Item 4.) The Herxheimer reaction: what it is; connection between reactions to antibiotic treatment and ALS

The definition of a “Herxheimer’s r[eaction]” from Dorland’s Illustrated Medical Dictionary 30th Edition refers the reader to the listing for “Jarisch-Herxheimer reaction” which is defined thus: “a transient, short-term immunologic reaction commonly seen following antibiotic treatment of early and later stages of syphilis and less often in other diseases, such as borreliosis, brucellosis, typhoid fever, and trichinellosis. Manifestations include fever, chills, headache, myalgias, and exacerbation of cutaneous lesions. The reaction has been attributed to liberation of endotoxin-like substances or antigens from the killed or dying microorganisms, but its exact pathogenesis is unclear. Called also Herxheimer’s r[eaction].” In common usage, many people refer to the reaction as a “Herxheimer” reaction, leaving off the possessive “s”; many patients and clinicians refer to it more briefly as a “Herx”; it is sometimes referred to as a “die-off reaction.” The Dorland’s definition is overly conservative, in my opinion, because the Herx is indeed very commonly seen in the treatment of Borreliosis as well as many other systemic infections. And, it can include many other symptoms in addition to the symptoms described in that definition. Many “official” medical documents explaining the Herxheimer reaction mention that it also can involve the release of histamine and can include anaphylaxis.

The definition of “anaphylaxis” from Dorland’s Illustrated Medical Dictionary 30th Edition includes the following: “1. systemic or generalized anaphylaxis; a type I hypersensitivity reaction (see under hypersensitivity reaction) in which exposure of a sensitized individual to a specific antigen or hapten results in urticaria, pruritis, and angioedema, followed by vascular collapse and shock and often accompanied by life-threatening respiratory distress. Common agents causing anaphylaxis include Hymenoptera venom, pollen extracts, certain foods, horse and rabbit sera, heterologous enzymes and hormones, and certain drugs, such as penicillin and lidocaine. 2. a general term originally applied to the situation in which exposure to a toxin resulted not in development of immunity (prophylaxis) but in hypersensitivity. The term was extended to include all cases of systemic anaphylaxis in response to foreign antigens […] .”

Although a Herxheimer reaction can definitely cause a patient’s symptoms to worsen, in my opinion a Herxheimer reaction should not be used as an excuse by a doctor to explain why a patient’s overall condition is worsening. The goal of the doctor, ideally, is to help the patient avoid developing a Herxheimer reaction, or to minimize a Herxheimer reaction if it occurs. A buildup of toxins resulting from the die-off of pathogens is not good for anyone’s health – especially not for people who are in fragile condition. So, when taking antimicrobial therapies, the goal should be to absorb, adsorb, and/or excrete toxins as efficiently as possible. (More information about this can be found in the “Item 9” page.) However, before you can solve the problem of the Herxheimer reaction, it is very helpful to understand the problem that needs to be solved. That’s why it could be helpful to look at the following information about some of the possible causes of Herxheimer reactions and anaphylaxis:

www.lymeinfo.net/medical/LDSupplement.pdf  (This is a PDF document called “Lyme Disease Symptoms Supplement: Additional topics in peer-reviewed literature reports.” Go to page 6, and look under the subhead “Jarish-Herxheimer Reaction to Antibiotics.” See two abstracts mentioned. The first abstract quoted includes a quote I was not able to find for free on the Internet. The abstract itself can be found at:  www.ncbi.nlm.nih.gov/pubmed/2682958 [“Epidemiology and clinical similarities of human spirochetal diseases” by Schmid, Reviews of Infectious Diseases, September-October 1989, Volume 2, Supplement 6, pages S1460-S1469.]) Details about the second abstract cited on page 6 of this PDF document follow next:

www.jem-journal.com/article/S0736-4679(98)00011-0/abstract  (This is an abstract titled: “Lyme Disease Complicated by the Jarisch-Herxheimer Reaction” by Maloy et al., The Journal of Emergency Medicine, May 1998, Volume 16, Issue 3, pages 437-438. Just in case the link doesn’t work, the text of this abstract says: “A 31-year-old woman diagnosed with Lyme disease was treated with amoxicillin. One hour after the first antibiotic dose, the patient became acutely ill. She developed hypertension, fever, and rigors. Shortly afterward, she became hypotensive and required fluid resuscitation. This systemic illness, the Jarisch-Herxheimer reaction, was first noted in association with antibiotic therapy for neurosyphilis. Thus, the institution of antibiotic therapy may be complicated by the Jarisch-Herxheimer reaction.” Please note that the Herxheimer reaction can take many forms, and in some cases it doesn’t become recognizable until many hours or even many days after beginning antibiotic therapy.)

