“Our results provide evidence of neuroinﬂammation in CFS/ME patients, as well as evidence of the possible contribution of neuroinﬂammation to the pathophysiology of CFS/ME.“
‘Show Me the Inflammation!’
It’s perhaps emblematic of a complex and difficult to nail down illness such as ME/CFS or CFS/ME (aptly illustrated by this uneasy compromise) that even the name has been a source of ongoing rancour since early clusters were attributed to outbreaks of epidemic ‘encephalitis’ or examples of mass hysteria.
In fact the ‘itis’ in myalgic encephalomyeltis has often been an easy target for those wishing to downplay the seriousness of the condition. The inability over many years to unambigously show encephalomyeltis (inflammation of the brain and spinal cord) made it difficult, to say the least, to counter the growth in usage of the unfortunate term chronic fatigue syndrome (or often just chronic fatigue). Even the UK ME Association’s own Dr. Shepherd has lately taken the pragmatic approach of using ‘encephalopathy’ rather than get into nitpicking arguments over terminology.
The 2014 IACFS/ME Conference may have just put ‘itis’ of the brain right back center stage. Komaroff’s Highlights of the IACFS/ME 2014 Conference Last month at the close of the IACFS/ME conference Professor Anthony Komaroff provided his customary end of conference summary followed by an audience Q&A session. Komaroff is known for his sober and measured assessment of emerging research, but even he was enthused at various parts of his presentation.
Focusing on the Brain
Two aspects of the brain session particularly piqued his interest; Stanford researchers using quantified QEEG were able to distinguish ME/CFS patients from healthy controls with remarkable accuracy, while a Japanese group was able to show objective evidence of activation of the brain’s resident immune cells – a key indicator of neuroinflammation. Commenting on these findings (comments compiled by Margaret Williams and posted at MEActionUK) Komaroff stated:
“There is, and you’ve heard it repeatedly in the last three days, a theory that CFS might reflect an ongoing activation of immune cells in the brain, not in the periphery, but in the brain”
In the Question and Answer session, Komaroff was asked if neuro-inflammation was not encephalomyelitis, to which he replied:
“Yes. If it were confirmed by multiple other investigators it would, for me, say that there is a low-grade, chronic encephalitis in these patients, that the image we clinicians have of encephalitis as an acute and often dramatic clinical presentation that can even be fatal has – may have – blinded us to the possibility that there may be an entity of long-lasting – many years long – cyclic, chronic, neuro-inflammation and that that underlies the symptoms of this illness”, commenting that it was “entirely plausible and these data are consistent with it”.
“A Small But Perfectly Formed Study”
This was quite a dramatic response from one not normally given to hyperbole. So what exactly did the Japanese researchers find and what does it mean?
This small study (9 ME/CFS patients – Fukuda) and 10 age and sex matched healthy controls, resulted from a collaboration between RIKEN, Japan’s largest comprehensive research institution which is renowned for its high-quality research in a diverse range of scientific disciplines, Osaka City University, and Kansai University of Welfare Sciences. Despite the small sample size the institutes were sufficiently impressed to issue a press release which was picked up by Science Daily amongst others.
The primary aim of the study was to look, for the first time in ME/CFS, for direct objective evidence of neuroinflammation – inflammation of the nervous system – in the brain.
They injected a compound that binds to a protein released during activation of the brain’s resident immune cells (microglia and astrocytes) – a key sign of neuroinflammation – and then used PET (positron emission tomography) scans to detect the binding that occurred. High levels of neuroinflammation created levels of high intensity in the scan. Neuroinflammation was measured for the whole brain and special ‘areas of interest’ – key brain areas known to be associated with some of the key ME/CFS symptoms.
The researchers also measured cytokine levels in whole blood (TNF-a, IFN-gamma, IL1b and IL6) and collected self-reported data on measures of fatigue, pain, cognitive dysfunction, and depression to determine if neuroinflammation in these key brain areas correlated with symptoms.
