[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 54.163.92.62. Please contact the publisher to request reinstatement.
Sign In
Individual Sign In
Create an Account
Institutional Sign In
OpenAthens Shibboleth
[Skip to Content Landing]
Download PDF
Figure 1.
A, Concentric ring–enhancing lesion with central pallor. B, Lesion with homogeneous contrast uptake.

A, Concentric ring–enhancing lesion with central pallor. B, Lesion with homogeneous contrast uptake.

Figure 2.
Correlation of mean ventricular diameter increases per month with mean monthly new gadolinium-enhancing lesions on monthly magnetic resonance imaging scans. The mean monthly number of new lesions was calculated by dividing the cumulative number of new monthly lesions by the length of follow-up. The mean monthly increase of ventricular diameter was calculated as the difference between the mean diameter measured on the last 3 scans and the mean diameter measured on the first 3 scans, divided by the length of follow-up. Shaded symbols indicate values for patients with a high percentage of concentric ring–enhancing lesions; and unshaded symbols, values for patients with a low percentage of concentric ring–enhancing lesions. Patients had 0 (squares), 1 (diamonds), 2 (triangles), or 3 (circles) courses of methylprednisolone sodium succinate per year during follow-up. The shaded left-pointing triangles indicate normal volunteers. A correlation analysis was performed (linear regression, R2 = 0.65 [95% confidence interval, 0.20-0.87], z= 2.68, P= .007).

Correlation of mean ventricular diameter increases per month with mean monthly new gadolinium-enhancing lesions on monthly magnetic resonance imaging scans. The mean monthly number of new lesions was calculated by dividing the cumulative number of new monthly lesions by the length of follow-up. The mean monthly increase of ventricular diameter was calculated as the difference between the mean diameter measured on the last 3 scans and the mean diameter measured on the first 3 scans, divided by the length of follow-up. Shaded symbols indicate values for patients with a high percentage of concentric ring–enhancing lesions; and unshaded symbols, values for patients with a low percentage of concentric ring–enhancing lesions. Patients had 0 (squares), 1 (diamonds), 2 (triangles), or 3 (circles) courses of methylprednisolone sodium succinate per year during follow-up. The shaded left-pointing triangles indicate normal volunteers. A correlation analysis was performed (linear regression, R2 = 0.65 [95% confidence interval, 0.20-0.87], z= 2.68, P= .007).

Figure 3.
Correlation of ventricular volume and diameter increase with cumulative number of new contrast-enhancing lesions (found by magnetic resonance imaging [MRI]) on monthly scans for 4 patients (A, patient 1; B, patient 2; C, patient 3; and D, patient 4). Upper panel, Correlation of ventricular volumes calculated on coregistered MRI scans with a slice thickness of 3 mm, as described in the "Patients and Methods" section (shaded squares), with cumulative number of new enhancing lesions (unshaded squares) on monthly MRI scans. Lower panel, Correlation between measurements for ventricular diameters (percentage enlargement [caliper]) and volumes (percentage enlargement coregistration).

Correlation of ventricular volume and diameter increase with cumulative number of new contrast-enhancing lesions (found by magnetic resonance imaging [MRI]) on monthly scans for 4 patients (A, patient 1; B, patient 2; C, patient 3; and D, patient 4). Upper panel, Correlation of ventricular volumes calculated on coregistered MRI scans with a slice thickness of 3 mm, as described in the "Patients and Methods" section (shaded squares), with cumulative number of new enhancing lesions (unshaded squares) on monthly MRI scans. Lower panel, Correlation between measurements for ventricular diameters (percentage enlargement [caliper]) and volumes (percentage enlargement coregistration).

Figure 4.
Comparison of atrophy in patients with a low (≤15%) or a high (>15%) proportion of concentric ring–enhancing lesions with central pallor. The 2 groups were significantly (P= .004) different. Shaded diamonds indicate mean of measurements; unshaded diamonds, individual measurements.

