Epileptic seizures associated with intrathecal baclofen application

Kofler, Markus; Kronenberg, Martina F.; Rifici, Carmela; Saltuari, Leopold; Bauer, G.

doi:10.1212/wnl.44.1.25

Cited by 95 publications

(44 citation statements)

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“…Although GABA B Rs are mediators of slow inhibitory effects of GABA in the brain, a series of experimental and clinical observations have shown that application of the canonical agonist baclofen can induce seizures in animal models, as well as patients (15,16,29,30). To address a possible mechanism, we performed in vivo experiments in a mouse model of TLE and found that baclofen acts in a dose-dependent manner: at a high dose (10 mg/kg), baclofen reduces network excitability and oscillatory activity, consistent with its inhibitory actions.…”

Section: Discussionmentioning

confidence: 99%

“…GABA B Rs are expected to have an overall antiepileptic effect, and indeed, the receptor KO animals show an epileptic phenotype (14). However, there is also evidence that the receptor agonist baclofen can induce seizures in patients after intrathecal application (15,16). The picture is further complicated by the fact that GABA B R expression can be altered in both epileptic patients, e.g., in mesial temporal lobe epilepsy (mTLE) (17), and animal models (18).…”

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confidence: 99%

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GABA _B autoreceptor-mediated cell type-specific reduction of inhibition in epileptic mice

Dugladze

Maziashvili

Börgers

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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GABA B receptors (GABA B Rs) mediate slow inhibitory effects on neuronal excitability and synaptic transmission in the brain. However, the GABA B R agonist baclofen can also promote excitability and seizure generation in human patients and animals models. Here we show that baclofen has concentration-dependent effects on the hippocampal network in a mouse model of mesial temporal lobe epilepsy. Application of baclofen at a high dose (10 mg/kg i.p.) reduced the power of γ oscillations and the frequency of pathological discharges in the Cornu Ammonis area 3 (CA3) area of freely moving epileptic mice. Unexpectedly, at a lower dose (1 mg/kg), baclofen markedly increased γ activity accompanied by a higher incidence of pathological discharges. Intracellular recordings from CA3 pyramidal cells in vitro further revealed that, although at a high concentration (10 μM), baclofen invariably resulted in hyperpolarization, at low concentrations (0.5 μM), the drug had divergent effects, producing depolarization and an increase in firing frequency in epileptic but not control mice. These excitatory effects were mediated by the selective muting of inhibitory cholecystokinin-positive basket cells (CCK + BCs), through enhanced inhibition of GABA release via presynaptic GABA B Rs. We conclude that cell type-specific up-regulation of GABA B R-mediated autoinhibition in CCK + BCs promotes aberrant high frequency oscillations and hyperexcitability in hippocampal networks of chronic epileptic mice.presynaptic inhibition | mTLE model | patch clamp N euronal activity in the hippocampus shows oscillations in behavior-relevant frequency ranges including γ frequencies (30-80 Hz) (1). γ activity is prominent in the aroused brain and has been implicated in higher-level brain functions, such as sensory binding, perception (2), and storage and recall of information (3, 4). At the same time, γ frequency oscillations are also prevalent in epileptic patients and are most often observed at seizure onset during in depth EEG recordings (5). The GABAergic system plays a pivotal role in the generation of γ oscillations (6-8). However, it remains to be resolved how distinct GABAergic receptor subtypes, in particular GABA B receptors (GABA B Rs), contribute to the generation and modulation of pathological network oscillatory activity.GABA B Rs mediate slow inhibitory effects and control synaptic transmission and the excitability of neurons in cortical networks. GABA B Rs are expressed both postsynaptically in somatodendritic compartments and presynaptically in axon terminals, in excitatory principal cell and inhibitory interneurons (9-11). The effects of GABA B R activation on the network are dominated by inhibition leading to an overall dampened population activity. However, if GABAergic interneurons are effected dominantly, as observed for example, during high-frequency stimulation, GABA B R activation can produce disinhibition in principal cells (12,13). Accordingly, the role of GABA B Rs in epilepsy and seizure generation remains ambiguous. GABA B Rs ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

GABA _B autoreceptor-mediated cell type-specific reduction of inhibition in epileptic mice

Dugladze

Maziashvili

Börgers

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…This is possible, though the brevity and frequency of episodes in these cases would be unusual for TGA (Bartsch & Butler, 2013). Baclofen is capable of provoking both generalised and focal seizures, making an epileptic mechanism plausible (Han, Cortez, & Snead, 2012;Kofler et al, 1994). The lack of associated symptoms of epilepsy, EEG abnormalities or response to anticonvulsant treatment, argue somewhat against this diagnosis in CS' case.…”

Section: What Caused the Episodes Of Transient Amnesia?mentioning

confidence: 95%

“…It can be given orally, or, in more severe cases, by infusion from an implanted pump into the CSF (Hsieh & Penn, 2006). This targets the drug on the desired spinal site of action, but the normal bulk flow of CSF toward the brain sometimes leads to CNS side-effects (Kofler, Kronenberg, Rifici, Saltuari, & Bauer, 1994). In overdose, intrathecal baclofen can cause coma and status epilepticus (Nugent, Katz, & Little, 1986;Saltuari, Marosi, Kofler, & Bauer, 1992).…”

