Severe Axonal Damage Research Articles

A new model of axon degeneration in the mouse optic nerve using repeat intraocular pressure challenge

We characterize a new experimental model for inducing retinal ganglion cell (RGC) dysfunction and degeneration in mice. C57BL/6J mice were subjected to two acute periods of intraocular pressure (IOP) elevation (50 mmHg for 30 min) by cannulation of the anterior chamber. We used full-field electroretinography and visual evoked potentials (VEPs) to measure subsequent changes in retina and optic nerve function, and histochemical techniques to assess RGC survival and optic nerve structure. In 12 month old mice, a single IOP challenge caused loss and subsequent recovery of RGC function over the following 28 days with minimal cell death and no observed axonal damage. A second identical IOP challenge resulted in persistent RGC dysfunction and significant (36%) loss of RGC somas. This was accompanied by a 16.7% delay in the latency and a 27.6% decrease in the amplitude of the VEP. Severe axonal damage was seen histologically with enlargement of axons, myelin disruption, reduced axon density, and the presence of glial scarring. In contrast, younger 3 month old mice when exposed to a single or repeat IOP challenge showed quicker RGC functional recovery after a single challenge and full functional recovery after a repeat challenge with no detectable optic nerve dysfunction. These data demonstrate a highly reproducible and minimally invasive method for inducing RGC degeneration and axonal damage in mice. Resilience of the optic nerve to damage is highly dependent on animal age. The time-defined nature of functional versus structural loss seen in this model stands to facilitate investigation of neuroglial responses in the retina after IOP injury and the associated evaluation of neuroprotective treatment strategies. Further, the model may be used to investigate the impact of aging and the cellular switch between neurorecovery and neurodegeneration.

Different visual evoked potentials in neuromyelitis optica spectrum disorder-related optic neuritis and idiopathic demyelinating optic neuritis: a prospective longitudinal analysis

BackgroundTo investigate different visual evoked potential (VEP) patterns in neuromyelitis optica spectrum disorder-related optic neuritis (NMOSD-ON) and idiopathic demyelinating optic neuritis (IDON).MethodsThis was a longitudinal, prospective, case-control study. Eighty-four Chinese patients with acute optic neuritis were enrolled, including 26 NMOSD-ON patients and 58 IDON patients. All the patients underwent best-corrected visual acuity (BCVA) and full-field pattern reversal VEP recordings at the onset, 1 month, 3 months, and 6 months.ResultsWithin 15′ checks, the NMOSD-ON patients had more severe VEP amplitude reduction at 6 months (2.39 ± 4.63 μV vs. 6.96 ± 8.88 μV, P = 0.034). However, the IDON patients showed more frequently normal VEP response at 3 months (24.0% vs. 4.5%, P = 0.017), and only prolonged P100 peak latency with normal amplitude (L) at 6 months (30.0% vs. 57.8%, P = 0.048). Within 60′ checks, no significant difference in VEP parameters between the two groups was found at each follow-up (P > 0.05). ConclusionsThe NMOSD-ON patients showed more severe axonal damage and worse axonal recovery than the IDON patients. VEP elicited by smaller check size was more sensitive to visual pathway abnormality in NMOSD-ON.

Presumed vincristine ganglion cell toxicity resulting in binasal visual field loss

Vincristine sulfate, a common chemotherapeutic, can be neurotoxic, causing severe axonal damage and loss of myelinated fibers. We describe a patient with bilateral optic disc pallor and binasal visual field loss secondary to presumed Vincristine neurotoxicity.

A Review of Traumatic Axonal Injury

Traumatic brain injury is a major cause of mortality and neurological disability worldwide and varies according to its cause, pathogenesis, severity and clinical outcome. This review summarizes a significant aspect of diffuse brain injuries – traumatic axonal injury – important cause of severe disability and vegetative state. Traumatic axonal injury is a type of traumatic brain injury caused by blunt head trauma. It is defined both clinically (immediate and prolonged unconsciousness, characteristically in the absence of space-occupying lesions) and pathologically (widespread and diffuse damage of axons). Following traumatic brain injury, progressive axonal degeneration starts with disruption of axonal transport, axonal swelling, secondary axonal disconnection and Wallerian degeneration, respectively. However, traumatic axonal injury is difficult to define clinically, it should be considered in patients with Glasgow coma score < 8 for more than six hours after trauma and diffuse tensor imaging and sensitivity-weighted imaging MRI sequences are highly sensitive in its diagnosis. Glasgow coma score at the time of presentation, location and severity of axonal damage are prognostic factors for clinical outcome.

