4Student Research Committee, Fasa University of Medical Sciences, Fasa, Iran

5Digestive Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran

Introduction

Celiac Disease (CD, also called non tropical sprue or gluten-sensitive enteropathy), an autoimmune enteropathy, was first described in 1888 by Samuel and was originally considered a rare malabsorption syndrome mainly occurring in childhood which is now recognized as the most common food intolerance disease in the world. CD is triggered by ingestion of wheat gluten and the related cereal proteins and may arise at any age with a growing proportion of new cases diagnosed in adults, especially in genetically predisposed individuals [1-3]. Recent studies have revealed that CD affects approximately 1% of the general population across the globe [4]. Almost all the CD patients have a genetic susceptibility characterized by HLA-DQ2 and/or HLADQ8 positivity. Genome-wide association studies during the last 3 years have reported more than a dozen new susceptibility loci for CD [1]. Analysis of eQTL data from these and previously established risk loci sheds light on the genetic pathways underlying this common autoimmune disease [5].

CD diagnosis requires the positivity of transglutaminase antibody and MARSH III grading at histology. It is still debated that MARSH I or II are overt in CD even in association with positive antibodies. Gluten hypersensitivity requires the positivity of transglutaminase antibody with normal histology or MARSH I and II grading at histology [6]. Small-bowel mucosal morphology was classified according to the Marsh criteria: normal histology (Marsh 0), infiltrative lesion (Marsh I), infiltrative-crypthyperplastic lesions (Marsh II), partial villous atrophy (Marsh IIIA), and subtotal villous atrophy crypt hyperplasia (Marsh IIIB)[7,8].

CD is associated with a wide spectrum of extra intestinal manifestations [9]. Although CD is one of the most common lifelong inflammatory diseases, most affected individuals remain undiagnosed [1]. The patients with asymptomatic CD who have no symptoms and respond to gluten withdrawal are often diagnosed through screening programs or in case-detecting strategies for the patients with disorders that are accompanied with a high risk for CD [10,11]. Among the affected subjects, only 25% developed the clinical symptoms. Many patients, especially those presenting in adulthood, have minimal or atypical symptoms, unexpected associations such as epilepsy, and various undefined neurological disorders [2,9]. Gluten intolerance is also another synonym used for CD to indicate the clinical improvement of the patients subsequent to Gluten Free Diet (GFD) initiation, even when they do not have CD [12-14].

Neurological manifestations of CD have been investigated and reported in a number of studies by many researchers. However, there are a few review studies regarding this aspect of CD presentations. In the present study we aimed to provide a narrative review on the neurological presentations of CD.

History and Demography

Carnegie Brown in 1908 reported the first neurological manifestations of CD in two patients with “peripheral neuritis” [15]. Besides, Elders reported the association between “sprue” and ataxia in 1925 [16]. In 1966, Cook and Smith described 16 patients with different neurological manifestations associated with adult CD, including severe progressive neuropathy, gait ataxia, and limb ataxia. They also reported the first postmortem neuropathological examinations of the patients with neurological involvement of CD showing extensive perivascular inflammatory changes in both central and peripheral nervous systems. A striking feature was the loss of Purkinje cells with atrophy and gliosis of the cerebellum [17]. Neurological involvements of CD were first attributed to malabsorption due to changes in the mucosal architecture of the small intestine[18]. Malabsorption theory has been outmoded as overt malabsorption in CD is rare due to developed diagnostic methods. Studies demonstrated the presence of neurological complications of CD in spite of normal amounts of essential nutritional elements. In 1966, Marks et al. suggested a probable association between inflammatory mechanisms and CD by demonstrating the similar pattern of enteropathy in both dermatitis herpetiformis, as an inflammatory disease, and CD [19]. On the other hand, Willis et al. also took detailed histories and performed careful clinical examinations in 35 patients with dermatitis herpetiformis and found no evidence for immune mediated neurological damage [20]. Presence of inflammatory cell infiltration in the histopathological findings of the patients with CD and neurological manifestations led the investigators to think of an autoimmune mechanism [17,21].

Prevalence

Table 1 shows retro/prospective series of the CD patients investigated for neurological manifestations. Overall, 334 out of the 1562 patients with CD had neurological manifestations. The Frequency of neurologic system involvement in CD in these series reveals high degree of variation. This variation may not only be due to the environmental and ethnic factors, but also related to variable definitions and methodologies in different studies.