To find many articles that are similar to the previous one, go to the PubMed listing for the abstract of “Lyme Disease Complicated by the Jarisch-Herxheimer Reaction” by Maloy et al., The Journal of Emergency Medicine, May 1998, Volume 16, Issue 3, pages 437-438:  www.ncbi.nlm.nih.gov/pubmed/9610974. Then, while you are looking at this abstract on your computer screen, look on the right side of the screen and see where it says “Related citations.” Then look beneath the links to the various document titles that are under “Related citations” and you’ll see listed, flush right, the words “See reviews…” and underneath that “See all…”. Click on “See all…”. This will bring you to a list of approximately 148 abstracts and articles about the Jarisch-Herxheimer reaction, including many that are specifically related to the Herxheimer reaction in neuroborreliosis and Lyme disease.

Also see:

http://lib.bioinfo.pl/pmid:1445982  (This is an abstract titled: “Antibiotic-induced release of endotoxin: a reappraisal.”)

http://grande.nal.usda.gov/ibids/index.php?mode2=detail&origin=ibids_references&therow=658849  (This is an abstract titled: “Histamine release induced by antimicrobial agents and effects of antimicrobial agents on vancomycin-induced histamine release from rat peritoneal mast cells.”)

www.jemsekspecialty.com/lyme_detail.php?sid=10  (This web page by the Jemsek Specialty Clinic, which specializes in the treatment of Lyme disease, is titled: “Section 10: The Herxheimer Reaction.”)

www.jemsekspecialty.com/files/DetailedLymeOverview.pdf  (Information about the Herxheimer reaction is approximately two-thirds of the way into this document, which has the heading: “Section 1: Introduction.”)

http://afp.google.com/article/ALeqM5gsIg9riY1yCtwOJpG9EMtiDWgocA  This Oct. 31, 2007, article, titled “Antibiotic accelerates tragic Lou Gehrig’s disease, says study” explains: “… in a study published by The Lancet Neurology, US researchers found that ALS patients who took minocycline deteriorated 25-percent faster than counterparts who took a dummy lookalike pill, called a placebo. … Gordon’s team enrolled 412 ALS patients, who were randomly assigned to receive a placebo or minocycline in escalating doses of up to 400 milligrams per day for nine months. … Patients were assessed according to standard measurements for coordination and muscle strength, as well as a ‘quality of life’ questionnaire. …”

The previously named article and its conclusions demand careful examination. On the one hand, it could be a warning that one antibiotic in particular may be harmful to people with ALS. On the other hand, the effects of the antibiotic minocycline on the ALS patients in the study may have been been misinterpreted by the people running the study. This article about the study says: “The drug, minocycline, was tested on human volunteers with amyotrophic lateral sclerosis (ALS) …. These trials were launched after tests on lab-dish cells and on mice engineered to have ALS symptoms suggested minocycline could inhibit inflammation ….” The drug minocycline is commonly described as “anti-inflammatory” in the medical literature, and yet people with chronic systemic infections who have been treated with minocycline have experienced severe exacerbations of their symptoms, and have even developed entirely new symptoms, that could be described as symptoms of severe inflammation. In one case that I know of, a severe Herxheimer reaction that included worsening of various existing neurological symptoms, plus some new neurological symptoms, and which lasted for over a week, was caused by a single 25 mg dose of Minocin. (Minocin is the brand-name version of minocycline. Minocycline is the generic version of Minocin.) And the patients in this ALS study were given “minocycline in escalating doses of up to 400 milligrams per day.”

If the researchers running this study were expecting the use of minocycline to be anti-inflammatory, when in fact the minocycline was provoking Herxheimer reactions that increased the symptoms of inflammation, they may have misinterpreted the responses of some patients in the study. If some of the patients in the study had symptoms of ALS that were actually caused by unidentified systemic infection, and if their infection was being unintentionally treated by the use of minocycline, the patients may have experienced Herxheimer reactions which do involve the worsening of symptoms.

