Revisiting phenobarbital for epilepsy
BMJ 2004; 329 doi: https://doi.org/10.1136/bmj.329.7476.1199 (Published 18 November 2004) Cite this as: BMJ 2004;329:1199All rapid responses
Rapid responses are electronic comments to the editor. They enable our users to debate issues raised in articles published on bmj.com. A rapid response is first posted online. If you need the URL (web address) of an individual response, simply click on the response headline and copy the URL from the browser window. A proportion of responses will, after editing, be published online and in the print journal as letters, which are indexed in PubMed. Rapid responses are not indexed in PubMed and they are not journal articles. The BMJ reserves the right to remove responses which are being wilfully misrepresented as published articles or when it is brought to our attention that a response spreads misinformation.
From March 2022, the word limit for rapid responses will be 600 words not including references and author details. We will no longer post responses that exceed this limit.
The word limit for letters selected from posted responses remains 300 words.
Most epileptic seizures are triggered by a focal area of abnormal or
chaotic electrical activity, or electrical storm, and are the overt
consequences of disordered excitation in relatively healthy cells in an
expanding region of normal brain. The inference is that medications which
prevent siezures do so either by suppressing abnormal activity within the
trigger area or by suppressing the activity the trigger area evokes in
adjacent areas of normal brain. [The mechanisms by which they do so is not
clear]. In either event the medications are going to have an effect upon
all normal cells in the brain. Might they work simply by impairing
cellular energetics (1), or is it more comples than that?
An impressive finding in patients having cardiac surgery, whose
higher cognitive functioning has been examined prospectively with a
battery of tests (2), is that many of the disorders acquired from surgery
are subclinical. That is to say they are very subtle and most likely to be
detected only by those who know the patients well. The observation that
"they are not the same" is particularly pertinent to a younger person
being placed upon anticonvulsants.
In the case of epileptic siezures postictal psychosis may even
develop but are said to be self-limited and phenomenologically distinct
from ictal or postictal confusion (3). That psychoses occur at all raises
the possiblity that in some cases anticonvulsants might have the same
effect and the effects too subtle to be detected by a clinician in the
absence of a battery of prospective tests such as those used in the
evaluation of patients having cardiac surgery.
To what extent might anticonvulsants have changed people and even
made them psychotic? As these medications are commonly prescribed for
extended periods the effects might be apparent for 10, 20, 40 or in
developed countries today even 80 years. In other words the putative
cognitive and phenological effects might not become apparent until decades
later and when they do be ascribed to other events.
German neurosurgeons appreciate the neuropsyciatric aspects of
epilepic siezures and have attempted to avoid them (4,5). In their view,
"Successful epilepsy surgery can stop or partly reverse the unfavourable
cognitive development, but left-temporal resections in particular have a
high risk of additional postoperative verbal memory impairment. Cognitive
recovery in the adult brain after successful surgery indicates functional
compensation and, to some degree, functional reorganisation or a
reactivation of functions previously suppressed by influence from distant
but connected epileptogenic areas". Might a much more aggressive surgical
approach be appropriate?
Neurosurgeons at the Mayo Clinic observe that, "Nearly one-third of
patients with newly diagnosed epilepsy will develop medically refractory
seizure disorders"(6). In their experiences, "early and effective epilepsy
surgery may not only render the patient with intractable partial epilepsy
seizure-free, but also allow the individual to become a participating and
productive member of society..Patients with surgically remediable
epileptic syndromes should be identified early in the evaluation and
treatment of their seizure disorders. Favorable candidates for focal
cortical resection include individuals with medial temporal lobe epilepsy
and partial seizures related to selected lesional pathology, e.g. primary
brain tumor or vascular anomalies".
What these reviews do not consider is the potential of sterotactic
radioablation. The concept is appealing for the radioablation could be
limited to the trigger area as in the case of cardiac arrhythmias. I was
not able to find any relevant reference to "radioablation" on Pubmed.
A major limitation in exploring new frontiers is getting the
patients, there inevitably being a huge gap between GPs/physicians and
surgeons in perception of risk/benefit ratio. It is not uncommon,
therefore, for patients to take matters in their own hands in the US and
find the surgeons who are exploring new frontiers. The danger in so doing
is allowing another frontal lobotomy saga to occur, one with which the
Kennedy family in Boston is very familar Rose having been
institutionalised as a consequence. It is, therefore, very clearly
desirable that further explorations of this nature be carried out
responsibly and competently. There will, however, inevitably be a learning
curve. But it is the failures from which one learns most. That epilepsy
surgery can be so successful in some cases should be regarded, therefore,
as proof of concept and there is nothing like a happy patient to bring in
the new cases. One should not be deterred by the failures. Surgery would
not be what it is today if surgeons had been. The lessons have been
learned. it is time to move forwards not backwards.
There would appear to be so many mutated memes and meme complexes
contaminating neurology and neurosurgery (7), and indeed the management of
all acute and even chronic intracranial pathology, that the place to
begin might be to identify and eliminate these memes and meme complexes so
that new procedures are given the best opportunty of succeeding.
