuroCybernetic Prosthesis (NCP) is emerging as a novel adjunct in the management of medically refractory epilepsy. We review the safety and efficacy of VNS 1 year after completion of the E05 study, the largest controlled clinical trial of VNS to date. METHODS: One hundred and ninety-nine patients with intractable epilepsy and at least 6 complex partial or secondarily generalized seizures per month enrolled in a randomized, double-blinded, partial crossover trial of high versus low parameters of stimulation (E05). After 3 months, all patients received high stimulation during an open-label, nonblinded extension trial (XE5). Seizure frequency, adverse events and multiple physiologic variables were monitored at regular intervals. RESULTS: At 3 months, the mean reduction in seizure frequency among patients receiving high stimulation during E05 was 28%. Of the 199 subjects participating in this acute-phase trial, 195 continued in the long-term protocol. Among the latter patients, 21 subsequently exited the study due to lack of efficacy, and 2 others died from causes unrelated to VNS. Complete data were obtained for 164 of the remaining subjects. Using a declining N analysis, the mean and median reduction in seizure frequency at 15 months was 37 and 45%, respectively. A last visit carried forward analysis, which controls for dropouts and incomplete follow-up, yielded comparable results (34 and 45%, respectively), indicating little potential for selection bias. At 15 months, 39% of the subjects had a greater than 50% reduction in seizures, including 21% who had a greater than 75% reduction, and 2% have remained seizure free. Few serious adverse events, physiological perturbation or device failures were reported. CONCLUSIONS: The long-term multicenter safety, efficacy, feasibility and tolerability of VNS, as well as the durability of the NCP device have been confirmed. Unlike chronic therapy with antiepileptic medication, the efficacy of VNS is maintained during prolonged stimulation, and overall seizure control continues to improve with time.     

Electrical Stimulation in Epilepsy: Vagus Nerve and Brain Stimulation

Vagus nerve stimulation (VNS) for epilepsy is a well established and effective treatment for medically intractable epilepsy. VNS is indicated if resective epilepsy surgery is unsuccessful or is not an option. About 50% of patients with VNS have a seizure reduction greater than 50%, but less than 10% become seizure-free. VNS also has an alerting effect on patients and may allow a reduction in sedating medications. The major adverse event is hoarseness, but treatment is generally well tolerated. The therapeutic effect can be delayed: patients may improve several months after VNS implantation. Direct brain stimulation (DBS) is an emerging treatment for epilepsy. Scheduled stimulation is similar to brain stimulation in Parkinson’s disease. Only the anterior thalamic nucleus has been studied in a larger randomized, controlled trial, in which patients with the stimulator turned on had a significantly reduced seizure frequency. Responsive stimulation applies an electrical stimulus at the site of seizure onset to terminate the seizure if one occurs. The seizure-onset zone must be well defined before implantation. Responsive stimulation requires seizure detection and application of a stimulus online. A large pivotal trial showed a significant reduction in seizure frequency. Both DBS and responsive neurostimulation are well tolerated, but there has been some concern about depression with DBS. Infection, hemorrhage, and lead breakage are adverse events possible with any type of stimulator. None of the brain stimulation devices have been approved by the US Food and Drug Administration, but final approval is expected soon. These devices are indicated for patients with bilateral seizure onset or seizure onset in eloquent areas. Although the initial trials of brain stimulation do not show overwhelming improvement in seizure frequency, the technology will improve with time as we continue to learn about the use of brain stimulation for epilepsy. Optimization of VNS has been going on for 10 years, and we need to ensure that brain stimulation is similarly developed further. In addition, sophisticated devices such as responsive neurostimulators can greatly enhance our understanding of the pathophysiology of epilepsy.     

Vagus nerve stimulation in pediatric patients with intractable epilepsy: case series and operative technique

Patients with epilepsy refractory to medical therapy or who experience intolerable side effects from the medication may benefit from placement and activation of a vagus nerve stimulator (VNS) (Cyberonics, Houston, TX). We present our experience with the VNS implanted by a pediatric surgeon and its activation managed by a pediatric neurologist. Six patients (one male and five females) with average age 11 years, 10 months (range 7 years, 4 months to 18 years, 1 month) received VNS implants at a community-based teaching hospital. One patient developed a self-inflicted wound complication secondary to persistent trauma at the implant site that led to removal of the implant. Before VNS implantation the frequency of seizures among the remaining five patients averaged 73 per patient per month (range 20-165). Length of follow-up averaged 6.5 months (range 1.5-11 months). At most recent follow-up seizure frequency averaged 14 per month (range 1-42); this represents an average reduction of 78 per cent (range 30-99%). We conclude that a pediatric surgeon with pediatric neurologic support can safely and effectively perform the VNS implantation at a hospital equipped to administer anesthesia to pediatric patients.     

