Yves Lazorthes

Safety and efficacy of deep brain stimulation in refractory cluster headache: a randomized placebo-controlled double-blind trial followed by a 1-year open extension

Chronic cluster headache (CCH) is a disabling primary headache, considering the severity and frequency of pain attacks. Deep brain stimulation (DBS) has been used to treat severe refractory CCH, but assessment of its efficacy has been limited to open studies. We performed a prospective crossover, double-blind, multicenter study assessing the efficacy and safety of unilateral hypothalamic DBS in 11 patients with severe refractory CCH. The randomized phase compared active and sham stimulation during 1-month periods, and was followed by a 1-year open phase. The severity of CCH was assessed by the weekly attacks frequency (primary outcome), pain intensity, sumatriptan injections, emotional impact (HAD) and quality of life (SF12). Tolerance was assessed by active surveillance of behavior, homeostatic and hormonal functions. During the randomized phase, no significant change in primary and secondary outcome measures was observed between active and sham stimulation. At the end of the open phase, 6/11 responded to the chronic stimulation (weekly frequency of attacks decrease >50%), including three pain-free patients. There were three serious adverse events, including subcutaneous infection, transient loss of consciousness and micturition syncopes. No significant change in hormonal functions or electrolytic balance was observed. Randomized phase findings of this study did not support the efficacy of DBS in refractory CCH, but open phase findings suggested long-term efficacy in more than 50% patients, confirming previous data, without high morbidity. Discrepancy between these findings justifies additional controlled studies (clinicaltrials.gov number NCT00662935).

Methodological and technical issues for integrating functional magnetic resonance imaging data in a neuronavigational system.

OBJECTIVEThe aim of this article was to analyze the technical and methodological issues resulting from the use of functional magnetic resonance image (fMRI) data in a frameless stereotactic device for brain tumor or pain surgery (chronic motor cortex stimulation). METHODSA total of 32 candidates, 26 for brain tumor surgery and six chronic motor cortex stimulation, were studied by fMRI scanning (61 procedures) and intraoperative cortical brain mapping under general anesthesia. The fMRI data obtained were analyzed with the Statistical Parametric Mapping 99 software, with an initial analysis threshold corresponding to P < 0.001. Subsequently, the fMRI data were registered in a frameless stereotactic neuronavigational device and correlated to brain mapping. RESULTSCorrespondence between fMRI-activated areas and cortical mapping in primary motor areas was good in 28 patients (87%), although fMRI-activated areas were highly dependent on the choice of paradigms and analysis thresholds. Primary sensory- and secondary motor-activated areas were not correlated to cortical brain mapping. Functional mislocalization as a result of insufficient correction of the echo-planar distortion was identified in four patients (13%). Analysis thresholds (from P < 0.0001 to P < 10−12) more restrictive than the initial threshold (P < 0.001) had to be used in 25 of the 28 patients studied, so that fMRI motor data could be matched to cortical mapping spatial data. These analysis thresholds were not predictable preoperatively. Maximal tumor resection was accomplished in all patients with brain tumors. Chronic motor cortex electrode placement was successful in each patient (significant pain relief >50% on the visual analog pain scale). CONCLUSIONIn brain tumor surgery, fMRI data are helpful in surgical planning and guiding intraoperative brain mapping. The registration of fMRI data in anatomic slices or in the frameless stereotactic neuronavigational device, however, remained a potential source of functional mislocalization. Electrode placement for chronic motor cortex stimulation is a good indication to use fMRI data registered in a neuronavigational system and could replace somatosensory evoked potentials in detection of the central sulcus.

Does ageing influence deep brain stimulation outcomes in Parkinson's disease?

We sought to define the influence of ageing in clinical, cognitive, and quality‐of‐life outcomes after subthalamic nucleus deep brain stimulation (STN‐DBS) in Parkinsons disease (PD). We performed motor assessment (UPDRS), mood tests, cognitive, and quality of life evaluation (PDQ‐39) on PD patients before surgery, and 12 and 24 months after, and we recorded adverse events. The variations of these parameters after surgery were correlated with age using regression statistical tests. Cerebral bleeding risk was evaluated by a nonparametric test. We enrolled 45 patients (mean age 60 ± 9 years, range 40–73). No significant correlation was found between age and motor scores and PDQ‐39 improvements at 12 months. At 24 months, there was a significant negative correlation between age and the improvement of three dimensions of PDQ 39 (mobility, activities of daily life, and cognition). Cognitive impairment showed no correlation, but apathy and depression were positively correlated with age. Significant statistical difference was observed between cerebral bleeding and age. STN‐DBS is an effective treatment for elderly patients with advanced PD. A longer follow‐up duration and a larger population seem necessary to better assess the quality of life perception in elderly patients and to determinate the real risk of hemorrage.

