FormalPara Key summary points

This report presents the first case of transverse myelitis following familial Mediterranean fever (FMF).

FMF could result in demyelinating disorders.

FMF-related demyelinating complications may be responsive to colchicine.

Rituximab could be used in colchicine-resistant FMF.

Rituximab is a potential therapeutic option in the co-occurrence of FMF and demyelinating conditions.

Introduction

Familial Mediterranean fever (FMF) is an autoinflammatory disorder characterized mainly by recurrent self-limited episodes of fever and polyserositis [1]. The mutation in the MEFV gene encoding PYRIN is responsible for FMF inflammatory symptoms through a PYRIN-mediated abnormal inflammasome activation pattern [1]. Although not common, previous reports demonstrated an increased rate of demyelinating conditions in patients with FMF [2,3,4,5,6]. These reports showed the co-occurrence of FMF with multiple sclerosis (MS) [3, 6, 7] and other unclassified demyelinating disorders [2, 3]. While due to the rarity of this co-occurrence, concluding a causative association could not be reached [7], existence of common pathologic pathways and the possibility of developing severe neurologic disability following FMF attacks necessitate further investigations of this condition [5, 8].

Here, in this study, we present the first report to our knowledge of recurrent isolated transverse myelitis following FMF attacks. We show the effectiveness of colchicine therapy in mitigating FMF-related transverse myelitis. We demonstrate the potential therapeutic effect of rituximab in FMF-associated demyelinating conditions.

Case Presentation

A 38-year-old woman was admitted to our hospital with a new episode of fever syndrome accompanied by subacute progressive weakness in the lower extremities. She had a history of recurrent episodes of unexplained fever, dyspnea, and cough lasting for 1–3 days in 2009 (first episode, Fig. 1). At the first episode, extensive paraclinical evaluations, including complete blood count (CBC), blood and urine culture, viral markers, vasculitis panel, ultrasonography of abdomen and pelvis, and chest, abdominal, and pelvic computed tomography (CT), determined no pathologic findings except for elevated levels of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) and unexplained polyserositis with pleural and peritoneal effusions. Pleural and peritoneal fluid analyses were also performed, excluding the possible infectious or malignancy sources for her symptoms. Based on Tel Hashomer criteria [1], diagnosis of FMF was suspected; therefore, treatment with oral colchicine (1.5 mg/day) was initiated, which resulted in a remarkable improvement of her symptoms. Therefore, the diagnosis of FMF was confirmed based on the Tel Hashomer criteria (recurrent episodes of fever and polyserositis + favorable response to colchicine) [1]. As the diagnosis of FMF is based on clinical criteria, the mutation in MEFV gene was not evaluated [1]. Unfortunately, despite our strong recommendation to continue colchicine therapy, the patient was non-compliant and decided to discontinue the treatment 2 years after the resolution of her symptoms.

Fig. 1
figure 1

Schematic timeline of the presented case

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Five years after the first episode, in her second episode of symptoms, she was admitted to our hospital because of a new episode of fever and cough accompanied by rapidly progressive paraparesis. Her expanded disability status scale (EDSS) score was three. Comprehensive evaluations could exclude an infectious cause of new relapse. Magnetic resonance imaging (MRI) of the spinal cord showed multiple high T2 and low T1 cervical cord lesions without enhancement in T1 post-gadolinium image. Thoracic spinal cord MRI demonstrated multiple high T2 and low T1 cord lesions in which one lesion had enhancement in T1 post-contrast image. Brain MRI was unremarkable. Signs of optic neuritis or other cardinal symptoms of neuromyelitis optica spectrum disorder (NMOSD) were not present. Serologic investigations, including vasculitis panel, cell-based assays for aquaporin-4 antibody (AQP4-Ab) and anti-myelin oligodendrocyte glycoprotein (MOG) antibody, and tests for biotin deficiency and neurosarcoidosis, were performed and reported normal for the patient. Biochemical and cytologic analyses of cerebrospinal fluid (CSF), including oligoclonal bands (OCBs) and AQP4-Ab, were also normal. We started intravenous methylprednisolone pulse therapy for 5 days (1000 mg/day). Since the patient was non-responsive to the treatment with methylprednisolone, we started a new treatment with oral colchicine due to clinical manifestations of a new FMF relapse. Her FMF and neurologic symptoms were resolved using colchicine treatment. As there was no definite evidence of FMF-associated myelitis, azathioprine was added to the treatment regimen. The patient was non-compliant and discontinued her treatment after the initial resolution of symptoms.

Five years after the second episode, on her current admission, she used a wheelchair and reported a new episode of fever and cough (third episode). On initial examination, she had severe paraparesis, a sensory level, and increased deep tendon reflexes. She had an EDSS score of seven. Other neurologic examination was normal. Spinal cord MRI determined longitudinal extensive transverse myelitis (LETM) lesions of cervical and thoracic sections, which were enlarged and became confluent compared to the last MRI (Fig. 2). Cerebral MRI was normal. Cell-based assays for AQP4-Ab and anti-MOG-antibody were negative. Considering the co-occurrence of FMF symptoms and myelitis, which was similar to the last episode of relapse, the possibility of FMF-associated myelitis was suspected. An ultrasound examination revealed mild ascites and pleural effusion during both exacerbations (second and third episodes). Therefore, a high-dose methylprednisolone therapy (1000 mg/day) for 3 days was started. Similar to the previous episode, the patient was non-responsive to the treatment. Hence treatment with colchicine (1.5 mg/day) was initiated, resulting in improvement in her paraparesis, fever, and cough. As her gait disturbance did not fully recover, therapeutic plasma exchange was started. The residual gait imbalance and disturbance did not resolve after plasma exchange. Two months later, despite treatment with colchicine, she had a relapse of FMF accompanied by fever, cough, and worsening paraparesis. Considering the recurrence of FMF attack, which was resistant to colchicine (colchicine-resistant FMF), in the absence of any other underlying disease, treatment with infliximab, two 1000 mg doses separated by 2 weeks, was administered. There are few reports about the successful treatment of FMF with infliximab [9]. However, infliximab may be associated with CNS inflammatory demyelinating activity [10]. Therefore, maintenance treatment with rituximab (1000 mg every 6 months) was replaced. Previous reports have proposed rituximab for FMF-MS cases [11]. The patient has been followed for the last 3 years and did not demonstrate any new FMF-paraparesis relapse, enlarging LETM, or disease progression. Moreover, her EDSS score was six, which was not changed during her follow-up examination.

