Peripheral Nerve Disease Research Articles

Chrysin attenuates experimental autoimmune neuritis by suppressing immuno-inflammatory responses

Guillain–Barré syndrome (GBS) is an acute, post-infectious, immune-mediated, demyelinating disease of peripheral nerves and nerve roots. Experimental autoimmune neuritis (EAN) is an animal model of GBS. Chrysin, which is a naturally occurring flavonoid, exhibits various biological activities. This study was designed to investigate the anti-inflammatory and neuroprotective properties of preventative and therapeutic chrysin treatment in EAN rats. For preventative treatment, chrysin was administered orally from day 1 to day 16 (50mg/kg once daily) while, for therapeutic treatment, rats received chrysin from day 7 to day 16 at the same dose once daily. Control animals received the same volume of the vehicle (phosphate-buffered saline/2% dimethylsulfoxide). Regardless of the treatment regimen, chrysin attenuated the severity and duration of the clinical course of EAN and reduced inflammatory cell infiltration and demyelination of sciatic nerves. In the sciatic nerves, the expression of inducible nitric oxide synthase, cyclooxygenase-2 and nuclear factor kappa B was reduced. Furthermore, chrysin inhibited the splenic mononuclear cell secretion of interleukin-1β, interleukin-2, interleukin-6, inteleukin-12, interferon γ and tumor necrosis factor α, and elevated the level of inteleukin-4. In summary, our data demonstrate that chrysin is a potentially useful agent for the treatment of EAN with its anti-inflammatory and neuroprotective effects.

Two faces of Schwann cell dedifferentiation in peripheral neurodegenerative diseases: pro-demyelinating and axon-preservative functions.

In vertebrates, Schwann cells are glial cells that form a myelin sheath, which produces the saltatory conduction of neural impulses in the peripheral nervous system (Sherman and Brophy, 2005). In the case of abnormal myelin sheath generation due to genetic mutations or myelin sheath destruction by acquired nerve damage induced by inflammation or drugs, problems arise in the peripheral nervous system, leading to muscle atrophy or sensory disorders (Sherman and Brophy, 2005; Jessen and Mirsky, 2008). During the embryonic period, the neural crest cells migrate along with growing peripheral axons. A Schwann cell precursor that has finished migrating and has attached to a growing nerve may wrap around a few or as many as dozens of axons, but ultimately only target a single axon that requires a myelin sheath in response to a certain stimulus (Sherman and Brophy, 2005; Jessen and Mirsky, 2008). In the period of Schwann cell generation, the cell is called Schwann cell progenitor or immature Schwann cell. Subsequently, the Schwann cell begins the process of myelin-related gene expression and wraps the axon with the elongated Schwann cell membrane, which continues throughout the postnatal period to complete the myelin sheath formation (Sherman and Brophy, 2005; Jessen and Mirsky, 2008). The mature myelin sheath will last a lifetime, except when damage, such as nerve injury, occurs. Acute and chronic demyelinating peripheral neuropathies are primary diseases that cause myelin destruction in adults (Jessen and Mirsky, 2008). When a peripheral nerve is physically severed, distal axons are completely degenerated, and the Schwann cells wrapped around the axons directly participate in the degeneration of the myelin sheath, which leads to demyelination (Jessen and Mirsky, 2008). Afterwards, macrophages that migrate from the blood assist in completely removing the degenerated axon and the myelin sheath (Martini et al., 2008). Meanwhile, in inflammatory demyelinating diseases, acute or chronic form of demyelination may occur regardless of axonal damage, and it is considered that demyelination occurs due to local inflammation caused by autoimmune mechanisms, which may attack components of the myelin sheath or junctional regions (Pollard and Armati, 2011).

