Childhood Cerebral Adrenoleukodystrophy: MR Perfusion Measurements and Their Use in Predicting Clinical Outcome after Hematopoietic Stem Cell Transplantation.

BACKGROUND AND PURPOSE: MR perfusion has shown abnormalities of affected WM in cerebral X-linked adrenoleukodystrophy, but serial data is needed to explore the import of such findings after hematopoietic stem cell transplantation. Our aim was to prospectively measure MR perfusion parameters in patients with cerebral adrenoleukodystrophy pre- and post-hematopoietic stem cell transplantation, and to correlate those measurements with clinical outcome. MATERIALS AND METHODS: Ten patients with cerebral adrenoleukodystrophy prospectively underwent DSC-MR perfusion imaging at <45 days pre- (baseline), 30-60 days post-, and 1 year post-hematopoietic stem cell transplantation. MR perfusion measurements in the 10 patients and 8 controls were obtained from the parieto-occipital WM, splenium of the corpus callosum, leading enhancing edge, and normal-appearing frontal white matter. MR imaging severity scores and clinical neurologic function and neurocognitive scores were also obtained. MR perfusion values were analyzed in the patients with cerebral adrenoleukodystrophy at each time point and compared with those in controls. Correlations were calculated between the pre-hematopoietic stem cell transplantation MR perfusion values and 1-year clinical scores, with P value adjustment for multiple comparisons. RESULTS: At baseline in patients with cerebral adrenoleukodystrophy, both relative CBV and relative CBF within the splenium of the corpus callosum and parieto-occipital WM significantly differed from those in controls (P = .005-.031) and remained so 1 year post-hematopoietic stem cell transplantation (P = .003-.005). Meanwhile, no MR perfusion parameter within the leading enhancing edge differed significantly from that in controls at baseline or at 1 year (P = .074-.999) or significantly changed by 1 year post-hematopoietic stem cell transplantation (P = .142-.887). Baseline Loes scores correlated with 1-year clinical neurologic function (r = 0.813, P < .0001), while splenium of the corpus callosum relative CBV also significantly correlated with 1-year neurologic function scale and the neurocognitive full-scale intelligence quotient and performance intelligence quotient scores (r = -0.730-0.815, P = .007-.038). CONCLUSIONS: Leading enhancing edge measurements likely remain normal post-hematopoietic stem cell transplantation in cerebral adrenoleukodystrophy, suggesting local disease stabilization. Meanwhile, parieto-occipital WM and splenium of the corpus callosum relative CBV and relative CBF values worsened; this change signified irreversible injury. Baseline splenium of the corpus callosum relative CBV may predict clinical outcomes following hematopoietic stem cell transplantation.

Childhood cerebral X-linked adrenoleukodystrophy: diffusion tensor imaging measurements for prediction of clinical outcome after hematopoietic stem cell transplantation.

BACKGROUND AND PURPOSE: DTI in cerebral X-linked adrenoleukodystrophy may demonstrate abnormalities in both affected and nonaffected WM; these values have not been studied serially after hematopoietic stem cell transplantation. The purpose of this study was to study pretransplant and posttransplant DTI parameters serially and ultimately to determine the ability of pretransplant DTI parameters to predict clinical outcome after HSCT in children with ALD. MATERIALS AND METHODS: Eight patients with posterior-pattern cerebral ALD underwent DTI at 3T before HSCT (T0), at 30-60 days (T1), 90-120 days (T2), 180 days (T3), and 1 year (T4) after HSCT. FA and MD were serially measured in 19 regions, and these measurements were compared with those in control patients. MR imaging severity (Loes) scores were recorded. Correlations were performed between DTI parameters and Loes scores, neurologic function scores, and several neuropsychologic scores. RESULTS: Both FA and MD in subjects differed significantly from that in controls at nearly every time point within cerebellar WM, callosal splenium, and parieto-occipital WM; FA alone was significantly different at each time point within the optic radiations, lateral geniculate, and the Meyer loop (P < .05). Loes scores at T0 correlated strongly with each clinical score at T4 (r = 0.771-0.986, P < .05). The only significant DTI correlation at T0 with a clinical score at T4 was callosal body FA with adaptive function (r = 0.976, P < .001). Correlating the change in DTI values with change in NFS (change between T0 and T4) showed that only ΔMD within the optic radiations correlated strongly with ΔNFS (r = 0.903, P < .05). CONCLUSIONS: DTI values at T0 were generally poor predictors of outcome at 1 year, whereas Loes scores were generally good predictors. ΔMD within the optic radiations strongly correlates with ΔNFS over that year. In addition, certain normal-appearing regions, such as cerebellar WM, may have DTI abnormalities before HSCT that persist after HSCT.

