Acquired inflammatory demyelinating polyneuropathies: clinical and electrodiagnostic features

The acquired demyelinating polyneuropathies include acute (AIDP, Guillain-Barré syndrome, GBS) and chronic (CIDP, dysproteinemic) forms which differ primarily in their temporal profile. They are inflammatory-demyelinating diseases of the peripheral nervous system and likely have an immunologic pathogenesis. Although these neuropathies usually have a characteristic presentation, the electromyographer plays a central role in their recognition, since the demyelinating component of the neuropathy, which greatly reduces the differential diagnosis, is often first identified in the electromyography laboratory. In AIDP, the electromyographer, in addition to establishing the diagnosis, can sometimes predict the prognosis. Recognition of the chronic and dysproteinemic forms of acquired demyelinating polyneuropathy is important since they are treatable. The dysproteinemic forms also may be associated with occult systemic disorders that also may require treatment, independent of the neuropathy.     

Hereditary neuropathy with liability to pressure palsy presenting with an acute inflammatory demyelinating polyneuropathy

INTRODUCTION: Hereditary neuropathy with liability to pressure palsy (HNPP) is an autosomal dominant peripheral neuropathy characterized by compressive focal neuropathies and an underlying sensorimotor demyelinative polyneuropathy. It is usually caused by a 1.5 Mb deletion of the PMP22 gene (17p11.2). CASE REPORT: We describe the case of a 31 year-old woman who presented with acute demyelinative peripheral polyneuropathy affecting the four limbs and elevated cerebrospinal fluid protein content a few days after a viral illness. Acute inflammatory demyelinating polyneuropathy (AIDP, Guillain-Barré syndrome) was suspected. However, electrophysiologic examination suggested HNPP and subsequent genetic testing was confirmatory. CONCLUSION: This case demonstrates that HNPP can present in an acute manner, mimicking AIDP.     

Chronic inflammatory demyelinating neuropathies and their variants

The Chronic Inflammatory Demyelinating Polyradiculoneuropathies (CIDP) constitute a syndrome whose incidence is difficult to evaluate, and is probably underestimated. In the course of this presentation, we deliberately restricted discussion to issues raised in recent years concerning the extent of this syndrome. We discuss diagnostic criteria, especially electrophysiological ones. As the criteria proposed by the ad hoc committee of the American Academy of Neurology in 1991 have been questioned due to lack of sensitivity, new ones have been proposed recently. We briefly discuss the different types of chronic dysimmune demyelinating neuropathy: not only the CIDP, but also the Lewis and Sumner syndrome or multifocal inflammatory demyelinating neuropathy and the multiple conduction block neuropathies. At last, we point out the consistent finding of axonal involvement in the course of a chronic demyelinating neuropathy; over time, it can become predominant, which may make diagnosis difficult by suggesting a chronic axonal neuropathy that may be assumed to be primary. Consideration of these points may help clinicians recognize more chronic dysimmune neuropathies, for which immunosuppressive therapy has been found to be effective.     

Diagnosis of motor neuropathy

Motor neuropathy is a clinical entity which leads to consideration of a wide spectrum of peripheral nerve disorders. Firstly, it may be distinguished from other causes of peripheral motor involvement such as muscle diseases and disorders of the neuromuscular junction. Secondly, it may be discussed in two different forms: acute and chronic. Acute chronic neuropathies are mainly observed in Guillain-Barré syndrome, in which electrophysiological studies allow us to recognize the classical demyelinating form and the axonal form. The other causes of acute motor neuropathy are mainly poliomyelitis and porphyrias. Chronic motor neuropathies are mainly observed in motor neuron diseases, mainly amyotrophic lateral sclerosis, but also Kennedy's disease and other lower motor neuron diseases which may be inherited or acquired. The other causes are multifocal motor neuropathy and the predominantly motor forms of chronic inflammatory demyelinating polyneuropathy. The characterization of these different types of chronic neuropathy is of major importance because of the therapeutic consequences which may lead to the proposal of specific treatments.     

