Epidemiology and geographical variation of myasthenia gravis in the province of Pavia, Italy.

BACKGROUND AND AIMS: Previous studies have reported a prevalence estimate of myasthenia gravis (MG) from 7.7 to 11.1 per 100,000 inhabitants in Europe. Moreover, the study of the geographical distribution of MG should be useful to generate specific hypotheses. The aims are to estimate MG prevalence and to investigate its geographical variation in a delimited area in Northern Italy. METHODS: The primary source of data was the MG database of the Neurological Institute of Pavia and all other sources of case collection in and outside the province. We adopted a Bayesian approach to analyze MG geographical variation within the finest geographical grid. RESULTS: We identified 119 live MG prevalent cases resident in the province of Pavia on December 31, 2008. The overall crude prevalence was 24 per 100,000 inhabitants. The Bayesian analysis identified a small cluster of higher MG prevalence in the northern area of the province. CONCLUSIONS: The estimated MG prevalence sets the province of Pavia among the high-risk areas. The identification of high/low MG risk areas deserves further investigation of genetic and environmental factors possibly related to a major risk of the disease in that area.

Inverse relationship between multiple sclerosis and allergic respiratory diseases.

Th1 up-regulation seems to favour autoimmunity, while Th2 up-regulation seems to favour humoral immunity. Accordingly, subjects affected by atopic diseases (such as allergic respiratory diseases, ARDs) should be less prone to autoimmune diseases (such as multiple sclerosis, MS), and vice versa. The recent identification of Th17 cells, which seem to favour the development of both autoimmunity and allergy, led to the revision of the classic Th1/Th2 paradigm. We studied 200 MS patients and 200 controls to analyze the relationships between ARDs and MS. MS patients had less probability to suffer from ARDs (OR = 0.30, p < 0.001) and allergic rhinitis (OR = 0.25, p < 0.001), after adjusting for environmental factors. MS tended to be less severe when associated to ARDs. Our findings add some elements for the comprehension of immune mechanisms involved in MS pathogenesis and suggest to analyze other MS cohorts, in order to evaluate if MS patients affected by allergic diseases show particular clinical findings.

Early prediction of the long term evolution of multiple sclerosis: the Bayesian Risk Estimate for Multiple Sclerosis (BREMS) score.

AIM: To propose a simple tool for early prediction of unfavourable long term evolution of multiple sclerosis (MS). METHODS: A Bayesian model allowed us to calculate, within the first year of disease and for each patient, the Bayesian Risk Estimate for MS (BREMS) score that represents the risk of reaching secondary progression (SP). RESULTS: The median BREMS scores were higher in 158 patients who reached SP within 10 years compared with 1087 progression free patients (0.69 vs 0.30; p<0.0001). The BREMS value was related to SP risk in the whole cohort (p<0.0001) and in the subgroup of 535 patients who had never been treated with immune therapies, thus reasonably representing the natural history of the disease (p<0.000001). CONCLUSIONS: The BREMS score may be useful both to identify patients who are candidates for early or for more aggressive therapies and to improve the design and analysis of clinical therapeutic trials and of observational studies.

The N3 potential compared to sound and galvanic vestibular evoked myogenic potential in healthy subjects and in multiple sclerosis patients.

Both sound (s-) and galvanic (g-) vestibular-evoked myogenic potential (VEMP) enable us to study the saccular pathways. However, the VEMP can be abnormal for non-vestibular factors, such as insufficient activation of the sterno-cleido-mastoid (SCM) muscle or a lesion that involves the accessory nucleus and/or nerve or the SCM muscle. These drawbacks do not affect another technique that evaluates the saccular function: the N3 potential. We recorded both the s- and the g-VEMP and the N3 potential in a group of 31 healthy subjects to establish a reference range. The N3 potential and the s-VEMP were recordable bilaterally from all the subjects, whereas the g-VEMP was undetectable uni- or bilaterally in 7 subjects. The latency and amplitude values of the s-VEMP did not differ from those of the g-VEMP. For all three techniques, the latency and amplitude values from the right and from the left recording and/or stimulation side were the same. We suggest using normative latency and amplitude values based on the mean and ratio of the right- and left-side values. The s-VEMP, the N3 potential and the auditory evoked response (ABR) were compared in 15 subjects suffering from multiple sclerosis. The three techniques detected a similar number of abnormalities, but these abnormalities were not correlated. This suggests that these different techniques should be regarded as complementary in evaluating saccular function.

