Nonlesional Sources of Contrast Enhancement on Postgadolinium "Black-Blood" 3D T1-SPACE Images in Patients with Multiple Sclerosis.

BACKGROUND AND PURPOSE: We hypothesized that 3D T1-TSE "black-blood" images may carry an increased risk of contrast-enhancing lesion misdiagnosis in patients with MS because of the misinterpretation of intraparenchymal vein enhancement. Thus, the occurrence of true-positive and false-positive findings was compared between standard MPRAGE and volumetric interpolated brain examination techniques. MATERIALS AND METHODS: Sampling perfection with application-optimized contrasts by using different flip-angle evolution (SPACE) images obtained from 232 patients with MS, clinically isolated syndrome, or radiologically isolated syndrome were compared with standard MPRAGE and volumetric interpolated brain examination images. The intraparenchymal vein contrast-to-noise ratio was estimated at the level of the thalami. Contrast-enhancing lesions were blindly detected by 2 expert readers and 1 beginner reader. True- and false-positives were determined by senior readers' consensus. True-positive and false-positive frequency differences and patient-level diagnosis probability were tested with the McNemar test and OR. The contrast-to-noise ratio and morphology were compared using the Mann-Whitney U and χ2 tests. RESULTS: The intraparenchymal vein contrast-to-noise ratio was higher in SPACE than in MPRAGE and volumetric interpolated brain examination images (P < .001, both). There were 66 true-positives and 74 false-positives overall. SPACE detected more true-positive and false-positive results (P range < .001-.07) but did not increase the patient's true-positive likelihood (OR = 1 1.29, P = .478-1). However, the false-positive likelihood was increased (OR = 3.03-3.55, P = .008-.027). Venous-origin false-positives (n = 59) with contrast-to-noise ratio and morphology features similar to small-sized (≤14 mm3 P = .544) true-positives occurred more frequently in SPACE images (P < .001). CONCLUSIONS: Small intraparenchymal veins may confound the diagnosis of enhancing lesions on postgadolinium black-blood SPACE images.

Dedicated 3D-T2-STIR-ZOOMit Imaging Improves Demyelinating Lesion Detection in the Anterior Visual Pathways of Patients with Multiple Sclerosis.

BACKGROUND AND PURPOSE: Demyelinating lesions in the anterior visual pathways represent an underestimated marker of disease dissemination in patients with MS. We prospectively investigated whether a dedicated high-resolution MR imaging technique, the 3D-T2-STIR-ZOOMit, improves demyelinating lesion detection compared with the current clinical standard sequence, the 2D-T2-STIR. MATERIALS AND METHODS: 3T MR imaging of the anterior visual pathways (optic nerves, chiasm, and tracts) was performed using 3D-T2-STIR-ZOOMit and 2D-T2-STIR, in patients with MS and healthy controls. Two experienced neuroradiologists assessed, independently, demyelinating lesions using both sequences separately. 3D-T2-STIR-ZOOMit scan-rescan reproducibility was tested in 12 patients. The Cohen κ was used for interrater agreement, and the intraclass correlation coefficient for reproducibility. Between-sequence detection differences and the effects of location and previous acute optic neuritis were assessed using a binomial mixed-effects model. RESULTS: Forty-eight patients with MS with (n = 19) or without (n = 29) past optic neuritis and 19 healthy controls were evaluated. Readers' agreement was strong (3D-T2-STIR-ZOOMit: 0.85; 2D-T2-STIR: 0.90). The 3D-T2-STIR-ZOOMit scan-rescan intraclass correlation coefficient was 0.97 (95% CI, 0.96-0.98; P < .001), indicating excellent reproducibility. Overall, 3D-T2-STIR-ZOOMit detected more than twice the demyelinating lesions (n = 89) than 2D-T2-STIR (n = 43) (OR = 2.7; 95% CI, 1.7-4.1; P < .001). In the intracranial anterior visual pathway segments, 33 of the 36 demyelinating lesions (91.7%) detected by 3D-T2-STIR-ZOOMit were not disclosed by 2D-T2-STIR. 3D-T2-STIR-ZOOMit increased detection of demyelinating lesion probability by 1.8-fold in patients with past optic neuritis (OR = 1.8; 95% CI, 1.2-3.1; P = .01) and 5.9-fold in patients without past optic neuritis (OR = 5.9; 95% CI, 2.5-13.8; P < .001). No false-positive demyelinating lesions were detected in healthy controls. CONCLUSIONS: Dedicated 3D-T2-STIR-ZOOMit images improved substantially the detection of MS disease dissemination in the anterior visual pathways, particularly in the intracranial segments and in patients without past optic neuritis.

