BRAIN ATTACK ©1999 Romesh Senewiratne
In an effort to analyse and understand the medical advertising industry, I have deliberately avoided informing the pharmaceutical industry about my postal or personal address for several years. When I resumed general practice earlier this year, however, they discovered my postal address and since then I have received more and more drug promotional mail. Some of this is personalised, but none of it is personal. I have refused to work for the pharmaceutical industry for as long as I have been a family physician. I do not believe that one can serve the pharmaceutical industry and the health interests of the public at the same time. I also do not think that medical education and research should serve pharmaceutical interests rather than the health and wellbeing of the world’s population, so I was disturbed by the brain attack I received in the mail today.
Today’s mail contained the following items:
1. A plastic envelope containing a copy of the “Australian Doctor” subtitled “The Independent Weekly Newspaper for Australian GPs”, with several glossy coloured enclosures, and a front cover sheet addressed to “DR RB SENEWIRATNE, PO BOX 2268, CAULFIELD JUNCTION, VIC 3161”.
2. A copy of the “MIMS ISSUE NO.5 1999”, wrapped in a glossy envelope that doubled as an ad for “New PriTor” from “Glaxo Wellcome”, with a cover note addressed to “Dr R B Senewiratne, Melbourne Wholistic Medicine, 257 Tucker Road, ORMOND” where I worked doing general practice sessions for most of this year.
3. An offer from Parke-Davis “Neurology Care” to send me some “Parke Davis Epilepsy Education” regarding epileptic patients’ fitness to drive with a fold-out glossy enclosure titled “epilepsy, driving and safety”.
4. An offer from Schering to send me “excellent resources on treatment and management along with practical education and support services”, should I have a particular interest in Multiple Sclerosis (MS) and specifically if I am “one general practitioner out of every twenty managing a Betaferon patient”.
5. A separate plastic envelope containing the “MIMS Supplement No.3 1999 Annual” introducing “Celebrex” for arthritis treatment and Micardis/Pritor, a “new angiotensin II receptor antagonist for mild to moderate hypertension”, enclosed with a A5 sized booklet described as a “MIMS Product Review” introducing “Clopidogrel: Plavix” credited to “Dr Greg Conner, Vascular Physician, Darlinghurst, NSW; Professor Geoffrey Donnan, Department of Neurology, Austin Hospital, Heidelberg, Victoria; and “Dr Andrew Taylor, Heart Centre, Alfred Hospital, Prahran Victoria”.
The last of these five items contained an A5 sized glossy covering letter which reads as follows:
“Dear Doctor,
We are pleased to announce an important advance for your patients at risk of myocardial infarction (MI) and ischaemic stroke and vascular death: New PLAVIX®.
“PLAVIX® is indicated for the prevention of vascular ischaemia associated with atherothrombotic events (myocardial infarction, stroke, vascular death) in patients with a history of symptomatic atherosclerotic disease.
“This new ADP receptor antagonist provides a targeted mechanism of action specifically designed to prevent thrombus formation that causes MI and ischaemic stroke.
“In fact, in the landmark CAPRIE trial of 19,185 patients, PLAVIX® provided an 8.7% relative risk reduction (p=0.043) of vascular ischaemic events, over and above the 25% risk reduction of vascular ischaemic events accepted to be provided by aspirin.
“Based on the CAPRIE trial and Antiplatelet Trialists’ Collaboration meta-analysis, aspirin can be expected to prevent 19 ischaemic events for every 1000 patients treated per year. In contrast, PLAVIX® can be expected to prevent 24 ischaemic events for every 1000 patients treated per year, a 26% difference.
“In addition, PLAVIX offers your patients with atherothrombosis a favourable safety profile with improved gastrointestinal safety and gastric tolerability (significantly lower incidence of gastric bleeding and GI ulcers than aspirin), (p<0.05). With one 75 mg tablet, once daily dosage, PLAVIX® is convenient and easy to use.
“Please note that PLAVIX® is contraindicated in the following conditions: hypersensitivity to the active substance or any component of the medicinal product, severe liver impairment, active pathological bleeding such as peptic ulcer or intracranial haemorrhage, and breast feeding.
“With its proven efficacy and favourable safety profile, PLAVIX® should be a valuable addition to your armamentarium.
“Your Sanofi representative will be contacting you soon with more important information about PLAVIX®. In the meantime, if you desire immediate information, please call 1800 188 206.”
It is 7.15 p.m. on Monday 22.11.99, and I called the number listed above, to find out more about “plavix” and the company that heralds this new miracle drug. I listened to a repeating recorded message from “the customer service section of Sanofi Synthelabo” which explained in a robotised, young, female voice that my call is important to them and to leave my name and number, so that the call could be answered during office hours. The problem is, no opportunity was provided to leave a message, and after three repetitions of the same message, I was given an engaged tone. I suppose I will have to find out about the drug from the “MIMS product review” and read the writing attributed to two specialist doctors and a professor of neurology.
The article begins:
“The term atherothrombosis refers to the two interrelated phases of development of occlusive cardiovascular disease, namely the development of atherosclerotic plaque followed by the development of a platelet rich thrombus at the site of plaque fissure or rupture”.
This sentence is followed by a small “1”, referring to the first of 42 references listed at the back of the article. This article is listed as “Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Eng J Med. 1992; 326: 242-50, 310-18.
I don’t subscribe to the “New England Journal of Medicine” and would not trust this article to support the idea that “platelet rich thrombus at the site of plaque fissure or rupture” is necessarily the “second stage of development of occlusive cardiovascular disease”. Nevertheless, I read on:
“Thus the modern management of preventative cardiovascular medicine is aimed at the control of processes contributing to the premature development of atherosclerotic plaque such as hypertension, diabetes mellitus and dyslipidaemia with medications such as antihypertensive agents, oral hypoglycaemic agents, insulin and lipid lowering agents, as well as control of the thrombotic process by the use of antiplatelet agents.”
