Progressive idiopathic axonal neuropathy

Abstract. Patients with a progressive disabling idiopathic axonal neuropathy could have a potentially treatable immune mediated neuropathy. To evaluate whether progressive idiopathic axonal neuropathy could be a pathologically difficult to prove vasculitic neuropathy pathologically difficult to prove or if it could be a separate clinical entity (i. e. with the axon as the primary immunological target), we performed a comparative clinical and histopathological study in 10 patients with progressive idiopathic axonal neuropathy, 10 patients with vasculitic neuropathy, and 12 patients with chronic idiopathic axonal polyneuropathy (CIAP). The clinical features and disease course in patients with progressive idiopathic axonal neuropathy and patients with vasculitic neuropathy were similar. Six patients with progressive idiopathic axonal neuropathy had been treated with prednisone and/or intravenous immunoglobulin. Disability decreased in all these six patients, but also in two of the four non-treated patients. Upon reviewing the sural nerve biopsy specimens, vasculitis was found in one patient with progressive idiopathic axonal neuropathy. Vasculitis-associated signs of ischemic injury or inflammation (most notably: large variation in fascicular axonal degeneration, perivascular inflammation, inflammation of the blood vessel wall without lumen obstruction) were found in four patients with progressive idiopathic axonal neuropathy, in all patients with vasculitic neuropathy, but were absent in patients with CIAP. The findings show that there is a small chance of finding sural nerve vasculitis upon scrutinising biopsy examination in progressive idiopathic axonal neuropathy. The presence of vasculitisassociated signs in progressive idiopathic axonal neuropathy suggests that some of these patients could have vasculitic neuropathy, even if vasculitic lesions cannot be demonstrated. However, if inflammatory changes cannot be demonstrated this does not preclude an immune-mediated origin.     

Is there a relationship between somatic and autonomic neuropathies in chronic alcoholics?

We investigated the relationship between somatic and autonomic neuropathy in 40 chronic alcoholics. Electromyographic and neurographic studies of upper and lower limbs and a battery of six cardiovascular reflex tests were carried out. A score for somatic or autonomic neuropathy was calculated. All parameters were investigated for possible relationship with total life dose (TLD) of alcohol intake. Somatic neuropathy was detected in 25 patients (62.5%) and autonomic neuropathy in 13 patients (32.5%). Nineteen patients (47.5%) presented only a somatic neuropathy, six patients (15%) had only an autonomic neuropathy, and seven (17.5%) had a combined somatic and autonomic neuropathy. TLD was significantly higher in the group of patients with combined neuropathy than in the group with isolated somatic neuropathy. There was no significant correlation between laboratory parameters of somatic and autonomic neuropathy. Our findings do not support the existence of a parallel involvement of peripheral somatic and autonomic cardiovascular nerve fibers in chronic alcoholism.     

The role of autonomic neuropathy in diabetic foot ulceration.

Five standard, non-invasive tests of cardiovascular, autonomic function were performed in each of four groups of 30 subjects: controls, group 1, diabetics without clinical evidence of neuropathy; group 2, diabetics with neuropathy, but without foot ulceration; group 3, diabetics with neuropathic ulceration of the foot. The results showed a significant impairment of autonomic function in diabetics without clinically demonstrable somatic neuropathy compared with controls diabetics with somatic neuropathy compared with those without diabetics with neuropathic ulceration compared with those with neuropathy without ulceration. Parasympathetic function was more seriously affected than sympathetic. In patients who had only mild sensory neuropathy on clinical assessment, those with ulcers had significantly greater impairment of autonomic neuropathy compared with those with uncomplicated neuropathy.     

Is the C677T polymorphism in methylenetetrahydrofolate reductase gene or plasma homocysteine a risk factor for diabetic peripheral neuropathy in Chinese individuals?