Concurrent axon and myelin destruction differentiates X-linked adrenoleukodystrophy from multiple sclerosis.

Cerebral disease manifestation occurs in about two thirds of males with X-linked adrenoleukodystrophy (CALD) and is fatally progressive if left untreated. Early histopathologic studies categorized CALD as an inflammatory demyelinating disease, which led to repeated comparisons to multiple sclerosis (MS). The aim of this study was to revisit the relationship between axonal damage and myelin loss in CALD. We applied novel immunohistochemical tools to investigate axonal damage, myelin loss and myelin repair in autopsy brain tissue of eight CALD and 25 MS patients. We found extensive and severe acute axonal damage in CALD already in prelesional areas defined by microglia loss and relative myelin preservation. In contrast to MS, we did not observe selective phagocytosis of myelin, but a concomitant decay of the entire axon-myelin unit in all CALD lesion stages. Using a novel marker protein for actively remyelinating oligodendrocytes, breast carcinoma-amplified sequence (BCAS) 1, we show that repair pathways are activated in oligodendrocytes in CALD. Regenerating cells, however, were affected by the ongoing disease process. We provide evidence that-in contrast to MS-selective myelin phagocytosis is not characteristic of CALD. On the contrary, our data indicate that acute axonal injury and permanent axonal loss are thus far underestimated features of the disease that must come into focus in our search for biomarkers and novel therapeutic approaches.

Chronic White Matter Inflammation and Serum Neurofilament Levels in Multiple Sclerosis.

ObjectiveTo assess whether chronic white matter inflammation in patients with multiple sclerosis (MS) as detected in vivo by paramagnetic rim MRI lesions (PRLs) is associated with higher serum neurofilament light chain (sNfL) levels, a marker of neuroaxonal damage.MethodsIn 118 patients with MS with no gadolinium-enhancing lesions or recent relapses, we analyzed 3D-submillimeter phase MRI and sNfL levels. Histopathologic evaluation was performed in 25 MS lesions from 20 additional autopsy MS cases.ResultsIn univariable analyses, participants with ≥2 PRLs (n = 43) compared to those with ≤1 PRL (n = 75) had higher age-adjusted sNfL percentiles (median, 91 and 68; p < 0.001) and higher Multiple Sclerosis Severity Scale scores (MSSS median, 4.3 and 2.4; p = 0.003). In multivariable analyses, sNfL percentile levels were higher in PRLs ≥2 cases (βadd, 16.3; 95% confidence interval [CI], 4.6–28.0; p < 0.01), whereas disease-modifying treatment (DMT), Expanded Disability Status Scale (EDSS) score, and T2 lesion load did not affect sNfL. In a similar model, sNfL percentile levels were highest in cases with ≥4 PRLs (n = 30; βadd, 30.4; 95% CI, 15.6–45.2; p < 0.01). Subsequent multivariable analysis revealed that PRLs ≥2 cases also had higher MSSS (βadd, 1.1; 95% CI, 0.3–1.9; p < 0.01), whereas MSSS was not affected by DMT or T2 lesion load. On histopathology, both chronic active and smoldering lesions exhibited more severe acute axonal damage at the lesion edge than in the lesion center (edge vs center: p = 0.004 and p = 0.0002, respectively).ConclusionChronic white matter inflammation was associated with increased levels of sNfL and disease severity in nonacute MS, suggesting that PRL contribute to clinically relevant, inflammation-driven neurodegeneration.

