Patterns of peripheral neuropathy in Sjogren's syndrome in a tertiary care hospital from South India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.250714
Source of Support: None, Conflict of Interest: None
Keywords: Peripheral neuropathy, Schirmer's test, seropositivity, Sjogren's syndrome
Sjogren's syndrome (SS) mainly affects exocrine glands and is characterized by dry eyes and dry mouth. Among the extraglandular manifestations, involvement of the peripheral nervous system (PNS) is the most common. A wide spectrum of neurological manifestations that include both the central and the peripheral nervous system has been reported. Prevalence of neurological manifestations in SS varies widely from 10 to 60%, with pure or predominantly sensory polyneuropathy (e.g., sensory ataxic or small fibre sensory painful neuropathy) as the most common, to the less common MNM. Sensory symptoms without substantial motor involvement are observed predominantly in sensory ataxic, painful sensory, trigeminal, and autonomic neuropathies. On the contrary, motor impairment is more apparent in multiple mononeuropathy, multiple cranial neuropathy, and radiculoneuropathy. SS-associated sensory neuropathy is often the presenting feature of SS. The clinicopathological features of neuropathies associated with SS and the therapeutic response to immunotherapy are highly variable. Hence, the classification of neuropathy is important from a therapeutic viewpoint.
In this study, we analyzed the clinicopathological and electrophysiological features of SS-associated neuropathy and determined the range of clinical presentations.
Case records of all outpatient and inpatient services from Neurology, Rheumatology, and Pathology specialities between 2010 and 2016 were reviewed and patients sufferiing from SS noted. Patients fulfilling the American College of Rheumatology [ACR]-European League against Rheumatism [EULAR] classification criteria for SS were identified. Based on this criteria, the patients were either anti-SSA/Ro antibody positive or had focal lymphocytic sialadenitis with a focus score of ≥1 foci/4 mm2 (which scored 3 each); an abnormal ocular staining score of ≥5, Schirmer's test result of more than 5 mm/5 min, and an unstimulated salivary flow rate of ≥0.1 ml/min, each scoring 1. Individuals with signs and/or symptoms suggestive of SS who have a total score of ≥4 for the above items met the criteria for primary SS.
The case records were studied and the data pertaining to the demographic and clinical profile of SS patients with peripheral neuropathy were obtained. Clinical details were recorded on a spreadsheet. Data included detailed description of their complaints, onset of symptom, whether the manifestation was a neuropathy or an exocrinopathy, the duration of complaints, other system involvement, and the treatment received. Neurological complaints of motor and sensory symptom onset, progression and distribution of symptoms, and cranial nerve manifestations were recorded.
General physical findings included a search for dry eyes /dry mouth, the presence of a thyroid swelling, thickened nerves, and evidence of arthritis and skin lesions. Data on the evidence of autonomic disturbances including the presence of urinary disturbances (frequency, urgency or retention of urine), constipation or nocturnal diarrhoea, sweating abnormalities (anhydrosis or hyperhydrosis), presence of pupillary abnormalities (Adie's pupil, elliptical pupils, or anisocoria), orthostatic hypotension (fall of systolic blood pressure (SBP) >30 mmHg from supine position), or orthostatic tachycardia was noted. Cranial nerve abnormalities, Medical Research Council power scale, and sensory maps were collected. Schirmer's test positivity in patients was documented. Data on nerve conduction study were obtained. Autonomic testing was done among patients with dysautonomia. A diagnosis of neuronopathy/ganglionopathy was made based on significant kinaesthetic manifestations, sensory ataxia without motor involvement, and preserved motor conduction with abnormal sensory conduction abnormalities. Motor nerve conduction was studied by assessing the upper limb and lower limb motor conduction including the assessment of distal latency, compound motor action potential, F wave latency, and conduction velocities. Sensory nerves were tested for conduction velocity and amplitude in the median, ulnar, and sural nerves. All patients underwent Schirmer's test; and, less than 5 mm wetting of the filter paper was taken to be significant enough to suggest a low basal tear production. The cumulative analysis of findings on history, examination, and electrophysiology aided in determining the type of neuropathy. The histology reports of the harvested biopsy were collected in patients who underwent either a lip or nerve biopsy based on the discretion of the treating neurologist.
