G.J. Lycklama à Nijeholt

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.

Spinal cord abnormalities in recently diagnosed MS patients Added value of spinal MRI examination

Objective: The most recent diagnostic criteria for multiple sclerosis (MS) ascertain that findings from spinal cord MRI can be used to demonstrate dissemination in space. Because little is known about the prevalence and characteristics of cord lesions early in the disease, the authors studied the prevalence of spinal cord abnormalities in patients with early-stage MS and assessed their impact on diagnostic classification. Methods: The brains and spinal cords of 104 recently diagnosed patients with MS were examined. Median interval between first symptom and diagnosis was 18.4 months. The brain MRI protocol included before and after gadolinium axial T1-weighted conventional spin-echo sequences and dual-echo spin-echo images. For spinal cord MRI, sagittal cardiac-triggered dual-echo T2-weighted and sagittal T1-weighted spin-echo images were included. Clinical assessment for each patient included age, sex, clinical signs for spinal cord involvement, and Expanded Disability Status Scale. Results: Abnormal cord MRIs were found in 83% of patients, usually with only focal lesions. Diffuse cord abnormalities were found in 13% of patients, although in isolation they were found in only three patients. Focal cord lesions were often multiple (median number, 3.0), small (median, 0.8 vertebral segments), and primarily (56.4%) situated in the cervical spinal cord. In 68 of 104 patients (65.4%), two or more focal lesions were visible on spinal cord images. The criteria for dissemination in space, as defined in the McDonald criteria for the brain, were met in only 66.3% of the patients. This percentage increased to 84.6% when spinal cord MRI abnormalities were also included. Conclusion: Spinal cord abnormalities are prevalent in patients with early-stage MS, have distinct morphologic characteristics, and help to determine dissemination in space at time of diagnosis.

Axonal damage in the spinal cord of MS patients occurs largely independent of T2 MRI lesions

Objective: To determine the degree of axonal damage in relationship to signal abnormalities on T2-weighted high-resolution MRI in spinal cord tissue of patients with MS. Methods: Spinal cord specimens of nine patients with MS and four controls were imaged at high resolution (4.7 T) in an axial plane and scored for lesions with increased signal intensity (SI). Histopathologic sections were cut and immunostained with NE14 (neurofilament marker) and Luxol fast blue (myelin stain). For each area, axonal density and diameter were quantified; axonal irregularity, NE14 axonal staining intensity, and myelin content were semiquantitatively scored. Included were 209 areas from MS cases and 109 areas from control cases distributed over lateral, posterior, and anterior columns. Results: In control cases, no SI changes were found, average density of axons was 26,989/mm2, average diameter was 1.1 μm, and all scores for axonal irregularity, NE14 staining intensity, and myelin were normal. In MS cases, areas with increased SI were found, average axonal density was 11,807/mm2 (p < 0.0001), and average axonal diameter 2.0 μm (p = 0.001). Areas with high SI on MRI had lowest axonal density (average count: 10,504/mm2; range: 3,433 to 26,325/mm2), largest diameter (average: 2.3 μm; range: 1.0 to 4.0 μm), and highest axonal irregularity and NE14 staining intensity compared to normal appearing cord tissue (NACT). However, NACT of MS cases also had lower axonal density (14,158/mm2) and higher average axonal diameter (1.6 μm) than controls. Conclusions: Marked axonal loss occurs in MS spinal cords, largely independent of the degree of signal abnormality on T2-weighted MRI.