Deep Spatial Profiling of COVID-19 Brains Reveals Neuroinflammation by Compartmentalized Local Immune Cell Interactions and Targets for Intervention

COVID-19 can cause acute and chronic neurological symptoms. The underlying pathophysiological mechanisms, the involved immune cells, their spatial distribution, cellular interactions and the role of virus tropism remain largely unclear. Here, we deeply interrogated the brain stem and olfactory bulb in COVID-19 patients with imaging mass cytometry to understand the local immune response at a spatially resolved, high-dimensional single-cell level. We observed significant immune activation in the CNS and identified distinct phenotypes of T cells and microglial clusters, their presence in specific anatomical regions and context-specific cellular interactions. Microglial nodules and perivascular immune cell clusters constitute key sites of the local immune response, with viral antigen present in ACE2-expressing cells in the perivascular compartment. Disease-associated neuroinflammation is associated with astrogliosis and severe axonal damage as a structural basis for the neurologic deficits. Finally, we identify compartment- and cluster-specific immune checkpoints that can be targeted for future therapeutic interventions.Funding: This project was supported by grants from the Deutsche Forschungsgemeinschaft (DFG, GermanResearch Foundation) (SFB 992, SFB1160, SFB/TRR167, SFB/TRR179, German Excellency strategyCIBSS - EXC-2189– Project ID390939984) and special research funds from the Ministry for Science, Research and Art of Baden-Wuerttemberg dedicated to “COVID-19 research” and “Neuroinflammation”.B.B. was further supported by DFG grant BE-5496/5-1 and M.P. was further supported by the Sobek Foundation, the Ernst-Jung Foundation, the Reinhart-Koselleck-Grant and Gottfried Wilhelm Leibniz-Prize.H.E.M. was supported by DFG ME-3644/5-1.Ethical Approval: The analyses were performed with the approval of the Institutional Review Boards (Ethic Committee of the Albert-Ludwigs-University, Freiburg: 322/20, 10008/09; Ethics Committee of the Hamburg Chamber of Physicians: WF-051/20, PV7311). The study was performed in agreement with the principles expressed in the Declaration of Helsinki (2013).Conflict of Interest: None to declare.

Co-existence of Guillain-Barré syndrome and Behcet syndrome: A case report

A 40-year-old male patient was referred to our department with complains of recurrent oral ulcer for more than 20 years and vulvar ulcer for more than 10 years. He presented with a 3-month history of right external ophthalmoplegia. More than 10 days ago, the patient received ganglioside infusion. And one week ago, he developed numbness and pain of his lambs, and progressive myasthenia, accompanied by right blepharoptosis and dysuria. On exam, motor strength was graded 0/5 in the lower and the upper extremities. Deep tendon reflexes were diminished in extremities. His admission medical examination: hemoglobin (HGB), white cell and platelet counts were normal. C-reactive protein (CRP) was negative. Erythrocyte sedimentation rate (ESR) 53 mm/h. Antinuclear antibody (ANA), anti-dsDNA antibody, anti-Smith antibody, anti-cardiolipin antibody and human leucocyte antigen B51 were all within normal range. The etiological tests of influenza A pathogen, influenza B pathogen, parainfluenza virus, enterovirus and parvovirus were all negative. He tested positive for serum anti-GM1 IgG. Cerebrospinal fluid had a normal white cell count, an elevated protein content. Gram staining, culture and PCR detection for varicella-zoster virus, cytomegalovirus and herpes simplex virus were all negative. Antibodies associated with autoimmune encephalitis and paraneoplastic syndrome were negative in cerebrospinal fluid. Electromyography and nerve conduction studies showed a severe axonal damage affecting motor nerves. No obvious abnormalities were observed in his magnetic resonance imaging of brain and cavernous sinus. The patient was diagnosed with Behcet syndrome complicated with acute Guillain-Barre syndrome. He received intravenous methylprednisolone, intravenous immunoglobulin (IVIg) therapy, plasma exchange and rituximab treatment. After treatment, the patient's muscle strength of limbs was restored to grade 1, blepharoptosis and pain disappeared. The nervous system involvement of Behcet syndrome is relatively rare, especially combined with Guillain-Barre syndrome, which is easy to cause misdiagnosis. The treatment of Behcet syndrome complicated with acute Guillain-Barre syndrome includes the treatment of primary disease, plasma exchange and IVIg therapy. In addition, supportive treatment is very important for such patients. The focus of treatment is to avoid respiratory insufficiency, prevent deep vein thrombosis, monitor cardiac function and hemodynamics. Pain-relieving, physical exercise and psychological support are often under-recognized. The rehabilitation treatment is very important to improve the prognosis and quality of life of patients. What we need to learn is that when the symptoms and signs of the nervous system are difficult to be explained by neuro-Behcet syndrome alone, we should be alert to the possibility of other nervous system diseases.

