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Uhthoff's phenomena in MS—clinical features and pathophysiology

Nature Reviews Neurology volume 9, pages 535–540 (2013)Cite this article

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Abstract

In the late 19th century, Wilhelm Uhthoff reported on a series of patients with acute optic neuritis who manifested similar recurrent, stereotyped visual symptoms that were of paroxysmal onset, short in duration, and reversible. These 'Uhthoff's phenomena', which are a feature of multiple sclerosis (MS) and other demyelinating diseases, can be triggered by factors including the perimenstrual period, exercise, infection, fever, exposure to high ambient temperatures, and psychological stress. Here, we characterize the clinical, pathophysiological and neurotherapeutic challenges associated with Uhthoff's phenomena, and discuss the differentiation of these events from other paroxysmal, acute or subacute changes in functional capabilities and neurological symptoms in MS. For instance, whereas MS exacerbations are contingent on immune dysregulation, Uhthoff's phenomena are predicated on ion channel modifications, in conjunction with thermoregulatory derangements that transiently alter the conduction properties of demyelinated axons. An understanding of these pathophysiological underpinnings of Uhthoff's phenomena is germane to their recognition and timely treatment.

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Figure 1: Effects of demyelination on axonal conduction.
Figure 2: INO in a patient with multiple sclerosis.
Figure 3: Dysconjugate eye movements in INO.
Figure 4: Pathophysiological mechanisms of Uhthoff's phenomena and potential treatment interventions.

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Acknowledgements

The authors thank Kimberly Hoggatt for her preparation of the artwork contained within Figures 1 and 4. The authors have received research funding from the National Multiple Sclerosis Society (grants RG 3780A3/3 and PP1485 to E. M. Frohman; RG 4091A3/1 to Robert Fox at Cleveland Clinic and subcontracted to E. M. Frohman; RG 4212-A-4 to Laura J. Balcer at New York University and subcontracted to E. M. Frohman; RG 4043A1/1 to S. L. Davis) and the National Eye Institute (grants R01 EY 014993 and R01 EY 019473 to Laura J. Balcer subcontracted to E. M. Frohman). E. M. Frohman has also received funding from Dale Energy Corporation, the Braxton Debbie Angela Dillon and Skip (DADS) Donor Advisor Fund, and the Cain Denius MS Research Fund. Written consent for publication of the case report was obtained from the family of the patient.

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Authors and Affiliations

  1. Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Centre, 5323 Harry Hines Boulevard, Dallas, 75235, TX, USA

    Teresa C. Frohman, Shin Beh, Benjamin M. Greenberg, Gina Remington & Elliot M. Frohman

  2. Department of Applied Physiology and Wellness, Annette Caldwell Simmons School of Education and Human Development, Southern Methodist University, PO Box 750382, Dallas, 75275-0382, TX, USA

    Scott L. Davis

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  1. Teresa C. Frohman
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All authors researched the data for the article, made substantial contributions to discussions of the content, wrote the text, and reviewed and/or edited the manuscript before submission.

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Correspondence to Elliot M. Frohman.

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The authors declare no competing financial interests.

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Frohman, T., Davis, S., Beh, S. et al. Uhthoff's phenomena in MS—clinical features and pathophysiology. Nat Rev Neurol 9, 535–540 (2013). https://doi.org/10.1038/nrneurol.2013.98

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