Serological tests included biochemistry, hematology, serum B12 level, serum folate level, T3, T4, thyroid stimulating hormone level, and the vasculitic profile (antinuclear antibody (ANA), anti-double stranded deoxyribose nucleic acid (dsDNA), immunoglobulin M rheumatoid factor (IgM RF), anti Ro/SS-A and anti La/SS-B antibodies, and Scl antibodies). Those patients who were seropositive for either Ro/SS-A or La/SS-B antibodies or for Schirmer's test and those with a high clinical index of SS underwent a lip biopsy. Histological evidence of the diagnosis was based on chronic lymphocytic sialadenitis on lip biopsy.
In total, 21 patients were identified to have a neuropathy due to SS. Majority (20) had primary SS and one patient had secondary SS associated with scleroderma. Fourteen patients were females and 7 were males (the female: male ratio = 2:1). The mean age of onset was 40 years (range: 16–70 years). The onset of clinical manifestation was acute in 8 and insidious in 13 patients. The course of illness was gradually progressive in 16, with remission and relapses in 2, was static in 2, and with a step-wise progression in 1 patient. Out of 21 patients with SS, not all had neuropathy as the initial presenting symptom. Fourteen patients (66.7%) presented with neuropathy that on work up turned out to be SS, while 4 patients had an exocrinopathy in the form of sicca syndrome that evolved into a neuropathy later in the course. Two patients had constitutional symptoms of myalgias, while one patient had skin manifestations in the form of scleroderma as the initial symptom that progressed and evolved into the neuropathy of SS.
The phenotypic pattern of neuropathy [Table 1] was mononeuritis multiplex in 7 (30%), ganglionopathy with sensory ataxia in 4 (20%), trigeminal neuropathy in 2 (10%), length-dependant sensorimotor neuropathy in 2 (10%), and of the CIDP pattern in 2 (10%) patients. Autonomic neuropathy (postural hypotension and focal hyperhidrosis) plus peripheral neuropathy was seen in 2 (10%) patients, cranial neuropathy in 1 (5%) patient who had sensorineural hearing loss with optic neuropathy, and painful small fibre neuropathy in 1 (5%) patient.
Sixteen patients tested positive with either Ro/SS-A antibodies while 2 were La/SS-B antibody positive [Figure 1]. Of them, 3 were also positive for anti-ds DNA, Scl-70, and IgM rheumatoid factor each. Three seronegative patients were diagnosed on minor salivary gland biopsy and a positive Schirmer's test.
Out of 1486 nerve biopsies performed during the study period, features suggestive of vasculitis were seen in 145 patients (data collected from the Pathology department). On collating the other laboratory features, 10 were finally diagnosed as having SS. Nerve biopsy showed probable vasculitis (without fibrinoid necrosis) in 5 patients [Figure 2] and a demyelinating picture and axonopathy in 2 patients each.
In 12 patients, the lip biopsy was done and 11 had findings suggestive of chronic lymphocytic sialadenitis, fulfilling the criteria required for the diagnosis of SS, while 1 had normal minor salivary glands.
In all 21 patients, the treatment included intravenous methylprednisolone (1g/day infusion for 5 days) followed by oral steroids (prednisolone 0.5–1mg/kg wt/day). Simultaneously, a steroid sparing agent was started and oral steroid was tapered off over 3 months as the other immunosuppressants started acting. Maintenance immunosuppressants included methotrexate, azathioprine, or mycophonelate mofetil. Two patients with ganglionopathy received intravenous immunoglobulin (2g/kg wt over 5 days) due to unresponsiveness to steroids. The improvement seen was more specific in them. The follow-up period was of approximately 2 years.
SS is one of the most common exocrinopathies with characteristic dryness of eyes and mouth. SS was reported to be uncommon in India., Absence of Sicca features does not exclude SS as sicca symptoms occur only in 38% patients preceding the onset of neurologic features, while in 47% of patients, neurologic features antedate the sicca symptoms, often by up to 12 years. Hence, it becomes pertinent for the neurologist to be aware of the neuropathic phenotypes of SS.