Neuromuscular junction maturation defects precede impaired lower motor neuron connectivity in Charcot-Marie-Tooth type 2D mice

Dominant mutations in GARS, encoding the essential enzyme glycyl-tRNA synthetase (GlyRS), result in a form of Charcot-Marie-Tooth disease, type 2D (CMT2D), predominantly characterized by lower motor nerve degeneration. GlyRS charges the amino acid glycine with its cognate tRNA and is therefore essential for protein translation. However, the underlying mechanisms linking toxic gain-of-function GARS mutations to lower motor neuron degeneration remain unidentified. The neuromuscular junction (NMJ) appears to be an early target for pathology in a number of peripheral nerve diseases and becomes denervated at later stages in two mouse models of CMT2D. We therefore performed a detailed longitudinal examination of NMJs in the distal lumbrical muscles and the proximal transversus abdominis (TVA) muscles of wild-type and Gars mutant mice. We determined that mutant lumbrical NMJs display a persistent defect in maturation that precedes a progressive, age-dependent degeneration. Conversely, the TVA remains relatively unaffected, with only a subtle, short-lived impairment in pre- and post-synaptic development and no reduction in lower motor neuron connectivity to muscle. Together, these observations suggest that mutant Gars is associated with compromised development of the NMJ prior to synaptic degeneration and highlight the neuromuscular synapse as an important site of early, selective pathology in CMT2D mice.

Progress in peripheral nerve disease research in the last two years

Peripheral nerve disorders have been a Cinderella subspecialty for neurologists because of the limited treatment options and difficulties in obtaining a genetic diagnosis. In the last decade, there has been great progress in the management of patients with peripheral nerve disease. In this paper, we review a selection of diagnostic and therapeutic papers in this area published in the Journal of Neurology over the last 24 months.

UNNOTICED IN CHILDHOOD, DISABLING IN ADULTHOOD: A PROGRESSIVE BUT TREATABLE DISEASE…

A 64 year old Caucasian man presented with subtle cognitive decline of uncertain duration and a six month history of progressive difficulty mobilising with falls. He reported increasing stiffness in...

Diabetic Schwann cells suffer from nerve growth factor and neurotrophin-3 underproduction and poor associability with axons

Schwann cells (SCs) are integral to peripheral nerve biology, contributing to saltatory conduction along axons, nerve and axon development, and axonal regeneration. SCs also provide a microenvironment favoring neural regeneration partially due to production of several neurotrophic factors. Dysfunction of SCs may also play an important role in the pathogenesis of peripheral nerve diseases such as diabetic peripheral neuropathy where hyperglycemia is often considered pathogenic. In order to study the impact of diabetes mellitus (DM) upon the regenerative capacity of adult SCs, we investigated the differential production of the neurotrophic factors nerve growth factor (NGF) and neurotrophin-3 (NT3) by SCs harvested from the sciatic nerves of murine models of type 1 DM (streptozotocin treated C57BL/6J mice) and type 2 DM (LepR(-/-) or db/db mice) or non-diabetic cohorts. In vitro, SCs from diabetic and control mice were maintained under similar hyperglycemic and euglycemic conditions respectively. Mature SCs from diabetic mice produced lower levels of NGF and NT3 under hyperglycemic conditions when compared to SCs in euglycemia. In addition, SCs from both DM and non-DM mice appear to be incapable of insulin production, but responded to exogenous insulin with greater proliferation and heightened myelination potentiation. Moreover, SCs from diabetic animals showed poorer association with co-cultured axons. Hyperglycemia had significant impact upon SCs, potentially contributing to the pathogenesis of diabetic peripheral neuropathy.

