Il-1antagonist Treatment in Recurrent Aseptic Meningitis Related to Familial Mediterranean Fever

Familial Mediterranean fever (FMF) is an autosomal recessive, auto-inammatory disease, presenting with recurrent bouts of fever and polyserositis. FMF has been associated with central nervous system (CNS) manifestations such as Headache and Myalgia. The occurrence of other forms of nervous system involvement is rare, including seizures, sinus vein thrombosis, pseudotumor cerebri and more. There are only few case reports of aseptic meningitis due to FMF. We present the case of a 14 year-old girl diagnosed with FMF, who experienced recurrent episodes of severe headache and aseptic meningitis while on maximal dose of colchicine therapy. She had a dramatic response to anakinra with symptoms resolving completely within a few days without recurrence. Subsequently, we identied seven cases in the literature describing recurrent aseptic meningitis in patients with underlying FMF; all showed response to colchicine treatment, without treatment failure. Our case suggests a role for Interleukin 1 (IL-1) antagonists for cases of CNS involvement secondary to FMF in patients who fail to respond to colchicine, and might imply that anakinra could be effective in other auto-inammatory diseases with CNS involvement.


Abstract
Background Familial Mediterranean fever (FMF) is an autosomal recessive, auto-in ammatory disease, presenting with recurrent bouts of fever and polyserositis. FMF has been associated with central nervous system (CNS) manifestations such as Headache and Myalgia. The occurrence of other forms of nervous system involvement is rare, including seizures, sinus vein thrombosis, pseudotumor cerebri and more. There are only few case reports of aseptic meningitis due to FMF.

Case presentation
We present the case of a 14 year-old girl diagnosed with FMF, who experienced recurrent episodes of severe headache and aseptic meningitis while on maximal dose of colchicine therapy. She had a dramatic response to anakinra with symptoms resolving completely within a few days without recurrence.
Subsequently, we identi ed seven cases in the literature describing recurrent aseptic meningitis in patients with underlying FMF; all showed response to colchicine treatment, without treatment failure.

Conclusion
Our case suggests a role for Interleukin 1 (IL-1) antagonists for cases of CNS involvement secondary to FMF in patients who fail to respond to colchicine, and might imply that anakinra could be effective in other auto-in ammatory diseases with CNS involvement.

Background
Familial Mediterranean fever (FMF) is the most common monogenic, auto-in ammatory disease, mostly found in Sephardic Jews, Armenians, Turks, and Arabs. FMF manifests as recurrent self-limiting attacks of fever and serositis, such as peritonitis, pleuritis, pericarditis, and arthritis 1 . The estimated number of patients globally exceeds 100,000, with 10,000 in Israel alone. The MEFV gene encodes for an in ammation regulatory protein termed Pyrin, which seems to comprise part of an in ammasome NLRP3 that regulates the level of IL-1b (interlukin 1-b), and thereby the degree of in ammation 2 . Neurological manifestations include headache accompanying FMF febrile attacks, and different types of muscle pain. Other nervous system manifestations are rare, and their relationship to FMF uncertain. These manifestations include seizures, sinus vein thrombosis, pseudotumor cerebri, optic neuritis, polyarteritis nodosa, multiple sclerosis, ischemic stroke and recurrent aseptic meningitis (RAM) 3,4 .
Colchicine has been shown to be effective in controlling in ammation in the majority of FMF patients, however, colchicine resistance is well described in the literature 4 . For these patients, a therapeutic alternative for colchicine is needed. Based on the role of pyrin in the regulation of interleukin (IL)-1β activation, the e cacy of IL-1 inhibitors has been assessed in few case series 56 . The three commercially available anti IL-1 drugs today are anakinra, rilonacept and canakinumab. In most patients, anakinra (recombinant non-glycosylated homolog of the human IL-1 receptor antagonist (rhlL-1Ra)) signi cantly improved abdominal pain and fever, and decreased FMF attacks. The relief of symptoms was evident within a very short period of time, accompanied by a rapid decline of in ammatory parameters such as Serum Amyloid A (SAA) and C-reactive protein. 7 In literature, few reports about the safety and tolerability of anakinra therapy in patients with FMF or rheumatoid arthritis have been published. One of the most commonly observed has been pain at site injections as well as local cutaneous reactions. Uncommonly, Patients with previous pneumonia or other risk factors for lung infections may have an increased risk to develop infectious complications of the respiratory system. Cytopenia as its potential side effect is generally mild. 25 In this case-based review, we present a pediatric patient with FMF, who suffered from acute chronic headaches and presented with three proven episodes of RAM while on colchicine and response dramatically to treatment with anakinra. We compare this patient to previously described patients with FMF who contracted aseptic meningitis.