The Medical Research Council focused upon the wrong end of the
spectrum of head injuries in their recent CRASH trial(8). The
multinational trial, which had 21 collaborators, had aimed to recruit
20000 patients but their data monitoring committee disclosed the unmasked
results to the steering committee, which stopped recruitment, after 10008
patients had been entered into the study. The collaborators concluded,
"Our results show there is no reduction in mortality with
methylprednisolone in the 2 weeks after head injury. The cause of the rise
in risk of death within 2 weeks is unclear".
In 1997, findings of a systematic review had concluded that steroids
reduced risk of death from head injuries by 1-2%. Why then was such a
massive study undertaken to test the validity of what at best could only
have been expected to be a fine-tuning effect on outcome? That no
difference was found does not exclude the credible possibility that had
the drug been given in a different way in different circumstances it
might have been as effective as it can be in allergic reactions. Might the
study have been conducted for political reasons, possibly to test the
credibility of a basic meme incorporated into routine neurosurgical
critical care? In which case might the conclusion be that routine
neurosurgical critical care is contaminated by at least one mutated meme?
No beause the study may have been rendered uninterpretable by the
inclusion of mutated memes and mme complexes in routine managment.
Routine management incorporated the mutated meme complexes of using
ICP monitoring without the support of metabolic monitoring (2). What of
the use of anticonvulsive therapy to prevent siezures after neurosurgery?
Might that be a mutatd meme? In neonates lidocaine is commonly use to
prevent and manage siezures, but this increases the risk of developing
cardiac arrhythmias (9). In adults intravenous amiodarone and beta-
blockers have replaced intravenous lidocaine in the management of cardiac
arrhythmias (10). Skeletal muscle paralysis would seem an appealing
alternative for it should not precipitate and might even prevent chaotic
cerebral and cardiac electrical storms and be as safe to use in an ICU
setting.
The use of beta blockers and amiodarone to treat arrhythmias may be
metabolically inappropriate(11). Indeed "electrical storms" either in the
heart or in the brain might well be the chaotic products of focal or
regional increases in the amplitude of synchronised metabolic variations
(12). In which case metabolic measures might be best directed at
decreasing the amplitude of any measurable metabolic variations to prevent
the development of chaotic patterns. This may even be what anticonvulsants
and antiarrythmics do, cosh all brain the cells to varying degrees.
1. Komissarova IA, Nartsissov YR, Burbenskaya NM Effects of
phenobarbital on activity of mitochondrial enzymes in peripheral blood
lymphocytes and oxidative phosphorylation in liver mitochondria.
Bull Exp Biol Med. 2001 Apr;131(4):330-2.
2. Carotid endartrectomy for neuropsychiatric disorders.
Richard G Fiddian-Green (19 November 2004) eLetter re: James F Toole
Surgery for carotid artery stenosis
BMJ 2004; 329: 635-636
3. So NK, Savard G, Andermann F, Olivier A, Quesney LF. Acute
postictal psychosis: a stereo EEG study.
Epilepsia. 1990 Mar-Apr;31(2):188-93.
4. Elger CE, Helmstaedter C, Kurthen M Chronic epilepsy and
cognition.
Lancet Neurol. 2004 Nov;3(11):663-72.
5. Schmidt D, Baumgartner C, Loscher W The chance of cure following
surgery for drug-resistant temporal lobe epilepsy What do we know and do
we need to revise our expectations?
Epilepsy Res. 2004 Jul-Aug;60(2-3):187-201
6. Cascino GD. Surgical treatment for epilepsy.
Epilepsy Res. 2004 Jul-Aug;60(2-3):179-86.
7. Might intracranial pressure be a passive reflection of
intracranial pH?
Richard G Fiddian-Green (16 November 2004) eLetter re: M Czosnyka and J
D Pickard
Monitoring and interpretation of intracranial pressure
J Neurol Neurosurg Psychiatry 2004; 75: 813-821
8. Roberts I, Yates D, Sandercock P, Farrell B, Wasserberg J, Lomas
G, Cottingham R, Svoboda P, Brayley N, Mazairac G, Laloe V, Munoz-Sanchez
A, Arango M, Hartzenberg B, Khamis H, Yutthakasemsunt S, Komolafe E,
Olldashi F, Yadav Y, Murillo-Cabezas F, Shakur H, Edwards P; CRASH trial
collaborators Effect of intravenous corticosteroids on death within 14
days in 10008 adults with clinically significant head injury (MRC CRASH
trial): randomised placebo-controlled trial.
Lancet. 2004 Oct 9;364(9442):1321-8.
9. Van Rooij LG, Toet MC, Rademaker KM, Groenendaal F, de Vries LS.
Cardiac arrhythmias in neonates receiving lidocaine as anticonvulsive
treatment.
Eur J Pediatr. 2004 Nov;163(11):637-641. Epub 2004 Aug 7.
10 Srivatsa UN, Ebrahimi R, El-Bialy A, Wachsner RY Electrical storm:
case series and review of management.
J Cardiovasc Pharmacol Ther. 2003 Sep;8(3):237-46.
11. Was the right organ biopsied?
Richard G Fiddian-Green (15 November 2004) eLetter re: Michael C. Ott,
Andras Khoor, Jack P. Leventhal, Timothy E. Paterick, and Charles D.
