RESEARCH AVENUES/POTENTIAL TREATMENTS
(Please note I have no medical background am in no way qualified to recommend any particular course of treatment for ME/CFS. The following is a theoretical discussion that logically flows from the proposed neuroinflammatory hypothesis and is intended to outline potential avenues for further investigation. Please see your physician before altering any component of your treatment plan).
“Why So Resistant to Treatment?” Plus “Is a Cure Possible?
The previous discussions propose that ME/CFS may be caused by an imbalance in GABA/Glutamate (and in the case of the ‘Wired and Tired’ type a hyperglutamatergic or high extracellular glutamate state). This suggests that anything that either boosts GABA or blocks glutamate (or assists with the other parts of the vicious cycle – oxidative stress and mitochondrial dysfunction) could be helpful.
This may indeed be the case however, many proposed ME/CFS ‘protocols’ are specifically aimed at addressing oxidative stress or mitochondrial dysfunction, and many of us do use either drugs (e.g. benzodiazepines), supplements or compounds that affect GABA/glutamate in this manner and we have not been ‘cured’.
‘Time The Healer’
If, we accept for the sake of discussion, that a GABA/glutamate imbalance underlies ME/CFS, then (referring back to Part II) it’s possible that the process of ‘kindling’ causes neuroplastic changes that result in the brain becoming easily hyper-aroused. It may help to think of this as an aberrant network or hub of interconnected neurons that have been primed to respond to little sensory input
The problem then (as I see it) is not just to break the vicious neuroinflammatory cycle but to do so completely and consistently, and for a sufficient period of time that the aberrant neural connections are themselves extinguished through the process of neuroplasticity. (You may recall that the repeated use and withdrawal of GABAergic benzodiazepines and alcohol can itself induce kindling).
The GABA-B receptor agonist (activator) Baclofen has been featured throughout this series, not only as a ‘cure’ for alcoholism, but also as a treatment for stiff person syndrome and tinnitus – all conditions in which a glutamate/GABA imbalance is likely to play a key role. Baclofen was a preferred med in Dr Jay Goldstein’s protocol for ME/CFS (who’s book ‘Betrayal by the Brain was discussed in Part I).
A similar situation may occur with Baclofen in the treatment of alcohol dependence/withdrawal symptoms where a high dose Baclofen regime (above the ‘threshold dose’ where alcohol cravings apparently cease) may be needed not just to break the cycle of addiction but to also prevent severe withdrawal symptoms due to ‘rebound’ induced glutamate excitotoxicity. Similarly an extended period of Baclofen treatment is also required to break the addiction and avoid serious withdrawal symptom. In fact, Baclofen treatment for alcohol dependency may require continuing (indefinitely) on a maintenance dose (see The Little Pill That Could Cure Alcoholism, in press).
Of interest is the fact that GABA B receptor agonists (like Baclofen) or modulators (that are only activated in the presence of endogenous GABA giving less undesirable side effects), block the rewarding effects of addictive drugs such as alcohol, nicotine or cocaine (Slattery et al, 2005). You may recall that the CDC (Unger et al 2012, abstract presented at conference) found decreased activation of the basal ganglia (a key part of the brain associated with reward, motivation and motor activity) in ME/CFS patients,and that this under-activation was correlated with fatigue levels.
Unger et. al.suspect dopamine dysregulation is occurring in ME/CFS but GABA-B receptors are also widespread in the basal ganglia and are increasingly seen to play a role in reward mechanisms. (Cohen et al, 2012). These receptors enable the brain to compute the balance between the expectation of reward and the actual reward received. (Note that the COMT gene associated with ME/CFS modulates both dopamine and GABA. See Part II).
Of course, as has been mentioned repeatedly, extreme caution is needed when any attempts are made to modulate the glutamate/GABA balance due to issues of tolerance and dependency and the danger of inducing neurological kindling (or exacerbating existing kindling). (In the case of stiff person syndrome baclofen pump failure in rare cases can be fatal (Mohammed, Hussein, 2004).)
It is also uncertain what adaptions might take place over time if attempts are made to modulate neurotransmitters e.g. it’s possible that exogenous boosting of GABA levels could result in reduced receptor sensitivity that potentially exacerbates the problem once supplementation ceases.
