Hi fellows

Hi fellows,

Here is part of what I will be presenting on Dec 6th in DC. Addresses some of the issues you are talking about with the IOM and their band of merry medical hired guns.
http://www.2ndbattalion94thartillery.com/Chas/HouseCom.htm

It might be advisable for one of the Edgewood testing Veterans to be there and even present if they choose.

Contact Gene Simes at gdsusa@rochester.rr.com

Kelley
DMZ 67-68

DRAFT

HOUSE COMMITTEE ON VETERANS AFFAIRS

PRESENTATION BY CHARLES KELLEY

PERIPHERAL NEUROPATHY CAUSED BY THE DIOXIN TCDD, OTHER TOXIC CHEMICALS THE VETERANS WERE EXPOSED, OR TO WARTIME SERVICE IN VIETNAM IN A TOXIC CHEMICALS (PLURAL) ENVIRONMENT

STILL DENIED BY THE VA AFTER 40 PLUS YEARS

I am the author of the newly released book "Vietnams Rain- Agents Orange, White, and Blue (Weapons of Mass Destruction)". This book documents a four year review of DOD/VA/Government activity in denying the many effects of our Toxic Chemicals (Plural) Legacy.

Up until our “Vietnam Veterans Toxic Chemicals (Plural) Legacy” it had always been the policy of the Veterans Administration (VA) and “Is currently the portrayed policy of the United States,” with respect to individual claims for service connection of diseases and disabilities, that when, after consideration of all the evidence and material of record, there is an approximate balance of positive and negative evidence regarding the merits of an issue material to the determination of a claim, the benefit of the doubt in resolving each such issue shall be given to the claimant.

The VA in promulgating the rules specified by the Dioxin Standards Act of 1984, not only confounded the intent of this perceived intent of Congress, but directly contradicted its own established practice of granting compensable service-connection status for diseases on the lesser showing of “an increased risk of incidence” or “significant correlation” demanding instead the more stringent requirement that compensation depends on establishing a “cause and effect” relationship.

Veterans are now calling this “Dioxin Standards Act” and this so-called “benefit of the doubt mandate” only a “painted and portrayed congressional deception.

In direct opposition to the stated purpose of the Dioxin Standards Act of 1984 to provide disability compensation to Vietnam Veterans suffering who were exposed to Agent Orange, the VA continues to improperly and illegally deny and stall compensation for death and disability. In fact, with the VA’s definition of when the Veteran’s claim ends, one would logically conclude the VA is now legally allowed to “stall to the death” of the Veterans which is a definite conflict of interest between the Veterans and the sole power given to the Secretary of the VA and this very adversarial federal agency.

This VA promulgating of the requirements was also found in a courts review in Nehmer v. U.S. Veterans Admin., 712 F. Supp. 1404, 1408. (N.D. Cal. (1989) wherein the court found after reviewing the legislative history of the Act that Congress intended service connection to be granted on the basis of “increased risk of incidence” or a “significant correlation” between the dioxin TCDD and various diseases.”

There are many Veterans, there are many members of Congress, there are many Americans who believe the Department of Defense and the Veterans Administration have been less than candid about the health effects that Agent Orange has had on them as well as on veterans' children. While the Government has acknowledged that some illnesses the Vietnam veterans developed are associated with Agent Orange exposure, and that these veterans can receive disability and death benefits. Many veterans believe that the health problems associated with Agent Orange are far more serious and widespread than the Government has acknowledged up to this point.

The search for latent illnesses associated with exposure to “herbicides” (plural) in our toxic chemical legacy demands persistence, confronting hard truths, and above all integrity. The United States Government has failed miserably with purpose and intent in these issues.

Twenty three years ago, the Air Force began a 25-year, $140 million research program to assess the relative health of 1,300 ranch hands, air and ground crew members who handled and sprayed Agent Orange and other herbicide defoliants in Vietnam. The Ranch Hand Study was designed to generate significant scientific data and analysis to be used by the Department of Veterans Affairs [VA], and others in making health care and compensation decisions regarding Vietnam Veterans.

Nevertheless, according the General Accounting Office [GAO], Ranch Hand has been slow to publish findings, unwilling to share data, inconsistent in conveying design limitations, and resistant to congressionally mandated participation by "independent parties."

Controversial from the outset, the Ranch Hand study has been consistently criticized for both scientific and administrative shortcomings. Many believe Ranch Hand has so far failed to fulfill its promise as the pivotal longitudinal study of herbicide toxicity. Some conclude it never will. Others believe this research was designed to fail, or manipulated to avoid controversial findings.

Senator Daschle concluded when the first report was released in 1984 when compared to the original scientific draft that this was not just an interpretation of the medical facts found but the “perpetration of fraudulent government conclusions.”

After reviewing the transcripts of the government oversight committee on Ranch Hand and the testimony of scientists themselves that were a lead part of the Ranch Hand, the head of medical research at Kansas State University (a two time member of the Ranch Hand study), and an advisor to the VA Secretary from Yale University; it was painfully obvious this study deserves this well-founded criticism.

There were direct charges of command influence being used, the changing of cleared for publication medical facts that were found, the changing of established protocols directed by using the name of the Surgeon General, linear dioxin dose responses to medical disorders that were not understood were and are not reported found, disorders found at a 50% increase or more are not reported because no dioxin linear dose response could be determined, etc, and an overall total lack of integrity.

The ultimate lack of integrity charge was that for 20 plus years the study had and continues such cover-ups to have never given the Veterans a fair and unbiased assessment of their toxic chemical health status in birth defects, other cancers, heart disease, vascular disease, neurological ailments, endocrine disturbances, and hematological difficulties.

I would also add even B and T cell dysregulaton found that may even be the secondary root cause of all of our wide variety of issues of death and disablement is ignored. This includes down and up regulation in Interleukins 4 and 10, Interferon, and some disturbance of the tumor necrosis factor.

Some suggested that the Congress had given entirely too much power to the Secretary of the VA and its White House directed philosophy. I would add that Congress assuming integrity gave too much power, when there is very little government integrity that accompanies that “sole power” in our government.

Some in congress have even suggested that data should be from some outside agency and not from a major role player such as the VA and the Air Force. I would add that after my four year review of these so called toxic chemical assessments, I would conclude it would have to almost be an international committee of totally independent scientists; not associated with the EPA, VA, FDA, any branch of the DOD, and certainly out of the mandatory influence of our own White House. Very similar to what the EPA did in their dioxin reassessments of 1992-1996 where they used over 100 independent scientists NOT associated with the EPA or any government influence. The EPA's previous history in the 1970's and the 1980's is certainly tainted with some EPA scientists with integrity finding the chemical company studies being presented in court were fraudulent. Their reward for demanding something be done was suspension. One EPA scientist wrote a scathing report shooting holes in the chemical company studies and issues. His report was summarily shelved in 1979 by the EPA. Yet, it documented many of the findings that would be presented in the EPA's "dioxin reassessment" some two decades later. Another 20 years went by while our most noble of all citizens died or became disabled since their doctors had no idea what to look for and no one in our government gave them a chance at a first medical strike against a cancer or an autoimmune disorder.

One of the most despicable events I ran across in my review of the Ranch Hand Transcripts was when one scientist, not wanting to duplicate his work asked; Would it not be better to wait to review the chapters until the Air Force gets done with all its changes? The leader of this group then stated we do not want to say "changed." The scientists then said, "OK how about Airbrushed" as laughter broke out in the room.

Veterans are going uncompensated in death and disability and this group is laughing at the fact the Air Force is going to change what they as scientists have found or suspect.

To include charges were made that totally rewriting some chapters was only to "deemphasize" the real findings.

This White House philosophy “not to support our Vietnam Veterans” in lieu of protecting and minimizing chemical company costs that would be incurred (*reference White House memo put out to federal agencies) and then deny Vietnam Veterans and their families death and disability benefits seems to be now “ a learned and accepted practice” by our government. This seems to permeate research and similar studies for Gulf War Syndrome, anthrax vaccine recipients, the Veterans of Project 112 testing and SHAD testing, and the Edgewood Arsenal testing, etc. There is also the previous history of DOD/VA cover-ups in Nuclear Testing and LSD testing.

The White House Bureau of the Budget put out a memo to all the agencies of government in essence not to find a correlation between Agent Orange and health affects. Stating that it would be most unfortunate for two reasons:

A) The cost of supporting the Veterans.

B) The court liability to which corporations would be exposed.

It is time all past; present, and future Veterans make this White House/DOD/VA philosophy a National Security Issue. This especially holds true for the mothers and fathers that this government wants to send their sons and daughters into harms way. They need to realize “the last battle they will fight” is against our own government.

In Attachment 1, I have provided the various and wide variety of symptoms of this peripheral neuropathy debilitating disorder in nerve damages as well as the wide variety of severity of this toxic chemical caused nerve damage disorder.

In Attachment 2, I have provided the overwhelming medical and statistical evidence that categorically supports this chronic and debilitating disorder of peripheral neuropathy is associated to the dioxin TCDD and/or Service in Vietnam regardless of which toxic chemical or group of toxic chemicals was the causation. This evidence goes back to 1949, as well as present day epidemiological studies; including Office of Technology Assessment results commissioned by congress itself in 1989.

While the VA wants to contend that only diabetes can create this nerve disorder you will see in ATTACHMENT 2 the p-values found concludes that this is far from only associated to diabetes and with respect to Agent Orange and is the most prolific disorder found as a stand-alone.

Time permitting I will review these submittals.

Time not permitting I will leave it up to the members to review this direct evidence and move on in the presentation. Most of you are lawyers, so when you review this evidence put yourself in the position of a practicing attorney and in a “real legal system” where evidence means something; not this trumped up Board of Veterans Appeals. Decide for yourself if I have proven my case medically, statistically, and scientifically to what congress intended to be compensated for government mistakes. Then multiple that by thousands of disabled Veterans with the same issue that this government is letting down with no financial support for “government wrong-doing.”

Also, please review the BVA case file in ATTACHMENT 3 that categorically demonstrates that even when everyone concluded this Marine’s nerve disorder was at least a 50/50 chance caused by his toxic chemical exposures. The BVA then states they give more evidentiary weight to the "statements made by the Secretary of the VA" that denies such associations.

ATTACHMENT 4 documents statements made by some of the Edgewood Arsenal testing Veterans. A despicable government act indeed.

