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IVIg, ICVM may help patients with small fiber neuropathy, neuropathic corneal pain

Digital EditionOphthalmology Times: April 15, 2021
Volume 46
Issue 7

NCP should be considered for patients with discomfort, irritation, dryness, grittiness.

Delu Song, MD, PhD, MTR

Ophthalmology Times
® is pleased to announce Delu Song, MD, PhD, MTR, a resident at the Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, with faculty mentor Mina Massaro-Giordano, MD, is the first-place winner of the 2020 Resident Writer’s Award Program, sponsored by Allergan. Song’s entry is featured here.

A 48-year-old female presented with complaints of severe, persistent, burning pain and foreign body sensation in both eyes for the past year. Ocular examination was unremarkable except for a few punctate epithelial erosions bilaterally.

The patient showed a poor response to frequent instillations of artificial tears and cyclosporine eye drops. In vivo confocal microscopy (IVCM) revealed damages of small corneal nerve fibers, which could be consistent with a diagnosis of neuropathic corneal pain (NCP).

Subsequently, a diagnosis of painful small fiber neuropathy (SFN) was confirmed by a positive serum IgM binding to trisulfated heparin disaccharide (TS- HDS) using an ELISA method.


A 48-year-old female presented with chronic burning pain and foreign body sensation in both eyes. Her symptoms were not relieved with frequent topical lubrication. She had no history of Sjogren syndrome, lupus, rheumatoid arthritis, or other autoimmune diseases. She also has no significant past medical or surgical history and no ocular history except dry eye disease.


On ophthalmic examination, the patient’s uncorrected visual acuity was 20/20 in both eyes. Slit-lamp examination revealed clear corneas bilaterally.

A drop of 1% fluorescein stain from a fluorescein strip instilled in the conjunctival cul-de-sac revealed a few punctate epithelial erosions on cornea bilaterally. The tear film height was normal in both eyes.

The tear film breakup time was 7 seconds in the right eye and 8 seconds in the left eye. The Schirmer test score without anesthetic was 30 mm at 5 minutes in both eyes, and with 0.5% proparacaine hydrochloride was 25 mm in the right eye and 26 mm in the left eye. Lissamine green stain did not reveal any staining.

In vivo confocal microscopy (IVCM) revealed reduced corneal fiber density, corneal nerve branch density, corneal nerve fiber length, and increased corneal fiber tortuosity and immune dendritic cells in both eyes compared with an exam 4 years ago.

The patient’s serum tested positive for IgM antibodies against trisulfated heparin disaccharide (TS-HDS). She was referred to the neurology department for comanagement.

Discussion and diagnosis

Small fiber neuropathy (SFN) is due to injury to the small unmyelinated C or thinly myelinated (Aδ) nerve fibers, which involve both sensory and autonomic functions.1,2

SFN commonly presents with disabling symptoms due to neuropathic pain and autonomic dysfunction. Diagnosing SFN requires confirmation of injury or disease that affects the somatosensory pathway of either peripheral and/or central nervous systems.3

One of the recently identified antibodies in patients with SNF is IgM binding to TS-HDS.4

Serum antibody against TS-HDS is associated with painful, primarily sensory, non-length polyneuropathy with more common symptoms of hand discomfort, presence of IgM M proteins, and evidence of capillary pathology.

Serum IgM against TS-HDS is considered a marker for a possible dysimmune etiology of SNF.5

SNF can involve the cornea, the most densely innervated tissue in the body, and presents with eye pain.6–10

However, neuropathic corneal pain (NCP), also termed corneal neuralgia, is an ill-defined disease that is not commonly recognized.

Diagnosing NCP has been challenging for vision care providers, partly due to the lack of understanding of this disease, as well as minimal or absent clinical signs.

Symptoms of NCP include pain, aching, burning, irritation, dryness, and grittiness. These symptoms often lead to a misdiagnosis of dry eye disease.

In this case, NCP was considered because the symptoms were out of proportion compared with objective findings and the patient’s response to topical

therapy was poor. In addition, patients with NCP are extremely challenging to treat as there are no evidence-based clinical recommendations for managing NCP.

IVCM is a noninvasive high-resolution real-time imaging device that can be informative as to the neuropathic basis of this condition.

The corneal nerve fibers originate from the ophthalmic branch of the trigeminal nerve, which can be visualized by confocal microscopy.

There was a correlation between the corneal nerve fiber loss detected by confocal microscopy and the severity of diabetic polyneuropathy, multiple sclerosis, and sarcoidosis.11-14

This patient had no history of the aforementioned diseases. The advantages of IVCM include quantitative and noninvasive measurements compared with skin biopsy.

