Patrizia Dacci

A smooth transition protocol for patients with multifocal motor neuropathy going from intravenous to subcutaneous immunoglobulin therapy: An open-label proof-of-concept study

Intravenous immunoglobulin (IVIG) is the first‐line therapy for multifocal motor neuropathy (MMN). This open‐label multi‐centre study (NCT00701662) assessed the efficacy, safety, and convenience of subcutaneous immunoglobulin (SCIG) in patients with MMN over 6 months, as an alternative to IVIG. Eight MMN patients (42–66 years), on stable IVIG dosing, received weekly SCIG at doses equivalent to previous IVIG using a “smooth transition protocol”. Primary efficacy endpoint was the change from baseline to week 24 in muscle strength. Disability, motor function, and health‐related quality of life (HRQL) endpoints were also assessed. One patient deteriorated despite dose increase and was withdrawn. Muscle strength, disability, motor function, and health status were unchanged in all seven study completers who rated home treatment as extremely good. Four experienced 18 adverse events, of which only two were moderate. This study suggests that MMN patients with stable clinical course on regular IVIG can be switched to SCIG at the same monthly dose without deterioration and with a sustained overall improvement in HRQL.

Analyzing Histopathological Features of Rare Charcot-Marie-Tooth Neuropathies to Unravel Their Pathogenesis

BACKGROUND Charcot-Marie-Tooth (CMT) neuropathies are very heterogeneous disorders from both a clinical and genetic point of view. The CMT genes identified so far encode different proteins that are variably involved in regulating Schwann cells and/or axonal functions. However, the function of most of these proteins still remains to be elucidated. OBJECTIVE To characterize a large cohort of patients with demyelinating, axonal, and intermediate forms of CMT neuropathy. DESIGN A cohort of 131 unrelated patients were screened for mutations in 12 genes responsible for CMT neuropathies. Demyelinating, axonal, and intermediate forms of CMT neuropathy were initially distinguished as usual on the basis of electrophysiological criteria and clinical evaluation. A sural nerve biopsy was also performed for selected cases. Accordingly, patients underwent first-level analysis of the genes most frequently mutated in each clinical form of CMT neuropathy. RESULTS Although our cohort had a particularly high percentage of cases of rare axonal and intermediate CMT neuropathies, we found mutations in 40% of patients. Among identified changes, 7 represented new mutations occurring in the MPZ, GJB1, EGR2, MFN2, NEFL, and HSBP1/HSP27 genes. Histopathological analysis performed in selected cases revealed morphological features, which correlated with the molecular diagnosis and provided evidence of the underlying pathogenetic mechanism. CONCLUSION Clinical and pathological analysis of patients with CMT neuropathies contributes to our understanding of the molecular mechanisms of CMT neuropathies.

The extracellular matrix affects axonal regeneration in peripheral neuropathies

Objective: Recent evidence in animal models suggests that components of the extracellular matrix (ECM) play a primary role in peripheral nerve degeneration and regeneration. Methods: We investigated the expression of several ECM molecules in human sural nerves by immunohistochemistry, Western blot, and reverse transcriptase PCR analysis. To unravel the possible role of these molecules in nerve regeneration, we compared results obtained from nerves with abundant signs of regeneration with those with complete absence of axonal regeneration. The role of some ECM components on neurite extension was further tested in dorsal root ganglion cultures. Results: We observed that the ECM composition significantly differs in regenerating compared with nonregenerating nerves, independently from their etiologic background. Fibronectin was abundantly expressed in regenerating nerves, whereas vitronectin and fibrin(ogen) prevailed in nonregenerating nerves. Whereas fibronectin is secreted by endoneurial cells, in vivo and vitro studies showed that the source of vitronectin and fibrin(ogen) is the bloodstream. Conclusions: These data indicate that nerve regeneration is impaired in the presence of breaches in the blood–nerve barrier or impaired extracellular matrix (ECM) degradation that leads to accumulation of plasma vitronectin and fibrin(ogen). The transformation into mature, fibronectin-enriched ECM is necessary for efficient nerve regeneration in humans.

