Vessel wall magnetic resonance and arterial spin labelling imaging in the management of presumed inflammatory intracranial arterial vasculopathy.

Optimal criteria for diagnosing and monitoring response to treatment for infectious and inflammatory medium-large vessel intracranial vasculitis presenting with stroke are lacking. We integrated intracranial vessel wall MRI with arterial spin labelling into our routine clinical stroke pathway to detect presumed inflammatory intracranial arterial vasculopathy, and monitor disease activity, in patients with clinical stroke syndromes. We used predefined standardized radiological criteria to define vessel wall enhancement, and all imaging findings were rated blinded to clinical details. Between 2017 and 2018, stroke or transient ischaemic attack patients were first screened in our vascular radiology meeting and followed up in a dedicated specialist stroke clinic if a diagnosis of medium-large inflammatory intracranial arterial vasculopathy was radiologically confirmed. Treatment was determined and monitored by a multi-disciplinary team. In this case series, 11 patients were managed in this period from the cohort of young stroke presenters (<55 years). The median age was 36 years (interquartile range: 33,50), of which 8 of 11 (73%) were female. Two of 11 (18%) had herpes virus infection confirmed by viral nucleic acid in the cerebrospinal fluid. We showed improvement in cerebral perfusion at 1 year using an arterial spin labelling sequence in patients taking immunosuppressive therapy for >4 weeks compared with those not receiving therapy [6 (100%) versus 2 (40%) P = 0.026]. Our findings demonstrate the potential utility of vessel wall magnetic resonance with arterial spin labelling imaging in detecting and monitoring medium-large inflammatory intracranial arterial vasculopathy activity for patients presenting with stroke symptoms, limiting the need to progress to brain biopsy. Further systematic studies in unselected populations of stroke patients are needed to confirm our findings and establish the prevalence of medium-large artery wall inflammation.

The role of the thalamus in amnesia: a tractography, high-resolution MRI and neuropsychological study.

Although it is well established that thalamic lesions may lead to profound amnesia, the precise contribution of thalamic sub-regions to memory remains unclear. In an influential article Aggleton and Brown proposed that recognition memory depends on two processes supported by distinct thalamic and cortical structures. Familiarity is mediated by the mediodorsal (MD) thalamic nucleus and the entorhinal/perirhinal cortex. Recollection is mediated by the anterior thalamic nucleus (AN), the mamillothalamic tract (MTT) and the hippocampus. The authors also suggested that the lateral dorsal nucleus (LD) may contribute to the thalamic/hippocampus system, thereby implying that the LD may play a role in recollection. Given the finding that material specific amnesia can occur following thalamic lesions, we tested an extension of the Aggleton and Brown model. We predicted that patients with bilateral lesions with a bias to the left or right MD or AN/MTT/LD may exhibit impaired familiarity or recollection on verbal or non-verbal memoranda. We report two patients with highly focal thalamic lesions and profound memory impairments affecting verbal and non-verbal memoranda. For the first time, diffusion-weighted imaging was employed to perform tractography of the MTT along with high-resolution anatomical MRI and detailed assessments of verbal and non-verbal memory. Our data support only some aspects of the Aggleton and Brown model. Both patients had left MD nucleus and AN/MTT lesions and performed poorly on familiarity and recall for verbal memoranda, just as predicted by the model. However, both patients' performance for non-verbal memoranda (human faces and topography) is more difficult to reconcile with the model. Patient 1 had damage to the right AN/MTT/LD with sparing of the MD: familiarity should therefore have been preserved but was not. Patient 2 had damage to the right MD with sparing of AN/MTT: recollection should have been preserved but was not. This finding raises the possibility that fractionation of familiarity and recollection to separate thalamic nuclei may not fully capture the role of thalamic sub-regions in memory function.

Cerebral microbleeds are common in ischemic stroke but rare in TIA.