Occupational radiation dose during transcatheter aortic valve implantation.

OBJECTIVES: To examine the occupational radiation dose during transcatheter aortic valve implantation (TAVI) in both transfemoral and transapical approach. BACKGROUND: Interventional fluoroscopic guided cardiac procedures lead inevitably to radiation exposure of workers, which over time may be associated with an increased incidence of cancer and cataract. METHODS: Using thermoluminescence dosimeters, the radiation dose of the cardiothoracic surgeon, cardiologist, and two assistants was measured on the apron at chest height and on both feet. In addition, dose measurements were performed on the hands of the two operators and on the eyes of the cardiothoracic surgeon. This study involved 11 transapical and 11 transfemoral TAVIs. The effective dose was estimated from the dose measured on the apron. RESULTS: In the transapical TAVI the cardiothoracic surgeon received a significantly higher equivalent hand dose (average ± SD), 1.9 ± 0.6 mSv, equivalent foot dose, 0.57 ± 0.31 mSv, equivalent eye dose, 0.11 ± 0.06 mSv, and effective dose, 0.03 ± 0.02 mSv, than any staff member in the transfemoral TAVI, with highest average doses of 0.03 ± 0.02 mSv, 0.22 ± 0.19 mSv, 0.03 ± 0.01 mSv, and 0.003 ± 0.005 mSv, respectively. CONCLUSIONS: This study provides hitherto unavailable data on the radiation exposure of staff during transfemoral and transapical TAVIs. Relatively high doses were observed in the transapical approach. The dose of the right hand of the cardiothoracic surgeon will reach the annual limit within about 250 procedures per year, implying that hand dose measurements should become standard and that the number of procedures performed by the cardiothoracic surgeon involving X-rays may have to be limited.

Reproducibility of anterior chamber angle measurements with anterior segment optical coherence tomography.

PURPOSE: To study the reproducibility and variability of iridocorneal angle (ICA) measurements by using anterior segment optical coherence tomography (AS-OCT) by expert and nonexpert observers. METHODS: Twenty-three healthy volunteers (nonexperts with a basic knowledge of ophthalmology) acquired five consecutive AS-OCT images in the enhanced anterior segment single mode in the 180° to 0° meridian of the right eyes of their peers. Two experts and the 23 nonexperts analyzed the images. The ICA software tool was used to determine the angle opening distance (AOD) and the trabecular iris surface area (TISA) at 500 and 750 µm. A random intercept model was fitted to evaluate the variability of acquiring an image. For both the experts and the nonexperts, inter- and intraobserver variability of analyzing an AS-OCT image was determined with the coefficient of variation (CV). Reproducibility was qualified by using the intraclass correlation coefficient (ICC). RESULTS: There was no statistically significant difference in the variability of acquiring an image. The range of intraobserver variability in image analysis was from 9.4% to 12.5% in the experts and from 4.2% to 17.4% in the nonexperts. Interobserver variability was 10.7% in the experts and 10.2% in the nonexperts. The reproducibility was high, 0.875 and 0.942 in the experts and 0.906 in the nonexperts. CONCLUSIONS: The overall reproducibility of the ICA measurements with the AS-OCT is good in open angles. Inter- and intraobserver variability showed similar mean values of reproducibility between the experts and nonexperts. The wide range of intraobserver variation in the nonexperts suggests that this group should undergo extensive instruction before routinely analyzing AS-OCT images.

Metachromatic leukodystrophy: a scoring system for brain MR imaging observations.

