Celiac Disease and Childhood Stroke Fiona C. Goodwin, MB, ChB*, R. Mark Beattie, BSc, MB, BS*, John Millar, BM, BS†, and Fenella J. Kirkham, BA, MB, BChir* Celiac disease is associated with a diversity of central nervous system manifestations although an association with stroke has not been documented. This case report describes a child who presented with a recurrent transient hemiplegia. Magnetic resonance imaging of the brain confirmed infarction; transcranial Doppler studies and magnetic resonance angiography were abnormal. Although there were virtually no gastrointestinal symptoms and the child was thriving, celiac disease serology was strongly positive and a duodenal biopsy confirmed the disease. Tissue transglutaminase is the major autoantigen in celiac disease and is thought to maintain vascular endothelial integrity. Antiendomysial immunoglobulin A antibodies, demonstrated to be the same autoantibody as antitransglutaminase, react with cerebral vasculature, suggesting an autoimmune mechanism for celiac disease associated vasculopathy. Because celiac disease is a potentially treatable cause of cerebral vasculopathy, serology—specifically antitissue transglutaminase antibodies—should be included in the evaluation for cryptogenic stroke in childhood, even in the absence of typical gut symptoms. © 2004 by Elsevier Inc. All rights reserved. Goodwin FC, Beattie RM, Millar J, Kirkham FJ. Celiac disease and childhood stroke. Pediatr Neurol 2004;31: 139-142. Introduction Stroke in childhood often has no identifiable underlying cause. In those children with idiopathic stroke, the risk of recurrence is difficult to predict and no intervention is of From the Departments of *Child Health and †Neuroradiology, Southampton General Hospital, Southampton, United Kingdom. © 2004 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2004.02.014 ● 0887-8994/04/$—see front matter proven benefit in reducing that risk. Celiac disease is a common disorder in childhood, caused by an inappropriate immune response to dietary gluten. An association with cutaneous vasculitis, other autoimmune disorders, malignancy, and a diversity of neurologic disorders are widely reported in adults, but, in contrast to both Crohn’s disease and ulcerative colitis, a link with childhood stroke has not previously been described. This study presents a child with stroke in whom celiac disease was also diagnosed, although no typical symptoms or signs of the disease were evident. Tissue transglutaminase has recently been identified as the major autoantigen in celiac disease. We postulate a mechanism by which a disease-specific vasculopathy could arise in association with celiac disease. This association, if confirmed, is of particular significance as celiac disease is common, treatable, and not always associated with gastrointestinal symptoms. Case Report A 3-year-old female presented with recurrent episodes of transient weakness of the left arm and unsteady gait, each episode lasting about 5 minutes. There was no systemic disturbance or change in conscious level. Five episodes occurred in 24 hours, and they continued to occur less frequently over the following 48 hours. Interim neurologic examinations were entirely normal. A further transient episode, lasting 4 hours, occurred 2 months later. At the age of 2, the child had had recurrent diarrhea, not severe nor protracted enough to impact on weight gain. This condition resolved after a period of milk reduction, and there had been no gastrointestinal symptoms in the 6 months before presentation. There was no history of misery, lethargy, abdominal distension, or pale stools, and there were no developmental concerns. She had chicken pox a year previously. The child was systemically well, with height and weight at the 91st centile for age. Her physical examination was entirely normal. Computed tomographic imaging demonstrated a low-density lesion in the head of the right caudate nucleus, within which was a small contrast-enhancing focus. There were two additional foci of abnormal signal adjacent to the lateral ventricle and one in the anterior limb of the internal capsule, none of which enhanced with contrast. These findings were consistent with infarcts in the territory of a perforator of the anterior or middle cerebral artery. Transcranial Doppler studies revealed significant asymmetry in mean flow velocity with increased velocity on the right (right middle cerebral artery velocity 127 cm/second [normal for age ⬍114 cm/second]; left middle cerebral artery velocity 87 cm/second; difference 46%, normal ⬍8%). Magnetic resonance imaging (without gadolinium) confirmed the lesions (Fig 1). Magnetic resonance angiography revealed narrowing of the supraclinoid segment of the right proximal middle cerebral artery (Fig 2). Antiendomysial immunoglobulin A antibodies were strongly