BACKGROUND: In patients with stroke, gradient-echo MRI commonly detects microbleeds, indicating small artery disease with increased risk of macroscopic intracranial bleeding. Antithrombotic treatments are frequently prescribed after TIA and stroke, but there have been no previous studies of microbleeds in TIA. Because microbleeds may predict the hemorrhagic risk of antithrombotic treatments, we studied the prevalence of microbleeds, risk factors, and pathophysiologic mechanisms in patients with ischemic stroke and TIA. METHODS: One hundred twenty-nine consecutive patients with ischemic stroke or TIA were studied with MRI including T2, fluid-attenuated inversion recovery, and gradient-echo MRI sequences. Blinded observers counted microbleeds and graded white matter T2 hyperintensities throughout the brain. TIA patients with previous ischemic stroke were excluded. RESULTS: Sixty-seven percent of patients had ischemic stroke; 33% had TIA. Microbleeds were found in 23% of ischemic stroke patients but only 2% of TIA patients (p < 0.001). There were no significant differences in conventional risk factors or the severity of white matter disease on T2 MRI between stroke and TIA patients. Patients with microbleeds were more often hypertensive (81 vs 59%; p = 0.04) and had more severe MRI white matter disease on T2 MRI (p = 0.003). CONCLUSIONS: Microbleeds are common in ischemic stroke but rare in TIA, an observation not explained by differences in vascular risk factors or severity of white matter disease seen on T2 MRI. This finding has implications for the safety of antithrombotic therapy and clinical trial design in the two groups. Microbleeds may also be a new marker for severe microvascular pathology with increased risk of permanent cerebral infarction.

Chlamydophila pneumoniae infection of the central nervous system in patients with multiple sclerosis.

BACKGROUND: Chlamydophila pneumoniae has been postulated as an aetiological agent in the pathophysiology of multiple sclerosis. Previous studies show conflicting results. OBJECTIVE: To investigate patients with multiple sclerosis and other neurological diseases for evidence of past or present infection with C pneumoniae. METHODS: 19 patients with multiple sclerosis and 29 with other neurological diseases were studied. Evidence was sought for past or present infection with C pneumoniae using polymerase chain reaction (PCR) and cell culture of cerebrospinal fluid (CSF), and enzyme linked immunosorbent assay and microimmunofluorescence of serum. RESULTS: C pneumoniae was grown from the CSF of one patient with multiple sclerosis. PCR was negative in all cases. Anti-chlamydial antibodies were detected in the same proportion in each group. CONCLUSIONS: This study does not support the theory of an association between C pneumoniae and multiple sclerosis.

A study of acute rehabilitation after head injury.

In 1999 a report from the Royal College of Surgeons of England drew attention to the fact that, in the UK, there is little structured acute inpatient rehabilitation for patients admitted after traumatic brain injury (TBI). This paper reports the results of a retrospective study of acute inpatient rehabilitation (AR) after TBI, comparing aspects of resource use in 92 patients who received structured unit-based multidisciplinary AR with 97 patients who received usual practice. About 10% of patients admitted via casualty after TBI required AR after neurosurgical consultation or care. These patients remained in AR for a mean of 20.5 days; length of stay in an acute bed was not prolonged compared with patients in usual practice. Sixty per cent of patients discharged home from unit-based care were referred to community-based rehabilitation on discharge compared with no patients discharged home from neurosurgical care. There is an urgent need to discuss and plan at national level the structured secondary provision of acute rehabilitation after acquired brain injury.

Cognitive dysfunction after isolated brain stem insult. An underdiagnosed cause of long term morbidity.

Cognitive dysfunction adversely influences long term outcome after cerebral insult, but the potential for brain stem lesions to produce cognitive as well as physical impairments is not widely recognised. This report describes a series of seven consecutive patients referred to a neurological rehabilitation unit with lesions limited to brain stem structures, all of whom were shown to exhibit deficits in at least one domain of cognition. The practical importance of recognising cognitive dysfunction in this group of patients, and the theoretical significance of the disruption of specific cognitive domains by lesions to distributed neural circuits, are discussed.

T1 lesion load and cerebral atrophy as a marker for clinical progression in patients with multiple sclerosis. A prospective 18 months follow-up study.

