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Immune-mediated neuropathies

Immune-mediated neuropathies
Authors:
Dale J Lange, MD
Jessica Robinson-Papp, MD
Section Editor:
Jeremy M Shefner, MD, PhD
Deputy Editor:
Richard P Goddeau, Jr, DO, FAHA
Literature review current through: Dec 2022. | This topic last updated: Feb 11, 2021.

INTRODUCTION — Polyneuropathy may be defined broadly as the dysfunction of many or all nerves. It is useful to classify polyneuropathies into two general categories based on pathophysiology: axonal and demyelinating. Axonal neuropathies cause symptoms and signs related to axon loss, while demyelinating neuropathies produce abnormalities based on the lack of appropriate interaction of Schwann cells with axons. The distinction between axonal and demyelinating polyneuropathies is clinically important because it guides the differential diagnosis, and ultimately the approach to treatment. Axonal neuropathies may be caused by a broad spectrum of systemic illnesses. The differential diagnosis of demyelinating neuropathies includes immune-mediated, toxic, and hereditary etiologies. In this article we specifically address the immune-mediated polyneuropathies, with emphasis on the demyelinating neuropathies.

CLASSIFICATION — Immune-mediated neuropathies can be divided into acute and chronic forms.

The acute immune-mediated polyneuropathies are classified under the eponym Guillain-Barré syndrome (GBS), a heterogeneous condition with several variant forms (see "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis"). These include:

Acute inflammatory demyelinating polyradiculoneuropathy (AIDP)

Acute motor axonal neuropathy (AMAN)

Acute motor and sensory axonal neuropathy (AMSAN)

Miller Fisher syndrome (MFS)

The phenotypes of the chronic immune-mediated neuropathies are typically described in terms of their similarities or differences to that of chronic inflammatory demyelinating polyneuropathy (CIDP) (see "Chronic inflammatory demyelinating polyneuropathy: Etiology, clinical features, and diagnosis"). While there is no established consensus regarding the classification of all these neuropathies [1], there is a general sense that multifocal motor neuropathy (MMN), the POEMS syndrome (osteosclerotic myeloma: polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes), and the anti-myelin-associated glycoprotein (anti-MAG)-related neuropathies are distinct from classic CIDP on the basis of clinical, electrodiagnostic, and therapeutic differences.

Neuropathies with a likely or possible immune-mediated mechanism may present with one of the following clinical phenotypes:

Classic, idiopathic CIDP

Multifocal acquired demyelinating sensory and motor neuropathy or Lewis-Sumner syndrome

Chronic immune sensory polyradiculopathy (CISP)

Sensory-predominant CIDP

Distal acquired demyelinating symmetric neuropathy (DADS)

Demyelinating neuropathy with central nervous system demyelination

Gait ataxia with late onset polyneuropathy (GALOP) syndrome

Chronic ataxic neuropathy with ophthalmoplegia, IgM paraprotein, cold agglutinins, and disialosyl antibodies (CANOMAD)

MMN

The following systemic disorders may be associated with one or more of the above clinical phenotypes, as discussed in subsequent sections:

Monoclonal gammopathy of undetermined significance (MGUS)

Multiple myeloma

Waldenström macroglobulinemia (WM)

Mixed cryoglobulinemia

Systemic disorders (eg, diabetes mellitus, lupus, systemic vasculitides, thyrotoxicosis, neoplasm)

GUILLAIN-BARRÉ SYNDROME — Guillain-Barré syndrome (GBS) is reviewed here briefly and discussed in detail elsewhere. (See "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis" and "Guillain-Barré syndrome in adults: Treatment and prognosis".)

GBS is an acute monophasic illness. It is thought to result from an immune response to a preceding infection that cross-reacts with peripheral nerve components because of molecular mimicry. The immune response can be directed towards the myelin or the axon of peripheral nerve, resulting in demyelinating and axonal forms of GBS. Campylobacter jejuni infection is the most commonly identified precipitant of GBS. COVID-19 [2], cytomegalovirus, Epstein-Barr virus, and human immunodeficiency virus (HIV) infection have also been associated with GBS. A small percentage of patients develop GBS after another triggering event such as immunization, surgery, trauma, and bone-marrow transplantation.

The cardinal clinical features of GBS are progressive, mostly symmetric muscle weakness and absent or depressed deep tendon reflexes. The weakness can vary from mild to severe, with nearly complete paralysis of all extremity, facial, respiratory, and bulbar muscles. Severe respiratory muscle weakness necessitating ventilatory support develops in approximately 30 percent, and dysautonomia occurs in 70 percent of patients. GBS usually progresses over a period of approximately two weeks.

