Dyspnea in amyotrophic lateral sclerosis: The Dyspnea-ALS-Scale (DALS-15) essentially contributes to the diagnosis of respiratory impairment.

BACKGROUND: Dyspnea is a cardinal but often underestimated symptom in amyotrophic lateral sclerosis (ALS). The newly developed Dyspnea-ALS-Scale (DALS-15) is highly relevant for therapeutic decisions because dyspnea is a separate criterion to consider noninvasive ventilation (NIV) in ALS. In comparison to the limited effects of neuroprotective compounds, NIV has the greatest impact on survival and improves quality of life. OBJECTIVE: To investigate whether dyspnea corresponds to parameters of respiratory status mainly used in clinical neurological practice. We also investigated if the DALS-15 could help identify patients for consideration of NIV in whom neither spirometry nor blood gas parameters indicate the need for NIV (forced vital capacity (FVC) < 50% or probable <75%, pCO2 ≥45  mmHg). METHODS: Seventy ALS patients with dyspnea according to the DALS-15 obtained blood gas analysis and spirometry (FVC in sitting and supine positions). The supine decline in FVC was calculated. RESULTS: There was no linear relationship between dyspnea and spirometry as well as blood gases. 83% of our patients had an upright FVC still greater than 50% and no daytime hypercapnia. CONCLUSIONS: Our study clearly shows that dyspnea can occur independently of objective indicators of respiratory impairment like spirometry or blood gases. Hence, the DALS-15 covers another aspect of respiratory impairment than these tests and refers to the subjective component of respiratory impairment. It detects dyspnea in a considerable proportion of patients in whom NIV should thus be considered although their spirometric and blood gas results do not point towards NIV. The DALS-15 therefore may help to improve the stratification of patients with respiratory impairment for more efficient symptom management and timely coordination of care.

Diagnostic criteria for amyotrophic lateral sclerosis: A multicentre study of inter-rater variation and sensitivity.

OBJECTIVE: This study assesses inter-rater agreement and sensitivity of diagnostic criteria for amyotrophic lateral sclerosis (ALS). METHODS: Clinical and electrophysiological data of 399 patients with suspected ALS were collected by eleven experienced physicians from ten different countries. Eight physicians classified patients independently and blinded according to the revised El Escorial Criteria (rEEC) and to the Awaji Criteria (AC). Inter-rater agreement was assessed by Kappa coefficients, sensitivity by majority diagnosis on 350 patients with follow-up data. RESULTS: Inter-rater agreement was generally low both for rEEC and AC. Agreement was best on the categories "Not-ALS", "Definite", and "Probable", and poorest for "Possible" and "Probable Laboratory-supported". Sensitivity was equal for rEEC (64%) and AC (63%), probably due to downgrading of "Probable Laboratory-supported" patients by AC. However, AC was significantly more effective in classifying patients as "ALS" versus "Not-ALS" (p < 0.0001). CONCLUSIONS: Inter-rater variation is high both for rEEC and for AC probably due to a high complexity of the rEEC inherent in the AC. The gain of AC on diagnostic sensitivity is reduced by the omission of the "Probable Laboratory-supported" category. SIGNIFICANCE: The results highlight a need for initiatives to develop simpler and more reproducible diagnostic criteria for ALS in clinical practice and research.

Effectiveness of a standardized patient education program on therapy-related side effects and unplanned therapy interruptions in oral cancer therapy: a cluster-randomized controlled trial.

PURPOSE: Oral agents for cancer treatment are increasingly prescribed due to their benefits. However, oral cancer medications are difficult to handle and have a considerable potential for side effects. This type of therapy requires a high level of self-management competence by the patient. A standardized patient education program provided by physicians and oncology nurses may positively influence the handling of oral agents. The aim of the study was to evaluate the impact of a standardized patient education program provided by specially trained oncology nurses on therapy management regarding side effects and unplanned therapy interruptions. METHODS: One hundred sixty-five patients from 28 office-based oncology practices from all over Germany participated in this cluster-randomized controlled study. Patients of both intervention (n = 111) and standard care groups (n = 54) received the usual oncologist counseling; in addition, the patients from the intervention group (k = 17 practices) received an education from specially trained oncology nurses. The time of observation was 3 months per patient. RESULTS: The patients of the intervention group reported fewer side effects (skin rash, pain, fatigue, nausea, vomiting). Patients in the standard care group interrupted the therapy more frequently without informing their oncologist, compared to the intervention group. CONCLUSIONS: Patients benefit from a standardized patient education program provided by specially trained oncology nurses. They tend to handle side effects and critical situations better.

