Immune-mediated neuropathies

INTRODUCTION — Polyneuropathy may be defined broadly as the dysfunction of many or all nerves. Polyneuropathies may be classified 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 due to impaired interaction between Schwann cells and their axons. 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. Immune-mediated polyneuropathies will be reviewed here.

An overview of the causes of toxic neuropathies is discussed separately. (See "Overview of polyneuropathy", section on 'Toxic'.)

Hereditary disorders that cause neuropathies and hereditary neuropathies are discussed elsewhere. (See "Neuropathies associated with hereditary disorders" and "Overview of hereditary 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 group of conditions 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)

●Bickerstaff brainstem encephalitis (BBE)

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). While there is no established consensus regarding the classification of these neuropathies [1], we use the following organization consistent with guidelines from the European Academy of Neurology/Peripheral Nerve Society [2]:

●Typical CIDP (symmetric sensorimotor)

●CIDP variants

•Multifocal CIDP (MADSAM, or Lewis-Sumner syndrome)

•Focal CIDP

•Motor CIDP

•Sensory CIDP

•Distal acquired demyelinating symmetric neuropathy (DADS) or distal CIDP

●Other immune-mediated neuropathies not classified as CIDP

•Multifocal motor neuropathy (MMN)

•Chronic immune sensory polyradiculopathy (CISP)

•Autoimmune nodopathies (AN)

•Gait ataxia with late onset polyneuropathy (GALOP) syndrome

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

•Neuropathies associated with hematologic conditions

-Neuropathy associated with monoclonal gammopathy of uncertain significance (MGUS)

-Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome

-Neuropathy associated with Waldenstrom macroglobulinemia

-Neuropathy associated with mixed cryoglobulinemia

-Neuropathy associated with multiple myeloma

•Neuropathy associated with systemic disorders (eg, systemic lupus erythematosus, diabetes mellitus, systemic vasculitis, thyrotoxicosis, chronic kidney disease, neoplasm)

GUILLAIN-BARRE SYNDROME — Guillain Barré syndrome (GBS) is an acute monophasic illness that commonly results from an immune response to a preceding infection that cross-reacts with peripheral nerve components because of molecular mimicry. Campylobacter jejuni infection is the most commonly identified precipitant of

GBS. Other infectious triggers of GBS include Epstein-Barr virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), cytomegalovirus, and human immunodeficiency virus (HIV). GBS may also occur after another triggering event such as immunization, surgery, trauma, and bone marrow transplantation.

The key 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. Dysautonomia accompanies weakness in 70 percent of patients. Variant forms of GBS associated with antibodies to GQ1b may present chiefly with ophthalmoplegia and ataxia, rather than limb weakness.

GBS usually progresses over a period of approximately two weeks. The clinical 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 up 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, acute motor axonal neuropathy [AMAN] or acute motor and sensory axonal neuropathy [AMSAN]) features. Testing for serum immunoglobulin G (IgG) antibodies to GQ1b is useful for the diagnosis of Miller Fisher syndrome (MFS).

GBS is discussed in detail separately. (See "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis" and "Guillain-Barré syndrome in adults: Treatment and prognosis".)

CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY — Chronic inflammatory demyelinating polyneuropathy (CIDP) is a chronic neuropathy characterized by electrodiagnostic and/or pathologic features of demyelination and a relapsing-remitting or progressive clinical course. 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.

Typical CIDP is characterized by a fairly symmetric weakness of both proximal and distal limb muscles. Most patients have globally diminished or absent reflexes. Sensory impairment in CIDP is usually more pronounced for vibration and position sense than for pain and temperature sense; sensory symptoms are usually less prominent than weakness. Cranial nerve impairment and dysautonomia occur in a minority. Most patients have a slowly progressive course, but a relapsing-remitting course may occur in at least one-third.

The following criteria support the diagnosis of typical 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

●Gait ataxia due to large fiber sensory loss

●Increased cerebrospinal fluid (CSF) protein without pleocytosis

●Nerve conduction evidence of a demyelinating neuropathy

●Nerve biopsy evidence of segmental demyelination with or without inflammation

●Response to immunotherapy

While the initial diagnosis of CIDP is clinical, peripheral nerve demyelination must be demonstrated by electrodiagnostic testing (table 1). Additional diagnostic modalities used for some patients when clinical and electrodiagnostic features are atypical may include CSF analysis, magnetic resonance imaging (MRI) of spine and peripheral nerves, peripheral nerve ultrasound, laboratory studies to assess for disorders that are either associated with or mimic CIDP, and nerve biopsy.