The present study enrolled 251 diabetic patients, including 101 with neuropathy and 150 without neuropathy. Of the 150 patients, 100 had no complications, such as retinopathy, nephropathy, or neuropathy. Polymerase chain reaction-restriction fragment length polymorphism analysis was used to identify methylenetetrahydrofolate reductase gene variants. Plasma homocysteine levels were also measured. Homocysteine levels and the frequency of hyperhomocysteinemia were significantly higher in patients with diabetic peripheral neuropathy compared with diabetic patients without neuropathy (P < 0.05). In logistic regression analysis with neuropathy as the dependent variable, the frequency of C677T in methylenetetrahydrofolate reductase was significantly higher in patients with diabetic peripheral neuropathy compared with patients without diabetic complications. Homocysteine levels were significantly higher in patients with diabetic peripheral neuropathy carrying the 677T allele and low folic acid levels. In conclusion, hyperhomocysteinemia is an independent risk factor for diabetic neuropathy in Chinese patients with diabetes. The C677T polymorphism in methylenetetrahydrofolate reductase and low folic acid levels may be risk factors for diabetic peripheral neuropathy in Chinese patients with diabetes.     

1000/Symptomatic and pathogenetic treatment of diabetic neuropathy. The role of alpha-lipoic acid

Diabetic neuropathy, the most common form of peripheral neuropathy worldwide, presents in different forms of focal or diffuse neuropathy, including the disabling, or potentially life-threatening clinical entities of painful diabetic neuropathy, autonomic neuropathy, and diabetic foot. The pathogenesis of diabetic neuropathy results from the concurrent action of various intersecting factors of nerve damage, i.e. oxidative stress and mitochondrial dysfunction, inflammation, microangiopathy and ischemia, triggered by hyperglycemia and related biochemical changes. Symptomatic treatment of diabetic neuropathy mainly concerns the therapy of neuropathic pain with antidepressants (tricyclics and serotonin-norepinephrine inhibitors), anticonvulsants (in particular, alpha2delta calcium channel modulator), opioids (oxycodone CR and tramadol), and local treatment and physical therapy. Symptomatic treatment of autonomic neuropathy includes different interventions targeted at the organ systems involved. The management of diabetic foot is directed at the various combined factors resulting in foot ulceration, such as infection, peripheral ischemia, and pressure relief. Various therapeutic approaches pathogenetically oriented have been proposed and investigated in experimental and clinical studies, targeted to the different components involved in the causation of nerve damage. In particular, oxidative stress has been demonstrated to play a central role in the cascade of events triggered by hyperglycemia, thus it appears as an ideal target for a pathogenetic therapeutic approach. Alpha-lipoic acid, a potent lipophilic free radical scavenger, has been used in a series of controlled randomized clinical trials in patients with diabetic neuropathy, with either oral administration or intravenous infusion. Most of the trials demonstrated the efficacy of alpha-lipoic acid on the chief symptoms of diabetic neuropathy, and in particular on neuropathic pain, also indicating that neuropathic deficits may be improved by treatment. Current evidence suggests a possible efficacy of alpha-lipoic acid not only for neuropathic symptoms, but also for modifying the natural history of diabetic neuropathy. The potential role of alpha-lipoic acid in contrasting the progression of diabetic neuropathy is being explored in the NATHAN 1 study, using an oral dose of 600 mg once daily over 4 years in diabetic patients with mild to moderate distal symmetric polyneuropathy, and evaluating the long-term effects with a composite score that combines clinical and neurophysiological assessment.     

