March 2006
Cardiac Autonomic Control in Patients with Refractory Epilepsy before and during Vagus Nerve Stimulation Treatment: A One-year Follow-up Study
Eija Ronkainen, Juha T. Korpelainen, Esa Heikkinen, Vilho V. Myllylä, Heikki V. Huikuri, and Jouko I.T. Isojärvi

Vagus nerve stimulation (VNS, vagus nerve stimulation/stimulator) is a non-pharmacological antiepileptic therapy for patients with refractory epilepsy who are not candidates for resective surgery or who have had resective surgery with unsatisfactory results. Prospective, randomised and multicenter studies have shown that VNS treatment is safe, well tolerated and effective in seizure reduction. Despite the close interaction between VNS and the centers controlling cardiovascular functions, the effects of VNS on cardiovascular autonomic regulation in patients with refractory epilepsy have not been widely studied. In the present study, our aim was to elucidate possible effect of VNS therapy on interictal heart rate (HR) variability in patients with refractory epilepsy before and after one-year VNS treatment. A 24-hour electrocardiogram (ECG, for the heart) was recorded at the baseline and after 12 months of VNS treatment in 14 patients with refractory epilepsy, and once in 28 healthy age- and sex-matched control subjects. Time and frequency domain measures, along with fractal and complexity measures of HR variability, were analysed from the ECG recordings. In the present study, HR variability was reduced and the nocturnal increase in HR variability was not present in patients with refractory epilepsy. One-year treatment with VNS did not have a marked effect on HR variability, suggesting that impaired cardiovascular autonomic regulation is associated with epileptic process itself rather than with recurrent seizures. Epilepsia 2006;47(3).

Giuseppe Capovilla, Antonio Gambardella, Guido Rubboli, Francesca Beccaria, Alessandra Montagnini, Umberto Aguglia, Maria Paola Canevini, Susanna Casellato, Tiziana Granata, Francesco Paladin, Antonino Romeo, Giuseppe Stranci, Paolo Tinuper, Pierangelo Veggiotti, Giuliano Avanzini, and Carlo Alberto Tassinari

On EEG recordings, photosensitivity is detected in about 5 % of epileptic patients and it represents a serious problem, since up to 25 % of them report visually induced seizures. Photosensitivity can cause subjective unpleasant sensation and induce a state of anxiety in photosensitive epileptic patients, being aware of possible reflex seizures. In the past, different types of lenses have been suggested for managing photosensitivity and there is now evidence that their effectiveness depends on both the lens color and lens transmittance. In 1999, Capovilla et al. tested 83 patients with epilepsy for photosensitivity suppression during intermittent photic stimulation by using different types of lenses. A type of lens named Z1 was significantly more effective in abolishing photosensitivity than were all other control lenses. Now, in this multicenter study, a Z1 lens was used to test 610 pediatric and adult patients with epilepsy and significant (so-called, type IV) photosensitivity. Z1 lenses made photosensitive EEG discharges disappear in 463 (75.9 %) patients, while photosensitive EEG response was considerably reduced in an additional 109 (17.9%). Photosensitive responses remained unchanged in the remaining 38 (6.2%) patients. The response was not significantly influenced by the patients age, sex, type of epilepsy or pharmacological treatment. The results of this study give good evidence that the Z1 lens has great effectiveness in controlling photosensitivity. Many photosensitive epileptic patients might avoid pharmacological treatment by using these blue sunglasses in daily life because they are well tolerated. The Z1 lens might become a valid resource in the daily activity of clinicians worldwide who care for patients with epilepsy. Epilepsia 2006;47(3).

February 2006
A Modified Atkins Diet is Effective for the Treatment of Intractable Pediatric Epilepsy
Eric H. Kossoff, Jane R. McGrogan, Renee M. Bluml, Diana J. Pillas, James E. Rubenstein, and Eileen P. Vining

The ketogenic diet has been used since 1921 to treat intractable childhood epilepsy. Over the past 85 years, it has not changed significantly. A modified Atkins diet may similarly induce ketosis without an admission or fasting period, and does not restrict protein, fluids, and calories. In a follow-up to our case series from 2003, we report on the first prospective study of a modified Atkins diet. Children ages 3-18 years, with at least 3 seizures per week, who had been treated with at least two anticonvulsants, were enrolled and received the diet for the 6-month study period. Carbohydrates initially were limited to 10 grams per day. All children became ketotic within days. After 6 months, 13 (65%) had >50% improvement and 7 (35%) had >90% improvement. Sixteen (80%) completed the 6-month study; 14 chose to remain on the diet afterwards. Side effects were minimal and weight did not significantly decrease. In fact, children who had their heights and weights remain relatively stable had better seizure control. A modified Atkins diet appears to be an effective and well-tolerated therapy. Epilepsia 2006;47(2).