Epidermal innervation morphometry by immunofluorescence and bright-field microscopy

We investigated the agreement between simple indirect immunofluorescence (IF) and bright‐field immunohistochemistry (BFI) on free‐floating sections for intraepidermal nerve fiber density (IENFD) quantification. Fifty‐five healthy subjects and 63 patients with probable small fiber neuropathy (SFN) underwent two adjacent skin biopsies at the distal leg processed by IF and BFI technique. Agreement between IENFD pairs obtained by each method was assessed by Bland–Altman testing. The area under the curve of the receiving operating characteristics (ROC) curves was used to compare the discrimination ability. The diagnostic judgment was based on sex and age‐adjusted normative values. IF and BFI showed good correlation (r = 0.81), with a ratio of about 2:1 and a mean difference of 5.5 ± 3.0 IENF per millimeter between paired measures, as demonstrated by linear regression and Bland–Altman test analyses. The square root transformation confirmed a Poisson distribution of the data and a fixed bias between IF and BFI measurements. The ROC curves analysis demonstrated a striking overlap between IF and BFI (0.83 and 0.82; p = 0.72). The diagnosis of SFN disagreed in only 6.7% of cases when the judgment was based on a difference of >1 IENF from 5% cut‐off value. IF and BFI showed comparable diagnostic efficiency when referred to appropriate normative reference values.

Foot pad skin biopsy in mouse models of hereditary neuropathy.

Numerous transgenic and knockout mouse models of human hereditary neuropathies have become available over the past decade. We describe a simple, reproducible, and safe biopsy of mouse skin for histopathological evaluation of the peripheral nervous system (PNS) in models of hereditary neuropathies. We compared the diagnostic outcome between sciatic nerve and dermal nerves found in skin biopsy (SB) from the hind foot. A total of five animal models of different Charcot‐Marie‐Tooth neuropathies, and one model of congenital muscular dystrophy associated neuropathy were examined. In wild type mice, dermal nerve fibers were readily identified by immunohistochemistry, light, and electron microscopy and they appeared similar to myelinated fibers in sciatic nerve. In mutant mice, SB manifested myelin abnormalities similar to those observed in sciatic nerves, including hypomyelination, onion bulbs, myelin outfolding, redundant loops, and tomacula. In many strains, however, SB showed additional abnormalities—fiber loss, dense neurofilament packing with lower phosphorylation status, and axonal degeneration—undetected in sciatic nerve, possibly because SB samples distal nerves. SB, a reliable technique to investigate peripheral neuropathies in human beings, is also useful to investigate animal models of hereditary neuropathies. Our data indicate that SB may reveal distal axonal pathology in mouse models and permits sequential follow‐up of the neuropathy in an individual mouse, thereby reducing the number of mice necessary to document pathology of the PNS.

Ischemic stroke as clinical onset of POEMS syndrome

Peripheral neuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome is a rare, multisystemic disorder associated with plasma cell dyscrasia. Ischemic stroke can complicate the clinical picture, with an overall 5-year risk of 13.4 % [1]. In recent studies, nine cases of recurrent stroke have been reported [2–4]. We describe the unique case of two patients in whom stroke was the presenting feature of POEMS syndrome. One of them experienced a recurrent stroke. A 49-year-old man complained of acute aphasia and right-side hemiparesis that recovered in 2 days, due to multiple ischemic lesions (Fig. 1). He did not have any risk factors for cerebrovascular diseases except for cigarette smoking (20 daily). Hematological exams were normal except for hyperhomocysteinemia (20 mmol/L; n.v. 5–15 mmol/L), thrombocytosis (511 9 10/L; n.v. 150–450) and IgA-k paraproteinemia. Electrocardiograms and carotid, vertebral, and transcranial Doppler ultrasonography findings were negative. Transesophageal echocardiogram disclosed a patent foramen ovale and the patient underwent percutaneous closure. One year later, he complained of progressive tingling, spontaneous pain, acrocyanosis, distal limb weakness and dysautonomic symptoms (erectile dysfunction, increased sweating and orthostatic dizzness). Hematological exams were unchanged. Screenings for systemic vasculitis, viral infections, malabsorption, and connective tissue disorders were negative. Based on cerebrospinal fluid (CSF) examination (protein 99 mg/dL; n.v. \45 mg/dL) and nerve conduction study (NCS) findings, he was diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy. Oral prednisone and monthly intravenous immunoglobulin (IVIG) treatment for 6 months were both unsuccessful. When referred to us, the neurological examination showed decreased proprioception at the first metatarsal joints (3/8, Rydel-Seiffer 64 Hz tuning fork), hand weakness, impaired walking on the heels, lower limb areflexia, acrocyanosis and hyperkeratosis of hypothenar eminences. NCS showed an axonal sensorimotor neuropathy, confirmed by sural nerve biopsy that demonstrated intense vascular endothelial growth factor (VEGF) deposition (Fig. 2). Abdominal echography revealed hepato-splenomegaly. As a result, he was diagnosed with POEMS syndrome. A bone marrow biopsy demonstrated lymphoid aggregates with rimmings of k-restricted monoclonal Ig and plasma cells. At a 12-month follow-up, evaluations indicated that an autologous stem cell transplant had successfully reduced neuropathy symptoms. A 46-yr-old man presented with facio-brachial left palsy caused by right temporal-parietal ischemic stroke (Fig. 1) that fully recovered in 2 weeks. Secondary prevention with acetylsalicylic acid was started. One month later, he complained of paraesthesia and progressive P. Dacci E. Dalla Bella G. Lauria (&) Headache and Neuroalgology Unit, IRCCS Foundation, ‘‘Carlo Besta’’ Neurological Institute, Via Celoria 11, 20133 Milan, Italy e-mail: glauria@istituto-besta.it