Progression of alpha-synuclein pathology in multiple system atrophy of the cerebellar type.

AIMS: The aim of this study was to identify early foci of α-synuclein (α-syn pathology) accumulation, subsequent progression and neurodegeneration in multiple system atrophy of the cerebellar type (MSA-C). METHODS: We analysed 70-µm-thick sections of 10 cases with MSA-C and 24 normal controls. RESULTS: MSA-C cases with the lowest burden of pathology showed α-syn glial cytoplasmic inclusions (GCIs) in the cerebellum as well as in medullary and pontine cerebellar projections. Cerebellar pathology was highly selective and severely involved subcortical white matter, whereas deep white matter and granular layer were only mildly affected and the molecular layer was spared. Loss of Purkinje cells increased with disease duration and was associated with neuronal and axonal abnormalities. Neocortex, basal ganglia and spinal cord became consecutively involved with the increasing burden of α-syn pathology, followed by hippocampus, amygdala, and, finally, the visual cortex. GCIs were associated with myelinated axons, and the severity of GCIs correlated with demyelination. CONCLUSIONS: Our findings indicate that cerebellar subcortical white matter and cerebellar brainstem projections are likely the earliest foci of α-syn pathology in MSA-C, followed by involvement of more widespread regions of the central nervous system and neurodegeneration with disease progression.

Guillain-Barré syndrome associated with autochthonous infection by hepatitis E virus subgenotype 3c.

In this report, we present a case of a 50-year-old immunocompetent man with Guillain-Barré syndrome (GBS) associated with an autochthonous hepatitis E virus (HEV) infection. The patient presented with tetraparesis and elevated liver enzymes. HEV infection was confirmed serologically and by polymerase chain reaction (PCR) from blood and stool. Phylogenetic analysis revealed a novel HEV genotype 3 isolate closely related to other subgenotype 3c isolates from pig livers purchased in Germany. This indicates an autochthonous, potentially food-related hepatitis E and is, to our knowledge, the first report about a neurological syndrome associated with an HEV subgenotype 3c infection.

Electrophysiological responses to emotional prosody perception in cochlear implant users.

The present electroencephalographic (EEG) study investigated the ability of cochlear implant (CI) users to recognize emotional prosody. Two CI speech-processing strategies were compared: the ACE (Advance Combination Encoder) and the newly developed MP3000. Semantically neutral sentences spoken in three different emotional prosodies (neutral, angry, happy) were presented to 20 post-lingually deafened CI users and age-matched normal-hearing controls. Event related potentials (ERPs) were recorded to study the N100 and the P200 responses. In addition, event-related spectral power modulations were calculated to study the brain activity corresponding to the recognition of prosody in earlier (0-400) as well as later (600-1200) part of the stimuli where the prosodic features differed maximally. CI users with MP3000 strategy showed a higher proportion of correctly recognized prosodic information compared to the ACE strategy users. Our ERP results demonstrated that emotional prosody elicited significant N100 and P200 peaks. Furthermore, the P200 amplitude in response to happy prosodic information was significantly more positive for the MP3000 strategy compared to the ACE strategy. On spectral power analysis, two typical gamma activities were observed in the MP3000 users only: (1) an early gamma activity in the 100-250 ms time window reflecting bottom-up attention regulation; and (2) a late gamma activity between 900 and 1100 ms post-stimulus onset, probably reflecting top-down cognitive control. Our study suggests that the MP3000 strategy is better than ACE in regard to happy prosody perception. Furthermore, we show that EEG is a useful tool that, in combination with behavioral analysis, can reveal differences between two CI processing strategies for coding of prosody-specific features of language.

