(This paper is based on ‘Chronic Fatigue Syndrome is an Acquired Neurological Channelopathy’ by Chaudhuri and Behan)
Background
Since 1982 when the first ion channel was cloned ion channels critical to the functioning of virtually every tissue in the body have been uncovered. A table of selected channelopathies lists 27 diseases including diabetes mellitus, dilated cardiomyopathy and cystic fibrosis. This list is hardly comprehensive; gene mutations involving sodium ion channels alone are known to cause 20 diseases (Kass 2005).
Ion channels are pores in the membranes through which ions travel often in great volume (1,000,000 and 100,000,000 ions a second!). Besides their roles in activating proteins in cells, ion channels plays a central role in maintaining an aspect of membrane integrity called the ‘membrane potential’.
The membrane potential is the difference between electrical potential inside and outside the cell. Given their role in maintaining the electric gradients in cells it is not perhaps surprising to find ion channels play a critical role in the functioning of another electrically driven system, the nervous system (Cooper and Yeh 1999).
Four ions are chiefly involved in ion channels. Potassium is typically found in higher concentrations inside the cell and sodium, chloride and calcium are found in higher concentrations outside the cell. Most ion channels have ‘gates’ that control the flows of ions. Voltage gated ion channels are specialized ion channels found at the synapses that respond to neurotransmitter induced changes in membrane potential.
Ion channels and muscle activity
A brief overview of the role ion channels play in muscle activity will help to understand the critical role they play in the body. In skeletal muscles ion channels help transmit the signal from the nerve at the neuromuscular junction to the muscles.
During the complex interplay between the nerve and muscle that accompanies muscular activity several waves of sodium, calcium, potassium and chloride influx and efflux occur (Cooper and Yeh 1999).
First a raft of ion channel activity involving sodium, calcium and potassium is needed for neurotransmitter release into the nerve synapse. Then once the neurotransmitter bridges the synaptic cleft a new round of sodium ion channel activity spreads the ‘action potential’ along the muscle cell membrane.
Next calcium ions from the sarcoplasmic reticulum flood the cytoplasm of muscle cells causing muscle contraction. Finally chloride channels open in order the restore the membrane potential to its original state.
Muscle ion channel dysfunction
Mutations in the genes governing muscle ion channel activity can cause a wide variety of symptoms including impaired muscle relaxation (sodium/chloride channels), reduced muscle excitability (sodium) and heightened contractions, fever and muscle injury (calcium).
Mutations in the genes coding for sodium and chloride channels cause myotonia, a disorder of impaired muscle relaxation and heightened muscle contraction. Mutations effecting sodium/calcium channels result in episodes of weakness sometimes strong enough to cause temporary paralysis. Mutated sodium channel genes cause reduced muscle excitability. Calcium channel gene mutations cause sustained muscle contractions, fever and muscle injury.
Cooper and Yeh note that while the ion channel interplay accompanying muscle activity is complex both the number and complexity of ion channels and their activities in the brain far exceeds that in the muscles. The roles played by these ion channels are still poorly understood (Cooper and Yeh 1999).
A neurological channelopathy in ME/CFS?
Chaudhuri and Behan set out their case for disrupted ion channel transport in the central nervous system of CFS patients in a 1999 paper (Chaudhuri and Behan 1999). In this paper they first establish that the kind of fatigue found in CFS also commonly occurs in neurological diseases and that CFS patients respond abnormally to the signaling agents – neurotransmitters – that drive nervous system functioning.
Then they show how altered ion channel functioning could disrupt both the response to neurotransmitters and their production of them. Finally they demonstrate some similarities between CFS and neurological ion disorders and suggest potential causes for ion channel dysfunction in CFS.
CFS-like fatigue is common in neurological diseases
Several neurological diseases such as Parkinson’s disease, multiple sclerosis, post – polio syndrome, and multiple system atrophy are also characterized by severe fatigue (Chaudhuri et. al. 2000).
