Axonal Lesions Research Articles

Tourniquet Paralysis may Reflect Injury of Muscle Spindles

Objective: Knee operation using pneumatic tourniquet may cause weakness of the quadriceps femoris muscle. A patient with a paresis of the quadriceps femoris muscle for two months postoperatively was studied. Methods: ENMG and lumbar magnetic stimulation (MEP) follow-up.Results: There was no distinct lesion of the motor axons of the femoral or other nerves in ENMG or MEP six weeks postoperatively. After a follow-up of eight months, the paresis was subsided and a complete recovery took place in two years.Conclusion: High pressure of the tourniquet may injure muscle spindles. Decreased Ia-afferent activity may severely inhibit voluntary motor effort.

Road Traffic Injuries and Road Safety Measures-Can We Do Any Better?

Purpose: Road traffic injuries are the leading cause of death under 30 years, causing over a million deaths every year. Helmets, seat-belts and child-restraints have an important role in death and injury prevention. Our purpose was to analyze how safety measures relate to pediatric polytrauma severity in road traffic injury. Methods: A retrospective observational study was conducted, including polytraumatized pediatric patients, hospitalized after road traffic accidents, from January 2011 to December 2015. Comparison groups were classified according to protective equipment use. Logistic regression and generalized liner models describe the probability of safety equipment use, head trauma, higher injury severity score and permanent sequelae. Results: Of a total of 149 inpatients, 63.8% were male with a median age of 11 years. Absence of personal protective equipment was predictive for head trauma (p-value=0.014) and diffuse axonal injury associated with neurologic sequelae and death (p-value<0.01). Multivariate analysis confirmed a higher risk of protective equipment misuse in unsupervised children and in two-wheel accidents (p-value<0.05). Injury Severity Score (ISS) and Glasgow Coma Scale (GCS) were inversely proportional (p-value<0.001). Sequelae were more frequent with lower GCS (p<0.001) and diffuse axonal lesion (p<0.001). Conclusions: Despite increasing alertness, helmet use in road accidents remains limited, reflecting on head trauma severity and subsequent neurological impairment. Absence of protective equipment on car collisions provoked more severe injury scores and prolonged hospital stay. In the Decade of Action for Road Safety we still find important handicaps in road safety measures, demanding more effective laws and alerting campaigns.

Guillain–Barré syndrome in north-western India: Demographic, clinical, electrophysiological profile and assessment of prognostic factors

Abstract Objectives To study demographic, clinical, electrophysiological characteristics, prevalent subtypes and factors associated with outcome of Guillain–Barre syndrome in north-western region of India. Material and methods It was a hospital-based prospective observational study. 60 patients with Guillain–Barre syndrome diagnosed as per Asbury and Cornblath criteria were enrolled and followed up for 3 months. Various epidemiological, clinical and electrophysiological parameters were evaluated. Result Most common variant in our study was acute motor axonal neuropathy (41.6%) while the most common age group was 15–29 years. There was history of antecedent event in 22 patients (37%) and sensory deficit in 31.7% (proprioceptive > exteroceptive). Cranial nerve involvement was seen in 40% (facial > bulbar > ophthalmoplegia) and autonomic dysfunction in 11.7%. Respiratory involvement was seen in 22 patients (36.7%). Nerve conduction abnormalities were observed in 96% of the cases. Sural sparing was found in 15% of cases at admission predominantly in acute inflammatory demyelinating polyneuropathy and F-wave abnormality (prolonged/delayed) in 72% of patients at admission which was most frequently seen in peroneal nerve. Severity at admission (high GBS disability score), need for ventilation, high modified Erasmus GBS outcome score were associated significantly ( p -value 55 years) and axonal lesion were non-significantly ( p -value >0.05) with poor outcome.

Attenuation of Axonal Degeneration by Calcium Channel Inhibitors Improves Retinal Ganglion Cell Survival and Regeneration After Optic Nerve Crush.

