TGI Friday! Our weekly round-up of recently published research abstracts | 24 April 2015

April 24, 2015

From PLOS One, 22 April 2015 (open access journal).

Response to Vitamin B12 and Folic Acid in Myalgic Encephalomyelitis and Fibromyalgia

Björn Regland*,Sara Forsmark, Lena Halaouate, Michael Matousek, Birgitta Peilot,
Olof Zachrisson, Carl-Gerhard Gottfries
Gottfries Clinic, affiliated with Institute of Neuroscience and Physiology, Gothenburg University, Gothenburg, Sweden



Patients with myalgic encephalomyelitis (ME, also called chronic fatigue syndrome) may respond most favorably to frequent vitamin B12 injections, in vital combination with oral folic acid. However, there is no established algorithm for individualized optimal dosages, and rate of improvement may differ considerably between responders.

To evaluate clinical data from patients with ME, with or without fibromyalgia, who had been on B12 injections at least once a week for six months and up to several years.


38 patients were included in a cross-sectional survey. Based on a validated observer’s rating scale, they were divided into Good (n = 15) and Mild (n = 23) responders, and the two groups were compared from various clinical aspects.


Good responders had used significantly more frequent injections (p<0.03) and higher doses of B12 (p<0.03) for a longer time (p<0.0005), higher daily amounts of oral folic acid (p<0.003) in good relation with the individual MTHFR genotype, more often thyroid hormones (p<0.02), and no strong analgesics at all, while 70% of Mild responders (p<0.0005) used analgesics such as opioids, duloxetine or pregabalin on a daily basis. In addition to ME, the higher number of patients with fibromyalgia among Mild responders was bordering on significance (p<0.09). Good responders rated themselves as “very much” or “much” improved, while Mild responders rated “much” or “minimally” improved.CONCLUSIONSDose-response relationship and long-lasting effects of B12/folic acid support a true positive response in the studied group of patients with ME/fibromyalgia. It’s important to be alert on co-existing thyroid dysfunction, and we suspect a risk of counteracting interference between B12/folic acid and certain opioid analgesics and other drugs that have to be demethylated as part of their metabolism. These issues should be considered when controlled trials for ME and fibromyalgia are to be designed.

From BMC Neurology, 12 April 2015 (open access journal).

Chronic fatigue syndrome and fibromyalgia in diagnosed sleep disorders: a further test of the ‘unitary’ hypothesis

Slobodanka Pejovic(1), Benjamin H Natelson(2*), Maria Basta(3), Julio Fernandez-Mendoza(1), Fauzia Mahr(1) and Alexandros N Vgontzas(1)
1) Department of Psychiatry, Sleep Research and Treatment Center, Penn State College of Medicine, Hershey 17033, PA, USA
2) Department of Neurology, Pain and Fatigue Study Center, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York 10003, NY, USA
3) Department of Psychiatry, School of Medicine, University of Crete, Iraklion, Greece
Corresponding author: Benjamin H Natelson,

Abstract (provisional)


Since chronic fatigue syndrome (CFS) and fibromyalgia (FM) often co-exist, some believe they reflect the same process, somatization. Against that hypothesis are data suggesting FM but not CFS was common in patients with sleep-disordered breathing (SDB).

The presence of discrete case definitions for CFS and FM allowed us to explore rates of CFS alone, CFS with FM, and FM alone in SDB patients compared to those with sleep complaints that fulfilled criteria for insomnia.


Participants were 175 sequential patients with sleep-related symptoms (122 had SDB and 21 had insomnia) and 39 healthy controls. Diagnoses were made by questionnaires, tender point count, and rule out labs; sleepiness was assessed with Epworth Sleepiness Scale and mood with Beck Depression Inventory.


Rates of CFS, FM or CFS + FM were high: 13% in SDB and 48% in insomnia. CFS occurred frequently in SDB and insomnia, but FM occurred frequently only in insomnia. SDB patients with CFS and/or FM had higher daytime sleepiness than those without these disorders.


