Case of mononeuritis multiplex onset with rituximab therapy for Waldenström's macroglobulinemia

Waldenström's macroglobulinemia (WM) is a lymphoplasmacytic disorder with associated monoclonal gammopathy. A wide variety of neuropathies can be associated with WM, but most commonly it is a mild length-dependent sensory neuropathy of unclear etiology. Rituximab is a monoclonal antibody which suppresses mature B-cell populations. It has increasingly been used in wide applications including WM, especially in those cases with severe neuropathy. The highlighted case provides an example of rituximab treatment complication in a WM patient with mild sensory neuropathy that evolved to multiple mononeuropathies with features of systemic vasculitis and unusual conversion of type I to type II cryoglobulinemia.     

Chronic dysimmune neuropathies: Beyond chronic demyelinating polyradiculoneuropathy

The spectrum of chronic dysimmune neuropathies has widened well beyond chronic demyelinating polyradiculoneuropathy (CIDP). Pure motor (multifocal motor neuropathy), sensorimotor with asymmetrical involvement (multifocal acquired demylinating sensory and motor neuropathy), exclusively distal sensory (distal acquired demyelinating sensory neuropathy) and very proximal sensory (chronic immune sensory polyradiculopathy) constitute the variants of CIDP. Correct diagnosis of these entities is of importance in terms of initiation of appropriate therapy as well as prognostication of these patients. The rates of detection of immune-mediated neuropathies with monoclonal cell proliferation (monoclonal gammopathy of unknown significance, multiple myeloma, etc.) have been facilitated as better diagnostic tools such as serum immunofixation electrophoresis are being used more often. Immune neuropathies associated with malignancies and systemic vasculitic disorders are being defined further and treated early with better understanding of the disease processes. As this field of dysimmune neuropathies will evolve in the future, some of the curious aspects of the clinical presentations and response patterns to different immunosuppressants or immunomodulators will be further elucidated. This review also discusses representative case studies.     

Utility of Skin Biopsy to Evaluate Peripheral Neuropathy

Skin biopsy for epidermal nerve fiber analysis provides an important objective test for the diagnosis of peripheral neuropathy, particularly small fiber sensory neuropathy (SFSN). The determination of epidermal nerve fiber density (ENFD) is reliable, with high diagnostic specificity and good sensitivity. Because of false negatives, biopsy results must be interpreted in conjunction with neurologic findings and laboratory results, including objective tests of sensory and autonomic function. SFSN most commonly is length dependent and is idiopathic in about half the patients. Biopsy of a proximal site (thigh) and a distal site (calf) typically shows greater abnormality of ENFD distally than proximally. More severe abnormality of ENFD in the thigh than in the calf raises the possibility of a non–length-dependent SFSN. The causes of this type of neuropathy, such as Sjögren’s syndrome, sarcoidosis, and celiac disease, may be treatable.     

Autoantibodies associated with peripheral neuropathy.

High titers of serum antibodies to neural antigens occur in several forms of neuropathy. These include neuropathies associated with monoclonal gammopathy, inflammatory polyneuropathies, and paraneoplastic neuropathies. The antibodies frequently react with glycosylated cell surface molecules, including glycolipids, glycoproteins, and glycosaminoglycans, but antibodies to intracellular proteins have also been described. There are several correlations between antibody specificity and clinical symptoms, such as anti-MAG antibodies with demyelinating sensory or sensorimotor neuropathy, anti-GM1 ganglioside antibodies with motor nerve disorders, antibodies to gangliosides containing disialosyl moieties with sensory ataxic neuropathy and Miller-Fisher syndrome, and antibodies to the neuronal nuclear Hu antigens with paraneoplastic sensory neuronopathy. These correlations suggest that the neuropathies may be caused by the antibodies, but evidence for a causal relationship is stronger in some examples than others. In this review, we discuss the origins of the antibodies, evidence for and against their involvement in pathogenic mechanisms, and the implications of these findings for therapy.     