SS-associated neuropathy has a broad clinical spectrum including ganglionopathy or sensory neuronopathy, axonal sensory and sensorimotor polyneuropathy, multiple mononeuropathy, autonomic neuropathy, small-fiber neuropathies, and cranial neuropathies. The most characteristic neuropathy is the sensory ataxic variant with posterior column sensory dysfunction.
The present study highlights the clinical presentation of primary SS patients with neuropathy. Data published in previous studies from India described the peripheral nervous system (PNS) and central nervous manifestations in SS.,, A large study involving 332 patients from India reported the predominant neuropathic pattern as mononeuritis multiplex. This is the only study that analyzed patients with peripheral manifestations of SS.
The onset usually varies with the pattern of neuropathy; an acute or a subacute onset is observed more frequently in multiple mononeuropathy and multiple cranial neuropathies, whereas the disease progression is usually chronic in predominant sensory neuropathies.
As in other connective tissue disorders, multiple mononeuropathies are well described in SS although they are relatively uncommon. Their reported incidence varies between 6–12%., Many studies reported a higher frequency of symmetric sensorimotor polyneuropathy and symmetric sensory neuropathy., In contrast to the previous studies, multiple mononeuropathy was the most common pattern in the present study. This could be explained by an evaluation bias for neuropathy. During evaluation of a patient with chronic sensory motor neuropathy, only a screening test for ANA is done, whereas a full serological workup is required for MNM. Patients with Sjogern's syndrome with vasculitic neuropathies are more likely to have full blown extraglandular manifestations.,, Vasculitis is the underlying mechanism of axonal multiple mononeuropathy and cranial neuropathies.
Ganglionopathy with ganglionitis is the pathological hallmark of SS. The current study had 4 patients with a ganglionopathy. Patients have severe ataxia, areflexia without any weakness and suffer from severe functional disability., In general, SS neuronopathies are minimally responsive or intractable to high doses of corticosteroids and even potent immunosuppressive therapy. Although smaller case-series and anecdotal reports have described a dramatic success with intravenous immunoglobulin (IVIG),, some have shown only a minimal response. A similar observation was seen in the present cohort.
Painful small fiber neuropathy may be the most common neuropathy in SS with a higher prevalence seen in specialized centres., Data from non-specialty cohorts of SS patients reveal a prevalence rate between 5% and 10%. The present study reports only 1 patient with this disorder. The symptoms and findings consistent with small-fiber dysfunction that disproportionately affect the proximal extremities, trunk, or face, frequently in a non-length dependant pattern, and which do not confirm to the dermatomal/peripheral nerve distribution should raise the possibility of SS. Autonomic symptoms may be encountered in up to 50% of SS patients. The clinical manifestations of autonomic neuropathy vary depending on the organs targeted and sympathetic versus parasympathetic control. Some, but not all the studies have demonstrated an objective parasympathetic dysfunction. Some authors have reported that the symptoms or signs of autonomic dysfunction were commonly seen in patients with sensory neuronopathy (57% had Adie's pupils, 40% had orthostatic hypotension, and 70% had abnormal sweating). Existence of autonomic neuropathy in patients with small-fiber symptoms may suggest a common mechanism of an underlying ganglionopathy. Symptomatic dysautonomia was seen in 3 patients with different patterns of neuropathy – focal hyperhydrosis plus painful small fiber neuropathy [Figure 3], postural hypotension plus MNM with vasculitis, and anisocoria with postural hypotension plus CIDP. These patients showed a good response to steroid therapy.
Cranial mononeuropathy has been reported in SS. The most common cranial neuropathy is trigeminal neuropathy, which is usually indolently progressive, can be bilateral, and generally requires symptomatic treatment. When the trigeminal neuropathies occur concomitantly with sensory neuronopathy or non-length-dependent small-fiber neuropathy, the unifying mechanism may be a ganglionopathy. Sensory neural deafness is also frequently seen in SS. We had only 1 patient with a sensorineural deafness and optic neuropathy. Motor dysfunction of cranial nerves is less common than sensory trigeminal neuropathies. Facial nerve is the most frequently affected motor cranial nerve, while other motor cranial mononeuropathies or polyneuropathies have also been reported.,,
Most studies report that demyelinating neuropathies may be the most uncommon PNS manifestations, as seen in the present study.,, The exception is that of the study by Goranson et al., that reported that demyelinating neuropathies were the most frequent peripheral nervous system manifestations encountered in 62 consecutively evaluated Sjogren's patients. More unusual single cases or large series of chronic idiopathic demyelinating polyneuropathy (CIDP) have been reported in SS patients.,
Myopathy is rare in SS. We had only 1 patient who presented with episodic hypokalemic weakness with renal tubular acidosis at onset, and later developed persistent myopathy (due to vitamin deficiency) and neuropathy during the follow-up period. Inflammatory myopathies are uncommon peripheral manifestations of SS. Myopathy due to vitamin D deficiency needs exclusion. In general, the diagnostic and treatment approach is similar to that utilized in inflammatory myopathies not associated with SS.
