A pilot study of the efficacy of IL1 blockade by anakinra in acute calcific periarthritis of the rotator cuff

Background/Purpose: Calcific periarthritis of rotator cuff can induce acute and severe shoulder pain and is accompnied by signs of acute inflammation. The calcific deposits are composed of calcium phosphate crystals such as hydroxyapatite or basic calcium phosphate. These crystals stimulate the production and release of IL1b from macrophages, in an analogous manner to MSU and CPPD crystals. As IL1 blockade is effective in reducing signs and symptoms of inflammation in acute gout, we performed a pilot study to study if it is also effective in calcific periarthritis Methods: 5 consecutive patients were included (mean age: 62, 3 females, 2 males) between March 2011 and March 2012. Symptoms of acute shoulder pain at rest had to be present for _7 days before inclusion, associated with limitation of shoulder mobility and the presence on calcification in the rotator cuff by conventional radiography. None of the patients had responded to at least 48 hours of high doses of NSAIDs. Exclusion criteria included no corticosteroid therapy in the last 2 weeks and the exclusion of other rheumatologic or infectious diseases- .Clinical evaluation consisted of patient assessment of pain (total, rest and activity) by VAS (100mm scale) at days 0, 1, 3, 15, 42 and clinical examination of shoulder mobility at days 0, 3, 15. ESR and CRP were measured at days 0, 3. Plain radiographs were performed at days 0 and 15 and an ultrasound examination (including Doppler) was performed at days 0, 3, 15. Anakinra 100mg daily was administered for 3 consecutive days after the first evaluation (day 0). Rescue analgesics were allowed and recorded. Results: At inclusion, all patients had severe shoulder pain: mean (SD) VAS day pain of 72mm (_25mm), mean VAS night pain of 96 (_ 5) and impaired shoulder mobility. CRP was elevated in all of them (mean of 3X). Treatment with anakinra lead to rapid relief of pain in all patients, starting already on the first night following the first injection. The reduction of VAS pain was particularly striking for rest pain: mean (SD) VAS of 4mm (_ 5) at day 1 and this response was maintained for the 5 patients at the end of the three injections without any need of rescue medication. Mean rest VAS was 6 (_8) at day 3. The effect on day pain was less spectacular: mean (SD) VAS at D1 of 30 (_ 18), at D3 of 27 (_ 11). Shoulder mobility also improved and the CRP normalized in 4 of 5 patients at day 3. At day 42, 4 of 5 the patients were still totally asymptomatic. On X rays and US, the calcifications were reduced in size: mean maximal diameter of 21 mm at day 0 to 12 mm at day 15, but did not disappear in any patient. The main change on US was a significant and rapid (at day 3) reduction of Doppler activity around the calcification. Conclusion: This pilot open study suggests that IL-1_ inhibition may be an interesting therapeutic approach in acute calcific periarthritis, especially in patients who have not responded adequately to NSAIDs. The effect on pain seems to be more rapid (within a few hours) than steroid injection although a randomized controlled study needs to be performed to confirm this observation.

Peripheral Nerve Neuropathy is Associated with a Glial Reaction in the Gracile Nucleus Associated with a regulation of the GABA transporter GAT-1

Allodynia (pain in response to normally non painful stimulation) and paresthesia (erroneous sensory experience) are two debilitating symptoms of neuropathic pain. These stem, at least partly, from profound changes in the non-nociceptive sensory pathway that comprises large myelinated neuronal afferents terminating in the gracile and cuneate nuclei. Further than neuronal changes, well admitted evidence indicates that glial cells (especially in the spinal cord) are key actors in neuropathic pain, in particular the possible alteration in astrocytic capacity to reuptake neurotransmitters (glutamate and GABA). Yet, the possibility of such a changed astrocytic scavenging capacity remains unexplored in the dorsal column pathway. The present study was therefore undertaken to assess whether peripheral nerve injury (spared nerve injury model, SNI) could trigger a glial reaction, and especially changes in glutamate and GABA transporters, in the gracile nucleus. SNI surgery was performed on male Sprague-Dawley rats. Seven days after surgery, rats were used for immunofluorescence (fixation and brain slicing), western-blot (fresh brain freezing and protein extraction) or GABA reuptake on synaptosomes. We found that SNI results in a profound glial reaction in the ipsilateral gracile nucleus. This reaction was characterized by an enhanced immunolabelling for microglial marker Iba1 as well as astrocytic protein GFAP (further confirmed by western-blot, p <0.05, n = 7). These changes were not observed in sham animals. Immunofluorescence and western-blot analysis shows that the GABA transporter GAT-1 is upregulated in the ipsilateral gracile nucleus (p <0.001; n = 7), with no detectable change in GAT-3 or glutamate transporters EAAT-1 and EAAT-2. Double immunoflurescence shows that GAT-1 and GFAP colocalize within the same cells. Furthermore, the upregulation of GFAP and GAT-1 were shown to occur all along the rostrocaudal axis of the gracile nucleus. Finally, synaptosomes from ipsilateral gracile nucleus show an increased capacity to reuptake GABA. Together, the data presented herein show that glial cells in the gracile nucleus react to neuropathic lesion, in particular through an upregulation of the GABA transporter GAT-1. Hence, this study points to role of an increased GABA transport in the dorsal column nuclei in neuropathic pain, calling attention to GAT-1 as a putative future pharmacological target to treat allodynia and paresthesia.

