Abstract
The occurrence of ataxic sensory neuronopathy (ASN) is rare in patients with connective tissue diseases (CTDs). ASN has been described in case reports and case series in patients with CTDs, mostly Sjögren’s syndrome, and most often occurring during middle or old age. ASN in association with systemic lupus erythematosus (SLE) is extremely rare; there has been only one reported case in the literature. In addition, to our knowledge, adolescent onset of symptoms in CTD-associated ASN has not been reported previously. We report the case of a young woman who presented with ASN, characterized by sensory ataxia, with elevated antinuclear antibodies, leukopenia and anemia; she fulfilled the diagnostic criteria for SLE about 7 years after the onset of sensory ataxia. Our case points out that ASN may be the initial presenting feature of SLE. SLE should be included in the differential diagnosis of ASN, especially in patients of young age.
Introduction
Sensory neuronopathy is a disease of the peripheral nervous system, in which the primary site of pathology is the sensory neuron in the dorsal root ganglion (DRG). The clinical presentation of sensory neuronopathy depends on the type of ganglionic neurons preferentially affected: large ones, small ones or both. Ataxic sensory neuronopathy (ASN), which preferentially involves large sensory neurons, is characterized by profound loss of the sensations of vibration and proprioception with relatively well-preserved superficial sensation and muscle strength, and patients typically present with sensory ataxia and pseudoathetoid movements of the hand. The clinical course of the disease was variable, ranging from acute onset to indolent evolution over years.
Patients with systemic lupus erythematosus (SLE) can develop several different types of peripheral neuropathies with a wide variety of clinical manifestations. However, the association of SLE with ASN is extremely rare. Furthermore, neuropathy is usually a late and relatively mild manifestation during the course of the disease. Appearance of neuropathy before other systemic disease manifestations of SLE is uncommon. 1 We report a young woman who presented with ASN, characterized by sensory ataxia, with elevated antinuclear antibodies, leukopenia and anemia; she fulfilled the diagnostic criteria for SLE about 7 years later.
Case description
Laboratory values during the course of disease
*positive in screening and confirmatory LAC testing using the dilute Russell viper venom time clotting assay.
Abbreviations: y/o, year-old; tx, treatment; ANA, antinuclear antibody; NT, not tested; dsDNA, double-stranded DNA; LAC, lupus anticoagulant; aCL, anticardiolipin antibody; Anti-β2GPI, Anti-β2 glycoprotein I antibody; ESR, erythrocyte sedimentation rate; WBC, white blood cell count; Hb, hemoglobin; Plt, platelet; RF, rheumatoid factor; c-ANCA, cytoplasmic-staining antineutrophil cytoplasmic antibody; p-ANCA, perinuclear-staining antineutrophil cytoplasmic antibody; ENA, extractable nuclear antigen; RNP, ribonucleoprotein; Sm, Smith; VDRL, venereal disease research laboratory test; TPHA, treponema pallidum hemagglutination assay; Ig, immunoglobulin.
In April 2010, she was admitted to the department of rheumatology with complaints of progressive painful swelling over the metacarpophalangeal joints, wrists, and knees. Neurological examination showed that her gait was ataxic and wide-based and that she was unable to perform tandem walking. She had severe limb and truncal ataxia, and Romberg’s test was positive. The sensations of vibration and joint position were markedly and symmetrically impaired in all extremities, with relative preservation of sensations of touch and pain. Cerebellar testing also indicated dyssynergia. Deep tendon reflexes were absent in all four limbs. Sensory NCS showed bilateral absence of SNAPs in the ulnar, median, radial, and sural nerves. The results of motor NCS and needle EMG were normal. Bilateral median and tibial nerve somatosensory evoked potentials (SSEPs) showed the absence of cortical response. Brain magnetic resonance imaging (MRI) excluded cerebellum or brainstem involvement. Whole spine MRI (Figure 1) showed abnormally high signal intensity on T2-weighted images involving bilateral posterior columns of the spinal cord at the level of the C3–6 vertebral bodies.
Axial T2-weighted image of the cervical cord at the C4 level showing a high intensity signal in the posterior column (white arrow).
The laboratory data in April 2010 (Table 1) indicated worsening of leukopenia (WBC 2990/µl) and anemia (Hb 10.8 g/dl) as well as the presence of mild thrombocytopenia (platelet 131,000/µl). The autoimmune profiles showed a high ANA titer of 1:1280 (homogeneous), an elevated erythrocyte sedimentation rate (58 mm/h), positive results for anti-dsDNA (108 IU/ml), lupus anticoagulant, and direct Coombs’ test, and decreased C3 (62 mg/dl) and C4 (10 mg/dl) level. Schirmer’s test and salivary scintigraphy as well as the CSF study were normal, as they were in 2006. Systemic work-up for an occult malignancy, including chest radiography, abdominal sonography, and tumor markers indicated no abnormalities.
The patient fulfilled four of the 11 ACR SLE classification criteria (positive ANA, positive anti-dsDNA antibody and lupus anticoagulant, hemolytic anemia and leukopenia, as well as arthritis). She was diagnosed with SLE and ASN. She did not receive intravenous immunoglobulin (IVIg) treatment because of financial constraints. Instead, she underwent pulse therapy with intravenous methylprednisolone (500 mg daily for 3 days), followed by oral administration of methylprednisolone (8 mg/day), hydroxychloroquine (200 mg/day), and aspirin (100 mg/day) for 1 year. Although the serological abnormalities diminished (ESR and anti-dsDNA levels decreased and leukopenia and anemia improved), the neurological symptoms remained static over a follow-up period of 1 year. Sequential sensory NCS results and SSEP were unchanged.
