Maria Codella

Functional Magnetic Resonance Imaging Correlates of Fatigue in Multiple Sclerosis

Although fatigue is a common and troublesome symptom of multiple sclerosis (MS), its pathogenesis is poorly understood. In this study, we used functional magnetic resonance imaging (fMRI) to test whether a different pattern of movement-associated cortical and subcortical activations might contribute to the development of fatigue in patients with MS. We obtained fMRI during the execution of a simple motor task with completely normally functioning hands from 15 MS patients with fatigue (F), 14 MS patients without fatigue (NF), and 15 sex- and age-matched healthy volunteers. F and NF MS patients were also matched for major clinical and MRI variables. FMRI data were analyzed using statistical parametric mapping. In all patients, severity of fatigue was rated using the Fatigue Severity Scale (FSS). Compared to healthy subjects, MS patients showed more significant activations of the contralateral primary somatomotor cortex, the contralateral ascending limb of the Sylvian fissure, the contralateral intraparietal sulcus (IPS), the contralateral supplementary motor area, and the ipsilateral and contralateral cingulate motor area (CMA). Compared to F MS patients, NF patients showed more significant activations of the ipsilateral cerebellar hemisphere, the ipsilateral rolandic operculum, the ipsilateral precuneus, the contralateral thalamus, and the contralateral middle frontal gyrus. In contrast, F MS patients had a more significant activation of the contralateral CMA. Significant inverse correlations were found between FSS scores and relative activations of the contralateral IPS (r = -0.63), ipsilateral rolandic operculum (r = -0.61), and thalamus (r = -0.62). This study provides additional evidence that fatigue in MS is related to impaired interactions between functionally related cortical and subcortical areas. It also suggests that fMRI might be a valuable tool to monitor the efficacy of treatment aimed at reducing MS-related fatigue.

Cerebral grey matter pathology and fatigue in patients with multiple sclerosis: a preliminary study

In patients with multiple sclerosis (MS), we investigated whether the extent of cerebral grey matter (GM) pathology is associated with the presence and severity of fatigue. We quantified cerebral GM pathology in 28 MS patients (14 with fatigue and 14 without fatigue) using magnetization transfer (MT) and diffusion tensor (DT) magnetic resonance imaging (MRI). The average MT ratio and mean diffusivity from cerebral GM did not differ between fatigued and non-fatigued patients. Fatigued and non-fatigued patients also did not differ in terms of GM pathology of the cerebral cortex of the frontal lobe and basal ganglia. No correlations were found between the fatigue severity scale scores and any of the MT- and DT-MRI quantities. These preliminary results suggest that structural GM pathology is not a major contributing factor to the development of fatigue in patients with MS.

A preliminary study of magnetization transfer and diffusion tensor MRI of multiple sclerosis patients with fatigue

To investigate whether multiple sclerosis (MS) tissue damage is associated with the presence and severity of fatigue, we obtained magnetization transfer (MT) and diffusion tensor (DT) magnetic resonance imaging from 28 patients with MS (14 with and 14 without fatigue). MT ratio and mean diffusivity did not differ between fatigued and non-fatigued MS patients. No correlation was found between Fatigue Severity Scale scores and any of the MT and DT MRI-derived quantities. This preliminary study suggests that the severity of overall MS pathology in the brain seems not to be a critical factor contributing to the development of fatigue in MS.

Evidence for Cortical Functional Changes in Patients With Migraine and White Matter Abnormalities on Conventional and Diffusion Tensor Magnetic Resonance Imaging

