Injection of the sciatic nerve with TMEV: a new model for peripheral nerve demyelination

Demyelination of the human peripheral nervous system (PNS) can be caused by diverse mechanisms including viral infection. Despite association of several viruses with the development of peripheral demyelination, animal models of the condition have been limited to disease that is either autoimmune or genetic in origin. We describe here a model of PNS demyelination based on direct injection of sciatic nerves of mice with the cardiovirus, Theiler's murine encephalomyelitis virus (TMEV). Sciatic nerves of FVB mice develop inflammatory cell infiltration following TMEV injection. Schwann cells and macrophages are infected with TMEV. Viral replication is observed initially in the sciatic nerves and subsequently the spinal cord. Sciatic nerves are demyelinated by day 5 post-inoculation (p.i.). Injecting sciatic nerves of scid mice resulted in increased levels of virus recovered from the sciatic nerve and spinal cord relative to FVB mice. Demyelination also occurred in scid mice and by 12 days p.i., hindlimbs were paralyzed. This new model of virus-induced peripheral demyelination may be used to dissect processes involved in protection of the PNS from viral insult and to study the early phases of lesion development.     

Optimal duration of percutaneous microballoon compression for treatment of trigeminal nerve injury简

Percutaneous microballoon compression of the trigeminal ganglion is a brand new operative technique for the treatment of trigeminal neuralgia. However, it is unclear how the procedure mediates pain relief, and there are no standardized criteria, such as compression pressure, compression time or balloon shape, for the procedure. In this study, percutaneous microballoon compression was performed on the rabbit trigeminal ganglion at a mean inflation pressure of 1,005 ± 150 mmHg for 2 or 5 minutes. At 1, 7 and 14 days after percutaneous microballoon compression, the large-diameter myelinated nerves displayed axonal swelling, rupture and demyelination under the electron microscope. Fragmentation of myelin and formation of digestion chambers were more evident after 5 minutes of compression. Image analyzer results showed that the diameter of trigeminal ganglion cells remained unaltered after compression. These experimental findings indicate that a 2-minute period of compression can suppress pain transduction. Immunohistochemical staining revealed that vascular endothelial growth factor expression in the ganglion cells and axons was significantly increased 7 days after trigeminal ganglion compression, however, the changes were similar after 2-minute compression and 5-minute compression. The upregulated expression of vascular endothelial growth factor in the ganglion cells after percutaneous microballoon compression can promote the repair of the injured nerve. These findings suggest that long-term compression is ideal for patients with recurrent trigeminal neuralgia.     

NG2 cells (polydendrocytes): Listeners to the neural network with diverse properties

NG2 cells (polydendrocytes) are the fourth major non‐neuronal cell type in the central nervous system parenchyma. They exhibit diverse properties, ranging from their well‐established role as oligodendrocyte precursors to their ability to respond to neurotransmitters released by synaptic and non‐synaptic mechanisms. The functional diversity of NG2 cells has prompted the question of whether they represent a single cellular entity or multiple distinct cell populations. This review first summarizes recent findings on the nature and mechanism underlying the diversity of NG2 cells with regard to their proliferative and differentiation behavior. This will be followed by a synopsis of observations on how their microenvironment, particularly neuronal activity, influences their dynamic behavior, and how these changes in NG2 cells could in turn influence neural function and animal behavior. GLIA 2014;62:1195–1210     

Inflammatory infratentorial progressive multifocal leukoencephalopathy in a patient with rheumatoid arthritis

An 84–year‐old man with rheumatoid arthritis (RA) treated with methotrexate, developed progressive confusion and cerebellar symptoms, and died approximately 2 months later. Neuropathological examination revealed progressive multifocal leukoencephalopathy (PML) involving the cerebellum and brainstem. The affected tissues displayed intense infiltrations by CD8+ T‐cells and microglia. JC virus was localized in oligodendroglia and cerebellar granule cells. This case illustrates unusual localization of inflammatory PML in a patient with RA treated with methotrexate.     

Axonal dysfunction,dysmyelination, and conduction failure in hereditary neuropathy with liability to pressure palsies

Introduction: Patients with hereditary neuropathy with liability to pressure palsies (HNPP) manifest with episodes of focal paresis when exposed to mechanical stress, although the basis for vulnerability to conduction block remains relatively unexplained. Methods: Axonal excitability techniques were utilized to provide insights into pathophysiological mechanisms in 13 HNPP patients, stimulating median motor and sensory axons at the wrist. Results: In HNPP, distal latencies were prolonged, and motor and sensory amplitudes were reduced. Threshold was increased. Depolarizing and hyperpolarizing electrotonus was greater, and resting current–threshold slope was reduced. There were greater threshold changes in superexcitability, and refractoriness was decreased. Conclusions: Taken together, excitability testing in patients with HNPP established axonal hyperpolarization in both motor and sensory axons that may be attributable to changes in nerve architecture. In turn, the hyperpolarized resting membrane potential in HNPP may be a major predisposing factor for development of conduction block with mechanical stresses. Muscle Nerve 49 : 858–865, 2014     

