Gianluca Isoardo

Autoimmune events during interferon beta-1b treatment for multiple sclerosis.

Autoimmune events, although rarely reported during interferon beta-1b (IFNB) treatment of relapsing-remitting (RR) multiple sclerosis (MS), may be more frequent than expected due to the many immunologic abnormalities associated with this disease. We report the prospective two-year follow-up of autoimmune events in 40 RR MS patients treated with IFNB and in 21 untreated MS controls. Thyroid and liver function and serum level of 12 autoantibodies (autoAbs) against organ- (thyroid, gastric, pancreatic) and non-organ-specific antigens were serially monitored. In contrast to control patients, autoAbs (anti-nuclear, -smooth muscle or -thyroid antigens) were detected in 13 IFNB-treated patients, and these were associated with thyroid or liver function alteration in many cases. Persistent autoimmune thyroid dysfunction occurred in three IFNB-treated patients, all of whom were women with a familial history of thyroid disease or baseline anti-thyroid autoAb positivity. For improvement of the MS relapse rate, thyroid dysfunction was adequately treated without stopping IFNB. Liver function alteration (17 IFNB-treated patients, associated with non-organ-specific autoAbs in four) was transient and did not require IFNB treatment to be stopped, with the exception of one patient who was already suffering from a drug-induced hepatopathy at baseline. During the IFNB treatment of MS, several autoimmune events may occur, indicating that thyroid and liver function and autoAbs must be carefully monitored.

Altered resting state attentional networks in diabetic neuropathic pain

Background Chronic pain can be considered as a highly salient stimulus that continuously taxes the attentional and salience processing networks, thus interfering with cognitive abilities and, more specifically, consuming attentional resources. The aim of the paper was to explore whether and how diabetic neuropathic pain (NP) affects attentional networks. Methods The authors sought to achieve this by investigating resting state functional connectivity (rsFC) in diabetic NP patients and comparing it with that of matched healthy controls. Results NP patients showed a widespread reduction in connectivity in both the dorsal and ventral attentional networks, as well as in the dorsal anterior cingulated cortex (ACC), typically implicated in salience processing. The authors also found a generalised reduction in the length of functional connections in the NP group: in all the examined networks, the Euclidean distance between connected voxels was significantly shorter in patients than in controls. Conclusion In diabetic NP, a parieto-fronto-cingulate network controlling attention to external stimuli is impaired. In line with previous studies, chronic pain can disrupt the synchrony of a common pool of brain areas, involved in self-monitoring, pain processing and salience detection.

Low-frequency BOLD fluctuations demonstrate altered thalamocortical connectivity in diabetic neuropathic pain

BackgroundIn this paper we explored thalamocortical functional connectivity in a group of eight patients suffering from peripheral neuropathic pain (diabetic pain), and compared it with that of a group of healthy subjects. We hypothesized that functional interconnections between the thalamus and cortex can be altered after years of ongoing chronic neuropathic pain.ResultsFunctional connectivity was studied through a resting state functional magnetic resonance imaging (fMRI) paradigm: temporal correlations between predefined regions of interest (primary somatosensory cortex, ventral posterior lateral thalamic nucleus, medial dorsal thalamic nucleus) and the rest of the brain were systematically investigated. The patient group showed decreased resting state functional connectivity between the thalamus and the cortex.ConclusionThis supports the idea that chronic pain can alter thalamocortical connections causing a disruption of thalamic feedback, and the view of chronic pain as a thalamocortical dysrhythmia.

Electrophysiological findings of peripheral neuropathy in newly diagnosed type II diabetes mellitus.

Abstract  This study was aimed at assessing the electrophysiological signs of peripheral neuropathy in diabetes mellitus (DM) type II patients at diagnosis. Nerve conduction studies (NCS) of median, ulnar, peroneal, tibial and sural nerves were performed in 39 newly diagnosed DM subjects and compared to those of 40 healthy controls. Metabolic indices were also investigated. Electrophysiological alterations were found in 32 (82%) of the DM patients, and more than half of them (62.2%) showed multiple (two to five) abnormal parameters. Because most of the subjects (84.4%) had from two to five nerves involved, these alterations were widespread in the seven nerves evaluated. Forty‐two percent of the patients had NCS alterations suggestive of distal median mononeuropathy, implying that metabolic factors in DM make the median nerve more susceptible to focal entrapment. A reduced sensory nerve action potential (SNAP) amplitude was observed in the median nerve in 70% of the patients, in the ulnar in 69% and in the sural nerve only in 22%. In the presence of a decrease in the SNAP amplitude of the ulnar or median nerve, the SNAP amplitude of the sural nerve was normal in 82 or 80% of the subjects, respectively. This finding may be in keeping with a distal involvement of the sensory fibres, as explored by routine median or ulnar NCS. No correlation was found between metabolic indices and NCS parameters. In conclusion, a high percentage of newly diagnosed DM patients show signs of neuropathy, and upper limb nerve sensory NCS seem to be more sensitive in detecting it than lower limb NCS.

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.

