First  published  December  2015  

  1  

Know the symptoms: Melfoquine Toxicity Syndrome To begin to decide wether your symptoms have been caused by taking mefloquine you first need to confirm without doubt that you have taken this drug, exactly when, and for how log. You then need to make a list of your symptoms, when you think they started, if that was before or after you took the drug, and then compare them to the list below. So, let’s start with what the manufacturer says you might experience as an ‘adverse reaction’ or ‘adverse event’ after taking this drug; the list below and it has been clustered into common features to make it easier to follow. For example, in the patient safety leaflet anxiety and panic attacks are not mentioned together but separately, but are really gradations of a similar symptom so they appear in the same section in this list below. Hopefully this will make it easier to understand how these symptoms are related and wether you suffer from one, more than one, or many of them. You can potentially suffer from some, or all, of the symptoms described. You can also suffer them in varying degrees, some severely, and some mildly. Make sure you write this down too. Some have been called ‘common’, others are described as ‘rare’ or the incidence is not known. From our experience of talking to many, many people who have been affected, as well as extensively reviewing what is presented in the medical literature, ‘common’ may be more than 50% of people who take the drug so if you find you suffer from many of the symptoms in the list, this is entirely possible. Timing of onset can also be variable. Symptoms can appear as early as the second dose of the drug, or may take several weeks, or months to appear. The most common ‘early’ adverse reactions seem to be depression, anxiety, paranoia, aggression, nightmares or unusual dreams, insomnia, nausea and cognitive disorders as well as nausea. As many of the symptoms in the list can be caused by other conditions, what is important is to think carefully about when your symptoms appeared, if you had them before taking mefloquine, or only after taking the drug. Write this down and be really thoughtful about this. If you had psychiatric issues prior to taking mefloquine, this can make those symptoms worse or add new symptoms to the ones you experience. Make sure you think about that too. Some of the common descriptions normally applied to neuropsychiatric symptoms will be common to many types of mental health disorder, (PTSD, bipolar disorder as examples) but some are very specific to mefloquine toxicity as reported by people who have suffered adverse reactions to this drug. will be described with particular reference to the experiences of those who have suffered them and this distinction is important. So also make sure you think carefully about how these symptoms are experienced by you, not just how you think they should be felt. Try to ask others around you how you appear and react to them. Some symptoms might only be recognised by others who know you well, live with you, and care for you. So show them this list and ask them to work through the same process. It will also help them understand what you are going through. So, the list of possible symptoms, it’s a long one, so bear with it:

First  published  December  2015  

  2  

Severe anxiety / Panic attacks / Restlessness Severe anxiety is a relatively common adverse reaction to mefloquine. This can present as overt fear of situations, spaces or people, or a more subtle but severe withdrawal from interpersonal interactions due to anxiety (not wanting to be around family and friend). In extreme cases this can manifest as severe agrophobia (fear of open spaces, leaving the house, being in public places) or acute panic attacks that can be incapacitating and debilitating. Restlessness is a common symptom and may be a precursor to more severe anxiety. Restlessness and a general feeling of ‘unrest’ can also contribute to sleep issues and paranoia. Changes of mood This is a rather non-descript term in the product safety leaflet and can cover a huge range of personality changes. Common changes in mood include: increased anxiety, irritability, ddepression, mild euphoria, with these modds changing quickly without warning. One key feature of mefloquine toxicity syndrome is often a lack of empathy. Emapthy is the ablity to recognise and respond to emotions of others. Mefdloquine toxicity sufferers are often flat and non-responsive to emotion in others, they are unable to engage when others are happy or sad, and frequently appear dismissive or disinterested in the emotion of others, or actively become angry when others are sad, happy, or upset. Again this will be a trait that was not present prior to taking mefloquine. Unusual behaviour It is not entirely clear what the patient information leaflet means by ‘unusual’ behaviour. It is possible that this is indicating that any behaviour that only presents after exposure to mefloquine, which was not present before (from the list) could be considered to be ‘unusual’. New or worsening feelings of anger or aggression ‘Anger management issues’ or increased, uncontrolled aggression, is a really common trait in melfoquine toxicity sufferers. Individuals commonly report that they cannot handle normal domestic situations, such as a crying child, without becoming overwhelmingly angry. This is a common cause of family trauma and anxiety, both in the person suffering, and for those living with a mefloquine toxicity sufferer. These aggressive outbursts might be directed at the person themselves (self-endangering behaviours, as discussed above), or others, or objects. Driving vehicles into stationary objects, road rage incidents, random acts of violence to others in nightclubs or bars, hitting walls, doors or smashing furniture or crockery have all been discussed. In the most extreme cases these feelings can result in actual bodily harm or homicide. Again, this level of uncontrolled violent emotion should not have been apparent in the sufferer before they took mefloquine, and these feelings can take some time to present, so may not be an immediate adverse reaction to mefloquine but appear with increasing frequency over a longer period of time. Attention deficits / memory deficits Attention issues could be said to be a ‘common’ side effect. Individuals have reported that mefloquine makes it hard to keep up a train on logical thought. This can include losing a train of thought or being unable to take a thought process to its conclusion. Examples include: cutting off sentences half way through and then starting another disconnected sentence; being unable to

