Pietro Annovazzi

Lifetime and actual prevalence of pain and headache in multiple sclerosis.

The aim of the present study is to assess the actual and lifetime frequency of neuropathic (trigeminal neuralgia, Lhermitte’s sign, dysesthesic pain) and somatic (painful muscle spasms and low back pain) pain and headache (tensive headache and migraine) in a cross-sectional sample of 428 consecutive multiple sclerosis (MS) outpatients followed-up in an Italian University MS center over a 3-month period. The impact of demographic and disease-related variables on pain and headache risk is also studied. A semi-structured questionnaire was administered during a face-to-face interview with MS patients and a multivariate logistic regression model is applied to obtain crude and adjusted risk measures. The mean age of the sample was 38.4 years, and female/male ratio was 1.65. The mean disease duration was 9.6 years and the median Expanded Disability Status Scale was 2.0, with most of the patients (74.8%) being affected by the relapsing–remitting form. Lifetime prevalence at the date of examination of at least one type of neuropathic or somatic pain was 39.8% in MS patients, with 58.5% also including headache, while the actual prevalence was 23.8% and 39.9%, respectively. After multivariate analysis, a progressive course of disease was shown to increase the risk of dysesthesic pain and painful muscle spasms, while greater disability was responsible for a higher risk of back pain. L’Hermitte’s sign was more frequent in younger patients, while females had a higher risk of headache. Pain and headache in MS are not negligible symptoms and a neurological examination should not miss the assessment of risk factors for specific types of pain for a more specific and individualized treatment.

A short-term randomized MRI study of high-dose oral vs intravenous methylprednisolone in MS

Objective: To compare the efficacy, tolerability, and safety of IV methylprednisolone (IV MP) vs oral methylprednisolone (oMP) at equivalent high doses in patients with multiple sclerosis (MS) experiencing a recent relapse. Methods: Patients with a clinical relapse within the previous 2 weeks and at least 1 gadolinium (Gd)-enhancing lesion on a screening brain MRI scan were included. Forty patients with MS were randomized to receive either 1 g/day for 5 days of oMP (20 patients) or 1 g/day for 5 days of IV MP (20 patients). Expanded Disability Status Scale (EDSS) and brain MRI (dual-echo and postcontrast T1-weighted scans) were assessed at baseline and at weeks 1 and 4. The study primary research question (endpoint) was to compare the efficacy of the 2 treatment routes in reducing the number of Gd-enhancing lesions after 1 week from treatment initiation. Secondary outcomes were safety, tolerability, and clinical efficacy profiles of the 2 routes of administration. Results: The 2 groups showed a reduction of Gd-enhancing lesions over time (p = 0.002 for oMP and p = 0.001 for IV MP) with a “non-inferiority effect” between the 2 routes of administration at week 1. Both groups showed an improvement of EDSS over time (p < 0.001) without between-group difference at week 4. Both treatments were well-tolerated and adverse events were minimal and occurred similarly in the 2 treatment arms. Conclusions: Oral methylprednisolone (oMP) is as effective as IV methylprednisolone in reducing gadolinium-enhancing lesions in patients with MS soon after an acute relapse with similar clinical, safety, and tolerability profiles. This study provides class III evidence that 1 g oMP × 5 days is not inferior to 1 g IV MP × 5 days in reducing the number of gadolinium-enhancing lesions over a period of 1 week (mean difference in lesion reduction comparing IV MP to oMP is −20%, 95% confidence interval −48% to + 5%).