Poor patient awareness and frequent misdiagnosis of migraine: findings from a large transcontinental cohort.

BACKGROUND AND PURPOSE: Although migraine is the second most disabling condition worldwide, there is poor awareness of it. The objective was to assess the awareness of migraine and previous diagnostic and therapeutic consultations and treatments in a large international population of migraineurs. METHODS: This was a multicentre study conducted in 12 headache centres in seven countries. Each centre recruited up to 100 patients referred for a first visit and diagnosed with migraine. Subjects were given a structured clinical questionnaire-based interview about the perceptions of the type of headache they suffered from, its cause, previous diagnoses, investigations and treatments. RESULTS: In all, 1161 patients completed the study. Twenty-eight per cent of participants were aware that they suffered from migraine. Sixty-four per cent called their migraine 'headache'; less commonly they used terms such as 'cervical pain' (4%), tension headache (3%) and sinusitis (1%). Eight per cent of general practitioners and 35% of specialists (of whom 51% were neurologists and/or headache specialists) consulted for migraine formulated the correct diagnosis. Before participating in the study, 50% of patients had undergone X-ray, computed tomography and/or magnetic resonance imaging of the cervical spine and 76% underwent brain and/or cervical spine imaging for migraine. Twenty-eight per cent of patients had received symptomatic migraine-specific medications and 29% at least one migraine preventive medication. CONCLUSIONS: Although migraine is a very common disease, poor awareness of it amongst patients and physicians is still an issue in several countries. This highlights the importance of the promotion of migraine awareness to reduce its burden and limit direct and indirect costs and the risk of exposure to useless investigations.

Infusion-related reactions during Natalizumab treatment: Do we still need a post-infusion observation period?

BACKGROUND: Natalizumab (NTZ) is a humanized monoclonal antibody used in the treatment of relapsing remitting multiple sclerosis. Although NTZ is usually well-tolerated, infusion-related reactions (IRRs) may occur, and the patients have to be monitored during the infusion and for one hour afterwards. OBJECTIVE: To identify frequency and severity of IRRs during NTZ infusions and one-hour post-infusion observation period in a clinical practice setting. METHODS: Multicenter, observational study involving three Swiss (Lugano, St. Gallen and Luzern) and two Italian (Milano and Napoli) tertiary MS centers. Predisposing factors to IRRs were investigated using multivariate Cox regression models. RESULTS: A total of 11'133 infusions received by 302 MS patients were analyzed (68.9% females, median age 33.6 years, median EDSS 2.5). IRRs occurred in 24 (8%) patients during NTZ infusions and in 7 (2%) during one-hour post-infusion. Only 8 patients needed pharmacological treatment, of whom 7 during NTZ infusion. Age, sex and history of allergies were not associated with risks for IRR. The frequency of post infusion IRRs after the fifth cycle was low compared to that during the first four infusions (0.83% vs 0.06%). CONCLUSION: In our cohort, NTZ associated IRR mainly occurred during the infusion period compared to the one-hour observational period. Also, the first IRR exclusively occurred within the first 4 NTZ administrations. However, further multi-center studies with a larger sample size are needed to capture rare and serious events that could emerge during the observational period and to make clinical recommendations.

Pseudobulbar affect as a negative prognostic indicator in amyotrophic lateral sclerosis.