GBS is a heterogeneous syndrome with several variant forms. Acute inflammatory demyelinating polyneuropathy (AIDP) is the most common variant of GBS in North America, Europe, and most of the developed world. The Miller Fisher syndrome (MFS) is a GBS variant characterized by ophthalmoplegia with ataxia and areflexia. Axonal forms of GBS include acute motor axonal neuropathy (AMAN), most common in Japan and China, and acute motor and sensory axonal neuropathy (AMSAN).

The initial diagnosis of GBS is based upon the clinical presentation. The diagnosis is confirmed by cerebrospinal fluid (CSF) analysis and clinical neurophysiology studies. An increased CSF protein with a normal CSF white blood cell count, called albuminocytologic dissociation, is found in 50 to 66 percent of patients with GBS in the first week after the onset of symptoms and in ≥75 percent of patients in the third week. Electrodiagnostic studies show evidence of acute polyneuropathy with either predominantly demyelinating (ie, acute inflammatory demyelinating polyradiculoneuropathy [AIDP]) or axonal (ie, AMAN or AMSAN) features. Testing for serum immunoglobulin G (IgG) antibodies to GQ1b is useful for the diagnosis of MFS.

Supportive care is extremely important in GBS since approximately 30 percent of patients develop neuromuscular respiratory failure requiring mechanical ventilation (see "Guillain-Barré syndrome in adults: Treatment and prognosis"). In addition, severe autonomic dysfunction occurs in approximately 20 percent and warrants intensive care unit (ICU) monitoring. The main modalities of therapy for GBS are plasma exchange and intravenous immune globulin (IVIG). The treatments are equivalent and improve outcome. Even with treatment, approximately 5 to 10 percent of patients have a prolonged course with very delayed and incomplete recovery, and 5 percent die despite intensive care. In addition, approximately 2 percent of patients with GBS will develop the chronic relapsing weakness of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).

CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY — Chronic inflammatory demyelinating polyneuropathy (CIDP) is reviewed here briefly and discussed in detail separately. (See "Chronic inflammatory demyelinating polyneuropathy: Etiology, clinical features, and diagnosis" and "Chronic inflammatory demyelinating polyneuropathy: Treatment and prognosis".)

Both the cellular and humoral components of the immune system appear to be involved in the pathogenesis of CIDP and its variants. However, the precise cause is unclear, since specific provoking antigens have not been identified. (See "Chronic inflammatory demyelinating polyneuropathy: Etiology, clinical features, and diagnosis", section on 'Pathogenesis'.)

The classic form of CIDP is fairly symmetric, and motor involvement is greater than sensory. Weakness is present in both proximal and distal muscles. Most patients also have sensory involvement and globally diminished or absent reflexes. Sensory impairment in CIDP is usually greater for vibration and position sense than for pain and temperature sense. Cranial nerve and bulbar involvement occur in a minority. Most patients have a slowly progressive course, but a relapsing-remitting course is noted in at least one-third. (See "Chronic inflammatory demyelinating polyneuropathy: Etiology, clinical features, and diagnosis", section on 'Clinical features'.)

The following criteria support the diagnosis of the classic form of CIDP:

Progression over at least two months

Weakness more than sensory symptoms

Symmetric involvement of arms and legs

Proximal muscles involved along with distal muscles

Reduced deep tendon reflexes throughout

Increased cerebrospinal fluid (CSF) protein without pleocytosis

Nerve conduction evidence of a demyelinating neuropathy

Nerve biopsy evidence of segmental demyelination with or without inflammation

While the initial diagnosis of CIDP is clinical, peripheral nerve demyelination must be demonstrated by either electrodiagnostic testing (table 1) or by nerve biopsy. Additional investigations that are often indicated include CSF analysis; magnetic resonance imaging (MRI) of the spinal roots, brachial plexus, and lumbosacral plexus; laboratory studies to look for disorders that are either associated with or mimic CIDP; and evaluation for inherited neuropathies. (See "Chronic inflammatory demyelinating polyneuropathy: Etiology, clinical features, and diagnosis", section on 'Diagnostic evaluation'.)

The primary therapies for CIDP are intravenous or subcutaneous immune globulin, glucocorticoids, and plasma exchange. For patients refractory to primary therapies, other agents, such as cyclosporine or rituximab, have been used [3,4]. While the long-term prognosis of CIDP is generally favorable in some patients, data are limited, and up to 15 percent of patients are severely disabled despite treatment. (See "Chronic inflammatory demyelinating polyneuropathy: Treatment and prognosis".)

