Pierre Brugières

Liver Cirrhosis: Intravoxel Incoherent Motion MR Imaging—Pilot Study

PURPOSE To retrospectively evaluate a respiratory-triggered diffusion-weighted (DW) magnetic resonance (MR) imaging sequence combined with parallel acquisition to allow the calculation of pure molecular-based (D) and perfusion-related (D*, f) diffusion parameters, on the basis of the intravoxel incoherent motion (IVIM) theory, to determine if these parameters differ between patients with cirrhosis and patients without liver fibrosis. MATERIALS AND METHODS The institutional review board approved this retrospective study; informed consent was waived. IVIM DW imaging was tested on three alkane phantoms, on which the signal-intensity decay curves according to b factors were logarithmically plotted. Ten b factors (0, 10, 20, 30, 50, 80, 100, 200, 400, 800 sec/mm(2)) were used in patients. Patients with documented liver cirrhosis (cirrhotic liver group, n = 12) and patients without chronic liver disease (healthy liver group, n = 25) were included. The mean liver D, D*, and f values were measured and compared with the apparent diffusion coefficient (ADC) computed by using four b values (0, 200, 400, 800 sec/mm(2)). Liver ADC and D, f, and D* parameters were compared between the cirrhotic liver group and healthy liver group. Means were compared by using the Student t test. RESULTS Signal-intensity decay curves were monoexponential on phantoms and biexponential in patients. In vivo, mean ADC values were significantly higher than D in the healthy liver group (ADC = 1.39 x 10(-3) mm(2)/sec +/- 0.2 [standard deviation] vs D = 1.10 x 10(-3) mm(2)/sec +/- 0.7) and in the cirrhotic liver group (ADC = 1.23 x 10(-3) mm(2)/sec +/- 0.4 vs D = 1.19 x 10(-3) mm(2)/sec +/- 0.5) (P = .03). ADC and D* were significantly reduced in the cirrhotic liver group compared with those in the healthy liver group (respective P values of .03 and .008). CONCLUSION Restricted diffusion observed in patients with cirrhosis may be related to D* variations, which reflect decreased perfusion, as well as alterations in pure molecular water diffusion in cirrhotic livers.

Motor and cognitive improvements in patients with Huntington's disease after neural transplantation.

BACKGROUND Huntingtons disease is a neurodegenerative disease of genetic origin that mainly affects the striatum. It has severe motor and cognitive consequences and, up to now, no treatment. Motor and cognitive functions can be restored in experimental animal models by means of intrastriatal transplantation of fetal striatal neuroblasts. We explored whether grafts of human fetal striatal tissue could survive and have detectable effects in five patients with mild to moderate Huntingtons disease. METHODS After 2 years of preoperative assessment, patients were grafted with human fetal neuroblasts into the right striatum then, after a year, the left striatum. Final results were assessed 1 year later on the basis of neurological, neuropsychological, neurophysiological, and psychiatric tests. The results obtained were compared with those of a cohort of 22 untreated patients at similar stages of the disease who were followed up in parallel. Repeated magnetic resonance imaging (MRI) and positron emission tomography (PET) scanning with fluorine-18-labelled fluorodeoxyglucose was also done to assess metabolic activity. FINDINGS The final PET-scan assessment showed increased metabolic activity in various subnuclei of the striatum in three of five patients, contrasting with the progressive decline recorded in the two other patients in the series, as seen in patients with untreated Huntingtons disease. Small areas of even higher metabolic activity, coregistering with spherical hyposignals on MRI were also present in the same three patients, suggesting that grafts were functional. Accordingly, motor and cognitive functions were improved or maintained within the normal range, and functional benefits were seen in daily-life activities in these three patients, but not in the other two. INTERPRETATION Fetal neural allografts could be associated with functional, motor, and cognitive improvements in patients with Huntingtons disease.

Chronic motor cortex stimulation in the treatment of central and neuropathic pain. Correlations between clinical, electrophysiological and anatomical data.

Thirty-two patients with refractory central and neuropathic pain of peripheral origin were treated by chronic stimulation of the motor cortex between May 1993 and January 1997. The mean follow-up was 27.3 months. The first 24 patients were operated according to the technique described by Tsubokawa. The last 13 cases (eight new patients and five reinterventions) were operated by a technique including localisation by superficial CT reconstruction of the central region and neuronavigator guidance. The position of the central sulcus was confirmed by the use of intraoperative somatosensory evoked potentials. The somatotopic organisation of the motor cortex was established peroperatively by studying the motor responses at stimulation of the motor cortex through the dura. Ten of the 13 patients with central pain (77%) and ten of the 12 patients with neuropathic facial pain had experienced substantial pain relief (75%). One of the three patients with post-paraplegia pain was clearly improved. A satisfactory result was obtained in one patient with pain related to plexus avulsion and in one patient with pain related to intercostal herpes zooster. None of the patients developed epileptic seizures. The position of the stimulating poles effective on pain corresponded to the somatotopic representation of the motor cortex. The neuronavigator localisation and guidance technique proved to be most useful identifying the appropriate portion of the motor gyrus. It also allowed the establishment of reliable correlations between electrophysiological-clinical and anatomical data which may be used to improve the clinical results and possibly to extend the indications of this technique.