The pathophysiological basis of SS-associated neuropathy is still unclear. Dorsal root ganglionitis and peripheral nerve vasculitis have been observed on histological examination of biopsy and autopsy samples. A few studies have explored the fundamental role of humoral autoimmune mechanisms.
Nerve biopsy is not mandatory for establishing the diagnosis of SS. Vasculitis, demyelination, and axonopathy are all seen. Vasculitis is commonly seen in the MNM pattern whereas axonal involvement is seen in the pure or predominant sensory neuropathy. The nerve biopsy was done at the discretion of the treating neurologist and did not add to the definite diagnosis of SS. Analysis of the nerve biopsy specimens has shown that vasculitis was the most common pattern followed by demyelinating and axonal pattern. Although not unequivocally established for SS, skin biopsies have equivalent diagnostic utility for the detection of small-fiber neuropathies.,
Unlike the previous studies, our study had a high seropositivity [18 (85%) patients]. Seropositivity of Ro/Ss-A was seen in 76.2% and for La/SS-B antibodies was seen in 57% patients. Other studies have shown a seropositivity of anti-Ro/SSA in 33–74% of patients with SS, of anti-La/SS-B in 23–52% patients, and of antinuclear antibodies in 59–85% patients. The fallacy that a diagnosis is solely dependent on these autoantibodies is to be countered by the neurologists as they encounter neuro-Sjogren's without Sicca more often. Three patients who were seronegative met the criteria for Sjogren's syndrome with a positive lip biopsy and a positive Schirmer's test. The index of suspicion was high as 2 of them presented with ganglionopathy while 1 had a mononeuropathy multiplex pattern with sensorineural hearing loss at presentation.
In the present study, a very high seropositivity could be explained based on a selection bias and the clinical practice methods. The methodology we adopted included preliminary evaluation of all the causative factors for neuropathy including the vasculitic profile. Patients who were found to be seropositive were included in the study and were diagnosed as SS if they met the other criteria.
Minor salivary gland biopsy of the lip may be diagnostic in 37–75% of patients with SS-associated neuropathy., The lip biopsy was positive in 11 patients (52.4%), which is comparable to the published literature.
A significant subset of patients may present with mild/no sicca symptoms with neurological manifestations. It is essential to identify these patients to diagnose SS. Evaluation for sicca symptoms, along with search of noninvasive, functional tests (i.e., Schirmer's evaluation <5 mm in 5 min; salivary flow) to establish glandular dysfunction is of utmost importance. In one series, Schirmer's test was positive in 56–89% of the patients with SS-associated neuropathies. Our study showed a similar result with Schirmer's positivity in 61.9% patients. Three seronegative patients in the present series had a positive Schirmer's test and the diagnosis was confirmed by lip biopsy.
The limitations of the study include the retrospective nature of the study; and, that autonomic function tests and lip biopsy were not done in all patients. The strength of the study lies in it being a single-centre study.
Our study showed that neuropathy is frequently the initial presentation of SS. The spectrum of neuropathies is varied and the most common phenotypic pattern is MNM followed by ganglionopathy/non-length dependant neuropathy, which is unique for SS. The pattern of neuropathy helps in arriving at a diagnosis of the syndrome. Serology is a very useful initial laboratory test and seronegativity should not exclude SS, if the clinical suspicion is very high. Confirmation of the Sicca syndrome by meticulous clinical evaluation and noninvasive functional tests followed by lip biopsy is essential, especially in seronegative patients.
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There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3]