positive and antitransglutaminase antibodies were grossly elevated at over 200 Communications should be addressed to: Dr. Goodwin; Department of Paediatric Neurology; Southampton General Hospital; Tremona Road; Southampton, SO16 6YD; UK Received July 17, 2003; accepted February 19, 2004. Goodwin et al: Celiac Disease and Childhood Stroke 139 Figure 1. Axial proton density weighted magnetic resonance imaging (TR 2500 ms; TE 14 ms; Slice thickness 5 mm; gap 2 mm) at the level of the lateral ventricles reveals high signal and atrophy in the head of the right caudate nucleus (arrow) consistent with an infarct. Images of the two additional areas of infarction are not shown. U/mL (normal 1-15 U/mL). Anti-tissue-transglutaminase antibody assay has recently been introduced into clinical practice as a serologic screening test for celiac disease; immunoglobulin A antibodies against tissue-transglutaminase are measured using an enzyme-linked immunosorbent assay. A duodenal biopsy confirmed the diagnosis of celiac disease. She had a persistent mild lymphopenia; complement C3 and C4 were at the lower limit of normal; erythrocyte sedimentation rate was 4 mm/hour. Immunoglobulin subclasses were normal; vitamin B12 428 ng/L (normal range 211-911) and serum folate 16.8 ␮g/L (normal range 1.1-20 ␮g/L). Echocardiography demonstrated a structurally normal heart with no thrombi or vegetations. Prothrombotic investigations, including thermolabile methylene tetrahydrofolate reductase, factor V Leiden, and prothrombin 20210, were normal. Urine organic acids, cholesterol, and triglycerides were also normal. The child was placed on a gluten-free diet, aspirin, and folate supplements; her energy levels and mood improved significantly, and in retrospect her parents realized she had been more miserable and lethargic than normal for many months. One year later she was neurodevelopmentally normal but had had two periods of stuttering speech lasting a few days. Doppler studies indicated that the right middle cerebral artery velocity had decreased to the upper limit of normal (115 cm/second) but the significant asymmetry between right and left middle cerebral artery velocities persisted (43%). Discussion Celiac disease is an autoimmune disease associated with intolerance to the gliadin component in dietary gluten [1]. 140 PEDIATRIC NEUROLOGY Vol. 31 No. 2 Ongoing dietary exposure to gluten perpetuates an enteropathy and may give rise to malabsorption, with chronic diarrhea, weight loss, and abdominal distention. Misery and irritability are characteristic features in children. Antiendomysial, antitransglutaminase, antigliadin, and antireticulin immunoglobulin A antibodies are associated with celiac disease and are used both for serologic diagnosis and monitoring; a definitive diagnosis is made by duodenal biopsy. Celiac disease is treated by exclusion of gluten from the diet, resulting in healing of the enteropathy and normalization of small bowel function. It has been suggested that neurologic disease occurs in 10% of adults with celiac disease, although there are no epidemiologic studies. The most common manifestations are ataxia, dementia, and peripheral neuropathy [2]; epilepsy, myelopathy, encephalopathy, internuclear ophthalmoplegia, brainstem encephalitis, and multifocal leucencephalopathy have also been reported [3,4]. A specific syndrome of occipital calcification and epilepsy is described [5], as well as a degenerative cerebellar syndrome with or without myoclonic epilepsy [6]. The neuropathology observed in these diverse presentations is heterogeneous, with both degenerative changes and evidence of autoimmune mechanisms such as inflammation and demyelination. Central nervous system manifestations are often relentlessly progressive despite dietary restriction. The role of nutritional deficiencies in the evolution of neurologic complications, in particular folate, cobalamin, or magnesium, is unclear. Celiac disease is associated with vasculitis in various tissues. Severe cutaneous vasculitis is well documented and does not always reflect the severity of gut disease nor necessarily respond to dietary restriction. Rush et al. reported biopsy-proven central nervous system vasculitis in association with celiac disease [7], and Ozge’s patient with recurrent stroke and celiac disease had evidence of a central nervous system vasculitis [8]. The syndrome of occipital calcification reported in association with celiac disease might arise as a consequence of autoimmune endothelial inflammation [5], to which the posterior cerebral circulation might be selectively vulnerable. Celiac disease often presents atypically and is underdiagnosed unless screening is undertaken [9]. Occult forms of celiac disease, where serology and duodenal biopsy confirm the disease in the absence of typical gut symptoms, are not infrequent and