Treatment of peripheral neuropathies with neutrotrophic factors: animal models and clinical trials

In vitro experiments and works with knock-out mice have demonstrated the physiological importance of neurotrophic factors (NF) in the development and the survival of peripheral nervous system neurons. Therefore, NF may be useful in the treatment of peripheral neuropathies. These pathologies may be more amenable than central nervous diseases to the systemic delivery of NF. Indeed, NF can readily access peripheral nerves from blood whereas penetration into the central nervous system is limited by the blood-brain barrier. The objectives of NF treatment are: 1) to compensate a putative deficiency of NF associated with the pathogenesis of some neuropathies, such as diabetic neuropathy; 2) to stop or slow disease progression by acting on the biochemical pathways involved in the neurodegenerative cascade; and 3) to enhance the physiological compensatory mechanism of axonal sprouting. The efficacy of treatment with NF has been demonstrated in animal models mimicking various neuropathies, such as neuropathies related to diabetes or treatment with chemotherapeutic agents. However, a phase 3 trial in diabetic neuropathy and a phase 2 trial in HIV-related neuropathy have failed to demonstrate any substantial effect of treatment with NGF. In this review, we discuss the factors that may explain these negative results. A major limitation of systemic administration is the poor bioavailability of NF due to their short half-life. Alternative modes of delivery may be more appropriate than systemic administration of the recombinant protein. In particular, muscular-based gene therapy allows the delivery of sustained levels of neurotrophic factor into the circulation. This strategy has shown to be effective in animal models of motor and sensory neuropathies. Another promising treatment is the use of small molecules that induce the endogenous synthesis of NF, such as xaliprodene or 4-methylcathecol.     

Ganglioside mimicry and peripheral nerve disease

Four criteria must be satisfied to conclude that a given microorganism causes Guillain-Barré (GBS) or Fisher (FS) syndrome associated with anti-ganglioside antibodies: (1) an epidemiological association between the infecting microbe and GBS or FS; (2) isolation in the acute progressive phase of illness of that microorganism from GBS or FS patients with associated anti-ganglioside IgG antibodies; (3) identification of a microbial ganglioside mimic; and (4) a GBS or FS with associated anti-ganglioside antibodies model produced by sensitization with the microbe itself or its component, as well as with ganglioside. Campylobacter jejuni is a definitive causative microorganism of acute motor axonal neuropathy and may cause FS and related conditions. Haemophilus influenzae and Mycoplasma pneumoniae are possible causative microorganisms of acute motor axonal neuropathy or FS. Acute and chronic inflammatory demyelinating polyneuropathies may be produced by mechanisms other than ganglioside mimicry.     

The clinical correlates of high-titer IgG anti-GM1 antibodies

Serum IgG anti-GM1 antibodies have been reported to occur in a variety of disorders, including Guillain-Barré syndrome and chronic polyneuropathies. Of over 5,000 serums tested in our laboratory, high titers of selective IgG anti-GM1 antibodies (>1: 1,000) and without binding to sulfatide were found in 35 patients. Clinical correlation revealed that almost all patients had axonal, motor neuropathies. One subgroup was comprised of individuals with an acute motor neuropathy, described either as an acute axonal Guillain-Barré–like syndrome that was occasionally associated with a prodrome of Campylobacter jejuni enteritis or as Chinese paralysis syndrome. A second group of patients had chronic asymmetric lower motor neuron (LMN) syndromes with no conduction block or other evidence of demyelination. The presence of selective high-titer IgG anti-GM1 antibody reactivity in serum is uncommon but when present is strongly associated with acute axonal motor neuropathies or chronic asymmetric LMN syndromes.     

POLYNEUROPATHIES IN THE ELDERLY: A CLINICO PATHOLOGICAL STUDY OF 74 CASES

In elderly patients, peripheral neuropathies are common and may lead to disability. In order to investigate the relative incidence of different polyneuropathies in the elderly focusing on the contribution of nerve biopsy to their diagnosis, the authors studied 74 patients over 65 years of age with clinical, laboratory, electrophysiological, and sural nerve biopsy findings of different types of polyneuropathy. Vasculitic polyneuropathy seemed to be the most common cause of disabling neuropathy in the elderly, followed by paraneoplasia and diabetes. The possible diagnosis of idiopathic axonal neuropathy in the nine cases with neuropathy of unknown origin is discussed.     