Background— In this study, we used functional MRI (fMRI) to investigate the pattern of cortical activations after a simple motor task in patients with migraine and white matter (WM) abnormalities on conventional MRI scans of the brain. We also investigated whether the extent of brain activations was correlated with WM structural pathology measured using diffusion tensor (DT) MRI. Methods— From 15 right-handed patients with migraine and 15 sex- and age-matched, right-handed healthy volunteers, we obtained the following: (1) fMRI (repetitive flexion-extension of the last 4 fingers of the right hand), (2) dual-echo turbo spin echo scans, and (3) pulsed-gradient spin-echo echo-planar sequence to calculate DT-MRI maps. fMRI analysis was performed using SPM99 and cluster detection. We measured the volume, the average mean diffusivity (&OV0430;), and the average fractional anisotropy of all lesions seen on the dual-echo scans. &OV0430; histograms of the normal-appearing WM were also produced. Results— Compared with healthy volunteers, migraine patients had a larger relative activation of the contralateral primary sensorimotor cortex (P =0.01) and a rostral displacement of the supplementary motor area (P =0.03). The shapes of the curves reflecting the time course for fMRI signal intensity changes were similar between migraine patients and controls for all of the cortical areas we studied. Compared with healthy subjects, migraine patients had significantly lower &OV0430; histogram peak height of the normal-appearing WM histogram (P =0.02), which was found to be correlated with the extent of displacement of the supplementary motor area (r =−0.80, P <0.001). Conclusions— This study suggests that functional cortical changes occur in patients with migraine and brain MRI abnormalities and that they might be secondary to the extent of subcortical structural damage.

Effect of glatiramer acetate on MS lesions enhancing at different gadolinium doses

This baseline-vs-treatment study of 20 patients with relapsing-remitting MS investigated whether glatiramer acetate (GA) has a graduated effect on MS inflammatory activity, which was measured using monthly, standard, and triple dose gadolinium (Gd)-enhanced MRI. GA significantly reduced the mean numbers of enhancing lesions/patient/month on both standard dose and triple dose scans, without interactions with the Gd dose. GA is effective in reducing MS activity, independent of the severity of the MRI-detectable inflammatory process.

Frequency and patterns of subclinical cognitive impairment in patients with ANCA-associated small vessel vasculitides.

We investigated the prevalence of disease-related cognitive impairment in patients with anti-neutrophil cytoplasmic antibodies (ANCA)-associated small vessel vasculitides (SVV). We studied 43 patients with ANCA-associated SVV (Wegeners granulomatosis (WG), Churg-Strauss syndrome (CSS) and microscopic polyangiitis (MP)), with no evidence of focal neurological deficits and dementia and in whom other potential causes of cognitive decline were carefully excluded. All patients underwent a detailed neuropsychological evaluation and their performances were compared with those of matched healthy controls. Patients were considered to be affected by subclinical cognitive impairment when they had abnormal results in at least two neuropsychological tests. Magnetic resonance imaging (MRI) scans of the brain were also obtained in 11 patients.The average neuropsychological test scores were not significantly different between the SVV patients and the control subjects. Thirteen patients had abnormal results in two tests (seven patients) or three or more tests (six patients). Most frequently, abnormal tests were the Rey Figure Recall (six cases), the Wisconsin Card Sorting Test (six cases), and the reaction times (eight cases). The frequency and extent of brain MRI abnormalities were higher in impaired than in unimpaired patients. This study demonstrates that 30% of clinically nondemented SVV patients can have a subclinical neuropsychological impairment, characterized by mild abstract reasoning loss, mental speed reduction and nonverbal memory impairment. MRI findings in impaired patients are consistent with the presence of an SVV-mediated subcortical damage of the brain.

Contribution of cervical cord MRI and brain magnetization transfer imaging to the assessment of individual patients with multiple sclerosis: a preliminary study

This study was performed to assess how established diagnostic criteria for brain magnetic resonance imaging (MRI) interpretation in cases of suspected multiple sclerosis (MS) (Barkhof’s criteria) would perform in the distinction of MS from other diseases and whether other MR techniques (cervical cord imaging and brain magnetization transfer imaging [MTI]), might help in the diagnostic work-up of these patients. We retrospectively identified 64 MS and 59 non-MS patients. The latter group included patients with systemic immune-mediated disorders (SID; n=44) and migraine (n=15). All patients had undergone MRI scans of the brain (dual echo and MTI) and of the cervical cord (fast short-tau inversion recovery). The number and location of brain T2-hyperintense lesions and the number and size of cervical cord lesions were assessed. Brain images were also postprocessed to quantify the total lesion volumes (TLV) and to create histograms of magnetization transfer ratio (MTR) values from the whole of the brain tissue. Barkhof’s criteria correctly classified 108/123 patients, thus showing an accuracy of 87.8%. “False negative” MS patients were 13, while 2 patients with systemic lupus erythematosus (SLE) were considered as “false positives”. Using brain T2 TLV, nine of the“false negative” patients were correctly classified. Correct classification of 10 MS patients and both the SLE patients was possible based upon the presence or absence of one cervical cord lesion. Two MS patients with negative Barkhof’s criteria and no cervical cord lesions were correctly classified based on their brain MTR values. Overall, only one MS patient could not be correctly classified by any of the assessed MR quantities. These preliminary data support a more extensive use of cervical cord MRI and brain MTI to differentiate between MS and other disorders in case of inconclusive findings on T2-weighted MRI scans of the brain.