Elisabeth B. Marsh, John M. Freeman, Eric H. Kossoff, Eileen P. Vining, James E. Rubenstein, Paula L. Pyzik, and Cheryl Hemingway

Children who have epilepsy that has not responded to two appropriately administered medications are termed “difficult-to-control”, or “intractable” and are widely believed to have only a 10-30 percent chance of responding to any additional medication. Our prior study of the effectiveness of the ketogenic diet in 150 children with these seizures documented that after one year, more than 25% had a 90% decrease in seizures. Similar seizure control was found 3-6 years later, when most children had discontinued the diet and were off medications. However, in that study, almost half of the children discontinued the diet it during the first year, 1/3 within 3 months, 2/3 by 6 months. Discontinuation was usually because of failure of the diet to adequately control their seizures. These children were also assessed by questionnaire 3-6 years later. To our surprise, 22% had become seizure-free and an additional 10% were mostly seizure-free (>90% decrease). Half had a greater than 50% reduction in seizures with or without surgery. It was unclear whether this improvement in seizure control was due to the natural history of the conditions causing the seizures, or to the use of newer anticonvulsant medications. In either event, the outlook for children with “difficult-to-control” or “intractable” seizures is not as bleak as was once believed. Epilepsia 2006;47(2).

Felipe Fregni, Sigride Thome-Souza, Michael Nitsche, Steven Freedman, Kette Valente, and Alvaro Pascual-Leone

Some patients with epilepsy do not have an adequate seizure control with use of medications. For these patients, new therapeutic approaches have been investigated. In this context, brain stimulation might be a good therapeutic option. Therefore, we aimed to investigate the effects of a novel technique of noninvasive brain stimulation, namely brain DC polarization, in patients with refractory epilepsy. Nineteen patients with refractory seizures and malformations of cortical development participated in this study. DC polarization is a simple technique that induces a continuous (DC – direct current) electric current into the brain. In this technique, electric current flows from cathode to anode electrode; and, thus, its effects depend on the electrode polarity: cathodal stimulation inhibits brain activity and anodal stimulation facilitates it. Therefore we placed the cathode electrode over the epileptogenic area (that is, the brain area in which seizures are originated) and the anode electrode over the silent area (that is, the brain area with normal brain activity). We measured epileptic activity before and after the treatment using an electroencephalogram (EEG) and the frequency of seizures. The results of this study showed that active treatment (DC polarization) compared to sham treatment was associated with a significant decrease in the number of epileptiform discharges (abnormal brain activity in the EEG related to seizure activity) and a trend toward a significant decrease in the frequency of actual seizures. This treatment was not associated with detectable adverse effects. The results of this study encourage future investigations of this new method of brain stimulation for epilepsy treatment. Epilepsia 2006;47(2).

January 2006
Refractory Generalized Seizures: Response to Corpus Callosotomy and Vagal Nerve Stimulation
Maromi Nei, Michael O’Connor, Joyce Liporace, and Michael R. Sperling

The vagal nerve stimulator (VNS) is an implantable device used in people with seizures that do not respond to anticonvulsant medication therapy alone. The corpus callosotomy (CC) is a neurosurgical procedure consisting of sectioning of the anterior one-half to two-thirds of the corpus callosum, a band of fibers connecting the two halves of the brain. Both procedures can reduce the frequency of seizures that do not respond adequately to medications. In this study, the efficacy and safety of these two procedures was evaluated for patients with refractory generalized seizures. For those with a CC and generalized tonic-clonic seizures (50 patients), 79.5% had >50% decrease in the frequency of generalized tonic-clonic seizures, and 60% had >80% seizure reduction. For those with a VNS and generalized tonic-clonic seizures (21 patients), 50% had > 50% seizure reduction and 33% had > 80% seizure reduction. Tonic and atonic seizures decreased after either VNS or a CC. The complication rate for CC was higher than for VNS, but complications due to either procedure were rarely permanent. Both corpus callosotomy and VNS are effective in reducing generalized seizures. CC is associated with greater efficacy but higher risk for complications, though these were generally transient. Epilepsia 2006;47(1).

