Clinical manifestations

Presentation and course

Patients with antisulfatide antibodies usually present with an insidious onset, slowly progressive, distal, and symmetrical sensory or sensorimotor neuropathy, affecting the legs and arms. Sensory disturbances may involve all modalities (or predominantly the small fibers) and are usually found in a stocking and glove distribution. Muscle weakness is usually mild and affects the distal muscles or is absent (33; 25; 48; 09). A few reported patients with elevated antisulfatide antibodies had Guillain-Barré syndrome or chronic inflammatory demyelinating polyradiculoneuropathy. Some patients with IgM anti-sulfatide antibodies and accompanying IgM paraproteinemia may have an ataxic gait disorder or tremor. The presence of high titers (greater than 1:4000) of IgM antisulfatide antibodies has an 80% to 90% specificity for a sensory rather than motor neuropathy syndrome (21). In a study of 23 patients with significantly elevated antisulfatide antibodies (greater than 1:25,600) and polyneuropathy, eight patients had predominantly small-fiber neuropathy; five had mixed small- and large-fiber axonal sensory neuropathy; seven had sensorimotor axonal neuropathy; and three had chronic inflammatory demyelinating polyradiculoneuropathy. Pain was a prominent symptom in 10 patients (06). In a series of nine neuropathy patients with high antisulfatide titers, one patient had an asymmetric predominantly motor neuropathy (09). Some have questioned the diagnostic utility of this test. Giannotta and colleagues reviewed 39 cases with high sulfatide antibodies and neuropathy (15). Thirty-three (85%) had coincident myelin-associated glycoprotein antibodies (MAG), and the authors concluded that the sulfatide added questionable value. However, there were six others with elevated sulfatide titers and various forms of neuropathy, including one with very high sulfatide titer, IgM gammopathy, demyelinating neuropathy, and negative anti-MAG.

Similarly, Campagnolo and colleagues reported 23 patients with chronic, distal, symmetric, slowly progressive polyneuropathy and predominant sensory impairment; most had underlying hematological disorders (04). Most patients had IgM monoclonal gammopathy of undetermined significance, four had Waldenstrom, one had non-Hodgkin lymphoma, and two had no underlying disease. Of this group, 15 had high MAG antibody titers, four had isolated high antisulfatide titers, and four had high titers to both antibodies. Response to rituximab did not appear to correlate with the antibody pattern.

GALOP syndrome is a progressive disabling gait disorder in the elderly (36). In a study of nine patients, Pestronk and colleagues reported gait ataxia and a distal sensory-predominant sensorimotor polyneuropathy. All sensory modalities may be impaired. Weakness is mild and mainly involves distal leg musculature (37).

Distal acquired demyelinating symmetric neuropathy is an overlapping entity linked to MAG antibodies; distinction must be made with IgM monoclonal versus no monoclonal protein patients. Some studies suggest that distal acquired demyelinating symmetric patients with more axonal form have a higher frequency of antisulfatide and anti-peripheral nerve myelin reactivity and a worse long-term prognosis (28).

Sulfatide measures, mainly in urine, are an important marker of metachromatic leukodystrophy. Neuropathy is a common manifestation. Dali and colleagues studied 13 children in Denmark with metachromatic leukodystrophy, 11 of which had evidence of neuropathy (07). Sural nerve and CSF sulfatide levels were studied. Nerve levels correlated with peripheral but CSF levels did not correlate with central disease severity. Other studies found no correlation between sulfatide levels and neuropathy, implicating other possible factors (02).

Antisulfatide antibodies are reported positive in some acute onset inflammatory neuropathy cases, including Miller Fisher syndrome, a pharyngeal-sensory-ataxic variant, and Miller Fisher/Guillain Barre overlap syndromes (23; 52). The findings are typically coincident with various ganglioside antibodies.

Vignette: a case of multiple antibodies and inflammatory manifestations. A 57-year-old woman had neuromyelitis optica, undifferentiated connective tissue disease, and primarily axonal sensorimotor peripheral neuropathy. The combined pattern was associated with aquaporin IgG, various ganglioside antibodies, and antisulfatide IgG antibodies in serum and cerebrospinal fluid (24). After methylprednisolone, IVIg, plasma exchange, and rituximab treatment, the patient clinically improved and showed improved nerve conduction motor and sensory amplitude responses.

Prognosis and complications

The neuropathy associated with antisulfatide antibodies is usually slowly progressive. Pain can be a disabling symptom (48; 06). If an IgM monoclonal gammopathy is present, then Waldenstrom macroglobulinemia or chronic lymphocytic leukemia should be considered; however, most of the monoclonal gammopathies are classified as monoclonal gammopathy of uncertain significance.

Biological basis

Etiology and pathogenesis

The cause for the development of antisulfatide antibodies and their role in the pathogenesis of neuropathy are unknown.

