Continuing Education Activity

Uhthoff phenomenon, also known as Uhthoff sign or Uhthoff syndrome, is a transient worsening of neurological function lasting less than 24 hours that can occur in multiple sclerosis patients due to increases in core body temperature. Knowledge of this phenomenon and its pathophysiology, therefore, is essential for recognition and appropriate treatment. This activity reviews the pathophysiologic basis of Uhthoff phenomenon and describes how Uhthoff phenomenon can be distinguished from a relapse of multiple sclerosis. This activity highlights the role of interprofessional team members in collaborating to provide well-coordinated care and enhance outcomes for affected patients.

Objectives:

• Identify the presentation of Uhthoff phenomenon.
• Determine how Uhthoff phenomenon may, in select cases, suggest that further evaluation for multiple sclerosis is warranted.
• Evaluate a patient for multiple sclerosis.
• Communicate the importance of improving coordination amongst the interprofessional team to enhance care for patients with multiple sclerosis.

Introduction

Uhthoff phenomenon (also known as Uhthoff sign or Uhthoff syndrome) is described as temporary, short-lived (less than 24 hours), and stereotyped worsening of neurological function among patients with multiple sclerosis (MS) in response to increases in core body temperature. This phenomenon is named after Wilhelm Uhthoff, a German ophthalmologist who described it. In 1890, Uhthoff first described exercise-induced amblyopia in multiple sclerosis patients. In 1961, this phenomenon was given his surname, Uhthoff henomenon, by G. Ricklefs.[1] In 4 out of 100 patients with MS, Uhthoff observed reversible optic symptoms induced by an increase in body temperature, "marked deterioration of visual acuity during physical exercise and exhausting."[2] Subsequent observations have shown that the same physiological mechanism responsible for visual dysfunction in the setting of heat exposure is responsible for a variety of other neurological symptoms experienced by patients with MS.[3]

When Uhthoff studied this phenomenon, exercise was thought to be the etiology, and the significance of elevation in body temperature escaped his notice. Six decades later, in 1950, the hot bath test was developed based on this phenomenon and was used as a diagnostic test for MS.[4] By 1980, with the advancement in neuroimaging, the hot bath test began to be replaced by other diagnostic tests such as MRI and cerebrospinal fluid analysis because of its unspecific nature and potential complications. The temporary worsening of neurological function in response to heat exposure affects the physical and cognitive function of multiple sclerosis patients. It interferes with their activities of daily life and functional capacity.[5] This worsening needs to be differentiated from a true relapse or exacerbation of MS. An understanding of this phenomenon and its pathophysiology, therefore, is essential for recognition and appropriate treatment.

Etiology

Uhthoff phenomenon is most commonly observed in multiple sclerosis but may occur in other optic neuropathies or disorders of afferent pathways,[6] for example, neuromyelitis optica.[7] In MS, several factors, including the blockade of ion channels, heat shock proteins, circulatory changes, effects of serum calcium, and unidentified humoral substances, have been hypothesized and investigated as a cause of Uhthoff phenomenon. Temperature-sensitive conduction blockade of partially demyelinated axons in the demyelinated plaques is the most widely accepted mechanism.[8] Several other factors, including perimenstrual period, exercise, fever, sun-tanning, hot showers, sauna, psychological stress, and even hot meals and smoking of cigarettes, have been reported in the literature as triggers for Uhthoff phenomenon.[9]

Epidemiology

Between 60% and 80% of patients with MS exhibit Uhthoff phenomenon with heat exposure. In one study, 52% reported experiencing Uhthoff phenomenon, with a follow-up range of 1 to 20 years. Of the patients with MS and Uhthoff phenomenon, 88% experienced nonvisual heat-related phenomena compared with 30% without Uhthoff phenomenon. About 16% of patients experienced complete recovery in 8 weeks, and persistence of the sign beyond 2 months may be a marker of poor remyelination.[1][10]