CIDP VARIANTS AND RELATED CONDITIONS — Variants of chronic inflammatory demyelinating polyneuropathy (CIDP) and other clinically related conditions include multifocal acquired demyelinating sensory and motor neuropathy (also known as Lewis-Sumner syndrome), sensory-predominant CIDP, distal acquired demyelinating symmetric neuropathy (DADS), chronic immune sensory polyradiculopathy (CISP), IgG4 neurofascin antibody (NF-155)-mediated CIDP, and contactin 1 antibody-mediated CIDP. These variants are discussed separately. (See "Chronic inflammatory demyelinating polyneuropathy: Etiology, clinical features, and diagnosis", section on 'CIDP variants and related conditions'.)

MULTIFOCAL MOTOR NEUROPATHY — Multifocal motor neuropathy (MMN) is a rare neuropathy characterized by progressive asymmetric weakness and atrophy without sensory abnormalities, a presentation similar to that of motor neuron disease. MMN is considered an immune-mediated disorder on the basis of its responsiveness to treatment with intravenous immune globulin (IVIG), its association with anti-GM1 antibodies (table 2), and inflammatory infiltrates on nerve biopsy in some reports. However, it is unclear whether anti-GM1 antibodies are involved in the pathogenesis of MMN or are merely an epiphenomenon of the disease. The clinical features, diagnosis, and management of MMN are reviewed in detail separately. (See "Multifocal motor neuropathy", section on 'Pathogenesis'.)

SYSTEMIC DISORDERS ASSOCIATED WITH IMMUNE-MEDIATED NEUROPATHIES — A number of systemic disorders may be associated with one or more of the clinical phenotypes associated with chronic inflammatory demyelinating polyneuropathy (CIDP) or CIDP variants described above. These include monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma, Waldenström macroglobulinemia (WM), mixed cryoglobulinemia, IgG4-related diseases, and other systemic diseases.

Monoclonal gammopathy of undetermined significance — Monoclonal gammopathies (also referred to as paraproteinemia, monoclonal protein, or M protein) may occur in association with malignancies (eg, multiple myeloma, lymphoma, WM) with or without evidence of peripheral neuropathy.

MGUS is an asymptomatic, premalignant clonal plasma cell or lymphoplasmacytic proliferative disorder. It is defined by the presence of a serum monoclonal protein (M-protein) at a concentration <3 g/dL, a bone marrow with <10 percent monoclonal plasma cells, and the absence of end organ damage (lytic bone lesions, anemia, hypercalcemia, renal insufficiency, hyperviscosity) related to the proliferative process. In general, patients with MGUS progress to more advanced disease with malignancy at a rate of 1 percent per year. (See "Clinical course and management of monoclonal gammopathy of undetermined significance" and "Diagnosis of monoclonal gammopathy of undetermined significance".)

There are three distinct clinical types of MGUS, each with a risk of progressing through a unique intermediate (more advanced) premalignant stage and then to a malignant plasma cell dyscrasia or lymphoproliferative disorder (see "Clinical course and management of monoclonal gammopathy of undetermined significance", section on 'Disease progression'):

Non-IgM MGUS (IgG, IgA, or IgD MGUS) is the most common type of MGUS and has the potential to progress to smoldering (asymptomatic) multiple myeloma and to symptomatic multiple myeloma. Less frequently, these patients progress to immunoglobulin light chain (AL) amyloidosis, light chain deposition disease, or another lymphoproliferative disorder.

IgM MGUS accounts for approximately 15 percent of MGUS cases. It is considered separately from the non-IgM MGUS because it has the potential to progress to smoldering WM and then symptomatic WM, lymphoma, or AL amyloidosis. Infrequently, IgM MGUS can progress to IgM multiple myeloma.

Light chain MGUS (LC-MGUS) may progress to idiopathic Bence-Jones proteinuria and to light chain multiple myeloma, AL amyloidosis, or light chain deposition disease.

MGUS can be associated with peripheral neuropathy, but it is often not clear whether the neuropathy is etiologically related to the gammopathy or merely represents a coincidental association, given the relatively frequent occurrence in the general population over age 50 years of MGUS (3 percent or more of the general population) and neuropathy. In patients with neuropathy, the most common monoclonal protein is of the IgM class (48 percent) followed by IgG (37 percent) and IgA (15 percent) [5].