The primary therapies for CIDP are intravenous or subcutaneous immune globulin, glucocorticoids, and plasma exchange. While the long-term prognosis of CIDP is generally favorable, data are limited, and up to 15 percent of patients are severely disabled despite treatment.

The clinical features, diagnosis, and management of CIDP are discussed in greater detail separately. (See "Chronic inflammatory demyelinating polyneuropathy: Etiology, clinical features, and diagnosis" and "Chronic inflammatory demyelinating polyneuropathy: Treatment and prognosis".)

CIDP VARIANTS — Variant forms of chronic inflammatory demyelinating polyneuropathy (CIDP) are distinguished from typical CIDP by clinical features but share similar features of CIDP of demyelinating pathophysiology and response to immune therapy. These include:

●Multifocal CIDP (MADSAM, or Lewis-Sumner syndrome)

●Focal CIDP

●Motor CIDP

●Sensory CIDP

●Distal acquired demyelinating symmetric neuropathy (DADS) or distal CIDP

CIDP variants are described in detail elsewhere. (See "Chronic inflammatory demyelinating polyneuropathy: Etiology, clinical features, and diagnosis", section on 'CIDP variants and related conditions'.)

IMMUNE NEUROPATHIES NOT CLASSIFIED AS CIDP

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. Electrodiagnostic evaluation shows focal demyelination of motor nerves with conduction block. Symptoms may improve with IVIG, but the clinical course of MMN is typically slowly progressive.

The clinical features, diagnosis, and management of MMN are reviewed in detail separately. (See "Multifocal motor neuropathy".)

Chronic immune sensory polyradiculopathy — Chronic immune sensory polyradiculopathy (CISP) is a pure or mostly sensory immune-mediated neuropathy characterized by selective involvement of the sensory nerve roots [3]. Motor nerves are typically spared. The clinical presentation is usually imbalance, gait impairment, and sensory loss. Cerebrospinal fluid (CSF) protein is usually elevated, and electrodiagnostic studies show normal nerve conduction studies and abnormal evoked potentials due to involvement of the nerve roots. While evidence of underlying demyelination in CISP is uncertain, IVIG is usually an effective treatment. (See "Chronic inflammatory demyelinating polyneuropathy: Etiology, clinical features, and diagnosis", section on 'Proximal (polyradiculopathy)'.)

Autoimmune nodopathies — Several immune neuropathies are associated with antibodies directed against the node and paranodal region of Ranvier at the nerve [4]. IgG4 antibodies against neurofascin or contactin may be identified. In addition to neuropathy, patients with autoimmune nodopathies (AN) may also have ataxia, tremor, cranial nerve involvement, and/or dysautonomia. Although a favorable response to IVIG may be seen early for some patients, most have a poor response. (See "Chronic inflammatory demyelinating polyneuropathy: Etiology, clinical features, and diagnosis", section on 'Nodal and paranodal disorders'.)

Gait ataxia with late onset polyneuropathy — 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 [5,6]. 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 neuropathy that causes a sensory ataxia with areflexia and an abnormal gait [7-9]. 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 [7]. In addition, most patients have a benign IgM monoclonal paraprotein and cold agglutinins.

Patients with CANOMAD syndrome may respond to IVIG or rituximab [9-12]. 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 [9]. 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.

Neuropathies associated with hematologic conditions — Several immune-mediated neuropathies are associated with hematologic disorders. These include monoclonal gammopathy of undetermined significance (MGUS), Waldenström macroglobulinemia (WM), multiple myeloma (MM), POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome, primary amyloidosis, and mixed cryoglobulinemia.

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

MGUS 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) MM and to symptomatic MM. 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 MM.