Fig. 2
figure 2

Spinal cord magnetic resonance imaging (MRI) following the third episode of familial Mediterranean fever (FMF) attack. Cervical MRI showed a low T1-weighted and b high sagittal short tau inversion recovery (STIR) longitudinal extensive transverse myelitis lesions. c Sagittal and d axial T2 views of cervical MRI. Thoracic spinal cord MRI demonstrated high T2-weighted long-segment transverse myelitis lesions in e sagittal and f axial sections

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Written informed consent and consent for publication were obtained from the patient. This study was approved by the Iranian National Committee for Ethics in Biomedical Research (Approval ID: IR.MUI.MED.REC.1399.1132) and performed in accordance with the Helsinki Declaration of 1964 and its later amendments.

Discussion

In this study, we reported a new presentation of FMF-related demyelination in a patient diagnosed with transverse myelitis following FMF attacks. Our patient had two temporally distinct FMF-paraparesis relapses, which had correlated transverse myelitis lesions in MRI. Her FMF symptoms and paraparesis at these time points were responsive to colchicine. However, due to the colchicine-resistant FMF accompanied by demyelinating lesions, rituximab was administered, which resulted in stabilizing disease activity.

Previous studies showed the co-existence of demyelinating disorders with FMF [2, 3, 6]. Studies by Akman-Demir et al. [3] and Kalyoncu et al. [5] showed a four-fold increased rate of FMF in patients with MS (9 out of 2268) and two times increase in MS prevalence among FMF patients (7 out of 3034) compared to the general Turkish population, respectively. Another study by Yahalom et al. [6] in the Israeli population showed two times increase in MS rates in FMF population (9 out of 12,000), which was similar to the study by Kalyoncu et al. [6]. There were also reports of the co-occurrence of other unclassified demyelinating conditions with FMF, like demyelinating brain disease, which did not have a high rate of prevalence (0.6%) [2, 3]. These studies mainly determined the prevalence of FMF co-occurrence with demyelinating disorders. In the current study, we presented a recurrent isolated transverse myelitis case and followed her in a time-course manner, which provided additional evidence on FMF-related demyelination. Besides this, there are also some pathophysiologic explanations for this phenomenon.

Mutation in MEFV gene that encodes PYRIN is responsible for FMF inflammatory symptoms. The consequence of this mutation is the blockade of PYRIN phosphorylation, which activates PYRIN inflammasome [1]. This activation results in the excessive production of inflammatory cytokines like IL-1β and IL-6 [1, 7]. The production of IL-1β and other pro-inflammatory cytokines, with a recognized role in the pathogenesis of demyelinating disorders, could explain FMF-associated demyelination [1, 2, 5, 7, 8]. Moreover, vascular damage and endothelial dysfunction due to FMF can disrupt the blood-brain barrier, predisposing the central nervous system to demyelination. Finally, fever attacks could also damage myelin and mitochondrial structures, resulting in demyelination, remyelination failure, and secondary axonal damage [8].

Various therapeutic options have been introduced to alleviate FMF complications. Colchicine is the first-line therapy in the management of FMF. In colchicine-resistant FMF, biologic agents including interferon α and β-1a, IL-1 inhibitor agents (anakinra, rilonacept, and canakinumab), tumor necrosis factor antagonists (etanercept, adalimumab, infliximab, and thalidomide), anti-IL-6 (tocilizumab), and anti-CD20 antibodies (rituximab, and ocrelizumab), which attenuate FMF inflammatory responses, showed promising effects in treatment of FMF [9, 11,12,13,14]. However, due to common pathologic pathways between FMF and demyelinating disorders, some of these agents were used in FMF-MS cases. A study by Ozdogan et al. [15] demonstrated the effectiveness of anakinra and canakinumab, two anti-IL-1 agents, in treatment of FMF-MS cases. Further reports demonstrated the therapeutic effects of INF β-1a, glatiramer acetate, and anti-CD20 drugs, i.e., rituximab and ocrelizumab, in management of FMF-MS cases [6, 11, 12]. Similarly, in the current report, we used rituximab to treat concurrent FMF and transverse myelitis. Our patient's neurologic, radiologic, and systemic conditions remained stable under 3 years of treatment with rituximab, indicating the promising effect of rituximab in controlling both FMF and its associated demyelination.

Conclusion

FMF is a rare autoinflammatory disorder that may have CNS demyelinating complications. There is a typical response to colchicine that may be effective in co-occurrence of neurologic and systemic manifestations. In refractory non-responsive conditions, rituximab is a favorable treatment to alleviate both polyserositis and demyelinating manifestations.