That old bugbear, fibromyalgia

Lately I dropped in to Textbook of Pain to see what it had to say about fibromyalgia, or as it is commonly referred to, FM. I found out quite a lot I never knew before, actually.

I already knew that people who are diagnosed with FM hurt - the main complaint is body pain. Careful differential diagnosis comes first; serious major depressions, panic and anxiety disorders are ruled out. Next, apparently there is more than one kind of FM, primary and secondary. They look and act a lot alike so clinical reasoning is key: Existence of a prior condition means the FM must be treated as secondary:

1. Rheumatoid arthritis - 30% of patients will also likely have FM
2. Systemic Lupus Erythematosus - 40%
3. Sjögren's Syndrome - 50%

What "secondary" means, is that patients will have two kinds of pain at once, and treatment of the primary condition must be managed in a way that won't aggravate the pain from the secondary FM. Furthermore, one kind of pain might be well-managed and the other not. For example, "increasing the dosage of antirheumatic medications in the absence of active inflammation may have little effect on the pain amplified by FMS." There are issues with steroid treatment - e.g., patients withdrawing from steroid treatment for their RA might find the FM pain increasing temporarily with each decrease in glucocorticoid dosage. This is a surprise in that primary FM has not been helped with glucocorticoid.

Various infectious and inflammatory conditions such as Hep C, TB, syphilis, and Lyme disease, are associated with FM. FM, and aches and pains from subacute bacterial endocarditis could be confused.

Primary FM is referred to these days as a "disorder of abnormal sensory processing of sensory information within the CNS, exhibiting a limited array of recognized objective physiological and biological abnormalities."

1. Mountz et al 1995: CT scans showed abnormally low regional cerebral blood flow in thalamic nuclei and other pain processing brain structures, correlated with spinal fluid substance P levels.
2. Gracely et al. 2002: fMRI evidence for augmented pain processing in brain
3. abnormal spinal cord "wind-up"
4. In over 60% of cases, there exists a temporal relationship to a physical trauma or febrile illness and FM onset.
5. Evidence relating FM to actual muscle abnormality or pathology is weak, scant, inconclusive, or completely missing, in both invasive and non-invasive testing compared to healthy controls.

At a neurochemical level, findings support the concept of objective pain amplification. Various pro-nociceptive substances, and a few anti-nociceptive substances, have been examined.
One of the pro-nociceptive substances is Substance P (P for pain):
1. Russell 1998: Elevated levels of Substance P found in cerebral spinal fluid of patients diagnosed with FM
2. Vaeroy et al 1988, Russell 1998, Mountz et al 1995: average concentrations of Substance P in CSF found to be 2 to 3-fold higher in FM than in healthy controls. Substance P levels in saliva, serum or urine were not elevated.
3. Cerebral spinal fluid contains an esterase for breaking down Substance P - this substance was normal, not deficient, so the elevated levels of Substance P must be because the body makes more than the esterase can take care of.
4. Substance P is elevated in other conditions such as rheumatic diseases with or without FM (Russell, unpublished).
5. In painful OA of the hip, levels of Substance P returned to normal after hip replacement.
6. Tsigos et al 1993, Sjostrom 1988: In chronic low back pain, and diabetic neuropathy, cerebral spinal fluid Substance P levels are lower than normal. (So go figure...)

Another substance is nerve growth factor, elevated in CSF of those who have primary but not secondary FM (Giovengo et al 1999). It may even be NGF that is responsible for elevated levels of Substance P, whereas in secondary FM, the primary condition (arthritis etc.) itself may be responsible.

Cytokines called interleukins were found to be elevated, specifically IL-8 and IL-6. IL-8 is stimulated by Substance P.

G-protein-coupled receptors were found to not be able to inhibit intracellular cyclic AMP production by adenylate cyclase - more cyclic AMP was found floating around. This is being considered as a cause of the allodynia characteristic of FM.

Apparently there is no opioid deficiency; levels of Dynorphin A are found to be normal.

Serotonin levels, however, are lower. Numbers of active FM tender points correlated nicely with concentrations of serotonin in body serum (Wolfe et al 1997b).