This statement is hopelessly reductionist, and ironically regressive, given the reference to “the modern management of preventative cardiovascular medicine. What about stress management, diet, anger management, exercise and rest? What about psychocardiology and holistic approaches to people rather than statistical analyses from “antiplatelet collaborators”?
The article continues:
“The central role of the platelet in the atherosclerotic process has provided the rationale for the use of antiplatelet agents in many clinical trials of vascular event reduction.”
This sentence is followed by a little “2”, referring to the second reference, which is described at the back of the article as “Antiplatelet Trialists’ Collaboration. Collaborative overview of randomized trials of antiplatelet therapy. 1: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Br Med J. 1994; 308: 80-106.”
This trial is described in the following way:
“The Antiplatelet Trialists’ Collaboration is a meta-analysis of 142 randomised clinical trials of more than 73,000 patients who were considered to be at high risk for the development of ischaemic cardiovascular events, and it showed clear benefit for the use of antiplatelet agents in the prevention of the commonly used combined endpoint of myocardial infarction, ischaemic stroke or cardiovascular death, with a calculated relative odds reduction in favour of the use of antiplatelet agents of 27%. This relative risk reduction was fairly consistent whatever the patients’ manifestation of cardiovascular disease.”
One of the problems with “randomised trials” comparing a new drug with an older “benchmark” drug becomes evident when “tolerability and safety” are discussed in the article:
“The safety profile of clopidogrel was well established in the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial. Patients taking clopidogrel had less indigestion, nausea and vomiting (clopidogrel 15.0% vs aspirin 17.59%), less liver function test abnormalities (clopidogrel 2.97% vs aspirin 3.15%), less intracranial haemorrhage, and less gastrointestinal haemorrhage (clopidrogel 0.52% vs aspirin 0.93%) and equal rates of any bleeding disorder (9.3% in both groups). There was a slight excess of rash (clopidrogel 6.0% vs aspirin 4.6%) and diarrhoea (clopidrogel 4.5% vs aspirin 3.4%) in the clopidogrel group.”
This adverse effect discussion raises some concerns barely hinted at in the Plavix promotional ad which refers only to Plavix having “significantly lower” likelihood of causing bleeding and gastrointestinal ulcers than aspirin. The whole of the CAPRIE trial was based on the assumption that aspirin causes as 25% improvement in risk from stroke, myocardial infarction and coronary death. If it caused a total improvement in life expectancy of 25% this would no doubt be mentioned, but it doesn’t. Likewise one could mistakenly get the impression that Plavix (clopidogrel) provides a 26% reduction in these events, but that would be misreading the small print.
The risks being discussed are “relative risk improvements” based on the assumption of a 25% reduction in risk from aspirin. Thus only 24 ischaemic events can be expected to be avoided per 1000 people treated with Plavix versus 19 per 1000 events with aspirin. But at what cost?
The actual and relative costs of Plavix are not mentioned in any of the literature about the new drug sent to doctors, not even the “MIMS Issue No 5” which has this to say about the new drug from Sanofi-Synthelabo:
“PLAVIX clopidogrel
Sanofi-Synthelabo [CMI]
Use: Platelet aggregation inhibitor. Prophylaxis of thromboembolic disorders.
Contra: Severe hepatic impairment; active bleeding; pregnancy, lactation
Prec: Patients at risk of bleeding incl elective surgery, intraocular lesions, GI lesions; hepatic impairment; acute cardiovascular, cerebrovascular or peripheral vascular event.
Interact: Aspirin, heparin, recombinant tissue plasminogen activator, warfarin, NSAIDS, drugs metabolised by P450 2C9 incl phenytoin, tamoxifen, tolbutamide, fluvastatin.
TABLETS Rx Clopidogrel hydrogen sulfate; lactose anhydrous; pink f-c [film-coated]
Pack 75 mg [28]: Authority- PBS/RPBS (Rp 5)
[Approved indication(s) for authority: Secondary prevention of ischaemic stroke and transient cerebral ischaemic events in patients (1) with a history of cerebrovascular ischaemic episodes while on therapy with low-dose aspirin; or (2) where low-dose aspirin poses an unacceptable risk of gastrointestinal bleeding; or (3) where there is a history of anaphylaxis, urticaria or asthma within four hours of ingestion of aspirin, other salicylates, or NSAIDS.
“Secondary prevention of myocardial infarction or unstable angina in patients (1) with a history of cardiac ischaemic events while on therapy with low-dose aspirin; (2) where low-dose aspirin poses an unacceptable risk of gastrointestinal bleeding; or (3) where there is a history of anaphylaxis, urticaria or asthma within four hours of ingestion of aspirin, other salicylates, or NSAIDS]
Dose 75 mg once daily
Refer MIMS Annual 1999 p 2-203”
Not having a copy of the MIMS Annual 1999 at hand, I am required to turn back to the “product review”, which I assume will have a full copy of the prescribing information including risks and dangers included at the back of the document. This is customary and required by the Pharmaceutical Industries Code of Practice. This information is likely to be closer to the truth about Plavix, provided one still reads between the lines.
Under “adverse reactions”:
“Clopidogrel has been evaluated for safety in more than 11,300 patients, including over 7,000 patients treated for one year or more
Clopidogrel was well tolerated compared to aspirin in a large controlled clinical trial (CAPRIE). The overall tolerability of clopidogrel in this study was similar to aspirin, regardless of age, gender and race. The clinically relevant adverse effects observed in CAPRIE are discussed below.
Haemorrhagic. The overall incidence of any bleeding in patients treated with either clopidogrel or aspirin was similar (9.3%). The incidence of severe bleeds was 1.4% in the clopidogrel group and 1.6% in the aspirin group.
