Long-Term Neuromodulatory Effects of Repetitive Transcranial Magnetic Stimulation (rTMS) on Plasmatic Matrix Metalloproteinases (MMPs) Levels and Visuospatial Abilities in Mild Cognitive Impairment (MCI).

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique that is used against cognitive impairment in mild cognitive impairment (MCI) and Alzheimer's disease (AD). However, the neurobiological mechanisms underlying the rTMS therapeutic effects are still only partially investigated. Maladaptive plasticity, glial activation, and neuroinflammation, including metalloproteases (MMPs) activation, might represent new potential targets of the neurodegenerative process and progression from MCI to AD. In this study, we aimed to evaluate the effects of bilateral rTMS over the dorsolateral prefrontal cortex (DLPFC) on plasmatic levels of MMP1, -2, -9, and -10; MMPs-related tissue inhibitors TIMP1 and TIMP2; and cognitive performances in MCI patients. Patients received high-frequency (10 Hz) rTMS (MCI-TMS, n = 9) or sham stimulation (MCI-C, n = 9) daily for four weeks, and they were monitored for six months after TMS. The plasmatic levels of MMPs and TIMPs and the cognitive and behavioral scores, based on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Beck Depression Inventory II, Beck Anxiety Inventory, and Apathy Evaluation Scale, were assessed at baseline (T0) and after 1 month (T1) and 6 months (T2) since rTMS. In the MCI-TMS group, at T2, plasmatic levels of MMP1, -9, and -10 were reduced and paralleled by increased plasmatic levels of TIMP1 and TIMP2 and improvement of visuospatial performances. In conclusion, our findings suggest that targeting DLPFC by rTMS might result in the long-term modulation of the MMPs/TIMPs system in MCI patients and the neurobiological mechanisms associated with MCI progression to dementia.

Neurophysiological Hallmarks of Axonal Degeneration in CIDP Patients: A Pilot Analysis.

In this work, we aim to identify sensitive neurophysiological biomarkers of axonal degeneration in CIDP patients. A total of 16 CIDP patients, fulfilling the clinical and neurophysiological criteria for typical CIDP, treated with subcutaneous immunoglobulin (ScIg) (0.4 g/kg/week) were evaluated at baseline (before ScIg treatment) and after long-term treatment with ScIg (24 months) by clinical assessment scales, nerve conduction studies (NCS) and electromyography (EMG). Conventional and non-conventional neurophysiological parameters: motor unit potential (MUP) analysis, MUP thickness and size index (SI)] and interference pattern (IP) features were evaluated after long-term treatment (24 months) and compared with a population of 16 healthy controls (HC). An increase of distal motor latency (DML) and reduced compound motor action potential (CMAP) amplitude and area in CIDP patients suggest axonal damage of motor fibers, together with a significant increase of MUP amplitude, duration and area. Analysis of non-conventional MUP parameters shows no difference for MUP thickness; however, in CIDP patients, SI is increased and IP area and amplitude values are lower than HC. Despite clinical and neurophysiological improvement after ScIg treatment, neurophysiological analysis revealed axonal degeneration of motor fibers and motor unit remodeling. Correlation analysis shows that the axonal degeneration process is related to the diagnostic and therapeutic delay. MUP area and SI parameters can detect early signs of axonal degeneration, and their introduction in clinical practice may help to identify patients with the worst outcome.

Whole plantar nerve conduction study: A new tool for early diagnosis of peripheral diabetic neuropathy.

AIMS: Peripheral neuropathy (PN) affects two-thirds of type 2 diabetes patients (T2DM). According to diabetic PN length-dependent pattern, neurophysiological evaluation of foot-sole nerves might increase NCS diagnostic sensitivity, hence allowing early diagnosis of PN. Thus, we aim to assess the ability of whole plantar nerve (WPN) conduction in diabetic PN early diagnosis. METHODS: This is a single center prospective observational cohort study on 70 T2DM patients referred to Internal Medicine Unit of A.O.U. "Luigi Vanvitelli" between October 2019/October 2020. Primary endpoint was WPN efficacy assessment in PN early detection. As secondary, we evaluated (i) a potential cut-off of SNAPs amplitude by WPN and (ii) WPN diagnostic accuracy vs. gold-standard distal sural nerve conduction. RESULTS: ROC curve analysis allowed to establish two potential cut-offs for people aged ≤60 years (AUROC: 0.83, 95%CI: 0.69-0.96, p < 0.001) and ≤60 years (AUROC: 0.76, 95%CI: 0.59-0.93, p = 0.017). In depth, we fixed a cut-off of WPN-SNAP amplitude of 4.55 µV and 2.65 µV, respectively, with subsequent 48 patients classified as PN-T2DM. CONCLUSIONS: Our data support WPN conduction study reliability in characterizing the most distal sensory nerve fibers at lower limbs. Thus, WPN may represent an extremely useful diagnostic tool for diabetic PN early detection.

Altered sensory-motor plasticity in amyotrophic lateral sclerosis and complex regional pain type I syndrome: a shared mechanism?