Improving interobserver variation in reporting gadolinium-enhanced MRI lesions in multiple sclerosis

Gadolinium-enhanced MRI is a sensitive and objective means to monitor disease activity in multiple sclerosis (MS). We evaluated the interobserver agreement and the value of observer training in reporting enhancing lesions from serial MRI. Scans of 16 MS patients were evaluated by five inexperienced and five experienced observers before and after consensus formation and training. The number of lesions at baseline, and the number of new and persistent lesions at follow-up were scored. For each condition, weighted kappa values (κ) and the mean average difference to the median (MADM) scores were calculated. Without training, the experienced readers showed good agreement on number of lesions at baseline and new lesions at follow-up, and moderate agreement for persistent lesions. The inexperienced readers showed poor agreement for baseline and persistent lesions, and moderate agreement for new lesions. After training, both groups reported lower absolute numbers of lesions, especially the inexperienced readers. The experienced readers showed good agreement for all lesion types, the inexperienced readers showed agreement for baseline and new lesions, and agreement was moderate for persistent lesions. In both groups MADM scores were <0.72 for baseline and new lesions, but >1.2 for persistent lesions. Interobserver agreement is improved by training, especially in inexperienced readers. Interobserver agreement in reporting gadolinium-enhanced lesions is high, which validates the use of serial, enhanced MRI as an outcome parameter in treatment trials in MS.

Interscanner variation in brain MRI lesion load measurements in MS: Implications for clinical trials

We evaluated the effect of interscanner variation on brain MRI-measured lesion volumes and measurement reproducibility in MS. Twenty clinically definite MS patients were each scanned on two or three scanners (a total of 14 scanners were used). In addition, a formalin-fixed MS brain was studied on eight scanners from different manufacturers and with different field strengths. For the formalin-fixed MS brain, on each machine we obtained two scans with slice thicknesses of 5 and 3 mm. Only 5-mm-thick slices were obtained from patients. The lesion volume present on each scan was evaluated three times by a single observer in random order, using a local thresholding technique. In two groups of eight patients scanned on machines with different field strengths, the mean lesion volumes present on scans obtained at 1.5 T were significantly higher than those measured on scans obtained with machines operating at 0.5 and 1.0 T (p < 0.01). When a single observer repeatedly evaluated the same scan, a median intraobserver agreement of 98.7%(95% CI, 97.9 to 99.1) was achieved. However, when the observer evaluated the scans from different MRI scanners, the agreement (an interscanner agreement) fell to 91.1% (CI, 90.2 to 94.1). When only scanners operating at 1.5 T were considered, the median interscanner agreement was 96.7% (CI, 95 to 97.5). Also, for the formalin-fixed MS brain, the intraobserver agreements obtained with both slice thicknesses were significantly higher than the corresponding interscanner agreements. The interscanner agreement, but not the intraobserver agreement, obtained with a slice thickness of 3 mm was higher than that obtained with a slice thickness of 5 mm. Our results indicate that lesion volume measurements in MS are influenced significantly by the use of different MR scanners and that a patient included in a serial study should be always scanned with the same MR machine using 3-mm thick slices.

Comparison of a conventional cardiac-triggered dual spin-echo and a fast STIR sequence in detection of spinal cord lesions in multiple sclerosis.

Abstract. The current optimal imaging protocol in spinal cord MR imaging in patients with multiple sclerosis includes a long TR conventional spin-echo (CSE) sequence, requiring long acquisition times. Using short tau inversion recovery fast spin-echo (fast STIR) sequences both acquisition time can be shortened and sensitivity in the detection of multiple sclerosis (MS) abnormalities can be increased. This study compares both sequences for the potential to detect both focal and diffuse spinal abnormalities. Spinal cords of 5 volunteers and 20 MS patients were studied at 1.0 T. Magnetic resonance imaging included cardiac-gated sagittal dual-echo CSE and a cardiac-gated fast STIR sequence. Images were scored regarding number, size, and location of focal lesions, diffuse abnormalities and presence/hindrance of artifacts by two experienced radiologists. Examinations were scored as being definitely normal, indeterminate, or definitely abnormal. Interobserver agreement regarding focal lesions was higher for CSE (ϰ = 0.67) than for fast STIR (ϰ = 0.57) but did not differ significantly. Of all focal lesions scored in consensus, 47 % were scored on both sequences, 31 % were only detected by fast STIR, and 22 % only by dual-echo CSE (n. s.). Interobserver agreement for diffuse abnormalities was lower with fast STIR (ϰ = 0.48) than dual-echo CSE (ϰ = 0.65; n. s.). After consensus, fast STIR showed in 10 patients diffuse abnormalities and dual-echo CSE in 3. After consensus, in 19 of 20 patients dual-echo CSE scans were considered as definitely abnormal compared with 17 for fast STIR. The fast STIR sequence is a useful adjunct to dual-echo CSE in detecting focal abnormalities and is helpful in detecting diffuse MS abnormalities in the spinal cord. Due to the frequent occurrence of artifacts and the lower observer concordance, fast STIR cannot be used alone.

