Management of adverse renal events related to alemtuzumab treatment in multiple sclerosis: a Belgian consensus.

Alemtuzumab is a humanized monoclonal antibody indicated for the treatment of adult patients with relapsing-remitting multiple sclerosis with active disease. Multiple sclerosis (MS) patients treated with alemtuzumab are at increased risk for autoimmune adverse events (thyroid disorders, immune thrombocytopenia, and renal disease). The use of alemtuzumab has been associated with the development of renal immune-mediated adverse events in 0.3% of patients in clinical trials in MS, which generally occurred within 39 months of the last administration. Both anti-GBM disease and membranous nephropathy have been associated with the use of alemtuzumab. Early detection is necessary to allow for early diagnosis and prevent adverse renal and patient outcomes. Through the implementation of the risk minimization measures, patients can be diagnosed, and treated if needed, early allowing for generally favorable outcomes. This important goal can be reached through health care professional and patient education, careful analysis of the monthly lab tests, and close collaboration between the patient, neurologist, and the nephrologist. This article presents the consensus of Belgian MS specialists and nephrologists on the practicalities of diagnosis, management, and treatment of alemtuzumab-associated renal adverse events based on good clinical practice.

Long-term follow up of glatiramer acetate compassionate use in Belgium.

Between June 1995 and November 1998, 228 patients with relapsing-remitting Multiple Sclerosis started treatment with glatiramer acetate (Copaxone) 20 mg once daily in the frame of a "compassionate use" protocol in 15 Belgian centers. Following an average treatment period of 5.8 years, treating neurologists were requested to fill in follow-up forms indicating neurological disability status and side effects during the previous 6 months. These data were available for 134 patients. In this group, the Expanded Disability Status Scale (EDSS) improved in 26.3% of patients. An additional 36.8% of patients remained neurologically stable. The Ambulation Index (AI) showed similar results: 12.5% of patients improved, 50% of patients remained stable, and 37.5% worsened. Only 10% of patients dropped out due to several reasons. The adverse events occurring in the period preceding the follow-up survey were non-serious and consistent with the current product information of glatiramer acetate. Among the 94 patients no longer followed-up in the compassionate program, reasons for lost to follow-up were obtained for 63; most of them (41) had stopped GA treatment or switched to another disease-modifying treatment. Overall these results are very similar to the ones reported in the extension study of the pivotal trial (Johnson et al., 2000), and indicate that patients treated with glatiramer acetate have a better outcome than expected on the basis of the natural course of the disease. Despite limitations of the study design, this report confirms the sustained efficacy of glatiramer acetate in reducing the disease progression in patients with relapsing-remitting multiple sclerosis treated in day-to-day clinical practice.

Cerebral blood flow and oxygen metabolism in symptomatic internal carotid artery occlusion by (traumatic) cervical artery dissection.

The present study investigates whether cerebral infarction resulting from internal carotid artery occlusion by cervical dissection is due to emboli, released from a superimposed luminal thrombus, or is due to haemodynamic failure and hypoperfusion. Ten patients with a history of stroke and with a visible cerebral infarct on computed tomographic scan, due to cervical dissection and thrombosis of the internal carotid artery, were studied with positron emission tomography in order to assess the regional cerebral blood flow (rCBF), the regional cerebral metabolic rate of oxygen (rCMRO2) and the regional oxygen extraction fraction (rOEF) in different regions of the brain. rCBF and rCMRO2 were only decreased in the infarct area but not in the peri-infarct zone or elsewhere in the brain. As rOEF was not increased in the affected cerebral hemisphere, the present study suggests artery-to-artery embolism rather than a haemodynamic event as the cause of the stroke. Use of anticoagulants thus appears to be the appropriate treatment in the acute stage.

Cerebral bloodflow and oxygen metabolism in borderzone and territorial infarcts due to symptomatic carotid artery occlusion.