Changes of gastric emptying rate and gastrin levels are early indicators of autonomic neuropathy in type II diabetic patients

The authors investigated the effect of a balanced meal on gastric emptying rate and gastrin plasma concentrations in patients with type II diabetes and autonomic neuropathy, in diabetic patients without autonomic neuropathy, and in healthy subjects (controls). Before food the gastrin plasma concentrations were higher in patients with diabetes with autonomic neuropathy. After food, gastric emptying rate was slower in patients with diabetes with autonomic neuropathy, whereas gastrin plasma concentrations increased in 30 minutes in all groups but to a greater extent in patients with diabetes with autonomic neuropathy. Sixty minutes after food, there was a significant decrease in gastrin plasma concentrations in patients with diabetes with autonomic neuropathy, compared with the other two groups. These data suggest that in patients with type II diabetes with autonomic neuropathy, food causes slower gastric emptying and different plasma gastrin level responses from those in patients with type II diabetes without autonomic neuropathy and controls. There are therefore differences in the responses to food ingestion between these groups because of vagal denervation induced by autonomic neuropathy. These tests should be reserved for patients with symptoms suggestive of disturbed gastric emptying, or for patients with autonomic neuropathy without symptoms of gastroparesis.     

Current issues in peripheral neuropathy

Twenty million people in the United States are estimated to have peripheral neuropathy. However, many patients are not aware of their diagnosis, are not given the diagnosis or being treated, or the diagnosis is delayed. Currently, the only treatments available for neuropathy are aimed at treating the underlying medical conditions that cause the neuropathy or treating symptoms such as pain. Neither treats the actual nerve fiber dysfunction or fiber loss, or helps nerve fibers regenerate. Idiopathic neuropathy, that is neuropathy for which a cause is not identified, is common, accounting in referral series for 25% in all neuropathy patients and 50% or more of patients with small fiber neuropathy. Currently, there is only one FDA-approved medication for a specific neuropathy (chronic inflammatory demyelinating polyneuropathy) while there are two FDA approved medications for diabetic neuropathy pain and four that are approved for post-herpetic neuralgia pain. For many patients with painful neuropathy, these medications are ineffective or not tolerated. Continued research into the underlying mechanisms of neuropathy and an increased understanding of nerve regeneration and neuropathic pain are needed to address this unmet medical need among patients with neuropathy.     

APOE epsilon4 is not a susceptibility gene in idiopathic or diabetic sensory neuropathy

The presence of an APOE epsilon4 allele may be a risk factor for neuropathy severity in diabetes. The authors assessed the frequency of APOE epsilon4 in patients presenting with sensory predominant neuropathy. APOE epsilon4 frequency among patients with early diabetic neuropathy and impaired glucose tolerance-associated neuropathy was 16 to 17%, and not different from patients with idiopathic neuropathy (17%) or published normative values (16%). APOE epsilon4 may not function as a susceptibility gene in sensory predominant neuropathy.     

First pathological report of a de novo CD5‐positive diffuse large B‐cell lymphoma patient presenting with Guillain–Barré syndrome‐like neuropathy due to neurolymphomatosis

Peripheral neuropathy occurs in approximately 5% of the patients with lymphoma. Two major causes of peripheral neuropathy associated with lymphoma are neurolymphomatosis and paraneoplastic neuropathy such as demyelinating neuropathy. The differential diagnosis between neurolymphomatosis and demyelinating neuropathy is difficult, because electrophysiological findings suggestive of demyelination are frequently observed even in patients with neurolymphomatosis. Here, we report a patient with de novo CD5‐positive diffuse large B‐cell lymphoma (DLBCL) who presented with Guillain–Barré syndrome (GBS)‐like neuropathy. Demyelination due to paraneoplastic neuropathy was clinically suspected. However, autopsy demonstrated that the cause of the neuropathy was neurolymphomatosis. Clinical courses of neurolymphomatosis vary and neurolymphomatosis cases presenting with GBS‐like neuropathy are reported. In addition, DLBCL is the most frequent histological type of malignant lymphoma that develops neurolymphomatosis. Furthermore, “CD5‐positive” DLBCL may tend to develop neurolymphomatosis. If a patient with “CD5‐positive” DLBCL develops peripheral neuropathy, neurolymphomatosis should be considered and imaging studies performed and, if possible, nerve tissue biopsy, regardless of clinical symptoms of the neuropathy. To our knowledge, this is the first report of a patient with de novo CD5‐positive DLBCL with neurolymphomatosis who presented with GBS‐like neuropathy.     