In short, this is a complex problem and any pharmaceutical interventions directly aimed at altering the glutamate/GABA balance should done only be under strict medical supervision.
Alternative approaches may have some benefits. Regular meditation has be shown to increase endogenous GABA levels (Guglietti et al, 2012) and a recent study has shown that following a low glutamate diet may be effective in reducing the symptoms of fibromyalgia and IBS (Holton et al, 2012).
Addressing Autonomic Dysfunction
As discussed previously, autonomic dysfunction is a common finding in ME/CFS with a a pattern of ‘sympathetic dominance’ which may be responsible for some of the more disabling symptoms such as exercise intolerance, POTS, cognitive and sleep problems. Glutamate could be responsible for long term alterations in autonomic function or indeed may induce autonomic neuropathy of the type seen in diabetic autonomic neuropathy (DAN).
Regardless of the cause of autonomic dysfunction, even autonomic neuropathy can be treated (if not reversed), and the earlier the treatment begins better as autonomic dysfunction can result in eventual neuropathy. In fact, in type 2 diabetes it is recommended that autonomic testing begin as soon as the condition is diagnosed as autonomic dysfunction can precede clinical symptoms. Strikingly, it is reported (Vinik and Murray, 2008) that (bolding added) :
“medical leadership including the American Diabetes Association (ADA), the American Heart Association, the American Academy of Neurology, the American Academy of Family Physicians, the Juvenile Diabetes Research Foundation International, and the National Institutes of Health have published recommendations for autonomic testing as part of the standard of care for chronic diseases.”
Treatment (usually using ANS modulating medications) needs to be individualized based on the overall pattern of dysfunction (sympathetic, parasympathetic dominant or mixed). With its chronic nature and frequently confirmed evidence of autonomic dysfunction, surely ME/CFS must be included in the list of chronic diseases that require early autonomic testing and treatment as part of ‘standard care’ to prevent autonomic dysfunction progressing to life threatening (sudden cardiac death) neuropathy.
In the absence of this, alternative and various ‘self-help’ approaches such as vagal nerve stimulation, biofeedback, diaphragmatic breathing exercises and meditation may all be helpful in restoring ANS balance. Reporting on the link between heart rate variability and cognitive dysfunction in CFS, Australian researchers (Beaumont et al, 2012) have proposed various methods including biofeedback and transcranial direct current stimulation for modulating vagal tone.
Recalling Rönnbäck and Hansson’s model of mental fatigue discussed in Part II :
“If our hypothesis is correct, it may be possible to further improve the symptoms by suppressing the production of proinflammatory cytokines and, thereby, restoring the normal astroglial glutamate uptake.”
Addressing neuroinflammation by other means may also be helpful. Various antioxidants, vitamin B12 (Zoccolella et al, 2009), magnesium (Poleszak et al, 2008), N-acetylcysteine (Dean et al, 2011) and CoQ10 (Dumont and Beal, 2011) may all help to reduce neuroinflammation.
Pharmaceuticals or natural compounds that inhibit pro-inflammatory TNF alpha or COX-2 may similarly help to protect against glutamate neurotoxicity and break the vicious cycle (Article – McIntyre and Cha, 2011) :
“Cyclooxygenase-2 (COX-2) inhibitors have been shown to protect against glutamate-induced neurotoxicity; to prevent normal aging-related increases of cytokines, prostaglandins, and TNF in neurons; and to modulate the hypothalamic adrenal axis”
COX-2 inhibitors may also help restore NK cell activity and counteract dysregulation of the HPA axis through also inhibiting pro-inflammatory PGE2 (Lin and Nelson, 2003; Scemes and Spray, 2011 -in print).
Fluge and Mella are currently trialing the TNF-a antagonist Etanercept in their ME/CFS patients including some who did not respond to Rituximab.
Drugs Worth Investigating
Stablon (Tianeptine) is a fast acting ‘atypical’ antidepressant that, as seen in Part II, appears to be able to protect the brain (particularly the amygdala and hippocampus) against stress induced glutamate excitotoxicity.