First  published  December  2015  

  3  

process ‘common’ pieces of information (does a red light mean ‘stop’ or ‘go’?) or being unable to maintain concentration to read, work out simple mathematics, remember schedules or be able to organise oneself to carry out simple tasks (putting washing in the machine and then taking it out). Finding it impossible to concentrate on reading a book, or work manual, or filling in forms. Things you could do easily before you took mefloquine. In severe cases people have reported ‘losing days’, waking in a strange location, sometimes in hospital, and have no recollection of the preceeding days or hours (see also seizures below). Paranoia Paranoia is a more severe and insipid adverse event. This can manifest in the mefloquine toxicity suffer as extreme distrust of family or friends, immediate supervisors, or members of the workplace. For example, the individual thinks that everyone in their job is trying to discredit them; their friends are talking behind their back; their wife is having an affair. Or it can exist in a more illogical manner more akin to the paranoia seen in schizophrenics but usually has a basis in reality in that the perpetrator of the ‘watching’ is known: ‘I’m being watched by my superiors; the CIA; the IRA; etc) Hallucinations (visual or auditory) Visual or auditory hallucinations are an uncommon side effect and usually only present in the most severe acute cases. These can include hearing voices telling the person to harm others or themselves, or persecuting them for something they have or have not done, seeing snakes or spiders climbing the walls. In a military setting often these have a military theme – the enemy is talking about the individual or their unit and is coming to get them, they can see the enemy in their tent or in the trees. It is possible that these sorts of hallucinations have been an underlying cause in some of the more inexplicable cases of aggression or homicide in military personnel suffering from melfoquine toxicity. Nightmares / Sleep problems / insomnia These are some of the most commonly reported side effects of mefloquine. These include severely disturbing dreams or nightmares. These have a physical component to them, they often make the sufferer feel unwell on waking, or physically depressed, and commonly have a distressing and unpleasant content; which can be aggressive or sexual in nature. They are commonly not associated with ‘real’ events, so these are not similar to the nightmares suffered by those with PTSD which mainly have a basis in real events and reliving components of those events (escape, fear of enclosure, encounters with the enemy, losing a comrade etc). These nightmares can begin soon after taking mefloquine, and can continue for many years after the drug is ceased, or be a permanent feature for the sufferer. Insomnia is another ‘common’ side effect and may well be related to anxiety, where anxiety causes an inability to relax and therefore to sleep. Sufferers can report only being able to sleep for 1-2 hours at a time, or a night. Which in turn can cause other mental health deficits in terms of memory and emotion due to sleep deprivation. Depression Depression is a ‘common’ adverse effect of taking melfoquine. Depression is one of the most frequent symptoms reported anecdotally by sufferers of melfoquine toxicity, and this may be due to it’s high prevalence in the population in general. However, wether present or not prior to mefloquine exposure, the depression suffered is deep and profound. It frequently occurs in the absence of any prior depressive event and can present as early as the second dose of mefloquine.