Pathophysiology

The precise mechanisms of Uhthoff phenomenon are not completely understood. Still, they are likely due to a combination of structural and physiological changes within the demyelinated axons in the central nervous system (CNS) in the setting of the elevated core body temperature. Studies have shown a decrease in conduction velocity in response to increased temperature in MS patients.[11] The temperature-related slowing of conduction velocity can be reversed with cooling, and this has been shown in experiments studying the adduction velocity in patients with internuclear ophthalmoplegia (INO) in MS. Adduction velocity of eye movements in MS-related INO as measured by infrared eye movement recording techniques was reduced by a systematic increase in core body temperature and reversed to baseline with active cooling.[12]

The normal myelinated nerve is a highly specialized structure, with clustering of sodium channels at the nodes of Ranvier. This facilitates saltatory conduction, whereas demyelination worsens the nodal region, leading to the transformation of faster saltatory conduction to slower membrane conduction.[13] Segmental demyelination involves a primary derangement in sodium channel-mediated axonal depolarization and the unmasking of potassium channels, resulting in K efflux and hyperpolarization, surpassing the action potential–generating processes. Newly assembled sodium channels are subsequently inserted within the axonal membrane as an ion channel adaptation, but the newly incorporated sodium channels may exhibit altered physiological properties.[14] 

Temperature escalation of as little as 0.2 °C to 0.5 °C is sufficient to close the axonally-derived sodium channel and terminate the depolarization phase of the action potential. Demyelination reduces the safety factor of axons, which is defined as the ratio of the current available to initiate an action potential to the minimal current required.[15] An increase in temperature further reduces the axon's safety factor. Hence, an increase in temperature (even as little as 0.5 °C) in individuals with MS results in the closure of the voltage-gated sodium channels in demyelinated axons, thereby compromising action potential depolarization and decreasing the safety threshold for high-fidelity nerve transmissions.[16] This can produce abnormalities ranging from delayed conduction to complete conduction block and clinically manifests as worsened MS symptoms (eg, decreased visual acuity or double vision). Almost all the precipitating factors of the Uthoff phenomenon cause elevated core body temperature. 

History and Physical

Events preceding the worsening of neurological symptoms should be analyzed during history taking. Factors including exercise, taking a hot bath or shower, exposure to the sun, menstrual cycle, psychological stress, hot meals, fever, and infection should be addressed as any of these can precipitate worsening of the symptoms in patients with MS. The transient worsening of the symptoms induced by such factors is termed "pseudo exacerbation" or "pseudo-relapse" as opposed to a true relapse or exacerbation in patients with MS.[3][17][3] This worsening typically should last less than 24 hours. Relapse or exacerbation is the hallmark of relapsing MS and is characterized by new focal neurological deficits lasting for at least 24 hours in the absence of fever or infection. Often, a detailed history can differentiate a true relapse from a pseudo-relapse. Examination reveals various neurological deficits of the location of demyelination, including amblyopia, nystagmus, INO, muscular weakness, and abnormal reflexes. 

Evaluation

Episodes of Uhthoff phenomenon are generally considered to be the result of established demyelinating plaques in the setting of thermal stress. The key to diagnosing is a detailed patient history regarding the circumstances in which the symptoms appeared. In patients with pseudo-relapse, care should be taken to rule out common precipitating factors like urinary tract infection,[18] upper respiratory tract infection, or metabolic abnormalities through laboratory tests. Thus, the workup should include a detailed history, physical examination, and laboratory investigations to rule out metabolic, toxic, and infectious derangements, including magnetic resonance imaging (MRI) of the brain and T- and C-spine, with and without contrast to assess for any new contrast-enhancing lesions that could reveal a new clinical attack for the demyelinating condition the patient suffers. For new diagnosis, a lumbar puncture may be indicated to pinpoint the demyelinating or inflammatory condition, including basic cerebral spinal fluid studies, meningoencephalitis panel, oligoclonal bands, immunoglobulin G index, neuromyelitis optical Aquaporin-4 or myelin oligodendrocyte glycoprotein antibodies, flow cytometry, cytology, among others.

