Acrodystrophic Axonal Polyneuropathy With Celiac Disease

A Case Report

S. N. Bardakov; Minh Duc Tran; S. V. Lapin; A. N. Moshnikova; E. U. Kalinina; E. G. Bogdanova; A. V. Bolekhan; B. L. Gavriluk


J Med Case Reports. 2021;15(615) 

In This Article

Discussion and Conclusions

The clinical symptoms of symmetric axonal sensorimotor polyneuropathy were an extraintestinal manifestation of celiac disease, as was the encephalopathy detected during subsequent examinations. The uncommon features that differentiated this case included pronounced trophic disorders (nonhealing trophic ulcers, hyperkeratosis, and anhidrosis), and the absence of clinical manifestations of enteropathy in the presence of gross morphological changes in the duodenal mucosa. Clinical–electroneuromyographic dissociation was also noted, which was represented by a significant decrease in the amplitudes of the M waves of the lower-extremity nerves with complete muscle-strength conservation in the distal regions. Together, these features caused a diagnostic delay of 8 years.

Gluten neuropathy is one of the most common extraintestinal manifestations of celiac disease and gluten hypersensitivity and usually occurs in males in their early fifties. In this case, however, the manifestation occurred much earlier in a 31-year-old.[3,10,11] Neuropathy was the only manifestation of celiac disease, which is in line with described cases of peripheral nerve damage that occurs before and after the development of intestinal manifestations, as well as in isolation.[10,21]

The gradual development of symmetric hypoesthesia in the lower extremities corresponded to the most common chronic course of gluten neuropathies,[3,10,23] which is in contrast to the more rare, acute forms described in children.[19,29,32] The ascending character of hypoesthesia, followed by impaired vibration sensitivity, made it possible to classify this variant as symmetric, sensorimotor polyneuropathy involving length-dependent neuropathy, which is the second most common after polyneuropathy of thin fibers.[10,14,15,21] Despite the duration of disease in this case, there was no muscle weakness, which has been reported in 10% of cases of sensorimotor axonal forms.[10,11,21] In the presence of NCS signs of axonopathy of sensory fibers, a pronounced dissociation was observed between the absence of muscle weakness and the presence of gross axonal damage to the motor fibers, with a complete block of the peroneal and tibial nerves in the distal regions.

Possible causes of polyneuropathy based on the idea of malabsorption[10] due to celiac disease were excluded by assessing the levels of vitamins B1, B6, and B12 and folic acid. In addition, antibodies to gangliosides (which are observed in 65% of cases[21] due to the presence of molecular mimicry mechanisms between gliadin epitopes and nerve antigens) were not detected.[10,33]

Gluten neuropathies can also be associated with ataxia, dysarthria, myoclonus, extrapyramidal, cognitive, and autonomic disorders.[10,12] In our case, sensitive ataxia was observed due to impaired vibration sensitivity, which occurs in 26% of cases of celiac polyneuropathy.[28]

An examination of the patient at 38 years of age revealed signs of slowly progressing encephalopathy, which was primarily represented by mild cognitive impairment and personality changes not previously observed by the patient or his relatives. The combined development of polyneuropathy and cognitive impairment (chronic and rapidly progressive) has been previously described in patients at an average age of 46.9 years,[3,28,34] although there have been reports of dementia-like syndromes, characterized by significant variability during childhood and adolescence.[35–37] It should be noted that encephalopathy, which occurs in 21% of celiac disease cases, is more often associated with enteropathy, in contrast to neuropathy and cerebellar ataxia.[22]

In our case, encephalopathy presented with mild frontal dysfunction (a FAB score 13 out of 18 points), mild cognitive impairment (including decreased attention and memory for separated events, and visual-spatial orientation disorder), which is consistent with reports from the literature.[36,37] These changes correspond to the front-subcortical type,[34] with no headache, acalculia, and diffuse or focal changes in the brain according to MRI results.[3,34]

During the DIF reaction of the patient's serum with cryosections of the cerebellum and cerebral cortex of rats, no pathological types of luminescence were detected, indicating the presence of autoreactive antibodies. Damage to the nervous system in celiac disease is due to the presence of TG2 in the smooth muscle layer of cerebral vessels, as well as the presence of antibodies to type 6 tissue transglutaminase (TG6) in the cerebellum.[22,38,39]