So much for the “Mandated Benefit of the Doubt,” the “Congressional Mandates,” and the "Congressional Dioxin Act of 1984." The VA just in turn, adds legal nomenclature to C.F.R 38 that trumps anything Congress has intended or at least on face value had intended to accomplish for Veterans.

The White House already decided this Marine’s case in 1984 with their philosophy "not to support the Veterans." It was not decided in 2003 at the BVA after fighting for eight years to even get that point of an appearance at the BVA. The whole VA legal system is a joke that operates around a mandated budget only. Not truth or evidence of facts as in a real legal system under the constitution. No different than they find a way to trump the entire congress at the behest of White House Budgets, not facts.

For a Federal Agency to be this poor in performance, it has to try real hard to be just that. Not only poor in performance but integrity as well. Make no mistake; this is a very adversarial agency that works at the behest of the White House, not the Veterans.

As a side note, I have to smirk at all the present political wrangling going on with the Supreme Court Justices. For Veterans of this nation it is irrelevant who is on the Supreme Court or even the constitutional legal system that guarantees protection for the rest of the Nation’s Citizens against government corruption and collaborations. With the power, congress has given to the Secretary of the VA and to each successive White House, for the Veterans and their widows the Secretary of the VA becomes not only the executive and legislative branch of government but also their Supreme Court as all their real legal rights “as citizens” are laid aside.

Without question, the Feres Doctrine has denied American service members, veterans, and their families “equal justice” under The United States Constitution.

Many federal judges, scholars, lawyers, doctors, veterans and their families argue that the Feres Doctrine is unconstitutional since it violates the “due process, equal protection and separation of powers” clauses of the Constitution. The most significant dissenter in modern times is sitting Supreme Court Justice Scalia as cited in the case of United States v. Johnson, (1987):

“Feres was wrongly decided and heartily deserves the widespread, almost universal criticism it has received.” Furthermore, "Congress's inaction regarding this doctrine and its doing little, if anything in the way of modifying it to prevent Constitutional claims is clearly unjust and irrational. Again, allowing such power to military leaders can and does result in abuse therefore, where are the checks and balances on the military."

Yet, still to this day Congress will not address this issue of the DOD is presently allowed to do anything it wants with no accountability, including what many consider crimes against humanity itself, which this very country hanged individuals for after WW2. Thus leaving the Veterans with no legal redress as guaranteed by the constitution that they alone so valiantly and honorably fought to protect.

Add to this the omnipotent sole power and a “totally separate legal system” with no rules of any constitutional oversight given to VA by Congress in C.F.R 38, paragraph 510 and you have total government anarchy for one complete segment of society in this nation called “Veterans.”

The evidence I have submitted to you in ATTACHMENTS 1 AND 2 are strictly on this one disorder of nerve damages but there are many disorders that have an equal amount of medical evidence that I can address should you choose to hear the truth. You just have to give me time to address each issue, as I am physically able to do so.

When President Clinton approved this nerve disorder as being associated the nomenclature used was; “ACUTE NEUROPATHY.”

The DVA/White House to control the Veterans’ compensation expenditures put a time limit on this prolific nerve disorder with a time limit of resolution and/or cure of this nerve disorder.

The first proposal was for a 10-year time limit and a two-year resolution. Many scientists and doctors protested even this VA action to Secretary Derwinski. What it ended up was a one-year time limit and a two-year resolution announced in 1996. Which makes about as much sense as concluding the following: “That within 678 and one-half days the Veteran must manifest in order to draw disability compensations.”

It does not take a mathematical genius to crunch the numbers and calculate that even when this nerve disorder was announced, “As Associated,” no Veteran at that time could qualify or would ever qualify. Nice propaganda move on the part of the VA, its’ Secretary, and the White House.

The VA then classified this nerve disorder; “transient acute and sub acute peripheral neuropathy,” which no Vietnam Veteran has submitted for compensations.

In the VA propaganda magazine “Agent Orange in Review” which should be “Dioxin TCDD in Review” since no (zero) “U.S. Government Study” has done any studies on the herbicide Agent Orange, the issue was falsely printed as Peripheral Neuropathy. Only after protests by Veterans, such as myself, that this was a VA mischaracterization to the public did they finally change the listing to some form of truth.

Including complaints from Veterans, such as myself, of Veterans’ Magazines reprinting the bogus VA claims. In which, editors printed retractions after realizing the truth.

By associating this medical disorder and two other disorders to a time limit, the VA has distanced themselves from the real causes of the three time limit disorders.

In fact, by determining a time limit and pronouncing that a cure is available or at least the nerve damage will resolve itself over time; the DVA and the National Academy of Science Institute of Medicine (NAS/IOM)**, the hired guns of the government replacing the despicable Veterans Affairs Chemical and Environmental Hazards Committee that operated from 1979 to 1991, certainly must have concluded the following:

The concluding morphology of how the dioxin TCDD directly creates this transient acute and sub acute peripheral neuropathy outside of an antigenic response since scientists categorically state that the single dioxin (TCDD) does not create a body antigenic response such as spider bite or even some poisonous plants that are ingested.

Therefore, one must conclude that the VA and the NAS/IOM have discovered this morphology and have kept this medical secret to themselves.

The VA and the NAS/IOM certainly have concluded not only the morphology, since the time limit of manifestation is now mandated. They certainly must have established either the minimum “total body threshold” regardless of means of ingestion or at least the minimum “dose rate” by specific methods of ingestion that equates to a mandated manifestation within one year of exposure to the dioxin TCDD.

The VA and the NAS/IOM have some how determined that every Veteran serving in theater during his or her 12 –18 months wartime service shall have achieved this magic “minimum exposure” required to the dioxin TCDD to manifest within the year after leaving the wartime theater. This would also include those that were wounded within three months of entering the war and left theater.

Yes, all of this is government/VA medical nonsense.

The VA and NAS/IOM have concluded a cure or resolution for this nerve disorder does exist. Yet, in seeing three board certified neurologists one of whom was the head of neurology at Emory University indicates this nerve damage is chronic, debilitating, and not curable. It is self-manifesting from the secondary effects of the toxic chemicals, not an antigenic response, and more in the form of an autoimmune disorder, which is one of the cruelest of all diseases and disorders.

Some have suggested that to have this nerve disorder this badly it had to be caused by either heavy metals or toxic chemicals and not a diabetic connection. Once again it seems the VA and the NAS/IOM know how to cure this nerve disorder when the rest of the nations board certified doctors seemed to be nothing but board certified quacks.

The Congress has gone along with this DOD/VA collaboration that everything is associated to one single toxic chemical component (the dioxin TCDD) of three major Herbicides used; which is shear and total nonsense.

We know that Agent Blue was a form of arsenic acid that is noted for its neurotoxicity properties including warnings of creating nerve damage such as peripheral neuropathy.

We now know that Agent White with its DOW chemical proprietary formula had other forms of dioxins, and closely related furans, as well as nitrosamines.

“Nitrosamines are another type of carcinogenic chemicals that are known to cause cancers and other medical problems.

Exposure to high concentrations of nitrosamines is associated with increased mortality from cancers of the esophagus, oral cavity, and pharynx. When used in pesticides or herbicides it may cause DNA damage and cell death.”

Congress must realize the synergy effect of all these toxic chemicals used in one area can increase the potency and generated outcomes by a factor of 1600 times when using only two toxic chemicals over what a single toxic chemical can produce.

The bottom line for Vietnam Veterans is that no one will ever know what caused what to some level of “cause and effect” that the DOD, the VA, and our White House is demanding to single toxic chemical element for death and disability compensations.

Attachment 2 documents just how ridiculous this stand by the VA really is with respect to actual science, medical facts, statistics, and above all common sense with regard to this most prolific Vietnam Veterans nerve disorder. With wide ranging symptoms from constant discomfort and much pain to mimicking a muscular dystrophy issue with wasting and weakness of the limbs requiring a wheel chair or leg braces.

**(NAS/IOM is the government-contracted agency that associates Veterans Medical Issues in assisting DOD cover-ups and mistakes. The same government contracted agency that for 10 years led the finger pointing that stress in a 100-hour war where the enemy was retreating and being slaughtered caused all the death, disability, and birth defects in our returning Gulf War Veterans.) Veterans now know better after 10’s of thousands became disabled and/or died and other INDEPENDENT studies show stress had nothing to do with this death and disablement.

Many Veterans that have dealt with the NAS/IOM and their total bias are now concluding they work at the behest of the White House/DVA connection only. Given requests to IOM to define the "evidences" of presumptive service and service connection, but in no way does anyone specify what that is or what level of proof is required; at least that anyone will admit.

Because NAS/IOM is a separate and private entity from the VA then the IOM is wholly subject and liable to both political and legal methods.

Many are suggesting Veterans and their families take NAS/IOM (and specific individuals within the NAS/IOM) to task under tort claims and malpractice, discrimination, and bias inside the Veteran’s arena. (Very similar to those individuals within the top levels of the VA that the Vietnam Veterans of America are now taking to court for their willful and wanton cover-ups of SHAD testing.) Since they signed the papers and documents, they must now defend their convictions regardless of who in the DOD/VA directed such nefarious actions against Veterans for the sake of the DOD and/or politics and money.

One of the jobs of our congress as our elected government officials is to make sure that no government collaboration or conspiratorial actions can or will take place against any single segment of society. It should not matter that we once wore the uniform of the United States Military.

When you created the Veteran, you do not lay aside the citizen.

Is this then their reward for serving an ungrateful Congress and President(s) who would rather protect chemical companies than support those who defended the constitution and then have no rights to its very protection.

One of the definitions of "honorable" is, "characterized by integrity: guided by a high sense of honor and duty." While that certainly fits the men this nation sent to do battle for 10 years. In our toxic chemicals (plural) legacy our own government has not been forthcoming nor honorable.

I will close with a statement by Congressman Shays from the 2000 Government Oversight Review of the Ranch Hand Study:

“At what level do you think Government should consider compensation? Should we have a no shadow of a doubt? The reason why I am asking the question is I have concluded, based on our work that we have done on Gulf War illnesses, based on our review of Agent Orange, that I have to be honest with our veterans. By the time we will know the scientific data, you are dead. You will either have died early or you will have died in your old age in pain, but you will not get help from the Federal Government.”

What the congressman left out was; this is all White House/DOD/VA purposefully calculated and planned.

