A. Di Costanzo

Brain atrophy and lesion load in a large population of patients with multiple sclerosis

Objective: To measure white matter (WM) and gray matter (GM) atrophy and lesion load in a large population of patients with multiple sclerosis (MS) using a fully automated, operator-independent, multiparametric segmentation method. Methods: The study population consisted of 597 patients with MS and 104 control subjects. The MRI parameters were abnormal WM fraction (AWM-f), global WM-f (gWM-f), and GM fraction (GM-f). Results: Significant differences between patients with MS and control subjects included higher AWM-f and reduced gWM-f and GM-f. MRI data showed significant differences between patients with relapsing-remitting and secondary progressive forms of MS. Significant correlations between MRI parameters and between MRI and clinical data were found. Conclusions: Patients with multiple sclerosis have significant atrophy of both white matter (WM) and gray matter (GM); secondary progressive patients have significantly more atrophy of both WM and GM than do relapsing-remitting patients and a significantly higher lesion load (abnormal WM fraction); lesion load is related to both WM and even more to GM atrophy; lesion load and WM and GM atrophy are significantly related to Expanded Disability Status Scale score and age at onset (suggesting that the younger the age at disease onset, the worse the lesion load and brain atrophy); and GM atrophy is the most significant MRI variable in determining the final disability.

3.0-T functional brain imaging: a 5-year experience

The aim of this paper is to illustrate the technical, methodological and diagnostic features of functional imaging (comprising spectroscopy, diffusion, perfusion and cortical activation techniques) and its principal neuroradiological applications on the basis of the experience gained by the authors in the 5 years since the installation of a high-field magnetic resonance (MR) magnet. These MR techniques are particularly effective at 3.0 Tesla (T) owing to their high signal, resolution and sensitivity, reduced scanning times and overall improved diagnostic ability. In particular, the high-field strength enhances spectroscopic analysis due to a greater signal-to-noise ratio (SNR) and improved spectral, space and time resolution, resulting in the ability to obtain highresolution spectroscopic studies not only of the more common metabolites, but also – and especially – of those which, due to their smaller concentrations, are difficult to detect using 1.5-T systems. All of these advantages can be obtained with reduced acquisition times. In diffusion studies, the high-field strength results in greater SNR, because 3.0-T magnets enable increased spatial resolution, which enhances accuracy. They also allow exploration in greater detail of more complex phenomena (such as diffusion tensor and tractography), which are not clearly depicted on 1.5-T systems. The most common perfusion study (with intravenous injection of a contrast agent) benefits from the greater SNR and higher magnetic susceptibility by achieving dramatically improved signal changes, and thus greater reliability, using smaller doses of contrast agent. Functional MR imaging (fMRI) is without doubt the modality in which high-field strength has had the greatest impact. Images acquired with the blood-oxygen-level-dependent (BOLD) technique benefit from the greater SNR afforded by 3.0-T magnets and from their stronger magnetic susceptibility effects, providing higher signal and spatial resolution. This enhances reliability of the localisation of brain functions, making it possible to map additional areas, even in the millimetre and submillimetre scale. The data presented and results obtained to date show that 3.0-T morphofunctional imaging can become the standard for highresolution investigation of brain disease.

T2 relaxometry of brain in myotonic dystrophy.

Abstract We investigated the nature and extent of brain involvement in myotonic dystrophy (DM), examining possible T2 relaxation abnormalities in the brain of 20 patients with adult-onset DM and 20 sex- and age-matched normal controls. Brain MRI was performed at 0.5 T, and T2 values were calculated from signal intensity in two echoes. Regions of interest included: frontal, parietal, temporal, occipital and callosal (rostral and splenial) normal-appearing white matter; frontal, occipital, insular and hippocampal cortex; caudate nucleus, putamen, globus pallidus and thalamus. All white-matter and occipital and right frontal cortex regions showed a significantly longer T2 in the patients. Multiple regression analysis, including grey- and white-matter T2 as dependent variables, plus age at onset and at imaging, disease duration, muscular disability, brain atrophy and CTG trinucleotide repeats as independent variables, revealed that only white-matter T2 elongation and disease duration correlated positively. White-matter involvement in DM is more extensive than previously reported by MRI and neuropathological studies and seems to be progressive in the course of disease.