Why They Looked for Evidence of Neuroinflammation
Several lines of circumstantial evidence that are suggestive but are not direct evidence of neuroinflammation in chronic fatigue syndrome include:
- ‘Neuropsychological’ symptoms (cognitive impairments, widespread pain, and depressive symptoms) suggest involvement of the brain in the pathophysiology of ME/CFS;
- Previous PET studies by the same team showed brain hypoperfusion and reduced synthesis of various neurotransmitters (glutamate, aspartate, GABA, acetylcarnatine, and serotonin transporters) in various brain regions while neuroimaging has suggested that reduced volume in the prefrontal cortex is associated with severity of fatigue;
- Other fatigue related diseases such as MS, Parkinson’s, and post polio fatigue arise from brain dysfunction with neuroinflammation thought to play a key role;
- Reported elevated levels of pro-inflammatory cytokines, either in peripheral blood or in cerebrospinal fluid, may reflect neuroinflammation.
- Needless to say ME/CFS patients had significantly higher levels of fatigue, pain, cognitive problems, and depression than healthy controls although levels of depression were below that required for a clinical diagnosis;
- Neuroinflammation in the brain overall was higher in ME/CFS patients than in healthy controls;
- Neuuroinflammation was higher in the key brain areas – the cingulate cortex, hippocampus, thalamus, midbrain, the pons, and the amygdala (many of which have previously been implicated as playing a role in ME/CFS and FM);
- Of the four proinflammatory cytokines measured only circulating levels of peripheral IFN-gamma were higher (but not significantly) in ME/CFS patients;
Neuroinflammation correlates with symptoms.
- The peak value reported in the patients in the ‘intraluminal nucleus’ of the left thalamus correlated positively (significantly) with cognitive impairment scores with a trend (not significant) correlation with fatigue. The findings in this brain area (and the midbrain) which are involved in the ‘reticular activating system’ (which plays a role in arousal) mirrored the Stanford qEEG study findings of disrupted ascending arousal systems reported in the same session);
Inflammation of the amygdala (which monitors incoming sensory information and modulates attention) was correlated with cognitive impairment;
- Self reported levels of depressive symptoms were correlated with neuroinflammation in the hippocampus (implicated in mood disorders);
- Inflammation in the thalamus and cingulate cortex was associated with pain. This accords with a previously reported interaction between the cingulate cortex and thalamus in pain suppression.
Taken together, these findings provided clear evidence of an association between neuroinflammation and the symptoms experienced by ME/CFS patients.
The researchers offered two possible mechanisms by which the neuroinflammation found may relate to ME/CFS:
- (a) Overactive neurons are driving the neuroinflammation. This possibility suggests patients have to exert greater efforts in these parts of the brain to overcome the daily functional limitations associated with ME/CFS. (This mirrors reports that ME/CFS patients use a much larger area of the brain than normal to process information). Overactivated neurons in turn trigger the glutamate receptors to release proinflammatory cytokines and neurotoxic factors that generate oxidative stress. In this scenario neuroinflammtion may be secondary to some other pathophysiology but may also contribute significantly to symptoms.
- (b) The immunological response to an initial infection that induces the production of proinflammatory cytokines and oxidative/nitrosative stress leads to neuroinflammation, which suggests that ongoing infection may not be a prerequisite for self-sustaining neuroinflammation.
Evidence of ‘Encephalomyelitis’ – Is this the smoking gun?
Do these findings then finally validate the name Myalgic ‘Encephalomyeltis’ thereby consigning ‘chronic fatigue’ to the historical dustbin? My view is that they do not – but they may pave the way to a better and more productive understanding of the underlying pathology of what is likely to be a heterogeneous disorder. The crux of the problem lies in the framing of the historical debate between users of the terms ME and CFS and in the nature of neuroinflammation.
As stated in the introduction, two views have tended to predominate in the debate about the nature and the name of ME/CFS.
Drawing on the clinical similarities between the Royal Free outbreak and previous outbreaks of encephalitis and poliomyelitis, one view clearly proposed a discrete disease, probably infectious and with the various neurological symptoms likely to result from the infection causing inflammation in the brain and spinal cord – hence ‘Encephalomyelitis’. A small number of post mortem examinations provided some support for this model. The result has been the ongoing hunt for ‘the’ pathogen underlying ‘ME’ which eluded investigators at the time.