Human chromaffin cell graft into the CSF for cancer pain management: a prospective phase II clinical study.

&NA; A number of pre‐clinical studies have demonstrated the value of adrenal medullary allografts in the management of chronic pain. The present longitudinal survey studied 15 patients transplanted for intractable cancer pain after failure of systemic opioids due to the persistence of undesirable side‐effects. Before inclusion, all the patients had their pain controlled by daily intrathecal (I‐Th) morphine administration. The main evaluation criteria of analgesic activity of the chromaffin cell allograft was the complementary requirement of analgesics and in particular the consumption of I‐Th morphine required to maintain effective pain control. Out of the 12 patients who profited from enhanced analgesia with long‐term follow‐up (average 4.5 months), five no longer required the I‐Th morphine (with prolonged interruption of systemic opioids as well), two durably decreased I‐Th morphine intake and five were stabilized until the end of their follow‐up. Durable decline and stabilization were interpreted as indicative of analgesic activity by comparison with the usual dose escalation observed during disease progression. In most cases, we noted a relationship between analgesic responses and CSF met‐enkephalin levels. The results of this phase II open study demonstrate the feasibility and the safety of this approach using chromaffin cell grafts for long‐term relief of intractable cancer pain. However, while analgesic efficacy was indicated by the reduction or stabilization in complementary opioid intake, these observations will need to be confirmed in a controlled trial in a larger series of patients.

Cortical Areas Involved in Virtual Movement of Phantom Limbs: Comparison with Normal Subjects

OBJECTIVETo demonstrate that amputees performing “virtual” movements of their amputated limb activate cortical areas previously devoted to their missing limb, we studied amputees with functional magnetic resonance imaging (fMRI) and positron emission tomographic (PET) scans and compared the results with those of normal volunteers performing imaginary movements during fMRI acquisitions. METHODSTen amputees (age range, 33–92 yr; average age, 49 yr; six men and four women; eight upper-limb and two lower-limb amputations) able to move their phantom limb at will were studied by fMRI (all patients) and PET scan (seven patients). The time between amputation and fMRI and PET studies ranged from 1 to 27 years (average, 13 yr). Patients were asked to perform virtual movements of the amputated limb and normal movements of the contralateral normal limb according to the functional images acquisition procedure. Movements of the stump were also used to differentiate stump cortical areas from virtual movement-activated areas. Ten right-handed volunteers, age- and sex-matched to the amputees, were also studied by fMRI. All volunteers were asked to perform four tasks during their fMRI study: imaginary movements of their right arm (1 task) and foot (1 task) and real movements of their left arm (1 task) and foot (1 task). RESULTSIn amputees, virtual movements of the missing limbs produced contralateral primary sensorimotor cortex activation on both fMRI and PET scans. These activation areas, different from the stump activation areas, were similar in location to contralateral normal limb-activated areas. Quantitatively, in two amputees who claimed to be able to perform both slow and fast virtual movements, regional cerebral blood flow measured by PET scan in the precentral gyrus increased significantly during fast movements in comparison with slow virtual movements. In normal subjects, significant differences between real versus imaginary fMRI activations were found (for both foot and hand movements); imaginary right hand and foot tasks activated primarily the contralateral supplementary motor areas, with no significant activation detected in the contralateral precentral or postcentral gyri. CONCLUSIONPrimary sensorimotor cortical areas can be activated by phantom-limb movements and thus can be considered functional for several years or decades after amputation. In this study, we found that the location of the activation of these areas is comparable to that of activations produced by normal movements in control subjects or in amputees.

Relief of intractable cancer pain by human chromaffin cell transplants: Experience at two medical centers

In addition to its possible role as a replacement source in CNS degenerative diseases, neural transplantation may be used to augment the normal production of neuroactive substances. Our laboratory at the University of Illinois at Chicago has shown, in both acute and chronic pain models, that transplantation of adrenal medullary tissue or isolated chromaffin cells into CNS pain modulatory regions can reduce pain sensitivity in rodents. Chromaffin cells were chosen as the donor source since they produce high levels of both opioid peptides and catecholamines, substances which reduce pain sensitivity when injected locally into the spinal subarachnoid space. The analgesia produced by these transplants probably results from the release of both opioid peptides and catecholamines since it can be blocked or attenuated by both opiate and adrenergic antagonists. Studies indicate that even over long periods there is no apparent development of tolerance. Promising results have been obtained in preliminary clinical studies using allografts of adrenal medulla to relieve cancer pain. This clinical review encompasses results at two Medical Centers-University of Illinois at Chicago and University Paul Sabatier, Toulouse, France-in assessing efficacy of subarachnoid adrenal medullary transplantation for alleviating cancer pain. Our clinical and autopsy data strongly support our previous laboratory studies, i.e., that chromaffin cell transplants into the subarachnoid space represent a promising new approach to the alleviation of chronic pain. It is suggested that further clinical studies are now warranted.