It remains controversial whether borderzone infarcts are due to compromised cerebral perfusion and whether territorial infarcts are caused by artery-to-artery emboli in case of occlusion of the internal carotid artery. The present positron emission tomography study compares with normal controls, the average regional cerebral bloodflow (rCBF), regional oxygen extraction fraction (rOEF) and regional cerebral metabolic rate for oxygen (rCMRO(2)) in the infarct area, the peri-infarct zone, the remaining homolateral hemisphere and in the contralateral hemisphere of 10 patients with borderzone and 17 patients with territorial infarcts, due to internal carotid artery occlusion by atherosclerosis and by cervical dissection. The steady-state technique with oxygen-15 was used. A nearly significant increase of rOEF with lowered rCBF and rCMRO(2) was observed in the peri-infarct zone of patients with territorial infarcts. In patients with borderzone infarcts rCMRO(2) was decreased in the peri-infarct zone, in the remaining homolateral hemisphere and in the contralateral hemisphere without changes in rCBF and rOEF. The present study finds no arguments that impaired cerebral perfusion is a more frequent cause of borderzone than of territorial infarcts.

57Co SPECT, 99mTc-ECD SPECT, MRI and neuropsychological testing in senile dementia of the Alzheimer type.

Inflammatory mechanisms contribute to the pathophysiology of senile dementia of the Alzheimer type (sDAT). Previous studies have shown that 57Co single photon emission computed tomography (SPECT) is able to visualize inflammatory lesions, probably by means of the final common pathway of Ca2+ homeostasis disturbance in both neuronal degeneration and inflammation. The aims of this study were: (1) to detect 57Co SPECT changes in sDAT patients; (2) to correlate these findings with those of conventional neuroimaging techniques and neuropsychological testing (NPT); and (3) to compare 57Co SPECT findings in sDAT patients with those in other types of dementia. Six patients suffering from probable sDAT were included and compared with four patients suffering from other types of dementia. All patients had a magnetic resonance imaging (MRI) scan, NPT, 57Co and 99mTc-ethyl cysteinate dimer (ECD) SPECT scan. Perfusion SPECT images were semiquantitatively evaluated by comparison with an age-matched normal database, while 57Co SPECT scans were assessed qualitatively. MRI and 99mTc-ECD SPECT scans yielded conclusive results with regard to the exclusion of other pathologies and the confirmation of the diagnosis. Using visual analysis, 57Co SPECT scans were unable to show any regional raised uptake, irrespective of the disorder, depth or extent of the perfusion defects, presence of atrophy on MRI or the results of NPT.

Parkinsonism in patients with vascular dementia: clinical, computed- and positron emission-tomographic findings.

PURPOSE: The present study investigates the vascular nature of parkinsonian features in patients with 'probable' vascular dementia. PATIENTS AND METHODS: Forty patients with vascular dementia were studied with positron emission tomography (PET) using the steady state technique with (15)O in order to assess regional cerebral blood flow (rCBF), regional oxygen extraction rate (rOER) and regional metabolic rate for oxygen (rCMRO(2)) in different brain regions. The findings in 10 patients with (VaDP) were compared to 30 without parkinsonism (VaD). RESULTS: The clinical and computed tomographic findings in the parkinsonian patients were similar to those described in the literature as probable vascular parkinsonism. The PET results showed decreased rCBF and rCMRO(2) in the frontal and parietal cortices and in the striatum of the VaDP compared to the VaD group. The decrease of rCBF and rCMRO(2) in frontal and parietal cortices is due to the more severe mental changes in the VaDP group. In the VaDP patients rCBF and rCMRO(2) were more decreased and rOER increased in the striatum contralateral to the most affected parkinsonian side. CONCLUSION: Our PET findings show that local ischemic changes in the striatum contribute to parkinsonism in vascular dementia patients.

Accurate differentiation of parkinsonism and essential tremor using visual assessment of [123I]-FP-CIT SPECT imaging: the [123I]-FP-CIT study group.

