Introduction

Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disease, presenting with recurrent episodes of febrile peritonitis, synovitis and pleuritis. More than 60 disease-associated mutations have been identified in the MEditerranean FeVer gene, designated ( MEFV) , which encodes for an inflammation regulatory protein, termed pyrin . Pyrin seems to comprise a part of the inflammasome NLRP3, that regulates the level of IL-1β (interleukin 1-β) and thereby the degree of inflammation . The devastating complication of FMF is amyloidosis that eventually may lead to end-stage renal failure and other organ dysfunction. Treatment with colchicine effectively prevents the FMF attacks as well as the development of amyloidosis .

Neurological manifestations unequivocally related to FMF include headache, as a constitutional symptom that accompanies FMF febrile attacks, and four various types of muscle pain. The first two are the short-term (1–5 days) and protracted (8–12 weeks) attacks of myalgia, affecting the muscles of the upper and lower extremities. The pain in the limbs is excruciating and is further increased by motion. The creatine kinase (CPK) and electromyography (EMG) are normal. The temperature and the acute phase reactants are significantly elevated. The protracted muscle pain is considered to be a form of vasculitis and is often associated with a macular rash and homozygosity for the M694V MEFV mutation, the most ‘severe mutation’ in FMF . Exertional muscle pain, the third type of myalgia, affects the calf and thigh muscles and is precipitated by exertion, usually prolonged standing or walking, and is relieved by bed rest. This manifestation is quite typical of FMF and forms a minor criterion in FMF . Recently, using magnetic resonance imaging (MRI) imaging, this type of myalgia was related to tenosynovitis (Eshed I et al. data in preparation for publication). The fourth type is the constitutional muscle pain, which may go along with FMF febrile attacks. This manifestation particularly refers to leg muscle pain, occurring during abdominal attacks. Other forms of muscle involvement that may be encountered in FMF or related to FMF-allied diseases or to treatment complications will be mentioned and discussed in the following ( Table 1 ).

The occurrence of other forms of nervous system manifestations in FMF is rare, and the relation of most of them to FMF is still uncertain. Nevertheless, a wide range of additional neurologic disorders has been reported in FMF. These include seizures , sinus vein thrombosis , pseudotumour cerebri , optic neuritis , central nervous system (CNS) complications of systemic vasculitidis (Henoch–Shonlein purpura (HSP) , polyarteritis nodosa (PAN) , Behcet’s disease (BD) and others ), demyelinating lesions and multiple sclerosis (MS) , ischaemic stroke and recurrent aseptic meningitis . Aside from that, the neurologic manifestations in FMF may reflect side effects of medications, to which FMF patients have been exposed.

The aim of this chapter is to review current knowledge on the neurologic diseases associated with FMF, combining our experience with published data. For that purpose, we reviewed all papers, which could be obtained using Pubmed search, looking for the association of the term FMF with neurological manifestations, CNS disease, neurologic involvement, autonomous nervous system, stroke, aseptic meningitis, demyelination, cognitive impairment, neurologic manifestations of vasculitis, neuropathy, myopathy, Creutzfeldt–Jakob disease (CJD), posterior reversible leukoencephalopathy (PRES) and seizures. To this we added our own experience with neurological involvement of our patients, based on the computerised database of both, the National FMF Center, and Sheba Medical Center diagnosis lists of patient admissions over the last 26 years (1984–2010).

Demyelinating diseases

Several lines of evidence favour an association between FMF and MS. From the MS perspective, there is a report from Turkey, which found that 9 of 2268 MS patients also had FMF. The rate of FMF in this MS cohort was almost 4 times the expected prevalence of FMF in the general population of Turkey . Another report from Turkey found a significantly increased rate of MEFV mutation carriers among 53 MS patients, compared to healthy subjects (38% vs. 11%, p < 0.0001) . This makes MEFV a susceptibility gene that predisposes the development of MS. In the same study, MEFV was found to be a modifier gene as well, aggravating the course of MS, as carriers of MEFV mutations were found to suffer of significantly more relapses than non-carriers. This finding of an association between harbouring a mutated MEFV and a more severe MS lends support to our original observation in non-Ashkenazi relapsing–remitting MS patients, that carriers of MEFV mutations, particularly M694V, displayed a more rapid progression to disability, than non-carriers. In this study, using the expanded disability status scale (EDSS), carriers were shown to advance to EDSS 3 within 2 versus 10 years, and to EDSS 6 within 6 versus 23 years, respectively . However, contrary to non-Ashkenazi, in Ashkenazi Jews MS progression was similar in carriers and non-carriers of MEFV mutations. In addition, and not in line with the study of Unal et al. , the frequency of MEFV mutations carriage by MS patients in our study was similar to the expected rate in ethnically adjusted general population.