Multifocal motor neuropathy during treatment with infliximab

Dear Editor, Infliximab (Remicade ) is a chimeric human/murine immunoglobulin G1 (IgG1) anti-tumour necrosis factor-a (TNF) antibody. Although TNF antagonists are among the most potent and rapidly effective treatments for rheumatoid arthritis (RA) (Olsen and Stein, 2004), a number of adverse effects, including induction or worsening of demyelinating central nervous system diseases, have been reported (Mohan et al., 2001; Sicotte and Voskuhl, 2001). Three cases of motor neuropathy with conduction blocks (Singer et al., 2004; Rodriguez-Escalera et al., 2005) have been reported in patients on infliximab; two of these patients had Crohn’s disease and seronegative arthritis, while one had polyarthritis and Hepatitis C with mixed cryoglobulinaemia. Herein, we report yet another patient with onset of multifocal motor neuropathy (MMN) and conduction blocks during infliximab treatment. A 40-year-old woman with a 10-year history of RA was started on infliximab treatment in January 2003 (3 mg/kg intravenous every 8 weeks) with a satisfactory response in the months that followed. However, she developed asymmetric progressive weakness of right forearm flexion and of intrinsic muscles of right hand in October 2003. Neurological evaluation (January 2004) disclosed the presence of severe weakness of the right biceps brachii (0/5 according to Medical Research Scale Score), the right extensor carpi radialis, extensor digitorum communis, extensor indicis, abductor pollicis brevis, abductor digiti minimi, and interossei (3/5) and moderate weakness of the left deltoid, extensor digitorum communis, extensor index, interossei, left tibialis anterior, and gastrocnemius (4/5). Tendon reflexes were normal apart from the absence of response in the right biceps. There was no detectable sensory loss. The neurological examination was otherwise unremarkable. Nerve conduction studies showed the presence of definite conduction block in both median and ulnar nerves, right radial, left peroneus, and tibial nerves. A significant decrease in motor conduction velocity was evident in both the median nerves. Sensory conduction studies of the bilateral median, radial, ulnar and sural nerves were unremarkable. Brain and spinal cord magnetic resonance imaging and cerebrospinal fluid examination were normal. DNA analysis was negative for the presence of the 1.5-Mb deletion in chromosome 17p11.2 associated with hereditary neuropathy with liability to pressure palsy. Routine screening tests for thyroid pathologies, hepatitis, cryoglobulinaemia and vasculitis were negative. IgM anti-GM1 antibodies were positive at high titre (1 : 640) (Antigen Coated Membrane Strips Euroimmun). The patient satisfied the diagnostic criteria for MMN established by Olney (Olney et al., 2003). Infliximab treatment was stopped in March 2004, and the patient was treated with intravenous immunoglobulins (1 g/kg/day for 2 days monthly), and muscle strength progressively improved. At the last follow up, in February 2005, there was a marked increase in the muscle strength, with only residual moderate weakness (4/5) affecting only the biceps, extensors carpi radialis and interossei muscles. Nerve conduction studies demonstrated a reduction in the number of blocks. The timing of the onset of neuropathy reported in literature varies greatly, i.e., after 2 years of infliximab therapy in one case, 3 months in another (Singer et al., 2004), 14 weeks in a case reported by RodriguezEscalera et al. (2005) and after 9 months in our case. The therapeutic schedule also varied in all cases. A spontaneous remission of the neuropathy was observed in the two cases reported by Singer, after suspension of the treatment. Whilst in our case and that of RodriguezEscalera, a therapy with immunoglobulins was administered in both cases with a positive outcome. Lastly, in both our cases and the case reported by RodriguezEscalera, there was a positivity to antiganglioside antibodies. MMN was not a neurologic complication of RA (Nobile-Orazio et al., 2005), and the onset of MMN Address correspondence to: Dr. Dario Cocito, MD, U.O. Neurofisiologia Clinica, Dipartimento di Neuroscienze, Università di Torino, Via Cherasco 15, 10126 Torino, Italy, Tel: þ39-0116-335243; Fax: þ39-0116-963487; E-mail: dariococito@yahoo.it Journal of the Peripheral Nervous System 10:386–387 (2005)

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.

Autoantibodies in Multiple Sclerosis Patients Before and During IFN-β1b Treatment: Are They Correlated with the Occurrence of Autoimmune Diseases?

Autoimmune side effects, namely autoantibody (autoAb) occurrence and thyroid function alteration, have been described during interferon-beta (IFN-beta) treatment for multiple sclerosis (MS). AutoAb occurrence and autoimmune thyroid diseases are also frequently detected in MS patients free of any treatment. The aim of this study was to evaluate the relationship between IFN-beta 1b treatment, autoAb occurrence, and autoimmune diseases in MS. Thyroid and liver function and serum autoAb (antithyroid, antinuclear, anti-liver, anti-kidney microsomes, anti-smooth muscle and parietal cell antigens) occurrence were evaluated in 156 relapsing-remitting MS (RRMS) patients before and every 3 months after starting IFN-beta 1b treatment (8 MIU subcutaneously [s.c.] on alternate days). The probability of having liver or thyroid function alteration or autoAb occurrence was analyzed longitudinally with the generalized estimating equations (GEE) approach. At baseline, 16.1% of patients had autoAb. During treatment, autoAb occurred de novo in 7.2% of patients. GEE analysis showed that the probability of having autoAb at any time during IFN-beta 1b treatment did not change significantly compared with baseline. AutoAb occurring de novo rarely persisted during treatment and significantly less than those already present at baseline. Positivity for autoAb at baseline or during treatment was not correlated with the development of thyroid or liver function alteration during IFN-beta 1b treatment. Our study indicates that IFN-beta treatment is a safe treatment for MS patients, free of risk of autoimmunity and of associated liver or thyroid function alteration.

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.