A diffusion tensor MRI study of basal ganglia from patients with ADEM

Using diffusion tensor (DT) MRI and histogram analysis, we measured mean diffusivity ((-)D) of basal ganglia grey matter (GM) from eight patients with acute disseminated encephalomyelitis (ADEM), 10 patients with multiple sclerosis (MS), and 10 healthy controls. Patients with ADEM had higher average (-)D (p=0.02) and lower (-)D histogram peak height (p=0.008) of the basal ganglia GM than patients with MS. Microscopic tissue damage occurs in the basal ganglia of ADEM patients, but not in MS patients with a similar burden of MRI-visible brain lesions.

Central nervous system angiitis in Hodgkin’s disease

Dear Sirs, Hodgkin’s disease (HD) is a B-lymphoid neoplasm that can cause neurological dysfunction due to rare central nervous system (CNS) invasion or most frequently to CNS paraneoplastic syndromes or treatment-related toxicity [1]. We report a patient with HD in complete remission who suffered CNS angiitis. A 20-year-old man was admitted to our department because of headache of insidious onset, nausea, vomiting, and diplopia. He suffered from a mixed-cellularity HD, stage III B, diagnosed 8 months before, in complete remission after six cycles of chemotherapy (adriamycin, bleomycin, vinblastine, dacarbazine) and radiotherapy. Neurological examination revealed paresis of the right VIth cranial nerve, bilateral papilledema, and spontaneous speech reduction. Routine and autoimmunity (antinuclear antibodies, rheumatoid factor, antineutrophil cytoplasmic antibodies, serum C3 and C4, serum cryoglobulins, antiphospholipid antibodies) blood tests were unremarkable. Cerebrospinal fluid (CSF) analysis showed pleocytosis (white blood cells, 66/mm), increased proteins concentration (50 mg/dl), negative cultures and small, mature lymphocytes, with normal morphology. Brain magnetic resonance imaging (MRI) showed left frontotemporal hyperintensity in the T2/FLAIR sequences (Fig. 1a–c), and diffuse small vessels enhancement after gadolinium administration, which was more severe in the left temporal lobe (Fig. 1d). Overall, CSF and imaging findings were strongly suggestive of CNS angiitis and a diagnosis of possible paraneoplastic CNS angiitis according to the criteria of Dalmau and Rosenfeld was performed [2]. Intravenous methylprednisolone (1,000 mg/day for 5 days) followed by oral prednisone (1 mg/kg/day) were started. Considering the supposed paraneoplastic etiology of CNS angiitis, intravenous immune globulin (400 mg/kg/ day for 5 days) were administered concurrently with corticosteroid treatment. During the two successive weeks, the patients progressively ameliorated up to complete symptoms resolution. Brain MRIs performed 1 and 3 months after the episode were negative (Fig. 2). At last follow-up, 1 year after the end of chemotherapy, the CT and PET scan revealed the presence of a large mediastinal mass, with histological diagnosis of thymic hyperplasia. In the meantime, mild symptoms and radiological signs of CNS angiitis re-appeared. CNS vasculitis associated with HD was first described by Greco and Colleagues in 1976 [3] and was reported in 17 cases. Although its pathophysiology is not completely understood, it may be considered a paraneoplastic disorder associated with a deregulation of the immune system. Differently from other paraneoplastic syndromes of the CNS [2], in HD it often arises after lymphoma diagnosis [4]. Clinical presentation includes headache, nausea, vomiting, seizures, and mental status change. CSF analysis usually reveals mild lymphocytic pleocytosis and protein increase [5]. CSF investigation is mandatory to rule out A. Morotti (&) M. Codella R. Rao A. Pezzini A. Padovani Dipartimento di Scienze Cliniche e Sperimentali, Clinica Neurologica, Università degli Studi di Brescia, Piazzale Spedali Civili 1, 25125 Brescia, Italy e-mail: a.morotti@ymail.com