Axonal degeneration is one of the initial steps in many traumatic and neurodegenerative central nervous system (CNS) disorders and thus a promising therapeutic target. A focal axonal lesion is followed by acute axonal degeneration (AAD) of both adjacent axon parts, before proximal and distal parts follow different degenerative fates at later time points. Blocking calcium influx by calcium channel inhibitors was previously shown to attenuate AAD after optic nerve crush (ONC). However, it remains unclear whether the attenuation of AAD also promotes consecutive axonal regeneration. Here, we used a rat ONC model to study the effects of calcium channel inhibitors on axonal degeneration, retinal ganglion cell (RGC) survival, and axonal regeneration, as well as the molecular mechanisms involved. Application of calcium channel inhibitors attenuated AAD after ONC and preserved axonal integrity as visualized by live imaging of optic nerve axons. Consecutively, this resulted in improved survival of RGCs and improved axonal regeneration at 28days after ONC. We show further that calcium channel inhibition attenuated lesion-induced calpain activation in the proximity of the crush and inhibited the activation of the c-Jun N-terminal kinase pathway. Pro-survival signaling via Akt in the retina was also increased. Our data thus show that attenuation of AAD improves consecutive neuronal survival and axonal regeneration and that calcium channel inhibitors could be valuable tools for therapeutic interventions in traumatic and degenerative CNS disorders.

Proximal humerus fracture associated with delayed axillary nerve injury

Axillary nerve injury is the most common complication in humerus fracture. The symptoms that are caused by affecting axillary nerve vary according to the structures involved such as sensory disturbance and weakness of muscles, e.g., three parts of deltoid and teres muscles in an affected limb. The severity of injury is classified in demyelinating and axonal lesions, which usually occurs at the onset of fracture. The author reports a case of humerus fracture with delayed axonal lesion of axillary nerve result from inadvertent traction.

The Triple Stimulation Technique: An Advanced Neurophysiological Method to Assess Motor Function in Multiple Sclerosis

The triple stimulation technique (TST) is a collision method enabling study of motor conduction within the central nervous system. By combining transcranial magnetic stimulation of the cortex to peripheral nerve stimulation, this method markedly improves the evaluation of the corticospinal pathways. In multiple sclerosis (MS) and other disorders affecting central motor conduction, it allows accurate detection and quantification of the proportion of normally conducting axons and of motor conduction failures caused by conduction block, neuronal or axonal lesions. This review aims to (1) describe briefly the TST, its yield, strengths and limitations, (2) summarize the observations made in MS to date, (3) discuss the potential of the method. The TST is non-invasive and safe. Its practicability has been optimized by use of efficient software. Several studies have demonstrated that it is suitable to explore corticospinal conduction in MS, that its findings mirror the disability and clinical neurological signs of patients, and that it is reliable to evaluate follow-up and responses to treatments, including during the critical early stages of MS. We believe that the method is ready to be implemented to research and to routine clinical acquisitions. It should demonstrate useful to evaluate new therapies, monitor achievement of “no evidence of disease activity” (NEDA) and eventually to better understand neurodegeneration and repair in MS.

Diagnostic Significance of Distal Compound Muscle Action Potential (CMAP) Duration-A Case Report

The diagnostic criteria of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) are based on clinical findings and auxiliary investigations, of which the most important ones are neurophysiological findings. Since the European Federation of Neurological Societies/ Peripheral Nerve Society (EFNS/PNS) incorporated distal CMAP duration into the neurophysiological diagnostic criteria, their sensitivity increased to 81.3% and specificity to 96.2%. We describe a case of a 58-year-old man who was referred to our electromyography (EMG) laboratory for a second opinion regarding his diagnosis. The patient exhibited sensory-motor polyneuropathy with prominent hypotrophy of the calf muscles. Electrodiagnostic testing prior to admission had revealed a probable axonal neuropathy. In our EMG laboratory, we accomplished nerve conduction studies (NCS) of both hands and legs and we noted a prominent increase of distal CMAP duration, whereas distal motor latencies (DML) were within normal limits. As the CMAP amplitude in the tibial and peroneal nerves was less than 1 millivolt (mV), the existence of myelinopathy could not be inferred from any other parameters identified in the lower extremities. Neurophysiological investigation of both hands was necessary, even though the clinical picture of polyneuropathy was substantially more prominent in the legs. It is important to distinguish between axonal and myelin sheath lesions in order to understand the pathogenetic aspects of neuropathy. In addition, treatment of demyelinating autoimmune neuropathies can be offered and it is effective. In our patient, distal CMAP duration was the main discriminating parameter among the various neurophysiological parameters of the CIDP diagnostic criteria.