Antisulfatide antibodies in neuropathy: clinical and electrophysiologic correlates

OBJECTIVE: To investigate the clinical and electrophysiologic characteristics of the neuropathy associated with elevated serum antisulfatide antibodies. METHODS: Clinical, electrophysiologic, morphologic, and laboratory data of 25 patients with significantly elevated (>25,600) antisulfatide antibodies were reviewed. RESULTS: Four groups were distinguished based on clinical and electrophysiologic data: Group 1, eight patients with predominantly small fiber sensory neuropathy (32%); Group 2, five patients with mixed large and small fiber sensory neuropathy (20%); Group 3, seven patients with axonal sensorimotor neuropathy (28%); and Group 4, three patients with demyelinating sensorimotor neuropathy (12%). One additional patient had mononeuritis multiplex and one had ALS. An immunoglobulin M (IgM) monoclonal gammopathy was found in 30% of the patients tested, but not in any of the Group 1 patients with small fiber sensory neuropathy. Serum IgM level was elevated in 12 patients, of whom six had a concomitant monoclonal gammopathy. Morphologic studies in five patients showed predominantly axonal degeneration, with three of the patients also exhibiting additional features of demyelination. CONCLUSIONS: Antisulfatide antibodies are associated with several subtypes of peripheral neuropathy. Predominantly sensory or sensorimotor axonal neuropathies are most common in this series, with the sensory component either small fiber or mixed fiber type. A smaller demyelinating group indistinguishable from patients with chronic inflammatory demyelinating polyradiculopathy was also seen. One third of patients had a concomitant IgM monoclonal gammopathy, and approximately one half had elevated serum IgM.     

Genetic axonal neuropathies and neuronopathies of pre-natal and infantile onset

The infantile-onset axonal neuropathies and neuronopathies are an uncommon and heterogeneous group of conditions causing weakness, wasting, and developmental delay in early childhood. Many are associated with central nervous system or other systemic manifestations and cause early mortality. We review the axonal Charcot-Marie-Tooth subtypes with onset in infancy, spinal muscular atrophy, and related syndromes of early infancy, giant axonal neuropathy, infantile neuroaxonal dystrophy, hereditary motor and sensory neuropathy with agenesis of the corpus callosum, early-onset neuropathies associated with mitochondrial disorders, and other less well-delineated clinical entities. Useful clinical and neuropathologic features in the diagnostic work-up of these conditions are also presented.     

Peripheral neuropathy associated with IgM monoclonal gammopathy: Correlations between M-protein antibody activity and clinical/electrophysiological features in 40 cases

Forty cases of polyneuropathy associated with IgM monoclonal gammopathy were retrospectively studied to investigate the relevance of clinical and electrophysiological features to M-protein antibody activity. There were 26 men and 14 women; mean age was 65 ± 11.7 years at the time of the study. Thirty-nine patients had a symmetrical polyneuropathy, of whom 13 had a predominantly sensory and 17 a purely sensory neuropathy (i.e., 30 sensory neuropathies). The remaining patient had a multifocal mononeuropathy. Electrophysiological studies allowed the polyneuropathies to be classified as demyelinating in 33 cases (82.5%) and axonal in 6 cases. Antibody studies disclosed anti-MAG antibodies in 65% and anti-SGPG antibodies in 82.5% of patients. Anti-MAG antibodies were associated with only demyelinating polyneuropathies. Anti-SGPG antibodies were found in 91% of demyelinating polyneuropathies and 50% of axonopathies. In addition, anti-MAG/SGPG antibody activity was significantly correlated with the subgroup of sensory neuropathies (P < 0.01). Last, antisulfatide antibodies were found at significant titers in 18 cases, and their presence was significantly correlated with anti-MAG/SGPG antibody activity, but not with some clinical/electrophysiological features. © 1998 John Wiley & Sons, Inc. Muscle Nerve, 21: 55–62, 1998.     

