Paolo Immovilli

Cough Efficacy Is Related to the Disability Status in Patients with Multiple Sclerosis

Background: Cough is an important defense mechanism, whose main function is to remove mucus and/or foreign bodies from the airways. In patients with multiple sclerosis (MS), respiratory muscle function may be affected and cough may be impaired. Objectives: Respiratory muscle strength and voluntary cough efficacy were determined in MS patients and controls, and the relationship between cough efficacy and patients’ degree of disability was investigated. Methods: We recruited 27 MS patients (age: 41 ± 11 years; 18 females) with mild-to-moderate disability, Expanded Disability Status Scale (EDSS) score range: 1–7, and 20 healthy controls (age: 37 ± 11 years; 12 females). The maximal inspiratory (PIMAX) and expiratory (PEMAX) pressures, maximal whistle mouth pressures (PMOW), cough peak flows (CPF), cough expiratory volumes (CEV) and cough gastric pressures (PGA) were measured in all subjects. Results: In MS patients, the EDSS score was significantly related to CPF, PEMAX, PMOW, cough PGA, PIMAX and CEV (p < 0.01, each correlation). The receiver-operating characteristic curve showed that an EDSS score ≧5.5 was consistent with impaired cough (CPF ≤5.6 l/s), with a sensitivity of 0.85 and a specificity of 0.95 (area under curve 0.90, p < 0.001). CPF was related to and predicted by PEMAX, PMOW, cough PGA and PIMAX in MS patients (p < 0.01 each correlation), but not in controls. Conclusions: MS can affect voluntary cough efficacy and respiratory muscle strength, which are inversely related to the patients’ degree of disability. In addition, this study shows that CPF is a measure of clinical relevance in MS patients.

Migraine and Stroke: “Vascular” Comorbidity

Several comorbidities are associated to migraine. Recent meta-analyses have consistently demonstrated a relationship between migraine and stroke, which is well-defined for ischemic stroke and migraine with aura (MA), even stronger in females on oral contraceptives or smokers. However, there seems to be no clear-cut association between stroke in migraineurs and the common vascular risk factors, at least in the young adult population. Migraineurs also run an increased risk of hemorrhagic stroke, while the association between migraine and cardiovascular disease remains poorly defined. Another aspect is the relationship between migraine and the presence of silent brain lesions. It has been demonstrated that there is an increased frequency of ischemic lesions in the white matter of migraineurs, especially silent infarcts in the posterior circulation territory in patients with at least 10 attacks per month. Although there is a higher prevalence of patent foramen ovale (PFO) in migraineurs, the relationship between migraine and PFO remains controversial and PFO closure is not a recommended procedure to prevent migraine. As an increased frequency of cervical artery dissections has been observed in migrainous patients, it has been hypothesized that migraine may represent a predisposing factor for cervical artery dissection. There still remains the question as to whether migraine should be considered a true “vascular disease” or if the comorbidity between migraine and cerebrovascular disease may have underlying shared risk factors or pathophysiological mechanisms. Although further studies are required to clarify this issue, current evidence supports a clinical management where MA patients should be screened for other concomitant vascular risk factors and treated accordingly.

Previous treatment influences fingolimod efficacy in relapsing–remitting multiple sclerosis: results from an observational study

Abstract Objective: Fingolimod (FTY) is licensed as a disease-modifying treatment in highly active relapsing–remitting multiple sclerosis. The aim of the study was to evaluate the efficacy and safety of FTY in a real-life setting and to explore the possible role of clinical and MRI parameters, including previous treatment type, in predicting its efficacy. Methods: Clinical and MRI data was collected on 127 patients assigned to treatment with FTY in six multiple sclerosis centers in Emilia-Romagna, Italy, between August 2011 and June 2013. Results: During a mean follow-up period of 10 months (range 1–22), we observed a total of 47 relapses in 39 patients (30.7%); new T2 lesions or gadolinium-enhancing (Gd+) lesions were present at follow-up MRI in 32/71 patients (45%). Expanded disability status scale (EDSS) at the end of the follow-up period was not different when compared to the baseline EDSS. Serious adverse events occurred in three patients (2.4%). A higher proportion of patients previously treated with natalizumab showed clinical (41%) or MRI activity (54%). Previous treatment with natalizumab increased the risk of a relapse within 30 days (versus immunomodulatory drugs; OR: 4.3; p = 0.011) and at survival analysis (versus remaining patients; HR: 1.9; p = 0.046). Study limitations include a small population sample, a short observation period with variable timing of follow-up MRI and different baseline characteristics of patients previously treated with natalizumab compared to those treated with immunomodulatory drugs. Conclusions: This study confirms the efficacy of FTY in reducing relapse rate in patients previously treated with immunomodulatory drugs, while it seems to be less effective in patients discontinuing natalizumab. Due to the short duration of follow-up it is not possible to evaluate disability progression; however, no difference was observed between the groups.

