Howzit 22

President’s message

It’s a wet, rainy Friday morning with nothing much going on in the clinic, our Howzit editor is screaming for articles, so I reckon it is about that time again to sit down and pen my usual words of wisdom.

This will be my last article as President of MAAM, and I must say it has been a pleasure and an honor to represent Manipal Alumni over the past few years. I am certainly happy to be going out on a high note. In just 50 days(at the point of writing), the biggest event in MAAM’s history will be launched.

There is not a day that goes by in our circle, without August 2014 being mentioned. Word is spreading, and to date, we have more than 400 registered participants. This is a good number, but it falls short of our target of 800. Perhaps everyone is afflicted with the usual problem of doing everything at the last minute. Do register soon, and get your friends to register too, so you don’t miss the conference!

All those involved in the preparation for the event have been extremely busy for several months now. It’s been ‘brother this’ and ‘brother that’, interspersed with occasional bouts of flying tempers. But it’s all in the spirit of cooperation, as we have a common aim – to deliver an event of the highest standards, as befits the Manipal tradition.

The schedule of events is in place but as with all events, final touches and alterations will inevitably happen as the date nears. The program certainly looks interesting, especially since, for the first time, we are combining the medical conference with a conference dealing with other fields covered by Manipal as well.

The scientific program comprises two full days of talks, with hands-on workshops in some breakout sesions.

The engineering program is in the able hands of Dr. PLNG Rao, the new Vice Chancellor of MIU, whose reputation precedes him (incidentally he is a pediatric surgeon from Manipal, having lectured some of our present day Doctors of MAAM).

On the medical side, the three precongress workshops – full day sessions in Emergency Medicine, Ultrasound in Obstetrics and Gynaecology, and Uro Gynaecology – have been confirmed. The ENT Primary Care post-congress workshop is also moving along very well. More and more participants are signing up, so please get your names down for these sessions; due to the “hands on” nature of the workshops, participant numbers have to be limited.

That’s the ‘work’ part of the conference. Of course we also have to have some ‘play’ time, and that’s what Saturday is all about. The Saturday is purely an Alumni fun day and absolutely should not be missed. It’s all about sports, fun and family togetherness.

The family and sports events for Saturday morning are being sponsored by our longstanding member Datuk Dr. Jagjit Singh Hullon (batch of 1972). I must mention here that Dr Jagjit Hullon has, in his individual capacity, been supporting our events very generously for many years now. I applaud him and trust you will do the same. He is a true, selfless Manipalite, an example for all of us to follow.

There will be golf on Saturday morning, and depending on numbers we may be able to organise a bus to ferry the golfers to the Templers Perangsang Golf Club (well known for roaming tigers in its early days; but don’t worry, you’re unlikely to encounter any today). I had the privilege to play there some years ago. Surrounded by thick jungle, it is a nice mature course with the right mix of water ways, and it is especially serene and cool in the early mornings. The morning ride will take about 40 minutes from the hotel so we encourage an early morning departure with an hour at the club for breakfast before tee off.

The rest of the morning will be a “family day”, with a 20-over cricket match, futsal, children’s telematch, ladies’ netball, and volleyball. After all this activity, there must naturally be lunch. This will be provided at Kelab Aman, the venue for these sporting events, which is less than 5 km away from the Royale Chulan. A shuttle bus service will be provided from the hotel. Lunch promises to be a delicious affair, as the club boasts excellent Punjabi Cuisine.

And of course, all this healthy outdoor activity has to be balanced by a bit of nightlife. The night starts at 6 pm with cocktails followed by a gala dinner. The event is aptly themed “Remember Yesterday”, so it will be about nostalgia, catching up with long-lost friends, and reliving our youth. I predict a huge turn out on the Saturday night. So come along, it’ll be well worth the effort.

But apart from remembering yesterday and wallowing in nostalgia for our glory days, we should also look towards our future. Our biggest effort in achieving that end is in fact our shift towards more scientific content in our events, as represented by this convention.