In a recent study , the FMF-MS association was studied from the perspective of FMF. Of 3034 FMF patients, seven had MS/demyelinating CNS lesions, in addition to FMF. The frequency of MS in FMF patients was 2 times higher than in the general population (0.23 vs. 0.10%, the p value was not indicated). Moreover, the percent of homozygosity or compound heterozygosity for MEFV (about 30% of FMF patients have only one MEFV mutation or none of their MEFV alleles is mutated) was much higher among FMF-MS patients, compared to those without MS. This supports the notion, that carriage of two MEFV mutations in the FMF population predisposes for MS. Importantly, only one patient in this group of seven FMF-MS patients has received continuous colchicine treatment, suggesting that colchicine has no role in demyelination in these patients; rather, colchicine under treatment and persistent inflammation may underlie the development of MS in FMF. Finally, in our FMF registry of about 12 000 patients we found nine MS patients; once again, twice the expected rate and significantly higher than in the general population ( p = 0.0057). Carriers of the M694V/M694V MEFV genotype displayed a much increased functional deterioration, as expressed by their higher EDSS scores . Thus, our data parallel Turkish results and therefore support the notion that in ethnicities at risk to develop FMF, MEFV is both a modifier gene in MS and a gene that predisposes to its occurrence.

In addition to MS, there is a rare entity, referred to as non-MS autoimmune demyelination, which might be a manifestation of systemic lupus erythematosus, systemic sclerosis, BD and Sjogren’s syndrome . In a prospective evaluation of 17 FMF patients during 4 years, using MRI and visual and auditory evoked potentials testing, Karabudak et al. failed to show, that demyelination is also a complication of FMF. The sample size of this study, however, was too small to draw any conclusion .

While some features of the association between FMF and MS are still unclear, all studies agree that mutated MEFV may aggravate MS. The mechanism for this effect, however, is not known. FMF activity is thought to be interleukin-1β (IL-1β) driven, and IL-1β activation is caspase-1 dependent . Caspase-1 and IL-1β are also important moderators in the pathogenesis of MS. It was shown that in MS the level of caspase-1 m-RNA of peripheral blood mononuclear cells (PBMCs) correlates with disease activity . In another study, accumulation of IL-1 (along with tumour necrosis factor (TNF)) was detected in the cerebrospinal fluid (CSF) of MS patients . Moreover, in an animal model of MS, demyelination was induced by chronic expression of IL-1β . Therefore, one may speculate that in some individuals, who are genetically prone to develop MS, or already suffer from MS, carriage of mutated MEFV that leads to abnormal production of IL-1β, may precipitate MS or modulate MS, respectively. In support of this view is the recent recognition of the role of the innate immunity and of the NLRP3 inflammasome in MS. The NLRP3 knockout mice experienced a dramatically delayed course and reduced severity of experimental autoimmune encephalitis, which serves as a model for MS. This attenuated response was accompanied by a significant reduction of the inflammatory infiltrate in the spinal cord, including macrophages, dendritic cells, CD4 and CD8 T cells and reduced production of interferon-γ (INF-γ) and interleukin-17 (IL-17) . Thus, the NLRP inflammasome, which brings about caspase-1 activation and increased production of IL-1β and was shown to play an important role in the mouse model of MS, may be the missing link that underlies the MS-FMF association. Table 2 summarises the clinical and laboratory observations associating FMF with MS.

Finally, one should be aware that the association between FMF or MEFV and other autoimmune and inflammatory diseases is not limited to MS. Among other diseases that might be precipitated or modified by mutated pyrin, one may find RA , Crohn’s disease and several types of vasculitides such as HSP , PAN and BD ( Table 3 ). These exceptional associations are intriguing and should serve a target for further investigation.

Demyelinating diseases

Several lines of evidence favour an association between FMF and MS. From the MS perspective, there is a report from Turkey, which found that 9 of 2268 MS patients also had FMF. The rate of FMF in this MS cohort was almost 4 times the expected prevalence of FMF in the general population of Turkey . Another report from Turkey found a significantly increased rate of MEFV mutation carriers among 53 MS patients, compared to healthy subjects (38% vs. 11%, p < 0.0001) . This makes MEFV a susceptibility gene that predisposes the development of MS. In the same study, MEFV was found to be a modifier gene as well, aggravating the course of MS, as carriers of MEFV mutations were found to suffer of significantly more relapses than non-carriers. This finding of an association between harbouring a mutated MEFV and a more severe MS lends support to our original observation in non-Ashkenazi relapsing–remitting MS patients, that carriers of MEFV mutations, particularly M694V, displayed a more rapid progression to disability, than non-carriers. In this study, using the expanded disability status scale (EDSS), carriers were shown to advance to EDSS 3 within 2 versus 10 years, and to EDSS 6 within 6 versus 23 years, respectively . However, contrary to non-Ashkenazi, in Ashkenazi Jews MS progression was similar in carriers and non-carriers of MEFV mutations. In addition, and not in line with the study of Unal et al. , the frequency of MEFV mutations carriage by MS patients in our study was similar to the expected rate in ethnically adjusted general population.