Besides the prominent motor syndrome, some patients affected by amyotrophic lateral sclerosis (ALS) complain of many non-motor symptoms during the disease course, in particular chronic pain that significantly reduces the patients' quality of life. Complex regional pain syndrome (CRPS) is a rare painful condition, rarely described in ALS patients. We present the clinical case of a patient affected by spinal-onset ALS, who developed a type I CRPS (CRPS-I) at the upper limbs. To the best of our knowledge, only five cases of ALS-CRPS-I have been reported and they share some peculiar features: ALS spinal-onset with classic phenotype, rapid deterioration of quality of life, and a poor prognosis. Different mechanisms have been supposed in the pathogenesis of both CRPS and ALS, resulting in distinctive clinical presentations. Altered plasticity of brain sensory and motor areas might represent a common feature that seems to influence negatively ALS progression and prognosis.

Clinical-neurophysiological correlations in chronic inflammatory demyelinating polyradiculoneuropathy patients treated with subcutaneous immunoglobulin.

INTRODUCTION: Despite the well-described clinical efficacy of long-term subcutaneous immunoglobulin (LT-SCIg) in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) patients, the neurophysiological effects of SCIg have been followed only for a short time and were not correlated with clinical parameters. METHODS: Fourteen CIDP patients were evaluated at baseline and after LT-SCIg administration for 24 to 48 months. Nerve conduction studies were performed and clinical features were assessed for: (a) overall strength, by Medical Research Council sum score; (b) sensory function, by Inflammatory Neuropathy Cause And Treatment score; (c) disability, by Rasch-built overall disability scale; (d) quality of life (QoL), by the EuroQol Visual Analog Scale. RESULTS: LT-SCIg treatment improved clinical and neurophysiological features, preserving strength and improving sensory deficits, disability, and QoL. Clinical scores correlated with the amplitude of distal motor action (dCMAP) and sensory nerve action (SNAP) potentials. DISCUSSION: LT-SCIg treatment demonstrates efficacy in maintaining and continuing clinical improvement at 24 to 48 months after start of treatment. dCMAP and SNAP amplitudes represent useful prognostic factors for functional outcome.

Stimulated single-fiber electromyography (sSFEMG) in Lambert-Eaton syndrome.

OBJECTIVE: To report the clinical features and the neurophysiological approach of a patient with Lambert-Eaton myasthenic syndrome (LEMS), highlighting the diagnostic role of the stimulated single fiber electromyography (sSFEMG). CASE REPORT: A 60-year-old woman presenting with the LEMS triad (proximal and axial weakness, autonomic dysfunction and areflexia) was evaluated by neurophysiological tests (electroneuromyography, repetitive stimulation test (TSR), voluntary and stimulated SFEMG). We reported: 1) increase of compound muscle action potential (CMAP) amplitude (>60%) following brief isometric exercise compared to the rest (baseline); 2) decremental/incremental response of CMAP amplitude at low- (3 Hz) and high-frequency (30 Hz) repetitive stimulation test (RST), respectively; 3) increased neuromuscular jitter and blocking at voluntary single-fiber electromyography (vSFEMG); 4) stimulation rate-dependent reduction of the neuromuscular jitter and blocking at sSFEMG. Diagnosis was confirmed by serological demonstration of circulating voltage gated calcium channels (VGCC) antibodies. SIGNIFICANCE: The present case highlights the role of the sSFEMG in the diagnosis of LEMS, underling the stimulation rate-dependency of both neuromuscular jitter and blocks.

Long-term neurophysiological and clinical response in patients with chronic inflammatory demyelinating polyradiculoneuropathy treated with subcutaneous immunoglobulin.

OBJECTIVE: To assess the long-term effects of subcutaneous immunoglobulin (SCIg) on neurophysiological and clinical parameters in patients affected by chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). METHODS: 16 drug-naïve CIDP patients, fulfilling the clinical and neurophysiological criteria for typical CIDP, were treated with one cycle of intravenous immunoglobulin (IVIg) (0.4 g/kg/day for 5 consecutive days) and then shifted to the subcutaneous treatment (SCIg) (0.4 g/kg/week) after 4 weeks. Patients were evaluated (i) at the diagnosis (t0), (ii) after 4 weeks since the last IVIg infusion (t1), and (iii) after long-term treatment with SCIg (t2 = 12 months; t3 = 24 months) by (1) neurophysiological parameters of nerve conduction studies and (2) clinical assessment scales for evaluation of (a) strength, by medical research council (MRC) sum score, (b) sensory functions, by inflammatory neuropathy care and treatment (INCAT) sensory sum score and (c) disability, by overall disability sum score (ODSS). RESULTS: Long-term SCIg treatment induced a significant improvement of neurophysiological parameters, in particular primary demyelinating features of nerve conduction, and clinical variables. Correlation analysis showed (1) a direct positive correlation between the MRC sum score and the amplitude of the distal compound muscle action potential (dCMAP) amplitude, (2) an inverse correlation between dCMAP amplitude and ODSS score, and (3) an inverse correlation between sensory nerve action potential (SNAP) amplitude and the INCAT sensory sum score. CONCLUSIONS: Our findings revealed a significant long-term effect of the SCIg treatment on the neurophysiological parameters, associated with improvement of global strength, sensory deficits and overall disability in patients with CIDP. SIGNIFICANCE: Early start of the SCIg treatment after IVIg infusions induced a significant and long-term improvement of clinical and neurophysiological parameters in CIDP patients.