Phosphorylated TDP-43 aggregates in peripheral motor nerves of patients with amyotrophic lateral sclerosis.

Phosphorylated TDP-43 (pTDP-43) aggregates in the cytoplasm of motor neurons and neuroglia in the brain are one of the pathological hallmarks of amyotrophic lateral sclerosis. Although the axons exceed the total volume of motor neuron soma by several orders of magnitude, systematic studies investigating the presence and distribution of pTDP-43 aggregates within motor nerves are still lacking. The aim of this study is to define the TDP-43/pTDP-43 pathology in diagnostic motor nerve biopsies performed on a large cohort of patients presenting with a lower motor neuron syndrome and to assess whether this might be a discriminating tissue biomarker for amyotrophic lateral sclerosis and non-amyotrophic lateral sclerosis cases. We retrospectively evaluated 102 lower motor neuron syndrome patients referred to our centre for a diagnostic motor nerve biopsy. Histopathological criteria of motor neuron disease and motor neuropathy were applied by two independent evaluators, who were blind to clinical data. TDP-43 and pTDP-43 were evaluated by immunohistochemistry, and results compared to final clinical diagnosis. We detected significant differences between amyotrophic lateral sclerosis and non-amyotrophic lateral sclerosis cases in pTDP-43 expression in myelinated fibres: axonal accumulation was detected in 98.2% of patients with amyotrophic lateral sclerosis versus 30.4% of non-amyotrophic lateral sclerosis samples (P < 0.0001), while concomitant positive staining in Schwan cell cytoplasm was found in 70.2% of patients with amyotrophic lateral sclerosis versus 17.4% of patients who did not have amyotrophic lateral sclerosis (P < 0.001). Importantly, we were also able to detect pTDP-43 aggregates in amyotrophic lateral sclerosis cases displaying normal features at standard histopathological analysis. Our findings demonstrated that a specific pTDP-43 signature is present in the peripheral nervous system of patients with amyotrophic lateral sclerosis, and could be exploited as a specific, accessible tissue biomarker. The detection of pTDP-43 aggregates within motor nerves of living patients with amyotrophic lateral sclerosis, occurring before axonal degeneration, suggests that this is an early event that may contribute to amyotrophic lateral sclerosis pathogenesis.

Feasibility of a fascial flap to avoid anterior transposition of unstable Ulnar nerve: A cadaver study.

Background: Compression of the ulnar nerve at the elbow is the second most frequent site of nerve compression in the upper limb. Upon release, anteposition of the nerve may be necessary to avoid dislocation of the latter when unstable. Numerous techniques are described in the literature (subcutaneous transposition, intramuscular transposition, subfascial transposition, medial epicondylectomy …), none of which is without complications. Based on Han's work, the authors propose a technique of covering the ulnar nerve with epicondylar fascial flap, avoiding transposition, but ensuring good stability of the ulnar nerve. Methods: As part of the SICM (Italian Society of Hand Surgery) cadaver dissection course (ICLO, Verona, Italy) the authors dissected 36 elbows, of which 20 presented subluxation of the ulnar nerve after its decompression. The fascial flap was therefore made on these 20 elbows, coming from 14 different donors (9 men, 5 women) with an average age of 78 years. The diameter of the ulnar nerve was then measured (at the level of the passage in the cubital canal), the diameter of the newly formed canal, the difference between the two previous measurements (residual space in the flexed elbow canal), and it was verified whether the ulnar nerve was unstable once covered by the flap. Results: The mean diameter of the ulnar nerve was 5.1 mm (range 4-6), while the mean diameter of the neo-canal was 10.1 mm (range 8-11) in elbow extension and 8.9 mm (range 7-10) in elbow flexion. The remaining space in the flexed elbow canal was 3.8 mm (range 3-5).In none of the 20 cases the ulnar nerve was dislocated after having made the fascial flap. Conlusions: In light of the results obtained, the authors think that the use of the epicondylar fascial flap may be a solution to keep in mind to avoid dislocation of the ulnar nerve when it becomes unstable following its decompression. This work obviously needs clinical confirmation on living patients. Level of evidence: V.

Motor nerve biopsy: clinical usefulness and histopathological criteria.

Early differential diagnosis of motor neuropathies (MN) and lower motor neuron diseases (LMND) is important, as prognosis and therapeutic approaches are different. We evaluated the diagnostic contribution of the biopsy of the motor branch of the obturator nerve and gracilis muscle in 21 consecutive patients in which, after proper clinical and neurophysiological studies, the differential diagnosis was still open. At baseline, motor biopsy was performed; diagnostic confirmation was obtained by 2-year clinical follow-up. Our results support the usefulness of this diagnostic procedure for selected cases of MN and LMND.

Chronic motor axonal neuropathy.

The identification of a distinct subgroup of patients within the spectrum of lower motor neuron syndromes (LMNS) is crucial as some are potentially treatable. We describe the clinical and neuropathological characteristics of a patient presenting with a rapidly progressive LMNS associated with high titers of anti-GM1 antibodies, leading to respiratory failure within 10 months. Histopathological study of a biopsy of a obturator nerve motor branch demonstrated a predominantly axonal motor neuropathy, while electron microscopy analysis localized macrophages located within the periaxonal space. Immunohistochemistry demonstrated deposits of complement activation products (C3i) and immunoglobulins (IgM) on nerve fibers. The patient's clinical, immunological and pathological findings are consistent with a diagnosis of a chronic motor axonal neuropathy (CMAN), likely of immune-mediated origin.

Feasibility of Homodigital Flexor Digitorum Superficialis transposition, a new technique for A2-C1 pulleys reconstruction: A kinematic cadaver study.

INTRODUCTION: Homodigital flexor digitorum superficialis transposition (HFT) is proposed as a new technique for A2-C1 pulley reconstruction. Flexor digitorum superficialis is transposed on the proximal phalanx and inserted on the pulley rims, crossing over flexor digitorum profundus and acting as a pulley. MATERIALS AND METHODS: The kinematic feasibility was investigated in a cadaveric bowstring model (after A2 and C1 pulley removal) on 22 fingers (thumb excluded). RESULTS: HFT was effective in restoring the correct flexion of proximal and distal interphalangeal joints, compared to bowstring model. No adverse events were registered. CONCLUSION: HFT is a feasible technique. Clinical application is encouraged.

Unraveling gene expression profiles in peripheral motor nerve from amyotrophic lateral sclerosis patients: insights into pathogenesis.

The aim of the present study is to investigate the molecular pathways underlying amyotrophic lateral sclerosis (ALS) pathogenesis within the peripheral nervous system. We analyzed gene expression changes in human motor nerve diagnostic biopsies obtained from eight ALS patients and seven patients affected by motor neuropathy as controls. An integrated transcriptomics and system biology approach was employed. We identified alterations in the expression of 815 genes, with 529 up-regulated and 286 down-regulated in ALS patients. Up-regulated genes clustered around biological process involving RNA processing and protein metabolisms. We observed a significant enrichment of up-regulated small nucleolar RNA transcripts (p = 2.68*10-11) and genes related to endoplasmic reticulum unfolded protein response and chaperone activity. We found a significant down-regulation in ALS of genes related to the glutamate metabolism. Interestingly, a network analysis highlighted HDAC2, belonging to the histone deacetylase family, as the most interacting node. While so far gene expression studies in human ALS have been performed in postmortem tissues, here specimens were obtained from biopsy at an early phase of the disease, making these results new in the field of ALS research and therefore appealing for gene discovery studies.