First  published  December  2015  

  4  

Suicidal thoughts Suicidal thoughts appear to be a ‘common’ side effect. These describe an overwhelming feeling of helplessness or despair, such that the individual does not want to continue to be alive. There will be no logical cause for these feelings and it is usual that the individual did not experience such strong negative feelings prior to taking mefloquine. These will also often appear without warning, so without a deepening of pre-existing depression or a life-trigger for this event to occur. Suicidal ideation Suicidal ideation means that you imagine ways of carrying out the act of suicide. Often the planning is not logical or practical, but will be complicated and definite. Sometimes this will lead to suicide or attempted suicide. Attempted suicide / suicide completion Suicide in those suffering from chronic severe depression is usually a well-planned event that follows a number of key demographics. Men more commonly hang or shoot themselves, so undertake a ‘physical’ death, women usually take an overdose of medication. Peak age is 25-35. In the case of mefloquine toxicity syndrome, these traumatic events frequently present as either bizarre end-of-life events (lying in the middle of a main road, jumping from windows, severe self mutilation, hanging in female sufferers) and will be without warning of any kind. These events are commonly reported to be totally unexpected by those around the sufferer and often inexplicable in nature. Self-endangering behaviour Self-endangering behaviour is anything that recklessly puts the health or welfare of the sufferer (or sometimes their family or others) at risk. This can take many forms. Examples include: reckless speeding in motor vehicles or use of machinery or weapons with disregard to self or others; road rage, fighting, engaging in deviant or risky sexual behaviour; self-mutilation or self-harm; excessive drinking or drug taking. What is important about the presentation of self-endangering behaviour in the mefloquine toxicity sufferer is that these out-of-character behaviours were not present prior to exposure to mefloquine. In other words, it is a new personality trait, not an exacerbation of an old one. Confusion / cognitive disorders We have touched on this a little already when talking about attention disorders, but this is the next step in the ladder. Confusion is where the individual is not sure of basic facts about time and place. These could include: who they are; where they are; why they are there; what they are doing; what date it is; etc. Cognitive disorders can present as an inability to remember dates and times, locations of future activities, how to carry out simple tasks, inability to formulate written sentences; being unclear how to carry out simple orders; the example given above of not knowing how to interpret a red or green stop light; inability to recognise civilian verses military aggressors”. These confusion states are usually very specific to the individual, and not related to general inability to recognise names, people or remember events, such as might be seen in people suffering from severe brain injury or dementia. Quite specific to mefloquine toxicity are effects on spatial learning and memory. These might present as a failure to remember routes, inability to negotiate simple spatial tasks like navigating to

First  published  December  2015  

  5  

persons house, or the local school, wandering away from home, getting ‘lost’ in the supermarket, not being able to remember where routine objects are placed. This can also present as an inability to carry out spatial tasks, like placing forks or spoons in the right drawer, putting objects in the correct location, or placing clothing on in the correct order. Although these effects can be subtle they can have a demoralising effect on the individual who cannot carry out ‘simple’ tasks, or be a significant worry where people get ‘lost’ on a simple routine journey.

