Distributional Patterns of Multiple Sclerosis Brain Lesions Magnetic Resonance ImagingClinical Correlation

Forty–one patients with multiple sclerosis were studied with magnetic resonance imaging (MRI) and a battery of neuropsychological tests to determine the pattern of lobar distribution of lesions in the relapsing–progressive and relapsing–remitting forms of the disease. Correlation of lesions with the patient's cognitive and emotional dysfunction was also obtained. The results of this study indicate that patients with relapsing–progressive multiple sclerosis are characterized by the large or coalescent lesions located predominantly in the periventricular area. These lesions were more frequently found in the parietooccipital areas and were accompanied by significant cognitive dysfunction and severe personality changes. The patients with relapsing–remitting disease, however, were characterized by punctiform or small discrete lesions predominantly located in the intermediate and subcortical areas. These lesions were more frequently seen in the parietooccipital regions and the patients had significantly less severe cognitive and emotional involvement than did the patients with relapsing–progressive disease. Recognition of these patterns was easily accomplished by MRI. In this investigation MRI studies were utilized as an index of the pathological changes occurring at one point in time in the evaluation of the disease. Only repeated MRI studies and continuous clinical observation can establish the final diagnosis.     

Reversible capsulo-tegmental locked-in state as first manifestation of multiple sclerosis

An 18-year-old girl developed a reversible locked-in state with bilateral ptosis and almost complete ophthalmoplegia. She later presented with a relapsing and remitting course suggestive of multiple sclerosis. Autopsy findings demonstrated bilateral capsular and tegmental demyelinating lesions. In addition to this unusual aetiology, this is the first report with pathological evidence of a locked-in syndrome due to lesions outside the ventral brainstem.     

Paradoxically aggressive multiple sclerosis in the face of natalizumab therapy

In the pivotal trials of natalizumab in the treatment of relapsing-remitting multiple sclerosis (AFFIRM and SENTINEL), a dramatic reduction in relapse rate, new or enlarging T2-hyperintense lesions, and mean number of gadolinium-enhancing lesions was observed. While both relapses and new MRI lesions were observed in these trials, there has been no comment on the presence of aggressive disease in the face of natalizumab treatment. I report a 31-year-old woman with relapsing remitting MS of 12 years duration who developed aggressive demyelinating disease four months after the initiation of natalizumab. The clinical worsening was accompanied by a significant increase in new large T2-hyperintense signal abnormalities and in both solid and C-shaped contrast-enhancing lesions. Neither the clinical severity nor the striking MRI abnormalities had been noted earlier in her disease course. Neutralizing antibodies to natalizumab were not detected. She subsequently responded to combination therapy of pulsed methylprednisolone and daily glatiramer acetate.     

Pontine lesions mimicking acute peripheral vestibulopathy

OBJECTIVES: Clinical signs of acute peripheral vestibulopathy (APV) were repeatedly reported with pontine lesions. The clinical relevance of such a mechanism is not known, as most studies were biased by patients with additional clinical signs ofbrainstem dysfunction. METHODS: Masseter reflex (MassR), blink reflex (BlinkR), brainstem auditory evoked potentials (BAEPs), and DC electro-oculography (EOG) were tested in 232 consecutive patients with clinical signs of unilateral APV. RESULTS: Forty five of the 232 patients (19.4%) had at least one electrophysiological abnormality suggesting pontine dysfunction mainly due to possible vertebrobasilar ischaemia (22 patients) and multiple sclerosis (eight patients). MassR abnormalities were seen in 24 patients, and EOG abnormalities of saccades and following eye movements occurred in 22 patients. Three patients had BlinkR-R1 abnormalities, and one had delayed BAEP waves IV and V. Clinical improvement was almost always (32 of 34 re-examined patients) associated with improvement or normalisation of at least one electrophysiological abnormality. Brain MRI was done in 25 of the 44 patients and confirmed pontine lesions in six (two infarcts, three inflammations, one tumour). CONCLUSIONS: Pontine dysfunction was suggested in 45 of 232 consecutive patients with clinical signs of APV on the basis of abnormal electrophysiological findings, and was mainly attributed to brainstem ischaemia and multiple sclerosis. The frequency of pontine lesions mimicking APV is underestimated if based on MRI established lesions only.     

