NIDS- migraine, fibromyalgia and CFS/CFIDS also related autism/ADHD

[Guest guest]

Headache 2001 Sep;41(8):764-7 Related Articles, Books, LinkOut

Immunological aspects in migraine: increase of IL-10 plasma levels during

attack.

Munno I, Marinaro M, Bassi A, Cassiano MA, Causarano V, Centonze V.

Department of Internal Medicine, Immunology, and Infectious Disease,

University of Bari, Italy.

In the present study, 23 patients with migraine without aura were monitored

during a migraine attack. Plasma levels of interleukin (IL)-4, IL-5, IL-10,

and interferon-gamma were measured by enzyme-linked immunosorbent assay

techniques. Interestingly, we observed low to undetectable IL-5 and IL-4

levels, whereas high IL-10 levels were seen in 52.2% of the patients.

Interferon-gamma plasma levels were undetectable in all patients. After

treatment with sumatriptan, 10 patients showed a subsequent decrease in

IL-10 and an increase in both IL-4 and IL-5 plasma levels. Although these

findings are derived from a limited number of patients, the apparent return

to the IL-4 and IL-5 cytokine profile observed during the interictal period

leads us to speculate that a preferential enhancement of TH2-type cytokine

production may contribute to the pathogenesis of migraine.

PMID: 11576199 [PubMed - indexed for MEDLINE]

Brain 2001 Dec;124(Pt 12):2490-502 Related Articles, Books, LinkOut

Delayed inflammation in rat meninges: implications for migraine

pathophysiology.

Reuter U, Bolay H, Jansen-Olesen I, Chiarugi A, del Rio M,

Letourneau R, Theoharides TC, Waeber C, Moskowitz MA.

Stroke and Neurovascular Regulation Laboratory, Massachusetts General

Hospital, Harvard Medical School, town, Massachusetts 02129, USA.

Nitric oxide (NO) has been implicated in migraine pathogenesis based on the

delayed development of typical migraine headache 4-6 h after infusing the NO

donor nitroglycerin [glyceryl trinitrate (GTN)] to migraineurs. Furthermore,

inhibiting the synthesis of NO by treatment with a NO synthase (NOS)

inhibitor attenuates spontaneous migraine headaches in 67% of subjects.

Because NO has been linked to inflammation and cytokine expression, we

investigated the delayed consequences of brief GTN infusion (30 min) on the

development of meningeal inflammation in a rat model using doses relevant to

the human model. We found dose-dependent Type II NOS [inducible NOS (iNOS)]

mRNA upregulation in dura mater beginning at 2 h and an increase in the

corresponding protein expression at 4, 6 and 10 h after infusion. Type II

NOS immunoreactivity was expressed chiefly within resident meningeal

macrophages. Consistent with development of a delayed inflammatory response,

we detected induction of interleukin 1beta in dura mater at 2 and 6 h and

increased interleukin 6 in dural macrophages and in rat cerebrospinal fluid

at 6 h after GTN infusion. Myeloperoxidase-positive cells were rarely found.

Leakage of plasma proteins from dural blood vessels was first detected 4 h

after GTN infusion, and this was suppressed by administering a specific Type

II NOS inhibitor [L-N(6)-(1-iminoethyl)-lysine (L-NIL)]. In addition to

cytokine induction, macrophage iNOS upregulation and oedema formation after

GTN infusion, dural mast cells exhibited granular changes consistent with

secretion at 4 and 6 h. Because iNOS was expressed in dural macrophages

following topical GTN, and in the spleen after intravenous injection, the

data suggest that the inflammatory response is mediated by direct actions on

the dura and does not develop secondary to events within the brain. Our

findings point to the importance of new gene expression and cytokine

expression as fundamental to the delayed response following GTN infusion,

and support the hypothesis that a similar response develops in human

meninges after GTN challenge.