In a recent study , the FMF-MS association was studied from the perspective of FMF. Of 3034 FMF patients, seven had MS/demyelinating CNS lesions, in addition to FMF. The frequency of MS in FMF patients was 2 times higher than in the general population (0.23 vs. 0.10%, the p value was not indicated). Moreover, the percent of homozygosity or compound heterozygosity for MEFV (about 30% of FMF patients have only one MEFV mutation or none of their MEFV alleles is mutated) was much higher among FMF-MS patients, compared to those without MS. This supports the notion, that carriage of two MEFV mutations in the FMF population predisposes for MS. Importantly, only one patient in this group of seven FMF-MS patients has received continuous colchicine treatment, suggesting that colchicine has no role in demyelination in these patients; rather, colchicine under treatment and persistent inflammation may underlie the development of MS in FMF. Finally, in our FMF registry of about 12 000 patients we found nine MS patients; once again, twice the expected rate and significantly higher than in the general population ( p = 0.0057). Carriers of the M694V/M694V MEFV genotype displayed a much increased functional deterioration, as expressed by their higher EDSS scores . Thus, our data parallel Turkish results and therefore support the notion that in ethnicities at risk to develop FMF, MEFV is both a modifier gene in MS and a gene that predisposes to its occurrence.

In addition to MS, there is a rare entity, referred to as non-MS autoimmune demyelination, which might be a manifestation of systemic lupus erythematosus, systemic sclerosis, BD and Sjogren’s syndrome . In a prospective evaluation of 17 FMF patients during 4 years, using MRI and visual and auditory evoked potentials testing, Karabudak et al. failed to show, that demyelination is also a complication of FMF. The sample size of this study, however, was too small to draw any conclusion .

While some features of the association between FMF and MS are still unclear, all studies agree that mutated MEFV may aggravate MS. The mechanism for this effect, however, is not known. FMF activity is thought to be interleukin-1β (IL-1β) driven, and IL-1β activation is caspase-1 dependent . Caspase-1 and IL-1β are also important moderators in the pathogenesis of MS. It was shown that in MS the level of caspase-1 m-RNA of peripheral blood mononuclear cells (PBMCs) correlates with disease activity . In another study, accumulation of IL-1 (along with tumour necrosis factor (TNF)) was detected in the cerebrospinal fluid (CSF) of MS patients . Moreover, in an animal model of MS, demyelination was induced by chronic expression of IL-1β . Therefore, one may speculate that in some individuals, who are genetically prone to develop MS, or already suffer from MS, carriage of mutated MEFV that leads to abnormal production of IL-1β, may precipitate MS or modulate MS, respectively. In support of this view is the recent recognition of the role of the innate immunity and of the NLRP3 inflammasome in MS. The NLRP3 knockout mice experienced a dramatically delayed course and reduced severity of experimental autoimmune encephalitis, which serves as a model for MS. This attenuated response was accompanied by a significant reduction of the inflammatory infiltrate in the spinal cord, including macrophages, dendritic cells, CD4 and CD8 T cells and reduced production of interferon-γ (INF-γ) and interleukin-17 (IL-17) . Thus, the NLRP inflammasome, which brings about caspase-1 activation and increased production of IL-1β and was shown to play an important role in the mouse model of MS, may be the missing link that underlies the MS-FMF association. Table 2 summarises the clinical and laboratory observations associating FMF with MS.

Finally, one should be aware that the association between FMF or MEFV and other autoimmune and inflammatory diseases is not limited to MS. Among other diseases that might be precipitated or modified by mutated pyrin, one may find RA , Crohn’s disease and several types of vasculitides such as HSP , PAN and BD ( Table 3 ). These exceptional associations are intriguing and should serve a target for further investigation.

Stroke

The association between FMF and cerebral stroke has not been studied yet thoroughly and is limited to a report of one case and a retrospective study. The case was of a child, who in addition to FMF had several prothrombotic defects, which actually seemed to be the culprit, rather than the FMF . The retrospective study by Kalyoncu et al. , reported seven cases of stroke among 3034 patients with FMF, a higher prevalence, compared with the general population (0.2 vs. 0.005–0.01% for adults <50 year old). The stroke cohort was featured with a young age (mean age 28.5 years) and a propensity to affect the vertebrobasilar vessels. All the patients were homozygous for the MEFV mutations, with M694V in most (six patients). Moreover, the initiation of treatment with colchicine in this group was usually late, suggesting an exposure to long-lasting inflammation. Of note, three patients had established risk factors for stroke, such as haemodynamically significant patent foramen ovale, thalassaemia major and carotid artery dissection. The authors thought that their surprising finding with regard to stroke is limited by a selection bias, typically being observed in a referral centre.