Polyneuropathy Burden Found Much Higher Among Elders in Population Study

SAN DIEGO – Polyneuropathy affects an estimated 2.1% of the general population but about 10% of older adults, results from a large analysis demonstrated. In addition, “surrogate markers of disability such as medication use, complications, and disabling symptoms seem to indicate that polyneuropathy confers significant disability,” Dr. Christopher J. Klein said regarding research he did with Dr. E. Matthew Hoffman, a PGY-2 resident in the neurology department at the Mayo Clinic, Rochester, Minn. Dr. Hoffman presented the research earlier this year at the annual meeting of the American Academy of Neurology. Dr. Klein of the neurology department at the Mayo Clinic spoke in an interview. “As the U.S. population ages and diabetes rates continue to rise, the disease burden of polyneuropathy will only increase,” Dr. Klein said. He added that population-based epidemiologic studies of polyneuropathy and peripheral nerve diseases are lacking in terms of sampling completeness, population size, and generalizability. “As far as we can determine, there are no population-based estimates of disability related to polyneuropathy,” he said. To ascertain the burden of polyneuropathy, Dr. Klein and his associates evaluated data from the Rochester Epidemiology Project (REP), which links the population of Olmsted County, Minn., to electronic medical records of virtually all residents. The REP census generally has exceeded the U.S. Census since 1970, making population sampling very complete, Dr. Klein said. In their analysis, the researchers studied 138,420 Olmsted County residents who received health care between 2006 and 2010, gathering five age- and gender-matched controls for each case with an ICD-9 code that implied a diffuse polyneuropathy, such as 337.0. They excluded 11,494 cases of isolated mononeuropathies, plexopathies, and radiculopathies. More than half of the studied population (56%) had comprehensive neurologic examinations available by certified neurologists with retrievable neurology sheets documenting motor, reflex, and sensory deficits; gait difficulties; and other components of a comprehensive neurologic examination. Electronically retrievable nerve conduction studies were also available in 43% of the studied population. Information on medications, complications related to polyneuropathy, and answers to survey questions about disabling symptoms were extracted for cases and controls as surrogate markers to quantify functional disability. Dr. Klein reported that 2,897 cases of polyneuropathy were identified, which translated into a prevalence of 2.1% for the entire population for the 5-year period. The prevalence rose with age and peaked in the eighth decade of life for both men (11.2%) and women (7.9%), which meant that about 10% of elderly overall were affected. Fifty percent of the polyneuropathy cases were idiopathic, followed by diabetic (38%), inflammatory (5%), hereditary (3%), toxic (3%), and other (1%). The researchers observed many statistically significant increases in surrogate markers of disability, compared with the matched controls, including an eightfold increase in pain medication use; a fivefold increase in lower-limb ulcers; and up to a threefold increase in difficulties in gait, need for gait aids, and trouble climbing stairs. This extent of witnessed surrogate marker disabilities is similar to what is observed with other major medical problems, said Dr. Klein, who is also co-editor of the Journal of the Peripheral Nervous System. One limitation of the analysis, he noted, was that polyneuropathy cases were identified from ICD-9 codes. “Therefore, for most patients, symptomatic presentation is most likely and asymptomatic cases may not be documented, possibly leading to underestimation,” Dr. Klein said. The study was supported by the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, and the Mayo Foundation. Dr. Klein reported having no relevant financial conflict of interest.

The fetal endothelium of the human placenta: advantages and perils of phenotypic plasticity

Successful regeneration of injured peripheral nerves is mainly attributed to the plastic behavior of Schwann cells. Upon loss of axons, these cells trans-differentiate into regeneration promoting repair cells which provide trophic support to regrowing axons. Among others, activation of cJun was revealed to be involved in this process, initiating the stereotypic pattern of Schwann cell phenotype alterations during Wallerian degeneration. Nevertheless, the ability of Schwann cells to adapt and therefore the nerve's potential to regenerate can be limited in particular after long term denervation or in neuropathies leading to incomplete regeneration only and thus emphasizing the need for novel therapeutic approaches. Here we stimulated primary neonatal and adult rat Schwann cells with Fingolimod/FTY720P and investigated its impact on the regeneration promoting phenotype. FTY720P activated a number of de-differentiation markers including cJun and interfered with maturation marker and myelin expression. Functionally, FTY720P treated Schwann cells upregulated growth factor expression and these cells enhanced dorsal root ganglion neurite outgrowth on inhibitory substrates. Our results therefore provide strong evidence that FTY720P application supports the generation of a repair promoting cellular phenotype and suggest that Fingolimod could be used as treatment for peripheral nerve injuries and diseases.

