PHYSICIAN'S INFORMATION SHEET
Diagnosis in Hypokalemic Periodic Paralysis
This sheet is based on questions asked frequently by physicians.
I have a patient whom I suspect has hypokalemic periodic paralysis. What tests are done to diagnose this disorder?
If the patient presents with a spontaneous episode of significant weakness (generalized or localized) accompanied by a fall in serum potassium, and the weakness responds to the administration of IV or oral potassium the diagnosis is relatively straightforward, though a thorough workup must then be done to determine any underlying causes for hypokalemia, i.e. renal or adrenal disorders, hyperthyroidism, diabetes mellitus. See our Physician's Sheet on Hypokalemic Periodic Paralysis for caveats on IV potassium administration.
How low is low?
The question of how low serum potassium must be to qualify as diagnostic of Hypokalemic PP is one that is constantly raised by physicians, and is the first question we will consider.
"Physiologic basis of flaccid weakness is inexcitability of muscle membrane (sarcolemma). Alteration of serum potassium is not the principal defect in primary PP; altered potassium metabolism is a result of PP. In genetic and thyrotoxic PP, flaccid paralyses occurs with relatively small changes in serum potassium, where as in secondary PP serum potassium levels are markedly abnormal."
Naganand Sripathi, MD, Director of Neuromuscular Clinic, Assistant Professor, Department of Neurology, Henry Ford Hospital
It has long been recognised as one of the salient features of HypoKPP is that weakness (and hypokalemic cardiac arrhythmias) often commence when the patient's serum potassium is within the limits of normal, 3.5 - 5.0 mmol/L. (2)
Ingrid Gamstorp campaigned vigorously for the rejection of the terms hypo and hyper kalemic, hypopotassemia and hyperpotassemia. She urged use of the terms decreasing and increasing serum potassium, as weakness in these disorders occurs in connection with changes in the serum potassium level, and is not necessarily related to the serum potassium level. She also stated that, ..."when weakness occurs when the serum potassium remains within normal levels the case is more likely to be one of the inherited forms of periodic paralysis. It is likely that the severity of symptoms are better related to the quotient between the intra and extracellular potassium than to the extracellular level alone." (1)
Additional comments from the literature:
- Normal subject do not (emphasis the author's) become weak until their blood potassium falls to less than 2.5 mmol/l. (5)
- Weakness (in HypoKPP) is often severe at levels of serum potassium that do not affect normal individuals. (2)
- In major attacks the serum potassium level decreases, but not always to below normal... (10)
- Johnsen's series of provocative studies recorded an episode of weakness of 11 hours duration provoked by a 0.3 mmol/l fall in the serum K, and an episode of total paralysis of 19 hours duration provoked by a one point drop. (3)
- "...people with hypoKPP are generally very sensitive to decreases in serum potassium that wouldn't bother the average person. Anyone can be made weak by a drastic lowering of serum potassium, but hypoKPP patients get weak with even a slight fall in potassium level." (11)
- During an attack, there is usually, but not always, a fall in levels of serum potassium. (6)
It becomes evident to those who read the entire body of literature that while some patients with HypoKPP exhibit serum potassium readings of 2.0 and below during episodes, others may experience paralysis and arrhythmias with K+ readings which are still within normal limits. The determining factor is not the level of the serum potassium written on the lab slip but the condition and response of the patient.
It is also expedient to track the level of potassium excreted in the urine during the course of an attack, since the amount of potassium excreted in the urine declines during major attacks and can serve as a further diagnostic marker.
The serum potassium may normalize several hours before weakness begins to resolve. By the time your patient presents at the ER the potassium may be perfectly normal. At times it is impossible to 'catch' an episode early enough to document a lowered potassium. At these times other measures become necessary.
Documenting an Attack
It is important to document a fall in serum potassium accompanied by weakness which responds positively to potassium administration, because patients with Hyperkalemic potassium sensitive periodic paralysis and Paramyotonia Congenita may also demonstrate low serum potassium during attacks, which may lead to misdiagnosis.
See our article called How to Determine Episode Triggers for instructions on how to keep a daily food and activity diary. The patient who maintains such a diary for a period of three to four weeks will learn what provokes episodes. Many will also become aware that they have minor daily episodes that went unnoticed before. The physician should review the diary to ensure that the triggers are consistent with Hypokalemic PP. Because HypoKPP is associated with a shift in potassium, provocative factors include exercise followed by a period of sleep or rest, carbohydrate load, or any other cause of increased insulin secretion. Epinephrine is a well recognized provocative factor of attacks and should be avoided. (5, 10) With this knowledge it is often possible for a patient who has frequent mild episodes to deliberately provoke an episode by eating a high carbohydrate food and the physician may choose to have them do that, in order to document a fall in potassium.
Usually this testing can be done outside the hospital setting. The patient is given several appropriate lab slips for both blood draws and urine tests and a prescription for K-Lyte effervescent tablets (25 mEq K). The first blood draw and urine sample are taken as a baseline when the patient has normal strength, the second set when the patient is having an episode of weakness.