Charles Kelley

DMZ Veteran 67-68

SP5Kelley2nd94th@aol.com

Update

Meeting in Washington DC on Dec 6^th at 10:00

What I will be presenting on the 6th and submitting as evidence in attachments are below:

Although I have made some corrections and cut down a few items, I am not going to post those, as you will get the idea.

http://www.2ndbattalion94thartillery.com/Chas/housecom.htm

http://www.2ndbattalion94thartillery.com/Chas/Vacattachment1.htm

http://www.2ndbattalion94thartillery.com/Chas/Vacattachment2.htm

http://www.2ndbattalion94thartillery.com/Chas/Vacattachment3.htm

http://www.2ndbattalion94thartillery.com/Chas/Vacattachment4.htm

http://www.2ndbattalion94thartillery.com/Chas/Vacattachment5.htm

I did find another study that shows the cytokine changes I discussed already and after I get back from DC again I am working on my failure matrix and "failure modes and effects" and hope to have the Emory University doctors who did the "Dioxin Exposure Risk Analysis" review it. Very possibly send it out for peer review after that and then get it published. That is the only way I see to fight this issue and force a very adversarial NAS/IOM to also review the published "peer reviewed" findings.

I also found some evidence that the chemical companies made an attempt to block the EPA's release of their "dioxin reassessment" in 1994 after the White House got out of their britches, which the VA continues to ignore anyway.

I did find even more info on the linear dose issues. It seems in some studies it works out that a lower dose develops medical issues that the higher dose will not or did not, such as thymus atrophy.

Those that read the book would recall I indicated that the linear dose "mandated by the government" did not exist in many disorders. Not in a toxic chemical that acts like a hormone. A higher dose does not always mean a more aggressive or an acute disorder only a “possible different disorder.”

Glenda will be presenting after me on the "neuropsychological issues" related to these neurotoxic chemicals. Her closing will be http://www.2ndbattalion94thartillery.com/Chas/claimdenied.htm

There is another in the series of planned meetings in DC in April just like this one. However, if we do not get at least some "action items" out of this meeting then to me it is just politicians playing the political game and that is the end of it for me. I got better things to do with my money and my time than play politics with politicians who could care less.

But I will give it one last shot!

Just got word yesterday they cut us from three hours of presentations to two hours of presentations. Almost not worth going. I guess if Veterans were taking steroids we would get all day and days on end.

Out of home from this Sunday till at least Wednesday.

Best to all,

Kelley

SP5Kelley2nd94th@aol.com

DEC. 29, 2005

Hi to all,

I posted a Status Update at http://www.2ndbattalion94thartillery.com/Chas/StatusUpdate.htm

I am also attaching a Department of Veterans Affairs .pdf file to this e-mail.

This .pdf is on the PTSD like symptoms caused by MEFLOQUINE.

Sorry about the attachment but I cannot post that on my site since I do not have the actual software.

Best to all,

Kelley

--------------------------------

code:

