Peripheral neuropathy in hepatitis C virus infection with and without cryoglobulinaemia.

OBJECTIVES: Hepatitis C virus (HCV) infection is often associated with cryoglobulinaemia (CG). Peripheral neuropathy (PN) is a comparatively common complication of CG associated with HCV infection and it is thought to be attributable to nerve ischaemia. Only few HCV CG patients with PN have been reported. The recent finding of HCV RNA in nerve biopsy specimens has suggested a possible direct role of HCV in the pathogenesis of PN. The authors studied 51 HCV patients to determine the prevalence of CG and to clarify the possible mechanism by which HCV determines the PN. METHODS: All the patients were studied clinically, by laboratory tests and electrophysiologically. Twenty eight patients underwent sural nerve biopsy where both morphological and morphometric evaluation of the biopsy specimen was performed, as well as statistical analysis. RESULTS: CG was found in 40 of 51 cases (78%). Polyneuropathy was significantly prevalent in CG+ patients compared with CG- (18 of 40 compared with 1 of 11 patients; p=0.01). HCV CG- patients more frequently developed well defined mononeuropathy or multiple neuropathy when compared with HCV CG+ (10 of 11 compared with 22 of 40; p<0.03). HCV CG+ patients showed significantly higher proportion of rheumatoid factor positivity (p<0.001) and low C4 levels (p=0.001). Nerve biopsy was performed in 25 of 40 HCV CG+ patients and in 3 of 11 HCV CG- patients: epineurial vasculitis was present in 8 of 25 HCV CG+ (32%) and in 2 of 3 HCV CG-. Differential fascicular loss of axons was found in 10 of 25 CG+ (40%) and 1 of 3 CG-, signs of both demyelination and axonal degeneration were present in 7 of 25 CG+ (28%). No significant difference was found in neuropathological features, while histometrical analysis disclosed more severe involvement in CG+ patients. CONCLUSIONS: These findings suggest that the presence of CG is a negative predictive factor for the associated PN. Morphological findings in the sural nerve from HCV CG- and CG+ are consistent with an ischaemic mechanism of nerve damage and are against a direct role of the virus in causing the associated PN.

In vivo assessment of the brain and cervical cord pathology of patients with primary progressive multiple sclerosis.

In patients with primary progressive (PP) multiple sclerosis, brain MRI lesion activity and burden are low, despite the presence of severe neurological impairment. On the contrary, the degree of cord atrophy and diffuse tissue damage in the brain and cervical cord have been found to be associated with clinical disability. Against this background, this study aimed at providing an in vivo indirect assessment of brain and cervical cord pathology in a large cohort of PP multiple sclerosis patients, using conventional MRI and magnetization transfer imaging (MTI). Ninety-one PP multiple sclerosis patients, 36 secondary progressive (SP) multiple sclerosis patients and 30 healthy controls underwent brain and cervical cord MRI scans, using dual echo (brain) or fast short-tau inversion recovery (cervical cord) MTI and T(1)-weighted sequences. For the brain, T(2) hyperintense and T(1) hypointense lesion volumes were calculated and the volume of the whole of the brain tissue measured. For the cervical cord, the number and burden of lesions and the cross-sectional area were assessed. MTI scans were post-processed and analysed to obtain magnetization transfer ratio (MTR) histograms from the whole of the brain and cervical cord tissue and from the normal-appearing brain tissue in isolation. In PP multiple sclerosis patients, brain, normal-appearing brain tissue and cervical cord MTR histogram-derived metrics revealed the presence of diffuse tissue damage whose characteristics did not significantly differ from those of SP multiple sclerosis patients, even though SP multiple sclerosis patients had higher MRI-visible lesion burdens. None of the correlations between MRI or MTI measures obtained from the brain and the cord were significant. PP multiple sclerosis patients' disability was significantly, albeit weakly associated with a composite MR model including measures of loss and intrinsic damage of cervical cord tissue. Our data indicate the presence of a diffuse tissue damage undetectable by conventional MRI in PP multiple sclerosis patients, whose extent seems to match that of SP multiple sclerosis patients with similar levels of disability. They also suggest that the severity of multiple sclerosis pathology in the cervical cord is one of the factors contributing to neurological impairment in PP multiple sclerosis.