Cerebral cavernomas, epilepsy and seizures. Natural history and therapeutic strategy

PURPOSE: To review, from a retrospective series of 48 patients presenting with seizures associated with one or more supratentorial cavernoma(s), the natural history of the seizures and outcome according to medical and surgical treatment. METHODS: Patients were divided into two groups: group A included patients presenting with a single seizure or rare seizures (n=21), and group B patients having intractable epilepsy (n=27). All received antiepileptic drugs and 35 were operated on (12 in the group A and 23 in the group B). Stereo-EEG was performed in 8 patients in group B. Surgery included lesionectomy alone (n=16), resection of the cavernoma and perilesional tissue (n=7) or tailored corticectomy including the cavernoma (n=12). RESULTS: The natural history of seizures was different in the two groups: mean age at seizure onset was 25 years in group B and 33 years in group A (p<0.05), seizures were partial in all patients in group B and 8 patients in group A (p<0.05). Seizure frequency and periodicity also varied. Prolonged seizure-free periods were observed. The cavernoma was temporal in 17 patients in group B and 4 patients in group A (p<0.01). In group A, seizure outcome was favorable following surgery or with antiepileptic medication only (7 patients out of 12 operated were seizure-free, as were 5 out of 7 non-operated). In group B, seizure outcome was better after surgery than with medication only (17 patients out of 23 operated were in Engel's Class I, while 3 patients of 4 non-operated patients had persisting seizures despite antiepileptic polytherapy). CONCLUSION: Variations in seizure severity in patients harboring cavernomas suggest different therapeutic approaches. In case of unique or rare seizures, surgical resection of the cavernoma is appropriate, but benefits of surgery over antiepileptic medication in terms of seizure control remains unclear. Intractable epilepsy associated with cavernomas is better controlled after surgery rather than with medication only. In these patients, a detailed preoperative work-up is necessary and should be followed by wide resection associated or not with corticectomy, especially in the temporal lobe. Evaluation of outcome after surgery should consider the surgical strategy, antiepileptic medications and the patient's seizure history.     

Vagus Nerve Stimulation Therapy: Indications,Programing, and Outcomes

Vagus nerve stimulation (VNS) provides palliation of seizure reduction for patients with medically refractory epilepsy. VNS is indicated for symptomatic localization-related epilepsy with multiple and bilateral independent foci, symptomatic generalized epilepsy with diffuse epileptogenic abnormalities, refractory idiopathic generalized epilepsy, failed intracranial epilepsy surgery, and other several reasons of contraindications to epilepsy surgery. Programing of the parameters is a principal part in VNS. Output current and duty cycle should be adjusted to higher settings particularly when a patient does not respond to the initial setting, since the pivotal randomized trials performed in the United States demonstrated high stimulation made better responses in seizure frequency. These trials revealed that a ≥ 50% seizure reduction occurred in 36.8% of patients at 1 year, in 43.2% at 2 years, and in 42.7% at 3 years in 440 patients. Safety of VNS was also confirmed because side effects including hoarseness, throat discomfort, cough, paresthesia, and headache improved progressively during the period of 3 years. The largest retrospective study with 436 patients demonstrated the mean seizure reduction of 55.8% in nearly 5 years, and also found 75.5% at 10 years in 65 consecutive patients. The intermediate analysis report of the Japan VNS Registry showed that 60% of 164 cases got a ≥ 50% seizure reduction in 12 months. In addition to seizure reduction, VNS has positive effects in mood and improves energy level, memory difficulties, social aspects, and fear of seizures. VNS is an effective and safe option for patients who are not suitable candidates for intracranial epilepsy surgery.     

Vagus nerve stimulation (VNS) is effective in treating catastrophic 1 epilepsy in very young children

The objective of this study is to evaluate the safety and efficacy of vagus nerve stimulation (VNS) in very young children suffering from catastrophic epilepsy and status epilepticus. We reviewed files of 60 VNS-implanted children at our institution and we selected six very young patients, less than 3 years old (mean age at implant 1.6 years). All patients suffered from severe cognitive impairment and catastrophic epilepsy with underlying diagnosis of hemimegalencephaly (1), hypoxic-ischemic encephalopathy (1), tuberous sclerosis complex (1), and malignant migrating partial epilepsy of infancy (3). Three patients were VNS-implanted during admission at intensive care unit (ICU) after developing life-threatening status epilepticus. The mean follow-up time was 41.6 months. The VNS was implanted using a single cervical incision. No surgery-related complications were observed. Four of six children have shown a significant, persistent improvement in seizure control (range, 60-90%). In patients with status, insertion of the vagal nerve stimulator allowed early cessation of status and discharge from ICU. Quality of life and parental satisfaction improved and for three children there was some milestone evolution. Catastrophic epilepsy in infancy can be devastating and difficult to treat with drugs and surgery. If resective surgery is inappropriate or refused, VNS can be considered as a well-tolerated and effective procedure even in toddlers affected by severe epilepsy and multiple developmental disabilities.     

