M. Fedor. Western Carolina University.

Changing the paradigm ing with drug-resistant partial epilepsy (radiosurgery included)] buy on line fertomid. Rev Neurolog of 1-stage total callosotomy for the treatment of pediatric generalized epilepsy purchase fertomid on line. Long-term seizure surgery for callosotomy in children with drug-resistant epilepsy buy discount fertomid 50 mg line. Child Nerv Syst outcome afer corpus callosotomy: a retrospective analysis of 95 patients order fertomid now. Efect of corpus callosotomy on atten- for treatment of refractory secondarily generalized epilepsy in patients with Len- tion defcit and behavioral problems in pediatric patients with intractable epilepsy. Corpus callosotomy intractable epilepsy using frameless stereotactic neuronavigation: 12-year experi- is a valuable therapeutic option for patients with Lennox-Gastaut syndrome and ence at the Hospital for Sick Children in Toronto. Corpus callosotomy for control of nerve stimulation in children with Lennox-Gastaut syndrome. Neurology 1988; 38: safety of anterior corpus callosotomy with keyhole in refractory seizures. Anterior corpus callosotomy in patients with in- Epilepsy and the Corpus Callosum, 2nd edn. New York: Plenum Press, 1995: 183– tractable generalized epilepsy and mental retardation. Corpus callosotomy in multistage epilepsy ispheric integration: insights from experiments with commissurotomy patients. Outcome of cor- vations following partial and complete section of the corpus callosum in man. J Neurosurg lesions afecting the third ventricle: surgical considerations and consequences. Intraoperative determination of the extent of partial callosotomy in patients with secondary generalized epilepsies. Efect of anterior callosotomy on sotomy in the management of refractory generalized epilepsy. Munch Med Wochenschr 1966; 108: 1707– tal lobe epilepsy: characteristics and surgical management. Surgical treatment of delayed knife radiosurgery for a case of intractable generalised epilepsy. Neurosurgery 1997; 41: 1–9; consequences of partial and complete cerebral commissurotomy. Dissociation of language and cognition: a psychological went callosotomy for drug-resistant epilepsy. Some contributions of the split-brain studies to the study of human 1974; 97: 263–272. Tere are no recognized ethnic Clinical features or geographical predilections, although several studies have shown Even within the intrahypothalamic subtype, variability in severity a slightly higher incidence in males [3,4,5]. Early surgical reports localized pathological laughter to those providing care to this population. Tey are usually brief, lasting less than 30 s, ofen other brain structures, usually within the limbic system [10,11], 5–10 s. Tese include ev- Superfcially resembling laughter, patients generally do not expe- idence of other treatment-resistant seizure types and cognitive rience mirth, and most family members can readily distinguish impairment. The latter can be progressive in approximately 50% gelastic seizures from true laughter. Not uncommonly, patients may of patients whose seizures become evident during infancy [12,13]. Gelastic seizures can be with abnormal regulation of mood and self-control, which for some quite subtle. A purely subjective sensation, described as stereotypi- can be the most disabling trait of the disease [14]. This subtype is referred to as the in- In retrospect, parents can identify the onset of peculiar laughing trahypothalamic (or sessile) subtype (Figure 71. The frequency of gelastic seizures The second subtype, known as parahypothalamic or pedunculated decreases as the frst decade of life progresses, and in some cases (Figure 71. The patient is a 9-year-old boy with refractory epilepsy, including multiple daily gelastic seizures. The patient is a 6-year-old girl with central precocious puberty and gelastic seizures. Note that this lesion has a broad base of attachment to the hypothalamus, in comparison to other parahypothalamic lesions that are attached by a narrow pedicle, and are not associated