184th ENMC international workshop: Pain and fatigue in neuromuscular disorders: 20–22 May 2011, Naarden, The Netherlands

This European Neuromuscular Centre (ENMC) care workshop was attended by 19 professionals working in the field of neuromuscular disorders (pediatric and adult), pain or fatigue from 8 different countries (USA, Great Britain, Germany, France, Italy, Sweden, Denmark and the Netherlands), and 3 patient representatives coming from the Netherlands. This ENMC organized workshop aimed to achieve consensus on the definition of pain and fatigue in NMD, to define a core set of measurement instruments for pain and fatigue in NMD, and to discuss possible interventions. Prior to the workshop, all participants received a questionnaire on the assessment instruments and interventions that they regularly used to, respectively, assess and treat pain and fatigue. Two experts on (chronic) pain and fatigue in general (Henriet van Middendorp and Hans Knoop) were invited to present an overview of definitions, mechanisms, and measurement instruments for pain and fatigue. Next to that, several participants presented data on the prevalence of pain and fatigue in the various NMD populations. Through group discussions with all participants, consensus was reached on the definition and core set of measurement instruments (to be used)/for use in future research and clinical practice in NMD.

Cochrane 20 years on: The Cochrane Neuromuscular Disease Group

The Cochrane Collaboration (CC) celebrates its 20th anniversary in 2013 and the Cochrane Neuromuscular Disease Group (CNMDG) its fifteenth. The Cochrane Database of Systematic Reviews is an internet-based resource of systematic reviews. The CNMDG has contributed over 100 Cochrane Systematic Reviews (CSRs) of interventions in neuromuscular disease, with almost 40 in preparative pre-publication. Over 100 potential titles still await author groups to tackle them. Cochrane Systematic Reviews not only provide the best summary of the evidence for individual interventions for diseases, but have contributed high quality and valuable data to international neuromuscular guidelines, each review coming at 1/10th of the cost of a NICE guideline. This efficient but high quality contribution is due both to the systematized Cochrane methods and the invaluable participation of over 26,000 Cochrane volunteer authors. Without Cochrane Systematic Reviews some questions about interventions for neuromuscular diseases would still remain ‘unanswered’. The CNMDG has made substantial contributions to literature in specific topics areas of both peripheral nerve and muscle disease. In Guillain-Barre Syndrome (GBS) one meta-analysis demonstrates the ineffectiveness of steroids and more importantly their potential harms, not evident from individual trials [1]. Systematized international multilingual searches for other treatments for GBS have uncovered potential new treatments requiring trial, such as the extract of Tripterygium wilfordii [2]. In Duchenne Muscular Dystrophy a meta-analysis of data from 249 children confirmed effectiveness of glucocorticoid corticosteroids in stabilizing muscle strength and improving function [3], and this is now considered the

Acetyl-L-carnitine: from a biological curiosity to a drug for the peripheral nervous system and beyond

Acetyl-L-carnitine (ALC) is a molecule derived from acetylation of carnitine in the mitochondria. Carnitine acetylation enables the function of CoA and facilitates elimination of oxidative products. Beyond this metabolic activity, ALC provides acetyl groups for acetylcholine synthesis, exerts a cholinergic effect and optimizes the balance of energy processes. Acetylcarnitine supplementation induces neuroprotective, neurotrophic and analgesic effects in the peripheral nervous system. In the recent studies, ALC, by acting as a donor of acetyl groups to NF-kb p65/RelA, enhanced the transcription of the GRM2 gene encoding the mGLU2 receptors, inducing long-term upregulation of the mGluR2, evidencing therefore that its long-term analgesic effects are dependent on epigenetic modifications. Several studies, including double-blind, placebo-controlled, parallel group studies and few open studies showed the effect of ALC in diseases characterized by neuropathies and neuropathic pain: the studies included diabetic neuropathy, HIV and antiretroviral therapy–induced neuropathies, neuropathies due to compression and chemotherapeutic agents. Double-blinded studies involved 1773 patients. Statistical evaluations evidenced reduction of pain, improvements of nerve function and trophism. In conclusion, ALC represents a consistent therapeutic option for peripheral neuropathies, and its complex effects, neurotrophic and analgesic, based on epigenetic mechanism, open new pathways in the study of peripheral nerve disease management.

Peripheral Nerve Disease in Pregnancy

Neuropathies during pregnancy and the postpartum period are common and are usually due to compression around pregnancy and childbirth. The most common peripheral neuropathies are Bell's palsy, carpal tunnel syndrome (CTS), and lower extremity neuropathies. Although most neuropathies are usually reversible, associated disabilities or morbidities can limit functioning and require therapy. Nerve conduction study tests and imaging should only be considered if symptoms are unusual or prolonged. Some neuropathies may be associated with preeclampsia or an inherent underlying neuropathy that increases the risk of nerve injury. All neuropathies in pregnancy should be followed as some may be persistent and require follow-up.

