Can restless legs be a sign of something else? a case of spondyloarthritis presenting with restless legs syndrome

doi:10.21203/rs.3.rs-2129070/v1

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Can restless legs be a sign of something else? a case of spondyloarthritis presenting with restless legs syndrome

https://doi.org/10.21203/rs.3.rs-2129070/v1

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Restless legs syndrome (RLS), is a chronic movement disorder, characterized by an urge or need to move the limbs, usually associated with uncomfortable sensations in the legs and sleep disorders. Two clinical forms of RLS are described in general: primary and secondary. Although primary RLS has a familial component, the underlying mechanism is still not fully understood but seems to be related to abnormalities in the dopaminergic pathways of the central nervous system. The secondary form of the syndrome is associated with iron deficiency, renal failure, pregnancy, diabetes mellitus, peripheral neuropathy, and many rheumatologic disorders such as rheumatoid arthritis (RA) and Sjögren’s syndrome. In a few clinical trials, an increased frequency of RLS has been reported in patients with spondyloarthritis. In this report, it is presented a case of coexistence spondyloarthritis and RLS showing satisfactory improvement with conservative treatment additionally adding naproxen. Anemia of chronic disease occurring in rheumatic diseases and associated iron deficiency may contribute to the development of RLS.

Restless legs syndrome

Spondyloarthritis

Awareness

Restless legs syndrome (RLS), is a chronic movement disorder, characterized by an urge or need to move the limbs, usually associated with uncomfortable sensations in the legs and sleep disorders. These symptoms are worse at rest, are relieved by movement, and mainly occur at night. Epidemiological studies indicate that the symptoms of RLS are present in about 5–15% of the general population. Two clinical forms of RLS are described in general: primary and secondary. Although primary RLS has a familial component, the underlying mechanism is still not fully understood but seems to be related to abnormalities in the dopaminergic pathways of the central nervous system. The secondary form of the syndrome is associated with iron deficiency, renal failure, pregnancy, diabetes mellitus, peripheral neuropathy, and many rheumatologic disorders such as rheumatoid arthritis (RA), Sjögren’s syndrome, scleroderma, and systemic lupus erythematosus (SLE) (1).

Spondyloarthropathies (SpA) are a group of diseases with similar clinical, laboratory, and radiological features and characterized by inflammation of vertebrae, peripheral joints, and periarticular tissues. SpA group is evaluated in two subgroups as axial (involvement in the sacroiliac joints, spine, or both) and peripheral (peripheral arthritis, enthesitis and dactylitis) according to clinical characteristics. Clinical findings are heterogeneous and inflammatory low back pain, oligoarthritis especially involving the large joints of the lower extremities, enthesitis, dactylitis, and various extra-articular findings such as psoriasis, anterior uveitis, and inflammatory bowel disease can be observed (2, 3). In a few clinical trials, an increased frequency of restless legs syndrome (RLS) has been reported in patients with SpA (4, 5, 6, 7). In this report, it was intended to notice a case of coexistence spondyloarthritis and RLS showing satisfactory improvement with conservative treatment additionally adding non-steroidal anti-inflammatory drug (NSAID).

A 44-year-old male submitted to the Physical Medicine and Rehabilitation department with pain in his bilateral legs for 10 years. Her pain got aggravated with rest at night and relieved by movement. He described an uncomfortable itching and creepy-crawling sensation on his legs, aching and tension in calf muscles, and a desire to move the legs in the evenings, and this has impacted negatively on his sleep and quality of life. He also had lower back pain when he got up in the morning and heel pain when he put his feet on the ground. He also had morning stiffness for about 30 minutes. He had hypertension and RLS on history. The diagnosis of RLS was made according to the International Restless Legs Syndrome Study Group (Table 1). He had been using pramipexole and quetiapine for RLS and sleep disorder for 5 years. He noted that his complaints did not improve despite the medication. On physical examination, the range of motion (ROM) values of all joints were within normal limits; muscle strength and neurological examination were also normal. He had no painful, tender, red or swollen joints. FABER (flexion-abduction-external rotation of the hip) and FADIR (flexion-adduction-internal rotation of the hip) tests were slightly positive. His measures of modified Schober test, chest expansion, tragus-wall distance, occiput-wall distance, and hand-ground distance were normal. His significant laboratory findings showed elevated C reactive protein (CRP) of 1,91 mg/L (range 0–0,5), elevated erythrocyte sedimentation rate (ESR) of 27 mm/hour (range 0–20), decreased hemoglobin of 12.8 g/dL (range 14–16), decreased iron of 31 ug/dL (range 70–180) and decreased 25(OH)D³ of 14,2 mg/dL. Laboratory tests releaved glucose, hemoglobin, thyroid, kidney and liver function tests, vitamin B12 and folate were within normal limits. The infective panels such as Epstein-Barr virus (EBV), toxoplasma, rubella, cytomegalovirus, herpes simplex virus (TORCH), Brucella and Salmonella tube agglutination, hepatitis panel, HIV/AIDS and VDRL tests were all negative. Tumor markers also were negative. Anti-nuclear antibody (ANA), rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP), anti-SSA (Ro), anti-SSB (La), anti-Scl70, anti-double-stranded DNA (anti-ds-DNA) and anti-neutrophilic cytoplasmic antibody (ANCA) were negative and complement dosage also was normal. HLA-B27 was negative. Nerve conduction tests performed by standard electromyography (EMG) were normal but the prolongation of latency and the shorter duration in cutaneous silent period, which is a non- invasive technique providing insight into the function of the small-diameter nerve fibers, in his bilateral lower extremities. In lumbosacral radiograph, there were enthesopathic changes on the bilateral superior posterior iliac spine and bilateral sacroiliitis (Fig. 1). Also, there were enthesopathic changes on the localization of the insertion of achilles tendon in calcaneus posterior bilaterally in lateral radiograph of bilateral foot and ankle (Fig. 2). Magnetic resonance imaging of sacroiliac joints showed the edema and narrowing of the bilateral sacroiliac joints (Fig. 3). The patient was diagnosed as axial SpA (axSpA) according to the ASAS criteria (8). The patients received oral Naproxen, iron, and Vitamin D3. The patient completely recovered and obtained normal sleep after one month. There was no complaint in the patient at 6 months of follow-up.