Extensive subpial cortical demyelination is specific to multiple sclerosis

Cortical demyelinated lesions are frequent and widespread in chronic multiple sclerosis (MS) patients, and may contribute to disease progression. Inflammation and related oxidative stress have been proposed as central mediators of cortical damage, yet meningeal and cortical inflammation is not specific to MS, but also occurs in other diseases. The first aim of this study was to test whether cortical demyelination was specific for demyelinating CNS diseases compared to other CNS disorders with prominent meningeal and cortical inflammation. The second aim was to assess whether oxidative tissue damage was associated with the extent of neuroaxonal damage. We studied a large cohort of patients diagnosed with demyelinating CNS diseases and non‐demyelinating diseases of autoimmune, infectious, neoplastic or metabolic origin affecting the meninges and the cortex. Included were patients with MS, acute disseminated encephalomyelitis (ADEM), neuromyelitis optica (NMO), viral and bacterial meningoencephalitis, progressive multifocal leukoencephalopathy (PML), subacute sclerosing panencephalitis (SSPE), carcinomatous and lymphomatous meningitis and metabolic disorders such as extrapontine myelinolysis, thus encompassing a wide range of adaptive and innate cytokine signatures. Using myelin protein immunohistochemistry, we found cortical demyelination in MS, ADEM, PML and extrapontine myelinolysis, whereby each condition showed a disease‐specific histopathological pattern. Remarkably, extensive ribbon‐like subpial demyelination was only observed in MS, thus providing an important pathogenetic and diagnostic cue. Cortical oxidative injury was detected in both demyelinating and non‐demyelinating CNS disorders. Our data demonstrate that meningeal and cortical inflammation alone accompanied by oxidative stress are not sufficient to generate the extensive subpial cortical demyelination found in MS, but require other MS‐specific factors.     

Increased vulnerability to demyelination in streptozotocin diabetic rats

Demyelination is a prominent feature in nerve biopsies of patients with diabetic neuropathy. The mechanism is unknown because diabetic rodents, unlike humans, do not consistently develop segmental demyelination. We examined how diabetes influences toxicant-induced demyelination, remyelination, Schwann cell nerve growth factor receptor (p75) expression, and endoneurial macrophage apolipoprotein E (apo E) synthesis in diabetic rats. Postnatal day 17 (P17) rats were given 110 mg/kg streptozotocin intraperitoneally and then fed a diet containing metallic tellurium (Te) from P20 to P27 to induce demyelination. Transverse electron micrographs and immunostained longitudinal cryosections were prepared from sciatic nerve during demyelination and remyelination. Diabetic rats had a mean serum glucose concentration of 490 mg/dl and consumed equivalent doses of peroral Te. The number of demyelinated fibers in electron micrographs was increased significantly by 17% (P < .0011). Endoneurial density of p75-stained Schwann cells was increased in diabetic rats in proportion to the increased number of injured internodes. Density of apo E- and ED1-positive macrophages also was significantly increased in diabetes. There was no delay in macrophage myelin clearance, and remyelination was not compromised. Increased Schwann cell vulnerability to stress, by increasing the turnover rate of myelinated units, may explain why myelin defects accumulate after long-standing diabetes. © 1996 Wiley-Liss, Inc.     

Concept of autoimmunity following spinal cord injury: Possible roles for T lymphocytes in the traumatized central nervous system

The effect of immunological activation on the neuropathologic sequelae and neurologic outcome from spinal cord injury is unclear. Similar to models of neuroinflammatory disease (e.g., experimental autoimmune encephalomyelitis; EAE), injury to the spinal cord precipitates the activation of resident microglia and the recruitment of circulating inflammatory cells (e.g., macrophages and lymphocytes). In EAE, these cells are known to cause tissue damage and loss of neurological function via autoimmune reactions to myelin proteins. The role these cells play in the pathology of traumatic injury to the spinal cord has not been clarified. In this review, data are presented that indicate that T cells isolated from spinal-injured rats are capable of causing neurologic deficits and histopathologic changes similar to EAE when injected intravenously into naive animals. These data are consistent with the concept of trauma-induced autoimmune reactions. However, disease transfer was only possible when T cells were obtained from animals at 1 week post-injury. Thus, the encephalitogenic T-cell repertoire appears to be rapidly regulated. It is possible that trauma-induced autoimmunity evolves into a mechanism by which the autoreactive repertoire regulates ongoing central nervous system (CNS) immunologic responses. Similar immunoregulatory networks have been proposed in EAE and are discussed here in the context of CNS trauma and neurodegenerative disease. © 1996 Wiley-Liss, Inc.     

AAEM case report #30: Multifocal motor neuropathy

A 73-year-old man with a 16-year history of fasciculations and 15 years of weakness in his right arm was diagnosed with focal motor neuron disease. After 10 years of purely motor symptoms, he developed mild parasthesias although his sensory examination remained normal. Reflexes were reduced or absent in the weak muscles but were normal elsewhere. Nerve conduction was studied in nerves innervating weak muscles and showed severe motor conduction block. Sensory nerve conduction studies were minimally abnormal, showing reduced amplitudes with normal velocities. Based on the clinical picture and the presence of severe motor conduction block, the patient was diagnosed with multifocal motor neuropathy. Treatment with high-dose intravenous immunoglobulin was given with significant improvement in strength and partial resolution of the conduction block. As this case demonstrates, this treatable disorder may occasionally be mistaken for motor neuron disease although the resemblance is only superficial, and it should never be mistaken for amyotrophic lateral sclerosis. Multifocal motor neuropathy is an inflammatory, demyelinating neuropathy which, like chronic inflammatory demyelinating polyneuropathy (CIDP), is probably immune-mediated. It differs from typical CIDP by virtue of a marked predilection for motor axons, a strikingly restricted distribution, and a protracted course. Treatment with high-dose intravenous immunoglobulin is frequently helpful, but other forms of immune manipulation are less effective. © 1996 Gareth J. Parry, MD, FRACP. Published by John Wiley & Sons, Inc.