Neurologic Deficits in Patients With Newly Diagnosed Celiac Disease Are Frequent and Linked With Autoimmunity to Transglutaminase 6.

BACKGROUND & AIMS: Celiac disease is an autoimmune disorder induced by ingestion of gluten that affects 1% of the population and is characterized by gastrointestinal symptoms, weight loss, and anemia. We evaluated the presence of neurologic deficits and investigated whether the presence of antibodies to Transglutaminase 6 (TG6) increases the risk of neurologic defects in patients with a new diagnosis of celiac disease. METHODS: We performed a prospective cohort study at a secondary-care gastroenterology center of 100 consecutive patients who received a new diagnosis of celiac disease based on gastroscopy and duodenal biopsy. We collected data on neurologic history, and patients were evaluated in a clinical examination along with magnetic resonance imaging of the brain, magnetic resonance (MR) spectroscopy of the cerebellum, and measurements of antibodies against TG6 in serum samples. The first 52 patients recruited underwent repeat MR spectroscopy at 1 year after a gluten-free diet (GFD). The primary aim was to establish if detection of antibodies against TG6 can be used to identify patients with celiac disease and neurologic dysfunction. RESULTS: Gait instability was reported in 24% of the patients, persisting sensory symptoms in 12%, and frequent headaches in 42%. Gait ataxia was found in 29% of patients, nystagmus in 11%, and distal sensory loss in 10%. Sixty percent of patients had abnormal results from magnetic resonance imaging, 47% had abnormal results from MR spectroscopy of the cerebellum, and 25% had brain white matter lesions beyond that expected for their age group. Antibodies against TG6 were detected in serum samples from 40% of patients-these patients had significant atrophy of subcortical brain regions compared with patients without TG6 autoantibodies. In patients with abnormal results from MR spectroscopy of the cerebellum, those on the GFD had improvements detected in the repeat MR spectroscopy 1 year later. CONCLUSIONS: In a prospective cohort study of patients with a new diagnosis of celiac disease at a gastroenterology clinic, neurologic deficits were common and 40% had circulating antibodies against TG6. We observed a significant reduction in volume of specific brain regions in patients with TG6 autoantibodies, providing evidence for a link between autoimmunity to TG6 and brain atrophy in patients with celiac disease. There is a need for early diagnosis, increased awareness of the neurologic manifestations among clinicians, and reinforcement of adherence to a strict GFD by patients to avoid permanent neurologic disability.

Vertical nystagmus associated with glutamic acid decarboxylase antibodies responding to cyclophosphamide.

Several neurological disorders have been described in patients with autoimmunity associated with GAD antibodies. Among these disorders, nystagmus and oculomotor dysfunction are increasingly recognized, although they have been rarely reported isolated or as the main manifestation of anti-GAD autoimmunity. Moreover, therapeutic approaches for such patients are unclear. Here we present a 44-year-old man with disabling oscillopsia secondary to downbeat nystagmus, abnormal saccades, ocular pursuit and optokinetic nystagmus, as well as mild gait ataxia and cerebellar atrophy associated with high serum GAD antibodies with intrathecal secretion of such antibodies. The patient did not have clinical benefit with plasma exchange, but had a robust symptomatic improvement with cyclophosphamide. We discuss the possible pathogenic role of GAD antibodies in nystagmus and the role of immunotherapy in these patients.

Disabling Central Paroxysmal Positioning Upbeat Nystagmus and Vertigo Associated With the Presence of Anti-Glutamic Acid Decarboxylase Antibodies.

An immune attack by anti-glutamic acid decarboxylase (GAD) antibodies is believed to cause a deficiency in gamma-aminobutyric acid-mediated neurotransmission in the cerebellum. This, in turn, leads to several eye movement disorders, including spontaneous downbeat (DBN) and periodic alternating nystagmus. We describe a 68-year-old diabetic woman with disabling paroxysmal positioning upbeat nystagmus (UBN) exclusively in the supine position, associated with asymptomatic spontaneous DBN, alternating skew deviation and hyperactive vestibulo-ocular reflex responses on head impulse testing, in whom high titers of anti-GAD antibodies were detected. After treatment with intravenous immunoglobulin, a complete resolution of positioning UBN and spontaneous DBN occurred, along with a decrease in anti-GAD antibody titers. Positioning UBN in this case may reflect a transient disinhibition of the central vestibular pathways carrying posterior semicircular canal signals, due to lack of normal inhibitory input from the cerebellar nodulus/uvula. Immunoglobulin restored cerebellar inhibitory output, possibly by improving gamma-aminobutyric acid neurotransmission.