BACKGROUND AND PURPOSE: Metachromatic leukodystrophy (MLD) is a devastating demyelinating disease for which novel therapies are being tested. We hypothesized that MR imaging of brain lesion involvement in MLD could be quantified along a scale. MATERIALS AND METHODS: Thirty-four brain MR images in 28 patients with proved biochemical and genetic defects for MLD were reviewed: 10 patients with late infantile, 16 patients with juvenile, and 2 patients with adult MLD. All MR images were reviewed by experienced neuroradiologists and neurologists (2 readers in Germany, 2 readers in the United States) for global disease burden, as seen on the T2 and fluid-attenuated inversion recovery images. A visual scoring method was based on a point system (range, 0-34) derived from the location of white matter involvement and the presence of global atrophy, analogous to the scoring system developed for adrenoleukodystrophy. The readers were blinded to the neurologic findings. RESULTS: Thirty-three of 34 MR images showed confluent T2 hyperintensities of white matter. The inter-rater reliability coefficient was 0.988. Scores between readers were within 2 points of each other. Serial MR imaging studies in 6 patients showed significant progressive disease in 3 patients (initial score average, 4; mean follow-up, 24.3) and no change or 1 point progression in 3 patients (initial score average, 12; mean follow-up, 12.66). Projection fibers and the cerebellum tended to be involved only in advanced stages of disease. CONCLUSIONS: The MLD MR severity scoring method can be used to provide a measure of brain MR imaging involvement in MLD patients.

Increased number of cerebral emboli during percutaneous endocardial pulmonary vein isolation versus a thoracoscopic epicardial approach.

OBJECTIVE: Pulmonary vein isolation (PVI) using ablation energy appears an effective treatment for atrial fibrillation (AF) with a success rate of approximately 80%. However, post-procedural neurological complications still occur in 0.5-10% of all patients undergoing PVI, presumably due to embolism. Therefore, we investigated the occurrence of cerebral micro-embolic signals (MES) as a surrogate marker for the risk of neurological impairment of two different PVI methods: (1) percutaneous endocardial radio-frequency (RF) ablation and (2) thoracoscopic epicardial ablation using RF energy. METHODS: Ten patients (eight persistent AF and two paroxysmal AF) underwent a minimally invasive thoracoscopic epicardial (EPI) RF ablation and 10 patients (one persistent AF and nine paroxysmal AF) underwent a percutaneous endocardial (ENDO) isolation. Transcranial Doppler (TCD) was used to detect an MES in the middle cerebral arteries. RESULTS: An average of 5 (+/-6) MES were detected during epicardial PVI procedure versus 3908 (+/-2816) MES during percutaneous endocardial PVI procedure. During the ablation application period, respectively, 1 (+/-1) and 2566 (+/-2296) cerebral MES were detected. CONCLUSIONS: Cerebral micro-emboli during epicardial ablation are almost absent when compared to the thousands of emboli measured during percutaneous endocardial ablation.

Transcranial measurement of cerebral microembolic signals during endocardial pulmonary vein isolation: comparison of three different ablation techniques.

INTRODUCTION: Isolation of the pulmonary veins (PVI) using high ablation energy is an effective treatment for atrial fibrillation (AF) with a success rate of 50-95%; however, postoperative neurological complications still occur in 0.5-10%. In this study the incidence of cerebral microembolic signals (MES) as a risk factor for neurological complications is examined during 3 percutaneous endocardial ablation procedure strategies: segmental PVI using a conventional radiofrequency (RF) ablation catheter, segmental PVI using an irrigated RF tip catheter, and circumferential PVI with a cryoballoon catheter (CB). METHODS AND RESULTS: Thirty patients underwent percutaneous endocardial PVI. Ostial isolation was performed in 10 patients with a conventional 4-mm RF catheter (CRF) and in 10 patients with a 4-mm irrigated RF catheter (IRF). A circumferential PVI was performed in 10 patients with a CB. Transcranial Doppler (TCD) monitoring was used to detect MES in the middle cerebral arteries. The total number of cerebral MES differs significantly among the 3 PVI groups; 3,908 cerebral MES were measured with use of the CRF catheter, 1,404 cerebral MES with use of the IRF catheter, and 935 cerebral MES with use of the CB catheter. CONCLUSION: This study demonstrates a significant difference in cerebral MES during PVI with 3 different ablation procedures. The use of an irrigated RF and a cryoballoon produces significantly fewer cerebral MES than the use of conventional RF for a PVI procedure, suggesting a higher risk for neurologic complications using conventional RF energy during a percutaneous PVI procedure.