Discussion
Neurologic manifestations of SLE are diverse. The most commonly reported neuropathic complication of SLE is length dependent, symmetric axonal sensory or sensorimotor polyneuropathy. However, ASN in patients with SLE is extremely rare. Only one case has been reported in the literature. Figueroa et al. 2 reported the case of a 34-year-old woman with acute onset of painful and ASN, who was diagnosed with SLE 3 years later. To the best of our knowledge, our case is only the second such reported case to date. In both cases, the occurrence of ASN predated the diagnosis of SLE by years, but in contrast to the acute onset of symptoms in the previously reported case, our case had an insidious onset of ASN before any manifestation of SLE.
The diagnosis of ASN is primarily made from characteristic clinical presentation and electrophysiological findings. Because ASN primarily involves the large DRG neurons causing the degeneration of both their central and peripheral sensory projections, it presents with a non-length-dependent involvement of peripheral nerve axons and should be distinguished from length-dependent sensory axonal neuropathy, which is a well-known complication in patients with SLE. Patients with ASN usually present with distal and proximal kinesthetic sensory loss, while patients with sensory axonal neuropathy present with a distal symmetrical stocking-glove pattern of cutaneous sensory loss. Also, NCS of patients with ASN frequently show normal or relatively preserved motor amplitudes, in conjunction with non-length-dependent abnormalities of SNAP rather than a proximal–distal gradient decrease in SNAP amplitudes, as in sensory axonal neuropathy. Besides, T2-weighted MRI in patients with chronic ASN sometimes shows high signal intensity in the spinal dorsal columns, reflecting the degeneration of central sensory axons. 3 Evidence of central sensory pathway involvement associated with widespread decrease in SNAPs could definitely localize the primary pathologic site to the DRG.
Our patient developed chronic progressive loss of proprioception in a widespread distribution, leading to severe gait ataxia as well as clumsiness and pseudoathetosis in the arms, and generalized areflexia, with minimal involvement of cutaneous sensation, and well-preserved muscle strength. The clinical features were consistent with ASN seen in Sjögren’s syndrome (SS). In addition, electrophysiological findings revealed preservation of motor nerves, in conjunction with widespread abnormalities of SNAP, and whole spine MRI showed hyperintensity in the posterior column of the cervical spine. These findings confirm that our patient was indeed a victim of ASN.
Acquired sensory neuronopathy is often associated with neoplastic diseases and dysimmune diseases. The pathogenesis is reported to be lymphocytic infiltration of DRG and destruction of the large T-shaped sensory neurons. Other reported causes include cisplatin toxicity, pyridoxine overdose, penicillin toxicity, and viral infections. In about 50% of the patients, no definite cause could be identified after extensive studies and prolonged follow-up.4,5 Dysimmune disease-associated ASN is most often found in patients with SS.6–9 Most patients were middle or old aged at the onset of the disease. To the best of our knowledge our patient, who experienced the onset of symptoms at 15 years of age, was the youngest patient ever reported to be diagnosed with dysimmune disease-associated ASN.
Paraneoplastic sensory neuropathy is usually subacute and rapidly progressive, and may precede cancer diagnosis by between 0.5–62 months. 10 Besides, it is characterized by elevated cell numbers and protein levels in the CSF. 6 Since our patient had an indolent onset, had symptoms for 7 years without developing evidence of a neoplasm, and had normal cell count and protein levels in the CSF, the ASN was unlikely to be associated with malignancy. ASN, when present in the context of CTDs, has been often associated with SS. However, our patient had no sicca symptoms and did not fulfill the diagnostic criteria of SS throughout the 5-year follow-up period.
In our patient, SLE was presumed to be the cause of ASN on the basis of the results of immunological investigations and the absence of neoplasms or other causes of ASN. Although the diagnosis of SLE was validated 7 years after the onset of ASN, her initial work-up for ASN showed a high titer of ANA (1:640, homogeneous), leukopenia (WBC 3380/μl), and anemia (Hb 11.3 g/dl), which fulfilled two of the ACR SLE classification criteria. Furthermore, follow-up 4 years later showed that the ANA titer increased, leukopenia and anemia worsened, mild thrombocytopenia occurred and arthritis emerged in concert with the progression of ASN. These findings suggest a possible association of ASN with SLE. It is well known that neuropsychiatric manifestation can be the sole initial feature of SLE and precede other systemic disease manifestations by months or several years. In light of the findings of our case and another case reported by Figueroa et al., 2 we suggest ASN may be the presenting manifestation of SLE.
Despite preservation of motor strength, profound loss of proprioceptive sensations may result in severe disability, and patients may become wheelchair-dependent. An effective treatment for ASN has not been established. The literature on therapeutic interventions for CTD-associated ASN consists mostly of case reports or small series reports. The response to corticosteroids and immunosuppressive agents has been disappointing. In one small study, four of five patients with long-standing ASN secondary to SS showed improvement after three courses of IVIg. 9 There are two case reports showing the efficacy of tumor necrosis factor-α inhibitors.2,8 Randomized controlled therapy trials are needed to determine the most effective treatment for CTD-associated sensory neuropathy. However, since CTD-associated ASN occurs rarely and the course of the disease varies from case to case, with some cases stabilizing spontaneously, such studies may be difficult to perform.
Our case highlights that ASN may be, despite its rarity, the initial presenting feature of SLE. In addition, the occurrence of ASN may predate the diagnosis of SLE by years. Evidence of SLE should be investigated in cases of ASN, especially in patients of young age. In addition to clinical and electrophysiological assessment, spinal cord MRI is useful in supporting the diagnosis of chronic ASN.
Footnotes
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest
We certify that no party having a direct interest in the results of the research supporting this article has or will confer a benefit on us or on any organization with which we are associated.