ICHD-II diagnostic criteria for Tolosa-Hunt syndrome in idiopathic inflammatory syndromes of the orbit and/or the cavernous sinus.

A bibliographical search was conducted for papers published between 1999 and 2007 to verify the validity of International Classification of Headache Disorders (ICHD)-II criteria for the Tolosa-Hunt syndrome (THS) in terms of (i) the role of magnetic resonance imaging (MRI); (ii) which steroid treatment should be considered as adequate; and (iii) the response to treatment. Of 536 articles, 48, reporting on 62 patients, met the inclusion criteria. MRI was positive in 92.1% of the cases and it normalized after clinical resolution. There was no evidence of which steroid schedule should be considered as adequate; high-dose steroids are likely to be more effective both to induce resolution and to avoid recurrences. Pain subsided within the time limit required by the ICHD-II criteria, but signs did not. We conclude that THS diagnostic criteria can be improved on the basis of currently available data. MRI should play a pivotal role both to diagnose and to follow-up THS.

The DYMUS questionnaire for the assessment of dysphagia in multiple sclerosis.

Swallowing problems can be relevant, even if underestimated, in Multiple Sclerosis (MS) patients. However, no specific questionnaire for the assessment of dysphagia in MS is available. We built a questionnaire (DYsphagia in MUltiple Sclerosis, DYMUS) that was administered to 226 consecutive MS patients (168 F, 58 M, mean age 40.5 years, mean disease duration 10.1 years, mean EDSS 3.1) during control visits in four Italian MS Centres. DYMUS was abnormal in 80 cases (35%). The patients who claimed to have swallowing problems had a significantly higher mean DYMUS score that the other patients (p<0.0001). Mean DYMUS scores were significantly higher in the progressive forms (p=0.003). DYMUS values were significantly correlated to EDSS (p=0.0007). DYMUS showed a very good internal consistency (Cronbach's alpha 0.877). Factor analysis allowed us to sub-divide DYMUS in two sub-scales, 'dysphagia for solid' and 'dysphagia for liquid', both of them had a very good internal consistency (Cronbach's alpha 0.852 and 0.870 respectively). DYMUS demonstrated to be an easy and consistent tool to detect dysphagia and its main characteristics in MS. It can be used for preliminary selection of patients to submit to more specific instrumental analyses, and to direct toward programs for prevention of aspiration.

Memory guided saccades in mesial temporal lobe epilepsy with hippocampal sclerosis.

OBJECTIVE: Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) may involve extrahippocampal areas of structural and functional damage. The incidence and the features of this damage are still a matter of debate and vary depending on the method applied. Memory guided saccades (MGSs) with a memorization delay longer than 20s can be used reliably to evaluate the parahippocampal cortex. METHODS: MGSs with 3 and 30s memorization delays were recorded with the search coil technique in six patients affected by right MTLE-HS, and in 13 healthy controls. RESULTS: The patients were not able to reduce the MGSs residual amplitude error after the first saccade with a 30s memorization delay. This finding was more evident with leftward saccades. CONCLUSIONS: MGS abnormalities suggested the functional involvement of the right parahippocampal cortex in most of the patients with MTLE-HS, and this supports the clinical and anatomopathological heterogeneity of the disease. SIGNIFICANCE: MGSs can be used in patients with right MTLE-HS to detect a possible functional involvement of the ipsilateral parahippocampal cortex.

Bayesian mapping of multiple sclerosis prevalence in the province of Pavia, northern Italy.

The geographical analysis of a disease risk is particularly difficult when the disease is non-frequent and the area units are small. The practical use of the Bayesian modelling, instead of the classical frequentist one, is applied to study the geographical variation of multiple sclerosis (MS) across the province of Pavia, Northern Italy. 464 MS-affected individuals resident in the province of Pavia were identified on December 31st 2000. The overall prevalence was 94 per 100,000 inhabitants. This estimate indicates an increasing MS prevalence in the province, in accordance with the vast majority of the Italian areas where prevalence studies have been repeated. We mapped the geographical variation of MS prevalence across the 190 communes of the province both with a classical approach and a Bayesian approach. The frequentist approach produced an extremely dishomogeneous map, while the Bayesian map was much smoother and more interpretable. Our study underlines the usefulness of Bayesian methods to obtain reliable maps of disease prevalence and to identify possible clusters of disease where to carry out further epidemiological investigations.