Parthenolide: a novel pharmacological approach to promote nerve regeneration.

Traumatic axonal lesions disrupt the connections between neurons and their targets, leading to loss of motoric and sensory functions. Although lesioned peripheral nerves can principally regenerate, the rate of recovery depends on the mode and severity of the respective injury (Grinsell and Keating, 2014). While injuries close to the innervation site have good chances of recovery, long distance regeneration is particularly problematic due to relatively slow axonal growth rates, which even under favorable conditions do not normally exceed 1–2 mm per day (Sunderland, 1947). For this reason, re-growth into the respective target tissue can take several months or even years after nerve injuries in arms and legs. Within months, however, the regenerative support of Schwann cells declines and denervated muscles atbecome atrophic. Under these conditions, re-innervation of appropriate targets and consequently functional recovery are at least impaired if not impossible. Moreover, regenerating axons are often misguided and form so-called neuromas around the injury site, causing chronic, difficult-to-treat pain. Despite a high capacity for axonal regrowth in the peripheral nervous system, nerve injuries therefore often seriously impair the quality of life of affected patients and are overall associated with high socio-economic costs and long professional downtimes (Lad et al., 2010).

Paraplejía espástica hereditaria ligada al cromosoma X por mutación en el gen L1CAM: presentación de tres casos del síndrome CRASH

Hereditary spastic paraplegia (HSP) is a set of neurodegenerative clinical features characterised by a progressive loss of strength in the lower limbs together with spasticity. It is the result of an axonal lesion in the corticospinal tracts. Type 1, known as SPG1, is the most common form of X-linked HSP. This is produced by a mutation in the gene for the L1 cell adhesion molecule (L1CAM). SPG1 presents with CRASH syndrome (corpus callosum hypoplasia, retardation, adducted thumbs, spasticity and hydrocephalus). We report the cases of three males, two brothers and a cousin (on the mother's side), with clinical features including intellectual disability, spastic paraparesis, long tract signs, facial dysmorphism and adducted thumbs. Neuroimaging revealed agenesis of the corpus callosum and ventriculomegaly in all three of them. Neurophysiological and metabolic studies were normal. The genetic study evidenced a specific mutation of the L1CAM gene (Xq28) in all three cases. We describe the clinical-radiological findings in three males with CRASH syndrome due to mutation c.516G>A in exon 5 of the L1CAM gene. These seem to be the first cases reported in Spain, according to the current literature. We recommend suspecting this syndrome when spastic paraparesis, intellectual disability and adducted thumbs are associated.

Differential expression of glucose-metabolizing enzymes in multiple sclerosis lesions.

IntroductionDemyelinated axons in multiple sclerosis (MS) lesions have an increased energy demand in order to maintain conduction. However, oxidative stress-induced mitochondrial dysfunction likely alters glucose metabolism and consequently impairs neuronal function in MS. Imaging and pathological studies indicate that glucose metabolism is altered in MS, although the underlying mechanisms and its role in neurodegeneration remain elusive. We investigated expression patterns of key enzymes involved in glycolysis, tricarboxylic acid (TCA) cycle and lactate metabolism in well-characterized MS tissue to establish which regulators of glucose metabolism are involved in MS and to identify underlying mechanisms.ResultsExpression levels of glycolytic enzymes were increased in active and inactive MS lesions, whereas expression levels of enzymes involved in the TCA cycle were upregulated in active MS lesions, but not in inactive MS lesions. We observed reduced expression and production capacity of mitochondrial α-ketoglutarate dehydrogenase (αKGDH) in demyelinated axons, which correlated with signs of axonal dysfunction. In inactive lesions, increased expression of lactate-producing enzymes was observed in astrocytes, whereas lactate-catabolising enzymes were mainly detected in axons. Our results demonstrate that the expression of various enzymes involved in glucose metabolism is increased in both astrocytes and axons in active MS lesions. In inactive MS lesions, we provide evidence that astrocytes undergo a glycolytic shift resulting in enhanced astrocyte-axon lactate shuttling, which may be pivotal for the survival of demyelinated axons.ConclusionIn conclusion, we show that key enzymes involved in energy metabolism are differentially expressed in active and inactive MS lesions. Our findings imply that, in addition to reduced oxidative phosphorylation activity, other bioenergetic pathways are affected as well, which may contribute to ongoing axonal degeneration in MS.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-015-0261-8) contains supplementary material, which is available to authorized users.

