Hartmut Meierkord

Non-convulsive status epilepticus in adults: clinical forms and treatment

Non-convulsive status epilepticus (NCSE) is one of the great diagnostic and therapeutic challenges of modern neurology. Because the clinical features of this disorder may be very discrete and sometimes hard to differentiate from normal behaviour, NCSE is usually overlooked and consequently not treated properly. It is important to be familiar with the clinical subtypes such as absence, simple and complex partial, and subtle status epilepticus because each requires tailored management. In order to improve overall care of patients with NCSE, strict diagnostic criteria are needed that should be based on clinical alterations and ictal electroencephalographic changes. NCSE should be terminated rapidly to prevent patients from serious injuries, particularly if consciousness is impaired.

Anticonvulsant properties of hypothermia in experimental status epilepticus.

Status epilepticus in patients often does not respond to first-line anticonvulsants, and subsequent treatment escalation with continuous intravenous anesthetics may be associated with significant side-effects. Therefore, alternative treatment regimens are urgently needed. Hypothermia has been shown to reduce excitatory transmission and may thus serve as an interesting adjunct in the management of status epilepticus. In the current experiments, three treatment groups were compared. Animals with self-sustaining status epilepticus were treated with external cooling for 3 h, with low-dose diazepam, or with a combination of both. The effect of these regimens on epileptic activity was compared with untreated controls. Animals that underwent cooling were rewarmed, and all animals were monitored for 5 h to assess occurrence and severity of motor seizures and frequency and amplitude of spontaneous epileptic discharges. Cooling alone significantly reduced number and severity of motor seizures but did not alter epileptic discharges. Cooling in addition to low-dose diazepam significantly diminished amplitudes and frequencies of epileptic discharges, while diazepam alone had only a minor reducing effect on discharge amplitudes. However, at later stages of status epilepticus, diazepam significantly reduced motor seizures. Following rewarming, the discharge frequency tended to increase again, suggesting partial reversibility. The current experiments show that in status epilepticus hypothermia exhibits anticonvulsant effects which are most pronounced if co-administered with low-dose diazepam. The results still require confirmation in other animal models and also clinical studies are urgently needed. However, our data indicate that cooling could well become a future adjunct in the treatment of status epilepticus in patients.

Erectile dysfunction with topiramate.

The antiepileptic drug (AED) topiramate (TPM) is efficient in new-onset partial epilepsies (1) as well as in refractory partial and generalized epilepsies (2). Several adverse events with this substance have been described; the most common and important include somnolence, fatigue, nausea, anorexia and weight loss, paresthesias, psychomotor slowing and confusion, dizziness, and headache (2). Interference with sexual function with TPM has, to our knowledge, not yet been reported. We recently encountered two patients with partial epilepsy in whom reversible erectile dysfunction developed while taking TPM. We describe the cases to draw attention to a distressing side effect of the drug.

Recurrent seizures do not cause hippocampal damage.

Abstract.Neuronal consequences of recurrent single epilepticnseizures have been discussed controversially for some time.nVarious cross-sectional magnetic resonance imaging (MRI) studiesnhave shown a positive correlation between the severity ofnepilepsy and the extent of hippocampal damage. However, the opennquestion whether recurrent epileptic seizures induce hippocampalnstructural pathology can be assessed only in longitudinalnstudies. The few recent follow-up studies have revealednconflicting results. In the current MRI study we have employednvolumetry and T2 relaxometry to quantify hippocampal structuralnchanges of patients with chronic partial epilepsies over anperiod of 3 years. Our main findings demonstrate that thesenpatients who experience continuing epileptic seizures do no shownany development of new pathology or any relevant deteriorationnof pre-existing hippocampal structural lesions. This arguesnagainst the assumption that recurrent epileptic seizures causenor increase structural hippocampal damage.

Transient loss of inhibition precedes spontaneous seizures after experimental status epilepticus.

