Minocycline for sporadic and hereditary cerebral amyloid angiopathy (BATMAN): study protocol for a placebo-controlled randomized double-blind trial.

BACKGROUND: Cerebral amyloid angiopathy (CAA) is a disease caused by the accumulation of the amyloid-beta protein and is a major cause of intracerebral hemorrhage (ICH) and vascular dementia in the elderly. The presence of the amyloid-beta protein in the vessel wall may induce a chronic state of cerebral inflammation by activating astrocytes, microglia, and pro-inflammatory substances. Minocycline, an antibiotic of the tetracycline family, is known to modulate inflammation, gelatinase activity, and angiogenesis. These processes are suggested to be key mechanisms in CAA pathology. Our aim is to show the target engagement of minocycline and investigate in a double-blind placebo-controlled randomized clinical trial whether treatment with minocycline for 3 months can decrease markers of neuroinflammation and of the gelatinase pathway in cerebrospinal fluid (CSF) in CAA patients. METHODS: The BATMAN study population consists of 60 persons: 30 persons with hereditary Dutch type CAA (D-CAA) and 30 persons with sporadic CAA. They will be randomized for either placebo or minocycline (15 sporadic CAA/15 D-CAA minocycline, 15 sporadic CAA/15 D-CAA placebo). At t = 0 and t = 3 months, we will collect CSF and blood samples, perform a 7-T MRI, and collect demographic characteristics. DISCUSSION: The results of this proof-of-principle study will be used to assess the potential of target engagement of minocycline for CAA. Therefore, our primary outcome measures are markers of neuroinflammation (IL-6, MCP-1, and IBA-1) and of the gelatinase pathway (MMP2/9 and VEGF) in CSF. Secondly, we will look at the progression of hemorrhagic markers on 7-T MRI before and after treatment and investigate serum biomarkers. TRIAL REGISTRATION: ClinicalTrials.gov NCT05680389. Registered on January 11, 2023.

Quantitative measurement of cortical superficial siderosis in cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) is a cerebrovascular disease affecting the small arteries in the brain with hallmark depositions of amyloid-ß in the vessel wall, leading to cognitive decline and intracerebral hemorrhage (ICH). An emerging MRI marker for CAA is cortical superficial siderosis (cSS) as it is strongly related to the risk of (recurrent) ICH. Current assessment of cSS is mainly done on T2*- weighted MRI using a qualitative score consisting of 5 categories of severity which is hampered by ceiling effects. Therefore, the need for a more quantitative measurement is warranted to better map disease progression for prognosis and future therapeutic trials. We propose a semi-automated method to quantify cSS burden on MRI and investigated it in 20 patients with CAA and cSS. The method showed excellent inter-observer (Pearson's 0.991, P < 0.001) and intra-observer reproducibility (ICC 0.995, P < 0.001). Furthermore, in the highest category of the multifocality scale a large spread in the quantitative score is observed, demonstrating the ceiling effect in the traditional score. We observed a quantitative increase in cSS volume in two of the 5 patients who had a 1 year follow up, while the traditional qualitative method failed to identify an increase because these patients were already in the highest category. The proposed method could therefore potentially be a better way of tracking progression. In conclusion, semi-automated segmenting and quantifying cSS is feasible and repeatable and may be used for further studies in CAA cohorts.

Evolutionary algorithms and decision trees for predicting poor outcome after endovascular treatment for acute ischemic stroke.

Despite the large overall beneficial effects of endovascular treatment in patients with acute ischemic stroke, severe disability or death still occurs in almost one-third of patients. These patients, who might not benefit from treatment, have been previously identified with traditional logistic regression models, which may oversimplify relations between characteristics and outcome, or machine learning techniques, which may be difficult to interpret. We developed and evaluated a novel evolutionary algorithm for fuzzy decision trees to accurately identify patients with poor outcome after endovascular treatment, which was defined as having a modified Rankin Scale score (mRS) higher or equal to 5. The created decision trees have the benefit of being comprehensible, easily interpretable models, making its predictions easy to explain to patients and practitioners. Insights in the reason for the predicted outcome can encourage acceptance and adaptation in practice and help manage expectations after treatment. We compared our proposed method to CART, the benchmark decision tree algorithm, on classification accuracy and interpretability. The fuzzy decision tree significantly outperformed CART: using 5-fold cross-validation with on average 1090 patients in the training set and 273 patients in the test set, the fuzzy decision tree misclassified on average 77 (standard deviation of 7) patients compared to 83 (±7) using CART. The mean number of nodes (decision and leaf nodes) in the fuzzy decision tree was 11 (±2) compared to 26 (±1) for CART decision trees. With an average accuracy of 72% and much fewer nodes than CART, the developed evolutionary algorithm for fuzzy decision trees might be used to gain insights into the predictive value of patient characteristics and can contribute to the development of more accurate medical outcome prediction methods with improved clarity for practitioners and patients.

