A bidirectional association between CD and epilepsy has been demonstrated by epidemiological studies.

Despite the pathogenic mechanisms underlying this connection have not yet been clarified, several hypotheses have been proposed over the time, ranging from free radical accumulation with oxidative stress to toxin deposition, malabsorption of vitamin B12, local deposition of anti tissue transglutaminase IgA antibodies (tTG IgA) leading to impaired function of immune complexes, and vasculitis (38, 39).

The theory of nutrients' malabsorption leading to epileptic manifestations was postulated in a case report by Lea in 1995. The authors described epilepsy and cerebral calcification in a CD patient with folate deficit and arose the theory that folate malabsorption could cause epileptic manifestation and cerebral calcifications, as already observed in children with leukemia treated with folate antagonists and in patients having congenital folate deficiency (40).

However, epilepsy has been observed in CD patients despite the presence of malabsorption and other pathogenic hypotheses were considered.

Specifically, a study found a connection between the level of tTG IgA in epileptic patients and the activity of their seizures which led to theorize a possible role of gluten toxicity and gluten-related antibodies in triggering epileptic manifestations (38). Gluten toxicity may lead to impaired capability of intestinal cells in absorbing vitamin B, which may cause alteration of the homocysteine metabolic pathways and subsequent hyperhomocysteinemia (H cy). Ferretti et al. hypothesised that Hcy—frequently observed in CD—might damage the blood-brain barrier, exposing neuronal tissue to all neuro-irritative metabolites, such as homocysteine itself, a neurotoxic excitatory and proconvulsant amino acid. Neurons respond to these stimuli through hyperexcitability, thereby predisposing subjects to EEG anomalies and epilepsy (41). Furthermore, Hcy may lead to persistent endothelial damage causing blood extravasation and subsequent deposition of calcium salts, leading to occipital calcifications described in the so-called CEC syndrome, a well-defined entity characterised by association among CD, epilepsy and bilateral occipital calcification (41).

Additionally, the production of autoantibodies itself may play a pathogenic role in EIMs of coeliac disease. Indeed, different typologies of autoantibodies (e.g., autoantibodies against gangliosides, anti-transglutaminase 6, collagen etc) have been detected in patients with systemic manifestations of CD, leading to the hypothesis that autoimmunity could be directly involved in pathogenesis of these symptoms (42).

In 2008 a novel enzyme of the group of transaminase proteins' family, transglutaminase 6 (TG6), was identified in CD patients with neurological manifestations such as peripheral neuropathy and cerebellar ataxia (43). Subsequent studies demonstrated that TG6 had the same enzymatic activity of transglutaminase 2 (TG2)—the main autoantigen of CD—and it was predominantly expressed in the central nervous system where it was involved in neurogenesis and motor control (44).

It has been hypothesized that CD patients may develop specific autoantibodies targeting TG6 due to a cross reactivity with TG2 and these antibodies may be involved in the pathogenesis of certain typologies of neuronal dysfunction associated with CD (45). Consistently with these theories, the injection of autoantibodies directed against TG6 in mice's brain has been proved to cause deficit in motor coordination (46) and mutation of TG genes have been observed in patients with spinocerebellar ataxia (47). Further studies are still required to define the pathogenic pathways connecting anti-TG6 antibodies with motor symptoms of CD and to investigate a possible role of TG6 in the context of other neurological manifestations of CD such as seizures.

Other studies demonstrated that CD-specific autoantibodies (e.g., antigliadin) may present a cross-reactivity with synapsin, a multifunctional protein involved in forming synaptic vesicles and neurotransmitter release, suggesting the production of these autoantibodies as a possible mechanisms of neurological impairment observed in patients with CD (41, 48). However, a clear link between antibodies anti-synapsin and neurological symptoms of CD is still lacking.

Furthermore, antigliadin antibodies have been also described in CD patients presenting cerebral vasculitis which led to postulate a possible role of circulating immune complexes of gliadin and anti-gliadin antibodies in pathogenesis of neurological symptoms of CD (49).

A comprehensive summary of all the proposed pathogenic mechanisms involved in the association between CD and epilepsy has been provided in Supplementary Figure S1.

Overall, epilepsy could be included in a broader spectrum of neurological manifestations of CD, which range from gluten neuropathy and ataxia to headache and cognitive impairment. To date, several hypotheses have been made to explain the mechanism of the different neurological symptoms in CD but the precise pathology is still unclear (50).

The cross reactivity between tTG IgA and neuronal antibodies may explain some manifestations such as gluten ataxia and peripheral neuropathy while a perivascular inflammation could be the cause of headache or cognitive impairment. Other etiopathogenic theories include abnormal brain perfusion, gut-micro-biota axis alterations and autonomic system involvement (51), but further studies are still required to clarify the pathogenic relevance of each of these hypotheses.

A broad spectrum of seizure semiology has been described in CD patients, ranging from focal seizures, mostly with symptoms related to temporal or occipital lobe, to generalised epilepsy, with variable outcome and response to gluten free diet (52).

The majority of studies available in literature describe the presence of generalised tonic-clonic seizures (GTCS) (14, 16, 19, 22–24, 26, 33, 38, 53–56) or focal impaired awareness seizures (14, 16, 19, 22, 29, 38, 52, 54, 55) in patients with CD and epilepsy. Less frequently, focal aware seizures or focal motor seizures were described (33, 34). In contrast, only a few studies have reported other types of seizure semiology, including typical or atypical absence seizures (38, 53) and myoclonic seizures (16).

In terms of specific epileptic syndromes, a few studies describe cases of self-limited epilepsy with centrotemporal spikes (SeLECTS) (16, 23, 33) or other forms of self-limited epilepsy, primarily with occipital discharges (18, 28–30). Only isolated cases of epileptic spasms or other epileptic and developmental encephalopathies, such as Lennox Gastaut syndrome are described among patients with positive CD-serology (16, 27).