Global transcriptional programs in peripheral nerve endoneurium and DRG are resistant to the onset of type 1 diabetic neuropathy in Ins2 mice.

While the morphological and electrophysiological changes underlying diabetic peripheral neuropathy (DPN) are relatively well described, the involved molecular mechanisms remain poorly understood. In this study, we investigated whether phenotypic changes associated with early DPN are correlated with transcriptional alterations in the neuronal (dorsal root ganglia [DRG]) or the glial (endoneurium) compartments of the peripheral nerve. We used Ins2(Akita/+) mice to study transcriptional changes underlying the onset of DPN in type 1 diabetes mellitus (DM). Weight, blood glucose and motor nerve conduction velocity (MNCV) were measured in Ins2(Akita/+) and control mice during the first three months of life in order to determine the onset of DPN. Based on this phenotypic characterization, we performed gene expression profiling using sciatic nerve endoneurium and DRG isolated from pre-symptomatic and early symptomatic Ins2(Akita/+) mice and sex-matched littermate controls. Our phenotypic analysis of Ins2(Akita/+) mice revealed that DPN, as measured by reduced MNCV, is detectable in affected animals already one week after the onset of hyperglycemia. Surprisingly, the onset of DPN was not associated with any major persistent changes in gene expression profiles in either sciatic nerve endoneurium or DRG. Our data thus demonstrated that the transcriptional programs in both endoneurial and neuronal compartments of the peripheral nerve are relatively resistant to the onset of hyperglycemia and hypoinsulinemia suggesting that either minor transcriptional alterations or changes on the proteomic level are responsible for the functional deficits associated with the onset of DPN in type 1 DM.

Increased axonal regrowth of lesioned rat sciatic nerve by veratrylguanidine methane sulfonate.

Neurotrophic factors appear as essential factors for normal development and repair of the nervous tissue. Veratrylguanidine methane sulfonate, has been shown to induce important neurite outgrowth of cultured dorsal root ganglia isolated from newborn rats. Its action was similar to that of NGF and was found to be additive to that of NGF. In order to see if this compound was able to stimulate axonal growth in adult animals, we examined the effect of this substance on the regeneration of the lesioned sciatic nerve. Using histochemical, immunohistochemical and ultrastructural studies, it is shown that a single intraperitoneal injection of veratrylguanidine methane sulfonate significantly increases the axonal growth during repair of the adult rat sciatic nerve. The efficiency of this substance is explained by its good targeting and long life time in the sciatic nerve.

Spatial distribution of motor units recruited during electrical stimulation of the quadriceps muscle versus the femoral nerve.

INTRODUCTION: In this study we investigated differences in the spatial recruitment of motor units (MUs) in the quadriceps when electrical stimulation is applied over the quadriceps belly versus the femoral nerve. METHODS: M-waves and mechanical twitches were evoked using over-the-quadriceps and femoral nerve stimulation of gradually increasing intensity from 22 young, healthy subjects. Spatial recruitment was investigated using recruitment curves of M-waves recorded from the vastus medialis (VM) and vastus lateralis (VL) and of twitches recorded from the quadriceps. RESULTS: At maximal stimulation intensity (Imax), no differences were found between nerve and over-the-quadriceps stimulation. At submaximal intensities, VL M-wave amplitude was higher for over-the-quadriceps stimulation at 40% Imax, and peak twitch force was greater for nerve stimulation at 60% and 80% Imax. CONCLUSIONS: For the VM, MU spatial recruitment during nerve and over-the-quadriceps stimulation of increasing intensity occurred in a similar manner, whereas significant differences were observed for the VL. Muscle Nerve, 2013.

New fibrin conduit for peripheral nerve repair.