The EmBlocker: efficiency of a new ultrasonic embolic protection device adjunctive to heart valve surgery.

PURPOSE: Perioperative cerebral microemboli in cardiac surgery are associated with postoperative neurologic complications. The EmBlocker (Neurosonix Ltd, Rehovot, Israel), a newly developed device should be positioned against the ascending aorta, and it produces an ultrasonic force expected to divert microemboli away from the cerebral vasculature and reduce cerebral emboli. DESCRIPTION: Twenty-one consecutive patients, undergoing a valve procedure, were enrolled into this nonrandomized pilot study. The EmBlocker (Neurosonix Ltd) was positioned in 11 consecutive patients and activated for 1 minute (1.5 W/cm(2)) during seven selected aortic manipulations and for 10 minutes (0.5 W/cm(2)) intermittently after cross-clamp removal. Transcranial Doppler-based quantification of microembolic signals was performed in all patients. EVALUATION: The use of the EmBlocker showed a significant overall reduction of the cerebral microembolic signals of 53%. CONCLUSIONS: The use of the EmBlocker during valve surgeries is associated with a reduction of perioperative cerebral microembolic signals. This new technology holds the potential to lower the risk of postoperative neurologic complications.

Combined Impella and intra-aortic balloon pump support to improve both ventricular unloading and coronary blood flow for myocardial recovery: an experimental study.

Some patients in need of hemodynamic support do not respond to intra-aortic balloon pump (IABP) therapy. Hemodynamic stability can then be obtained by a more potent cardiac assist device, like the Impella catheter pump. Whether additional IABP support additional to Impella support can provide more optimal hemodynamic myocardial conditions is examined in this study. Seven sheep were implemented with IABP and Impella. An acute myocardial infarction was induced. Hemodynamic performance was assessed during baseline, during Impella support and IABP support individually, and during the combined Impella plus IABP support. The Impella support provided a reduction of afterload with 30% and an increase of coronary artery flow with 47%. The IABP increased coronary artery flow (13%), carotid artery flow (16%), and aortic ascending blood pressure (6%); a similar (but stronger) effect was provided when using the IABP support additional to Impella support and, respectively, increases of 33, 21, and 19% were established. The oxygen demand-supply ratio decreased by 25% due to the extra use of the IABP. A combination of IABP and Impella provides the most optimal hemodynamic myocardial conditions compared to either stand-alone support.

New ultrasonic radiation reduces cerebral emboli during extracorporeal circulation.

OBJECTIVE: Cardiac surgery is associated with intraoperative cerebral emboli, which can result in postoperative neurological complications. A new ultrasonic transducer (EmBlocker) can be positioned on the ascending aorta and activation of the EmBlocker is expected to divert emboli to the descending aorta, thereby decreasing emboli in the cerebral arteries. In this preliminary animal study, safety and efficiency of this technology were examined. METHODS: In 14 pigs (+/-70 kg), a median sternotomy was performed and the EmBlocker was positioned on the aorta ascendens at the level of the bifurcation of the aorta and the innominate artery. In one animal temperature measurements were performed. During these measurements, the EmBlocker was activated for four periods of 120 s of high power (1.5 W/cm(2)) and for four periods of 600 s of low power (0.5 W/cm(2)). In the safety study (n=6), the EmBlocker was activated twice the expected clinical duration (eight periods of 120 s of high power and, subsequently, one period of 20 min of low power). Tissue samples (control and sonicated) were collected after 1 week for histopathological evaluation (aorta, trachea, esophagus, vagus nerves). In the efficiency study (n=7), extracorporeal circulation was installed. Emboli (air and solid (1200, size 500 microm-750 microm)) were introduced in the proximal ascending aorta and the EmBlocker was alternately activated with high power for solid emboli injections and low power for air emboli injections. Transcranial Doppler (TCD) was used to analyse middle cerebral artery blood flow for occurrence of embolic signals, which were manually counted offline. RESULTS: Histopathology revealed no difference between control and sonicated tissue. There is a rise in temperature during EmBlocker activation, but in all measured tissues it was within limits; less then 42 degrees C for 2 min in the aorta wall directly under the EmBlocker. Use of the EmBlocker significantly reduced emboli in the cerebral arteries in an animal model; air emboli with 65% (left) and 69% (right) and solid emboli with 49% (left) and 50% (right). CONCLUSIONS: The new ultrasound technology can safely be applied and is capable of reducing emboli in the cerebral arteries during extracorporeal circulation. Use of the EmBlocker in cardiac surgery bears the potential to lower the risk of postoperative neurological complications. Clinical feasibility studies are in progress.