α-Synuclein pathology in the cranial and spinal nerves in Lewy body disease.

Accumulation of phosphorylated α-synuclein in neurons and glial cells is a histological hallmark of Lewy body disease (LBD) and multiple system atrophy (MSA). Recently, filamentous aggregations of phosphorylated α-synuclein have been reported in the cytoplasm of Schwann cells, but not in axons, in the peripheral nervous system in MSA, mainly in the cranial and spinal nerve roots. Here we conducted an immunohistochemical investigation of the cranial and spinal nerves and dorsal root ganglia of patients with LBD. Lewy axons were found in the oculomotor, trigeminal and glossopharyngeal-vagus nerves, but not in the hypoglossal nerve. The glossopharyngeal-vagus nerves were most frequently affected, with involvement in all of 20 subjects. In the spinal nerve roots, Lewy axons were found in all of the cases examined. Lewy axons in the anterior nerves were more frequent and numerous in the thoracic and sacral segments than in the cervical and lumbar segments. On the other hand, axonal lesions in the posterior spinal nerve roots appeared to increase along a cervical-to-sacral gradient. Although Schwann cell cytoplasmic inclusions were found in the spinal nerves, they were only minimal. In the dorsal root ganglia, axonal lesions were seldom evident. These findings indicate that α-synuclein pathology in the peripheral nerves is axonal-predominant in LBD, whereas it is restricted to glial cells in MSA.

Correlation between visuo-spatial working memory and brain Magnetic Resonance Imaging (MRI) lesion five years after Traumatic Brain Injury (TBI)

To describe the changes in fractional anisotropy (FA) measured with Diffusion Tensor Imaging (DTI) and the changes in Regional Homogeneity (ReHo) signal measured with resting state functional MRI on patients with visuo-spatial working memory deficit, 5 years after a severe TBI. We included TBI patients from a neurosurgical intensive care cohort of the Pitié-Salpêtrière Parisian Hospital. Patients were hospitalized between 2005 and 2011. A French version of the Glasgow Outcome Scale Extended (GOSE) assessed the global functional outcome. A large neuropsychological assessment including working memory tests was performed. We present here the results of the backward visuo-spatial span as standard notes. FA were measured on DTI and ReHo were extracted from resting state functional MRI acquisition on a voxel-based approach. Fifty-four patients were included 65 months after their TBI. The median age at evaluation time was 34 years [19–71]. Median Glasgow Coma Score was 8 [3–15]. Seventeen patients had a GOSE score below 6, 18 had a GOSE at 6 and 19 had a GOSE higher than 6. Thirty patients had a standard note on backward visuo-spatial span inferior to 7, which corresponds to a deficit. In this group, FA was lower in the left hemisphere, in the anterior limb of the internal capsule and in the external capsule. Patients also had an increased ReHo in the right hemisphere in the superior temporal gyrus, Heschl's gyrus, putamen, medium frontal gyrus and inferior frontal gyrus triangularis. Despite the fact that axonal lesions observed after TBI are diffuse, decreased FA was predominant in the left hemisphere of patients with the most severe working memory deficits and in whom ReHo appeared higher in the right hemisphere. These observations should open the discussion about contralateral inhibition of hemispheres.

Genotype/phenotype correlations in AARS-related neuropathy in a cohort of patients from the United Kingdom and Ireland.