A placebo-controlled trial of isoprinosine in patients with multiple sclerosis.

Isoprinosine was used under double-blind, randomised, and placebo-controlled conditions in 52 patients with relapsing/remitting or progressive multiple sclerosis. All patients received pulsed treatment with methylprednisolone. There was no significant effect of treatment on clinical disability or the accumulation of MRI abnormalities, after correction of results for multiple comparisons. It is concluded that isoprinosine is not effective therapy for multiple sclerosis.     

Clinical worsening in multiple sclerosis is associated with increased frequency and area of gadopentetate dimeglumine–enhancing magnetic resonance imaging lesions

It is now well established that clinically stable patients with relapsing–remitting multiple sclerosis have ongoing disease activity when evaluated by serial gadolinium–enhanced (Gd-DTPA) magnetic resonance imaging (MRI) scans. Despite this, the relationship between clinical disease and MRI lesions, though suspected, has not been extensively documented. The relationship between Gd-DTPA MRI lesions, and clinical disease was examined in this study of 9 patients with mild relapsing–remitting multiple sclerosis (Expanded Disability Status Scale [EDSS] <3.5) who had 24 to 37 monthly Gd-DTPA MRI scans, neurological examinations, and EDSS score assignments. The area and frequency of Gd-DTPA lesions were examined during months with and without clinical worsening as measured by EDSS. Forty-one episodes of clinical worsening were noted during the study. A significant association was observed between these periods of clinical worsening and MRI parameters, including increases in total number, number of new lesions, and the total area of enhancement. Logistic regression analysis showed a signficant effect of the number and area of Gd-DTPA MRI lesions on both the onset and continuation of clinical worsening, confirming an imporant relationship between clinical disease and an increase in cerebral Gd-DTPA MRI activity. A relationship with long-term disability was suggested, but cannot be confirmed without longer follow-up of these patients.     

Platelet activating factor is elevated in cerebral spinal fluid and plasma of patients with relapsing-remitting multiple sclerosis.

Platelet-activating factor (PAF) is a phospholipid mediator of inflammation with a wide range of biological activities, including the alteration of barrier function of endothelium. A biological assay combined with high pressure liquid chromatography-tandem mass spectrometry showed that plasma and cerebral spinal fluid (CSF) PAF levels in 20 patients with relapsing/remitting or secondary progressive multiple sclerosis (MS) studied by magnetic resonance imaging (MRI) were significantly higher than in healthy controls (plasma: 3.29+/-4.52 vs. 0.48+/-0.36 ng/ml, p < 0.002; CSF: 4.95+/-6.22 ng/ml vs. 0.01+/-0.04 ng/ml, p < 0.0001). Values were also significantly higher in relapsing/remitting than in secondary progressive (plasma: 5.10+/-4.97 vs. 0.52+/-0.85 ng/ml, p < 0.005; CSF: 8.59+/-6.39 vs. 0.55+/-0.68 ng/ml, p < 0.002). It was also found that both plasma (R2: 0.65) and CSF (R2:0.72) levels were correlated with the MRI number of gadolinium enhancing lesions, which are markers of blood-brain barrier (BBB) injury, whereas their peaks were not correlated with the MRI number of white matter lesions, nor with the expanded disability status score (EDSS) according to Kurtze [Kurtze, J.F., 1983. Rating neurological impairment in multiple sclerosis: an expanded disability scale (EDSS). Neurology 33, 1444-1452]. Both plasma and CSF in patients with relapsing/remitting MS and marked gadolinium enhancement contained the two major molecular species of PAF: 1-0-hexadecyl- (C16:O) and 1-0-octadecyl-sn-glycero-3-phosphocholine (C18:O). The ratio of the two molecular species was different in the two biological fluids, being PAF C18:0 more abundant in CSF and PAF C16:0 in plasma, indicating a different cellular origin of PAF or different enzymatic processing. These findings suggest that PAF is a significant mediator of BBB injury in the early stages of MS, rather than a marker of its progression and severity.     