Evaluation of the yield of post-clipping angiography and nationwide current practice.

BACKGROUND: Surgical treatment of intracranial saccular aneurysms aims to prevent (re)hemorrhage by complete occlusion of the aneurysmal lumen. It is unclear whether routine postoperative imaging, to assess aneurysmal occlusion, is necessary since intraoperative assessment by the neurosurgeon may be sufficient. We assessed routine clinical protocols for post-clipping imaging in the Netherlands and determined whether intraoperative assessment of aneurysm clippings sufficiently predicts aneurysm residuals. METHODS: A survey was conducted to assess postoperative imaging protocols in centers performing clipping of intracranial aneurysms in the Netherlands (n = 9). Furthermore, a retrospective single-center cohort study was performed to determine the predictive value of intraoperative assessment of aneurysm occlusion in relation to postoperative digital subtraction angiography (DSA) findings, between 2009 and 2017. RESULTS: No center performed intraoperative DSA in a hybrid OR, routinely. Respectively, four (44.4%), seven (77.8%), and three (33.3%) centers did not routinely perform early postoperative imaging, late follow-up imaging, or any routine imaging at all. Regarding our retrospective study, 106 patients with 132 clipped aneurysms were included. There were 23 residuals ≥ 1 mm (17.4%), of which 10 (43.5%) were unexpected. For the presence of these residuals, intraoperative assessment showed a sensitivity of 56.5%, a specificity of 86.2%, a positive predictive value of 46.4%, and a negative predictive value of 90.4%. CONCLUSIONS: There is lack of consensus regarding the post-clipping imaging strategy in the Netherlands. Since intraoperative assessment is shown to be insufficient to predict postoperative aneurysm residuals, we advocate routine postoperative imaging after aneurysm clipping unless this is not warranted on the basis of patient age, clinical condition, and/or comorbidity.

Comparison of CTA- and DSA-Based Collateral Flow Assessment in Patients with Anterior Circulation Stroke.

BACKGROUND AND PURPOSE: Collateral flow is associated with clinical outcome after acute ischemic stroke and may serve as a parameter for patient selection for intra-arterial therapy. In clinical trials, DSA and CTA are 2 imaging modalities commonly used to assess collateral flow. We aimed to determine the agreement between collateral flow assessment on CTA and DSA and their respective associations with clinical outcome. MATERIALS AND METHODS: Patients randomized in MR CLEAN with middle cerebral artery occlusion and both baseline CTA images and complete DSA runs were included. Collateral flow on CTA and DSA was graded 0 (absent) to 3 (good). Quadratic weighted κ statistics determined agreement between both methods. The association of both modalities with mRS at 90 days was assessed. Also, association between the dichotomized collateral score and mRS 0-2 (functional independence) was ascertained. RESULTS: Of 45 patients with evaluable imaging data, collateral flow was graded on CTA as 0, 1, 2, 3 for 3, 10, 20, and 12 patients, respectively, and on DSA for 12, 17, 10, and 6 patients, respectively. The κ-value was 0.24 (95% CI, 0.16-0.32). The overall proportion of agreement was 24% (95% CI, 0.12-0.38). The adjusted odds ratio for favorable outcome on mRS was 2.27 and 1.29 for CTA and DSA, respectively. The relationship between the dichotomized collateral score and mRS 0-2 was significant for CTA (P = .01), but not for DSA (P = .77). CONCLUSIONS: Commonly applied collateral flow assessment on CTA and DSA showed large differences, indicating that these techniques are not interchangeable. CTA was significantly associated with mRS at 90 days, whereas DSA was not.