Relative contributions of brain and cervical cord pathology to multiple sclerosis disability: a study with magnetisation transfer ratio histogram analysis.

OBJECTIVE: To assess (a) the correlations between magnetisation transfer ratio (MTR) histogram derived measures of the brain and the cervical cord from patients with different multiple sclerosis phenotypes and (b) the correlation between these metrics and clinical disability. Magnetisation transfer imaging is sensitive to the most destructive aspects of multiple sclerosis pathology. Magnetisation transfer ratio histogram analysis encompasses the macroscopic and the microscopic lesion burdens. METHODS: Seventy seven patients with multiple sclerosis were studied (40 relapsing-remitting (RR), 28 secondary progressive (SP), and nine primary progressive (PP)). For the brain, we obtained dual echo, T1 weighted, and gradient echo (GE) scans (with and without an MT saturation pulse). For the cervical cord, fast short tau inversion recovery (STIR) and GE scans (with and without an MT saturation pulse) were obtained. Brain T2 and T1 weighted lesion volumes (LVs) were measured. The number and length of cord lesions on fast STIR scans were assessed. Magnetisation transfer ratio maps were created from GE images and MTR histograms of the entire brain and cervical cord were obtained. RESULTS: Brain T1 LV, and number and size of cord lesions were significantly higher and brain MTR histogram peak location was significantly lower in patients with SPMS than those with RRMS or PPMS. Cord MTR histogram peak location was also significantly lower in patients with SPMS than in those with RRMS. The univariate correlations between MTR histogram derived metrics obtained from the brain and the cervical cord were all non-significant, with the exception of that between average brain MTR and cord MTR histogram peak location. On a multivariable analysis, both increasing brain T2 LV and decreasing cord MTR histogram peak location values were significantly associated with a higher probability for patients to have SPMS or to have locomotor disability. CONCLUSIONS: This study shows that the extent and severity of tissue damage in the brain and cervical cord are both relevant to determine disability in multiple sclerosis and that the assessment of brain and cord pathology provides complementary information.

Cortical/subcortical disease burden and cognitive impairment in patients with multiple sclerosis.

BACKGROUND AND PURPOSE: We assessed whether the extent of macro- and microscopic disease in the cortical and subcortical brain tissue, as revealed by MR and magnetization transfer (MT) imaging, correlates with cognitive dysfunction in patients with multiple sclerosis (MS). METHODS: Dual-echo rapid acquisition with relaxation enhancement (RARE), fast fluid-attenuated inversion recovery (fast-FLAIR), T1-weighted, and MT MR images of the brain were obtained from 16 MS patients with cognitive impairment and from six without. Impaired and unimpaired patients were similar across demographic and other disease-related variables. Total and cortical/subcortical lesion loads were assessed using RARE, fast-FLAIR, and T1-weighted sequences. In each patient, cortical/subcortical disease was also assessed by means of MT ratio (MTR) histographic analysis. RESULTS: All the impaired patients had multiple hyperintense lesions in the cortical/subcortical regions on both RARE and fast-FLAIR images; two unimpaired patients had such lesions on the RARE images and four had them on the fast-FLAIR images. Total and cortical/subcortical RARE/fast-FLAIR hyperintense and T1 hypointense lesion loads were significantly greater in the group of cognitively impaired patients. Patients with cognitive deficits also had significantly lower MTR histographic values for all the variables. A multivariate regression model showed that average cortical/subcortical brain MTR was the only factor that was significantly associated with cognitive impairment. CONCLUSION: The extent and severity of MS disease in the cortical and subcortical regions significantly influence the cognitive functions of MS patients. MTR histographic findings suggest that subtle changes undetectable by conventional imaging are also important in determining MS cognitive decline.

A multiparametric MRI study of frontal lobe dementia in multiple sclerosis.