PMID: 11701602 [PubMed - indexed for MEDLINE]

J Rheumatol 2002 Feb;29(2):358-61 Related Articles, Books, LinkOut

Cytokines and depression in cases with fibromyalgia.

Gur A, Karakoc M, Nas K, Remzi, Cevik, Denli A, Sarac J.

Department of Physical Medicine and Rehabilitation, School of Medicine,

Dicle University, Diyarbakir, Turkey. alig@...

OBJECTIVE: Fibromyalgia (FM) is a chronic, painful musculoskeletal disorder

characterized by widespread pain, pressure, hyperalgesia, morning stiffness,

and an increased incidence of depressive symptoms. The etiology, however,

has remained elusive. The aim of the present study was to examine the

inflammatory response system in FM and to investigate the effect of

depression level on serum cytokines. METHODS: Serum interleukin-1 (IL-I),

IL-2 receptor (IL-2r), IL-6, and IL-8 and the Hamilton Depression Rating

Scale (HDRS) score were determined in 32 healthy volunteers and in 81

patients with FM, classified according to the American College of

Rheumatology criteria. RESULTS: In our study, serum IL-1 and IL-6 were not

statistically significant, but serum IL-8, IL2r, and HDRS score were

significantly higher in patients with FM than the control group (p < 0.01).

In addition, in patients with FM, IL-8 was found to be related to pain

intensity (r = 0.35; p < 0.01). CONCLUSION: IL-8 may play an important role

in the occurrence of pain in FM.

PMID: 11838856 [PubMed - in process]

Rheumatology (Oxford) 2001 Jul;40(7):806-10 Related Articles, Books, LinkOut

Autoantibodies to a 68/48 kDa protein in chronic fatigue syndrome and

primary fibromyalgia: a possible marker for hypersomnia and cognitive

disorders.

Nishikai M, Tomomatsu S, Hankins RW, Takagi S, Miyachi K, Kosaka S, Akiya K.

National Tokyo Medical Center, Tokyo, Japan.

OBJECTIVE: To identify antinuclear antibodies (ANA) specific for chronic

fatigue syndrome (CFS), and in related conditions such as fibromyalgia (FM)

or psychiatric disorders. METHODS: One hundred and fourteen CFS patients and

125 primary and secondary FM patients were selected based on criteria

advocated by the Centers for Disease Control and Prevention and by the

American College of Rheumatology, respectively. As controls, healthy

subjects and patients with either various psychiatric disorders or diffuse

connective tissue diseases were included. Autoantibodies were examined by

immunoblot utilizing HeLa cell extracts as the antigen. RESULTS:

Autoantibodies to a 68/48 kDa protein were present in 13.2 and 15.6% of

patients with CFS and primary FM, respectively. In addition, autoantibodies

to a 45 kDa protein were found in 37.1 and 21.6% of the patients with

secondary FM and psychiatric disorders, respectively. Meanwhile, these two

autoantibodies were not found at all in connective tissue disease patients

without FM, nor in healthy subjects (P<0.05). As a group, the anti-68/48

kDa-positive CFS patients presented more frequently with hypersomnia

(P<0.005), short-term amnesia (P<0.07) or difficulty in concentration

(P<0.05) than those CFS patients without the antibodies. CONCLUSIONS: The

presence of the anti-68/48 kDa protein antibodies in a portion of both CFS

and primary FM patients suggests the existence of a common immunological

background. These antibodies may find utility as possible markers for a

clinicoserological subset of CFS/FM patients with hypersomnia and cognitive

complaints.

PMID: 11477286 [PubMed - indexed for MEDLINE]

Rheumatology (Oxford) 2001 Jul;40(7):743-9 Related Articles, Books, LinkOut

Cytokines play an aetiopathogenetic role in fibromyalgia: a hypothesis and

pilot study.

Wallace DJ, Linker-Israeli M, Hallegua D, Silverman S, Silver D, Weisman MH.