OBJECTIVE: To evaluate whether the presence of pseudobulbar affect (PBA) in an early stage of the disease influences survival in a population-based incident cohort of amyotrophic lateral sclerosis (ALS). METHODS: Incident ALS cases, diagnosed according to El Escorial criteria, were enrolled from a prospective population-based registry in Puglia, Southern Italy. The Center for Neurologic Study-Lability Scale (CNS-LS), a self-administered questionnaire, was used to evaluate PBA. Total scores range from 7 to 35. A score ≥13 was used to identify PBA. Cox proportional hazard models were used for survival analysis. The modified C-statistic for censored survival data was used for models' discrimination. RECursive Partitioning and AMalgamation (RECPAM) analysis was used to identify subgroups of patients with different patterns of risk, depending on baseline characteristics. RESULTS: We enrolled 94 sporadic ALS, median age of 64 years (range: 26-80). At the censoring date, 65 of 94 (69.2%), 39 of 60 (65.0%), and 26 of 34 (76.5%) patients reached the outcome (tracheotomy/death), in the whole, non-PBA and in the PBA groups, respectively. Kaplan-Meier survival curves for the two subgroups were not significantly different (log-rank test: 1.3, P = .25). The discrimination ability of a multivariable model with demographic and clinical variables of interest was not improved by adding PBA. In the RECPAM analysis, ALSFRSr and the total score of CNS-LS scale (

Real-life long-term effectiveness of fingolimod in Swiss patients with relapsing-remitting multiple sclerosis.

BACKGROUND AND PURPOSE: In 2011, fingolimod was approved in Switzerland for the treatment of relapsing-remitting multiple sclerosis (RRMS). The aim of the present study was to assess the effectiveness and retention of fingolimod in a real-life Swiss setting, in which patients can receive fingolimod as both first- and second-line treatment for RRMS. METHODS: This cross-sectional, observational study with retrospective data collection was performed at 19 sites that comprised both hospitals and office-based physicians across Switzerland. Sites were asked to document eligible patients in consecutive chronological order to avoid selection bias. Demographic and clinical data from 274 consenting adult patients with RRMS who had received treatment with fingolimod were analyzed. RESULTS: Mean treatment duration with fingolimod was 32 months. Under fingolimod, 77.7% of patients remained free from relapses and 90.3% did not experience disability progression. The proportion of patients who were free from any clinical disease activity, i.e. without relapses and disability progression, was 72.1%. A total of 28.5% of patients had been RRMS treatment-naïve prior to fingolimod therapy. High long-term treatment retention rates ranging between 95.7% at 24 months and 87.8% at 36 months were observed. CONCLUSION: In this Swiss cohort of naïve and pre-treated subjects with RRMS, the majority of patients under fingolimod treatment showed freedom from relapses and disability progression. In addition, treatment retention rate over 2 and 3 years was high, irrespective of previous treatment.

Severe multiple sclerosis reactivation during prolonged lymphopenia after dimethyl fumarate discontinuation.

BACKGROUND: Delayed-release dimethyl fumarate (DMF) treatment can be associated with reduced lymphocyte and leucocyte counts, which might persist after DMF discontinuation. CASE PRESENTATION: We report the case of a patient with severe disease reactivation despite prolonged lymphopenia after DMF discontinuation. We describe the frequency and impact of prolonged lymphopenia after DMF discontinuation at two tertiary MS centres. A 36-year-old female patient with multiple sclerosis was switched to DMF after 14 years of treatment with interferon beta-1a. DMF was suspended after 4 months because of persistent lymphopenia for 3 months. Six months later, the patient had a severe relapse with multiple enhancing brain lesions at MRI although lymphopenia was still persistent. Haematological assessment excluded other causes of lymphopenia, which was evaluated as a probable iatrogenic complication of DMF. The patient was treated with i.v. methylprednisolone 1 gr daily for 3 days with clinical recovery. CONCLUSIONS: Prolonged lymphopenia after DMT discontinuation does not protect against disease reactivation. Starting a new immune therapy should be balanced against the option of a "wait and see." A different immunotherapeutic strategy such as an anti-B therapeutic approach could be considered.