If a Herxheimer reaction is not well managed, the symptoms it causes can make life so miserable that the patient cannot continue the treatment, and it can actually be life-threatening. To escalate the dose of minocycline during a Herxheimer reaction that is not being carefully managed would only make the Herxheimer reaction worse. So, if the researchers were expecting the minocycline to be anti-inflammatory, and then, after the ALS patients took the minocycline and experienced increased symptoms of inflammation, the researchers increased the dosage of the minocycline in the hope that the increased symptoms of inflammation would be quelled by the supposed anti-inflammatory effects of the minocycline, it makes sense that the ALS patients’ symptoms would get worse – that is, if the ALS patients actually had an unrecognized infection such as neuroborreliosis and were actually experiencing Herxheimer reactions. (This is, of course, speculation on another possible interpretation of the study’s results.) So, it’s possible that the problem with the study was in the researchers’ expectation that minocycline would have anti-inflammatory effects, and in their misunderstanding that while minocycline can be anti-inflammatory under some circumstances, under other circumstances, such as when the minocycline is used to treat an infection which affects the nervous system (as is the case with neuroborreliosis), minocycline can actually cause the symptoms of severe inflammation.

For more information about The Lancet Neurology study discussed in the Oct. 31, 2007 article mentioned above (“Antibiotic accelerates tragic Lou Gehrig’s disease, says study”) and articles related to that study, see:

Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial, by Gordon et al., The Lancet Neurology, December 2007; Volume 6, Issue 12, pages 116-121:  www.ncbi.nlm.nih.gov/pubmed/17980667. (Also note and follow the links within that abstract.)

Minocycline unexpectedly hastens decline in ALS, by Osterweil, MedPage Today, November 1, 2007:  www.medpagetoday.com/Neurology/GeneralNeurology/7175

CLINICAL RESEARCH: ALS trial raises questions about promising drug, by Couzin, Science, November 2007; Volume 318, Number 5854, page 1227:  www.sciencemag.org/cgi/content/short/318/5854/1227a .  (One paragraph in this article by Couzin, that is commenting on the study “Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial,” says: “[…] neurologist Nigel Leigh of King’s College London, […] still hopes that minocycline will prove useful for ALS. Leigh says it’s possible that high doses of the antibiotic were neurotoxic for patients, whereas lower doses might be neuroprotective. He’d been planning with colleagues to launch a minocycline study in 1000 ALS patients; now he’s seeking approval for a revised proposal to identify an ideal minocycline dose in a smaller group of patients.”

Negative findings on minocycline for ALS prompts reassessment of study designs, by Hurley, Neurology Today, January 2008; Volume 8, Issue 2, pages 16, 20, and 21:  http://journals.lww.com/neurotodayonline/Fulltext/2008/01170/Negative_Findings_on_Minocycline_for_ALS_Prompts.9.aspx

Therapy development for ALS: Lessons learned and path forward, by Lanka and Cudkowicz, Amyotrophic Lateral Sclerosis, 2008; Volume 9, Number 3, pages 131-140:  http://informahealthcare.com/doi/abs/10.1080/17482960802112819

Minocycline as a potential therapeutic agent in neurodegenerative disorders characterised by protein misfolding, by Noble et al., Prion, April/May/June 2009; Volume 3, Number 2, pages 78-83:  www.ncbi.nlm.nih.gov/pmc/articles/PMC2712603/?report=abstract.  (This very technical article discusses theories of potentially positive and negative effects of minocycline on various neurodegenerative disorders, including motor neuron disease [MND], based upon pre-clinical studies using animal and cell models. This article includes discussion of the presumed anti-inflammatory effects of minocycline.)

Correlates of quality of life in ALS: Lessons from the minocycline study, by Lou et al., Amyotrophic Lateral Sclerosis, 2010; Volume 11, Number 1-2, pages 116-121:   www.ncbi.nlm.nih.gov/pubmed/19551536

Keep in mind that my suggestion that minocycline may have induced Herxheimer reactions in ALS patients in that “phase III randomised trial” written about by Gordon et al. is just my theory, which is a fancy way of referring to “speculation.” It has been known for a long time that many side-effects can occur with the use of Minocin/minocycline, but frequently the cause of the side-effects is not known. Many theories as to the causes of various side-effects exist. See:

Prescribing information for Minocin, which includes information on side-effects and adverse events:  www.drugs.com/pro/minocin.html?printable=1

Safety of Doxycycline and minocycline: a systematic review, by Smith and Leyden, Clinical Therapeutics, September 2005; Volume 27, Issue 9, pages 1329-1342:  www.ncbi.nlm.nih.gov/pubmed/16291409