Burger
Pulmonary Toxicity in Patients Receiving Low-Dose Amiodarone
Chest 2003; 123: 646-651
12. SUD: product of an abnormally increased amplitude of synchronised
metabolic variations?
Richard G Fiddian-Green (16 November 2004) eLetter re: A M A Shehab, R J
MacFadyen, M McLaren, R Tavendale, J J F Belch, and A D Struthers
Sudden unexpected death in heart failure may be preceded by short term,
intraindividual increases in inflammation and in autonomic dysfunction: a
pilot study
Heart 2004; 90: 1263-1268
Competing interests:
None declared
Competing interests: No competing interests
Readers of this article might also bear in mind that along with the
exclusion of benzodiazepines by the Medicare Modernization Act in the
United States, barbiturates are as an entire class banned from
reimbursement come January 1, 2006. To date there has been one newspaper
article referring to this in the United States.
See:
http://a257.g.akamaitech.net/7/257/2422/06jun20041800/edocket.access.gpo...
-17234.pdf
Competing interests:
None declared
Competing interests: No competing interests
Phenobarbital for epilepsy
Editor,
Re:- Phenobarbital for epilepsy.
Kale and Perucca (1) raise interesting ethical and practical
questions in contrasting the widespread use of Phenobarbital for epilepsy
in the developing world with its disfavour in the developed world.
In the developing world the main problem is the “treatment gap”. Up
to two thirds or more of people with epilepsy receive no treatment at all
(2). In these circumstances of limited resources and infrastructure the
promotion by Health Authorities of a cheap but effective drug,
Phenobarbital, is both understandable and desirable. In developed
countries the problem is often the over treatment of epilepsy. In the UK,
in addition to three other standard anti-epileptic drugs (Phenytoin,
Carbamazepine, Valproate), 8 new anti-epileptic drugs have been marketed
in the last 15 years. Polytherapy is again on the increase. Many
physicians are bewildered by the potential choice of drug or drug
combinations.
I and my colleagues have conducted one of the very few randomised
comparative efficacy and toxicity studies of Phenobarbital against other
standard anti-epileptic drugs (3, 4). In both adults and children with
newly diagnosed generalised or partial seizures we found no difference in
long term efficacy between Phenobarbital, Phenytoin, Carbamazepine and
Valproate. However, although we found only slightly greater neuro-
toxicity with Phenobarbital in adults this problem was much greater in
children. Phenobarbital remains a very useful drug in adults, whether or
not it is the only drug available, but there is a real ethical dilemma in
children in whom it should be used with caution if it is the only
available drug. When a single drug has failed we still do not know
whether any particular combination of two drugs is superior to switching
to an alternative single drug, or which combination of two drugs is
superior to any other combination(5)?
I agree with Kale and Perucca that after more than 80 years of use
there is still much to learn about Phenobarbital, the most widely used
anti-epileptic drug in the world. The same unfortunately is true of the
standard and newer drugs, and even more so of any particular drug
combination. It is unrealistic however to expect the WHO or the ILAE to
undertake the necessary clinical trials and basic research. The WHO is a
public health organisation whose job it is to promote best practice within
limited existing knowledge and resources, as is now underway in the
ILAE/IBE/WHO Global Campaign against Epilepsy (2). There is no reason
however why scientific institutions in the developing world should not
undertake such studies either alone or in collaboration with similar
institutions in the developed world, especially those that are designated
WHO collaborating centres.
Edward Reynolds, Honorary Senior Lecturer
Institute of Epileptology, King’s College,
London SE5 6PJ
e-mail: reynolds@buckles.u-net.com
Competing interests: I was President of ILAE 1993-1997 and first
Chairman of the ILAE/IBE/WHO Global Campaign against Epilepsy 1997-2001.
References:
1. Kale R, Perucca E. Revisiting phenobarbital for epilepsy. BMJ;
329: 1199-200.
2. Reynolds EH (Ed). Epilepsy in the world: Launch of the second
phase of the ILAE/IBE/WHO Global Campaign against Epilepsy. Epilepsia
2002; 43: Supplement 6.
3. Heller AJ, Chesterman P, Elwes RDC et al. Phenobarbitone,
phenytoin, carbamazepine, or sodium valproate for newly diagnosed adult
epilepsy; a randomised comparative monotherapy trial. J Neurol Neurosurg
Psychiatry 1995; 58: 44-50.
4. de Silva M, MacArdle B, McGowan M et al. Randomised comparative
monotherapy trial of Phenobarbitone, phenytoin, carbamazepine, or sodium
valproate for newly diagnosed childhood epilepsy. Lancet 1996; 347: 709-
13.
5. Beghi E, GattiG, Tanini C et al. Adjunctive therapy versus
alternative monotherapy in patients with partial epilepsy failing on a
single drug: a multicentre, randomised, pragmatic controlled trial:
Epilepsy Res 2003; 57: 1-13.
Competing interests:
I was President of ILAE 199-1997 and first Chairman of the ILAE/IBE/WHO Global Campaign against Epilepsy 1997-2001.
Competing interests: No competing interests