Role of advanced MR imaging modalities in diagnosing cerebral gliomas

The objective of this study was to evaluate the potential role of newly developed, advanced magnetic resonance (MR) imaging techniques (spectroscopy, diffusion and perfusion imaging) in diagnosing brain gliomas, with special reference to histological typing and grading, treatment planning and posttreatment follow-up. Conventional MR imaging enables the detection and localisation of neoplastic lesions, as well as providing, in typical cases, some indication about their nature. However, it has limited sensitivity and specificity in evaluating histological type and grade, delineating margins and differentiating oedema, tumour and treatment side-effects. These limitations can be overcome by supplementing the morphological data obtained with conventional MR imaging with the metabolic, structural and perfusional information provided by new MR techniques that are increasingly becoming an integral part of routine MR studies. Incorporation of such new MR techniques can lead to more comprehensive and precise diagnoses that can better assist surgeons in determining prognosis and planning treatment strategies. In addition, the recent development of new, more effective, treatments for cerebral glioma strongly relies on morphofunctional MR imaging with its ability to provide a biological interpretation of these characteristically heterogeneous tumours.RiassuntoLo scopo del lavoro è di illustrare le potenzialità delle nuove e più avanzate modalità di studio RM (spettroscopia, diffusione, perfusione) nella diagnostica dei gliomi cerebrali, con particolare riferimento alla definizione dell’istotipo e del grading, alla pianificazione del trattamento e al follow-up post-trattamento. Con la RM di base è possibile nei casi tipici identificare la lesione neoplastica, stabilirne la sede e la topografia e proporre un’ipotesi di natura. Vi è però una limitata sensibilità e specificità nella definizione dell’istotipo e del grading, nell’individuazione dei margini neoplastici e nella differenziazione tra tumore ed edema o effetti del trattamento. È necessario pertanto integrare le informazioni fornite dalla RM di base con le informazioni di carattere metabolico, strutturale ed emodinamico fornite dalle più recenti tecniche RM, oramai parte integrante di uno studio di routine. In tal modo sono possibili diagnosi sempre più precise ed esaustive per il chirurgo, necessarie per definire la prognosi e l’impostazione delle diverse strategie terapeutiche. Inoltre, il recente sviluppo di nuovi e più efficaci trattamenti ha reso sempre più necessario uno studio RM morfofunzionale con cui ottenere in maniera non invasiva una “neuropatologia in vivo” e quindi un’interpretazione biologica della eterogeneità tipica di tali tumori.Abstract The objective of this study was to evaluate the potential roleof newly developed, advanced magnetic resonance (MR)imaging techniques (spectroscopy, diffusion and perfusionimaging) in diagnosing brain gliomas, with specialreference to histological typing and grading, treatmentplanning and posttreatment follow-up. Conventional MRimaging enables the detection and localisation of neoplasticlesions, as well as providing, in typical cases, someindication about their nature. However, it has limitedsensitivity and specificity in evaluating histological typeand grade, delineating margins and differentiating oedema,tumour and treatment side-effects. These limitations can beovercome by supplementing the morphological dataobtained with conventional MR imaging with themetabolic, structural and perfusional information providedby new MR techniques that are increasingly becoming anintegral part of routine MR studies. Incorporation of suchnew MR techniques can lead to more comprehensive andprecise diagnoses that can better assist surgeons indetermining prognosis and planning treatment strategies. Inaddition, the recent development of new, more effective,treatments for cerebral glioma strongly relies onmorphofunctional MR imaging with its ability to provide abiological interpretation of these characteristicallyheterogeneous tumours.

Brain atrophy evolution and lesion load accrual in multiple sclerosis: a 2-year follow-up study

Background To investigate in a large cohort of patients with multiple sclerosis (MS), lesion load and atrophy evolution, and the relationship between clinical and magnetic resonance imaging (MRI) correlates of disease progression. Methods Two hundred and sixty-seven patients with MS were studied at baseline and two years later using the same MRI protocol. Abnormal white matter fraction, normal appearing white matter fraction, global white matter fraction, gray matter fraction and whole brain fraction, T2-hyperintense, and T1-hypointense lesions were measured at both time points. Results The majority of patients were clinically stable, whereas MRI-derived brain tissue fractions were significantly different after 2 years. The correlation between MRI data at baseline and their variation during the follow-up showed that lower basal gray matter atrophy was significantly related with higher progression of gray matter atrophy during follow-up. The correlation between MRI parameters and disease duration showed that gray matter atrophy rate decreased with increasing disease duration, whereas the rate of white matter atrophy had a constant pattern. Lower basal gray matter atrophy was associated with increased probability of developing gray matter atrophy at follow-up, whereas gray matter atrophy progression over 2 years and new T2 lesion load were risk factors for whole brain atrophy progression. Conclusions In MS, brain atrophy occurs even after a relatively short period of time and in patients with limited progression of disability. Short-term brain atrophy progression rates differ across tissue compartments, as gray matter atrophy results more pronounced than white matter atrophy and appears to be a early phenomenon in the MS-related disease progression.

Does abnormal neuronal excitability exist in myotonic dystrophy? II. Effects of the antiarrhythmic drug hydroquinidine on apathy and hypersomnia

Abstract An abnormal neuronal excitability in myotonic dystrophy (MD) might contribute to psychomotor and beharioral disturbances of MD patients. To gain new insights into the pathophysiology of MD, we determined whether the antiarrhythmic drug hydroquinidine could amenorate apathy and hypersomnia besides slow saccadic eye movements in these patients. The study was conducted in a randomized, plazebo-controlled, double-blind, crossover manner. Ten ambulatory patients without contraindications to hydroquinidine administration were enrolled. Hydroquinidine (450 mg/day) or placebo was given orally for 6 weeks with a washout period of 6 weeks between treatments. Apathy was evaluated by means of the apathy evaluation scale (AES) and hypersomnia by a sleep diary. Two patients withdrew in the first week of active treatment because of nausea and epigastralgia. The drug significantly reduced AES scores and daily sleep time compared to placebo. Thus, hydroquinidine can ameliorate apathy and hypersomnia in MD. However, the possibility of proarrhythmia and the high frequency of cardiac disturbances in MD seriously limit the therapeutic perspective. The effects on eye movements are presented in a companion paper.

