May 2002
Vol.9 No. 3
Editors: Dr. KY Wong
Drs. Elaine YW Kwan,
Karen L Kwong,
Sam SP Lau

Treatment of Epilepsy: When to Start and Withdraw? (Part I)

Dr. KL Kwong and Dr. WK ChaK
Department of Paediatrics, Tuen Mun Hospital


Editor's Notes

In this issue, Dr Kwong and colleague discuss the rationale of starting and withdrawing anticonvulsants for the treatment of seizure based on current evidence. Dr Lee illustrates the local scene of ketamine abuse in Hong Kong, the information that certainly helps us a lot when we communicate with our youngsters.

Summary:

Introduction

Antiepileptic drugs should be started when the risks of further seizure outweigh the risks of treatment. Risks of recurrent seizure that might be decreased by treatment are (1) death, (2) physical injury as a result of seizure, (3) brain damage, and (4) psychosocial consequences. However, medication is not completely effective in preventing further recurrence. On the other hand, risks of treatment include biologic and cognitive effects of medication.

Seizure related risks

Death
Sudden death is very rare in children with epilepsy. The incidence and risk of sudden death in patients with idiopathic epilepsy may not be greater than that in the general population. In a cohort of 693 epileptic children followed up over 15 to 20 years, only one case had been reported. "Sub-therapeutic" drug levels have been noted in postmortem specimens of epileptic patients. This has led to a speculation that sudden discontinuation of medication might have precipitated a severe seizure with cardiac arrhythmia or pulmonary edema. Other possible risk factors for sudden death in epileptic patients include severity of epilepsy, polytherapy and mental handicap. Since the risk of death associated with epilepsy is small, this should not be an important factor when one considers starting antiepileptic drugs.

Physical injury
In a long-term study of children with absence seizures, 27% of children sustained a serious injury during a seizure. Systemic data for other types of epilepsy causing physical injury in children are lacking. Over an observation period of two months, 2 of 733 adults with intractable seizures had aspiration pneumonia after a generalized tonic-clonic seizure, and 5 of 806 had shoulder dislocation during an attack. Physical injury may also result from seizure during potentially dangerous activities. Buck and colleagues reported in a community survey of 344 adults with at least one seizure in the previous 12 months that 13% had experienced a seizure while swimming or bathing - a potential disaster.

Brain damage
Debates continue over the effect of seizures on the brain. The National Collaborative Perinatal Project found that a short seizure of any sort did not appear to injure the brain in children. In a population-based study of 478 children with newly diagnosed epilepsy, neither seizure control nor remission appeared to be compromised if medication was only started after the 10th seizure. However, kindling is still a theoretic concern and every effort should be made to control seizures in children with catastrophic epilepsy. Catastrophic seizures are those that are difficult to control and are strongly associated with mental retardation. Many children with catastrophic epilepsy develop seizures as a result of underlying brain abnormalities. These brain abnormalities will inevitably lead to mental retardation, whether or not seizures are present. In some children, however, catastrophic seizures may result in mental retardation.

Treatment considerations

Risks from medication
The risk of severe reaction to antiepileptic drug is about 1 in 30,000. About 15% of patients will have a cognitive or behavioral reaction to the first medication. Fatal hepatic failure has occurred in patients taking valproate. However, this risk seems to be age specific. No fatalities have been reported in certain age ranges of patients receiving monotherapy (11-20 years and older than 40 years). Other risk factors for development of reaction to valproate include: children <2 years of age, organic brain disease, mental retardation with severe seizure disorders, metabolic disorders, and patients on multiple anticonvulsants. Laboratory monitoring is of little value in predicting fatal hepatic failure.

Medication effectiveness
Forty-two percent of children with newly diagnosed epilepsy have recurrent seizures despite excellent drug compliance. In no groups of children could successful treatment be guaranteed. A population-based study noted that only 20% of children experienced no recurrence of seizures with medication. Successful treatment is more likely in children who have: seizure onset before 12 years, normal intelligence, no previous neonatal seizures, and less than 21 seizures before treatment.

When should treatment be started?
Almost no children should be treated after a first seizure. Prospective follow-up studies of individuals with a first unprovoked seizure suggested that only about 25% of them would experience a second seizure within the next 2 years. A prior neurologic insult has been the most powerful and consistent predictor of recurrence. Other risk factors include partial seizure type, abnormal electroencephalogram findings, febrile seizures, status epilepticus and multiple seizures in the index episode. Regardless of the risk of recurrence, the potential adverse effects of daily medication in children with only one seizure outweigh its benefits. Several studies have shown that prescribing medication after a first unprovoked seizure does not alter the rate of relapse. Treatment failure in this group of patients may, however, be related to poor drug compliance.

The risk of recurrence after two seizures is about 80% to 90%. The conventional recommendation for most patients is to initiate therapy after a minimum of two seizures. Possible exceptions to this recommendation include benign rolandic epilepsy, widely spaced seizures, and some simple partial seizures or auras.