Sporadic hereditary neuropathies misdiagnosed as chronic inflammatory demyelinating polyradiculoneuropathy: Pitfalls and red flags.

Hereditary neuropathies may be misdiagnosed with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). A correct diagnosis is crucial for avoiding unnecessary therapies and access genetic counseling. We report on nine patients (seven men, mean age 49.2 ± 16.1) diagnosed with and treated as CIDP, in whom mutations or variants of unknown significance (VUS) in genes associated with hereditary neuropathies were reported. All underwent neurological and neurophysiological examination, eight also cerebrospinal fluid (CSF) analysis. In 4/9, nerve ultrasound and/or MR-neurography were performed. All the patients complained of progressive upper or lower limbs sensory-motor symptoms, with heterogeneous disease duration (1-34 years, mean 8.6 ± 10.8). Neurophysiology showed demyelinating signs in seven patients, mixed findings with predominant axonal damage in two patients. Neuroimaging disclosed diffuse abnormalities at proximal and distal segments. Molecular screening showed PMP22 duplication in two patients, mutations in the MPZ, EGR2, and GJB1 genes were reported in each of the remaining patients. The two patients with mixed neurophysiological findings had p.Val30Met mutation in the transthyretin gene. Two patients had VUS in the MARS and HSPB1 genes. Four patients had partial response to immunomodulant therapies, and CSF and neurophysiological features suggesting an inflammatory condition concomitant with the hereditary neuropathy. Hereditary neuropathy may be misdiagnosed with CIDP. The most common pitfalls are CSF (high protein levels and oligoclonal bands), incorrect interpretation of neurophysiology, and transient benefit from therapies. Neuroimaging may be helpful in cases with atypical presentations or when severe axonal damage complicate the neurophysiological interpretation.

Distinctive Patterns of Seizure-Related White Matter Alterations in Right and Left Temporal Lobe Epilepsy.

Background: We hypothesized that right and left temporal lobe epilepsy (RTLE and LTLE, respectively) have distinctive spatial patterns of white matter (WM) changes that can be differentiated and interpreted with the use of multiple diffusion parameters. We compared the global microstructure of fiber bundles with regard to WM alterations in both RTLE and LTLE, addressing some of the methodological issues of previous studies.Methods: Diffusion tensor imaging data from 17 patients with RTLE (age: 40.7 ± 10.4), 15 patients with LTLE (age: 37.3 ± 10.4), and 15 controls (age: 34.8 ± 11.2) were used in the study. WM integrity was quantified by fractional anisotropy (FA), mean diffusivity (MD), longitudinal diffusivity (LD), and radial diffusivity (RD). The diffusion parameters were compared between the groups in tracts representing the core of the fiber bundles. The volumes of hippocampi and amygdala were subsequently compared across the groups, while the data were adjusted for the effect of hippocampal sclerosis.Results: Significantly reduced FA and increased MD, LD, and RD were found bilaterally over widespread brain regions in RTLE. An increase in MD and RD values was observed in widespread WM fiber bundles ipsilaterally in LTLE, largely overlapping with regions where FA was lower, while no increase in LD was observed. We also found a difference between the LTLE and RTLE groups for the right hippocampal volume (with and without adjustment for HS), whereas no significant volume differences were found between patients and controls.Conclusions: It appears that patients with RTLE exhibit a more widespread pattern of WM alterations that extend far beyond the temporal lobe in both ipsilateral and contralateral hemisphere; furthermore, these changes seem to reflect more severe damage related to chronic degeneration. Conversely, more restrained changes in the LTLE may imply a pattern of less severe axonal damage, more restricted to ipsilateral hemisphere. Comprehensive finding of more prominent hippocampal atrophy in the RTLE raises an interesting issue of seizure-induced implications on gray matter and WM microstructure that may not necessarily mean a straightforward causal relationship. Further correlations of diffusion-derived metrics with neuropsychological and functional imaging measures may provide complementary information on underlying WM abnormalities with regard to functional hemispheric specialization.

