Category: Overlapping Illnesses

Activation of cell-mediated immunity in depression: association with inflammation, melancholia, clinical staging and the fatigue and somatic symptom cluster of depression

Abstract:

BACKGROUND: Depression is characterized by activation of cell-mediated immunity (CMI), including increased neopterin levels, and increased pro-inflammatory cytokines (PICs), such as interleukin-1 (IL-1) and tumor necrosis factor-α (TNFα). These PICs may induce depressive, melancholic and chronic fatigue (CF) symptoms.

METHODS: We examined serum neopterin and plasma PIC levels in depressive subgroups in relation to the depressive subtypes and the melancholic and CF symptoms of depression. Participants were 85 patients with depression and in 26 normal controls. Severity of depression was assessed with the Hamilton Depression Rating Scale (HDRS) and severity of CF with the Fibromyalgia and Chronic Fatigue Syndrome (FF) Rating Scale.

RESULTS: Serum neopterin was significantly higher in depressed patients and in particular in those with melancholia. There were positive correlations between serum neopterin, the plasma PICs and the number of previous depressive episodes. Neopterin and TNFα were associated with melancholia, while both PICs were associated with CF. Melancholia-group membership was predicted by the HDRS and neopterin, and CF group membership by age, the FF score and serum TNFα.

DISCUSSION: Depression and melancholia are accompanied by CMI activation, suggesting that neopterin plays a role in their pathophysiology, e.g. through activation of oxidative and nitrosative stress and apoptosis pathways. The intertwined CMI and inflammatory responses are potentially associated with the onset of depression and with the melancholic and CF symptoms of depression. Exposure to previous depressive episodes may magnify the size of CMI and PIC responses, possibly increasing the likelihood of new depressive episodes. CMI activation and inflammation may contribute to the staging or recurrence of depression.

Copyright © 2011 Elsevier Inc. All rights reserved.

 

Source: Maes M, Mihaylova I, Kubera M, Ringel K. Activation of cell-mediated immunity in depression: association with inflammation, melancholia, clinical staging and the fatigue and somatic symptom cluster of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2012 Jan 10;36(1):169-75. doi: 10.1016/j.pnpbp.2011.09.006. Epub 2011 Sep 16. https://www.ncbi.nlm.nih.gov/pubmed/21945535

 

IgM-mediated autoimmune responses directed against multiple neoepitopes in depression: new pathways that underpin the inflammatory and neuroprogressive pathophysiology

Abstract:

BACKGROUND: There is evidence that depression is accompanied by oxidative and nitrosative stress (O&NS), as indicated by increased free radical levels, lipid peroxidation, and lowered antioxidant levels. The aims of the present study are to examine whether depression is accompanied by autoimmune responses directed against a) neoepitopes that are formed following O&NS damage; and b) the major anchorage molecules, i.e. palmitic and myristic acids and S-farnesyl-L-cysteine.

METHODS: We examined serum IgM antibodies to the conjugated fatty acids, palmitic and myristic acids; acetylcholine; S-farnesyl-L-cysteine; and NO-modified adducts in 26 depressed patients and 17 normal controls. Severity of depression was measured with the Hamilton Depression Rating Scale and severity of fatigue and somatic (F&S) symptoms with the Fibromyalgia and Chronic Fatigue Syndrome (FF) Rating Scale.

RESULTS: The prevalences and mean values for the serum IgM levels directed against conjugated palmitic and myristic acids, acetylcholine, S-farnesyl-L-cysteine; and the conjugated NO adducts, NO-tyrosine, NO-phenylalanine, NO-aspartate, NO-histidine, and NO-creatine were significantly higher in depressed patients than in normal controls. The autoimmune responses were significantly related to FF symptoms, such as fatigue and a flu-like malaise, whereas the indicants of nitrosative stress were related to gastro-intestinal and autonomic symptoms.

DISCUSSION: Depression is characterized by IgM-related autoimmune responses directed against a) neoepitopes that are normally not detected by the immune system but that due to damage by O&NS have become immunogenic; and b) anchorage epitopes, i.e. palmitic and myristic acids, and S-farnesyl-L-cysteine. These autoimmune responses play a role in the inflammatory and O&NS pathophysiology of depression and may mediate the cellular dysfunctions that contribute to neuroprogression, e.g. aberrations in signal transduction, cellular differentiation and apoptosis.