Neuropathies associated with excessive exposure to lead

Exposure to lead is a ubiquitous problem of the modern era. The majority of cases of all forms of lead intoxication, especially lead neuropathy, result from industrial exposure. In the Western world meticulous monitoring in industry has reduced the risk of overt lead neuropathy. The classic form of lead neuropathy consists of weakness that primarily involves the wrist and finger extensors but which later spreads to other muscles. There is only minimal sensory involvement. Less commonly, there is a more typical toxic neuropathy with distally accentuated sensory and motor involvement. The motor neuropathy is more likely to develop following relatively short-term exposure to high lead concentrations and evolves in a subacute fashion. Prognosis for recovery is good as long as exposure is terminated promptly. The distal sensory and motor neuropathy develops after many years of exposure, evolves more slowly, and recovery is less certain. There is a generally weak relationship between the development of lead neuropathy and blood lead levels, at least for the subacute motor neuropathy, leading to speculation that the metabolic basis for the neuropathy is interference with porphyrin metabolism. Lead intoxication in humans causes axonal degeneration, but in some other species it causes a primarily demyelinating neuropathy. It should be possible to prevent lead neuropathy by good industrial hygiene. Close monitoring should identify excessive lead exposure before it causes overt neuropathy. If evidence of excessive exposure is found or if overt neuropathy develops, exposure must be terminated immediately. The role of chelation therapy in the treatment of lead neuropathy is controversial.     

Peripheral neuropathy associated with mitochondrial disease in children

Mitochondrial diseases in children are often associated with a peripheral neuropathy but the presence of the neuropathy is under-recognized because of the overwhelming involvement of the central nervous system (CNS). These mitochondrial neuropathies are heterogeneous in their clinical, neurophysiological, and histopathological characteristics. In this article, we provide a comprehensive review of childhood mitochondrial neuropathy. Early recognition of neuropathy may help with the identification of the mitochondrial syndrome. While it is not definite that the characteristics of the neuropathy would help in directing genetic testing without the requirement for invasive skin, muscle or liver biopsies, there appears to be some evidence for this hypothesis in Leigh syndrome, in which nuclear SURF1 mutations cause a demyelinating neuropathy and mitochondrial DNA MTATP6 mutations cause an axonal neuropathy. POLG1 mutations, especially when associated with late-onset phenotypes, appear to cause a predominantly sensory neuropathy with prominent ataxia. The identification of the peripheral neuropathy also helps to target genetic testing in the mitochondrial optic neuropathies. Although often subclinical, the peripheral neuropathy may occasionally be symptomatic and cause significant disability. Where it is symptomatic, recognition of the neuropathy will help the early institution of rehabilitative therapy. We therefore suggest that nerve conduction studies should be a part of the early evaluation of children with suspected mitochondrial disease.     

Restoration of blood-nerve barrier in neuropathy is associated with axonal regeneration and remyelination.

We investigated the temporal course of blood-nerve barrier (BNB) breakdown during the evolution of tellurium neuropathy, ricin neuropathy, and Wallerian degeneration following nerve transection or nerve crush. Blood-nerve barrier permeability was assessed with a 4,000-molecular weight fluoresceinated dextran from three days to 19 weeks after onset of neuropathy. Blood-nerve barrier breakdown was present during the first two weeks in all four models of neuropathy. Restoration of the BNB to the dextran began within four weeks and was complete by 14 weeks in tellurium neuropathy, a model of demyelinating neuropathy characterized by rapid remyelination, and after nerve crush, a model of Wallerian degeneration characterized by rapid axonal regeneration into distal stump. In contrast, there was persistence of BNB breakdown beyond 14 weeks in ricin neuropathy, a model of neuropathy with no axonal regeneration or remyelination, and after nerve transection, a model of Wallerian degeneration characterized by minimal axonal regeneration into distal stump. We conclude from these data that alterations in the BNB over the course of neuropathy differ among various types of neuropathy, and that these alterations are dependent on the form of nerve fiber injury. The lack of regenerating or remyelinating axons in ricin neuropathy and after nerve transection may be responsible for the persistent BNB breakdown found in these neuropathies.     

