Diffusion restriction in the corticospinal tract and the corpus callosum of term neonates with hypoxic-ischemic encephalopathy.

BACKGROUND: Diffusion-weighted imaging performed shortly after brain injury has been shown to facilitate visualization of acute corticospinal tract injury known as "pre-Wallerian degeneration." OBJECTIVE: The aim of this study was to determine whether diffusion restriction in the corticospinal tract and corpus callosum occurs within the first 2 weeks after birth in neonates with neonatal hypoxic-ischemic encephalopathy. MATERIALS AND METHODS: We enrolled a consecutive series of 66 infants diagnosed with hypoxic-ischemic encephalopathy who underwent MRI. We evaluated diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) values to assess the presence of restricted diffusion in the corticospinal tract and corpus callosum. Next, we compared ADC values in the corticospinal tract and in the splenium and genu of the corpus callosum of infants with abnormal pattern on MRI with those of control infants, who showed a normal pattern on MRI. We attempted to follow all infants with hypoxic-ischemic encephalopathy until 18 months of age and assess them using a standardized neurologic examination. RESULTS: After exclusions, we recruited 25 infants with abnormal MRI and 20 with normal MRI (controls). Among these 45 neonates, pre-Wallerian degeneration was visualized in the corticospinal tract in 10 neonates and in the corpus callosum in 12. The ADC values in the corticospinal tract in the first week were significantly lower than they were in the second week. Infants with pre-Wallerian degeneration in the corticospinal tract showed an unfavorable outcome. CONCLUSION: Pre-Wallerian degeneration was visualized in the corticospinal tract and corpus callosum and was associated with extensive brain injury caused by hypoxic-ischemic encephalopathy. The changes in signal were observed to evolve over time within the first 2 weeks. The clinical outcome of infants having pre-Wallerian degeneration in the corticospinal tract was unfavorable.

Potential Use of 18F-THK5351 PET to Identify Wallerian Degeneration of the Pyramidal Tract Caused by Cerebral Infarction.

A 41-year-old man underwent F-THK5351 PET 2 years after a right middle cerebral artery infarction. F-THK5351 PET imaging revealed intense radioligand uptake along the ipsilateral pyramidal tract from the corona radiata to the medulla; intense uptake changed from the right side to the left side with descending axial sections at the level of the pyramidal decussation. F-THK5351 reportedly binds to monoamine oxidase B, which is highly expressed in astrocytes, suggesting that F-THK5351 concentrates in the lesion where gliosis occurs. Hence, in this case, F-THK5351 uptake may represent Wallerian degeneration accompanied with gliosis in the ipsilateral pyramidal tract.

Inflammatory responses in Multiple Sclerosis normal-appearing white matter and in non-immune mediated neurological conditions with wallerian axonal degeneration: A comparative study.

Inflammatory-like changes in the white matter (WM) are commonly observed in conditions of axonal degeneration by different etiologies. This study is a systematic comparison of the principal features of the inflammatory-like changes in the WM in different pathological conditions characterized by axonal damage/degeneration, focusing in particular on Multiple Sclerosis (MS) normal-appearing white matter (NAWM) compared to non immune-mediated disorders. The study was performed on sections of NAWM from 15 MS cases, 11 cases of non immune-mediated disorders with wallerian axonal degeneration (stroke, trauma, amyotrophic lateral sclerosis), 3 cases of viral encephalitis, 6 control cases. Common features of the inflammatory-like changes observed in all of the conditions of WM pathology were diffuse endothelial expression of VCAM-1, microglial activation with expression of M2 markers, increased expression of sphingosine receptors. Inflammation in MS NAWM was characterized, compared to non immune-mediated conditions, by higher VCAM-1 expression, higher density of perivascular lymphocytes, focal perivascular inflammation with microglial expression of M1 markers, ongoing acute axonal damage correlating with VCAM-1 expression but not with microglia activation. Inflammatory changes in MS NAWM share all the main features observed in the WM in non immune-mediated conditions with wallerian axonal degeneration (with differences to a large extent more quantitative than qualitative), but with superimposition of disease-specific perivascular inflammation and ongoing acute axonal damage.

