Innovative minimally invasive options to treat drug-resistant epilepsies.

Despite the regular discovery of new molecules, one-third of epileptic patients are resistant to antiepileptic drugs. Only a few can benefit from resective surgery, the current gold standard. Although effective in 50-70% of cases, this therapy remains risky, costly, and can be associated with long-term cognitive or neurological side effects. In addition, patients are increasingly reluctant to have a craniotomy, emphasizing the need for new less invasive therapies for focal drug-resistant epilepsies. Here, we review different minimally invasive approaches already in use in the clinic or under preclinical development to treat drug-resistant epilepsies. Localized thermolesion of the epileptogenic zone has been developed in the clinic using high-frequency thermo-coagulations or magnetic resonance imaging-guided laser or ultrasounds. Although less invasive, they have not yet significantly improved the outcomes when compared with resective surgery. Radiosurgery techniques have been used in the clinic for the last 20years and have proven efficiency. However, their efficacy is not better than resective surgery, and various side effects have been reported as well as the potential risk of sudden unexpected death associated with epilepsy. Recently, a new strategy of radiosurgery has emerged using synchrotron-generated X-ray microbeams: microbeam radiation therapy (MRT). The low divergence and high-flux of the synchrotron beams and the unique tolerance to MRT by healthy brain tissues, allows a precise targeting of specific brain regions with minimal invasiveness and limited behavioral or functional consequences in animals. Antiepileptic effects over several months have been recorded in animal models, and histological and synaptic tracing analysis suggest a reduction of neuronal connectivity as a mechanism of action. The possibility of transferring this approach to epileptic patients is discussed in this review.

[On the use of corticosteroids for critically ill patients with SARS-CoV-2 interstitial pneumonia]. / La corticothérapie chez le patient critique atteint d'une pneumopathie interstitielle à SARS-CoV-2.

The health crisis caused by SARS-Cov2 continues to question the scientific community on an effective treatment to combat the disease. To do this, understanding the pathophysiology is a key element of the research. Although the use of corticosteroids is debated, recent publications on pathogenesis and histologic pattern allow us to consider their use on a different way. Through these two case reports, it seemed interesting to take stock of the most recent data in the literature and on the potential interest of the corticotherapy in specific critically ill patient's cases.

La crise sanitaire provoquée par le SARS-CoV-2 n'a de cesse de questionner la communauté scientifique sur un traitement efficace pour combattre la maladie. La compréhension de la physiopathologie constitue un élément clé de la recherche. Bien que l'utilisation des corticoïdes soit débattue, des publications récentes sur la pathogenèse et l'analyse anatomopathologique nous permettent d'envisager leur utilisation avec un autre angle d'approche. À travers ces deux cas cliniques, il nous semblait intéressant de faire le point sur les données les plus récentes de la littérature sur l'intérêt de la corticothérapie chez le patient critique atteint par la COVID-19.

Significant dose reduction using synchrotron radiation computed tomography: first clinical case and application to high resolution CT exams.

Since the invention of Computed Tomography (CT), many technological advances emerged to improve the image sensitivity and resolution. However, no new source types were developed for clinical use. In this study, for the first time, coherent monochromatic X-rays from a synchrotron radiation source were used to acquire 3D CTs on patients. The aim of this work was to evaluate the clinical potential of the images acquired using Synchrotron Radiation CT (SRCT). SRCTs were acquired using monochromatic X-rays tuned at 80 keV (0.350 × 0.350 × 2 mm3 voxel size). A quantitative image quality comparison study was carried out on phantoms between a state of the art clinical CT and SRCT images. Dedicated iterative algorithms were developed to optimize the image quality and further reduce the delivered dose by a factor of 12 while keeping a better image quality than the one obtained with a clinical CT scanner. We finally show in this paper the very first SRCT results of one patient who received Synchrotron Radiotherapy in an ongoing clinical trial. This demonstrates the potential of the technique in terms of image quality improvement at a reduced radiation dose for inner ear visualization.

[Oxynorm® instant versus Tradonal® odis as level 2 analgesic in an emergency service : a monocentric double blind randomized non-inferiority study]. / Utilisation de l'oxynorm® instant versus tradonal® odis, antalgiques de Palier 2 dans un service d'urgence : une étude monocentrique comparative, randomisée en double aveugle, de non-infériorité.