with epilepsy. Functional studies implicate spread to gelastic seizures deserves special note [28]. Specifcally, ictal record- the thalamus via the mammilothalamic tract and then to cingulate ings using conventional electrode placement over the scalp may gyrus and distributed regions of neocortex [33,36,39,40,41]. As a result, these records may be interpreted as normal, and gelastic events may Other seizure types be mistakenly attributed to non-epileptic causes. The age at which other seizures be- den decrease in interictal spike transients, for example), or ictal ac- come symptomatic varies, but is most likely to occur between 4 and tivity may falsely localize to cortical regions, usually with temporal 10 years of age [12]. Conversely, patients with parahypo- when gelastic seizures are the only seizure type [22,25,26,28]. Tese problems can be disabling, and ofen represent spike or spike–wave fndings in 47%, multifocal independent spikes the most signifcant day-to-day problem for the family. Mood labil- in 18% and focal spikes (most frequently over the temporal regions) ity and rage attacks are the most frequent and disabling symptoms. Tese seizures may or may not have a clinical- Tere is a strong association between refractory epilepsy, cog- ly apparent gelastic component at onset. With time, however, usually over a period of years, the second focus becomes permanently independent and removal of the orig- Pallister–Hall syndrome inal lesion no longer infuences the secondary seizure focus. With or without the cognitive deterioration noted above, cogni- Antiepilepsy drugs tive impairment is evident in more that 80% of patients with int- Tere is broad consensus in the literature on the lack of efcacy rahypothalamic subtype [25,43,63]. Tere is no evidence for superior efcacy for also been identifed as a treatment option. Of these, four had 50–90% reduction in total seizure fre- (intrahypothalamic versus parahypothalamic subtypes). Currently, pus callosotomy have been reported with universally disappointing our preference is to utilize the classifcation proposed by Delalande outcomes [46,62,86]. A controlled trial has established attached to the inferior (horizontal) surface of the hypothalamus. Tese lesions are best resected or disconnected through a pte- various targets within the limbic circuit, but with mixed success rional approach, or one of its modifcations, in which the lesion is [36,62,88,89,90]. How- are ofen approachable with stereotactic thermoablation or treat- ever, some of these patients also had epilepsy as a comorbid prob- able with gamma knife radiosurgery. Type I lesions have a horizontal base of attachment, below the normal position of the foor of the third ventricle. If attached by a narrow stalk to the tuber cinereum, they result in central precocious puberty, whereas more posterior attachment to the region of the mammillary bodies results in epilepsy. Consequently, these lesions have both vertical and horizontal planes of attachment. Pterional approach to hypothalamic hamartoma lesions base of attachment within the third ventricle. However, a ventral or inferior approach is All patients had multiple seizure types, including gelastic seizures. With at least 1 year of majority of patients (55%) developed mild, asymptomatic postop- follow-up, 40% are completely seizure-free (including 66% of those erative hypernatraemia, but none had persistent disturbances of fu- with 100% hypothalamic hamartoma resection). Five patients (17%) required thyroid are at least 50% improved in seizure frequency (see Table 71. Disconnection strategy Lesion safe for No Yes Lesion safe for No Lesion safe for Individualize is appropriate. This approach is utilized at our institution (Barrow Neurological Institute) as a guide to treatment decision making. The algorithm was developed on the basis of expert opinion and the available literature as discussed in this chapter. Decision making should always be individualized to the clinical circumstances of each patient and the experience of the local institution.

