Small Fiber Neuropathy in Ehlers-Danlos Syndrome

Small Fiber Neuropathy (SFN) is a type of peripheral neuropathy that affects the small nerve fibers responsible for detecting pain, temperature, and autonomic functions. Its manifestation in individuals with Ehlers-Danlos Syndrome (EDS) adds complexity to this already intricate disorder. Recent research has begun to shed light on the prevalence and implications of SFN in EDS, particularly in hypermobile EDS (hEDS).

What is Small Fiber Neuropathy?

Small Fiber Neuropathy (SFN) is a disorder that involves damage to the small nerve fibers of the peripheral nervous system, specifically Aδ and C fibers. These fibers play a critical role in relaying sensory information, such as pain, temperature, and itching, as well as regulating autonomic functions, including heart rate, blood pressure, digestion, and sweating​​.

The hallmark of SFN is the degeneration or dysfunction of these small fibers, which can result in a variety of symptoms, including burning pain, tingling, numbness, hypersensitivity to temperature changes, and autonomic dysfunction like dizziness, irregular heartbeat, and gastrointestinal disturbances. SFN is often diagnosed using a skin biopsy to measure intraepidermal nerve fiber density (IENFD), as well as quantitative sensory testing to assess thermal and pain thresholds​​.

Overview of Small Fiber Neuropathy in Ehlers-Danlos Syndrome

Small Fiber Neuropathy (SFN) is increasingly recognized as a significant comorbidity in individuals with Ehlers-Danlos Syndrome (EDS), particularly in its hypermobile (hEDS) and classical forms. SFN involves damage to the small nerve fibers responsible for sensory and autonomic functions, resulting in symptoms like burning pain, paresthesia, and autonomic dysfunction. Recent studies have demonstrated a high prevalence of SFN among EDS patients, with evidence from skin biopsies showing reduced intraepidermal nerve fiber density (IENFD) in affected individuals​​.

The clinical presentation of SFN in EDS includes a mix of sensory and autonomic symptoms, such as allodynia, dysautonomia, gastrointestinal disturbances, and temperature regulation issues. These symptoms often overlap with other EDS manifestations, complicating diagnosis. SFN may be linked to genetic, autoimmune, or idiopathic factors, with some studies suggesting an immune-mediated component in certain cases​​.

Diagnosis relies on a combination of clinical evaluations, quantitative sensory testing, and the gold standard of skin biopsy. Emerging treatments include immunomodulatory therapies like intravenous immunoglobulin (IVIG) in cases with autoimmune underpinnings. While SFN remains a chronic condition, early diagnosis and tailored interventions can improve quality of life for those with EDS​

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Prevalence of Small Fiber Neuropathy

SFN Prevalence in the General Population

Small Fiber Neuropathy (SFN) is considered relatively rare in the general population, with an estimated prevalence of 53 cases per 100,000 individuals. However, the condition is likely underdiagnosed due to its subtle and diverse symptoms, as well as the complexity of confirming a diagnosis through specialized tests like skin biopsies and quantitative sensory testing​​.

SFN can occur as a standalone condition (idiopathic SFN) or as a secondary complication of underlying diseases. It is commonly associated with metabolic disorders like diabetes and prediabetes, which together account for a significant portion of SFN cases. Other contributors include autoimmune diseases (e.g., Sjögren's syndrome, lupus), genetic mutations (e.g., SCN9A, SCN10A), vitamin deficiencies, infections, and exposure to neurotoxic substances​.

While research on the exact prevalence of SFN continues to evolve, its growing recognition in both primary care and specialized settings has highlighted the need for increased awareness and diagnostic capabilities to identify and manage this challenging condition effectively​​.

Prevalence of Small Fiber Neuropathy in EDS

Recent studies suggest that Small Fiber Neuropathy is a common and underdiagnosed complication of Ehlers-Danlos Syndrome (EDS). Research has identified significant small nerve fiber abnormalities in a large proportion of EDS patients, particularly those with hypermobile EDS (hEDS). For example, in one cohort, up to 78% of patients with hEDS were found to have reduced IENFD, a diagnostic marker for SFN​​.