Pain is one of the most common reasons for consultation in the ER. As far as class II analgesics are concerned, tramadol is most usually used. According to some data from the literature, it would seem that oxycodone and tramadol are equivalent in terms of analgesia. We have tried to prove that oxycodone (Oxynorm® instant) is not less effective than tramadol (Tradonal® odis) in an emergency unit. This is a prospective, monocentric, randomized study carried out amongst ambulatory patients. Those included in the study were given 1 g of paracetamol and a weight-ajusted dose of either tramadol or oxycodone. Every 30 minutes, a simple numerical scale (NS) was established and the clinical parameters were checked. We studied a total of 121 patients divided into 2 groups. There is an average difference of -1.47 between the average ?NS of the oxycodone group and the average ?NS of the tramadol group, with a confidence interval of 95 % (-9.42 - 6.48). The confidence interval does not cross the -10 line considered as the acceptable loss of efficiency, which allows us to conclude that oxycodone is not inferior to tramadol. As far as the adverse effects studied are concerned, there is no significant link between the treatment and the appearance of any side effect.

La douleur est l'un des motifs de consultation le plus fréquent en salle d'urgence. Au sein du palier 2, l'utilisation du tramadol est la plus fréquente malgré ses effets secondaires fréquents. Des données de la littérature suggèrent une équivalence en termes d'analgésie entre l'oxycodone et le tramadol. Nous avons tenté de montrer la non-infériorité de l'oxycodone (Oxynorm® instant) en comparaison au tramadol (Tradonal® odis) dans un service d'urgence. Cette étude est prospective monocentrique randomisée menée au sein d'une population de patients désignés comme ambulants. Les patients inclus recevaient 1 g de paracétamol et une dose de tramadol ou d'oxycodone ajustée au poids corporel. Une échelle numérique simple (EN), outil d'évaluation de la douleur, a été réalisée toutes les 30 minutes, accompagnée par la prise des paramètres cliniques. Nous avons étudié un total de 121 patients. La moyenne de la différence entre la moyenne de ?EN du groupe oxycodone et la moyenne de ?EN du groupe tramadol est de -1,47 (IC à 95 % -9,42 ­ 6,48). L'intervalle de confiance ne vient pas croiser la valeur de -10 fixée comme la perte d'efficacité acceptable, ce qui nous permet de conclure à la non-infériorité de l'oxycodone par rapport au tramadol. Il n'y a pas d'association significative entre le traitement et le fait de présenter des effets secondaires.

[Ultrasonographic measurement of the optical nerve sheath for the diagnosis of intracranial hypertension in the emergency room : a case report]. / Le cas clinique du mois. Mesure échographique du diamètre de la gaine des nerfs optiques et diagnostic de l'hypertension intracrânienne au Service des Urgences.

Early diagnosis and treatment of intracranial hypertension (ICHT) are major components of the management of neurological emergencies. The optic nerve sheath diameter is closely dependent on intracranial pressure and can be measured by bedside ultrasound (US). We report the story of a 70-year-old COPD patient initially admitted to the emergency room for a sepsis of pulmonary origin. An unusual confusion prompted us to perform an US of the optic nerve sheath. This exam clearly suggested the presence of an ICHT. Hence, the diagnostic approach was proceeded and a herpetic encephalitis was demonstrated and successfully treated. In this clinical report, the optic nerve sheath US guided the diagnostic approach and, eventually, therapeutic decision. Several papers have shown the close relationship between increased optic nerve sheath diameter and intracranial hypertension, but we still need further studies to validate a threshold value of this diameter. The clinical relevance of the US optic nerve diameter measure appears interesting. However, further studies on larger samples of patients are needed to confirm this and to establish a validated threshold value.

La précocité du diagnostic et du traitement de l'hypertension intracrânienne (HTIC) est un élément majeur de la prise en charge des pathologies neurologiques aux urgences. Le diamètre de la gaine des nerfs optiques est le reflet direct de la pression intracrânienne et peut être mesuré à l'aide de l'échographie au lit du patient. Nous relatons le cas d'un patient de 70 ans, initialement pris en charge pour un sepsis d'origine pulmonaire dans un contexte de BPCO, et chez qui une confusion inhabituelle a mené à la réalisation d'une échographie de la gaine des nerfs optiques. Celle-ci ayant mis en évidence une HTIC, la démarche diagnostique a été poussée plus en avant et une encéphalite zostérienne a été mise en évidence et traitée précocement avec efficacité. Dans ce cas clinique, l'échographie des nerfs optiques occupe une place prépondérante dans la démarche diagnostique et thérapeutique. L'efficacité de la mesure de la gaine des nerfs optiques pour diagnostiquer une HTIC est démontrée; cependant, il n'existe pas, à l'heure actuelle, de consensus sur une valeur «seuil¼ de diamètre de la gaine. De nouvelles études sont nécessaires pour préciser ce paramètre.