Comparison of atrophy in patients with a low (≤15%) or a high (>15%) proportion of concentric ring–enhancing lesions with central pallor. The 2 groups were significantly (P= .004) different. Shaded diamonds indicate mean of measurements; unshaded diamonds, individual measurements.

1.
Reisner  TMaida  E Computerized tomography in multiple sclerosis. Arch Neurol.1980;37:475-477.
2.
Cala  LAMastaglia  FLBlack  JL Computerized tomography of brain and optic nerve in multiple sclerosis: observations in 100 patients, including serial studies in 16. J Neurol Sci.1978;36:411-426.
3.
Simon  JHJacobs  LDCampion  MK  et al A longitudinal study of brain atrophy in relapsing multiple sclerosis: the Multiple Sclerosis Collaborative Research Group (MSCRG). Neurology.1999;53:139-148.
4.
Rao  SMGlatt  SHammeke  TA  et al Chronic progressive multiple sclerosis: relationship between cerebral ventricular size and neuropsychological impairment. Arch Neurol.1985;42:678-682.
5.
Losseff  NAWang  LLai  HM  et al Progressive cerebral atrophy in multiple sclerosis: a serial MRI study. Brain.1996;119:2009-2019.
6.
Trapp  BDPeterson  JRansohoff  RMRudick  RMork  SBo  L Axonal transection in the lesions of multiple sclerosis. N Engl J Med.1998;338:278-285.
7.
Bentson  JReza  MWinter  JWilson  G Steroids and apparent cerebral atrophy on computed tomography scans. J Comput Assist Tomogr.1978;2:16-23.
8.
Lassmann  HRaine  CSAntel  JPrineas  JW Immunopathology of multiple sclerosis: report on an international meeting held at the Institute of Neurology of the University of Vienna. J Neuroimmunol.1998;86:213-217.
9.
Willoughby  EWGrochowski  ELi  DKOger  JKastrukoff  LFPaty  DW Serial magnetic resonance scanning in multiple sclerosis: a second prospective study in relapsing patients. Ann Neurol.1989;25:43-49.
10.
Miller  DHGrossman  RIReingold  SCMcFarland  HF The role of magnetic resonance techniques in understanding and managing multiple sclerosis. Brain.1998;121:3-24.
11.
Miller  DHRudge  PJohnson  G  et al Serial gadolinium enhanced magnetic resonance imaging in multiple sclerosis. Brain.1988;111:927-939.
12.
van Waesberghe  JHvan Walderveen  MACastelijns  JA  et al Patterns of lesion development in multiple sclerosis: longitudinal observations with T1-weighted spin-echo and magnetization transfer MR. AJNR Am J Neuroradiol.1998;19:675-683.
13.
Kermode  AGThompson  AJTofts  P  et al Breakdown of the blood-brain barrier precedes symptoms and other MRI signs of new lesions in multiple sclerosis. Brain.1990;113:1477-1489.
14.
Filippi  MYousry  TBaratti  C  et al Quantitative assessment of MRI lesion load in multiple sclerosis: a comparison of conventional spin-echo with fast fluid-attenuated inversion recovery. Brain.1996;119:1349-1355.
15.
Smith  MEStone  LAAlbert  PS  et al Clinical worsening in multiple sclerosis is associated with increased frequency and area of gadopentate dimeglumine–enhanced magnetic resonance imaging lesions. Ann Neurol.1993;33:480-489.
16.
Goldszal  AFDavatzikos  CPham  DLYan  MXBryan  RNResnick  SM An image-processing system for qualitative and quantitative volumetric analysis of brain images. J Comput Assist Tomogr.1998;22:827-837.
17.
Arnold  DLWolinsky  JSMatthews  PMFalini  A The use of magnetic resonance spectroscopy in the evaluation of the natural history of multiple sclerosis. J Neurol Neurosurg Psychiatry.1998;64(suppl 1):S94-S101.
18.
Tanttu  JISepponen  RELipton  MJKuusela  T Synergistic enhancement of MRI with Gd-DTPA and magnetization transfer. J Comput Assist Tomogr.1992;16:19-24.
19.
Truyen  Lvan Waesberghe  JHvan Walderveen  MA  et al Accumulation of hypointense lesions ("black holes") on T1 spin-echo MRI correlates with disease progression in multiple sclerosis. Neurology.1996;47:1469-1476.
20.
McFarland  HFFrank  JAAlbert  PS  et al Using gadolinium-enhanced magnetic resonance imaging lesions to monitor disease activity in multiple sclerosis. Ann Neurol.1992;32:758-766.
Original Contribution
January 2001

