Presenting Symptoms and 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 the 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.

Some signs and symptoms noted at the PPA Conference that may also be part of familial hypokalemic periodic paralysis (but have not been formally validated) are:

• muscle pain with and after attacks,
• mental confusion with attacks,
• having an off-mood/bad mood/irritability during attacks,
• non-restorative sleep with attacks,
• dark circles under the eyes prior to and during an attack,
• feeling sleepy after attacks,
• attacks due to exposure to cold.

Diagnostic Work Up

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

Primary Medical Doctor can do:

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

Neurologist can:

• Neurological investigation – CMAP (exclude myotonia) and exercise test (if abnormal then suggestive, but if normal, does not exclude)
• 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
• Genetic testing
• Empiric therapy sequentially with potassium supplementation, and either eplerenone or acetazolamide
• Repeat MRI after 4-6 weeks of empiric therapy looking for a decrease in edema
• Refer back to PMD once the diagnosis is established for continued management

Other Types of Specialists Involved

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. CPK is a helpful test as it shows muscle breakdown during an attack. The CPK can be very high.

Involve an Endocrinologist to rule out adrenal causes of hypokalemia.
Involve a Nephrologist to rule out renal disease and to get advice about electrolyte management.

CMAP (McMannis Protocol)

McManis EMG protocol to diagnose periodic paralysis:
The Long exercise nerve conduction test:

• 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.
• Compound muscle action potentials (CMAPs) are evoked with a single supramaximal stimulus and repeated every minute for 5 minutes to ensure a stable baseline.
• 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.
• 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 the 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. 

Emergency Management

Acute Attack

Management of Potassium:

• Oral K preferred over IV K. Aqueous K favored over pill form.
• Dosing: 40-60mEq p.o. of potassium, in the absence of underlying deficit (as is the case in hypokalemic periodic paralysis), should cause a rise of 1.0-1.5 mEq in serum potassium. 135-160mEq p.o. of potassium should cause a rise of 2.5 to 3.5 mEq in serum potassium.
• No D5 in i.v. fluids. If possible, no saline in fluids – may try mannitol 5% to give a bolus of potassium.
• No more than 10-20mEq/hr [i.e. 250-500cc of 40mEq/L solution/hr]. Concentrations >= 60mEq/L causes pain and phlebitis in peripheral veins. So, expect pain with 10-20 mEq K+ in 100cc of 5% mannitol.
• Albuterol and insulin EXACERBATE attacks.
• If the patient has not taken K+ before coming to ER, consider dosing a bolus of 60mEq p.o. by aqueous solution. Wait 1 hour. Then re-dose.
• Be careful not to overcorrect. Wait 20-60min. before re-dosing. Patience is key.
• Position patient comfortably in “coma position” if possible. This means turning them to the left or right side so they do not aspirate.
• EKG for rhythm, especially QT interval.
• Monitor serum potassium q30min to q120min, depending on the condition of the patient and medications being administered.
• Do not leave the patient unattended! The condition can change for better or worse rapidly. Risk of aspiration.
• There is probably no role for acetazolamide or potassium-sparing diuretics in the management of an acute paralysis attack; however, no evidence-based study has proven this hypothesis.
• If associated with myoclonus (jerks), consider a small dose of benzodiazepine as jerk represents exercise, and the trigger of paralysis is rest after exercise.
• For myotonia, keep muscles warm (temperature).
• Fluid to deliver potassium can be Ringers Lactate as well as Mannitol as many hospitals do not stock Mannitol.

Potassium Metabolism and Dosing

Potassium replacement must be done in accordance with clinical findings (muscle weakness and cardiac rhythm abnormalities) taking precedence over the numerical value of serum potassium.

In normal people:
A decrease from 4.0 to 3.0 mEq can correspond to 200-400mEq potassium deficit.
A decrease from 3.0 to 2.0 mEq can correspond to 200-400mEq potassium deficit.

Decreases below 2.0mEq can represent a deficit larger than 800mEq as intracellular potassium begins to compensate.
In periodic paralysis, these deficits may or may not hold true. The hypokalemia in hypokalemic periodic paralysis is due to POTASSIUM SHIFTS rather than a deficit. Therefore, more conservative (i.e., less aggressive) potassium replacement is needed. Doses above 200mEq over a period of two hours are rarely ever required.

Therapy

Exercise:

There is no reason to believe that patients with periodic paralysis have an impaired muscle repair capability. In general, patients should remain as active as possible. How much exercise they can do depends on their individual threshold for inducing an attack of periodic paralysis is. If a particular exercise is inducing an attack then they are doing too much. For all patients with muscle disease, it is less desirable to do progressive resistive exercises meant to “bulk up”. Rather, patients should do more toning/aerobic types of exercises with less weight/resistance and more repetition. Specifically, eccentric contraction should be avoided.

Patients should NOT do repetitive exercise. It is better to do exercise that uses all muscles at the same time such as swimming (only with a partner), martial arts, and yoga.

The role of a physical therapist has yet to be defined. Some find passive stretching and massage to be helpful, but no formal recommendations can be made at this time.

Diet and Nutrition

The National Kidney Foundation is an excellent resource on the potassium content of foods.
The potassium fact sheet can be resourceful
Newsletter on potassium

Contact the National Kidney Foundation: 1-800-622-9010

HypoKPP can benefit from increased dietary potassium and in general, should:

• Avoid Sodium
• Avoid High Carbohydrate Meals
• Avoid Sugar, Honey, and other natural sweeteners

Useful Articles

Levitt J. Practical Aspects in the Management of Hypokalemic Periodic Paralysis.

J Transl Med. 2008; 6:18.

http://neuromuscular.wustl.edu/mtime/mepisodic.html#hopp

An excellent discussion of potassium metabolism and management can be found in:
Rose, Burton David. Clinical Physiology of Acid-Base and Electrolyte Disorders Fourth Edition. New York, 1994, McGraw-Hill, Inc. Health Professions Division, pp. 763-852.

Additional Resources

We thank Periodic Paralysis International for this link:

http://www.hkpp.org/faq/hypokalemic_periodic_paralysis.html