Acute-onset multifocal motor neuropathy (AMMN): how we meet the diagnosis

Multifocal motor neuropathy (MMN) usually progresses insidiously with lower motor neuron-type weakness, minimal or no sensory symptoms. Diagnostic criteria include motor conduction block (CB) at sites not exposed to compression or entrapment. CBs may persist or reverse irrespective of clinical outcome. Acute onset with generalized weakness is uncommon. We report four patients who presented acutely areflexia, pure motor deficits without sensory disturbances, multifocal CBs persisting at the same motor nerves on serial electrophysiological studies. Three patients had preceding infections; two showed IgM reactivity against the ganglioside GM1. Intravenous immuneglobulin (IVIg) improved or stabilized symptoms. Patients 2,3,4 receive maintenance therapy with IVIg for years. Acute-onset MMN (AMMN) should be differentiated from other immune-mediated neuropathies such as acute inflammatory polyneuropathy either demyelinating (AIDP) or axonal (AMAN), acute motor conduction block neuropathy (AMCBN), acute-onset chronic inflammatory demyelinating polyneuropathy (CIDP). The correct diagnosis deserves implications for patient long-term treatment and prognosis. Moreover, the authors address the problem of defining the spectrum of MMN particularly in the acute setting.     

Serial nerve conduction studies provide insight into the pathophysiology of Guillain-Barré and Fisher syndromes

The electrodiagnosis of Guillain-Barré syndrome (GBS) can be broadly divided into acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN). Fisher syndrome (FS) is a variant of GBS, although the underlying neuropathy of FS has yet to be established. Serial nerve conduction studies (NCS) can provide further insight into the likely pathophysiology by further subtyping of GBS and FS. We present a patient with an initial diagnosis of AIDP in whom repeated NCS revealed the AMAN variant. This led us to investigate serial NCS in five patients with GBS, FS and FS/GBS overlap presenting over a period of a year. Three patients with AIDP showed a gradual increase in distal motor latencies during the acute phase of illness. NCS of two patients with FS and FS/GBS overlap showed no demyelinating features suggesting underlying axonal neuropathy in this group of patients. The importance of serial NCS in establishing the underlying pattern of neuropathy in GBS and FS is further emphasized in this study. Larger studies incorporating serial NCS are required to confirm the observations seen in our case series especially when pathological studies are often not justified in this group of patients.     

Immunotherapy of idiopathic inflammatory neuropathies

Evaluation of peripheral neuropathy is a common reason for referral to a neurologist. Recent advances in immunology have identified an inflammatory component in many neuropathies and have led to treatment trials using agents that attenuate this response. This article reviews the clinical presentation and treatment of the most common subacute inflammatory neuropathies, Guillain-Barré syndrome (GBS) and Fisher syndrome, and describes the lack of response to corticosteroids and the efficacy of treatment with plasma exchange and intravenous immunoglobulin (IVIG). Chronic inflammatory demyelinating polyneuropathy, although sharing some clinical, electrodiagnostic, and pathologic similarities to GBS, improves after treatment with plasma exchange and IVIG and numerous immunomodulatory agents. Controlled trials in multifocal motor neuropathy have shown benefit after treatment with IVIG and cyclophosphamide. Also discussed is the treatment of less common inflammatory neuropathies whose pathophysiology involves monoclonal proteins or antibodies directed against myelin-associated glycoprotein or sulfatide. Little treatment data exist to direct the clinician to proper management of rare inflammatory neuropathies resulting from osteosclerotic myeloma; POEMS syndrome; vasculitis; Sj?gren's syndrome; and neoplasia (paraneoplastic neuropathy).     

