LET or SET

In patients who present with characteristic episodes of flaccid weakness with abnormal potassium levels, especially when a family history is present, or in patients in whom genetic testing for one of the periodic paralyses confirms a pathogenic mutation, the clinical diagnosis is made rather easily. However, in those patients for whom this is not the case, the long exercise test (LET) is an electrodiagnostic technique that can be used to help establish the diagnosis.  The LET is performed in the electromyography laboratory and entails measuring the baseline compound muscle action potential (CMAP) area or amplitude at rest and then measuring the CMAP amplitude or area over a period of 40– 60 min after 5 min of isometric exercise of the recorded muscle, looking for an increment followed by a prolonged gradual decline. This methodology takes advantage of the fact that, in the periodic paralyses, attacks of weakness are known to be provoked by periods of rest after vigorous exercise.

Prior to the SET and LET, routine EMG/NCS is performed. 

Short exercise test: useful in non-dystrophic myotonias, Paramyotonia congenita, and Myotonia congenita.  It shows decrement in PC and MC.

1. Immobilize hand and forearm.

2. Maintain limb temperature 32-34° C

3. Record supramaximal CMAP at ADM stimulating the ulnar nerve at wrist with muscle at rest to ensure that the baseline CMAP is stable.

4. Have the patient perform maximal voluntary contraction (isometrically) for 10 seconds.

5. Record supramaximal CMAP at ADM stimulating the ulnar nerve at the wrist post-exercise, immediately. 

6. Six additional single stimuli every 8 seconds are delivered over the next 50 seconds. 

7. Sequence (post-exercise): 2 s > 10 s > 18 s > 26 s > 34 s > 42 s > 50 s. 

8. After 10 seconds of rest, perform 2 subsequent identical trials each preceded by 10 seconds of isometric exercise. 

Total: 3 trials.  

Baseline CMAP from the initial trial is referenced – the same stimulus intensity is used.

Each trial has a total of 7 stimuli: immediate (2s) followed by 6 additional stimuli

In hyperkalemic PP patients carrying T740M mutations, increase in CMAP amplitude (approximately 23%) occurs.  In HypoKPP1 and HypoKPP2 patients, the increase is not significantly different from the controls subjects (about 5%). 

SET with cooling:

1. Same algorithm as above

Cooling is delivered for 7 minutes with a target cutaneous temperature of 15 degrees centigrade.  In normal individuals, cooling with or without rewarming the limb does not alter the normal pattern. 

Long Exercise Test: McManis Protocol: Useful in Periodic Paralysis, HyperKPP, HypoKPP, Andersen-Tawil Syndrome. In the long exercise test (LET) a focal attack of paralysis is induced by exercise of a single muscle. 

1. Immobilize hand and forearm.

2. Maintain limb temperature 32-34° C

3. Record supramaximal CMAP at ADM stimulating ulnar nerve at wrist to ensure stable baseline.

4. Have the patient perform maximal voluntary contraction (isometrically) for 5 minutes, resting every 15 seconds for at least 4 seconds to prevent muscle ischemia.

5. During the period of exercise, single supramaximal stimuli are delivered at 1 minute intervals.

6. Have the patient relax completely after completion of 5 minutes of exercise.

7. Single supramaximal stimuli using the same stimulus intensity are delivered at 1 minute intervals during the period of exercise. 

8. Record CMAP immediately, then every minute for 5 minutes, and then every 5 minutes for upto 50 minutes post-exercise or until no decrement is observed in the amplitude of CMAP.

9. Percentage of Decrement is calculated as = (Highest CMAP amplitude after exercise minus smallest CMAP amplitude after exercise) divided by (highest CMAP amplitude after exercise) and multiplied by 100 to get %. Any decrement of > 40% is definitely abnormal.

After a brief increase in CMAP amplitude, a decrease of more than 40% in the CMAP amplitude after 20 minutes is considered abnormal.  An abnormal result is highly suggestive of periodic paralysis (98% specificity) but does not distinguish between hyperkalemic, hypokalemic, and thyrotoxic periodic paralysis.  Different electrophysiological patterns are identified in different groups of patients with distinct mutations by using both these tests.  

Repetitive Nerve Stimulation test (10 Hz and 3 Hz):  RNS is performed in suspected non-dystrophic myotonia cases only when the Edx assessment is inconclusive. 

• MC – 10 Hz, warm limb: CMAP amplitude continuously declines.

• PMC – 10 Hz, cold limb: CMAP amplitude continuously declines.

• PMC – 3 Hz, warm limb: Initial reduction in CMAP amplitude following exercise which then declines further and then gradually increases with 3 Hz stimulation.

5 patterns are seen.  The first, three utilize the SET alone.  The other 2 patterns are defined by a combination of LET and SET.

• Normal.  Slight CMAP amplitude and/or area increment immediately following exercise that rapidly returns to baseline during the 1st trial and does not differ with the 2nd and 3rd trials.  An increment of <10% or decrement of <20% in CMAP amplitude and/or area compared to baseline in considered normal. 

• Paramyotonica congenita (PMC):  type 1 pattern

  • SET: Little or no decrement in CMAP amplitude or area immediately following exercise. With the subsequent 6 stimuli the amplitude declines providing a curve with a negative slope. The magnitude of this response becomes more dramatic in the 2nd or 3rd trials. There is most dramatic response with cooling, however.  

  • SET with limb cooling, or rewarming following cooling demonstrates a CMAP amplitude or area decrement of >20% in response to cooling with or without rewarming is thought to be pathognomonic of PMC.  

  • PEMPs seen in response to single or repetitive stimuli following brief exercise – found in all PMC patients.  PEMPs dissipate within an individual trials and between subsequent SETs. 