In this case, there was five times the normal level in the level of recombinant TG2 IgA antibodies, which was likely due to their decrease when the diet therapy for alimentary obesity had begun, as antibodies may be present for 6–12 months after the start of diet therapy.[3] Anti-DGP (IgG and IgA) antibodies were within normal limits. EMAs were not available for investigation; therefore, a biopsy of the distal duodenum was performed to verify the diagnosis.[3,40]

The development of neurological manifestations in the absence of clinical signs of enteropathy was observed in our 41-year-old patient, and is also observed in one-third of adult celiac disease and gluten hypersensitivity cases.[3] Moreover, our morphological study revealed signs of chronic atrophic duodenitis with grade III crypt hyperplasia and erosion, which corresponds to stage IIIb of the Marsh histological classification of Marsh–Oberhuber.[7] Similar dissociation has also been observed in 94.2% of asymptomatic children with high titers of anti-TG (IgA) antibodies in the II–III stages of Marsh.[40] Therefore, the diagnosis of latent (silent) celiac disease was confirmed based on a combination of a positive test for anti-TG-IgA, morphological changes in the duodenum that corresponded to the Marsh II–III classification stages, and the detection of HLA-DQ2 and HLA-DQ8 antigens.[3,6,40]

One distinct feature of this case was the pronounced trophic changes in the skin, which caused the formation of long-healing ulcers following minor trauma. This feature was considered to be a manifestation of the insufficiency of neurogenic trophic influences. However, DIF performed in a skin biopsy revealed an autoimmune factor. Bullous dermatitis was absent in this patient, but in the skin biopsy specimen a primary deposition of C1q complement was observed in the papillary layer of the dermis (2+) where TSH type 3 was located (a high-affinity antibody that determines the development of herpetiform dermatitis or Dühring's disease). However, IgA deposits were minimal at the border of the papillary dermis along the basement membrane and in the intercellular contacts of the epidermis, which corresponded to the localization of TSH type 2.[41] Typical herpetiform Dühring dermatitis is characterized by itchy papules and the absence of obvious intestinal symptoms[42] and is caused mainly by the presence of antibodies to TSH type 3. These determine the presence of granular IgA deposits in the area of the basement membrane between the epidermis and dermis with complement C3 deposition during DIF.[43] Changes in the skin had a linear form of IgA deposition, but, unlike linear bullous dermatosis, there were no characteristic vesicular, erythematous papules or itchy skin.[8,41,44] Some authors consider this type of dermatosis to be associated with celiac disease.[45] Due to the complement with mediated lesions of the dermis, prolonged nonhealing wounds are probable, and not only due to neurogenic trophic disorders.

Seven months after the start of a strict GFD, and with the addition of short-term immunomodulation (two cycles of membrane plasma exchange and intravenous pulse methylprednisolone), a decrease in the severity of sensitivity disorders, normalization of the trophic status of the skin, and complete regression of encephalopathy were observed. Concurrently, a sevenfold decrease in the level of antibodies to TSH type 2 was noted, which is in line with reports concerning the efficacy of diet therapy.[2,16] The effectiveness of a strict GFD does not depend on the presence or absence of enteropathy.[22] Moreover, the reported effectiveness of a therapeutic apheresis is variable. In particular, the positive effect of the treatment for neuromyelitis optica and herpetiform dermatitis had been shown.[46] In contrast, the lack of an effect of therapeutic apheresis has been observed in a patient with cognitive impairment and celiac disease,[34] as well as in three cases of multifocal neuropathy.[21] There are studies showing unchanged levels of antibodies to TSH type 6 and gliadin during a GFD.[3,21,39] However, the positive effects of intravenous Ig,[24] as well as the presence of incomplete regression of the clinical manifestations of neuropathy following implementation of the diet,[3] substantiate the use of membrane plasma exchange to accelerate and increase the effectiveness of therapy.

In conclusion, sensorimotor axonal polyneuropathy with severe trophic disorders may be one of the variants of celiac neuropathy and is due to neurogenic autoimmune factors. Celiac disease is a heterogeneous, autoimmune disease and may be a potential cause of neuropathy and encephalopathy in adult patients. With cases of incomplete regression or refractoriness during a gluten-free diet in patients, further immunosuppressive treatment protocols for both intestinal and extraintestinal manifestations of celiac disease are required.