We investigated the relationship between local tissue destruction, diffuse cerebral atrophy and clinical progression in patients with established multiple sclerosis (MS). Twenty-nine patients with MS (13 patients with relapsing--remitting and 16 with secondary progressive disease) were included in a prospective serial study. Cerebral volumes, T1 hypointense lesion volumes, T2 hyperintense lesion volumes at baseline and at 18 months follow-up, and the volume of monthly enhancing lesions from month 0 to month 9 were assessed on magnetic resonance imaging (MRI) brain scans using highly reproducible semi-automated quantitative techniques. The main outcome measures were the MRI parameters and disability on Kurtzkes' Expanded Disability Status Scale. There was a significant correlation between the change (increase) in T1 lesion volume and progressive cerebral atrophy, whereas no correlation between the T2 lesion volume and atrophy was seen over the same follow-up period. The change in T1 lesion volume correlated more strongly than did T2 lesion volume change with the change in disability. We conclude that hypointense abnormalities detected in T1-weighted brain scans and cerebral atrophy may be directly linked. Although one should bear in mind some potential for reversibility due to inflammatory, oedematous lesions, these MR measures are a useful marker of progressive tissue damage and clinical progression in established MS.

Serum inflammatory markers and clinical/MRI markers of disease progression in multiple sclerosis.

The aim of this study was to assess whether mean serum levels of inflammatory markers when measured serially correlate with disease progression or putative MRI markers of axonal loss in a cohort of well-characterised multiple sclerosis (MS) patients. Serial serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1), nitric oxide metabolites nitrate and nitrite (NOx), C-reactive protein (CRP), neopterin and tumour necrosis factor alpha (TNF-alpha) were measured in 29 MS patients, 13 with a relapsing remitting (RR) and 16 with a secondary progressive (SP) course, who were participating in a phase II clinical trial of anti-CD4 therapy. Short-term whole blood stimulated TNF-alpha production was also measured. Patients were studied 12 times over an 18-month period. MRI variables included the number and volume of Gd-enhancing lesions and the change in T2-hyperintense, T1-hypointense lesions and cerebral volume between the baseline and exit studies. Disease progression required a sustained change in the EDSS. There was no correlation between mean levels of inflammatory markers over the study period and disease progression or changes in any of the MRI measures. However, mean sICAM-1 levels from the first 6 months of the study were higher in patients who progressed during the study than in those that did not (443 (SD439) vs. 235 (SD162) ng/mL, p=0.05). Mean levels of NOx were significantly higher in patients with RR MS than in patients with SP disease (59.1 micromol/L (SD 12.8) vs. 48.7 micromol/L (SD 11.9), p=0.02). Patients with either a single relapse or no relapse had significantly higher NOx levels than to patients with multiple relapses during the 18 month follow-up (59.0 micromol/L (SD 12.3) vs. 47.9 micromol/L (SD 12.0), p=0.02). The mean levels of the other inflammatory markers did not correlate with disease course or relapse-rate. Serum levels of many inflammatory markers do not correlate with short-term disease progression. Some of the data suggest that the effects of inflammation on disease progression are delayed. In addition raised levels of serum nitric oxide metabolites are associated with a lower number of clinical relapses and a non-progressive disease course. These findings, although preliminary, pose interesting questions on the role of nitric oxide in the pathogenesis of MS. Inducible NO production in the early stages of the disease may be beneficial.

T1 hypointensity of the spinal cord in multiple sclerosis.

It has recently been shown in multiple sclerosis (MS) that the volume of T1 hypointense lesions in the brain explains more of the variance in disability amongst patients than T2 lesion volume. T1 hypointense lesions may therefore represent areas of underlying pathology likely to be of functional significance, such as axonal loss. The spinal cord is a common area of involvement in MS and its dysfunction is likely to be responsible for much of the motor disability seen. Hence it serves as a useful model by which to examine the functional relevance of differing imaging sequences. We have therefore examined the relationship between T1 signal intensity in the spinal cord and disability in 60 patients with MS. We have also examined the relationship between T1 signal intensity and atrophy of the cord, as the latter is another potential marker of axonal loss. Sixty patients with MS underwent spinal cord imaging with a T1 weighted sequence to acquire axial sections of the cord at the C2 level. These sections were histogram matched to allow comparison of image intensity and a manual outlining technique was applied from which the mean cord intensity was calculated. Within the patient group there was a significant relationship between T1 signal intensity and disability as measured with the EDSS (r = -0.4, p < 0.005) and also between T1 signal intensity and atrophy (r = 0.36, p < 0.005). This study demonstrates that disability and atrophy are associated with a generalised reduction in cord signal on T1 weighted images. A lower T1 signal intensity in the spinal cord may be more pathologically specific than T2 hyperintensity and may represent underlying axonal loss, although gliosis and predominant white matter atrophy are alternative possibilities.