Assessment of Collateral Status by Dynamic CT Angiography in Acute MCA Stroke: Timing of Acquisition and Relationship with Final Infarct Volume.

BACKGROUND AND PURPOSE: Dynamic CTA is a promising technique for visualization of collateral filling in patients with acute ischemic stroke. Our aim was to describe collateral filling with dynamic CTA and assess the relationship with infarct volume at follow-up. MATERIALS AND METHODS: We selected patients with acute ischemic stroke due to proximal MCA occlusion. Patients underwent NCCT, single-phase CTA, and whole-brain CT perfusion/dynamic CTA within 9 hours after stroke onset. For each patient, a detailed assessment of the extent and velocity of arterial filling was obtained. Poor radiologic outcome was defined as an infarct volume of ≥70 mL. The association between collateral score and follow-up infarct volume was analyzed with Poisson regression. RESULTS: Sixty-one patients with a mean age of 67 years were included. For all patients combined, the interval that contained the peak of arterial filling in both hemispheres was between 11 and 21 seconds after ICA contrast entry. Poor collateral status as assessed with dynamic CTA was more strongly associated with infarct volume of ≥70 mL (risk ratio, 1.9; 95% CI, 1.3-2.9) than with single-phase CTA (risk ratio, 1.4; 95% CI, 0.8-2.5). Four subgroups (good-versus-poor and fast-versus-slow collaterals) were analyzed separately; the results showed that compared with good and fast collaterals, a similar risk ratio was found for patients with good-but-slow collaterals (risk ratio, 1.3; 95% CI, 0.7-2.4). CONCLUSIONS: Dynamic CTA provides a more detailed assessment of collaterals than single-phase CTA and has a stronger relationship with infarct volume at follow-up. The extent of collateral flow is more important in determining tissue fate than the velocity of collateral filling. The timing of dynamic CTA acquisition in relation to intravenous contrast administration is critical for the optimal assessment of the extent of collaterals.

Whole brain CT perfusion in acute anterior circulation ischemia: coverage size matters.

INTRODUCTION: Our aim was to compare infarct core volume on whole brain CT perfusion (CTP) with several limited coverage sizes (i.e., 3, 4, 6, and 8 cm), as currently used in routine clinical practice. METHODS: In total, 40 acute ischemic stroke patients with non-contrast CT (NCCT) and CTP imaging of anterior circulation ischemia were included. Imaging was performed using a 320-multislice CT. Average volumes of infarct core of all simulated partial coverage sizes were calculated. Infarct core volume of each partial brain coverage was compared with infarct core volume of whole brain coverage and expressed using a percentage. To determine the optimal starting position for each simulated CTP coverage, the percentage of infarct coverage was calculated for every possible starting position of the simulated partial coverage in relation to Alberta Stroke Program Early CT Score in Acute Stroke Triage (ASPECTS 1) level. RESULTS: Whole brain CTP coverage further increased the percentage of infarct core volume depicted by 10% as compared to the 8-cm coverage when the bottom slice was positioned at the ASPECTS 1 level. Optimization of the position of the region of interest (ROI) in 3 cm, 4 cm, and 8 cm improved the percentage of infarct depicted by 4% for the 8-cm, 7% for the 4-cm, and 13% for the 3-cm coverage size. CONCLUSION: This study shows that whole brain CTP is the optimal coverage for CTP with a substantial improvement in accuracy in quantifying infarct core size. In addition, our results suggest that the optimal position of the ROI in limited coverage depends on the size of the coverage.

Dynamic 320-section CT angiography in cranial arteriovenous shunting lesions.

Novel 320-section CT scanning equipment enables dynamic noninvasive angiographic imaging of the entire cranial vasculature (4D-CTA). We describe this technique and demonstrate its potential in arteriovenous shunting lesions. 4D-CTA imaging resulted in a correct diagnosis, lesion classification, and treatment-strategy selection in 3 patients, compared with CA. We think that 4D-CTA can further reduce the need for CA, sparing the patient the discomfort and risk associated with an invasive procedure.

Association between MRI parameters and the MS severity scale: a 12 year follow-up study.