Brain white matter impairment in congenital adrenal hyperplasia.

BACKGROUND: Congenital adrenal hyperplasia (CAH) is an inherited recessive disorder of adrenal steroidogenesis. Past reports suggested that brain white matter could be involved in CAH. OBJECTIVE: To detect the presence, and possible changes over time, of brain white matter abnormalities in patients with CAH. DESIGN: Neurological examination and brain magnetic resonance imaging (MRI) that were repeated in 12 patients after a mean interval of 11 years. SETTING: Pavia, northern Italy. Patients Twenty-two patients with CAH. MAIN OUTCOME MEASURES: Evaluation of clinical neurological findings and brain MRI T2-weighted images. RESULTS: Ten (45%) of 22 patients with CAH had white matter abnormalities (diffuse in 4 cases, focal in 3 cases, and both diffuse and focal in 3 cases) on MRI. The MRI findings never changed over repeated assessments. CONCLUSIONS: Subclinical brain white matter involvement is frequent in CAH. This might be due to hormonal imbalance during brain development or corticosteroid treatments. Our study findings indicate that a relationship with demyelinating diseases can also be suggested. Diagnosis of CAH should be suspected in young subjects with brain MRI white matter abnormalities that are not otherwise explicable.

Binocular control of saccades in idiopathic Parkinson's disease.

We focused on the saccade disconjugate control in idiopathic Parkinson's disease patients. Our data showed that in IPD patients the saccade precision was differently impaired in the two eyes--namely, the disconjugate component was larger than in controls--more for the remembered than for the reflexive task.

Congenital adrenal hyperplasia and multiple sclerosis: is there an increased risk of multiple sclerosis in individuals with congenital adrenal hyperplasia?

BACKGROUND: Congenital adrenal hyperplasia (CAH) is an inherited recessive disorder of adrenal steroidogenesis, generally caused by a total or partial deficiency in 21-hydroxylase, due to a deletion of or mutations in the CYP21 gene (the gene that codes for 21-hydroxylase). Impaired cortisol biosynthesis results in corticotropin hypersecretion, which leads to overproduction of intermediate metabolites and androgens. OBJECTIVE: To describe for the first time, to our knowledge, a patient with CAH and multiple sclerosis (MS). DESIGN: Case report. PATIENT: A 22-year-old woman, diagnosed at birth as having a salt-losing 21-hydroxylase deficiency, had sudden visual loss in the right eye and pyramidal, sensory, and cerebellar signs. Repeated brain magnetic resonance images showed focal white matter lesions in periventricular areas, the corpus callosum, the cerebellum, and the brainstem. A cerebrospinal fluid examination revealed several oligoclonal bands. Thereafter, she had 2 relapses, characterized by ataxia and diplopia, and recovered after corticosteroid treatment. RESULTS: The reported case fulfills the diagnostic criteria for CAH and MS. CONCLUSIONS: Some clues suggest that the association between CAH and MS could be nonincidental: a possible MS susceptibility locus is on chromosome 6p21, on which the CYP21 gene is located; the CYP21 gene and the CYP21P pseudogene alternate in tandem with the C4 genes (the genes that code for the homonym complement protein) (C4AQ0 is particularly frequent in patients with relapsing-remitting MS); and, in previous studies, brain magnetic resonance imaging showed T2-hyperintense focal areas in the white matter of CAH patients. Our observation should alert neurologists to the presence of signs and symptoms suggestive of late-onset CAH in MS patients and, in turn, endocrinologists to the appearance of neurological signs and symptoms in CAH patients.

IL-1 genes in myasthenia gravis: IL-1A -889 polymorphism associated with sex and age of disease onset.

Myasthenia gravis (MG) is a multifactorial autoimmune disease of the neuromuscular junction. We investigated the relation between four polymorphisms of the interleukin (IL)-1 gene cluster on 2q12-22, and MG susceptibility and clinical features in a large cohort of individuals. No polymorphism was associated with MG susceptibility. However, the IL-1A -889 CC genotype was associated with early disease onset (p=0.0044) in the whole MG group and the subgroup of CC males developed MG about 18 years earlier than males carrying other IL-1A -889 genotypes (p=0.022). This finding suggests that IL-1A is a disease modifier in MG, or is in linkage disequilibrium with an unknown locus on chromosome 2.