November 2005
Vagus Nerve Stimulation Induces Concomitant Respiratory Alterations and a Decrease in SaO2 in Children
Boubker Zaaimi, Claire Héberlé, Patrick Berquin, Mickael Pruvost, Reinhard Grebe and Fabrice Wallois

Vagus nerve stimulation (VNS) is a treatment for medication-resistant epilepsy used in Europe since 1994. We analyzed respiratory alterations caused by VNS as well as its effect on blood saturation in oxygen (SaO2) during night sleep in 10 children with epilepsy. During each VNS period a significant increase in respiratory frequency (p<0.05) occurred throughout the whole stimulation period accompanied by a decrease in thoraco-abdominal distension amplitude most pronounced at the beginning of the stimulation. These respiratory alterations induced a decrease in SaO2 between 1-5%. The effects of VNS on respiration differed significantly between REM (dreaming) and NREM (non-dreaming) sleep states. These findings are discussed in light of the hypothesis of a possible neuroprotective effect of VNS treatment, for which verification further investigations will be necessary. Epilepsia 2005;46(11).

A.G. Christina Bergqvist, Joan I. Schall, Paul R. Gallagher, Avital Cnaan, and Virginia A. Stallings

The ketogenic diet (KD) is a high fat diet used to treat intractable epilepsy. Initiation of the KD requires a hospital admission due to the complex protocol and potential for adverse events, and is therefore not available to all patients that may benefit. This study describes the efficacy and adverse events of a new gradual KD initiation (GRAD-KD) compared to the standard KD initiation preceded by a fast (FAST-KD) in 48 children with intractable epilepsy, randomized to either protocol. Baseline seizure activity was recorded daily beginning 28 days before admission and then for the 3-month duration of the study. Effectiveness was measured as the proportion of subjects with >50 % reduction in target seizure type, and as % reduction in the frequency of the target seizure type from baseline to 3-month evaluation. Adverse events were assessed over the 6-day KD initiation. In the FAST-KD protocol, 58% of the children had >50% reduction in the target seizure type at 3- months and 21% were seizure free. In the GRAD-KD protocol, 67% had a >50% reduction at 3-months and 21% were seizure free. The two protocols were equivalent in terms of efficacy.. Children in the GRAD protocol lost significantly less weight, had fewer and less severe episodes of hypoglycemia, and required fewer treatments for acidosis and dehydration during initiation. In children with intractable epilepsy the new GRAD-KD protocol maintained seizure efficacy and was better tolerated than the FAST-KD. Epilepsia 2005;46(11).

October 2005
Tuberous Sclerosis Complex and the Ketogenic Diet
Eric H. Kossoff, Elizabeth A. Thiele, Heidi H. Pfeifer, Jane R. McGrogan, and John M. Freeman

One might suspect that the complex partial seizures seen in children with tuberous sclerosis complex and intractable epilepsy would not respond to the ketogenic diet. However, in this limited case series of 12 children seen over a 5 year period at the Johns Hopkins Hospital and Massachusetts General Hospital, efficacy was surprisingly high. All but one child had a 50% seizure reduction, and two-thirds had a greater than 90% improvement in their seizures. Five children had at least a 5-month period of seizure freedom. The ketogenic diet was well-tolerated and continued for a mean of 2 years in these patients. For the often intractable epilepsy associated with tuberous sclerosis complex, the ketogenic diet is a reasonable option. Epilepsia 2005;46(10).

September 2005
Safety and Tolerability of the Ketogenic Diet in Pediatric Epilepsy: Effects of Valproate Combination Therapy
David A. Lyczkowski, Heidi H. Pfeifer, Soumit Ghosh, and Elizabeth A. Thiele

The ketogenic diet (KGD) is a high-fat, low-carbohydrate, restricted-protein diet that can effectively treat intractable epilepsy. Valproate (VPA) is a widely-used anti-epileptic drug. Like other treatments, both the KGD and VPA are associated with side effects. Previous limited studies have suggested that the combination of the KGD and VPA might possibly increase the risk of serious side effects including pancreatitis, kidney dysfunction, and liver toxicity,. Because of the potential for such side effects, some have avoided using these two therapies in combination. We studied 71 children with epilepsy treated with the KGD, of whom 24 were also taking VPA. In general, side-effect profiles and efficacy of the KGD were not affected by VPA. The patients on VPA and KGD co-therapy did not show signs of pancreatitis, kidney dysfunction, or serious liver toxicity. In some patients, the combination of VPA and KGD provided optimal seizure control. Co-therapy with the KGD and VPA should not be excluded because of concerns about safety and tolerability. Epilepsia 2005;46(9).