Copyright © 2011 Elsevier B.V. All rights reserved.

 

Source: Maes M, Mihaylova I, Kubera M, Leunis JC, Geffard M. IgM-mediated autoimmune responses directed against multiple neoepitopes in depression: new pathways that underpin the inflammatory and neuroprogressive pathophysiology. J Affect Disord. 2011 Dec;135(1-3):414-8. doi: 10.1016/j.jad.2011.08.023. Epub 2011 Sep 17. https://www.ncbi.nlm.nih.gov/pubmed/21930301

 

Neurohumoral and haemodynamic profile in postural tachycardia and chronic fatigue syndromes

Abstract:

Several studies recognized an overlap between CFS (chronic fatigue syndrome) and POTS (postural tachycardia syndrome). We compared the autonomic and neurohormonal phenotype of POTS patients with CFS (CFS-POTS) to those without CFS (non-CFS-POTS), to determine whether CFS-POTS represents a unique clinical entity with a distinct pathophysiology.

We recruited 58 patients with POTS, of which 47 were eligible to participate. A total of 93% of them reported severe fatigue [CIS (Checklist of Individual Strength), fatigue subscale >36], and 64% (n=30) fulfilled criteria for CFS (CFS-POTS). The prevalence of CFS symptoms (Centers for Disease Control and Prevention criteria) was greater in the CFS-POTS group, but the pattern of symptoms was similar in both groups.

Physical functioning was low in both groups (RAND-36 Health Survey, 40±4 compared with 33±3; P=0.153), despite more severe fatigue in CFS-POTS patients (CIS fatigue subscale 51±1 compared with 43±3; P=0.016). CFS-POTS patients had greater orthostatic tachycardia than the non-CFS-POTS group (51±3 compared with 40±4 beats/min; P=0.030), greater low-frequency variability of BP (blood pressure; 6.3±0.7 compared with 4.8±1.0 mmHg2; P=0.019), greater BP recovery from early to late phase II of the Valsalva manoeuvre (18±3 compared with 11±2 mmHg; P=0.041) and a higher supine (1.5±0.2 compared with 1.0±0.3 ng/ml per·h; P=0.033) and upright (5.4±0.6 compared with 3.5±0.8 ng/ml per h; P=0.032) PRA (plasma renin activity).

In conclusion, fatigue and CFS-defining symptoms are common in POTS patients. The majority of them met criteria for CFS. CFS-POTS patients have higher markers of sympathetic activation, but are part of the spectrum of POTS. Targeting this sympathetic activation should be considered in the treatment of these patients.

 

Source: Okamoto LE, Raj SR, Peltier A, Gamboa A, Shibao C, Diedrich A, Black BK, Robertson D, Biaggioni I. Neurohumoral and haemodynamic profile in postural tachycardia and chronic fatigue syndromes. Clin Sci (Lond). 2012 Feb;122(4):183-92. doi: 10.1042/CS20110200. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3203411/ (Full article)

 

Mitochondrial enzymes discriminate between mitochondrial disorders and chronic fatigue syndrome

Abstract:

We studied the extent of mitochondrial involvement in chronic fatigue syndrome (CFS) and investigated whether measurement of mitochondrial respiratory chain complex (RCC) activities discriminates between CFS and mitochondrial disorders.

Mitochondrial content was decreased in CFS compared to healthy controls, whereas RCC activities corrected for mitochondrial content were not. Conversely, mitochondrial content did not discriminate between CFS and two groups of mitochondrial disorders, whereas ATP production rate and complex I, III and IV activity did, all with higher activities in CFS. We conclude that the ATP production rate and RCC activities can reliably discriminate between mitochondrial disorders and CFS.

Copyright © 2011 Elsevier B.V. and Mitochondria Research Society. All rights reserved.

 

Source: Smits B, van den Heuvel L, Knoop H, Küsters B, Janssen A, Borm G, Bleijenberg G, Rodenburg R, van Engelen B. Mitochondrial enzymes discriminate between mitochondrial disorders and chronic fatigue syndrome. Mitochondrion. 2011 Sep;11(5):735-8. doi: 10.1016/j.mito.2011.05.005. Epub 2011 Jun 2. https://www.ncbi.nlm.nih.gov/pubmed/21664495

 

Factors affecting duration of chronic fatigue syndrome in pediatric patients

Abstract:

OBJECTIVE: To determine factors affecting duration of chronic fatigue syndrome (CFS) in pediatric patients.