The effects of collinearity and orientation on texture visual evoked potentials.

OBJECTIVE: The aim of the research was to study the effects of stimulus orientation at both the local (textons) and the global (segregated elements) level on texture visual evoked potentials (tVEPs). METHODS: Two tVEP paradigms were presented to 10 volunteers. The paradigms were characterized by alternating uniform textures (random mixture of square dots and lines) and textures in which stripes of randomly disposed lines segregated from a square dots' background. In one paradigm, the stripes were horizontal and in the other, vertical. The lines could be either horizontal or vertical in single stimuli of both paradigms. Thus, two stimuli with local/global collinearity and two stimuli without local/global collinearity were available. tVEPs were derived from Oz referenced to the left earlobe and averaged separately for each condition. Segregation-related components were obtained subtracting the traces without segregation from the traces with segregation. RESULTS: A negative segregation component starting at the latency of P1 and extending until the end of N2 characterized the tVEPs, without significant differences among the 4 stimulus conditions. In the presence of local/global collinearity, we found an early modulation of N1 amplitude. This modulation was orientation-dependent, as vertical collinearity increased N1 negativity and horizontal collinearity reduced N1 negativity. CONCLUSIONS: Our experiment confirms previous findings about the segregation negativity, which may depend on contextual modulation of V1 neurons by long-range horizontal and feed-back connections. The early effect of collinearity may depend on more local modulatory connections.

Vestibular evoked myogenic potentials in multiple sclerosis patients.

OBJECTIVES: Vestibular evoked myogenic potentials (VEMPs) are saccular responses to loud acoustic stimuli and are recordable from the sterno-cleido-mastoid muscle ipsilaterally to the stimulated ear. This study aimed to investigate VEMPs in patients suffering from multiple sclerosis (MS), and to compare these findings with both clinical and instrumental data. METHODS: We recorded VEMPs from 70 MS patients, whose clinical data were retrospectively evaluated for the possible occurrence of: past and current (with respect to VEMP recording) brainstem and/or cerebellar symptoms; current brainstem and/or cerebellar signs. Sixty-five patients underwent brainstem auditory evoked potentials (BAEPs) recording; 63 of the same patients underwent saccadic eye movement recording and subjective visual vertical (SVV) evaluation. RESULTS: VEMPs were abnormal in 31%, BAEPs in 38% and SVV in 21% of the patients. Saccadic eye movements showed a possible brainstem dysfunction in 44.4% of the patients. There was no correlation between the occurrence of abnormalities and the technical means of detection. The same held true for correlations with clinical data, with the exception of the BAEPs; these proved to be more frequently abnormal in patients presenting at neurological examination with brainstem and/or cerebellar signs that were possibly related to the complaint of dizziness. CONCLUSIONS: VEMPs should be considered a useful complementary neurophysiological tool for the evaluation of brainstem dysfunction.

Caspase-1 levels in biological fluids from patients with multiple sclerosis and from patients with other neurological and non-neurological diseases.

In multiple sclerosis (MS), pathological white matter damage in the central nervous system is sustained by immune-inflammatory response. Caspase-1 plays a pivotal role in immune-mediated inflammation, as it regulates the cellular export of IL-1beta and IL-18. We carried out a preliminary in vitro study of the kinetics of extracellular caspase-1 release. We then measured caspase-1 levels in paired serum and cerebrospinal fluid (CSF) samples of 75 MS patients, 15 healthy subjects, and patients with other neurological diseases. Paired synovial fluid and serum samples of patients with juvenile idiopathic arthritis, and paired sputum and serum samples of asthma patients were also studied. Mean serum caspase-1 concentrations did not differ between groups. Caspase-1 was detected in the CSF of patients with acute, but not stable, MS [7.5 +/- (SEM) 0.9 pg/ml; test's sensitivity, 56% and specificity, 100%]. Its levels correlated with pleocytosis. The highest mean caspase-1 levels were found in the arthritic synovial fluids (945.5 +/- 126.6 pg/ml, which correlated with erythrocyte sedimentation rate), and in the sputum samples (370.1 +/- 71.0 pg/ml, which correlated with the number of macrophages in the sputum). On condition that caspase-1 is determined in the fluids pertaining to the disease-specific inflammatory sites, its level is a reliable marker of ongoing immune-inflammatory response. The enzyme measurement in CSF can also help define state-trait in MS.