Gastrointestinal haemorrhage was significantly less frequent with clopidogrel (1.99%) compared to aspirin (2.66%). The incidence of intracranial haemorrhage was 0.35% for clopidogrel compared to 0.49% for aspirin.”
Intracranial haemorrhage is, like cerebrovascular thrombosis or embolism, a cause of “stroke”, or cerebrovascular accident (CVA). The results above suggest that 3.5 out of every 1000 people treated by Plavix will actually have a stroke because of it, and 4.9 out of every 1000 treated with aspirin will suffer the same fate, even though the drugs are being promoted for the prevention of strokes and heart attacks. In addition to the bleeding risk, it becomes clear that there are many other dangers associated with both Plavix and aspirin, including the risk of the potentially fatal allergic reaction of “anaphylaxis”.
Under “adverse reactions” is reported:
“The post-marketing experience confirms the safety profile defined during the clinical development: hypersensitivity reactions have been reported; these mainly include skin reactions (maculopapular or erythematous rash, urticaria) and/or pruritus. Very rare cases of bronchospasm, angioedema or anaphylactoid reactions have been observed.”
In addition to these risks, the following list of adverse effects which occurred in greater than 2.5 percent of people receiving Plavix is reported in the full prescribing information from Sanofi-Synthelabo:
“Chest pain (8.3%), accidental injury (7.9%), influenza-like symptoms (7.5%), pain (6.4%), fatigue (3.3%), hypertension (4.3%), headache (7.6%), dizziness (6.2%), abdominal pain (5.6%), dyspepsia (5.2%), diarrhoea (4.5%), nausea (3.4%), hypercholesterolaemia (4.0%), arthralgia (6.3%), back pain (5.8%), angina pectoris (10.1%), coronary artery disorder (6.2%), purpura (5.3%), epistaxis (2.9%), depression (3.6%), infection (4.7%), upper respiratory tract infection (8.7%), dyspnoea (4.5%), rhinitis (4.2%), bronchitis (3.7%), coughing (3.1%), rash (4.2%), pruritus (3.3%), urinary tract infection (3.1%), claudication intermittent (3.8%), peripheral ischaemia (3.2%) and cerebrovascular disorder (2.6%).”
The review article by Professor Donnan and doctors Conner and Taylor have less to say about these adverse effects and essentially ignores any meaningful discussion about them in a short section titled “tolerability and safety”, described before.
One of the drug side interactions to be expected with new Plavix occurs when phenytoin is used concomitantly with the new drug. This is because clopidogrel interferes with the important cytochrome P 450 enzyme pathway, an important drug detoxification pathway in humans and other animals. Phenytoin is the generic name for the crippling antiepileptic drug “Dilantin”, marketed in Australia by Parke-Davis who also sent me information about the brain today, in the form of a personalised letter offering educational materials, hopefully of a higher standard than the enclosed “newsletter” titled “epilepsy, driving and safety”.
The letter, which is addressed to Dr R B Senewiratne, 257 Tucker Road, ORMOND reads:
“Epilepsy may affect 1 out of 50 Australians. Whilst a serious condition, it can be treated in a variety of ways so that the sufferer is able to maintain quality of life.
Epilepsy Society of Australia benefits
from continued support from Parke Davis.
One important factor in treating this condition is education. Providing medical professionals with the latest developments on epilepsy and informing their patients and carers about quality of life issues help to promote better health outcomes. To this end, Parke Davis has joined forces with the Epilepsy Society of Australia to support their endeavours and to distribute the Society’s special release on epilepsy and assessing driving fitness. This has been achieved through an unrestricted educational grant from Parke Davis.
More educational materials available now.
For over 40 years, we have sponsored clinical trials and collected information relating to epilepsy, Dilantin (phenytoin) and Neurontin (gabapentin). We now invite you to ‘tap into’ our libraries and utilise our resources to gain additional knowledge and insight into this condition.
Currently in production are case study videos that will be available in the near future. To register your interest in receiving a copy, please refer to the attached Request Form. We also offer new abstracts, copies of the “Neon” paper plus practical tools such as Seizure Classification and Drug Interaction Charts.
To ensure prompt delivery of the materials you request, please post your request before Friday, 17 December 1999.
Should you have any other requests or suggestions on how we can assist you, please enclose a separate letter with the Request Form.
We look forward to hearing from you
Sincerely
Danielle Mayne
Marketing Assistant”
The reverse side of this personalised mass-produced letter gives details of the offer from Parke Davis. One has the choice of selecting “New in Epilepsy”(a “bulletin containing abstracts of recently published papers”), a “seizure classification chart”, the “Neon Paper”, a “Drug Interaction Chart” and a “Neurontin Dosage Chart”. The “Neon Paper” is explained as “Bruni J on behalf of the “Neon” Study investigators group. Outcome evaluation of gabapentin as add-on therapy for partial seizures. Can J Neorol Sci 1998; 25: 134-40.”
As an “optional” section at the bottom of the page five questions are listed:
1. How many epileptic patients are currently under your care?
2. Are any of your patients taking Neurontin now?
3. Would like [sic] to receive patient information material about Neurontin?
4. Would you be interested in attending an education meeting next year?
5. Are you interested in receiving information about Parke Davis sponsorship for
Clinical trials
Overseas meetings
Local meetings
Other, please specify
In small print at the bottom of the page is printed:
“Dialantin and Neurontin are registered trademarks of Warner Lambert Co, USA”
Is the last line a deliberate or accidental misprint of the well known name “Dilantin”?
Brain attack?
Dilantin has been a “benchmark anticonvulsant” for several decades now, and in that time it has become clear that the drug can cause horrendous side-effects, including deformity of the face, teeth and gums with prolonged exposure. It can also cause nervous system and brain damage when the level of the drug in the blood is excessive. Because of the toxicity of phenytoin (Dilantin) regular blood tests need to be done if the drug is used for the treatment and control of epilepsy. This is also the case with other toxic anticonvulsant drugs such as Tegretol (carbamazepine) and Epilim (sodium valproate).