Assessment of MRI abnormalities of the brainstem from patients with migraine and multiple sclerosis

BACKGROUND In patients with migraine, functional changes have been described in the red nucleus (RN), substantia nigra (SN) and periaqueductal gray matter (PAG). PURPOSE To evaluate whether and at which frequency these structures are involved by MRI-detectable structural abnormalities in migraineurs and to investigate the pathogenic role of these abnormalities by assessing their frequency and extent in patients with multiple sclerosis (MS) and migraine. METHODS On brain dual-echo scans obtained from 58 migraineurs (40 without and 18 with aura), 37 MS patients with migraine without aura and 42 MS patients without migraine, the presence of hyperintense lesions involving the brainstem structures was recorded. A test of heterogeneity between groups was used to compare the presence of lesions among patient groups. RESULTS Lesions of RN, SN and PAG were found in all patient groups, with frequency from 57.5% to 86.5%. Significant between-group differences for all these regions were found. No difference was found between migraine patients with and without aura. Compared with MS patients without migraine, MS patients with migraine had more significant involvement of the SN (p=0.02) and RN (p<0.0001). Compared with migraine patients, MS patients with migraine had more significant involvement of the SN and PAG (p ranging from 0.009 to 0.02). CONCLUSIONS T2-visible lesions in the brainstem are frequent in patients with migraine, but do not seem to be associated with the presence of aura. Demyelinating lesions in the RN, SN and PAG might be among the factors responsible for the presence of migraine in patients with MS.

Visual evoked potentials may be recorded simultaneously with fMRI scanning: A validation study

Integrating electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) data may help to optimize anatomical and temporal resolution in the investigation of cortical function. Successful removal of fMRI scanning artifacts from continuous EEG in simultaneous recordings has been reported. We assessed the feasibility of recording reliable visual evoked potentials (VEPs) during fMRI scanning using available artifact removing procedures. EEG during administration of visual stimuli was recorded using MRI‐compatible 32‐channel equipment in nine normal subjects (mean age, 23.9 ± 2.5 years), with and without fMRI acquisition. fMRI scanning and cardioballistographic artifacts were removed after subtraction of averaged artifact waveforms. Consistency between VEPs waveforms and of P1 and N1 peak latencies and amplitudes in the two conditions was assessed. Good correlation was found between VEP waveforms (Pearsons correlation coefficient: rP between 0.76–0.94 across subjects; P < 0.0001) and between latency or amplitude of P1 and N1 peaks (latencies: r = 0.7, P < 0.035; amplitudes: r > 0.65, P < 0.05; Spearman rank correlation coefficient) in the two recording conditions. No significant differences were found between P1 and N1 parameters in the two conditions (Wilcoxon signed rank test). Consistent VEP waveforms, latencies, and amplitudes with and without fMRI scanning indicate that reliable VEPs may be obtained simultaneously with fMRI recording. This possibility might be helpful by shortening recording times and reducing variability from learning, habituation, and fatigue phenomena from separate recordings for the integration of event‐related EEG and fMRI data. Hum. Brain Mapping 24:291–298, 2005.

Natalizumab versus fingolimod in patients with relapsing-remitting multiple sclerosis non-responding to first-line injectable therapies

Background: Natalizumab and fingolimod have not been compared in controlled trials but only in observational studies, with inconclusive results. Objectives: The objective of this study is to compare the effect of natalizumab and fingolimod in reducing disease activity in relapsing-remitting multiple sclerosis (RRMS). Methods: We included all consecutive RRMS patients switched from first-line agents (glatiramer acetate/interferons) to natalizumab or fingolimod, with a follow-up of 24 months. Data of relapses, Expanded Disability Status Scale score and brain magnetic resonance imaging (MRI) scans were collected. We used propensity score (PS) matching and intention-to-treat analysis. Results: We retained 102 patients in each cohort after PS matching, with similar baseline characteristics. More patients discontinued natalizumab compared to fingolimod (33% vs 11%, p < 0.001), mainly for progressive multifocal leukoencephalopathy (PML) concern. No serious adverse events occurred in the two cohorts. Compared to fingolimod, the natalizumab group presented a higher percentage of relapse-free patients (66% vs 80%, p = 0.015), a higher percentage of disability-improved patients (6% vs 15%, p = 0.033), a lower percentage of MRI-active patients (38% vs 14%, p = 0.001) and a higher percentage of patients with no evidence of disease activity (NEDA-3; 44% vs 70%, p < 0.001) after 2 years of follow-up. Disability worsening was not statistically different in the two groups. Conclusion: Natalizumab is superior to fingolimod in RRMS patients non-responding to first-line agents.

