Brain Advance Access originally published online on June 23, 2003
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Brain, Vol. 126, No. 8, 1782-1789,
August 2003
© 2003 Guarantors of Brain
doi: 10.1093/brain/awg182
Evolution of T1 black holes in patients with multiple sclerosis imaged monthly for 4 years
1 National Institute of Neurological Disorders and Stroke and 2 Experimental Neuroimaging Section, Laboratory of Diagnostic Radiology Research, National Institutes of Health, Bethesda, MD, USA
Correspondence to: Francesca Bagnato, MD, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 10, Room 5B16, 10 Center Drive MSC 1400, Bethesda, MD 20892-1400, USA E-mail: bagnatof{at}ninds.nih.gov
Received January 21, 2003. Revised March 26, 2003. Accepted March 31, 2003.
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Summary |
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T1 black holes (BHs) on MRIs may represent either areas of oedema or axonal loss in patients with multiple sclerosis. BHs begin as contrast enhancing lesions (CELs) and evolve differently from patient to patient, and within the same patient over time. We analysed BHs formation over a 4-year period. Forty-eight monthly MRIs of nine non-treated multiple sclerosis patients were evaluated for numbers of CELs and BHs. A BH was defined as a hypointense lesion on a T1 pre-constrast image that coincided with a region of high signal intensity on the T2-weighted images. A BH was considered as acute (ABH) when it occurred coincidently with the presence of enhancement and as persisting (PBH) when present after the cessation of enhancement. The present study aimed to analyse: (i) the incidence of CELs and new PBHs, and the accumulation of PBHs; (ii) the relationship between the quantity of the CELs in a given month and the likelihood of accumulating PBHs in the subsequent month; and (iii) the relationship between the duration of CELs and PBHs. Pitman’s correlation test evaluated the effect of time on either the increase of CELs and new PBHs or the accumulation of PBHs, while a multiple logistic regression analysis evaluated the relationship between progression of time and CELs, and the increase of PBHs in a multivariate model. The relationship between the enhancing lesions duration and the PBHs duration, or the time to revert back to an isointense lesion was analysed using Kaplan–Meier survival models. PBHs accumulated (P < 0.001) in all patients, but the formation of new PBHs increased in four patients (P
0.007) in conjunction with an increase in either the quantity of CELs (P < 0.001, for two patients) or the proportion of CELs turning into PBHs (P 0.02, for two patients). Logistic regression analysis showed that neither progression of time nor the number of CELs in a given month were able to predict the probability of increasing the number of PBHs in the subsequent month in any patient. Out of 397 ABHs, 55.7% evolved to a PBH. The duration of PBHs correlated with the duration of enhancement. PBHs preceded by CELs observable on a single MRI persisted for a shorter time (P < 0.002) than those preceded by CELs visible on 
2 monthly MRIs. The formation of a new PBH was found to be related to CELs activity; however, duration of PBHs is most likely a consequence of the duration of the enhancement. Keywords: axonal loss; black holes; inflammatory activity; MRI; multiple sclerosis
Abbreviations: ABHs = acute black holes; BHs = black holes; CELs = contrast enhancing lesions; EDSS = Expanded Disability Status Scale; IFN-ß = interferon beta; KM = Kaplan–Meier; NAWM = normal-appearing white matter; PBHs = persisting black holes; RRMS = relapsing–remitting multiple sclerosis; SE = spin echo; TE = echo time; TR = repetition time
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Introduction |
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MRI is a useful tool in understanding the course of natural history and the effect of treatment (Paty and McFarland, 1998
; Miller, 2002) in patients with multiple sclerosis. The focal inflammatory events of the CNS that accompany a clinical multiple sclerosis relapse are usually evident on MRI as contrast enhancing lesions (CELs) on T1-weighted images (Bastianello et al., 1990; Harris et al., 1991; Miller et al., 1993). However, the natural history of a CEL is highly variable and unpredictable. Among the possible evolutions, axonal loss and axonal degeneration are thought to be major contributors to clinical worsening and disability in multiple sclerosis (van Walderveen et al., 1995; De Stefano et al., 1998; Sailer et al., 2001). Hypointense lesions on T1-weighted images with low signal intensity relative to the surrounding white matter have been shown to be areas of axonal loss on histopathology (Bruck et al., 1997; van Walderveen et al., 1998; van Waesberghe et al., 1999; Bitsch et al., 2001). In vivo magnetic resonance spectroscopy studies indicate that severe T1 hypointense lesions show a lower concentration of the N-acetylaspartate compared with the normal-appearing white matter (NAWM) of multiple sclerosis patients and controls (Bitsch et al., 1999; van Walderveen et al., 1999). Those T1 hypointense lesions have been termed black holes (BHs).
