Gluten-Associated Neurological Disorders: A Cases Series

Abstract

Introduction

Gluten-associated disorders, including celiac disease (CeD) and non-celiac gluten sensitivity (NCGS), can present with various extraintestinal neurologic manifestations, including sensory neuropathy, ataxia, headaches, and seizures.

Case Presentations

In this case series, we present 3 interesting patients with gluten-associated neurological disorders (GAND) across a spectrum of gluten-associated disorders severity, from gluten sensitivity, to CeD, to refractory CeD, illustrating variable presentations and treatment approaches for this underdiagnosed population.

Conclusion

For many patients with neurological presentations who initially lack gastrointestinal symptoms, diagnosis remains challenging. Once diagnosed, while a gluten-free diet has been the mainstay of treating GAND for many years, this approach may only prevent progression of disease without reversal of symptoms. Further studies are needed to help guide the development and standardization of treatments for this patient population.

Introduction

Gluten-associated disorders (GAD) encompass a range of conditions, from celiac disease (CeD) – an autoimmune enteropathy triggered by gluten exposure in genetically predisposed individuals – to non-celiac gluten sensitivity (NCGS), characterized by immune-mediated symptoms in individuals without CeD or a wheat allergy. Symptoms of NCGS manifest upon gluten exposure, improve upon gluten avoidance, and recur upon rechallenge. GAD, traditionally perceived as gastrointestinal (GI) conditions, frequently include extraintestinal immune-mediated neurologic manifestations [1, 2] such as sensory ataxia and peripheral neuropathy [1, 3, 4]. Other less common neurologic symptoms include headaches, cognitive impairment, and even seizures [1, 5]. Diagnosing GAD can be challenging when patients present with less typical symptoms, prompting multiple medical societies to advocate for screening based on different clinical presentations. The 2023 American College of Gastroenterology guidelines advises screening for CeD in those with epilepsy, unexplained ataxia, recurrent migraines, headaches, or “brain fog,” while the European Society for the Study of Coeliac Disease guidelines [6] advises broader screening of all patients with peripheral neuropathy, attention-deficit disorder, or mood disorders, in addition to the previously mentioned symptoms. Screening for GAD typically relies on a variety of approaches including assessing patient symptomatology, serologic testing for antibodies (Ab) such as tissue-transglutaminase, deamidated gliadin peptide, and endomysium, as well as intestinal biopsy. The mainstay of treating gluten-associated neurological disorders (GAND) [1, 7, 8] is a gluten-free diet (GFD), though recent evidence supports immunosuppression for symptoms refractory to dietary modification. Here we discuss three interesting cases of GAND.

Case I

A patient in her fourth decade of life presented with a 15-year long history of migraines and foggy mind associated with nausea and alternating bowel habits. Their celiac serology, tested by a neurologist, was positive for deamidated gliadin peptide (DGP) immunoglobulin (Ig)G Ab (158.3 u; reference <15 u) with normal DGP IgA, anti-tissue-transglutaminase (tTG) IgA, and anti-endomysial Abs. CBC values indicated a hemoglobin of 13.2 g/dL with MCV 92 fL. Their primary care provider initiated a GFD, with subsequent normalization of serology and improved symptoms. Genetic testing for CeD was negative (absent HLA DQ2.5, HLA DQ2.2, and HLA DQ8), excluding the diagnosis of CeD and therefore their planned upper endoscopy during a gluten challenge was deferred, especially in light of reported worsening of migraines with inadvertent gluten exposure. The patient started an ultra-strict GFD and subsequently their headaches significantly reduced in frequency and severity. Their infrequent mild residual migraines were well controlled following her transition from sumatriptan to ubrogepant. Given their gluten-associated symptoms per these criteria, normalized serology on a GFD, and absent genes, they were diagnosed with non-celiac GAND and advised to limit gluten intake for symptom control. Of note, this patient did not report experiencing other extraintestinal symptoms, including oral thrush, rhinitis, dermatitis, arthralgia, mood disorders, and unexplained asthenia, which may be seen in NCGS according to the Salerno Expert criteria [2, 9].