Roberto Horacio Caraballo, Ricardo Oscar Cersósimo, Diego Sakr, Araceli Cresta, Nidia Escobal, and Natalio Fejerman

The ketogenic diet (KD) has been used as a therapeutic alternative to antiepileptic drugs (AEDs) for refractory epilepsy. The diet consists of an intake of three or four times as much fat as carbohydrates and protein combined. In this retrospective study, we evaluate the efficacy and tolerability of the KD in patients with Dravet Syndrome (DS), a severe myoclonic epilepsy occurring in infants. Between March 1, 1990 and August 31, 2004, 52 patients who met diagnostic criteria of DS were enrolled in our study. Twenty of them were placed on the KD using the Hopkins protocol and followed for a minimum of one year. Three of the 20 original children stayed on the diet for 12 months, four children for 2 years, four children for 3 years and two children for 4 years. One year after initiating the diet, 13 of the initial patients (65%) remained on the diet. Two patients (15%) were seizure free and eight children (61.7%) had a 75-99% decrease in seizures and the remaining three children (23%) had a 50% to 74% decrease in seizures. Thus, 1 year after starting the diet, 10 children (77%) had achieved a > 75% decrease in their seizures. Four patients have been off the diet for more than two years; one of them is seizure free, two have sporadic seizures and one, who abandoned the diet after two years of adhering to it, relapsed. No differences in seizure control when compared to age, sex, or seizure type were found. Considering the severity and intractability of seizures in patients with Dravet syndrome, the fact that 11 of the 13 children who remained on the diet had a significant reduction in number of seizures shows that the KD is at present an interesting therapeutic alternative. Even in patients in whom seizure reduction was not dramatic, quality of life improved and in all of them the number of AEDs was lowered to one or two. We consider that children with Dravet syndrome should be offered the KD immediately after failing three adequate trials of AEDs. Epilepsia 2005;46(9).

August 2005
A Comparison of the Ability of a 4:1 Ketogenic Diet and a 6.3:1 Ketogenic Diet to Elevate Seizure Thresholds in Adult and Young Rats
Kirk Nylen, Sergei Likhodii, Peter A. Abdelmalik, Jasper Clarke, and W. McIntyre Burnham

The ketogenic diet (KD) is a high fat, low carbohydrate and adequate protein diet used to treat drug-resistant seizures. It is currently unknown exactly how the KD exerts its anticonvulsant effects. As such, animal models are used to study the KD’s anticonvulsant mechanism of action. In the present study, we explored the ability of two KDs, a 4:1 KD and a 6.3:1 KD (more severe ketosis), to elevate pentylenetetrazole (PTZ) seizure thresholds in adult rats and young rats. When calculating PTZ thresholds, one can use either “absolute latencies” (i.e., the number of seconds until a seizure occurs) or “threshold doses” (i.e., the mg/kg dose of PTZ required to elicit a seizure). When absolute latencies were used, neither KD significantly increased the latency to seizure in adult rats and young rats. Similarly, neither KD elevated threshold doses in adult rats. The 4:1 KD did not elevate threshold doses in young rats, however, the 6.3:1 KD did. Threshold doses are sensitive to differences between group weights, and the largest difference between group weights existed between the 6.3:1 KD group and its respective control group. It remains unclear whether threshold doses, absolute latencies, or some combination of the two methods should be used when determining seizure thresholds in rats fed a KD and seizure tested using the PTZ infusion test. We conclude that the PTZ infusion test is not suitable for modeling the anticonvulsant effects of the KD seen clinically, especially when dietary treatments lead to significantly mismatched body weights between the groups. Epilepsia 2005;46(8).

July 2005
Epilepsy Care in Zambia: A Study of Traditional Healers
Roy Baskind and Gretchen L. Birbeck

Most of the world’s population lives in developing countries where modern medical healthcare services are extremely limited. In sub-Saharan Africa (SSA), poverty and HIV/AIDS strain an already fragile medical infrastructure and access to medical care for people with epilepsy (PWE) is very limited, particularly in rural areas. Traditional healers (THs) play a prominent role in caring for PWE in SSA, yet we know little about THs’ conceptualization of epilepsy or their approach to care. We conducted a qualitative study in rural Zambia using focus group discussion with THs, in-depth semi-structured interviews with a well-recognized TH at his place of work, and multiple informal interviews with healthcare providers in rural Zambia to better understand epilepsy care provision by THs. We found that THs recognize the same symptoms that a neurologist elicits to characterize seizures. THs believe witchcraft plays a central, provocative role in most seizures. Treatment is initiated after the first seizure and usually incorporates certain plant and animal products. Signs of concomitant systemic illness are the most common reason for referral to a hospital. Given their predominance as care providers for PWE, collaborative relationships between physicians and THs must be established if we hope to expand treatment to all PWE in Zambia. Epilepsia 2005;46(7).