Charcot–Marie–Tooth disease (CMT) is the most common inherited neuropathy with heterogeneous clinical presentation and genetic background. The axonal form (CMT2) is characterised by decreased action potentials indicating primary axonal damage. The underlying pathology involves axonal degeneration which is supposed to be related to axonal protein dysfunction caused by various gene mutations. The overlapping clinical manifestation of CMT2 with distal hereditary motor neuropathy (dHMN) and intermediate CMT causes further diagnostic difficulties. Aminoacyl-tRNA synthetases have been implicated in the pathomechanism of CMT2. They have an essential role in protein translation by attaching amino acids to their cognate tRNAs. To date six families have been reported worldwide with dominant missense alanyl-tRNA synthetase (AARS) mutations leading to clinically heterogeneous axonal neuropathies. The pathomechanism of some variants could be explained by impaired amino acylation activity while other variants implicating an editing defect need to be further investigated. Here, we report a cohort of six additional families originating from the United Kingdom and Ireland with dominant AARS-related neuropathies. The phenotypic manifestation was distal lower limb predominant sensorimotor neuropathy but upper limb impairment with split hand deformity occasionally associated. Nerve conduction studies revealed significant demyelination accompanying the axonal lesion in motor and sensory nerves. Five families have the c.986G>A, p.(Arg329His) variant, further supporting that this is a recurrent loss of function variant. The sixth family, of Irish origin, had a novel missense variant, c.2063A>G, p.(Glu688Gly). We discuss our findings and the associated phenotypic heterogeneity in these families, which expands the clinical spectrum of AARS-related neuropathies.Electronic supplementary materialThe online version of this article (doi:10.1007/s00415-015-7778-4) contains supplementary material, which is available to authorized users.

CRANIAL NEUROPATHY, INDUCED BY VINCRISTINE ADMINISTRATION AT A CHILD SUFFERING WITH EWING,S SARCOMA

The pharmaceutical neuropathy is the most often complication from the part of the nervous system at children, receiving the therapy with chemical therapeutic agents. Among most unfavorable substance vincristine (VNC) is highlighted, which neurotoxicity often causes the dose reduction or its full withdrawal from the used treatment protocol. The clinical pattern of the VNC induced neuropathy in most cases is represented by the lesion of nerve fibers of upper and lower extremities with the development of symptoms of the peripheral polyneuropathy. In more rare cases VNC causes the lesion of axons of cranial and brain nerves. The given clinical case describes the monitoring of the cranial neuropathy, the lesion of the oculomotor nerve, presented by bilateral ptosis at a child with Ewing,s sarcoma, treated by С WS-2009 protocol.

Ultrasound in dual nerve impairment after proximal radial nerve lesion.

IntroductionSonography in classical nerve entrapment syndromes is an established and validated method. In contrast, few publications highlight lesions of the radial nerve, particularly of the posterior interosseus nerve (PIN).MethodFive patients with a radial nerve lesion were investigated by electromyography, nerve conduction velocity and ultrasound. Further normative values of 26 healthy subjects were evaluated.ResultsFour patients presented a clinical and electrophysiological proximal axonal radial nerve lesion and one patient showed a typical posterior interosseous nerve syndrome (PINS). The patient with PINS presented an enlargement of the PIN anterior to the supinator muscle. However four patients with proximal lesions showed an unexpected significant enlargement of the PIN within the supinator muscle.ConclusionHigh-resolution sonography is a feasible method to demonstrate the radial nerve including its distal branches. At least in axonal radial nerve lesions, sonography might reveal abnormalities far distant from a primary proximal lesion site clearly distinct from the appearance in classical PINS.

Compartmentalized intrathecal immunoglobulin synthesis during HIV infection - a model of chronic CNS inflammation?

HIV infects the central nervous system (CNS) during primary infection and persists in resident macrophages. CNS infection initiates a strong local immune response that fails to control the virus but is responsible for by-stander lesions involved in neurocognitive disorders. Although highly active anti-retroviral therapy now offers an almost complete control of CNS viral proliferation, low-grade CNS inflammation persists. This review focuses on HIV-induced intrathecal immunoglobulin (Ig) synthesis. Intrathecal Ig synthesis early occurs in more than three-quarters of patients in response to viral infection of the CNS and persists throughout the course of the disease. Viral antigens are targeted but this specific response accounts for < 5% of the whole intrathecal synthesis. Although the nature and mechanisms leading to non-specific synthesis are unknown, this prominent proportion is comparable to that observed in various CNS viral infections. Cerebrospinal fluid-floating antibody-secreting cells account for a minority of the whole synthesis, which mainly takes place in perivascular inflammatory infiltrates of the CNS parenchyma. B-cell traffic and lineage across the blood–brain-barrier have not yet been described. We review common technical pitfalls and update the pending questions in the field. Moreover, since HIV infection is associated with an intrathecal chronic oligoclonal (and mostly non-specific) Ig synthesis and associates with low-grade axonal lesions, this could be an interesting model of the chronic intrathecal synthesis occurring during multiple sclerosis.