Previous studies achieved conflicting results when correlating magnetic resonance imaging (MRI) abnormalities and cognitive impairment in multiple sclerosis (MS) patients. Recently, the estimation of MS lesion load on T1-weighted images and the analysis of magnetization transfer ratio (MTR) histograms, increased the degree of the correlation between physical disability and MRI findings in MS. We assessed the relationship of conventional and non-conventional MRI-derived measures with frontal lobe dementia in MS. Dual echo, T1-weighted and MT MRI scans of the brain were obtained in 11 MS patients with and in 11 without frontal lobe dementia, matched for age, sex, education and disability. Total (TLL) and frontal (FLL) lesion loads were assessed from T2- and T1-weighted scans. MTR histogram analysis was performed for the whole brain, the frontal lobe and the cerebellum. Median TLL and FLL were significantly higher in cognitively impaired patients on both T2- and T1-weighted scans. The MRI measure that better discriminated the two groups of patients was T1-weighted TLL (median values were 19.1 ml for demented and 1.9 ml for non-demented patients, P=0.006). Average MTR, peak height and location of overall brain and frontal lobe histograms were significantly lower for cognitively impaired than for cognitively intact patients (P values ranged from 0.0001 to 0.001). Cerebellar MTR histogram metrics did not significantly differ in patients with and without cognitive decline. The presence of cognitive decline in MS is associated with the extent and pathological severity of brain MRI abnormalities.

Measuring evoked responses in multiple sclerosis.

Evoked potentials (EPs) have been widely utilised in Multiple Sclerosis (MS) patients to demonstrate the involvement of sensory and motor pathways. Their diagnostic value is based on the ability to reveal clinically silent lesions and to objectivate the central nervous system damage in patients who complain frequently of vague and indefinite disturbances which frequently occurs in the early phases of the disease. The advent of magnetic resonance imaging (MRI) techniques has greatly reduced the clinical utilisation of EPs, which is not fully justifiable, as the information provided by EPs are quite different from those provided by MRI. The abnormalities of evoked responses reflect the global damage of the evoked nervous pathway and are significantly correlated with the clinical findings, while the vast majority of MRI lesions are not associated to symptoms and signs. Transversal and longitudinal studies have demonstrated that EP changes in MS are more strictly related to disability than MRI lesion burden. On the contrary, MRI is more sensitive than EPs in revealing the disease activity. Evoked responses modifications observed in MS are not disease-specific; moreover longitudinal studies showed latency and morphology changes of evoked responses not always related to clinical changes. Such a dissociation can be explained both by technical factors and by subclinical disease activity. To reduce the negative impact of technical aspects, only reproducible parameters of the evoked responses should be used to monitor disease evolution and therapeutic interventions.

Relevance of hypointense lesions on fast fluid-attenuated inversion recovery MR images as a marker of disease severity in cases of multiple sclerosis.

BACKGROUND AND PURPOSE: Hypointense lesions can be visible on fast fluid-attenuated inversion recovery (FLAIR) MR images of the brain of patients with multiple sclerosis (MS), and they may be produced by severely damaged white matter. To test the role of these lesions as an MR marker of MS severity, we assessed their relationship with clinical findings and other MR measures. METHODS: Using a 1.5-T scanner, dual-echo rapid acquisition with relaxation enhancement, fast FLAIR, and T1-weighted MR images (24 axial, 5-mm-thick contiguous interleaved sections) were obtained from 50 patients (32 with relapsing-remitting and 18 with secondary progressive MS). RESULTS: Hypointense lesions were visible on the fast FLAIR images of 19 patients (mean number of lesions, 7.8; range 1-22); their median load was 1.4 mL (range, 0.05-12.6 mL). The median lesion load was significantly higher in patients with secondary progressive MS than in those with relapsing-remitting MS on the T1-weighted images. Both the number and the load of hypointense lesions shown by fast FLAIR imaging were significantly higher in patients with secondary progressive MS. Significant correlations were found between Expanded Disability Status Scale scores and MR lesion load. A multivariate analysis showed that only the presence of hypointense lesions on fast FLAIR images significantly separated cases of relapsing-remitting MS from cases of secondary progressive MS (relative risk, 7.1; 95% confidence interval, 2.0-25.9). CONCLUSION: The presence of hypointense lesions on fast FLAIR images was a strong predictor of disease severity in cases of MS, although the low sensitivity of this approach might limit its use for the assessment of MS evolution.