Disease reactivation after fingolimod discontinuation in two multiple sclerosis patients

Fingolimod (FTY) is the first oral drug approved for relapsing-remitting (RR) multiple sclerosis (MS). Little is known about MS evolution after its suspension and three reports of high disease activity after FTY withdrawal have recently been published [1–3]. Here we describe two MS patients with massive disease reactivation after FTY discontinuation. Patient 1: This 47-year-old lady presented the first neurological episode in 1995. She was initially treated with interferon-beta in 2000, and thereafter with glatiramer acetate. As she continued to experience many relapses, in February 2004 she entered a phase 2 trial comparing FTY against placebo, followed by an extension study in which all subjects were treated with FTY [4]. She remained free from relapses and disease progression until October 2009, but since then she entered a progressive phase of the disease. In February 2011, she reached EDSS 6.0; brain magnetic resonance imaging (MRI) showed a gadolinium (Gd)enhancing lesion. In July 2011, she reached EDSS 7, but brain and spinal cord MRI showed no disease activity. Intravenous methylprednisolone pulses did not lead to clinical amelioration and FTY was withdrawn because the disease continued to progress. In November 2011 she presented a rapid deterioration of her mental status and generalized seizures. Brain MRI showed multiple Gd-enhancing lesions ([20) and the presence of a severe atrophy. She was again treated with intravenous methylprednisolone pulses for five consecutive days and levetiracetam 1,000 mg daily with benefit. To date, the patient is free from seizures, EDSS is unchanged, but brain MRI, performed in March 2012, showed 15 Gd-enhancing lesions (Fig. 1). Patient 2: This 30-year-old lady presented the initial symptoms of MS in 2002, at the age of 20 years. She was initially treated with glatiramer acetate, and then with interferon-beta without significant effects on relapse rate or brain MRI activity. In March 2007 she was included in the TRANSORMS study [5]; during the blind phase (about 13 months), in which the patient could be treated with FTY or Avonex, she developed two clinical relapses. In April 2008 she entered the extension phase of the study (in which all patients received FTY), and remained clinically stable until June 2008 when FTY was suspended because of genital human papilloma virus infection. From August to December 2008 the patient had three severe relapses which led to a deterioration of her EDSS score from 1.5 to 4.0. Brain MRI showed 20 Gd-enhancing lesions. Intravenous methylprednisolone pulses led to a partial clinical recovery (EDSS = 2.5) and, in January 2009, she started natalizumab, which resulted in a complete suppression of clinical and MRI activity. In April 2011 she decided to A. Ghezzi D. Baroncini P. Annovazzi M. Zaffaroni Multiple Sclerosis Study Center, Hospital of Gallarate, Gallarate, Italy

Alemtuzumab long-term immunologic effect: Treg suppressor function increases up to 24 months

Objective: To analyze changes in T-helper (Th) subsets, T-regulatory (Treg) cell percentages and function, and mRNA levels of immunologically relevant molecules during a 24-month follow-up after alemtuzumab treatment in patients with relapsing-remitting multiple sclerosis (RRMS). Methods: Multicenter follow-up of 29 alemtuzumab-treated patients with RRMS in the Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) I and CARE-MS II trials. Peripheral blood (PB) samples were obtained at months 0, 6, 12, 18, and 24. We evaluated (1) mRNA levels of 26 immunologic molecules (cytokines, chemokines, chemokine receptors, and transcriptional factors); (2) Th1, Th17, and Treg cell percentages; and (3) myelin basic protein (MBP)–specific Treg suppressor activity. Results: We observed 12 relapses in 9 patients. mRNA levels of the anti-inflammatory cytokines interleukin (IL)–10, IL-27, and transforming growth factor–β persistently increased whereas those of proinflammatory molecules related to the Th1 or Th17 subsets persistently decreased after alemtuzumab administration throughout the follow-up period. PB CD4+ cell percentage remained significantly lower than baseline while that of Th1 and Th17 cells did not significantly change. A significant increase in Treg cell percentage was observed at month 24 and was accompanied by an increase in Treg cell suppressive activity against MBP-specific Th1 and Th17 cells. Conclusions: The long-lasting therapeutic benefit of alemtuzumab in RRMS may involve a shift in the cytokine balance towards inhibition of inflammation associated with a reconstitution of the PB CD4+ T-cell subsets that includes expansion of Treg cells with increased suppressive function.