Contribution of MRI to the topography of oculomotor disorders in multiple sclerosis

Magnetic resonance imaging (MRI) was performed in 20 patients with multiple sclerosis and abnormal electro-oculographic examination. All but 2 patients showed MRI abnormalities in the infratentorial region: hypersignal on T2-weighted sequences and/or images of atrophy. Usually, each patient had multiple abnormalities, which could prevent anatomico-oculographic correlations. With oculomotor disorders of cerebellar origin, correlations between clinical findings and MRI images were satisfactory, but with disorders due to brainstem lesions correlations were not so good, as shown by the results in 9 patients with internuclear ophthalmoplegia.     

Survey of the distribution of lesion size in multiple sclerosis: implication for the measurement of total lesion load

OBJECTIVES—Quantitative measurement of lesionload on proton density or T2 weighted brain MRI in multiple sclerosisis a widely used marker of disease progression in treatment trials andnatural history studies. However, it has proved difficult to obtainhighly reproducible measurements. Several factors account for this, one of which is uncertainties in lesion identification, particularly verysmall white matter abnormalities. This paper aims to ascertain thesignificance of very small white matter abnormalities in the measurement of lesion load in multiple sclerosis.
METHODS—All visible lesion areas identified by anexperienced observer on proton densityweighted spin echo brain MRI with 5 mm thick slices were measured byusing a contouring technique in 15 patients with secondary progressivemultiple sclerosis (SPMS) and 13 with relapsing remitting multiplesclerosis (RRMS). The size distribution of these lesionswas analysed.
RESULTS—80% of the number of the lesions weresmaller than 80 mm². Lesions that were smaller than 10 mm² (equivalent diameter <3.5 mm) made up nearly 20% ofall lesions; their relative contribution to the total lesion loadvaried from 0.0-5.7% (mean=1.1%, median=0.65%) in individualpatients, and was larger when the total lesion load was smaller(r = −0.65, P<0.001). Median lesion size wassignificantly smaller in the SPMS group than the RRMS group.
CONCLUSIONS—The results suggest that it isprudent to identify and measure small lesions in evaluating treatmenteffects, and that measures are undertaken (for example, using thinnerslices such as 3 mm) to improve their detection.

     

T2 lesions and rate of progression of disability in multiple sclerosis

Background and purpose: To assess the predictive value of T2 lesions on the rate of progression of disability in multiple sclerosis (MS). Methods: We reanalyzed T2 lesion number and load on brain MRI scans, performed before 1997, of 186 MS patients, who were clinically followed. There were 90 patients with progressive MS (35 secondary progressive and 55 primary progressive), and 96 with relapsing remitting MS. The rate of progression of disability was measured by time to sustained progression of disability (defined as an increase in ≥ 1 point when the Expanded Disability Status Scale (EDSS) was 5.5 or less and an increase in EDSS of ≥ 0.5 point when the EDSS was 6.0 or higher), and by the Multiple Sclerosis Severity Score (MSSS). Results: During follow‐up (median 15 years, IQR 12–17 years), 94% of the patients with progressive MS and 50% of the patients with relapsing remitting MS had progression of disability. Higher T2 lesion number and load were modestly associated with a higher rate of disease progression on the MSSS and a shorter time to progression of disability in relapsing remitting MS, but not in progressive MS. Conclusions: Our findings indicate that the amount of T2 lesions has a small predictive value for progression of disability in relapsing remitting MS, but has no influence on the rate of progression in progressive MS.     

Three-dimensional human pattern visual evoked potentials. II. Multiple sclerosis patients.

Pattern visual evoked potentials were obtained from 46 patients with definite relapsing/remitting multiple sclerosis, using both a conventional 5-channel occipital array and a 3-D recording technique consisting of three bipolar derivations approximating the three dimensions of space. These three orthogonal wave forms were displayed as a 3-D Lissajous trajectory for each subject. Two of the 15 patients with completely normal conventional pattern VEPs had abnormalities of the orientation of the B-C curvilinear segment of the 3-D pattern VEPs. Delays in the first major occipital positive component (P100) were evident using both techniques; the correlation between P100 latency and the latency of the corresponding trajectory apex was r = 0.99 (P less than 0.01). Post-chiasmal MRI abnormalities were associated with 3-D VEP orientation abnormalities. Three-dimensional pattern VEPs are moderately more sensitive than conventional pattern VEPs at detecting dysfunction posterior to the optic chiasm in demyelinating disease and do not require the use of eccentric fixation to do so.     