The acute effect of intra-aortic balloon counterpulsation during extracorporeal life support: an experimental study.

Hemodynamically unstable patients supported by an extracorporeal life support (ECLS) circuit often receive additional support by intra-aortic balloon pump (IABP). However, it is not established whether support of the failing heart is improved by adjunctive IABP in both peripheral cannulation (PC) and central cannulation (CC) settings. Seven sheep were supported by an IABP and an ECLS system which were cannulated centrally as well as peripherally. In each cannulation configuration, hemodynamic and cardiac function indices were measured at baseline, ECLS, and ECLS plus IABP. The primary variables were mean coronary artery flow (Qcor), diastolic pressure time index (DPTI), left ventricular (LV) pressure-volume area (PVA), and tension time index (TTI). Additional IABP with ECLS support (CC/PC) decreased LV afterload (LV systolic peak pressure -4%, P<0.05/-8%, P<0.02), as well as TTI -2%/-10% and PVA -10%/-12% (P<0.03). Coronary perfusion was increased by additional IABP: CC, Qcor, +9%, and DPTI, +18% (P<0.02); PC, Qcor,+6%, and DPTI, +11% (P<0.05). IABP augmented the myocardial oxygen supply/demand ratios (CC/PC): Qcor/(PVA.heart rate) (+21%/+22%, P<0.02) and DPTI/TTI (+27%/+24%, P<0.03). In case of low arterial pressure (<50 mm Hg) and reduced ECLS flow, the overall hemodynamic profile improved only with central cannulation. We conclude that in both central and peripheral ECLS cannulation settings, adjunctive IABP improves the myocardial oxygen supply demand balance. In case of low cardiac output and insufficient extracorporeal flow with PC, adjunctive IABP may be contraindicated.

Synchronously counterpulsating extracorporeal life support enhances myocardial working conditions regardless of systemic perfusion pressure.

OBJECTIVE: A new pulsatile extracorporeal life support (pECLS) system has entered the market. We wanted to investigate what potential advantages pECLS may have over current non-pulsatile systems (NPS). Our research was focused on the pump's functional interaction with the left ventricle and the coronary circulation. METHODS: Extensive hemodynamic measurements were performed during asynchronous and synchronous pECLS in 10 calves. The two extremes regarding LV afterload, namely systolic arrival (SA) and diastolic arrival (DA) of the pump pulse were studied. RESULTS: SA was associated with increased oxygen consumption (+57%) and decreased diastolic coronary perfusion (-43%). DA increased left ventricular output (DA: 4.5+/-2.4 l/min vs SA: 3.5+/-2.2 l/min), LV ejection fraction (+10%), and ventricular efficiency (+17%). Mean aortic pressure and mean coronary flow were only marginally affected by pulse incidence. Systolic impairment was more pronounced with higher bypass flows. These results indicate that myocardial working conditions can be optimized by phasing pECLS ejection into cardiac diastole. CONCLUSION: We conclude that during pECLS, myocardial working conditions can be improved by avoidance of systolic impairment. Synchronously counterpulsating pECLS could be a more economic and versatile alternative to NPS or NPS combined with intra-aortic balloon pumping. The potential benefits of synchronously counterpulsating pECLS over the current alternatives remain to be investigated.

Analysis of MRI patterns aids prediction of progression in X-linked adrenoleukodystrophy.