Case II

A 43-year-old female presented with NCGS and reported abdominal pain, bloating, constipation, and headache since childhood, which had worsened a decade prior to presentation, prompting self-initiation of a GFD with subsequent symptom resolution. Prior serologic testing (tTG IgA and DGP IgA Abs) and endoscopic evaluation on a GFD for 3 months were normal. The patient carried a celiac gene (HLA DQ8) but was unable to tolerate a gluten challenge due to subsequent diarrhea, bloating, and headache lasting several days. Since diagnosis of NCGS requires the exclusion of CeD, which could not be accomplished, her umbrella diagnosis remained “GAD, cannot rule out CeD.” She was asymptomatic until a decade later when she developed ataxia, neuropathy, bilateral hand tremors, and cognitive impairment. Neurological examination was notable for patchy sensory loss in all extremities, reduced vibration sense at the feet, a wide-based and unsteady gait due to sensory loss, and normal cerebellar testing. Initial extensive testing ruled out other etiologies including nutritional deficiencies (vitamin B12, folate, vitamin D), metabolic etiologies (normal hemoglobin A1c), hypothyroidism (normal TSH), and paraneoplastic syndromes. Nerve conduction study was most consistent with an axonal sensory neuropathy.

Repeat serology was positive for DGP IgA (>100 u; reference <20 u) and negative for tTG IgA. She was then started on intravenous immunoglobulin (IVIG), which improved the severity of her neurological symptoms. She remained on nortriptyline and duloxetine for neuropathy, sumatriptan and topiramate for migraines, and gabapentin for neuropathy and tremor. Endoscopic evaluation on a GFD was normal without active CeD. Repeat testing showed improved DGP IgA (80 u) after which she started an ultra-strict GFD. Serological normalization of DGP IgA was achieved following a year on an ultra-strict GFD. Presently, 4-year later, her axonal sensory neuropathy persists but is stable and she has been gradually weaned off IVIG. Unable to confirm her diagnosis of CeD, she was diagnosed and managed with gluten neuropathy/ataxia. Patients with GAND may continue to have neurological symptoms, but a strict GFD usually halts progression.

Case III

A 29-year-old patient with biopsy-confirmed CeD and dermatitis herpetiformis for 2 years presented with persistent diarrhea despite a strict GFD. Serology remained elevated (tTG IgA 130.4 cu and DGP IgA 26.4 cu, down from 388 cu and 75.5 cu at diagnosis, respectively; reference <20 cu). The patient carries both celiac genes (HLA DQ2.5 and HLA DQ8). Similar to her initial pathology demonstrating duodenal mucosa with intraepithelial lymphocytosis and villous blunting (consistent with Marsh 3a lesions), endoscopy after a year on a strict GFD revealed continued proximal duodenal fissures and nodularity, with biopsies showing Marsh 3b lesions (without aberrant T cells), compatible with type I refractory CeD (RCD). Though the differential diagnosis of slow responsive CeD was considered, in light of her worsening enteropathy and severe malabsorptive symptoms (along with foggy mind), she started RCD therapy with open-capsule budesonide protocol for 8 months, leading to resolution of her dermatitis herpetiformis and CeD, with repeat biopsies after 6 months showing Marsh 0 (resolved enteropathy) lesions. After a year, she developed vestibular migraines, confusion, and neuropathic back pain. Malabsorptive work-up revealed decreased vitamin B12 level (216 pg/mL), normal B1, B6, folate, electrolytes, copper, thyroid-stimulating hormone, hemoglobin A1c. Despite vitamin B12 normalization on supplements, she remained symptomatic and was subsequently diagnosed with gluten neuropathy. Notably, her pain was unrelieved by topical ointments including lidocaine and capsaicin. Per expert opinion, she restarted her budesonide for 6 months for suspected GAND with complete resolution of her neurological symptoms. Surveillance endoscopy following therapy confirmed that her CeD remained in near remission (Marsh 1).