Department of Medicine/Division of Rheumatology, Cedars-Sinai Medical

Center/UCLA School of Medicine, Los Angeles, CA, USA.

OBJECTIVE: To measure soluble factors having a possible role in fibromyalgia

(FM) and compare the profiles of patients with recent onset of the syndrome

with patients with chronic FM. METHODS: The production of cytokines,

cytokine-related molecules, and a CXC chemokine, interleukin (IL)-8, was

examined. Fifty-six patients with FM (23 with <2 yr and 33 with >2 yr of

symptoms) were compared with age- and sex-matched healthy controls.

Cytokines and cytokine-related molecules were measured in sera and in

supernatants of peripheral blood mononuclear cells (PBMC) that were

incubated with and without lectins and phorbol myristate acetate (PMA).

RESULTS: No differences between FMS and controls were found by measuring

IL-1beta, IL-2, IL-10, serum IL-2 receptor (sIL-2R), interferon gamma

(IFN-gamma), and tumour necrosis factor alpha (TNF-alpha). Levels of IL-1R

antibody (IL-1Ra) and IL-8 were significantly higher in sera, and IL-1Ra and

IL-6 were significantly higher in stimulated and unstimulated FM PBMC

compared with controls. Serum IL-6 levels were comparable to those in

controls, but were elevated in supernatants of in vitro-activated PBMC

derived from patients with >2 yr of symptoms. In the presence of PMA, there

were additional increases in IL-1Ra, IL-8 and IL-6 over control values.

CONCLUSIONS: In patients with FM we found increases over time in serum

levels and/or PBMC-stimulated activity of soluble factors whose release is

stimulated by substance P. Because IL-8 promotes sympathetic pain and IL-6

induces hyperalgesia, fatigue and depression, it is hypothesized that they

may play a role in modulating FM symptoms.

PMID: 11477278 [PubMed - indexed for MEDLINE]

J Rheumatol 2001 Mar;28(3):601-3 Related Articles, Books, LinkOut

Comparison of viral antibodies in 2 groups of patients with fibromyalgia.

Wittrup IH, Jensen B, Bliddal H, Danneskiold-Samsoe B, Wiik A.

Research Institute, Department of Rheumatology, Frederiksberg

University Hospital, Copenhagen, Denmark.

OBJECTIVE: The etiologies of fibromyalgia (FM) are unknown. In some cases an

acute onset following a flu-like episode is described; in other cases

patients report slowly developing disease. We previously found increased

prevalence of enterovirus IgM antibodies in patients with acute onset of FM

compared to healthy controls. We looked for differences in antimicrobial IgM

antibodies in acute versus nonacute onset FM. METHODS: Two well defined,

comparable groups of patients with FM (acute 19, nonacute 20) were studied

for antibodies in serum to an array of viruses including IgM antibodies.

RESULTS: In most viruses no IgM antibodies were found. However, about 50% of

the patients with acute FM onset had IgM antibodies against enterovirus

compared to only 15% of the slow onset patients. CONCLUSION: The higher

prevalence of IgM antibodies against enterovirus in patients with acute

onset of FM may indicate a difference in the etiology or the immune response

in these patients.

PMID: 11296966 [PubMed - indexed for MEDLINE]

Anti-nuclear envelope antibodies: Clinical associations.

Journal: Semin Arthritis Rheum 2001 Apr;30(5):313-320

Authors: Nesher G, Margalit R, Ashkenazi YJ.

Affiliations: Department of Rheumatology Service, Hebrew University

Medical School, Jerusalem, and the Departments of Internal Medicine and

Hematology, Shaare-Zedek Medical Center, Jerusalem., Gideon Nesher, MD:

Adjunct Associate Professor, St. Louis University School of Medicine,

Senior Lecturer, The Hebrew University Medical School, and Director of

Rheumatology Service, Shaare-Zedek Medical Center, Jerusalem, Israel;

Ruth Margalit, MD: Former Resident, Department of Internal Medicine,

Shaare-Zedek Medical Center, Jerusalem, Israel; Yaacov J. Ashkenazi, MD:

Director of Internal Medicine-Hematology Day-Care Center, Shaare-Zedek

Medical Center, Jerusalem, Israel.