With the exception of POEMS (see 'POEMS syndrome' below), there is no evidence that the demyelinating neuropathy in patients with an IgG or IgA paraprotein is distinct from CIDP without a paraprotein. The demyelinating neuropathy is otherwise indistinguishable from CIDP and shows a similar response to treatment [6]. By contrast, the neuropathy associated with an IgM paraprotein can be distinguished from CIDP on the basis of clinical and pathological differences (see 'Neuropathy with IgM gammopathy' below). Nevertheless, there is significant overlap of the clinical features among the neuropathies associated with different types of paraprotein [6].

Diagnostic evaluation of a patient with peripheral neuropathy and associated MGUS should include a physical exam to detect lymphadenopathy and organomegaly (especially splenomegaly). A nerve biopsy may help identify the mechanism of peripheral nerve involvement guiding therapy [7]. At a minimum, patients suspected of having MGUS should be evaluated with the following studies (see "Diagnosis of monoclonal gammopathy of undetermined significance", section on 'Evaluation'):

Complete blood count

Serum calcium and creatinine

Serum protein electrophoresis and immunofixation

Urine protein electrophoresis and immunofixation

Serum free light chain assay

Quantitation of immunoglobulins

Metastatic bone survey in patients with intermediate- or high-risk MGUS and in any patient where there is a concern for myeloma (see "Clinical course and management of monoclonal gammopathy of undetermined significance", section on 'Risk stratification')

POEMS syndrome — The presence of polyneuropathy and monoclonal gammopathy associated with osteosclerotic myeloma must raise the suspicion for the POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome. The POEMS syndrome is reviewed in detail separately. (See "POEMS syndrome".)

The clinical manifestations of POEMS syndrome are protean. By definition, all patients have peripheral neuropathy and a monoclonal plasma cell disorder; the monoclonal protein light chain is almost always of the lambda type, while the associated heavy chain is usually IgG or IgA, and rarely IgM. Nearly all patients have either osteosclerotic myeloma (solitary or multiple) or Castleman disease (angiofollicular lymph node hyperplasia). The prevalence of other manifestations (eg, organomegaly, endocrinopathy, skin changes, edema, and papilledema) varies greatly. Additional findings associated with POEMS include peripheral edema, ascites, polycythemia, and fatigue. Elevation of serum or plasma vascular endothelial growth factor (VEGF) levels is an important feature. (See "POEMS syndrome", section on 'Clinical features'.)

Peripheral neuropathy usually dominates the clinical picture in POEMS. Symptoms begin in the feet and consist of tingling, paresthesias, and feelings of coldness. Motor involvement follows the sensory symptoms. Both are distal, symmetric, and progressive, with a gradual proximal spread. Severe weakness occurs in more than one-half of patients. The course is progressive, and patients may become nonambulatory. Autonomic symptoms are not a feature. Physical examination reveals a symmetric sensorimotor neuropathy involving the extremities. Muscle weakness is more marked than sensory loss. Touch, pressure, vibratory, and joint position senses are often involved. Less frequently, loss of temperature discrimination and nociception occurs. Cranial nerves are not affected. (See "POEMS syndrome", section on 'Peripheral neuropathy'.)

Cerebrospinal fluid (CSF) protein levels are increased in virtually all patients, usually >100 mg/dL, while the total cell count is typically normal. Electrodiagnostic studies show slowing of nerve conduction, prolonged distal latencies, and severe attenuation of compound muscle action potentials. Conduction block is rarely found, but slowing of motor conduction is proportionately greater than the reduction in the compound muscle action potential amplitude. Distal fibrillation potentials are found on needle electromyography. Biopsy of the sural nerve usually shows both axonal degeneration and demyelination; severe endoneurial edema may also be seen. A loss of myelinated fibers and an increased frequency of axonal degeneration in teased fibers have been reported, along with high expression of VEGF in vasa nervorum and some non-myelin-forming Schwann cells. Endoneurial deposits of immunoglobulins of the same type as in the serum have been reported in three of four patients with POEMS syndrome. (See "POEMS syndrome", section on 'Peripheral neuropathy'.)

The diagnosis of POEMS syndrome requires the presence of at least three major criteria (ie, polyneuropathy plus monoclonal plasma cell disorder plus any one of the following three: osteosclerotic bone lesion[s], Castleman disease, or elevated serum or plasma VEGF levels), along with the presence of at least one of the six minor criteria (table 3). The absence of either osteosclerotic myeloma or Castleman disease should make the diagnosis of POEMS syndrome suspect. (See "POEMS syndrome", section on 'Diagnosis'.)