BACKGROUND: Several magnetic resonance imaging (MRI) parameters are known to be associated with short-term outcome in multiple sclerosis (MS) patients. MS-related disability typically progresses over decades, stressing the need for longer follow-up studies. Until now, these studies are relatively sparse and, therefore, the predictive value of MRI parameters for clinical disability remains largely unknown. OBJECTIVE: To assess the predictive value of brain MRI parameters, which are obtained during the first 3.3 years of the study for overall disease severity as measured by the MS Severity Score (MSSS) after 12.2 years follow-up. METHODS: Forty-six MS patients were included in the study. MRI parameters included both lesion loads and atrophy measures. Average and change parameters were calculated for MRI parameters and subsequently used as independent variables in regression models, while MSSS was the dependent variable. RESULTS: Follow-up (FU) was obtained in 43/46 patients (94%) and median expanded disability status scale (EDSS) score increased significantly from 2.5 to 4.0. At last FU median MSSS was 4.3 (range 2.2-6.9). In univariate analyses, both change and cross-sectional T1-hypointense lesion load and ventricular atrophy measures were associated with MSSS. A multiple regression model included the change parameter of hypointense T1-lesion load (BHLL). This model explained 20% of variance in MSSS, which increased to 34% when type of disease (relapsing remitting or secondary progressive), age, and sex were entered additionally. CONCLUSION: MRI measures of axonal loss are associated with higher overall disease severity in MS patients.

Giant intracranial aneurysm in a ten-year-old boy with parry romberg syndrome. A case report and literature review.

SUMMARY: Parry-Romberg syndrome (PRS) is a rare acquired syndrome consisting of progressive hemiatrophy of the face.We present a child with PRS and progressive neurological deficit caused by a giant intracranial aneurysm and reviewed the literature concerning all intracranial abnormalities in patients with PRS.A literature search identified 27 articles reporting on 88 patients ith PRS and intracranial abnormalities. Ipsilateral brain calcification and hemiatrophy are the most prominent features on CT scan and hyperintense white matter lesions are most frequently seen on T2-weighted MRI. Although lacking precise prevalence data, intracranial abnormalities are not uncommon in patients with PRS. We found three other PRS patients with intracranial aneurysms. Our case and literature search suggests a possible association between PRS and intracranial aneurysms. We consider this association important for clinical practice and recommend including intracranial vascular diseases in the differential diagnosis when dealing with a PRS patient with neurological symptoms.

Diagnostic accuracy of CT angiography with matched mask bone elimination for detection of intracranial aneurysms: comparison with digital subtraction angiography and 3D rotational angiography.

BACKGROUND AND PURPOSE: Our aim was to determine the diagnostic accuracy of multisection CT angiography combined with matched mask bone elimination (CTA-MMBE) for detection of intracranial aneurysms compared with digital subtraction angiography (DSA) and 3D rotational angiography (3DRA). MATERIALS AND METHODS: Between January 2004 and February 2006, 108 patients who presented with clinically suspected subarachnoid hemorrhage underwent both CTA-MMBE and DSA for diagnosis of an intracranial aneurysm. Two neuroradiologists, independently, evaluated 27 predefined vessel locations in the CTA-MMBE images for the presence of an aneurysm. After consensus, diagnostic accuracy of CTA was calculated per predefined location and per patient. Interobserver agreement was calculated with kappa statistics. RESULTS: In 88 patients (81%), 117 aneurysms (82 ruptured, 35 unruptured) were present on DSA. CTA-MMBE detected all ruptured aneurysms except 1. Overall specificity, sensitivity, positive predictive value, and negative predictive value of CTA-MMBE were 0.99, 0.90, 0.98, and 0.95 per patient and 0.91, 1.00, 0.97, and 0.99 per location, respectively. Sensitivity was 0.99 for aneurysms >/=3 mm and 0.38 for aneurysms <3 mm. Interobserver agreement for aneurysm detection was excellent (kappa value of 0.92 per location and 0.80 per patient). CONCLUSION: CTA-MMBE is accurate in detecting intracranial aneurysms in any projection without overprojecting bone. CTA-MMBE has limited sensitivity in detecting very small aneurysms. Our data suggest that DSA and 3DRA can be limited to the vessel harboring the ruptured aneurysm before endovascular treatment, after detection of a ruptured aneurysm with CTA.