June 2005
Target-Specific Catecholamine Elevation Induced by Anticonvulsant Thalamic-Deep Brain Stimulation (DBS)
Wendy C. Ziai, David L, Sherman, Anish Bhardwaj, Ning Zhang, Penelope M. Keyl, and Marek A. Mirski

More than 15% of patients with recurrent seizures are diagnosed as having medically intractable epilepsy. The Anterior Thalamic Nuclear Complex (AN) is a key thalamic site mediating the expression of experimental seizures. AN deep brain stimulation (DBS) is effective in raising EEG and clonic seizure threshold in experimental models. Little is known, however, about the anticonvulsant mechanisms of electrical stimulation. This study evaluated the specific biochemical mechanisms underlying the effect of DBS on antagonizing seizure spread in a rodent model of seizures induced by the convulsant drug, pentylenetetrazol (PTZ). Using micro-sampling techniques, we determined baseline and DBS-induced changes of extracellular concentrations of norepinephrine, serotonin and the amino acids GABA and glutamate in the rat AN and PT (posterior thalamus) following infusion with intravenous PTZ. Experimental groups included AN DBS, NO DBS and PT DBS. Bilateral AN stimulation delayed the onset of EEG seizures compared to controls. PTZ and DBS together enhanced the non-selective release of norepinephrine in thalamic nuclei, while specifically stimulating AN-localized serotonin. We observed no major changes in extracellular glutamate or GABA during either stimulation or seizures. Modulation of serotonin-related activity specifically in the AN of thalamus may be an important neurotransmitter system underlying the efficacy of AN DBS. Epilepsia 2005;46(6).

May 2005
Effect of ACTH Therapy for Epileptic Spasms without Hypsarrhythmia
Hirokazu Oguni, Makoto Funatsuka, Kaori Sasaki, Tae Nakajima, Keisuke Yoshii, Tsutomu Nishimura, and Makiko Osawa

ACTH is a natural hormone in the steroid, which is produced by brain. For decades, ACTH has been advocated for treatment of infantile spasms in children. Infantile spasms, abnormal EEGs (with a pattern called hypsarrhythmia) and developmental problems are features of the syndrome called West syndrome. However, not all children with epileptic spasms (ES) meet the full diagnostic criteria for West syndrome. We analyzed the short- and long-term effects of ACTH therapy for patients with epileptic spasms (ES) who did not meet the criteria of West syndrome (WS). The subjects were 30 patients, including 13 boys and 17 girls, who had received ACTH therapy between 1970 and 2003. We excluded patients with WS, but included those with a history of WS who no longer showed hypsarrhythmia at the period of ACTH therapy. The age at onset of ES and at ACTH therapy ranged from 2 to 82 months, with a median of 18 months, and from 11 to 86 months, with a median of 29 months, respectively. Excellent responses were obtained in 19 patients (63%) and poor responses in 11 patients (37%), as a short–term effect. Among 17 of the 19 patients with excellent short-term outcomes and a follow-up of longer than 1 year after the ACTH therapy, 8 patients have continued to be seizure-free (29%; excellent long-term effect), while the remaining 9 patients had a recurrence of seizures (complex partial seizures in 4, generalized tonic seizures in 3, ES in 2) at 9 months to 198 months (median= 49 months) after ACTH therapy. In addition, 9 of the 17 patients demonstrated a localized frontal EEG focus after the ACTH therapy, although most of these had previously shown diffuse epileptic EEG abnormality. ACTH therapy is worth trying for patients with resistant ES, even without features of West syndrome. However, the long-term effect is uncertain because recurrences of various types of seizures, including focal seizures, frequently were observed. Epilepsia 2005;46(5).

April 2005
Can You Predict an Immediate, Complete, and Sustained Response to the Ketogenic Diet?
Khoi D. Than, Eric H. Kossoff, James E. Rubenstein, Paula L. Pyzik, Jane R. McGrogan, and Eileen P. G. Vining

Which children with intractable epilepsy are the most likely to have a dramatic, sudden, and complete seizure-free response to the ketogenic diet? In this study, patients who became permanently seizure-free within two weeks of diet onset were compared to all others treated with the diet. 18 early dramatic responders over a 3-year period were identified and compared to 89 patients who were not similarly improved. The only factor with a significant correlation was a lack of complex partial seizures (0% of dramatic responders with this as the primary seizure type, vs. 23%, p=0.02). The presence of infantile spasms (39% vs. 20%, p=0.09) approached significance. Interestingly, in all other patient demographics and diet parameters, there was equal likelihood of early, dramatic success. Epilepsia 2005;46(4).