Discussion

Neurologic manifestations are relatively common in GAD [10] secondary to vitamin malabsorption or immune response associated with cross-reactivity between gluten peptides and specialized cells in the nervous system [11]. In gluten ataxia specifically, elevated tTG/DGP are present in less than 40% of patients [12], and interestingly, a fifth lack the CeD genes [13]. While GAD is more readily diagnosed when gastrointestinal symptoms are present, we highlight the spectrum of GAND in our cases. From case I without CeD to case III with RCD, a strict GFD can prevent progression but rarely leads to regression of neurological symptoms.

Since patients with neurological presentation may lack GI symptoms, diagnosis remains challenging [1]. Patients with GI symptoms were diagnosed with CeD within 2.3 months versus 42 months in those without GI symptoms [5]. Adding to the complexity is the temporal variability of the neurologic manifestations (before or after GI symptoms), making timely treatment difficult. GAND can be the only chief symptom [5], present alongside or without CeD, as in this case series [6]. NCGS should be considered in those who experience symptom relief upon avoiding gluten but symptom re-emergence and exacerbation during a gluten challenge. Typical CeD serology (tTG-2) is normal in NCGS unlike GAND-specific tTG-6 which is not commercially available in North America. Of note, DGP may be elevated in both CeD and when gluten-related neuropathy is present secondary to NCGS. Further, blood lymphograms detecting activated gut-homing CD8+ cells have recently shown high sensitivity and specificity for diagnosing seropositive CeD in individuals on a GFD, although this test is not yet widely available [14].

Neurological symptoms in CeD may result from autoimmune mechanisms, such as molecular mimicry, where the immune system targets neural tissue due to structural similarities with gluten peptides. In gluten ataxia, Ab to gangliosides, important components of nerve cell membranes, may contribute to neurodegeneration. Additionally, vitamin deficiencies – especially B12, folate, and other B vitamins – due to malabsorption exacerbate neuropathy and cognitive dysfunction, though these are not the primary drivers of symptoms in GAND. Unlike thrombotic manifestations of CeD such as deep vein thrombosis/pulmonary embolism, and stroke, which are linked to coagulation abnormalities, neurological symptoms in CeD are primarily immune-mediated.

Even after successful diagnosis, treatment of GAND is non-standardized and understudied [15]. When dietary modification is insufficient, literature suggests immune modulators like IVIG and immunosuppressants such as mycophenolate mofetil and rituximab [3, 5]. For our patients, IVIG and budesonide were chosen based on UK evidence, leading to mitigation of symptoms after a minimum 6-month trial. We advise referral to tertiary CeD centers who collaborate with neurologists specialized in GAND.

Overall, diagnosis and management of GAND remains challenging due to variable presentation and lack of clear diagnostic criteria and treatment guidelines. Moreover, further trials studying immunosuppressive agents in GAND, and development and standardization of treatment protocols are needed.

The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000544765).

Statement of Ethics

Ethical approval is not required for this study in accordance with local or national guidelines. Written informed consent for the publication of their medical case details was obtained from 2 of the 3 patients included in the study. Efforts to contact the third patient were unsuccessful despite multiple attempts; therefore, any identifying information has been removed. After extensive review, the UCLA IRB board, Compliance Office, and Media Office found our submission to be abiding by their guidelines regarding patient confidentiality.

Conflict of Interest Statement

All authors declare that they have no conflict of interest.

Funding Sources

There were no sources of funding in relation to this work.

Author Contributions

V.S.B. and F.G. wrote the manuscript. G.A.W. clinically evaluated the patients. B.L.F. and G.A.W. edited the manuscript and provided guidance. G.A.W. is the article guarantor.

Funding Statement

There were no sources of funding in relation to this work.

Data Availability Statement

The data that support the findings of this study are not publicly available as it could compromise the privacy of research participants. Data are available from the corresponding author (V.S.B.) upon reasonable request.