Enhancing Magnetic Resonance Imaging Lesions and Cerebral Atrophy in Patients With Relapsing Multiple Sclerosis

Author Affiliations

From the Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke (Drs Leist, Gobbini, and McFarland), and Laboratory of Diagnostic Radiology Research, Clinical Center (Dr Frank), National Institutes of Health, Bethesda, Md.

Arch Neurol. 2001;58(1):57-60. doi:10.1001/archneur.58.1.57
Abstract

Objective  To examine the relation between the frequency of enhancing magnetic resonance imaging lesions and their characteristics of enhancement and atrophy in patients with early relapsing multiple sclerosis.

Design  Analysis of number of enhancing lesions, ventricular volumes and diameters, and lesion characteristics on monthly magnetic resonance imaging scans during natural history follow-up.

Setting  A clinical research institution.

Patients  Sixteen patients with confirmed early relapsing multiple sclerosis.

Main Outcome Measure  Cerebral atrophy as measured by ventricular enlargement.

Results  Numbers of enhancing lesions correlated well with an increase of ventricular size. This correlation was strongest for patients with a high proportion of concentric ring–enhancing lesions with central contrast pallor.

Conclusions  Inflammatory events, especially those within lesions with associated blood-brain barrier breakdown, affect the ensuing loss of brain parenchyma. Patients with a high proportion of lesions with central contrast pallor, which is likely associated with more extensive tissue damage, have a higher rate of atrophic changes.

PATIENTS WITH multiple sclerosis exhibit a varying degree of cerebral atrophy.13 Little is known about the underlying mechanisms and individual disease characteristics that affect the rate at which brain parenchyma decreases.4,5 Loss of neurons,6 oligodendrocytes, the formation of glial scars, and the effects of therapeutics, such as corticosteroids,7 may contribute to reduction of brain matter and atrophy.8 Magnetic resonance imaging (MRI) has had a major impact on the understanding and management of multiple sclerosis.9,10 Blood-brain barrier breakdown is a consistent early feature of new lesion development in patients with relapsing and secondary progressive multiple sclerosis, which usually correlates with active inflammation and myelin breakdown. On the MRI scan, these lesions are visualized by T1-weighted, contrast-enhanced images.11 Characteristics of enhancing lesions vary greatly, with individual patients often having predominant types regarding size, location, or ring enhancement (Figure 1).12 T2-weighted brain imaging remains the standard diagnostic tool; however, it is limited by poor pathological specificity.13,14

To assess the impact of ongoing disease activity on atrophy development, we correlated the increase of ventricular volume and diameter with the cumulative number of contrast-enhancing lesions and their characteristics on serial monthly MRI scans. In contrast to the spinal cord, most supratentorial lesions do not affect primary efferent pathways. Their effects on neurologic function may be, therefore, less readily assessable. Disability as a function of ventricular enlargement or cumulative lesion count was, therefore, not a primary objective of this study. Contrast enhancement is a transient feature of some acute lesions. In general, lesions do not remain enhancing for more than 2 to 4 weeks and the volume of enhancement varies with time after the onset of blood-brain barrier breakdown.15 Since MRI scans were performed monthly, we elected to account for the number and the characteristics of the lesions rather than the volume of enhancement.