Immediately following the second blood draw the patient takes one tablet of K-Lyte dissolved in water, followed by a second tablet half an hour later if the response has not been sufficient. Usually the patient will feel increased strength within half an hour to forty-five minutes and as soon as they feel strength is returned they should have the third blood draw.
The diagnosis of HypoKPP need not be a challenge, when one realizes that many patients experience only a .5 drop in their potassium level, and many never even approach the lower limits of normal. We have a substantial number of clients who have full paralytic episodes and cardiac arrhythmias when their serum potassium dips below 4 mmol/L. It is not the level itself, but the drop that precipitates the episode (3).
Cardiac Signs
Sinus bradycardia and electrocardiographic (ECG) signs of hypokalemia (U waves in leads II, V-2, V-3, and V-4, progressive flattening of T waves and depression of ST segment) may appear when the serum potassium falls below normal. Prolongation of the PR and QT intervals and T-wave flattening are associated with prominent U-waves.
Johnsen's study of 106 Danish patients with HypoKPP revealed two patients who developed transient diastolic murmurs during paralysis and another who developed a transient, partial a-v block. He also describes patients who developed bradycardia and unspecified arrhythmias during episodes.
Some patients do not exhibit cardiac signs even when serum potassium falls quite low, and others may exhibit profound cardiac signs of hypokalemia with the serum potassium within low normal range. (1,3,5,9)
Further Screening
All patients diagnosed with HypoKPP should be further screened for Andersen's syndrome, a distinct periodic paralysis occurring in the setting of either hyper- or hypokalemia, with severe cardiac involvement and skeletal anomalies . Electrocardiographic (EKG) findings in AS include a prolonged QTc interval, which predisposes to sudden cardiac death, and a variety of rhythm disturbances. Andersen's screening consists of both a resting and moderate exercise ECG and evaluation for prolongation of the QT interval by a cardiologist experienced in Long QT Syndrome. This is a relatively new field and experience has taught us that not all cardiologists are trained to recognize LQT (4).
Patients should also be screened for thyrotoxicity. Screening for thyrotoxicity is especially critical for those who have very low levels of potassium during attacks, as it may indicate Thyrotoxic HypoKPP (TPP). While TPP occurs in all races and in both sexes as a consequence of Graves disease, it is most often found in males of Asian, Latin American or Native American descent.
Specialized Testing
Other tests are more specialized, and require a neurologist experienced in the periodic paralyses. Most of our clients have been diagnosed based on changes in their serum potassium levels before, during and after episodes. This document contains abstracts describing a range of tests, and links to entries which describe others in greater detail.
Provocative Tests
In HypoKPP the serum potassium is normal between attacks, which has led to the development of provocative tests. The Glucose/Insulin provocative test is an old standby but provocative tests are potentially hazardous and require careful monitoring.
Provocative tests must be avoided in patients with any possibility of cardiac involvement. (2,5). Provocative tests can be terrifying to patients, who report being left alone, unable to breathe adequately or cry for help. It is possible for death to result from cardiac arrhythmias or bulbar paralysis during provoked attacks, so it is wise to be cautious. Many patients report that they have been subjected to provocative tests without adequate cardiac or respiratory monitoring, and even without nursing supervision or the presence of a family member. Furthermore many patients report that provocative testing exacerbated their weakness for a long period of time, and in some cases produced disabling permanent muscle weakness. When other methods of diagnosis are now available and pose no such risk to the patient it seems difficult to justify using provocative testing.
We include the following information for the insights it provides on the effects of carbohydrate and on the response of the ECG during attacks. We urge physicians to choose alternate testing procedures.
Gamstorp recommended that if a provocative test is necessary that the patient be brought into the hospital in the morning in a fasting state and be given 50 g glucose in 150 ml water by mouth every hour until weakness commences. Serum potassium, oxygen levels and cardiac activity must be monitored and the patient kept under continuous observation from the beginning of the test period. A transient attack of weakness combined with reversible decrease in serum potassium and/or transient hypotassemic ECG abnormalities proves the diagnosis (1,3).
A fall in serum potassium may be also induced by an insulin provocation test in which 100 g glucose given orally is combined with 25 IU soluble insulin given subcutaneously. The glucose/insulin task may also be performed by giving the glucose and the insulin intravenously. Since weakness induced by this test may occasionally be severe it is wise to begin with glucose alone since this is a less potent stimulus, and glucose and insulin together may produce life-threatening arrhythmia if the blood potassium falls to very low levels (5).
Muscle Biopsy
In all three varieties of periodic paralysis abnormalities are seen only during attacks; biopsies taken between attacks of weakness usually show little or no abnormality unless there is some degree of fixed weakness. In attacks of weakness there are often large vacuoles in some or many muscle fibers. These vacuoles are situated in the central part of muscle fibers...