Practice of yoga may cause damage of both sciatic nerves: a case report.

Sciatic nerve traumatic damage very rarely occurs bilaterally. We describe the case of a 67-year-old woman who reported a bilateral traumatic lesion of the sciatic nerve during practice of yoga. Nerve conduction studies showed a bilateral sciatic nerve neuropathy, mostly affecting the peroneal component. Lumbar plexus MRI documented regular anatomical features of the main principal nerve roots with bilateral T2 signal alteration of roots L4, L5 and S1 that extended into the sciatic nerves showing both increase in size, probably related to chronic injury of nerves, and an alteration in diffusion signal that suggested a recent acute overlapped process.

Myelin protein zero Arg36Gly mutation with very late onset and rapidly progressive painful neuropathy

Mutations in myelin protein zero (MPZ) protein result in a wide spectrum of peripheral neuropathies, from congenital hypomyelinating to late onset sensory and motor axonal forms. In some patients, neuropathic pain can be a prominent symptom, making the diagnosis challenging mainly in those with other risk factors for neuropathy. We describe a 77‐year‐old woman with impaired glucose tolerance presenting with rapidly progressive axonal neuropathy leading to excruciating pain and severe weakness of lower limbs within 2 years from the onset. Her son abruptly complained of similar painful symptoms at the age of 47 years. Molecular analysis revealed a novel heterozygous missense mutation (c.106A>G) in MPZ exon 2, causing the substitution of arginine‐36 with glycine in the extracellular domain. Our observation suggests that MPZ‐related neuropathy should be considered in the diagnostic work up of patients with painful axonal neuropathy even presenting with rapid progression and at a very late age of onset.

Functioning and quality of life in patients with neuropathy associated with anti-MAG antibodies

Although anti-myelin-associated glycoprotein (MAG) antibody neuropathy is reported as a slowly progressive disease, it can lead to significant disability and impairment of health-related quality of life (HR-QoL) and social participation. The aim of this cross-sectional study was to evaluate the functioning and HR-QoL determinants in 67 patients with anti-MAG neuropathy in terms of the International Classification of Functioning, Disability, and Health (ICF). Evaluations included: Medical Research Council (MRC) sum score, Sensory Modality Sum score (SMS), Berg balance scale (BBS), Fatigue Severity Scale (FSS), Visual Analogue Scale (VAS) for pain, 9-Hole Peg Test (9-HPT), 6-min Walk Distance (6MWD), Impact on Participation and Autonomy (IPA) and the physical component score (PCS) and mental component score (MCS) of the short-form-36 health status scale (SF-36) HR-QoL measure. In the regression models, 6MWD was the most reliable predictor of PCS, explaining the 52% of its variance, while the strongest determinants of 6MWD were BBS and FSS, explaining the 41% of its variance. Consistently, VAS and BBS were good predictor of PCS, explaining together 54% of its variance. FSS was the most reliable determinant of MCS, explaining 25% of its variance. SMS and MRC were not QoL determinants. The results of our study suggest that 6MWD and FSS might be considered as potential meaningful outcome measures in future clinical trials. Furthermore, neurorehabilitation interventions aimed at improving balance and walking performance, fatigue management, and specific pain relief therapy should be considered to ameliorate participation in social life and HR-QoL in anti-MAG neuropathy patients.