Hardware failure in vagus nerve stimulation therapy

Summary A 20 year old male patient who had been successfully treated for epilepsy with vagus nerve stimulation (VNS) for 7 years (50% seizure frequency reduction), had experienced multiple episodes of severe hoarseness, throat pain and impaired breathing during physical exercise. As malfunctioning of the pulse generator was suspected, it was decided to replace the device. During surgery, the pulse generator was found to have broken in two, due to an unstable connection between the battery subunit and the connector subunit. With a new pulse generator seizure frequency reduction was restored. No side effects occurred. Correspondence: Kim Rijkers, M.D., Department of Neurosurgery, Maastricht University Hospital, PO BOX 5800, 6202 AZ Maastricht, The Netherlands.     

Vagus nerve stimulation for epilepsy: a meta-analysis of efficacy and predictors of response

Vagus nerve stimulation (VNS) was approved by the US FDA in 1997 as an adjunctive treatment for medically refractory epilepsy. It is considered for use in patients who are poor candidates for resection or those in whom resection has failed. However, disagreement regarding the utility of VNS in epilepsy continues because of the variability in benefit reported across clinical studies. Moreover, although VNS was approved only for adults and adolescents with partial epilepsy, its efficacy in children and in patients with generalized epilepsy remains unclear. The authors performed the first meta-analysis of VNS efficacy in epilepsy, identifying 74 clinical studies with 3321 patients suffering from intractable epilepsy. These studies included 3 blinded, randomized controlled trials (Class I evidence); 2 nonblinded, randomized controlled trials (Class II evidence); 10 prospective studies (Class III evidence); and numerous retrospective studies. After VNS, seizure frequency was reduced by an average of 45%, with a 36% reduction in seizures at 3-12 months after surgery and a 51% reduction after > 1 year of therapy. At the last follow-up, seizures were reduced by 50% or more in approximately 50% of the patients, and VNS predicted a ≥ 50% reduction in seizures with a main effects OR of 1.83 (95% CI 1.80-1.86). Patients with generalized epilepsy and children benefited significantly from VNS despite their exclusion from initial approval of the device. Furthermore, posttraumatic epilepsy and tuberous sclerosis were positive predictors of a favorable outcome. In conclusion, VNS is an effective and relatively safe adjunctive therapy in patients with medically refractory epilepsy not amenable to resection. However, it is important to recognize that complete seizure freedom is rarely achieved using VNS and that a quarter of patients do not receive any benefit from therapy.     

Insertion of vagal nerve stimulator using local and regional anesthesia

BACKGROUND: Vagal nerve stimulation (VNS) is a valuable therapy for patients with intractable epilepsy. Placement of a vagal nerve stimulator typically requires general anesthesia, which frequently interrupts anticonvulsant therapy. Insertion of the stimulator using regional/local anesthesia may offer the advantages of continuity of anticonvulsant therapy and implantation in the outpatient setting. METHODS: We retrospectively compared the first 10 consecutive patients undergoing VNS implantation under general anesthesia with the first 12 consecutive patients undergoing VNS implantation under regional/local anesthesia. Patients for the regional/local anesthesia were selected on the basis of their ability to cooperate and follow commands. Regional anesthesia for implantation of the VNS leads was achieved by performing superficial and deep cervical plexus blocks. A local anesthetic field block of a small area of the posterior chest provided anesthesia for insertion of the generator. RESULTS: All of the patients undergoing regional/local anesthesia completed the procedure without difficulty and on an outpatient basis. None complained of discomfort, sedation, nausea, or vomiting and none had seizures in the perioperative period. These results contrasted with the group that underwent general anesthesia (n = 10), who had an 80% incidence of nausea and vomiting and a 30% incidence of postoperative seizures. CONCLUSION: VNS implantation under regional/local anesthesia is proficiently performed as an outpatient procedure with minimal postoperative side effects.     