MRI and brainstem auditory evoked potential evidence of eighth cranial nerve involvement in multiple sclerosis.

An MS patient experienced sudden hearing loss. Brainstem auditory evoked potentials, previously normal, showed substantial abnormalities that suggested the impairment of the distal part of the acoustic nerve. MRI detected a small hyperintense lesion along the acoustic nerve; the lesion decreased in size and then disappeared after steroid treatment. This demonstrates that a demyelinating lesion in the distal tract of the eighth cranial nerve may cause an acute hearing loss in MS.

Antibody-induced degradation of acetylcholine receptor in myasthenia gravis: clinical correlates and pathogenetic significance.

Sera of myasthenic patients containing anti-AChR antibodies increase the rate of degradation of mammalian AChR. This phenomenon, antigenic modulation (AMd), was tested on AChR of rat myotubes in serum from 48 myasthenic patients. Sixty-six percent of the sera increased AChR degradation. AMd activity was higher in more severely affected patients, paralleled clinical evolution in individual patients, and was related to AChR-antibody titer. Steroid treatment and thymectomy did not affect AMd activity. Patients who had a thymoma always had greater AMd activity.

Serum and CSF levels of MCP-1 and IP-10 in multiple sclerosis patients with acute and stable disease and undergoing immunomodulatory therapies.

The two chemokines, monocyte chemoattractant protein (MCP)-1 and gamma-interferon inducible protein (IP)-10, are thought to be involved in the pathogenesis of multiple sclerosis (MS). We measured MCP-1 and IP-10 levels in serum and CSF samples from 38 acute and 25 stable MS patients and from 40 controls. The latter consisted in patients with other inflammatory neurological diseases (OIND) or with non-inflammatory neurological diseases, and healthy controls. CSF MCP-1 levels exceeded those found in serum in all the patients studied as well as in healthy controls. CSF MCP-1 levels were significantly lower in acute MS [468+/-(S.E.M.) 18 pg/ml] than in stable MS (857+/-104 pg/ml). When detectable, serum and CSF IP-10 levels were significantly higher in acute MS (serum 331+/-66 pg/ml; CSF 118+/-16 pg/ml) than in stable MS (serum 69+/-7 pg/ml; CSF 25+/-2 pg/ml). Among OIND patients, those with HIV-1-associated dementia showed high serum and CSF levels of both MCP-1 and IP-10. Those with encephalitis showed high serum and CSF levels of IP-10 and CSF mononuclear pleiocytosis. We also evaluated the effects of 6-methylprednisolone or IFN-beta1a therapy on circulating MCP-1 and IP-10 levels. Neither MCP-1 nor IP-10 post-therapy levels varied significantly from baseline values. Our findings suggest that (a) MCP-1 could be constitutively produced within the brain; (b) MCP-1 and IP-10 CSF levels in acute MS vary significantly from those in stable MS, and these variations are inverse; and (c) current MS therapies do not modify circulating levels of MCP-1 and IP-10.

Quantitative evaluation of saccadic and smooth pursuit eye movements. Is it reliable?

PURPOSE: The authors evaluated the reliability of the coefficients of the (1) amplitude/duration and (2) amplitude/peak velocity relationships of the mean precision values and the mean latency values (saccadic eye movements) and the coefficients of the target velocity/gain relationship (smooth pursuit eye movements). They computed test-retest maximum variability limits for these parameters. METHODS: After a 1-week interval, saccadic and smooth pursuit eye movements were recorded twice from 20 healthy subjects; 12 of these subjects underwent a third recording session. The estimate of the intraclass coefficient of reliability, R, was adopted to evaluate the reliability of eye movement quantitative analysis. RESULTS: The data demonstrated that the reliability was fairly good for the amplitude/peak velocity relationship, was good for the precision, and was excellent for the amplitude/duration, the target velocity/gain relationships, and the latency. CONCLUSIONS: Quantitative analysis of both saccadic and smooth pursuit eye movements is reliable. One statistic used to estimate reliability, ie, the within-subjects mean square value, also enables the determination of test-retest normal variability values for both the variances and the differences of measurements.

Prognosis of myasthenia gravis: a retrospective study of 380 patients.