Autophagic myelin destruction by Schwann cells during Wallerian degeneration and segmental demyelination.

As lysosomal hydrolysis has long been suggested to be responsible for myelin clearance after peripheral nerve injury, in this study, we investigated the possible role of autophagolysosome formation in myelin phagocytosis by Schwann cells and its final contribution to nerve regeneration. We found that the canonical formation of autophagolysosomes was induced in demyelinating Schwann cells after injury, and the inhibition of autophagy via Schwann cell-specific knockout of the atg7 gene or pharmacological intervention of lysosomal function caused a significant delay in myelin clearance. However, Schwann cell dedifferentiation, as demonstrated by extracellular signal-regulated kinase activation and c-Jun induction, and redifferentiation were not significantly affected, and thus the entire repair program progressed normally in atg7 knockout mice. Finally, autophagic Schwann cells were also found during segmental demyelination in a mouse model of inflammatory peripheral neuropathy. Together, our findings suggest that autophagy is the self-myelin destruction mechanism of Schwann cells, but mechanistically, it is a process distinct from Schwann cell plasticity for nerve repair.

Short-term diabetic hyperglycemia suppresses celiac ganglia neurotransmission, thereby impairing sympathetically mediated glucagon responses.

Short-term hyperglycemia suppresses superior cervical ganglia neurotransmission. If this ganglionic dysfunction also occurs in the islet sympathetic pathway, sympathetically mediated glucagon responses could be impaired. Our objectives were 1) to test for a suppressive effect of 7 days of streptozotocin (STZ) diabetes on celiac ganglia (CG) activation and on neurotransmitter and glucagon responses to preganglionic nerve stimulation, 2) to isolate the defect in the islet sympathetic pathway to the CG itself, and 3) to test for a protective effect of the WLD(S) mutation. We injected saline or nicotine in nondiabetic and STZ-diabetic rats and measured fos mRNA levels in whole CG. We electrically stimulated the preganglionic or postganglionic nerve trunk of the CG in nondiabetic and STZ-diabetic rats and measured portal venous norepinephrine and glucagon responses. We repeated the nicotine and preganglionic nerve stimulation studies in nondiabetic and STZ-diabetic WLD(S) rats. In STZ-diabetic rats, the CG fos response to nicotine was suppressed, and the norepinephrine and glucagon responses to preganglionic nerve stimulation were impaired. In contrast, the norepinephrine and glucagon responses to postganglionic nerve stimulation were normal. The CG fos response to nicotine, and the norepinephrine and glucagon responses to preganglionic nerve stimulation, were normal in STZ-diabetic WLD(S) rats. In conclusion, short-term hyperglycemia's suppressive effect on nicotinic acetylcholine receptors of the CG impairs sympathetically mediated glucagon responses. WLD(S) rats are protected from this dysfunction. The implication is that this CG dysfunction may contribute to the impaired glucagon response to insulin-induced hypoglycemia seen early in type 1 diabetes.

Effect of Lycium barbarum (Wolfberry) on alleviating axonal degeneration after partial optic nerve transection.

Our previous results showed that the polysaccharides extracted from Lycium barbarum (LBP) could delay secondary degeneration of retinal ganglion cell bodies and improve the function of the retinas after partial optic nerve transection (PONT). Although the common degeneration mechanisms were believed to be shared by both neuronal bodies and axons, recently published data from slow Wallerian degeneration mutant (Wld(s)) mice supported the divergence in the mechanisms of them. Therefore, we want to determine if LBP could also delay the degeneration of axons after PONT. Microglia/macrophages were thought to be a source of reactive oxygen species after central nervous system (CNS) injury. After PONT, however, oxidative stress was believed to occur prior to the activation of microglia/macrophages in the areas vulnerable to secondary degeneration both in the optic nerves (ONs) and the retinas. But the results did not take into account the morphological changes of microglia/macrophages after their activation. So we examined the morphology in addition to the response magnitude of microglia/macrophages to determine their time point of activation. In addition, the effects of LBP on the activation of microglia/macrophages were investigated. The results showed that (1) LBP reduced the loss of axons in the central ONs and preserved the g-ratio (axon diameter/fiber diameter) in the ventral ONs although no significant effect was detected in the dorsal ONs; (2) microglia/macrophages were activated in the ONs by 12 h after PONT; (3) LBP decreased the response magnitude of microglia/macrophages 4 weeks after PONT. In conclusion, our results showed that LBP could delay secondary degeneration of the axons, and LBP could also inhibit the activation of microglia/macrophages. Therefore, LBP could be a promising herbal medicine to delay secondary degeneration in the CNS via modulating the function of microglia/macrophages.

