The clinical heterogeneity of immune sensory and autonomic neuropathies with (or without) sicca

In this issue of Brain, Mori and co-workers from several collaborating Japanese medical schools report on the clinical patterns of neuropathy associated with primary Sjögren's syndrome. The criteria for primary Sjögren's syndrome used were accepted by Japanese and American-European consensus groups: (i) symptoms of dry eyes (keratoconjunctivitis or sicca) or a dry mouth (xerostomia); (ii) objective evidence of keratoconjunctivitis (abnormal Schirmer's or Rose Bengal test) and (iii) evidence of lymphocytic sialoadenitis (e.g. from a lip biopsy) and the presence of antibodies (SS-A or SS-B). Of 92 patients reviewed, mean age ∼60 years, there was a strong female preponderance (76 of 92). The following varieties of neuropathy were recognized: sensory ataxia in 36 (39%); sensory painful in 18 (20%); multiple mononeuropathy in 11 (12%); multiple cranial neuropathies in 5 (5%); trigeminal neuropathy in 15 (17%); autonomic neuropathy in 3 (3%); and radiculoneuropathy in 4 (4%). Although each pattern of neuropathy has already been reported as associated with Sjögren's syndrome, the present series provides the frequency distribution for patterns of neuropathy based on evaluation of a single large cohort of such patients. The authors also provide information on characteristic electrophysiologic alterations, patterns of abnormal sweating and pathology. They emphasize the clinical heterogeneity of neuropathies associated with sicca and provide information on the distribution of lymphocytic inflammation in lip, parotid gland, spinal ganglia and nerve (vascular and perivascular). They suggest differences in response to immunotherapy by variety of neuropathy. Accepting the ideas that neuropathies associated with sicca are clinically heterogenous and that altered immunity is probably involved, not only in Sjögren's syndrome but also the associated neuropathies, other questions might be raised. What functional classes of nerve fibres are preferentially affected? Clinical, quantitative sensation tests, autonomic function, and electrophysiological studies clearly demonstrate selective involvement of sensory and autonomic neurons or fibres. This selectivity of involvement is illustrated by Mori and colleagues and also in the Fig. 1 (seeDyck et al., 1996). Considering first the involvement of sensory neurons and fibres, several patterns of sensory loss are recognized. In the ataxic variety, large primary afferent neurons or fibres are selectively affected. The inflammatory infiltrates found in spinal ganglia presumably explain this selectivity. In trigeminal neuropathy, quantitative sensation tests have previously shown pan-modality sensory loss implicating involvement of all classes of sensory neurons or fibres (Dyck et al., 1993).In sensory and autonomic neuropathy affecting limb or trunk, all classes of sensory neurons or fibres are known to be dysfunctional but symptoms relate more to small than large fibre sensory involvement. In these latter neuropathies, the pattern of symptoms and sensory loss is often asymmetric or even patchy and may involve proximal or distal regions not infrequently it has a radicular pattern (seeFig. 1). An important feature of small fibre sensory involvement is that it may be expressed as hypersensitivity or hyposensitivity. Hypersensitivity may be recognized as tactile (allodynia) or thermal hypersensitivity (hyperalgesia). Formal quantitative sensation testing is helpful in recognizing the hypersensitivity (seeFig. 1; Dyck et al., 1993, 2005). Different patterns of autonomic nerve fibre involvement may also be recognized. Several patterns of sweating abnormality consistent with neuropathies associated with sicca are recognized (seeFig. 1). Increased sweating is hard to demonstrate but decreased sweating may occur symmetrically in toes and feet and perhaps more typically is asymmetrical and somewhat radicular in distribution. Sweat loss may occur in regions over the face, trunk or upper limbs. This pattern suggests multifocal involvement of both proximal and distal limb nerves and can be found in other inflammatory neuropathies (e.g. sarcoid neuropathy). The region of sweat loss often corresponds to anatomical regions of pain (as in Case 3 shown in the Fig. 1). The variability of findings in four patients with chronic immune sensory and autonomic neuropathy ± sicca. The pattern of sweating (purple) is