The alternative view, citing the subsequent lack of clear evidence for inflammation of the brain or a single causative pathogen, instead proposed models where infections may play only an initial role but where the ‘syndrome’ is perpetuated largely by psychological factors – citing frequent ‘co-morbid’ mood and anxiety disorders as supporting evidence.
Neuroinflammation – A Different Kind of Brain Injury
Should we have expected to find gross physical changes to the brain? Acute ‘insults’ to the brain such as traumatic brain injury or viral encephalitis may result in an acute phase inflammation with gross structural changes such as edema (swelling) or distinct lesions that may be readily apparent using structural imaging techniques such as MRI scans.
In contrast, ‘neuroinflammation’ generally concerns a much more subtle chronic, low-grade and sustained activation of the brain’s resident immune (glial) cells associated not with acute traumatic brain injury or acute viral encephalitis but with the long term sequelae of brain injury or infection, autoimmune diseases, normal aging, neurodegnerative diseases such as Alzheimers’ and Parkinson’s, and ‘classic psychiatric’ disorders such as major depression, bipolar disorder, schizophrenia, and OCD. Microglial activation has also been reported in association with stress/anxiety, with diabetes, and with neuropathic pain.
Neuroinflammation is not easily detected using the structural imaging techniques used heretofore in this disorder because it may result in damage too small or subtle to be imaged or may not result in structural changes. It can still, however, cause functional, metabolic, or even temporal dysfunction between various brain regions.
Neuroinflammation qualifies as inflammation of the brain (an ‘itis’), then, but not the type originally described by ‘encephalomyelitis’. It describes a type of ‘encephalomyelitis’ that scientific and technological advances have only recently identified as underlying a wide range of conditions.
The researchers concluded that they have provided evidence for neuroinflammation in ME/CFS. The fact that inflammation in key brain regions correlates with ME/CFS symptoms suggests that neuroinflammation may contribute to the underlying pathophysiology.
They further suggest that:
“our results demonstrate the usefulness of PET imaging for the development of objective diagnostic criteria, evaluation of disease severity, and effective medical treatment strategies using anti-inﬂammatory agents in CFS/ME.”
Of course, all of this depends on these results being replicated with a larger sample and preferably independently replicated by another institution using a different cohort. The press release suggests that Dr. Yasuyoshi Watanabe, who led the study at RIKEN, is confident that will happen. He stated
“We plan to continue research following this exciting discovery in order to develop objective tests for CFS/ME and ultimately ways to cure and prevent this debilitating disease.”
The team has already started follow-up studies (a) to examine the possible impact of neuroinflammation on serotonin transport, and (b) they report that they are currently performing a ”next-phase international collaboration study”.
The international collaboration may be critical, as these studies are costly (reportedly in the region of $10,000 per patient – hence the small sample size) so are unlikely to be viable for small research teams.
Other Markers of Neuroinflammation
Smaller research teams needn’t be totally excluded, though. As detailed earlier, this study was initiated in response to converging evidence that was compatible with neuroinflammation. Other markers of neuroinflammation may be found (and may already have been recorded in the existing literature) without the need for PET scans (which are expensive and still not widely available).
Neuroinflammation, like all metabolic processes, may leave chemical traces (metabolites) that can be compared to healthy norms. For example elevated levels of the metabolite quinolinic acid in cerebrospinal fluid may be indicative of neuroinflammation. Other objective ‘epiphenomena’ such as impaired sensorimotor gating are associated with a range of conditions in which neuroinflammation is now suspected of playing a key role.
A Paradigm Shift?
At the very least, the possibility that neuroinflammation may play a central role in the pathophysiology of ME/CFS opens up new areas of investigation and provides a new lens through which to interpret previous findings and may suggest new possibilities for treatment. Who knows, for instance, how neuroinflammation of the ME/CFS brain would look following physical or mental challenges?
- Check out Marco’s blogs on Neuroinflammation and ME/CFS here.
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