Pierangelo Barbero

Thalidomide neuropathy: clinical, electrophysiological and neuroradiological features

Objective – Thalidomide is a promising therapy for multiple myeloma. Sensory neuropathy is a side effect of thalidomide and resulted to be partially reversible in 50% of cases, suggesting a sensory ganglionopathy. Spinal cord magnetic resonance imaging (MRI) was found to be useful in the diagnosis of sensory ganglionopathies and we use it to determine if thalidomide neuropathy has features of a ganglionopathy.

Terminal latency index in polyneuropathy with IgM paraproteinemia and anti‐MAG antibody

Criteria for the diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) are met by the polyneuropathy associated with immunoglobulin M (IgM) paraproteinemia and anti‐myelin–associated glycoprotein (MAG) antibody (MAG‐CIDP). However, MAG‐CIDP differs from other types of CIDP, mainly in its poorer response to treatment. The utility of terminal latency index (TLI) as an electrophysiological marker for MAG‐CIDP has been debated. In this study we confirmed its diagnostic usefulness and evaluated TLI threshold values for motor nerves investigated in routine nerve conduction studies. Median, ulnar, peroneal, and tibial TLIs of 11 subjects with MAG‐CIDP, 18 with CIDP, and 76 healthy controls were compared, and threshold values for MAG‐CIDP evaluated as the lowest value with a likelihood ratio higher than 10. Mean TLI values and TLIs of all but the peroneal nerve were significantly lower in MAG‐CIDP. Median nerve TLI of 0.26 and ulnar nerve TLI of 0.33 were identified as the threshold TLI values for MAG‐CIDP.

High-dose, frequently administered interferon beta therapy for relapsing–remitting multiple sclerosis must be maintained over the long term: the interferon beta dose-reduction study

Long-term trials have demonstrated the continued efficacy of interferon (IFN) beta treatment in patients with relapsing-remitting (RR) multiple sclerosis (MS) during prolonged administration. The objective of the work was to evaluate the effects of reducing IFN beta administration frequency and total weekly dose in patients with RR MS who have achieved clinical and MRI disease activity stabilization during long-term IFN beta-1b treatment. Prospective 1-year follow-up of 27 RR MS patients on long-term 250 microg every other day (standard dose) IFN beta-1b treatment were randomized either to gradually reduce dose to 30 microg once-a-week IFN beta-1a (13 patients), or to continue on IFN beta-1b standard dose (14 patients). We found significant differences in the two group of patients. In the group of patients continuously treated with IFN beta-1b standard dose, 79% remained relapse free compared to 23% in the group receiving once-weekly IFN beta-1a (p=0.006). The number of patients without new PD/T2 lesions was higher in the group of patients continuously treated with IFN beta-1b standard dose (77%) compared to the once-weekly IFN beta-1a group (23%) (p=0.04). IFN beta is a long-term treatment for MS. The reduction of IFN beta-1b administration frequency and dose is not advisable even in patients free from clinical and MRI disease activity for many years.

Intravenous immunoglobulin as first treatment in diabetics with concomitant distal symmetric axonal polyneuropathy and CIDP.

Abstract. The authors investigated the impact of IVIg as first line treatment of diabetic patients suffering from chronic inflammatory demyelinating polyneuropathy (CIDP) concomitant with distal symmetric axonal polyneuropathy. Nine patients with these clinical and electrophysiological features were treated with IVIg (0.4 g/Kg/day for 5 days). Clinical and electrophysiological evaluations were performed before and after treatment. Following IVIg treatment there was no significant improvement in clinical deficit. However, there was a significant and persistent decrease in the Rankin scale score and an improvement in the demyelinating feature on nerve conduction studies. Our findings suggest that IVIg had small but detectable beneficial effects on diabetic patients with CIDP and a high degree of axonal damage.

Thyroid function and anti-thyroid antibodies in MS patients screened for interferon treatment. A multicenter study

Interferon beta (IFNB) treatment for multiple sclerosis (MS) has been associated with thyroid disorders (TD), in particular in patients with subclinical TD or anti-thyroid (AT) autoantibodies (autoAb) before starting treatment. TD and AT autoAb frequency was reported increased in MS. To determine whether MS patients have subclinical thyroid function abnormalities or anti-thyroid autoimmunity predisposing to develop TD, we performed a prospective multicenter screening of thyroid function and autoimmunity in 152 relapsing-remitting (RR) MS patients selected to receive IFNB treatment and in 437 healthy normothyroidal controls. Thyroid-related hormones and anti-thyroid microsomal antigen (anti-TMA) autoAb were tested with sensitive immunoradiometric or chromatographic assays. Cases were stratified for different progressively decreasing or increasing cutoff values of thyroid-stimulating hormone (TSH) (0.3, 0.2, 0.1, 3 and 5 mIU/l), and odds ratios (OR) with 95% confidence intervals (CI) calculated using logistic regression adjusted for gender, age, and anti-TMA autoAb positivity. The frequency of cases below or above the TSH cutoff values was not significantly different in MS patients and controls, and the risk to have an abnormal TSH level was not significantly increased in MS patients (OR ranging 0.37-0.84; CI, 0.05-3.01), even if anti-TMA autoAb positive (OR ranging 0.35-0.85; CI, 0.04-3.00). Frequencies of subclinical hypothyroidism and of anti-TMA autoAb positivity were, however, trending higher in MS men (ranging 5-7%) than in controls (3%). MS patients do not have an increased risk of subtle thyroid function abnormalities, subclinical TD, or anti-TMA autoAb positivity that may predispose to develop thyroid dysfunction during IFNB treatment. The positive trend for subclinical hypothyroidism and anti-TMA autoAb positivity, however, advises a longitudinal study of thyroid function and autoimmunity during IFNB treatment to see whether patients with baseline subclinical thyroid dysfunction develop clinically significant alteration during treatment.