Sciatic Nerve Injection Palsy in a Dog: Electrodiagnostic Testing and Microsurgical Treatment

Background: Iatrogenic damage to the ischiatic nerve is considered uncommon and may cause dysfunction with variable clinical signs dependent on type and severity of injury. Due to important role of this nerve in locomotion and weightbearing limb, a poor prognosis for recovery may be observed in many cases. Electromyography analysis may suggest the neuroanatomic localization, diagnosis information, and severity of lesion to determine better therapeutic intervention. Therefore, the aim of this report is to describe the possible cause, diagnosis and treatment of a postinjection ischiatic nerve injury in a dog with complete recovery.Case: A 3-year-old neutered male dachshund dog was referred to the Veterinary Hospital due to inability to weight support in the right hind limb after diminazene diaceturate intramuscular injection. The gait evaluation showed dropped-hock and knuckling into the digits of the right hind limb and neurologic examination revealed moderate muscle atrophy below tofemorotibial joint of the right hind limb with sensory analgesia (superficial and deep) on the lateral, dorsal, and plantar surfaces, absent patellar reflex, and proprioceptive deficit. Electrophysiologic testing was done under general anesthesia in a 2-channel Nicolet Compass Meridian apparatus. Absence of compound muscle action potentials after right fibular and tibial nerve stimulations, and abnormal spontaneous activity in cranial tibial, gastrocnemius and deep digital extensor muscles were observed. A diagnosis of moderate/severe axonotmesis of sciatic nerve was achieved. Under microscope magnification, all adherent adjacent tissue and epineural sheat were removed. Due this, a small epineural window was created. On neurological examination performed 30 days after surgery, complete recovery of sensitivity of the right hind limb, and normal proprioception were observed. The muscle atrophy was also noted to have improved.Discussion: The ischiatic nerve mechanisms of injury include direct needle trauma, the drug or vehicle used for injection, or secondary constriction by scar, factors that may be associated to damage nerve observed in the present case. During a sciatic nerve injection, the combination of intrafascicular placement of a needle and high-pressure injection may cause severe fascicular damage and persistent neurologic deficits. In the present case, damage to the nerve probably was not caused bythe injection needle, but due to injection agent. Chemical irritation or toxic reaction to the agent may cause different degrees of nerve injury. The electrophysiologic testing is an important tool for determining alteration of function and integrity of the axonal motor unit. In the present report, the electrophysiologic testing showed denervation potentials in the musclesinnervated by the sciatic nerve (positive waves and fibrillation potentials), and the absence of compound muscle action potentials was indicative of severe axonal damage of the right ischiatic nerve. In human patients with postinjection ischiatic nerve injury, early surgical treatment with neurolysis or resection and anastomosis are the procedures recommended. In the present report, external neurolysis and epineural window were used showing excellent functional results. The epineural window was performed due to adherence of tissue and scar surrounding the nerve, permitting neural decompression.Keywords: axonotmesis, neurophysiology, neurolysis, dogs.

Localized cortical chronic traumatic encephalopathy pathology after single, severe axonal injury in human brain

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive mild impact traumatic brain injury from contact sports. Recently, a consensus panel defined the pathognomonic lesion for CTE as accumulations of abnormally hyperphosphorylated tau (p-tau) in neurons (neurofibrillary tangles), astrocytes and cell processes distributed around small blood vessels at sulcal depths in irregular patterns within the cortex. The pathophysiological mechanism for this lesion is unknown. Moreover, a subset of CTE cases harbors cortical β-amyloid plaques. In this study, we analyzed postmortem brain tissues from five institutionalized patients with schizophrenia and history of surgical leucotomy with subsequent survival of at least another 40 years. Because leucotomy involves severing axons bilaterally in prefrontal cortex, this surgical procedure represents a human model of single traumatic brain injury with severe axonal damage and no external impact. We examined cortical tissues at the leucotomy site and at both prefrontal cortex rostral and frontal cortex caudal to the leucotomy site. For comparison, we analyzed brain tissues at equivalent neuroanatomical sites from non-leucotomized patients with schizophrenia, matched in age and gender. All five leucotomy cases revealed severe white matter damage with dense astrogliosis at the axotomy site and also neurofibrillary tangles and p-tau immunoreactive neurites in the overlying gray matter. Four cases displayed p-tau immunoreactivity in neurons, astrocytes and cell processes encompassing blood vessels at cortical sulcal depths in irregular patterns, similar to CTE. The three cases with apolipoprotein E ε4 haplotype showed scattered β-amyloid plaques in the overlying gray matter, but not the two cases with apolipoprotein E ε3/3 genotype. Brain tissue samples from prefrontal cortex rostral and frontal cortex caudal to the leucotomy site, and all cortical samples from the non-leucotomized patients, showed minimal p-tau and β-amyloid pathology. These findings suggest that chronic axonal damage contributes to the unique pathology of CTE over time.