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

Peripheral neuropathy occurs in up to 20 percent of patients with MGUS [13], 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 M-protein is of the IgM class (48 percent) followed by IgG (37 percent) and IgA (15 percent) [14]. The demyelinating neuropathy in patients with an IgG or IgA paraprotein is indistinguishable from chronic inflammatory demyelinating polyneuropathy (CIDP) without a paraprotein and shows a similar response to treatment [15]. By contrast, the neuropathy associated with an IgM paraprotein can be distinguished from CIDP on the basis of clinical and pathological differences. Nevertheless, there is significant overlap of the clinical features among the neuropathies associated with different types of paraprotein [15].

The diagnostic evaluation of a patient with peripheral neuropathy and associated MGUS should include a physical exam to detect lymphadenopathy and organomegaly (especially splenomegaly). The laboratory, imaging, and bone marrow evaluation for the diagnosis of MGUS is discussed in detail separately. (See "Diagnosis of monoclonal gammopathy of undetermined significance", section on 'Evaluation'.)

Distal sensory and motor acquired symmetric neuropathy — The most frequent neuropathy seen in patients with IgM MGUS is distal sensory and motor acquired demyelinating symmetric neuropathy (DADS-M), clinically similar to the distal CIDP variant, distal acquired demyelinating symmetric neuropathy (DADS). However, unlike DADS, an IgM gammopathy is present in DADS-M, and up to 75 percent of patients have anti-MAG antibodies (DADS-MAG) [16]. Patients with DADS-M and DADS-MAG should be evaluated for the genetic variant MYD88 L265P to assess risk of developing WM. (See 'Waldenström macroglobulinemia' below.)

Patients with DADS-M or DADS-MAG do not respond to the immunotherapies typically used for CIDP. The nerve conduction findings are also different from CIDP, with distal accentuated slowing being the hallmark of IgM neuropathy. The pathology appears to differ from CIDP, with widening of myelin sheaths seen in approximately half of patients in reports of anti-MAG IgM neuropathies [17-20].

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 'Overview'.)

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, 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 for patients with an IgM gammopathy [21]. 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 [20]. 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.

In patients with WM and 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. (See "Treatment and prognosis of Waldenström macroglobulinemia".)

Multiple myeloma — MM is a neoplastic condition characterized by proliferation of plasma cells that produce a monoclonal immunoglobulin. Patients with MM can develop anemia, bone pain, pathologic fractures, and kidney failure as well as a peripheral neuropathy. Peripheral neuropathy in patients with MM may also be due to coexisting AL amyloidosis. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Neurologic disease'.)

POEMS syndrome — The presence of polyneuropathy and monoclonal gammopathy associated with osteosclerotic myeloma may indicate the presence of 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). A distal, symmetric, and progressive peripheral neuropathy is usually a prominent clinical feature in POEMS. Severe weakness occurs in more than one-half of patients. The prevalence of other manifestations (eg, organomegaly, endocrinopathy, skin changes, edema, and papilledema) varies greatly.

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. Biopsy of the sural nerve usually shows both axonal degeneration and demyelination. Treatment for POEMS syndrome may include radiation therapy or chemotherapy.

The clinical features, diagnosis, and management of POEMS syndrome are reviewed in greater detail separately. (See "POEMS syndrome".)

AL (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, MM or WM).

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. Less common but suggestive signs include 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, autonomic neuropathy, and median neuropathy at the carpal tunnel are the most common types of neuropathy associated with AL amyloidosis [22]. 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. Diagnosis is made by tissue biopsy showing amyloid deposition and high levels of serum-free immunoglobulin light chains. Treatment for AL amyloidosis includes hematopoietic cell transplantation or immunotherapy.

The clinical features, diagnosis, and management of amyloidosis are discussed in greater detail separately. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis" and "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis".)

Mixed cryoglobulinemia — 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.

●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's disease), 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), kidney disease, arthralgias, lymphadenopathy, hepatosplenomegaly, hypocomplementemia, and peripheral neuropathy. Patients may present with various combinations of these features, and different manifestations may predominate at different times in an individual patient.

Neuropathy in cryoglobulinemia is variable and can include 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. Immunosuppression is initial therapy for those with a rapidly progressive, organ-threatening, or life-threatening course, regardless of the etiology of the mixed cryoglobulinemia. 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.