Prevalence and prognostic impact of comorbidities in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is characterized by rapidly progressive paralysis of striated muscles due to the loss of upper and lower motor neurons. The disease leads to death within 2-5 years, mainly due to respiratory failure. The pathogenesis of ALS is still unexplained for the most part. In this study, we aimed to determine the prevalence of different cardiovascular, metabolic, and neuropsychiatric comorbidities in a large ALS cohort and to evaluate their influence on the disease course. METHODS: A cohort of 514 patients with ALS of our ALS outpatient clinic was investigated retrospectively with reference to known prognostic factors and comorbidities. The prevalence of concomitant diseases was compared with the data from the German general population. Uni- and multivariate survival analyses were performed using the Cox proportional hazards model and Kaplan-Meier analysis. RESULTS: The prevalence of cardiovascular diseases and cardiovascular risk factors was significantly lower in patients with ALS compared to the German general population, whilst the prevalence of dementia, parkinsonism, and depressive symptoms was significantly higher in the ALS cohort. None of the investigated comorbidities had an influence on the disease course or on the survival of patients. CONCLUSIONS: Persons with cardiovascular diseases or risk factors seem to be at lower risk of ALS. Although these diseases are apparently somehow protective regarding ALS susceptibility, their presence did not modify disease progression and survival in patients with ALS. Our study further confirms the well-known continuum between ALS and dementia. It also suggests a link with other neurodegenerative diseases such as Parkinson's disease.

[Carpal tunnel syndrome in children with mucopolysaccharidosis type 1H: diagnosis and therapy in an interdisciplinary centre]. / Karpaltunnelsyndrom bei Kindern mit Mukopolysaccharidose Typ 1H. Diagnostik und Therapie im Rahmen eines interdisziplinären Zentrums.

Carpal tunnel syndrome is common in children with mucopolysaccharidosis type 1H (MPS type 1H). Clinical signs of carpal tunnel syndrome are frequently absent in these children and it is often very difficult to perform and interpret neurophysiological investigations. In this article we wish to present our experience and results regarding the diagnosis and postoperative results after decompression of the median nerve.In an interdisciplinary set-up we are currently treating 11 MPS type 1H children following blood stem cell transplantation. 7 patients were operated 12 times (5 bilateral operations) because of a carpal tunnel syndrome (age at the time of operation 83,3 months, (43-143 months), 2 male, 5 female). 6 patients had a follow up after 23,7 months (9-59 months). 6 patients had a histological analysis of the flexor retinaculum. Three patients had a postoperative neurophysiological investigation.Each of the operated patients had at least 1 preoperative clinical sign of a carpal tunnel syndrome. We found at least 1 pathological finding in motor and sensory nerve conduction studies in each patient. 6 of the 7 children operated on were symptom-free at postoperative follow-up. 1 of the 3 patients with a postoperative neurophysiological follow up showed a deterioration of the nerve conduction studies. This patient was free of symptoms postoperatively. Biopsy of the flexor retinaculum confirmed abundant proteoglycan deposition. We had neither postoperative complications nor were revisional operations necessary.The Diagnosis of a carpal tunnel syndrome in children with MPS Typ 1H needs a thorough medical history, the correct interpretation of the clinical symptoms and sophisticated nerve conduction studies. Wether the improvement of the postoperative clinical situation lasts has to be evaluated in a long term investigation especially because in one patient in our group we saw a deterioration of the nerve conduction studies postoperatively.

Human hypothalamus shows differential responses to basic motivational stimuli--an invasive electrophysiology study.

The hypothalamus supports basic motivational behaviours such as mating and feeding. Recording directly from the posterior inferior hypothalamus in a male patient receiving a deep brain stimulation (DBS) electrode for the alleviation of cluster headache, we tested the hypothalamic response to different classes of motivational stimuli (sexually relevant: pictures of dressed and undressed women; pictures of food) and pictures of common objects as control. Averaged local field potentials (LFP) to sexually relevant stimuli were characterized by a biphasic significantly enhanced response (relative to objects; bootstrapping statistics) with a first phase starting at around 200 ms and a second phase peaking at around 600 ms. Sexually relevant stimuli also showed a greatly enhanced positivity relative to other stimulus classes in surface event-related potentials in a group of 11 male control participants. It is suggested that the hypothalamus is involved in the recruitment of attentional resources by sexually relevant stimuli reflected in this surface positivity. In a second session, the response to food stimuli relative to objects was tested in two states: after fasting for 14 h, LFPs to food and object stimuli showed significant differences in between 300 and 850 ms, which disappeared after a full high-calorie meal, thus replicating classic studies in monkeys [Rolls et al., Brain Res (1976) 111:53-66]. The current data are the first to demonstrate hypothalamic responses to the sight of motivational stimuli in man and thus shows that recording from DBS electrodes might provide important information about the cognitive functions of subcortical structures.

Deficient recognition of emotional prosody in primary focal dystonia.