METHODS: This Retrospective cohort consisted of patients with CFS at the regional referral infectious disease clinic for evaluation of fatigue in children and adolescents. Demographic, clinical, and laboratory data were analyzed to identify the impact on duration and severity of pediatric CFS.

RESULTS: A total number of 53 predominantly white (98.1%) patients with CFS, aged 9-18 years, were included in the study. Other than fatigue, headaches and sleep disturbance were the most common symptoms of pediatric CFS. Seropositive status for Borrelia burgdorferi (B. burgdorferi) and Epstein-Barr virus (EBV) was identified in 66% of the patients with the diagnosis of CFS by CDC criteria. No association was found between the CFS symptoms, gender, or age at diagnosis and duration of fatigue symptoms. Duration of CFS was associated with high Body-Mass Index (BMI) in a regression model after adjustment for patient’s age, gender, and seropositive status for B. burgdorferi and/or EBV (0.34 ± 0.15, P < 0.04).

CONCLUSIONS: BMI is significantly associated with prolonged duration of CFS.

 

Source: Petrov D, Marchalik D, Sosin M, Bal A. Factors affecting duration of chronic fatigue syndrome in pediatric patients. Indian J Pediatr. 2012 Jan;79(1):52-5. doi: 10.1007/s12098-011-0463-4. Epub 2011 May 27. https://www.ncbi.nlm.nih.gov/pubmed/21617905

 

Decades of delayed diagnosis in 4 levodopa-responsive young-onset monogenetic parkinsonism patients

Abstract:

BACKGROUND: We report 4 patients with young-onset monogenetic parkinsonism, each of whom was misdiagnosed with either a psychogenic movement disorder or chronic fatigue syndrome for 10 to 23 years after the onset of their first symptoms.

RESULTS: Once the diagnosis was eventually made, they all had a rapid and excellent response to levodopa, albeit with the early appearance of interdose dyskinesias in 3.

CONCLUSIONS: We discuss possible reasons for the missed diagnosis despite the relentless progression of their motor handicap. DAT scanning supported the revised clinical diagnosis of parkinsonism.

Copyright © 2011 Movement Disorder Society.

 

Source: Ling H, Braschinsky M, Taba P, Lüüs SM, Doherty K, Hotter A, Poewe W, Lees AJ. Decades of delayed diagnosis in 4 levodopa-responsive young-onset monogenetic parkinsonism patients. Mov Disord. 2011 Jun;26(7):1337-40. doi: 10.1002/mds.23563. Epub 2011 Mar 29. https://www.ncbi.nlm.nih.gov/pubmed/21449012

 

Chronic widespread musculoskeletal pain, fatigue, depression and disordered sleep in chronic post-SARS syndrome; a case-controlled study

Abstract:

BACKGROUND: The long term adverse effects of Severe Acute Respiratory Syndrome (SARS), a viral disease, are poorly understood.

METHODS: Sleep physiology, somatic and mood symptoms of 22 Toronto subjects, 21 of whom were healthcare workers, (19 females, 3 males, mean age 46.29 yrs.+/- 11.02) who remained unable to return to their former occupation (mean 19.8 months, range: 13 to 36 months following SARS) were compared to 7 healthy female subjects. Because of their clinical similarities to patients with fibromyalgia syndrome (FMS) these post-SARS subjects were similarly compared to 21 drug free female patients, (mean age 42.4 +/- 11.8 yrs.) who fulfilled criteria for fibromyalgia.

RESULTS: Chronic post-SARS is characterized by persistent fatigue, diffuse myalgia, weakness, depression, and nonrestorative sleep with associated REM-related apneas/hypopneas, an elevated sleep EEG cyclical alternating pattern, and alpha EEG sleep anomaly. Post- SARS patients had symptoms of pre and post-sleep fatigue and post sleep sleepiness that were similar to the symptoms of patients with FMS, and similar to symptoms of patients with chronic fatigue syndrome. Both post-SARS and FMS groups had sleep instability as indicated by the high sleep EEG cyclical alternating pattern rate. The post-SARS group had a lower rating of the alpha EEG sleep anomaly as compared to the FMS patients. The post-SARS group also reported less pre-sleep and post-sleep musculoskeletal pain symptoms.