PATIENTS AND METHODS

Patients were enrolled in clinical research protocols approved by the Institutional Review Board; provided signed and informed consent; and were followed up monthly in the Neuroimmunology Clinic, National Institute of Neurological Disorders and Stroke, Bethesda, Md. Sixteen patients were identified according to the following inclusion criteria: (1) relapsing remitting course of disease; (2) a diagnosis within 2 years of the first scan; (3) at least 2 gadolinium-enhancing lesions during the first 3 monthly MRI scans; (4) a natural history follow-up of at least 16 months (mean ± SD, 23.0 ± 11.7 months); and (5) no treatment with immunomodulatory medication other than methylprednisolone sodium succinate, 1 g/d given intravenously for 3 to 5 days, for acute exacerbations. Five individuals did not have clinically significant exacerbations during the study period. The remaining patients had between 1 and 3 attacks per year requiring treatment with corticosteroids (Figure 2). The mean ± SD age of the cohort (9 women and 7 men) at the time of diagnosis was 29.7 ± 6.4 years. Four normal volunteers (2 women and 2 men [mean ± SD age, 34.7 ± 10.9 years]) were followed up for up to 5 years (mean ± SD follow-up, 3.8 ± 3.2 years) with unenhanced MRI scans.

Magnetic resonance imaging was performed on a 1.5-T MRI unit (General Electric, Milwaukee, Wis) with a quadrature head coil. Unenhanced and gadopentate dimeglumine (Magnevist; Berlex Laboratories, Wayne, NJ), 0.1 mmol/kg, enhanced T1-weighted sequences were analyzed (echo time, 20 ms; and repetition time, 600 ms) for this study. Reproducible head positioning was attempted by application of vitamin E–containing capsules in the external acoustic meatus and over the lateral canthus of the orbit. Depending on when enrolled, patients and volunteers underwent imaging with either a 5-mm (n = 9) or a 3-mm (n = 7) slice thickness. Measurement of third ventricular width and the diameter of the lateral ventricles was performed on all scans. Images with 3-mm section thicknesses were evaluated with computer analysis of ventricular volume after 3-dimensional reconstruction and with linear measurements to cross validate the 2 methods.

Reconstruction and coregistration of scans with 3-mm section thicknesses were performed with image processing software (MEDx; Sensor Systems Inc, Sterling, Va). A graded caliper with a 0.1-mm scale was used for linear measurements on film copies. The predominant head position on monthly scans was identified, and scans with nonconforming head positions were not included in the analysis. Third ventricular width was determined, and diameters of the left and right lateral ventricles were measured at the level of the interventricular foramen. The percentage of ventricular enlargement was calculated with equal weighing of measurements for the third ventricle and the mean of the lateral ventricles as follows: percentage of ventricular enlargement = {(Vti/Vt0) + [(Vri/Vr0) + (Vli/Vl0) × 0.5] × 100} − 100, with Vt being the measurement for the third ventricle; i, month of study; 0, baseline; and Vr and Vl, the width of the right and left lateral ventricles at the level of the interventricular foramen, respectively.

Linear regression of the values obtained for linear and volume measurements yielded R2 = 0.84 and P= .009. Good correlation between the 2 measures could also be seen for longitudinal data in 4 individuals (Figure 3).

For regression analysis, the t test, and nonparametric analysis, statistical software (StatView 4.5, Macintosh version; SAS Institute Inc, Cary, NC) was used.

Characteristics of enhancing lesions were analyzed on the initial MRI scans. Enhancing lesions on at least 3 monthly MRI scans (a minimum of 25 consecutive lesions) were studied. Patients were grouped according to the percentage of concentric ring–enhancing lesions exhibiting central contrast pallor.

RESULTS

The cumulative number of enhancing lesions and enlargement of the ventricles were compared longitudinally based on the mean monthly changes between patients (Figure 2) and among individual patients (Figure 3). To elucidate an association between the number of enhancing lesions and atrophy, the numbers of mean monthly lesions and mean monthly changes in ventricular measures were studied. A correlation analysis was performed on data from a natural history follow-up of at least 16 months (Figure 2) (linear regression, R2 = 0.65, P = .007). The correlation between enhancing lesions and atrophy was also maintained when patients were stratified according to corticosteroid use.