Our experience with stroke in FMF is in the same line, as we found the diagnosis of stroke/transient ischaemic attack (TIA) in 11 FMF patients younger than 50 years, admitted to Sheba Medical Center over the last 25 years (from 1985 to 2010, unpublished data). Given the FMF population at risk, with respect to the age and size of the FMF population served by our hospital, our results are comparable to those of Kalyonku et al. Also in our hands, other risk factors prevailed: two of the stroke patients had renal amyloidosis and were on haemodialysis, and three had at least one risk factor for stroke including smoking, hypertension, diabetes mellitus and obesity.

Being the prototype of autoinflammatory disease, all of which are characterised by massive inflammation, both during attacks and on remission , FMF cohorts are expected to display an increased rate of atherosclerotic vascular disease, including cerebral stroke. Indeed, studies showing increased intima-media thickness of the carotid artery and other markers of enhanced atherosclerosis in FMF are available ( Table 4 ). Of particular interest is a study, showing an association between high serum fibrinogen and stroke in non-FMF population , alluding to the risk in FMF, where 30% of the patients demonstrate hyperfibrinogenaemia continuously . In addition, inflammation is a well-known prothrombotic condition and FMF is not an exception , not to mention reactive amyloidosis of FMF, which is characterised by a thrombophilic profile, with an increased frequency of venous and arterial thrombosis, altogether, insinuating that FMF is expected to exhibit increased vascular morbidity.

Nevertheless, the only controlled study on overt cardiovascular disease in FMF has shown the prevalence to be normal . An important limitation of this study is colchicine treatment, which has significantly reduced the burden of inflammation. But, since an increased level of inflammation remains even in colchicine-treated FMF , one may nevertheless view an increased stroke rate in FMF, particularly in poorly treated populations, not surprising. Presently, it seems that the question of whether FMF constitutes a risk factor for stroke is not yet settled.

Recurrent aseptic meningitis

Recurrent aseptic meningitis, known as Mollaret’s meningitis, presenting like FMF, with self-limited episodes, lasting 3–5 days, was described in FMF. Aseptic meningitis is a recognised manifestation also of BD and some other autoinflammatory diseases such as cryopyrin associated periodic syndromes (CAPS) . Since aseptic meningitis simulating Mollaret’s meningitis may result from human, herpes virus 2 (HSV2), or rarely, HSV1 , one must exclude viral aetiology before designating it autoinflammatory. In FMF, seven cases of recurrent aseptic meningitis have been reported (refs. and Delgado JL et al, 1st international conference on FMF, 1997, Israel. Book of abstracts). Studies for viral aetiology were negative in five and not available in two. In one case, the recurrent aseptic meningitis was the only manifestation of the periodic disease (accompanied with rash) . The patient has eventually developed renal amyloidosis. The episodes of meningitis in this case resolved with colchicine treatment, as was the case in the most other reported patients. In another case an episode of meningitis was provoked by metaraminol, a substance once used to elicit an FMF attack, as a diagnostic test . Another child experienced two episodes of meningitis, followed by convulsive disorder, which was resistant to antiepileptic therapy, but subsided when colchicine was added to the treatment regimen . Due to lack of epidemiology studies, these observations keep the status of recurrent meningeal inflammation in FMF as observations of uncertain significance.

Using our computerised registry, we found seven FMF patients in 25 years (1985–2010), who experienced a single event of aseptic meningitis, manifested with severe headache, meningeal irritation, pleocytosis, sterile CSF and negative CSF testing for herpes virus. None suffered of meningitis previously to this episode, or subsequently during a mean of 12 years (Feld O. unpublished data). Again, as the frequency of aseptic meningitis of undetermined cause in the general population is not known, it is impossible to view aseptic meningitis in our cohort as FMF related. Rather, an extensive effort should be carried out to exclude in addition to infectious agents, another autoinflammatory disease, causing aseptic meningitis, and considered to be more frequent in FMF. Relevant published autoinflammatory co-morbidities include BD ⁶⁸ and PAN .

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  Recurrent aseptic meningitis was rarely reported in FMF and its significance is uncertain

  
  
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  Another or additional inflammatory diseases such as Behcet’s disease and PAN should be excluded in patients with FMF and aseptic meningitis

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