Failures of nerve regeneration caused by aging or chronic denervation are rescued by restoring Schwann cell c-Jun

After nerve injury, myelin and Remak Schwann cells reprogram to repair cells specialized for regeneration. Normally providing strong regenerative support, these cells fail in aging animals, and during chronic denervation that results from slow axon growth. This impairs axonal regeneration and causes significant clinical problems. In mice, we find that repair cells express reduced c-Jun protein as regenerative support provided by these cells declines during aging and chronic denervation. In both cases, genetically restoring Schwann cell c-Jun levels restores regeneration to control levels. We identify potential gene candidates mediating this effect and implicate Shh in the control of Schwann cell c-Jun levels. This establishes that a common mechanism, reduced c-Jun in Schwann cells, regulates success and failure of nerve repair both during aging and chronic denervation. This provides a molecular framework for addressing important clinical problems, suggesting molecular pathways that can be targeted to promote repair in the PNS.

Fístula liquórica cervical ventral simulando doença do neurônio motor: relato de caso

Introduction: Motor neuron disease is currently irreversible, and the grave implications of the diagnosis should raise concerns over missing a potencial mimic disorder. The cervical region should be carefully evaluated, since many pitfalls are encounterd there. We present a case of a longitudinal extensive ventral cervical cecerebrospinal fluid leak causing a progressive monomelic amyothrophy associated with intracranial hypotension, mimicking a motor neuron disorder. Objective: To describe the course, clinical manifestations and to raise concern about a rare disorder, potentially treatable that could mimic a motor neuron disease. Methods: A case report seen in the neuromuscular service of the federal university of São Paulo.SP. Results: Cervical pain irradiating to the left shoulder was the first symptom. Pogression to weakness of the bíceps and shoulder girdle with fasciculations happened months after. The patient also complained about severe headache worsening when lowering the head or lyind down. Eletroneuromiography showed chronic denervation. Magnetic ressonance imaging of the cervical spine demonstrated ventral dural displacement with longitudinal extensive cerebrospinal fluid colection. Epidural blood patch procedure was indicated. After the treatment the patient showed complete improvement of the headache, significant decrease in fasciculations and evolutionary strength improvement. Conclusion: We described a rare form of amyothrophy that could be associated or not with intracranial hypotension. Ventral cervical cerebralpinal fluid leak should always be on the list of differential diagnosis and early indentification should be sought, since its a treatable cause.

Failures of nerve regeneration caused by aging or chronic denervation are rescued by restoring Schwann cell c-Jun

ABSTRACTAfter nerve injury, myelin and Remak Schwann cells reprogram to repair cells specialized for regeneration. Normally providing strong regenerative support, these cells fail in aging animals, and during the chronic denervation that results from the slow growth of axons. This impairs axonal regeneration and causes a significant clinical problem. In mice, we find that repair cells express reduced c-Jun protein as the regenerative support provided by these cells declines in aging animals and during chronic denervation. In both cases, genetically restoring Schwann cell c-Jun levels restores regeneration to that in controls. We identify potential gene candidates mediating this effect and implicate Shh in the control of Schwann cell c-Jun levels. This establishes that a common mechanism, reduced c-Jun in Schwann cells, regulates the success and failure of nerve repair both during aging and chronic denervation. This provides a molecular framework for addressing important clinical problems, and suggests molecular pathways that can be targeted to promote repair in the PNS.

Mills hemiparetic or hemiplegic variant of amyotrophic lateral sclerosis

Mills hemiplegic variant of Amyotrophic lateral sclerosis (ALS) is a gradually progressive, spastic ascending or descending hemiparesis or hemiplegia without any sensory involvement. Authors presented a 47 years old female with history of gradually progressive left sided wasting of muscles including the tongue, left hemiparesis along with dysarthria and fasciculation’s of tongue and left sided muscles with left sided cortico-spinal tract signs of 2 years duration. There were no sensory as well as bowel bladder involvement. Her cognition was intact. Relevant blood and CSF examinations were within normal limit. MRI Brain and whole spine were unremarkable. Nerve conduction study was essentially normal. Electromyography(EMG) showed chronic denervation potentials which is in accordance to Revised El Escorial criteria, 2015 for the diagnosis of this extremely uncommon entity- Mills hemiplegic variant of ALS. The major challenge in diagnosis of this disease entity is to exclude other diseases/disorders that may mimic its symptomatology.