Because of differences in size, a low percentage loss of brain volume may be leveraged into a large percentage increase of ventricular and other fluid-filled spaces. For 2 patients (patients 1 and 2) (Figure 3), fractional brain volumes were available16 and were compared with ventricular changes. These 2 patients had reductions of 1.7% and 1.9% of the fractional brain volumes per year, respectively. When expressed based on the nonparenchymal volume, the total fluid-filled volume increased by 1.1% and 1.3% per months during the study period, respectively.

Lesion characteristics vary between patients, with some individuals exhibiting more concentric ring–enhancing lesions with central contrast pallor. These latter areas are thought to arise in zones of fulminate tissue destruction or glial scars. Seven of the 16 patients in the study cohort had greater than 1 in 7 lesions with central pallor. In the other 9 individuals, less than 1 in 10 lesions had this characteristic. Patients with high numbers of lesions with central contrast pallor had the strongest correlation between atrophy and cumulative lesion load (Figure 3). The presence of concentric ring–enhancing lesions with central pallor in itself strongly correlated with ensuing ventricular enlargement and loss of brain parenchyma (Figure 4). However, this group of patients had received the most corticosteroid treatments (Figure 2).

COMMENT

Focal inflammatory events leading to demyelination and repair are hallmark characteristics of multiple sclerosis. Serial MRI studies have added much to our understanding of the natural history and pathophysiological features of this disease. Many short-term MRI changes are readily reversible, but several MRI variables, such as a reduced N-acetylaspartate level,17 low magnetization transfer ratios,18 and T1 hypointensity, are more persistent.12,19 To gain further insight into whether short-term inflammatory events lead to irreversible damage and associated loss of brain parenchyma, we studied the correlation between atrophy, cumulative number, and the characteristics of gadolinium-enhancing lesions. To control for the variability of atrophy rate as a function of disease duration, only patients with a long-term natural history of MRI follow-up, starting within 2 years of the clinical diagnosis, were included in this analysis. Ventricular enlargement was assessed using image processing software or measurement of ventricular diameters.

In patients with ongoing inflammatory activity and blood-brain barrier breakdown, the results presented in this study favor a strong relation between cumulative lesion load and atrophy (Figure 2 and Figure 3). Since month to month ventricular changes are incremental, it is not possible to temporally link enhancing lesions, regional edema in the area of inflammatory lesions with resulting ventricular changes, and ensuing atrophy. The cumulative number of enhancing lesions varies greatly between patients.20 Similarly, individual patients exhibit varying degrees of cerebral atrophy.2 The correlation between ventricular enlargement and cumulative enhancing lesion load was particularly strong for patients with more concentric ring–enhancing lesions with central pallor (Figure 1 and Figure 4). This group of patients also had the highest rate of clinical relapses and, therefore, the greatest number of corticosteroid treatments (Figure 2). Concentric ring–enhancing lesions with central contrast pallor are thought to arise either in previously damaged areas with avascular glial scars and peripheral neovascularization or from a fulminate local inflammation with destruction of parenchyma and passing microvasculature and peripheral angiogenesis. Rapid ventricular enlargement in this high-risk group of patients is probably multifactorial, especially in view of the high corticosteroid use.7

The results of this study also indicate that enhancing lesions and atrophy can have predictive value, especially in patients with early disease. Patients with recurring enhancing disease activity on an MRI scan are at high risk for the development of cerebral atrophy, and may profit from early immunomodulatory intervention with medications such as interferon. The presence of many concentric ring–enhancing lesions seems to correlate with a more aggressive course of the disease.

Back to top
Article Information

Accepted for publication May 8, 2000.

Corresponding author: T. P. Leist, PhD, MD, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 9000 Rockville Pike, Bldg 10, Room 5B16, Bethesda, MD 20892.