Nystagmus and ataxia associated with antiganglioside antibodies.

BACKGROUND: Antiganglioside antibodies are found in various neurological disorders that constitute a continuum from peripheral neuropathy to encephalitis. However, nystagmus has rarely been described in patients with ataxia associated with antiganglioside antibodies. METHODS: From January 2008 to July 2009, we identified 3 patients with acute ataxia and nystagmus in 2 University Hospitals of Korea, who were found to have anti-GD1b, anti-GM1, or anti-GQ1b antibodies. RESULTS: In addition to acute ataxia, all 3 patients showed various combinations of nystagmus, which included central positional nystagmus (n = 3), vertical nystagmus (n = 1), and periodic alternating nystagmus (n = 1). The spontaneous and positional nystagmus were mostly detectable only with the elimination of fixation and magnification of the eyes using video goggles. Two patients also exhibited gaze-evoked nystagmus that was noticeable without the aid of video goggles. Patients had serum IgG antibodies to GD1b, GM1, or GQ1b. Cerebrospinal fluid examination, nerve conduction studies, and brain MRI were normal. In all patients, the symptoms and signs resolved over 3-12 months. CONCLUSIONS: Various forms of nystagmus with acute ataxia may be a sole or predominant manifestation of disorders related to antiganglioside antibodies. The nystagmus indicates a central pathology involving the cerebellum or brainstem in this antibody-associated disorder. Antiganglioside antibodies should be measured in patients with nystagmus and acute ataxia of undetermined etiology.

Downbeat nystagmus, ataxia and spastic tetraparesis due to coeliac disease.

A 25-year-old female presented to a university neurology clinic with a 1-month history of progressive ataxia, downbeat nystagmus and spastic tetraparesis. Personal history revealed polyarthralgias and weight loss. Family history was negative. Following thorough history, laboratory, neurophysiological and MRI investigations, a diagnosis of cerebellar ataxia due to coeliac disease was done. The patient was treated with strict gluten-free diet and intravenous administration of immunoglobulins. Although there are many controversies about neurological manifestations of coeliac disease, this case pointed to strong association between these two disorders. The findings of elevated protein content in the cerebrospinal fluid with positive oligoclonal bands suggested an immune-mediated process, further supported by positive anti-endomysium antibodies and anti-transglutaminase antibodies in the cerebrospinal fluid.

Wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) syndrome in a patient with neuromyelitis optica spectrum disorder and anti-aquaporin-4 antibody.

This report describes, for the first time, an occurrence of wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) in a 19-year-old female with neuromyelitis optica (NMO) spectrum disorder, who had anti-aquaporin-4 (AQP4) antibody. A high signal intensity lesion on T2-weighted MRI was detected in the midbrain tegmentum adjacent to the aqueduct, and presumably involved the medial longitudinal fasciculus bilaterally at the caudal levels. Plasma exchange resolved both WEBINO syndrome and the midbrain lesion. Although WEBINO syndrome is occasionally reported in multiple sclerosis patients, diagnosis of NMO should not be excluded in patients with WEBINO syndrome, because AQP4 is expressed abundantly around the periaqueductal region.

Oculomotor involvement in myotonic dystrophy type 2.

Oculomotor function has not been studied in patients with myotonic dystrophy type 2 (DM2). We report the presence of rebound nystagmus in seven of eight patients with DM2 in the absence of a structural brainstem or cerebellar lesion. The rebound nystagmus observed in these patients is very suggestive of ocular myotonia, and examination of patients using video-Frenzel goggles may be a useful method for diagnosing myotonia of the extraocular muscles.

Anti-GAD antibodies and periodic alternating nystagmus.

BACKGROUND: Autoantibodies directed against glutamic acid decarboxylase (GAD-Ab) have recently been described in a few patients with progressive cerebellar ataxia, suggesting an autoimmune physiopathologic mechanism. OBJECTIVE: To determine the exact role of GAD-Ab and gamma-aminobutyric acid (GABA)-ergic neurotransmission in the pathogenesis of cerebellar ataxia. DESIGN: Case report. SETTING: University neurological hospital. PATIENT: We report the case of a patient with subacute cerebellar ataxia associated with GAD-Ab showing periodic alternating nystagmus (PAN). INTERVENTION: Baclofen, a GABAergic medication, was given to the patient. MAIN OUTCOME MEASURES: Eye movement recording of spontaneous nystagmus and postrotatory vestibular responses. RESULTS: Baclofen was effective in suppressing PAN and improving postrotatory vestibular responses but not for improving cerebellar ataxia. CONCLUSION: The presence of PAN and the response to baclofen provide a unique opportunity to suggest a direct role of GAD-Ab in cerebellar dysfunction in this patient.