Urinary incontinence in multiple sclerosis: prevalence, severity and impact on patients' quality of life.

BACKGROUND AND PURPOSE: Lower urinary tract symptoms (LUTS) including frequent urination, nocturia and urge urinary incontinence negatively impact quality of life. This project aimed at characterizing the prevalence and severity of urinary incontinence in multiple sclerosis (MS) patients and its association with demographic and clinical features. METHODS: In all, 403 consecutive clinically stable MS patients answered the International Consultation on Incontinence Questionnaire (ICIQ) and the Patient Perception of Bladder Condition (PPBC) questionnaire. Demographic and clinical parameters including the Expanded Disability Status Scale (EDSS) were collected. Statistical analyses were performed using univariate and multivariate linear regression models. RESULTS: Females represented 72%, relapsing-remitting patients 82%. The mean (SD) disease duration and EDSS were 11.8 (8.6) years and 3.1 (1.9) respectively. Approximately 35% of patients reported urine incontinence. ICIQ scores were positively associated with EDSS, female gender, presence of LUTS therapies and absence of disease modifying treatments (P < 0.001). PPBC scores were positively associated with EDSS and the presence of LUTS therapies (P < 0.001). DISCUSSION: Urinary incontinence is frequent in MS, prevailing in more disabled and female patients. Currently available LUTS therapies appear insufficient in the treatment of this symptom. The negative impact of urinary incontinence on quality of life is high and requires more attention in clinical management and research.

Relevance of asymptomatic spinal MRI lesions in patients with multiple sclerosis.

BACKGROUND: The impact of new asymptomatic spinal cord lesions (a-SL) in multiple sclerosis (MS) course is poorly characterized. OBJECTIVE: The objective of this research paper is to assess the prognostic value of a-SL in predicting MS course. METHODS: Relapsing-remitting MS patients who received serial MRI (brain and spinal) at baseline (t1) and within 12 to 36 months (t2) during clinical stability, and had a follow-up (t2-t3) ⩾24 months were included. Relapses and disability progression were evaluated between t2 and t3. RESULTS: Of 413 consecutive screened MS patients, 103 patients (65 females, median age 43 years) were included. After a median t1-t2 interval of 17 (IQR 13-26) months, 25.2% and 43.7% patients had ⩾1 new a-SL (a-SL+) and asymptomatic brain lesions (a-BL+), respectively. Relapse risk between t2 and t3 (median interval: 42 (IQR 32-57.5) months) was significantly increased in a-SL+ and/or a-BL+ vs a-BL- and a-SL- (HR = 2.31, 95% CI = 1.13-4.72, p = 0.02). No differences in the risk of disability progression were found in a-SL+ and/or a-BL+ vs a-SL- and a-BL-. CONCLUSION: a-SL occur in one-quarter of clinically stable RRMS, and combined with a-BL contribute significantly in predicting future disease course.

Fumaric acid esters in psoriasis and multiple sclerosis.

Fumaric acid esters (FAEs) are effective in patients with moderate to severe psoriasis. Recent studies also report the efficacy of one FAE component, dimethylfumarate, in relapsing forms of multiple sclerosis (MS). We describe the case of a patient with MS who developed severe plaque psoriasis during interferon-ß-1a treatment for MS. The psoriasis was unresponsive to usual topical treatments and phototherapy. The patient was started on FAE 720 mg daily, with complete remission of the psoriatic lesions and neurological stabilization at follow-up at 24 months. Our case suggests that FAEs could represent a therapeutic option for patients with MS who develop plaque psoriasis following exposure to immune-modulating agents.

Motor and sensory responses after percutaneous tibial nerve stimulation in multiple sclerosis patients with lower urinary tract symptoms treated in daily practice.