Idiopathic neuropathy, prediabetes and the metabolic syndrome

Peripheral neuropathy is a common problem encountered by neurologists and primary care physicians. While there are many causes for peripheral neuropathy, none can be identified in a large percentage of patients ("idiopathic neuropathy"). Despite its high prevalence, idiopathic neuropathy is poorly studied and understood. There is evolving evidence that impaired glucose tolerance (prediabetes) is associated with idiopathic neuropathy. Preliminary data from a multicenter study of diet and exercise in prediabetes (the Impaired Glucose Tolerance Neuropathy Study) suggests a diet and exercise counseling regimen based on the Diabetes Prevention Program results in improved metabolic measures and small fiber function. Prediabetes is part of the Metabolic Syndrome, which also includes hypertension, hyperlipidemia and obesity. Individual aspects of the Metabolic Syndrome influence risk and progression of diabetic neuropathy and may play a causative role in neuropathy both for those with prediabetes, and those with otherwise idiopathic neuropathy. Thus, a multifactorial treatment approach to individual components of Metabolic Syndrome may slow prediabetic neuropathy progression or result in improvement.     

Unusual peripheral neuropathies. Part III: intrinsic inherited causes

Peripheral neuropathy is common and has many different etiologies. This is the last of three articles that review the less-common causes of peripheral neuropathy. Part III reviews the genetically coded causes of peripheral neuropathy, including those related to amyloidosis, neoplasm, paraproteinemias, as well as autosomal dominant, autosomal recessive, and x-linked causes. The extrinsic causes of neuropathy and the reactive or induced causes of neuropathy are covered in separate articles, Part I and Part II, respectively. The brief series reviews unusual causes of neuropathy and describes common presentations and the constellation of clinical findings. The goal is to help the clinician increase the diagnostic yield when sorting out the unusual causes of peripheral neuropathy.     

Unusual peripheral neuropathies. Part II: intrinsic reactive causes

Peripheral neuropathy is common with many different etiologies. This is the second of three articles to review the less-common causes of peripheral neuropathy. Part II reviews the intrinsic "reactive" causes of peripheral neuropathy, including those related to connective tissue, vasculitis, sarcoid, organ failure, and inflammatory bowel disease. The extrinsic causes of neuropathy and the induced or inherited causes of neuropathy are covered in separate articles in this issue of SEMINARS IN NEUROLOGY, Part I and Part III, respectively. The brief series of reviews of causes of neuropathy describe common presentations and constellation of clinical findings. The goal is to help the practicing clinician increase the diagnostic yield when sorting out the unusual causes of peripheral neuropathy.     

Evaluation of pre-existing neuropathy and bortezomib retreatment as risk factors to develop severe neuropathy in a mouse model

Pre-existing neuropathy, a not uncommon feature in oncologic patients, is a potential but non-confirmed risk factor to develop early or severe chemotherapy-induced neuropathy. The main goal of this study is to evaluate the role of pre-existing neuropathy induced by vincristine (VNC) or bortezomib (BTZ) as a risk factor to develop more severe BTZ-induced neuropathy in a mouse model. VNC, at doses of 1 and 1.5 mg/kg given twice per week for 4 weeks, induced a moderate and severe sensory-motor neuropathy, primarily axonal, with predominant involvement of myelinated sensory axons. The neuropathy induced by BTZ at dose of 1 mg/kg given twice per week for 6 weeks was a mild axonal sensory neuropathy involving myelinated and unmyelinated fibers. The neuropathy in mice previously treated and retreated with the same schedule of BTZ after 4 weeks of washout period was similar in profile and severity to the one observed after the first treatment. When basal neuropathy was classified as moderate (most of BTZ-treated animals) or severe (all VNC-treated animals and two BTZ-treated animals), there was a more marked decline in sensory nerve function during BTZ retreatment in the group with basal severe neuropathy (-86%) than in the groups with basal mild (-57%) or without neuropathy (-52%; p < 0.001). Histopathological findings supported the functional results. Therefore, this study shows that the presence of a severe neuropathy previous to treatment with an antitumoral agent, such as BTZ, results in a more marked involvement of peripheral nerves.     