References
1.
Reisner  TMaida  E Computerized tomography in multiple sclerosis. Arch Neurol.1980;37:475-477.
2.
Cala  LAMastaglia  FLBlack  JL Computerized tomography of brain and optic nerve in multiple sclerosis: observations in 100 patients, including serial studies in 16. J Neurol Sci.1978;36:411-426.
3.
Simon  JHJacobs  LDCampion  MK  et al A longitudinal study of brain atrophy in relapsing multiple sclerosis: the Multiple Sclerosis Collaborative Research Group (MSCRG). Neurology.1999;53:139-148.
4.
Rao  SMGlatt  SHammeke  TA  et al Chronic progressive multiple sclerosis: relationship between cerebral ventricular size and neuropsychological impairment. Arch Neurol.1985;42:678-682.
5.
Losseff  NAWang  LLai  HM  et al Progressive cerebral atrophy in multiple sclerosis: a serial MRI study. Brain.1996;119:2009-2019.
6.
Trapp  BDPeterson  JRansohoff  RMRudick  RMork  SBo  L Axonal transection in the lesions of multiple sclerosis. N Engl J Med.1998;338:278-285.
7.
Bentson  JReza  MWinter  JWilson  G Steroids and apparent cerebral atrophy on computed tomography scans. J Comput Assist Tomogr.1978;2:16-23.
8.
Lassmann  HRaine  CSAntel  JPrineas  JW Immunopathology of multiple sclerosis: report on an international meeting held at the Institute of Neurology of the University of Vienna. J Neuroimmunol.1998;86:213-217.
9.
Willoughby  EWGrochowski  ELi  DKOger  JKastrukoff  LFPaty  DW Serial magnetic resonance scanning in multiple sclerosis: a second prospective study in relapsing patients. Ann Neurol.1989;25:43-49.
10.
Miller  DHGrossman  RIReingold  SCMcFarland  HF The role of magnetic resonance techniques in understanding and managing multiple sclerosis. Brain.1998;121:3-24.
11.
Miller  DHRudge  PJohnson  G  et al Serial gadolinium enhanced magnetic resonance imaging in multiple sclerosis. Brain.1988;111:927-939.
12.
van Waesberghe  JHvan Walderveen  MACastelijns  JA  et al Patterns of lesion development in multiple sclerosis: longitudinal observations with T1-weighted spin-echo and magnetization transfer MR. AJNR Am J Neuroradiol.1998;19:675-683.
13.
Kermode  AGThompson  AJTofts  P  et al Breakdown of the blood-brain barrier precedes symptoms and other MRI signs of new lesions in multiple sclerosis. Brain.1990;113:1477-1489.
14.
Filippi  MYousry  TBaratti  C  et al Quantitative assessment of MRI lesion load in multiple sclerosis: a comparison of conventional spin-echo with fast fluid-attenuated inversion recovery. Brain.1996;119:1349-1355.
15.
Smith  MEStone  LAAlbert  PS  et al Clinical worsening in multiple sclerosis is associated with increased frequency and area of gadopentate dimeglumine–enhanced magnetic resonance imaging lesions. Ann Neurol.1993;33:480-489.
16.
Goldszal  AFDavatzikos  CPham  DLYan  MXBryan  RNResnick  SM An image-processing system for qualitative and quantitative volumetric analysis of brain images. J Comput Assist Tomogr.1998;22:827-837.
17.
Arnold  DLWolinsky  JSMatthews  PMFalini  A The use of magnetic resonance spectroscopy in the evaluation of the natural history of multiple sclerosis. J Neurol Neurosurg Psychiatry.1998;64(suppl 1):S94-S101.
18.
Tanttu  JISepponen  RELipton  MJKuusela  T Synergistic enhancement of MRI with Gd-DTPA and magnetization transfer. J Comput Assist Tomogr.1992;16:19-24.
19.
Truyen  Lvan Waesberghe  JHvan Walderveen  MA  et al Accumulation of hypointense lesions ("black holes") on T1 spin-echo MRI correlates with disease progression in multiple sclerosis. Neurology.1996;47:1469-1476.
20.
McFarland  HFFrank  JAAlbert  PS  et al Using gadolinium-enhanced magnetic resonance imaging lesions to monitor disease activity in multiple sclerosis. Ann Neurol.1992;32:758-766.
×