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What is CINCH?

Q: What concerns are there for the patient with an ion channel disease who must have anesthesia for surgery?

MALIGNANT HYPERTHERMIA

Patients with ion channel diseases are at increased risk of malignant hyperthermia reactions with general anesthesia for surgery. In malignant hyperthermia, muscle cells become overactive (hypermetabolic) in response to the most commonly used drugs for general anesthesia. With inhaled agents (such as halothane, isoflurane, enflurane, desflurane, sevoflurane and even agents such as ether, cyclopropane and methoxyflurane ) the ion channels in the muscle cells open and remain open. This results in excessive calcium release causing muscles to continuously contract, producing massive amounts of heat, rapid rise in temperature and disruption of nearly every organ system in the body. In the past this reaction was fatal in 70% of cases. However, with the introduction of the medication, dantrolene, the mortality has now fallen to 5% of cases. It is essential that anesthetists and surgeons are made aware that a patient has periodic paralysis or even that a parent suffers with the disorder, if a son or daughter is going for surgery. The anesthetists and surgeons should be familiar with neuromuscular disorders and the associated risks. If they are not in a specialist center, the patient may need to be transferred to such a center or at the least the patient's neurologist should be contacted prior to surgery.

PROLONGED PARALYSIS

Other medicines used during general surgery are called depolarizing agents (such as Succinylcholine). These medicines act by blocking the signal from the nerve (Acetylcholine) from reaching it's receptor on the muscle. This causes temporary paralysis in patients during surgery, relaxing the muscles to make surgery easier. In patients with ion channel disorders, such as periodic paralysis, this can result in prolonged paralysis.

Normally, when people are given the drug succinylcholine to relax muscles, a little bit of potassium from inside the muscle cells leaks out into the bloodstream. This is because succinylcholine, like acetylcholine, docks on the receptors and opens some gates in the cell, letting certain molecules flow in and out. Normally, this poses no problem. In the periodic paralyses, ion channels that normally open when acetylcholine docks on membrane receptors don't function normally, and people experience temporary paralysis attacks in response to a variety of dietary, exercise, stress-related and other environmental changes.

After surgery, patients with periodic paralysis have found they woke up in the recovery room and couldn't move; they may not get full strength back for hours or days. The exact cause of the prolonged paralysis with anesthesia in some people with periodic paralysis isn't known. It could be the stress of the surgery and/or any of the anesthetic drugs. It is critical for the medical team to distinguish between a periodic paralysis attack and a malignant hyperthermia reaction as the treatments are completely different.

SEVERE MYOTONIC REACTION

Other ion channel disorders, such as myotonia congenita (MC), involve an inability to relax muscles at will (myotonia). Depolarizing agents such as potassium, suxamethonium and anticholinesterases aggravate the myotonia. As a result these patients become rigid instead of relaxing. Masseter spasm and stiffness of respiratory and occasionally other skeletal muscles can occur and impair intubation and mechanical ventilation. These agents are therefore strictly contraindicated. If muscle relaxation during surgery is needed in people with hyperkalaemic periodic paralysis or myotonia congenita, care must be taken with the choice of relaxing agent. As generalized muscle spasms occur that may lead to an increase in body temperature, patients with Hyperkalaemic Periodic Paralysis and Myotonia Congenita have been considered to be susceptible to malignant hyperthermia. It may be that the anesthesia-related complications suggestive of a malignant hyperthermia crisis actually result from severe myotonic reactions instead.

PREVENTION AND SAFETY

In ion channel disorders, preventive therapy before surgery, such as maintaining a normal body temperature, maintaining serum potassium concentration at low level, and avoiding hypoglycemia help to prevent such attacks. Local or regional anesthesia and monitored anesthesia care are safe. Intravenous drugs are safe, including propofol, barbiturates, benzodiazapines and etomidate.

Q: Are there special diets that can prevent periodic paralysis "attacks"?

HYPOKALEMIC PERIODIC PARALYSIS

Patients with Hypokalemic Periodic Paralysis (HypoKPP) typically want to avoid foods high in sodium, but should eat foods that are high in potassium. By eating high potassium and low sodium foods these patients can reduce their frequency of attacks of weakness.

