Thread by @AvrahamCooperMD

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Why can multiple sclerosis symptoms worsen with heat exposure, something known as the Uhthoff phenomenon?

This question is especially relevant in the era of record-breaking heat waves and climate change.

#tweetorial #medtwitter

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In 1890, Wilhelm Uhthoff noted multiple sclerosis (MS) patients having a “marked deterioration of visual acuity during exercise" or after a hot bath, which ⬆️ body temperature.

1 patient lost vision just by walking vigorously in Uhthoff's clinic.

pubmed.ncbi.nlm.nih.gov/20375511/

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The Uhthoff phenomenon is now recognized as exceedingly common in MS.

Up to 80% of patients experience ⬆️ neurological symptoms w/ even small body temp increases. These can include diminished physical (eg gait) and cognitive (eg mental fog) function.

journals.sagepub.com/doi/abs/10.117…

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Strikingly, almost any source of increased body heat can trigger the Uhthoff phenomenon:

Fevers and hot weather can do it, but even things like sitting in a hot bath/jacuzzi or using a hair dryer (!).

ncbi.nlm.nih.gov/books/NBK47024…

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This 1959 case series vividly demonstrated the Uhthoff phenomenon in 14 MS patients.

9 were heated w/ infrared lamps and 4 were immersed in hot water baths.

Raising core body temps 0.5-2.5 deg F caused neurological symptoms in 13/14.

pubmed.ncbi.nlm.nih.gov/13655099/

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So what is the mechanism of the Uhthoff phenomenon?Why would heat worsen MS symptoms?

Let's quickly review MS pathogenesis.

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Recall that the hallmark pathology of MS involves autoimmune-mediated demyelination of central nervous system neurons.

This leads to impaired conduction of impulses between the Nodes of Ranvier, and slower overall axonal conduction.

ncbi.nlm.nih.gov/pmc/articles/P…

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Eventually a neurodegenerative phase can lead to progressive decline in neurological function.

pubmed.ncbi.nlm.nih.gov/24871874/

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Returning to the Uhthoff phenomenon, a 2004 study found that heat exposure led to decreased neuronal conduction in MS patients. This could be "rescued" by cold exposure.

Conduction in normal controls was unaffected by heat.

pubmed.ncbi.nlm.nih.gov/15465437/

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In the same study, both the amount of heat-induced neuronal conduction blockage and subjective impairment of neuronal function correlated w/ decreases in walking speed.

In essence, heat-induced impairment of nerve conduction led to objective neurological dysfunction.

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So why would heat slow conduction specifically in demyelinated neurons?

Neurons adapt to demyelination by adding additional axonal membrane Na channels, a process called ion channel adaptation, to try to maintain conduction speed...

pubmed.ncbi.nlm.nih.gov/30377640/

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But these new Na channels have altered physiologic properties so that they are more heat-sensitive, and CLOSE if the temperature increases even slightly.

This premature closure w/ ⬆️ temperature hyperpolarizes the axon and dramatically ⬇️ conduction.

pubmed.ncbi.nlm.nih.gov/23732530/

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Demyelinated axons also have excessive potassium efflux, which further hyperpolarizes the membrane and slows conduction, contributing to a predilection for the emergence of the Uhthoff phenomenon.

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In terms of treatment, active cooling re-opens closed Na channels and helps resolve symptoms.

The K channel blocker 4-Aminopyridine (4-AP), used for motor symptoms in MS, also improves axonal conduction by prolonging action potential duration.

pubmed.ncbi.nlm.nih.gov/23732530/

15/SUMMARY
🧠The Uhthoff phenomenon in MS involves worsening neurological symptoms w/ heat exposure
🧠Any source of increased body temperature can provoke
🧠It results from increased density of heat-sensitive Na channels in demyelinated axons, which close w/ increased temperature