Gluten Ataxia and Celiac Disease–Associated Cerebellar Degeneration in a Septuagenarian

Introduction

Once thought to be predominantly a disease of the young, celiac disease is being increasingly diagnosed in older patients. Celiac disease commonly presents with gastroenterological symptoms; however, extraenteric presentations may occur, including neurological disease. Unexplained cerebellar ataxia in an elderly patient should prompt serological screening for celiac disease, even in the absence of gastrointestinal symptoms. We describe a case of celiac disease–associated cerebellar ataxia in a septuagenarian.

Case Presentation

A 72-year-old woman presented to the emergency department with a 4-year history of progressive unsteadiness and mild but progressive slurring of speech. She had been examined by an ear, nose, and throat specialist 3 years earlier because of symptoms of unsteadiness, and had been noted to have mild nystagmus at that time. Her medical history included a duodenal tissue biopsy–proven diagnosis of celiac disease, which was made after she had developed chronic diarrhea 2 years before her current presentation. The patient reported poor compliance with a gluten-free diet, and was teetotal (ie, she did not consume alcoholic beverages).

Physical examination revealed a heart rate of 90 beats per minute, blood pressure of 130/65 mm Hg, respiratory rate of 18 breaths per minute, and temperature of 98.24°F (36.8°C). Neurological examination demonstrated bilateral horizontal nystagmus. Marked bilateral limb and gait ataxia and cerebellar dysarthria were present . No pyramidal or extrapyramidal tract signs were elicited. Examination of the respiratory, abdominal, and cardiovascular systems were unremarkable.

Complete blood count was within normal limits on admission, with a normal differential, platelet count, prothrombin time, and partial thromboplastin time. The patient’s electrolyte levels (sodium, potassium, calcium, magnesium, phosphate), vitamin B₁₂ levels, and liver and thyroid function were all within normal limits. Her chest x-ray revealed no abnormalities. Paraneoplastic antibodies were not detected. Antiendomysial and anti-tissue transglutaminase antibodies were present in high titers, indicative of celiac disease. Initial computed tomography scan of the brain demonstrated striking cerebellar atrophy, with the rest of the brain being well preserved. These findings were subsequently confirmed on magnetic resonance imaging of her brain (Figure).

A diagnosis of cerebellar ataxia associated with celiac disease was made. (Of note: the patient had reported ataxic symptoms and had a documented examination finding of nystagmus over 1 year before presenting with gastroenterological features of celiac disease.) She underwent inpatient neurological rehabilitation and was put on a strict gluten-free diet, both of which resulted in functional improvement and discharge from the hospital. The patient returned home, where she was independently mobile.

Discussion

Once considered to be a disease of childhood or young adulthood, celiac disease is relatively common in the elderly population, with one study reporting that more than one-third of patients with a diagnosis of celiac disease were over 60 years of age.¹ In addition to the two- to fivefold increase in cases seen in U.S. cohorts over 15 years from 1974 to 1989, longitudinal studies demonstrate that the disease’s prevalence increases with age, as increasing numbers of patients lose their immunological tolerance to gluten in their adulthood.² The condition is underdiagnosed, with current data from the National Institute for Health and Clinical Excellence, a special health authority of the National Health Service in England and Wales, indicating that only 10% to 15% of those with celiac disease have a clinical diagnosis, despite a prevalence of 1 in 100.³

Celiac disease is a chronic inflammatory condition that affects the proximal small intestine and may progress distally in more marked disease. Persons with celiac disease have an intolerance to gluten, a substance found in barley, rye, and, most notably, wheat.⁴ It is a human leukocyte antigen (HLA)–associated condition, with approximately 72% of sufferers found to have the HLA-DQ2 genotype.⁵ There is an autoimmune component to celiac disease, but the main pathogenesis involves a cellular antigluten T-cell response causing villous atrophy and crypt hyperplasia in the mucosa of the small intestine.⁶

The clinical classification of celiac disease is based on the presence of gastrointestinal symptoms. In symptomatic, or classic, celiac disease, patients report diarrhea, with or without malabsorption, whereas in asymptomatic, or silent, celiac disease, gastrointestinal symptoms are absent or not prominent even though the patient might report other nonintestinal symptoms. Latent celiac disease describes a case in which it is thought that celiac disease will develop in the future (ie, with evidence of circulating antibodies in keeping with a serological diagnosis of celiac disease) or in which the patient had previous biopsy-proven celiac disease but currently has normal mucosa despite ingesting gluten.⁶

