Howard W. Sander

Immune Cross-Reactivity in Celiac Disease: Anti-Gliadin Antibodies Bind to Neuronal Synapsin I

Celiac disease is an immune-mediated disorder triggered by ingestion of wheat gliadin and related proteins in genetically susceptible individuals. In addition to the characteristic enteropathy, celiac disease is associated with various extraintestinal manifestations, including neurologic complications such as neuropathy, ataxia, seizures, and neurobehavioral changes. The cause of the neurologic manifestations is unknown, but autoimmunity resulting from molecular mimicry between gliadin and nervous system proteins has been proposed to play a role. In this study, we sought to investigate the immune reactivity of the anti-gliadin Ab response toward neural proteins. We characterized the binding of affinity-purified anti-gliadin Abs from immunized animals to brain proteins by one- and two-dimensional gel electrophoresis, immunoblotting, and peptide mass mapping. The major immunoreactive protein was identified as synapsin I. Anti-gliadin Abs from patients with celiac disease also bound to the protein. Such cross-reactivity may provide clues into the pathogenic mechanism of the neurologic deficits that are associated with gluten sensitivity.

Etanercept (Enbrel®) therapy for chronic inflammatory demyelinating polyneuropathy

Patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and/or variants who were refractory or intolerant of standard therapies were treated with etanercept, 25 mg twice per week. Ten patients underwent treatment, and manual muscle strength, sensory thresholds and functional abilities were tested prior to and 4-6 months after initiating therapy. Three patients had significant improvement and three others had possible improvement. Based on these preliminary observations, treatment with etanercept may be considered in patients with CIDP, who cannot undergo standard therapies, although its efficacy in CIDP needs to be examined in a double-blinded, controlled clinical trial.

Ganglioside reactive antibodies in the neuropathy associated with celiac disease

We tested patients with celiac disease (CD) for the presence of serum anti-ganglioside antibodies. Six of twenty-seven patient sera were reactive against brain gangliosides by an agglutination immunoassay. Neurological examination in all six revealed the presence of distal sensory loss, consistent with the diagnosis of peripheral neuropathy. When tested by ELISA for antibodies to isolated GM1, GM2, GD1a, GD1b, GT1b, and GQ1b gangliosides, all six were positive for IgG antibodies to at least one. The neuropathy of celiac disease may be autoimmune and associated with anti-ganglioside antibodies. The presence of IgG reactivity furthermore implicates a T cell-mediated response to ganglioside antigens.

Quadriplegic areflexic ICU illness: Selective thick filament loss and normal nerve histology

Areflexic quadriplegia that occurs in the intensive care unit (ICU) is commonly ascribed to critical illness polyneuropathy based upon electrophysiology or muscle light microscopy. However, electron microscopy often documents a selective thick filament loss myopathy. Eight ICU patients who developed areflexic quadriplegia underwent biopsy. Seven patients had received steroids, and 2 had also received paralytic agents. Electrodiagnostic studies revealed absent or low‐amplitude motor responses in 7. Sensory responses were normal in 5 of 6 and absent in 1. Initial electromyography revealed absent (n = 3), small (n = 3), or polyphasic (n = 1) motor unit potentials, and diffuse fibrillation potentials (n = 5). In all 8, light microscopy of muscle revealed numerous atrophic‐angulated fibers and corelike lesions, and electron microscopy revealed extensive thick filament loss. Morphology of sural and intramuscular nerves, and, in one autopsied case, of the obturator nerve and multiple nerve roots, was normal. Although clinical, electrodiagnostic, and light microscopic features mimicked denervating disease, muscle electron microscopy revealed thick filament loss, and nerve histology was normal. This suggests that areflexic ICU quadriplegia is a primary myopathy and not an axonal polyneuropathy.

Mechanisms underlying celiac disease and its neurologic manifestations

Abstract.The extra-intestinal manifestations of celiac disease (CD), including ataxia and peripheral neuropathy, are increasingly being recognized as the presenting symptoms of this autoimmune disease. Although there is a greater understanding of the pathogenesis of the intestinal lesions in CD the mechanisms behind the neurologic manifestations of CD have not been elucidated. In this article, the authors review the cellular and molecular mechanisms behind the histopathologic changes in the intestine, discuss the presentation and characteristics of neurologic manifestations of CD, review the data on the mechanisms behind these manifestations, and discuss the diagnosis and treatment of CD. Molecular mimicry and intermolecular help may play a role in the development of neurologic complications.