Liver damage associated with minocycline use in acne: a systematic review of the published literature and pharmacovigilance data, by Lawrenson et al., Drug Safety, 2000; Volume 23, Issue 4, pages 333-349:  www.ncbi.nlm.nih.gov/pubmed/11051220

Vestibular reactions associated with minocycline, by Jacobson and Daniel, Antimicrobial Agents and Chemotherapy, October 1975; Volume 8, Number 4, pages 453-456:  www.ncbi.nlm.nih.gov/pmc/articles/PMC429369/pdf/aac00328-0071.pdf

 Wikipedia’s Minocycline page:  http://en.wikipedia.org/wiki/Minocycline

Note that minocycline has been used as a treatment for Lyme disease, sometimes with reported success. Some forms of Borrelia have been found to be sensitive to (treatable by) minocycline, and some forms of Borrelia have been found to be resistant to minocycline. (Google: “Lyme borrelia minocycline”) A Herxheimer reaction would only occur with significant levels of Borrelia die-off, so it is logical to assume a Herxheimer reaction during treatment with minocycline would only happen with infections by Borrelia that are sensitive to minocycline.

Minocycline, by the way, is known to be an effective treatment against some mycoplasmal infections. Therefore, it is possible for a patient with a systemic mycoplasmal infection (and who, perhaps, does not have any other systemic bacterial infection) to experience a Herxheimer reaction during treatment with minocycline. Minocycline (or, more specifically, the trademarked drug Minocin) is promoted by The Road Back Foundation as a treatment for arthritis and scleroderma.

See:  www.roadback.org  (Also see the articles linked within “Item 5” that note a connection between ALS and mycoplasma infections.)

Also see articles about treatments for arthritis, scleroderma and Lyme disease on this web page:  www.arthritistrust.org/menu_list/Articles_important.html

This clinical trial, “Northeast ALS Consortium Stage III Trial of Ceftriaxone,” is studying the effects of the antibiotic ceftriaxone on ALS patients. See: www.alsa.org/patient/drug.cfm?id=583. Here is part of the information from that web page about that trial: “Detailed Description:  It is known that nerve cells called motor neurons die in the brains and spinal cords of people with amyotrophic lateral sclerosis (ALS). However, the cause of this cell death is unknown. Researchers think that increased levels of a chemical called ‘glutamate’ may be related to the cell death. For this reason researchers want to study drugs that decrease glutamate levels near nerves. Ceftriaxone – a semi-synthetic, third generation cephalosporin antibiotic – may increase the level of a protein that decreases glutamate levels near nerves. Studies of ceftriaxone in the laboratory suggest that it may protect motor neurons from injury. […]”

Now note that ceftriaxone is used to treat Lyme disease. In an article about Lyme disease, images of SPECT scans are reproduced that show the state of blood flow in the patient’s brain both before and after treatment with ceftriaxone. This patient had Lyme disease that was expressed in a wide variety of symptoms, but nevertheless had been misdiagnosed as depression. After treatment with ceftriaxone, the blood flow in the patient’s brain improved dramatically. This article, by Robert C. Bransfield, MD, is titled “Lyme Disease, Comorbid Tick-Borne Diseases, and Neuropsychiatric Disorders,” and was published in Psychiatric Times, December 1, 2007, Vol. 24, No. 14, pages 59-62. See:  www.lymepa.org/02%20Lyme%20Disease%20-Tick-Borne%20Diseases%20and%20Neuropsychiatric%20Disorders.pdf

See also the Lyme and Tick-Borne Diseases Research Center’s (www.columbia-lyme.org) explanation for why minocycline and ceftriaxone have been tested for ALS patients. They say: “Clinical trials have been underway using antibiotics for ALS (such as minocycline and ceftriaxone) not because there is a belief that ALS is caused by a microbe but because these antimicrobial agents have other properties as well, such as decreasing inflammation or decreasing glutamatergic excitotoxicity.” To find this, see:  http://asp.cumc.columbia.edu/lymedisease/askthedr/for_pt/faq.asp and look under the “Category: LYME OVERLAP WITH OTHER DISEASES” and click on the link for question “2263 Is it possible for Lyme disease to be misdiagnosed as ALS? Are there similarities in symptoms between these two diseases?”

See the “Item 9” page for suggestions on how to deal with a Herxheimer, or die-off, reaction and/or anaphylaxis.

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