HPERKALEMIC PERIODIC PARALYSIS / PARAMYOTONIA CONGENITA/ POTASSIUM AGGRAVATED MYOTONIAS

Patients with Hyperkalemic Periodic Paralysis (HyperKPP) and patients with Paramyotonia congenita, Myotonia Fluctuans, Myotonia Permanens and Acetazolamide-responsive myotonia should avoid foods high in potassium. In these individuals, when their potassium rises it places them at increased risk of developing episodes of weakness.

HypoKPP Can benefit from increased dietary potassium and in general should:

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

HyperKPP Can benefit from Potassium Restricted diets:

  • Avoid foods high in potassium

Q: What kind of exercise should people with ion channel diseases undertake?

HYPOKALEMIC PERIODIC PARALYSIS

There are no specific guidelines as to what level of exercise is appropriate for HypoKPP. What we do know is that most people with HypoKPP note that if they undertake strenuous exercise which is atypical for them, followed by rest or sleep, they will precipitate an attack. Factors that increase the likelihood of an attack after exercise include a meal rich in carbohydrates and sodium, alcohol consumption, exposure to cold and emotional stress. The severity of the episode may vary from mild weakness to severe generalized paralysis. The facial, respiratory and sphincter muscles are generally spared.

If those with HypoKPP feel weakness coming on, mild exercise may stave off the full-blown attack of weakness; however this is not always successful. The episode of weakness may be preceded by a vague sensation of heaviness in the lumbosacral region, thighs and calves. The heaviness feeling may then spread to involve other muscle groups, primarily those in the arms.

So, based on what is known about these conditions, it is recommended to avoid strenuous or unusual activity. If strenuous activity is undertaken, then following it with some mild continued activity may postpone or abort an attack of weakness. Avoidance of other precipitating factors such as cold, carbohydrate and sodium rich meals, alcohol and emotional stress is advised.

HPERKALEMIC PERIODIC PARALYSIS / PARAMYOTONIA CONGENITA

No specific guidelines exist on the appropriate level of exercise for HyperKPP, either. We do know that most people with this disorder, can experience attacks of weakness at any time, but episodes are precipitated by rest following exercise or fasting. Episodes of weakness occur more frequently on holidays and weekends when patients rest in bed longer than usual. By rising early and having a full breakfast, patients may avoid this scenario. A warning of a sense of heaviness in the legs or small of the back heralds the onset of an attack in some people with HyperKPP. Attacks can be mild or severe. Severe attacks seem to be more common following vigorous exercise. Some people with HyperKPP find they can postpone or prevent an attack by continuing to engage in some mild exercise after the strenuous activity. In fact the muscles they continue to exercise may remain strong while the unused muscles become weak. The duration of weakness is usually less than 2 hours, though some mild weakness may remain for a few days. Pain in the affected muscles for a few days, may follow a bout of weakness.

Based on the observations above it is recommended to avoid strenuous or unusual activity in HyperKPP. Following strenuous exertion with some mild activity may postpone or abort an attack of weakness. Avoidance of fasting and lying late in bed is recommended.

HYPERKPP, EXERCISE AND MYOTONIA

Activity in HyperKPP can elicit myotonia in the type accompanied by myotonia. Myotonia is a failure of the muscles to relax. There may be a mild sensation of stiffness or muscle ache associated with the contraction. In HyperKPP this tends to improve with continued exercise.

PARAMYOTONIA, EXERCISE AND MYOTONIA

In Parmayotonia, the myotonia can also be elicited by activity. However, in this condition, continued exercise makes the myotonia para doxically worse, rather than better - hence the name Para myotonia. Cold can exacerbate or precipitate weakness and myotonia in both HyperKPP and Paramyotonia.

Q: What is the relationship between potassium and hyper- or hypokalemic periodic paralysis?

HPERKALEMIC PERIODIC PARALYSIS

Hyperkalemic periodic paralysis attacks of weakness are usually associated with an increase in serum potassium levels (up to 5-6 mmol/L). However, this is not always the case. Potassium levels can be normal during an attack. For this reason a number of experts in the field have recommended that this disorder be called Potassium Sensitive Paralysis. Between episodes the serum potassium is normal. During episodes urinary excretion of potassium is also increased. After an attack, there may be excessive urination and the serum potassium level may actually be low.