Perinephric Hematoma Description: A perinephric hematoma is a collection of blood that is confined to Gerota fascia (i cheap fertomid 50 mg line. It is common for a hemorrhage to occur in the perinephrotic space following a renal biopsy generic 50 mg fertomid amex. Signs and Symptoms: Depending on the extent of the injury and time to treatment order on line fertomid, patients may present with abdominal pain generic fertomid 50 mg, an open wound, signs of internal bleeding with blood in the urine, increased heart rate, declining blood pressure, and hypovolemic shock, nausea and vomiting, decreased alertness, and moist clammy skin. Treatment: Surgical intervention may be required in emergent situations for the hemodynamically unstable patient. Conservative treatment for the stable patient may include bed rest, analgesics, and patient monitoring. Prognosis: Depends on the extent of the injury, patient response to treatment, and any other associated injuries. These cysts cause lobulated enlargements of the kidneys that result in cystic compression and progressive failure of the renal tissue. Etiology: Adult polycystic kidney disease is a hereditary (autosomal dominant) disorder. Signs and Symptoms: Patients may present with hypertension, hematuria, palpable kidneys, hepatomegaly, abdominal pain, and flank pain. Treatment is aimed at preserving renal parenchyma and preventing infectious complications. Progressive renal failure requires treatment such as dialysis or, rarely, kidney transplant. Axial (A) and coronal (B) T2W images show enlarged kidneys which are nearly replaced with cysts. Pyelonephritis Description: Pyelonephritis is an inflammation of the kidney and renal pelvis. T1-weighted fat-suppression images may show proteinaceous material in the renal tubules as high-signal substance. Treatment: All symptoms usually resolve within 72 hours following administration of the appropriate antibiotic therapy. Renal Artery Stenosis Description: the most common cause of correctable hypertension is stenosis of the renal artery. Hypertension of the renal artery can occur as a result of either atherosclerosis or fibromuscular dysplasia. Etiology: Results from the accumulation of atherosclerotic plaques or fibromuscular dysplasia in the renal artery. Fibromuscular dysplasia causes a beading (string of pearls) appearance and involves the distal two-thirds of the renal artery as well as other peripheral branches. Treatment: Methods of treatment include angioplasty, stenting, and surgical revascularization. Renal Calculus Description: Renal calculi (kidney stones) may form anywhere throughout the urinary tract. Etiology: the exact cause is unknown; however, predisposing factors include dehydration (increased concentration of calculus-forming substances), infection (changes in pH), obstruction (urinary stasis, such as may be seen in spinal cord injuries), metabolic disorders (e. Epidemiology: Renal calculi result in roughly 1 per 1000 hospitalizations annually. Signs and Symptoms: Patients may present with back pain (renal colic), pain radiating into groin area, hematuria, dysuria, polyuria, chills, and fever associated with infection due to obstruction, nausea, vomiting, diarrhea, abdominal distention, and costovertebral angle tenderness. Treatment: Treatment includes pain management, fluid management, straining urine for urine analysis and stone collection, and extracorporeal shock wave lithotripsy. Prognosis: A good prognosis is expected with complete return to the patient’s previous state of health. Etiology: the cause of renal cell carcinoma is unknown; however, it is known to arise from the proximal convoluted tubule. Epidemiology: Approximately 30,000 new cases are diagnosed annually with about 12,000 deaths. The average age of occurrence appears between the fifth and sixth decades of life. Signs and Symptoms: Patients may present with a solid renal mass (6 to 7 cm), hematuria, abdominal mass, anemia, flank pain, hypertension, and weight loss. Postcontrast T1-weighted images appear hyperintense with heterogeneous enhancement. Treatment: Surgical removal of the kidney (nephrectomy) when the cancer is confined to only one kidney. Postcontrast axial T1W image shows enhancement of the solid portions of the left renal mass. T2W image shows areas of increased signal in the mass consistent with central necrosis of the