Evaluation of dermal myelinated nerve fibers in diabetes mellitus

Skin biopsies have primarily been used to study the non-myelinated nerve fibers of the epidermis in a variety of neuropathies. In this study, we have expanded the skin biopsy technique to glabrous, non-hairy skin to evaluate myelinated nerve fibers in the most highly prevalent peripheral nerve disease, diabetic polyneuropathy (DPN). Twenty patients with DPN (Type I, n = 9; Type II, n = 11) and 16 age-matched healthy controls (age 29-73) underwent skin biopsy of the index finger, nerve conduction studies (NCS), and composite neuropathy scoring. In patients with DPN, we found a statistically significant reduction of both mechanoreceptive Meissner corpuscles (MCs) and their afferent myelinated nerve fibers (p = 0.01). This myelinated nerve fiber loss was correlated with the decreased amplitudes of sensory/motor responses in NCS. This study supports the utilization of skin biopsy to quantitatively evaluate axonal loss of myelinated nerve fibers in patients with DPN.

High-Resolution Magnetic Resonance Imaging of the Lower Extremity Nerves

Magnetic resonance (MR) imaging of the nerves, commonly known as MR neurography is increasingly being used as noninvasive means of diagnosing peripheral nerve disease. High-resolution imaging protocols aimed at imaging the nerves of the hip, thigh, knee, leg, ankle, and foot can demonstrate traumatic or iatrogenic injury, tumorlike lesions, or entrapment of the nerves, causing a potential loss of motor and sensory function in the affected area. A thorough understanding of normal MR imaging and gross anatomy, as well as MR findings in the presence of peripheral neuropathies will aid in accurate diagnosis and ultimately help guide clinical management.

Ultrasound assessment of sural nerve in Charcot–Marie-Tooth 1A neuropathy

ObjectiveNerve ultrasound (US) has been used to study peripheral nerve disease, and increase of the cross-sectional area (CSA) has been described in demyelinating polyneuropathy. The objective of the current study is to characterise the US features of the sural nerve in a sample of Charcot–Marie-Tooth (CMT) 1A patients. MethodsA total of 20 CMT1A patients were enrolled. As control group we studied 37 age- and sex-matched subjects. All patients underwent clinical examination, neurophysiology and US evaluation of the bilateral sural nerve and right ulnar nerve. US results were correlated with neurophysiology and clinical data. ResultsSural nerve CSA was not increased in the majority of patients (70%), whereas an increased ulnar nerve CSA was present in the whole sample. Inverse relations were found between CSA of the ulnar nerve and body mass index (BMI) (p<0.0002, R=−0.8) and CSA of the sural nerve and age (right 0.006, R=−0.6, left 0.002, R=−0.6 and left and right p=0.00003, R=−0.4). ConclusionsUS showed ulnar CSA enlargement and normal sural nerve CSA. SignificanceThe significance of normal sural nerve CSA in CMT1A patients need to be further investigated, possibly through longitudinal studies.

Spotlight on the April 30 issue

In 53 patients with mononeuropathy or brachial plexopathy imaged with ultrasound and MRI, ultrasound was more sensitive (43/46 [93%] vs 31/46 [67%]), was equally specific (6/7 [86%]), and identified more multifocal lesions. Ultrasound is the preferred initial imaging modality for anatomic evaluation of suspected peripheral nervous system lesions. See p. 1634 From editorialists Padua & Hobson-Webb: “Less expensive, more comfortable, and less time-consuming than either MRI or electrodiagnostic testing, nerve US may eventually become the first choice for the evaluation of focal diseases of peripheral nerves.” See p. 1626 The risk of stroke was studied in 24,544 …