BACKGROUND: Primary dystonia is a movement disorder attributed mainly to basal ganglia dysfunction. Besides motor control, striatopallidal structures are known to implement also non-motor functions including processing of cognitive and emotional information. Previous research has already demonstrated deficient recognition of emotional faces in patients with primary focal dystonia. However, it remains elusive if emotional prosody processing in dystonia is also affected. METHODS: In this study, 30 patients with primary cervical dystonia (CD) and 30 healthy control subjects (HC) had to classify auditory presented words according to their emotional prosody (angry, happy, relaxed, sad). RESULTS: Analysis of hit rates and reaction times revealed a significantly poorer performance of patients with CD in judging angrily intonated words. Additional psychological assessment (SCL-90 R) demonstrated a higher level of psychological distress in patients with CD who displayed symptoms of somatization, anxiety and depression. CONCLUSIONS: Together these findings bring further insight into the basal ganglia involvement in processing of emotional prosody and emphasize the importance to identify the psychopathological symptoms in patients with CD as complementary to the motor deficit.

The temporal profile of inflammatory markers and mediators in blood after acute ischemic stroke differs depending on stroke outcome.

BACKGROUND: Early inflammation has been suggested as an important factor contributing to unfavorable prognosis after acute ischemic stroke. The present study aimed to clarify the temporal dynamics of discrete inflammatory markers/mediators for future mechanism-targeting anti-inflammatory strategies in ischemic brain damage. METHODS: Blood samples of 69 patients with transient ischemic attack or ischemic stroke were taken upon admission and at time points 6, 12 and 24 h, as well as 3 and 7 days after symptom onset for analysis of monocyte chemotactic protein-1 (MCP-1), matrix metalloproteinase-9 (MMP-9), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), interleukin-6 (IL-6), C-reactive protein (CRP) and the brain damage marker S100B. Clinical scores (modified Rankin Scale, National Institute of Health Stroke Scale) were assessed on day 90. RESULTS: MCP-1, MMP-9, TIMP-1, IL-6, CRP and S100B showed significantly different time courses depending on stroke outcome. While the levels of IL-6, MCP-1 and MMP-9 increased already a few hours after symptom onset, CRP and S100B gradually rose commencing at 12-24 h. TIMP-1 demonstrated an extended plateau. By multiple linear regression analysis IL-6, MCP-1, TIMP-1 and S100B were determined to be independently related to clinical outcome scores at specific time points. CONCLUSIONS: Our data show important differences in the early time course of several potential markers for the complex network of inflammation and brain damage after ischemic stroke depending on stroke outcome. This must be considered for any therapeutical approach using anti-inflammatory treatment.

Modulation of synaptic transmission and analysis of neuroprotective effects of valproic Acid and derivates in rat embryonic motoneurons.

Amyotrophic lateral sclerosis is a devastating motoneuron disorder for which no effective treatment exists. There is some evidence for neuroprotective effects of valproic acid (VPA). The beneficial effects, however, are limited due to the adverse effects of VPA. To overcome this problem, a number of VPA derivates with fewer side effects have been synthesized. In the present study, we investigated the viability of highly purified embryonic motoneurons cultured on glial feeder layers, composed of either astrocytes or Schwann cells, or in monoculture, in presence of VPA and its three derivates 3-propyl-heptanoic acid (3-PHA), PE-4-yn enantiomers (R- and S-PE-4-yn). An excitotoxic stimulus, kainate (KA), was added at day in vitro 9 (DIV9) and the neuroprotective effect of either simultaneous incubation (DIV9) or pre-incubation (DIV1) of VPA and its derivates was tested. The survival of motoneurons under simultaneous application of KA and VPA derivates was not remarkably increased. Pre-incubation with VPA and even more with the derivates before the addition of KA, however, significantly reduced their vulnerability against the KA-induced neurotoxic effect. Our data suggest that the neuroprotective capacities of VPA and its three derivates tested here drastically increase when they are added several days before KA. Most prominent neuroprotective effects were seen for the PE-4-yn enantiomers. Patch-clamp experiments revealed an antiexcitotoxic effect of the S-PE-4-yn enantiomer that reduces the frequency of postsynaptic currents and enhances the inhibitory postsynaptic transmission dependent on the co-culture condition.

Long-term treatment of spasticity with botulinum toxin type A: an analysis of 1221 treatments in 137 patients.