Approximately 80% of CELs appear hypointense on the corresponding unenhanced T1-weighted images (van Waesberghe et al., 1998). However, once contrast enhancement ends, these so-called ‘acute’ BHs (ABHs) may become isointense to the NAWM on T1-weighted images, and <40% of ABHs develop into persisting BHs (PBHs) over time. The longevity of PBHs may vary after contrast enhancement. Some lesions may be visible for a relatively short period of time, some enlarge or shrink (Freitag et al., 2001) and some others may eventually become permanent. These permanent BHs are likely to be a key factor of disability in multiple sclerosis (Bitsch et al., 2001). Until now the natural evolution of CELs into BHs has been based on limited duration longitudinal data. Most data originate from the placebo arms of clinical trials and are based upon observing the outcome of CELs longitudinally over 12 months when monthly scans were performed (van Waesberghe et al., 1998; Ciccarelli et al., 1999; Brex et al., 2001; Filippi et al., 2001) or for up to 2 years when 6-month scans were obtained (Simon et al., 2000; Wolinsky et al., 2000; Barkhof et al., 2001; Zivadinov et al., 2001; Panitch et al., 2002). Therefore, documentation as to the duration in time of PBHs still needs to be delineated. To provide new insights in the long-term natural history of PBHs, nine untreated multiple sclerosis patients were imaged for 48 consecutive months. The aims of the present study were as follows: (i) to investigate how heterogeneously new PBHs might develop among several patients; (ii) to analyse the effect of the progression of time and the presence of CELs on the increase of PBHs; and (iii) to investigate how the duration of the enhancement might effect the duration of PBHs over time.
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Patients and methods |
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Patient selection
The study was performed at the National Institutes of Health in Bethesda, MD, USA. The Intramural Research Board of the National Institute of Neurological Disorders and Stroke approved the study. Informed written consent was obtained from each patient. Nine patients with multiple sclerosis in accordance with Poser criteria (Poser et al., 1983
) were sequentially enrolled. Patients were enrolled in the study if they had never been treated with immunomodulatory or immunosuppressive drugs, except for intravenous methylprednisolone at 1 g/day for 3–5 days, or oral prednisone taper for a clinical relapse. In addition, patients were required to be able to complete monthly MRI scans and to have been steroid-free for at least 1 month at study entry.
Patient evaluation
After a complete neurological examination, including rating disability using the Expanded Disability Status Score (EDSS) (Kurtzke, 1983) and initial MRI scan at baseline, patients were subsequently examined and imaged monthly. An extra neurological examination was performed within the month following a clinical relapse. An exacerbation was defined as the appearance of a new symptom or worsening of previous symptoms associated with significant changes in neurological signs and lasting more than 24 h.
MRI scans
All patients underwent up to 48 monthly MRI scans without missing any scans. A total of 432 contrast-enhanced and unenhanced MRI scans were obtained and analysed. MRI examinations were performed at 1.5 T (General Electric Medical Systems, Milwaukee, WI, USA) with a standard quadrature head coil. The following pulse sequences were obtained: a T2-weighted spin echo (SE) pulse sequence with an echo time (TE) of 100 ms and a repetition time (TR) of 2000 ms, two excitations and a 128 x 256 acquisition matrix. A SE sequence with a TE of 16 ms and a TR of 600 ms, two excitations and a 192 x 256 matrix was used for T1-weighted images. Post-contrast images were obtained within 15 min after the injection of gadopentate dimeglumine (Magnevist, Berlex Labs, Cedar Knolls, NJ, USA) at 0.1 mmol/kg. Twenty-seven 5-mm thick contiguous slices with 24-cm of field view were obtained for all the studies.
