Current Case: Fall 2019

Contributed by Angela Aziz-Donnelly, MD and Ioannis Karakis, MD, PhD, MSc, FACNS
Emory University School of Medicine

Clinical Presentation

A 22-year-old man presented with episodes of weakness. He reported that the first episode occurred at the age of 10, and that the weakness affected his neck and limbs to varying degrees. At times, he was completely paralyzed from the neck down, whereas at other times he reported just mild weakness. He did not experience any ocular, bulbar, or respiratory involvement during these attacks which typically lasted hours to days and were provoked by alcohol and exercise. There was no numbness or tingling during the attacks, no radicular complaints, no sphincteric disturbances, and his sensorium remained clear. In between these episodes he was completely normal. He had frequent ED admissions for these episodes, during which his potassium was found to be significantly low. His father had similar episodes of weakness. On examination between episodes, he had normal tone and bulk with full strength throughout with the exception of mild left tibialis anterior weakness. Reflexes were diminished. Mental status, cranial nerves, sensation, and coordination were intact. There were no dysmorphic features. He underwent routine NCS and needle EMG, in addition to a short exercise test, results of which are shown below:

Question 1: What condition does this patient have?

  1. Hyperkalemic Periodic Paralysis
  2. Myasthenia Gravis
  3. Hypokalemic Periodic Paralysis
  4. Andersen-Tawil Syndrome
Answer: (click here)

A1: Correct answer: C. Hypokalemic Periodic Paralysis

The patient’s clinical history and exam suggest a muscle channelopathy. Given the clinical history of lengthy triggered episodes with alcohol and rest after exercise, as well as low potassium levels during attacks, the diagnosis of Hypokalemic Periodic Paralysis is most likely. EDX studies showing lack of after-discharges on regular NCS, electrical myotonia on needle EMG, and major abnormalities in the short exercise test further supports this diagnosis. Of note, a long exercise test was not performed. Hypokalemic Periodic Paralysis has autosomal dominant inheritance, though there is decreased penetrance in women and about one third of cases are sporadic, so there may not be a family history. Secondary Hypokalemic Periodic Paralysis needs to be excluded in patients with no family history or onset after the third decade of life.

Question 2: What channel is most commonly affected in this disorder?

  1. Calcium: CACNA1S α1-subunit on chromosome 1q
  2. Sodium: SCN4A α-subunit on chromosome 17q
  3. Chloride: CLCN1 on chromosome 7q
  4. Potassium: KCNJ2 on chromosome 17q
Answer: (click here)

A2: Correct answer: A. Calcium: CACNA1S α1-subunit on chromosome 1q

The majority of patients with Hypokalemic Periodic Paralysis demonstrate a mutation in the alpha subunit of a voltage-sensitive muscle calcium channel gene on chromosome 1q 31-32 (CACNA1S), and less commonly in the alpha subunit of the sodium channel gene on chromosome 17q 23-25 (SCN4A). Patients with the SCN4A mutation are classified as Hypokalemic Periodic Paralysis type 2. This mutation has also been associated with Hyperkalemic Periodic Paralysis and Paramyotonia Congenita. Mutations in CLCN1 on chromosome 7q are associated with Myotonia Congenita, while mutations in KCNJ2 on chromosome 17q are associated with Andersen-Tawil syndrome. Of note, in about 30% of patients, a genetic mutation may not be found, and the diagnosis is made on the basis of clinical presentation.

Question 3: What pattern is typically seen on short and long exercise testing of patients with this disorder?

  1. Short exercise test: Sustained decrement in CMAP amplitude within 1 minute post-exercise. The decrement increases with subsequent trials.
    Long exercise test: Immediate significant decrement in CMAP amplitude after exercise, followed by slow improvement as the test proceeds.
  2. Short exercise test: Immediate decrement on CMAP amplitude after exercise, followed by recovery to baseline by 60 seconds. Decrement lessens with subsequent trials.
    Long exercise test: Transient immediate decrement in CMAP amplitude after exercise, followed by quick return to baseline.
  3. Short exercise test: Increase in CMAP amplitude after exercise. Amplitude increase is more profound with subsequent trials.
    Long exercise test: Slight transient increase in CMAP amplitude immediately after exercise, followed by gradual decrease within 10-20 minutes post-exercise.
  4. Short exercise test: Minimal change of CMAP amplitude after exercise.
    Long exercise test: Slow decrement following exercise.
Answer: (click here)

A2: Correct answer: D. Short exercise test: Minimal change of CMAP amplitude after exercise.
Long exercise test: Slow decrement following exercise.

Hypokalemic Periodic Paralysis typically demonstrates Fournier Pattern 5 on short and long exercise test. Choice A corresponds with Fournier Pattern 1 and is seen in Paramyotonia Congenita. Choice B corresponds with Fournier Pattern 2 and is seen in Myotonia Congenita. Choice C corresponds with Fournier Pattern 4 and is seen in Hyperkalemic Periodic Paralysis.

Question 4: Patients with this disorder can be treated with which of the following medications/lifestyle modifications?

  1. Furosemide
  2. Increase salt intake
  3. Acetazolamide
  4. Increase carbohydrate intake
Answer: (click here)

A2: Correct answer: C. Acetazolamide

Patients with Hypokalemic Periodic Paralysis can be treated with acetazolamide, a potassium-sparing diuretic; those with CA-channel mutations are more likely to benefit than those with Na-channel mutations. Patients with Hypokalemic Periodic Paralysis should also avoid triggers, such as alcohol and carbohydrate-rich or salty meals. Acute attacks of weakness can be treated with oral potassium salts every 30 minutes until strength improves. Hypokalemic Periodic Paralysis may be allelic to malignant hyperthermia, hence patients undergoing surgery should be monitored accordingly.

 

References

  1. Fournier E, Arzel M, Sternberg D, et al. ‘Electromyography guides toward subgroups of mutations in muscle channelopathies.’ Ann Neurol 2004;56:650–661.
  2. Hehir MK, Logigian EL. ‘Electrodiagnosis of Myotonic Disorders.’ Physical Medicine and Rehabilitation Clinics of North America 2013;24 (1):209-220
  3. Kuntzer T, Flocard F, Vial C, et al. ‘Exercise test in muscle channelopathies and other muscle disorders.‘ Muscle Nerve 2000;23:1089–1094.
  4. Miller, TM. ‘Differential diagnosis of myotonic disorders.’ Muscle Nerve 2007;37:293-299
  5. Preston DC & Shapiro BE. (2013) ‘Electromyography and Neuromuscular Disorders.’ St. Louis: Elsevier
  6. Saperstein, DS. ‘Muscle Channelopathies.’ Continuum 2006;12(3):121-139
  7. Statland JM, Fontaine B, Hanna MG, et al. ‘Review of the Diagnosis and Treatment of Periodic Paralysis.’ Muscle Nerve 2017;57:522-530
  8. Amato, AA and Russell, JR. ‘Neuromuscular Disorders’. (2008). McGraw Hill.