Pro-inflammatory cytokine and chemokine mRNA blood level in multiple sclerosis is related to treatment response and interferon-beta dose

Of 37 multiple sclerosis patients, 19 suboptimal responders were randomized to 375 (n=12) or 250µg (n=7) interferon (IFN)-β-1b. mRNA levels of 23 cytokines, chemokines, and chemokine receptors were quantified by TaqMan low-density array (TLDA) real-time polymerase chain reaction. Better treatment responses or increased IFN-β doses were associated with elevated IL-10 and TGF-β and decreased CXCL10, IL-18, IFN-γ, and TNF-α transcript levels. Adjusting for dose, poor treatment responses resulted in a 4-fold increase in CXCL10 and IFN-γ expression (Mantel-Haenszel RR=3.74, p<0.0001). CXCL10 and IFN-γ mRNA levels were reliable indicators of treatment response. TLDA can be used to tailor IFN-β-1b therapy.

The OPTimization of Interferon for MS Study: 375 μg interferon beta-1b in suboptimal responders

We aimed to evaluate the safety and MRI efficacy of interferon beta-1b (IFNβ-1b) 375 μg (subcutaneously [sc] every other day [eod]) in relapsing-remitting multiple sclerosis (RRMS) patients with a suboptimal response to IFNβ-1b 250 μg, i.e., with MRI activity or relapses. The OPTimization of Interferon for MS (OPTIMS) study was a prospective multicenter randomized phase 2 trial comprising a 6-month run-in phase (to identify suboptimal responders) and a 6-month randomized phase of open-label clinical and blinded MRI follow-up. During run-in all patients were treated with IFNβ-1b 250 μg sc eod; during the study phase suboptimal treatment responders were randomized either to IFNβ-1b 250 or 375 μg sc eod. Primary outcome was the proportion of patients without MRI activity during study Months 9–12 according to the intention-totreat principle. 216 RRMS patients entered the study: 83 suboptimal responders were identified and randomized, 7 refused to continue treatment, 76 were included in the analysis. More patients treated with 375 μg had no MRI activity at Months 9–12 (30/36 vs.16/40; relative risk, 0.28; 95 % confidence interval, 0.08–0.47; p = 0.0001). Sensitivity analysis (“worst case scenario”) confirmed the results. No new or unexpected adverse events were observed, but there was a trend towards more withdrawals in the 375 μg group. Increasing the dose of IFNβ-1b from 250 μg to 375 μg is a successful strategy for reducing subclinical signs of disease activity in RRMS patients. Further studies are needed to show whether this dose may also improve clinical efficacy.

Interferon-β dose and efficacy: the OPTIMS study

Abstract. Interferon beta (IFN-β) reduces exacerbation rates in patients with relapsing-remitting multiple sclerosis (MS), but some patients do not respond to treatment. Recent studies have shown a clear dose-response effect on the reduction of exacerbation rates, and on burden of disease accumulation and active lesion frequency seen on MRI. During treatment with 8 MIU IFN-β we noticed a 30% rate of treatment failure. We then treated non-responders with 12 MIU IFN-β and observed significant improvement in the clinical signs of disease activity. In order to compare the efficacy of two different doses of IFN-β-1b, a multicenter study for the optimization of interferon for MS (OPTIMS) has been organized. The design of the study is presented here.

Does high-dose interferon beta-1b improve clinical response in more severely disabled multiple sclerosis patients?

Prospective clinical open label follow-up of 52 multiple sclerosis patients treated with interferon beta-1b. After 18 months of treatment at standard 8 million international units (MIU) dose, subcutaneously on alternate days, IFNB dose was increased to 12 MIU in ten clinically non-responder patients. Eighteen months after, mean exacerbation rate, number and severity of exacerbations and number of patients with exacerbations or requiring corticosteroid treatment significantly improved, becoming similar to those of IFNB responders, always treated with 8 MIU. Baseline EDSS score of non-responders was higher than that of responders. Frequency and severity of adverse events were trending higher and dropout frequency higher in 12 MIU IFNB-treated patients.

Natalizumab in Multiple Sclerosis: Long-Term Management

Natalizumab is a monoclonal antibody highly effective in the treatment of relapsing remitting multiple sclerosis (RRMS) patients. Despite its effectiveness, there are growing concerns regarding the risk of progressive multifocal leukoencephalopathy (PML), a brain infection caused by John Cunningham virus (JCV), particularly after 24 doses and in patients who previously received immunosuppressive drugs. Long-term natalizumab treated, immunosuppressive-pretreated, and JCV antibody-positive patients are asked to rediscuss natalizumab continuation or withdrawal after 24 doses. Until now, there has not been a clear strategy that should be followed to avoid PML risk and in parallel reduce clinical and radiological rebound activity. In this review, we analyzed the results of clinical trials and case reports in relation to the following situations: natalizumab continuation, natalizumab discontinuation followed by full therapeutic suspension or switch to other first or second line MS treatments. Quitting all MS treatment after natalizumab increases MS activity occurrence. The results regarding the therapeutic switch are not homogeneous, so at the moment there are no established guidelines regarding natalizumab treatment after 24 administrations; the choice is currently based on the professional experience of the neurologist, and on patients’ clinical features and preferences.