Image evaluation
Three observers visually recorded on film the numbers of CELs. The evaluation of BHs in the corresponding unenhanced T1- and T2-weighted scans was performed twice for each patient by the same observer. CELs and BHs were defined as follows: the number of total CELs in each month was calculated as the sum of all the CELs that were enhancing at that month for the last time. Thus, each CEL considered for the analysis was counted only once. A BH was defined as any hypointense region visible on the T1-weighted images coincident with a region of high signal intensity on the T2-weighted images. BHs were considered to be ABHs when they coincided with a CEL and to be PBHs when the previously identified CELs were no longer present in the corresponding scan. Therefore, an ABH became a PBH as soon as the contrast enhancement disappeared. Each PBH was counted until it was no longer seen. Some of the PBHs were not permanent and therefore did not persist until the end of the study period. BHs observed at the time of entry into the study, occurring without any evidence of visible CELs during the 48 months of observation or separated by a gap after the cessation of the enhancement were not counted. Thus, only BHs originating from identified CELs were considered for this analysis. Each month we identified either the total number of PBHs or number of new PBHs. The total number of PBHs was counted from the sum of all PBHs, while the number of new PBHs was counted from the sum of only those PBHs that were arising at that time point for the first time. According to this definition, changes in the total number of PBHs were the results of both the formation of new PBHs and the disappearance of previously formed (i.e. within the study period) PBHs. A BH was still counted separately even when it coalesced into the ventricles or with other BHs.
Statistical analysis
Descriptive statistics were used to evaluate the clinical and MRI variables of the patient cohort. Furthermore, three types of statistical analysis were performed in this study. Because there were only nine individuals, and all exhibited heterogeneous patterns, each patient’s data were considered separately over the subsequent three types of statistical analysis performed for this study. First, a non-parametric trend test, Pitman’s correlation as discussed by Good (1994), was used to determine whether the monthly number of total PBHs, newly formed PBHs, CELs and the proportion of CELs turning into PBHs increased over time. Secondly, a logistic regression analysis was used to investigate whether the probability of increasing the number of total PBHs was associated with time (i.e. more likely toward the end of the 48-month window) or number of CELs in the previous month. In this model the dichotomous outcomes were an increase or a decrease/no change in total PBHs count from the previous month and time integer values between 1 and 48, indicating month within the study window. The significance and P values reported correspond to results from a multivariate model, i.e. both time and number of CELs in the previous month was simultaneously included as explanatory variables. In some instances, significant univariate associations between PBHs formation and either CELs count or time were weakened to non-significant levels in the combined multivariate model. The logistic regression analysis was used to complement the results from Pitman correlation analysis. While the Pitman correlation analysis tested whether the number of CELs, total PBHs and newly formed PBHs increased significantly over time, the logistic regression analysis was used to investigate how the progression of time and/or CEL counts in a given month may influence the likelihood of an increase in the number of total PBHs in the subsequent month in each individual. Finally, Kaplan-Meier (KM) survival models were used to investigate the differences in enhancement period (measured in months) between those CELs that would subsequently develop into an ABH or a PBH and those that would not be classified as a BH. For this analysis the data from the nine individuals were combined. Within-patient similarity was addressed by treating each patient’s lesion data as separate strata though the log rank test statistic using data pooled across the strata. A second KM survival analysis was used to evaluate the relationship between the length of enhancement and the duration in time (measured in months) of the CELs’ corresponding PBHs. The duration of the enhancement period was treated as a factor with two levels, corresponding to duration periods of 1 month and 2 months. Again, the results were pooled across the different strata that were formed by the different individuals. The factor’s effects were modelled to be the same across the different strata. The statistical analysis was performed using SAS version 8.02 for the trend analysis and the logistic regression and SPSS version 11.5 for the survival analysis.
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Results |
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Clinical and MRI characteristics of patients
Table 1 reports the baseline clinical features for each individual. One of the patients (patient 5) was recovering from the last relapse (4 months earlier) at the study entry. Tables 2 and 3 report the clinical and MRI outcome of the patients during the study period. The number of relapses treated with steroids pulses, EDSS score and multiple sclerosis type at month 48 served as clinical metrics. The mean (± SD) monthly number of CELs, ABHs, newly formed PBHs, total PBHs, the mean duration in time of each PBH and the proportion of active scans were considered as MRI outcome measures. Descriptive statistics of the MRI variables per individual patient over the study period are provided in Table 3.
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Changes of CELs and PBHs over time
As expected, all patients showed an accumulation of PBHs over time (P < 0.001). In some patients (patients 1, 4, 6 and 8) such an accumulation was accompanied by an increase in the formation of new PBHs over time (P
0.007). These four patients showed an increase in activity of CELs as measured either by an increase in the number of CELs (P < 0.001 in patients 6 and 8) or by the proportion of CELs turning into a PBH (P 0.02 in patients 1 and 4). For the remaining five patients there were no changes in the formation rate of either new PBH count or the CEL activity over time.