have recently been classified [10]. The frequency with which neurologic disease may be manifest in occult celiac disease is not yet certain. Hadjivassiliou et al. [3] estimated that undiagnosed celiac disease was evident in 16% of patients with neurologic disease of unknown cause, ataxia being the commonest symptom. Seven percent of patients newly diagnosed with celiac disease presented initially with neurologic symptoms in Luostarinen’s series [2]; there was a striking paucity of gastroenterologic symptoms in this group despite severe neurologic disease. Kieslich et al. [4] prospectively assessed a group of children with biopsy-proven Figure 2. Maximum intensity projections from a 3D “time of flight” magnetic resonance angiogram (TR 36 ms; TE 7 ms; slice thickness 1 mm; gap 0 mm) reveals narrowing of the proximal middle cerebral artery. celiac disease for neurologic disease. Twenty percent of the group manifested white matter lesions on computed tomography or magnetic resonance imaging, unrelated to clinical features, which the authors suggested might arise from vasculitic ischemia or inflammatory demyelination. Celiac disease is an autoimmune disorder, and tissue transglutaminase has recently been identified as the major autoantigen [1]. Transglutaminase is an enzyme with numerous isoforms, of which tissue transglutaminase is thought to be integral to the maintenance of vascular endothelial integrity and cellular apoptosis [1,11,12]. Tissue transglutaminase is released in response to cellular injury, crosslinking proteins to stabilize the wound and protect it from further injury [1]. It is widely distributed throughout the brain and is most abundant in the caudate, putamen, and substantia nigra [12]; its involvement in apoptosis of neuronal cells has been specifically demonstrated [12]. Tissue transglutaminase appears to be transformed into an immunogenic pathogen by its interaction with dietary gluten in the gut. Although a susceptible population with the human leukocyte-associated antigen subtype DQ2 and 8 is identified, the initiating trigger for autoimmune pathogenesis remains to be established [1,10,11]. Pratesi and coworkers elegantly demonstrated in vitro that antiendomysial antibodies immunofluoresce with cerebral vasculature [13]. The work of Korponay-Szabo et al., which suggests that antiendomysial and antitransglutaminase antibodies are identical [14], makes it likely that the immunofluorescence observed by Pratesi et al. was with cerebrovascular transglutaminase. Autoimmune activation against transglutaminase in brain vascular endothelium can therefore be postulated. The dominant antibody profile in celiac disease is directed against epitopes in the functional domains of tissue transglutaminase [15]. This phenomenon might give rise to a disease-specific vasculopathy as a consequence of impaired tissue transglutaminase function. Laboratory data suggest a role for tissue transglutaminase in blood– brain barrier mechanisms [12]; thus disruption of cerebrovascular transglutaminase could interfere with blood– brain barrier integrity, facilitating activation of autoimmune mechanisms within the central nervous system. Neuronal degeneration might then arise as a consequence of disrupted transglutaminase apoptotic function. Transglutaminase is implicated in a variety of degenerative neurologic diseases including dementia, Huntington’s disease, and Parkinson’s disease [1,11]. Altered function and expression of tissue transglutaminase in atheromatous disease has been demonstrated [11] and although the pathogenesis is clearly different, the possibility that tissue transglutaminase is involved in degenerative vascular disease is of interest. We initially considered this child to have chickenpoxassociated vasculopathy. Varicella zoster has been demonstrated to infect cerebral vessels, directly invading the vascular wall. Varicella, or other infectious agents, might provide the initial vascular injury, which cannot be adequately repaired as a result of impaired tissue transglutaminase function. The neurologic presentation of this child appears to be a manifestation of celiac disease. Despite high titers of autoantibodies and definite duodenal biopsy abnormalities, the gut symptoms usually observed with celiac disease were absent. We hypothesize that a diseasespecific autoimmune vasculopathy is the mechanism un- Goodwin et al: Celiac Disease and Childhood Stroke 141 derlying the child’s stroke. The autoimmunity against tissue transglutaminase in celiac disease, expression of tissue transglutaminase in brain vascular endothelium, and demonstration that antiendomysial antibodies immunofluoresce with cerebral vasculature provide a mechanism by which vascular disease could arise. References [1] Dieterich W, Ehnis T, Bauer M, et al. 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