Uhthoff’s 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 multiple sclerosis patients 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’s Phenomenon (UP), by G. Ricklefs.  In four out of 100 MS patients, Uhthoff observed the appearance of reversible optic symptoms induced by an increase in body temperature, “marked deterioration of visual acuity during physical exercise and exhausting”.  Subsequent observations have shown that the same physiological mechanism responsible for visual dysfunction in the setting of heat exposure, are also responsible for a variety of other neurological symptoms experienced by multiple sclerosis (MS) patients. 
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 multiple sclerosis. By 1980, with advancement in neuroimaging, 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 and interfere with their activities of daily life and functional capacity. 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.
Uhthoff’s phenomenon is most commonly observed in multiple sclerosis but may occur in other optic neuropathies or disorders of afferent pathways  for example neuromyelitis optica. In multiple sclerosis, several factors including the blockade of ion channels, heat shock proteins, circulatory changes, effects of serum calcium and unidentified humoral substance have been hypothesized and investigated as a cause of Uhthoff’s phenomenon. Temperature sensitive conduction blockade of partially demyelinated axons in the demyelinated plaques is the most widely accepted mechanism. Several other factors including perimenstrual period, exercise, fever, sun-tanning, hot shower, sauna, psychological stress and even hot meal and smoking of cigarettes have been reported in the literature as triggers for Uhthoff’s phenomenon. 
Between 60% to 80% of patients with multiple sclerosis (MS) exhibit Uhthoff’s phenomenon with heat exposure. In one study, 52% reported experiencing Uhthoff’s phenomenon, with a follow-up range of 1 to 20 years. Of the MS patients with Uhthoff’s phenomenon, 88% experienced non-visual heat-related phenomena compared with 30% without Uhthoff’s 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.
The precise mechanisms of Uhthoff’s phenomenon are not completely understood but 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 an increase in temperature in MS patients. 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.
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 results in widening of the nodal region leading to the transformation of faster saltatory conduction to slower membrane conduction. Segmental demyelination involves both a primary derangement in sodium channel-mediated axonal depolarization and unmasking of potassium channels resulting in K efflux and, thereby, hyperpolarization which surpass 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. 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, defined as the ratio of the current available to initiate an action potential to the minimal current required. 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 closure of the voltage-gated sodium channels in demyelinated axons, thereby compromising action potential depolarization and decreases the safety threshold for high-fidelity nerve transmissions. This can produce abnormalities ranging from delayed conduction to complete conduction block and clinically manifests as worsened MS symptom, e.g., decreased visual acuity or double vision. Almost all the precipitating factors of Uthoff phenomenon cause elevated core body temperature.
Events preceding the worsening of neurological symptom should be analyzed during history taking. Factors including exercise, taking a hot bath or shower, exposure to sun, menstrual cycle, psychological stress, hot meals, fever, and infection should be addressed as any of these can precipitate worsening of the symptoms in MS patients. 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 MS patients. 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 is able to differentiate a true relapse from a pseudo-relapse. Examination reveals various neurological deficits pertaining to the location of demyelination including amblyopia, nystagmus, INO, muscular weakness, and abnormal reflexes.
Episodes of Uhthoff's phenomenon is generally considered to be the result of established demyelinating plaques in the setting of thermal stress. The key to making a diagnosis is detailed history from the patient 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, upper respiratory tract infection or metabolic abnormalities through laboratory tests. Thus, the work up should include a detailed history and physical examination in addition to laboratory investigations to rule out metabolic, toxic and infectious derangements. An MRI brain with and without contrast might be necessary in cases wherever a clear source is not identified to assess for any new contrast enhancing lesion consistent with a true progression.
A fundamental principle in the prevention and treatment of Uhthoff's phenomena is to be familiar with the antecedent factors that can result in 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 sauna, exposure to the sun when the outside temperature is greater than 30 C, hydrotherapy with water at high temperatures, short-wave radiotherapy, and paraffin application. Patients should be advised about performing an exercise during early morning and late evening hours when the temperature is cooler.
Uhthoff phenomenon fully resolves following variable periods of rest (generally ranging from minutes to an hour), and under circumstances where heat stressors are removed, or active cooling measures are applied. Simple and convenient strategies such as taking cold showers, application of ice packs, use of regional cooling devices, and cold beverages can also be tried for heat sensitivity. Cooling garments have been shown to improve neurological function (motor performance and visual acuity) and perceived subjective benefits (feeling less fatigued) in MS patients with Uhthoff's phenomenon.
There are reports showing that oral administration of 4-aminopyridine reduces the worsening of the visual impairment after an increase in body temperature in MS patients.  4-Aminopyridine (4-AP) is a dose-related potassium channel blocker that prolongs action potential duration by reducing potassium efflux and thereby increasing the hyperpolarization threshold. It enhances the fidelity of conduction in segmentally demyelinated nerve fibers. FDA has approved dalfampridine, an extended release formulation of this agent in improving the walking capacity of MS patients.
Differentiation between Uhthoff's phenomena and multiple sclerosis exacerbations is of paramount importance to avoid the harm of unnecessary and additional courses of corticosteroid treatments and plasma exchange in addition to the risk of cessation of effective disease-modifying therapy, and ultimately rendering the patient vulnerable to the risks associated with escalation to a higher efficacy disease-modifying therapy, which usually are associated with higher side effect profile.