Effect of fetal neural transplants in patients with Huntington's disease 6 years after surgery: a long-term follow-up study

BACKGROUND Although we have shown in three out of five patients with Huntingtons disease that motor and cognitive improvements 2 years after intracerebral fetal neural grafts are correlated with recovery of brain metabolic activity in grafted striatal areas and connected regions of the cerebral cortex, neural grafts are not known to have protective effects on the host brain per se. We undertook long-term follow-up of previously reported patients with the disease to ascertain the nature and extent of any secondary decline after grafting. METHODS Five patients with Huntingtons disease from our pilot study were assessed annually with the unified Huntingtons disease rating scale, neuropsychological tests, and MRI, for up to 6 years after neural grafting. Resting cerebral activity was recorded at 2 and 6 years. FINDINGS Clinical improvement plateaued after 2 years and then faded off variably 4-6 years after surgery. Dystonia deteriorated consistently, whereas chorea did not. Cognitive performance remained stable on non-timed tests, whereas progression of motor disability was shown by deterioration on timed tests. Hypometabolism also affected the brain heterogeneously, sparing the benefits in the frontal cortex and at the precise location of the grafts, but showing a progressive deterioration in other areas. Two patients who had no benefit from grafting at 2 years continued to decline in the same way as non-grafted patients. INTERPRETATION Neuronal transplantation in Huntingtons disease provides a period of several years of improvement and stability, but not a permanent cure for the disease. Improvement of the surgical procedure and in patient selection could improve the therapeutic value, but neuroprotective treatment seems to be unavoidable in the disease.

Zika Virus Associated with Meningoencephalitis

As Zika virus spreads, the associated clinical syndromes need to be defined. In this report, an 81-year-old man is found to have Zika virus–associated meningoencephalitis.

Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson's disease: a dose escalation, open-label, phase 1/2 trial

BACKGROUND Parkinsons disease is typically treated with oral dopamine replacement therapies; however, long-term treatment leads to motor complications and, occasionally, impulse control disorders caused by intermittent stimulation of dopamine receptors and off-target effects, respectively. We aimed to assess the safety, tolerability, and efficacy of bilateral, intrastriatal delivery of ProSavin, a lentiviral vector-based gene therapy aimed at restoring local and continuous dopamine production in patients with advanced Parkinsons disease. METHODS We undertook a phase 1/2 open-label trial with 12-month follow-up at two study sites (France and UK) to assess the safety and efficacy of ProSavin after bilateral injection into the putamen of patients with Parkinsons disease. All patients were then enrolled in a separate open-label follow-up study of long-term safety. Three doses were assessed in separate cohorts: low dose (1·9×10(7) transducing units [TU]); mid dose (4·0×10(7) TU); and high dose (1×10(8) TU). Inclusion criteria were age 48-65 years, disease duration 5 years or longer, motor fluctuations, and 50% or higher motor response to oral dopaminergic therapy. The primary endpoints of the phase 1/2 study were the number and severity of adverse events associated with ProSavin and motor responses as assessed with Unified Parkinsons Disease Rating Scale (UPDRS) part III (off medication) scores, at 6 months after vector administration. Both trials are registered at ClinicalTrials.gov, NCT00627588 and NCT01856439. FINDINGS 15 patients received ProSavin and were followed up (three at low dose, six mid dose, six high dose). During the first 12 months of follow-up, 54 drug-related adverse events were reported (51 mild, three moderate). Most common were increased on-medication dyskinesias (20 events, 11 patients) and on-off phenomena (12 events, nine patients). No serious adverse events related to the study drug or surgical procedure were reported. A significant improvement in mean UPDRS part III motor scores off medication was recorded in all patients at 6 months (mean score 38 [SD 9] vs 26 [8], n=15, p=0·0001) and 12 months (38 vs 27 [8]; n=15, p=0·0001) compared with baseline. INTERPRETATION ProSavin was safe and well tolerated in patients with advanced Parkinsons disease. Improvement in motor behaviour was observed in all patients. FUNDING Oxford BioMedica.