Epidemiology and clinical features of HIV-1 associated neuropathies

Peripheral neuropathy is common in human immunodeficiency virus type-1 (HIV-1) infection. Peripheral neuropathies complicate all stages of the HIV-1 disease and cause considerable morbidity and disability in HIV-1 infected individuals and acquired immunodeficiency syndrome (AIDS) patients. Whereas symptomatic neuropathies occur in approximately 10% to 15% of HIV-1-infected patients overall, pathologic evidence of peripheral nerve involvement is present in virtually all end-stage AIDS patients. There are 6 major clinical types of HIV-associated neuropathies that are regularly seen in large HIV-1 clinics. Distal sensory polyneuropathy (DSP) is the most common among the HIV-1-associated neuropathies. DSP generally occurs in later stages of HIV-1 infection and it follows an indolent and protracted clinical course. The dominant clinical features in DSP include distal pain, paresthesia and numbness in a typical length-dependent fashion with proximal to distal gradient. Whereas toxic neuropathies--secondary to certain antiretroviral agents--are clinically similar to DSP, their temporal relation to neurotoxic medication helps distinguish them from other HIV-1-associated neuropathies. DSP and toxic neuropathy may coexist in a single patient. Acute and chronic inflammatory demyelinating polyradiculoneuropathies (AIDP and CIDP) produce global limb weakness. AIDP may occur at seroconversion and it can therefore be the initial manifestation of HIV-1 infection. CIDP generally occurs in the mid to late stages of HIV-1 infection. Progressive polyradiculopathy (PP) occurs in patients with advanced immunodeficiency and is generally caused by the opportunist cytomegalovirus (CMV) infection. Mononeuropathy multiplex (MM) in early stages of HIV-1 infection is immune mediated, whereas in advanced AIDS it is caused by the CMV infection. Finally, subclinical autonomic nervous system involvement is common in all stages of HIV-1 infection. Because HIV-1-associated neuropathies are diverse in their etiology and pathogenesis, a precise clinical diagnosis is required to formulate a rational therapeutic intervention.     

Humoral antibodies in immune mediated neuropathy

Immune mediated neuropathy includes acute inflammatory demyelinating polyneuropathy (AIDP), chronic inflammatory demyelinating neuropathy (CIDN), paraproteinemic polyneuropathy (PPN) and Crow-Fukase syndrome (CFS). Serum antibodies as humoral immunity in patients with immune mediated neuropathy were measured by the method of immunoblots and ELISA. P0 protein, P2 protein, 170K-Mr glycoprotein and ganglioside (GGD) of human peripheral nerve myelin and MBP, myelin associated glycoprotein (MAG) of human central nerve myelin were used as antigens. In AIDP anti P2 antibodies were elevated significantly. However, anti MBP antibodies were also elevated in parallel. In PPN anti MAG antibodies were detected in 4 patients with IgM-M proteinemia and demyelinating neuropathy. High titers of anti MAG antibodies were also detected in the same 4 patients. Characteristic pathological findings of biopsied sural nerve were segmental demyelination with widening of the intraperiod line of the outer myelin lamella in all 4 patients. Positive rate of anti myelin antibodies were 23% in 23 cases with PPN. Anti 170K-Mr glycoprotein was detected only in one patient with IgM-M proteinemia, polyneuropathy and incurable dermatitis. Anti GGD antibodies were not detected in PPN or CFS. A few patients with GBS or CIDN have anti GGD antibodies in ELISA. It is well known that various antibodies to peripheral nerve myelin are detected in neuropathy, especially demyelinating state. The most important antigen established in this study in the pathogenesis of neuropathy is MAG. IgM monoclonal protein including anti MAG antibodies was absorbed by purified MAG completely. Anti 170K Mr glycoprotein was also absorbed by purified 170K-Mr glycoprotein. Role of humoral antibody to peripheral nerve myelin specific 170K-Mr glycoprotein remains to be solved.     

Autonomic function in demyelinating and axonal subtypes of Guillain-Barré syndrome

OBJECTIVES: To investigate whether or not the pattern and extent of autonomic involvement differ between the two subtypes of Guillain-Barré syndrome (GBS), namely acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN). METHODS: Head-up tilt test, R-R interval variation, plasma noradrenaline concentration, skin vasomotor reflex (SVR) and sympathetic sweat response (SSwR) were used to estimate autonomic function in seven AIDP and eight AMAN patients. RESULTS: Heart rate and plasma noradrenaline concentration were significantly high in the AIDP group but not in the AMAN group. Skin vasomotor reflexes were generally preserved and SSwRs were impaired in patients with severe neurological deficits for both AIDP and AMAN groups. CONCLUSION: The patterns of autonomic involvement are qualitatively different between AIDP and AMAN. Acute inflammatory demyelinating polyneuropathy is characterized by cardio-sympathetic hyperactivity, excessive or reduced sudomotor function and preserved skin vasomotor function, while AMAN is not necessarily generally associated with marked autonomic dysfunction except for the sudomotor hypofunction seen in patients with severe neurological deficits.     