The adverse effects of Dilantin listed in the 1993 MIMS annual were listed as follows:
Central nervous system. The central nervous system is the most common place where manifestations with Dilantin therapy are encountered. These include nystagmus, ataxia, slurred speech and mental confusion. Cases of dizziness, insomnia, transient nervousness, motor twitching and headache, have also been reported. These side effects may disappear by continuing therapy at a reduced dosage level.
Gastrointestinal. Dilantin may cause nausea, vomiting, and constipation. To prevent gastric irritation due to alkalinity, Dilantin should be taken with at least half a glass of water. Gastric irritation may often be minimised by administering Dilantin during or following meals or by using Dilantin Suspension.
Dermatological. Manifestations sometimes associated with fever have included scarlatiniform or morbilliform rashes. The latter case is the most common with other types of dermatitis being more rare. In general, rashes are more common in children and young adults. More serious forms which may be fatal have also been reported and they include bullous, exfoliative or purpuric dermatitis, lupus erythematosus and Stevens-Johnson syndrome.
Haematological. Some fatal haemopoietic complications have occasionally been reported in association with the administration of phenytoin. Included in these are thrombocytopenia, leucopenia, granulocytopenia, agranulocytosis and pancytopenia. Although macrocytosis and megaloblastic anaemia have occurred, these conditions are more a consequence of folic acid deficiency.
Other. Gingival hyperplasia occurs frequently and its incidence may be reduced by good oral hygeine, including gum massage, frequent brushing, and appropriate dental care. Occasionally, polyarthropathy and hirsuitism as well as potentially fatal cases of toxic hepatitis, liver damage and periarteritis nodosa may occur.”
Some might consider the above a good reason to ban the use of this chemical, especially in children.
EPILEPSY
Epilepsy is a medical term used to describe a condition characterised by seizures affecting the brain and nervous system. These seizures involve uncontrolled electrical discharges which form “short circuits” in the brain and a spread of the “epileptic focus” to other parts of the brain resulting in different clinical presentations of epilepsy. These are named according to the type of epileptic seizure that results, such as “grand mal”, “focal seizures”, “petit mal”, and “temporal lobe epilepsy”. The recommended drugs for the treatment of different types of epilepsy depend, to a point on the type of seizure, and other factors such as duration of each seizure and the frequency of seizures. The drug Dilantin is recommended for grand mal and psychomotor seizures. In the 1993 MIMS Annual the indications are described as:
“Control of grand mal and psychomotor seizures. Dilantin will prevent or effectively decrease the incidence and severity of convulsive seizures in a high percentage of cases, with patients exhibiting little tendency to become resistant to its action. Besides its effectiveness in controlling seizures, Dilantin frequently improves the mental condition and outlook of epileptic patients, and there is also increasing evidence that Dilantin is valuable in the prevention of seizures occurring during or after neurosurgery, and in the treatment of certain cardiac arrhythmias.” (p.3-228)
An important factor to consider in the holistic medical management of epilepsy is identification of seizure triggers, and several of these have been clearly identified over the years. These are variable between individuals, but several common triggers can cause epileptic convulsions in different people who share a tendency to epilepsy. These include flashing artificial lights and other repetitive visual experiences involving electrovisual stimuli. Particular music with artificial repetitive rhythms can also trigger convulsions in the susceptible. Hypnotic induction into seizures can also be done, and this can be done via videos and television, computer games and video games. Fatigue and sleep deprivation can also trigger epilepsy, especially if combined with drug and alcohol intoxication. Even small intakes of alcohol can lower the seizure threshold and trigger seizures in susceptible people. Drugs such as amphetamines, methyl phenidate (Ritalin) and other stimulants are notorious for causing seizures, and seizures can also occur during withdrawal from these and other drugs and during withdrawal from alcohol.
Damage to the brain from trauma and infection can also cause seizures, including seizures during the acute insult and later, when scar tissue has formed in the affected area of the brain. Trauma can be accidentally or deliberately inflicted on the brain. In Australia and Canada there has occurred a recent resurgence of popularity for operations on the brain to treat neurological and psychiatric abnormalities, particularly for an interesting condition termed “temporal lobe epilepsy”.
In The Brain (1997), an Oxford University Press publication, a paper was written by doctors from the Montreal Neurological Hospital and Institute, Quebec, Canada titled, “Results of surgical treatment in temporal lobe epilepsy with chronic psychosis”. The summary of the paper reads as follows:
“The combination of psychosis and refractory temporal lobe epilepsy is not rare. However, patients with chronic interictal psychosis and refractory epilepsy are rejected from many epilepsy surgery programmes purely on psychiatric grounds. It is often assumed that disturbed behaviour will prevent adequate preoperative evaluation or that the patients are unable to provide informed consent for preoperative investigations and for surgery. The observation that the psychosis usually does not improve after operation and fears of an exacerbation of psychosis with post-surgical seizure remission, analogous to ‘forced normalization’, are further deterrents to surgery in these patients. We describe five patients with the dual diagnoses of medically intractable temporal lobe epilepsy and chronic psychosis who underwent temporal lobe resection. The patients were able to provide informed consent and were easily managed during preoperative investigation. Seizure outcome has been excellent in all. Neither temporal lobe resection nor remission of seizures influenced the nature or evolution of the psychosis. Subjectively the patients functioned better in activities of daily living and freedom from seizures improved integration into psychiatric treatment facilities. With appropriate psychiatric intervention, patients with chronic psychosis and refractory epilepsy can participate in presurgical investigation successfully, and can undergo surgery uneventfully.”