BACKGROUND AND PURPOSE: Posterior tibial nerve stimulation (PTNS) is an effective treatment option for lower urinary tract symptoms (LUTS) in multiple sclerosis (MS) patients. METHODS: Patients with MS and LUTS unresponsive to medical treatment received PTNS for 12 weeks after saline urodynamics to evaluate the prevalence of motor, sensory and combined responses during PTNS and to determine whether the type of response can predict treatment outcome. LUTS were also assessed using a 3-day bladder diary, patient perception of bladder condition (PPBC) questionnaire, patient perception of intensity of urgency scale (PPIUS), Kings Health QOL questionnaire (KHQ) and Overactive Bladder Questionnaire (OAB-q) before and after treatment. Patients were considered as "responders" if they reported an improvement >50% in their LUTS according to the PPBC. Sensory, motor and combined sensory/motor responses were compared between responders and non-responders. RESULTS: Eighty-three patients were included. 61% (51/83) of patients were responders. Sensory, motor and combined sensory/motor responses were found in 64% (53/83), 6% (5/83) and 30% (25/83) of patients respectively. A sensory response alone, or in combination with a motor response, was better associated with a successful outcome than the presence of a motor response alone (P = 0.001). CONCLUSIONS: A sensory response, either alone or in combination with a motor response, is more frequent and seems to be better associated with a successful outcome of PTNS than motor response alone.

Maintenance percutaneous posterior nerve stimulation for refractory lower urinary tract symptoms in patients with multiple sclerosis: an open label, multicenter, prospective study.

PURPOSE: Percutaneous tibial nerve stimulation is an effective second line therapy for lower urinary tract symptoms. Data on percutaneous tibial nerve stimulation maintenance treatment are scarce. In this study we evaluate its effectiveness and propose an algorithm of percutaneous tibial nerve stimulation maintenance treatment in patients with multiple sclerosis. MATERIALS AND METHODS: In this prospective, multicenter, open label trial consecutive patients with multiple sclerosis and lower urinary tract symptoms unresponsive to medical therapy were treated with 12 weekly sessions of percutaneous tibial nerve stimulation. Responder patients (50% or greater improvement of lower urinary tract symptoms as measured by the patient perception of bladder condition questionnaire) entered a maintenance phase with individualized treatment frequency based on patient response. Lower urinary tract symptoms were assessed using a 3-day frequency volume chart, urodynamics and patient perception of bladder condition questionnaire. Treatment satisfaction was evaluated using a global response assessment scale and a treatment satisfaction visual analog scale. RESULTS: A total of 83 patients were included in the study and 74 (89%) responded to initial treatment. Persistent efficacy occurred in all initial responders after a mean treatment of 24 months. The greatest frequency of maintenance percutaneous tibial nerve stimulation was every 2 weeks. Lower urinary tract symptoms and patient treatment satisfaction improved with time compared to initial treatment (p <0.05). Bladder diary parameters and voiding parameters improved compared to baseline (p <0.05). CONCLUSIONS: Prolonged percutaneous tibial nerve stimulation treatment leads to a persistent improvement of lower urinary tract symptoms in patients with multiple sclerosis.

Tumefactive demyelinating lesions during etanercept treatment requiring decompressive hemicraniectomy.

Tumor necrosis factor alpha (TNF-α) is a pro-inflammatory and immunoregulatory cytokine involved in the pathogenesis of several autoimmune disorders. Etanercept, a TNF-α antagonist (anti-TNF-α) acting as a soluble TNF-α receptor, has been associated with neurological demyelinating disorders. This paper aims to report an unusual case showing tumefactive central nervous system (CNS) inflammatory demyelination in a patient in the course of TNF -α antagonist therapy, requiring decompressive hemicraniectomy. This report is based on magnetic resonance imaging (MRI) findings and histology. A biopsy confirmed the inflammatory demyelinating nature of the lesions. The clinical presentation is unusual due to the severity of the disease process, requiring decompressive hemicraniotomy with a clinically favorable outcome.

Methods of enteral feeding in preterm infants.