Optimal Vagus Nerve Stimulation Frequency for Suppression of Spike‐and‐Wave Seizures in Rats

Vagus nerve stimulation (VNS) is used as an adjunctive therapy for drug‐resistant epilepsy and results in a 50% seizure reduction in up to 50% of treated patients. The VNS frequency used in the clinic today is in the range of 10–30 Hz. The evidence for choosing the stimulation frequency is limited, and little knowledge is available on the effect of other VNS frequencies. Deep brain, trigeminal nerve, or spinal cord stimulation studies have suggested the use of stimulation frequencies above 80 Hz for seizure control. Therefore, our objective for the present study was to investigate if VNS using frequencies higher than those currently used in the clinic could be more effective in attenuating seizures. Spike‐and‐wave (SW) discharges were induced in 11 rats, which then were subjected to VNS sessions applied at the frequencies of 10, 30, 80, 130, and 180 Hz combined with control intervals without stimulation. The anticonvulsive effect of VNS was evaluated by comparing the normalized mean power (nMP) and frequency (nMSF) of the SW discharges derived from intracortical recordings collected during the stimulation and control intervals. Compared with the control intervals, all the tested VNS frequencies significantly reduced the nMP (in the range of 9–21%). However, we found that 130 and 180 Hz VNS induced a 50% larger attenuation of seizures than that achieved by 30 Hz VNS. In addition, we found that 80, 130, and 180 Hz VNS induced a significant reduction of the nMSF, that is by 5, 7, and 8%, respectively. These results suggest that a VNS stimulation frequency in the range of 130–180 Hz may be more effective in inhibiting seizures than the 30 Hz VNS applied in the clinic today.     

Outcome of long-term vagus nerve stimulation for intractable epilepsy

The outcome of long-term vagus nerve stimulation (VNS) was evaluated in 13 Japanese patients with intractable epilepsy, all followed up for more than 4 years (48-91 months, median 56 months). VNS achieved a long-lasting and cumulative seizure-control effect in nine of 13 patients. The mean reduction of seizure frequency in the 1st to 4th year was 28%, 47%, 54%, and 63%, respectively. The percentage of patients with >60% seizure reduction in the 1st to 4th year was 15%, 46%, 54%, and 69%, respectively. One patient did not respond to the treatment at all. No patient became completely free from seizure or free from medication, but the number and/or dosage of antiepileptic drugs was reduced in five patients. Ten patients underwent exchange of the generator and continued treatment, and two patients underwent removal of the generator because of the unsatisfactory result. VNS controlled more disabling seizures earlier and more efficiently than less disabling seizures in seven patients. The cumulative reduction of seizures was partly associated with changes in the device setting toward increased stimulation. These effects were similar in patients with or without previous resective surgery. Long-term VNS therapy achieved a favorable outcome in a significant proportion of patients with intractable epilepsy.     

Seizures after carotid endarterectomy: hyperperfusion, dysautoregulation or hypertensive encephalopathy?

OBJECTIVES: Presentation, management and outcome following seizure after carotid endarterectomy (CEA). MATERIALS AND DESIGN: Prospective audit. RESULTS: Eight patients (0.8%) suffered a seizure (three bilateral) <30 days following 949 CEAs. Seizure was not associated with age, gender or presentation. Seven were treated hypertensives but four had labile BP pre-operatively. Five had severe bilateral carotid disease and four had vertebral/subclavian stenoses. Six had a >50% drop in middle cerebral artery blood flow velocity (MCAV) with clamping. Only three had >100% increase in MCAV with flow restoration. Five required treatment for post-operative hypertension. Two suffered seizures <36 hrs of CEA, the remainder were at 3-8 days. All eight had significantly elevated blood pressure at onset of seizures. Four underwent immediate MCAV monitoring and each was elevated. Emergency CT scanning/autopsy showed normal scans (n = 3), white matter oedema (n = 3), oedema and diffuse haemorrhage (n = 1), intracranial haemorrhage (n = 1). Seven developed a post-ictal neurological deficit (stroke = 5, TIA = 2). Overall, two patients either died or suffered a disabling stroke. CONCLUSIONS: Post-CEA seizure was associated with adverse outcome. Most were labile hypertensives with severe bilateral carotid/vertebral disease. MCAV changes suggested poor collateral recruitment, but no consistent pattern of early hyperperfusion emerged. It remains uncertain whether high MCAVs and severe hypertension after seizure onset are cause or effect. Clinicians treating these patients in acute medical units were generally unaware of the "post-CEA hyperperfusion syndrome" and tended to treat the hypertension less aggressively.     

