Marino Zorzon

A longitudinal study of brain atrophy and cognitive disturbances in the early phase of relapsing-remitting multiple sclerosis

OBJECTIVE (a) To establish whether the cognitive decline of the early phase of relapsing-remitting multiple sclerosis depends on the progression of the burden of disease, or on the loss of brain parenchyma, or is influenced by both; (b) to monitor the loss of brain parenchyma in the early phase of the disease; and (c) to examine its possible relation with the progression of physical disability. METHODS For 2 years 53 patients with clinically definite relapsing-remitting multiple sclerosis with disease duration 1–5 years and expanded disability status scale⩽5.0 at baseline were monitored. The neuropsychological performances, the psychological functioning, the neurological impairment, and the disability have been assessed at baseline and after 2 years. Patients also underwent PD/T2 and T1 weighted brain MRI. T2 and T1 lesion volumes were measured by a semiautomatic technique. Quantification of brain parenchymal volumes was obtained using a highly reproducible computerised interactive program. The relation between cognitive impairment and MRI findings has been investigated by partial correlation and stepwise multiple regression analyses excluding the effects of age, education, anxiety, depression, and total days of steroid use. RESULTS In the 2 years of the study the mean change for T2 and T1 lesion volumes and brain parenchymal volumes were +1.7 ml (95% confidence interval (95% CI) 1.3–2.2, p=0.005, (29.8%); +0.2 ml, 95% CI 0.15–0.26, p=0.004, (25%); and –32.3 ml, 95% CI 24.2–42.3, p<0.0001, (2.7%), respectively. Overall, 14 patients (26.4%) were judged to be cognitively impaired at baseline and 28 (52.8%) at the end of the follow up. Of the 18 neuropsychological tests and subtests employed in the study, patients with multiple sclerosis failed 5.8 (SD 2.3) tests at the baseline and 8.4 (SD 2.9) (p<0.0001) tests at the end of the study. When the cognitive changes were examined in individual patients, five (9.4%) of them were considered cognitively improved, 33 (62.3%) remained stable, and 15 (28.3%) worsened over 2 years. T2 and T1 volume changes in improved, stable, and worsened patients did not show any significant difference, whereas brain parenchymal volume decrease in cognitively worsened patients was significantly greater (−66 ml (5.4%), 95% CI 37–108.9, p=0.0031). The cognitive impairment was independently predicted over 2 years only by the change of brain parenchymal volumes (R=0.51, p=0.0003). Ten patients (18.9%), who worsened by one or more points in the EDSS during the follow up period had significant decreases in brain parenchymal volumes (−99 ml (8%), 95% CI 47.6–182.3, p=0.005). At the end of the study the loss of brain parenchyma correlated significantly with change in EDSS (r= 0.59, p<0.0001). CONCLUSIONS In the early phase of relapsing-remitting multiple sclerosis the cognitive deterioration relies more on the development of brain parenchymal volume atrophy than on the extent of burden of disease in the brain. The loss of brain parenchymal volume underlies the progressive accumulation of physical disability from the initial phase of the disease, which becomes more demonstrable only if studied with longer observation periods. Probably, the main pathological substrate of brain atrophy in the early stage of the disease is early axonal loss, which causes the progression of neurological deficits and the development of cognitive impairment. These data support the debated opinion that disease modifying therapy should be initiated as early as possible.

