IVIG – Intravenous Gamma Globulin Therapy for Chronic Fatigue Syndrome (ME/CFS), Fibromyalgia and POTS

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Intravenous Gamma Globulin Therapy or IVIG is…

Gamma globulin therapy (IVIG) is used to treat viral activation in chronic fatigue syndrome.

an antiviral treatment and immunomodulator used to treat active infections or regulate immune functioning in those with immune deficiencies or autoimmune disorders.  IVIG contains  antibodies (IgG immunoglobulins) that  target pathogens found in the bloodstream for destruction.

The gamma globulins are pooled from the blood products of many blood donors that have been treated to kill any infections present. Gamma globulin therapy is FDA approved to treated several diseases but is used off-label in a many others including many autoimmune ones.

Gamma globulin’s downsides include high expense and low availability although both have improved somewhat recently.  It can be administered intramuscularly or intravenously.

Chronic Fatigue Syndrome (ME/CFS), Fibromyalgia (FM) and Small Fiber Neuropathy Studies

Chronic Fatigue Syndrome (ME/CFS)

Significant interest in gamma globulin resulted in several clinical trials in the 1990’s which had mixed results. Hickie et. al found improved mood and immune functioning in a smaller 1992 IVIG trial and Lloyd’s placebo-controlled 1990 trial found significant improvement in approximately 40% of patients with many resuming work and other activities.  Lloyd’s larger followup trial, however, was unsuccessful, as was a smaller American trial that targeted IgG deficient individuals.

Rowe’s 1997 IVIG trial, on the other hand, found significant functional improvement as did her five year  followup.  Rowe’s five year followup – reported in a publication –  Journal for Chronic Fatigue Syndrome that was not included in medical indexes – was not unfortunately widely disseminated.

More recently, gamma globulin therapy was successful with several parvovirus-B19 associated cases of chronic fatigue syndrome.

Fibromyalgia and Small Fiber Polyneuropathy

Fibromyalgia patients with evidence of nerve demyelination caused by immune dysfunction responded positively (reduced pain, tenderness, increased strength) to a short-term IVIG trial.

Dr. Oaklander reported promising results using IVIG in children with a putative diagnosis of small-fiber polyneuropathy (SFPN); e.g. small fiber neuropathy (SFN). SFPN or SFN has been documented in fibromyalgia and is currently being documented in chronic fatigue syndrome (ME/CFS). (Both Dr. Systrom and Dr. Kaufman have found SFPN extensively in ME/CFS; Systrom will presumably report on this soon in a study). A small fiber neuropathy diagnosis could help patients get IVIG covered by insurance companies.

Of the 8 patients IVIG was tried on sixty percent received significant functional improvements which included improvement on autonomic tests such as the tilt table, HRV and Valsalva tests.

IVIG in Autoimmune SFPN (AsSFPN)

With the evidence of autoimmunity increasing Oakland called SFPN “autoimmune SFPN (aaSFPN)” in a larger (n=55) 2018 study. The study lasted for three months and used the highest suggested dose first (1.3–2.0 g/kg/4 weeks) before titrating down if necessary. Except for common infusion reactions (60%) such as headaches, flu-like symptoms, nausea and stiff neck which were addressed at the clinic by slowing infusion rates, hydrating patients, etc., side effects were low.

Oaklander’s retrospective IVIG study found 74% of the participants ‘improved’ with neurologists reporting 77%  were “responders”.  Furthermore, 16% achieved a sustained remission lasting, by the time of study report, an average of 20 months.

Oaklander found that the autoimmunity in three quarters of the participants was restricted to their small nerve fibers and therefore wouldn’t be picked up by standard blood tests.

The data is clearly calling out for a large placebo-controlled trial.  A successful larger trial should open the door for IVIG treatment of for ME/CFS/FM patients with rigorously documented SFPN and/or autoimmunity. Dr. Oaklander is surely working on bringing a larger trial to fruition.

Oaklander asserted that the results “imply that aaSFPN may be far more common than appreciated” and “provide strong evidence that medical insurers should no longer reflexively decline to pay for IVIg treatment of aaSFPN.”

 

IVIG in Postural Orthostatic Tachycardia Syndrome (POTS)

Given the recent autoimmune findings in postural orthostatic tachycardia syndrome (POTS) IVIG sounds like a no-brainer.  No studies, however, have investigated the use of IVIG in POTS but in 2018 Dysautonomia International funded a trial.

Goodman recently reported high rates of success using IVIG in POTS. (See report from the 2018 Dysautonomia International Conference).  Goodman’s 2018 published case report described a “dramatic and sustained response”  using a combination of IVIG, low dose naltrexone and antibiotic therapy (for small intestinal bacterial overgrowth (SIBO)) in a patient with POTS, mast cell activation syndrome (MCAS) and SIBO.

Chronic Fatigue Syndrome (ME/CFS) Doctors Report

Given its expense Dr. Teitelbaum turns to IVIG only after other means of fighting chronic infections have been exhausted. He has, however, found that IVIG can ‘dramatically help’ some patients. Dr Tae Park of Korea uses IVIG extensively and reports high levels of success.  Dr. Peterson finds it very helpful in some of his patients. Dr. Chia has found it helpful for fibromyalgia patients. Dr. Susser and Rosenbaum call it their most effective treatment.

Dosing Regimens and Safety

IVIG is usually given every couple of weeks, often needs to be given continuously (is not a cure) and is incredibly expensive (can cost $100K a year). The risk of aseptic meningitis is low but increased in patients with autoimmune dysautonomia. That problem can be ameliorated by slower infusions and hydration.  Blood clots and kidney toxicity are two other rare complications.

Dr. Teitelbaum recommends intramuscular injections of 2 cc a week or 4 cc every other week (or weekly) but notes that even 1 gram a week for six months can be helpful. He recommends using IVIG for six weeks or longer.

Two dosing regimens exist: a low dose one for patients with low antibody levels (immune deficiencies) and a higher dose for patients with autoimmune dysautonomia who need the extra antibodies in the high-dose IVIG to swamp the bad ones producing their disease.

Dr. Schofield usually starts off in her POTS patients with 1 gram/per kg in her autoimmune patients, and that’s usually enough, but she can go up to two g/kg monthly.

The Case for IVIG Treatment in Chronic Fatigue Syndrome (ME/CFS), Fibromyalgia, Small Fiber Neuropathy, and POTS : IVIG#3

Schofield warned that giving IVIG slowly and using aggressive hydration is important in her POTS patients. She generally starts off with 1/4 g/kg weekly and works up to 1 g/kg given all at once. (Some patients peak at ½ g per kg. She warned never to give IVIG and fluids at the same time.)

Schofield and Dr. Klimas agreed that in ME/CFS (where IgG1 and IgG3 – which fight off viruses – are more important), weekly injections are more likely needed to ensure constant antiviral protection in some patients because the half-lives of these antibodies are shorter.

Cost

IVIG therapy can be extremely expensive costing several thousand dollars a month. Both Dr. Teitelbaum and Dr. De Meirleir have found that using low doses to cut costs can be effective. Finding no extra benefits from IV’s Dr Teitelbaum advises using the less expensive intramuscular injections (@$50/vial).

Side Effects

Side effects can include fevers, chest pain, muscle aches, headaches, shortness of breath, etc. Die-off reactions can occur with the first few injections. Dr. Teitelbaum recommends that one to three weeks of Nexavir be given prior to IVIG therapy.

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Teitelbaum, J., From Fatigued to Fantastic, Avery Press. 2007.

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