NLM Citation: PMID: 11303304

Summary:

OBJECTIVES: Characterization of the clinical associations and clinical

implications of antibodies reacting with antigens of the nuclear

envelope.

METHODS: Description of an illustrative case and a MEDLINE

search-assisted literature review of relevant cases.

RESULTS: With indirect immunofluorescence, autoantibodies directed

against various antigens of the nuclear envelope stain the nucleus in a

ring-like (rim) pattern. Autoantibodies against 5 antigenic components of

the nuclear envelope have been described: anti-gp210, p62, lamina,

lamina-associated polypeptides, and lamin B receptor. Antibodies to

antigens of the nuclear pore complex, such as gp210 and p62, are highly

specific (>95%) for primary biliary cirrhosis and may aid in the

serologic diagnosis of this condition, especially in cases in which

antimitochondrial antibodies are not detectable. In contrast, antilamin

antibodies are not disease-specific but seem to be associated with lupus

anticoagulant or anticardiolipin antibodies, antiphospholipid syndrome,

thrombocytopenia, autoimmune liver diseases, and arthralgia. High-titered

antilamin antibodies help to define a subset of lupus patients with

antiphospholipid antibodies who are at a lower risk of developing

thrombotic events. In addition, preliminary data suggest that the

presence of antilamin antibodies may be helpful in the diagnosis of

chronic fatigue syndrome.

CONCLUSIONS: Each of the antibodies reacting with nuclear membrane

antigens has its own spectrum of disease associations.

RELEVANCE: Determination of anti-nuclear envelope antibody pattern by

indirect immunofluorescence, with subsequent determination of the

specific antibody, carries important diagnostic and prognostic

implications in various autoimmune conditions.

© Copyright 2001 by W.B. Saunders Company

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Below is info from a Dec. conference that I thought some of you might be

interested in. Notice how more are making the connection between our

children and what is happening to alot of us adults.

The Third International Clinical and Scientific Meeting

Sydney Conference 2001

Kenny de Meirleir (Brussels, Belgium) gave an overview of the

possible immunological pathways that are disrupted in illnesses

such as CFS. He presented data suggesting improper activation

of 2-5OAS in monocytes in both CFS and chronic MS. (not

however in relapsing/remitting MS) This results in inappropriate

activation of RNaseL This process ultimately leads to blockade

of RNaseL-mediated apoptosis. A complex series of

biochemical/immunological events then follows. Resultant RNA

fragments are then capable of either activating or down

regulating PKR. A subsequent release of NO at high (CFS) rates

or low (MS) rates by lymphocytes leads to effects on ion channel,

NK cell function, COX2 activation and glutamine release by

activated T cells in the brain. The Belgian results suggest that

CFS and chronic MS are extremes of an array of dysfunctions in

the 2-5A/RNaseL/PKR pathways.

Evidence of active HHV6 infection and its correlation with

RNaseL (LMW) protein in CFS patients was presented by

Dharam Ablashi (Washington, USA). His team had looked at

HHV6 in plasma, CSF and white blood cells. The aim was to

correlate HHV6 with presence of the 37KDa protein. The 35

CFS patients studied showed that 65% had active HHV6

infection with varying HHV6 IgM antibody and HHV6 infected

PBMCs. In the CSF, 26.7% had HHV6 DNA. Nested PCR

showed 34% patients had HHV6 in plasma, but using TaqMan

PCR, 48.5% were shown positive in plasma, and 40% in CSF.

