Clinical Features and Treatment Response in Immune-Mediated Small Fiber Neuropathy with Trisulfated Heparin Disaccharide or Fibroblast Growth Factor Receptor 3 Antibodies

Zeidman, Lawrence A.; Kubicki, Konrad

doi:10.1097/cnd.0000000000000355

Cited by 15 publications

(42 citation statements)

References 19 publications

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“…168,169 Antibodies binding to trisulfated heparin disaccharide (TS-HDS), 191,192 and the intracellular domain of the fibroblast growth factor receptor 3 (FGFR3) 193 have been detected in patients with apparently idiopathic sensory neuropathy, often with features of sensory neuronopathy, 193 including NLD-SFN. [170][171][172][173][174] It is still unclear whether these are autoantibodies playing a pathogenic role or are only biomarkers of a dysimmune process, and whether they can identify patients who would respond to immune intervention. 194 Finally, predispositions towards dysimmunity in some patients with idiopathic SFN is suggested by findings of minor abnormalities of immune and inflammatory biomarkers, 42,115,195 as also observed in NLD-SFN.…”

Section: Associated Conditionsmentioning

confidence: 99%

Non‐length‐dependent small fiber neuropathy: Not a matter of stockings and gloves

et al. 2021

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The clinical spectrum of small fiber neuropathy (SFN) encompasses manifestations related to the involvement of thinly myelinated A‐delta and unmyelinated C fibers, including not only the classical distal phenotype, but also a non–length‐dependent (NLD) presentation that can be patchy, asymmetrical, upper limb‐predominant, or diffuse. This narrative review is focused on NLD‐SFN. The diagnosis of NLD‐SFN can be problematic, due to its varied and often atypical presentation, and diagnostic criteria developed for distal SFN are not suitable for NLD‐SFN. The topographic pattern of NLD‐SFN is likely related to ganglionopathy restricted to the small neurons of dorsal root ganglia. It is often associated with systemic diseases, but about half the time is idiopathic. In comparison with distal SFN, immune‐mediated diseases are more common than dysmetabolic conditions. Treatment is usually based on the management of neuropathic pain. Disease‐modifying therapy, including immunotherapy, may be effective in patients with identified causes. Future research on NLD‐SFN is expected to further clarify the interconnected aspects of phenotypic characterization, diagnostic criteria, and pathophysiology.

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Section: Associated Conditionsmentioning

confidence: 99%

Non‐length‐dependent small fiber neuropathy: Not a matter of stockings and gloves

et al. 2021

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“…48 Eight of the seropositive patients improved on IVIGs, with a 42% reduction in pain scores (p = 0.02), a 44% reduction in the Utah Neuropathy Score, and improved IENFD post-treatment. 48 In another study of idiopathic SFN with IVIG, no significant therapeutic benefit could be documented, why it was concluded that the use of IVIG for idiopathic SFN should be discouraged. 5 In a study of two patients with Ehlers-Danlos syndrome, immune-mediated SFN was suspected and successfully treated with IVIG.…”

Section: Immunoglobulinsmentioning

confidence: 91%

“…7 Recently, novel antibodies to tri-sulfated heparan disaccharide (TS-HDS) and to fibroblast growth factor receptor-3 (FGFR-3) have been found in otherwise cryptogenic SFN cases. 47,48 Whether they can serve as biomarkers of SFN, however, remains speculative. CCM has shown that not only the number of small fibers is reduced but also the number of Langerhans cells.…”

Section: Secondary Sfnmentioning

confidence: 99%

“…Skin biopsy is currently regarded as the gold standard for diagnosing SFN and can be taken from the proximal or distal lower limbs, depending on whether a length‐dependent or NLD‐SFN is suspected 7 . Recently, novel antibodies to tri‐sulfated heparan disaccharide (TS‐HDS) and to fibroblast growth factor receptor‐3 (FGFR‐3) have been found in otherwise cryptogenic SFN cases 47,48 …”

Section: Diagnosismentioning

confidence: 99%

“…In a 35‐year‐old woman with autoimmune‐mediated, neurogenic POTS, intravenous, respectively, subcutaneous immunoglobulins reduced symptoms and improved quality of life 76 . In a study of 40 patients with cryptogenic SFN, 55% had either antibodies against the TS‐HDS or the FGFP‐3 receptor 48 . Eight of the seropositive patients improved on IVIGs, with a 42% reduction in pain scores ( p = 0.02), a 44% reduction in the Utah Neuropathy Score, and improved IENFD post‐treatment 48 .…”