Effects of IV methylprednisolone on brain atrophy in relapsing-remitting MS

Background: IV methylprednisolone (IVMP) has been used to treat relapses in patients with relapsing-remitting (RR) MS, but its effect on disease progression is not known. Furthermore, there are no data on the impact of IVMP on T1 black holes or whole-brain atrophy. Objective: To determine the effect of IVMP on MRI measures of the destructive pathology in patients with RR-MS and secondarily to determine the effect of IVMP on disability progression in patients with RR-MS. Methods: The authors conducted a randomized, controlled, single-blind, phase II clinical trial of IVMP in patients with RR-MS. Eighty-eight patients with RR-MS with baseline Expanded Disability Status Scale (EDSS) scores of ≤5.5 were randomly assigned to regular pulses of IVMP (1 g/day for 5 days with an oral prednisone taper) or IVMP at the same dose schedule only for relapses (IVMP for relapses) and followed without other disease-modifying drug therapy for 5 years. Pulsed IVMP was given every 4 months for 3 years and then every 6 months for the subsequent 2 years. Patients had quantitative cranial MRI scans at study entry and after 5 years and standardized clinical assessments every 4 to 6 months. Results: Eighty-one of 88 patients completed the trial as planned, and treatment was well tolerated. Baseline demographic, clinical, and MRI measures were well matched in the two study arms. Patients on the pulsed IVMP arm received more MP than patients on the control arm of the study (p < 0.0001). Mean change in T1 black hole volume favored pulsed IVMP therapy (+1.3 vs +5.2 mL; p < 0.0001), as did mean change in brain parenchymal volume (+2.6 vs −74.5 mL; p = 0.003). There was no significant difference between treatment arms in the change in T2 volume or annual relapse rate during the study. However, there was significantly more EDSS score worsening in the control group, receiving IVMP only for relapses. There was a 32.2% reduction (p ≤ 0.0001) in the probability of sustained EDSS score worsening in the pulsed MP arm compared with the relapse treatment arm. At the end of the study, EDSS was better in the pulsed MP group (1.7 vs 3.4; p < 0.0001). Prolonged treatment with pulsed IVMP was safe and well tolerated; only two patients dropped out for toxic side effects over 5 years. Conclusions: In patients with RR-MS, treatment with pulses of IVMP slows development of T1 black holes, prevents or delays whole-brain atrophy, and prevents or delays disability progression. A phase III study of IVMP pulses is warranted.

Sexual dysfunction in multiple sclerosis: a case-control study. I. Frequency and comparison of groups.

Sexual dysfunction is a very important but often overlooked symptom of multiple sclerosis. To investigate the type and frequency of symptoms of sexual dysfunction in patient suffering from multiple sclerosis, we performed a case-control study comparing 108 unselected patient with definite multiple sclerosis, 97 patient with chronic disease and 1 10 healthy individuals with regard to sexual function, sphincteric function, physical disorders impeding sexual activity and the impact of sexual dysfunction on social life. Information has been collected from a face-to-face structured interview performed by a doctor of the same gender as the patient. The disability, the cognitive performances, the psychiatric conditions and the psychological profile of patien t a nd co ntrols have bee n assessed. Sexul a dysfu nction was prese nt in 73.1% of cases, in 39.2% of chronic disease co ntrols and in 12.7% of h e althy co ntrols (P < 0.000 1). Male cases reported symptoms of sexual dysfunction more freq ue ntly th an female cases (P <0.002). Symptoms of sexual dysfunction more commonly reported in patient with multiple scerosis were anorgasmia or hyporgasmia (37.1%), decreased vaginal lubrication (35.7%) and reduced libido (31.4%) in women, and impotence or erectile dysfunction (63.2%), ejaculatory dysfunction and/or orgasmic dysfunction (50%) and reduced libido (39.5%) in men. Seventy-five per cent of cases, 51.% of chronic disease controls and 28.2% of healthy controls (P <0.0001) experienced symptoms of sphincteric dysfunction. In conldusion, a substantial part of our sample of patient with multiple sclerosis reported symptoms of sexual and sphincteric dysfunction. Both sexual and sphincteric dysfunction were significantly more common in patient with multiple sclerosis than in either control group. Our findings suggest that a peculiar damage of the structures involved in sexual function is responsible for the dysfunction in patient with multiple scerosis, but the highly significant lower frequency of symptoms of depression and anxiety in healthy controls may also imply a possible causative role of psychological factors.