This test was therefore more sensitive in this assay. HHV6

variant A was identified by TaqMan PCR in almost all positive

patients. Variant A tends to be acquired in adult life, variant B in

early childhood. Ratio of LMW to HMW(80KDa) protein was

detected in 70% PMBC samples. Correlation with HHV6 was

significant when the ratio was greater than 4. IgM antibody and

PCR correlation was less significant.

Rey Casse (Adelaide SA) used SPECTscans to study regional

cerebral blood flow in CFS. He recommended that a triple

headed camera be used for accuracy and reliability. 13 CFS

patients' scans were compared with 11 people suffering from

other conditions with normal scans. Visually, deficit in regional

cerebral blood flow was found in the temporal areas in 7

patients, and equivocal in 3. Statistical Parametric Mapping was

applied to show location and amplitude of significant focal

deficits. Most deficits were found in the brainstem, temporal

lobes, frontal lobe and anterior cingulate gyrus.

Autism and CFS were considered by Robyn Cosford (Mona

Vale NSW) to be part of the same spectrum of disease, which

also included ADHD, in light of her findings of similar

neuro-immune and gastro-intestinal dysfunction. Similar trends in

urinary amino-acid and organic acid output are typically seen in

all these disorders. There are also some similarities in plasma

lipid analysis and bacterial faecal studies. She found the children

with autism are a more metabolically homogenous group than

CFS patients, who typically fall into 5 symptom clusters

correlating to metabolic findings. However the subgroup of CFS

patients with neuro-cognitive and GI symptoms has similar

patterns to autistics, and this could indicate commonality in

aetiology. She mentioned the fact that many children with autism

have had frequent infections, particularly otitis media prior to

diagnosis.

Biochemical anomalies in those with CFS who have visual

problems were discussed by Gregg (Newcastle

NSW). It has been found that these patients do have biochemical

abnormalities similar to those reported as suffering from a visual

sub-type of dyslexia, known as Irlen Syndrome (IS). The same

visual symptoms occur in both conditions: headaches,

photophobia and concentration difficulties. A large percentage

have visual processing problems, and there may be a genetic

vulnerability. A number of abnormalities of fatty acid metabolism

were described. The bacterial fatty acid C17:0 was found to be

positively correlated with eye strain and may indicate the

presence of a pathogen, and this anomaly was also found in

those with CFS.

Neil McGregor (Newcastle NSW) retrospectively reviewed

available data to develop a model of disease processes in CFS.

Using factor analysis, 4 symptom groups are recognised in

CFS: General CFS, neurocognitive, musculo-skeletal and mood

changes. The general symptoms are associated with

reactivation of viruses, increased RNaseL fragmentation and

infectious symptoms. This group are predominantly

cytokine-inducing or pathogen associated events. The other

groups represent the host's response or cytokine-mediated

symptoms. Reactivation of different viruses is associated with

symptom variation, while co-morbid infections increase patient

morbidity. Pain is associated with increased metabolite

excretion and cytokine mediation leads to release of metabolites

from the tissues. As amino acids are lost, fatty acids increase

and the patient becomes more reactive.

That food intolerance exists as a co-morbidity in CFS was

addressed by Tania Emms (Newcastle NSW). Food

intolerances are a non-immune mechanism with no increase in

IgE. Food intolerance appears to be a significant factor in up to

30% CFS patients. A chemical to which an individual is

intolerant needs to accumulate and reach a threshold before

symptoms develop, so reactions maybe delayed over hours or

days, and many symptoms may occur. Patients were studied

using food elimination and food challenge. 90% reported

positive outcome after elimination, with improvement in a

number of symptoms. Bowel symptoms in particular decreased.

Food intolerance therefore may be of aetiological significance in

the development of IBS symptoms in CFS. She concluded that

symptom management involving attention to food intolerances is

under-utilised but maybe a useful approach.

Burnet's final words echoed the consensus of the

conference that the brain, limbic systems and gut are implicated

in CFS with the causation being usually infection plus a

predisposition and various trigger factors

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