Natalizumab discontinuation in patients with multiple sclerosis: Profiling risk and benefits at therapeutic crossroads

Objective: The objective of this paper is to estimate the risk of reaching well-established disability milestones after withdrawal of natalizumab (NTZ) due to concern about the risk of progressive multifocal leukoencephalopathy in patients with multiple sclerosis (MS). Methods: Data from 415 patients with MS followed-up for six years after starting NTZ were collected from seven tertiary MS centers. The risk of disability worsening, i.e. reaching Expanded Disability Status Scale (EDSS) scores of 4.0 or 6.0, and the likelihood of experiencing a disability reduction of one EDSS point (or more), were assessed by propensity score-adjusted analyses in patients who discontinued and in those still on treatment at the end of follow-up. Results: A total of 318 patients who received standard NTZ treatment without experiencing evidence of disability worsening in the first two years were included in the six-year follow-up analysis, with 196 (61.6%) still on treatment and 122 (38.4%) discontinuing after a median time of 3.5 years. Patients in the discontinuing group had a more than two-fold increased risk of disability worsening (p = 0.007), and a 68% decreased likelihood of experiencing disability reduction (p = 0.009) compared with the continuing group. Conclusion: While discussing the overall risk/benefit profile of NTZ, patients should be advised that, in case of treatment discontinuation, the risk of disability worsening is one in three, and increases to one in two if the EDSS score at NTZ start is above 3.0.

Adverse events after endovascular treatment of chronic cerebro-spinal venous insufficiency (CCSVI) in patients with multiple sclerosis

Although it is debated whether chronic cerebro-spinal venous insufficiency (CCSVI) plays a role in multiple sclerosis (MS) development, many patients undergo endovascular treatment (ET) of CCSVI. A study is ongoing in Italy to evaluate the clinical outcome of ET. Severe adverse events (AEs) occurred in 15/462 subjects at a variable interval after ET: jugular thrombosis in seven patients, tetraventricular hydrocephalus, stroke, paroxysmal atrial fibrillation, status epilepticus, aspiration pneumonia, hypertension with tachicardia, or bleeding of bedsore in the remaining seven cases. One patient died because of myocardial infarction 10 weeks after ET. The risk of severe AEs related to ET for CCSVI must be carefully considered.

Movement preparation is affected by tissue damage in multiple sclerosis: Evidence from EEG event-related desynchronization

OBJECTIVE To investigate the impact of brain tissue damage in Multiple Sclerosis (MS) on the efficiency of programming of voluntary movement, assessed using event-related desynchronization of the EEG. METHODS The onset latency of mu ERD (percent desyncronization of the mu rhythm preceding movement onset) to hand movement was studied in 34 MS patients. ERD onset was compared with normative data and correlated with T1 and T2 total lesion volume (TLV) at magnetic resonance imaging (MRI). RESULTS ERD onset latency was significantly correlated with T1-TLV (r = 0.53, P = 0.001) and T2 lesion load (r = 0.5, P = 0.003), even after correcting for disability. Patients with higher T1-TLV had significantly delayed ERD onset compared with normal subjects and with patients with lower T1-TLV; patients with higher T2-TLV had significantly delayed ERD compared with normal subjects only. ERD onset latency was not correlated to clinical disability. CONCLUSIONS Our finding of delayed ERD onset in patients with more severe measures of brain damage, independently from clinical disability, suggests that functional cortico-cortical and cortico-subcortical connections underlying the expression of ERD during programming of voluntary movement are disrupted by the MS related pathological process. Further, studies are needed to evaluate the role of specific anatomical cortico-subcortical circuits in determining this abnormality. SIGNIFICANCE The extent of brain lesion load in multiple sclerosis affects cortical changes related to motor preparation, detected by analysis of onset latency of event-related desynchronization (ERD) of the mu rhythm to self-paced movement.