Memantine (or other drugs that block glutamate NMDA receptors) have been shown to help with anxiety and sleep (Schwartz et al, 2012) and with neuropathic pain (Jamero et al, 2011).
Lyrica (pregabalin) an anticonvulsant, is one of only three FDA approved drugs for the treatment of fibromyalgia, and has been found in several clinical trials to significantly reduce pain (and fatigue, anxiety and sleep problems). Aside from fibromyalgia, Lyrica is also used to treat diabetic peripheral neuropathies, generalized anxiety disorder (GAD) and social anxiety disorder (peripheral neuropathies and anxiety have been discussed previously in the context of this neuroinflammatory model). Although a GABA analogue, Lyrica does not bind to GABA receptors like benzodiazepines. Instead it appears to block certain neurotransmitters including glutamate (Kim et al, 2009). A Lyrica trial in ME/CFS under the direction of the Lights is underway in Utah.
Doxycycline (and other tetracycline antibiotics such as Minocycline) has been shown to reduce glutamate excitotoxicity and may be effective in treating pain via its inhibitory effects on TNF-alpha (Cazalis et al, 2008) which may also contribute to neurotoxicity (Takeuchi et al, 2006). One theory (yet to be tested) proposes that Doxycycline treatment may help improve the mitochondrial content of skeletal muscle in metabolic syndrome (White, 2010 – research proposal).
Nuvigil (armodafinil) a recent stimulant medication commonly used to treat narcolepsy (also used off-label for ADHD) may help with improving cognitive issues and other sensory problems by increasing available dopamine levels (McIntyre and Cha, 2011). You may recall from Part II that dopamine also improves sensory gating by acting as a ‘gatekeeper’ of glutamate transmission by boosting strong (salient) signals and suppressing weak signals.
Similarly, Citicholine (CDP-choline), a psychostimulant, which increases dopamine receptor densities may help with focus and mental energy and has shown some efficacy in treating ADHD. CDP-Choline also modulates the HPA, reduces oxidative stress and lowers excess glutamate by increasing the re-uptake of glutamate and increasing the expression of the EAAT2 glutamate transporter (Wikipedia). Also notable is that under-activity of the EAAT2 gene may be implicated in common migraine (Antilla et al, 2010), while recent research suggests that some 80% of ME/CFS patients experience migraines (Ravindran et al, 2011).
Investigations into triptan migraine drugs suggest that their effects are due to reducing CSF extracellular glutamate (Vieira et al, 2007) and one case study reports complete remission of migraine after administration of the NMDA receptor blocker memantine discussed above (Spengos et al, 2008).
As discussed in Part II, Tecfidera (dimethyl fumarate) which has been recently approved by the FDA for the treatment of relapsing/remitting MS also appears to owe its neuroprotective effects to stimulation of the EAAT2 glutamate transporter.
Antibiotics – Interestingly, the EAAT2 glutamate transporter has also been implicated in neurodegenerative diseases such as Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis (ALS). Screening of over 1,000 FDA approved compounds showed that common beta lactam type antibiotics (which include penicillin derived antibiotics) activate the EAAT2 protein and in an animal model one such antibiotic, ceftriaxone, increased glutamate re-uptake thereby reducing excitotoxicity and providing neuroprotection (Kim et al, 2011).
GABA and the Immune System
Several GABAergic drugs are currently used for epilepsy and migraines associated with MS and may have additional protective effects in MS due to the proven inhibitory effects of GABA on immune mediated inflammation.
While GABA is usually considered solely as a neurotransmitter it now appears that certain immune components contain GABA receptors and that GABA actively influences immune activity (and GABA is also produced by the immune system). Multiple sclerosis patients have a low level of serum GABA and the GABA synthesising enzyme GAD. In an animal model of MS (experimental autoimmune encephalitis) GABA agonists can reduce inflammation (acting directly on antigen presenting cells, and indirectly on T cells leading to diminished production of inflammatory cytokines including IL1β, IL6 and TNF-alpha) thereby slowing or even reversing the neuronal damage (Bhat et al, 2010).