Sirolimus (rapamycin) for the treatment of steroid-refractory acute graft-versus-host disease.

BACKGROUND: In a pilot trial we evaluated the toxicity and efficacy of sirolimus (rapamycin) as second-line therapy for the treatment of acute graft-versus-host disease (GVHD) in 21 patients (1-46 years of age) after allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: All patients were treated with methylprednisolone at 2 mg/kg/day, but failed to respond satisfactorily. Sirolimus was started 19-78 (median 37) days after HSCT when 10 patients had grade III and 11 had grade IV GVHD. The first four patients received a loading dose (15 mg/m2) of oral sirolimus on day 1 followed by 5 mg/m2/day for 13 days. The next 17 patients received either 5 (n=7) or 4 (n=10) mg/m2/day for 14 days without a loading dose. Eleven patients completed the 14-day sirolimus course. Five patients were treated for 9-13 days, two for 6 days, and three for 1-3 days. RESULTS: Sirolimus was discontinued early in 10 patients because of lack of improvement in GVHD (n=5), myelosuppression (n=2), seizure (n=2), and attending physician preference (n=1). The most common and significant adverse events were thrombocytopenia (n=7) and neutropenia (n=4). Other side effects included increased blood triglycerides (n=8) and cholesterol (n=3). Five patients had evidence of a hemolytic uremic syndrome concurrently with or after sirolimus treatment. Eighteen of the 21 patients received 6 or more doses of sirolimus and 12 responded, 5 with complete and 7 with partial responses. Six of the 12 responders (28% of all patients enrolled) and 1 nonresponder are currently alive at 400-907 days after HSCT, 3 with chronic GVHD. Fourteen of the 21 patients (66%) died 40-263 days after transplant. CONCLUSION: These data suggest that sirolimus has activity in the treatment of steroid-refractory acute GVHD. However, there was considerable toxicity and further dose optimization studies seem warranted.     

Application of spectral analysis of the heart rhythm variability for estimation of the autonomic nervous system state in patients with ulcer disease

In 57 patients with ulcer disease the spectral analysis of the heart rhythm variability (HRV) was conducted for estimation of the vegetative nervous system (VNS) state. In 66.7% of patients there was noted prevalence of the parasympathetic part of VNS tone, in 14.0% - sympathetic one. Dystonic activity of various parts of VNS had accompanied by raising of definite mediators (markers) of VNS: acetylcholine (r = 0.75), adrenaline and noradrenaline (r = 0.25), complicated course of ulcer disease. Sympathicotonia was associated with ulcerative hemorrhage (r = 0.5), vagotonia with perforation of the ulcer (r = 0.75). So, choosing the surgical intervention volume in patients with the ulcer disease it is expedient to apply the method of spectral analysis of HRV for estimation of the VNS state.     

Strategies for reoperation after comprehensive epilepsy surgery

OBJECT: Prior reports of seizure control following reoperation for failed epilepsy surgery have shown good results. These studies included patients who presented during the era preceding magnetic resonance (MR) imaging, and the patients were often not monitored intracranially or underwent subtotal hippocampal resections. In this study, the authors hypothesized that reoperation for recurrent seizures following a more comprehensive initial workup and surgery would not yield such good results. METHODS: The authors examined a consecutive series of patients who underwent two operations at Yale-New Haven Hospital for medically intractable epilepsy and in whom there was a minimum of 1-year follow up after the second surgery. All patients were evaluated and treated according to a standard protocol, including preoperative MR imaging, a low threshold for invasive monitoring, and a radical amygdalohippocampectomy when indicated. Twenty-seven patients were identified (five with mesial temporal sclerosis, 20 with neocortical disease, and two with multifocal sites of seizure onset) of whom six (22%) underwent intentionally palliative second surgery (corpus callostomy or placement of a vagus nerve stimulator [VNS]). Of the remaining 21 patients, only four (19%) became seizure free after a second resective operation. The most common causes of treatment failure were dual pathology, recurrent tumor, limited resection to preserve function, widespread developmental abnormalities, and electrographic sampling error. Successful outcomes resulted from removal of recurrent tumors, completion of a functional hemispherectomy, or repeated invasive monitoring to correct a sampling error. Five (83%) of the six intentionally palliative second operations resulted in more than a 50% decrease in seizure frequency. CONCLUSIONS: If an aggressive preoperative evaluation and surgical resection are performed, reoperation for recurrent seizures has a much lower likelihood of cure than previously reported. Intentionally palliative surgery such as placement of a VNS unit may be considered for patients in whom the initial operation fails to decrease seizure frequency.