Motor cortex stimulation in the treatment of central and neuropathic pain.

BACKGROUND Motor cortex stimulation has been proposed for the treatment of central pain. METHODS Thirty-two patients with refractory central and neuropathic pain of peripheral origin were treated by chronic stimulation of the motor cortex between May 1993 and January 1997. The mean follow-up was 27.3 months. The first 24 patients were operated on according to the technique described by Tsubokawa. The last 13 cases (8 new patients and 5 reinterventions) were operated on by a technique including localization by superficial CT reconstruction of the central region and neuronavigator guidance. The position of the central sulcus was confirmed by the use of intraoperative somatosensory evoked potentials. The somatotopic organization of the motor cortex was established preoperatively by studying the motor responses at stimulation of the motor cortex through the dura. RESULTS Ten of the 13 patients with central pain (77%) and 10 of the 12 patients with neuropathic facial pain experienced substantial pain relief (83.3%). One of the three patients with post-paraplegia pain was clearly improved. A satisfactory result was obtained in one patient with pain related to plexus avulsion and in one patient with pain related to intercostal herpes zoster. None of the patients developed epileptic seizures. CONCLUSIONS Our results confirm that chronic stimulation of the motor cortex is an effective method in treating certain forms of refractory pain.

Neuroprotective Gene Therapy for Huntington’s Disease Using a Polymer Encapsulated BHK Cell Line Engineered to Secrete Human CNTF

Huntingtons disease (HD) is an autosomal dominant genetic disease with devastating clinical effects on cognitive, psychological, and motor functions. These clinical symptoms primarily relate to the progressive loss of medium-spiny GABA-ergic neurons of the striatum. There is no known treatment to date. Several neurotrophic factors have, however, demonstrated the capacity to protect striatal neurons in various experimental models of HD. This includes the ciliary neurotrophic factor (CNTF), the substance examined in this protocol. An ex vivo gene therapy approach based on encapsulated genetically modified BHK cells will be used for the continuous and long-term intracerebral delivery of CNTF. A device, containing up to 106 human CNTF-producing BHK cells surrounded by a semipermeable membrane, will be implanted into the right lateral ventricle of 6 patients. Capsules releasing 0.15-0.5 microg CNTF/day will be used. In this phase I study, the principal goal will be the evaluation of the safety and tolerability of the procedure. As a secondary goal, HD symptoms will be analyzed using a large battery of neuropsychological, motor, neurological, and neurophysiological tests and the striatal pathology monitored using MRI and PET-scan imaging. It is expected that the gene therapy approach described in this protocol will mitigate the side effects associated with the peripheral administration of recombinant hCNTF and allow a well-tolerated, continuous intracerebroventricular delivery of the neuroprotective factor.

Multiple-domain dissociation between impaired visual perception and preserved mental imagery in a patient with bilateral extrastriate lesions.

A brain-damaged patient is described whose pattern of performance provides insight into both the functional mechanisms and the neural structures involved in visual mental imagery. The patient became severely agnosic, alexic, achromatopsic and prosopagnosic following bilateral brain lesions in the temporo-occipital cortex. However, her mental imagery for the same visual entities that she could not perceive was perfectly preserved. This clear-cut dissociation held across all the major domains of high-level vision: object recognition, reading, colour and face processing. Our findings, together with other reports on domain-specific dissociations and functional brain imaging studies, provide evidence to support the view that visual perception and visual mental imagery are subserved by independent functional mechanisms, which do not share the same cortical implementation. In particular, our results suggest that mental imagery abilities need not be mediated by early visual cortices.

Long-term persistence of vaccine-derived aluminum hydroxide is associated with chronic cognitive dysfunction

Macrophagic myofasciitis (MMF) is an emerging condition, characterized by specific muscle lesions assessing long-term persistence of aluminum hydroxide within macrophages at the site of previous immunization. Affected patients mainly complain of arthromyalgias, chronic fatigue, and cognitive difficulties. We designed a comprehensive battery of neuropsychological tests to prospectively delineate MMF-associated cognitive dysfunction (MACD). Compared to control patients with arthritis and chronic pain, MMF patients had pronounced and specific cognitive impairment. MACD mainly affected (i) both visual and verbal memory; (ii) executive functions, including attention, working memory, and planning; and (iii) left ear extinction at dichotic listening test. Cognitive deficits did not correlate with pain, fatigue, depression, or disease duration. Pathophysiological mechanisms underlying MACD remain to be determined. In conclusion, long-term persistence of vaccine-derived aluminum hydroxide within the body assessed by MMF is associated with cognitive dysfunction, not solely due to chronic pain, fatigue and depression.