In severe attacks some fibers become necrotic, and the typical sequence of necrosis, ingestion by macrophages and basophilic regeneration, usually subsarcolemmal, then occurs. In biopsies of patients with longstanding periodic paralysis Weller and McArdle (1971) demonstrated calcium salts in the vacuoles and in the muscle fibers themselves. The vacuoles themselves are usually more prominent in older patients in whom many attacks have occurred. The fixed myopathy found in some patients with periodic paralysis is associated with a typical non-specific features of the myopathy, including the variability in fiber size, central nucleation, single-fiber necrosis and regeneration and increased endomysial fibrous tissue. However, even in these cases there may be vacuolation of fibers and this is then an important clue to the diagnosis (6).
Excellent slides of muscles biopsies in both early and advanced HypoKPP can viewed at the Neuromuscular Disease Center maintained by Washington University School of Medicine, St. Louis Missouri The link on the biopsy page will take you to their resource, which is technical and excellent. To return to this page, hit your "Back" button.
Electromyography
EMGs are done routinely by many, if not most neurologists, to rule out other possibilities, but EMGs done on HypoKPP patients between attacks are essentially normal, unless the patient has myopathy. Patients who have read the literature and know this to be true are often extremely frustrated when faced with a neurologist who insists they cannot have HypoKPP because of a 'normal' EMG (7).
EMGs done during attacks demonstrate reduced number of motor units and myopathic abnormalities. Between attacks patients with permanent weakness show myopathic abnormalities on EMG. An exciting test which was first described by Mcmanis et al. in 1986 is finally gaining acceptance with neurologists. The Exercise EMG is relatively painless compared to the trauma and long-term weakness inflicted on patients by the insulin-glucose challenge. Read The Exercise EMG
What about DNA tests?
Genetic testing is being used for research, but it is not yet reliable enough to be entirely relied upon for diagnostic purposes. While a positive genetic test can prove your patient has HypoKPP, a negative result does NOT rule out the possibility of HypoKPP. While eleven mutations have been identified the commercial genetic labs currently only offer tests for the three most common mutations. There are also other mutations yet to be identified. So far genetic tests can identify about 30-70 out of 100 of positively diagnosed patients, which means that a substantial number of patients have genetic variants which have yet to be identified.
Where is the best place to send my patient for treatment?
While there are undoubtedly some specialized centers which are excellent resources for diagnosis and the institution of a treatment plan, the best place for day-to-day management is almost always the patient's own family physician, if that person is willing to read about the condition and learn how to manage it. Every patient responds a bit differently to treatment and we have found that among our clients those who are, on the whole, the most satisfied with their care are those who are cared for by the person who cares for their overall health. Common illnesses like a 24-hour stomach flu can rapidly turn into life-threatening emergencies for a HypoKPP patient, and in these instances there is no time or opportunity to go to a far away specialist.
Please feel free to contact us for names of neurologists or specialized centers who are experienced in diagnosing the periodic paralyses.
References
- Gamstorp, I: Disorders Characterised by Spontaneous Attacks of Weakness Connected with Changes of Serum Potassium; Genetics of Neuromuscular Disorders, pp 175-195 1989; Alan R. Liss Inc.
- Ptacek L.J., et al.: Periodic paralysis. In: Fauci AS, et al, eds. Harrison's Principles of Internal Medicine. 14th Ed. NYC, McGraw Hill, 1998
- Johnsen, Torsten: Familial Periodic Paralysis with Hypokalaemia; Danish Medical Bulletin, March 1981 Vol. 28 No. 1
- Tawil, R; Ptacek, L.J.; Pavlakis, SG; et al.: Andersen's syndrome: potassium-sensitive periodic paralysis, ventricular ectopy, and dysmorphic features. Ann. Neurol. 35:326-330, 1994.
- Swash, Michael; Schwartz, Martin S: Neuromuscular Diseases: A practical approach to diagnosis and management; 2nd ed. London; Springer-Verlagg 1988 The Periodic Paralyses pp 344-348
- Brooke M.H. Disorders of Skeletal Muscle. Neurology in Clinical Practice, Third Edition, Bradley, W.G.; Daroff, R.B.; Fenichel G.M. & Marsden, C.D. Eds. Boston, MA; Butterworth/Heinemann. 2000
- Falck, B; Sterg, E; Korpinen, L: The Expert Electromyographer: Strategies in electrodiagnostic medicine; differential diagnosis, expected findings and procedures; Univ of Finland, 1999
- McManis, PG; Lambert E.H.; Daube, J.R.: Exercise test in periodic paralysis. Muscle Nerve 1986; 9:704
- Schlichtmann, J, Graber, M. University of Iowa Family Practice Handbook, 3rd Edition, Chapter 5, 1999 Hematologic, Electrolyte, and Metabolic Disorders: Potassium
- Engel, A; Metabolic and endocrine myopathies: In "Disorders of Voluntary Muscle, 5th ed."; Edinburgh: Churchill Livingstone, 1988 ed. Walton, Sir John
- Ptacek, L; quoted, Quest, The Muscular Dystrophy Association Magazine; Not Crazy or Lazy, Periodic Paralysis Brings Frustration, Misunderstanding, But Can Be Managed by Margaret Wahl; July, 1998