The pathophysiological mechanisms that cause spontaneous seizures following status epilepticus are largely unknown. Erosion of inhibition is regarded as an important pathophysiological hallmark of ongoing status epilepticus. Therefore, we investigated if loss of inhibitory functions also plays an important role in the development of spontaneous seizures after status epilepticus. Furthermore, we analyzed possible changes in excitation that might contribute to epileptogenesis. Finally, neuronal cell loss in the dentate gyrus granule cell layer was analyzed. In rats, inhibition and excitation in the dentate gyrus were monitored 1, 4, and 8 weeks after electrically induced self-sustaining status epilepticus (SSSE). Control animals had electrodes implanted either without subsequent stimulation or with stimulation but under barbiturate anesthesia, neither of which resulted in subsequent spontaneous seizures or impairment of inhibition. Following SSSE 80% of animals developed seizures after 8 weeks. A pronounced impairment of inhibition 1 week after SSSE was followed by gradual recovery over 8 weeks. In the dentate gyrus, cell damage was highly variable most likely explaining the heterogeneity of changes in excitatory parameters. Loss of GABAergic inhibition in the dentate gyrus may facilitate initiation of epileptogenesis but impaired inhibition is not required for the process of epileptogenesis to be maintained.

Furosemide Terminates Limbic Status Epilepticus in Freely Moving Rats

Summary:u2002 Purpose: To evaluate the anticonvulsant properties of furosemide and to determine sedative side effects compared with pentobarbital and diuretic side effects compared with saline‐treated controls in an experimental model of limbic status epilepticus.

Optical imaging reveals reduced seizure spread and propagation velocities in aged rat brain in vitro

Old age is the most common time for patients to develop epileptic seizures, and due to their frequent unusual clinical presentation the diagnosis of epilepsy is often delayed in the elderly. It is as yet unknown if pronounced alterations in the plastic properties of aging nervous tissue contribute to these phenomena. We employed a non-lesional in vitro epilepsy model to study seizure susceptibility, spread pattern, and propagation velocities in combined hippocampal-entorhinal cortex slices of aged rats and controls using electrophysiological methods and imaging of intrinsic optical signals. In aged animals we saw a less extensive spread of seizure-like events into areas adjacent to the region of onset of activity and a decreased spread velocity in various anatomical regions. In addition, both the activity-dependent shrinkage of the extracellular space (ECS)-volume and the extracellular K(+) concentration were significantly reduced compared to controls. The results of this study are consistent with the clinical observation that epileptic seizures in the elderly have a reduced tendency to spread. In addition, our data suggest that in the absence of structural lesions seizure susceptibility in the aging brain is not increased.

Status epilepticus induces increasing neuronal excitability and hypersynchrony as revealed by optical imaging.

In the wake of acquired brain insults such as status epilepticus (SE), time-dependent neuronal network alterations may occur resulting in cortical hyperexcitability and enhanced synchrony merging into chronic epilepsy. To better understand the underlying processes, we performed electrophysiological and optical imaging studies on combined hippocampal-entorhinal cortex slices. These were prepared from rats 1, 4 and 8 weeks after electrically-induced SE. Non-invasive imaging using intrinsic optical signal changes allowed detailed analysis of onset and spread patterns of seizure-like events (SLE) since coverage of the entire preparation is possible. The latency to occurrence of first SLEs after omission of Mg(2+) from the artificial cerebrospinal fluid was significantly reduced at 4 and 8 weeks after SE compared with all other groups indicating increased brain excitability. Optical imaging displayed multiregional onset and discontiguous propagation of SLEs 8 weeks after SE. Such patterns indicate neuronal hypersynchrony and are not encountered in naïve rodents in which SLEs commonly begin in the entorhinal cortex and display contiguous spread to invade adjacent regions. The electrophysiological and optical findings of the current study indicate evolving fundamental brain plasticity changes after the detrimental event predisposing to chronic epilepsy. The current results should be incorporated in any strategies aiming at prevention of chronic epilepsy.

Functional and morphological changes in the dentate gyrus after experimental status epilepticus

Status epilepticus may cause long-term functional and structural consequences possibly resulting in brain dysfunctions such as chronic epilepsy. In epileptogenesis, the dentate gyrus plays a key role in regulating the excitability of highly vulnerable and potentially epileptogenic downstream structures in the hippocampus proper. One, four and eight weeks after electrically induced status epilepticus, excitability and neuronal degeneration in the rat dentate gyrus were examined with intracerebral electrodes and Fluoro Jade (FJ) staining, respectively. Half of the animals had developed chronic epilepsy by 8 weeks after status epilepticus. Sham-operated controls did not exhibit seizures, and the excitatory parameters remained unchanged. Compared to controls, 8 weeks after status epilepticus the population spike latency in the dentate gyrus was significantly reduced (p<0.05) and substantial neuronal degeneration was seen (p<0.05). In summary, status epilepticus results in functional and morphological alterations in the dentate gyrus likely contributing to epileptogenesis.

