Serge Goldman

The locked-in syndrome : what is it like to be conscious but paralyzed and voiceless?

The locked-in syndrome (pseudocoma) describes patients who are awake and conscious but selectively deefferented, i.e., have no means of producing speech, limb or facial movements. Acute ventral pontine lesions are its most common cause. People with such brainstem lesions often remain comatose for some days or weeks, needing artificial respiration and then gradually wake up, but remaining paralyzed and voiceless, superficially resembling patients in a vegetative state or akinetic mutism. In acute locked-in syndrome (LIS), eye-coded communication and evaluation of cognitive and emotional functioning is very limited because vigilance is fluctuating and eye movements may be inconsistent, very small, and easily exhausted. It has been shown that more than half of the time it is the family and not the physician who first realized that the patient was aware. Distressingly, recent studies reported that the diagnosis of LIS on average takes over 2.5 months. In some cases it took 4-6 years before aware and sensitive patients, locked in an immobile body, were recognized as being conscious. Once a LIS patient becomes medically stable, and given appropriate medical care, life expectancy increases to several decades. Even if the chances of good motor recovery are very limited, existing eye-controlled, computer-based communication technology currently allow the patient to control his environment, use a word processor coupled to a speech synthesizer, and access the worldwide net. Healthy individuals and medical professionals sometimes assume that the quality of life of an LIS patient is so poor that it is not worth living. On the contrary, chronic LIS patients typically self-report meaningful quality of life and their demand for euthanasia is surprisingly infrequent. Biased clinicians might provide less aggressive medical treatment and influence the family in inappropriate ways. It is important to stress that only the medically stabilized, informed LIS patient is competent to consent to or refuse life-sustaining treatment. Patients suffering from LIS should not be denied the right to die - and to die with dignity - but also, and more importantly, they should not be denied the right to live - and to live with dignity and the best possible revalidation, and pain and symptom management. In our opinion, there is an urgent need for a renewed ethical and medicolegal framework for our care of locked-in patients.

Impaired effective cortical connectivity in vegetative state: preliminary investigation using PET.

Vegetative state (VS) is a condition of abolished awareness with persistence of arousal. Awareness is part of consciousness, which itself is thought to represent an emergent property of cerebral neural networks. Our hypothesis was that part of the neural correlate underlying VS is an altered connectivity, especially between the associative cortices. We assessed regional cerebral glucose metabolism (rCMRGlu) and effective cortical connectivity in four patients in VS by means of statistical parametric mapping and [18F]fluorodeoxyglucose-positron emission tomography. Our data showed a common pattern of impaired rCMRGlu in the prefrontal, premotor, and parietotemporal association areas and posterior cingulate cortex/precuneus in VS. In a next step, we demonstrated that in VS patients various prefrontal and premotor areas have in common that they are less tightly connected with the posterior cingulate cortex than in normal controls. These results provide a strong argument for an alteration of cortical connectivity in VS patients.

Frontal and parietal metabolic disturbances in unipolar depression

The authors investigated brain glucose utilization using positron emission tomography (PET) in 12 normal volunteers and 12 unipolar unmedicated depressed patients (six endogenous; six nonendogenous) following injection of [18F]fluoro-deoxyglucose (FDG). Compared by analyses of variance, absolute and relative regional glucose metabolic rates appeared different in depressed patients and control subjects, especially in parietal and frontal lobes. In patients with unipolar depression, metabolic rates were increased in the orbital part of the frontal lobe and decreased in a frontal dorsolateral area. The metabolic supero-basal gradient calculated in the frontal cortex was significantly lower in depressed patients than in normal subjects. Decreased glucose metabolism was also observed in the parietal cortex of depressed patients. No differences in glucose metabolic rates have been detected between endogenous and nonendogenous patients. No correlation has been found between the metabolic data and the Hamilton Rating Scale.

BRAIN GLUCOSE METABOLISM IN BORDERLINE PERSONALITY DISORDER

We searched for regional cerebral metabolic disturbances in patients with borderline personality disorder (BPD). Ten inpatients with BPD, no current DSM-IIIR Axis I diagnosis and free of any psychotropic substances, were compared with 15 age-matched control subjects using positron emission tomography with 2-deoxy-2-[18F]fluoro-D-glucose and semiquantitative analysis of regional glucose metabolic activity. We found relative hypometabolism in patients with borderline personality disorder at the level of the premotor and prefrontal cortical areas, the anterior part of the cingulate cortex and the thalamic, caudate and lenticular nuclei. This study shows significant cerebral metabolic disturbances in patients with borderline personality disorder. These metabolic disturbances, which are similar to some of those described in other psychiatric entities, may help to understand the characteristic clinical aspects of this disorder.