CFS patients should complete Epworth scales, and sleep evaluation should be considered for those with scores ≥ 16 before receiving the diagnosis of CFS; the coexistence of depressed mood in these patients suggests some may be helped by treatment of their depression. That FM was underrepresented in SDB suggests FM and CFS may have different underlying pathophysiological causes.

From Mediators of Inflammation, 24 March 2015 (open access journal).

Role of polymorphisms of inducible nitric oxide synthase and endothelial nitric oxide synthase in idiopathic environmental intolerances.

Chiara De Luca(1,2), Agnese Gugliandolo(3), Carlo Calabrò(3), Monica Currò(3), Riccardo Ientile(3), Desanka Raskovic(4), Ludmila Korkina(1) and Daniela Caccamo(3)
1) Centre of Innovative Biotechnological Investigations (Cibi-Nanolab), 197 Vernadskogo Prospekt, Moscow 119571, Russia
2) Active Longevity Clinic “Institut Krasoty na Arbate”, 8 Maly Nikolopeskovsky lane, Moscow 119002, Russia
3) Department of Biomedical Sciences and Morpho-Functional Imaging, Polyclinic University of Messina, 98125 Messina, Italy
4) 2nd Dermatology Division, Dermatology Institute (IDI IRCCS), Via dei Monti di Creta 104, 00167 Rome, Italy


Oxidative stress and inflammation play a pathogenetic role in idiopathic environmental intolerances (IEI), namely, multiple chemical sensitivity (MCS), fibromyalgia (FM), and chronic fatigue syndrome (CFS).

Given the reported association of nitric oxide synthase (NOS) gene polymorphisms with inflammatory disorders, we aimed to investigate the distribution of NOS2A -2.5 kb (CCTTT) n as well as Ser608Leu and NOS3 -786T>C variants and their correlation with nitrite/nitrate levels, in a study cohort including 170 MCS, 108 suspected MCS (SMCS), 89 FM/CFS, and 196 healthy subjects.

Patients and controls had similar distributions of NOS2A Ser608Leu and NOS3 -786T>C polymorphisms. Interestingly, the NOS3 -786TT genotype was
associated with increased nitrite/nitrate levels only in IEI patients.

We also found that the NOS2A -2.5 kb (CCTTT)11 allele represents a genetic determinant for FM/CFS, and the (CCTTT)16 allele discriminates MCS from SMCS patients. Instead, the (CCTTT)8 allele reduces by three-, six-, and tenfold, respectively, the risk for MCS, SMCS, and FM/CFS. Moreover, a short number of (CCTTT) repeats is associated with higher concentrations of nitrites/nitrates.

Here, we first demonstrate that NOS3 -786T>C variant affects nitrite/nitrate levels in IEI patients and that screening for NOS2A -2.5 kb (CCTTT) n polymorphism may be useful for differential diagnosis of various IEI.

From Vaccine, 13 April 2015 [Epub ahead of print].

Orthostatic intolerance and postural tachycardia syndrome as suspected adverse effects of vaccination against human papilloma virus.

Brinth LS(1), Pors K(1), Theibel AC(1), Mehlsen J(2).
1) Coordinating Research Centre, Frederiksberg Hospital, Nordre Fasanvej 57, 2000 Frederiksberg, Denmark.
2) Coordinating Research Centre, Frederiksberg Hospital, Nordre Fasanvej 57, 2000 Frederiksberg, Denmark. Electronic address:



Infections with human papilloma virus (HPV) can result in cervical, oropharyngeal, anal, and penile cancer and vaccination programs have been launched in many countries as a preventive measure.

We report the characteristics of a number of patients with a syndrome of orthostatic intolerance, headache, fatigue, cognitive dysfunction, and neuropathic pain starting in close relation to HPV vaccination.