Optimizing the association between disability and biological markers in MS.

OBJECTIVE: Axonal damage is an important feature of MS pathology and the likely substrate of development of progressive disability. Brain volume measurement on MRI can be used as an overall marker of tissue damage and axonal loss. The authors studied the relation of brain volume measurements with the MS Functional Composite (MSFC) in an attempt to improve the clinico-radiologic association. METHODS: In 137 patients with MS (80 relapsing-remitting [RR], 36 secondary progressive [SP], and 21 primary progressive [PP]) and 12 healthy controls, a brain MRI scan was obtained. Patients also underwent MSFC and Expanded Disability Status Scale (EDSS) assessments. MRI analysis included determination of hypointense T1- and hyperintense T2-weighted lesion load, and two brain volume measurements: 1) the parenchymal fraction (PF): whole brain parenchyma/intracranial volume; and 2) the ventricular fraction (VF): ventricular volume/whole brain parenchyma. RESULTS: The median PF was smaller and the median VF larger in the patient group (0.81 for PF and 0.029 for VF) than in the control group (0.87 for PF, p < 0.001; and 0.013 for VF, p < 0.01). For the patient population, moderate correlations were found between brain volume measurements and MSFC (0.36 for PF and -0.40 for VF). Patients with short disease duration showed a correlation of MSFC with both brain and lesion volume measurements on MRI, whereas patients with long disease duration only showed a correlation with brain volume measurements. CONCLUSION: Brain volume measurements are correlated with disability as assessed by the MSFC. Although in the early phase of the disease the amount of focal demyelination is important, the residual brain volume seems to be more relevant in determining disability in later phases of the disease.

Concurrent validity of the MS Functional Composite using MRI as a biological disease marker.

INTRODUCTION: The MS Functional Composite (MSFC), a recently developed outcome measure for MS clinical trials measuring three dimensions (ambulation/leg function, arm/hand function, and cognition), was applied to 134 patients with MS to study the concurrent validity, using MRI measurements as a biological disease marker. The results were compared to correlations between the traditionally applied Expanded Disability Status Scale (EDSS) and MRI measurements in the same patients. METHODS: The assessments of MSFC and EDSS were performed in combination with brain MRI. MRI consisted of T1- and T2-weighted images, from which the hypointense and hyperintense lesion loads were quantified. RESULTS: The MSFC score ranged from -2.54 to 0.99. The median EDSS was 3.0 (interquartile range [IQR] 1.5 to 6.0). The median T2-weighted lesion load was 8.4 cm(3) (IQR 3.4 to 19.8) and the median T1-weighted lesion load was 1.1 cm(3) (IQR 0.3 to 3.2). Correlations between the MSFC and both T1 (-0.24) and T2 (-0.25) lesion loads were demonstrated, but not between the EDSS and both MRI parameters. Significant correlations between MSFC components and T1 and T2 lesion loads existed for cognitive function and arm/hand function, but not for ambulation. If relapse-onset patients (relapsing-remitting and secondary progressive) were combined, the correlation between MSFC and MRI parameters became stronger for both T1 (-0.37) and T2 lesion loads (-0.35). CONCLUSIONS: The authors present the concurrent validity of the MSFC with a biological disease marker by showing correlations with MRI. Specifically, they demonstrate significant correlations with cognition and arm/hand function assessments, domains that are not well represented in the EDSS.

Hypointense lesions on T1-weighted spin-echo magnetic resonance imaging: relation to clinical characteristics in subgroups of patients with multiple sclerosis.