Intranasal Versus Intravenous Neostigmine in Myasthenia Gravis: Assessment by Computer Analysis of Saccadic Eye Movements

Summary: Intranasal (i.n.) neostigmine has been developed to obtain a quicker onset of action and a more adaptable dosage regimen than oral neostigmine. The effect of this neostigmine formulation in myasthenia gravis (MG) was studied by means of computer analysis of saccadic eye movements (SEMs). Six MG patients were selected on the basis of a positive effect of Tensilon on hypometria of the first saccade. The effect of the i.v. formulation (0.5 mg) was compared to 1, 2, 3, and 4 puffs of i.n. neostigmine (one puff = 4.6 mg). The drug effect on SEMs was monitored at intervals up to 2 h. Administration of i.v. neostigmine produced a marked effect immediately after the injection and the benefit lasted over 1 h. Following administration of i.n. neostigmine a marked effect was found for two, three, and four puffs. The drug effect was evident within 3 min, peaked at 18–33 min, and lasted over 2 h. Our data indicate the efficacy of the new formulation of neostigmine in MG as measured by means of quantitative analysis of SEMs.

Treatment of multiple sclerosis with interferon beta in clinical practice: 2-year follow-up data from the South Italy Mobile MRI Project

This follow-up study assessed the 2-year clinical and magnetic resonance imaging (MRI) outcomes of patients with multiple sclerosis (MS) originally enrolled in an MRI study conducted at eight centres in south Italy (the South Italy Mobile MRI Project). Of the 597 MS patients recruited at baseline, 391 returned for the follow-up study. Of these, 363 provided 2-year clinical and MRI follow-up data, and 215 were still undergoing treatment with one of four interferon beta regimens: Avonex, 30 mcg intramuscularly once weekly; Betaferon, 250 mcg subcutaneously (sc) every other day; Rebif 22 mcg sc three times weekly (tiw; Rebif 22); or Rebif 44 mcg sc tiw (Rebif 44). Over the 2-year follow-up period, patients receiving the higher dose of Rebif were more likely to remain free from relapses [odds ratio (OR) = 2.23] and from developing both new T2 (OR = 0.15) and new T1 black hole lesions (OR = 0.22), when compared with patients in the Avonex group. Despite some limitations in the trial design, the results from this follow-up study provide helpful clinical and MRI data on the efficacy of interferon beta regimens in MS patients treated in the clinical setting.

Does abnormal neuronal excitability exist in myotonic dystrophy? I. Effects of the antiarrhythmic drug hydroquinidine on slow saccadic eye movements

Abstract The abnormal neuronal excitability hypothesized in myotonic dystrophy (MD) might contribute to psychomotor and behavioral disturbances of MD patients. To gain new insights into the pathophysiology of MD, we determined whether the antiarrhythmic drug hydroquinidine would ameliorate slow saccadic eye movements (SEMs), apathy and hypersomnia in MD patients. SEMs were selected as simple modality for psychomotor investigation. The study was conducted in a randomized placebo-controlled, double-blind, crossover manner. Ten ambulatory patients without contraindications to hydroquinidine administration were enrolled. Hydroquinidine (450 mg/day) or placebo was given orally for 6 weeks with a washout period of 6 weeks between treatments. SEMs were recorded by electrooculography and analyzed by a computer system. Two patients withdrew in the first week of active treatment because of nausea and epigastralgia. Hydroquinidine significantly increased the normalized peak saccadic velocity and shortened the saccadic reaction time compared to placebo. The drugs effects on apathy and hypersomnia are presented in a companion paper.

Central action of cinnarizine and flunarizine: a saccadic eye movement study.

The mechanism of action of flunarizine (FZ) and cinnarizine (CZ) on the CNS is not fully understood. Computer analysis of saccadic eye movements (SEM) provides a sensitive and objective method for evaluating drug effect on the function of specific brain structures. This study aimed to assess the effect of a single oral dose of FZ (20 mg) and CZ (150 mg) on CNS function by means of computer analysis of SEM. Ten healthy volunteers were studied according to a double-blind, cross-over, placebo-controlled design. Peak saccadic velocity (PSV), which is related to the function of a specific group of burst neurons located in the brain stem, was significantly reduced by FZ. No significant effect of FZ on saccade accuracy (SA) and saccade latency (SL) was found. CZ did not produce significant effects on SEM, but a trend to decrease PSV. The possibility that a FZ central effect may be related to a stabilizing action on burst activity of neurons is discussed.