Depression and anxiety in multiple sclerosis. A clinical and MRI study in 95 subjects

Abstract The aim of the present study was to investigate the relationship between involvement of specific areas of the brain and the occurrence of depression and anxiety in patients with multiple sclerosis. We studied 95 patients (62 women and 33 men, mean age 39.5 years, SD 11.2) with definite MS, 97 patients (65 women and 32 men, mean age 40.7, SD 11.9) suffering from chronic rheumatoid diseases and 110 healthy subjects (71 women and 39 men, mean age 40.1, SD 12.7). The disability, the independence, the cognitive performances, the depressive and anxiety symptoms were assessed. The diagnosis of major depression was made according to the DSM-IV. The patients with multiple sclerosis underwent a 1.5 Tesla magnetic resonance examination including T1 and T2 weighted images. Calculation of regional and total lesion loads and brain volumes were performed. The number (%) of subjects with a diagnosis of major depression was 18 (18.9) among MS cases, 16 (16.5) among controls with chronic disease (p=NS), and 4 (3.6) among healthy volunteers (p < 0.0001). The Hamilton Depression and Anxiety rating scales median scores were 5 and 18, respectively in the MS patients, 5 (p= NS) and 14 (p= NS) in the chronic rheumatoid diseases controls, and 3 (p= < 0.0001) and 6 (p= < 0.0001) in the healthy controls. Both severity of depressive symptoms and diagnosis of major depression correlated, albeit weakly, with right frontal lesion load (r=0.22, p=0.035, and r=0.23, p=0.026, respectively) and right temporal brain volume (r=0.22, p=0.005 and r=0.22, p=0.036, respectively). The severity of depression was related significantly also with total temporal brain volume (r=0.26, p=0.012), right hemisphere brain volume (r=0.25, p=0.015), disability (r=0.30, p=0.003) and independence of MS cases (r=−0.26, p=0.01). The anxiety did not correlate significantly with any of the measures of regional and total lesion loads and brain volume or with any of the considered clinical variables. The similar frequency of depression and severity of depressive symptoms in MS patients and in chronic disease patients, the significant difference in this respect with the normal controls, and the significant correlation between depression and the disability measures would suggest a psychological reaction to the impact of the disease but the relationship between depression and the alterations in the frontal and temporal lobes of the right hemisphere supports, on the contrary, the causative role of organic brain damage. The lack of any significant association between symptoms of anxiety and either MRI abnormalities or clinical variables led us to the opinion that anxiety is a reactive response to the psychosocial pressure put on the patients.

Gaucher’s disease with Parkinson’s disease Clinical and pathological aspects

The association between type 1 Gaucher disease and PD has been reported in the literature. The clinical picture is characterized by the predominance of bilateral akinetic-rigid signs and poor response to levodopa therapy. The authors describe four patients (two siblings) with type 1 Gaucher disease presenting with the following signs of typical PD: asymmetric onset of rigidity, resting tremor, bradykinesia, and a favorable response to Parkinson therapies.

Transient Global Amnesia and Transient Ischemic Attack Natural History, Vascular Risk Factors, and Associated Conditions

BACKGROUND AND PURPOSE The purpose of the present study was to make an attempt to ascertain the etiology of transient global amnesia (TGA), which is still disputed more than 30 years after the first description of this clinical entity. METHODS In a case-control study, we compared the prevalence of vascular risk factors in 64 TGA patients with 64 first-ever transient ischemic attack (TIA) control subjects and 108 normal community-based control subjects matched for age and sex. We prospectively studied the vascular events and mortality rates of the TGA cases and of the TIA control subjects. Then we compared the outcome of the two groups using actuarial analysis based on survival curves. RESULTS We did not find evidence of an increased risk of TGA associated with any vascular risk factor. In contrast to TIA control subjects, no TGA patient suffered stroke, myocardial infarction, or TIA during the follow-up period. Migraine was more common in TGA patients than in both normal and TIA control subjects. In three patients (4.5%), the TGA was eventually considered to be of epileptic origin. CONCLUSIONS The results of our case-control and longitudinal studies point to the conclusion that TGA and TIA do not share the same etiology. Since half of our patients had a precipitating event in their history, it is reasonable to hypothesize that spreading depression may play a role in TGA. The significant positive association between migraine and TGA may support this hypothesis. Epilepsy may mimic TGA in a minority of cases.