Spinal cord magnetic resonance imaging in suspected multiple sclerosis.

Abstract. We examined the value of spinal cord magnetic resonance imaging (MRI) in the diagnostic work-up of multiple sclerosis (MS). Forty patients suspected of having MS were examined within 24 months after the start of symptoms. Disability was assessed, and symptoms were categorized as either brain or spinal cord. Work-up further included cerebrospinal fluid analysis and standard proton-density, T2-, and T1-weighted gadolinium-enhanced brain and spinal cord MRI. Patients were categorized as either clinically definite MS (n = 13), laboratory-supported definite MS (n = 14), or clinically probable MS (n = 4); four patients had clinically probable MS, and in nine MS was suspected. Spinal cord abnormalities were found in 35 of 40 patients (87.5 %), consisting of focal lesions in 31, only diffuse abnormalities in two, and both in two. Asymptomatic spinal cord lesions occurred in six patients. All patients with diffuse spinal cord abnormality had clear spinal cord symptoms and a primary progressive disease course. In clinically definite MS, the inclusion of spinal imaging increased the sensitivity of MRI to 100 %. Seven patients without a definite diagnosis had clinically isolated syndromes involving the spinal cord. Brain MRI was inconclusive, while all had focal spinal cord lesions which explained symptoms and ruled out other causes. Two other patients had atypical brain abnormalities suggesting ischemic/vascular disease. No spinal cord abnormalities were found, and during follow-up MS was ruled out. Spinal cord abnormalities are common in suspected MS, and may occur asymptomatic. Although diagnostic classification is seldom changed, spinal cord imaging increases diagnostic sensitivity of MRI in patients with suspected MS. In addition, patients with primary progressive MS may possibly be earlier diagnosed. Finally, differentiation with atypical lesions may be improved.

Permeable Thrombi Are Associated With Higher Intravenous Recombinant Tissue-Type Plasminogen Activator Treatment Success in Patients With Acute Ischemic Stroke

Background and Purpose— Preclinical studies showed that thrombus permeability improves recombinant tissue-type plasminogen activator (r-tPA) efficacy. We hypothesize that thrombus permeability estimated from radiological imaging is associated with improved recanalization after treatment with intravenously administered r-tPA (r-tPA) and with better functional outcome. Methods— We assessed thrombus attenuation increase (TAI) in patients from the Dutch Acute Stroke Study with an occlusion of an intracranial artery on computed tomographic angiography. Patients were included within 9 hours after the stroke onset. After dichotomization of TAI as pervious or impervious, logistic regressions analyses were performed to estimate associations of intravenous r-tPA therapy with complete recanalization and with favorable functional outcome (modified Rankin Scale score of ⩽2). Results— Three hundred eight patients matched the inclusion criteria. The median TAI was 20.1 (interquartile range, 8.5–37.8) Hounsfield unit (HU). We found a significant increase in the odds of complete recanalization with increasing TAI for patients treated with intravenous r-tPA (P=0.030). One hundred thirty-one (42%) thrombi were classified as pervious with TAI of ≥23 HU. In patients with a pervious thrombus, complete recanalization was more frequent after treatment with intravenous r-tPA than after conservative treatment (odds ratio, 6.26; 95% confidence interval, 2.4–16.8; P<0.001). In patients with an impervious thrombus, the effect of intravenous r-tPA was not significant (odds ratio, 1.4; 95% confidence interval, 0.5–4.1; P=0.47). Favorable outcome was more common in patients with a pervious thrombi than without (odds ratio, 2.1; 95% confidence interval, 1.3–3.4; P=0.001). Conclusions— Thrombus perviousness, as measured on computed tomography in the acute stage of ischemic stroke, is strongly associated with recanalization after intravenous r-tPA treatment and with favorable functional outcome.