Physiologic-pathologic correlation in Guillain-Barré syndrome in children

OBJECTIVE: To correlate electrophysiologic patterns with sural nerve pathology in children with Guillain-Barré syndrome (GBS). BACKGROUND: Based on electrophysiologic and pathologic observations, GBS has been divided into demyelinating and axonal subtypes. The acute motor axonal neuropathy (AMAN) involves predominantly motor nerve fibers with a physiologic pattern suggesting axonal damage, whereas the acute inflammatory demyelinating polyneuropathy (AIDP) involves both motor and sensory nerve fibers with a physiologic pattern suggesting demyelination. In this study, we sought to confirm these observations by correlating sural nerve pathology with electrophysiologic findings in GBS patients. METHODS: Biopsies of sural nerve from 29 of 50 prospectively studied GBS patients were obtained. Nerves were examined by light and electron microscopy, and with immunocytochemistry for macrophages, lymphocytes, and complement activation products. RESULTS: Sural nerves from AMAN patients were normal or had only a few (0.1% to 0.7%) degenerating fibers without lymphocytic infiltration or complement activation. One patient with reduced sural sensory nerve action potential classified as acute motor sensory axonal neuropathy (AMSAN) had many degenerating fibers (2.3%) in the sural nerve. All three AIDP patients displayed active demyelination, and in two patients, lymphocytic infiltration and complement activation products were observed on the abaxonal Schwann cell surface. CONCLUSION: Classification of Guillain-Barré syndrome subtypes based on motor conduction studies correlates closely with pathologic changes seen in sural nerve. In acute motor axonal neuropathy cases, the sural nerve is almost completely spared pathologically. In acute inflammatory demyelinating polyneuropathy cases, macrophage-mediated demyelination and lymphocytic infiltration are common in the biopsies of sural nerves.     

Acute Motor Axonal Neuropathy Associated with Pandemic H1N1 Influenza A Infection

Background  

Guillain–Barre syndrome (GBS) is a well known entity that has many infectious agents reported as antecedent events. The spectrum of GBS includes acute inflammatory demyelinating polyneuropathy (AIDP), acute motor axonal neuropathy (AMAN), acute motor sensory axonal neuropathy (AMSAN), and some other variants like Miller-Fisher syndrome (MFS).     

Contrast-enhanced Magnetic Resonance Imaging of the Lumbosacral Roots in the Dysimmune Inflammatory Polyneuropathies

The diagnosis of acute Guillain-Barre syndrome and chronic inflammatory demyelinating polyradiculoneuropathy is based on clinical characteristics, abnormalities on nerve conduction studies, and nerve biopsy specimens indicating demyelination. Inflammation and edema are also common findings in nerve specimens Immunotherapy is helpful in these dysimmune conditions. Occasionally the diagnosis is difficult to make, particularly when electrophysiological testing or nerve biopsy findings are not characteristic. The authors found contrast enhancement of lumbosacral roots in patients with chronic inflammatory demyelinating polyradiculoneuropathy and Guillain-Barre syndrome, but not m those with other demyelinating neuropathies. Contrast-enhanced magnetic resonance imaging could be a useful tool in the diagnosis of the dysimmune inflammatory neuropathies.     