Volume ratio of spinal canal and its contents in patients with congenital kyphosis

Congenital anomalies of the spine combine formation and seg­mentation failures, resulting into asymmetrical and altered growth and kyphotic or kyphoscoliotic deformations that pro­gressing during all the life with the following neurological dis­turbances. There is no consensus today on the main indications for the surgical treatment. Objective: To study the volume ratios of the spinal canal and its contents in patients with congenital kyphosis (CK) before surgery and to compare the findings with the clinical neurological manifestations. Methods: A retrospec­tive analysis of medical records, the results of computer (CT) and magnetresonance tomography (MRI) of 15 patients (3 to 20 years) with the CK who received surgical treatment. All the patients were taken about the clinical, radiological, electroneuromyographic (EMG) examination and MRI. Results: ver­tebromedular (VMC) conflict based on MRI data diagnosed in all patients: I degree — in 6, II — in 8, IV — at 1. As a result of electroneuromyographic studies in patient with an IV degree of VMC revealed severe axonal damage of peroneal and tibial nerves. In the group with grade II VMC in 3 patients decreased motor potential and the conduction of the tibial nerve, and 4 has a violation of conduction and synchronization of motor neurons. Such disorders also detected in 4 of 10 patients with VMC degree I and II, but without evidence of neurological deficit. Conclu­sion: all patients with CK had failures and VMC varying degrees independently of clinical manifestations of spinal cord compres­sion.Using ENMG in patients with I and II degree of VMC, it is identified violation of motoneuron function and decreased motor conduction in peripheral nerves even without motor and sensory disorders. Indicator of VMC may be informative for predicting the neurological complications, so that all patients with CK CT and MRI studies are indicated.

Neuralgic amyotrophy. An update

A century after the first description of neuralgic amyotrophy (NA), its pathophysiology remains unknown. An inflammatory (auto)immune pathophysiology is presumed, with mechanical or infectious precipitating conditions, which triggers attacks. Clinically, NA is an acute and painful unique or multiple mononeuropathy that causes palsy, amyotrophy and sensory loss in an asymmetric and patchy distribution. It involves the upper brachial plexus rather than the other parts but also may involve the cervical plexus, lumbosacral plexus and cranial nerves. The impairment can be restricted to one fascicule of one nerve, plexus or root; limited to a few ones; or extensive, involving both upper limbs. Its evolution is usually monophasic and auto-limited and never leads to generalized polyneuropathy. Electrodiagnostically, NA is characterized by severe axonal damage. The recovery is usually good after 6 months to 3 years in 80% of cases. Persistent disability is present in 20% of idiopathic NA cases and is more frequent in hereditary NA, with frequent recurrences, more frequent bilateral impairment, and more atypical distribution (cervical plexus, lumbosacral plexus or cranial nerves) than with idiopathic NA. Hereditary NA is mainly linked to a mutation in the gene of the Septin-9 protein. When the patient is seen early after disease onset, treatment with corticosteroids for 2 weeks seems to shorten the pain duration and the delayed recovery. With diagnosis during the palsy period, treatment is based on pharmacologic and non-pharmacologic therapies according to the complaints of the patient.

Apport de l’électroneuromyographie dans les paralysies faciales périphériques

In case of peripheral facial palsy, electroneuromyogram of the facial nerve provides an indication of the nature (myelinic and/or axonal) and severity of nerve damage, thereby facilitating establishment of a prognosis, which is favorable for myelin damage, and guarded for severe axonal damage. The initial examination must be carried out during the second week. In case of severe axonal damage, examination results can be monitored at the third, and more particularly the sixth and the twelfth months. Stable neurophysiological data between the sixth and the twelfth months signal damage stability and open the way to possible palliative surgery. In the event of trigeminal damage, neurophysiological exploration furthers analysis of temporal muscle innervation. ENMG can confirm and precisely indicate peripheral hemifacial spasm.

