J. A. Castelijns

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.

Modern imaging techniques and ultrasound-guided aspiration cytology for the assessment of neck node metastases: a prospective comparative study

SummaryAlthough palpation has proved to be an unreliable staging procedure, the indications for and the implications of more reliable radiologic staging methods for the neck in patients with a primary squamous cell carcinoma of the head and neck remain controversial. Only a very accurate imaging technique can replace neck dissection in clinical NO disease. This study compares the value of palpation with computed tomography (CT), magnetic resonance imaging (MRI) and ultrasound (US) with or without guided aspiration cytology for neck node staging. One hundred and thirty-two patients with squamous cell carcinoma of the head and neck were examined radiologically before undergoing a total of 180 neck dissections as part of their treatment. CT, US and MRI proved to be significantly more accurate than palpation for cervical lymph node staging. The accuracy of US-guided aspiration cytology was significantly better than of any other technique used in this study. Modern imaging techniques are essential for appropriate assessment of neck node metastases. In view of advances in the accuracy of contemporary imaging, the need for elective treatment of the neck requires reappraisal.

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.

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. Ann Neurol 1999;46:79–87

Accumulation of cortical lesions in MS: relation with cognitive impairment.

Background Gray matter (GM) lesions are frequently found in multiple sclerosis (MS) and their in-vivo detection has been improved using new magnetic resonance imaging sequences, such as double inversion recovery (DIR). However, little is known about progression of GM lesions over time. Objective To study the longitudinal behavior of GM lesions and to explore their relation to cognitive impairment in MS. Methods DIR images were acquired from 13 MS patients and seven healthy controls at two time points with a median interval of 3 years. At follow-up, all subjects underwent cognitive testing. Lesions were classified as white matter, cortical or hippocampal lesions. Results In patients, median cortical lesion number had increased from 18 to 26 at follow-up (P = 0.01), median white matter (WM) lesion number had increased from 56 to 65 (P = 0.02), and no significant increase over time was found for hippocampal lesions. Cortical lesion number at follow-up was significantly higher in secondary progressive (SP) than in relapsing-remitting patients. Significant relations were found between cortical and WM lesion number at follow-up on the one hand and visuospatial memory and processing speed on the other hand. Hippocampal lesion number was related to visuospatial memory. Conclusion Cortical lesions increase significantly over a 3-year time period, are most frequent in SP patients, and are associated with cognitive impairment.

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.

Imaging of lymphadenopathy in the neck

Abstract. Imaging is playing a major role in the assessment of cervical lymphadenopathy. In infectious disease, the assessment of abscess formation and the relation of the abscess to surrounding vital structures is crucial for its management. In head and neck malignancies, imaging can be helpful for staging. Imaging of the neck for the assessment of nodal metastases can be used to detect occult metastases or to assess operability of palpable metastases. The detection of small occult metastases has limitations, as micrometastases cannot be depicted; however, imaging can fulfill a role in diminishing the risk of occult metastases, and thus influence management. For this purpose a very sensitive technique is necessary. The currently used radiological criteria are not sensitive enough to accomplish enough reduction of the risk of occult metastases; therefore, more sensitive CT and MRI criteria, but especially ultrasound-guided aspiration, should be employed to assess the clinically negative neck.

Wait-and-see policy for the N0 neck in early-stage oral and oropharyngeal squamous cell carcinoma using ultrasonography-guided cytology: Is there a role for identification of the sentinel node?

Management of the N0 neck in patients with head and neck squamous cell carcinoma (SCC) remains controversial. We describe the outcome of patients who underwent transoral tumor excision and a wait‐and‐see policy for the neck staged N0 by ultrasonography‐guided cytology (USgFNAC). Because selection of lymph nodes for USgFNAC is currently based on size criteria, we investigated the additional value of sentinel node (SN) identification.

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.

POSTWITHDRAWAL REBOUND INCREASE IN T2 LESIONAL ACTIVITY IN NATALIZUMAB-TREATED MS PATIENTS

Natalizumab significantly reduces relapse rate, disability progression, and lesion development in relapsing multiple sclerosis (MS).1,2 Dosing was suspended when cases of progressive multifocal leukoencephalopathy were reported and reintroduced after a safety analysis of all patients being treated with natalizumab had been completed.3 Our center participated with 23 patients in the phase III program (13 in AFFIRM [Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis], 10 in SENTINEL [Safety and Efficacy of Natalizumab in Combination with Interferon β-1a in Patients with Relapsing Remitting Multiple Sclerosis]). All patients underwent safety MRI shortly after dose suspension and unenhanced MRI as part of the baseline assessments before reintroduction of natalizumab. The neuroradiologist who reviewed these images noticed that in some patients a considerable number of new lesions had developed in this 15-month interval. As for these patients longitudinal MRI data were available from the period before natalizumab treatment, we performed a formal analysis comparing the annualized number of new MRI lesions in the period before patients started with natalizumab vs the 15-month interval after withdrawal of natalizumab. ### Methods. Patients randomized to natalizumab had active treatment during the double-blind and extension phases of the study (30 to 37 infusions, median 36). Patients randomized to …