Psychosis Psychosis is a loss of our normal grasp on reality. This is a very severe side effect of mefloquine and can result in extreme outbursts of violent behaviour, suicide, homicide or murder-suicide. Loss of reality can be abstract or targeted at individuals (“there are dragons chasing me and I need to run away”; ”the enemy is evil and must be stopped”; ‘my wife is having an affair and I must stop her”; “I must stab myself in the chest with a carving knife”). Psychosis is usually accompanied by paranoid delusions, and can be accompanied by seizures. These are very severe reactions and need urgent medical assistance. Seizures Seizure can present in a number of ways. A seizure means the occurrence of abnormal electrical activity in the brain and can appear as a classic ‘seizure’ that results in loss of consciousness for seconds or minutes, shaking and muscle spasms. These seizures can be life-threatening and require medication to control them. They can be rare, or frequent, sometimes occurring many times a day. Again, these did not exist prior to exposure to mefloquine. and require urgent medical assistance. Seizures can also present as brief absences of thought (absence seizure) where the person just appears to stop, and then ‘returns’ without knowledge of the ‘absence’ some moments later. These can be accompanied by a loss of memory of what was being discussed prior to the absence, or the person can continue where they left off as though they had not been ‘absent’. Usually these incidents are noticed only by family or friends and not by the person affected. Tiredness or malaise Overwhelming tiredness accompanied by weakness or loss of will to engage in everyday tasks can also be a feature of mefloquine toxicity. This can be as a result of constant anxiety or caused by depression. It is a fairly non-specific descriptor in this list, but can definitely come and go in episodes with sufferers feeling washed out, unable to move or do anything for weeks at a time. Pins and needles, numbness, tremor of the hands or feet People have reported not just numbness but also neuropathic pain (severe pain which usually burns and is very acute) in their hands, feet or in rare cases one or more limbs. Dizziness / Loss of balance / vertigo These effects are related and are caused by the damage that mefloquine does to the vestibular system. The vestibular system comprises sensitive balance regulators present in your inner ear, and links to areas of the brain called the brain stem and cerebellum. Together these areas identify where your body is in space, and also responds to changes in your balance. Normally, they work together to keep you upright without you noticing or be able to move without overstepping, or under-stepping, or falling over. If the delicate receptor cells in the inner ear are damaged, as occurs in mefloquine toxicity, this careful feedback between where your body is, and where it wants to go, is disrupted. This can either cause a severe sense of imbalance, or vertigo, a little like being on a ship on dry land. This can be mild, where there is perpetual general feeling of being slightly unbalanced,

First  published  December  2015  

  6  

or severe, where unexpected movement can cause the individual to pitch over. This can also cause a feeling of nausea in conjunction with the feeling of loss of balance or dizziness. Mild vertigo is a common side effect, and can be transient or permanent. Severe vertigo can also be transient, resolving to mild, or permanent. This is a key feature of mefloquine toxicity syndrome that differentiates it from PTSD and mild traumatic brain injury. Tinnitus Tinnitus means ‘ringing in your ears’. It is that annoying noise you get sometimes when you have a cold and It has affected your inner ear, or you have been exposed to a very loud noise and your ear is compensating. In cases of mefloquine toxicity this is caused by damage to the very sensitive nerve cells inside the inner ear, and can be permanent. Blurred vision, photophobia, conversion disorder (inability to move the eyes in a coordinated manner) Vision problems have been reported after taking mefloquine. These include a sudden deterioration in vision, a supreme sensitivity to light (photophobia) and difficulty in focussing. Area of the brain affected by melfoquine include those regions that control how the eyes move and interact with signals from the vestibular system, as that balance system also controls how your eyes move in your head. Again, problems with focussing on objects (conversion disorder – literally getting your eyes to ‘converge’ on an object), or developing severe sensitivity to bright lights are an indicator if they were not present prior to being exposed to mefloquine. Physical symptoms: Physical symptoms included in the patient information leaflet are: Liver problems, including raised liver enzymes, jaundice or enlargement of the liver Like many, many other drugs, mefloquine is toxic to the liver if taken in high quantities or if you are sensitive to it. Liver function should be checked on a regular basis if you have had an adverse reaction to this drug. Palpitations, racing heartbeat Just as mefloquine caused abnormal activity in ‘active’ cells in the brain, it can cause similar effects in the heart, cause abnormal firing of cardiac muscle cells which can cause a racing heartbeat or palpitations, or cause the heart to slow, or beat irregularly. Difficulty talking Breathing difficulty Severe itching Skin rashes Changes in the texture of your skin, (especially of the mouth and eyes) Fever Chills Cough of shortness of breath Muscle pains, muscle weakness, muscle cramps, joint pain Haemolysis (in patients who are G6PD deficient)

First  published  December  2015  

  7  

Most of these are fairly general to many drugs, or are present due to an ‘allergic’ reaction to the drug. More specific to identifying the syndrome in this case are those specifically related to the brain that are described above. Other symptoms that have been suggested anecdotally or in the medical literature but are not included in the patient safety information are: Thyroid dysfunction Reproductive abnormalities (in women) Pancreatic dysfunction If you have any of the above symptoms, and believe them to be related to taking mefloquine (or tafenoquine), you need to seek medical advice and document this process carefully.