Cases

Neurology® Clinical Practice

Sensory neuronopathy associated with tumor necrosis factor inhibitor therapy Julius Birnbaum, MD, MHS

Practical Implications Consider a sensory neuronopathy as a peripheral nervous complication of tumor necrosis factor (TNF)-inhibitor therapy.

T

umor necrosis factor inhibitors (TNF inhibitors) have improved the treatment of inflammatory arthropathies, psoriasis, and inflammatory bowel disease.1 The spectrum of neuropathies reported in association with TNF inhibitors has not appreciably changed over the past decade.1 Sensory neuronopathies have not been described as such a neuropathy associated with TNF inhibitors. Such neuronopathies cause considerable proprioceptive impairment due to neuronal degeneration affecting the dorsal root ganglia (DRG).2 We describe neuronopathy associated with TNF inhibitors that improves with discontinuation of TNF inhibitor therapy.

Case report A 65-year-old, right-handed woman with a history of seronegative Sjögren syndrome (SS) and psoriatic arthritis that had been intractable to nonbiological agents was started on the TNF inhibitor infliximab. The induction dose was 3 mg/kg, given IV over weeks 0, 2, and 6, and subsequently infused at 8 mg/kg every 8 weeks. She had resolution of both skin lesions and her polyarthritis within 4 doses. However, after 1 year of infliximab therapy, she described a “wobbly” gait. Over the course of 1–2 months, there was subacute gait deterioration associated with frequent falls and the need to ambulate with canes. She subsequently experienced further falls over the remaining year, and was ultimately relegated to a wheelchair. She was subsequently referred to our center. Her clinical evaluation and electrodiagnostic studies confirmed a sensory neuronopathy (table). She had diffuse hyporeflexia, sensory ataxia, and impaired proprioception at the fingers and all toes, and was confined to a wheelchair. Electrodiagnostic studies revealed the loss of all sensory nerve action potentials (SNAPs) in the radial, ulnar, median, and sural nerves, with normal compound motor action potentials. The table emphasizes how the neuronopathy evolved in the absence of SS disease activity, and highlights diagnostic studies that excluded other causes of a neuronopathy. Testing for rapid plasma reagin/Venereal Disease Research Laboratory and fluorescent treponemal antibodies were not performed given there was no other evidence of neurosyphilis (i.e., Argyll-Robertson pupils). Although neuronopathies had not previously been described as a complication of TNF inhibitor therapy, we decided to discontinue infliximab after 6 additional months of therapy Division of Rheumatology and Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD. Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the author is available with the full text of this article at Neurology.org/cp. Correspondence to: [email protected] 516

© 2014 American Academy of Neurology

Sensory neuronopathy associated with tumor necrosis factor inhibitor therapy

Table

Characteristics of neuronopathy in the patient receiving infliximab therapy and after discontinuation of infliximab therapy During infliximab treatment

After discontinuation of infliximab

Romberg sign

Present

Absent

Proprioception

Absent at toes and fingers

Intact

Gait

1–2 steps with 2-person assistance, otherwise relegated to wheelchair

Able to ambulate with mildly wide-based gait for unlimited distances

Radial nerve

Absent

10

Median nerve

Absent

14

Sural nerve

Absent

Absent

Tibial nerve

Absent

Absent

Absent

Absent

Characteristics Examination and electrodiagnostic findings

Sensory nerve action potentials, mV

Presence of Sjögren-associated antibodies, immunologic markers, and disease activity Anti-Ro/SS-A and anti-La/SS-B antibodies Antinuclear antibodies

Absent

Absent

Antirheumatoid factor antibodies

Absent

Absent

Polyclonal gammopathy

Absent

Absent

Cryoglobulins

Absent

Absent

Absent

Absent

Absent

Absent

Glucose intolerance or diabetes, by 2-h glucose tolerance test

Absent

NAc

Celiac disease, by antiendomysial IgA/IgG and anti-TTG IgA/IgG antibodies

Absent

NA

Monoclonal gammopathy (i.e., M-protein) by SPEP/IPEP

Absent

NA

Anti-Hu and other antisulfatide antibodies

Absent

NA

CT scan of chest/abdomen/pelvis

No evidence of occult malignancy

NA

Antisulfatide antibodies

Absent

NA

Infectious causes (including HIV and hepatitis C)

Absent

NA

Metabolic causes (including vitamin B12 deficiency)

Absent

NA

Evidence of nerve root thickening on MRI of lumbosacral spine

Absent

NA

Protein concentration in the CSF, mg/dL

31

NA

Hypocomplementemia a

b

Lung, kidney, rash, arthritis, or CNS disease Alternative causes of a sensory neuronopathy

Abbreviations: IgA 5 immunoglobulin A; IgG 5 immunoglobulin G; IPEP 5 immunoglobulin protein electrophoresis; SPEP 5 serum protein electrophoresis. a Includes bronchiectasis and interstitial lung disease. b

Includes renal tubular acidosis or evidence of interstitial nephritis.

c

Indicates not applicable, as workup for alternative causes of neuronopathy was not repeated after patient improved on infliximab.