DEPARTMENT OF VETERANS AFFAIRS
Veterans Health Administration
Washington DC 20420
IL 10-2004-007
In Reply Refer To: 13
June 23, 2004
UNDER SECRETARY FOR HEALTH'S INFORMATION LETTER
POSSIBLE LONG-TERM HEALTH EFFECTS FROM THE MALARIAL PROPHYLAXIS MEFLOQUINE (LARIAM)
1. Purpose. This Under Secretary for Health’s Information Letter provides information to clinicians who examine and provide care to veterans who may have taken mefloquine as a malaria prophylaxis while on active duty in Southwest Asia during Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF).
2. Background
a. During OIF and OEF, the United States (U.S.) Department of Defense (DOD) provided mefloquine (Lariam) to some U.S. service members to protect them against endemic malaria.
b. Mefloquine is approved by the U.S. Health and Human Services Food and Drug Administration (FDA) for protection against malaria, and since the late 1980s it has become widely recommended for malaria chemoprophylaxis. Mefloquine can cause common mild side effects including vivid dreams and mild psychiatric symptoms, which can be sufficiently uncomfortable as to affect compliance. In addition, a number of anecdotal and media reports have suggested that mefloquine has caused more serious effects, including violent and suicidal behavior, and symptoms similar to Post-traumatic Stress Disorder (PTSD). These media accounts link reports of such behavior to mefloquine use among returning OIF and OEF veterans, for example, homicides and suicides among five service members returning to Ft. Bragg, NC, in the Summer of 2002. Concerns that mefloquine might cause violent behavior is not new; a Canadian soldier accused of homicide claimed that taking mefloquine, while deployed to Somalia in 1992, had caused his violent behavior.
c. Adding to this concern, the DOD warning label “Information for Clinicians” for mefloquine (taken essentially from the equivalent FDA label), includes the following:
“Rare instances of suicide in patients taking mefloquine have been reported but no studies have demonstrated a statistical association between mefloquine use and suicide, suicidal ideas, suicide attempts, or any other violent behavior. Patients with a history of psychiatric illness may be vulnerable to mefloquine-related psychiatric symptoms, and the package insert recommends against prescribing (it) to patients with a history of psychiatric or alcohol problems. Often, potential neuropsychiatric side effects are the greatest concern for patients. Side effects may include anxiety, paranoia, depression, agitation, restlessness, mood changes, panic attacks, forgetfulness, hallucinations, aggression, and psychotic behavior. Symptoms may continue long after mefloquine use has been stopped. If neuropsychiatric symptoms occur, mefloquine use should be discontinued in favor of other prophylactic medications or
IL 10-2004-007
June 23, 2004
2
measures. Potential side effects that can impair reaction time and thinking include sensory and motor neuropathies, encephalopathy, convulsions, psychosis, nightmares, dizziness, and confusion. Studies indicate that these may occur in 1 in 2,000 to 1 in 13,000 people who receive prophylactic mefloquine.”
d. VHA held a meeting April 13, 2004, to discuss possible responses to this issue. The meeting included representatives from the Office of Public Health and Environmental Hazards and Office of Patient Care Services’ Medical-Surgical, Mental Health, and Pharmacy Benefits & Management, and other VHA leaders and experts in neurology, mental health, infectious disease, and toxicology. The group concluded that the Department of Veterans Affairs (VA) needed a well-grounded response to current concerns among veterans, their families, Congress, the media, VA health care providers, and others about possible long-term health effects and disability among OIF and OEF veterans from taking mefloquine. In particular, VHA health care providers will need concise and accurate medical information about mefloquine health effects to answer questions and concerns of veterans who are returning from deployments in Southwest Asia.
e. To develop guidance on possible long-term and chronic health effects from mefloquine, this group conducted a literature review of more than sixty reports that included eight surveys of travelers, 34 case reports of adverse events, two Cochrane reviews, seven epidemiological studies including clinical trials and prospective studies, and nine general reviews of multiple case reports, which included manufacturer and FDA warning label summaries. The most recent Cochrane review (2004) examined ten clinical trials involving 2750 adult participants, five of which were field trials, mainly of male soldiers.
3. Guidance
a. The following summary is to assist VA health care providers when they are providing care to veterans who may have taken mefloquine while on active duty. Since there are no practical tests for mefloquine, nor are there any specific tests that can be recommended specifically for veterans who took mefloquine while on active duty, medical care needs to focus upon occupational health issues: e.g., taking a thorough military and medical history, including taking of mefloquine, along with a basic medical examination that includes appropriate laboratory tests relating to the veteran's complaints and medical findings.
b. Review of available literature (see Att.A for references and summaries) suggests that certain health effects may be associated with mefloquine, some of which may persist after the drug is stopped. Self-reported symptoms in “travelers surveys” include: insomnia, mood impairment, depression, “strange thoughts,” altered spatial perception, sleeping disturbances, fatigue, dizziness and other neuropsychiatric effects, lasting in some instances more than 2 months. Clinical trials and epidemiological studies suggest that reported side effects are not common, are self-limiting, and include: depression, panic attacks, anxiety, insomnia, vertigo, nausea and headache, and strange or vivid dreams. However, such studies have only limited power to detect more rare and serious adverse events.
c. The most severe and persistent adverse effects appear in “case reports.” In those instances, consistent with the nature of a case report, the relevant signs and symptoms began while mefloquine was being taken, and persisted in some reports for weeks, months or even years after the drug was stopped. NOTE: Mefloquine has a long half-life in humans of 15 to 30 days. Adverse effects that are reported to persist for significant periods after the drug is stopped, or that could be associated with long-term health effects, include the following which lists in decreasing frequency the cases; NOTE: The reported number of individual cases and the number of published reports for that health effect are shown in parenthesis; i.e., 16/12 means that there were sixteen reported cases and twelve published reports.
(1) Anxiety, paranoia, hallucinations, depression, suicidal ideation, cognitive and other neuropsychiatric symptoms (16/12),
(2) Acute and paranoid psychosis (10/9),
(3) Convulsions, grand mal seizures, coma and abnormal electroencephalography (EEG) (9/4),
(4) High frequency sensorineural hearing loss and tinnitus, with partial or no remission (3/1),
(5) Acute lung injury with diffuse alveolar damage (2/1),
(6) Elevated liver function tests or fatty liver (2/2),
(7) Multifocal myoclonus (1/1),
(8) Fatal toxic epidermal necrolysis (1/1),
(9) Trigeminal sensory neuropathy (1/1),
(10) Atrial flutter (1/1), and
(11) Mefloquine overdose induced encephalopathy (1/1).
d. Veterans need to be informed that seeking care for possible mefloquine-related conditions does not constitute a claim for compensation. NOTE: Veterans wishing to file a compensation claim need to be referred to a Veterans Benefits Counselor, or advised to contact the appropriate VA Regional Office at 1-800-827-1000.
4. Contact. Questions regarding this information letter may be addressed to the Environmental Agents Service (131) at (202) 273-8579.
S/ Arthur S. Hamerschlag for
Jonathan B. Perlin, MD, PhD, MSHA, FACP
Acting Under Secretary for Health
DISTRIBUTION: CO:
E-mailed 6/23/04
FLD:
VISN, MA, DO, OC, OCRO, and 200 – E-mailed 6/23/04
IL 10-2004-007
June 23, 2004
ATTACHMENT A
SUMMARY OF LITERATURE ON POSSIBLE LONG-TERM CHRONIC HEALTH EFFECTS FROM MEFLOQUINE
1. To develop guidance on possible long-term health effects from mefloquine, a Veterans Health Administration (VHA) expert group that included representatives from the Office of Public Health and Environmental Hazards and Office of Patient Care Services’ Medical-Surgical, Mental Health, and Pharmacy Benefits & Management, and other VHA leaders and experts in neurology, mental health, infectious disease, and toxicology, conducted a literature review that located seven health surveys of travelers, thirty-four case reports of adverse events, two Cochrane reviews, six epidemiological studies including clinical trials and prospective studies, and nine general reviews of multiple case reports including manufacturer and Food and Drug Administration (FDA) warning label summaries. In addition the two Cochrane reviews (the most recent dated 2004) examined ten clinical trials involving 2750 adult participants. Five of those were field trials, mainly of male soldiers. The following table, sorted by study-type, then by date, summarizes this information.
Title, Authors, Reference
Date
Study Type - Subjects
Major Findings
“Low body mass index is associated with an increased risk of neuropsychiatric adverse events and concentration impairment in women on mefloquine,” van Riemsdijk MM, Sturkenboom MC, Ditters JM, Tulen JH, Ligthelm RJ, Overbosch D, Stricker BH; British Journal of Clinical Pharmacology, 2004;57(4):506-12.
2004
Survey of 151 Dutch travelers from 1999 to 2000 before and up to 3 weeks (pre travel) after taking mefloquine
Significant impairment of mood state observed subjects with body mass index (BMI) < or = 20 kg m(-2); Stratification for gender showed that the total mood disturbance in females in the lowest BMI category significantly increased by 8.42 points [95 percent confidence interval (CI) 3.33, 13.50], whereas BMI did not affect the risk in males; Stratification for history of use of mefloquine showed that the risks were highest in first-time users; An sustained attention performance test showed reaction time in women with a BMI < or = 20 kg m(-2) increased significantly by 22.5 ms (95 percent CI 7.80, 37.20), whereas reaction time in men showed a slight and nonsignificant decrease. CONCLUSION: Risk factors for mefloquine-associated neuropsychiatric adverse events and concentration impairment are female gender, low BMI, and first-time use. The frequency of neuropsychiatric effects is highest in women with a BMI < or = 20 kg m(-2).
“Many travelers suffer of side-effects of malaria prophylaxis,” Rietz G, Petersson H, Odenholt I; Lakartidningen, 2002 Jun 27;99(26-27):2939-44.
2002
Survey of about 500 Swedish travelers before and after their trip, with 62 percent response rate
Travelers taking any malarial prophylaxis reported greater rate of symptoms compared to controls (59 percent vs. 41 percent), and that their trip had been negatively affected by their symptoms; Neuropsychiatric symptoms most common among mefloquine takers but the difference was not significant; Travelers taking mefloquine more frequently associated their symptoms with that drug; travelers most worried about taking malaria prophylaxis prior to the trip reported symptoms more often than those not feeling any anxiety.
A-1
IL 10-2004007
June 23, 2004
Title, Authors, Reference
Date
Study Type - Subjects
Major Findings
“Neuropsychiatric events during prophylactic use of mefloquine before traveling,” van Riemsdijk MM, Ditters JM, Sturkenboom MC, Tulen JH, Ligthelm RJ, Overbosch D, Stricker BH; European Journal of Clinical Pharmacology, 2002 Sep;58(6):441-5.
2002
Survey 179 Dutch travelers from 1999 to 2000 before and for three weeks after taking mefloquine (prior to traveling)
Females reported adverse events more frequently than males ( P=0.005); Small but significant increase in the score on the domain fatigue [0.74 points, 95 percent confidence interval (CI) 0.18, 1.30 exclusively in females and not in males; First-time users increased 2.81 points (95 percent CI 0.70, 4.92) on mood state test, and among those, women showed the largest increase of 4.58 points (95 percent CI 0.74, 8.43). The use of mefloquine was associated with neuropsychiatric adverse effects. Females encountered neuropsychiatric effects more frequently than males, which could be confirmed by validated psychological tests. Neuropsychiatric effects were more common in first-time users than in individuals who had used mefloquine before.
“Reported side effects to chloroquine, chloroquine plus proguanil, and mefloquine as chemoprophylaxis against malaria in Danish travelers,” Petersen E, Ronne T, Ronn A, Bygbjerg I, Larsen SO; Journal of Travel Medicine, 2000 Mar-Apr;7(2):79-84.
2000
Survey of self reports among 5, 446 Danish travelers from 1996 to 1998
5, 446 Danish travelers surveyed (76.3 percent response) on drug compliance, hospitalization and premature termination of travel, following use of chloroquine, chloroquine plus proguanil, or mefloquine; Compliance significantly better for mefloquine users (83.3 percent among short term travelers re. 76.3 percent among chloroquine plus proguanil users); 84.8 percent, 59.3 percent and 69.5 percentreported no symptoms using chloroquine, chloroquine plus proguanil, and mefloquine, respectively; 0.6 percent, 1.1 percent and 2.8 percent reported "unacceptable" symptoms, respectively; Compared to chloroquine, mefloquine users had a significantly higher relative risk (RR) of reporting depression, RR 5.06 (95 percent CI 2.71 - 9.45), "strange thoughts," RR 6.36 (95 percent CI 2.52 - 16.05) and altered spatial perception, RR 3.00 (95 percent CI 1.41 - 6.41). CONCLUSION: Overall mefloquine is tolerated at least as well as chloroquine plus proguanil and shows better compliance, however, symptoms related to the central nervous system are more prevalent in mefloquine users and when symptoms develop, they are perceived as more severe.
“Neuropsychiatric problems in 2,500 long-term young travelers to the tropics,” Potasman I, Beny A, Seligmann H;,Journal of Travel Medicine, 2000 Jan;7(1):5-9.
2000
Survey ofneuropsychiatric problems and previous psychological consultation of 2,500 young travelers to tropical countries
Out of 1,340 respondents, 151 (11.3 percent) reported they had neuropsychiatric problems (NPP) during travel compared to 2.3 percent who needed psychological consultation before travel (probability (p) <.001); In a follow up, 117 of 151 responded to a study questionnaire (mean age 24.4 years, 54.7 percent female, mean stay abroad 5.3 months) the most common reported NPP were sleeping disturbances (52.1 percent), fatigue (48.7 percent) and dizziness (39.3 percent).; 33 (2.5 percent) reported severe symptoms, 16 (1.2 percent) had symptoms lasting more than 2 months; 7 had pure or mixed depressive symptoms; Consumption of recreational drugs admitted by 22.2 percent; Mefloquine used significantly more often by those who suffered NPP, compared to the entire cohort (98.2 percent vs. 70.7 percent; p<.001); CONCLUSIONS: Long-term travel to the tropics was associated, in this cohort, with a considerable rate of neuropsychiatric symptoms. The majority of the responding travelers were females, used mefloquine as prophylaxis, and at least one fifth used recreational drugs. A-2