The predictive value of gadolinium enhancement for long term disability in relapsing-remitting multiple sclerosis--preliminary results.

As short-term MRI studies are increasingly being used to monitor disease activity in multiple sclerosis (MS) it is vital to establish if short-term MRI activity is predictive of long term clinical outcome. We followed up after 5 years a group of 10 benign (relapsing-remitting MS with a disease duration > 10 years and EDSS < or = 3) and 10 early relapsing-remitting patients who previously had monthly serial MRI scans for 6 months. In the early relapsing-remitting group median EDSS at entry to the initial serial study was three and in the benign group 2.5. At 5-year follow up, five of these 20 patients had developed a definite deterioration in EDSS. The median number of new enhancing lesions detected originally in the group that had deteriorated was 11 (7-17) compared to 0 (0-5) new enhancing lesions, for those who had not deteriorated (P < 0.05). There was a trend towards a higher baseline T2 lesion load in the group with a definite change in EDSS but this was not significant This study suggests that short-term measurement of the number of gadolinium enhancing lesions may predict long term outcome in relapsing-remitting MS.

The effect of interferon beta-1b treatment on MRI measures of cerebral atrophy in secondary progressive multiple sclerosis. European Study Group on Interferon beta-1b in secondary progressive multiple sclerosis.

The recently completed European trial of interferon beta-1b (IFNbeta-1b) in patients with secondary progressive multiple sclerosis (SP multiple sclerosis) has given an opportunity to assess the impact of treatment on cerebral atrophy using serial MRI. Unenhanced T(1)-weighted brain imaging was acquired in a subgroup of 95 patients from five of the European centres; imaging was performed at 6-month intervals from month 0 to month 36. A blinded observer measured cerebral volume on four contiguous 5 mm cerebral hemisphere slices at each time point, using an algorithm with a high level of reproducibility and automation. There was a significant and progressive reduction in cerebral volume in both placebo and treated groups, with a mean reduction of 3.9 and 2.9%, respectively, by month 36 (P = 0.34 between groups). Exploratory subgroup analyses indicated that patients without gadolinium (Gd) enhancement at the baseline had a greater reduction of cerebral volume in the placebo group (mean reduction at month 36: placebo 5.1%, IFNbeta-1b 1.8%, P < 0.05) whereas those with Gd-enhancing lesions showed a trend to greater reduction of cerebral volume if the patient was on IFNbeta-1b (placebo 2.6%, IFNbeta-1b 3.7%; P > 0.05). These results are consistent with ongoing tissue loss in both arms of this study of secondary progressive multiple sclerosis. This finding is concordant with previous observations that disease progression, although delayed, is not halted by IFNbeta. The different pattern seen in patients with and without baseline gadolinium enhancement suggests that part of the cerebral volume reduction observed in IFNbeta-treated patients may be due to the anti-inflammatory/antioedematous effect of the drug. Longer periods of observation and larger groups of patients may be needed to detect the effects of treatment on cerebral atrophy in this population of patients with advanced disease.

MRI of the intraorbital optic nerve in patients with autosomal dominant optic atrophy.

Measurements of the intraorbital optic nerve were made using high-resolution coronal MRI in 10 adults with autosomal dominant optic atrophy. Comparisons were made with previous studies of 10 normal adult subjects. The cross-sectional diameters of the optic nerve and the perineural subarachnoid space were measured and a ratio of there diameters at anterior, mid and posterior positions along the optic nerve was determined. We found a statistically significant difference in the mean optic nerve: sheath ratio between the control group and patients with autosomal dominant optic atrophy. At anterior, mid and posterior locations along the optic nerve it is significantly smaller in patients with optic atrophy. We have demonstrated that the loss of ganglion cells, previously documented in dominant optic atrophy, is associated with a significant loss of optic nerve tissue and thinning of the nerve along its length.