Neurology: Clinical Practice

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Julius Birnbaum

(i.e., after a total of 21 infusions). She was subsequently followed by her local physicians. She initially reported no change in her symptoms. However, in the ensuing 1–2 years after discontinuation of infliximab, she gradually reported improvement in her gait, and eventually was able to ambulate unlimited distances without assist devices. She was therefore evaluated at our center 19 months after discontinuation of infliximab. Clinical and electrodiagnostic features of improvement were striking and are illustrated in the table. She now had normal proprioception, was able to walk unlimited distances, and had complete recovery of SNAPs at the radial and median nerve (table). When followed over the next 6 months, she continued to have sustained improvement.

DISCUSSION We describe neuronopathy developing in the context of TNF inhibitor therapy and then improving with withdrawal of TNF inhibitor therapy. Our patient was not on other medications prior to or after discontinuation of infliximab, which could have led to precipitation or improvement of her neuronopathy. At nadir, our patient was relegated to a wheelchair and had diffuse loss of all SNAPs. Upon withdrawal of infliximab, she was able to independently ambulate for unlimited distances and had SNAPs that were elicited and normal in some sensory nerves (table). Although our patient also had SS, SS is an unlikely cause of this patient’s neuronopathy. As noted in the table, our patient’s neuronopathy developed in the absence of background SS disease activity. In particular, there were no immunologic markers of B-cell hyperreactivity (i.e., SS-associated antibodies), and no systemic manifestations that affected other end organs (i.e., lungs, joints, kidney, skin). Furthermore, SS-associated neuronopathies inevitably progress, and are not characterized by such striking clinical and electrodiagnostic improvement in the absence of immunomodulatory therapy.3,4 It is possible that SS may have constituted a unique “host” factor associated with subclinical DRG injury. Mechanisms proposed to explain the association of TNF inhibitor therapy with other neuropathies may be relevant. Just as TNF inhibitor therapy can induce antineuronal antibodies, it is interesting to consider whether infliximab was able to induce anti-DRG antibodies in our neuronopathy patient. Although our patient’s subacute onset of gait impairment is potentially consistent with such antibody-mediated and other inflammatory mechanisms, a more direct DRG neurotoxic effect of TNF inhibitors could also cause this subacute pattern of gait decline. REFERENCES 1. Stubgen JP. Tumor necrosis factor-alpha antagonists and neuropathy. Muscle Nerve 2008;37:281–292. 2. Sheikh SL, Amatoo AA. The dorsal root ganglia under attack: the acquired sensory ganglionopathies. Pract Neurol 2010;10:326–334. 3. Birnbaum J. Peripheral nervous system manifestations of Sjögren syndrome: clinical patterns, diagnostic paradigms, etiopathogenesis, and therapeutic strategies. Neurologist 2010;16:287–297. 4. Mori K, Iijima M, Koike H, et al. The wide spectrum of clinical manifestations in Sjögren’s syndromeassociated neuropathy. Brain 2005;28:2518–2534.

STUDY FUNDING No targeted funding reported.

DISCLOSURES The author is supported by an NIH P30 AR053503 grant. Full disclosure form information provided by the author is available with the full text of this article at Neurology.org/cp.

518

© 2014 American Academy of Neurology

Sensory neuronopathy associated with tumor necrosis factor inhibitor therapy Julius Birnbaum Neurol Clin Pract 2014;4;516-518 Published Online before print March 24, 2014 DOI 10.1212/CPJ.0000000000000010 This information is current as of March 24, 2014 Updated Information & Services

including high resolution figures, can be found at: http://cp.neurology.org/content/4/6/516.full.html

References

This article cites 4 articles, 1 of which you can access for free at: http://cp.neurology.org/content/4/6/516.full.html##ref-list-1

Subspecialty Collections

This article, along with others on similar topics, appears in the following collection(s): Clinical neurology examination http://cp.neurology.org//cgi/collection/clinical_neurology_examination Peripheral neuropathy http://cp.neurology.org//cgi/collection/peripheral_neuropathy

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Neurol Clin Pract is an official journal of the American Academy of Neurology. Published continuously since 2011, it is now a bimonthly with 6 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 2163-0402. Online ISSN: 2163-0933.

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