Noradrenaline levels might be low; concentration of methoxyhydroxyphenylglycol, the inactive metabolite of noradrenaline, was found to be significantly lower than normal in FMS cerebrospinal fluid (Russell et al 1992).

Up to 35% of patients with FM, when tested using hypoglycemic hyperinsulinaemic clamp procedures, show inadequate responsiveness, or excessive response to feedback inhibition, of the hypothalamic-pituitary portion of the HPA axis (Adler et al 1999). This shows exaggerated adrenocorticotropic hormone response to insulin-induced hypoglycemia or stressful exercise and indicates poor tolerance for physiological stress.

Women are more commonly affected than men, and FM onset is often perimenopausal. About 30% of female FM patients are prematurely menopausal due to surgical removal of female reproductive organs. Forty-four % of female FM patients have premenstrual syndrome and pain which cycles in phase with their menstrual cycle (Anderberg et al 1998). It is thought that these differences are less a feature of estrogen and more to do with serotonin (Nishizawa et al 1997).

Sleep is a problem in FM. Deep stage IV non-REM sleep is when human growth hormone is released. It stimulates the liver to produce a long half-life peptide called insulin-like growth factor-1, found to be deficient in FM (Bennett et al 1997). It has been hard to develop a treatment based on administering this, even though it helps; growth hormone therapy is expensive at $1000/month.

Iyengar et al 2005: in a study of 80 multi-case families, 8 genetic markers were detected.

Who *isn't* afraid of Alzheimer's?

I have found microglia interesting to learn about in the past, and have written here, here, here, here, and here, about their proposed relationship to pain.

Yesterday I saw a news story about researchers in Germany who carefully studied the relationship between microglia and neurons undergoing Alzheimer-like changes in mice, Dangerous custodians: Immune cells as possible nerve-cell killers in Alzheimer's disease,
and was immediately intrigued.

An advance online publication of the paper, Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer's disease, is freely accessible, at least for now.

That stressed neurons exude the chemokine, fractalkine, or that this substance attracts microglia, isn't fresh news. Like a bunch of little cellular opportunists, microglia catch the "scent" and begin moving toward it. Like any bunch of scavengers converging on a picnic, in this case, the amyloid-β forming and piling up, they also secrete/excrete (while gorging and multiplying, I suppose). What they signal/secrete/excrete isn't really explained, but what is news, is that it, or else just the sheer numbers of microglia converging, apparently sickens the affected neurons even more, kills them, according to this story.

In the paper, the authors, Fuhrmann etal., state,

"In Alzheimer's disease, microglia represent a double-edged sword. On the one hand, microglia can have a beneficial effect by secreting neurotrophic factors and phagocytosing amyloid beta (Aβ)², the latter of which remains controversial³. On the other hand, microglia may also be neurotoxic⁴. Little is known about the neurotoxic role of microglia in Alzheimer's disease. Human peripheral blood monocytes that are stimulated with Aβ induce neuron loss in vitro⁵. Neurons cultured without microglia are resistant to Aβ-induced neurotoxicity⁶."

The authors decided to interfere, genetically, with the receptors in the microglia that allow them to sense fractalkine; CX₃CR1,

"the unique receptor for fractalkine/CX₃CL1, which is expressed in neurons and presumably acts as a membrane-bound adhesion molecule and/or cleaved chemoattractant and is important for recruiting CX₃CR1-expressing microglia to injured neurons^{9, 10}."

They managed to show that it was definitely the microglia causing the neuron death, not any other factor. Furthermore, knocking out the ability of microglia to "smell" fractalkine didn't seem to interfere with their ability to clear the amyloid material associated with Alzheimer's. Moreover, the same treatment of the microglial receptor gives inconclusive results in other kinds of conditions - only in Alzheimer's does it seem to be a helpful intervention.

Supplementary information for this paper.

Fuhrmann, M., Bittner, T., Jung, C., Burgold, S., Page, R., Mitteregger, G., Haass, C., LaFerla, F., Kretzschmar, H., & Herms, J. (2010). Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer's disease Nature Neuroscience DOI: 10.1038/nn.2511