Section: Treatmentmentioning

confidence: 99%

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Small fiber neuropathy

Finsterer

Scorza

2022

Acta Neuro Scandinavica

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Small fiber neuropathy (SFN) is a peripheral nervous system disease due to affection of A‐delta or C‐fibers in a proximal, distal, or diffuse distribution. Selective SFN (without large fiber affection) manifests with pain, sensory disturbances, or autonomic dysfunction. Though uniform diagnostic criteria are unavailable, most of them request typical clinical features and reduced intra‐epidermal nerve fiber density on proximal or distal skin biopsy. Little consensus has been reached about the treatment of SFN, why this narrative review aims at summarizing and discussing treatment options for SFN. Treatment of SFN can be classified as symptomatic, pathophysiologic, or causal. Prerequisites for treating SFN are an established diagnosis, knowledge about the symptoms and signs, and the etiology. Pain usually responds to oral/intravenous pain killers, antidepressants, anti‐seizure drugs, or topical, transdermal specifications. Some of the autonomic disturbances respond favorably to symptomatic treatment. SFN related to Fabry disease or hATTR are accessible to pathogenesis‐related therapy. Immune‐mediated SFN responds to immunosuppression or immune‐modulation. Several of the secondary SFNs respond to causal treatment of the underlying disorder. In conclusion, treatment of SFN relies on a multimodal concept and includes causative, pathophysiologic, and symptomatic measures. It strongly depends on the clinical presentation, diagnosis, and etiology, why it is crucial before initiation of treatment to fix the diagnosis and etiology. Due to the heterogeneous clinical presentation and multi‐causality, treatment of SFN should be individualized with the goal of controlling the underlying cause, alleviating pain, and optimizing functionality.

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A double‐blind placebo‐controlled pilot study of immunoglobulin for small fiber neuropathy associated with TS‐HDS and FGFR‐3 autoantibodies

et al. 2022

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Introduction/Aims Small fiber neuropathies (SFN) have been associated with two autoantibodies, trisulfated heparin disaccharide (TS‐HDS) and fibroblast growth factor receptor 3 (FGFR‐3), and intravenous immune globulin (IVIG) has been suggested as a potential therapy. The study objective is to determine the efficacy of IVIG on nerve density, pain and neurologic examinations in patients with SFN associated with TS‐HDS and FGFR‐3 autoantibodies. Methods This was a double‐blind placebo‐controlled pilot study. Subjects with SFN confirmed by history, examination, and skin biopsy with elevated autoantibodies to TS‐HDS and/or FGFR‐3 received IVIG (or blinded placebo) 2 grams/kg followed by 1 gram/kg every 3 wk for a total of 6 treatments. All subjects had Utah Early Neuropathy Scores (UENS), questionnaires and skin biopsies with quantitation of intra‐epidermal nerve fiber density (IENFD) taken from adjacent sites at the distal leg at baseline and 6 mo later. The primary outcome was the change in IENFD over 6 mo. Results Twenty subjects were enrolled; 17 completed treatment (8 IVIG, 9 placebo). Three did not have final data due to coronavirus disease 2019 (COVID‐19). Skin biopsy IENFD improved by 0.5 ± 0.8 fibers/mm in the placebo group and improved by 0.6 ± 0.6 fibers/mm in the IVIG‐treated group (p = NS).Over 24 wk the change in pain scores (11 point pain scale) was −1.9 ± 2.6 in the placebo group, and − 1.7 ± 0.9 in the IVIG group (p = NS), the UENS improved by 3.0 ± 5.8 in the placebo group and improved by 1.8 ± 3.9 in the IVIG group (p = NS). Discussion This pilot study did not detect a benefit of treatment with IVIG in patients with SFN and autoantibodies to TS‐HDS and FGFR‐3.

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Clinical Features and Treatment Response in Immune-Mediated Small Fiber Neuropathy with Trisulfated Heparin Disaccharide or Fibroblast Growth Factor Receptor 3 Antibodies

Cited by 15 publications

References 19 publications

Non‐length‐dependent small fiber neuropathy: Not a matter of stockings and gloves

Non‐length‐dependent small fiber neuropathy: Not a matter of stockings and gloves

Small fiber neuropathy

A double‐blind placebo‐controlled pilot study of immunoglobulin for small fiber neuropathy associated with TS‐HDS and FGFR‐3 autoantibodies

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