Merlin isoform 2 in neurofibromatosis type 2–associated polyneuropathy

The autosomal dominant disorder neurofibromatosis type 2 (NF2) is a hereditary tumor syndrome caused by inactivation of the NF2 tumor suppressor gene, encoding merlin. Apart from tumors affecting the peripheral and central nervous systems, most NF2 patients develop peripheral neuropathies. This peripheral nerve disease can occur in the absence of nerve-damaging tumors, suggesting an etiology that is independent of gross tumor burden. We discovered that merlin isoform 2 (merlin-iso2) has a specific function in maintaining axonal integrity and propose that reduced axonal NF2 gene dosage leads to NF2-associated polyneuropathy. We identified a merlin-iso2-dependent complex that promotes activation of the GTPase RhoA, enabling downstream Rho-associated kinase to promote neurofilament heavy chain phosphorylation. Merlin-iso2-deficient mice exhibited impaired locomotor capacities, delayed sensory reactions and electrophysiological signs of axonal neuropathy. Sciatic nerves from these mice and sural nerve biopsies from NF2 patients revealed reduced phosphorylation of the neurofilament H subunit, decreased interfilament spacings and irregularly shaped axons.

Aberrant Schwann Cell Lipid Metabolism Linked to Mitochondrial Deficits Leads to Axon Degeneration and Neuropathy

Mitochondrial dysfunction is a common cause of peripheral neuropathy. Much effort has been devoted to examining the role played by neuronal/axonal mitochondria, but how mitochondrial deficits in peripheral nerve glia (Schwann cells [SCs]) contribute to peripheral nerve diseases remains unclear. Here, we investigate a mouse model of peripheral neuropathy secondary to SC mitochondrial dysfunction (Tfam-SCKOs). We show that disruption of SC mitochondria activates a maladaptive integrated stress response (ISR) through the actions of heme-regulated inhibitor (HRI) kinase, and causes a shift in lipid metabolism away from fatty acid synthesis toward oxidation. These alterations in SC lipid metabolism result in depletion of important myelin lipid components as well as in accumulation of acylcarnitines (ACs), an intermediate of fatty acid β-oxidation. Importantly, we show that ACs are released from SCs and induce axonal degeneration. A maladaptive ISR as well as altered SC lipid metabolism are thus underlying pathological mechanisms in mitochondria-related peripheral neuropathies.

Endoscopic Carpal Tunnel Release

Carpal tunnel syndrome is a common peripheral nerve disease, often requiring surgical intervention. After the first description of endoscopic carpal tunnel release 20 years ago, several endoscopic techniques have been described. The endoscopic procedure seems to have a better outcome in terms of time to return to work. A feared complication of endoscopic carpal tunnel release is injury to the median nerve or branches of the median nerve. We developed a new guiding cannula with raised borders, which will prevent accidental injury to the median nerve. A single-portal anterograde technique, to release the transverse carpal ligament, is described with the use of this new guiding device.

The epidemiology of intermittent and chronic ataxia in children in Manitoba, Canada

To determine the epidemiology of chronic ataxia in children in Manitoba, Canada. A retrospective study using multiple sources and disease codes identified children (age 0-16y) with chronic ataxia (>2mo duration or recurrent episodes of ataxia) seen at Winnipeg Children's Hospital from 1991 to 2008. Patients with isolated peripheral nerve diseases, vestibular disorders, or brain tumors were excluded. We identified 184 patients (males=females; mean age 15y, SD 7y 8mo) with chronic ataxia. Median age at the presenting symptom onset was 1 year 3 months and at ataxia onset 3 years 1 month. Median duration of follow-up was 6 years 5 months. During the study period, the crude incidence rate was 5.77 in 10,000; the crude prevalence rate was 6.59 in 10,000; and the crude mortality rate 0.446 in 10,000. The most common presenting symptoms were developmental delay, ataxia, or seizures. The most common diagnoses (known in 129) were Angelman syndrome (n=16), ataxia telangiectasia (n=13), mitochondrial disease (n=9), Friedreich ataxia (n=7), stroke (n=7), and familial/genetic episodic ataxia (n=7). Chronic ataxia is a relatively common early-presenting symptom in childhood. A specific diagnosis is possible in 70% of patients after extensive investigations. The mortality rate is relatively low and the disease burden is high with significant comorbidities including developmental delay and epilepsy.