Frank Kerling

Cyclophosphamide for anti-GAD antibody-positive refractory status epilepticus.

Glutamic acid decarboxylase (GAD) is the enzyme which catalyzes the production of gamma aminobutyric acid (GABA), the main inhibitory neurotransmitter in the central nervous system (CNS). There is increasing evidence that severe GAD autoimmunity may be associated with refractory epilepsy. Immunomodulation and GABAergic drugs have been suggested as treatment options. We report here for the first time on a patient with sudden onset of refractory status epilepticus in the presence of strong intrathecal anti‐GAD antibody synthesis who was successfully treated with cyclophosphamide, and give an overview of available data on epilepsy associated with GAD autoimmunity.

Drug withdrawal after successful epilepsy surgery: how safe is it?

Discontinuation of antiepileptic drugs (AEDs) is one reason patients undergo epilepsy surgery, but little is known about the risk of seizure recurrence. We describe a prospective pilot study of withdrawal performed at our epilepsy center. Sixty completely seizure-free patients were included between 1997 and 2003. AED withdrawal was proposed 1 year after surgery after a detailed discussion of the risks and benefits. On the basis of their decision on withdrawal, patients were stratified into two cohorts (withdrawal group, N=34; control group, N=26). Discontinuation was carried out in small tapering steps over 1 year with yearly follow-up visits. Withdrawal was stopped when seizures recurred or the patients objected to further discontinuation. Twenty-six of 34 (76.5%) persons in the withdrawal group and 16 of 26 (61.5%) persons in the control group were seizure free 5 years after surgery. In this study, AED discontinuation 1 year after successful epilepsy surgery was not associated with a risk of seizure recurrence higher than that of controls.

1H‐MR Spectroscopy Indicates Severity Markers in Temporal Lobe Epilepsy: Correlations between Metabolic Alterations, Seizures, and Epileptic Discharges in EEG

Summary:  Purpose: In this study, hippocampal metabolite alterations in 1H‐MR spectroscopy (1H‐MRS) were correlated to the findings of intensive video‐EEG monitoring and duration of seizure symptoms in patients with temporal lobe epilepsy (TLE).

18Fluoroethyl‐l‐tyrosine‐PET in long‐term epilepsy associated glioneuronal tumors

Purpose:  Long‐term epilepsy associated tumors (LEATs) are a frequent cause of drug‐resistant partial epilepsy. A reliable tumor diagnosis has an important impact on therapeutic strategies and prognosis in patients with epilepsy, but often is difficult by magnetic resonance imaging (MRI) only. Herein we analyzed a large LEAT cohort investigated by 18fluoroethyl‐l‐tyrosine–positron emission tomography (FET‐PET).

Cognitive Impairment and Abnormal Behaviour Related to Ring Chromosome 20 Aberration

Aggression and impulsivity in combination with cognitive impairment are feature patients often present with in child and adolescent psychiatric services. However, concurrent epileptic seizures should alert the clinician to be on the outlook for genetic causes. The first description of epileptic seizures occurring with mental retardation and abnormal behaviour in connection with a ring chromosome 20 aberration (r(20)) was reported in 1972 (Atkins et al. 1972). Further case reports that suggested a possible causal link between epilepsy and r(20) were published in the same year (Uchida and Lin 1972; de Grouchy et al. 1972; Faed et al. 1972). Based on similarities in the clinical morphology of these cases and the common link to r(20) the existence of a genetic ring chromosome 20 syndrome was hypothesized (Borgaonkar et al. 1976). Subsequently, in many other reported cases intractable epilepsy, mental retardation, behavioural problems and dysmorphisms, without a consistent pattern of dysmorphology, were put together to a syndrome related to this specific chromosomal aberration (Inoue et al. 1997; Stewart et al. 1979). Since cognitive and behavioural decline develops after the first seizure, r(20) syndrome has also been considered as an epileptic encephalopathy (Vignoli et al. 2009) albeit there is no consensus towards this etiologic labelling. Though the clinical experience renders epilepsy as the main clinical feature of this rare chromosomal defect, mild to moderate mental impairment and behavioural problems can also occur throughout the r(20) syndrome (Hosain 2009). Furthermore, this syndrome has been characterized by phenotypic variability, particularly concerning cognitive deficits, behavioural disturbances and malformations or rather dysmorphisms (Kobayashi et al. 1998). As behavioural aspects can dominate the clinical picture, especially when the patient predominantly presents with impulsivity or aggression, the physician’s attraction can easily be distracted from an etiological relation to r(20) syndrome. In the following we present a case of r(20) syndrome with mosaicism that presented primarily with aggressive behaviour and cognitive decline which impeded and protracted the diagnosis of r(20) syndrome.