renal cell carcinoma. Renal Infarct Description: A renal infarct is a localized area of necrosis in the kidney. Etiology: An acute infarct of the kidney may follow a thromboembolic (most common), renal artery occlusion (due to atherosclerosis), blunt abdominal trauma, or a sudden, complete renal venous occlusion. Epidemiology: the most common cause of renal emboli occurs in patients with atrial arrhythmias or patients who have a history of a myocardial 362 infarction. In addition, patients who have experienced blunt abdominal trauma may develop renal emboli. Signs and Symptoms: This condition may go unnoticed; however, some patients may experience pain with tenderness in the region of the costovertebral angle of the affected side. Convention renal arteriogram is the gold standard for the evaluation of an occlusion of renal artery or its branches. T1-weighted postcontrast images demonstrate a wedge-shaped low- signal area of the renal parenchyma. Wilm Tumor Description: the most common type of renal cancer in children and the fifth most common cancer affecting children is a Wilm tumor. Wilm tumor may also be called nephroblastoma (a malignant tumor arising from the 364 embryonic kidney). About 80% of this tumor presents between 1 and 5 years of age, with the peak age at the time of diagnosis between 3 and 4 years old. Hypertension, hematuria, and anemia are other signs and symptoms associated with Wilm tumor. Imaging Characteristics: Ultrasound initial modality of choice, especially for pediatric patients and radiation dose. Helpful in staging and metastatic spread (lung metastases are more frequently involved than the liver). Prognosis: With appropriate therapy and early detection, a good outcome is expected. Epidemiology: Appendicitis can occur at any age and affects males and females equally. Signs and Symptoms: Patient may present with abdominal pain or tenderness in the right lower quadrant (McBurney point), anorexia, nausea and vomiting, and constipation. If the appendix ruptures, there is a variable degree of morbidity and mortality based on the age of the patient. Diverticulitis is an abscess or inflammation initiated by the rupture of the diverticula into the pericolic fat. About 40% to 50% of the general population is affected by the time they reach their sixth to eighth decades of life. When considering diverticulitis, in addition to the above, patients will experience fever with chills, anorexia, nausea and vomiting, and tenderness in the left lower quadrant. Prognosis: With early detection and treatment the patient should experience a good recovery. Perinephric Abscess 370 Description: A perinephric abscess is a collection of pus within the fatty tissue around the kidney. Epidemiology: Perinephric abscesses usually arise from a preexisting renal inflammatory disease. However, they may occur as a result of complication of surgery and trauma, or spread from other organs.

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Seizure freedom across all seizure the frequency of all focal seizures in patients taking concomitant types for perampanel versus placebo was 23 order 50 mg fertomid with mastercard. The adverse Extension open label studies and additional events most frequently reported with perampanel versus placebo observational studies were dizziness (32 cheap fertomid line. Patients were titrated to 12 mg/day (or their indi- adverse events order fertomid 50mg without prescription, including two deaths [accidental drowning (per- vidual maximally tolerated dose) during the blinded conversion ampanel) and sudden unexpected death in epilepsy (placebo)] buy 50 mg fertomid. Afer perampanel titration or conversion, re- consistent with previous observations. Median percentage reduc- tion in frequency of secondary generalized seizures ranged from Overview of the tolerability and safety profle 77% at 9 months (n = 422) to 90% at 2 years (n = 141). Among the Safety and tolerability data of perampanel during clinical tri- 694 patients with maintenance data exceeding 12 months, 5. Only the 16% and 18% for 4, 8 and 12 mg/day, versus 7% for placebo), fatigue published data are discussed in this chapter. In a multicentre survey (8%, 8% and 12% for 4, 8 and 12 mg/day, versus 5% for placebo), of clinical experiences with perampanel in Germany and Austria irritability (4%, 7% and 12% for 4, 8 and 12 