IL 10-2004-007
June 23, 2004
Title, Authors, Reference
Date
Study Type - Subjects
Major Findings
“Adverse effects associated with antimalarial chemoprophylaxis,” Corominas N, Gascon J, Mejias T, Caparros F, Quinto L, Codina C, Ribas J, Corachan M.; Medicina Clinica, 1997 May 24;108(20):772-5.
1997
Survey of 1,054 Spanish travelers who traveled from 1992 to 1994
Self reports among 1,054 travelers taking various malarial prophylaxis including mefloquine; 18.4 percent reported adverse reactions including 12.4 percent on chloroquine, 17.2 percent on chloroquine + proguanil, and 20.3 percent on mefloquine (differences not significant); Neuropsychiatric reactions more frequent in the mefloquine group (p < 0.01); Gastrointestinal reactions less common in the chloroquine group (p = 0.04); Transitory eye disorders more frequent in the chloroquine + proguanil group (p = 0.01); Travelers with adverse reactions in mefloquine group had significantly lower weight than those who did not present them (p < 0.01); Mefloquine has greater neuropsychiatric toxicity and is worse tolerated in low weight patients.
“Neuro-psychiatric effects of antimalarials,” van Riemsdijk MM, van der Klauw MM, van Heest JA, Reedeker FR, Ligthelm RJ, Herings RM, Stricker BH; European Journal of Clinical Pharmacology, 1997;52(1):1-6.
1997
Survey 394 Dutch travelers taking mefloquine, within 14 days of return, compared to travelers taking other malarial prophylaxes
Questionnaire consisted of questions regarding use of alcohol, smoking, general health, medical history, tropical diseases during the trip, and other medicines, and contained an extensive list of general complaints regarding all body systems at four levels of severity. A modified and validated version of the Profile of Mood States was included. RESULTS: In the study period, 2541 persons visited the Travel Clinic, of whom 1791 (70 percent) were both eligible and willing to co-operate. Of these 1791, data were obtained from 1501 (84 percent). Insomnia was most frequently encountered in users of mefloquine and mouth ulcers in proguanil users. After adjustment for gender, age, destination, and alcohol use, the relative risk for insomnia to mefloquine versus non-users of antimalarials was 1.6, and the excess risk was 6 per 100 users over an average period of 2 months. There were no significant differences between groups in depression, anxiety, agitation, and confusion. Stratification by gender demonstrated that insomnia was more common in women on mefloquine, but not in men. Also, women more frequently mentioned palpitations as an adverse event. After adjustment for age, destination, and alcohol use in women, the relative risks for insomnia and palpitations to mefloquine versus non-use of antimalarials were 2.4, and 22.5, respectively. When travelers were specifically asked for the adverse reactions they had experienced, anxiety, vertigo, agitation, and nightmares were significantly more frequently mentioned by mefloquine users. CONCLUSION: Insomnia was more commonly encountered during use of mefloquine than proguanil or during non-use of antimalarials. A-3
IL 10-2004007
June 23, 2004
Title, Authors, Reference
Date
Study Type - Subjects
Major Findings
“Comparison of adverse events associated with use of mefloquine and combination of chloroquine and proguanil as antimalarial prophylaxis: postal and telephone survey of travelers,” Barrett PJ, Emmins PD, Clarke PD, Bradley DJ; British Medical Journal, 1996; 313:528-8.
1996
Survey of 1214 British travelers from 1993 to 1995 who received advice from the travelers telephone health line run by the Medical Advisory Services for Travelers Abroad. Travelers received a questionnaire upon returning from their trip.
27 percent of travelers taking mefloquine reported neuropsychiatric adverse events. The traveler sought medical advice in 2.2 percent of the cases and 0.3 percent required hospital attention. Of those taking chloroquine and proguanil, 16 percent reported neuropsychiatric adverse events with 0.9 percent requiring medical advice and 0.1 percent hospital attention. Of those reporting any adverse event with mefloquine, 5.1 percent discontinued antimalarial prophylaxis and 0.7 percent switched to another agent. The corresponding numbers for chloroquine and proguanil were 6.3 percent and 0.3 percent. Disabling neuropsychiatric adverse events included hallucinations, panic attacks, dissociation from reality, confusion, difficulty concentrating, depression, anxiety, emotional instability depression, anxiety, personality changes, and nightmares.
Centers for Disease Control & Prevention (CDC) National Center for Infectious Diseases, Travelers’ Health, Information for the Public: Prescription Drugs for Malaria, accessed 4-21-04 at www.cdc.gov/travel/malariadrugs.htm
2004
Review -- Travelers Advisory from CDC
The most common side effects reported by travelers taking mefloquine include headache, nausea, dizziness, difficulty sleeping, anxiety, vivid dreams, and visual disturbances. Mefloquine has rarely been reported to cause serious side effects, such as seizures, depression, and psychosis. These serious side effects are more frequent with the higher doses used to treat malaria; fewer occurred at the weekly doses used to prevent malaria. Mefloquine is eliminated slowly by the body and thus may stay in the body for a while even after the drug is discontinued. Therefore, side effects caused by mefloquine may persist weeks to months after the drug has been stopped. Most travelers taking mefloquine do not have side effects serious enough to stop taking the drug.
Travelers Who Should Not Take Mefloquine. The following travelers should not takmefloquine and should ask their health care provider for a different antimalarial drug
a. Persons with active depression or a recent history of depression
b. Persons with a history of psychosis, generalized anxiety disorder, schizophrenia, or other major psychiatric disorder
c. Persons with a history of seizures (does not include the type of seizure caused by high fever in childhood)
d. Persons allergic to mefloquine
Mefloquine is not recommended for persons with cardiac conduction abnormalities (for example, an irregular heartbeat). A-4
IL 10-2004-007
June 23, 2004
Title, Authors, Reference
Date
Study Type - Subjects
Major Findings
CDC National Center for Infectious Diseases, Travelers’ Health, Information for Health Care Providers, Prescription Drugs for Malaria, accessed 4-21-04 at www.cdc.gov/travel/malariadrugs2.htm.
2004
Review -- Physicians Advisory put out by CDC
Mefloquine is contraindicated in persons allergic to mefloquine and in persons with active depression or a previous history of depression, generalized anxiety disorder, psychosis, schizophrenia, other major psychiatric disorders, or seizures. Not recommended for persons with cardiac conduction abnormalities. Mefloquine primary prophylaxis should begin 1-2 weeks before travel to malarious areas. It should be continued once a week, on the same day each week, during travel to malarious areas, and for 4 weeks after the traveler leaves such areas. Mefloquine has been associated with rare serious adverse reactions (including psychoses or seizures) at prophylactic doses; these reactions are more frequent with the higher doses used for treatment. Other side effects that occur with prophylactic doses include gastrointestinal disturbance, headache, insomnia, abnormal dreams, visual disturbances, depression, anxiety disorder, and dizziness. Mefloquine is contraindicated for use by travelers with a known hypersensitivity to mefloquine and in persons with active depression or a history of depression, or in persons with generalized anxiety disorder, psychosis, schizophrenia, or other psychiatric disturbances. Mefloquine is contraindicated in persons with a history of seizures (not including the type of seizure caused by high fever in childhood). Mefloquine is not recommended for persons with cardiac conduction abnormalities.
U.S. Department of Health & Human Services, U.S. Food and Drug Administration, FDA News, P03-52, July 9, 2003, “FDA Creates Medication Guide for Lariam.” Accessed 4-21-04 at www.fda.gov/bbs/topics/NEWS/2003/NEW00921.html
2004
Review -- FDA Medication Guide
FDA developed the Lariam (mefloquine) Medication Guide in collaboration with the drug's manufacturer, Roche Pharmaceuticals of Nutley, NJ, to help ensure patients understand the risks of malaria, and the rare but potentially serious psychiatric adverse events associated with use of Lariam. Sometimes these psychiatric adverse events may persist even after stopping the medication. Some rare reports have claimed that Lariam users think about killing themselves. There have been rarer reports of suicides, although FDA does not know if Lariam use was related to these suicides. A-5
IL 10-2004007
June 23, 2004
Title, Authors, Reference
Date
Study Type - Subjects
Major Findings
“Mefloquine for preventing malaria in non-immune adult travelers, Review,” The Cochrane Database of Systematic Reviews, Copyright 2004 The Cochrane Library, Volume (1), Croft, AMJ; Garner, P.
2004
Review – Cochrane review of We included 10 trials involving 2750 non-immune adult participants. Five were field trials, mainly male soldiers. Also reviewed 516 published case reports of mefloquine adverse effects, 63 percent involved tourists and business travelers
Mefloquine prevents malaria, but has adverse effects that limit its acceptability. Evidence from non-randomised studies shows mefloquine has potentially harmful effects in tourists and business travellers. No-one knows if mefloquine is well or poorly tolerated. Many of the standard textbooks of tropical medicine assert that mefloquine is well tolerated in prophylaxis and that the only side effects of importance are neuropsychiatric reactions or seizures, experienced by around one in 10,000 users. This much-cited estimate of the frequency of neuropsychiatric side effects from mefloquine is based not on experimental data, but on spontaneous reports of severe adverse events in mefloquine users, and undoubtedly under-estimates the true incidence of undramatic but nevertheless unpleasant side effects from mefloquine. The main problem with mefloquine is that its tolerability is a major concern of the public, with questions raised repeatedly in the news media. Yet evidence to reassure the public, or confirm their fears, is not available. Withdrawals during clinical trials of mefloquine group were consistently higher in four placebo controlled trials (odds ratio 3.56, 95 percent confidence interval 1.67 to 7.60). In five trials comparing mefloquine with other chemoprophylaxis, no difference in tolerability was detected. There were four fatalities attributed to mefloquine.
Roche Pharmaceuticals "Dear Healthcare Professional" letter about mefloquine side effects, “Copyright © 2003 by Roche Laboratories Inc. All rights reserved,” at www.fda.gov/cder/foi/label/2003/19591s19lbl_Lariam.pdf,
2003
Review--Manufacturer’s warning letter to clinicians
“Lariam can rarely cause serious mental problems in some patients. The most frequently reported side effects with Lariam, such as nausea, difficulty sleeping, and bad dreams are usually mild and do not cause people to stop taking the medicine. However, people taking Lariam occasionally experience severe anxiety, feelings that people are against them, hallucinations (seeing or hearing things that are not there, for example), depression, unusual behavior, or feeling disoriented. It has been reported that sometimes, in some patients, these side effects continue after Lariam is stopped. Some patients taking Lariam think about killing themselves, and there have been rare reports of suicides. We do not know if Lariam was responsible for these suicides. Do not take Lariam to prevent malaria if you have 1) depression or had depression recently; 2) recent mental illness or problems, including anxiety disorder, schizophrenia or psychosis; 3) seizures; 4) allergic to quinine or quinidine 5) Heart disease; 6) Pregnancy; 7) Breast feeding; or 8) Liver problems.”
“Adverse effects of the antimalaria drug, mefloquine: due to primary liver damage with secondary thyroid involvement?” Croft AM, Herxheimer A; BioMed Central Public Health, 2002 Mar 25;2(1):6.
2002
Review of 516 published case reports – Cochrane Review
Postulate many mefloquine adverse effects are a post-hepatic syndrome caused by primary liver damage; “Mefloquine syndrome” presents in a variety of ways including headache, gastrointestinal disturbances, nervousness, fatigue, disorders of sleep, mood, memory and concentration, and occasionally frank psychosis. Previous liver or thyroid disease, and concurrent insults to the liver (such as from alcohol, dehydration, an oral contraceptive pill, recreational drugs, and other liver-damaging drugs) may be related to the development of severe or prolonged adverse reactions to mefloquine.
A-6
IL 10-2004-007
June 23, 2004
Title, Authors, Reference
Date
Study Type - Subjects
Major Findings
“Drug interactions with antimalarial agents,” Griffin JP; Adverse Drug Reactions and Toxicological Reviews, 1999 Mar;18(1):25-43.
1999
Review of case reports
Case reports enumerates “common” side effects including nausea, vomiting, dizziness and vertigo, loss of balance, headache, sleep disorders, diarrhea and abdominal pain; More rare serious side effects include: 1) psychiatric effects as including depression, anxiety, confusion, psychosis, paranoia, aggression and agitation; 2) Neurological effects including convulsions, sensory and motor neuropathy, paraesthesia, tinnitus, tremor, ataxia and visual disturbances, and encephalopathy has been reported; 3) Cardiovascular effects including blood pressure changes, syncope, bradycardia, extrasystoles, cardiac conduction defects including atrioventricular block; 4) Skin rashes including urticarial rashes, pruritis, hair loss and Stevens-Johnson syndrome; 5) Hematological effects including leucopenia and thrombocytopenia; and 6) Liver enzyme changes. No discussion of how long these effects might last after the drug is stopped.
“Dermatological Adverse Effects with the Antimalarial Drug Mefloquine: a Review of 74 Published case Reports,” Smith HR, Croft AM, Black MM; Clinical and Experimental Dermatology, 1999, 24; 249-254.
1999
Review of 74 case reports on mefloquine dermatological effects published between 1983 and 1997
There is good circumstantial evidence that mefloquine can cause mild and occasionally severe adverse dermatological effects in health travelers and in hospital patients with malaria. These effects are mostly self-limiting and rarely require treatment. Pruritus is the most frequent dermatological reaction and maculopapular rash is also common. Stevens-Johnson syndrome and toxic epidermal necrolysis have all been associated with mefloquine. The incidence of dermatological adverse effects with mefloquine may be between 4 to 10 percent for short-term use and as high as 30 percent for prolonged use.