Table 1

The diagnostic criteria suggested by the International restless legs syndrome (RLS) Study Group
The four essential criteria are as follows: 1) the urge to move the legs are usually accompanied by or caused by uncomfortable sensations deep in the legs, 2) the above symptoms begin or worsen when resting or inactivity such as lying or sitting, 3) the symptoms can be partially or totally relieved by movement such as walking or stretching, 4) the symptoms are worse in the evening or at night rather than during the day or they only occur in the evenings or at night.

In previous studies, it has been shown that the frequency of RLS is increased in patients with SpA (4, 5, 6, 7). It has even been suggested that RLS is much higher in patients with SpA than in the general population (7). In this report, a patient with axSpA presenting RLS being relieved via conservative treatment additionally adding NSAID is mentioned.

RLS is a chronic sensorimotor disorder that causes leg movements to relieve discomfort and unpleasant sensations in the legs. Also, RLS may cause sleep disturbance and impaired quality of life. RLS is common in rheumatologic disorders such as RA, Sjögren’s syndrome, scleroderma, SLE and fibromyalgia (FM) as well as SpA (1, 4, 5, 6, 9). In a review conducted by Hening et al., 31% of patients with FM, 25% with RA, 24% with Sjögren syndrome, and 22% with scleroderma had RLS (9). The pathophysiology of RLS is focused on the dopaminergic system, reduced central nervous system iron levels, and genetic linkages. Therefore, dopaminergic and iron replacement therapy relieve the most symptoms of RLS. A possible association between RLS symptoms and iron deficiency has long been recognized. Low serum iron levels were presented in 25% of patients with severe RLS. The severity of the symptoms was found to be correlated with serum ferritin levels (1, 10). It has been proposed that dopaminergic dysfunction can be mediated by low brain iron levels since iron is needed as a cofactor for tyrosine hydroxylase, which is the rate-limiting enzyme in the synthesis of dopamine, and because the D2 dopaminergic receptor is a protein containing iron (3, 11). The serum iron level decreased in this case and his complaints improved after replacement therapy.

In a review conducted by Weinstock et al., it has been demonstrated that 95% of RLS-related conditions are associated with systemic inflammation and/or immune alterations, 47% peripheral iron deficiency, 37% peripheral neuropathy, and 32% bacterial overgrowth in the small intestine. This suggests that RLS is associated with altered immune mechanisms. Also, altered host defenses due to genetic variants may predispose individuals to inflammation or an altered immunological response leading to RLS. Chronic inflammation may lead to iron deficiency because it causes iron to be retained in macrophages and reduced iron supply to the bone marrow subsequently, iron deficiency in the central nervous system may result in RLS. Moreover, an immune reaction to gastrointestinal bacteria or other antigens may lead to RLS through a direct immunological attack on the central or peripheral nervous system. Bacterial overgrowth in the small intestine may also cause systemic iron deficiency anemia due to decreased iron malabsorption from the duodenum and enhanced uptake of the iron by the bacterium. Beside, peptide hepcidin, the primary iron-regulating hormone, has been found to be associated with RLS, and upregulated hepcidin by inflammation has been shown to be responsible for increased iron stores in the liver. Lipopolysaccharides (LPS), which are breakdown products of gram-negative bacteria, interleukin-6, and hypoxia can increase hepcidin levels. Hepcidin binds to ferroportin on human choroid plexus cells and decreases the availability of iron for the central nervous system, resulting in RLS (12). Immune system abnormality has been suggested as one of the reasons why RLS is more common in rheumatic diseases (4). Demirci et al. also proposed that increased frequency of RLS in AS patients may also be related to an abnormality of the immune system (5).