mg/day, versus 3% for [27], 169 out of 281 recruited patients were still taking the drug placebo), nausea (3%, 6% and 8% for 4, 8 and 12 mg/day, versus afer 6 months’ treatment (60% retention rate). Overall, 43 patients 5% for placebo) and falls (2%, 5% and 10% for 4, 8 and 12 mg/day, (15%) remained seizure-free for the preceding 3 months. Adverse events reported in 75% of patients continuing in the perampanel doses ranged from 4 to 14 mg/day (mean 8. Comparing the last 3 months of observation with baseline, 34 day, versus 9% for placebo), somnolence (9%, 16% and 18% for 4, 8 patients (46%) were responders, with 10 (14%) being seizure-free. Weight In a multicentre, double-blind trial, patients > 12 years with pri- increase >7% was observed in 14. Perampanel 553 Adverse events in the long-term extension study reported in history of psychiatric illness. Of the 12 patients who developed ag- >10% included dizziness, somnolence, headache, fatigue, irrita- gression, seven withdrew from the study, one responded to dosage bility and weight gain [26]. No clinically relevant changes in vital signs, electrocardio- In the core phase 3 perampanel studies, 143 adolescents gram or laboratory parameters were reported. Al- (8%) in the perampanel group versus none randomized to placebo most 4000 patients had been recruited, 2627 of whom were rand- [34]. No serious adverse events with term efect of adjunctive perampanel (2–12 mg/day) versus placebo perampanel were reported throughout these trials. Of 15 identi- on cognition in adolescents (12–17 years of age) with inadequate- fed adverse events, dizziness, ataxia, somnolence, irritability and ly controlled focal seizures was evaluated in a randomized dou- weight increase were found to be signifcantly associated with per- ble-blind study (6 weeks titration, 13 weeks maintenance). Tose most relevant were somno- serious in two perampanel patients (one each on 8 and 12 mg/day). The (n = 13, 18%), followed by ataxia, irritability falls, cognitive slowing situation is made more complicated by the high prevalence of and depression in single cases [28]. This was identifed based on review of the full clinical studies patients with a history of serious anger management issues and/ safety database. Anger, aggression and hostile behaviour have been or hostile or aggressive behaviour. In all other patients, the pos- reported in patients taking adjunctive perampanel, particularly at sibility of irritability, impulsivity anger and aggression should be higher dosage. Most of the events were either mild or moderate sensitively discussed with the patient and their close family when and some patients recovered either spontaneously or with dosage prescription of perampanel is being considered. However, thoughts of harming others, physical assault not themselves notice the change in their behaviour and so family or threatening behaviour were observed in around 1% of patients input is essential. Suicidal ideation has also been the perampanel dose is titrated to the optimum amount for each reported with perampanel during post-marketing use [32,33]. Documentation of any personal or family his- In a pooled analysis of the three phase 3 studies of adjunctive tory of psychiatric disorders will alert the prescriber to consider perampanel in patients with focal seizures (n = 1480; safety anal- slower introduction of the drug. The most common problem was are particularly susceptible to developing behavioural side-ef- aggression (n = 3; perampanel 12 mg/day in two patients, peram- fects with perampanel and hence its introduction should be panel 2 mg/day in the third). Tere are no good data to suggest quency of 5%, 12% and 20% with perampanel 4, 8, and 12 mg/day, that behavioural problems with perampanel are likely to be any versus 6% for placebo. Aggres- were irritability (4 mg/day, 4%; 8 mg/day, 7%; 12 mg/day, 12%; ver- sion and hostility have the potential for serious medico-legal im- sus 3% for placebo) and aggression (4 mg/day, 1%; 8 mg/day, 2%; plications and so accurate documentation in the case notes and 12 mg/day 3%; versus 1% for placebo). Tese symptoms can be managed data for over 850 patients and 100-week data for over 350 patients. Serious psychiatric adverse events cide whether or not to discontinue the drug should a behavioural were reported by 47 patients (3. Efcacy and safety of adjunctive