Autonomic peripheral neuropathy

Most generalized peripheral polyneuropathies are accompanied by clinical or subclinical autonomic dysfunction. There is a group of peripheral neuropathies in which the small or unmyelinated fibers are selectively targeted. In these neuropathies, autonomic dysfunction is the most prominent manifestation. The features associated with an autonomic neuropathy include impairment of cardiovascular, gastrointestinal, urogenital, thermoregulatory, sudomotor, and pupillomotor autonomic function.     

Polyneuropathy syndromes associated with serum antibodies to sulfatide and myelin-associated glycoprotein.

We studied a series of 64 patients with sensory +/- motor peripheral neuropathies by comparing clinical and physiologic features to serum antibody reactivity against compounds containing sulfated carbohydrate moieties. We determined antibody reactivity by an enzyme-linked immunosorbent assay (ELISA) using purified glycolipids and glycoproteins as antigens, and we used high-performance thin-layer chromatography and Western blotting to test the specificity of results. Twelve patients with high titers of IgM antibodies directed against the myelin-associated glycoprotein (MAG) had sensory-motor polyneuropathies with physiologic evidence of demyelination. IgM antibody reactivity to MAG was associated with an IgM serum M protein in five patients. Eight other patients, most with sensory greater than motor polyneuropathies, had high titers of antibody reactivity to sulfatide but not of IgM to MAG. Two had an associated IgM paraprotein. None of the patients with selective serum antisulfatide activity had predominantly demyelinating features on physiologic testing. We conclude that (1) high ELISA titers of antibodies to MAG may be more common than previously suspected in patients with chronic demyelinating sensory-motor neuropathies, and (2) the presence of high titers of antisulfatide antibodies in serum may provide clues to the pathogenesis of otherwise idiopathic, axonal, predominantly sensory neuropathies.     

Lesion mechanism dependent, differential changes in neurofilaments and microtubules: a pathological and experimental study

INTRODUCTION: The consequences of axonal or demyelinating injuries on the axonal cytoskeleton have rarely been described. METHODS: We have compared the density of fibers labeled by anti-neurofilaments (NF) and -beta tubulin (TUB) to the density of total fibers in nine patients with axonal neuropathies of undetermined etiology (AUE), six with necrotizing angeitis with neuropathy (NAN), seven with chronic inflammatory demyelinating neuropathy (CIDP) and in five controls, as well as in six patients with chronic multiple sclerosis (MS). We also studied demyelinated rat corpus callosum after lysophosphatidyl (LPC) microinjection. RESULTS: In AUE and NAN NF positive fibers decreased together with total fiber density, whereas TUB increased. In demyelinating lesions TUB was not altered (CIDP) or strongly decreased (MS, LPC); NF were strongly reduced in MS (where axon loss was prominent) and in LPC lesions (despite the lack of fiber degeneration) and for fiber densities<3900/mm2 in CIDP. CONCLUSION: The initial mechanism of a disease, either axonal degeneration or demyelination, could result into a specific pattern of axonal cytoskeleton alterations.     

Peripheral nervous system neuroimmunology seen by a neuro-pathologist

In most dysimmune neuropathies, historically the microscopical lesions were described prior to immunological studies. The latter along with neuropathological studies have found some immune, albeit incomplete, explanations of the mechanisms of these lesions which we will describe in two main syndromes: the primitive auto-immune inflammatory peripheral polyneuropathies (GBS and CIDP) and polyneuropathies induced by a monoclonal dysglobulinemia. In some patients who have to be discussed case by case pathology (nerve biopsy) will confirm the diagnosis, may help to delineate the molecular anomalies and identify lesional mechanisms. We will review the high variability of nerve lesions which is characteristic of dysimmune neuropathies. Pathological studies confirm that both humoral and cellular immune reactions against Schwann cell and/or axonal antigens are implicated in primitive dysimmune neuropathies due to a dysfunction or failure of immune tolerance mechanisms. In case of a polyneuropathy associated to a monoclonal dysglobulinemia, pathological and immunological studies have shown that in many patients, the dysglobulinemia did harm the peripheral nerve; knowledge of the pathological lesions and their mechanisms is of major interest for orienting specific treatments.     