“Patient 1” in this paper is described as a 30 year old man “with severe schizoaffective disorder” and “medically intractable right temporal lobe epilepsy” who “underwent a selective amygdalohippocampectomy for control of his seizures”. This man’s seizures apparently began at the age of 2 years when he had a prolonged febrile convulsion followed by transient paralysis of his left side, after which he developed “temporal lobe seizures at the age of 4 years”. This man’s “psychiatric history” is described as follows:
“The patient completed grade 10 at school and has never been employed. In early adolescence, he became non-compliant with anticonvulsant drugs, attempted suicide with impulsive drug overdoses and refused psychiatric help. He made no lasting emotional attachments, began to use street drugs and drove without a license despite uncontrolled seizures. He developed thought blocking and a sense of being possessed by the devil. At the age of 27 years, at the behest of auditory hallucinations commanding him to exorcise himself, he doused himself with coal oil, mutilated himself with an axe and set himself alight. Having sought no help, he was discovered by his family a day later, lying in bed severely burned and cut. He required admission to an intensive care unit and received extensive skin grafts. A diagnosis of schizoaffective disorder was made. Neuroleptic treatment was started and antidepressants added later. There was never a clear temporal relation between exacerbations of psychosis and seizures.”
This tragic story of religious confusion, drug addiction and psychiatric abuse has an ending which is described as a success by the authors of the article, but sounds much like a chronic invalid state, the resultant of torture and a broken spirit in a young man who had earlier shown anger towards the medical profession who had started drugging him with anticonvulsants and other drugs when he was still a young child. His “postoperative course” is described as follows:
“Two years after surgery, the patient lives in his own home, works in a supervised workshop for chronically ill psychiatric patients and complies with ongoing out-patient psychiatric follow-up. He no longer takes antidepressant medication but is now treated with chlorpromazine (75mg/day), risperidone (8 mg/day) and loxapine (100 mg/day). He continues to take carbamazepine (800 mg/day) and clonazepam (2 mg/day) and has had only one postoperative seizure.”
Prior to the surgery on his limbic system and temporal lobes, this unfortunate man was being treated with the following drugs: phenytoin (300 mg/day), carbamazepine (1200 mg/day) and clonazepam (2 mg/day) for his “temporal lobe epilepsy” and haloperidol (12.5 mg/day), fluvoxamine (100 mg/day) and procyclidine (10 mg/day) for his “chronic psychosis”.
A major difficulty encountered in understanding this case and where the medical profession failed this young man is the lack of proper neurological, social and psychological assessment, analysis and historical presentation. Of what racial and cultural background is this man? What reasons did he have for rejecting anticonvulsant drugs and psychiatric treatment when he was younger? What did he look like? Where and why did he develop the idea that he was possessed by the devil? What was his religious, political and philosophical background? What was his family background and sibling relationships like? What music and television programs influenced his thinking? What “street drugs” did he “experiment with” and how did these affect his health, mental state and chronic epilepsy? What was he interested in and why? What skills and talents did he have?
A difficulty with understanding this man’s problems is that symptoms attributable to “temporal lobe epilepsy” overlap with symptoms attributable to “psychosis”. Temporal lobe epilepsy associated with distinctive electroencephalogram readings can result in trance or fugue states, visual and auditory hallucinations, visions, and dissociative states of various sorts. Such states can also result from drug intoxication and toxicity.
A clear example of the latter is given in the second case described in this article, which is of a 42 year old women who, in the course of her treatment developed visual hallucinations and uncharacteristically aggressive behaviour as a direct result of Dilantin (phenytoin) toxicity:
“On one occasion, paranoid hallucinations became unusually florid and she was uncharacteristically aggressive and socially inappropriate. This exacerbation coincided with excessive plasma phenytoin levels and resolved with cessation of the drug.” (p.1931)
The actual manifestations of what was considered to be the result of temporal lobe epilepsy is unclear from the paper, and only a brief description of vague symptomatology from the man’s childhood are given:
“In the seizures an initial feeling of fear and a sensation of pressure in the lower abdomen was followed by cessation of activity, a blank stare and loss of awareness.” (p.1930)
This could be a description of terror, and it is important to differentiate a loss of awareness from a loss of consciousness, which would be more suggestive of a genuine epileptic cause for these episodes, which do not sound serious or severe enough to warrant the extraordinarily aggressive treatment that the man received prior to and following the surgery.
It would be interesting to speculate about how this man could have been better treated by understanding his religious views and beliefs in an effort to understand the “psychosis” which was subsequently diagnosed as “schizoaffective disorder” according to criteria of the American Psychiatric Association’s DSMIV (1994). The DSM IV is also used in Australia to make diagnoses of this and other psychotic illnesses, although it makes few recommendations for treatment. It is a book of labels, devoid of cause and cure.
Schizoaffective disorder is described in this book in the following manner:
“The essential feature of Schizoaffective Disorder is an uninterrupted period of illness during which, at some time, there is a Major Depressive, Manic, or Mixed Episode concurrent with symptoms that meet Criterion A for Schizophrenia (Criterion A). In addition, during the same period of illness, there have been delusions or hallucinations for at least 2 weeks in the absence of prominent mood symptoms (Criterion B). Finally, the mood symptoms are present for a substantial portion of the total duration of the illness (Criterion C). The symptoms must not be due to the direct physiological effects of a substance (e.g., cocaine) or a general medical condition (e.g., hyperthyroidism or temporal lobe epilepsy) (Criterion D).” (p.292)
In the Montreal Neurological Hospital and McGill University in Montreal, however, while claiming an adherence to the DSM classification, brain surgery is being done on people with known temporal lobe epilepsy who have been additionally diagnosed with “schizoaffective disorder” in direct contravention of the criteria in the DSM. At the same time as claiming that these people are “chronically psychotic” the authors of the article claim that they are also capable of giving “informed consent” for surgery to their brain. Did the surgical candidate understand that the surgery was not intended to cure his psychiatric condition, and was only intended to treat the “temporal lobe epilepsy”?
Brain attack?