Monochromatic minibeam radiotherapy: theoretical and experimental dosimetry for preclinical treatment plans.

Monochromatic x-ray minibeam radiotherapy is a new radiosurgery approach based on arrays of submillimetric interlaced planar x-ray beams. The aim of this study was to characterize the dose distributions obtained with this new modality when being used for preclinical trials. Monte Carlo simulations were performed in water phantoms. Percentage depth-dose curves and dose profiles were computed for single incidences and interleaved incidences of 80 keV planar x-ray minibeam (0.6 × 5 mm) arrays. Peak to valley dose ratios were also computed at various depths for an increasing number of minibeams. 3D experimental polymer gel (nPAG) dosimetry measurements were performed using MRI devices designed for small animal imaging. These very high spatial resolution (50 µm) dose maps were compared to the simulations. Preclinical minibeams dose distributions were fully characterized. Experimental dosimetry correlated well with Monte Carlo calculations (Student t-tests: p > 0.1). F98 tumor-bearing rats were also irradiated with interleaved minibeams (80 keV, prescribed dose: 25 Gy). This associated preclinical trial serves as a proof of principle of the technique. The mean survival time of irradiated glioma-bearing rats increased significantly, when compared to the untreated animals (59.6 ± 2.8 days versus 28.25 ± 0.75 days, p < 0.001).

Dosimetry protocol for the forthcoming clinical trials in synchrotron stereotactic radiation therapy (SSRT).

PURPOSE: An adequate dosimetry protocol for synchrotron radiation and the specific features of the ID17 Biomedical Beamline at the European Synchrotron Radiation Facility are essential for the preparation of the forthcoming clinical trials in the synchrotron stereotactic radiation therapy (SSRT). The main aim of this work is the definition of a suitable protocol based on standards of dose absorbed to water. It must allow measuring the absolute dose with an uncertainty within the recommended limits for patient treatment of 2%-5%. METHODS: Absolute dosimetry is performed with a thimble ionization chamber (PTW semiflex 31002) whose center is positioned at 2 g cm(-2) equivalent depth in water. Since the available synchrotron beam at the ESRF Biomedical Beamline has a maximum height of 3 mm, a scanning method was employed to mimic a uniform exposition of the ionization chamber. The scanning method has been shown to be equivalent to a broad beam irradiation. Different correction factors have been assessed by using Monte Carlo simulations. RESULTS: The absolute dose absorbed to water at 80 keV was measured in reference conditions with a 2% global uncertainty, within the recommended limits. The dose rate was determined to be in the range between 14 and 18 Gy/min, that is to say, a factor two to three times higher than the 6 Gy/min achievable in RapidArc or VMAT machines. The dose absorbed to water was also measured in a RW3 solid water phantom. This phantom is suitable for quality assurance purposes since less than 2% average difference with respect to the water phantom measurements was found. In addition, output factors were assessed for different field sizes. CONCLUSIONS: A dosimetry protocol adequate for the specific features of the SSRT technique has been developed. This protocol allows measuring the absolute dose absorbed to water with an accuracy of 2%. It is therefore satisfactory for patient treatment.

Treatment plans optimization for contrast-enhanced synchrotron stereotactic radiotherapy.