Chemotherapy-induced neuropathy

Abstract Neurotoxic side effects of cancer therapy are second in frequency to hematological toxicity. Unlike hematological side effects that can be treated with hematopoietic growth factors, neuropathies cannot be treated and protective treatment strategies have not been effective. For the neurologist, the diagnosis of a toxic neuropathy is primarily based on the case history, the clinical and electrophysiological findings, and knowledge of the pattern of neuropathy associated with specific agents. In most cases, toxic neuropathies are length‐dependent, sensory, or sensorimotor neuropathies often associated with pain. The platinum compounds are unique in producing a sensory ganglionopathy. Neurotoxicity is usually dependent on cumulative dose. Severity of neuropathy increases with duration of treatment and progression stops once drug treatment is completed. The platinum compounds are an exception where sensory loss may progress for several months after cessation of treatment (“coasting”). As more effective multiple drug combinations are used, patients will be treated with several neurotoxic drugs. Synergistic neurotoxicity has not been extensively investigated. Pre‐existent neuropathy may influence the development of a toxic neuropathy. Underlying inherited or inflammatory neuropathies may predispose patients to developing very severe toxic neuropathies. Other factors such as focal radiotherapy or intrathecal administration may enhance neurotoxicity. The neurologist managing the cancer patient who develops neuropathy must answer a series of important questions as follows: (1) Are the symptoms due to peripheral neuropathy? (2) Is the neuropathy due to the underlying disease or the treatment? (3) Should treatment be modified or stopped because of the neuropathy? (4) What is the best supportive care in terms of pain management or physical therapy for each patient? Prevention of toxic neuropathies is most important. In patients with neuropathy, restorative approaches have not been well established. Symptomatic and other management are necessary to maintain and improve quality of life.     

Sensory correlates of pain in peripheral neuropathies

ObjectiveTo characterize sensory threshold alterations in peripheral neuropathies and the relationship between these alterations and the presence of pain.MethodsSeventy-four patients with length-dependent sensory axonal neuropathy were enrolled, including 38 patients with painful neuropathy (complaining of chronic, spontaneous neuropathic pain in the feet) and 36 patients with painless neuropathy. They were compared to 28 age-matched normal controls. A standardized quantitative sensory testing protocol was performed in all individuals to assess large and small fiber function at the foot. Large fibers were assessed by measuring mechanical (pressure and vibration) detection thresholds and small fibers by measuring pain and thermal detection thresholds.ResultsBetween patients with neuropathy and controls, significant differences were found for mechanical and thermal detection thresholds but not for pain thresholds. Patients with painful neuropathy and those with painless neuropathy did not differ regarding mechanical or thermal thresholds, but only by a higher incidence of thermal or dynamic mechanical allodynia in case of painful neuropathy. Pain intensity correlated with the alteration of thermal detection and mechanical pain thresholds.ConclusionsQuantitative sensory testing can support the diagnosis of sensory neuropathy when considering detection threshold measurement. Thermal threshold deterioration was not associated with the occurrence of pain but with its intensity.SignificanceThere is a complex relationship between the loss or functional deficit of large and especially small sensory nerve fibers and the development of pain in peripheral neuropathy.     

Acute and chronic ataxic neuropathies with disialosyl antibodies: A continuous clinical spectrum and a common pathophysiological mechanism

Acute ataxic neuropathies with disialosyl antibodies include Fisher syndrome, ataxic Guillain–Barré syndrome (GBS), and acute sensory ataxic neuropathy. Fisher syndrome and ataxic GBS are more strongly associated with IgG anti‐GQ1b and anti‐GT1a than with anti‐GD1b antibodies, whereas the association is reversed in the case of acute sensory ataxic neuropathy. Chronic ataxic neuropathy with disialosyl antibodies is associated with IgM paraprotein to GD1b and GQ1b, which occasionally reacts with GT1a. The clinical, electrophysiological, and pathological features, along with experimental findings, suggest that acute and chronic ataxic neuropathies with disialosyl antibodies form a continuous clinical and pathophysiological spectrum characterized by a complement‐mediated disruption at the nodal region and are better classified in the new category of nodo‐paranodopathies. Muscle Nerve 49 : 629–635, 2014     

Epidermal nerve fiber density in sensory ganglionopathies: clinical and neurophysiologic correlations.

We assessed the involvement of somatic unmyelinated fibers in sensory ganglionopathies by skin biopsy and quantitative sensory testing (QST). Sixteen patients with ganglionopathy, 16 with axonal neuropathy, and 15 normal controls underwent skin biopsy at the proximal thigh and the distal leg. Intraepidermal nerve fibers (IENF) were immunostained by antiprotein gene product 9.5, and their linear density was quantified under light microscopy. Confocal microscopy studies with double staining of nerve fibers and basement membrane were also performed. Healthy subjects and neuropathy patients showed the typical proximodistal gradient of IENF density; in neuropathies, values were significantly lower at the distal site of the leg, confirming the length-dependent loss of cutaneous innervation. Conversely, ganglionopathy patients with hyperalgesic symptoms did not show any change of IENF density between the proximal thigh and the distal leg. The distinct pattern of epidermal denervation seen in sensory ganglionopathy reflected the degeneration of somatic unmyelinated fibers in a fashion that was not length-dependent, which was consistent with both clinical and neurophysiologic observations and supported the diagnosis.     