Progressive cerebral atrophy in MS: a serial study using registered, volumetric MRI.

OBJECTIVE: To assess the potential of registered volumetric MRI in measuring rates of atrophy in MS. BACKGROUND: Pathologic and imaging studies suggest that the development of permanent neurologic impairment in MS is associated with progressive brain and spinal cord atrophy. Atrophy has been suggested as a potential marker of disease progression. Conventional atrophy measurements requiring manual outlining are time-consuming and subject to reproducibility problems. Registration of serial MRI may offer a useful alternative in that cerebral losses may be measured directly from automated subtraction of brain volumes. METHODS: Twenty-six patients with MS and 26 age- and gender-matched controls had two volumetric brain MR studies 1 year apart. Baseline brain and ventricular volumes were measured using semiautomated techniques, and follow-up scans were registered to baseline. Rates of cerebral atrophy were calculated directly from the registered scans. RESULTS: Baseline brain volumes in the MS group were smaller (mean difference 78 mL [95% CI 13 to 143; p = 0.02]) and ventricular volumes greater (mean difference 12 mL [95% CI 6 to 18; p < 0.001]) than controls. The rate of cerebral atrophy in the MS group (0.8% per year) was over twice that of controls (0.3%), and the rate of ventricular enlargement was five times greater than the controls (1.6 versus 0.3 mL/year). CONCLUSION: Progressive cerebral atrophy is an important feature of MS. Registration-based measurements are sensitive and reproducible, allowing progressive atrophy to be detected within 1 year and may have potential as a marker of progression in monitoring therapeutic trials.

Texture analysis of spinal cord pathology in multiple sclerosis.

Texture analysis was applied to MR images of the spinal cord in an attempt to quantify pathological changes that occur in multiple sclerosis (MS). Texture features quantify macroscopic lesions and also the microscopic abnormalities that may be undetectable using conventional measures of lesion volume and number. Significant differences in texture between normal controls and MS patients were seen. Texture differences were detected between normal controls and relapsing-remitting patients before detectable spinal cord atrophy. There was also significant correlation between texture and disability. The segmentation and texture analysis technique demonstrates intraobserver coefficients of variation ranging from 0. 6-8.2%. Texture analysis has potential as a tool for monitoring changes associated with the development of disability in patients with MS. Reproducibility and sensitivity must be improved to use the technique for serial monitoring in individuals. Magn Reson Med 42:929-935, 1999.

Spinal cord atrophy and disability in MS: a longitudinal study.

OBJECTIVE: To assess whether it is possible to measure changes in cord cross-sectional area during a 1-year period in patients with MS reliably. BACKGROUND: Involvement of the spinal cord in MS is extremely common and an important element in the development of disability. Although little relation has been shown between the cord lesion load and disability, a strong correlation between spinal cord atrophy and the expanded disability status scale (EDSS) has been demonstrated in cross-sectional studies. METHOD: A highly reproducible semiautomated technique that measures the cross-sectional area of the cord at the C2 level was applied to 13 healthy control subjects and 28 patients serially. RESULTS: This study confirms that patients have significantly smaller cords than control subjects at baseline (control subjects: mean 80.95 mm2, patients: mean 71.25 mm2, p = 0.01) and demonstrates that patients have a significant loss in cord cross-sectional area during 12 months, which was not seen in control subjects (p < 0.001). This reduction in cord size was most marked in the primary progressive patients who had a mean cord cross-sectional area loss of 3.52 mm2 (5.2%) and least in the secondary progressive (-0.26 mm2, 0.7%) and benign patients (-0.41 mm2, 0.8%). The baseline cord cross-sectional area correlated strongly with the EDSS (r = -0.52, p = 0.005) and with disease duration (r = -0.75, p < 0.001); however, there was no significant difference in cord area (p = 0.69) or change in cord area (p = 0.51) between those patients with a definite increase in EDSS and those without. CONCLUSION: This study demonstrates, for the first time, that it is possible to measure changes in cord cross-sectional area over time. The serial measurement of spinal cord atrophy may thus make an important contribution to the evaluation of therapeutic efficacy, especially in primary progressive disease.