When to discontinue antiepileptic drug therapy
Before we decide to withdraw antiepileptic drug therapy, the following factors should be considered:

Studies in children and adults indicate that most patients who are seizure free for 2 or more years while on antiepileptic drugs will remain so when medications are withdrawn. Therefore a 2-year seizure-free period is generally sufficient. An even shorter seizure-free interval may be sufficient in selected cases. Given the uncertainty, a decision to withdraw drugs must be made jointly with the family, after thorough discussion that includes not only an assessment of the risks and benefits of withdrawing medication, but also a review of measures to be taken in the event of recurrence.

Suggested readings

  1. Camfield CS, Camfield PR, Gordon KE, et al. Predicting the outcome of childhood epilepsy-a population-based study yielding a simple scoring system. J Pediatr 1993;122:861-8.
  2. Detoldo JC, Lowe MR. Seizures, lateral decubitus, aspiration and shoulder dislocation. Time to change the guidelines? Neurology 2001; 56:290-1.
  3. Tennis P, Thomas TB, Annegers JF, et al. Cohort study of incidence of sudden unexplained death in persons with seizure disorder treated with antiepileptic drugs in Saskatchewan, Canada. Epilepsia 1982;23:531-44.
  4. Buck D, Baker GA, Jacoby A, et al. Patients' experiences of injury as a result of epilepsy. Epilepsia 1997;38:439-44.
  5. Ellenberg JH, Hirtz DG, Nelson KB. Do seizures in children cause intellectual deterioration? N Engl J Med 1986;314:1085-8.
  6. Camfield CS, Camfield PR, Gordon KE, et al. Does the number of of seizures before treatment influence ease of control or remission of childhood epilepsy? Not if the number is <10. Neurology 1996;46:41-4.
  7. Canadian Study Group for Childhood Epilepsy. Clobazam has equivalent efficacy to carbamazepine and phenytoin as monotherapy for childhood epilepsy. Epilepsia 1998;39:952-9.
  8. Camfield PR, Camfield CS, Smith E, et al. Newly treated childhood epilepsy: a prospective study of recurrence and side effects. Neurology 1985;35:722-5.
  9. Hauser WA, Hesdorffer DC. Epilepsy: Frequency, Causes and Consequences. New York: Demos Publications;1990.
  10. Camfield CS, Camfiled PR. Initiating Drug Therapy in the Treatment of Epilepsy. Principles & Practice. Ed. Wyllie E. Third Edition. 759-68.
  11. American Academy of Pediatrics, Committee on Drugs. Behavioral and cognitive effects of anticonvulsant therapy. Pediatrics 1995;96:538-40.
  12. Shinnar S, O'Dell C. Treating childhood seizures: when and for how long. In Shinnar S, Amir N, Branski D, eds. Childhood seizures. Basel: Skarger, 1995:100-10.

Ketamine Abuse in Local "Rave" Scenes

Dr. Dominic TS LEE
Department of Psychiatry, The Chinese University of Hong Kong

Summary:

Introduction

In recent years, the local pattern of substance abuse has undergone a major transformation. The emergence and popularization of ketamine and ecstasy in mega-dance parties (commonly known as 'Rave Parties') and discos have rendered mind-altering substances more accessible to local youth. The governmental Central Registry of Drug Abuse (CRDA) recorded a sharp rise of ketamine and ecstasy users in 1999 and 2000. In 2001, the prevalence and incidence of ketamine abuse as recorded by the CRDA exceeded those of ecstasy. Ketamine is not a common substance of abuse in Europe and North America, and hence research data are few and far between. There is therefore a pressing need for a succinct summary on the abuse of ketamine in the local context.

Local drug scene

In Hong Kong and many other parts of the world, ketamine is predominantly consumed in mega-dance parties, discos and clubs. The drug is used in such contexts because it helps the users to better engage in the party experience. There are occasional reports of ketamine use in private parties, karaokes, and even schools in Hong Kong.

In Hong Kong, ketamine is mostly used in conjunction with MDMA (ecstasy) in rave parties and discos. Ketamine is used with MDMA because the latter has two major shortcomings that seriously compromise the party experience. First, it takes 20-40 minutes for MDMA to begin its action. The users will therefore use ketamine, which is rapid acting to fill the gap in the first half an hour after MDMA has been taken. Otherwise, they will feel "too alert" for the party. Second, MDMA's effects last for around 4 hours. As MDMA users usually take their MDMA at around 1 am, by 5 am the drug effects begin to wear off. To overcome this problem, some users will cover the period from 5 am to 7 am (when the party or disco finishes) with ketamine. Ketamine is also used with MDMA for synergistic effects.

In Hong Kong, ketamine is mostly sold in powder form, wrapped in paper packets. The weight of individual packet varies, and generally it is about 200 mg per packet locally. Ketamine is commonly shared among a group of peers in party or disco. Local users who have developed tolerance may use as many as 9 packets per night. The powder, spreaded on a flat surface (e.g. a name card holder or an identity card), is passed around the group and snorted. This may happen in the chill area (the recovery area of a mega-dance party) or in the dance venue. The ketamine sold in Hong Kong is mostly of high purity. Adulterant is rare but is becoming common; samples adulterated with paracetamol (Panadol) and caffeine have been encountered very occasionally. Ketamine is also available locally in tablets; most of these ketamine tablets are sold as fake ecstasy tablets in party and disco scenes.