Treatment / Management

A fundamental principle in the prevention and treatment of Uhthoff phenomena is to be familiar with the antecedent factors that can result in the elevation of core body temperature and their corresponding impact on the patient's neurological functioning and safety. Patients should be counseled about the stimulating effects of taking hot showers or baths regarding reducing appendicular and core muscle strength leading to profound weakness and thereby placing them in grave danger of drowning. Also, they should be cautioned against saunas, exposure to the sun when the outside temperature is greater than 30 ºC, hydrotherapy with water at high temperatures, short-wave radiotherapy, and paraffin application. Patients should be advised about exercising during early morning and late evening hours when the temperature is cooler.[19][20][21]

Uhthoff phenomenon fully resolves following variable periods of rest (generally ranging from minutes to an hour) under circumstances where heat stressors are removed, or active cooling measures are applied. Simple and convenient strategies such as taking cold showers, applying ice packs, using regional cooling devices, and using cold beverages can also be tried for heat sensitivity. Cooling garments have improved neurological function (motor performance and visual acuity) and perceived subjective benefits (feeling less fatigued) in patients with MS and Uhthoff phenomenon.

Reports show that oral administration of 4-aminopyridine (4-AP) reduces the worsening of visual impairment after increased body temperature in MS patients.[22] 4-AP is a dose-related potassium channel blocker that prolongs action potential duration by reducing potassium efflux, thereby increasing the hyperpolarization threshold. It enhances the fidelity of conduction in segmentally demyelinated nerve fibers. The Food and Drug Administration (FDA) has approved dalfampridine, an extended-release formulation of this agent, to improve the walking capacity of patients with MS.[23][24]

Differential Diagnosis

The differential diagnoses for [title of article] include the following:

• Antiphospholipid antibody syndrome
• Behçet disease
• CNS lupus
• CNS lymphoma
• CNS vasculitis
• Copper deficiency
• HIV
• Human T-lymphotropic virus (HTLV)
• Leukodystrophies
• Lyme disease
• Sarcoidosis [25]
• Sjögren syndrome
• Small vessel disease
• Osmotic demyelination syndrome [26]

Prognosis

The prognosis of this phenomenon is good as long as pseudo-exacerbation triggers are avoided. Treating the underlying neuroimmunological disorder is instrumental in avoiding recurrence.

Complications

There are no known complications related to the treatment of this symptom. Common adverse events related to dalfampridine use include dysuria, hematuria, urinary frequency, and back pain. Less common side effects include formication, memory issues, mood issues, dysarthria, dysphagia, diffuse fatigue, urinary, and bowel incontinence.

Deterrence and Patient Education

Education and reassurance about the symptoms and the underlying etiology should be provided to patients. This includes avoiding triggers such as hot baths or exposure to excessive heat. Education about what new and old symptoms can be related to a demyelinating disease such as MS can empower patients to report them to the physician for further workup, including the presence of possible new lesions or exacerbation. This could alert physicians of loss of effectiveness of the patient's current treatment and progression.

Pearls and Other Issues

• Uhthoff phenomenon (also known as Uhthoff sign or Uhthoff syndrome) is described as a transient worsening of neurological symptoms related to a demyelinating disorder such as multiple sclerosis when the body becomes overheated in hot weather, exercise, fever, saunas, or hot tubs.
• The pathophysiology and etiology are complex and related to the effects of demyelination on sodium and potassium channels, heat shock proteins, circulatory changes, effects of serum calcium, and unidentified humoral substance surrounding myelinated axons, causing increased threshold for depolarization and decreased conduction velocity after increased in temperature.
• Historical factors such as exertional activity, hot climates, hot showers, menses, psychological stress, and viral or bacterial illness with fever can trigger this phenomenon in the setting of chronic, subacute, or acute lesions related to multiple sclerosis
• Pseudoexacerbation often resolves after the underlying infectious trigger is resolved. At the same time, a true exacerbation will present with new focal neurological deficits, including diplopia or amblyopia, dysarthria, nystagmus, internuclear ophthalmoplegia, focal hemiplegia, dysesthesias, dysmetria, ataxia, allodynia, neuropathic pain, spasms, abnormal reflexes, among other central demyelinating symptoms.
• Evaluation of Uhthoff phenomenon includes using history and physical examination to determine whether it is a true exacerbation or pseudo-exacerbation
• Pseudo-exacerbation evaluation includes a serum laboratory complete metabolic and blood count with differential, urinalysis, and chest X-ray, among others, to rule out infectious, toxic, and metabolic triggers.
• A true exacerbation should be worked up with advanced imaging, including an MRI of the brain and T- and C-spine, with and without contrast, to assess for any new contrast-enhancing lesions that could reveal a new clinical attack for the demyelinating condition the patient suffers. For new diagnosis, a lumbar puncture may be indicated to pinpoint the demyelinating or inflammatory condition, including basic CSF studies, meningoencephalitis panel, oligoclonal bands, immunoglobulin G index, neuromyelitis optical Aquaporin-4 or myelin oligodendrocyte glycoprotein antibodies, flow cytometry, cytology, among others.
• Symptomatic treatment of Uhthoff syndrome includes avoidance of heat triggers, active cooling measures, and, in severe or recurrent cases, oral 4-aminopyridine or dalfampridine
• A true exacerbation should be treated acutely with intravenous high-dose corticosteroids, intravenous immunoglobulin, plasmapheresis, chronic disease-modifying immunomodulatory therapy, physical rehabilitation, and treatment of complications related to the chronic neurological sequela of the underlying disorder