OBJECTIVES: Spasticity is a complex disorder that causes significant disability in affected patients. We here present long-term results of botulinum toxin type A (BoNT-A) treatment in spasticity of various etiologies in the upper and lower limbs. PATIENTS AND METHODS: We evaluated long-term results of BoNT-A treatment with Dysport and Botox for up to 12 years in 137 patients with spasticity of various etiologies. The focus was laid on efficacy, dosage, safety and side effects over time in a retrospective analysis of the database of our movement disorder clinic. RESULTS: The mean clinical benefit, latency and duration of response were comparable for both products. Side effects were generally mild and comparable for the two products. We found a significant negative correlation between time from onset of spasticity to start of BoNT-A treatment and degree of improvement after treatment. CONCLUSION: Our data confirm the safety and efficacy of BoNT-A treatment of spasticity of different etiologies over a long period of time. Furthermore, the data imply that BoNT-A treatment should be started early after appearance of spasticity to obtain better treatment response.

Interaction of androsterone and progesterone with inhibitory ligand-gated ion channels: a patch clamp study.

Gamma-aminobutyric acid receptor type A (GABA(A)) receptor channels mediate fast inhibitory neurotransmission throughout the central nervous system while the expression of ionotropic glycine receptors is mainly restricted to the spinal cord and brain stem. Neuroactive steroids are well known as positive allosteric modulators of GABA(A) receptor function. Furthermore, there have been hints for an interaction of neuroactive steroids with ionotropic glycine receptors. The aim of the study was to characterize the effect of androsterone and progesterone on alpha(1) and alpha(1)beta glycine receptor and alpha(1)beta(2)gamma(2) GABA(A) receptor channels and to examine the molecular interactions between ligands and receptors. Electrophysiological recordings were performed on HEK 293 cells using the patch clamp technique in combination with an ultrafast perfusion system. A direct activation of inhibitory ionotropic receptors was observed for androsterone at GABA(A) receptor channels. A coactivation of currents elicited by nonsaturating agonist concentrations was observed with androsterone and progesterone at glycine and GABA(A) receptor channels. We could show that association of beta subunits with alpha subunits affects the sensitivity of glycine receptors to androsterone. In contrast to previous reports in which recombinant glycine receptors were inhibited by progesterone, a potentiating effect was revealed by our experiments. At concentrations of 0.1 mM and higher, there were also hints to a channel block-like mechanism. In conclusion, different molecular mechanisms of interaction between neuroactive steroids and GABA as well as glycine receptors could be identified and quantitatively described. Our data clarify the role of steroid compounds in the modulation of inhibitory receptor channel function.

[Acute brain stem syndromes]. / Akute Hirnstammsyndrome.

The brain stem consists of the mesencephalon, pons, and medulla oblongata and contains the nuclei of the cranial nerves III to XII, their complex connectivity, the ascending and descending fibre tracts, and the cerebellar connections. The corticobulbar and corticospinal tracts and the medial lemniscus cross its midline. Vital functions such as wakefulness, respiration, swallowing, and circulation are controlled there. Here we discuss acute brain stem syndromes of vascular, inflammatory, and toxic-metabolic origin. They present frequently with alternating symptoms, i.e. ipsilateral cranial nerve deficits associated with contralateral signs of long-fibre tract involvement and with various disturbances of the oculomotor system. Modern diagnostic and therapeutic approaches are described along with clinical presentation.

A long-term follow-up of botulinum toxin A in cervical dystonia.

OBJECTIVE: Cervical dystonia (CD) is the most common form of adult-onset focal dystonia, and botulinum toxin A (BoNT-A) has become the first-line treatment for this condition. METHODS: In this work, we present data of 207 CD patients treated with BoNT-A for 6.7 +/- 3.5 years. One hundred and sixty-three patients were treated with Dysport (mean dose, 389 +/- 144 U) and 44 with Botox (mean dose, 145 +/- 44 U). RESULTS: The mean clinical benefit, based on a 0-3 scale (0=no effect, 1=slight, 2=moderate and 3=marked improvement) was similar for Dysport (2.5 +/- 0.3) and Botox (2.2 +/- 0.4). Adverse events were mild and similar for both products. Fewer than 2% of the patients developed neutralizing antibodies. DISCUSSION: These data confirm the efficacy and safety of BoNT-A treatment in CD over an extended period of up to 14 years.

Anterior cysts of the spine: a difficult differential diagnosis to amyotrophic lateral sclerosis.