A reliability study of impairment and disability scales for myasthenia gravis patients.

The authors developed two scales to be adopted for the evaluation of myasthenia gravis (MG) patients. The first scale (MG impairment scale) is based on objective patient evaluation and on patients' responses to standardized questions relating to the functioning of specific muscle groups. It consists of 13 items exploring strength and 10 items exploring fatigability. The second scale (MG disability scale) evaluates disability in those everyday activities that are often impaired in MG patients. Test-retest reliability of each item and of the global score (sum of single item scores) was assessed by the weighted K statistic and by the intraclass correlation coefficient. Reliability was invariably 'substantial', and for single items 'almost perfect' for the MG impairment scale, and invariably 'almost perfect' for the MG disability scale. The internal structure of the MG impairment scale was explored by means of the principal component analysis. This analysis resulted in three main (rotated) factors, which loaded respectively onto 'ocular', 'spinal' and 'bulbar' functions. For these factors, we report factor score coefficients that can be used to compute single patients' scores, which in turn may be used in further analyses, particularly for follow-up studies. We also report the results of an analysis of the correlations between the two scales. The MG impairment and the MG disability scales are proposed for application in both clinical and research settings.

Dizziness and migraine: a causal relationship?

Both migraine and dizziness are very frequent complaints, but the comorbidity of the two disorders is higher than it might be expected to be on the basis of chance alone. This implies a possible causal relationship, but definite diagnostic criteria for migraine-related vertigo are still lacking. Very recent attempts in this direction have shown that migraine may be the third leading cause of vertigo and that migraine-related vertigo may be effectively treated. A review of the literature on this topic, which includes some preliminary data of our own, demonstrates the difficulty in pinpointing migraine-associated vertigo as a clearly-defined entity. However, there is a measure of agreement on a few points: the spells of vertigo occur in patients who habitually suffer from motion sickness, and who have a history of migraine, either without or with aura; the delay between migraine and vertigo onset may be several years; migraine-related vertigo may be described as rotatory and/or as a feeling of unsteadiness, and single spells can occur without any other accompanying symptoms, however, when spells do occur in association with headache, they usually precede it. The vertigo duration may be shorter or longer than that of the migraine aura since it ranges from a few seconds to a continuous condition of unsteadiness.

Risk factors for tumor occurrence in patients with myasthenia gravis.

There is still uncertainty regarding risk factors for cancer occurrence in patients with myasthenia gravis (MG). The objective of this study is to determine the prevalence of extrathymic neoplasms in patients with MG and the factors associated with tumor occurrence. The archives of four tertiary MG centers were consulted and patients were interviewed on the main clinical features of the disease, the presence and type(s) of extrathymic neoplasms and other autoimmune disorders, and their symptomatic and immunosuppressant treatments (with detailed schedules). A retrospective cohort survey was undertaken comparing the demographic and clinical variables of patients with extrathymic neoplasms to those of the remaining MG population. 2,479 patients were traced and interviewed personally or through informants. The sample included 1,490 women and 989 men (mean age 54.7 years). Other autoimmune disorders were present in 216 cases (8.7%). Thymectomy was performed in 1,549 cases (62.5%), thymic hyperplasia and thymoma being the most common findings. Acetylcholinesterase-inhibitors were the most common treatment (93.5%), followed by steroids (64.3%), azathioprine (35.0%), plasma exchange (13.2%), immunoglobulins (7.5%), cyclosporine (5.3%), and cyclophosphamide (5.0%). 221 patients (8.9%) had one or more extrathymic tumors, 168 of which occurred after disease onset. Patients with and without extrathymic neoplasms were followed for 14.8 and 13.9 years, respectively. Variables shown by multivariate analysis to be associated with increased neoplastic risk included older age, thymoma and immunoglobulin use. Extrathymic tumors are a common finding in patients with MG and tend to be associated with age, thymoma, and immunoglobulin use.

Multiple memory-guided saccades: movement memory improves the accuracy of memory-guided saccades.