Fatigue is often the most common presenting system in Parkinson’s disease, ALS and multiple sclerosis and is the most disabling symptom for about 40% of MS patients. Parkinson’s is a disease of basal ganglia dysfunction; basal ganglia abnormalities are seen in both CFS and MS and a recent study found a similar pattern of altered brain activation in CFS and MS (See The Fatigue in Chronic Fatigue Sydrome – Is it Central?).
Tumors of the hypothalamus, a nexus of autonomic and endocrine activity, often first present with severe fatigue, forgetfulness and irritability. Indeed, many symptoms in CFS (fatigue, sleep disorder, abnormal sweating, altered temperature, mood disorder, weight changes) suggest hypothalamic involvement. Thus there is ample circumstantial evidence that the fatigue in CFS may be due to a ‘central’, i.e. central nervous system disruption.
*Update – Increased activity levels in an organ lying next to the hypothalamus called the thalamus involved in motor planning and integration in CFS suggests reduced efficiency in this area (MacHale et. al. 2000).
Neurotransmitter responses are disrupted in CFS
The neuroendocrine abnormalities in CFS could be caused by alteredsensitivity to neurotransmitters such as acetylcholine. This probably occurs either through altered sensitivity of the synaptic receptors – increased post synaptic receptivity or decreased pre-synaptic receptivity.
The synapse is the empty space between the ending of a nerve and the tissue it excites. Some ion channels regulate the level of ‘synaptic strength’ present.
This is a key point in this paper. Changes in the sensitivity to neurotransmitters in the nerve synapses could disrupt nerve signal transmission to many parts of the body. Increased numbers of post synaptic receptors would increase the reaction to a neurotransmitter as it bridges the synaptic gap and presumably lead to an overly excitable response.
Reduced pre-synaptic sensitivity to neurotransmitters, on the other hand, would presumably result in increased neurotransmitter production. Neurotransmitter receptor number is particularly sensitive to neurotransmitter levels.
Low numbers of neurotransmitter receptors are usually indicative of increased neurotransmitter levels and vice versa.
What roles do channels play in this system? Proper nervous system functioning requires that a complex and reciprocal interaction between ion channels and neurotransmitters take place.
Because ‘neurochemicals’ use ion channels in order to carry out their functions a defect in ion channel functioning could modify how a cells responds to neurotransmitters or hormones. Snake and fish toxin often target ion channels. Their sometimes fatal effects illustrates how important ion channel activities are to nervous system functioning.
For example, mutations in the genes encoding the receptor for acetylcholine, the neurotransmitter regulating neuromuscular activity, are often associated with disrupted ion channel functioning. Some ACh mutations alter the number of ion channels, others the rate at which ion channels open and close, still others cause them to open at inappropriate times.
An example of this may occur in familial migraine where impaired calcium channel function appears to be related to defective serotonin release (Chaudhuri et. al. 2000).
There is evidence of abnormal neurotransmitter activity in CFS. Response to a serotonin agonist (enhancer – busiprone) suggests hypersensitive serotonin receptors are present in CFS. CFS patients also often suffer from IBS, a problem that is possibly related to increased colonic activity due to a hypersensitive serotonin response.
*Update – Since this paper was published several studies suggest that several neurotransmitters appear to be functioning differently in CFS. See below.
Serotonin
Studies have suggested increased sensitivity of hypothalamic serotonin receptors (R-HTIa) (Dinan et. al. 1997), increased 5-TH1a receptor sensitivity (Bakheit et. al.1992, Cleare et. al. 1995) and reduced serotonin receptor density (Yamamoto et. al. 2004, Cleare et. al. 2005).
Norepinephrine
FS patients displayed supersensitive central post-synaptic alpha-2 adrenoceptor activity in response to an AR-2 enhancer (Morriss et. al. 2002). Increased plasma epinephrine levels upon standing and/or tilt have been found in some but not all studies in CFS (Streeten and Bell 2000)
Acetylcholine
Two reports suggest problems with receptors for acetycholine in CFS. Increased autoantibodies against IgA muscarinic receptors could indicate reduced IgA muscarinic receptor levels (Tanka et. al. 2003). Fifty percent of CFS patients have antibodies to the acetylcholine muscarinic receptor (Bell and Vodjani 2005). These studies appear to suggest an autoimmune disruption rather than a channelopathy.