An ideal substitute to treat a nerve gap has not been found. Initially, silicone conduits were employed. Later, conduits were fabricated from collagen or polyesters carbonates. More recently, it has been shown that a bioresorbable material, poly-3-hydroxybutyrate (PHB), can enhance nerve repair. The present investigation shows the use of fibrin as a conduit to guide nerve regeneration and bridge nerve defects. In this study we prepared and investigated a novel nerve conduit made from fibrin glue. Using a rodent sciatic nerve injury model (10-mm gap), we compared the extent of nerve regeneration through the new fibrin conduits versus established PHB conduits. After 2 and 4 weeks, conduits containing proximal and distal stumps were harvested. We evaluated the initial axon and Schwann cell stimulation using immunohistochemistry. The conduits presented full tissue integration and were completely intact. Axons crossed the gap after 1 month. Immunohistochemistry using the axonal marker PGP 9.5 showed a superior nerve regeneration distance in the fibrin conduit compared with PHB (4.1 mm versus 1.9 mm). Schwann cell intrusion (S100 staining) was similarly enhanced in the fibrin conduits, both from the proximal (4.2 mm versus 2.1 mm) and distal ends (3.2 mm versus 1.7 mm). These findings suggest an advantage of the new fibrin conduit for the important initial phase of peripheral nerve regeneration. The use of fibrin glue as a conduit is a step toward a usable graft to bridge peripheral nerve lesions. This might be clinically interesting, given the widespread acceptance of fibrin glue among the surgical community.

KIAA1985, a Protein Mutant in Charcot-Marie-Tooth Neuropathy, Links Peripheral Nerve Myelination to Endosomal Recycling Pathways

Charcot-Marie-Tooth neuropathy (CMT) represents a heterogenous group of inherited disorders of the peripheral nervous system. One form of autosomal recessive demyelinating CMT (CMT4C, 5q32) is caused by mutations in the gene encoding KIAA1985, a protein of so far unknown function. Here we show that KIAA1985 is exclusively expressed in Schwann cells. KIAA1985 is tethered to cellular membranes through an N-terminal myristic acid anchor and localizes to the perinuclear recycling compartment. A search for proteins that interact with KIAA1985 identified the small GTPase Rab11, a key regulator of recycling endosome functions. CMT4C-related missense mutations disrupt the KIAA1985/Rab11 interaction. Protein binding studies indicate that KIAA1985 functions as a Rab11 effector, as it interacts only with active forms of Rab11 (WT and Q70L) and does not interact with the GDP locked mutant (S25N). Consistent with a function of Rab11 in Schwann cell myelination, myelin formation was strongly impaired when dorsal root ganglion neurons were co-cultured with Schwann cells infected with Rab11 S25N. Our data indicate that the KIAA1985/Rab11 interaction is relevant for peripheral nerve pathophysiology and place endosomal recycling on the list of cellular mechanisms involved in Schwann cell myelination.

Microcystic Macular Edema in Optic Nerve Atrophy: A Case Series.

Background:Microcystic macular edema can occur after optic neuropathies of various etiologies, and is easily demonstrated by OCT. We report a cohort of patients with microcystic macular edema. Patients and Methods: All patients with optic neuropathy and microcystic macular edema were enrolled. Demographics, visual function, retinal angiographies and OCT parameters were studied. Results: Nineteen patients (23 eyes) exhibited microcystic macular edema: 10 men/9 women, aged 17-91 years. Etiologies of optic nerve atrophy were compressive (5), inflammatory (4), glaucoma (3), ischemic (3), trauma (2), degenerative (1), and hereditary (1). Median visual acuity was 4/10 (NLP-12/10). Fluorescein angiography showed no leakage. Topography of the microcystic macular edema correlated with near infrared images but with visual field defects in only 26 %. OCT parameters were all abnormal. Conclusions: Microcystic macular edema is a non-specific manifestation from an optic neuropathy of any etiology. The precise mechanism leading to microcystic macular edema remains unknown but trans-synaptic retrograde degeneration with Müller cells dysfunction is likely.

Results of Anterior Tucking of the Superior Oblique Muscle Tendon in Bilateral Fourth Nerve Palsy.

Background: Bilateral fourth nerve palsy is characterised by excyclotorsion, which can be corrected by reinforcement of the anterior tendon fibres of the superior oblique muscle. Patients and Methods: A retrospective study of 40 consecutive patients with bilateral acquired fourth nerve palsy operated by a selective tuck of the anterior portion of the superior oblique tendon between 1994 and 2012 was undertaken. Horizontal, vertical and torsional deviations were measured in 9 diagnostic positions of gaze and the field of binocular single vision was evaluated with the Harms tangent screen. Postoperative follow-ups took place at 1 week, 6 months, and ≥ 3 years. Results: Preoperative mean excyclotorsion was 9° in the primary position and 15° in downgaze. These values decreased to 2° and 5° 6 months after surgery, and 2.5° and 6° at ≥ 3 years. Immediate post-operative incyclotorsion in upgaze (28 patients) and Brown syndrome (15 patients) regressed spontaneously. The median score of field of binocular single vision improved from 4 % preoperatively to 76 % postoperatively. Conclusions: The selective tuck of the anterior tendon fibers of the superior oblique tendon enables an efficient and long-lasting correction of the ocular torsion induced by bilateral trochlear palsy.