Diffusion in the corpus callosum in patients with early schizophrenia.

Diffusion in the cerebral corpus callosum in patients with early schizophrenia was studied by diffusion tensor MRT and magnetic resonance spectroscopy. The fraction anisotropy coefficient in the corpus callosum knee was low as a result of high radial diffusion. Spectroscopy detected a decrease of N-acetylaspartate level in the corpus callosum knee indicating axonal lesion during the early stage of schizophrenia.

Increased migration of olfactory ensheathing cells secreting the Nogo receptor ectodomain over inhibitory substrates and lesioned spinal cord.

Olfactory ensheathing cell (OEC) transplantation emerged some years ago as a promising therapeutic strategy to repair injured spinal cord. However, inhibitory molecules are present for long periods of time in lesioned spinal cord, inhibiting both OEC migration and axonal regrowth. Two families of these molecules, chondroitin sulphate proteoglycans (CSPG) and myelin-derived inhibitors (MAIs), are able to trigger inhibitory responses in lesioned axons. Mounting evidence suggests that OEC migration is inhibited by myelin. Here we demonstrate that OEC migration is largely inhibited by CSPGs and that inhibition can be overcome by the bacterial enzyme Chondroitinase ABC. In parallel, we have generated a stable OEC cell line overexpressing the Nogo receptor (NgR) ectodomain to reduce MAI-associated inhibition in vitro and in vivo. Results indicate that engineered cells migrate longer distances than unmodified OECs over myelin or oligodendrocyte-myelin glycoprotein (OMgp)-coated substrates. In addition, they also show improved migration in lesioned spinal cord. Our results provide new insights toward the improvement of the mechanisms of action and optimization of OEC-based cell therapy for spinal cord lesion.

Evoked Potentials as Neurophysiologic Tools to Evaluate Stroke

Stroke is one of most common cause of death in development countries and the most common disabling neurologic disorder. Diagnosis of the disease is base in clinical exam, history of patient and image techniques like computerized tomography scan (CT scan) and magnetic resonance images (MRI). Evoked potentials, usually not employed in diagnosis of stroke, are very useful in the evaluation of the patient functions and disabilities. For this reason we have a brief review of the utility of evoked potentials in the evaluation of the stroke in acute or subacute phase. Visual evoked potential modality evaluates the visual way, principally at optic nerve and optic chiasm level, or abnormalities of occipital areas. In patients with stroke that affect occipital cortex it usually show enlargements of P100 wave latency or amplitude diminish if there is axonal lesion of the nerve fibers. Brainstem evoked potential is useful to evaluate stroke when it occurs in brain structures that are irrigated for vertebrobasilar system. Somatosensory evoked potential show absence of N20/P25 complex or P40 response or amplitude diminishes of these responses; we can observe increase of the N13-N20 interval, always there is normality of the rest of the wave. Motor evoked potential parameters represent a useful early prognostic marker of motor function recovery in ischemic stroke patients. For other hand endogenous evoked potential such as: P300, N400, Mismatch negativity, Contingent negative variation and Premotor potential are very useful in the evaluation of cortical function in the stroke patients.

Autophagy in degenerating axons following spinal cord injury: evidence for autophagosome biogenesis in retraction bulbs.

Macroautophagy (here autophagy) is a catabolic mechanism responsible for the degradation of bulk cytoplasm, long-lived proteins and organelles. During autophagy, the cargos are engulfed by double-membrane structures named phagophores, which expand to form the autophagosomes. Subsequently, these autophagosomes fuse with lysosomes, in which the cytoplasmic cargos are degraded. Autophagy is a constitutive process, which plays an important role in cellular homeostasis. In primary neurons autophagosome formation occurs continuously and preferentially at the distal end of axons. On the other hand, autophagy is increased by different stresses, and its dysregulation or excessive induction may lead to detrimental effects. Many neurological disorders have been associated with alterations in the autophagic pathway and an increase in autophagy during axonal degeneration was described.