ary generalization, in adults and children over 12 years of age. Perampanel, a selective, noncom- experience and are becoming more confdent in using the drug for petitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antag- patients with less severe epilepsies. Perampanel study 207: long-term open-label Approaches to control side-efects, particularly irritability and ag- evaluation in patients with epilepsy. Long-term safety of perampanel References and seizure outcomes in refractory partial-onset seizures and secondary generalised 1. New avenues for anti-epileptic es with perampanel in real life in Germany and Austria. First clinical experience with perampanel: the structure, regulation and function. Perampanel as adjunctive therapy in patients with partial-onset sei- ampanel: a review of clinical trial data. Novel treatment options for double-blind, placebo-controlled phase 3 (core) studies in patients with refractory epilepsy: focus on perampanel. Acta European Congress on Epileptology, 29 June to 3 July 2014, Stockholm, Sweden. Review of psychiatric and behavioural adjunctive perampanel for refractory partial-onset seizures. Inefective useful for the treatment of status in absences N epilepticus and neonatal seizures. H C2H5 Inefective in absences O Usual preparations Tablets: 15, 30, 50, 60 and 100 mg Tablets: 250 mg Elixir: 15 mg/5 mL Suspension: 50 mg/mL Injection: 200 mg/mL Usual dosage Oral Adults and children >9 years Initial: 30 or 50 mg/day in adults Initial: 62. Serum phenobarbital phenobarbital also apply to levels are increased by co- primidone. Enzyme-inducing administration of valproic acid and drugs increase the phenobarbital– some other drugs primidone ratio in serum. Isoniazid and nicotinamide increase serum primidone levels The Treatment of Epilepsy. A conductance possible contribution of phenylethylmalonamide to clinical efects has not been ascertained Bioavailability >95% >90% Time to peak levels 0. Initially believed to have only sedative properties, barbitu- 3 2 rates have been recognized as antiepileptic agents since 1912, when 5 4 3N H H O N Hauptmann discovered serendipitously a dramatic reduction of sei- C2H5 H O H zure frequency in patients with bromide-resistant epilepsy treated with phenobarbital (phenobarbitone) [1]. Its frst century in clinical (b) (d) O O use was recently celebrated with a special symposium [2,3]. Because C4 3 2C C4 3 2C O N O O N O of its broad spectrum, recognized efcacy, low cost and ease of use H H with once daily dosing, it is recommended by the World Health Or- ganization as a frst-line agent for focal and tonic–clonic seizures in Figure 42. Over the years, attempts have been made to modify the molecular clonic seizures and electrically kindled seizures [8]. It also appears structure of phenobarbital in order to identify agents with greater to prevent seizures induced by a variety of chemicals (such as efcacy and lesser toxicity. Primidone was introduced into clinical strychnine, thiosemicarbazide and bicuculline) and photic seizures practice in 1952 and is still relatively widely used. In contrast, phenobarbital worsens spike–wave can be attributed largely to metabolically derived phenobarbital. This pattern of activity in various anticonvulsant ileptic properties and were introduced into therapeutics in 1932 and tests, and particularly its ability to limit the spread of seizure activity 1948, respectively; however, neither drug achieved widespread use. This is borne out in keted with the aim of decreasing the sedation associated with phe- clinical practice, and phenobarbital has proven value in controlling nobarbital. The clinical success of phenobarbital also infuenced the generalized tonic–clonic seizures, other generalized seizure types development of subsequent distinct molecules (i. Dif- In this chapter, the comprehensive features of phenobarbital, ferent efects are noted at diferent serum concentrations [7]. A number of excel- high concentrations – such as those achieved in patients during lent reviews devoted to this subject are already available [7,8,9,10,1 treatment of status epilepticus – phenobarbital limits high-frequen- 1,12,13,14,15,16,17,18]. Phenobarbital also decreases the Ca2+ infux in presynaptic nerve endings, which could result in decreased release Chemistry of excitatory neurotransmitters, such as glutamate and aspartate.