Case Presentation
A 14 year old, Sephardic Jewish girl was diagnosed with FMF at 7 years of age, based upon typical clinical attacks of abdominal pain accompanied by fever and recurrent erysipelas-like reaction. She has several family members with FMF, and genetic studies showed homozygosity to M694V mutation.
After treatment with 2 mg/day of colchicine, she was doing fairly well with occasional abdominal pain attacks.
For the past two years, she suffered recurrent episodes of acute headaches (for several weeks, resolved spontaneously) and was hospitalized on several occasions. Her headaches were described as occipital, awakening from sleep, and were accompanied by fever, nausea and photophobia. During these attacks no meningeal signs or neurological de cits were found on physical examination, and funduscopic examination was normal on several occasions. Between acute episodes she had chronic headaches of lesser severity. She underwent a thorough work up including MRI, MRA, and spinal taps on three occasions. All spinal taps specimens showed pleocytosis with 55-200 cells/ml, with lymphocytic predominance and normal to mild increase in protein levels (40-75 mg/ml). Opening pressures and Glucose levels were normal; bacterial cultures and serology tests for Q fever and toxoplasma were negative. PCR examinations in search of different viral pathogens, including HSV-2, were negative. CSF cytology was normal. Blood CRP levels were elevated (13-103 mg/L) during the attacks, and then returned to normal (0-5 mg/L). Neurological consult described the complaints pattern as acute on chronic headaches due to atypical migraine, with pleocytosis.
After a presumptive diagnosis with RAM due to FMF, 100 mg/day of anakinra, an Il-1 interleukin 1 (IL1) receptor antagonist drug was added to colchicine treatment and all headaches resolved completely within a few days. Currently she has been treated with anakinra for > 36 months, with resolution of both headache and FMF attacks.
Subsequently, a systematic search of the literature was performed retrieving English-language original case reports, case series, case-based reviews, and review articles on aseptic meningitis in FMF patients, up to January 2020. Pubmed/MEDLINE was queried for "familial Mediterranean fever" and "aseptic meningitis". Articles involving patients with FMF suffering from aspetic meningitis, recurrent or single episode -were included 8,9,10,11,12 . Publications not detailing treatment modalities were excluded. Information obtained in a systematic fashion included demographics, FMF diagnostic criteria, treatment and outcomes.
In addition to our case, as of January 2020, we identi ed seven articles with seven cases describing aseptic meningitis in patients with underlying FMF; 6 of 7 cases were described in the adult population, with patient age ranging from 32 to 64 years of age, two (including our case) were in the pediatric population (13 and 14 years old). All cases in the literature responded well to colchicine treatment and aseptic meningitis episodes were diminished.

Discussion And Conclusions
We describe a case of RAM caused by FMF according to current diagnostic standards 13 . Acute headache attacks coincided with exacerbation of her FMF in most attacks and were accompanied by high in ammatory markers and laboratory characteristics of aseptic meningitis, with chronic headaches between episodes. The events continued despite colchicine treatment, and resolved after adding anti IL-1 receptor treatment.
Central nervous system (CNS) manifestations of FMF are rare and under debate. Neurologic involvement associated with FMF shows a wide spectrum, including pseudotumor cerebri 14 , optic neuritis 15 , CNS complications of polyarteritis nodosa (PAN) 16 , recurrent aseptic meningitis, and demyelinating lesions 17 .
Primary headaches are common among FMF patients, although believed to be unrelated to the immunologic illness itself 18 . Nonetheless, there are several reports of headaches due to recurrent episodes of RAM presumed to be related to FMF, mainly in adults (Table 1). In most cases, events subsided or resolved following colchicine treatment, however, reports are scarce and vary signi cantly in criteria for FMF diagnosis (with or without genetic proof). This makes it di cult to determine whether the headaches resulted from aseptic meningitis. Furthermore, not all reports addressed response to treatment.  22 Therefor it is questionable weather RAM in those cases is part of the FMF manifestations or can be explain by an alternative diagnosis.
On the contrary, in our case report, the patient was diagnosed with M694V mutation homozygosity, and there was no other phenotype implying for other diagnosis. The fast response observedto the treatment with IL-1 antagonist strengthen the presumed e cacy of anakinra in the FMF patients with CNS involvement.
Colchicine is the main therapeutic modality for reducing in ammatory attacks and preventing amyloidosis due to FMF. Nevertheless, 30-40 percent of FMF patients continue to suffer from recurrent attacks despite therapy, and 5-10 percent are considered resistant to colchicine 5 . Until recently there was no other known effective treatment for FMF.
The revelation that FMF is caused by mutations in the MEFV gene, which encodes for the pyrin protein, increased understanding of the pathological events in the disease. The functional role of pyrin was discovered only recently 19 . Based on the role of pyrin in the regulation of interleukin (IL)-1β activation, the e cacy of IL-1 inhibitors has been assessed in more than 60 cases, and in one controlled study of patients with FMF who were resistant or intolerant of colchicine 5,7,20,21) . The three commercially, currently available anti IL-1 drugs are anakinra, Rilonacept and Canakinumab. Anakinra, an IL-1receptor antagonist, is given subcutaneously on a daily basis, and has demonstrated its e cacy in other autoin ammatory disorders. An anakinra treatment has been shown to improve CNS involvement in patients with neonatal onset multisystem in ammatory disorder (NOMID), halting the progression of hearing loss in most patients treated with NOMID. 20 Our study is the rst report of RAM due to FMF that is responsive to anakinra. The immediate response strongly suggests there was a relationship between FMF and RAM in this patient. Our experience also offers a novel therapeutic option for cochicine resistent RAM and maybe even other CNS manifestations of FMF.

Declarations
Ethics approval and consent to participate Not applicable.

Consent for publication
Not applicable.