BACKGROUND: X-linked adrenoleukodystrophy (X-ALD) has variants with widely different outcomes, hampering clinical counseling and evaluation of therapies. OBJECTIVE: To evaluate the degree to which MRI patterns can predict lesion progression. METHODS: Two hundred six boys and men with cerebral X-ALD (median age 12.2 years, mean age 18.5 years, age range 1.7 to 73.8 years) were studied. In 140 individuals, follow-up MRI were available. Data after bone marrow transplantation (BMT) were excluded. The patterns of MRI abnormalities were subdivided into five groups based on the anatomic location of the initial T2 signal hyperintensity (pattern 1: parieto-occipital white matter, pattern 2: frontal white matter, pattern 3: corticospinal tract, pattern 4: cerebellar white matter, pattern 5: concomitant parieto-occipital and frontal white matter). The X-ALD MRI Severity Scale, a 34-point scale previously described, was used in the analysis. RESULTS: Pattern 1 patients had rapid progression if contrast enhancement was present and if the MRI abnormality manifested at an early age. The latter was also true for pattern 2 patients. Based on these variables, predictive formulas were constructed for these two patterns using multiple regressions. MRI progression was much slower in pattern 3 and 4 patients, whereas in the few pattern 5 patients, it was more rapid than in any other of the patterns. Patterns 1 and 5 occurred mainly in childhood, patterns 2 and 4 in adolescence, and pattern 3 in adults. CONCLUSIONS: MRI progression in X-ALD depends on patient age, initial MRI Severity Scale score, and anatomic location of the lesion. When used in combination, these data aid the prediction of disease course and the selection of patients for BMT.

Evolution of phenotypes in adult male patients with X-linked adrenoleukodystrophy.

Our objective was to study the phenotype evolution of X-linked adrenoleukodystrophy (X-ALD) and the relation between axonal degeneration and cerebral demyelination. Although different X-ALD phenotypes are recognized, little is known about their evolution. Neuropathological and electrophysiological studies have shown that X-ALD is a disease with mixed features of axonal degeneration, leading to myeloneuropathy, and a severe inflammatory reaction in the cerebral white matter, resulting in demyelination. Retrospectively, 129 men with X-ALD were studied who were 1) at least 20 years presently or at the time of death, and 2) regularly monitored. Phenotype assignments were made at diagnosis and at present, or at death, using medical history and findings of neurological examination. Handicap was studied with the modified Rankin scale, and cerebral abnormalities with the X-ALD MRI severity (Loes) score. The mean follow-up interval was 10.1 +/- 5.0 years. Among 32 patients neurologically asymptomatic at diagnosis, 16 (50%) developed neurological deficits. Among 68 adrenomyeloneuropathy (AMN) patients initially without clinical brain involvement, 13 (19%) additionally developed cerebral demyelination. In a subset of 60 AMN patients, a moderate handicap evolved over a period of 16.2 +/- 8.9 years. Among 13 AMN patients with additional definite or probable cerebral involvement at diagnosis, eight died and one remained in a vegetative state. Most of the 16 patients with the cerebral phenotypes deteriorated. There is a high risk for adult neurologically asymptomatic patients to develop neurological deficits and for AMN patients to develop cerebral demyelination. Axonal degeneration and cerebral demyelination emerge in X-ALD independently of each other. This may have implications for the phenotype classification, the search for modifying factors, and the development and evaluation of new therapies.

Long-term effect of bone-marrow transplantation for childhood-onset cerebral X-linked adrenoleukodystrophy.