Gabapentin–induced severe myoclonus in a patient with impaired renal function

Sirs: A 66-year-old male patient presented with severe spontaneous brief jerks of all extremities resulting in repeated falls. Less pronounced jerks had already developed over recent weeks but substantial aggravation had evolved only within the last 24 hours. The previous medical history included vasculitis on the basis of macroglobulinemia that had caused painful sensorimotor neuropathy. The analgesic drug treatment included a 50-μg/h fentanyl patch every 3 days and 900 mg gabapentin daily for the past 2 years. Severe generalised atherosclerosis had caused impairment of renal function which was still compensated with only a slight increase in creatinine to 1.32 mg/dl (normal range, < 1.2) and normal blood urea nitrogen (BUN) in the previous 2 years. On neurological examination the patient’s speech was dysarthric and the patient showed mental slowing. There were brief lapses of muscle contraction with loss of posture affecting the upper and lower limbs. There was no weakness. The ankle reflexes were absent, bilaterally, the plantar responses were flexor. The patient was unable to stand and walk owing to continuing generalised myoclonus. In the sensory system there was moderate hypesthesia and slight pallhypesthesia of the distal lower extremities. Immediate laboratory findings revealed increased creatinine of 2.67 mg/dl and BUN of 104 mg/dl (normal range, 14 to 46). There were no features of impaired liver function and aspartate-aminotransferase serum concentration was within the normal range. The acute serum concentration of gabapentin 4 h after the last dose was taken yielded 23.8 μg/ml (range of serum concentration with common dosages, 2 to 16) [1]. The serum concentration of the substance was determined using liquid chromatography mass-spectrometry. After discontinuation of gabapentin for 24 h, the myoclonus disappeared and the patient was no longer dysarthric or mentally slow. An analysis 23 h later yielded decreased serum concentrations of gabapentin down to 10.9 μg/ml at the time. At this time creatinine (2.46 mg/dl) and BUN (103 mg/dl) were still elevated. Myoclonus is usually seen in patients with metabolic encephalopathies (mainly due to liver failure) or intoxication with antiepileptic drugs [3]. The present patient was treated with gabapentin for neuropathic pain. Given the known impaired renal function in the patient and the fact that gabapentin is exclusively eliminated by renal excretion [5], we suspected gabapentin intoxication as the cause of his severe myoclonus. Laboratory examinations confirmed a markedly increased gabapentin serum concentration amounting to values well above the assumed upper limit of the therapeutical range. The causal relationship between massively increased serum levels of gabapentin and severe myoclonus was further emphasized by cessation of symptoms after temporary drug discontinuation. As renal parameters had not improved at the stage at which myoclonus resolved uremic encephalopathy is unlikely to have contributed to the occurrence of severe myoclonus. Gabapentin at a mean daily dosage of 2,000 mg (range, 800 to 3,200) has been reported to cause subtle myoclonus in 13 out of 104 consecutive patients with epilepsy [2]. Furthermore, three patients with end-stage renal disease have been reported with disabling myoclonus following initiation or dosage-increase of gabapentin [6]. In these cases gabapentin dosages between 600 and 1,600 mg daily caused myoclonus but serum concentrations were not available. The present patient developed severe myoclonus with gabapentin serum concentrations of 24 μg/ml. The decrease in serum concentrations down to 11 μg/ml within 23 h indicates an elimination half-life of more than 20 h compared with 4.8 to 8.7 h in patients with normal renal function [5]. In this patient, creatinine had doubled within 4 weeks prior to the onset of severe myoclonus because of reduced fluid intake. It is likely that gabapentin serum concentration rose slowly because of increasing renal dysfunction in the weeks before although aggravation of myoclonus had occurred rapidly. This may indicate that gabapentininduced myoclonus results from a threshold effect rather than from a linear increase in concentration. Interestingly, a threshold effect for myoclonus has already been shown for the pharmacologically similar substance pregabalin [4]. In conclusion, administration of gabapentin should be performed with caution in patients with endstage renal disease and also in those with compensated renal dysfunction. Fortunately, even disabling myoclonus resolved following discontinuation of the LETTER TO THE EDITORS