The 9139 follow-up records of 438 myasthenia gravis (MG) patients were reviewed. Excluding those patients who were diagnosed 5 or more years after symptom onset (n = 37) and those who experienced only oculomotor symptoms throughout follow-up (n = 21), there were 380 patients. A survival analysis approach was used to assess the influence of prognostic factors on the following endpoints: (a) stable complete remission, (b) complete remission of at least 6 months and (c) pharmacological remission of at least 6 months. Early diagnosis was associated with a better prognosis with respect to all endpoints. Thymectomy also improved the prognosis but only for those patients without thymoma. Later MG onset was associated with a higher tendency to achieve pharmacological remission.

HLA complement gene polymorphisms in multiple sclerosis. A study on 80 Italian patients.

We studied C4A, C4B, and Bf complement gene polymorphisms in 80 Italian patients with multiple sclerosis (MS). We observed a significantly higher frequency of C4AQ0 allele in patients with the relapsing-remitting form of MS than in ethnically homogeneous controls. Restriction fragment length polymorphism analysis by Southern blotting of the C4/CYP21 gene complex showed that a structural gene deletion was present in 45% of patients with the C4AQ0 allele. Our data support the hypothesis that relapsing-remitting MS and primarily chronic progressive MS are immunogenetically distinct diseases; further, complement factor abnormalities typical of autoimmune diseases could influence the pathogenesis of MS.

A multicentre follow-up study of 1152 patients with myasthenia gravis in Italy.

A multicentre retrospective study was carried out on the characteristics and course of myasthenia gravis (MG) in Italy. Data from 1152 patients, fairly representative of the myasthenic population seeking medical advice, were analysed for diagnostic criteria, clinical aspects and therapeutic approaches. Mean follow-up was 4.9 years. The disease was correctly diagnosed within 2 years of the onset in 80% of cases. Onset of symptoms peaked in the second and third decade in females and fell between 20 and 59 years in males. At first observation 87% of the patients had generalized MG. Maximal worsening was observed within 3 years in 77% of patients. At the last follow-up, 35% of cases were symptom-free (pharmacological remission 24%, remission without treatment 11%). The more severe the disease at the first observation and at the maximal worsening of symptoms, the lower was the proportion of remissions. Steroids were given in 54% and immunosuppressants in 18%. Thymectomy was performed in 72%, mostly in women, younger than age 40, and with generalized MG. Thymectomy seemed to improve the course of the disease, mostly in patients operated on shortly after diagnosis and those with generalized mild-to-moderate disease and with a normally involuted thymus. MG was lethal in 4% of patients, principally men, older than 40, in grade 3 or worse at first observation, with a short history of disease, and with thymona.

Efficacy of intranasal administration of neostigmine in myasthenic patients.

The efficacy of intranasally administered neostigmine was tested in 22 patients with generalized myasthenia gravis (MG). Topical therapy to the highly vascularized oropharynx proved to be quickly effective in 5-15 min both clinically and electrophysiologically. Twenty-eight MG patients were then recruited from different centres and their morning doses of oral pyridostigmine were substituted with intranasal neostigmine over a period of 2 or 3 weeks. Intranasal neostigmine proved to be equally efficacious in this regimen. No side-effect was noted even in 4 patients treated in this way for 1 year. Intranasal administration of anti-acetylcholinesterase may be very beneficial: (1) for patients with irregular absorption of oral doses; (2) early in the morning and every time a fast and temporary effect is needed; (3) in bulbar impairment and emergencies, in which a handy atomizer may be life-saving.

Sensitivities and predictive values of paraclinical tests for diagnosing multiple sclerosis.

The sensitivities and predictive values of visual, somatosensory, and brain auditory evoked potentials (EPs), cerebrospinal fluid oligoclonal banding (CSF-OB) and magnetic resonance imaging (MRI) were evaluated for the early diagnosis of clinically definite multiple sclerosis (CDMS). Paraclinical evidence of asymptomatic lesions allows a diagnosis of CDMS. Eighty-two patients in whom MS was suspected but diagnosis of CDMS was not possible entered the study prospectively. Paraclinical examinations were performed at entry. Patients were examined and underwent EPs every 6 months, and MRI yearly. After a mean follow-up of 2.9 years, 28 patients (34%) had developed CDMS (McDonald-Halliday criteria). The initial MRI was strongly suggestive of MS in 19 of these (68%), while 27 (96%) had at least one MS-like abnormality in the initial MRI. CSF-OB and EPs had lower sensitivities. CDMS developed during follow-up in 19 of the 36 patients (53%) who had an initial MRI strongly suggestive of MS but in only 1 of the 25 who had normal MRI when first studied. These results support previous conclusions that MRI is the most sensitive test for detecting white matter asymptomatic lesions, and the most predictive for the diagnosis of CDMS.