CONCLUSIONS: The clinical and sleep features of chronic post-SARS form a syndrome of chronic fatigue, pain, weakness, depression and sleep disturbance, which overlaps with the clinical and sleep features of FMS and chronic fatigue syndrome.

 

Source: Moldofsky H, Patcai J. Chronic widespread musculoskeletal pain, fatigue, depression and disordered sleep in chronic post-SARS syndrome; a case-controlled study. BMC Neurol. 2011 Mar 24;11:37. doi: 10.1186/1471-2377-11-37. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3071317/ (Full article)

 

Relationships among rhinitis, fibromyalgia, and chronic fatigue

Abstract:

New information about the pathophysiology of idiopathic nonallergic rhinopathy indicates a high prevalence in chronic fatigue syndrome (CFS). This article shows the relevance of CFS and allied disorders to allergy practice. CFS has significant overlap with systemic hyperalgesia (fibromyalgia), autonomic dysfunction (irritable bowel syndrome and migraine headaches), sensory hypersensitivity (dyspnea; congestion; rhinorrhea; and appreciation of visceral nociception in the esophagus, gastrointestinal tract, bladder, and other organs), and central nervous system maladaptations (central sensitization) recorded by functional magnetic resonance imaging (fMRI).

Neurological dysfunction may account for the overlap of CFS with idiopathic nonallergic rhinopathy. Scientific advances are in fMRI, nociceptive sensor expression, and, potentially, infection with xenotropic murine leukemia-related virus provide additional insights to novel pathophysiological mechanisms of the “functional” complaints of these patients that are mistakenly interpreted as allergic syndromes. As allergists, we must accept the clinical challenges posed by these complex patients and provide proper diagnoses, assurance, and optimum care even though current treatment algorithms are lacking.

 

Source: Baraniuk JN, Zheng Y. Relationships among rhinitis, fibromyalgia, and chronic fatigue. Allergy Asthma Proc. 2010 May-Jun;31(3):169-78. doi: 10.2500/aap.2010.31.3311. https://www.ncbi.nlm.nih.gov/pubmed/20615318

 

An intriguing and hitherto unexplained co-occurrence: Depression and chronic fatigue syndrome are manifestations of shared inflammatory, oxidative and nitrosative (IO&NS) pathways

Abstract:

There is a significant ‘comorbidity’ between depression and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Depressive symptoms frequently occur during the course of ME/CFS. Fatigue and somatic symptoms (F&S), like pain, muscle tension, and a flu-like malaise, are key components of depression. At the same time, depression and ME/CFS show major clinical differences, which allow to discriminate them with a 100% accuracy.

This paper aims to review the shared pathways that underpin both disorders and the pathways that discriminate them. Numerous studies have shown that depression and ME/CFS are characterized by shared aberrations in inflammatory, oxidative and nitrosative (IO&NS) pathways, like systemic inflammation and its long-term sequels, including O&NS-induced damage to fatty acids, proteins and DNA; dysfunctional mitochondria; lowered antioxidant levels, like zinc and coenzyme Q10; autoimmune responses to neoepitopes formed by O&NS; lowered omega-3 polyunsaturated fatty acid levels; and increased translocation of gram-negative bacteria. Some IO&NS-related pathways, like the induction of indoleamine 2-3-dioxygenase, neurodegeneration and decreased neurogenesis, are more specific to depression, whereas other pathways, like the 2′-5′ oligoadenylate synthetase/RNase L pathway, are specific to ME/CFS.

Most current animal models of depression, e.g. those induced by cytokines, are not reminiscent of human depression but reflect a mixture of depressive and F&S symptoms. The latter symptoms, sometimes called sickness behavior, differ from depression and ME/CFS because the former is a (sub)acute response to infection-induced pro-inflammatory cytokines that aims to enhance recovery, whereas the latter are characterized by long-term sequels in multiple IO&NS pathways.