PURPOSE: Synchrotron stereotactic radiotherapy (SSRT) is a treatment that involves the targeting of high-Z elements into tumors followed by stereotactic irradiation with monochromatic x-rays from a synchrotron source, tuned at an optimal energy. The irradiation geometry, as well as the secondary particles generated at a higher yield by the medium energy x-rays on the high-Z atoms (characteristic x-rays, photoelectrons, and Auger electrons), produces a localized dose enhancement in the tumor. Iodine-enhanced SSRT with systemic injections of iodinated contrast agents has been successfully developed in the past six years in the team, and is currently being transferred to clinical trials. The purpose of this work is to study the impact on the SSRT treatment of the contrast agent type, the beam quality, the irradiation geometry, and the beam weighting for defining an optimized SSRT treatment plan. METHODS: Theoretical dosimetry was performed using the MCNPX particle transport code. The simulated geometry was an idealized phantom representing a human head. A virtual target was positioned in the central part of the phantom or off-centered by 4 cm. The authors investigated the dosimetric characteristics of SSRT for various contrast agents: Iodine, gadolinium, and gold; and for different beam qualities: Monochromatic x-ray beams from a synchrotron source (30-120 keV), polychromatic x-ray beams from an x-ray tube (80, 120, and 180 kVp), and a 6 MV x-ray beam from a linear accelerator. Three irradiation geometries were studied: One arc or three noncoplanar arcs dynamic arc therapy, and an irradiation with a finite number of beams. The resulting dose enhancements, beam profiles, and histograms dose volumes were compared for iodine-enhanced SSRT. An attempt to optimize the irradiation scheme by weighing the finite x-ray beams was performed. Finally, the optimization was studied on patient specific 3D CT data after contrast agent infusion. RESULTS: It was demonstrated in this study that an 80 keV beam energy was a good compromise for treating human brain tumors with iodine-enhanced SSRT, resulting in a still high dose enhancement factor (about 2) and a superior bone sparing in comparison with lower energy x-rays. This beam could easily be produced at the European Synchrotron Radiation Facility medical beamline. Moreover, there was a significant diminution of dose delivered to the bone when using monochromatic x-rays rather than polychromatic x-rays from a conventional tube. The data showed that iodine SSRT exhibits a superior sparing of brain healthy tissue in comparison to high energy treatment. The beam weighting optimization significantly improved the treatment plans for off-centered tumors, when compared to nonweighted irradiations. CONCLUSIONS: This study demonstrated the feasibility of realistic clinical plans for low energy monochromatic x-rays contrast-enhanced radiotherapy, suitable for the first clinical trials on brain metastasis with a homogeneous iodine uptake.

[Synchroton radiotherapy]. / Radiothérapie par rayonnement synchrotron.

Radiation therapy is commonly used in the treatment of cancer. The normal tissue tolerance can be a limit to deliver enough dose to the tumor to be curative. The synchrotron beam presents some interesting physical properties, which could decrease this limitation. Synchrotron beam is a medium energy X-ray nearly parallel beam with high intensity. Three methods are under preclinical investigations: the microbeam, the minibeam and the stereotactic radiotherapy. The first two use a geometric irradiation effect called spatial fractioning. The last one use highly conformational irradiation geometry combined with a dose enhancement due to the presence of high-Z element in the target. Synchrotron radiotherapy preclinical experiments have shown some curative effect on rodent glioma models. Following these encouraging results a phase I/II clinical trial of iodinated enhanced stereotactic synchrotron radiotherapy is currently being prepared at the European Synchrotron Radiation Facility.

Simulation of dose deposition in stereotactic synchrotron radiation therapy: a fast approach combining Monte Carlo and deterministic algorithms.

A hybrid approach, combining deterministic and Monte Carlo (MC) calculations, is proposed to compute the distribution of dose deposited during stereotactic synchrotron radiation therapy treatment. The proposed approach divides the computation into two parts: (i) the dose deposited by primary radiation (coming directly from the incident x-ray beam) is calculated in a deterministic way using ray casting techniques and energy-absorption coefficient tables and (ii) the dose deposited by secondary radiation (Rayleigh and Compton scattering, fluorescence) is computed using a hybrid algorithm combining MC and deterministic calculations. In the MC part, a small number of particle histories are simulated. Every time a scattering or fluorescence event takes place, a splitting mechanism is applied, so that multiple secondary photons are generated with a reduced weight. The secondary events are further processed in a deterministic way, using ray casting techniques. The whole simulation, carried out within the framework of the Monte Carlo code Geant4, is shown to converge towards the same results as the full MC simulation. The speed of convergence is found to depend notably on the splitting multiplicity, which can easily be optimized. To assess the performance of the proposed algorithm, we compare it to state-of-the-art MC simulations, accelerated by the track length estimator technique (TLE), considering a clinically realistic test case. It is found that the hybrid approach is significantly faster than the MC/TLE method. The gain in speed in a test case was about 25 for a constant precision. Therefore, this method appears to be suitable for treatment planning applications.

Biological equivalent dose studies for dose escalation in the stereotactic synchrotron radiation therapy clinical trials.