Enhancing Healthcare Team Outcomes

The main strategy in preventing and treating Uhthoff phenomena or other pseudo-relapses is to be familiar with the precipitating factors. Educating patients about the triggers and measures to avoid such triggers is important.  Patients with MS usually need an interprofessional team that consists of the primary care provider, neurologist, and other specialists depending on the functional status (eg, ophthalmologist and urologist, as well as physical and occupational therapists and social workers). Early and easy access to a care coordinator and education may decrease unnecessary emergency room visits and enhance patient outcomes.[27]  

Review Questions

• Access free multiple choice questions on this topic.
• Click here for a simplified version.
• Comment on this article.

References

1.

Opara JA, Brola W, Wylegala AA, Wylegala E. Uhthoff`s phenomenon 125 years later - what do we know today? J Med Life. 2016 Jan-Mar;9(1):101-105. [PMC free article: PMC5152601] [PubMed: 27974923]

2.

Pearce JM. Early observations on optic neuritis and Uhthoff's sign. Eur Neurol. 2010;63(4):243-7. [PubMed: 20375511]

3.

Ontaneda D, Rae-Grant AD. Management of acute exacerbations in multiple sclerosis. Ann Indian Acad Neurol. 2009 Oct;12(4):264-72. [PMC free article: PMC2824954] [PubMed: 20182574]

4.

Rolak LA, Ashizawa T. The hot bath test. JAMA. 1983 Dec 23-30;250(24):3281-2. [PubMed: 6645021]

5.

Smith KJ, McDonald WI. The pathophysiology of multiple sclerosis: the mechanisms underlying the production of symptoms and the natural history of the disease. Philos Trans R Soc Lond B Biol Sci. 1999 Oct 29;354(1390):1649-73. [PMC free article: PMC1692682] [PubMed: 10603618]

6.

Lepore FE. Uhthoff's symptom in disorders of the anterior visual pathways. Neurology. 1994 Jun;44(6):1036-8. [PubMed: 8208395]

7.

Park K, Tanaka K, Tanaka M. Uhthoff's phenomenon in multiple sclerosis and neuromyelitis optica. Eur Neurol. 2014;72(3-4):153-6. [PubMed: 25195501]

8.

Guthrie TC, Nelson DA. Influence of temperature changes on multiple sclerosis: critical review of mechanisms and research potential. J Neurol Sci. 1995 Mar;129(1):1-8. [PubMed: 7751837]

9.

Perkin GD, Rose FC. Uhthoff's syndrome. Br J Ophthalmol. 1976 Jan;60(1):60-3. [PMC free article: PMC1017468] [PubMed: 1268162]

10.

Fraser CL, Davagnanam I, Radon M, Plant GT. The time course and phenotype of Uhthoff phenomenon following optic neuritis. Mult Scler. 2012 Jul;18(7):1042-4. [PubMed: 22146611]

11.

Humm AM, Beer S, Kool J, Magistris MR, Kesselring J, Rösler KM. Quantification of Uhthoff's phenomenon in multiple sclerosis: a magnetic stimulation study. Clin Neurophysiol. 2004 Nov;115(11):2493-501. [PubMed: 15465437]

12.

Frohman TC, Davis SL, Frohman EM. Modeling the mechanisms of Uhthoff's phenomenon in MS patients with internuclear ophthalmoparesis. Ann N Y Acad Sci. 2011 Sep;1233:313-9. [PubMed: 21951010]

13.