NCP should be considered when patients present with pain, aching, burning, irritation, dryness, and grittiness that are out of proportion with exam findings. These patients also may be poor responders to topical therapy.

SFN should be suspected in patients with widespread body pain. In cases with systemic symptoms, referral to a neurologist is suggested for further systemic somatosensory testing.

Intravenous immunoglobulin (IVIg) therapy has been demonstrated as an effective therapy in patients with SFN secondary to fibromyalgia.15 Therefore, IVIg holds promise as a potential treatment for patients with NCP.

IVCM is a noninvasive imaging technique that quantifies corneal nerve fiber density, branch density, and length. Its ability to identify small nerve damage is as good as, possibly even superior to, skin biopsy.

It potentially can be used to monitor disease progression and response to treatment in patients with NCP and SFN. Autoantibodies directed against TS-HDS can be used as a diagnostic test for autoimmune SFN, which will justify and guide the treatment plan.


1. Hovaguimian A, Gibbons CH. Diagnosis and treatment of pain in small-fiber neuropathy. Curr Pain Headache Rep. 2011;15(3):193-200. doi:10.1007/s11916-011-0181-7

2. Tavee J, Zhou L. Small fiber neuropathy: a burning problem. Cleve Clin J Med. 2009;76(5):297-305. doi:10.3949/ccjm.76a.08070

3. Jensen TS, Baron R, Haanpää M, et al. A new definition of neuropathic pain. Pain. 2011;152(10):2204-2205. doi:10.1016/j.pain.2011.06.017

4. Pestronk A, Schmidt RE, Choksi RM, Sommerville RB, Al-Lozi MT. Clinical and laboratory features of neuropathies with serum IgM binding to TS-HDS. Muscle Nerve. 2012;45(6):866-872. doi:10.1002/mus.23256

5. Farhad K. Current diagnosis and treatment of painful small fiber neuropathy. Curr Neurol Neurosci Rep. 2019;19(12):103. doi:10.1007/s11910-019-1020-1

6. Rosenthal P, Borsook D. The corneal pain system. Part I: the missing piece of the dry eye puzzle. Ocul Surf. 2012;10(1):2-14. doi:10.1016/j.jtos.2012.01.002

7. Rosenthal P, Borsook D. Ocular neuropathic pain. Br J Ophthalmol. 2016;100(1):128-134. doi:10.1136/bjophthalmol-2014-306280

8. Rosenthal P, Borsook D, Moulton EA. Oculofacial pain: corneal nerve damage leading to pain beyond the eye. Invest Ophthalmol Vis Sci. 2016;57(13):5285-5287. doi:10.1167/iovs.16-20557

9. Aggarwal S, Kheirkhah A, Cavalcanti BM, et al. Autologous serum tears for treatment of photoallodynia in patients with corneal neuropathy: efficacy and evaluation with in vivo confocal microscopy. Ocul Surf. 2015;13(3):250-262. doi:10.1016/j.jtos.2015.01.005

10. Hamrah P, Qazi Y, Shahatit B, et al. Corneal nerve and epithelial cell alterations in corneal allodynia: an in vivo confocal microscopy case series. Ocul Surf. 2017;15(1):139-151. doi:10.1016/j.jtos.2016.10.002

11. Tavakoli M, Quattrini C, Abbott C, et al. Corneal confocal microscopy: a novel noninvasive test to diagnose and stratify the severity of human diabetic neuropathy. Diabetes Care. 2010;33(8):1792-1797. doi:10.2337/dc10-0253

12. Petropoulos IN, Alam U, Fadavi H, et al. Corneal nerve loss detected with corneal confocal microscopy is symmetrical and related to the severity of diabetic polyneuropathy. Diabetes Care. 2013;36(11):3646-3651. doi:10.2337/dc13-0193

13. Bitirgen G, Akpinar Z, Malik RA, Ozkagnici A. Use of corneal confocal microscopy to detect corneal nerve loss and increased dendritic cells in patients with multiple sclerosis. JAMA Ophthalmol. 2017;135(7):777-782. doi:10.1001/jamaophthalmol.2017.1590

14. Parambil JG, Tavee JO, Zhou L, Pearson KS, Culver DA. Efficacy of intravenous immunoglobulin for small fiber neuropathy associated with sarcoidosis. Respir Med. 2011;105(1):101-105. doi:10.1016/j.rmed.2010.09.015

15. Metyas S, Chen C, Quismorio A, Abdo N, Kamel K. Improvement in fibromyalgia symptoms and skin biopsy results in patients with fibromyalgia related small fiber neuropathy. Curr Rheumatol Rev. 2019;16(4):280-284. doi:10.2174/1573397115666191106120622

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