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The efect of transcutaneous vagus nerve stimu- term results of vagus nerve stimulation in refractory epilepsy order 50mg fertomid with amex. Epilepsia 2012; gus nerve stimulation: clinical experience in drug-resistant pediatric epileptic pa- 53: e115–118 generic 50mg fertomid mastercard. Automated seizure onset stimulation for the treatment of pharmacoresistant epilepsy cheap 50mg fertomid fast delivery. Vagus nerve stimulation re- ilepsy: transcutaneous auricular vagus nerve stimulation cheap fertomid master card. Chin Med J 2014; 127: duces cardiac electrical instability assessed by quantitative T-wave alternans anal- 300–304. Direct brain stimulation has been patients with focal epilepsy, the most common seizure type. In the studies of patients with epilepsy these have epilepsy, the goal is to prevent seizures or reduce seizure frequen- typically had 100–200 patients. Stimulation of subdural grid contacts in patients who All neurostimulation modalities share the benefts of a lack of are undergoing presurgical evaluations can, on occasion, trigger drug-related side-efects (e. While the exact mech- question as to whether direct stimulation of some human brain re- anisms of any benefcial efects of neurostimulation remain to be gions (e. Typically, neurostimulation is combined with and indeed is typically not noticed by the patient. In contrast, one alternative stimulation therapies that might be more efective, spe- of the basic concepts of neurostimulation is that it is targeted ther- cifcally stimulation of intracranial structures. The target of stimulation could be the presumed seizure focus, The Treatment of Epilepsy. The diferences between these two types of ther- focus focus apy will be discussed below. Open-loop system Closed-loop system No event detection required Designed to detect events with Concept and requirements for high sensitivity programmed or chronic stimulation Programmed periodic Programmed to respond to Vagus nerve stimulation therapy uses a treatment paradigm that stimulation; chronic repetitive detected events, intermittent employs chronic, programmed therapy [7]. Stimuli can be varied in stimulation stimulation intensity, pulse duration and frequency. Reduced background synchrony could conceivably in about a quarter of patients, but there are no studies completed reduce or prevent the onset of focal seizures or afect the subse- or designed to provide Level I evidence [8]. Brain stimulation for quent network recruitment and reduce or prevent secondarily gen- the treatment of neurological disorders other than epilepsy, for in- eralized seizures. Although clinical trials of neurostimulation have stance Parkinson disease, typically employs continuous (i. Primary general- The mechanisms of therapeutic brain stimulation are largely un- ized seizures, however, are ofen readily controlled with medication, known. Depending upon intensity of stimulation and proximity to whereas only about 50% of patients with symptomatic focal seizures stimulating electrodes, individual neuronal elements may be either have their seizures controlled with available therapies [16]. However, efects on intact While the chronic programmed device needs to employ a program- brain networks are much more complex, and can involve mixtures mable stimulator, there is no need for the obligatory detector for of excitatory and inhibitory efects. Current thinking emphasizes closed-loop systems and no need for storage of recorded events. The modulatory roles of neurostimulation and disruption of patholog- stimulating electrodes for programmed stimulation are placed in the ical network activity, rather than simple inhibition [11]. Much of the experience with chronic stimulation de- cillations of the basal ganglia. The stimulation devices being solved and mechanisms may difer for focal and primary general- used for chronic programmed trials of epilepsy treatment are simi- ized seizures. Tere is evidence for a preictal state in some patients lar to those approved for use in these movement disorders. It is not known whether the background synchrony of Epileptic seizures are brief, transient periods of focal, regional or the epileptic brain or focus is increased over controls. Focal The goal of chronic programmed brain stimulation is to provide seizures are rapidly evolving dynamic events, characterized by in- modulation of neural network activity that would reduce or pre- creased signal complexity, which include periods of seizure onset, vent the transitions to the hyperexcitable ictal state. Whether chronic brain given patient are remarkably stereotyped as determined by both stimulation acts by producing reduced synchronization or modu- time–frequency decompositions and measures of signal complexity lation of specifc pathways or receptors is not known and may be [19,20]. This stereotyped onset pattern is an extremely important Brain stimulation for epilepsy 969 characteristic for application of closed-loop therapies. The typical Detection algorithms that can utilize many seconds of seizure focal seizure lasts less than 120 s [20] and spontaneously terminates activity or entire seizures can be both very sensitive and specifc. Patients in epilepsy monitoring units Tese programs are very useful in the