“CNS adverse events associated with antimalarial agents. Fact or fiction?;” Phillips-Howard PA, ter Kuile FO; Drug Safety : An International Journal of Medical Toxicology and Drug Experience, 1995 Jun;12(6):370-83.
1995
Review
Mefloquine therapy causes dose-related transient dizziness; and serious central nervous system (CNS) events occur in 1:1200 Asians and 1:200 Caucasians/Africans; Risk factors include dosage, concomitant drug use/interactions, previous history of a CNS event and disease severity; Retreatment (within a month) increases the risk in Asians 7-fold; Irreversible effects are extremely rare and usually associated with overdosing or prior history of a serious CNS event.
“Mefloquine prophylaxis: an overview of spontaneous reports of severe psychiatric reactions and convulsions,” Bem JL, Kerr L, Stuerchler D; The Journal of Tropical Medicine and Hygiene, 1992 Jun;95(3):167-79.
1992
Review of adverse reaction reports since 1991 (about 1 year) by the manufacturer Hoffmann-La Roche .
59 serious neurologic and psychiatric adverse reaction reports reviewed: 26 convulsions, 12 depressions, 20 psychotic episodes, and one toxic encephalopathy; none were fatal; Only patient population identified at increased risk of developing these serious reactions are persons with a history of seizures or manic-depressive illness.
“Neuropsychiatric side effects after the use of mefloquine,” Weinke T, Trautmann M, Held T, Weber G, Eichenlaub D, Fleischer K, Kern W, Pohle HD; Am The Journal of Tropical Medicine and Hygiene, 1991 Jul;45(1):86-91.
1991
Review of case reports
Reviewed neuropsychiatric side effects in German patients after treatment with mefloquine; Reactions consisted mainly of seizures, acute psychoses, anxiety neurosis, and major disturbances of sleep-wake rhythm; Effects occurred after both therapeutic and prophylactic intake; Estimated that one of 8,000 mefloquine users suffers from such reactions (one of 215 among therapeutic users, one of 13,000 among prophylaxis users). A-7
IL 10-2004007
June 23, 2004
Title, Authors, Reference
Date
Study Type - Subjects
Major Findings
“The acute neurotoxicity of mefloquine may be mediated through a disruption of calcium homeostasis and ER function in vitro,” Dow GS, Hudson TH, Vahey M, Koenig ML; Malaria Journal, 2003 Jun 12;2(1):14.
2003
Mechanistic study
Investigated the possibility that the acute in vitro neurotoxicity of mefloquine might be mediated through a disruptive effect of the drug on endoplasmic reticulum (ER) calcium homeostasis. Mefloquine was found to disrupt neuronal calcium homeostasis and induce an ER stress response at physiologically relevant concentrations, effects that may contribute, at least in part, to the neurotoxicity of the drug in vitro
“The risk of severe depression, psychosis or panic attacks with prophylactic antimalarials,” Meier CR, Wilcock K, Jick SS; Drug Safety : An International Journal of Medical Toxicology and Drug Experience, 2004;27(3):203-13.
2004
Epidemiologic study.A population-based observational study using a database of medical records to quantify and compare the risk of psychiatric disorders during or after use of mefloquine with the risk during use of proguanil and/or chloroquine, or doxycycline
The study population was drawn from the large UK-based General Practice Research Database (GPRD). Subjects were aged from 17-79 years and were exposed to mefloquine, proguanil, chloroquine or doxycycline (or a combination of these drugs) at some time between 1990 and 1999. We performed a person-time and a nested case-control analysis to assess the risk of developing a first-time diagnosis of depression, psychosis or panic attack during or after use of these antimalarial drugs. RESULTS: Within the study population of 35 370 subjects (45.2 percent males), we identified 580 subjects with a first-time diagnosis of depression (number of subjects (n) = 505), psychosis (n = 16) or panic attack (n = 57) and two subjects committed suicide. The incidence rates of first-time diagnoses of depression during current use of mefloquine, proguanil and/or chloroquine, or doxycycline, adjusted for age, gender and calendar year, were 6.9 (95 percent CI 4.5-10.6), 7.6 (95 percent CI 5.5-10.5) and 9.5 (95 percent CI 3.7-24.1)/1000 person-years, respectively. The incidence rates of psychosis or panic attacks during current mefloquine exposure were 1.0/1000 person-years (95 percent CI 0.3-2.9) and 3.0/1000 person-years (95 percent CI 1.6-5.7), respectively, approximately 2-fold higher (statistically nonsignificant) than during current use of proguanil and/or chloroquine, or doxycycline. The nested case-control analysis encompassed 505 cases with depression and 3026 controls, 16 cases with psychosis and 96 controls, and 57 cases with a panic attack and 342 controls. Current use of mefloquine was not associated with an elevated risk of developing depression. In a comparison between patients currently using mefloquine with all past users of antimalarials combined, the risk estimate was elevated for current users of mefloquine for both psychosis (odds ratio (OR) 8.0, 95 percent CI 1.0-62.7; p < 0.05) and panic attacks (OR 2.7, 95 percent CI 1.1-6.5; p < 0.05). CONCLUSION: The absolute risk of developing psychosis or panic attack appears low with all the antimalarials tested. No evidence was found in this large observational study that mefloquine use increased the risk of first-time diagnosis of depression when compared with the use of other antimalarials investigated in this study. A-8
IL 10-2004-007
June 23, 2004
Title, Authors, Reference
Date
Study Type - Subjects
Major Findings
“Atovaquone plus chloroguanide versus mefloquine for malaria prophylaxis: a focus on neuropsychiatric adverse events,” van Riemsdijk MM, Sturkenboom MC, Ditters JM, Ligthelm RJ, Overbosch D, Stricker BH; Clinical Pharmacology and Therapeutics, 2002 Sep;72(3):294-301.
2002
Epidemiologic study,prospective, double-blind, randomized study on neuropsychiatric adverse events and concentration impairment during prophylactic use of mefloquine or atovaquone plus chloroguanide
119 Subjects (mean age 35 years) followed from baseline screening to 7 days after leaving malaria area, measuring changes in mood disturbance and neurobehavioral indices including sustained attention, coding speed, and visuomotor accuracy; Significant deterioration in depression, anger, fatigue, vigor, and total mood disturbance domains occurred during use of mefloquine but not during use of atovaquone plus chloroguanide; Stratification on sex showed between-treatment differences in female patients but not in male patients; In both treatment groups, sustained attention deteriorated after travel, especially with increased duration of stay. CONCLUSIONS: Prophylactic use of mefloquine was associated with significantly higher scores on scales for depression, anger, and fatigue and lower scores for vigor than prophylactic use of atovaquone plus chloroguanide.
“Neurological, cardiovascular and metabolic effects of mefloquine in healthy volunteers: a double-blind, placebo-controlled trial,” Davis TM, Dembo LG, Kaye-Eddie SA, Hewitt BJ, Hislop RG, Batty KT; British Journal of Clinical Pharmacology, 1996 Oct;42(4):415-21.
1996
Epidemiologic study,Double-blind, randomized, placebo-controlled trial -- 106 healthy adult subjects over 4 weeks
Mefloquine did not alter calcium homoeostasis but produced a mean 0.5 mmol l-1 fall in serum glucose over the study period (p < 0.001) and relative hyperinsulinaemia; Symbol digit modalities, and digit forwards and backwards test scores similar in active and placebo groups across the three assessments, as were lying/standing blood pressure and high-tone hearing loss; Electrocardiographic QTc interval prolongation and diarrhea were mild but transient side-effects of mefloquine (p < 0.01); Neurological symptoms comparable in two groups throughout study; No evidence of drug toxicity in eleven subjects who withdrew. Concluded mefloquine prophylaxis does not appear to produce low-grade but debilitating neurological symptoms or to alter the results of sensitive tests of cerebral function, but it might contribute to hypoglycaemia and cardiac dysrhythmias. A-9
IL 10-2004007
June 23, 2004
Title, Authors, Reference
Date
Study Type - Subjects
Major Findings
“Tolerability of malaria chemoprophylaxis in non-immune travellers to sub-Saharan Africa: multicentre, randomised, double blind, four arm study,” Schlagenhauf P, Tschopp A, Johnson R, Nothdurft HD, Beck B, Schwartz E, Herold M, Krebs B, Veit O, Allwinn R, Steffen R; British Medical Journal,, 2003 Nov 8;327(7423):1078.
2003
Clinical trial;randomized, double blind, with placebo, 623 subjects receiving various malaria prophylaxis including mefloquine
Many subject reported adverse events (even in the initial placebo group); none were serious; Chloroquine and proguanil trial had highest mild to moderate adverse events; followed by mefloquine (64/153; 42 percent, 34 percent to 50 percent), doxycycline, and atovaquone and proguanil (p = 0.048 for all); Mefloquine and combined chloroquine and proguanil arms had the highest proportion of more severe events (n = 19; 12 percent, 7 percent to 18 percent and n = 16; 11 percent, 6 percent to 15 percent, respectively), whereas the combined atovaquone and proguanil and doxycycline arms had the lowest (n = 11; 7 percent, 2 percent to 11 percent and n = 9; 6 percent, 2 percent to 10 percent, respectively: p = 0.137 for all); Mefloquine arm had the highest proportion of moderate to severe neuropsychological adverse events, particularly in women (n = 56; 37 percent, 29 percent to 44 percent versus chloroquine and proguanil, n = 46; 30 percent, 23 percent to 37 percent; doxycycline, n = 36; 24 percent, 17 percent to 30 percent; and atovaquone and proguanil, n = 32; 20 percent, 13 percent to 26 percent: p = 0.003 for all); Highest proportion of moderate or severe skin problems were reported in the chloroquine and proguanil arm (n = 12; 8 percent, 4 percent to 13 percent versus doxycycline, n = 5; 3 percent, 1 percent to 6 percent; atovaquone and proguanil, n = 4; 2 percent, 0 percent to 5 percent; mefloquine, n = 2; 1 percent, 0 percent to 3 percent: P = 0.013). CONCLUSIONS: Combined atovaquone and proguanil and doxycyline are well tolerated antimalarial drugs; Broader experience with both agents is needed to accumulate reports of rare adverse events.
“Unexpected frequency, duration and spectrum of adverse events after therapeutic dose of mefloquine in healthy adults,” Rendi-Wagner P, Noedl H, Wernsdorfer WH, Wiedermann G, Mikolasek A, Kollaritsch H; Acta Tropica, 2002 Feb;81(2):167-73.
2002
Clinical trial; 22 healthy volunteers monitored 21 days with therapeutic mefloquine (750 and 500 mg at 6 hour (h) intervals)
Unexpected high frequency of side effects of any grade reported by all 22 subjects; Most common were vertigo (96 percent), nausea (82 percent) and headache (73 percent); Subjects with severe vertigo (73 percent) required bed rest and specific medication for 1 to 4 days; More females than males reported severe adverse reactions; Majority (77.3 percent) participants (f: 8/12, m: 9/10) showed symptom resolution within 3 weeks (510 h) after drug administration; Biochemical and hematological findings stayed within the normal range of values, but showed nevertheless a significant rise of Na, Cl, Ca, bilirubin, GGT and LDH.
A-10
IL 10-2004-007
June 23, 2004
Title, Authors, Reference
Date
Study Type - Subjects
Major Findings
“Atovaquone-proguanil versus mefloquine for malaria prophylaxis in nonimmune travelers: results from a randomized, double-blind study,” Overbosch D, Schilthuis H, Bienzle U, Behrens RH et al. Clinical infectious diseases, 2001; 33:1015-21
2001
Clinical trial;randomized, double-blind, with placebo evaluating frequency of adverse events. 976 travelers from the Netherlands, UK, Canada, and S. Africa traveling to malaria endemic areas for up to 28days. Individuals were monitored 7, 28, and 60 days after travel.
Treatment emergent neuropsychiatric events occurred in 29 percent of travelers randomized to mefloquine and in 14 percent randomized to atovaquone-proguanil (p=0.001). Events included strange or vivid dreams, insomnia, dizziness, visual difficulties, anxiety, and depression. Most adverse events were considered mild. Treatment was discontinued due to neuropsychiatric events in nineteen subjects receiving mefloquine, in five receiving mefloquine placebo, and in three receiving atovaquone-proguanil.
“Serious adverse events of mefloquine in relation to blood level and gender,” Schwartz E, Potasman I, Rotenberg M, Almog S, Sadetzki S; The American Journal of Tropical Medicine and Hygiene, 2001 Sep;65(3):189-92.
2001
Clinical trial; Mechanistic
Evaluated association between mefloquine serum levels and serious side effects, with seventeen patients presenting to emergency rooms or travel clinics with symptoms suggesting serious adverse effects of mefloquine and twenty-eight controls (healthy people, still taking mefloquine after travel; Mean age patients and controls was 31.5 +/- 11.6 years and 34 +/- 12.2 years, respectively; More women among the patients (76 percent versus 40 percent, respectively; p = 0.03); Most complaints related to central nervous system (13 of 17); five patients interrupted their trip and two were hospitalized; No difference in mefloquine blood levels found comparing patients to control groups; No significant difference found between blood mefloquine levels among men and women; mefloquine blood levels do not correlate with severe adverse events; Women more susceptible than men, despite having similar blood levels of the drug.
“Paranoid psychosis related to mefloquine antimalarial prophylaxis,” Fuller SJ, Naraqi S, Gilessi G; Papua and New Guinea Medical Journal, 2002 Sep-Dec;45(3-4):219-21.
2002
Case report – one subject
A 39-year old marine biologist medically evacuated from New Guinea with paranoid ideation and irrational behavior; Taken mefloquine 2 weeks earlier; No history of illicit drug use or other medications; On admission disoriented, speech rambling, agitated and fearful of medical staff; Afebrile; No unusual lab tests; Diagnosed with acute psychosis secondary to mefloquine, which resolved over the next 2 to 3 days; Patient admitted suffered from endogenous depression for 19 years and had taken meds for that.
“Mefloquine-induced paranoid psychosis and subsequent major depression in a 25-year-old student,” Dietz A, Frolich L; Pharmacopsychiatry, 2002 Sep;35(5):200-2.
2002
Case report – one subject
Patient developed paranoid psychosis followed by depression after taking mefloquine for a vacation; Recovered fully within 9 months of receiving his first dose of mefloquine.
A-11
IL 10-2004007
June 23, 2004
Title, Authors, Reference
Date
Study Type - Subjects
Major Findings
“Multifocal Myoclonus Associated with Mefloquine Chemoprophylaxis,” Jimenez-Huete, A, Gil-Nagel, A, and Franch O; Clinical Neuropharmacology, 25; 5 243, 2002.
2002
Case report – one subject