The prevalence of SFN in EDS highlights the potential role of peripheral nervous system dysfunction in contributing to the chronic pain, sensory disturbances, and autonomic symptoms that are commonly reported in this population. Moreover, the overlap of symptoms between SFN and EDS underscores the importance of considering SFN as a possible comorbidity in individuals presenting with widespread pain and autonomic dysfunction​.

Although SFN can affect individuals with any EDS subtype, studies suggest it is particularly prevalent in those with hypermobile and classical forms of the condition. Its recognition has helped to improve understanding of the neurological aspects of EDS and guide more targeted diagnostic and therapeutic approaches​​.

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Symptoms of Small Fiber Neuropathy in EDS

SFN symptoms in EDS patients are multifaceted and may include:

• Neuropathic Pain: Burning or tingling sensations, often in a stocking-glove pattern starting in the feet and progressing upwards.
• Autonomic Dysfunction: Manifesting as dizziness, gastrointestinal issues, dry eyes, dry mouth, palpitations, and irregular sweating patterns​​.
• Allodynia and Hyperalgesia: Increased sensitivity to touch and pain​.
• Restless Legs and Pruritus: Frequently reported among EDS patients with SFN​​.

The overlap of these symptoms with other EDS-related manifestations, such as chronic pain and dysautonomia, makes diagnosis challenging.

Causes and Pathophysiology

SFN in EDS is often idiopathic, but potential contributors include:

• Genetic Mutations: Mutations in sodium channel genes (e.g., SCN9A, SCN10A) are associated with SFN and may exacerbate EDS-related neuropathy​​.
• Autoimmune Processes: Co-occurring autoimmune disorders, such as Sjögren’s syndrome, can lead to SFN​​.
• Structural Joint Instability: Chronic joint microtrauma in EDS may contribute to nerve damage​​.

The exact mechanisms remain unclear, but evidence points to intraepidermal nerve fiber (IENF) degeneration as a key diagnostic marker​​.

Diagnosis

Diagnosing SFN in EDS involves several key steps:

1. Clinical History and Neurological Examination: Focus on neuropathic and autonomic symptoms​.
2. Nerve Conduction Studies (NCS): Used to rule out large fiber involvement​.
3. Skin Biopsy: The gold standard for SFN diagnosis. A reduction in IENF density is indicative of SFN​​.
4. Quantitative Sensory Testing (QST): Measures thermal thresholds, aiding in identifying sensory deficits​.

Treatment Options

Treatment of SFN in EDS is often multimodal:

• Addressing Underlying Causes: Management of autoimmune conditions or deficiencies when applicable​​.
• Pharmacotherapy: Includes tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors (SNRIs), and anticonvulsants like pregabalin and gabapentin​.
• Lifestyle and Supportive Measures: Regular exercise, stress management, and dietary interventions may improve symptoms​​.
• Emerging Therapies: Intravenous immunoglobulin (IVIG) has shown promise in cases with autoimmune involvement​​.

SFN vs. Fibromyalgia

Distinguishing SFN from fibromyalgia is a clinical challenge due to symptom overlap, including chronic pain and fatigue. However, key differences include:

• SFN Symptoms: Neuropathic pain (burning, stabbing), autonomic dysfunction, and reduced IENF density on skin biopsy​​.
• Fibromyalgia Symptoms: Central pain sensitization, widespread tenderness, and associated symptoms like jaw dysfunction and cognitive difficulties​.

Advanced diagnostic techniques, including skin biopsies and QST, can clarify diagnoses in complex cases.