Baseline Blood Pressure Effect on the Benefit and Safety of Intra-Arterial Treatment in MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands).

Background and Purpose— High blood pressure (BP) is associated with poor outcome and the occurrence of symptomatic intracranial hemorrhage in acute ischemic stroke. Whether BP influences the benefit or safety of intra-arterial treatment (IAT) is not known. We aimed to assess the relation of BP with functional outcome, occurrence of symptomatic intracranial hemorrhage and effect of IAT. Methods— This is a post hoc analysis of the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands). BP was measured at baseline, before IAT or stroke unit admission. We estimated the association of baseline BP with the score on the modified Rankin Scale at 90 days and safety parameters with ordinal and logistic regression analysis. Effect of BP on the effect of IAT was tested with multiplicative interaction terms. Results— Systolic BP (SBP) had the best correlation with functional outcome. This correlation was U-shaped; both low and high baseline SBP were associated with poor functional outcome. Higher SBP was associated with symptomatic intracranial hemorrhage (adjusted odds ratio, 1.25 for every 10 mm Hg higher SBP [95% confidence interval, 1.09–1.44]). Between SBP and IAT, there was no interaction for functional outcome, symptomatic intracranial hemorrhage, or other safety parameters; the absolute benefit of IAT was evident for the whole SBP range. The same was found for diastolic BP. Conclusions— BP does not affect the benefit or safety of IAT in patients with acute ischemic stroke caused by proximal intracranial vessel occlusion. Our data provide no arguments to withhold or delay IAT based on BP. Clinical Trial Registration— URL: http://www.isrctn.com. Unique identifier: ISRCTN10888758.

Residual High-Grade Stenosis After Recanalization of Extracranial Carotid Occlusion in Acute Ischemic Stroke

Background and Purpose— Residual stenosis after recanalization of an acute symptomatic extracranial occlusion of the internal carotid artery (ICA) might be an indication for carotid endarterectomy. We evaluated the proportion of residual high-grade stenosis (≥70%, near occlusions not included) on follow-up imaging in a consecutive series of patients with an acute symptomatic occlusion of the extracranial ICA. Methods— We included patients participating in the Dutch Acute Stroke Study (DUST), who had an acute symptomatic occlusion of the extracranial ICA that was diagnosed on computed tomographic angiography within 9 hours after onset of neurological symptoms. Follow-up imaging of the carotid artery had to be available within 7 days after admission. Results— Of the 1021 patients participating in DUST between May 2009 and May 2013, an acute symptomatic occlusion of the extracranial ICA was found in 126 (12.3%) patients. Follow-up imaging was available in 86 (68.3%) of these patients. At follow-up, a residual stenosis of <30% was found in 15 (17.4%; 95% confidence interval, 10.8–26.9) patients, a 30% to 49% stenosis in 3 (3.5%; 95% confidence interval, 0.8–10.2) patients, a 50% to 69% stenosis in 2 (2.3%; 95% confidence interval, 0.1–8.6) patients, and a ≥70% stenosis in 14 (16.3%; 95% confidence interval, 9.8–25.6) patients. A near or persistent occlusion was present in the remaining 52 (60.5%) patients. Conclusions— A residual high-grade stenosis of the extracranial ICA occurs in 1 of 6 patients with a symptomatic occlusion in the acute stage of cerebral ischemia. Because this may have implications for secondary prevention, we recommend follow-up imaging in these patients within a week after the event. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00880113.