Sex: Hadjivassilliou and colleagues reported female to male ratio of the patients with neurological manifestations of CD as approximately 1:1 in one series [29].

Age: Neurological manifestations were more frequent in middle-aged adults, but rare in children [27, 30, 31]. In addition, the mean age at the onset of neurological manifestations was 48 years in one series [29].

Pathology

The pathological findings of CNS involvement in CD include lymphocytic infiltration (mainly T cell), especially in the spinal cord, hypothalamus, cerebellum, and brainstem [17,32], astrocytic gliosis, vacuolization of the neuropil of the cerebellar white matter [32], cerebellar purkinje cell loss [17,21,32,33], and demyelination in the posterior, lateral, and anterior cortico-spinal tracts in the cord [17,21]. Shams et al. reported extensive infiltration by medium sized cells with pleomorphic nuclei and prominent nucleoli in the cerebellar cortex and white matter which stained positively for CD45, CD3, and TIA-1 (cytotoxic granule marker) [34]. Moreover, Hadjivassiliou et al. found widespread Ig A deposition around the vessels in the brain of the patient with gluten ataxia. The deposition was most pronounced in the cerebellum, pons, and medulla [35]. In two CD patients with headache, autopsy results showed evidence of vasculitis [36].

The pathological findings in sural nerve biopsy of the patients with CD and neuropathy revealed changes of chronic axonopathy [37,38], wallerian degeneration, and degeneration-regeneration of nerve fibers [39].

Pathogenesis

Etiopathogenesis of the neurological manifestations of CD remains to be elucidated. There are cohorts of studies advocating the theory that gluten can affect cell function in cell culture systems, apparently in the absence of the immune system involvement. Gluten has shown this effect by inducing agglutination of K562(S) myelogenous leukemia cells, leading to actin rearrangement, and finally triggering apoptosis in Caco-2 cells [40]. Meanwhile, the presence of inflammatory reactions in the neural tissue of the postmortem pathological examination of the patients with CD and neurological complications led the investigators to think about an immunological mechanism, too [17,21,32]. In general, two speculated immunological mechanisms may explain the association between gluten sensitivity and neurological manifestations: Antigen molecular mimicry and Intermolecular help.

Antigen molecular mimicry (Antibody cross -reactivity): The speculated mechanisms of molecular mimicry in the patients with gluten sensitivity are:

1. 1. Cross reactivity between gliadin species and gangliosides: Antigliadin antibodies may cross-react with Purkinje cells. Gliadin proteins and cerebellar Purkinje cells may share common epitopes. Such common epitopes have also been demonstrated to exist between gliadin proteins and enterocytes [41]. Up to 65% of the patients with celiac neuropathy had antibodies targeting one or more gangliosides [37,38]. It has been shown that some gluten species are glycosylates containing epitopes probably similar to ganglioside carbohydrates [42]. This may justify the induction of the antibody cross-reactivity. Moreover, in experimental studies, serum of the neurologically symptom-free CD patients demonstrated cross-reactivity with epitopes on Purkinje cells of both human and rat cerebellum [41]. Interestingly, elimination of antigliadin antibodies (AGA) from serum of the patients with CD and ataxia did not ameliorate the reaction to the Purkinje cells. This might have led the investigators to assume the presence of other antibodies against Purkinje cells in the patients with CD and cerebellar manifestations. Anti-ganglioside antibodies may be the example. Alaedini et al. proposed synapsin I, a cytosolic phosphoprotein, as the target of cross reactivity with anti-gliadin antibodies in both central and peripheral nervous systems [43].
2. 2. Predisposition to infection with organisms, such as Campylobacter jejuni or Haemophilus influenzae which have lipopolysaccharides similar to CNS or PNS gangliosides. This mode has analogies to the hypothesized pathogenesis of Guillain–Barre´ syndrome [44].
3. 3. Another unknown mechanism: Investigations are still needed in order to approve this hypothesis and since there may be other unknown mechanisms involved in or facilitating the antibody cross-reactivity.

Intermolecular help theory

Gliadin molecules are deamidated by tissue transglutaminase (tTG). It has been speculated that tTG-specific B cells engulf the gliadin-tTG complex and present the gliadin portion to gliadin-sensitized T cells. The ensuing gliadin-reactive T cell helper could induce the ganglioside- specific B cells and produce anti-ganglioside antibodies in the absence of ganglioside-specific T cells [45].