Sudden unexpected death in epilepsy (SUDEP)

By definition, the diagnosis “SUDEP” means that the exact cause of death cannot be determined. The death is “without (obvious) explanation”. Still, there are several hints to the underlying pathophysiological mechanisms of SUDEP. Epidemiologic studies have identified risk factors for the occurrence of SUDEP. These risk factors comprise, e. g., male sex, increased seizure frequency, subtherapeutic drug levels, frequently changing combinations of antiepileptic drugs. Autopsies of SUDEP victims demonstrated subendocardial myocardial ischemia or cerebral as well as pulmonary edema. The occurrence of SUDEP might be related to dysfunction of the central autonomic nervous system. Studies on epilepsy patients as well as animal experiments support the hypothesis that (inter)ictal epileptic activity leads to excessive sympathetic stimulation resulting in, e. g., neurogenic pulmonary edema, myocardial ischemia or cardiac arrhythmia. Further studies investigating the pathophysiology of SUDEP are necessary to establish reasonable preventive measures that might contribute to a reduction of the 2- to 5-fold increased mortality rates in epilepsy patients.ZusammenfassungDefinitionsgemäß kann bei der Diagnose „SUDEP“ keine exakte Todesursache bestimmt werden. Der Tod bleibt „ohne (offensichtliche) Erklärung“. Dennoch gibt es zahlreiche Hinweise auf die bei SUDEP-Patienten zugrunde liegenden pathophysiologischen Vorgänge. Mehrere epidemiologische Studien konnten Risikofaktoren für das Auftreten von SUDEP identifizieren. Hierzu zählen z. B. männliches Geschlecht, hohe Anfallsfrequenz, subtherapeutische Medikamentenspiegel, häufig wechselnde Kombinationen von Antiepileptika etc. Durch Autopsien konnten bei SUDEP-Opfern v. a. subendokardiale Myokardischämien bzw. Hirnödeme und neurogene Lungenödeme nachgewiesen werden. Eine pathophysiologisch plausible Erklärung für das Auftreten von SUDEP könnte in einer Funktionsstörung des zentral-autonomen Nervensystems liegen. Aufgrund von Untersuchungen an Epilepsiepatienten sowie tierexperimentellen Ergebnissen kann die Hypothese aufgestellt werden, dass (inter)iktuale epileptische Aktivität zu einer exzessiven Stimulation des sympathischen Nervensystems führt, die dann z.B. ein neurogenes Lungenödem, Myokardischämien oder kardiale Arrhythmien bewirkt. Weitere Untersuchungen zur Entstehung des SUDEP sind notwendig, um pathophysiologisch begründete Maßnahmen zu treffen, die das im Vergleich zur Allgemeinbevölkerung 2- bis 5fach erhöhte Mortalitätsrisiko für Epilepsiepatienten verringern könnten.

Störung der kardialen sympathischen Innervation als Ursache für SUDEP

Sudden unexpected death in epilepsy (SUDEP) concerns 7–17% of the mortality in epilepsy patients. The pathophysiological mechanism is not clearly defined. Autopsy studies show lung as well as brain oedema or myocardial ischemia. Autonomic disregulations are also discussed as a reason for SUDEP. During 10 years of presurgical video-EEG monitoring at the epilepsy center in Erlangen 663 patients were studied. Four patients showed in 8 out of 36 seizures asystoles with a duration up to 25 seconds. Cardiologic tests (Holter ECG, echocardiography etc.) and an examination of the sympathetic cardiac innervation (MIBG-SPECT) were performed. Whereas the cardiological measurements were without pathological findings, the MIBG-SPECT revealed diminished tracer uptake in the two patients with longer asystoles. This lack of sympathetic cardiac activity may lead to an insufficient counter regulation of the sympathicus, when there is an increased ictal vagotonus and might be a reason for SUDEP.ZusammenfassungEin plötzlicher unerwarteter Tod bei Epilepsie (SUDEP) wird in 7–18% der Todesfälle bei Epilepsiepatienten diagnostiziert. Der Pathomechanismus ist bisher noch nicht ausreichend geklärt. Diskutiert werden neben Lungen- oder Hirnödemen auch subendokardiale Myokardischämien. Ebenso werden autonome Störungen vermutet. Während der von 1994–2004 durchgeführten Video-EEG-Ableitungen im Rahmen der prächirurgischen Diagnostik im Epilepsiezentrum Erlangen wurden 663 Patienten aufgenommen. Insgesamt kam es bei 4 Patienten in 8 von 36 Anfällen zu einer Asystolie bis 25 s. Neben der kardiologischen Diagnostik erhielten diese Patienten eine Untersuchung der sympathischen Herzinnervation mittels MIBG-SPECT. In den zwei Fällen mit längerer Asystolie zeigte sich einmal eine Minderbelegung der postganglionären sympathischen Nervenendigungen. Bei einer Patientin fehlte sogar jegliche Anreicherung des Radiopharmakons im Herzmuskel bei unauffälliger kardiologischer Diagnostik. Die hier nachgewiesene fehlende bzw. verminderte sympathische Innervation des Herzens könnte eine insuffiziente Gegenregulation des Sympathikus bedingen, wenn es iktual zu einem erhöhten Vagotonus kommt, und könnte eine von mehreren möglichen Ursachen des SUDEP darstellen.