Sex difference in 5HT2 receptor in the living human brain

Serotonergic mechanisms are involved in gender-related behaviors and psychiatric conditions like aggression, eating disorders, depression, impulsivity or suicide. We studied gender differences in the living human brain type-2 serotonin receptor (5HT2r). Twenty-two healthy age-matched men and women were investigated using positron emission tomography and the selective radiotracer, 18F-labeled altanserin. Binding was quantified using a non-linear least-squares minimization procedure. We found significantly higher 5HT2r binding capacity in men than in women, especially in the frontal and cingulate cortices. Distinct liability for men and women to suffer from some psychiatric disorders responding to serotonergic agents may be related to differences in brain serotonin receptors.

Regional glucose metabolism and histopathology of gliomas: A study based on positron emission tomography‐guided stereotactic biopsy

Positron emission tomography (PET) with 18F‐2‐fluoro‐2‐deoxy‐D‐glucose (FDG) is widely applied to the study of gliomas. The histology of most gliomas is regionally heterogeneous. The relationship between histologic features and glucose metabolism evaluated by PET with FDG may therefore vary within the limits of the tumor. PET with FDG integrated in the planning of stereotactic brain biopsy allows precise comparison between local FDG uptake and histology. Using this approach, the authors investigated whether glucose metabolism of gliomas is related to anaplasia, and whether PET with FDG detects metabolic heterogeneity that parallels histologic heterogeneity of gliomas.

Statistical parametric mapping of regional glucose metabolism in mesial temporal lobe epilepsy.

We investigated statistical parametric mapping (SPM) use for positron emission tomography (PET) with [(18)F]fluorodeoxyglucose (FDG) data analysis in mesial temporal lobe epilepsy. The study involved 14 patients with temporal lobe epilepsy ultimately treated by anterior temporal lobectomy. Surgical outcome in terms of seizure control was favorable in 12 patients. Two different SPM approaches were designed to analyze each FDG-PET scan: a direct comparison with a control group (n = 27) and a search for significant interhemispheric asymmetry considering the asymmetry existing in the control group. Statistical inference was performed, first, without correction for multiple comparisons (making the hypothesis of temporal hypometabolism) and, second, after correction for multiple comparisons. Search for temporal interhemispheric asymmetry under the hypothesis of temporal hypometabolism was the most reliable SPM approach: hypometabolism was identified on the side chosen for resection in most cases (sensitivity, 71%; specificity, 100%) and was predictive of favorable postsurgical outcome in 90% of the patients. There was no false-positive result within the control group using this approach. After correction for multiple comparisons, SPM also identified in some patients temporal hypermetabolic areas as well as extratemporal cortical and subcortical hypometabolic areas on the side of resection but also on the contralateral side. In a further step, SPM was used for a group analysis of patients with favorable outcome after reversing scans when needed to set an identical lateralization in all patients. This analysis identified multiple ipsilateral temporal and extratemporal hypometabolic regions; when temporal metabolic changes were specifically assessed, the contralateral mesiotemporal region was found hypermetabolic, possibly as a manifestation of compensatory mechanisms in the presence of a unilateral epileptogenic lesion.

Positron emission tomography-guided volumetric resection of supratentorial high-grade gliomas: a survival analysis in 66 consecutive patients.