Isolated superior oblique palsies with electrophysiologically documented brainstem lesions

Over a 13.5-year period, we observed 10 patients with isolated superior oblique palsies in whom electrophysiological abnormalities indicated brainstem lesions. In 7 patients unilateral masseter reflex abnormalities were seen, and were located on the side of the superior oblique palsy in 2 patients and on the opposite side in 5 patients. Two patients had slowed gain of following eye movements to the side contralateral to the superior oblique palsy. Slowed adduction saccades in the eye contralateral to the superior oblique palsy were seen in 1 patient. Clinical improvement was frequently (in 7 of 10 patients) associated with improvement or normalization of electrophysiologic findings. Magnetic resonance imaging (MRI) was normal, showing no evidence of brainstem lesions in 6 patients. Unilateral superior oblique palsy may be the only clinical sign of a brainstem lesion. Although such a cause may be underdiagnosed if based on MRI-documented lesions only, it remains a rare condition.     

Serial gadolinium-enhanced MRI in relapsing/remitting multiple sclerosis of varying disease duration.

In the planning of MRI protocols to monitor disease activity in multiple sclerosis (MS), the clinical subtype needs to be considered. In this serial gadolinium-enhanced MRI study, we demonstrated differences between patients with early relapsing/remitting MS and benign MS in both the production of new lesions and the occurrence of enhancement.     

Familial congenital facial diplegia: electrophysiologic and genetic studies

A 13-year-old boy with autosomal-dominant congenital facial diplegia was evaluated by electrophysiologic and genetic investigations. Thirteen members of his family were affected over 4 generations. The electrophysiologic studies revealed blink reflex abnormalities. Both R1 and R2 responses were prolonged on the left side after ipsilateral stimulation, while R2 was also delayed by contralateral stimulation. Ipsilateral R1 and R2 were of normal latencies when the right side was stimulated. A third ipsilateral response at 63 msec of latency could be obtained when stimulating the left side. These findings suggest functional damage to the brainstem. Further support for this interpretation was provided by the prolonged time between waves I and V, bilaterally, documented by study of brainstem auditory evoked potentials.     

Hydrosyringomyelia in demyelinating diseases

Spinal cord cavitation is a frequent finding in optic neuromyelitis (Devic's syndrome) (DS) but it is also, although rarely, observed in patients with multiple sclerosis (MS). The objective of our study was to compare the MRI characteristics of the syringomyelic cavities in 6 patients with DS and 3 patients with MS. All the patients with DS had a relapsing clinical form with normal brain MRI. Spinal MRI revealed unenhanced central cavities which extended more than 3 vertebral bodies and remained unchanged in follow-up studies. Two patients presented multiple cavities.MS patients suffered a relapsing remitting form of the disease, they all had hyperintense T2 enhancing lesions on their spinal MRI. Moreover spinal MRI also revealed non communicating cavities which extended less than 2 vertebral bodies. Follow-up studies in MS patients revealed a reduction of both the spinal lesions and the cavities. It is still debated whether DS represents a distinct clinical entity different from MS. These findings help distinguishing both disorders in cases when spinal cavities are present and also contribute to the therapeutic choice.     

Evaluation of patients with multiple sclerosis by evoked potentials and magnetic resonance imaging: a comparative study

We compared the diagnostic usefulness of evoked potential (EP) studies and magnetic resonance imaging (MRI) in the evaluation of 27 patients with definite or probable multiple sclerosis (MS). MRI scans demonstrated multiple lesions in 21 patients whereas EP studies showed multiple abnormalities in 14 patients (4 of whom had only somatosensory EP abnormalities). Eighteen patients had similar MRI and EP results (e.g., normal or multiple abnormalities), 8 had multiple abnormalities shown by MRI but normal or single-modality abnormal EPs, and 1 had multiple abnormal EPs but a normal MRI scan. There was no significant difference in the sensitivity of the two techniques in detecting multiple lesions in the patients with definite MS, whereas among those with probable MS, MRI had a significantly higher yield. Seventeen patients showed clinical evidence of posterior fossa involvement, 6 patients had abnormal brainstem auditory evoked potentials (BAEPs), and 4 patients had areas of increased signal intensity revealed by MRI of the brainstem. There was no clinical evidence of brainstem involvement in 2 patients with BAEP abnormalities, 2 with an abnormal posterior fossa shown by MRI, and one patient with abnormalities shown by both BAEP and MRI. We conclude that MRI is more sensitive in detecting multiple lesions than are multimodality EP studies, but that BAEP assessment may be slightly more sensitive than MRI in detecting brainstem lesions.     