Similarities between inherited demyelinating neuropathies and Wallerian degeneration: an old repair program may cause myelin and axon perturbation under nonlesion conditions.

Wallerian degeneration (WD) and inherited demyelinating neuropathies of the Charcot-Marie-Tooth type 1 (CMT1) appear to represent completely distinct events. CMT1-like diseases are chronic disorders of peripheral nerves that are genetically caused and lead to secondary neurodegenerative events, resulting in usually non-treatable disabilities, whereas WD is an acute, usually transient, reaction on injuries, aiming to allow peripheral nerve regeneration. Despite these differences, there are some striking similarities regarding molecular characteristics of neural cells in the affected peripheral nerves. The most conspicuous similarities might comprise the inflammatory component in both situations, as identified in appropriate mouse models. However, although inflammation is a beneficial component in WD, leading to removal of regrowth-repellent myelin debris, inflammation in CMT1 mouse models causes damage of initially intact nerve fibers. We hypothesize that, in CMT1 models, molecular pathways are activated that are shared with an important repair program after peripheral nerve injury, but lead to neural perturbation when activated under nonlesion conditions, as is the case in CMT1. These novel insights into the pathogenesis of CMT1 might be instrumental for the development of new therapeutic options in humans.

Targeting anti-inflammatory treatment can ameliorate injury-induced neuropathic pain.

Tumor necrosis factor-α plays important roles in immune system development, immune response regulation, and T-cell-mediated tissue injury. The present study assessed the net value of anti-tumor necrosis factor-α treatment in terms of functional recovery and inhibition of hypersensitivity after peripheral nerve crush injury. We created a right sciatic nerve crush injury model using a Sugita aneurysm clip. Animals were separated into 3 groups: the first group received only a skin incision; the second group received nerve crush injury and intraperitoneal vehicle injection; and the third group received nerve crush injury and intraperitoneal etanercept (6 mg/kg). Etanercept treatment improved recovery of motor nerve conduction velocity, muscle weight loss, and sciatic functional index. Plantar thermal and von Frey mechanical withdrawal thresholds recovered faster in the etanercept group than in the control group. On day 7 after crush injury, the numbers of ED-1-positive cells in crushed nerves of the control and etanercept groups were increased compared to that in the sham-treated group. After 21 days, ED-1-positive cells had nearly disappeared from the etanercept group. Etanercept reduced expression of interleukin-6 and monocyte chemotactic and activating factor-1 at the crushed sciatic nerve. These findings demonstrate the utility of etanercept, in terms of both enhancing functional recovery and suppressing hypersensitivity after nerve crush. Etanercept does not impede the onset or progression of Wallerian degeneration, but optimizes the involvement of macrophages and the secretion of inflammatory mediators.

Correlation analysis of quantitative diffusion parameters in ipsilateral cerebral peduncle during Wallerian degeneration with motor function outcome after cerebral ischemic stroke.

BACKGROUND AND PURPOSE: To evaluate the time periods of Wallerian degeneration (WD) in which the diffusion parameters of ipsilateral corticalspinal tract (CST) can be used to predict the motor function outcome after brain infarction. METHODS: This retrospective study classified 48 diffusion tensor imaging patients with WD along CST into four groups based on the following time points after stroke onset, Group 1: within the first 2 weeks; Group 2: from 3 to 4 weeks; Group 3: from 5 to 14 weeks; Group 4: after 14 weeks. The apparent diffusion coefficient (ADC), fractional anisotropy (FA), and their ratios (=ipsilateral diffusion value/contralateral value) of cerebral peduncle were evaluated. The correlation between imaging parameters in each group and the motor function scores appraised at 8 months after stroke onset were assessed. RESULTS: There was no evident correlation of FA ratio (rFA) in Group 1 with motor function score (P = .05). The rFA and FA correlated with motor function score in other groups (P < .001 in each group). The ADC ratio and ipsilateral ADC value only showed significant correlation of with motor function score in Group 4 (P= .016 and .029, respectively). CONCLUSIONS: The rFA and ipsilateral FA values after 2 weeks of stroke onset correlate with the motor function outcome.