OBJECTIVE: To evaluate whether visual assessment of [123I]-FP-CIT (DaTSCAN, Nycomed Amersham, plc) single photon emission computerized tomography (SPECT) images can differentiate between parkinsonism and essential tremor (ET). METHODS: [123I]-FP-CIT SPECT imaging was conducted in a six-center study of 158 patients with a clinical diagnosis of parkinsonism compared with 27 ET cases and 35 healthy volunteers. Striatal uptake of the radioligand was graded normal or abnormal, and abnormal images were further graded to three levels of severity. An institutional read whereby each center visually assessed the images blinded to the clinical data and a consensus blinded read by a panel of five was undertaken. RESULTS: The institutional reading scored 154 of 158 cases of parkinsonism abnormal, all 27 cases of ET as normal, and 34 of 35 healthy volunteers as normal compared with the consensus blinded read scoring 150 cases of parkinsonism as abnormal, 25 ET cases as normal, and 33 healthy volunteers as normal. Sensitivity for the clinical diagnosis of parkinsonism was 97% and specificity for ET was 100% for the institutional read, whereas sensitivity was 95% and specificity 93% for the consensus blinded read. Semiquantitative analysis of specific: nonspecific caudate and putamen uptake were consistent with the results of visual inspection. CONCLUSION: Visual assessment of [123I]-FP-CIT SPECT images is an easily applied diagnostic test which is helpful in the differential diagnosis of tremor disorders and in confirming a clinical diagnosis of a hypokinetic-rigid syndrome.

Acetazolamide vasoreactivity in vascular dementia: a positron emission tomographic study.

The present study investigates the vasoreactivity of the brain in patients with large infarcts and dementia (multi-infarct dementia; MID) and in patients with microangiopathy, lacunes, white matter changes and dementia (lacunar dementia; LD) using positron emission tomography (PET) and 13NH3 as regional cerebral blood flow (rCBF) tracer. In the control group, an increase in rCBF ranging from 32 to 43% was found in all brain regions after intravenous acetazolamide administration. In both the MID group and the group with multiple infarcts without dementia, moderate loss of vasoreactivity was observed in the frontal, temporal and parietal cortex compared to the control values. Vasoreactivity was severely impaired in all cerebral regions of the LD group and restricted to the thalamus in the group with lacunes and white matter changes without dementia (lacunar stroke; LS). This suggests that global loss of vasoreactivity is not a determining factor in the occurrence of MID, but might be important in LD. The present study shows that loss of the vascular reserve leading to exhausted metabolic reserve of the whole brain is one of the possible mechanisms for the occurrence of vascular dementia.

Positron emission tomography in vascular dementia.

BACKGROUND: Vascular dementia (VaD) is an ill-defined entity. It is not known how acute brain failure related to stroke becomes chronic leading to dementia. PURPOSE: The present study investigates whether positron emission tomography (PET) can detect different metabolic patterns in VaD. PATIENTS AND METHODS: Four groups of stroke patients were selected. The PET findings of 14 stroke patients with multiple large infarcts and dementia (MID) and 14 without dementia (MS) were compared. Sixteen stroke patients with lacunes, leukoaraiosis and dementia (LD) were assessed against nine without dementia (LS). The PET examination utilised the 15-O-steady-state technique in order to determine regional cerebral blood flow (rCBF), regional oxygen extraction rate (rOER) and regional cerebral metabolic rate for oxygen (rCMRO2) in different pre-established cortical, subcortical and cerebellar regions. RESULTS: Decreased coupled mean rCBF and rCMRO2 with comparable rOER values were observed in all cerebral regions except in the cerebellum of the MID compared to the MS group. In the LD group mean rCBF and rCMRO2 were decreased with increased rOER in all cerebral regions except in the cerebellum compared to the LS group. CONCLUSIONS: The PET findings in demented patients with multiple large infarcts are in agreement with the concept of multi-infarct dementia. In demented patients with lacunes and leukoaraiosis, the PET pattern suggests a state of misery perfusion not only in the deep structures but also in the whole cerebral cortex. The present PET study argues that there are at least two possible mechanisms that can explain the occurrence of VaD in stroke patients.

Biodistribution and dosimetry of carbon-11-methoxyprogabidic acid, a possible ligand for GABA-receptors in the brain.