Dependence of PBHs on CELs and time
The results showed a certain amount of heterogeneity among the nine patients. Figure 1A is an example from patient 4 that demonstrates how the progression of time alone had a positive influence (P = 0.02) on the probability of increasing the number of total PBHs. In this patient, the CEL count from the previous month was an insignificant factor. For patients 2 and 6, only CELs counts affected (P < 0.05) the probability of accumulating PBHs (Fig. 1B). Both time (P 0.04) and CELs (P 0.007) influenced PBH accumulation in patients 1 and 7. In the other four individuals (patients 3, 5, 8 and 9) neither time nor the number of CELs in the previous month were significantly associated with the increase of PBHs. However, for patient 8 there was a trend (P = 0.06) towards progression in time being associated with an increase in PBHs. In all of the significant findings discussed above, the relationships were positive, i.e. where time was significant, the likelihood of accumulating PBHs increased over time, and when CEL count was significant, increases in this count increased the likelihood of PBHs in the subsequent months.
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Dependence of new PBH formation and PBH duration on the length of the enhancement
Of the 966 CELs identified, 397 (41.1%) had corresponding ABHs and 221 [55.7% (221/397) out of the ABHs, or 22.9% (221/966) out of the total CELs] had evolved into PBHs. Using a log rank test in KM analysis, differences in the duration pattern of CELs that did not evolve into BHs, and CELs that did evolve into an ABH or a PBH were detected (P
0.0001). In order to analyse the duration of PBHs, those lesions were sorted between censored and non-censored lesions (see Table 4). If a PBH was still present at the end of the study, its duration was recorded as if the lesion had disappeared at the end of the 48-month study period and counted as censored PBH. A PBH was counted as non-censored PBH if it resolved before the end of the study period.
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Figure 2 is a KM survival curve that accommodates the complication of censored observations. Figure 2A represents the rate of PBH disappearance (i.e. PBHs becoming isointense on T1-weighted images) over time for PBHs with different durations of enhancement (i.e. 1 month and
2 months) and also includes the overall resolution pattern (combined from the two groups). From the survival curve we estimated a 34% probability that a PBH will persist for at least 4 years and a 53% probability it will disappear within the first 12 months. As further represented in Fig. 2B, PBHs with only 1 month of enhancement [63.3% (140/221)] generally persisted for a shorter time (P < 0.002) than those with 2 months of enhancement [36.7% (81/221)] [log rank statistic (1 df) = 9.96, P < 0.002]. The median duration of PBHs was 7 months for a PBH arising from a CEL lasting for 1 month, and 21 months for a PBH resulting from a lesion enhancing for 2 months.
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Discussion |
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TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
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We evaluated the natural evolution of PBHs formation in a cohort of nine patients with multiple sclerosis. Though the cohort is small, the extensive longitudinal follow-up of 48 months represents a valuable data set. In the present study we primarily focused on analysing individual changes, rather than on providing information about patients as a group for a long (48 months) monthly follow-up. The individual analysis and the length of the follow-up are the novel aspects of the current study. Previous reports focused on a larger sample size or lesions that were only analysed as a group; hence those studies masked inter-patient variability and variations over longer time periods. A limitation of these previous studies is that the likelihood that they included in the analysis transient BHs, some of which would be expected to spontaneously resolve over a time period longer than 12 months.
Patterns of accumulation of PBHs over the 48-month study period demonstrated a certain amount of heterogeneity among patients. Disease duration did not seem to be a discriminating factor, since we were able to identify different patterns among those patients with similar duration of multiple sclerosis (i.e. 3 years). However, because of the small sample size, care needs to be taken in drawing any definitive conclusion.
The increase in PBHs was not accompanied by an increase in the rate of newly formed PBHs in any of the patients, suggesting that other factors besides the quantity of newly formed BHs may contribute to their persistence and accumulation over time. On the other hand, an increase in the rate of formation of new PBHs, regardless of their persistence over time, was always accompanied by an increase in the inflammatory activity, as measured by either the number of CELs or by the proportion of CELs converting into PBHs. These findings lead us to postulate that acute inflammatory activity has a strong influence over the formation of new but more likely transient PBHs (i.e. those BHs representing areas of subacute oedema) (Bitsch et al., 2001), and may be only weakly related to the persistence of these BHs over longer time periods. We performed a logistic regression analysis to test the strength of this argument and to generalize the longitudinal relationship between CEL activity and the accumulation of PBHs over 48 months. With the large number of available monthly scans, we had the chance to carefully follow only those PBHs arising from pre-existing and visible CELs. We did not include PBHs that arose without evidence of a previous identified CEL or those that appeared with a time-gap after the cessation of the enhancement. This was done because we thought that we could not unambiguously rule out the fact that those PBHs would be potentially related to a CEL arising or re-enhancing within the preceding month and lasting <4 weeks (Cotton et al., 2003). In this case a potential bias could be created, since we could not have the chance to know how many other CELs would arise within the month as well, without leaving a T1 hypointensity.