STROKE
The clopidogrel (Plavix) MIMS Product Review is credited to two doctors and a professor. The professor is Professor Geoffrey Donnan of the Department of Neurology at the Austin Hospital in Heidelberg, Melbourne. This hospital is also home to Professor Graham Burrows, chairman of the drug promoting “Mental Health Foundation” and several other drug promoting organizations. Professor Burrows is also a senior editorial consultant for the MIMS organization, and consults at the Austin Hospital (for his public patients). At this hospital, as in Canada, neurosurgery for temporal lobe epilepsy has been done in recent years.
During a recent visit to this hospital to visit a friend who had just had surgery to excise part of her bowel, I picked up a series of public education pamphlets in several languages about the diagnosis, treatment and prevention of stroke. The pamphlet in English is titled “STROKE IS A BRAIN ATTACK”.
The front cover announces:
“Answers to the top ten questions about stroke (Brain attack)” credited to the “National Stroke Foundation”. These questions are:
1. What is a stroke?
2. Does a stroke “just happen”?
3. How common is a stroke?
4. What are my chances of having a stroke?
5. What risk factors can I control?
6. Are there warning signs of stroke?
7. What happens after a stroke?
8. Can stroke be prevented?
9. Can a stroke be cured?
10.What sort of research into stroke is taking place?
Under the final question is given this rather intriguing answer:
“Australia is one of a number of countries undertaking major research studies into the causes and prevention of stroke.
“The National Stroke Research Institute Laboratories (NSRI) are located at the Austin and Repatriation Medical Centre. The research projects are being conducted by the Director, Professor Geoffrey Donnan. Professor Donnan and his staff of researchers are continuing to provide valuable insights in the process and treatment of stroke, or “brain attack”, in our community.
“The National Stroke Foundation seeks to raise funds to support this world-class research activity. NSF also provides leadership and offers to act as a coordinator when joint research programs involve several hospitals.
“As the lead agency for Brain Attack nationally, the National Stroke Foundation seeks to raise much needed funds for research, prevention, treatment, education and awareness into Brain Attack, so as to improve stroke health for all Australians and help reduce the morbidity and mortality rate from stroke.”
Morbidity and mortality from stroke refers to illness and death from stroke respectively. Illness from stroke includes both residual disability from the acute injury as well as the long-term illness that treatment for stroke can cause. The latter is ignored completely in the pamphlet, which states categorically that stroke cannot be cured. Question nine, titled “can a stroke be cured” is answered thus:
“Once the stroke has occurred, the short answer is “NO”. There is no known drug which can completely eliminate the possibility of a stroke or offer a guaranteed “cure”. However, early diagnosis and quick action when a stroke does occur can reduce its severity. For Brain Attack patients suffering loss of speech, movement, thought processes or sensory reaction, rehabilitation is also possible with the assistance of physical, occupational or speech therapists.”
In other words, the medical profession cannot aid in recovery, but the “allied health professionals” can. This may hold true for Professor Donnan and his drugs, but it certainly does not apply to the entire medical profession, which can do a great deal to assist in the rapid and complete recovery from “stroke”, provided it is not too extensive. Many people make complete recoveries from cerebral infarctions as far as their brain function is concerned, although histologically irretrievable loss of neurones and other brain cells may have occurred. The reason for this is probably that connections between undamaged cells compensate for those which are lost. New axonal and dendritic processes are known to form and atrophy throughout life, and it seems clear that active use of the brain facilitates new connections. The people who make a complete recovery from stroke tend to be those who believe it to be possible, and work towards regaining lost function whilst adapting to the current disability by developing new skills. The development of new skills requires active use of the brain and mind, and it is obvious as to why this aids in recovery. Management that results in such recovery is necessarily holistic and aimed at identifying risk factors and remedying them together with maximising the brain’s capacity to heal itself and regain function after injury, regardless of cause.
“Strokes” are a popular term for “cerebral infarctions”, which can be caused by either haemorrhage into the brain, or obstruction to the blood flow of the brain. For this reason, another term used by the medical profession has been “cerebrovascular accidents” or “CVAs”. The term “brain attack” is as appropriate as “heart attack” and implies the urgency of the situation more so than “cerebrovascular accident” does. It is, indeed a medical emergency if the delicate tissue of the brain is being deprived of blood or being compressed by it, as occurs with intracranial haemorrhages.
The cause of cerebral blood flow obstruction includes blockage of blood vessels in the neck and head, and embolism, when a blockage is caused by a solid object such as a piece of blood clot that travels to the brain through the arterial circulation. Common aetiological processes that can underlie blockage of different sorts include atherosclerosis and atherothrombosis affecting arteries in the neck, hypertension and diabetes. These conditions also cause susceptibility to haemorrhagic strokes, following rupture of blood vessels in the brain.
Some of these aetiological processes are referred to in the “brain attack” pamphlet, which explains:
“The most common form of stroke is the result of a sudden disruption in the flow of blood to parts of the brain.
“When blood cannot reach parts of the brain, the oxygen supply to those areas is cut off and the brain cells die (infarct). Less frequently, blood vessels burst and blood spreads into nearby brain (haemorrhage) and as a result of either of these processes, functions normally controlled by these damaged areas become affected. In many cases, unconsciousness and/or partial paralysis may occur. This is often the immediate “outward sign” that a stroke has occurred.”
Embolic strokes are not mentioned, and question two is answered with a refutation of the term “cerebrovascular accident”:
“…even though a stroke is often referred to by doctors as a “cerebrovascular accident”, the term is not an accurate one, since stroke is rarely an “accident”.
Is “brain attack” a more accurate term? Who is attacking whom? Where is the attack coming from? Is it coming from the “National Stroke Foundation”?