Clinical and electrophysiological characteristics of neuropathy associated with Tangier disease

Tangier disease (TD) (OMIM#205400) is a rare autosomal recessive disorder resulting from mutations in the ABCA1 gene, leading to decreased levels of plasma high-density lipoproteins (HDL). Peripheral neuropathy is a common finding in this disease, and may present as relapsing/remitting mono/polyneuropathies or as syringomyelia-like neuropathy. We retrospectively analyzed four patients, and report here their clinical, biological, electrophysiological, imaging, and genetic findings. Three patients had a typical pseudosyringomyelic neuropathy including facial diplegia, but asymmetrical onset was observed in one patient who had first been misdiagnosed with Lewis-Sumner syndrome. Electrophysiological pattern was heterogeneous, showing both signs of demyelination and axonal degeneration. Truncating mutations of the ABCA1 gene, including two previously undescribed mutations, were constantly found. Atypical symptom onset and demyelinating features on electrophysiological examination can be misleading in case of pseudosyringomyelic neuropathy. These reports illustrate two different neurological phenotypes in TD, namely the pseudosyringomyelic type and the Lewis-Sumner-like type, and advocate for a systematic assessment of lipid profile including HDL cholesterol in demyelinating neuropathies.     

Early-onset axonal Charcot-Marie-Tooth disease due to SACS mutation

Axonal Charcot-Marie-Tooth disease (CMT) represents an expanding group of inherited motor and sensory neuropathies in clinical practice. SACS-gene related disorders have been associated with complex neurological phenotypes of early-onset cerebellar ataxia, spastic-ataxia, spastic paraplegia, demyelinating neuropathy and variable ophthalmological, cognitive and psychiatric disturbances, but never related to pure axonal neuropathy phenotypes. Two unrelated Brazilian men with early-onset axonal CMT-like presentations associated with SACS gene mutations are presented. Both patients presented with pure sensorimotor axonal neuropathy without cerebellar ataxia, spastic paraplegia or other systemic and neurological involvement. Classical neuroimaging findings observed in other sacsinopathies were observed in both cases. Homozygous pathogenic mutations were found in SACS gene in both patients. SACS gene mutations can be associated with pure axonal sensorimotor neuropathy without other neurological features, but with typical neuroimaging features of other sacsinopathies, disclosing the importance of performing neuroimaging studies in patients with suspected axonal CMT.     

Axonal multifocal motor neuropathy without conduction block or other features of demyelination

BACKGROUND: Conduction block is considered an essential finding for the distinction between motor neuropathies and lower motor neuron disorders. Only a small number of reports describe patients with multifocal motor neuropathies who lack overt conduction block, although in these cases other features of demyelination still suggest the presence of a demyelinating disorder. In contrast, a purely axonal multifocal motor neuropathy has not been described. METHODS: This report describes nine patients with slowly or nonprogressive multifocal motor neuropathies who had purely axonal electrodiagnostic features. RESULTS: GM1 antibodies titers were normal in all nine cases. Six patients were treated with either prednisone or IV immunoglobulin and three showed convincing improvement. CONCLUSIONS: These findings suggest an immune-mediated motor neuropathy with axonal electrophysiologic features that appears to be distinct from both multifocal motor neuropathy and established motor neuron disorders.     

Peripheral neuropathies after bariatric surgery

IntroductionPeripheral neuropathies sometimes complicate bariatric surgery.Patients and methodsWe report the detailed clinical, electrophysiological, biological and histological characteristics of five patients who developed peripheral neuropathy after bariatric surgery.ResultsThree patients presented with small fiber neuropathy, one presented with axonal polyneuropathy, and one with demyelinating polyradiculoneuropathy. All patients had in common prominent neuropathic pain, massive weight loss, and multiple nutritional deficiencies. The pathophysiology of postbariatric surgery polyneuropathies is complex and involves nutritional, infectious and dysimmune mechanisms.ConclusionThe spectrum of peripheral neuropathies complicating bariatric surgery is wide, and includes pure small fiber neuropathy, axonal polyneuropathy, and demyelinating polyradiculoneuropathy. Treatment is mainly preventive, but sometimes surgical revision is needed.     