Migraine and tension-type headache in Croatia : A population-based survey of precipitating factors

The careful monitoring of the trigger factors of headache could be an important step in treatment, because their avoidance may lessen the frequency and severity of attacks. Furthermore, they may provide a clue to the aetiology of headache. The aim of the present study was to estimate the prevalence of tension-type headache (TTH) and to establish the frequency of precipitating factors in subjects with migraine and TTH in the adult population of Bakar, County of the Coast and Gorski Kotar, Croatia. Another important purpose of the study was to examine the relationship of the precipitating factors with migraine and TTH, and with migraine subtypes: migraine with aura (MA) and migraine without aura (MO). We performed a population-based survey using a ‘face-to-face door-to-door’ interview method. The surveyed population consisted of 5173 residents aged between 15 and 65 years. The 3794 participants (73.3%) were screened for headache history according to the International Headache Society (IHS) criteria. Headache screen-positive responders, 2475 (65.2%), were interviewed by trained medical students with a structured detailed interview focused on the precipitating factors. The following precipitating factors in lifetime migraineurs and tension-type headachers have been assessed: stress, sleep disturbances, eating habits, menstrual cycle, oral contraceptives, food items, afferent stimulation, changes in weather conditions and temperature, frequent travelling and physical activity. A total of 720 lifetime migraineurs and 1319 tension-type headachers have been identified. The most common precipitants for both migraine and TTH were stress and frequent travelling. Stress (odds ratio (OR) 1.4, 95% confidence interval (CI) 1.17, 1.69) was associated with migraine, whereas physical activity (OR 0.72, 95% CI 0.59, 0.87) was related to TTH. Considering MA and MO, frequent travelling (OR 2.2, 95% CI 1.59, 2.99), food items (OR 2.2, 95% CI 1.35, 3.51) and changes in weather conditions and temperature (OR 1.75, 95% CI 1.27, 2.41) exhibited a significant positive association with MA. The present study demonstrated that precipitant-dependent attacks are frequent among both migraineurs and tensiontype headachers. Lifetime migraineurs experienced headache attacks preceded by triggering factors more frequently than tension-type headachers. MA was more frequently associated with precipitating factors than MO. We suggest that some triggering factors may contribute to the higher occurrence of precipitant-dependent headache attacks in susceptible individuals.

MRI techniques and cognitive impairment in the early phase of relapsing-remitting multiple sclerosis.

Abstract Correlation studies between various conventional and non-conventional MRI parameters and cognitive impairment in the early stages of multiple sclerosis (MS) are lacking, although it is known that a number of patients with early MS have mild cognitive impairment. Our aim was to explore whether this cognitive impairment is dependent on the extent and severity of the burden of disease, diffuse microscopic brain damage or both. We studied 63 patients with clinically definite relapsing-remitting (RR) MS, duration of disease 1–10 years and Expanded disability status scale scores ≤ 5.0. Mean age was 35.4 years, mean duration of disease 5.8 years and median EDSS score 1.5. Neuropsychological performance, psychological function, neurological impairment and disability were assessed. The patients also underwent MRI, including magnetisation-transfer (MT) studies. We quantified the lesion load on T2- and T1-weighted images, the magnetisation transfer ratio (MTR) of normal-appearing brain tissue (NABT) and the brain parenchymal fraction (BPF). No significant difference was found between lesion loads in patients with and without cognitive impairment. In 15 patients (23.8 %) with overall cognitive impairment, median BPF and average NABT MTR were significantly lower than those in patients without cognitive impairment (0.868 vs 0.892, P = 0.02 and 28.3 vs 29.7 P = 0.046, respectively). Multiple regression analysis models demonstrated that the only variables independently correlated with cognitive impairment were: BPF (R = 0.89, P = 0.001) and average NABT MTR (R = 0.76, P = 0.012). Our findings support the hypothesis that, cognitive decline in patients with MS, a low disability score and short duration of disease is directly associated with the extent and severity of diffuse brain damage. The loss of brain parenchyma did not correlate with the severity of microscopic damage in the NABT, indicating that the two processes could be distinct in the early stages of the disease.