epilepsy monitoring unit, par- who have their medications reduced or withdrawn have more fre- ticularly for retrospective detection of seizures that do not produce quent seizures and more frequent secondarily generalized seizures clinical manifestations or seizures that have gone unrecognized. In but the seizures are still typically self-limited and not necessary contrast, on-line detection of seizure activity afer only a few sec- longer, unless they generalize [21]. Even patients with status epilep- onds (a requirement of closed-loop responsive systems) presents ticus usually have recurrent seizures rather than continuous seizure additional challenges. Because of the stereotyped seizure-onset activity, although the latter certainly occurs. In contrast specifcity; all epileptiform activity that is detected is not destined to open-loop programmed stimulation where the principle is to re- to evolve into a clinical seizure. At present, however, seizure prediction is at best result in a shorter, brief seizure. For responsive neurostimulation very computationally demanding and cannot be carried out with to be clinically benefcial, intervention has to be early, to prevent small hardware devices, online, or with sufcient sensitivity to be seizure evolution from an electrical or simple partial event (i. A provocative report of long-term prediction of no altered awareness) to a disabling seizure (complex partial or sec- seizure likelihood in patients with drug-resistant focal epilepsy im- ondarily generalized). If a focal seizure is limited to one of several planted with intracranial electrodes has been published [31]. Ac- seconds duration without alteration of consciousness this provides curate seizure prediction depends upon a detectable preictal state valuable beneft. If the seizure is just reduced in duration but still and even when this is present, the false-positive rate is ofen high. In the treatment of focal seizures, it therefore seems cations may facilitate future closed-loop systems based on predic- desirable to have the recording and stimulating electrode near the tion of a preictal state. It is possible that more remote stimulation could still have potentially, but delayed, benefcial efects. A number of cerebral structures have been targets for chronic or Because epileptic seizures are characterized by periods of in- programmed brain stimulation. Cerebellar stimulation, the earliest creased synchronous excitatory network activity, the idea that ex- target of therapy in humans, is discussed in Section Stimulation of ternal excitation may be benefcial is at frst counterintuitive, but the cerebellum in the historical context, as there have been no large in fact there is experimental evidence supporting the potential controlled trials. Studies in neural network models incorpo- subthalamic nuclei have been targets for modulation by high-fre- rating both excitatory and inhibitory neurons have shown that quency chronic neurostimulation. Although preliminary unblinded excitatory stimulation can terminate abnormal bursting activity studies have been promising with stimulation of a number of these [22,23,24,25,26]. Indeed, in these same model networks, termina- brain regions, true measures of efcacy require evidence-based tion can be produced when there is no functioning inhibition. Because the brain is pain insensitive, the patient is is not to say that inhibitory networks are not important in modu- not aware of whether stimulation is activated or not, and controlled lating human brain activity, just that inhibition may not be neces- blinded studies are feasible. In some neurostimulation trials, one sary for seizure termination, either spontaneous or triggered. The investigator is unblinded to allow for adjustment of stimulation pa- human brain and hippocampus comprise predominantly (80–90%) rameters. This investigator needs to be careful to ‘preserve the blind’ excitatory connections [27]. Stimulation of the cerebellum was the frst site of attempted ther- Recurrent seizures from single seizure focus in a patient have apeutic neurostimulation for epilepsy. This is apparent with visual inspection and utilized two eight-contact strip electrodes, placed on the upper sur- is supported by the application of time–frequency analyses [28]. In face of the anterior lobe of the cerebellum through a burr hole or addition to somewhat stereotyped patterns of frequency, the onset craniotomy. Stimulus intensities of 1–9 mA, at 10 cycles per second, of a seizure is characterized by an increase in signal complexity were used. The fact that these seizure-onset patterns recorded from in- lar stimulation was used in attempts to reduce spasticity in patients tracranial electrodes in a given patient are very similar facilitates with cerebral palsy [32]. Cerebellar tient and their seizures so that seizure detection can be very sensi- stimulation had been shown to shorten trains of hippocampal dis- tive. The fact that artefacts are markedly reduced with intracranial charges induced in humans [33] and to provide inhibition of corti- electrodes also facilitates accurate detection. Two double-blind trials of chronic cerebellar stimulation in the treatment of epilepsy comprised a total of 17 patients [38].

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