Epidemiology

Ketamine abuse was first captured by the Government drug surveillance system, Central Registry of Drug Abuse (CRDA), in 1997. In 1999, 0.2% of all reported individuals abused ketamine. This increases to 9.7% in 2000, compared with 8.7% for cannabis, 14.1% for ecstasy, 18.7% for methadone, and 74.3% for heroin in the same year.

Among the newly reported individuals (i.e. newly identified drug users) in 2000, 30.7% used ketamine, 42.2% used ecstasy, 27.6% used heroin, and 19.7% used cannabis. In the same year, among the under 21-year-old newly reported individuals, 44.3% used ketamine, 62.7% used ecstasy, 10.6% used heroin, and 19.9% used cannabis.

Pharmacology

When administered nasally, ketamine has an average onset of 5 to 15 minutes. Its drug effects last between 10 to 30 minutes. Most users return to the baseline conscious state within 90 minutes. It is reported that about 0.3 mg/kg of ketamine produces light drug effect. A dose of 1-1.5 mg/kg produces a strong effect. The K-hole effect (see below) is usually experienced when the dose reaches 2 mg/kg. The intravenous anesthetic dose is 1-4.5 mg/kg. The intravenous lethal dose (LD50) is around 77 mg/kg.

Desired effects

At low dose, ketamine produces a drunken state, in which the users may feel weightless and uninhibited (commonly referred as "drifting" or "free" by local users). Such effects help the ketamine users to better engage in the atmosphere and the party. At a higher dose, ketamine users can experience psychedelic effects, but few local users sought the psychedelic effects deliberately. Local drug users label the psychedelic state as "OD" – a short form for "overdose". This represents a lay misconception on the psychedelic effects -- as users who are engaged in their psychedelic experience tend to dissociate from reality, they are often misconstrued as "overdosed" by their peers.

The psychedelic state includes two major experiences: the near death experience and the out-of-body experience. In the near death experience, the individual feels that he or she entering a tunnel that leads to a black hole. As the drug effect wears off, the individual will feel that he or she is leaving the tunnel, re-entering "consciousness". This "black hole" or "tunnel" is commonly referred as "K-hole" or "K-tunnel."

Apart from near death experience, experienced ketamine users may also enter a state whereby they feel that they leave their bodies while witnessing their own bodies from the outside. This out-of-body state is also commonly referred as hallucinatory or dissociative experience in the literature. Again, such psychedelic effects tend to vary with individuals and may be affected by a variety of factors, such as mood state and daytime experience. More importantly, not all ketamine users experience out-of-body dissociation. Inexperienced users who encounter near death experience or out-of-body experience can become panicky and dangerous behavior can follow, according to western literature.

Adverse effects, risks and toxicity

Common adverse effects of ketamine include dry mouth, nervousness and tachycardia. Many people also experience nausea and/or vomiting when the effects of ketamine wear off. Vomiting can be very dangerous if the user becomes unconscious, as the vomitus, if aspirated, can cause life threatening pneumonia. Occasionally, severe vomiting may also lead to oesophageal tear and peptic erosion. Snorting behaviour may also lead to nasal mucosal irritation and bleeding.

Other adverse effects include hypertension, laryngospasm, respiratory depression, mild gastrointestinal distress, double vision, increased intra-ocular pressure and muscular movement resembling seizure.

Ketamine can cause psychomotor impairment, which in turn may increase the risk of accident. Inexperienced users, who have access to large amount of ketamine, may unknowingly overdose themselves.

Because ketamine is colourless, odourless, and causes memory blackout, it has been used as a date rape drug in the U.S. It is possible that ketamine is misused in the same fashion in Hong Kong, but relevant data are few and far between.

Paranoia and egocentrism have been reported for those who use ketamine regularly. Ketamine is also reported to be associated with psychosis.

In animal studies, ketamine has been shown to have the potential to reinforce repeated use. Animals who are given unlimited supply of ketamine tend to consume an increasing amount. This is generally regarded as a sign of dependence in animal studies. In human, repeated use of ketamine can cause tolerance (i.e. a larger dosage is needed to produce the same desired effects). However, unlike other addictive substances (such as heroin, methamphetamine, benzodiazepines, alcohol and nicotine), distinctive withdrawal symptoms or syndromes have not yet been reported. There are sporadic (not more than 10) reports of dependence in the literature, and they mostly involve individuals who had convenient or cheap access to large amount of ketamine.

Psychosocial management

In general, party/disco drug abusers are difficult to engage because most of them believe that ketamine is non-addictive, and no treatment is required. It is hence more useful to focus on the underlying psychosocial problems (such as depression, family discord, unemployment) instead of arguing with the patients on the potential risk and addictiveness. Referral to social workers and psychiatrists who specialize in substance abuse should be considered.

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