Peripheral neuropathies of infancy

Over a 33-year period, 260 patients (< 17 years of age; 119 males, 141 females) from New South Wales, Australia who had peripheral neuropathies confirmed by nerve biopsy, were studied. Of these, 50 infants presented with symptoms or signs of neuropathy under 1 year of age: including 24 patients with demyelinating neuropathies and 21 axonal neuropathies; a further five patients had spinal muscular atrophy with associated secondary sensory axonopathy. Nineteen infants had hereditary motor sensory neuropathy, of whom 13 had myelin protein mutations confirmed by molecular genetic studies. Peripheral neuropathy is not an unusual diagnosis in infancy. Awareness of this association will aid early diagnosis and prognosis as well as facilitate interventional patient management.     

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.     

Paraneoplastic peripheral neuropathies

Paraneoplastic peripheral neuropathies constitute a heterogeneous group of conditions. A link between the tumor and the neuropathy has been demonstrated in a subgroup only. Definite paraneoplastic neuropathies correspond to neuropathies associated with antibodies reacting with antigens common to the peripheral nervous system and the cancer. Neuropathies associated with anti-Hu antibodies are the most frequent and consist mainly in subacute sensory neuronopathy. Sensory or sensory-motor neuropathies with anti-CV2 antibodies are less frequent. The link between the cancer and the neuropathy is less clear in the other forms. The frequency of cancer in this group varies from 1 to 18 p.cent.These neuropathies include inflammatory demyelinating neuropathies, neuropathy and vasculitis, lower motor neurone diseases, and autonomic neuropathies. Occasionally, the neuropathy improves with treatment of the tumor. Recent data suggest that gangliosides may be the target of the immune process in neuropathies associated with melanoma.     

Hereditary sensory neuropathies

PURPOSE OF REVIEW: The hereditary sensory neuropathies, also known as the hereditary sensory and autonomic neuropathies, are a clinically and genetically heterogeneous group of disorders. As they are not as common as Charcot-Marie-Tooth disease, they do not receive the same level of attention, but there have been major advances in the identification of the causative genes in the past decade. Certain forms of hereditary sensory and autonomic neuropathy, especially hereditary sensory and autonomic neuropathy type I, which has minimal autonomic involvement and is more accurately termed hereditary sensory neuropathy type I, can present in a very similar fashion to certain forms of Charcot-Marie-Tooth disease (Charcot-Marie-Tooth type 2B, see below), and therefore it is important that clinicians who regularly manage patients with neuropathy are familiar with the latest developments in the hereditary sensory and autonomic neuropathies. This review will concentrate on the recent genetic advances in hereditary sensory and autonomic neuropathy, and especially on those forms that overlap clinically with Charcot-Marie-Tooth disease, hence the title of the review 'Hereditary sensory neuropathies' rather than hereditary sensory and autonomic neuropathies.     

Peripheral neuropathy associated with alpha 1-antitrypsin deficiency

Peripheral neuropathy associated with alpha 1-antitrypsin deficiency is an uncommon condition. Several recent studies have investigated the possible roles of serum proteinase inhibitors in inflammatory neuropathies, such as multiple sclerosis, Landry-Guillain-Barré syndrome, and various chronic inflammatory demyelinating peripheral neuropathies. We present a case in which alpha 1-antitrypsin deficiency (proteinase inhibitor ZZ phenotype) was diagnosed in a young white man with clinical signs and symptoms of peripheral neuropathy and a history of Landry-Guillain-Barré syndrome. We wish to emphasize the importance of serum protein electrophoresis in the diagnostic workup of patients presenting with the clinical manifestations of peripheral neuropathy.     

Hereditary sensory and autonomic neuropathy with autonomic crises: a Turkish variant of familial dysautonomia?

Hereditary sensory and autonomic neuropathies have different phenotypes. We report 2 cousins with differing clinical courses of a hereditary sensory and autonomic neuropathy. The progressive disease in case 1 is dominated by loss of sensation, autonomic crises, and pain. Case 2 shows loss of sensation, mental retardation, and deafness, clinically similar to patients with hereditary sensory and autonomic neuropathy type II. Detailed molecular studies in case 1 for all known genes that are associated with hereditary sensory and autonomic neuropathies were negative. However, the occurrence of the 2 cases within 1 kindred makes a common genetic background likely. We, therefore, propose a Turkish variant of familial dysautonomia in these 2 patients.     

Diabetic neuropathies. Classification, clinical features, and pathophysiological basis

Diabetes mellitus is associated with a wide spectrum of neuropathy syndromes, ranging from a mild asymptomatic distal sensory neuropathy to a severe disabling radiculoplexus neuropathy. As the pathophysiology of these separate conditions is better understood, classification of the various phenotypes becomes important because of treatment implications. Here we provide a short summary of the history of the classification of diabetic neuropathies and try to describe the most common forms classified according to their presumed pathophysiology. We have tried to include epidemiological data where available, as well as histopathology of nerve in several diabetic neuropathies.     