Virtual movements activate primary sensorimotor areas in amputees: report of three cases.

OBJECTIVEIn our multidisciplinary pain clinic, three patients with amputated limbs and with surgical indications for chronic motor cortex stimulation for phantom limb pain were selected for their ability to voluntarily move the missing limb. The sensation of being able to move a missing limb at will occurs quite frequently among traumatic amputees, but the ability to control it sufficiently to perform a functional magnetic resonance imaging (fMRI) examination is more rarely encountered. We used motor fMRI to study these virtual movements. METHODSIn two patients with upper-limb amputations, movements of the stump, the normal hand, and the missing arm were studied. In a third patient with both legs amputated, movements of the stumps and of the missing feet were studied. The fMRI data were analyzed with the Statistical Parametric Map 96 software and reformatted for integration into anatomic slices. RESULTSVirtual movements of the missing limbs produced contralateral primary sensorimotor cortex and central sulcus activations in the patients with upper-limb amputation. Interhemispheric and bilateral activations were found in the patient with both legs amputated. These activation areas were different from the stump activation areas. Additionally, the significance thresholds chosen to generate the activation maps in virtual movements (although individual) were globally the same as those used to detect motor activation in the normal side of the patients. CONCLUSIONCortical areas devoted to the missing limb seem to persist for several years after amputation. The precentral activations found in our patients are in agreement with the statement that the neural mechanisms involved in the mental representation of an action and in its execution are the same. Data from fMRI can be used to evaluate phantom limb virtual movements and to study cortical reorganization phenomena that can appear with time or as a result of some therapies. In these patients, fMRI data may be useful in assisting the neurosurgeon in the placement of chronic motor cortex electrodes.

One-year chromaffin cell allograft survival in cancer patients with chronic pain: Morphological and functional evidence

The control of chronic pain through transplantation of chromaffin cells has been reported over the past few years. Analgesic effects are principally due to the production of opioid peptides and catecholamines by chromaffin cells. Clinical trials have been reported with allografts consisting of whole-tissue fragments implanted into the subarachnoid space of the lumbar spinal cord (14,19,36). In the present study, allogeneic grafts were successfully used to control chronic pain in two patients over a period of 1 yr based on patient reported pain scores, morphine intake, and CSF levels of Met-enkephalin. Macroscopic examination at autopsy located the transplanted tissue fragments in the form of multilobulated nodules at the level of the spinal axis and cauda equina. Immunocytochemical microscopy showed neuroendocrine cells are positive for chromagranin A (CGA), and enzymes tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DbetaH). The results suggest that there is a relationship between analgesic effect, Met-enkephalin levels in CSF, and the presence of chromaffin cells surviving in spinal subarachnoid space.

Spinal versus Intraventricular Chronic Opiate Administration with Implantable Drug Delivery Devices for Cancer Pain

Early publications have separately reported the efficacy, specificity and conservative character of direct spinal and intraventricular morphine analgesia in the treatment of intractable cancer pain. The objectives of this study are to compare efficacy and safety of these sites of local administration in order to determine the indication for each, the clinical effects of different opiates and the choice of various drug administration devices.

Intracerebroventricular administration of morphine for control of irreducible cancer pain.

Intracerebroventricular morphine analgesic for the treatment of cancer pain was administered, using implanted access ports, in 82 patients from 1984 to January 1994. All of the patients who were selected for treatment were no longer responsive and had developed drug side effects to oral or parenteral opiates in varying doses (60-400 mg/d). The mean follow-up was 66 days (range, 12-443 d) for this series of 82 patients. The effective control of pain was achieved in nearly all of the patients, with only two failures. During the treatment, the daily morphine doses were moderately increased. The initial doses of morphine were a mean of 0.30 mg (range, 0.10-2 mg), and the final doses were a mean of 2.5 mg (range, 0.10-60 mg). The results show that the ratio of the terminal dose to the initial dose increased more rapidly for patients who had a follow-up of over 60 days. However, the increase seems to have been because of the progress of the disease rather than because of drug tolerance.