Ion channel abnormalities are often found in neurological diseases
Abnormal ion channel functioning in a wide array of neurological diseases suggests channelopathies are common in these diseases. As noted earlier ion channels play a key role in nervous system functioning. Interestingly fatigue is not an uncommon side effect of a central nervous system channelopathy.
Inflammatory demylinating polyneuropathies and multiple sclerosis (MS) are both associated with ion channel dysfunction. A potassium channel dysfunction is postulated to occur in multiple sclerosis (MS), a disease with a similar fatigue presentation as CFS. Antibodies to voltage gated calcium channels occur in neuromyotonia, another fatiguing neurological disease as well as ALS.
Interestingly a familial (genetic) migraine involving a calcium channelopathy is often precipitated by the same stressors (stress, exercise, viral infection) that exacerbate or appear to initiate CFS.
The myotonias are of special interest in CFS because some people purported to have CFS have turned out to have a myotonia instead (Graves and Hanna 2005). They occur when overly excitable muscle membranes respond to a single nerve impulse with multiple contractions.
Graves and Hanna state myotonias should be considered in anyone who complains of muscle stiffness. Although these diseases are genetically based the symptoms they evoke sometimes do not occur until maturity. In Thomsen’s disease, a chloride channel dysfunction causes constant or intermittent muscle stiffness that is relieved during exercise (the warm up phenomena).
A sodium channel dysfunction in paradoxical myotonia results in muscle stiffness that increases during exercise and can be precipitated by low temperatures. Testing for some of these diseases involves measurements taken in the post- exercise period – obviously a key period in CFS as well (Graves and Hanna 2005).
In the malignant hyperthermias (MH’s) sudden calcium releases from the sarcoplasmic reticulum into the cytoplasm cause excessive muscle contraction, hypermetabolism (increased oxygen use), rhabdomyolysis and fever. (The NCF recently reported that an autopsy of a CFS patient found evidence of rhabdomyolysis. I’ve met someone with both CFS and rhabdomyolysis.) A recent study found increased oxygen use by the muscles in CFS.
A symptom complex called malignant hypothermia-like is used to describe patients who do not have the genetic mutations found in classical MH but who evidence calcium channel dysregulation and a similar symptom presentation.
Several diseases appear to put one at increased risk from sarcoplasmic reticulum calcium channel dysregulation including myotonia congenita, mitochondrial disorders, carnitine-palmityol transferase deficiency and Brody’s myopathy.
These patients may have an adverse reaction to anesthesia; MH is the most common cause of anesthesia related death (Graves and Hanna 2005). CFS patients share several features with MH including weakness, muscle stiffness, sympathetic hyperactivity, tachycardia, hemodynamic instability (orthostatic intolerance), exercise as a stressor and possibly a poor reaction to anesthestics.
The two most common neurological disorders, epilepsy and migraine, are believed to derive from abnormal electrochemical activities in the cortex and brainstem that result in altered neurotransmitter release, cerebral blood flows and ANS functioning.
The typical depression in the electrical activity observed after an epileptic episode or migraine attack is believed due to increased extracellular and increased intracellular potassium and calcium levels respectively (ion channel dysfunction) and altered serotonin sensitivity.
Speculation
Based on the information in the Chaudhuri paper calcium channelopathies appear to be particularly associated with fatigue. Six of the eight neurological diseases associated with fatigue cited by the authors involve calcium channel abnormalities. The authors note a calcium channel blocker, nimodipine, is partially effective in treating myalgia in CFS (Chaudhuri et. al. 2000).