Acute and Chronic Dopaminergic Depletion Differently Affect Motor Thalamic Function

The motor thalamus (MTh) plays a crucial role in the basal ganglia (BG)-cortical loop in motor information codification. Despite this, there is limited evidence of MTh functionality in normal and Parkinsonian conditions. To shed light on the functional properties of the MTh, we examined the effects of acute and chronic dopamine (DA) depletion on the neuronal firing of MTh neurons, cortical/MTh interplay and MTh extracellular concentrations of glutamate (GLU) and gamma-aminobutyric acid (GABA) in two states of DA depletion: acute depletion induced by the tetrodotoxin (TTX) and chronic denervation obtained by 6-hydroxydopamine (6-OHDA), both infused into the medial forebrain bundle (MFB) in anesthetized rats. The acute TTX DA depletion caused a clear-cut reduction in MTh neuronal activity without changes in burst content, whereas the chronic 6-OHDA depletion did not modify the firing rate but increased the burst firing. The phase correlation analysis underscored that the 6-OHDA chronic DA depletion affected the MTh-cortical activity coupling compared to the acute TTX-induced DA depletion state. The TTX acute DA depletion caused a clear-cut increase of the MTh GABA concentration and no change of GLU levels. On the other hand, the 6-OHDA-induced chronic DA depletion led to a significant reduction of local GABA and an increase of GLU levels in the MTh. These data show that MTh is affected by DA depletion and support the hypothesis that a rebalancing of MTh in the chronic condition counterbalances the profound alteration arising after acute DA depletion state.

Effect of External Calcium and other Divalent Cations on K+ Contractures in Denervated Slow Skeletal Muscle Fibers of the Frog

The influence of Ca2+ and other divalent cations on contractile responses of slow skeletal muscle fibers of the frog (Rana pipiens) under conditions of chronic denervation was investigated.Isometric tension was recorded from slow bundles of normal and denervated cruralis muscle in normal solution and in solutions with free calcium concentration solution or in solutions where other divalent cations (Sr2+, Ni2+, Co2+ or Mn2+) substituted for calcium. In the second week after nerve section, in Ca2+-free solutions, we observed that contractures (evoked from 40 to 80 mM-K+) of non-denervated muscles showed significantly higher tensions (p<0.05), than those from denervated bundles. Likewise, in solutions where calcium was substituted by all divalent cations tested, with exception of Mn2+, the denervated bundles displayed lower tension than non-denervated, also in the second week of denervation. In this case, the Ca2+ substitution by Sr2+ caused the higher decrease in tension, followed by Co2+ and Ni2+, which were different to non-denervated bundles, as the lowest tension was developed by Mn2+, followed by Co2+, and then Ni2+ and Sr2+. After the third week, we observed a recovery in tension. These results suggest that denervation altering the binding capacity to divalent cations of the voltage sensor.

NCMP-09. NEUROLYMPHOMATOSIS, A RARE INDEX MANIFESTATION OF CD5/CD10 NEGATIVE MATURE B CELL LYMPHOMA PRESENTING AS SUBACUTE SENSORIMOTOR LAMBOSACRAL POLYRADICULONEUROPATHY

INTRODUCTION Neurolymphomatosis (NL) is a rare entity characterized by direct invasion of neoplastic cells into endoneurium of cranial or peripheral nerves, nerve roots or plexuses. It is most commonly seen with non-Hodgkin’s lymphoma with occurrence rate of 0.2%. Here we report a case of subacute length-dependent sensorimotor lumbosacral polyradiculoneuropathy secondary to NL as the first manifestation of CD5−/CD10− mature B-cell lymphoma. CASE REPORT: A 54-year old man with diabetes mellitus type 2, hypertension and psoriasis presented with subacute onset of progressive lower extremity weakness with pertinent examination findings of bilateral mildly asymmetrical distal greater than proximal lower extremities weakness, length depended hypoesthesia, fasciculations and decreased reflexes. EMG/NCS study showed active and chronic denervation changes concerning for multilevel lumbosacral polyradiculopathy. Routine blood investigations produced normal findings. CSF examination showed nucleated cells at 125 cells/HPF with lymphocyte predominance, protein at 538 mg/dL, and glucose 18 mg/dL. Flow cytometry identified mature CD5-/CD10- B cell lymphocytes. MRI spine identified marked enhancement, thickening, nodularity of cauda equine nerve roots and focus of myelopathy at the left posterior conus. Based on the clinical and radiographic findings a diagnosis of neurolymphomatosis was made and her underwent workup for systemic lymphoma. DISCUSSION Our case demonstrates the importance of comprehensive evaluation of sensorimotor polyradiculoneuropathy as rare entities such as neurolymphomatosis could mimic common etiologies.