We describe three patients referred to our ALS/MND clinic with suspected diagnosis of amyotrophic lateral sclerosis (ALS). The patients were all male, middle aged, and their initial symptoms were weakness and fasciculations in upper limb muscles. Results of clinical and electrophysiological examination in all cases were in accordance with possible ALS according to the revised El Escorial criteria. Other conditions mimicking ALS appeared to be excluded by extensive technical examinations and laboratory tests. Only repeated MRI examinations revealed anterior spinal cysts several years after symptom onset. This report intends to highlight this rare and difficult differential diagnosis of ALS and underlines the value of the revised El Escorial criteria in conjunction with electrophysiology to asses the certainty of the diagnosis ALS.

High-affinity blockade of voltage-operated skeletal muscle and neuronal sodium channels by halogenated propofol analogues.

BACKGROUND AND PURPOSE: Voltage-operated sodium channels constitute major target sites for local anaesthetic-like action. The clinical use of local anaesthetics is still limited by severe side effects, in particular, arrhythmias and convulsions. These side effects render the search for new local anaesthetics a matter of high interest. EXPERIMENTAL APPROACH: We have investigated the effects of three halogenated structural analogues of propofol on voltage-operated human skeletal muscle sodium channels (Na(V)1.4) and the effect of one compound (4-chloropropofol) on neuronal sodium channels (Na(V)1.2) heterologously expressed in human embryonic kidney cell line 293. KEY RESULTS: 4-Iodo-, 4-bromo- and 4-chloropropofol reversibly suppressed depolarization-induced whole-cell sodium inward currents with high potency. The IC(50) for block of resting channels at -150 mV was 2.3, 3.9 and 11.3 microM in Na(V)1.4, respectively, and 29.2 microM for 4-chloropropofol in Na(V)1.2. Membrane depolarization inducing inactivation strongly increased the blocking potency of all compounds. Estimated affinities for the fast-inactivated channel state were 81 nM, 312 nM and 227 nM for 4-iodopropofol, 4-bromopropofol and 4-chloropropofol in Na(V)1.4, and 450 nM for 4-chloropropofol in Na(V)1.2. Recovery from fast inactivation was prolonged in the presence of drug leading to an accumulation of block during repetitive stimulation at high frequencies (100 Hz). CONCLUSIONS AND IMPLICATIONS: Halogenated propofol analogues constitute a novel class of sodium channel-blocking drugs possessing almost 100-fold higher potency compared with the local anaesthetic and anti-arrhythmic drug lidocaine. Preferential drug binding to inactivated channel states suggests that halogenated propofol analogues might be especially effective in suppressing ectopic discharges in a variety of pathological conditions.

Molecular mechanisms of interaction between the neuroprotective substance riluzole and GABA(A)-receptors.

The antiepileptic drug riluzole is used as a therapeutic agent in amyotrophic lateral sclerosis due to its neuroprotective effects. Besides presynaptic inhibition of GABAergic and preferentially glutamatergic transmission, it also potentiates postsynaptic GABA(A)-receptor function. We investigated the postsynaptic effects of riluzole on GABA(A)-receptor channels by use of the patch-clamp technique. Recombinant alpha1beta2gamma(2s) and alpha1beta2 GABA(A) receptors were expressed in HEK 293 cells by transient transfection. Pulses of GABA were applied in combination with different concentrations of riluzole to whole cell or outside-out patches with either alpha1beta2gamma(2s) or alpha1beta2 GABA(A)-receptor channels. Co-application of riluzole led to a slight decrease of absolute peak current amplitudes and steady-state currents in prolonged presence of GABA at saturating concentrations. In the presence of riluzole, enhancement of current amplitudes was observed with lower concentrations of GABA at alpha1beta2gamma(2s) receptors and to a lower extent also at alpha1beta2 receptors. Thus, the potentiating effect of riluzole was shown to be not abolished in the absence of the gamma(2s)-subunit. A further prominent effect of riluzole was a highly significant acceleration of the time course of current decay, most probably pointing to an open-channel block-like mechanism of action. As both receptor subtypes were affected similarly by the block, it could be concluded that the respective binding sites should be assumed within a region of high sequence homology like it is given for the channel-lining M2 domain of GABA(A)-receptor subunits. In conclusion, three different molecular mechanisms of interaction of the neuroprotective compound riluzole were observed at two different subtypes of GABA(A) receptor channels. The results further point to the impact of the inhibitory as well as the excitatory synaptic activity as a pharmacological target to counteract chronic excitotoxicity and reveal molecular mechanisms of action of the only one neuroprotective drug in current clinical use in patients suffering from amyotrophic lateral sclerosis.