The role of antisulfatide antibodies in the pathogenesis of neuropathy is not yet understood. Sulfatide is mainly located in the noncompact myelin of Schwann cells but can also be found in the node and paranode (43). It seems unlikely that these antibodies are simply a secondary response to axonal damage; sulfatide is a major component of myelin. Patients with widespread axonal degeneration do not generally have high titers of these antibodies. The specificity of the antibody reactivity and the occurrence of monoclonal antibodies in many patients suggest that humoral processes play a role in the pathogenesis. Mice deficient in sulfatide by knockout of cerebroside sulfotransferase enzyme develop severe neurologic abnormalities and disruption of both central and peripheral myelin, especially in paranodal regions; the mice have slow sciatic nerve conduction velocity (16).

Antisulfatide antibodies have been reported in various neurologic disorders; however, significantly elevated titers (greater than 1:12,800) were closely associated with neuropathy (42). A 1:4,000 titer for IgM antisulfatide antibodies was found to be the threshold titer for autoimmune peripheral neuropathy (19). These antibodies have been reported to bind to the surface of dorsal root ganglia neurons and peripheral nerve myelin and axons, where they might exert their effect (42; 27; 39). The binding pattern has been found to correlate with the type of neuropathy (27). It seems that antibodies against sulfatide, which is expressed in myelin and axonal membranes, bind to various antigenic epitopes, producing different types of neuropathy. Axonal, demyelinating, or mixed neuropathies have all been described with antisulfatide antibodies. However, axonal predominantly sensory neuropathy is most common. In one study of patients with antisulfatide antibodies and demyelinating neuropathy, deposits of IgM and complement were seen on myelin sheaths in peripheral nerve biopsies; in another study, passive transfer of antisulfatide antibodies was reported to induce demyelination in experimental rabbits (32; 12). However, similar findings have not been reported in nerves or sera from patients with axonal neuropathies. Sera from patients with antisulfatide antibodies can cross-react with or contain antibodies to myelin-associated glycoprotein or possibly unidentified nerve antigens (38; 17). In a series of 25 patients with antisulfatide antibody titers greater than 1:25,600, two patients with axonal neuropathy had pathological findings of primary demyelination in addition to axonal degeneration, suggesting that both processes can occur in the same nerves. However, neither had detectable deposits of IgM or complement proteins (06).

Antisulfatide antibodies (IgM and IgG) show increased titers in some rheumatological conditions, including systemic lupus erythematosus, antineutrophil cytoplasmic antibody-related small vessel vasculitis, mixed cryoglobulinemia, and Sjögren syndrome; these increases may be nondiagnostic or associated with neuropathy (01).

Monoclonal proteins are detected in some patients. Dabby and colleagues found a monoclonal gammopathy in 30% of patients (06). Interestingly, monoclonal antibodies were detected in patients with axonal sensory, sensorimotor, and demyelinating neuropathies but not in patients with small-fiber neuropathy. Total IgM was elevated in one half of the patients. In another published study of patients with antisulfatide antibodies, monoclonal gammopathy was closely associated with demyelination rather than axonal degeneration (25). Other small series also reported demyelinating neuropathy with antisulfatide antibodies and monoclonal gammopathy (05; 41). Eurelings and colleagues analyzed whether the presence of antisulfatide antibodies influences the outcome of polyneuropathy associated with IgM monoclonal gammopathy (10). This study involved 65 patients in whom known causes of neuropathy were excluded. Although antisulfatide titers were elevated in 25 patients, the antibodies did not impact the clinical course, leading the authors to conclude that antisulfatide activity in IgM paraprotein-associated neuropathies does not have prognostic value. Farhad and colleagues analyzed a large series of patients diagnosed with idiopathic neuropathy and assessed for overlooked underlying causes (11). One case out of 284 (0.3%) was found to have associated high antisulfatide titers. Another study of 87 patients with monoclonal gammopathy of undetermined significance and neuropathy found a heterogeneous group with increased sulfatide titers, but affected cases tended to be younger (29).

Klehmet and colleagues assayed ganglioside and sulfatide reactivity in inflammatory neuropathy patients, including typical CIDP and known variants (61), other neuropathy (15) and other non-neuropathy immune conditions (54), and healthy controls (54) (20). They found at least one positive assay in 28% of inflammatory neuropathy patients compared to 5% of other neuropathy and 7% in multiple sclerosis patients and healthy controls. GM1 and GD1b were most prevalent. Patients that demonstrated antisulfatide were younger and demonstrated more typical CIDP and MMN phenotypes rather than multifocal or other variants. All except one positive antisulfatide patient in this cohort also were MAG positive. Some patients in the study were receiving intravenous immunoglobulin. The study drew the study sample on the first day of the infusion cycle before the infusion.

Boso and colleagues screened 229 patients by enzyme-linked immunosorbent assay (ELISA) testing for IgM sulfatide, galactocerebroside, and a combination of the two to determine if the combined assay increased sensitivity or specificity (03). They included 73 patients with IgM paraproteinemic neuropathy, mostly anti-MAG, and 156 patients with other neuropathy forms. Controls included IgM MGUS patients without neuropathy and 28 healthy controls. They found isolated antibodies to galactocerebroside in two patients with CIDP and in one patient with anti-MAG antibody neuropathy. The combined assay Sulf/GalC, however, was positive in half of the patients with paraprotein neuropathy and few others. When a strict abnormal cutoff was employed, only the patients with IgM paraproteinemic neuropathy had an abnormal combined test. The Sulf/GalC assay increased by 24 the number of positive results in that group; in the other groups, none had more than a weak positive result.