There is no standard treatment for POEMS syndrome. In general, the mode of therapy is based upon whether the patient has limited or widespread sclerotic bone lesions, with radiation therapy employed for those with limited disease, and chemotherapy similar to multiple myeloma for those with widespread bone lesions. Hematopoietic cell transplantation is an option for patients with rapidly progressive neuropathy and for younger patients with widespread osteosclerotic lesions. (See "POEMS syndrome", section on 'Therapy'.)

Neuropathy with IgM gammopathy — Neuropathies associated with IgM gammopathy include distal acquired demyelinating symmetric neuropathy (DADS) with IgM paraprotein, MGUS, WM, myelin-associated glycoprotein (MAG) gammopathy, mixed cryoglobulinemia, gait ataxia with late onset polyneuropathy (GALOP) syndrome, and chronic ataxic neuropathy with disialosyl antibodies.

Most patients with a demyelinating neuropathy and an IgM paraprotein have MGUS or WM, and they usually have a distal and sensory-predominant phenotype. Even if proximal muscles are involved, they do not respond to the primary therapies for CIDP, which are intravenous immune globulin (IVIG), glucocorticoids, and plasma exchange. The response to plasma exchange is inconsistent, possibly because IgM is replaced within five days so that plasma exchange does not have a long-lasting effect. The nerve conduction findings are also different from classic CIDP, with distal accentuated slowing being the hallmark of IgM neuropathy. The pathology appears to differ from classic CIDP, with widening of myelin sheaths seen in approximately half of patients in reports of anti-MAG IgM neuropathies [8-11].

Waldenström macroglobulinemia — WM is reviewed here briefly and discussed in detail elsewhere. (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia" and "Treatment and prognosis of Waldenström macroglobulinemia".)

WM is a form of lymphoplasmacytic tumor that is slow growing and usually does not warrant treatment unless there are complicating factors, such as neuropathy. It produces IgM monoclonal proteins that may have anti-MAG activity. The quantity of monoclonal protein may be very high, leading to hyperviscosity syndrome. Patients usually present in their seventh decade with symptoms related to the infiltration of the hematopoietic tissues (eg, anemia, lymphadenopathy, hepatosplenomegaly) and/or symptoms related to the IgM monoclonal protein in their blood (eg, hyperviscosity, peripheral neuropathy). (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia", section on 'Clinical presentation'.)

Approximately 20 percent of patients with WM present with symptoms of neuropathy at the time of diagnosis. The neuropathy is often demyelinating, with sensory involvement more common than motor involvement, but may be purely motor. The most frequent neurologic abnormality is a distal, symmetric, and slowly progressive sensorimotor peripheral neuropathy causing pain, paresthesia, and weakness. The lower extremities are usually more involved than the upper extremities. Additional but less common neurologic manifestations of WM include cranial nerve palsies, mononeuropathy, mononeuritis multiplex, multifocal motor neuropathy (MMN) or motor neuron-like syndromes, multifocal leukoencephalopathy, and sudden deafness.

The genetic variant MYD88 L265P occurs in over 90 percent of patients with WM and may help identify WM as the underlying source of neuropathy [12]. Anti-MAG activity is found in approximately one-half of patients with WM-associated neuropathy, but there is no correlation between the presence or titer of these antibodies and the severity of symptoms [11]. Other autoantibodies of uncertain pathogenetic significance have also been described, including those directed against GM1 ganglioside and asialo-GM1 ganglioside. (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia", section on 'Neuropathy'.)

Among patients with WM and peripheral neuropathy, sural nerve biopsy may reveal myelin degeneration, cellular infiltration of the nerve, or IgM deposits on the myelin sheath. However, it is impossible to determine whether the presence of IgM in the biopsy specimen is a causative factor or whether it represents passive deposition of IgM in an already damaged nerve. Amyloid deposition in the nerve may be responsible for the sensorimotor peripheral neuropathy in some patients. Amyloid may be investigated using Congo red staining of a subcutaneous fat pad aspirate or bone marrow biopsy.

In patients with severe neuropathy, plasma exchange, IVIG, and treatment of the primary disease with rituximab-based regimens may produce short-term relief and/or slow the progression of symptoms. The presence of MYD88 L265P may predict response to therapies like ibrutinib, a Bruton tyrosine kinase inhibitor [3]. (See "Treatment and prognosis of Waldenström macroglobulinemia".)