HYPOKALEMIC PERIODIC PARALYSIS

Hypokalemic periodic paralysis attacks are usually accompanied by low potassium, typically less than 3.0 mmol/l. Between episodes of weakness the potassium level is normal. In this disorder, reduced potassium levels contribute to the underlying problem with calcium channels in muscle and render the muscle inexcitable. It is the resultant muscle inexcitability that causes the weakness. High carbohydrate meals and sweet foods cause insulin release. Insulin also causes potassium uptake by cells; this lowers the extracellular potassium. Thus, high carbohydrate meals can precipitate attacks of weakness in those with hypokalemic periodic paralysis.

Q: Are there drug treatments for periodic paralysis or the myotonias?

There are no FDA approved treatments for periodic paralysis or the myotonias. Any medications currently prescribed for these disorders are used "off-label". "Off-label" means the drug is approved to treat another condition/disease, but was not scrutinized under the quality control protection of the FDA's clinical trials process for treatment of myotonias or periodic paralysis. CINCH (Consortium for Clinical Investigation of Neurological Channelopathies) is currently carrying out a number of trials to test treatments for these disorders. CINCH is a member of the National Institute of Health's Rare Diseases Clinical Research Network (RDCN), which was set up to address the lack of approved treatments for rare disorders, including the channelopathies. To learn more about current CINCH trials click on the following link. "Learn about current research studies".

Q: Is gene therapy for channel diseases a possibility?

Gene therapies are a definite possibility in the future. However, gene therapy is still undergoing development. There have been very few trials of gene therapy in humans. This is partly due to early problems with the first such trials carried out.

Two bad outcomes in particular cast a shadow over this exciting field. One was cast by the unfortunate death of an 18-year-old man at the University of Pennsylvania in 1999.The patient was part of a trial in which an adenovirus containing a gene for ornithine transcarbamylase was infused into patients with partial deficiencies of the enzyme. The death highlighted the potential dangers of the direct administration of adenoviruses and, perhaps, other viruses to patients

The second shadow was cast by a clinical trial involving children with X-linked severe combined immunodeficiency (SCID). Two shadows have recently been cast over the exciting field of gene therapy. The trial had an added measure of safety in that the genetic defect was first corrected in white blood cells from the patients; the modified cells were then infused into the patients. The initial results were hailed as the first instance of successful gene therapy. Unfortunately, leukemia subsequently developed in two of the nine patients. The retrovirus inserted itself near a cancer gene and thereby triggered premalignant proliferation of the cells in these patients. Until the SCID trial, the unfortunate effects of inserted genes causing cancer seemed more a theoretical than a practical danger, since it had rarely, if ever, been seen in hundreds of experiments in animals.

To date, studies of gene expression through vectors has shown successful modification of potassium channels excitability in cultured muscle cells. So the potential for the development of this technology as a future treatment is possible. However, these techniques will need to undergo numerous trials in cultured cells and animal models before they are approved for human studies.

Frequently asked questions about Episodic Ataxia

What is episodic ataxia?

Episodic ataxia is an inherited disease characterized by attacks of imbalance, incoordination and slurring of speech, often triggered by exercise and stress. There are two types of episodic ataxia for which the genetic cause is known., EA-1 and EA-2. Other types occur but the genes are not known. Some patients will have symptoms between attacks, such as muscle twitching and rippling (EA-1) and mild imbalance (EA-2).

Can episodic ataxia be treated?

Yes, a drug called acetazolamide or Diamox is often effective in stopping attacks, particularly with EA-2.

Is there a test for episodic ataxia?

Since the genes for EA-1 and EA-2 are known, there is a genetic test for these two conditions. We expect that, in the near future, there will be additional genes found for other episodic ataxia syndromes (EA-3, EA-4 etc.).

Can I be tested?

At the present time, testing for EA-1and EA-2 can only be done as part of a research project since these tests are difficult to do and are not available in commercial laboratories. This means that you would need to sign an informed consent form indicating your willingness to provide your medical history.

How is the test done?

All that is required is a standard blood sample (about 2 or 3 tablespoons of blood).

Can I still have episodic ataxia if the test is not positive?

Yes, because genes for many of the episodic ataxia syndromes have yet to be identified.

Can other family members be tested?

Yes, but they would also have to sign an informed consent form indicating their willingness to participate in a research protocol.

If I have the disease, what is the likelihood that it will be passed on to my children?

Since it is inherited as a dominant trait, there is a 50% chance for each child to inherit the disease.