CONTEXT: Hypointense lesions on T1-weighted spin-echo magnetic resonance images (T1 lesions) represent destructive multiple sclerosis (MS) lesions, consisting of axonal loss and matrix destruction. These lesions are being used as a secondary outcome measure in phase III clinical trials. Clinical determinants of T1 lesions may differ between subgroups of patients with MS and subsequently may have implications for the selection of patients for clinical trials. OBJECTIVE: To determine if clinical characteristics of patients with MS are related to T1 lesion volume. DESIGN: A survey of 138 patients with MS (52 with relapsing-remitting MS, 44 with secondary progressive MS, and 42 with primary progressive MS). SETTING: The Magnetic Resonance Center for Multiple Sclerosis Research, University Hospital "Vrije Universiteit," Amsterdam, the Netherlands. MAIN OUTCOME MEASURES: Type of MS, Expanded Disability Status Scale (EDSS) score, sex, age at first symptoms, and T1 lesion volume. RESULTS: Patients with secondary progressive MS have the highest T1 lesion volume. Patients with relapsing-remitting MS have a lower T1/T2 ratio than patients with secondary progressive MS and patients with primary progressive MS. In patients with relapsing-remitting MS and secondary progressive MS, T1 lesion volume relates to disease duration and EDSS score, while in patients with primary progressive MS sex is important. A trend toward higher T1 lesion volume was shown for male patients with primary progressive MS when compared with female patients with primary progressive MS (1.0 cm(3) vs 0.3 cm(3), P=.03); a trend toward higher T1 lesion volume was found with age at onset in patients with relapsing-remitting MS and in patients with primary progressive MS. CONCLUSIONS: In patients with MS different clinical characteristics associate with T1 lesion volume, suggesting a more destructive type of lesions in certain subgroups. A possible sex difference in (destructive) lesion development on magnetic resonance imaging should be evaluated in more detail, preferably in a cohort.

MR venography of multiple sclerosis.

BACKGROUND AND PURPOSE: The distribution of multiple sclerosis (MS) lesions in the brain follows a specific pattern, with most lesions in the periventricular regions and in the deep white matter; histopathologic studies have shown a perivenous distribution. The aim of this study was to illustrate these distribution patterns in vivo using high-resolution MR venography. METHODS: Seventeen MS patients underwent MR imaging at 1.5 T. Venographic studies were obtained with a 3D gradient-echo technique. MS lesions were identified on T2-weighted images, and their shape, orientation, and location were compared with the venous anatomy on the venograms. RESULTS: The use of contrast material facilitated the visualization of small veins and increased the number of veins seen. A total of 95 MS lesions could be identified on both the T2-weighted series and the venograms; a central vein was visible in all 43 periventricular lesions and in all but one of the 52 focal deep white matter lesions. The typical ovoid shape and orientation of the long axis of the MS lesions correlated well with the course of these veins. CONCLUSION: With MR venography, the perivenous distribution of MS lesions in the brain can be visualized in vivo. The venous anatomy defines the typical form and orientation of these lesions.

T1 hypointensities and axonal loss.

T1 hypointensities are lesions that are hypointense on moderately T1-weighted conventional spin-echo sequences and serve as markers of matrix destruction and axonal loss. They correlate better with clinical disability than T2-weighted images, are found in patients with progressive multiple sclerosis, and can be used as surrogate outcome measures in treatment trials.

Axonal loss in multiple sclerosis lesions: magnetic resonance imaging insights into substrates of disability.

Magnetic resonance imaging (MRI) monitoring of disease progression in multiple sclerosis is limited by the lack of correlation of abnormalities seen on T2-weighted imaging, and disability. We studied the histopathology of multiple sclerosis lesions, as depicted by MRI, in a large postmortem sample, focusing on axonal loss. Tissue samples from 17 patients were selected immediately postmortem for histopathological analysis on the basis of T2-weighted imaging, including normal appearing white matter and T1 hypointense lesions. In each region, we measured magnetization transfer ratios (MTR), T1 contrast ratio, myelin, and axonal density. T2 lesions (109 samples) were heterogeneous with regard to MRI appearance on T1 and MTR, whereas axonal density ranged from 0% (no residual axons) to 100% (normal axonal density). Of 64 T2 lesions, 17 were reactive (mild perivascular inflammation only), 21 active, 15 chronically active, and 11 chronically inactive. MTR and T1 contrast ratio correlated strongly with axonal density. Also in normal appearing white matter (24 samples), MTR correlated with axonal density. In conclusion, postmortem tissue sampling by using MRI revealed a range of pathology, illustrating the high sensitivity and low specificity of T2-weighted imaging. T1 hypointensity and MTR were strongly associated with axonal density, emphasizing their role in monitoring progression in multiple sclerosis.

Neuronal damage in T1-hypointense multiple sclerosis lesions demonstrated in vivo using proton magnetic resonance spectroscopy.