Mixed cryoglobulinemia — The mixed cryoglobulinemia syndrome is reviewed here briefly and discussed in greater detail separately. (See "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis" and "Mixed cryoglobulinemia syndrome: Treatment and prognosis".)

Cryoglobulins are immunoglobulins that precipitate in the cold and dissolve on rewarming. The mixed cryoglobulinemia syndrome is a systemic disease caused by the deposition of antigen-antibody complexes (immune complexes) in small- and medium-sized arteries. The syndrome can be associated with either type II or type III cryoglobulins. (See "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis", section on 'Terminology'.)

In type II mixed cryoglobulinemia, the cryoglobulin contains both a polyclonal IgG and a monoclonal IgM rheumatoid factor; it is most often due to chronic infection with hepatitis C virus, although infection with hepatitis B virus and Epstein-Barr virus has been implicated in some patients.

In type III mixed cryoglobulinemia, both the IgG and the IgM rheumatoid factor are polyclonal. This disorder is often seen in chronic inflammatory and autoimmune diseases (such as systemic lupus erythematosus and Sjögren syndrome), lymphoproliferative malignancies, and, in as many as one-half of cases, hepatitis C virus infection.

The major clinical manifestations of mixed cryoglobulinemia syndrome include palpable purpura (suggesting some form of small vessel vasculitis), renal disease, arthralgias, lymphadenopathy, hepatosplenomegaly, peripheral neuropathy, and hypocomplementemia. Patients may present with various combinations of these features, and different manifestations may predominate at different times in an individual patient. (See "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis", section on 'Clinical manifestations'.)

Cryoglobulins can cause different types of neuropathy, including a painful, primarily sensory polyneuropathy, a sensorimotor axonal polyneuropathy, or mononeuropathy/mononeuropathy multiplex due to focal ischemia.

The diagnosis of mixed cryoglobulinemia syndrome is made from the history, the presence of skin purpura and other manifestations, low complement levels, and demonstration of circulating cryoglobulins. (See "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis", section on 'Diagnosis'.)

Immunosuppression is initial therapy for those with a rapidly progressive, organ-threatening, or life-threatening course, regardless of the etiology of the mixed cryoglobulinemia, and usually combines a short course of glucocorticoids with either rituximab or cyclophosphamide and, in some patients, plasmapheresis. In addition, all patients should receive therapy directed against the underlying etiology of the mixed cryoglobulinemia. As examples, patients with hepatitis C virus who have chronic hepatitis should receive antiviral therapy, while patients with an underlying lymphoproliferative disorder should receive appropriate disease-specific therapy. In some cases, this will involve continuation of immunosuppression for a prolonged period. (See "Mixed cryoglobulinemia syndrome: Treatment and prognosis".)

Gait ataxia with late onset polyneuropathy — GALOP syndrome is associated with a monoclonal elevation of an IgM kappa protein (table 2). The antibody binds specifically to galopin, a component of white matter in the central nervous system [13,14]. Patients have a predominantly sensory peripheral neuropathy with ataxia, which responds to IVIG.

CANOMAD syndrome — The syndrome of chronic ataxic neuropathy, ophthalmoplegia, IgM paraprotein, cold agglutinins, and disialosyl antibodies (CANOMAD) is a sensory ataxia with areflexia and an abnormal gait [15-17]. Distal limb and perioral paresthesias are typical features. Motor weakness often affects oculomotor and bulbar muscles as a relapsing-remitting or fixed manifestation, causing ophthalmoplegia and difficulty swallowing or speaking. Electrophysiologic studies may show either a demyelinating or an axonal pattern.

In some cases, respiratory muscle weakness can occur. Patients have IgM antibodies that react with disialosyl epitopes common to gangliosides including GD1b, GD3, GT1b, and GQ1b [15]. In addition, most patients have a benign IgM monoclonal paraprotein and cold agglutinins.

Patients may respond to IVIG as well as rituximab [17-20]. In a French registry that included 45 patients, more than half of patients treated with either IVIG or rituximab had a complete or partial response; corticosteroids and immunosuppressive agents were found largely ineffective [17]. IVIG was given at 2 g/kg every four weeks and rituximab infusions were given in divided doses over one month at a dose of 375 mg/m2.

Primary amyloidosis — Amyloidosis is a generic term that refers to the extracellular tissue deposition of fibrils composed of low molecular weight subunits of a variety of normal serum proteins. AL amyloidosis (previously called primary amyloidosis) is a clonal plasma cell proliferative disorder in which fibrils of monoclonal light chains are deposited in the kidney and other tissues. Affected patients may have amyloidosis alone or in association with other plasma cell dyscrasias (eg, multiple myeloma or Waldenström macroglobulinemia). (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis".)

