Leg pain in neuropathic postural tachycardia syndrome is associated with altered muscle membrane properties, 2021, Rodriguez et al

[Ryan31337]

Leg pain in neuropathic postural tachycardia syndrome is associated with altered muscle membrane properties, 2021, Rodriguez et al

Abstract
Purpose
In neuropathic postural tachycardia syndrome, peripheral sympathetic dysfunction leads to excessive venous blood pooling during orthostasis. Up to 84% of patients report leg pain and weakness in the upright position. To explore possible pathophysiological processes underlying these symptoms, the present study examined muscle excitability depending on body position in patients with neuropathic postural tachycardia syndrome and healthy subjects.

Methods
In ten patients with neuropathic postural tachycardia syndrome and ten healthy subjects, muscle excitability measurements were performed repeatedly: in the supine position, during 10 min of head-up tilt and during 6 min thereafter. Additionally, lower leg circumference was measured and subjective leg pain levels were assessed.

Results
In patients with neuropathic postural tachycardia syndrome, muscle excitability was increased in the supine position, decreased progressively during tilt, continued to decrease after being returned to the supine position, and did not completely recover to baseline values after 6 min of supine rest. The reduction in muscle excitability during tilt was paralleled by an increase in lower leg circumference as well as leg pain levels. No such changes were observed in healthy subjects.

Conclusions
This study provides evidence for the occurrence of orthostatic changes in muscle excitability in patients with neuropathic postural tachycardia syndrome and that these may be associated with inadequate perfusion of the lower extremities. Insufficient perfusion as a consequence of blood stasis may cause misery perfusion of the muscles, which could explain the occurrence of orthostatic leg pain in neuropathic postural tachycardia syndrome.

Open access, https://link.springer.com/article/10.1007/s10286-021-00830-5

 

[Sean]

"misery perfusion"

???

 

[Hutan]

But not a typo! "The term misery perfusion refers to a condition of the cerebral circulation in which regional blood flow is reduced relative to regional metabolic demand for oxygen."

We've talked about misery perfusion before (in the brain). Looks as though any part of the body can have it.

 

[Hutan]

I think this is an interesting study; I think they found real differences! Yes, I have allowed myself an exclamation mark. The leg pain and increase in leg circumference upon standing fit with what happens to me; I do have postural orthostatic tachycardia, especially on bad days.

@Snow Leopard

See in Figure 3, the muscle relative refractory period is shorter in the POTS people before and during the tilt test, and slower after the tilt test. (The bars showing the measurements during the tilt test are in the section with the grey background.)


The authors say that the results they found before the tilt test look like what they found in people who had been training hard for two weeks. They think it's an adaptation to repeated ischaemia.

The ESN and MRRP values measured in patients with neuropathic POTS in the supine position before HUT (ESN 13.9%; MRRP 2.94 ms) correspond to the values measured in healthy subjects with hyperpolarized muscles after force training. One possible interpretation is that the muscles of patients with neuropathic POTS hyperpolarize as a consequence of the orthostatic stress, as in the upright body position muscle activity may be constantly increased due to the altered blood perfusion (see below). The excessive blood pooling during standing may cause an “ischemia-like” environment as it exists also during forced muscle activity, e.g., during training. As a consequence, the density of the Na+/K+ pump increases, resulting in membrane hyperpolarization at rest.

This pattern of decreasing ESN and prolonged MRRP has been shown to be a sign of muscle membrane depolarization. Similar changes have been previously reported in a study investigating muscle excitability in healthy subjects during induced muscle ischemia

Another finding was present the whole time, regardless of body position - lowered late supernormality. The authors say they saw this in healthy subjects with muscle fatigue.

LSN was significantly lower overall in patients with neuropathic POTS compared to healthy subjects, but did not change as a function of body position in either group. While both ESN and MRRP are closely related to muscle membrane potential, LSN is thought to be a parameter representing transverse tubular function. Our results therefore indicate an altered transverse tubular state in neuropathic POTS patients that is independent of body position. In a recent study, we investigated changes in MVRC parameters during muscle fatigue in healthy subjects, which was induced by intermittent 37 Hz stimulation. This stimulation paradigm produced a gradual decrease in LSN, with delayed recovery after cessation of stimulation, suggesting that longer muscle activation may lead to a progressive decrease in LSN [26]. The mechanisms that are reflected by LSN are assumed to depend on ion accumulation in the transverse tubule system and passive diffusion of accumulated ions during the recovery phase [8, 27,28,29]. Earlier studies have shown that chloride channels and thus chloride conductance in the transverse tubular system counteract the fatiguing effects of potassium accumulation to maintain muscle excitability

The authors are hypothesising that the leg circumference increase is due to 'impaired vasoconstriction caused by the peripheral sympathetic dysfunction'.