Memory-guided saccades (MGSs) with 3 s memorization delay were recorded in healthy subjects using four different paradigms: two "regular" MGS paradigms with the peripheral target lit for 0.2 s (MGS2) and for 1.8 s (MGS18); a multiple memory-guided saccade (MMGS) paradigm with the target lit for 1.8 s and the instruction to perform a visually guided saccade (VGS) towards it before the MGS; a trained memory-guided saccades (TMGSs) paradigm where the same target was presented so that the subjects should made 10 VGSs before the MGS. The longer target presentation interval (MGS18 paradigm) did not improve the accuracy of MGS. The execution of the VGSs improved the accuracy of the corrective saccades made after the first MGS to drive the eyes closer to the target, and this improvement was independent from the number of the VGSs (there was no difference between the MMGS and the TMGS paradigms). The VGSs provide a template that improves the capability of the corrective saccades to compensate for the residual position error at the end of the first saccade.

Quantitative diffusion weighted imaging measures in patients with multiple sclerosis.

Diffusion-weighted imaging (DWI) has been proposed as a sensitive measure of disease severity capable of detecting subtle changes in gray matter and white matter brain compartments in patients with multiple sclerosis (MS). However, DWI has been applied to the study of MS clinical subtypes in only a few studies. The objective of this study was to demonstrate the validity of a novel, fully automated method for the calculation of quantitative DWI measures. We also wanted to assess the correlation between whole brain (WB)-DWI variables and clinical and MRI measures of disease severity in a large cohort of MS patients. For this purpose we studied 432 consecutive MS patients (mean age 44.4+/-10.2 years), 16 patients with clinically isolated syndrome (CIS) and 38 normal controls (NC) using 1.5 T brain MRI. Clinical disease subtypes were as follows: 294 relapsing-remitting (RR), 123 secondary-progressive (SP) and 15 primary-progressive (PP). Mean disease duration was 12+/-10 years. Mean Expanded Disability Status Scale (EDSS) was 3.3+/-2.1. Brain parenchymal fraction (BPF), gray matter fraction (GMF) and white matter fraction (WMF) were calculated using a fully automated method. Mean parenchymal diffusivity (MPD) maps were created. DWI indices of peak position (PP), peak height (PH), MPD and entropy (ENT) were obtained. T2- and T1-lesion volumes (LV), EDSS, ambulation index (AI) and nine-hole peg test (9-HPT) were also assessed. MS patients had significantly lower BPF (d=1.26; p<0.001) and GMF (d=0.61; p=0.003), and higher ENT (d=1.2; p<0.0001), MPD (d=1.04; p<0.0001) and PH (d=0.47; p=0.045) than NC subjects. A GLM analysis, adjusted for age and multiple comparisons, revealed significant differences between different clinical subtypes for BPF, GMF, ENT, PH, PP, T2-LV and T1-LV (p<0.0001), WMF (p=0.001) and MPD (p=0.023). In RR and SP MS patients, ENT showed a more robust correlation with other MRI (r=0.54 to 0.67, p<0.0001) and clinical (r=0.31 to 0.36, p<0.0001) variables than MPD (r=0.23 to 0.41, p<0.001 for MRI and r=0.13 to 0.18; p=0.006 to p<0.001 for clinical variables). The GMF and BPF showed a slightly stronger relationship with all clinical variables (r=0.33 to 0.48; p<0.0001), when compared to both lesion and DWI measures. ENT (R2=0.28; p<0.0001) and GMF (R2=0.26; p<0.001) were best related with SP disease course. This study highlights the validity of DWI in discerning differences between NC and MS patients, as well as between different MS subtypes. ENT is a sensitive marker of overall brain damage that is strongly related to clinical impairment in patients with SP MS.

Disability and mortality in a cohort of multiple sclerosis patients: a reappraisal.

The aim of the study was to evaluate how the natural history of multiple sclerosis (MS) had changed over a 15-year period. We compared disability and mortality in a cohort of 83 MS patients hospitalised in the Neurological Institute of Pavia, northern Italy, from January 1, 1990, to December 31, 1991, with a similar cohort of 52 patients analysed in the past. After the follow-up, an unfavourable course (death or relevant disability) was observed in 41% of the patients in the new cohort, compared to 63.5% of the patients in the old one. The percentage of deceased patients was reduced from 25 to 6%. The analysis of the pooled data of the two cohorts indicates a recent tendency of firstly hospitalised patients having a shorter disease duration and a lower disability level, which could explain the relevant decrease both in mortality and disability. Finally, our findings confirmed that age at onset, early disability and a short interval between onset and secondary progression increase the risk of an unfavourable course.