Ulnar entrapment neuropathy in patients with type 2 diabetes mellitus: an electrodiagnostic study.

AIMS This study aimed to assess the prevalence and electrophysiological features of ulnar entrapment neuropathy in patients with type 2 diabetes mellitus (DM). METHODS Nerve conduction studies (NCS) were performed in a sample of consecutive diabetic patients aged 25-75 years, referred by the Diabetology Unit. NCS of the median, ulnar, radial, peroneal and sural nerves were performed on the non-dominant side. Median entrapment neuropathy at the wrist (MNW) and ulnar neuropathy at the elbow (UNE) and wrist (UNW) were diagnosed according to standard electrodiagnostic criteria. RESULTS Sixty-four patients were enrolled, 28 male (44%), average age 61, average DM duration 14.5 years. Polyneuropathy was diagnosed in 45 subjects (70%). UNE was detected in 22 patients (34%) (4 did not have polyneuropathy), in the abductor digiti minimi in 16, the first interosseus in 14 and in both in 8. UNW was detected in 7 (11%) subjects and MNW in 40 (63%). NCS alterations consistent with ulnar neuropathy were detected in a high proportion of patients (45%), suggesting that the ulnar nerve is very susceptible to focal entrapment in DM. CONCLUSIONS Upper limb sensory and motor NCS, including motor conduction velocity across the elbow, should be considered in the staging of DM patients.

Short-latency afferent inhibition predicts verbal memory performance in patients with multiple sclerosis

BackgroundThe pathogenesis of cognitive deficits in multiple sclerosis (MS) patients is the subject of debate. A causative role of grey matter impairment has been suggested. Acetylcholinesterase inhibitors have been proposed in the treatment of cognitive impairment in MS. Short-latency afferent inhibition (SAI) is a cortical phenomenon assessed by a transcranial magnetic stimulation protocol that provides an in vivo index of central cholinergic function.MethodsWe recruited 20 consecutive relapsing-remitting or secondary progressive MS patients showing normal upper limb somatosensory and motor evoked potentials. SAI of the left-hand motor cortex from median nerve stimuli was tested. A matched group of 20 healthy subjects was also assessed. All patients underwent neuropsychological assessment with Rao’s Brief Repeatable Battery (BRB). Multiple regression was performed on the number of failed tests and on scores of single BRB tests as dependent variables with Extended Disability Status Scale (EDSS) score, SAI, age, gender and disease duration as regressors. Patients with impaired SAI, were reassessed after a single oral dose of rivastigmine.ResultsSAI was a significant predictor of the score in tests that assess verbal memory. EDSS score and age were found as predictors of the other BRB tests. SAI was significantly improved by oral rivastigmine.ConclusionsOur data confirm that cognitive impairment in MS is multifactorial. The performances in the subdomain of verbal memory are predicted by SAI. These results favour the hypothesis of grey matter involvement and suggest a role of acetylcholine dysfunction in the pathogenesis of some aspects of cognitive deficits in MS.