In patients with neuropathic POTS, a continuous increase in the circumference of the lower leg was measured during the HUT position, most likely due to the increased pooling of blood as a consequence of the impaired vasoconstriction caused by the peripheral sympathetic dysfunction

They think this explains muscle weakness and exercise intolerance:

Patients with neuropathic POTS are known to experience exercise intolerance [2]. The overall decreased LSN as well as the progressive muscle membrane depolarization during HUT explain the reduced potential for muscle activation and the occurrence of exercise intolerance. The occurrence of muscle fatigue depends on the degree of membrane depolarization. Thus, a more hyperpolarized muscle membrane potential at rest will delay the onset of critical depolarization for fatigue.

Unfortunately, they then go on to suggest exercise as a treatment. I don't understand their point about increasing hyper polarisation - because muscles of people with POTS had already adapted to be hyper polarised, and it wasn't preventing the problems. Certainly, it doesn't seem likely that exercise will cure the problem.

These findings taken together support regular exercise as a treatment modality in neuropathic POTS [34] and at least partially explain its beneficial effect: Training increases hyperpolarization in the long term and reduces muscle membrane depolarization. Furthermore, measures that reduce pooling and enhance perfusion of the lower extremities can be expected to be beneficial in neuropathic POTS.

 

[Ryan31337]

Useful summary & comments, @Hutan, thank you.

Interesting study for me as lower leg pain was one of my primary complaints at on-set, long before other more overt POTS signs & symptoms started.

The leg pain and increase in leg circumference upon standing fit with what happens to me; I do have postural orthostatic tachycardia, especially on bad days.

I thought it interesting to note that the patients did not actually meet POTS heart rate criteria at the time of HUT.

In this study the patients were allowed to continue with most of the usual POTS medications and eat/drink normally - its fairly well recognised that HUT sensitivity for diagnosing POTS is influenced by these factors, as well as time of day, so this isn't surprising and the authors came to the same conclusion. Can't help but wonder how much of the misery perfusion is still happening in patients without the significant heart rate increase, for whatever reasons. Much like what we've seen from CBF measurements in CFS patients with & without clinical POTS.

 

[Ryan31337]

The only other medication besides midodrine that could have had an effect on the muscle excitability measurements is pyridostigmine. Theoretically, pyridostigmine would be associated with muscle membrane depolarization. This was not the case in our study, as the baseline muscle excitability measurements in the supine position showed the opposite (hyperpolarization)

Would be interested to know if anyone here has an understanding of this point made in the paper.

Specifically how that might relate to David Systrom's theories of Pyridostigmine action in SFN/POTS.

 

[Snow Leopard]

The authors are hypothesising that the leg circumference increase is due to 'impaired vasoconstriction caused by the peripheral sympathetic dysfunction'.

But perhaps the sympathetic response is itself a response to dysregulated perfusion of blood in the muscle capillaries?

Pooling and shunting (as observed post-exercise by Systrom et al) could be a result of trying to maintain blood flow across the capillary bed.

 

[Mithriel]

I cant follow the science very well but one of the strange symptoms of my ME is pain in my lower leg which is relieved by my husband squeezing it tightly with both hands starting at the ankle then working towards my knee.

 

[Blueskytoo]

I cant follow the science very well but one of the strange symptoms of my ME is pain in my lower leg which is relieved by my husband squeezing it tightly with both hands starting at the ankle then working towards my knee.

Me too, and my daughter who has POTS as well also struggles with this. We’ve both found lower leg compression stockings help with the pain immensely, although they’re an absolute bugger to get on and off (especially if you have extremely high arches on your feet…).

 

[Mithriel]

I'd forgotten. Years ago I kept a pair from when I was in hospital and they worked great until they fell apart!

My daughter got a fancy pair of compression stockings to wear as all the other nurses on her ward use them to stop aching legs. Maybe Santa will bring me some