Evaluation of visual structural and functional factors that predict the development of multiple sclerosis in clinically isolated syndrome patients.

To evaluate visual pathway structure and function in patients with clinical isolated syndrome (CIS) by using spectral-domain optical coherence tomography (OCT) and multifocal visual-evoked potentials (mfVEP), predicting CIS conversion to clinically definite multiple sclerosis (MS). This observational, longitudinal study assessed the eyes with no previous history of optic neuritis of 29 consecutive patients with CIS according to the McDonald criteria. The relationships of the mfVEP results with the clinical findings, and psychophysical (Humphrey perimetry) and structural (OCT) diagnostic test data were investigated. The mfVEP amplitude responses (interocular and monocular probability analysis) showed abnormal cluster visual field defects in 48.3% of the CIS eyes, whereas mfVEP latency analysis showed significant delays in 20.7%. The OCT average retinal nerve fiber layer thickness (RNFLT) was significantly reduced compared with the control group (P = 0.02). Significant differences between CIS eyes with abnormal and normal mfVEP latencies were found for the OCT RNFLT (P < 0.001) with a longer latency being linked to more severe axonal damage. Using multivariate logistic regression analysis, OCT average RNFLT was found to be an independent predictor of clinically definitive MS diagnosis at 12 months. The combined use of OCT and mfVEP is helpful to detect significant subclinical visual pathway abnormalities and axonal loss in CIS patients. Retinal axonal loss measured by OCT is an important prognostic factor of conversion to MS in patients with CIS in absence of symptomatic optic neuritis.

Transcorneal alternating current stimulation after severe axon damage in rats results in “long-term silent survivor” neurons

Transcorneal alternating current stimulation (tACS) was proposed to decrease acute death of retinal ganglion cells after optic nerve transection in rats, but it is not known if cell survival is long-term and associated with functional restoration. We therefore evaluated the effects of tACS in a rat model of optic nerve crush using anatomical, electrophysiological and behavioural measures. Rats were trained in a brightness discrimination visual task and the retinal ganglion cell number was quantified with in vivo confocal neuroimaging. Thereafter, severe optic nerve crush or sham crush was performed and rats were treated under anaesthesia either with tACS or sham stimulation immediately after the lesion and on day 3, 7, 11, 15, 19 and 23. Brightness discrimination was evaluated for 6 weeks and retinal ganglion cells were counted in vivo on post-crush days 7 and 28. In additional rats we studied the influence of tACS on bioelectrical activity. On post-lesion day 28, the tACS-treated group showed a neuronal survival of 28.2% which was significantly greater than in sham operates (8.6%). All animals with optic nerve crush were significantly impaired in brightness discrimination and did not recover performance, irrespective to which group they belonged. In accordance with this, there was no significant influence of the stimulation on EEG power spectra. In conclusion, tACS induced long-term neuronal protection from delayed retrograde cell death, but in this case of severe axonal damage tACS did not influence functional restoration and EEG signals recorded over the visual cortex.

The Liver X Receptor Agonist GW3965 Improves Recovery from Mild Repetitive Traumatic Brain Injury in Mice Partly through Apolipoprotein E

Traumatic brain injury (TBI) increases Alzheimer’s disease (AD) risk and leads to the deposition of neurofibrillary tangles and amyloid deposits similar to those found in AD. Agonists of Liver X receptors (LXRs), which regulate the expression of many genes involved in lipid homeostasis and inflammation, improve cognition and reduce neuropathology in AD mice. One pathway by which LXR agonists exert their beneficial effects is through ATP-binding cassette transporter A1 (ABCA1)-mediated lipid transport onto apolipoprotein E (apoE). To test the therapeutic utility of this pathway for TBI, we subjected male wild-type (WT) and apoE−/− mice to mild repetitive traumatic brain injury (mrTBI) followed by treatment with vehicle or the LXR agonist GW3965 at 15 mg/kg/day. GW3965 treatment restored impaired novel object recognition memory in WT but not apoE−/− mice. GW3965 did not significantly enhance the spontaneous recovery of motor deficits observed in all groups. Total soluble Aβ40 and Aβ42 levels were significantly elevated in WT and apoE−/− mice after injury, a response that was suppressed by GW3965 in both genotypes. WT mice showed mild but significant axonal damage at 2 d post-mrTBI, which was suppressed by GW3965. In contrast, apoE−/− mice showed severe axonal damage from 2 to 14 d after mrTBI that was unresponsive to GW3965. Because our mrTBI model does not produce significant inflammation, the beneficial effects of GW3965 we observed are unlikely to be related to reduced inflammation. Rather, our results suggest that both apoE-dependent and apoE-independent pathways contribute to the ability of GW3965 to promote recovery from mrTBI.