Upper leg conduction time distinguishes demyelinating neuropathies

Background: The objective of this study was to determine whether differentiation between demyelinating and axonal neuropathies could be enhanced by comparing conduction time changes in defined segments of the total peripheral nerve pathway. Methods: Compound muscle action potentials (CMAPs) were elicited by cathodal stimulation of the tibial nerve at the ankle and popliteal fossa, and by paravertebral neuromagnetic stimulation at proximal and distal cauda equina while recording from muscles of the foot, shin, and thigh. Segmental conduction times were calculated in normal subjects; in patients with lumbosacral radiculopathy, distal symmetric diabetic neuropathy, amyotrophic lateral sclerosis, acute and chronic inflammatory demyelinating polyneuropathy; and in patients with anti–myelin‐associated glycoprotein, myelomatous, and Charcot–Marie–Tooth type 1a polyneuropathies. Results: Distal cauda equina latency and CMAP duration and segmental conduction times in upper leg and cauda equina facilitated differentiation of demyelinating from axonal neuropathies, even in the presence of a range of reduced amplitude CMAPs. Conclusions: Within the demyelinating neuropathy spectrum, it was further possible to distinguish subtypes. Muscle Nerve, 2011     

Polyneuropathies in the elderly: a clinico pathological study of 74 cases

In elderly patients, peripheral neuropathies are common and may lead to disability. In order to investigate the relative incidence of different polyneuropathies in the elderly focusing on the contribution of nerve biopsy to their diagnosis, the authors studied 74 patients over 65 years of age with clinical, laboratory, electrophysiological, and sural nerve biopsy findings of different types of polyneuropathy. Vasculitic polyneuropathy seemed to be the most common cause of disabling neuropathy in the elderly, followed by paraneoplasia and diabetes. The possible diagnosis of idiopathic axonal neuropathy in the nine cases with neuropathy of unknown origin is discussed.     

Clinical and Electrodiagnostic Features Of Nontraumatic Sciatic Neuropathy

Introduction: In this study we sought to characterize etiologies and features of sciatic neuropathy unrelated to penetrating nerve trauma. Methods: This investigation was a retrospective review of 109 patients with electrodiagnostically confirmed sciatic neuropathies. Results: Hip replacement surgery represented the most common (34.9%) etiology, whereas inflammatory sciatic neuropathy was seen in 7.3%. Electrodiagnostic testing revealed an axonal neuropathy in 95.4% and a demyelinating neuropathy in 4.6%. Predominant involvement of the peroneal division was seen in 39.4% and was tibial in 5.5%. Nine of 31 (29.0%) patients who had MRI or neuromuscular ultrasound study showed abnormalities within the sciatic nerve. At the final visit, 46.4% of patients required assistance for ambulation. Young age, lack of severe initial weakness, and presence of tibial compound muscle action potential or sural sensory nerve action potential were predictors of favorable outcome. Discussion: Sciatic neuropathies are usually axonal on electrodiagnostic testing, affect preferentially the peroneal division, and are commonly associated with incomplete recovery. Muscle Nerve 59 :309–314, 2019     

Genetically determined neuropathies

There have been major advances in the understanding of the genetically determined neuropathies in recent years. The underlying genetic defects are now known for many of the demyelinating hereditary motor and sensory neuropathies, and linkage data are available for some of the axonal hereditary motor and sensory neuropathies. This has important implications for both diagnosis and genetic counselling in this group of conditions. The genetic defect in most cases of familial amyloid polyneuropathy is also now known. In the most common form of familial amyloid polyneuropathy (FAP), transthyretin-related FAP, liver transplantation has been established as the first definitive treatment for a hereditary neuropathy and should be considered especially in young adult patients. This review will concentrate on the advances in the molecular genetics of the hereditary motor and sensory neuropathies, the hereditary sensory and autonomic neuropathies and the familial amyloid polyneuropathies with particular emphasis on the difficulties in classifying the first group. Received: 29 July 1997 Accepted: 2 September 1997