Licchetta et al. reported 7 patients with epilepsy onset in pediatric age, all of these presenting focal seizures (3 occipital, 3 temporal and 1 indeterminate focal seizures). Notably one patient received a diagnosis of progressive myoclonic epilepsy (PME) during a long term follow-up and another one was diagnosed with limbic encephalitis (52).

Some of the cited studies also included patients with febrile seizures (FS), either in the form of FS alone or in the context of a genetic epilepsy with febrile seizures plus (GEFS+) (16, 18, 56, 57).

Finally, Hijaz et al. described an interesting case of status epilepticus and encephalopathy as the presenting manifestation of celiac crisis, with good response to steroid therapy in addition to gluten-free diet (58).

Table 2 provides a brief summary of different typologies of seizures reported in studies involving children with CD.

In addition, some authors considered the prevalence of EEG findings in patients with CD in the absence of clinical seizures. Işıkay et al. investigated a cohort of 307 CD children and 197 healthy controls, finding a 7.8% prevalence (24/307 patients) of epileptiform discharges (spike/sharp-wave discharges) in the CD group compared to 0.5% prevalence in the control group. Among the 24 cases of CD patients with EEG abnormalities, 8 patients had never experienced any seizure. In this group, the epileptiform abnormalities were characterized by generalized sharp waves or in the occipital and centrotemporal regions. Overall, the frequency of these EEG anomalies was higher in the new diagnosed CD subgroup compared with the patients on a gluten free diet for at least six months (59).

Furthermore, Parisi et al. reported a 47.4% prevalence of abnormal findings at the EEG examinations (focal or generalised sharps and/or spikes and spike-waves) in a small group of 19 CD children without recognizable clinical manifestations. The EEG abnormalities were either diffuse or localized in the frontal, occipital, or parietal regions. These anomalies disappeared after a 6-months GFD in 78% of cases (60).

Similarly, Zochowska-Sobaniec et al. reported a higher prevalence of abnormalities in EEG recordings, including focal sharp waves or slow waves, in 85 CD children compared to the control group; the consumption of gluten by newly diagnosed celiac patients was associated with a high prevalence of EEG abnormalities, while the 6-months or better 12-months GFD showed a positive impact with EEG improvement or normalization (61).

CEC syndrome (Celiac disease, Epilepsy, and bilateral occipital Calcification) is a well-defined clinical picture of both adults and children characterized by the combination of focal seizures usually originating from the occipital lobe, neuroimaging findings of bilateral cortical and subcortical occipital calcification, and CD (62).

In terms of semiology, the majority of children present focal seizures as described in a large case series by Gobbi in 1982 (24 out of 29 of CEC patients with focal seizures) and by Arroyo in 2002 (31 out of 32 of CEC patients) and confirmed by smaller case series by Piattella (62–64). Other patients may present with both focal seizures and GTCS (21, 65, 66). Interestingly, the diagnosis of CD seems to follow the onset of epilepsy in the majority of case series (62, 65) and symptoms of malabsorption may be even absent, with patients undergoing EGDS after diagnostic evaluation for epilepsy (65).

However, the involvement of occipital lobe in CD-associated epilepsy has been demonstrated regardless of presence of calcifications and some evidence suggest that children presenting occipital epilepsy may have an increased risk of CD (31, 32). The reason for this preferential occipital localization in CEC patients is still unclear although it has been hypothesised a selective susceptibility of occipital lobe to immunological phenomena connected with CD (62). Similarly, the pathogenic role of calcification is controversial as they may appear after the onset of epilepsy and their surgical removal seems not to influence the seizure control (52).

In terms of treatment of CEC, it has been noted a positive effect of GFD in seizure control in these patients. Gobbi reported a significant improvement of seizure control in a half of patients treated with GFD, a substantial stability in another half during follow up; the GFD seemed to be more efficient in patients who had been experiencing epilepsy for less years before the diagnosis of CD (62).

A case report by Ventura et al. described a 5-year old patient experiencing occipital focal seizures associated with occipital calcifications who did not respond to conventional antiepileptic drugs (AEDs) until a diagnosis of CD was made and a GFD was started and a supplement with folic acid was started (55).

It seems that the prognosis of epilepsy in CEC depends on a precocious diagnosis and beginning of gluten restriction (52).

In terms of treatment, the effect of GFD on seizure control is variable. In a sizable percentage of patients, adherence to a gluten restriction seems to improve the seizure control allowing weaning dosage or discontinuing one or more AEDs (26). This positive response has been observed in patients presenting with occipital epilepsy (52, 55) Some authors added folic acid supplementation in patients with CD and occipital epilepsy, as the folate deficit has been previously proposed as a possible pathogenic cause of epilepsy in this subgroup of patients (40, 55).

On the other hand, in other studies Essid et al. reported a significant reduction of seizures only in a minority of patients with CD and IGE after the beginning of GFD (31).

A study by Swartwood et al. investigated the risk of DRE in the CD children and adult population with epilepsy. These patients with DRE showed an improvement in seizure control thanks to adherence to GFD (37).

The interpretation of data regarding the association between CD and epilepsy should be cautious due to the heterogeneity of the information published in literature.

Specifically, most of epidemiological results derive from different studies in term of design (retrospective, prospective, cross-sectional), sample size, criteria adopted to define epileptic manifestations (chronic epilepsy vs. self-limited epileptic features as febrile seizures) or diagnostic approach to CD (serology vs. biopsy) and enrollment methods (self questionnaire proposed vs. routinary neurological evaluation).

Additionally, data regarding the semiology and therapeutic management of children with CD and epilepsy are provided by case series and case reports with an increased risk of bias.