Progressive myoclonic ataxia in celiac disease: mysterious gut-brain entanglement

Dear Sir, Progressive myoclonic ataxia (PMA) is a neurological syndrome characterized by cerebellar ataxia, myoclonus, and infrequent epilepsy without significant cognitive decline.[1] While it is classically associated with inherited metabolic or mitochondrial disorders, acquired immune-mediated conditions such as celiac disease (CD) can present similarly and may be under-recognized if not actively considered.[1] CD is triggered by gluten ingestion in genetically predisposed individuals and is characterized histologically by small intestinal villous atrophy. Though commonly associated with gastrointestinal symptoms and malabsorption, it often manifests extra-intestinal features, especially neurological manifestations, including ataxia, peripheral neuropathy, seizures, and rarely, myoclonus.[2] Among these, gluten ataxia is the most recognized entity. However, the combination of ataxia, myoclonus, and epilepsy resembling PMA has rarely been reported in CD.[2,3] A 22-year-old female, born of a nonconsanguineous parentage, presented with a 12-year history of progressive neurological symptoms. At age 10, she developed episodes of focal and generalized tonic-clonic seizures along with myoclonic jerks, with an incomplete response to antiepileptics. The jerks were generalized and affected both feet on movement or when trying to walk. Over the subsequent year, she developed slurred speech, hand incoordination, gait imbalance, and repeated falls. She became wheelchair-bound by age 16. At age 17, she reported recurrent abdominal pain and vomiting without diarrhea, accompanied by weight loss and anorexia. Anti-tissue transglutaminase (anti-TTG), anti-endomysial, and anti-gliadin antibodies were negative. However, moderate villous atrophy on duodenal biopsy confirmed CD. A gluten-free diet (GFD) resulted in resolution of gastrointestinal symptoms and a significant decline in seizure frequency. Although ataxia and myoclonus did not improve, they have remained static since then. Neurological examination at presentation revealed intact cognition, oculomotor apraxia, pan-cerebellar ataxia, and generalized myoclonic jerks with stimulus-sensitive myoclonus involving both feet [Video 1]. While brain magnetic resonance imaging revealed pan-cerebellar atrophy [Figure 1], the electroencephalogram showed no epileptiform discharges. Serum B12 was low at 188 pmol/L (normal value = 211–941 pmol/L). A repeat duodenal biopsy at age 22 was normal. Although genetic evaluation for ataxia and myoclonus could not be performed due to financial constraints, a diagnosis of CD-associated PMA was considered in view of the significant reduction in seizure frequency and stabilization of ataxia and myoclonus following the institution of a GFD. The GFD was continued, and vitamin B12 and levetiracetam 750 mg orally twice daily were advised. Ataxia and myoclonus remained static and failed to improve at the 1-year follow-up. {"href":"Single Video Player","role":"media-player-id","content-type":"play-in-place","position":"float","orientation":"portrait","label":"Video 1","caption":"","object-id":[{"pub-id-type":"doi","id":""},{"pub-id-type":"other","content-type":"media-stream-id","id":"1_ri1ktivk"},{"pub-id-type":"other","content-type":"media-source","id":"Kaltura"}]} Figure 1: Brain magnetic resonance imaging. Brain magnetic resonance imaging showing sagittal (A) and axial (B) T2 sequences demonstrating pan-cerebellar atrophyAlthough CD is classically associated with gastrointestinal symptoms, neurological manifestations may precede them in up to 36% of patients.[2] Nearly 2% of CD cases can be triple (anti-TTG, anti-endomysial, and anti-gliadin) antibody negative and pose a diagnostic challenge, wherein duodenal biopsy remains essential for confirmation.[4] The underlying mechanisms of neurological manifestations are largely immune-mediated, with both humoral and cell-mediated processes being implicated.[2] Furthermore, malabsorption-related deficiencies of cobalamin (B12) and other B vitamins can aggravate neurological manifestations,[2] as was seen in our patient. While immune-mediated involvement of the cerebellum and motor cortex in CD appears to be the likely cause of stimulus-sensitive foot myoclonus, its exact pathophysiology remains unclear. Although cortical myoclonus results from hyperexcitability of the primary sensorimotor cortex, it has also been linked to pathological involvement of the cerebellum. Moreover, neurophysiological studies have suggested an inhibitory cerebellar control, via the cerebello-thalamo-cortical pathway, over the motor cortex. Therefore, cerebellar involvement may precipitate or aggravate cerebral hyperexcitability or disinhibition, as seen in CD.[5] CD-related PMA may benefit from early diagnosis and institution of a GFD. While early initiation of a GFD can stabilize or improve symptoms, established cerebellar atrophy with loss of Purkinje cells may be irreversible.[6] With a diagnostic delay of 7 years, it is likely that cerebellar atrophy in our patient became irreversible, resulting in failure to respond to GFD. While all five cases of CD-related PMA in a recent series failed to improve on a GFD, three of them showed minimal symptomatic benefit with levetiracetam.[3] CD should be suspected in a patient with PMA, as neurological features may predate the onset of gastrointestinal symptoms. Acknowledgement Nil. Author contribution 1. Research project: a. Conception: Niraj Kumar b. Organization: Ishita Desai, Rajat Manchanda, Mritunjai Kumar, Ashutosh Tiwari, Niraj Kumar c. Execution: Ishita Desai, Rajat Manchanda, Mritunjai Kumar, Ashutosh Tiwari 2. Statistical analysis: a. Design: b. Execution: c. Review and Critique: 3. Manuscript preparation: a. Writing of the first draft: Ishita Desai b. Review and Critique: Rajat Manchanda, Mritunjai Kumar, Ashutosh Tiwari, Niraj Kumar Ethical compliance statement The authors obtained approval from Institute ethics committee. The authors confirm that this work is consistent with the Journal’s position on issues involved in ethical publication. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.