The main strategy in the prevention and treatment of Uhthoff's 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, e.g. 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. 
|||Opara JA,Brola W,Wylegala AA,Wylegala E, Uhthoff`s phenomenon 125 years later - what do we know today? Journal of medicine and life. 2016 Jan-Mar; [PubMed PMID: 27974923]|
|||Pearce JM, Early observations on optic neuritis and Uhthoff's sign. European neurology. 2010; [PubMed PMID: 20375511]|
|||Ontaneda D,Rae-Grant AD, Management of acute exacerbations in multiple sclerosis. Annals of Indian Academy of Neurology. 2009 Oct; [PubMed PMID: 20182574]|
|||Rolak LA,Ashizawa T, The hot bath test. JAMA. 1983 Dec 23-30; [PubMed PMID: 6645021]|
|||Smith KJ,McDonald WI, The pathophysiology of multiple sclerosis: the mechanisms underlying the production of symptoms and the natural history of the disease. Philosophical transactions of the Royal Society of London. Series B, Biological sciences. 1999 Oct 29; [PubMed PMID: 10603618]|
|||Lepore FE, Uhthoff's symptom in disorders of the anterior visual pathways. Neurology. 1994 Jun [PubMed PMID: 8208395]|
|||Park K,Tanaka K,Tanaka M, Uhthoff's phenomenon in multiple sclerosis and neuromyelitis optica. European neurology. 2014; [PubMed PMID: 25195501]|
|||Guthrie TC,Nelson DA, Influence of temperature changes on multiple sclerosis: critical review of mechanisms and research potential. Journal of the neurological sciences. 1995 Mar; [PubMed PMID: 7751837]|
|||Perkin GD,Rose FC, Uhthoff's syndrome. The British journal of ophthalmology. 1976 Jan [PubMed PMID: 1268162]|
|||Fraser CL,Davagnanam I,Radon M,Plant GT, The time course and phenotype of Uhthoff phenomenon following optic neuritis. Multiple sclerosis (Houndmills, Basingstoke, England). 2012 Jul [PubMed PMID: 22146611]|
|||Humm AM,Beer S,Kool J,Magistris MR,Kesselring J,Rösler KM, Quantification of Uhthoff's phenomenon in multiple sclerosis: a magnetic stimulation study. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology. 2004 Nov [PubMed PMID: 15465437]|
|||Frohman TC,Davis SL,Frohman EM, Modeling the mechanisms of Uhthoff's phenomenon in MS patients with internuclear ophthalmoparesis. Annals of the New York Academy of Sciences. 2011 Sep [PubMed PMID: 21951010]|
|||Giuliodori MJ,DiCarlo SE, Myelinated vs. unmyelinated nerve conduction: a novel way of understanding the mechanisms. Advances in physiology education. 2004 Dec; [PubMed PMID: 15149966]|
|||Berdjis H,Schnaudigel OE, Uhthoff's phenomenon in the low-frequency flash-evoked cortical potential. Developments in ophthalmology. 1984; [PubMed PMID: 6526103]|
|||Howells J,Czesnik D,Trevillion L,Burke D, Excitability and the safety margin in human axons during hyperthermia. The Journal of physiology. 2013 Jun 15; [PubMed PMID: 23613528]|
|||Frohman TC,Davis SL,Beh S,Greenberg BM,Remington G,Frohman EM, Uhthoff's phenomena in MS--clinical features and pathophysiology. Nature reviews. Neurology. 2013 Sep [PubMed PMID: 23732530]|
|||Wingerchuk DM,Rodriguez M, Premenstrual multiple sclerosis pseudoexacerbations: Role of body temperature and prevention with aspirin. Archives of neurology. 2006 Jul; [PubMed PMID: 16831971]|
|||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. Multiple sclerosis and related disorders. 2019 Oct; [PubMed PMID: 31344604]|
|||Alfredsson L,Olsson T, Lifestyle and Environmental Factors in Multiple Sclerosis. Cold Spring Harbor perspectives in medicine. 2019 Apr 1; [PubMed PMID: 29735578]|
|||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. Neurodegenerative disease management. 2019 Jun; [PubMed PMID: 31116081]|
|||Olsson T,Barcellos LF,Alfredsson L, Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis. Nature reviews. Neurology. 2017 Jan; [PubMed PMID: 27934854]|
|||van Diemen HA,van Dongen MM,Dammers JW,Polman CH, Increased visual impairment after exercise (Uhthoff's phenomenon) in multiple sclerosis: therapeutic possibilities. European neurology. 1992 [PubMed PMID: 1324180]|
|||Espejo C,Montalban X, Dalfampridine in multiple sclerosis: from symptomatic treatment to immunomodulation. Clinical immunology (Orlando, Fla.). 2012 Jan; [PubMed PMID: 21742559]|
|||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. International journal of MS care. 2014 Fall; [PubMed PMID: 25337058]|
|||Haupert CL,Newman NJ, Prolonged Uhthoff phenomenon in sarcoidosis. American journal of ophthalmology. 1997 Oct; [PubMed PMID: 9323955]|
|||Papandony M,Wesselingh R,Stark R, Uhthoff phenomenon in osmotic demyelination syndrome. Internal medicine journal. 2014 Nov; [PubMed PMID: 25367730]|
|||2014 Oct; [PubMed PMID: 25340249]|