The clinical presentation in AL amyloidosis depends on the number and nature of the organs affected. Nonspecific systemic symptoms, including fatigue and unintentional weight loss, are common. Other common clinical presentations include nephrotic syndrome, restrictive cardiomyopathy, peripheral neuropathy, and hepatomegaly with elevated liver enzymes. Other less common but suggestive signs are macroglossia, purpura, and an unexplained bleeding diathesis. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis", section on 'Systemic presentations'.)

Sensorimotor axonal polyneuropathy neuropathy, autonomic neuropathy, and median neuropathy at the carpal tunnel are the most common types of neuropathy associated with AL amyloidosis [21]. The neuropathy is related to excessive deposition of the immunoglobulin, particularly the kappa light chain. Symptoms of numbness, paresthesia, and pain are common. Compression of peripheral nerves, especially the median nerve within the carpal tunnel, can cause more localized sensory changes. Symptoms of bowel or bladder dysfunction and findings of orthostatic hypotension may be due to autonomic nervous system damage.

Other paraneoplastic neuropathies — Paraneoplastic neurologic syndromes are a heterogeneous group of disorders associated with systemic cancer and caused by mechanisms other than metastases, metabolic and nutritional deficits, infections, coagulopathy, or side effects of cancer treatment (table 4). Patients being treated with immune checkpoint inhibitors may develop a polyradiculoneuropathy responsive to immunomodulation [22]. (See "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle".)

The classic syndrome of paraneoplastic neuropathy is the sensory neuronopathy, which involves degeneration of the sensory fiber from the level of the cell body in the dorsal root ganglion. Paraneoplastic demyelinating polyneuropathy is rare but has been described in patients with anti-Hu and anti-CRMP5/CV2 antibodies. (See "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle", section on 'Subacute sensory neuronopathy'.)

Chronic sensorimotor neuropathy is common in cancer patients, occurring in approximately 10 to 15 percent of patients with solid tumors. In most cases this is not disabling. Exceptions include those with anti-CV2 (or CRMP5) antibodies that are associated with small cell lung cancer or thymoma. Patients with plasma cell dyscrasias may also develop a disabling neuropathy. (See "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle", section on 'Chronic sensorimotor neuropathy'.)

Acute sensorimotor neuropathy or the Guillain-Barré syndrome (GBS) may occur as a paraneoplastic syndrome, usually in association with Hodgkin lymphoma. Treatment and prognosis is similar to that for GBS that is not associated with cancer. (See "Guillain-Barré syndrome in adults: Treatment and prognosis" and "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle", section on 'Acute sensorimotor radiculoneuropathy'.)

Paraneoplastic autonomic dysfunction manifests with a variety of symptoms, including dry mouth, blurry vision, erectile dysfunction, hypothermia, hypoventilation, sleep apnea, gastroparesis, intestinal pseudo-obstruction, and cardiac arrhythmias that can lead to sudden death. This syndrome is associated most often with small cell lung cancer and anti-Hu antibodies. It is usually treatment resistant. Some patients may have ganglionic acetylcholine receptor antibodies (against a3 subunit), and these cases are more responsive to immunotherapy. (See "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle", section on 'Autonomic neuropathy'.)

Paraneoplastic peripheral nerve vasculitis typically presents with painful, asymmetric sensorimotor deficits resembling a mononeuritis multiplex. Biopsy demonstrates the vasculitis. Immunotherapy and antitumor treatment may improve symptoms. (See "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle", section on 'Vasculitic neuropathy'.)

Neuropathy with systemic autoimmune disease — Neuropathies are associated with many systemic autoimmune diseases characterized by the production of abnormal antibodies (table 2), including the following:

Systemic vasculitides

Polyarteritis nodosa (see "Clinical manifestations and diagnosis of polyarteritis nodosa in adults", section on 'Neurologic disease')

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (see "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)", section on 'Neurologic')

Granulomatosis with polyangiitis (see "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis", section on 'Other manifestations')

Rheumatoid arthritis (see "Neurologic manifestations of rheumatoid arthritis", section on 'Peripheral nervous system')

Systemic lupus erythematosus (see "Manifestations of systemic lupus erythematosus affecting the peripheral nervous system", section on 'Peripheral neuropathies')

Sjögren syndrome (see "Neurologic manifestations of Sjögren's syndrome")

Celiac disease (see "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults" and "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in children")

These syndromes most often present with axonal neuropathies, typically mononeuropathy multiplex with the vasculitides, and distal symmetric sensorimotor polyneuropathy with the connective tissue diseases. Sjögren syndrome and celiac disease are associated with a sensory neuronopathy, but acute and chronic demyelinating neuropathies are also rarely associated with these syndromes. A causal relationship is not proven.