There is some evidence for increased intracellular calcium levels in CFS patients. Decreased serum calcium levels were associated with poor NK cell function and increased RNase L fragmentation in CFS patients. That they did not display the increased serum potassium levels expected in a calcium channelopathy, however, cast doubt on whether the increased calcium levels were due to a channelopathy.
The symptoms of CFS patients display some similarities to those found in neurological channelopathies
One of the symptoms CFS has in common with ion channel disorders is its fluctuating nature. All known channelopathies of the excitable tissues result in episodic episodes of fatigue. As in CFS some cause symptoms that indicate both peripheral and central disruption.
Neurological channelopathies (hyopakalemic periodic paralysis, episodic ataxia) are often characterized by sudden attacks of fatigue, weakness, cramping or even paralysis. As in CFS many channelopathies can be induced by physical activity and/or stress.
A personal experience: while there has been much discussion regarding the need for longitudinal studies to capture the fluctuations present in CFS I question how episodic CFS is. My experience is that it is no more episodic than would probably be expected in a chronic disorder; that is, there are better or worse days but few days with truly dramatic shifts in well-being.
CFS patients share with epileptics a predisposition to several autonomic related symptoms such as frequent near syncope (fainting) and low blood pressure, particularly during TILT table testing.
A great deal of evidence since 1999 indicates many CFS patients display abnormalities during TILT table testing (or during standing (see Orthostatic Intolerance I: The Evidence). Since the hypothalamus is involved in autonomic regulation a channelopathy there could conceivably cause symptoms of orthostatic intolerance.
CFS patients share with migraine sufferers such symptoms as headache, confusion, increased sensitivity to lights, sounds and smells as well as exacerbated responses to serotonin. Symptom exacerbation during menstruation and muscle pain, disequilibrium and unusual sweating are often seen in both diseases.
White brain matter abnormalities and reduced cerebral blood flows are also seen in both diseases and stress, alcohol and caffeine can exacerbate symptoms in both diseases. Transient or chronic fatigue is also common in migraine.
Evidence of a Channelopathy in CFS
Some indirect evidence of ion channel disruption is provided by Chaudhuri et al’s finding of increased resting energy expenditure (REE) in CFS patients. Since about 25% of the energy expended during resting goes to maintaining ion gradients in the cell, the authors speculate the increased REE seen in CFS could be due to compensation for faulty ion channel functioning.
CFS patients also appear to be particularly susceptible to some substances (alcohol, anesthesia, some cholesterol lowering drugs) known to effect either membrane integrity (alcohol) and/or ion function (anesthethetics). Indeed fatigue is a common symptom of a new anti-epileptic drug, dezinamide, targeting sodium channels.
Results from a thallium scan of the cardiac muscle in CFS patients suggest a potassium ion channel dysfunction that may be responsible for the cardiomyopathy reported by Lerner and now advocated by Cheney. Chaudhuri and Behan believe a potassium channelopathy is mostly likely to occur in CFS.
Potential causes of channel dysfunction – The natural history of CFS suggests that an early pathogenic or toxic insult often occurs. Several viruses, including HIV and the picornaviruses are able to alter ion channel flow. Herpesviruses have also been linked, interestingly enough given their history in CFS, to altered ion channel functioning.
Ciguatoxin, a neuronal sodium channel disruptor, produces many symptoms, including fatigue, similar to those that occur in CFS. Studies indicate a substantial number of CFS patients have extremely high levels of the ciguatera epitope. (Hokama et al. 2002, 2003a/b). Toxic insults from organophosphates, lead, insecticides, pesticides can also alter ion channel activity.
Toxins can be key ion channels disrupters because they often attack the membrane surrounding the cell. Some toxins can even create new channels that cause severe ionic imbalances through the leakage of ions out of the cell. Other toxins block ion channel activity by binding to them while others (e.g. ciguatoxin) can freeze them open.
Venomous substances produced by scorpions, sea anemones, puffer fish and many other species often target sodium ion channels. Because sodium channel activity is involved in determining the action potential in the first phase of neurotransmitter activity they play a key role in regulating neuronal excitability.