Patients were referred for orthostatic intolerance following HPV vaccination. Symptoms of autonomic dysfunction were quantified by standardised questionnaire. The diagnosis of postural orthostatic tachycardia syndrome (POTS) rested on finding a sustained heart rate increment of >30min-1 (>40min-1 in adolescents) or to levels >120min-1 during orthostatic challenge.


35 women aged 23.3±7.1 years participated. Twenty-five had a high level of physical activity before vaccination and irregular periods were reported by all patients not on treatment with oral contraception.

Serum bilirubin was below the lower detection limit in 17 patients. Twenty-one of the referred patients fulfilled the criteria for a diagnosis of POTS (60%, 95%CI 43-77%).

All patients had orthostatic intolerance, 94% nausea, 82% chronic headache, 82% fatigue, 77% cognitive dysfunction, 72% segmental dystonia, 68% neuropathic pain.


In a population referred for symptoms of orthostatic intolerance and other symptoms consistent with autonomic dysfunction that began in close temporal association with a quadrivalent HPV vaccination, we identified a 60% prevalence of POTS.

Further work is urgently needed to elucidate the potential for a causal link between the vaccine and circulatory abnormalities and to establish targeted treatment options for the affected patients.

From Advances in Psychosomatic Medicine, 30 March 2015.

Fibromyalgia and Chronic Fatigue Syndrome: Management Issues

Bourke J(*)
Centre for Psychiatry at The Wolfson Institute for Preventive Medicine, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK
* Author Contacts. Dr. Julius Bourke, MBBS, MRCPsych. The Brain in Pain Study, 3rd floor Dominion House 59 Bartholomew Close, London EC1A 7ED (UK). E-Mail


Fibromyalgia and chronic fatigue syndrome represent two of the most commonly encountered functional somatic syndromes in clinical practice. Both have been contentious diagnoses in the past, and this diagnostic dispute has resulted in a therapeutic nihilism that has been of great detriment to their management and to alleviation of the intense suffering and disability that they have caused their innumerable sufferers.

A new age has dawned in terms of a better understanding of these syndromes' physiology and improved approaches to their management. Here, the diagnosis and management of these closely related disorders are discussed, with particular reference to the recent empirical evidence that has come to light as a consequence of neurophysiological insights and robustly designed randomised clinical trials.

Much work remains to be done in this vein, but we are better placed to facilitate recovery from these disorders than we have been previously. Whilst remission should always be a goal, complete symptom resolution is not the norm, but ‘moderate' improvements are certainly attainable with appropriate management.

From BMC Medical Genomics, 2 April 2015.

Transcriptomic signatures in whole blood of patients who acquire a chronic inflammatory response syndrome (CIRS) following an exposure to the marine toxin ciguatoxin.

James C Ryan(1,2*), Qingzhong Wu(2) and Ritchie C Shoemaker(1.3).
1) ProteoGenomics, LLC, Vero Beach 32963, FL, Florida
2) NOAA Center of Excellence for Oceans and Human Health at Hollings Marine Laboratory, Charleston, SC, USA
3) Center for Research on Biotoxin-Associated Illnesses, Pocomoke, MD, USA
* Corresponding author: James C Ryan



Ciguatoxins (CTXs) are polyether marine neurotoxins found in multiple reef-fish species and are potent activators of voltage-gated sodium channels. It is estimated that up to 500,000 people annually experience acute ciguatera poisoning from consuming toxic fish and a small percentage of these victims will develop a chronic, multisymptom, multisystem illness, which can last years, termed a Chronic Inflammatory Response Syndrome (CIRS).

Symptoms of ciguatera CIRS include fatigue, cognitive deficits, neurologic deficits, pain and sensitivity to light. There are few treatment options for ciguatera CIRS since little is known about its pathophysiology.


This study characterizes the transcriptional profile in whole blood of 11 patients with ciguatera-induced CIRS and 11 normal controls run in duplicate using Agilent one color whole genome microarrays. Differential expression was determined by using a combination of moderated t-test p-value and fold change (FC). Significant genes were subjected to gene ontology, principal component analysis and SVM classification. Seven significant genes found by microarray were validated by PCR.