UNLABELLED: Carbon-11-methoxyprogabidic acid (11C-MPGA) was recently synthetized as a possible ligand for PET studies of gamma-amino-butyric acid (GABA) receptors in the brain. The data for human absorbed dose estimates are calculated based on the biodistribution of 11C-MPGA in mice and humans. METHODS: Eighteen mice were killed at preset time intervals after an intravenous bolus injection of 3.7 MBq (100 microCi) 11C-MPGA. Time-activity curves were reconstructed for several organs. Three healthy men each had whole-body PET scans after an intravenous bolus injection of 37 MBq (1 mCi) to determine activity in the critical organs. Animal data were fitted into these human findings to calculate residence times, and the MIRDOSE 3 protocol was used to calculate the radiation absorbed dose. RESULTS: Animal studies demonstrated a rapid distribution of 11C-MPGA in several organs. The highest activity was detected in the intestines, liver and kidneys. Brain activity was low throughout compared to these organs. The human whole-body study yielded similar results, with the intestines, liver and kidneys showing the highest activity. The estimated dose to the urinary bladder compartment turned out to be significant. The mean effective dose was 4.8 microSv/MBq (s.d.= 0.5 microSv/MBq). CONCLUSION: PET studies using 185 MBq (5 mCi) 11C-MPGA are within the International Commission on Radiological Protection risk Category II for healthy volunteers.

Co-registration of PET and MRI in different courses of MS using Cobalt-55 as a Calcium-tracer.

Multiple Sclerosis (MS) is an auto-immune central nervous system (CNS) inflammation. At this moment, MRI is the most accurate paraclinical test in MS to monitor disease activity, although poorly correlated with clinical impairment. PET using Co-55 as a Ca-tracer may visualize Co-transport across the neuronal membrane, Ca-mediated inflammatory processes and passive leakage through a breach in the blood-brain barrier. Co-registration of MRI and Co-PET may actually allow identification of clinically active lesions. MRI and Co-PET were performed as described elsewhere. Based on a statistic parametric mapping (SPM-96)-software package, MRI and Co-PET were superimposed. A semi-automated technique was used to count the MS-lesions. We included four groups of eight MS-patients with relapsing-remitting (RR), primary progressive (PP), progressive relapsing (PR) and secondary progressive (SP) courses and eight healthy volunteers. MS was assessed in terms of impairment using Kurtzke's Expanded Disability Status Scale (EDSS) and Scripps Neurological Rating Scale (NRS). Co-PET displayed focal uptake throughout the MS brain, both in the grey and white matter. All four patients groups (as compared to controls) demonstrated a more inhomogeneous distribution of Co-spots with a tendency to show clustering, most evident in RR-MS. SPM-analysis revealed an essentially different distribution pattern of MS spots on MRI and Co-PET. (Merging of) Co-PET and MRI may eventually form complementary tools for identifying clinically relevant lesions, thus providing a more reliable secondary outcome measure in MS.

PET studies in epilepsy.

Positron emission tomography (PET) plays a major role in the pre-surgical evaluation of patients with refractory partial epilepsy. In this review we discuss the limitations of PET data, the possibilities of fluorodeoxyglucose PET studies, neuroreceptor PET studies and alternatives, such as SPECT and MRI.

Crossed cerebellar diaschisis after middle cerebral artery infarction.

It is unclear whether crossed cerebellar diaschisis (CCD) is merely an epiphenomenon, as its clinical significance remains uncertain. We retrospectively analysed the positron emission tomographic (PET) findings in 28 patients with a chronic, stable middle cerebral artery (MCA) infarct and in 22 controls, using the steady state technique and 15O. Also, the Orgogozo scores on admission and at the time of the PET examination were compared in the patients with MCA infarction. Based on the asymmetry index and the 95% confidence limits for regional cerebellar blood flow (rCBF) and oxygen consumption (rCMRO2) in the control group, the stroke patients were subdivided in a group with (n = 8) and a group without (n = 20) CCD. The CCD group had lower values of rCMRO2 in the infarct and border areas compared to those of the non-CCD patients. The infarct location within the MCA territory was similar but the size was somewhat larger in the CCC group. The degree of neurological improvement was better in the non-CCD group. Although persistence of CCD has no real clinical significance it appears to be correlated to more severe and widespread ischaemia in the affected MCA territory and to the lack of significant clinical improvement.