Case report of a 54 year old Spanish woman developed multifocal myoclonus during mefloquine prophylaxis; Presented with abnormal movements in four limbs; Cerivastatin started 10 months earlier for treatment of hypercholesterolemia; 8 weeks previously started prophylactic mefloquine, and two weeks later during a trip noticed sudden brief shock-like irregular muscular contractions that appeared without pattern in all four limbs, and were more intense at the end of the day; Complained of slight frontal headache, dizziness and slowness of thinking; No known exposures including recreational drugs and friends were asymptomatic; Continued taking mefloquine 3 more weeks while symptoms increased until she could not drive a car; On the 6th week treatment stopped mefloquine and symptoms rapidly abated; Neurological exam 2 weeks later showed infrequent irregular non-synchronous brief muscular contractions in her proximal and distal upper limbs, consistent with multifocal myoclonus; No brain lesions by magnetic resonance imaging (MRI) and EEG normal; Blood tests showed only slight hypercholesterolemia; Follow up exam 2 weeks later showed no abnormal signs.
“Pulmonary toxicity with mefloquine,” Udry E, Bailly F, Dusmet M, Schnyder P, Lemoine R, Fitting JW; The European Respiratory Journal, 2001 Nov;18(5):890-2.
2001
Case report – two subjects
Case 1: Patient developed acute lung injury within hours following mefloquine treatment for a low-level P. falciparum, which was halofantrine resistant; Extensive microbiological investigation remained negative; Video-assisted thoracoscopic lung biopsy demonstrated diffuse alveolar damage; Progress was favorable without treatment; Case 2: Patient experienced acute lung injury and diffuse alveolar damage related to mefloquine; Glucose-6-phosphate dehydrogenase deficiency was present in the former (but not the later, suggesting that it is not a predisposing condition) case and was thought to contribute to the lung injury.
“Mefloquine-induced trigeminal sensory neuropathy,” Watt-Smith S, Mehta K, Scully C; Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and EnDODontics, 2001 Aug;92(2):163-5.
2001
Case report – one subject
Patient with sudden-onset trigeminal sensory neuropathy of the lip associated with taking mefloquine.
“Cognitive and neuropsychiatric side effects of mefloquine,”; Javorsky DJ, Tremont G, Keitner GI, Parmentier AH; The Journal of Neuropsychiatry and Clinical Neurosciences, 2001 Spring;13(2):302.
2001
Case report – one subject
52 year old woman no psychiatric history used mefloquine prophylactically once a week for 3 weeks prior and during a trip to Africa; Previously used mefloquine 4 years without problems; During return flight developed anxiety, paranoia, visual hallucinations, confusion and depressive symptoms; Outpatient treatment continued to show suicidal ideation, other neuropsychiatric symptoms, and cognitive disturbances 3 months after last dose of mefloquine; Hospitalized for inpatient psychiatric treatment; Mildly elevated TSH, positive past exposure to hepatitis A, normal brain MRI, medical history was no help; Drug therapy led to improvement over 4 days; after briefly living with a relative following discharge returned to independent functioning.
A-12
IL 10-2004-007
June 23, 2004
Title, Authors, Reference
Date
Study Type - Subjects
Major Findings
“Danger of malaria self-treatment. Acute neurologic toxicity of mefloquine and its combination with pyrimethamine-sulfadoxine,” Nicolas X, Granier H, Laborde JP, Martin J, Talarmin F; La Presse medicale, 2001 Sep 29;30(27):1349-50.
2001
Case report – one subject
A patient did not follow the prescribed mefloquine dosage and developed acute neurological disorders after overdosing; Patient developed mefloquine related encephalopathy.
“Bipolar disorder after mefloquine treatment,” Even C, Friedman S, Lanouar K; Journal of Psychiatry & Neuroscience, 2001 May;26(3):252-3.
2001
Case report – one subject
50 year old man took mefloquine for a vacation in the Far East, developed after his second 250mg dose depressive symptoms that interrupted his trip; Two weeks later he ended up in a psychiatric hospital with worsening depressive symptoms, suicidal ideation and elusions of guilt and economic ruin (still taking mefloquine); received electroconvulsive therapy over 11 days! He was given drugs for depression for 6 years!
“Prolonged visual illusions induced by mefloquine (Lariam): a case report,” Borruat FX, Nater B, Robyn L, Genton B; Journal of Travel Medicine, 2001 May-Jun;8(3):148-9.
2001
Case report – one subject
[Neuropsychiatric symptoms in preventive antimalarial treatment with mefloquine: apropos of 2 cases]; Lebain P, Juliard C, Davy JP, Dollfus S; L'Encephale, 2000 Jul-Aug;26(4):67-70.
2000
Case report – two subjects
Severe neuropsychiatric reactions in two patients following chemoprophylaxis with mefloquine; Case 1: 43 year old woman developed severe depression with visual and auditive hallucinations and a paranoid delusion; Treated by clomipramine and risperidone; Case 2: 55 year old man presented twice with acute psychosis with confusion following mefloquine prophylaxis; treated with halopridol.
“Mefloquine-induced psychosis,” Havaldar PV, Mogale KD; The Pediatric Infectious Disease Journal, 2000 Feb;19(2):166-7.
2000
Case report – one subject
Case report of mefloquine induced psychosis in a 7-year old Indian child. Hospitalized and diagnosed with cerebrial malaria, quinine treatment failed, mefloquine treatment started. On third day of mefloquine treatment he had loss of sleep and irrelevant talk, and the following day had hallucinations, which worsened. All symptoms of psychosis subsided within 24 hours of stopping mefloquine.
“Seizures after antimalarial medication in previously healthy persons,” Schiemann R, Coulaud JP, Bouchaud O; Journal of Travel Medicine, 2000 May-Jun;7(3):155-6.
2000
Case report – one subject
Case of a grand mal seizure after chloroquine prophylaxis followed by mefloquine therapy in a 19 year old girl who contracted malaria while on vacation, while taking chloroquine and proguanil; Therapy was with mefloquine 1,500 mg, and on the same day she suffered a grand mal seizure.
“Mefloquine-induced acute hepatitis,” Gotsman I, Azaz-Livshits T, Fridlender Z, Muszkat M, Ben-Chetrit E; Pharmacotherapy, 2000 Dec;20(12):1517-9.
2000
Case report – one case
Patient with elevated liver function tests attributed to heart failure experienced acute elevation of liver transaminases 6 weeks after taking mefloquine 250 mg per week; Cessation of the drug caused test results to return to normal.
“Long-lasting neuropsychiatric side-effects following mefloquine prophylaxis. A case after six weeks of initiating and lasting six months,”; Bygbjerg IC, Ronn AM; Ugeskrift for Laeger, 1999 Mar 8;161(10):1422-3.
1999
Case report – one subject
Case of severe neuropsychiatric side-effects arising six weeks after initiating mefloquine prophylaxis, requiring repeated hospitalization, and NOT resolving completely after 6 months, in a previously healthy 30 year-old female.
“Neuropsychiatric side effects of malarial prophylaxis with mefloquine (Lariam),”; Minei-Rachmilewitz T; Harefuah, 1999 Jul;137(1-2):25-7, 87.
1999
Case report – one subject
39-year-old woman who developed acute psychosis after being given mefloquine prophylaxis.
A-13
IL 10-2004007
June 23, 2004
Title, Authors, Reference
Date
Study Type - Subjects
Major Findings
“Acute paranoid hallucinatory psychosis following mefloquine prophylaxis (Lariam),” Kruger E, Grube M, Hartwich P; Psychiatrische Praxis, 1999 Sep;26(5):252-4.
1999
Case report – one subject
Case-report of a patient suffering for the first time from an acute paranoid psychosis induced by mefloquine prophylaxis.
“Mefloquine and ototoxicity: a report of 3 cases,” Fusetti M, Eibenstein A, Corridore V, Hueck S, Chiti-Batelli S; Clinica Terapeutica, 1999;150:379-382.
1999
Case report – 3 subjects
Three cases of high-frequency sensorineural hearing loss and tinnitus following malaria prophylaxis with mefloquine; one patient had partial remission of hearing loss after stopping mefloquine; the remaining two cases the symptomatology remained unchanged; no patients reported improvement of tinnitus.
“Acute fatty liver after malaria prophylaxis with mefloquine,” Grieco A, Vecchio FM, Natale L, Gasbarrini G; Lancet, 1999 Jan 23;353(9149):295-6.
1999
Case report – one subject
“A severe adverse reaction to mefloquine and chloroquine prophylaxis,” Lysack JT, Lysack CL, Kvern BL; Australian Family Physician, 1999 Apr;28(4):310.
1998
Case report – one subject
A 23 year old man no history neurological or psychiatric illness ingested three weekly 228 mg doses mefloquine malaria prophylaxis while in India; Experienced increasingly severe adverse reaction after each dose, including symptoms of paranoia, hallucinations, and suicidal ideation; Discontinued mefloquine switched to chloroquine, but symptoms acutely intensified and became debilitating; Severe symptoms persisted for 12 months following the discontinuation of both antimalarial drugs.
“Convulsions during prophylactic use of mefloquine,” Heeringa M, Kuster JA, Meyboom RH, Bouvy M; Nederlands Tijdschrift voor Geneeskunde, 1999 Jan 30;143(5):273-4.
1999
Case report – 6 subjects
Six patients reported with convulsions attributed to prophylactic use of mefloquine; five had no neurological history; one had history of epilepsy but had had no convulsion during the preceding 5-years; convulsions occurred 1 to 23 days after mefloquine treatment began, and treatment was discontinued after convulsions; four patients with follow-up showed full recovery from convulsions.
“Case study: neuropsychiatric symptoms associated with the antimalarial agent mefloquine,” Clattenburg RN, Donnelly CL; Journal of the American Academy of Child and Adolescent Psychiatry, 1997 Nov;36(11):1606-8.
1997
Case report – one subject
Report on acute neuropsychiatric symptoms in a 10-year-old boy subsequent to his return from travel abroad in Africa, where he had taken the antimalarial agent mefloquine; 4-week course of cognitive-behavioral therapy effectively treated this disorder.
“Fatal toxic epidermal necrolysis associated with mefloquine antimalarial prophylaxis.” McBride SR, Lawrence CM, Pape SA, Reid CA; Lancet, 1997 Jan 11;349(9045):101.
1997
Case report – one subject
“Psychopathological phenomena in long-term follow-up of acute psychosis after preventive mefloquinine (Lariam) administration.” Meszaros K, Kasper S; Der Nervenarzt, 1996 May;67(5):404-6.
1996
Case report – one subject
Report long-term observation of a patient suffering for the first time an acute psychosis following mefloquine prophylaxis
“Atrial flutter with 1:1 conduction after administration of the antimalarial drug mefloquine,” Fonteyne W, Bauwens A, Jordaens L; Clinical Cardiology, 1996 Dec;19(12):967-8.
1996
Case report – one subject
63-year-old male patient with atrial flutter in whom mefloquine use was associated with 1:1 AV conduction; responded to therapy with digoxin and sotalol; patient had a history of palpitations.
A-14
IL 10-2004-007
June 23, 2004
Title, Authors, Reference
Date
Study Type - Subjects
Major Findings
“Acute glomerulonephritis without fever: an unusual presentation of malaria on mefloquine prophylaxis,” Martinez-Ocana JC, Serra A, Bonet J, Fernandez-Crespo P, Caralps A; Nephron, 1996;73(2):372.
1996
Case report – one subject
“Neuropsychiatric reactions with mefloquine chemoprophylaxis,” Croft AM, World MJ; Lancet, 1996 Feb 3;347(8997):326.
1996
Case report -- summary
“Acute psychosis after mefloquine. Report of six cases.” Sowunmi A, Adio RA, Oduola AM, Ogundahunsi OA, Salako LA; Tropical and Geographical Medicine, 1995;47(4):179-80.
1995
Case report – six subjects
Self-limiting psychosis characterized by acute onset of visual and auditory hallucinations and poor sleep developed in six adults between 8 and 24 hours after oral administration of 750-1500 mg of the antimalarial mefloquine. All patients had no personal or family history of psychosis and were neurologically and mentally normal before mefloquine ingestion.
“Adverse reaction to mefloquine associated with ethanol ingestion,” Wittes RC, Saginur R; Canadian Medical Association Journal, 1995 Feb 15;152(4):515-7.
1995
Case report – one subject
A 40 year old man no history of neuropsychiatric illness took one 250-mg tablet mefloquine weekly for malaria prophylaxis while in Tanzania; No adverse reaction following first two doses, but with his third and his fourth dose he consumed about half a litre whisky; On those two occasions he experienced hallucinations, paranoid delusions and suicidal ideation; Subsequently continued taking mefloquine, but abstained from alcohol ethanol and had no recurrence of psychiatric symptoms.
“Mefloquine-induced grand mal seizure during malaria chemoprophylaxis in a non-epileptic subject,” Pous E, Gascon J, Obach J, Corachan M; Transactions of the Royal Society of Tropical Medicine and Hygiene, 1995 Jul-Aug;89(4):434.
1995
Case report
“Acute brain syndrome after mefloquine treatment,” Ronn AM, Bygbjerg IC; Ugeskrift for Laeger, 1994 Oct 10;156(41):6044-5.
1994
Case report – one subject, treated for P. falciparum.
Patient rehospitalized 12 days after mefloquine treatment with fever, nausea, dizziness and headache; 15 days after treatment generalized convulsions and coma; EEG severely abnormal; discharged 37 days after mefloquine treatment, but two months before the EEG and patient were normal.
“Acute psychosis after mefloquine: a case report,” Sowunmi A; East African Medical Journal, 1994 Dec;71(12):818-9.
1994
Case report – one subject
A self-limiting psychosis characterized by visual and auditory hallucinations and isomnia occurred in a 17-year old male after mefloquine administration for presumed chloroquine resistant falciparum malaria.
“Encephalopathy and memory disorders during treatments with mefloquine,” Marsepoil T, Petithory J, Faucher JM, Ho P, Viriot E, Benaiche F; Rev Med Interne. 1993;14(8):788-91.
1993
Case report – two subjects
Cas e1: excessive mefloquine therapy lead to an acute psychotic state that ultimately regressed without treatment; Case 2: Patient suffered a transient memory failure following prophylactic mefloquine treatment.
“Psychotic episode caused by prevention of malaria with mefloquine. A case report,” Folkerts H, Kuhs H; Der Nervenarzt, 1992 May;63(5):300-2.
1992
Case report – one subject
Developed psychosis, dizziness, confusion and delusions, which were more intensive and remained longer than previously reported.
A-15
IL 10-2004007
June 23, 2004
Title, Authors, Reference
Date
Study Type - Subjects
Major Findings
“Recurrent psychiatric manifestations during malaria prevention with mefloquine. A case report,” Rodor F, Bianchi G, Grignon S, Samuelian JC, Jouglard J; Therapie, 1990 Sep-Oct;45(5):433-4.
1990
Case report – one subject
A 22 year old woman without psychiatric antecedent took mefloquine for a journey in a chloroquine resistant area; First tablet induced an acute psychiatric syndrome that lasted 5 days; Following the second tablet the patient attempted suicide by drowning.
2. Summary. Medical literature, and in particular case reports, indicate that mefloquine may rarely be associated with certain long-term chronic health problems that persist for weeks, months, and even years after the drug is stopped.
A-16