Presence of T-cell subset abnormalities in newly diagnosed cases of multiple sclerosis and relationship with short-term clinical activity.

Abnormalities of T-cell subsets in patients with multiple sclerosis are well known; in order to assess whether immunological abnormalities are relevant in the pathogenesis of the disease after its clinical onset, peripheral blood lymphocyte subsets (CD3+, CD4+, CD4(+)-CD45RA+, CD4+CD45RA-, CD8+, CD8+CD57+, CD57+, CD25+) were analysed serially in 25 patients at the first clinical episode suggestive of inflammatory demyelinating disease and in an equal number of age- and sex-matched controls. During the follow-up period (12-18 months, mean 14) 6 of 25 patients presented new relapses: in this subgroup of patients, significant changes in CD4+ ratio (% CD4+CD45RA-/%CD4+CD45RA+) were detected in comparison both with healthy controls and with clinically stable patients. Patients clinically stable at follow-up did not display immunological abnormalities, regardless of the presence or absence of cerebrospinal fluid and/or magnetic resonance imaging alterations consistent with multiple sclerosis. These findings suggest a possible prognostic role of early T-cell subset imbalance in multiple sclerosis.

Palmoplantar keratoderma and Charcot-Marie-Tooth disease.

A close association was noted between palmoplantar keratoderma (PPK) and Charcot-Marie-Tooth disease (CMT) in nine members of a family in five generations. Clinical, genealogic, electroneurophysiologic, chromosome, urinary amino acid, and histopathologic studies were performed to define the two entities. Charco-Marie-Tooth disease occurred with advancing age in all of the members with PPK, but in none without PPK. Palmoplantar keratoderma and CMT appear to be genetically associated and transmitted as an autosomal dominant trait. This is the first report, to our knowledge, of an association between PPK and CMT.

Edge detection and surface 'filling in' as shown by texture visual evoked potentials.

OBJECTIVES: We designed a stimulation paradigm that was designed to ascertain whether specific components of the texture visual evoked potentials were attributable to edge detection or to surface 'filling-in' processes. METHODS: The stimuli were textures of parallel line elements, which were either uniform (all horizontal or vertical lines) or segregated (checkerboards in which texture line elements of neighbor checks were oriented orthogonally). A sequence of 4 stimuli, two uniform followed by two segregated stimuli, was repeated cyclically. Accordingly, segregation could appear from a uniform display; it could also be maintained, with the checkerboard illusory margin location unchanged but with alteration in the orientation of all line elements. Each stimulus was presented for 487 ms and instantly replaced by the following one. RESULTS: Segregation-related components for segregation-appearance (Sa) and for segregation-maintenance (Sm) conditions were obtained separately by subtraction. In both conditions, a negative component was obtained with a peak latency of about 140-150 ms. However, the onset of Sa was earlier than that of Sm, whereas the respective offsets were almost identical. CONCLUSIONS: We hypothesize that the segregation component in VEPs is composed of two subcomponents: an early part, which is related to the segregation of edges, and a final part, which is related to the 'filling-in' of the homogeneous texture surface within the boundary defined by these edges.

Periodic alternating nystagmus and vestibulo-spinal system facilitating activity.

OBJECTIVE: Periodic alternating nystagmus has been associated with the instability of the velocity storage mechanism, which is known to play an important role in both the vestibulo-oculomotor and the optokinetic systems. In the present study we looked for a possible spinal equivalent to PAN. METHODS AND RESULTS: In 3 PAN patients, the H-reflex amplitude proved to be slightly but significantly influenced by nystagmus direction, in that it was greater when the nystagmus was beating toward the stimulation side. CONCLUSIONS: This finding suggests that projections from velocity storage may play a role not only in the ocular motor but also in assisting postural stability through the vestibulo-spinal system.

Circadian and hypothermia-induced effects on visual and auditory evoked potentials in multiple sclerosis.