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confidence: 99%

The GABAB receptor agonist, baclofen, contributes to three distinct varieties of amnesia in the human brain – A detailed case report

Zeman

Hoefeijzers

Milton

et al. 2016

Cortex

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We describe a patient in whom long-term, therapeutic infusion of the selective gamma-amino-butyric acid type B (GABAB) receptor agonist, baclofen, into the cerebrospinal fluid gave rise to three distinct varieties of memory impairment: i) repeated, short periods of severe global amnesia, ii) accelerated long-term forgetting, evident over intervals of days and iii) a loss of established autobiographical memories. This pattern of impairment has been reported in patients with temporal lobe epilepsy, in particular the subtype of Transient Epileptic Amnesia. The amnesic episodes and accelerated forgetting remitted on withdrawal of baclofen, while the autobiographical amnesia persisted. This exceptional case highlights the occurrence of 'non-standard' forms of human amnesia, reflecting the biological complexity of memory processes. It suggests a role for GABAB signalling in the modulation of human memory over multiple time-scales and hints at its involvement in 'epileptic amnesia'.Dear Professor Gilboa, Thank you for your comments on our paper, and for the reviews, which we found stimulating and helpful .We were glad that you found the paper 'of great value' overall.We have done as you suggested, resubmitting as a regular manuscript, as we found that dealing with the points raised by the reviewers required some additions to the main text of the paper and to the reference list.We decided to leave the description of the control experiment alluded to in the Results (section 3.3, final sentence) in the Supplementary data, as we felt that its inclusion in the main text of the paper was unnecessary. If you disagree, however, we would of course be happy to move it into the main text.We could supply a version of the paper with all changes 'tracked' if you wish.We hope that you now find the paper acceptable for publication. In these responses, for ease of navigation, we have left the reviewers' original remarks in plain text, have italicised our responses and have highlighted the resulting changes to the text:Reviewer #1: In this manuscript (MS) an interesting case of a 52 year old woman is described who showed a complex symptomatology of memory impairments which were attributed to her treatment with intrathecal baclofen for spasticity. While the paper is well-written in general, I have several concerns and comments, which I am going to outline below.The results are in my eyes not as straight-forward as the authors interpret them. I would therefore recommend that the authors devote some more room to discussing other possible interpretations.a) Although the control participants were matched to CS (the patient) with respect to "age, education and performance on standard psychometric tests" the question is whether baclofen (additionally) affected other functions than memory. In particular one would like to know if it impacted on attention and concentration, motivation (to be tested), mood (depression?), and executive functions. There were no significant differences between CS and control participants on standard measur...

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“…There are reports of new-onset seizures after introduction of the IT baclofen, but nearly all describe patients after significant head trauma. 43 In fact, Buonaguro et al 44 recently reported a reduced seizure rate of 13% in 150 children studied, with two patients worsening and one experiencing new onset ictus. Additionally, there are reports of scoliosis exacerbation after IT baclofen.…”

Section: Patient Selection For Intrathecal Baclofenmentioning

confidence: 97%

Intrathecal Pumps

2008

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Summary: Direct neuroaxis drug delivery has expanded the physician's armamentarium to provide treatment options to those who have failed more conservative interventions. Starting from Bier's 'cocainization of the spinal cord' in 1898, direct nervous system pharmacy delivery has long been recognized as an effective means to treat pain. Intrathecal pump systems are now commonplace in the management of numerous pain states, as well as of neuromuscular sequelae of central nervous system injury. There has been much advancement in the physiologic and pharmacologic understanding of direct neuromodulation, providing a growing number of treatment options depending on the specific disease state. As well, surgical techniques and catheter systems have undergone refinements providing improved long-term safety and efficacy. We present a review of the historical evolution to current intrathecal therapies, as well as a dialog regarding patient selection, drug options, and side effects. Also, included is a discussion of surgical techniques, current delivery options and complications concerning pump placement.

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Epileptic seizures associated with intrathecal baclofen application

Cited by 95 publications

References 0 publications

GABA _B autoreceptor-mediated cell type-specific reduction of inhibition in epileptic mice

GABA _B autoreceptor-mediated cell type-specific reduction of inhibition in epileptic mice

The GABAB receptor agonist, baclofen, contributes to three distinct varieties of amnesia in the human brain – A detailed case report

Intrathecal Pumps

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Epileptic seizures associated with intrathecal baclofen application

Cited by 95 publications

References 0 publications

GABA B autoreceptor-mediated cell type-specific reduction of inhibition in epileptic mice

GABA B autoreceptor-mediated cell type-specific reduction of inhibition in epileptic mice

The GABAB receptor agonist, baclofen, contributes to three distinct varieties of amnesia in the human brain – A detailed case report

Intrathecal Pumps

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GABA _B autoreceptor-mediated cell type-specific reduction of inhibition in epileptic mice

GABA _B autoreceptor-mediated cell type-specific reduction of inhibition in epileptic mice