BACKGROUND: The childhood-onset cerebral form of X-linked adrenoleukodystrophy, a demyelinating disorder of the central nervous system, leads to a vegetative state and death within 3-5 years once clinical symptoms are detectable. The hypothesis to be tested was whether bone-marrow transplantation can over an extended period of time halt the inexorable progressive demyelination and neurological deterioration. METHODS: 12 patients with childhood onset of cerebral X-linked adrenoleukodystrophy have been followed for 5-10 years after bone-marrow transplantation. Magnetic resonance imaging (MRI), neurological, neuropsychological, electrophysiological, and plasma very-long-chain fatty acid (VLCFA) measurements were used to evaluate the effect of this treatment. FINDINGS: MRI showed complete reversal of abnormalities in two patients and improvement in one. One patient showed no change from baseline to last follow-up. All eight patients who showed an initial period of continued demyelination stabilised and remained unchanged thereafter. Motor function remained normal or improved after bone-marrow transplantation in ten patients. Verbal intelligence remained within the normal range for 11 patients. Performance (non-verbal) abilities were improved or were stable in seven patients. Decline in performance abilities followed by stability occurred in five patients. Plasma VLCFA concentrations decreased by 55% and remained slightly above the upper limits of normal. INTERPRETATION: 5-10-year follow-up of 12 patients with childhood-onset cerebral X-linked adrenoleukodystrophy shows the long-term beneficial effect of bone marrow transplantation when the procedure is done at an early stage of the disease.

X-linked adrenoleukodystrophy: the role of contrast-enhanced MR imaging in predicting disease progression.

BACKGROUND AND PURPOSE: Early assignment of disease progression among patients with X-linked adrenoleukodystrophy (ALD) is critical for the appropriate selection of effective therapy. We evaluated the association between contrast enhancement on T1-weighted spin-echo MR images and disease progression. METHODS: Clinical charts of patients with X-linked ALD were reviewed for age, availability of MR images of the brain, severity of neurologic impairment, and duration and number of follow-up evaluations. Forty-three male patients with X-linked ALD had undergone multiple MR imaging examinations of the brain that consisted of at least sagittal and axial T1-weighted spin-echo, axial double-echo spin-echo, and contrast-enhanced axial T1-weighted spin-echo imaging. The MR images were reviewed for the presence of contrast enhancement. In addition, global disease burden, as shown by the double-echo spin-echo images, was assessed using a visual scoring method (Loes score). RESULTS: Enhancement was seen on the initial T1-weighted spin-echo MR images of 21 (49%) patients; 18 (86%) of the 21 patients had disease progression revealed by the follow-up evaluations based on MR imaging (Loes) and neurologic scores. No enhancement was seen on the initial T1-weighted spin-echo MR images of 22 (51%) patients; for 18 (82%) of the 22 patients, no evidence of disease progression was revealed by the follow-up evaluations. CONCLUSION: There is a very strong association between the presence of contrast enhancement on T1-weighted MR images and X-linked ALD progression based on clinical evaluation and MR imaging.

X-Linked adrenoleukodystrophy: overview and prognosis as a function of age and brain magnetic resonance imaging abnormality. A study involving 372 patients.

The phenotypic expression of X-linked adrenoleukodystrophy (X-ALD) ranges from the rapidly progressive childhood cerebral form to the milder adrenomyeloneuropathy (AMN) in adults. It is not possible to predict phenotype by mutation analysis or biochemical assays. This study reports on 372 patients ranging in age from less than 3 years to adulthood, who have been followed at the Kennedy Krieger Institute. With the aim of determining whether a method could be developed to predict clinical course by analysis of data available at time of first contact, the patients were subdivided into 18 subgroups on the basis of age and the extent of brain magnetic resonance (MRI) abnormality utilizing the MRI scoring system devised by Loes et al. Scores to grade degree of neurologic and neuropsychologic impairment were also developed. There was strong correlation between MRI and the neurology and neuropsychology scores at baseline. Information based exclusively on age and MRI score at time of first contact was highly predictive of future clinical course and should aid the evaluation of the effects of bone marrow transplantation and the selection of patients for this procedure, as well as the evaluation of other therapies that may be developed in the future.

Globoid cell leukodystrophy: distinguishing early-onset from late-onset disease using a brain MR imaging scoring method.