Hypointense T1 lesions in multiple sclerosis patients correlate with axonal loss at autopsy and biopsy. We evaluated the chemical substrate of hypointense T1 lesions by using in vivo proton magnetic resonance spectroscopy, and analyzed the spectroscopic correlate of increased T1-relaxation time measurements. Localized proton magnetic resonance spectroscopy and T1-relaxation time measurements were performed in lesions, selected on T1-weighted spin-echo magnetic resonance images according to degree of hypointensity, in normal appearing white matter (NAWM) and in normal white matter of controls. In NAWM, prolongation of T1-relaxation time and a decrease in N-acetylaspartate (NAA) were present, compared with normal white matter. Severely hypointense lesions showed a lower concentration of NAA and creatine compared with NAWM and a lower concentration of NAA compared with isointense to mildly hypointense lesions. NAA concentration correlated with degree of hypointensity of lesions and with T1-relaxation time within the spectroscopic voxel. Our results provide the first in vivo evidence of axonal damage in severely hypointense T1 lesions in multiple sclerosis patients. T1-relaxation time correlates with the concentration of NAA in both multiple sclerosis lesions and NAWM, indicating that this parameter deserves further evaluation to monitor disease progression.

Cardiovascular autonomic function in patients with relapsing remitting multiple sclerosis: a new surrogate marker of disease evolution?

Twenty patients with active relapsing remitting multiple sclerosis (MS) were examined annually for 2 years with a set of autonomic function tests (AFT) consisting of heart rate variability during deep breathing (IE), standing-up, and ratios of Valsalva manoeuvre (VR). Disease characteristics, including T2-weighted magnetic resonance imaging (MRI) of the brain and the expanded disability status scale (EDSS) score were documented each year within 1 week of the AFT. The EDSS score, MRI load lesion and VR did not change significantly over the follow-up period. The IE and initial heart-rate on standing during the first 30 s (DeltaHRMAX) showed significant worsening during follow-up. No relationship was found between deterioration of AFT and EDSS score, number of exacerbations, duration of disease, gender, age, size and number of lesions on MRI. We conclude that patients with active relapsing remitting MS show progression of autonomic dysfunction over a relatively short time. Therefore, in the absence of changes in clinical disability or brain MRI lesion load, AFT might be useful as a sensitive surrogate outcome measure for demonstrating subclinical change in MS.

Development of hypointense lesions on T1-weighted spin-echo magnetic resonance images in multiple sclerosis: relation to inflammatory activity.

OBJECTIVE: To evaluate whether degree of inflammatory activity in multiple sclerosis, expressed by frequency of gadolinium enhancement, has prognostic value for development of hypointense lesions on T1-weighted spin-echo magnetic resonance images, a putative marker of tissue destruction. DESIGN: Cohort design with long-term follow-up. Thirty-eight patients with multiple sclerosis who in the past had been monitored with monthly gadolinium-enhanced magnetic resonance imaging for a median period of 10 months (range, 6-12 months) were reexamined after a median period of 40.5 months (range, 33-80 months). SETTING: Magnetic Resonance Center for Multiple Sclerosis Research, Amsterdam, the Netherlands, referral center. MAIN OUTCOME MEASURES: The new enhancing lesion rate (median number of gadolinium-enhancing lesions per monthly scan) during initial monthly follow-up; hypointense T1 and hyperintense T2 lesion load at first and last visit. RESULTS: The number of enhancing lesions on entry scan correlated with the new enhancing lesions rate (r = 0.64; P<.001, Spearman rank correlation coefficient). The new enhancing lesion rate correlated with yearly increase in T1 (r = 0.42; P<.01, Spearman rank correlation coefficient) and T2 (r = 0.47; P<.01, Spearman rank correlation coefficient) lesion load. Initial T1 lesion load correlated more strongly with yearly increase in T1 lesion load (r = 0.68; P<.01, Spearman rank correlation coefficient). CONCLUSIONS: Degree of inflammatory activity only partially predicted increase in T1 (and T2) lesion load at long-term follow-up. Initial T1 lesion load strongly contributed to subsequent increase in hypointense T1 lesion load, suggesting that there is a subpopulation of patients with multiple sclerosis who are prone to develop destructive lesions.