High prevalence of neuropathies in patients with end‐stage liver disease

Cocito D, Maule S, Paolasso I, Castelli L, Ciaramitaro P, Poglio F, Ottobrelli A, Grimaldi S. High prevalence of neuropathies in patients with end‐stage liver disease.
Acta Neurol Scand: 2010: 122: 36–40.
© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objectives – Peripheral neuropathy has been reported in association with end‐stage liver disease, but there is only a limited number of reports on the incidence and features of these neuropathies. Materials and methods – In this study, 83 patients awaiting liver transplantation were evaluated for the presence of peripheral and autonomic neuropathy. Results – Sixty‐five percent of the patients had evidence of neuropathy, in agreement with peripheral NCS or cardiovascular autonomic function test. The neuropathy was more frequent in patients with advanced hepatic failure, evaluated with the MELD score. The most frequent abnormalities in nerve conduction studies were sensory‐motor neuropathies and sensory neuropathies, with a length‐dependent pattern. Conclusion – Peripheral neuropathy and autonomic neuropathy are common in patients with end‐stage liver disease with different etiology and correlate with the severity of the liver disease.     

Paraneoplastic peripheral neuropathies

The PNS Euronet group criteria have classified paraneoplastic peripheral neuropathies as definite or possible according as to whether the neuropathy is a classical paraneoplastic disorder, the presence of onconeural antibodies, the delay between tumor and neuropathy, and improvement of the neuropathy with tumor treatment. Denny Brown's subacute sensory neuronopathy and neuropathies with anti-Hu or anti-CV2 antibodies are definite paraneoplastic disorders. Possible paraneoplastic neuropathies are heterogeneous. This classification is useful for the diagnostic of these disorders and the selection of patients in whom a search for cancer is warranted.     

Recent developments in the HIV neuropathies

PURPOSE OF REVIEW: With the introduction of highly active antiretroviral therapy peripheral neuropathies have become the most common neurological complications in HIV infection. The frequency and spectrum of these neuropathies are changing, as the various toxic and immune factors are modified by new treatment strategies. Recent studies have provided a better understanding of the risk factors, markers and relevant pathogenic mechanisms, and a thorough review of these is critical for an improved understanding of this important and increasingly common complication. RECENT FINDINGS: The combined use of dideoxynucleosides, in association with immune-mediated mechanisms triggered by HIV infection, are critical in the development of distal sensory polyneuropathy. Valuable markers of neuropathy such as intraepidermal nerve fiber density from skin biopsies have been validated and promise to be a valuable tool in the detection and monitoring of distal sensory polyneuropathy. Markers of virological activity have also been associated with the severity of neuropathic pain in distal sensory polyneuropathy. In some instances, the enhanced viral suppression from antiretroviral agents may actually improve or decrease the frequency of certain types of neuropathy. New evidence supports mitochondrial toxicity as a principal mechanism for dideoxynucleoside-associated sensory neuropathy, and questions arise about enhanced risk with pre-existing mitochondrial defects. Confirmed treatments are limited to the reduction of symptoms, with a need for the further investigation of corrective therapies. SUMMARY: Increased and improved surveillance for HIV-associated neuropathy will allow earlier interventions to improve quality of life and prevent severe toxicities. A better understanding of the prevailing mechanisms will allow for more effective interventions.     

A common mechanism and a new categorization for anti-ganglioside antibody-mediated neuropathies

Serum antibodies to different gangliosides have been identified in some Guillain-Barré (GBS) subtypes and variants. In the January issue of Experimental Neurology Susuki and colleagues (2012) showed that in experimental neuropathies associated with antibodies to GM1, GD1a and GD1b the common mechanism is a complement mediated dysfunction and disruption of the nodes of Ranvier which causes a pathophysiological continuum from early reversible conduction failure to axonal degeneration. These observations, correlated and integrated with electrophysiological and pathological findings in humans indicate that the GBS subtypes acute motor conduction block neuropathy, acute motor axonal neuropathy, acute motor and sensory neuropathy and acute sensory neuropathy and possibly also a chronic disorder as multifocal motor neuropathy represent a spectrum of the same immunopathologic process. Being the nodal axolemma and the paranode the focus of the nerve injury, these immune mediated neuropathies could be more properly classified as nodo-paranodopathies.     

Paraneoplastic neuropathy

Paraneoplastic neuropathies occur in various settings. This article focuses on recent neuroimmunologic findings regarding paraneoplastic neuropathy. Entities such as sensorimotor and sensory neuropathy, sensory neuronopathy; motor, autonomic, demyelinating and vasculitic mononeuropathies; and cranial nerve lesions and neuropathies in association with leukaemia and paraproteinaemas are discussed. Finally, the article considers the issue of 'overlap' syndromes--the occurrence of several paraneoplastic phenomena in the same patient.