Low dose Naltrexone (LDN) is an off-label treatment with a substantial following amongst those with ME/CFS, fibromyalgia and multiple sclerosis. Naltrexone is a powerful opioid antagonist used in the treatment of opioid and alcohol dependence. Anecdotal reports have attributed LDN’s effectiveness to partial blockage of the opioid receptors that upregulate endogenous opioid production, a reduction in proinflammatory cytokines impacting on microglia and certain unspecified ‘immune boosting’ effects.
One hypothesis posits LDN increases glutamate reuptake and prevents glutamate induced neurotoxicity in MS (Agrawal, 2005). While the effectiveness of LDN in MS has yet to be confirmed in clinical trials a small LDN trial has shown some promise in treating pain in fibromyalgia (Younger et al, 2013).
- Dig Deeper – Successful Low Dose Naltrexone Fibromyalgia Trial Points to Safe, Low Cost Therapy; Implications for Chronic Fatigue Syndrome
- Dig Deeper – Low Dose Naltrexone
N- acetylcysteine (NAC) is another commonly used treatment that may have potential in treating ME/CFS. Originally used as a mucolytic (relieving congestion in the common cold), this powerful antioxidant is the first line treatment for paracetamol overdose. As previously seen, NAC has also shown promise in the treatment of certain ‘neuropsychiatric’ disorders including OCD and bipolar disorder.
Being a glutathione precursor, NAC may support mitochondrial function peripherally and in the brain. Trials have shown NAC pretreatment can enhance endurance by reducing oxidative stress in exercised muscles (Medved et al, 2004). In addition to its antioxidant properties NAC has other properties that might address neuroinflammation.
A review of NAC’s potential use in psychiatry (Dean et al, 2011) indicated NAC attenuates neurotoxicity by reducing the levels of the pro-inflammatory cytokines IL1-b, TNF-a and IL6 and by modulating glutamate and dopamine levels. NAC has also been found to reduce levels of the pro-inflammatory factor C-reactive protein (CRP) in type II diabetes (Jeremias et al, 2009) (as discussed last time IL1-b, TNF-a, IL6 and high-sensitivity CRP are the inflammatory markers found to be raised in ME/CFS.) NAC has been shown to attenuate disease progression in experimental autoimmune encephalitis (the animal model for MS – Stanislaus et al, 2005). NAC has the added advantages of being cheap, readily available and with demonstrated safety in normal clinical doses.
Heat Shock Proteins
One final avenue worth exploring is whether it’s possible to enhance the protective role of heat shock proteins which appears to be attenuated in ME/CFS patients.
As was seen earlier, enhancing heat shock protein activity has the potential to break the ‘vicious-glutatmate production circle’ at each stage via HSPs’ ability to reduce oxidative stress, prevent glutamate induced excitotoxicity, and induce the expression of mitochondrial regulating PGC1a. It appears that in low energy states (due to poorly functioning mitochondria) even minimal levels of extracellular glutatmate can make the brain highly vulnerable to glutamate induced excitotoxicity (Blaylock, Maroon, 2012).
HSP’s may be induced by exercise (if tolerated), heat or cold stress exposure (an effect that may be enhanced by pre-treatment with common aspirin – Fawcett et al, 1997), certain ‘nutraceuticals’ and glutamine (Wischmeyer, 2006).
The CFIDS Association of America/Biovista drug repurposing project (now completed although details of the compounds identified as potentially useful have not been released) searched a veritable mountain of data to find novel connections between the mechanisms of action of existing drugs and the key symptoms of CFS using an ‘unbiased’ computational approach (CFIDS association, Partnering for Cures conference, 2012).
I hope I have shown, in this and previous blogs that there is converging evidence to link ME/CFS to a range of other neuroinflammatory diseases and that (currently licensed and often cheap) medications used in these disorders may be useful in treating ME/CFS. This suggests, of course, that drug repurposing efforts that examine symptoms found both in ME/CFS and other neuroinflammatory disorders could be fruitful.
However, such associations are only likely to be made if all the overlapping symptoms (such as sensory processing disorders) have been noted in the ME/CFS literature. While laudable, there is no certainty that such connections are likely to surface using an ‘unguided’ sift of the existing literature.