Research and Future Directions

Emerging studies continue to explore the intersection of SFN and EDS:

1. Understanding Mechanisms: Ongoing research into sodium channel gene mutations (e.g., SCN9A) and their role in SFN may illuminate the pathophysiology of EDS-related neuropathy​​.
2. Treatment Advances: Clinical trials, such as those involving sodium channel blockers or IVIG, are testing new therapeutic options​​.
3. Early Detection: Improved diagnostic protocols, including corneal confocal microscopy and expanded QST methods, may enhance early detection​​.

FAQ

1. Can EDS cause small fiber neuropathy? Yes, SFN is a recognized complication in EDS, particularly in hypermobile and classical subtypes​​.
2. What doctor diagnoses small fiber neuropathy? Neurologists or specialized clinics typically diagnose SFN using skin biopsies and QST​.
3. What is the root cause of small fiber neuropathy? It varies but includes genetic mutations, autoimmune diseases, and idiopathic factors​​.
4. What autoimmune diseases cause small fiber neuropathy? Autoimmune diseases like Sjögren’s syndrome, lupus, and sarcoidosis are commonly associated with SFN​​.
5. How do you treat autoimmune small fiber neuropathy? Treatment involves addressing the autoimmune activity with medications like immunosuppressants or IVIG. Pain management includes antidepressants, anticonvulsants, and lifestyle interventions​​.
6. What are the neurological symptoms of Ehlers-Danlos syndrome? Neurological symptoms in EDS include chronic pain, autonomic dysfunction (e.g., POTS), headaches, and symptoms consistent with SFN, such as burning pain and paresthesia​​.
7. How debilitating is small fiber neuropathy? SFN can be highly debilitating, with symptoms like severe burning pain, autonomic dysfunction, and sleep disturbances significantly impairing quality of life​.
8. What can be mistaken for small fiber neuropathy? Conditions like fibromyalgia, complex regional pain syndrome (CRPS), and polyneuropathy are often mistaken for SFN​​.
9. How quickly does small fiber neuropathy progress? Progression varies widely. In some patients, SFN symptoms may remain stable for years, while in others, they can progress rapidly depending on the underlying cause​.
10. What is the best treatment for small fiber neuropathy? The best treatment depends on the underlying cause. For idiopathic SFN, symptomatic management with neuropathic pain medications is the standard. Addressing underlying conditions, such as diabetes or autoimmune disease, can also be effective​​.
11. How rare is SFN? SFN is considered rare, with a prevalence of approximately 53 cases per 100,000 individuals. However, it may be underdiagnosed, especially in complex conditions like EDS​.
12. What vitamin deficiency causes small fiber neuropathy? Deficiencies in vitamin B12 and, less commonly, vitamin B6 can contribute to SFN​​.
13. Can IVIG cure small fiber neuropathy? IVIG has shown promise in treating autoimmune SFN but is not considered a cure. It can reduce symptoms and potentially slow progression in autoimmune-mediated cases​​.

References

1. Cook, Melissa K. MD; Jordan, Morgan DO. Autoimmune Small Fiber Neuropathy Associated With Ehlers–Danlos Syndrome Treated With Intravenous Immunoglobulins. Journal of Clinical Neuromuscular Disease, 22(3):p 160-163, March 2021. | DOI: 10.1097/CND.0000000000000341.
2. Cazzato, D., Castori, M., Lombardi, R., et al. (2016). Small fiber neuropathy is a common feature of Ehlers-Danlos syndromes. Neurology, 87(2), 155–159. https://doi.org/10.1212/WNL.0000000000002847.
3. Fernandez, A., Aubry-Rozier, B., Vautey, M., Berna, C., & Suter, M. R. (2022). Small fiber neuropathy in hypermobile Ehlers Danlos syndrome/hypermobility spectrum disorder. Journal of Internal Medicine, 292(6), 957–960. https://doi.org/10.1111/joim.13539.
4. Margot Geerts, et al. (2023). Small Fiber Neuropathy: A Clinical and Practical Approach. The Journal for Nurse Practitioners. DOI: https://doi.org/10.1016/j.nurpra.2023.104547.

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