Fraktionierte, stereotaktisch geführte Radiotherapie der pharmakoresistenten Epilepsie@@@Fractionated Stereotactically Guided Radiotherapy for Pharmacoresistant Epilepsy

Ziel: Diese prospektive Studie untersuchte die Effizienz einer fraktionierten stereotaktischen Radiotherapie (RT) bei therapieresistenter Temporallappenepilepsie. Patienten und Methoden: Einschlusskriterien waren Patienten im Alter von 17 bis 65 Jahren, die weder medikamentös noch epilepsiechirurgisch anfallsfrei wurden und einen einseitigen Fokus aufwiesen. Zwei Patientenkohorten zu je sechs Patienten wurden zwischen 1997 und 1999 einer fraktionierten, stereotaktisch geführten Radiotherapie mit 21 Gy (7 × 3 Gy) bzw. 30 Gy (15 × 2 Gy) unterzogen. Endpunkte der Untersuchung waren Anfallsfrequenz, Intensität und Dauer sowie neuropsychologische Verlaufsparameter. Ergebnisse: Alle elf auswertbaren Patienten profitierten im Sinne einer Reduktion der Anfallsfrequenz. Die mittlere Reduktion der komplex-partiellen Anfälle betrug im 18. Monat der Nachbeobachtungszeit 37% (9–77%, entsprechend 1–23 Anfälle pro Monat) bzw. 46% (23–94%, entsprechend 0,2–23 Anfälle monatlich) gemittelt über den 18-monatigen Beobachtungszeitraum. Eine Verkürzung der Anfälle trat bei 46% (fünf von elf) der Patienten ein. Die Anfallsintensität verringerte sich gleichzeitig bei 64% (sieben von elf), bei drei Patienten (27%) gab es keine Besserung, eine Person (9%) klagte über eine Anfallsintensivierung. Schlussfolgerung: Die Radiotherapie bei pharmakoresistenten Epilepsien bewirkte dauerhaft einen relativ hohen Rückgang der Anfallsfrequenz und stellt damit für Patienten mit operativen Kontraindikationen bzw. nicht anhaltend effektiven epilepsiechirurgischen Eingriffen eine geeignete Alternative dar.Aim: This prospective study evaluated the efficiency of fractionated stereotactically guided radiotherapy as a treatment of pharmacoresistant temporal lobe epilepsy. Patients and Methods: Inclusion criteria were patients aged between 17 and 65 years with one-sided temporally located focus, without sufficient epilepsy control by antiepileptic drugs or neurosurgery. Between 1997 and 1999, two groups of six patients each were treated with 21 Gy (7 times 3 Gy) and 30 Gy (15 times 2 Gy). Study end points were seizure frequency, intensity, seizure length and neuropsychological parameters. Results: All patients experienced a marked reduction in seizure frequency. The mean reduction of seizures was 37% (range 9–77%, i. e. seizures reduced from a monthly mean number of 11.75 to 7.52) at 18 months following radiation treatment and 46% (23–94%, i. e. 0.2–23 seizures per month) during the whole follow-up time. Seizure length was reduced in five out of eleven patients and intensity of seizures in seven out of eleven patients. Conclusion: Radiotherapy was identified as safe and effective for pharmacoresistant epilepsy since a very good reduction of seizure frequency was observed. It is no substitute for regular use of antiepileptic drugs, but means an appropriate alternative for patients with contraindication against neurosurgery or insufficient seizure reduction after neurosurgery.