PBHs already present at the time of enrollment were excluded from the analysis. The number of CELs counted at any given month was the sum of the CELs ceasing enhancement at that time. Such an evaluation led us to exclude from the analysis those lesions that could still be present in the subsequent month and eventually correspond to an ABH.
The results from the logistic regression analysis confirmed that the increase of PBHs in a given month was not always associated with the quantity of CELs activity in the previous month. This observation applied for almost 50% of the patients. For the rest of the patients, PBHs accumulated over time regardless of the CEL disease activity. Since the number of patients was small, we did not analyse the relationship between these specific MRI patterns and different clinical outcomes of patients. Furthermore, examining the cohort of patients at the extremes with respect to the number of CELs (either low or high) may be misleading. Nevertheless, the high variability of the MRI patterns among patients is noteworthy and strengthens the hypothesis that despite the sensitivity of MRI, the disease course of multiple sclerosis cannot be explained solely on the basis of measures derived from conventional MRI. The lack of histopathological specificity is a limitation of these measures. CELs represent areas of inflammation that are considered the first event in multiple sclerosis (Kermode et al., 1990; McFarland et al., 1992). Nevertheless, despite the stringent definition of an active lesion, a profound heterogeneity in the immunopathologic features of this type of lesion can be observed (Trapp et al., 1998; Lucchinetti et al., 2000) and the type of inflammatory lesion and resulting damage, rather than the absolute number of CELs, is the important contribution to the formation of subsequent BHs. Differences observed in CEL evolution and BH accumulation among patients might reflect pathological differences in lesion development that are not reflected in the number of CELs. Previous MRI studies have partially tried to overcome this issue by evaluating CELs of different shape and size, and correlating this with the accumulation of atrophy (Leist et al., 2001), disability and clinical relapses (Morgen et al., 2001). In addition, 1-year follow-up studies have demonstrated that ring-enhancing CELs and those with a longer duration of the enhancement are associated with more destructive damage, as measured by magnetization transfer analysis (Filippi et al., 1998; Rovira et al., 1999) and are more likely to form BHs (van Waesberghe et al., 1998; Ciccarelli et al., 1999; Rovira et al., 1999).
Based upon the results from others and this present study, we reasoned that the duration in time of CELs might partially reflect biological differences among CELs and therefore correlate to the duration of PBHs over time. The KM analysis was used to identify the effect of the length of the enhancement of a given CEL evolving into a PBH. We identified relevant differences in CEL duration between those CELs that would develop into ABHs or PBHs, and those that were not associated with a hypointense lesion either at the time of the enhancement or afterwards. A further KM analysis revealed that longer inflammatory periods were associated with longer BHs duration. When considering CELs as a group we confirmed previous results showing that 34% of PBHs did not disappear over the whole study period. However, as an extension of previous findings, we found that the majority of the PBHs disappear over the first year of follow-up, while 13% would probably still disappear over the following 15 months. Finally, it appeared unlikely that a PBH could disappear after persisting for a median time of 28 months. When sorting CELs according to the duration of the enhancement, we found that the median duration of PBHs was 7 months when the enhancement was only observed on a single monthly MRI, compared with 21 months when CELs were observed on two or more monthly MRI examinations. These results indirectly support the hypothesis that the duration of enhancement may indicate different pathological processes and characterize more aggressive subtypes of lesions. CELs persisting for >1 month have a greater chance of having an associated ABH that evolves into a PBH with longer time duration. In addition, once a PBH has developed, the duration of the CEL that preceded its formation plays a key role in PBH longevity.
A limitation of the present findings may be that images, the thickness of which was 5 mm, were read on hard copy films and therefore not registered. However, our findings confirm results reported by previous authors who evaluated the short-term natural history of BHs. Moreover, we extended the previous knowledge on the formation of BHs from inflammatory lesions, by demonstrating that the number of CELs was associated with the formation of new PBHs, and that the duration of a CEL was an important contributor as to whether a lesion ultimately evolved into a longer lasting PBH. The current study emphasizes the importance of the quality of the inflammatory activity, rather than the quantity and may help clinicians to identify patients likely to accumulate BHs and clinical disability over time.
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