The clinical features, diagnosis, and management of mixed cryoglobulinemia syndrome are discussed in greater detail separately. (See "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis" and "Mixed cryoglobulinemia syndrome: Treatment and prognosis".)

Neuropathy with systemic autoimmune conditions — 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's disease (see "Neurologic manifestations of Sjögren's disease")

●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's disease 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 conditions — Neuropathies are also associated with several infectious and other systemic disorders. These include:

●Diabetes mellitus (see "Epidemiology and classification of diabetic neuropathy")

●HIV (see "Epidemiology, clinical manifestations, diagnosis, and treatment of HIV-associated distal symmetric polyneuropathy (HIV-DSPN)")

●Hyperthyroidism and hypothyroidism (see "Neurologic manifestations of hyperthyroidism and Graves' disease", section on 'Peripheral neuropathy' and "Neurologic manifestations of hypothyroidism", section on 'Peripheral neuropathy')

●Sarcoidosis (see "Neurologic sarcoidosis", section on 'Peripheral neuropathy')

●Lyme disease (see "Nervous system Lyme disease")

●Hepatitis C (see "Extrahepatic manifestations of hepatitis C virus infection", section on 'Neurologic and neuropsychiatric disease')

The mechanisms of these neuropathies, particularly those associated with infectious agents, may be in part immune-mediated, but this is unclear.

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 3). Patients treated with immune checkpoint inhibitors may develop a polyradiculoneuropathy responsive to immunomodulation [23]. (See "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle" and "Toxicities associated with immune checkpoint inhibitors", section on 'Neurologic'.)

●Sensory neuronopathy – 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. (See "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle", section on 'Subacute sensory neuronopathy'.)

●Chronic sensorimotor neuropathy – 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'.)

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'.)

●Acute 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 are 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'.)

●Autonomic neuropathy – 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'.)

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 key 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-Barre syndrome' above.)

●Chronic inflammatory demyelinating polyneuropathy – Chronic inflammatory demyelinating polyneuropathy (CIDP) is a chronic neuropathy characterized by electrodiagnostic and/or pathologic features of demyelination and a relapsing-remitting or progressive clinical course. Typical CIDP is characterized by a fairly symmetric weakness of both proximal and distal limb muscles. Most patients have globally diminished or absent reflexes. The course is most often slowly progressive but can be relapsing-remitting. (See 'Chronic inflammatory demyelinating polyneuropathy' above.)

Several variant forms of CIDP and other related immune-mediated neuropathies share some clinical features with CIDP and/or a favorable response to immunomodulation. (See 'CIDP variants' 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.)

●Chronic immune sensory polyradiculopathy – Chronic immune sensory polyradiculopathy (CISP) is a pure or mostly sensory immune-mediated neuropathy characterized by selective involvement of the sensory nerve roots. The clinical presentation is usually imbalance, gait impairment, and sensory loss. (See 'Chronic immune sensory polyradiculopathy' above.)

●Autoimmune nodopathies – Immune neuropathies are associated with antibodies directed against the node and paranodal region of Ranvier such as neurofascin or contactin may cause neuropathy along with ataxia, tremor, cranial nerve involvement, and/or dysautonomia. (See 'Autoimmune nodopathies' above.)

●Immune-mediated neuropathies associated with hematologic disorders – Several immune-mediated neuropathies are associated with hematologic disorders. These include (see 'Neuropathies associated with hematologic conditions' above):

•Monoclonal gammopathy of undetermined significance (MGUS) (see 'Monoclonal gammopathy of undetermined significance' above)

•Waldenström macroglobulinemia (WM) (see 'Waldenström macroglobulinemia' above)

•Multiple myeloma (MM) (see 'Multiple myeloma' above)

•POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome (see 'POEMS syndrome' above)

•Primary amyloidosis (see 'AL (primary) amyloidosis' above)

•Mixed cryoglobulinemia (see 'Mixed cryoglobulinemia' above)

●Neuropathies with autoimmune and other systemic 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's disease, and celiac disease. Infectious and other systemic disorders such as diabetes mellitus, thyroid disease, sarcoidosis, and HIV may also be complicated by neuropathies. (See 'Neuropathy with systemic autoimmune conditions' 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 3). (See 'Paraneoplastic neuropathies' above.)

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.