OBJECTIVES: Body cooling has been proposed as a symptomatic treatment for multiple sclerosis. This study aimed to assess the effects of body cooling and of circadian variations on clinical parameters and on visual and auditory evoked potential measures in multiple sclerosis patients. METHODS: Clinical status was assessed and VEPs, BAEPs and MLAEPs (all with two stimulus frequencies) were recorded a total of 4 times on two separate days (two times per day at 08:30 and 15:00 h each day) in 10 multiple sclerosis patients and 10 controls. On one of these days, the subjects were submitted to body cooling before the afternoon session. RESULTS: Tympanic temperature was significantly higher in the afternoon. Cooling lowered the temperature by 1.4 degrees C. No clinical effects were observed. Circadian effects were detected on VEP amplitude, which increased both in controls and in patients at low stimulus frequency (P<0.01), and increased in controls and decreased in patients at high stimulus frequency (interaction: P<0.01). Cooling determined an increase in BAEP I-V peak-to-peak time in controls, and a reduction in patients at high stimulus frequency (interaction: P<0.01). In patients, cooling also determined a great increase in MLAEP amplitude (interaction: P<0.001). We did not find cooling effects on VEP measures. CONCLUSIONS: Visual and auditory evoked potentials showed differences in circadian and cooling effects between controls and multiple sclerosis patients. These differences are consistent with the hypothesis of temperature-dependent conduction blocks in demyelinated fibers. Cooling may have a clinical effect in selected patients only.

Predicting secondary progression in relapsing-remitting multiple sclerosis: a Bayesian analysis.

With the aid of a Bayesian statistical model of the natural course of relapsing remitting Multiple Sclerosis (MS), we identify short-term clinical predictors of long-term evolution of the disease, with particular focus on predicting onset of secondary progressive course (failure event) on the basis of patient information available at an early stage of disease. The model specifies the full joint probability distribution for a set of variables including early indicator variables (observed during the early stage of disease), intermediate indicator variables (observed throughout the course of disease, prefailure) and the time to failure. Our model treats the intermediate indicators as a surrogate response event, so that in right-censored patients, these indicators provide supplementary information pointing towards the unobserved failure times. Moreover, the full probability modelling approach allows the considerable uncertainty which affects certain early indicators, such as the early relapse rates, to be incorporated in the analysis. With such a model, the ability of early indicators to predict failure can be assessed more accurately and reliably, and explained in terms of the relationship between early and intermediate indicators. Moreover, a model with the aforementioned features allows us to characterize the pattern of disease course in high-risk patients, and to identify short-term manifestations which are strongly related to long-term evolution of disease, as potential surrogate responses in clinical trials. Our analysis is based on longitudinal data from 186 MS patients with a relapsing-remitting initial course. The following important early predictors of the time to progression emerged: age; number of neurological functional systems (FSs) involved; sphincter, or motor, or motor-sensory symptoms; presence of sequelae after onset. During the first 3 years of follow up, to reach EDSS> or =4 outside relapse, to have sphincter or motor relapses and to reach moderate pyramidal involvement were also found to be unfavourable prognostic factors.

Polymorphic markers in MHC class II/III region: a study on Italian patients with myasthenia gravis.

With an Italian case series of 81 Italian patients and 130 controls, we analysed associations between myasthenia gravis (MG) and genetic polymorphisms in the MHC class II/III region. Increases in the frequency of the TNF-B*1, C4A*Q0, C4B*1, DRB1*03 supratype, which is likely part of the 8.1 ancestral haplotype, were maximal in females with early onset (EO) MG vs. controls [p<0.05, relative risk (RR)=9.9]. These patients showed neither a significantly high frequency of thymic hyperplasia, nor high levels of serum anti-acethylcholine receptor antibodies. The DRB1*03 allele was absent in patients with thymoma; however, in comparison with controls, occurrence of this marker was frequent in MG patients (p<0.005; RR=6.2), more frequent in females (p<0.005; RR=7.8) and most frequent in EOMG female patients (p<0.005; RR=15.1). Analysis of the TNF-B*1, C4A*Q0, C4B*1, DRB1*03 supratype and its recombinants showed that the MHC region between C4 and TNF might contain genes that influence susceptibility to MG in females. Polymorphic markers within the supratype, e.g. TNF-B*1 and C4A*Q0, might contribute to pathogenetically significant abnormalities in immune responses in a subset of female MG patients. The combined effect of other intervening genes cannot be excluded.