Epidemiology

Early studies detected antisulfatide antibodies in approximately one quarter of patients with predominantly sensory polyneuropathy that otherwise would have been classified as idiopathic (38; 33). However, later studies did not duplicate such a high frequency of antisulfatide activity in this common patient population, suggesting that no more than 1% to 2% of patients with chronic unclassified sensory or sensorimotor polyneuropathies had antisulfatide antibodies (51). The gender ratio for antisulfatide-associated neuropathies remains unclear. Dabby has reported a male-to-female ratio of 1:1.3 (06). In Erb’s series, the male-to-female ratio was 7:4 (09).

Differential diagnosis

Antisulfatide-associated neuropathy shares common features with other types of chronic neuropathies. Diabetic polyneuropathy, which is typically slowly progressive, predominantly sensory, and often painful, may resemble antisulfatide neuropathy. In rare cases, patients with diabetes and neuropathy have been reported to have antisulfatide antibodies, but measured titers were low (46). Toxic or drug-induced polyneuropathies can be distinguished from antisulfatide neuropathy by a careful medical history and improvement or stabilization after withdrawal of the offending agent. Neuropathies associated with vitamin deficiencies or metabolic disorders such as renal, hepatic, or thyroid dysfunction can be reliably diagnosed with laboratory testing.

Other immune-associated neuropathies can closely resemble antisulfatide neuropathy. Antimyelin-associated glycoprotein neuropathy is characterized by markedly slow nerve conduction velocities, prolonged distal latencies, and an IgM monoclonal gammopathy in most patients. Chronic inflammatory demyelinating neuropathy usually involves both motor and sensory nerves and commonly presents with distal and proximal weakness. CSF protein is characteristically high in chronic inflammatory demyelinating polyradiculoneuropathy, and electrodiagnostic studies show a demyelinating pattern. Paraneoplastic neuropathies can be secondary to solid tumors such as small-cell lung carcinoma. Identifying the primary tumor or detection of humoral factors such as anti-Hu antibodies leads to the correct diagnosis.

A study of autoantibodies in patients with active celiac disease found low levels of various IgG and IgM ganglioside antibodies. Sulfatide IgG (36%) and IgA (19%) were found. On a strict gluten-free diet, the IgG antibodies resolved, whereas IgA persisted in two cases, although a correlation with neurologic symptoms was not clearly established (45). This link also reinforces the utility of screening neuropathy patients for celiac disease.

Diagnostic workup

Nerve conduction studies usually show features of axonal sensory or sensorimotor neuropathy (33; 48). In some patients, there is a predominantly demyelinating neuropathy with slow conduction velocities and dispersed potentials (32; 25; 31; 05; 41). In patients with predominantly small-fiber neuropathy, conduction studies may be normal. In those patients, quantitative sensory testing may show selective small-fiber involvement (38; 42; 06).

The neuropathy associated with the GALOP syndrome appears to be heterogeneous. Some features suggesting demyelination are found in 80% of patients. Prolonged distal latencies and slow conduction velocities are commonly seen, although conduction block is not evident.

Information about the pathological changes in the nerves of patients with neuropathy and elevated antisulfatide antibodies is limited. Biopsy studies can reveal normal histology, axonal degeneration, or demyelination (42; 33; 27; 12). In one series, two patients with axonal neuropathy had pathological findings of primary demyelination (ie, thinly myelinated fibers and small onion bulbs). These findings were superimposed over evidence of axonal degeneration (06).

Antisulfatide antibodies are most reliably detected by enzyme-linked immunosorbent assay, using sulfatide as the antigen. Several factors increase the likelihood of a positive test, such as age greater than 50 years, disability from neuropathic symptoms, gait disorder, tremor, electrophysiologic evidence of demyelination, and IgM monoclonal gammopathy (35). Detection of the monoclonal protein, which occurs in a substantial number of patients, is best done by serum protein immunoelectrophoresis or immunofixation electrophoresis. If a monoclonal protein is present, a bone marrow biopsy is indicated to rule out Waldenstrom macroglobulinemia.

Management

Supportive measures are discussed in Peripheral neuropathies: supportive measures and rehabilitation.

There is little information to guide the management of neuropathies associated with antisulfatide antibodies or the GALOP syndrome. Patients with demyelinating features are treated similarly to those with chronic inflammatory demyelinating polyradiculopathy. Pain management is often the focus for patients with painful, small-fiber presentations; they may respond to antidepressants or anticonvulsants used for other causes of neuropathic pain. Patients with monoclonal gammopathies should be evaluated for the presence of a B-cell lymphoproliferative disorder.

Pestronk and colleagues successfully treated a few patients with GALOP syndrome using immunomodulators such as intravenous gammaglobulin, plasmapheresis, and cyclophosphamide (36).