Friday, 30 March 2012
Medical Intervention for Someone in Crisis
Through my journey with having experienced the extreme struggles of trying to survive with severe ME, this disease has been relentless and 'good days' need to be clearly defined. From my perspective my days don't vary any great deal - there is always significant muscle weakness, cognitive impairment and all the other many symptoms which at present my memory evades me.
Of the many many interventions I have tried to improve the outcome of my illness, none seem to induce any noticeable benefit relatively quickly (as in minutes or hours, not days) other than that but a few. As outlined in many studies into neuroinflammation that affects the brain and Central Nervous System, these regions are seperated from the rest of the body by the Blood Brain Barrier (BBB) . Within this separate compartment, the environment is patroled by microglia: the resident macrophages of the brain and spinal cord. It is quite probable that in ME microglia are chronically activated in a state where they respond to some form of viral or other infection that they are unable to neutralise. This activation induces significant up regulation of pro-inflammatory cytokine production: Il-1a, Il-1b and TNF-a. It must not be forgotten that blood tests for the aforementioned cytokines will most often show no abnormalities due to the compartmentalisation of the immune system behind the blood brain barrier. Doctors by and large do not seem capable of understanding ME simply because the pathology is complex compared to diseases such as rheumatoid arthritis, where elevated levels of TNF-a often show up on blood tests  due to the location of the inflammation in the synovial fluid that has access to the peripheral circulation.
Chronic sustained production of these cytokines results in neuronal degeneration . Activated microglia produce profound levels of Glutamate, an excitotatory neurotransmitter, or when in abundance may be referred to as an excitotoxin . This induces an increase in the concentration of intracellular calcium ions, which subsequently has many detrimental effects on the cell inducing apoptosis (programmed cell death).
Getting some relief from acute paralysing symptoms
Seeing as neuroinflammation and subsequent up regulated glutamate production is most likely present, I tried various strategies to see if I could improve some of the most disabling, paralysing symptoms of this disease.
The medication 'Flupirtine', an NMDA receptor antagonist and potassium channel opener has given me significant relief from some of the most crippling symptoms such as complete muscle weakness and visual and auditory excitation. This drug is not readily available in the UK at present, but has been used in other European countries for quite some time primarily as a non-opiate non-NSAID pain killer. It reduces the effect of glutamate on neurons and thus reduces excitation A compound structurally akin to Flupirtine and that is available in the UK under prescription and at present licensed and indicated for epilepsy is 'Retigabine'. This however can be prescribed off-label for a variety of conditions to include ME. For safety, Liver Function Tests should be performed intermittently to ensure hepatic enzymes are within the normal range and not grossly elevated.
'Memantine' a mild NMDA receptor antagonist, used in Alzheimer's disease can reduce the effect of glutamate in stimulating neurons via blockade of the NMDA channel. This drug has some other effects on other receptors such as D2, 5HT3 and Nicotonic Acetylcholine receptors of which D2 agonism may provide benefit for symptoms of Restless leg syndrome and Periodic Limb Movement Disorder.
Currently due to the recent deterioration of my condition and failure to improve on a concoction of D-ribose, Carnitine, Manganase, Zinc, Selenium, Ascorbic Acid, Omega 3 (2 grams daily), Malic Acid, Methylcobalamin (Subcutaneous), Metafolate (6mg daily), S-Adenosyl Methionine (Sam-e) and Magnesium Sulphate (Subcutaneous) I have instigated and maintained a regime of glutamate down regulation that has been of great therapeutic value:
Daily, I take:
Flupirtine - instant release capsule 100 mg every 6 hours.
Memantine - 20 mg at 7:00 and 20mg at 19:00 hours.
I have found that if symptoms put you at breaking point and the above combination does not provide sufficient relief, in emergencies I intermittently use low doses (0.5 to 1mg) of Clonazepam (Rivotril), a long acting benzodiazepine GABA-a agonist. GABAergic drugs have the ability to indirectly down regulate the N-Methyl D Aspartic Acid (NMDA) receptor - the receptor that receives and induces the effects of glutamate. I have not found tolerance to be an issue if this medication is not used every day, but only rarely as needed. I have not found I have incurred any tolerance to the Flupirtine and Memantine combination - this does not seem to be a problem with these drugs when used chronically over extended periods.
Of course, the above medications may not be suitable for everyone due to the extreme chemical sensitivities present for many sufferers.
Disclaimer: These medications must only be tried under the supervision of a qualified medical professional. If you need further information about who can prescribe them please contact me.
The only more natural alternaitves that seem to be of any efficacy from personal experience are Lithium Orotate - this is not a prescription drug and does not have the toxicity issues that are present from the prescription only Lithium Carbonate, which is used at very high doses.
With Lithium Orotate, 5 to 15 mgs may be of quite to some use when in an acute crisis.
Sun Theanine, a patented specially processed high purity form of the amino acid L-Theanine can increase the synthesis of GABA. GABA has inhibitory effects on the glutamatergic system 
In ALS, also known as Lou Gehrig's disease, the drug 'Riluzole' is employed and has the capacity to indirectly down regulate glutamate. Therefore the effect of glutamate on motor neurons is drastically reduced and this can improve symptoms such as muscle weakness .
Rituximab & B Cell Depletion Therapy
It is interesting to note that elevated levels of IL-8 can induce the differentiation and growth of B cells. Work done by the Whittemore Peterson Institute observed a trend for various cytokines to be elevated in so called XMRV+ subjects - in other words I think for the time being these patients should simply be considered as well defiend severe ME patients due to the controversy surrounding XMRV. However there was a trend for IL-8 to be quite substantially elevated in this group. With the recent findings demonstrating the benefits of employing B cell depletion therapy using the monoclonal antibody Rituximab, it would seem logical that autoimmunity may arise at least in part from the dysregulation of IL-8. In various autoimmune diseases upregulation of IL-8 seems to be prominent  .
I do hope that the information obtained from this post may help those ME patients in desperate need for some form of effective medical intervention. Evidently there are only but less than a few doctors in the UK that know how to effectively help patients. Even then I do not have confidence in their ability to help patients in an acute crisis that may endanger their survival. If you have any questions please feel free to contact me.
 Wood, Paul (2003). Neuroinflammation: Mechanisms and Management. Humana Press.
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 Riluzole prolongs survival and delays muscle strength deterioration in mice with progressive motor neuronopathy (pmn) PMID: 11090865
 Enhanced activity of GABA receptors inhibits glutamate release induced by focal cerebral ischemia in rat striatum. PMID: 17531382
Posted by Max at 12:38