  • LET in PMC: Significant and persistent CMAP amplitude and area decrement occurs averaging a 66% reduction in comparison to baseline.  

  • Myotonic discharges in EMG. 

  • PMC phenotype (Q270K) SET has a unique signature. SET test with cooling demonstrates type 2 pattern identical to MC (ie) an initial CMAP amplitude and/or area decrement immediately post-exercise that improves within the 1st trial and then between subsequent trials.  SET with cooling reverts to type I pattern typically seen in PMC, that is CMAP amplitude/area decrements with a downward slope within the 1st trial and declines further with each subsequent two trials. 

• Myotonic congenita (MC):

  • MC – AR (Becker disease). Type 2 pattern. 

    • SET: CMAP amplitude and area decrement is the greatest in initial response following exercise.  If decrement is >40% of baseline, CMAP amplitude, it is considered pathognomonic of a chloride channel disorder.  With the next 6 stimuli delivered over the ensuring 50 seconds, the decrement lessens and CMAP amplitude and areas gradually approach the baseline thus rendering a curve with an ascending positive slope.  With subsequent 2 trials, the magnitude of decrement lessens but the trajectory of curves remain the same. 

  • MC (AD – Thomsen).  Type 2 pattern but not as marked as the AR type of MC.

    • SET with cooling of limb: Decrement is marked in autosomal dominant MC.

  • PEMPs is seen in 1/3 of patients with MC with single or repetitive stimuli

  • Myotonic discharges on EMG is all patients with MC

  • LET in MC produces a pattern that is indistinguishable from normal controls. 

• Potassium aggravated myotonia (PAM): Type 3 pattern. 

  • SET is normal.  

  • No PEMPs.  

  • SET with cooling is normal.  

  • LET is normal.  

  • Myotonic discharges seen on EMG. 

• HyperKPP: Type 4 pattern.  Fournier et al.  

  • SET demonstrates immediate CMAP amplitude and area increment that exceeds that seen in controls both in amplitude and in duration of effect.  It persists throughout the minute of study.  With repetitive trials of SET, the CMAP amplitude and area increments in comparison to baseline by an average of 64%.  According to Tan et al. SET is normal in HyperKPP.  

  • Myotonic discharges are seen occasionally in some HyperKPP patients. 

  • PEMPs are absent.  

  • LET shows long, slow decrement.  A decrement of at least 40% of CMAP amplitude and area with LET is found in majority of periodic paralysis patients and may be seen in Anderson-Tawil syndorme. 

• HyperKPP or HypoKPP1: Type 4 or 5

• LET shows long, slow decrement.  A decrement of at least 40% of CMAP amplitude and area with LET is found in majority of periodic paralysis patients and may be seen in Anderson-Tawil syndorme. 

• HpoKPP1: type 5 pattern.  

• No myotonic discharges.  

• No PEMPs.  

• SET is normal. 

• LET shows slowly developing decremental pattern as see in type 5 pattern. 

• Mean time to reach decrement is ~25 minute but may take 50 minutes or even longer. 

LET- Normal.  Minimal initial decrement in CMAP amplitude and/or area with return to baseline. 

McManis Protocol (LET):

A long exercise study was performed on the left Abductor Digiti Quinti muscle with surface stimulation of the Ulnar nerve at the wrist. The muscle was of normal strength and the study was performed while taking daily supplemental potassium chloride. The evoked potential amplitude was 6.7mV at a temperature of 34° C. Repetitive stimulation was performed using the technique described by Mayo Clinic [McManis, et.al., Muscle and nerve 9:704, 1986]. Initial CMAP amplitude was 5.7mV to 6.7mV [average = 6.2 mV] during the 5 minutes prior to exercise. Maximum Voluntary effort was made for 5 minutes with 3 to 4 second rest periods every 15 seconds. 

There was an immediate post-activation facilitation of 68 percent. Continuing a single stimulation at that same temperature at 1 minute intervals through 56 minutes produced a progressive CMAP amplitude reduction to 3.0 mV that was maximal at 46 minutes. Specific CMAP amplitudes were 8.1 mV at 5 min, 6.3 mV at 10 min, 5.2 mV at 15 min, 4.5 mV at 20 min, 3.8 mV at 25 min, 3.4 mV at 30 min, 3.3 mV at 35 min, 3.6 mV at 40 min, 3.1 mV at 45 min, and 3.4 mV at 50 min.

Summary: The prolonged exercise test demonstrates an initial facilitatatory response and subsequent decremental response to greater than 50% of initial values.

A short exercise study was performed on the left Abductor Digiti Quinti muscle with surface stimulation of the Ulnar nerve at the wrist. The muscle was of normal strength and the study was performed while taking daily supplemental potassium chloride. The evoked potential amplitude was 5.3 mV at a temperature of 34° C. Repetitive stimulation was performed using the technique described by [Fournier, et.al., Annals of Neurology 56:650, 2004]. Maximum voluntary effort was made for 10 seconds. 

There was an immediate post-activation facilitation of 24 percent. Continuing a single stimulation at that same temperature at 5 second intervals through 40 seconds produced CMAP amplitudes ranging from 6.6 mV to 5.2 mV. The CMAP amplitude drops to slightly below baseline by the end of the study period [50 seconds total].

Summary: The short exercise test demonstrates normal parameters.

Summary:

These electrodiagnostic findings are most consistent with a primary disorder of the muscle membrane that is best characterized as a channelopathy as seen in periodic paralysis syndromes. Given his clinical response to the supplementation of potassium this may represent Hypokalemic Periodic Paralysis