Synchrotron radiation is an innovative tool for the treatment of brain tumors. In the stereotactic synchrotron radiation therapy (SSRT) technique a radiation dose enhancement specific to the tumor is obtained. The tumor is loaded with a high atomic number (Z) element and it is irradiated in stereotactic conditions from several entrance angles. The aim of this work was to assess dosimetric properties of the SSRT for preparing clinical trials at the European Synchrotron Radiation Facility (ESRF). To estimate the possible risks, the doses received by the tumor and healthy tissues in the future clinical conditions have been calculated by using Monte Carlo simulations (PENELOPE code). The dose enhancement factors have been determined for different iodine concentrations in the tumor, several tumor positions, tumor sizes, and different beam sizes. A scheme for the dose escalation in the various phases of the clinical trials has been proposed. The biological equivalent doses and the normalized total doses received by the skull have been calculated in order to assure that the tolerance values are not reached.

Quantitative functional imaging and kinetic studies with high-Z contrast agents using synchrotron radiation computed tomography.

1. There is an increasing demand in diagnostic radiology for extracting additional morphological and functional quantitative parameters from three-dimensional computed tomography (CT) images. Synchrotron radiation computed tomography (SRCT) is the state-of-the-art method in preclinical X-ray CT, because its performance is close to the theoretical limits in terms of accuracy and precision. 2. The SRCT method with monochromatic X-ray beams yields absolute high-Z element contrast agent concentrations, without errors arising from beam hardening or scatter artefacts, by using digital subtraction techniques of the sinograms. Each pixel of the reconstructed difference images provides a quantitative concentration versus time curve of inhaled or injected high-Z contrast agents (xenon or iodine) with a high sensitivity. This is the key point of two functional imaging techniques that were developed at the European Synchrotron Radiation Facility: brain perfusion and lung function (ventilation and perfusion). 3. These two imaging techniques provide parametric images expressed in absolute perfusion parameters (blood volume, blood flow, mean transit time and capillary permeability) or ventilation parameters (lung volume, regional lung ventilation, bronchial lumen size, regional airway and lung compliance) with a high accuracy and precision. 4. The aim of the present brief review is to give a snapshot of the status and perspectives of these two imaging techniques, with emphasis on the performances and interests for functional imaging. Two separate sections will then describe the results obtained so far using SRCT as an in vivo functional imaging tool for measuring changes in haemodynamics and ventilation, in the investigation of experimental pathophysiology and in the effects of therapeutic intervention.

Heavy element enhanced synchrotron stereotactic radiotherapy as a promising brain tumour treatment.

Synchrotron stereotactic radiotherapy (SSR) is a treatment that involves selective accumulation of high-Z elements in tumours followed by stereotactic irradiation, in CT mode, with monochromatic X-rays from a synchrotron source, tuned at an optimal energy. The irradiation geometry, characteristic X-rays, photoelectrons, and Auger electrons generated on high-Z atoms by kilovoltage X-rays produce a localized dose enhancement. Two complimentary SSR approaches have been successfully developed in the past 5 years in our team, and may be promising in high-grade glioma management: iodine-enhanced SSR, with an iodinated contrast agent; and Pt-enhanced SSR; a concomitant radio-chemotherapy treatment with locoregional injection of platinated chemotherapy drugs. The results for iodine-enhanced SSR using contrast agents are presented in this paper. IUdR-enhanced SSR was also tested in this study. Up to 15 Gy, intracarotid infusion of iodine significantly improved the rats' survival compared to irradiation alone. SSR provides the most protracted survivals of F98 glioma-bearing rats. The technique is currently transferred to clinical trials. Iodine-enhanced SSR will be implemented first, because of its simplicity; and pave the way for Pt-enhanced SSR, the most efficient technique, but still needing to be improved in terms of intrinsic toxicity.

Polymer gel dosimetry for synchrotron stereotactic radiotherapy and iodine dose-enhancement measurements.

Synchrotron stereotactic radiotherapy (SSR) is a radiotherapy technique that makes use of the interactions of monochromatic low energy x-rays with high atomic number (Z) elements. An important dose-enhancement can be obtained if the target volume has been loaded with a sufficient amount of a high-Z element, such as iodine. In this study, we compare experimental dose measurements, obtained with normoxic polymer gel (nPAG), with Monte Carlo computations. Gels were irradiated within an anthropomorphic head phantom and were read out by magnetic resonance imaging. The dose-enhancement due to the presence of iodine in the gel (iodine concentration: 5 and 10 mg ml(-1)) was measured at two radiation energies (35 and 80 keV) and was compared to the calculated factors. nPAG dosimetry was shown to be efficient for measuring the sharp dose gradients produced by SSR. The agreement between 3D gel dosimetry and calculated dose distributions was found to be within 4% of the dose difference criterion and a distance to agreement of 2.1 mm for 80% of the voxels. Polymer gel doped with iodine exhibited higher sensitivity, in good agreement with the calculated iodine-dose enhancement. We demonstrate in this preliminary study that iodine-doped nPAG could be used for measuring in situ dose distributions for iodine-enhanced SSR treatment.