Clinical manifestations

Neurological involvement in gluten sensitivity can be categorized into central and peripheral nervous system manifestations. The most common central nervous system manifestations include cerebellar syndromes, seizures, and dementias. Multiple sclerosis like presentations, motor neuron diseases, headaches, movement disorders, and neuro-psychiatric presentations, have been reported, as well. On the other hand, the peripheral nervous system involvement includes different types of peripheral neuropathies and muscular involvement. Mixed neurological syndromes are also prevalent; 45-68% of the patients with gluten sensitivity ataxia revealed electrophysiological evidences of neuropathy, too [29,32].

Central nervous system involvement

1- Ataxia

Gait and limb ataxia, myoclonus, occulomotor abnormalities, and dyarthria are the various cerebellar manifestations of CD. In a study by Hadjivassiliou et al., gait ataxia, lower limb ataxia, ocular signs, upper limb ataxia, and dysarthria were seen in 100%, 90%, 84%, 75%, and 66% of the patients, respectively [46]. Deconinck et al. reported a single case with opsoclonus- myoclonus associated with CD [47]. The frequencies of CD and gluten sensitivity in patients with ataxia of unknown origin have been reported between 1.9-15% and 12-47%, respectively [46,48,49]. In other studies, 13% of the patients with hereditary cerebellar ataxias and 23% of those with spinocerebellar ataxia type 2 had positive AGA [49-52]. On the contrary, some other studies showed no association between CD and idiopathic cerebellar ataxia [53-55]. Table 2 shows reports regarding the association between CD and epilepsy ataxia

2- Seizures

Several reports are available regarding the association between CD and epilepsy (Table 3). These studies did not separate drug-naïve epileptic patients from those who were on anti-epileptic drugs at time of study. As several anti-epileptic drugs induce the immune system and auto-antibodies are frequently seen in epileptic patients, clinical significance of this finding should be considered with caution. Gobbi et al. considered constellation of CD, epilepsy, and cerebral calcifications as a particular entity, CEC syndrome [56]. Efficacy of Gluten restriction seems to be inversely related to the duration of epilepsy and the young age of the patients. As cerebral calcification was not seen in the patients of Cronin et al. with epilepsy and CD, CEC syndrome may be a geographically based association rather than a distinct entity [57].

3- Multiple Sclerosis

In all [58-61] but one [62] case-control studies, no association was found between CD and gluten sensitivity, and MS. There are also some case reports on the association between Neuromyelitis optica and CD [63,64].

4- Headache

In one study on pediatric age group [65] and one study on adults [66], CD was significantly more prevalent in the patients with migraine headaches in comparison to the healthy controls. Headac0he was also more prevalent in the CD patients compared to the healthy controls [67]. Besides, migraine and tension-type headaches were the most common types of headaches in the patients with CD [68]. Yet, adherence to GFD was efficacious in decreasing the frequency of headaches in some CD populations [36,67,69,70].

Hadjivassiliou et al. considered the term “gluten encephalopathy” for the patients with gluten sensitivity, migraine-like headache, possible focal neurological deficits, and vascular type white matter Magnetic Resonance Imaging (MRI) abnormalities [36].

5- Dementia

There are a few case series about the association between dementia and CD [71,72]. In one study, the frequency of CD in Alzheimer’s patients was not higher than the controls [73]. Furthermore, in another study, cognitive impairment was not found in CD patients [74]. Of course, both studies had been conducted on small sample sizes.

6- Neuro-Psychiatric Manifestations

Psychological reactions to a chronic disabling illness, such as CD, may interfere with the diagnosis of neurological complications. For instance, 19-35% of the patients with CD had a positive history of psychiatric diseases [75,76]. Although some studies revealed no associations between CD and schizophrenia in adults and autism in children [77-79], several authors have declared that an association may exist between CD and autism and between CD or gluten sensitivity and psychiatric disorders [14]. A few studies have also mentioned the efficacy of dietary intervention in autism [80-82].

7- Movement Disorders

Palatal myoclonus [21], opsoclonus-myoclonus syndrome [47], dystonia paralysis [83], Rhabdomyolysis [84], and choreathetosis [85,86] were reported in the patients with CD.

8- Hearing loss

Increased frequency of sensori-neural hearing loss in the patients with CD compared to the healthy controls was reported in two studies [87,88].

9- Stroke

There were case reports of stroke in the children and young adults with diagnosis of CD [89,90]. However, as the majority of these patients had other contributing factors, a cause and effect relationship between CD and stroke is a matter of debate.

10- Spinal cord disorders