Cerebral oxygen metabolism in patients with progressive supranuclear palsy: a positron emission tomography study.

To investigate cerebral oxygen metabolism in progressive supranuclear palsy (PSP), 5 patients with a clinical diagnosis of PSP and a variable degree of cognitive deficit were selected for positron emission tomography (PET) of the brain. In 4 of them, a significant decrease in oxygen metabolism was found in all cortical regions, without frontal accentuation. In the group as a whole, this decrease was even slightly more marked in parietal and temporal regions. These findings are not consistent with earlier PET studies that demonstrated frontal targeting of hypometabolism in PSP patients. Part of this discrepancy can be explained by differences in methodology, although the use of different clinical criteria and overlap of PSP with other neurodegenerative diseases must be taken into account. It is concluded that the absence of frontal hypometabolism on PET examination does not exclude the diagnosis of PSP.

Late-onset epileptic seizures in patients with leukoaraiosis: a positron emission tomographic study.

Leukoaraiosis, found on computed tomographic scans of the brain, is suspected to be of ischemic origin and is frequently associated with progressive decline of cognitive functions in elderly persons. Some of them also develop late-onset epilepsy. The present positron emission tomographic study investigates if these seizures in mentally nonaffected patients with leukoaraiosis are related to an underlying ischemic process. Patients with leukoaraiosis and late-onset seizures have a more important decline of regional blood flow and oxygen consumption in the cortical areas, compared to normal age-matched controls, to patients with cryptogenic symptomatic late-onset epilepsy and to patients with a similar degree of leukoaraiosis but without epilepsy. The present study suggests that both the late-onset seizures and the leukoaraiosis in patients with, at that time, no obvious mental deterioration are premonitory signs of an encephalopathy of unknown origin, possibly leading to cognitive decline.

Ipsilateral thalamic diaschisis after middle cerebral artery infarction.

The significance of ipsilateral thalamic diaschisis (ITD) among patients with chronic, stable middle cerebral artery (MCA) infarcts was investigated. Twenty eight subjects with chronic MCA infarction and twenty two normal controls were studied with positron emission tomography (PET), using the steady state technique with 15O. Stroke patients were subdivided into a group with ITD (n = 12) and a group without ITD (n = 16). Patients with ITD had greater decreases of regional blood flow (rCBF) and oxygen consumption (rCMRO2) in the infarcted MCA territory, compared to MCA infarction without ITD. The neurological deficits at the time of PET scanning were similar between both groups. Extent of infarction by CT brain scan appeared more predominant in peri-insular regions of patients with ITD, while in non diaschisis patients infarcts were more widely distributed throughout the MCA territories. Occurrence of ITD and of crossed cerebellar diaschisis (CCD) did not correlate. Occurrence of ITD seems to be linked to diffuse reductions of blood flow and oxygen metabolism in cortical territories of the MCA. Mechanisms of ITD were different from those of CCD.

Positron emission tomographic study of late-onset cryptogenic symptomatic seizures.

Ten patients with epilepsy of unknown origin, starting after the age of 50 years, and without clear evidence of cognitive decline were studied with positron emission tomography, using the steady state technique with 15O. Cerebral blood flow and oxygen metabolism were significantly decreased in all cortical areas. No focal areas of hypometabolism were detected. Treatment with phenytoin did not influence the results. It is suggested that late-onset seizures could be the premonitory signs of a progressive encephalopathy of unknown origin.

Positron emission tomography in spastic diplegia.

In this study, three patients with spastic diplegia were examined with magnetic resonance imaging (MRI) and positron emission tomography (PET), using the steady state technique with 15O. Two of them had untractable seizures and mental retardation. On MRI the cortical structures were normal; increased T2 signals in the periventricular white matter in the second patient were the main findings. PET scan showed in the two patients with a seizure disorder and mental retardation a large left cortical area of decreased regional blood flow and oxygen consumption during the interictal phase. The third patient without epileptic spells had a normal PET scan examination. It is concluded that the epileptic disorder in two of our cases is due to an additional cortical lesion, while the spastic diplegia is caused by subcortical white matter destruction.