Familial and environmental risk factors in Parkinson's disease: a case-control study in north-east Italy.

Background and objective– The aetiology of Parkinsons disease remains unknown, although both genetic susceptibility and environmental factors are considered putative contributors to its origin. We performed a case–control study to investigate the association of familial and environmental risk factors with Parkinsons disease (PD). Methods– We studied 136 patients with neurologist confirmed PD and 272 age‐ and sex‐matched controls, affected by neurological diseases not related to PD. The risk of developing idiopathic PD associated with the following familial and environmental factors: positive family history of PD, positive family history of essential tremor (ET), age of mother at subjects birth, rural birth, rural living, well water use, farming as an occupation, exposure to pesticides, head tremor, exposure to general anaesthesia and to ionizing radiations, food restriction, concentration camp imprisonment and smoking has been assessed by using univariate and multivariate statistical techniques. Results– In the conditional multiple logistic regression analysis, positive family history of PD (OR 41.7, 95% CI 12.2–142.5, P < 0.0001), positive family history of ET (OR 10.8, 95% CI 2.6–43.7, P < 0.0001), age of mother at subjects birth (OR 2.6, 95% CI 1.4–3.7, P=0.0013), exposure to general anaesthesia (OR 2.2, 95% CI 1.3–3.8, P=0.0024), farming as an occupation (OR 7.7, 95% CI 1.4–44.1, P=0.0212) and well water use (OR 2.0, 95% CI 1.1–3.6, P=0.0308) exhibited a significant positive association with PD, whereas smoking showed a trend toward an inverse relationship with PD (OR 0.7, 95% CI 0.4–1.1, P < 0.06). Conclusions– We conclude that both familial and environmental factors may contribute to PD aetiology.

The use of standardized incidence and prevalence rates in epidemiological studies on multiple sclerosis. A meta-analysis study.

Objective: To demonstrate whether or not the age and sex adjustment of incidence and prevalence rates in multiple sclerosis (MS) could allow more reliable comparison between epidemiological studies performed in different areas of the world and to establish if the latitude gradient theory could be confirmed after the standardization for age and sex distribution. Methods: A meta-analysis of population-based incidence and prevalence studies on MS from 1980 through 1998 using the terms ‘multiple sclerosis’, ‘prevalence’ and ‘incidence’ in the bibliographic databases MEDLINE and EMBASE was performed. We included studies that reported the diagnostic criteria, number of cases and the population studied, the date of the study, the latitude, and the age- and sex-specific crude incidence and prevalence rates. According to the inclusion criteria, 69 of 127 papers on prevalence and 22 of 70 papers on incidence were considered for age adjustment and 27 prevalence and 8 incidence studies for sex adjustment. The mean incidence and prevalencerates and the 95% confidence intervals age- and sex-adjusted to the World and the European standard populations were calculated. Results: The Spearman rank correlation and the multiple regression analyses indicated that age adjustment to standard populations could overcome the limitations in comparing the crude prevalence and incidence rates of different epidemiological studies on MS. When the mean crude and age- and sex-adjusted prevalence and age-adjusted incidence rates were stratified by latitude (from south to north), the latitudinal gradient, which was highly significant for the crude rates, became less remarkable for the age- and sex-adjusted prevalence rates and not significant for the age-adjusted incidence rates. Conclusions: The crude incidence and prevalence rates in epidemiological studies on MS should be age- and sex-adjusted to a common standard population to permit a more reliable comparison among studies performed in different countries. Our findings support the opinion that the latitude does not play a key role in determining the onset of MS. Whenever possible, the crude incidence and prevalence rates should be adjusted to the ethnic origin and migration characteristics.