Cerebrospinal fluid amounts of HLA-G in dimeric form are strongly associated to patients with MRI inactive multiple sclerosis

Background: The relevance of human leukocyte antigen (HLA)-G in dimeric form in multiple sclerosis (MS) is still unknown. Objective: To investigate the contribution of cerebrospinal fluid (CSF) HLA-G dimers in MS pathogenesis. Methods: CSF amounts of 78-kDa HLA-G dimers were measured by western blot analysis in 80 MS relapsing–remitting MS (RRMS) patients and in 81 inflammatory and 70 non-inflammatory controls. Results: CSF amounts of 78kDa HLA-G dimers were more frequent in RRMS than in inflammatory (p<0.01) and non-inflammatory controls (p<0.001) and in magnetic resonance imaging (MRI) inactive than in MRI active RRMS (p<0.00001). Conclusion: Our findings suggest that HLA-G dimers may be implicated in termination of inflammatory response occurring in MS.

Metoclopramide-induced facial and palatopharyngeal myoclonus

A 61-year-old woman developed acute dyslalia, dysphonia, dysphagia, and facial rhythmic jerks 8 hours after the intake of 2 tablets of metoclopramide 10 mg, prescribed for nausea during respiratory infection. Examination revealed dysphonia, dyslalia, dysphagia, and myoclonus in the orbicularis oculi (video 1 on the Neurology® Web site at Neurology.org), orbicularis oris, and palatopharyngeal (video 2); no clicking was audible. Brain MRI, angio-MRI, and EEG were unremarkable. Biperidene 4 mg was given per os: palatopharyngeal myoclonus, dysphonia, and dyslalia improved in 30 minutes and disappeared in 12 hours. Palatal myoclonus may be a rare metoclopramide-induced movement disorder.1,2

CT and MR myelography in superficial siderosis

Dear Editor, A 54-year-old woman presented with subacute spastic and ataxic paraparesis. Sensorineural hearing loss had required a cochlear implant 5 years previously. Laboratory tests for coagulation, liver/kidney functions, and blood ion concentration were all unremarkable. MRI detected a leptomeningeal hemosiderin deposit in the neuraxis (Fig. 1a–d). A spinal epidural fluid collection and dural defect at the T2-T4 level were identified onMR-myelography (MR-m) and ultrafast dynamic CT myelography (ud-CTM) (Fig. 1 e–i). Therefore, superficial siderosis, due to a spinal dural tear, was diagnosed, and subsequent surgical repair was performed, with small sutures and a muscle graft. Superficial siderosis (SS) of the central nervous system (CNS) is due to hemosiderin deposition in the subpial layers of the brain and spinal cord [1], and it is a consequence of recurrent and persistent bleeding into the subarachnoid space. The source of the bleeding often remains undetected, despite extensive neuroimaging. Tumors such as ependymoma, meningioma, oligodendroglioma, pineocytoma, and paraganglioma have been reported in 35% of cases, while vascular abnormalities such as arteriovenous malformations or aneurysms were present in 18% of cases. A previous history of trauma or intradural surgery is a possible finding. Extraarachnoid longitudinally extensive intrathecal fluid-filled collection has frequently been noted in SS patients. The brain’s ability to biosynthesize ferritin and hemosiderin, a defensive mechanism in response to a prolonged hemoglobin iron overload, is an important etiopathogenetic factor in SS. The gliosis and neuronal loss associated with ferritin and hemosiderin deposition may result in an increased signal intensity in the adjacent nervous tissue. Indeed, hemosiderin formation occurs mainly within the microglia, as it can synthesize ferritin so that hemosiderin is taken up selectively by CNS areas rich in microglia and/or by those close to the cerebrospinal fluid (CSF) flow [2]. Notably, the 8th cranial nerve may be considered vulnerable as it is not only particularly rich in microglia, but also, before entering the internal acoustic canal, it travels a relatively long distance outside the brain and is exposed to the damaging effects of a chronic subarachnoid hemorrhage within the CNS. The classical clinical presentation of SS includes adult onset of slowly progressive gait ataxia with cerebellar dysarthria and sensorineural hearing impairment. CT myelography (CTM) may identify a dural defect connecting the intrathecal space to the fluid-filled collection. In CTM, the introduction of iodinated contrast medium (ICM) into the thecal sac allows for specific visualization of the CSF, including the one that has leaked into the epidural space [3]. In cases of high-flow CSF leaks, the contrast agent may spill so quickly from the thecal sac that by the time the images are acquired, myelographic ICM may have spread widely into the epidural space, making a precise localization of the bleeding source almost impossible. However, the ud-CTM, a technique previously described by Thielen and Luetmer [4], provides a sufficient temporal and spatial resolution to overcome this shortcoming and can also detect high-flow leaks. These leaks form a Bfork^ or Bsplitlike^ shape in the column of the flowing myelographic ICM, where the extra-arachnoid ICM continues to flow downwards in a cranial direction. MR-m can also be used to evaluate CSF leaks. A leak on an MR-m is evidenced by a hyperintense fluid collection (T2w) in the epidural space. Heavily T2weighted imaging (steady-state sequences) has been explored to obtain images with a greater contrast between the CSF and background tissues [5]. Compared with CTM, MR-m has the * Nicola Morelli nicola.morelli.md@gmail.com