Neurological conditions are observed in 6% of patients with gluten sensitivity.⁷ It has been proposed that celiac disease is associated with a wide range of both common and rare neurological conditions, including migraine, encephalopathy, chorea, brain stem dysfunction, myelopathy, mononeuritis multiplex, Guillain-Barré–like syndrome, and peripheral neuropathy; however, the evidence for many of these proposed associations is weak.⁸ Cerebellar ataxia is the most common celiac disease–related neurological condition and also has the most robust evidence to suggest an association.⁴

The term gluten ataxia was first adopted by Hadjivassiliou and colleagues⁹ following a study of patients with idiopathic cerebellar ataxia demonstrated that circulating antibodies to gliadin were present in a significant proportion of these patients. Ataxia may be the only manifestation of celiac disease in some patients and, for many, the neurological symptoms precede the gastrointestinal symptoms of celiac disease,⁹ as in the case patient. Further studies have confirmed a high prevalence of antigliadin antibody positivity in sporadic cerebellar ataxia, with 41% of patients with sporadic idiopathic ataxia being positive for antigliadin antibodies in a study published in 2003.⁵

The exact neuropathology of gluten ataxia is unknown, but it is hypothesized that antigliadin antibodies cross-react with Purkinje cells in the cerebellum, causing irreversible depletion of Purkinje cells. Irreversible loss of Purkinje cells coupled with lymphocytic infiltration of the dorsal columns, cerebellum, and even peripheral nerves is the cause of the ataxic symptoms at presentation.^4,5 The most common clinical features of gluten ataxia are ataxia of limb, stance, and gait, as well as dysarthria.⁴ Over one-third of patients present with bladder dysfunction, dysphagia, and spontaneous nystagmus.⁴ Oculomotor symptoms may also be a feature of gluten ataxia.¹⁰

Gluten restriction has been proposed as a treatment for gluten ataxia, and should be mandatory for persons with a diagnosis of celiac disease. Pellecchia et al¹¹ reported a case of gluten ataxia that improved after 2 years of adhering to a gluten-free diet. A more recent study of 43 patients with a diagnosis of gluten ataxia demonstrated significant improvement in the objective measures of ataxia in subjects with serological confirmation of compliance with a gluten-free diet; no significant improvement was seen in those who were noncompliant with a gluten-free diet. Significant improvements were found in patients with biopsy-proven celiac enteropathy and in those with positive serology but no bowel involvement.¹²

Intravenous immunoglobulins (IVIGs) have also been proposed as potential treatment for patients with sporadic cerebellar ataxia in the context of positive celiac serology.¹⁰ Sander and colleagues¹⁰ reported a patient with ataxia and positive celiac serology who showed improvement in gait, speech, stair climbing, and other activities of daily living after being administered IVIGs. A more recent case series demonstrated an improvement of celiac-related ataxic symptoms in three patients who were treated with IVIGs.¹³ Symptoms were found to worsen with the cessation of IVIGs and to resolve with the recommencement of IVIG therapy. These patients had previously shown no symptomatic improvement, despite adherence to a strict gluten-free diet.¹³

In conclusion, unexplained cerebellar syndrome in an elderly patient should prompt screening for celiac disease, even in the absence of gastrointestinal symptoms.

Key Points
• More than one-third of cases of celiac disease are diagnosed in patients over 60 years of age
• Cerebellar ataxia is the most common neurological condition associated with celiac disease
• Ataxia may be the presenting feature of celiac disease and often precedes gastrointestinal symptoms
• Evidence for the efficacy of treatments for gluten ataxia (gluten-free diet and IVIGs) is limited
• Unexplained cerebellar syndrome in an elderly patient should prompt screening for celiac disease, even in the absence of gastrointestinal symptoms

The authors report no relevant financial relationships.

Dr. Fitzsimmons is a Specialist Registrar in Geriatric Medicine, Dr. Hulley is a Foundation Year 2 Doctor, and Dr. Loharuka is a Consultant Geriatrician, Royal Liverpool University Hospital, Liverpool, United Kingdom.