Neuropathy with other systemic diseases — Neuropathies are described in association with numerous systemic disorders including diabetes mellitus, HIV, Lyme disease, hepatitis B and C, sarcoidosis, and thyrotoxicosis. The mechanisms of these neuropathies, particularly those associated with infectious agents, may be in part immune mediated, but this is unclear.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Neuropathy".)

SUMMARY

Guillain-Barré syndrome – Guillain-Barré syndrome (GBS) is an acute monophasic illness with several variant forms. The cardinal clinical features of GBS are progressive, mostly symmetric muscle weakness and absent or depressed deep tendon reflexes. The weakness can vary from mild to severe, with nearly complete paralysis of all extremity, facial, respiratory, and bulbar muscles. GBS usually progresses over a period of approximately two weeks. (See 'Guillain-Barré syndrome' above.)

Chronic inflammatory demyelinating polyneuropathy – The classic form of chronic inflammatory demyelinating polyneuropathy (CIDP) is fairly symmetric; motor involvement is greater than sensory. Weakness is present in both proximal and distal muscles. Most patients also have globally diminished or absent reflexes. The course is most often slowly progressive but can be relapsing-remitting. Several atypical variants of CIDP also exist. (See 'Chronic inflammatory demyelinating polyneuropathy' above and 'CIDP variants and related conditions' above.)

Multifocal motor neuropathy – Multifocal motor neuropathy (MMN) is a rare neuropathy characterized by progressive asymmetric weakness and atrophy without sensory abnormalities, a presentation similar to that of motor neuron disease. (See 'Multifocal motor neuropathy' above.)

Neuropathies associated with systemic disorders

Monoclonal gammopathies

-MGUS – Monoclonal gammopathies of undetermined significance (MGUS) can be associated with peripheral neuropathy, but it is often not clear whether the neuropathy is related to the gammopathy or is a coincidental association. The most common monoclonal protein is of the IgM class followed by IgG and IgA. (See 'Monoclonal gammopathy of undetermined significance' above.)

Monoclonal gammopathies may also occur in association with malignancies (eg, multiple myeloma, lymphoma, Waldenström macroglobulinemia) with or without evidence of peripheral neuropathy.

-POEMS syndrome – Polyneuropathy and monoclonal gammopathy associated with osteosclerotic myeloma must raise the suspicion for the POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome (table 3). (See 'POEMS syndrome' above.)

-IgM gammopathies – Neuropathies associated with IgM gammopathy include distal acquired demyelinating symmetric neuropathy (DADS) with IgM paraprotein, MGUS, Waldenström macroglobulinemia, myelin-associated glycoprotein (MAG) gammopathy, mixed cryoglobulinemia, gait ataxia with late onset polyneuropathy (GALOP) syndrome, and CANOMAD syndrome. (See 'Neuropathy with IgM gammopathy' above.)

Primary amyloidosis – Amyloidosis is a clonal plasma cell proliferative disorder in which fibrils of monoclonal light chains are deposited in the kidney and other tissues. Sensorimotor axonal polyneuropathy neuropathy, autonomic neuropathy, and median neuropathy at the carpal tunnel are the most common types of neuropathy associated with immunoglobulin light chain (AL) amyloidosis. (See 'Primary amyloidosis' above.)

Paraneoplastic neuropathies – Paraneoplastic neurologic syndromes are a heterogeneous group of disorders associated with systemic cancer and caused by mechanisms other than metastases, metabolic and nutritional deficits, infections, coagulopathy, or side effects of cancer treatment (table 4). Paraneoplastic neuropathies include sensory neuronopathy, chronic sensorimotor neuropathy, and paraneoplastic autonomic dysfunction. In addition, acute sensorimotor neuropathy or GBS may occur as a paraneoplastic syndrome. (See 'Other paraneoplastic neuropathies' above.)

Neuropathies with autoimmune diseases – Neuropathies are associated with many systemic autoimmune diseases characterized by the production of abnormal antibodies (table 2), including systemic vasculitides, rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, and celiac disease. (See 'Neuropathy with systemic autoimmune disease' above.)

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Topic 14174 Version 22.0

References