There is growing evidence that a number of ‘natural’ compounds (including curcumin, resveratrol, quercetin) may prevent neurodegeneration due to inflammation/excitotoxicity and can induce production of neuroprotective HSPs (including curcumin – Blaylock, Maroon, 2012). If it can be shown that the core pathology in ME/CFS is a neuroinflammatory state, there may be scope for improvement through simple supplementation or dietary changes.
As seen previously, a glutamate/GABA imbalance may underpin peripheral and autonomic neuropathies which may be exacerbated by a thiamine (vitamin B1) deficiency. As discussed earlier, thiamine deficiency results in peripheral and autonomic neuropathy. Benfotiamine, a synthetic form of thiamine is a popular dietary supplement treatment for diabetic peripheral neuropathy in Germany. Thiamine may have additional benefits in a neuroinflammatory model by supporting the functioning of the GLAST glutamate transporter. In addition CoQ10 supplementation reduces neuron loss in the dorsal root ganglia in a mouse model of diabetes (Shi et al 2013) while a meta-analysis supported the efficacy of alpha-lipoic acid in reducing peripheral neuropathic pain in diabetics (Mijnhout et al, 2012).
Is a Cure Possible?
My gut feeling is that there is the potential for many of our symptoms to be resolved with appropriate treatment. It may be likely though, that the neuroinflammatory state, over a long period of time, results in long-lasting damage including peripheral and/or autonomic neuropathies that may not resolve easily.
I also feel that an underlying predisposition (perhaps genetic) may be present for the neuroinflammatory state to develop when we are faced with stressors which could result in any of the previously mentioned conditions developing at some stage including the typical ailments of ageing
Interestingly, given her key role in the upcoming Pathogen Discovery and Pathogenesis Program at the Chronic Fatigue Initiative (as blogged lately by Cort), a similar ‘multi-hit’ model appears to be very much in the mind of Dr Mady Hornig.
- Dig Deeper: Infection, Autoimmunity and PANDAS: Dr. Hornig on Chronic Fatigue Syndrome at Dr. Klimas’ NSU Conference
Dr Hornig has co-authored a paper (along with Dr ian Lipkin – Miranda et al, 2010) which, using an animal model for schizophrenia and autism, demonstrated how maternal infection could increase the risk of the offspring developing ‘neuropsychiatric’ conditions. The mechanism suggested involved Toll-Like Receptors (TLRs). Intriguingly, the putative ME/CFS therapy Ampligen targets TLRs (Hemispherx Biopharma presentation to the FDA, 2012). In the context of this and previous discussions it is also worth noting that one of the neurological effects noted in the offspring in this animal model was a sensory gating deficit (the very neurological deficit that started this whole discussion). You may also recall from Part II that maternal infection with the H1N1 virus was shown to cause changes to glutamatergic and GABAergic genes.
- Dig Deeper: Not Fatigue After All? New Model Suggests Other Symptoms Better Explain Chronic Fatigue Syndrome (ME/CFS)?
Dr. Hornig proposes that ‘Chronic Fatigue Syndrome’ results from a genetic predisposition, a ‘window of opportunity’ or vulnerability and an environmental insult. A maternal infection during the gestation period that produces disruptive genetic changes may be one such window of vulnerability. This model suggests that the development of ME/CFS (or other ‘neuropsychiatric’ conditions) may take years or even decades and occurs when a genetically vulnerable person encounters any of a wide range stressors (including psychological stress, viruses and environmental toxins).
It may be that the condition of ME/CFS must be treated in a similar way to diabetes requiring a lifelong attention to ‘lifestyle’ and potentially ‘maintenance’ medication.
This may require some compromise in how we lead our lives including some moderation of previously cherished activities or ambitions in the knowledge that we may have a lifelong vulnerability. As Rönnbäck and Hansson said in respect of dealing with mental exhaustion ;
“Furthermore, it is important for the patient to imagine and learn how much sensory stimulation they can tolerate prior to feeling too exhausted.”
This may sound like pacing and indeed it is. But it is also valuable advice that might have been useful for many to have had prior to onset of the ‘state’ of ME/CFS.