First-line disease-modifying drugs in relapsing-remitting multiple sclerosis: an Italian real-life multicenter study on persistence

Abstract Objective: The introduction of oral disease-modifying drugs (DMDs) in addition to the available, injectable, ones for relapsing–remitting multiple sclerosis (RRMS) could be expected to improve medication persistence due to a greater acceptability of the route of administration. The aim of the study was to compare the proportion of patients discontinuing injectable DMDs (interferon beta 1a/1b, pegylated interferon, glatiramer acetate) with those discontinuing oral DMDs (dimethylfumarate and teriflunomide) during an observation period of at least 12 months. Secondary aims were to compare the time to discontinuation and the reasons for discontinuation between the two groups and to explore the demographic and clinical factors associated with DMD discontinuation. Methods: In this prospective, multi-center, real-life observational study, patients commencing any first-line DMD between 1 January 2015 and 31 July 2016 were enrolled and followed up for at least 12 months or until the drug was discontinued. Results: Of the 520 included patients, 262 (49.6%) started an injectable and 258 (50.4%) an oral DMD. There was no difference in the proportion of patients on oral (n = 62, 24%) or on injectable (n = 60, 23%) DMDs discontinuing treatment, the most frequent reason being adverse events/side-effects. Higher baseline Expanded Disability Status Scale (EDSS) scores and younger age increased the odds of treatment withdrawal. Time to treatment discontinuation was not different between the two groups and was not influenced by the initiated DMD (oral versus injectable), even after adjustment for baseline differences. Conclusion: The route of administration alone (i.e. oral versus injectable) was not a significant predictor of persistence with first-line DMDs in RRMS.

A multicenter study on the diagnostic significance of a single cerebrospinal fluid IgG band

The analysis of paired cerebrospinal fluid (CSF) and serum samples with isolectric focusing (IEF) can yield different patterns which can be of aid in the differential diagnosis of central nervous system (CNS) disorders. Rarely, a single CSF-restricted IgG band, which is not included within these patterns, can be detected in association with inflammatory disorders, multiple sclerosis (MS) above all. However, the diagnostic meaning of this abnormality is still uncertain. The main aim of our multicenter study was to establish the frequency and disease associations of single CSF IgG bands. Differences in the CSF profiles between MS and other diseases, and the follow-up patterns were also evaluated. Medical records of patients who underwent CSF analysis, which included IEF, over a 11.5-year period were retrospectively scrutinized at the participating centers, which used similar IEF techniques. One hundred and fifty-one of 9422 CSF reports (1.6%) showed single CSF-restricted IgG bands. Of the 129 patients with a definite diagnosis, 58.2% had CNS inflammatory-demyelinating diseases (the most frequent being MS: 21.7%), 6.2% tumours, 5.4% inflammatory peripheral nervous system diseases and 30.2% miscellaneous diseases. At follow-up, 3 out of the 10 patients with a repeated CSF analysis had developed an oligoclonal band pattern. Our findings indicate that single CSF IgG bands tend to associate with diseases characterized by the involvement of intrathecal humoral immune responses, and strongly support the notion that this abnormality should be regularly reported, thus alerting clinicians of possible inflammatory disorders of the CNS.