A Curious History

Prior to the advent of more effective diagnostic methodologies, cases of apparent periodic paralysis, in which blood serum potassium levels were reported to be within normal limits, were given the designation Normokalemic Periodic Paralysis.

The disease concept of NormoKPP was proposed by Poskanzer and Kerr in 1961 (Am J Med 1961;31:328-342), and was described as normokalemic sodium responsive periodic paralysis.

It is well established that variants of the sodium and calcium channel disorders do present with serum potassium levels considered well within the normal range. In some individuals the serum potassium level may consistently be at the high or low ends of normal even though random testing may show important fluctuations. It has been suggested that relatively small shifts (as little as 0.4) in serum potassium levels can induce symptoms in sensitive individuals.

Very few families have ever been described with normokalemic periodic paralysis. Attacks have been described as lasting for several days without an increase in the serum K+ concentration. Since it was shown for one family that the Na+ channel gene is mutated at a locus (Thr704) that causes Hyperkalemic Periodic Paralysis in other families, it has been suggested that this form of periodic paralysis without hyperkalemia is actually a variant of Hyperkalemic Periodic Paralysis.

More than one researcher has considered the term hyperkalemic, to be misleading, based on the evidence that patients are most often normokalemic during attacks.

This was the position of Gamstorp, in 1989, stating, "That this term ever appeared is due to the fact that changes in serum potassium, when it still remained within normal limits, were not appreciated as such. Thus, the term is due to a misinterpretation, it is unnecessary and confusing." Gamstorp even states that the use of the term "has caused harm, and it must not be used."

Actually, Gamstorp, took the position that the normo- and hyper- variants of this disease are not separate entities, as early as 1956, in her work leading to naming this class of disorder adynamia episodica hereditaria. Others have taken similar positions through the years.

Poskanzer and Kerr, considered these variations in their 1961 review of apparently different forms, and what they described as "A Third Type of Periodic Paralysis, with Normokalemia and Favorable Response to Sodium Chloride."

Poskanzer's observations are interesting, given the state of knowledge at the time.

"It soon became apparent that the change in serum potassium was not the basic defect in the disease. Not only do some patients show no alteration in serum potassium levels and no response to the administration of potassium, but also when serum potassium levels are low they are still within limits which fail to produce weakness in normal subjects or patients with renal potassium loss" (Poskanzer and Kerr, 1961).

The current state of knowledge regarding the so-called Normokalemic Periodic Paralysis is expressed differently by three contemporary references:

1. Principles of Neurology, Adams, Victor, and Ropper, Sixth Edition, 1997.

This is a rare form of episodic paralysis, which resembles the hyperkalemic form in practically all respects, except for the fact that serum potassium does not increase, even during the most severe attacks. However, some patients with normokalemic periodic paralysis are sensitive to potassium loading (Poskanzer and Kerr); other kindreds are not (Meyers et al). The disorder is transmitted as an autosomal dominant trait, and the basic defect has proved to stem from the same mutation as that of hyperkalemic periodic paralysis.

2. Harrison's 'Principles of Internal Medicine' 14th ed. published 1998, Chap 14, Authors, Jerry Mendell, Robert Griggs, Louis Ptacek:

"The term 'hyperkalemic' is misleading since patients are most often normokalemic during attacks. It is the fact that attacks are precipitated by potassium administration that best defines the disorder...Diagnosis is suggested by a modest elevation of serum potassium during attacks in nearly half of patients; however at times the serum K+ is normal or even low. The so-called hyperkalemic and normokalemic entities of this disease are not separate entities."

3. The published review found in: Muscle Channelopathies: Malignant Hyperthermia, Periodic Paralyses, Paramyotonia, and Myotonia, Rudel, Hanna, Lehmann-Horn. In Muscle Diseases, 1999 A. H. Schapira and R. C. Griggs, Editors.

Normokalemic periodic paralysis, a rare disorder, is a variant of the hyperkalemic form. It resembles hyperkalemic periodic paralysis in many respects, but differs from it in that the serum potassium does not increase, even during serious attacks. The existence of normokalemic periodic paralysis as a nosologic entity (a unique medical classification) has been questioned, because some patients with this condition are sensitive to oral potassium salts. The disorder is transmitted as an autosomal dominant trait with high penetrance in both sexes. The attacks begin in the first decade of life and are provoked by or worsened by rest after exercise, exposure to cold, and potassium loading. Large doses of sodium improve the weakness, but glucose loading has no effect.

There are no consistent changes in serum electrolytes, but increased sodium excretion and potassium retention occur during attacks. Urinary potassium retention, lack of a beneficial effect of glucose, and failure of serum potassium to increase in attacks distinguish this disease from primary hyperkalemic periodic paralysis.

However, in at least one such family, the condition is caused by the common Val-704-Met mutation in SCN4A normally associated with hyperkalemic periodic paralysis.

Many of the leading researchers, including Poskazer, Gamstorp, Lehmann-Horn, Engle, Ricker, Ptacek, and Rudel, have suggested various mechanisms and relationships. The process is an excellent object lesson in the evolution of medicine.

Despite the reports by Fumio, et al. (Fumio Otsuka, Toshio Ogura, Takayoshi Yamauchi, Hirofumi Makino, Department of Medicine III, Okayama University Medical School, Japan, 1998), of new SCN4A mutations in Hyperkalemic Periodic Paralysis (HyperKPP), doubts remained as to whether NormoKPP existed as a discrete entity.

Chinnery PF, Walls TJ, Hanna MG, Bates D, Fawcett PR (Ann Neurol 2002 Aug;52(2):251-2) report that they have identified the Met1592Val mutation of SCN4A in an affected descendent of the original NormoKPP family, stating emphatically, “This is the final piece in the puzzle: normoKPP is actually a variant of hyperKPP and is not a distinct disorder.”

One hesitates to accept anything with such finality in today’s environment of rapid discovery and reevaluation. Designations can be confounded at the next opportunity for characterization. We may yet discover an appropriate attribution for this designation, though Chinnery, et al seem for now to have put this long debate to rest.

REFERENCES

1. Ruedel R, Ricker K, Lehmann-Horn F. Genotype-phenotype correlations in human skeletal muscle sodium channel diseases. Arch Neurol. 1993;50:1241-1248.

2. European Neuromuscular Center Workshop. Workshop report: non-dystrophic myotonias and periodic paralyses. Neuromuscul Disord. 1993;3:161-168.

3. Ptacek LJ, Gouw L, Kwiecinski H, et al. Sodium channel mutations in paramyotonia congenita and hyperkalemic periodic paralysis. Ann Neurol. 1993;33:300-307.

4. Hudson AJ, Ebers GC, Bulman DE. The skeletal muscle sodium and chloride channel diseases. Brain. 1995;118:547-563.

5. Poskanzer DC, Kerr DNS. A third type of periodic paralysis with normokalemic and favorable response to sodium chloride. Am J Med. 1961;31:328.

6. Ptacek LJ, George AL, Griggs RC, et al. Identification of a mutation in the gene causing hyperkalemic periodic paralysis. Cell. 1991;67:1021-1027. (Arch Neurol. 1998;55:1487)