The advice given in the pamphlet regarding “Risk factors that cannot be controlled” include gender, family history, individual history, diabetes and irregular heart beat. The “risk factors which can be controlled” are listed as “high blood pressure”, “high cholesterol level”, “diet”, “alcohol”, “obesity”, “smoking”, “exercise” and “birth control pills”. Stress is mentioned only in the context of “controlling blood pressure”:
“Controlling high blood pressure, whether by a low-sodium diet, weight control, stress management and/or medication will reduce your risk of stroke.”
In actuality, all but a person’s gender can be “controlled” by physicians capable of the holistic management of stroke and cardiac risk factors. Even family history can be altered by addressing problems in communication between family members, since they can influence each other to improve their health and wellbeing generally, including their cardiovascular and cerebral health. Diabetes and irregular heart beats are readily treatable with modern drugs and good dietary advice combined with stress management. The latter is essential for the successful management of coronary and cerebral risk factors generally. This definitely includes the lowering of elevated blood pressure, but also the management of diabetes, eating disorders and obesity, cigarette smoking, alcohol abuse, and high plasma cholesterol levels.
CHOLESTEROL
Aggravation of elevated LDL cholesterol levels by stress is not mentioned in the pamphlet, which instead gives outdated and misleading advice regarding treatment of elevated cholesterol levels with diet:
“a high cholesterol level is a contributing factor to arterial disease, which often leads to a predisposition for stroke. Try to avoid foods which have excess fat, cholesterol, or have been fried. Choose lean meats and low-fat dairy products. Limit your intake of eggs.”
In truth, the link between cholesterol and cardiovascular disease is much more complex than the pamphlet makes out. Total cholesterol includes subfractions of low density (LDL) cholesterol and high density (HDL) cholesterol. While an elevated LDL cholesterol level has been associated with increased rate of blockage of arterial blood vessels, a high HDL cholesterol level has an effect of protecting against such disease. It is well recognised that fish, cereal and vegetable fibre and exercise can raise HDL levels. A modest intake of alcohol is also said to help raise HDL levels, but this possible beneficial effect may be offset by concomitant rises in other blood lipid levels.
Fresh fruits and vegetables, cereals, fish and other foods widely accepted to be of benefit for persons suffering from heart disease, obesity and diabetes are not mentioned at all in the pamphlet, even in the rather bizarre section on “diet” which, following the section on “high cholesterol level” reads:
“In addition to the above, avoid foods which have excess salt. Try to eat fresh foods wherever possible. When buying processed or canned foods, check the sodium content on the list of ingredients which, by law, should be on the label. Sodium can be in the form of disodium phosphate, monosodium glutamate, sodium nitrate or any other sodium compound. Avoid food with high sodium levels.”
Cholesterol is a ubiquitous bio-molecule that is the precursor to all the steroid hormones, including cortisol, oestrogen, progesterone and testosterone. It is essential for vertebrate life and is found in the cell membrane of virtually every cell in the body. Elevated serum cholesterol was one of the several “risk factors” identified in the 1960s “Framingham Study” to predispose to atherosclerosis and heart disease. Since then a massive industry has grown based on frightening people about “cholesterol” and selling treatments for “high cholesterol”. Prominent amongst these treatments are drug treatments with “cholesterol lowering drugs” such as the “statins” Zocor (simvastatin) and Pravachol (pravastatin).
The MIMS Issue No 5 1999 lists 18 different cholesterol lowering agents in section 2 (f) titled “hypolipidaemic agents”. These include the following “HMG CoA reductase inhibitors”, also called “statins”:
1. Lescol (fluvastatin) from Novartis
2. Lipex (simvastatin) from AMRAD
3. Lipitor (atorvastatin) from Parke Davis
4. Lipobay (cerivastatin) from Bayer
5. Pravachol (pravastatin) from Bristol Myers Squibb
6. Vastin (fluvastatin) from Astra
7. Zocor (simvastatin) from Merck Sharp & Dohme
The cost of these drugs is not mentioned in the MIMS Issue No 5, but these are very expensive drugs, and can bring a range of adverse effects which are rarely written or spoken about by the drug representatives or the companies advertisements.
In the section on hypolipidaemic agents are several glossy ads for these expensive drugs. These include four for Lipitor, one for Pravachol, one for Zocor, and two for Lipex. The slogans for the ads demonstrate how far the drug companies have gone down the road of commercial exploitation. The ad from the American pharmaceutical giant Mercke Sharpe and Dohme features a monolithic Z with the slogan “Zocor takes control of the entire lipid profile”. At the three apexes of the Z are printed “decreased trigs”, “increased HDL-C” and “decreased LDL-C”. No evidence is presented to back up this claim in the ad, which urges “before prescribing, please review Product Information by referring to Section 2 (f).
This section has a “general statement for lipid lowering drugs prescribed as pharmaceutical benefits”. This reads as follows:
“The following criteria, as recommended by the Pharmaceutical Benefits Advisory Committee, qualify the indications for the prescribing of atorvastatin calcium, cerivastatin sodium, fluvastatin sodium, pravastatin sodium, simvastatin and gemfibrozil as pharmaceutical benefits.
By writing PBS prescriptions for these drugs, the prescriber is signifying that the drugs are being prescribed in accordance with the criteria that follow.
Qualifying criteria for lipid lowering drugs. Note that the registered indications for individual agents may differ. Refer to the current product information.
Dietary therapy. All patients should receive dietary therapy, typically for six weeks, before resorting to drug treatment.
For obese patients, a longer dietary period should be considered.
In addition to dietary advice, specific advice should be provided about lifestyle changes to modify risk factors such as smoking, obesity, excessive alcohol intake and physical inactivity.
Cholesterol/triglyceride levels. In addition to dietary therapy, drug therapy is indicated in patients in accordance with the information that follows, where patients must have both the specified risk category and the stated lipid level.
Patients with existing coronary heart disease and cholesterol level > 4 mmol/L.