Diabetic autonomic neuropathy

Diabetic autonomic neuropathy is the most frequent autonomic neuropathy in western countries. Diabetic autonomic neuropathy affects almost every organ. Among the most common symptoms are cardiovascular disturbances such as reduced heart rate variability and pathologic orthostatic reaction. The diagnosis of diabetic autonomic neuropathy is mainly based on the analysis of cardiovascular challenge maneuvers. The following article describes epidemiology, clinical findings, diagnosis, pathogenesis, therapeutic options and prognosis in diabetic autonomic neuropathy.     

Electrodiagnostic evaluation of ulnar neuropathy and other upper extremity mononeuropathies

Upper extremity mononeuropathies are some of the common disorders seen in neurophysiology laboratories. Electrophysiologic studies rely on accurate localization based on knowledge of applicable anatomy and features of history and physical examination. Careful electrodiagnostic studies provide an accurate diagnosis, help localize the lesion site, exclude alternate diagnoses, reveal unsuspected diagnoses, determine pathophysiology of lesions, and assess severity, timeframe, and prognosis of lesions. This article discusses the electrodiagnostic approach to ulnar neuropathy, proximal median neuropathy, radial neuropathy, musculocutaneous neuropathy, axillary neuropathy, suprascapular neuropathy, and long thoracic neuropathy. Pertinent aspects of the history and physical examination, nerve conduction studies, and electromyography are presented.     

Sensory neuropathy and primary biliary cirrhosis

Primary biliary cirrhosis (PBC) may associate an axonal neuropathy, a somatic and autonomic neuropathy and a very infrequently sensory neuropathy (with or without xanthomata). The aim of this paper is to describe the case of a 46 year old man diagnosed with PBC in stage I-II and a progressive sensory neuropathy (axonopathy) confined to his upper limbs with distal predominance. It had progressed slowly an began asymmetrically. A complete clinical study excluded other causes of neuropathy. We followed him clinically and electromyographically and he remains stable after two years evolution. The sensory neuropathy in this case, a primary biliary cirrhosis, is compatible with an assymetric sensory neuropathy limited to the upper limbs with assymmetric beginning.     

Symptomatic diabetic and non-diabetic neuropathies in a series of 100 diabetic patients

We have reviewed the clinical and pathological data of a series of 100 consecutive diabetic patients with symptomatic neuropathy in order to learn more about the causes of neuropathy in this population and on the signs and symptoms that could suggest another cause than diabetes in this setting. After diagnostic procedures, patients were assigned one (at most two) of a final total of 18 different causes of neuropathy. Diabetes accounted for 74 % of the neuropathies in the whole group of patients and for 79 % of those with a fiber length dependent pattern of neuropathy. One third of patients had a neuropathy unrelated to diabetes. As a group, 71 % of the patients presented either a length dependent diabetic polyneuropathy (LDDP) or a proximal diabetic neuropathy (PDN). The LDDP group was biased towards more severely affected patients owing to our specialization. Conversely, most patients with proximal diabetic neuropathy had usual features. Chronic inflammatory demyelinating neuropathy that was diagnosed in 9 % of the patients was the most common non-diabetic cause of neuropathy in this population. We conclude that a short interval between diagnosis of diabetes and the onset of the neuropathy, early motor deficit, markedly asymmetrical deficit and generalized areflexia, which are all uncommon in the LDDP, argue in favor of a non diabetic origin of the neuropathy and should lead to further investigation. Received: 19 June 2001, Received in revised form: 21 September 2001, Accepted: 8 October 2001