BACKGROUND AND PURPOSE: Our purpose was to determine the characteristic MR features of early-onset (before age 2 years) versus late-onset (after age 2 years) globoid cell leukodystrophy (GLD). METHODS: Thirty-four brain MR images in 22 patients with GLD were reviewed. A severity score (0 to 32), based on a point system derived from the location and extent of disease and the presence of focal and/or global atrophy, was calculated for each examination. RESULTS: Of the 22 patients, three were asymptomatic and 19 were symptomatic. Ten patients had early-onset disease, whereas nine had late-onset disease. MR images of all patients showed abnormalities. In the early-onset group (n = 10; mean maximum MR score, 8.1; range, 3-18), 90% had pyramidal tract involvement, 80% had cerebellar white matter involvement, 70% had deep gray matter involvement, 60% had posterior corpus callosal involvement, 50% had parietooccipital white matter involvement, and 40% had cerebral atrophy. Serial MR imaging in four of these patients revealed progressive disease. In the late-onset group (n = 9; mean maximum MR score, 5.6; range, 4-10), 100% had pyramidal tract involvement, 100% had parietooccipital white matter involvement, 89% had posterior corpus callosal involvement, and none had cerebellar white matter involvement, deep gray matter involvement, or cerebral atrophy. Serial MR imaging in one patient with late-onset GLD did not reveal any change. A spectrum of findings was observed in the three patients who were asymptomatic. CONCLUSION: Cerebellar white matter and deep gray matter involvement are present only in early-onset GLD. Pyramidal tract involvement is a characteristic finding in both early- and late-onset GLD. This scoring method for brain MR observations will assist in the objective assessment of the impact of hematopoietic stem cell transplantation in patients with GLD.

Hematopoietic stem-cell transplantation in globoid-cell leukodystrophy.

BACKGROUND: Globoid-cell leukodystrophy is caused by a deficiency of galactocerebrosidase, which results in progressive central nervous system deterioration. We investigated whether allogeneic hematopoietic stem-cell transplantation can provide a source of leukocyte galactocerebrosidase and thereby prevent the decline of central nervous system function in patients with the disease. METHODS: Five children with globoid-cell leukodystrophy (one with the infantile type and four with late-onset disease) were treated with allogeneic hematopoietic stem-cell transplantation. Measurement of leukocyte galactocerebrosidase levels, neurologic examinations, neuropsychological tests, magnetic resonance imaging of the central nervous system, cerebrospinal fluid protein assays, and neurophysiologic measurements were performed before and after transplantation, with follow-up ranging from one to nine years. RESULTS: Engraftment of donor-derived hematopoietic cells occurred in all patients and was followed by restoration of normal leukocyte galactocerebrosidase levels. In the four patients with late-onset disease, the central nervous system deterioration was reversed, and in the patient with the infantile form of the disease, signs and symptoms have not appeared. Magnetic resonance imaging showed a decrease in signal intensity in the three patients with late-onset disease who were assessed both before and after transplantation. Abnormalities in cerebrospinal fluid total protein levels were corrected in three patients with late-onset disease and substantially reduced in the patient with the infantile form. CONCLUSIONS: Central nervous system manifestations of globoid-cell leukodystrophy can be reversed by allogeneic hematopoietic stem-cell transplantation.

Proton MR spectroscopy of childhood adrenoleukodystrophy.

PURPOSE: To determine the potential of proton MR spectroscopy to monitor patients with childhood-onset cerebral adrenoleukodystrophy (COCALD). METHODS: Single-voxel MR spectroscopy was performed in 16 children with COCALD (24 examinations) who had had no treatment and in 7 children (13 examinations) who had had bone marrow transplantation. RESULTS: In the untreated children with clinically active COCALD, the metabolite ratios N-acetyl-aspartate (NAA)/creatine (Cr) and NAA/choline (Ch) were decreased while Ch/Cr was increased. This trend agrees well with those reported by other researchers, although different experimental sequences and parameters were used in our study. Comparison of these ratios with those from a control group yielded significant differences in the occipital region. In the children who were clinically stable after bone marrow transplantation, the mean levels of the three ratios were between those of the control subjects and the patients with untreated COCALD: the differences in these ratios approached significance. In patients who had been monitored periodically, MR spectroscopy metabolite ratios correlated well with the dementia rating score, reflecting clinical status. CONCLUSION: There is good correlation between MR spectroscopy metabolite ratios and a patient's clinical status. MR spectroscopy appears to be a useful, noninvasive tool to monitor patients with adrenoleukodystrophy, and it increases the overall sensitivity of MR techniques in clinical applications.