Ipsilateral Lower Limb Neuropathies Following Hip Surgery Can Be Due to Inflammation (P06.129)

Objective: To assess for an inflammatory etiology of new lower limb neuropathies occurring ipsilateral to hip surgery. Background New neuropathic pain, numbness or weakness after hip surgery is often attributed to mechanical factors (stretch, compression or transection). Recently we described inflammatory neuropathy as a treatable cause of post-surgical neuropathy. Here, we focus on patients who presented with ipsilateral lower limb neuropathy after hip surgery with progressive symptoms (suggesting a non-mechanical cause). Design/Methods: We characterized the clinical, electrophysiological and pathological features of new ipsilateral neuropathy in post-hip surgery patients who had nerve biopsy. Results: We identified 7 patients (8 surgeries) who developed ipsilateral leg weakness within 4 weeks of surgery. Three were men with median age 63 years (range 18-75). All patients developed focal neuropathies (5 lumbosacral plexopathies, 2 sciatic) presenting as acute pain and weakness that was progressive. Electrophysiology showed severe axonal damage. All biopsies were abnormal showing 1) ischemic injury: perineurial thickening (3/7), multifocal fiber loss (5/7), neovascularization (4/7) and 2) increased inflammation: epineurial perivascular inflammatory infiltrates (7/7), vessel wall infiltration (6/7) that was diagnostic (2/7) or suggestive (4/7) of microvasculitis. All patients were treated with intravenous methylprednisolone. In 6 patients with longitudinal follow-up (median 5 months), all showed improvement of neuropathy impairment score [median: 25 (first evaluation) to 16.5 (second) (p=0.003)]. Conclusions: Herein, we show that in a subset of patients with progressive neuropathic symptoms ipsilateral to the side of hip surgery, inflammatory (not mechanical) factors played the prominent etiological role. Identification of these patients through nerve biopsy may lead to improved outcome with use of immunotherapy. A major question remains about the role of inflammatory mechanisms in post-hip surgery patients who present with new, non-progressive, ipsilateral neuropathies previously assumed to be due to mechanical factors and what benefit more intensive evaluation and immunotherapy might play. Supported by: In part by NIH grant NS36797. Disclosure: Dr. Laughlin has nothing to disclose. Dr. Staff has nothing to disclose. Dr. Watson has received personal compensation for activities with Nevro as a consultant. Dr. Dyck has nothing to disclose.

Accumulation of exogenous amyloid-beta peptide in hippocampal mitochondria causes their dysfunction: a protective role for melatonin.

Amyloid-beta (Aβ) pathology is related to mitochondrial dysfunction accompanied by energy reduction and an elevated production of reactive oxygen species (ROS). Monomers and oligomers of Aβ have been found inside mitochondria where they accumulate in a time-dependent manner as demonstrated in transgenic mice and in Alzheimer's disease (AD) brain. We hypothesize that the internalization of extracellular Aβ aggregates is the major cause of mitochondrial damage and here we report that following the injection of fibrillar Aβ into the hippocampus, there is severe axonal damage which is accompanied by the entrance of Aβ into the cell. Thereafter, Aβ appears in mitochondria where it is linked to alterations in the ionic gradient across the inner mitochondrial membrane. This effect is accompanied by disruption of subcellular structure, oxidative stress, and a significant reduction in both the respiratory control ratio and in the hydrolytic activity of ATPase. Orally administrated melatonin reduced oxidative stress, improved the mitochondrial respiratory control ratio, and ameliorated the energy imbalance.