Patients with diabetes mellitus and/or familial hypercholesterolaemia and/or family history of coronary hear disease (first degree relative < 60 years of age) and/or hypertension and/or peripheral vascular disease and cholesterol level > 6.5 mmol/L or cholesterol level > 5.5 mmol/L with HDL < 1 mmol/L.
Patients with HDL < 1 mmol/L and cholesterol level > 6.5 mmol/L.
Patients without the risk factors described previously but who are men aged 35 to 75 years or postmenopausal women aged up to 75 years and who have a cholesterol level > 7.5 mmol/L or a triglyceride level > 4 mmol/L.
Patients not included in any of the previous categories but who have a cholesterol level > 9 mmol/L or a triglyceride level > 8 mmol/L.
Choice of drug
Predominant hypercholesterolaemia. The preferred drugs are the HMG CoA reductase inhibitors (‘statin’ drugs), bile acid resins, gemfibrozil or nicotinic acis.
Mixed hyperlipidaemia. The preferred drugs are gemfibrozil, HMG CoA reductase inhibitors or nicotinic acid.
Predominant hypertriglyceridaemia. The drugs recommended are gemfibrozil or nicotinic acid.
Measurement of plasma lipids.
The decision to commence drug therapy should be based on at least two measurements made at an accredited laboratory”
These criteria are routinely ignored by many doctors in Australia, particularly by cardiologists who are often obsessed by lowering cholesterol levels despite the fact that the drugs often cause impotence, muscle damage and pain, gastrointestinal problems, fatigue, depression and other side effects which can be avoided by good dietary and psychological advice. The adverse effects listed under Liptor are listed in the MIMS Issue No 5 as “rhabdomyolysis (theoretical); myopathy; myalgia; GI upset; headaches; insomnia; flu-like syndrome; sinusitis; other see MIMS Annual.”
These are ignored in the glossy ad for Lipitor which features a metallic statue with arms raised superimposed over a line of 36 white-skinned people, mainly of middle age who appear to be interacting socially with each other. Most are dressed casually with a few male “executives” wearing ties. 23 of the 36 people are male, one of whom is engaged in a conversation whilst wearing sunglasses. The people are all posing, and the picture has been carefully crafted. The caption reads:
“ONCE…AND FOR ALL.” Subcaptioned under the slogan is the lipitor logo below which is printed in italics “Once daily for all cholesterol levels”.
The “Australian” company AMRAD have two full paged glossy ad in the MIMS Issue No 5 for their HMG CoA reductase inhibitor Lipex (simvastatin). This is their version of the original statin drug marketed as Zocor by Mercke in the 1980s. The ad for Lipex features a telescopic photograph of the sun, with the slogan “SOME THINGS IN LIFE JUST KEEP ON DELIVERING”. Below this is the caption:
The sun delivers power, day in day out.
LIPEX delivers power too – the power of simvastatin
The second slogan, printed above the LIPEX logo claims:
“FROM LIPIDS TO LIFESTYLE, LIPEX DELIVERS”
The Squibb ad for Pravachol features a photograph of Winston Churchill with cigar in mouth giving his famous V for victory sign (which ironically doubles as the “peace sign”) below the slogan “IT’S OFFICIAL! NOW WITH TWO UNIQUE INDICATIONS”. In the right hand lower corner if the Pravachol logo beneath which is printed “POSITIVELY DIFFERENT”.
Ironically, amongst the drug ads is a full page glossy ad from the Australian Dairy Corporation extolling the virtues of low fat dairy products, despite the fact that dairy products are a major problem for people with elevated blood fats. The ad reads:
“ Low fat dairy can help lower cholesterol
A low fat dairy diet is ideal for your high cholesterol patients. It will reduce their intake of saturated fats, which lowers their cholesterol levels and lessens their risk of heart attack. By recommending low fat dairy food everyday your patients will get the essential vitamins and minerals they need.”
At the bottom right hand corner is the caption:
“Dairy. Every day for life.”
It is true that saturated fats, which include most animal fats, can raise the LDL fraction of the total cholesterol, and also contribute towards obesity and diabetes. They can also worsen hypertension, especially if mixed with alcohol and a high salt intake. All of these dietary problems can be solved by a diet rich in fresh fruits, vegetables and cereals, with the predominant protein sources in the diet coming from legumes (beans, lentils, chick-peas etc), nuts and fish. The bones in canned fish are a good source of calcium as are various nuts. A low fat dairy diet does not lower cholesterol, it just does not do as much damage as a high fat dairy diet does.
The relationship between cholesterol and oestrogen should be mentioned. Cholesterol is the precursor molecule for the synthesis in the ovaries of oestrogen as well as progesterone, the female sex hormones. It could be theoretically predicted that drugs which block the synthesis of cholesterol will have an effect on levels of these hormones. It is also thought that oestrogen provides a protective effect against atherosclerosis and known that it protects the bones against osteoporosis. Osteoporosis is a common problem in older women, especially after menopause, and the pharmaceutical industry and gynecology profession have, for many years, been urging women to take “hormone replacement therapy” to protect themselves against calcium loss from bones, or “demineralisation” as it is called.
On the page opposite the glossy Lipex ad in the MIMS Issue No 5 is a small green ad for Rocaltrol from Roche. Rocaltrol is a drug treatment for osteoporosis.
Bone attack?
REFERENCES:
1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition). APA:Washington, D.C.
2. Brain Attack. Published by National Stroke Foundation, Australia (1999)
3. MIMS Issue No 5 1999. Published by MultiMedia Australia (1999)
4. MIMS Annual 1993. Published by MultiMedia Australia (1993)
5. Neurology Care. Promotional material from Parke Davis (1999)
6. Reubens, D., Savard, G., Andermann, F., Dubeau, F., and Olivier, A.
Results of surgical treatment in temporal lobe epilepsy with chronic
psychosis. The Brain (1997), 120, 1929-1936. Published by Oxford
University Press (1997)