Brain atrophy in relapsing-remitting multiple sclerosis: relationship with 'black holes', disease duration and clinical disability

Recent MRI studies in multiple sclerosis have highlighted the potential role of brain atrophy evaluation as a putative marker of disease progression. In the present study, we evaluated the supratentorial and infratentorial brain volume in patients with relapsing remitting multiple sclerosis (RR MS) and in healthy subjects. Moreover, we determined whether brain volumes of MS patients are associated with different aspects of brain MRI abnormalities and clinical findings. Two-dimensional acquired MRI was performed on 52 relapsing-remitting multiple sclerosis and 30 healthy subjects. The volume of supratentorial and infratentorial structures was measured in selected representative slices. Gd-enhancement, T2 hyperintense, T1 hypointense (i.e. 'black holes') total lesion load, as well as the area of corpus callosum was calculated in the MS group and related to brain volume measures. Correlations between MRI parameters and clinical features were also considered. MS patients had significantly lower supratentorial, infratentorial brain volume and corpus callosum area than healthy subjects (P<0.01). Supratentorial brain volume was significantly related to corpus callosum area (r=0.58; P<0.01) and T1 hypointense lesion load (r=0.48; P<0.01), but not with T2 hyperintense lesion load. Infratentorial/supratentorial ratio was significantly associated with disease duration and EDSS score (r=-0.34; P=0.02 and r=-0.49; P<0.01, respectively). This study documents that brain atrophy is an early MRI finding in RR MS and it is closely related to 'black holes' burden. The use of relative values (infratentorial/supratentorial ratio) may increase the conspicuity of correlation between clinical and MRI findings.     

Chronic progressive multiple sclerosis: serial magnetic resonance brain imaging over six months

Eight patients in the chronic progressive stage of multiple sclerosis were studied prospectively with magnetic resonance imaging of the head and neurological examination every 2 weeks for 6 months. There were no clinical relapses and disability ratings did not change between the start and completion of the study. Despite the clinical inactivity, a total of 86 active events (new, reappearing, or enlarging lesions) were identified by magnetic resonance imaging over the 6 months, with 50 (51%) of 98 follow-up scans showing evidence of one or more active lesions. New and changing lesions were indistinguishable in appearance, distribution, and temporal pattern from those previously seen in patients who had relapsing and remitting multiple sclerosis. However, as noted previously, the patients in the chronic progressive stage had many more confluent lesions than did the group in relapse. These results strongly suggest that the frequently observed clinical evolution of multiple sclerosis into a chronic progressive course is not accompanied by a fundamental change in the disease process. In fact the chronic progressive stage seems associated with more active changes demonstrated by scans than does relapsing and remitting multiple sclerosis. This study also confirms our previous experience that serial magnetic resonance imaging is much more sensitive than clinical examination in detecting disease activity in multiple sclerosis.     

Immunological disturbances in the central nervous system linked to MRI findings in multiple sclerosis

To clarify immunological disturbances in the central nervous system (CNS) in multiple sclerosis (MS) by linking to magnetic resonance imaging (MRI) findings, 22 patients with relapsing remitting MS were studied. Cerebrospinal fluid (CSF) samples were analyzed during a total of 27 independent MS stages (20 active, 7 inactive) on 25 occasions during which gadolinium (Gd)-enhanced MRI scans were performed. The number of Gd-enhanced lesions was significantly correlated with CSF cell counts, as well as the number of CD4(+)CD29(+) helper inducer and IL-2 receptor (CD25)-positive activated helper T cells. In contrast, T(2) lesion load in the brain showed a trend of association with elevated IgG index.