Depression and ME/CFS are not ‘comorbid’ disorders, but should be regarded as ‘co-associated disorders’ that are clinical manifestations of shared pathways.

Copyright © 2010 Elsevier Inc. All rights reserved.

 

Source: Maes M. An intriguing and hitherto unexplained co-occurrence: Depression and chronic fatigue syndrome are manifestations of shared inflammatory, oxidative and nitrosative (IO&NS) pathways. Prog Neuropsychopharmacol Biol Psychiatry. 2011 Apr 29;35(3):784-94. doi: 10.1016/j.pnpbp.2010.06.023. Epub 2010 Jul 4. https://www.ncbi.nlm.nih.gov/pubmed/20609377

 

Cervical spine stenosis as a cause of severe ME/CFS and orthostatic intolerance symptoms

Background: Comparatively little has been published on the clinical features and management of severe forms of ME/CFS.

Objectives: To describe the presenting symptoms and neurological examination findings in three young adult women whose disabling ME/CFS symptoms and orthostatic intolerance improved after the recognition and surgical management of cervical spine stenosis (CSS).

Methods: This retrospective case series includes three consecutive individuals who (1) met the Fukuda and criteria for CFS, (2) had evidence of refractory orthostatic intolerance, (3) were unable to work or attend school, and (4) were minimally responsive to medical and psychiatric management. To investigate pathological reflex findings, all underwent MRI evaluations. CSS was considered present if the AP cervical spinal canal diameter (SCD) was less than 10 mm at any level. Overall function was assessed before and after cervical disc replacement surgery using (1) a clinician-assigned Karnofsky score (range 0 to 100) and (2) the SF-36 physical function (PF) subscale score (range 10-30). Higher scores indicate better function on both measures.

Results: Age at onset of symptoms was 12, 29, and 29 years. The onset of ME/CFS was acute in all three. Neurological exam findings included > 3+ (brisk) deep tendon reflexes (DTR) in 2/3, positive Hoffman sign in 2/3, tremor in 2/3, and absent gag reflex in 1/3. Diagnosis was delayed for 6-9 years after the onset of symptoms. Brain MRIs were normal. The youngest patient had congenital CSS with a single level disc protrusion at C5-6 that caused further ventral cord compression and a SCD of 7 mm. Her mother also has cervical stenosis. A second
patient had two disc protrusions at C5-6 and C6-7 with SCD of 7 and 9 mm, and myelomalacia (this patient has a sibling with Chiari I malformation). The third had acquired CSS due to a single level disc bulge at C5-6 (SCD = 8.5 mm).

Improvements were evident within 2 months of single-level cervical disc replacement surgery (one patient also had fusion at an adjacent level). After 16-40 months of follow-up, all reported improved fatigue, cognitive dysfunction, PEM, lightheadedness, and anxiety. The pre- to post-op SF-36 PF scores improved from 13 to 30, 18 to 30, and 16 to 26, respectively, and the Karnofsky scores improved from 40 to 90, 40 to 90, and 50 to 100, respectively. Standing tests conducted at variable intervals from pre- to post-op showed a reduction in the maximal heart rate (HR) change during 5 minutes of standing from 64 to 22 bpm, 42 to 29 bpm, and 34 to 27 bpm, respectively.

Conclusion: This case series draws attention to the potential for CSS to contribute to ME/CFS and orthostatic symptoms, extending work by Heffez in fibromyalgia (Eur Spine J 2004;13:516). Further work is needed to define indications for surgery. However, the improvements in HR and function following surgery emphasize the importance of detecting and treating CSS, especially in the subset of those with ME/CFS whose severe symptoms are refractory to other interventions.

Peter C. Rowe, M.D.
Professor of Pediatrics
Johns Hopkins University School of Medicine/200 N. Wolfe Street/Room 2077
Baltimore, MD 21287
prowe@jhmi.edu

Dr. Rowe is supported by the Sunshine Natural Wellbeing Foundation Professorship in Chronic Fatigue and Related Disorders. No author has a conflict of interest.

 

Source: Peter C. Rowe, M.D*, Colleen L. Marden, Scott Heinlein, PT, Charles Edwards II, M.D. Cervical spine stenosis as a cause of severe ME/CFS and orthostatic intolerance symptoms. Poster presentation, IACFS/ME 2016 conference.