Electrodiagnostic criteria for Guillain-Barrè syndrome: a critical revision and the need for an update

Electrophysiology plays a determinant role in Guillain-Barré syndrome (GBS) diagnosis, classification of the subtypes and in establishing prognosis. In the last three decades, different electrodiagnostic criteria sets have been proposed for acute inflammatory demyelinating neuropathy (AIDP), acute motor axonal neuropathy (AMAN) and acute motor and sensory axonal neuropathy (AMSAN). Criteria sets for AIDP varied for the parameters indicative of demyelination considered, for the cut-off limits and the number of required abnormalities (all a priori established) showing different sensitivities. Criteria sets for AMAN and AMSAN were proposed on the initial assumption that these subtypes were pathologically characterised by simple axonal degeneration. However, some AMAN patients show transient conduction block/slowing in intermediate and distal nerve segments, mimicking demyelination but without the development of abnormal temporal dispersion, named reversible conduction failure (RCF). The lack of distinction between RCF and demyelinating conduction block leads to fallaciously classify AMAN patients with RCF as AIDP or AMAN with axonal degeneration. Serial electrophysiological studies are mandatory for proper diagnosis of GBS subtypes, identification of pathophysiological mechanisms and prognosis. More reliable electrodiagnostic criteria should be devised to distinguish axonal and demyelinating subtypes of GBS, taking into consideration the RCF pattern and focussing on temporal dispersion.     

Inflammatory neuropathies: update

This review focuses on recent neuroimmunological findings in autoimmune inflammatory neuropathies. In Guillain-Barré syndrome and paraneoplastic neuropathy most current investigations are centred on the hypothesis of molecular mimicry. In chronic inflammatory demyelinating polyradiculoneuropathy and multifocal motor neuropathy the data on immunopathology are more fragmentary. Why and how patients with autoimmune inflammatory neuropathies raise an increased anti-self-reactivity and how this leads to disease remains a major challenge for future research.     

Electrophysiological studies in the Guillain–Barré syndrome: Distinguishing subtypes by published criteria

Guillain–Barré syndrome (GBS) is recognized clinically by the presence of acute, rapidly progressive weakness, areflexia, and albuminocytological dissociation in cerebrospinal fluid. Although GBS was initially considered to be primarily an acute inflammatory demyelinating polyneuropathy (AIDP), several other subtypes have been recognized: acute motor axonal neuropathy (AMAN), acute motor-sensory axonal neuropathy (AMSAN), and Fisher syndrome (FS). Because each of these subtypes may have an independent immunopathogenesis and, therefore, may require selective treatments in the future, recognition of these subtypes is important. When using nerve conductions to classify the subtypes, the most easily and confidently identified subtype is AIDP. Therefore, most electrodiagnostic criteria have attempted to identify demyelination in this acute setting, in which physiology is constantly changing. In a single well-defined GBS population, we compared the various published criteria for demyelination in GBS. We reviewed charts of 43 patients with GBS between 1991 and 1996. Applying six available criteria sets, the number of patients categorized as having AIDP ranged from 21% to 72%. Until investigators can agree on a single set of criteria, considerable variability will continue to exist when identifying cases of AIDP. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21:1275–1279, 1998.     

Pathogenesis and treatment of inflammatory demyelinating polyradiculoneuropathy

Inflammatory demyelinating polyradiculoneuropathy causes a spectrum of conditions ranging from acute (Guillain-Barré syndrome), through subacute to chronic forms. The pathogenesis of acute forms is related to antibody responses against glycolipid epitopes which mimic bacterial, especially Campylobacter jejuni, structures but T cells are also involved. The pathogenesis of chronic forms is poorly understood. Different forms differ in their responses to steroids. Chronic inflammatory demyelinating polyradiculoneuropathy responds to steroids but a variant multifocal motor neuropathy and the acute forms of inflammatory demyelinating polyradiculoneuropathy do not. Acute and chronic forms respond to plasma exchange and intravenous immunoglobulin.     

Neurophysiologic findings in early acute inflammatory demyelinating polyradiculoneuropathy.

