Normokalemic periodic paralysis (NormoKPP)

Presenting Symptoms

Common Characteristics Associated with the Periodic Paralyses

  • Attacks may last from minutes to days, and occur sporadically.
  • Weakness can be local or generalized.
  • The deep tendon reflexes become depressed, diminished, or lost in the course of the attacks.
  • The muscle fibers become unresponsive to either direct or indirect electrical stimulation during attacks.
  • The generalized attacks usually begin in proximal muscles and then spread to distal ones.
  • Respiratory and cranial muscles tend to be spared but eventually may also be paralyzed.
  • Rest after exercise tends to provoke weakness of the muscles that had been exercised, but continued mild exercise may abort attacks.
  • Exercise restricted to a single muscle or a small group of muscles can induce weakness of the exercised muscles without a detectable change of the potassium level in systemic circulation.
  • Exposure to cold may provoke weakness in the primary forms of the disease.
  • Complete recovery usually occurs after initial attacks.
  • Permanent weakness and irreversible pathological changes in muscle can develop after repeated attacks.
  • Onset at puberty is common.  The reason for this still remains a mystery.

Differential Diagnosis


Diagnostic Work Up

Chief Complaint:  I had a bout of weakness. I think I have periodic paralysis.

Primary Medical Doctor can do:

  1. Attack triggers (diet history to exclude licorice, diuretic abuse, laxative abuse)
  2. Duration of attack
  3. Family history
  4. Medication history
  5. Features of attacks – describe what happens to you
  6. Do attacks have periodicity/recurrent
  7. The above gives you pre-test probability
  8. Suspect hypoPP or hyperPP
    1. Check serum potassium in an attack (often difficult to catch, may require standby EMS and/or arrangements with a local emergency room)
    2. Check serum potassium outside an attack (if normal, speaks less for renal disease)
    3. CK (skeletal muscle)
    4. EKG
  9. Thyroid studies (for hypoPP) – TSH, free T4, and free T3
  10. Rarely, rule out RTA IV, licorice use, diuretic abuse, laxative abuse, renin-aldosterone-angiotensis axis in context of hypokalemia or hyperkalemia (r/o Conn’s syndrome vs. Addison’s disease). Ask nephrologist about specific tests

Neurologist can do:

  1. Neurological investigation – EMG (exclude myotonia) and exercise test (if abnormal then suggestive, but if normal, does not exclude)
  2. Routine MRI to judge how much muscle bulk is preserved and presence of edema (should be done before diuretic therapy); if possible, Na MRI is ideal but only investigational now
  3. Genetic testing
  4. Empiric therapy sequentially with potassium supplementation, and either eplerenone or acetazolamide
  5. Repeat MRI after 4-6 weeks of empiric therapy looking for a decrease in edema
  6. Biopsy if genetic testing is negative
  7. Provocative test – dangerous
  8. Refer back to PMD once diagnosis is established for continued management

Genetic testing

MRI of muscles looking for fatty degeneration, which is a feature of permanent muscle weakness (PMW)

The significance of elevated Creatine Phosphokinase (CK or CPK) during or after attacks is unclear, and for now, does not aid in the diagnosis.  Further study is warranted given that some patients may present with this lab abnormality.

Involve an Endocrinologist to rule out adrenal causes of hypokalemia. Specific studies they might perform to rule in or out hypoPP are:  (more information to follow)

Involve a Nephrologist to rule out renal disease and to get advice about electrolyte management. Specific tests they might perform to rule in or out hypokalemic periodic paralysis are: (more information to follow)

Muscle Biopsy

There are some images of muscle from someone with HypoPP at http://neuromuscular.wustl.edu/pathol/hopp.htm. These muscles have vacuoles, often seen in lipid storage diseases, but here described as containing “amorphous debris”.

In the era of genetic testing, the glucose or glucose/insulin challenge test, which is dangerous, is essentially obsolete.  Indeed, those with an obvious diagnosis of familial hypokalemic periodic paralysis would likely not need a challenge test.  Those with unclear diagnoses are often more sick, many times with cardiac symptoms during attacks, such that the challenge tests are disfavored unless absolutely necessary.

CMAP (McMannis Protocol)

McManis EMG protocol to diagnose periodic paralysis:

The Long exercise nerve conduction test:

  1. This will be performed in accordance with the protocol described by McManis. All nerve conduction testing will be done on the abductor digiti minimi muscle with stimulation of the ulnar nerve at the wrist. Ambient skin temperature should be approximately 31-32 degrees F or 0 degrees C.
  2. Compound muscle action potentials (CMAPs) are evoked with a single supramaximal stimulus and repeated every minute for 5 minutes to ensure a stable baseline.
  3. Maximal, voluntary, isometric exercise of the muscle is performed in 10 second intervals followed by 5 seconds of rest for a total of 5 minutes. CMAP amplitudes are then recorded every 1 minute for 5 minutes then every 5 minutes for 30 minutes.
  4. A decrement of >40% is highly suggestive of periodic paralysis. It does not differentiate, however, between the primary and secondary forms of periodic paralysis.

Genetic Testing

Please see the following link for Genetic Testing

In terms of genetic counseling, the disease is autosomal dominant. A variety of mutations in sodium, calcium, and potassium channel genes in muscle have been reported to cause hypokalemic periodic paralysis. One Lab in the United States, one lab in Germany, one lab in France, and one lab in the U.K. perform the genetic testing. The genetic test has very high specificity but poor sensitivity — that is, a positive test is confirmatory, but a negative test DOES NOT rule out periodic paralysis. Currently, there are only limited data to support a certain genotype predicting disease phenotype (i.e. severity and likelihood of responding to treatment). So, at this time, genetic testing may be helpful in establishing the diagnosis, for family planning, or for research purposes. There is a 50% chance the patient will give the disorder to his offspring. Penetrance is felt to be less in females.


Emergency Management


Therapy


Diet and Nutrition


Useful Articles


Additional Resources

link to HKPP.org and to Additional Resources section in this site