Bacterial neurotoxins also often wreak havoc on ion channel activity. Many ion channel binding sites in the nervous system were elucidated using bacterial neurotoxins.
Testing the hypothesis
The authors recommend three preliminary efforts to establish ion channel dysfunction in CFS (patch clamping, a search for humoral antibodies to ion channels, toxin binding studies). More detailed studies would be needed to definitively characterize the abnormalities but doing so, they report most encouragingly, should ‘rapidly lead to the development of a natural mode of therapy’.
Patch clamping, the most valuable method of studying ion channel activity, is an amazing process. In the patch clamp researchers place an extremely small glass or quartz pipet against a cell membrane. By blowing or sucking on it either manually (!) or by using machine they can see ion channels open and close.
*Update – Since this paper was published in 1999 channelopathies have become a more prominent research topic in CFS.
Ciguatoxin
Greatly increased levels of the ciguatoxin epitope, a marker of altered sodium channel activity, in most CFS patients provide the best evidence yet a (sodium) channelopathy occurs in CFS. Whether these findings reflect a chronic disease process or something more specific to CFS is unclear but research, thankfully, is underway to elucidate the intersection between CFS and ciguatera (Pearn 2001, Hokama et .al. 2002, 2003a/b).
RNase L
The breakup of the RNase L enzyme releases fragments that appear able to interact with the ABC transporters that control the flow of ions in and out of the cell (Englebienne et. al. 2001, Nijs et. al 2004). De Meirleir et. al. did not, however, find strong evidence of systemic channelopathy in CFS (see Patrick Englebienne’s review). Reports from the 2004 AACFS conference indicate, however, that RNase L fragmentation affects the ability of the multi-drug resistant transporter to remove toxins from the cell.
Gene microarray studies
Perhaps most intriguing of all a recent study found that genes involved in ion channel functioning were among those most prominently altered between CFS patients and controls both prior to and after exercise (Whistler et. al. 2005).
Summary
Neurological diseases with channelopathies are quite often associated with fatigue and other symptoms common to CFS. Altered neurotransmitter activity and abnormal brain scan images in CFS have provided results consonant with Chaudhuri and Behan’s predictions.
Indirect evidence of a channelopathy continues to grow in CFS but there is, as yet, however, no direct evidence of a nervous system channelopathy in CFS. The resolution of that question requires the kinds of studies suggested by Chaudhuri and Behan in 1999.
Ongoing Research
*The Belgium Research group headed by De Meirleir, Englebiene and Nijs anticipates the upcoming publication of a paper on multi-drug transporter dysfunction in cells with increased rates of RNase L fragmentation.
*The Vernon research group studying genomics and proteonomics at the CDC will attempt to duplicate and expand upon their studies suggesting, among other things, the abnormal expression of genes involved in ion channel function.
* The Hokama Group at the University of Hawaii-Manoa investigating ciguatoxin is the only group known by CFS Phoenix to be directly engaged in research on a channelopathy in CFS. The information below is from The Pacific Research Center for Marine Biomedicine.
- The specificity of the test used to find the ciguatera epitope is being improved. Various techniques (NMR mass spectroscopy) are being used to further characterize ciguatoxin.
- Ciguatera toxin will be added to sodium channels of cells to determine if it effects sodium channel function.
- Perhaps most importantly for CFS patients the composition of the lipids the monoclonal antibody test picked up in CFS, hepatitis B and some cancer patients is being determined. These lipids will be added to sodium channels on cells to determine if they effect sodium channel functioning.
- Lastly, in an attempt to determine where the lipids are coming from, liver cells will be exposed to ciguatoxin, and then monitored to determine if they are the site of lipid manufacture.
The Hokama group’s most recent report to the NSF stated their purification of the ciguatera epitope has enabled them to resolve 2/3rds of the indeterminate results, and that the source of the sodium channel disruption due to ciguatoxin has been identified. The antibody test formerly used latched onto a part of the toxin that was not involved in sodium channel disruption. A new antibody test presumably has been or will be created.
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