Using a low stringency (p < 0.05 and FC > 1.4) and a high stringency (p < 0.01 and FC > 1.5) filter, the resulting gene sets of 185 and 55, respectively, showed clear separation of cases and
controls by PCA as well as 100% classification accuracy by SVM, indicating that the gene profiles can separate patients from controls.

PCR results of 7 genes showed a 95% correlation to microarray data. Several genes identified by microarray are important in wound healing (CD9, CD36, vWF and Factor XIII), adaptive immunity (HLA-DQB1, DQB2, IL18R1 and IL5RA) and innate immunity (GZMK, TOLLIP, SIGIRR and VIPR2), overlapping several areas shown to be disrupted in a mouse model of acute exposure to ciguatoxin. Another area of interest was differential expression of long, non-coding sequences, or lncRNA.


Disruptions of innate and adaptive immune mechanisms were recorded at both the genomic and proteomic level. A disruption in the HLA-T cell receptor axis could indicate HLA haplotype sensitivity for this chronic syndrome, as noted in many autoimmune conditions.

Taken together, these indicators of illness provide additional insights into pathophysiology and potential therapies.

From Behavioural and Cognitive Psychotherapy, 21 April 2015.

Treatment Outcome and Metacognitive Change in CBT and GET for Chronic Fatigue Syndrome

Bruce A. Fernie(a1), Gabrielle Murphy(a2), Adrian Wells(a3), Ana V. Nikčević(a4) and Marcantonio M. Spada(a5,c1)
a1) King's College London, Institute of Psychiatry, Psychology and Neuroscience, and Cascaid, South London and Maudsley NHS Foundation Trust, UK
a2) Royal Free Hampstead NHS Foundation Trust, London, UK
a3) University of Manchester, UK
a4) Kingston University, Kingston upon Thames, UK
a5) London South Bank University, UK



Studies have reported that Cognitive Behavioural Therapy (CBT) and Graded Exercise Therapy (GET) are effective treatments for Chronic Fatigue Syndrome (CFS).


One hundred and seventy-one patients undertook a course of either CBT (n = 116) or GET (n = 55) and were assessed on a variety of self-report measures at pre- and posttreatment and follow-up.


In this paper we present analyses on treatment outcomes for CBT and GET in routine clinical practice and evaluate whether changes on subscales of the Metacognitions Questionnaire-30 (MCQ-30) predict fatigue severity independently of changes in other covariates, and across the two treatment modalities.


Both CBT and GET were equally effective at decreasing fatigue, anxiety, and depression, and at increasing physical functioning. Changes on the subscales of the MCQ-30 were also found to have a significant effect on fatigue severity independently of changes in other covariates and across treatment modalities.


The findings from the current study suggest that CFS treatment protocols for CBT and GET, based on those from the PACE trial, achieve similar to poorer outcomes in routine clinical practice as in a RCT.

1 thought on “TGI Friday! Our weekly round-up of recently published research abstracts | 24 April 2015”

  1. In the last study (Behavioural & Cognitive Psychotherapy), does anyone understand please what ‘Changes on the subscales of the MCQ-30 ..’ means and how this applies in practice? i.e Are the implications that study results depend entirely on how questions are framed/phrased, for eg? This study concludes that, compared to the PACE trial, CFS patients are achieving ‘similar to poorer outcomes in (actual) clinical practice’, after CBT/GET (if I have understood correctly).

    The other question of course is what variety of CFS patients were actually in the trial, ie according to what protocols were the patients diagnosed (Oxford, Fukuda etc) in order to be included, & did this include some who could also have qualified on the Canadian & International criteria scales with more severe ME symptoms?

    If anyone has a psychology/medical background who could answer the first question it would be much appreciated. Thanks!

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