normal in Case 1 but abnormal in the other three patients. Areas with loss of sweating lack the purple colour. The face is not tested. Case 1, a patient with symptoms of dry eyes and Rose Bengal staining has an elevated extractable nuclear antigen value, a normal distribution of sweating pattern, and in the foot decreased vibration sensation and hyperalgesia of heat-pain tests in the foot. The other three cases had symptoms of dry eyes, but ENA values were within normal limits. They had evidence of selective and patchy involvement of sensory and autonomic neuron or fibre dysfunction. Note that patchy and asymmetric proximal and radicular sweat loss is characteristic—with little, if any, motor neuron or fibre involvement. Sweat distribution tests provided courtesy of R. Fealey, MD. A second key question is what pathologic alterations explain the heterogenous manifestations? By contrast to the extensive clinical and electrophysiologic localization data, there is a real dearth of information on the distribution of underlying pathologic alterations, and Mori et al. confirm that lymphocytic infiltration is found in the vicinity of minor salivary glands and in parotid and lacrimal glands. Inflammatory infiltrates in spinal ganglia might explain degeneration of primary afferent neurons (Dyck et al., 1992), and development of microvasculitis could explain a multiple mononeuropathy (Mellgren et al., 1989). Generally, however, studies have been too incomplete to know whether the inflammation is confined to spinal ganglia and to reconcile the degree to which multifocal lesions along the proximal to distal length of nerves contribute to the symptomatology. The preferential involvement of salivary and lacrimal glands, and of sensory and autonomic neurons or fibres, suggests that these tissues display antigens. If the varieties described by Mori et al. clearly stand apart without intermediate forms, it might suggest different patho-immune mechanisms causing different varieties. If, on the other hand, transition between typical forms occurs, the differences might simply be explained by variations in severity and anatomical location of lesions. Detailed three-dimensional studies of lesions and of fibre degeneration in proximal to distal levels of nerves at necropsy might provide important new insights. I raise a question about the naming of varieties of neuropathy associated with primary Sjögren's syndrome. Does the disorder cause these neuropathies and do similar neuropathies occur without Sjögren's? Is ‘Sjögren's neuropathy’ an appropriate name? There is little question that all the patterns of neuropathies described by Mori et al. may occur without or with variable degrees of lacrimal or salivary gland dysfunction and with or without Sjögren's antibodies. From very incomplete pathologic studies, lymphocytic infiltration in nerve and microvasculitis may occur in these neuropathies with or without clinical manifestations of Sjögren's. Furthermore, it seems unlikely that the lacrimal and salivary abnormalities themselves induce neuropathy. Perhaps more important is the fact that the neuropathic symptoms, especially the positive hyperalgesia, various pains and paresthesia, cause the major dysfunction and disability of these neuropathies. Therefore, in many cases it is the immune sensory and autonomic neuropathy, which should be seen as the primary manifestation, not the Sjögren's phenomenon. We agree with Mori et al. that since the immune sensory and autonomic neuropathy may occur with little or no evidence of Sjögren's it might be more appropriate to designate these neuropathies as acute, chronic (or relapsing) varieties of immune sensory and autonomic neuropathies ± sicca and then additionally classify them as ataxic, painful, multiple mononeuropathy, trigeminal or other. Finally, the issue of treatment response raised by Mori and colleagues needs further consideration. Because this was a retrospective and open study, it is unclear whether disease improvement, assuming that it occurred, can be attributed to disease remission or to a treatment effect. We have observed such remission with or without treatment. It is evident that prospective controlled, double-blind trials are needed. However, the heterogeneity of clinical expression and the variability in course will make it difficult to conduct such trials. It seems evident that outcome measures will probably need to be different for ataxic than for hyperalgesic varieties.