new links posted

Saturday, January 28, 2006 10:34 AM

Hi to all,

I have posted a few more links:

One concerns - how do you get the VA to comply with a direct court order. As you will see, I am not sure the VA has to comply with any court order all be it I am not well versed in legal affairs. Nevertheless, it seems the USC 38 and such guarantee the VA immunity from any court mandates and are above the law when it comes to any issues that are associated to any Veteran or Veterans Benefits.

http://www.2ndbattalion94thartillery.com/Chas/ResponsetoVeteran1.htm

The other - I was contacted by an Aussie Veteran on their meeting with the biased NAS/IOM some time next week. He wanted to know what I considered biased, so they might be able to address some issues and get some questions answered.

This is a long posting but I did not want to leave anything out. The last two sections are most important although in my opinion the evidence I documented is also overwhelming.

That is located at: http://www.2ndbattalion94thartillery.com/Chas/aussieinformation.htm

I received a nice e-mail from Fred Wilcox who is the author of "Waiting for an Army to Die: The Tragedy of Agent Orange.

Mr. Wilcox has been in this fight much longer than I have and I appreciate all his efforts and his continuing efforts, as we all should.

I have had to stop answering a few e-mails to get the Aussie report done but will get to those as soon as I can.

The response to the posting on the VSO's has been just great, most suggest the data, and philosophy is right on target. That previous posting was at:

http://www.2ndbattalion94thartillery.com/Chas/ResponsetoDAV.htm

Some have written in asking what is next - how do we fix it.

I do not know but I will get a link up of what I intend to do, what I am currently working on, and what I think Veterans and their families should be doing to put an end to this form of treatment starting NOW!

All the best,

Kelley