[Urinary incontinence after radical prostatectomy. Neurophysiological and urodynamic diagnosis]. / L'incontinenza urinaria dopo prostatectomia radicale. Diagnosi urodinamica e neurofisiologica.

OBJECTIVES: Urinary incontinence after radical prostatectomy presents different clinical features. We propose to clarify the etiology and the therapeutic approaches. METHODS: 51 patients with urinary incontinence after radical prostatectomy underwent urodynamics, perineal EMG, perineal EMG frequency analysis and study of computerized sensory pudendal somatosensory evoked potentials. RESULTS: 18 patients (35%) were suffering from urinary incontinence secondary to overactive bladder, 14 patients (28%) had both an overactive bladder and a sphincter failure associated with Wallerian degenerative axonal neuropathy or segmental demyelination, 3 patients (6%) showed no significant urodynamics alterations but had signs of an incompetent sphincter neurapraxia, while 16 patients (31%) had urinary incontinence secondary to a degenerative neuropathy. CONCLUSIONS: Urinary incontinence after radical prostatectomy shows an etiologic diversification and therefore requires different therapeutic approaches

Ipsilateral wallerian degeneration of the distal optic radiations after infarction at their root.

A 54-year-old man who developed a left homonymous inferior quadrantanopia showed MRI findings of infarction of the proximal portion of the right superior optic radiations and high T2 signal along the entire distal course of the ipsilateral optic radiations consistent with Wallerian degeneration. Frequently reported in other settings, this imaging abnormality has rarely been described in anterior optic radiation lesions.

Segmental neuropathic pain does not develop in male rats with complete spinal transections.

In a previous study using male rats, a correlation was found between the development of "at-level" allodynia in T6-7 dermatomes following severe T8 spinal contusion injury and the sparing of some myelinated axons within the core of the lesion epicenter. To further test our hypothesis that this sparing is important for the expression of allodynia and the supraspinal plasticity that ensues, an injury that severs all axons (i.e., a complete spinal cord transection) was made in 15 male rats. Behavioral assessments were done at level throughout the 30-day recovery period followed by terminal electrophysiological recordings (urethane anesthesia) from single medullary reticular formation (MRF) neurons receiving convergent nociceptive inputs from receptive fields above, at, and below the lesion level. None of the rats developed signs of at-level allodynia (versus 18 of 26 male rats following severe contusion). However, the terminal recording (206 MRF neurons) data resembled those obtained previously post-contusion. That is, there was evidence of neuronal hyper-excitability (relative to previous data from intact controls) to high- and low-threshold mechanical stimulation for "at-level" (dorsal trunk) and "above-level" (eyelids and face) cutaneous territories. These results, when combined with prior data on intact controls and severe/moderate contusions, indicate that (1) an anatomically incomplete injury (some lesion epicenter axonal sparing) following severe contusion is likely important for the development of allodynia and (2) the neuronal hyper-excitability at the level of the medulla is likely involved in nociceptive processes that are not directly related to the conscious expression of pain-like avoidance behaviors that are being used as evidence of allodynia.

The Wallerian degeneration slow (Wld(s)) gene does not attenuate disease in a mouse model of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a severe neuromuscular disease characterized by loss of spinal alpha-motor neurons, resulting in the paralysis of skeletal muscle. SMA is caused by deficiency of survival motor neuron (SMN) protein levels. Recent evidence has highlighted an axon-specific role for SMN protein, raising the possibility that axon degeneration may be an early event in SMA pathogenesis. The Wallerian degeneration slow (Wld(s)) gene is a spontaneous dominant mutation in mice that delays axon degeneration by approximately 2-3 weeks. We set out to examine the effect of Wld(s) on the phenotype of a mouse model of SMA. We found that Wld(s) does not alter the SMA phenotype, indicating that Wallerian degeneration does not directly contribute to the pathogenesis of SMA development.