Synchrotron radiation-based experimental determination of the optimal energy for cell radiotoxicity enhancement following photoelectric effect on stable iodinated compounds.

This study was designed to experimentally evaluate the optimal X-ray energy for increasing the radiation energy absorbed in tumours loaded with iodinated compounds, using the photoelectric effect. SQ20B human cells were irradiated with synchrotron monochromatic beam tuned at 32.8, 33.5, 50 and 70 keV. Two cell treatments were compared to the control: cells suspended in 10 mg ml(-1) of iodine radiological contrast agent or cells pre-exposed with 10 microM of iodo-desoxyuridine (IUdR) for 48 h. Our radiobiological end point was clonogenic cell survival. Cells irradiated with both iodine compounds exhibited a radiation sensitisation enhancement. Moreover, it was energy dependent, with a maximum at 50 keV. At this energy, the sensitisation calculated at 10% survival was equal to 2.03 for cells suspended in iodinated contrast agent and 2.60 for IUdR. Cells pretreated with IUdR had higher sensitisation factors over the energy range than for those suspended in iodine contrast agent. Also, their survival curves presented no shoulder, suggesting complex lethal damages from Auger electrons. Our results confirm the existence of the 50 keV energy optimum for a binary therapeutic irradiation based on the presence of stable iodine in tumours and an external irradiation. Monochromatic synchrotron radiotherapy concept is hence proposed for increasing the differential effect between healthy and cancerous tissue irradiation.

Limited internal shocks for atrial fibrillation refractory to external cardioversion.

UNLABELLED: We investigated the feasibility and long-term results of low-energy internal defibrillation using a limited number of shocks in patients with persistent atrial fibrillation resistant to external cardioversion. A relatively high number of shocks of lower energy are usually required in those cases and can be poorly tolerated. METHODS AND RESULTS: Twenty-five patients with persistent atrial fibrillation underwent internal defibrillation, using biphasic R wave synchronous shocks between two catheters in the high right atrium and the coronary sinus. Conversion to sinus rhythm was obtained in all patients, with a median of two shocks. Early recurrence of atrial fibrillation (AF) occurred in eight cases (32%). Seven patients (41%) out of 17 discharged in sinus rhythm remained free of AF after a median follow-up of 8.9 months. Severe mitral insufficiency (P=0.05) and low left ventricle ejection fraction (P=0.002) were correlated with earlier recurrence. Amiodarone significantly favored (P=0.019) maintenance of sinus rhythm. CONCLUSION: Internal defibrillation using a limited number of shocks equal to or less than 30 Joules is effective in terminating refractory atrial fibrillation and could be more acceptable for patients. However, the recurrence rate remains high, particularly in patients with severe mitral insufficiency or poor ventricular function. Amiodarone delays recurrences of atrial fibrillation.

[Claude Bernard-Horner syndrome and lumbar epidural analgesia]. / Syndrome de Claude Bernard-Horner et analgésie péridurale lombaire.

Lumbar epidural analgesia was performed in a 28 year old primigravida through a L2-L3 catheter. The first dose induced satisfactory analgesia for 1 h. After the second dose of 8 ml of 0.25 bupivacaine, the patient's systolic blood pressure fell from 110 to 80 mmHg. As vena caval compression can contribute to hypotension, the patient was immediately placed in the left lateral position and oxygen was administered through a mask. Rapid infusion of 250 ml of modified gelatin resulted in a prompt and lasting restoration of blood pressure to its initial level. The third dose of 8 ml of 0.25% bupivacaine produced satisfactory analgesia without any adverse effect. The last dose (4 ml of 0.50% bupivacaine administered with the patient in half sitting) gave a left-sided Horner's syndrome and weakness in the left arm. An epidurogram, performed through the catheter 2 h after delivery, with the patient lying supine, showed unilateral left spread ascending to upper thoracic levels with delayed spread toward the right lumbar epidural space. The troubles persisted 6 h after the final bupivacaine dose, then resolving completely.