OBJECTIVEIntegrating positron emission tomographic (PET) images into the image-guided resection of high-grade gliomas (HGG) has shown that metabolic information on tumor heterogeneity and distribution are useful for planning surgery, improve tumor delineation, and provide a final target contour different from that obtained with magnetic resonance imaging (MRI) alone in about 80% of the procedures. Moreover, PET guidance helps to increase the amount of tumor removed and to target image-guided resection to anaplastic tissue areas. The present study aims to evaluate whether PET-guided volumetric resection (VR) in supratentorial HGG might add benefit to the patients outcome. METHODSPET images using [18F]fluorodeoxyglucose (n=23) and [11C]methionine (n=43) were combined with MRI scans in the planning of VR procedures performed at the initial stage in 66 consecutive patients (43 M/23 F) with supratentorial HGG according to the technique previously described. In all cases (35 anaplastic gliomas [20 astrocytomas, 10 oligoastrocytomas, 5 oligodendrogliomas] and 31 glioblastomas [GBM]), level and distribution of PET tracer uptake were analyzed to define a PET contour projected on MRI scans to define a final target contour for VR. Maximal tumor resection was accomplished in each case, with the intention to remove the entire abnormal metabolic area comprised in the surgical planning. Early postoperative MRI and PET assessed tumor resection. Survival analysis was performed separately in anaplastic gliomas and glioblastoma multiforme according to the presence or absence of residual tracer uptake on postoperative PET and according to the presence or absence of residual contrast enhancement on postoperative MRI. RESULTSPreoperatively, metabolic information helped the surgical planning. In all procedures, PET contributed to define a final target contour different from that obtained with MRI alone. Postoperatively, 46 of 66 patients had no residual PET tracer uptake (total PET resection), 23 of 66 had no residual MRI contrast enhancement. No additional neurological morbidity due to the technique was reported. A total PET tracer uptake resection was associated with a significantly longer survival in anaplastic gliomas (P = 0.0071) and in glioblastoma multiforme (P = 0.0001), respectively. A total MRI contrast enhancement resection was not correlated with a significantly better survival, neither in anaplastic gliomas (P = 0.6089) nor in glioblastoma multiforme (P = 0.6806). CONCLUSIONSComplete resection of the increased PET tracer uptake prolongs the survival of HGG patients. Because PET information represents a more specific marker than MRI enhancement for detecting anaplastic tumor tissue, PET-guidance increases the amount of anaplastic tissue removed in HGG.

Cognitive function in the locked-in syndrome.

ObjectiveThe lockedin syndrome (LIS) originates from a ventro-pontine lesion resulting in a complete quadraplegia and anarthria. Classically, communication remains possible by means of spared vertical eye movements and/or blinking. To allow assessing cognitive functions in LIS patients, we propose here a neuropsychological testing based on eye-coded communication.MethodsTen chronic LIS survivors were assessed 1 to 6 years after their brain insult.One patient was evaluated subacutely (at 2 months) and retested at 6 and 16 months.Neuropsychological testing encompassed short- and long-term memory, attention, executive functioning, phonological and semantic processing and verbal intelligence.ResultsNone of the patients showed alterations in verbal intelligence. Impairments in one or several tests were found in five patients. In three of these patients, neuropsychological deficits could be related to additional cortical or thalamic structural brain lesions. In the other 2 patients, weakness or signs of fatigue only were observed in one or two cognitive tasks. Repeated measures in a subacute patient with pure brainstem lesion indicate the recovery of good levels of cognition 6 months after injury.ConclusionResults indicate that LIS patients can recover intact cognitive levels in cases of pure brainstem lesions, and that additional brain injuries are most likely responsible for associated cognitive deficits in the LIS. Furthermore, a systematic neuropsychological assessment in LIS patients would allow detecting their cognitive deficits,which will contribute to improve their quality of life and of communication with family and medical caretakers.

Noradrenergic function in generalized anxiety disorder, major depressive disorder, and healthy subjects

Plasma norepinephrine (NE), free 3-methoxy-4-hydroxyphenethylene glycol (MHPG), and binding of tritiated yohimbine to platelet membranes were measured in 14 patients with generalized anxiety disorder (GAD), who were matched for age and sex with 14 patients with unipolar major depressive disorder (MDD) and 14 normal subjects. Plasma NE and MHPG levels were increased and the number of alpha2-adrenoreceptors (Bmax) was decreased in GAD patients compared with MDD and normal subjects. No differences were found between MDD patients and normal subjects for plasma NE, MHPG, and alpha2-adrenoreceptor binding. Plasma NE and MHPG were significantly correlated in MDD patients and tended toward a significant positive correlation in GAD patients. Plasma MHPG and affinity of binding platelet alpha2-adrenoreceptors (Kd) were significantly correlated in normal subjects. Thus, noradrenergic activity seems to be increased in patients with GAD, but not in patients with MDD. In GAD patients, higher levels of catecholamines may lead to a down-regulation of presynaptic alpha2-adrenoreceptors.