Giuliodori MJ, DiCarlo SE. Myelinated vs. unmyelinated nerve conduction: a novel way of understanding the mechanisms. Adv Physiol Educ. 2004 Dec;28(1-4):80-1. [PubMed: 15149966]

14.

Berdjis H, Schnaudigel OE. Uhthoff's phenomenon in the low-frequency flash-evoked cortical potential. Dev Ophthalmol. 1984;9:188-94. [PubMed: 6526103]

15.

Howells J, Czesnik D, Trevillion L, Burke D. Excitability and the safety margin in human axons during hyperthermia. J Physiol. 2013 Jun 15;591(12):3063-80. [PMC free article: PMC3832120] [PubMed: 23613528]

16.

Frohman TC, Davis SL, Beh S, Greenberg BM, Remington G, Frohman EM. Uhthoff's phenomena in MS--clinical features and pathophysiology. Nat Rev Neurol. 2013 Sep;9(9):535-40. [PubMed: 23732530]

17.

Wingerchuk DM, Rodriguez M. Premenstrual multiple sclerosis pseudoexacerbations: Role of body temperature and prevention with aspirin. Arch Neurol. 2006 Jul;63(7):1005-8. [PubMed: 16831971]

18.

Fitzgerald KC, Cassard LA, Fox SR, Probasco JC, Cassard SD, Mowry EM. The prevalence and utility of screening for urinary tract infection at the time of presumed multiple sclerosis relapse. Mult Scler Relat Disord. 2019 Oct;35:61-66. [PubMed: 31344604]

19.

Alfredsson L, Olsson T. Lifestyle and Environmental Factors in Multiple Sclerosis. Cold Spring Harb Perspect Med. 2019 Apr 01;9(4) [PMC free article: PMC6444694] [PubMed: 29735578]

20.

Jakimovski D, Guan Y, Ramanathan M, Weinstock-Guttman B, Zivadinov R. Lifestyle-based modifiable risk factors in multiple sclerosis: review of experimental and clinical findings. Neurodegener Dis Manag. 2019 Jun;9(3):149-172. [PubMed: 31116081]

21.

Olsson T, Barcellos LF, Alfredsson L. Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis. Nat Rev Neurol. 2017 Jan;13(1):25-36. [PubMed: 27934854]

22.

van Diemen HA, van Dongen MM, Dammers JW, Polman CH. Increased visual impairment after exercise (Uhthoff's phenomenon) in multiple sclerosis: therapeutic possibilities. Eur Neurol. 1992;32(4):231-4. [PubMed: 1324180]

23.

Espejo C, Montalban X. Dalfampridine in multiple sclerosis: from symptomatic treatment to immunomodulation. Clin Immunol. 2012 Jan;142(1):84-92. [PubMed: 21742559]

24.

Goodman AD, Brown TR, Schapiro RT, Klingler M, Cohen R, Blight AR. A pooled analysis of two phase 3 clinical trials of dalfampridine in patients with multiple sclerosis. Int J MS Care. 2014 Fall;16(3):153-60. [PMC free article: PMC4204376] [PubMed: 25337058]

25.

Haupert CL, Newman NJ. Prolonged Uhthoff phenomenon in sarcoidosis. Am J Ophthalmol. 1997 Oct;124(4):564-6. [PubMed: 9323955]

26.

Papandony M, Wesselingh R, Stark R. Uhthoff phenomenon in osmotic demyelination syndrome. Intern Med J. 2014 Nov;44(11):1144-5. [PubMed: 25367730]

27.

National Clinical Guideline Centre (UK). Multiple Sclerosis: Management of Multiple Sclerosis in Primary and Secondary Care. National Institute for Health and Care Excellence (UK); London: Oct, 2014. [PubMed: 25340249]

Disclosure: Sreelakshmi Panginikkod declares no relevant financial relationships with ineligible companies.

Disclosure: Appaji Rayi declares no relevant financial relationships with ineligible companies.

Disclosure: Franklyn Rocha Cabrero declares no relevant financial relationships with ineligible companies.

Disclosure: Lokesh Rukmangadachar declares no relevant financial relationships with ineligible companies.