Regional grey matter atrophy in clinically isolated syndromes at presentation.

BACKGROUND: The presence and degree of neuronal degeneration already existing in patients at their initial presentation with a clinically isolated syndrome suggestive of multiple sclerosis (CIS) is unclear, and whole brain or whole normalised grey matter analyses have not demonstrated significant atrophy in CIS cohorts at clinical presentation. Voxel-based analyses allow detection of regional atrophy throughout the brain and, therefore, may be sensitive to regional atrophy in CIS patients, and these changes may correspond with clinical disability. METHODS: This study used a modified voxel-based morphometry (VBM) method to correct for lesion effects to analyse regional atrophy and perform voxel-wise correlations between volume and clinical metrics in 41 untreated CIS patients at presentation compared with 49 healthy controls. RESULTS: The results confirmed that there was no significant difference in whole normalised grey matter volume between CIS and controls, whereas VBM showed significant areas of bilateral thalamic, hypothalamic, putamen and caudate atrophy. Voxel-wise correlations with clinical measures showed that cerebellar volumes correlated with clinical cerebellar function, nine-hole peg test scores and the Multiple Sclerosis Functional Composite (MSFC) score, and that the MSFC score was also correlated with putamen volume. Lastly, T1 lesion volumes were found to correlate with thalamic and hippocampal atrophy, suggesting a link between white matter lesions and grey matter degeneration at the earliest stages of multiple sclerosis. CONCLUSIONS: Atrophy is present in CIS patients at presentations, particularly in the thalamus, and other deep grey matter structures. Furthermore, the correlations with clinical metrics suggest the importance of this atrophy to clinical status and the correlation with T1 lesion load suggests a possible role of Wallerian degeneration.

Origin of fatigue in multiple sclerosis: review of the literature.

Fatigue is one of the most common and most disabling symptoms of multiple sclerosis (MS). Although numerous studies have tried to reveal it, no definite pathogenesis factor behind this fatigue has been identified. Fatigue may be directly related to the disease mechanisms (primary fatigue) or may be secondary to non-disease-specific factors. Primary fatigue may be the result of inflammation, demyelination, or axonal loss. A suggested functional cortical reorganization may result in a higher energy demand in certain brain areas, culminating in an increase of fatigue perception. Higher levels of some immune markers were found in patients with MS-related fatigue, whereas other studies rejected this hypothesis. There may be a disturbance in the neuroendocrine system related to fatigue, but it is not clear whether this is either the result of the interaction with immune activation or the trigger of this process. Fatigue may be secondary to sleep problems, which are frequently present in MS and in their turn result from urinary problems, spasms, pain, or anxiety. Pharmacologic treatment of MS (symptoms) may also provoke fatigue. The evidence for reduced activity as a cause of secondary fatigue in MS is inconsistent. Psychological functioning may at least play a role in the persistence of fatigue. Research did not reach consensus about the association of fatigue with clinical or demographic variables, such as age, gender, disability, type of MS, education level, and disease duration. In conclusion, it is more likely to explain fatigue from a multifactor perspective than to ascribe it to one mechanism. The current evidence on the pathogenesis of primary and secondary fatigue in MS is limited by inconsistency in defining specific aspects of the concept fatigue, by the lack of appropriate assessment tools, and by the use of heterogeneous samples. Future research should overcome these limitations and also include longitudinal designs.

Wallerian degeneration of the corticospinal tracts: postmortem MR-pathologic correlations.

Postmortem magnetic resonance (MR) images were correlated with the histological findings in two autopsy-proven cases of Wallerian degeneration of the corticospinal and corticopontine tracts associated with cerebral embolic infarction. T2 hyperintensities seen in Wallerian degeneration showed vacuolation of myelin in the early stage, and marked loss of myelin and axons with macrophages in the subacute and chronic stages. Similar T2 hyperintensities seen in the different stages of Wallerian degeneration reflect different histological findings.