Whenever possible, oral feeding is the preferred method in neonatal feeding. However, many premature infants are unable to suck and swallow effectively; in these cases alternative methods of nutrient delivery must be used. We briefly review the different feeding methods used in neonatal units, with particular attention to their theoretical advantages, disadvantages and to the current best evidence available.

Percutaneous posterior tibial nerve stimulation as an effective treatment of refractory lower urinary tract symptoms in patients with multiple sclerosis: preliminary data from a multicentre, prospective, open label trial.

BACKGROUND: Percutaneous tibial nerve stimulation (PTNS) has been proposed as a new, minimally invasive neuromodulation technique to treat lower urinary tract symptoms (LUTS). OBJECTIVE: To evaluate efficacy, safety and impact on quality of life (QoL) of PTNS on patients with multiple sclerosis (MS) who have LUTS. METHODS: 21 patients (5 men, 16 women) with MS and LUTS unresponsive to anticholinergics were treated with 12 sessions of PTNS. Assessment of LUTS was by validated, self-administered chart and questionnaires, testing the subjective and objective relevance of LUTS for patients and their impact on QoL before and after treatment; the mean post-micturition residual was assessed by trans-abdominal ultrasound scanning. Analysis was by intention to treat. RESULTS: There was a significant reduction of daytime frequency (from 9 to 6, p = 0.04), nocturia (from 3 to 1, p = 0.002) and mean post-micturition residual (from 98 ± 124 ml to 43 ± 45 ml, p = 0.02). The mean voided volume increased from 182 ± 50 ml to 225 ± 50 ml (p = 0.003). Eighty-nine percent of patients reported a treatment satisfaction of 70%. Significant improvement in QoL was seen in most domains of the King's Health QoL questionnaire (p < 0.05). No adverse events were reported. CONCLUSIONS: PTNS is an effective, safe and well-tolerated treatment for LUTS in patients with MS.

Urinary aldosterone excretion and renal function in extremely-low-birth-weight infants following acute furosemide therapy.

BACKGROUND: Increased activity of the renin-angiotensin-aldosterone system (RAAS) has been reported in the neonatal period. Until now, it has been demonstrated that the RAAS of healthy neonates responds to acute furosemide challenge while no data concerning the responsiveness of RAAS in extremely low birth weight (ELBW) infants are available. OBJECTIVE: To assess urinary aldosterone excretion (UAE) and renal function in ELBW infants who received diuretics for the purpose of reducing the incidence of chronic lung disease (CLD). METHODS: Infants with birth weights < or =1,000 g, at high risk to develop CLD, were studied in a prospective observational study. UAE and renal function were investigated before and after administration of furosemide given in a single dose of 2 mg/kg. RESULTS: UAE and renal function were evaluated in 20 ELBW infants. Diuretic administration resulted in a significant rise in UAE and urinary sodium, potassium and chloride excretion. No change occurred in creatinine clearance, while urine volume increased significantly. CONCLUSIONS: ELBW infants respond to acute furosemide challenge by increasing urine volume, urinary electrolytes and UAE.

Clinical, morphological and immunological evaluation of six patients with dysferlin deficiency.

Limb girdle muscular dystrophy (LGMD) type 2B and distal Miyoshi myopathy (MM) are caused by mutations in a recently discovered mammalian gene coding for a skeletal muscle protein called dysferlin. The protein is normally expressed at the skeletal muscle level and absent or reduced in affected patients. We selected a clinically heterogeneous population of Italian myopathic patients with clinical evidence of myopathy and/or hyperCKemia, EMG myopathic pattern, and no alterations of the dystrophin-sarcoglycan complex. Calpain, merosin, emerin and caveolin were also tested and found normal in all patients. Dysferlin immunohistochemical and Western blot analyses allowed us to identify six patients with dysferlin deficiency: one with distal myopathy, four with limb girdle myopathy and one with hyperCKemia. No apoptosis was found in any of the six muscle specimens, although expression of the pro-apoptotic Fas antigen was mildly increased in two cases. Inflammatory reactions were present in two of the six cases, but we found no evidence of immune-mediated processes.