Cerebellar ataxia and coeliac disease

A 37-year-old woman presented in July, 2002, with a 12-year history of progressive dysarthria and ataxia. Her symptoms became noticeably worse during pregnancy in 1999 and 2001. She had also been anaemic for the past 7 years, and coeliac disease had been diagnosed in 1997. At that time, she had high serum concentrations of IgG and IgA antibodies to gliadin, an endomysial titre of 1:32, and duodenal atrophy on endoscopy; a duodenal biopsy showed subtotal villous atrophy. Neurological tests were done at the same time; median somatosensory evoked potentials showed a delay between the lower brainstem and cortex. She underwent tests for spinocerebellar ataxia, 1–3 brainstem auditory and visual evoked potentials, and cerebral MRI, none of which showed any abnormalites. Cervical spine MRI showed mild degenerative changes. For 5 years, she had followed a strict gluten-free diet, but on examination in 2002 she had severe dysarthria, left finger-to-nose dysmetria, poor right rapid-alternating and fine-finger movements, diminished pedal pin-perception, ankle areflexia, and a severely ataxic, wide-based gait. A modified (without Archimedes Spiral) International Cooperative Ataxia Rating scale (ICARS) score was 31/96. 4 We did many serological tests for autoimmune disease including IgG and IgA antibodies to gliadin, purkinje cells, and voltage-gated calcium channels. The only abnormal results were increased IgA antibodies to transglutaminase, and glutamic acid decarboxylase (GAD). Cerebral MRI showed superior vermis atrophy, whereas lumbosacral MRI was normal. Sensory nerve conduction amplitudes were low. H reflexes were absent. Electromyography showed prolonged durations of motor unit potentials distally. We did not do a nerve biopsy, and we do not have the facilities to do indirect immunohistochemistry or immunofluoresence. We treated her with intravenous immunoglobulin (IVIg) 2 g/kg initially, and 0.5 g/kg 2 weeks later. Within a month, she reported substantial improvements in her speech and gait. She was able to safely hold her children. Acquaintances noted that the audible slap of her walk CASE REPORT disappeared. Squatting, walking, stair-climbing, tandem gait, and standing on one leg all became much easier, and she no longer spilt cups of liquid. On examinaton, we found that all the neurological signs had improved; she still had slight dysarthria and left finger-nose dysmetria, an unsteady gait with a widened base and very slight slapping, and impaired tandem walking, and we calcuated a modified ICARS score of 3/96. She developed a slight rash, so we stopped IVIg and gave her a single dose of methylprednisolone. However, 5 …

Quantitative sensory testing: high sensitivity in small fiber neuropathy with normal NCS/EMG

Abstract  We evaluated the diagnostic sensitivity of quantitative sensory testing (QST), using the CASE IV system, in 14 patients with clinically diagnosed small‐fiber neuropathy and normal traditional electrodiagnostic studies. All patients had at least 1 abnormal threshold, 13 patients had abnormal heat‐pain thresholds, 8 had abnormal cold thresholds, and 7 had abnormal vibration thresholds. QST is therefore highly effective in documenting dysfunction in small fiber neuropathy patients.

Characteristics of patients with sensory neuropathy diagnosed with abnormal small nerve fibres on skin biopsy

Clinical, laboratory and electrodiagnostic (EDX) characteristics of 62 patients with sensory neuropathy with abnormal skin biopsies were reviewed. Reduced epidermal nerve fibre density (ENFD) was seen in 71% and morphological changes with normal ENFD were seen in 29% of the patients. Patients with small fibre sensory neuropathy may have associated large fibre loss undetected by routine EDX. Identified associations included abnormal glucose metabolism, Lyme vaccination, monoclonal gammopathy, vitamin B12 deficiency, coeliac disease, and diseases of the connective tissue, inflammatory bowel and thyroid. Sensory neuropathy remained undetermined in 50% of the patients.

Effect of intravenous immunoglobulin on cerebellar ataxia and neuropathic pain associated with celiac disease

Background:  Cerebellar syndrome and small fiber neuropathy may complicate celiac disease (CD) and may be resistant to a strict gluten‐free diet.

Neurologic Complications of Celiac Disease

Neurologic complications of celiac disease (CD) include ataxia and peripheral neuropathy, which can be the presenting symptoms and signs. Early diagnosis and intervention could prevent development of further neurologic and systemic complications. Questions remain regarding the prevalence of the neurologic complications, the pathophysiological mechanisms, and the effectiveness of therapy or response to a gluten-free diet.