Autoantibodies to glutamic acid decarboxylase in downbeat nystagmus.

The cause of downbeat nystagmus (DBN) remains undiagnosed in about 40% of patients. This paper reports the presence of antiglutamic acid decarboxylase antibodies (GAD-Ab) in a patient with DBN. Antibodies against GABAergic neurons located in the vestibular complex may induce chemical denervation of the floccular neurons, which normally suppress the peripheral imbalance between vertical semicircular canal systems, thereby causing DBN. Testing for GAD-Ab may be indicated in DBN patients without an identifiable anatomical brain lesion.

Ocular flutter and truncal ataxia may be associated with enterovirus infection.

We report on three patients who presented a rare, uniform clinical syndrome consisting of ocular flutter and truncal ataxia. In all patients the symptoms followed an upper respiratory infection and resolved without sequelae within a few weeks. Previous reports have emphasized the apparent relationship of this entity to infectious disease, but the infectious agent remained uncertain. In one patient we could find a significant rise in antibody titres to enterovirus. We are not aware of any other similar documented case.

Medical treatments for abnormal eye movements: pharmacological, optical and immunological strategies.

PURPOSE: To review current medical treatments for nystagmus and saccadic intrusions, and their visual consequences. METHODS: Evaluation of studies that have used reliable measurement of eye movements and visual acuity before and after treatment. Interpretation of results in light of physiological and pharmacological studies in animals, and recent immunological advances. RESULTS: There are many case reports of patients with abnormal eye movements being improved by a variety of drugs, but few double-blind, controlled studies have been carried out. Most promising are agents that mediate their effects through the neurotransmitter gamma-aminobutyric acid; such drugs include baclofen and gabapentin. Botulinum toxin, injected into selected extraocular muscles or the retrobulbar space, can abolish nystagmus for several months, but often produces troublesome side-effects, such as diplopia and ptosis, which limit its value. Optical measures to either reduce nystagmus by manipulating vergence angle, or reduce retinal image motion, help some patients. Opsoclonus occurring in association with cancer may be successfully treated with an immuno-adsorption technique using a protein A column. CONCLUSIONS: There is need for controlled, blinded studies to evaluate the many agents reported to improve visual symptoms in individual patients with abnormal eye movements.

Recurrent hearing impairment and nystagmus induced by repeated antigen exposure in actively sensitized guinea pigs.

Although many studies have suggested a relation between allergy and Ménière's disease, the pathophysiology of this condition remains controversial. The aim of this study was to clarify whether an anaphylactic reaction in the inner ear can disturb hearing and equilibrium, and whether such disturbances recur in response to repeated anaphylactic reactions. Increases in audiological threshold, nystagmus, and endolymphatic hydrops were observed in response to a single exposure to antigen administered to actively sensitized guinea pigs. The increase in audiological threshold was maximal 10 h after antigen challenge (p < 0.005) and returned to the baseline level after 7 days. Nystagmus and the increase in audiological threshold induced by antigen exposure were inhibited by prior administration of pemirolast potassium (p < 0.05), an inhibitor of chemical mediator release from mast cells. A second challenge with antigen 7 days after the first also induced an increase in audiological threshold (p < 0.05) and nystagmus. These results suggest that studies of repeated antigen challenge in actively sensitized animal models may increase our understanding of the pathophysiology of Ménière's disease.

Anti-Hu antibody in a neuroblastoma-associated paraneoplastic syndrome.

A 20-month-old infant with Turner syndrome presented with opsoclonus-myoclonus and tonic pupils in association with an abdominal neuroblastoma. Despite complete removal of the tumor, the child developed progressive hearing loss, areflexia, and seizures. Immunohistochemical and Western blot studies of serum and cerebrospinal fluid revealed the presence of anti-Hu antineuronal antibody, which cross-reacted with areas of the patient's tumor. Treatment with intravenous immunoglobulin coincided with the resolution of opsoclonus-myoclonus and the cessation of new neurologic symptoms. This case provides direct support for the autoimmune basis of paraneoplastic symptoms associated with neuroblastoma and suggests that treatment with intravenous immunoglobulin may be of value.