Another reason for the development of RLS is anemia due to chronic disease. Chronic inflammation may play a role in the pathogenesis of RLS by causing anemia of chronic disease with the effect of hepcidin preventing iron absorption from the intestine or the release of iron from the reticuloendothelial system (12). Demirci et al. found that there was a negative correlation between the RLS severity score and hemoglobin (5). In this case, anemia of chronic disease occurring in rheumatic diseases and associated iron deficiency may contribute to the development of RLS.

Another reason for the pathogenesis of RLS is peripheral neuropathy (12). As in other rheumatic diseases, peripheral nervous system involvement due to immune dysfunction has been reported in SpA (4). RLS is a common manifestation in cases of acquired polyneuropathy involving particularly small sensory fibers. Dopaminergic cells have been found to have a potentially nociceptive functional capacity. The structures underlying RLS associated with polyneuropathy may presumably include spinal generators that are a crossroads for signals traveling either in peripheral nerves or in pyramidal and extrapyramidal pathways. The pathomechanisms of RLS may be activated not only by impaired dopaminergic control but also by peripherally disrupted sensory modulation. It has been proposed as a peripheral mechanism that painful stimuli are transmitted to the spinal cord by A-delta fibers and create a strong postsynaptic inhibition on motor neurons via spinal interneurons (4, 13). Although the findings of standard EMG were normal in this case, the prolongation of latency and the shorter duration in the cutaneous silent period in his bilateral lower extremities.

Moreover, vitamin D3 deficiency has been reported to be associated with RLS, and vitamin D3 replacement therapy has been effective in reducing the symptoms of RLS patients. One of the important functions of this vitamin is the regulation of nervous system development and function. It has been shown that vitamin D3 can protect the mesencephalic dopaminergic neurons against toxins that cause a decrease in glutathione content and increases the levels of dopamine or its metabolites in the nigrostriatal dopaminergic pathway (14). In this case, the serum level of vitamin D3 was low and his complaints improved after replacement therapy.

Tekatas et al. determined the prevalence of RLS in patients with AS and also examined factors potentially related to RLS. They found that the frequency of RLS was significantly higher in AS patients (30.8%) than in healthy subjects (13.2%). They also found that peripheral arthritis, uveitis, anemia, smoking and polyneuropathy were significantly higher in AS patients with RLS (4). Demirci et al. assessed the frequency of RLS and the connections between RLS and quality of sleep and life in patients with AS. They found that the frequency of RLS and mean RLS severity score was significantly higher in AS patients (36.4%) than in controls (14%). They also found that RLS severity was positively correlated with the scores of disease activity, functional status, sleep quality, and quality of life. They proposed that clinicians should be aware of RLS for early diagnosis and treatment in AS patients, as RLS may adversely affect sleep and quality of life in AS patients (5). Yüksel et al. explored the prevalence of RLS and sleep quality and defined the link between RLS and measures of disease activity and physical function in patients with AS. They found that the prevalence of RLS was 55% (11 of 20 patients) in patients with AS and 5% in healthy control. They also found that the scores of disease activity (Bath AS Disease Activity Index) and physical function (Bath Ankylosing Spondylitis Functional Index) were significantly lower in the RLS group compared to the non-RLS group. They suggested that it is significant to define the presence of RLS and poor sleep quality in patients with AS (6). Zontul et al. evaluated the link of quality of sleep with disease parameters and other possible reasons (such as depression, anxiety and RLS) of sleep disorder in patients with AS. They found that the frequency of RLS was %36.1 (44 of 122 patients) in patientes with AS. They observed that patients with poor sleep quality had a higher rate of RLS. They proposed that RLS is a common situation in patients with AS. They also suggested that RLS was much higher than the general population (7). Depending on the characteristic feature of inflammatory low back pain in patients with SpA, sleep disturbances may occur due to axial pain and stiffness in the second half of the night. In addition, patients may have complaints of poor sleep quality even if the disease activity is low (7).

A cross-sectional study, which was investigated the prevalence of insomnia and RLS outpatients with rheumatic disease, was demonstrated that half of the patients with RLS developed RLS after the diagnosis of rheumatic disease, the RLS, and rheumatic disease had developed at almost the same time in less of the patients and the RLS developed before the diagnosis of rheumatic disease in a small proportion of the patients. In this study, it was proposed that it is necessary to determine whether RLS develops secondary to rheumatic disease (15). Therefore, additional investigations based on rheumatic disease should be performed, especially in patients with RLS who are unresponsive to treatment.

Clinicians should be aware of the relationship between rheumatological disorders and RLS. The secondary causes must be carefully investigated in unresponsive patients to treatment.

Informed Consent

Informed consent was taken from the patient.

Conflict of Interests

The author declares that there is no conflict of interest regarding the publication of this paper.

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Can restless legs be a sign of something else? a case of spondyloarthritis presenting with restless legs syndrome

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