BACKGROUND: Patients with early acute inflammatory demyelinating polyradiculoneuropathy (AIDP) may not meet the current neurophysiologic criteria. OBJECTIVE: To document neurophysiologic findings in early AIDP. METHODS: Clinical and neurophysiologic data from 38 AIDP patients, assessed within 10 days of symptom onset were reviewed. RESULTS: In addition to absent H reflexes and abnormal F-wave responses in the acute stage of AIDP, abnormalities of blink reflexes, upper limb sensory responses abnormalities with spared sural responses, presence of distal CMAP dispersion, and A-waves were frequently observed. Established demyelinating neurophysiologic parameters were infrequently seen. CONCLUSIONS: Abnormalities of H reflexes and F responses were most frequently noted in early AIDP. Additionally, distal temporal dispersion, prolonged or absent blink reflexes, and A-waves were often present in the acute stage of AIDP when classic diagnostic criteria of AIDP were not satisfied. SIGNIFICANCE: Neurophysiologic studies in early AIDP frequently reveal abnormalities that are not specific of primary demyelinating neuropathy.     

Fine specificities of anti-LM1 IgG antibodies in Guillain-Barré syndrome

We investigated the prevalence of anti-LM1 IgG antibody and its fine specificity in Guillain-Barré syndrome (GBS). Anti-LM1 IgG and IgM antibodies from sera of 47 patients with GBS--19 with acute inflammatory demyelinating polyneuropathy (AIDP), 27 with acute motor axonal neuropathy (AMAN), and 1 with acute motor-sensory axonal neuropathy (AMSAN)--were tested. Anti-LM1 IgG antibody was detected in only one patient with AIDP, whereas it was present in seven with AMAN and in one with AMSAN. Sera from the eight IgG anti-LM1-positive patients with AMAN/AMSAN also had IgG activity against the gangliosides GM1, GM1b, GD1a, GalNAc-GD1a, GD1b, or GQ1b. Anti-LM1 IgG antibodies from the AMAN/AMSAN patients cross-reacted with other gangliosides, whereas IgG antibody from the AIDP patient was monospecific against LM1. Anti-LM1 IgG antibody therefore, cannot be a marker of AIDP. In addition, whether monospecific anti-LM1 IgG antibody is associated with AIDP remains to be concluded. Larger studies are needed to verify whether monospecific anti-LM1 IgG antibody could be a marker of AIDP.     

Treatment of immune-mediated, dysimmune neuropathies

This review focuses on the actual status and recent advances in the treatment of immune-mediated neuropathies, including: Guillain-Barre syndrome (GBS) with its subtypes acute inflammatory demyelinating polyradiculoneuropathy, acute motor axonal neuropathy, acute motor and sensory axonal neuropathy, Miller Fisher syndrome, and acute pandysautonomia; chronic inflammatory demyelinating polyneuropathy (CIDP) with its subtypes classical CIDP, CIDP with diabetes, CIDP/monoclonal gammopathy of undetermined significance (MGUS), sensory CIDP, multifocal motor neuropathy (MMN), multifocal acquired demyelinating sensory and motor neuropathy or Lewis-Sumner syndrome, multifocal acquired sensory and motor neuropathy, and distal acquired demyelinating sensory neuropathy; IgM monoclonal gammopathies with its subtypes Waldenstrom's macroglobulinemia, myelin-associated glycoprotein-associated gammopathy, polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes syndrome, mixed cryoglobulinemia, gait ataxia, late-onset polyneuropathy syndrome, and MGUS. Concerning the treatment of GBS, there is no significant difference between intravenous immunoglobulins (IVIG), plasma exchange or plasma exchange followed by IVIG. Because of convenience and absent invasiveness, IVIG are usually preferred. In treating CIDP corticosteroids, IVIG, or plasma exchange are equally effective. Despite the high costs and relative lack of availability, IVIG are preferentially used. For the one-third of patients, who does not respond, other immunosuppressive options are available. In MMN IVIG are the treatment of choice. Inadequate response in 20% of the patients requires adjunctive immunosuppressive therapies. Neuropathies with IgM monoclonal gammopathy may respond to various chemotherapeutic agents, although the long-term effects are unknown. In addition, such treatment may be associated with serious side effects. Recent data support the use of rituximab, a monoclonal antibody against the B-cell surface-membrane-marker CD20.