The convention has taken up practically all our time and attention over the past two years. After all, organising a global event on this scale takes a great deal of effort. This isn’t just about catching up with old friends. We have been determined to ensure that we deliver a quality event that really puts Manipal on the scientific map. In line with this, we also intend to initiate a scientific journal, to continue the scientific dialogue that will begin in August at the convention. And to ensure that the dialogue continues at an international level, we have plans in the pipeline to create a Global Alumni Association. More on these big initiatives in August 2014!

And now on to the other issues which have occupied us over the past couple of years.

We have seen a dramatic increase in membership over the past two years, from 800+ to more than 1400! This is an excellent development, because we can only carry out all our ambitious plans if we have enough hands on deck to do the hard work. It is also exciting to see more and more young people joining us – they are the ones who will be taking over from the more ‘vintage’ members, and it’s good that they involve themselves from an early stage

We are also making greater efforts to link with our members through the internet. Our website has been undergoing steady improvement. Right now, we are in the process of adding a picture gallery, which will allow members to log on and view pictures of all our events. These pictures can be downloaded, so members can keep their own copies and maybe build up their own albums.

Apart from cyber communications, we also have our more traditional form of communication with members, namely our newsletter, Howzit, which was started by the illustrious Dr. Simon Martin. It’s been upgraded – more articles! more photographs! – but it still aims to keep members connected with what’s happening with MAAM.

In relation to our determination to add value to your membership in MAAM, we have embarked on several initiatives in partnership with various organisations. We have, for example, formed an affilliation with Manipal Hospitals, which will help us in terms of recruiting members as well as sourcing relevant speakers for our CME programs.

MAAM has also appointed Anika Insurance Brokers as our official insurance provider. This will benefit our members in several ways. For example, they will provide members with preferred rates, as well as providing a very favourable clinic insurance scheme. Another bonus is that, as our official insurance provider, they will give us top-notch personalized service, especially with more members joining their scheme. I’d like to encourage you all to take advantage of these schemes, as they will greatly benefit both yourselves and MAAM.

Apart from this, we also have an agreement with Alliance Bank, giving preferred services to our MAAM members. This will really benefit members in a very tangible way, as they have agreed to give preferred rates to MAAM members for a variety of services such as fixed deposit, as well as housing, car and shop lot loans.

So far, the take-up rate among our members for the services provided by Anika Insurance and Alliance Bank has not been very good. Please do take advantage of the schemes and benefits we have negotiated – the better the take-up rate, the better our chance of continuing and perhaps even improving these schemes.

Lest you think that our focus is on ourselves, rest assured that we are also very aware of our responsibility to society and the community. We have organised several CSR activities, such as running free medical camps in conjunction with some church groups. However, we have realised that there are far more pressing problems that need to be dealt with, and that from our privileged positions, we should be making the effort to deal actively with these problems.

Therefore, a more long-term project in Sungai Siput has seen MAAM take on a broader social role, rather than just providing free healthcare advice. We are actively funding a scheme to help single mothers and their children, to try and provide these children with a brighter future. When their mothers go off to work, the children are often left unsupervised, and might easily be tempted to dabble in drugs and crime. There is an initiative among several retired teachers to provide education for the children, and MAAM has decided to help by funding some of these teachers. It costs a mere RM6K to fund one teacher for one year – not much when you think what a valuable service is being provided. Some individuals in MAAM have been donating RM6K per annum for the last 2 years. We hope more members will follow suit.

We believe that such hands-on work brings us into contact with society in a meaningful and relevant way. Our CSR efforts are not focused on local events only – we made a concerted effort among our members and their families to collect donations for the victims of 2013’s Typhoon Haiyan in the Philippines.

And finally, we are learning to market ourselves more effectively for a higher public profile and more recognition – which will assist not only in attracting more members, but also in putting us in the public eye, which should help us with gaining sponsorship. In conjunction with our 2014 global convention, we have been featured in several local newspapers as well as on some radio stations, thus gaining us some recognition.

My friends, in the 2nd announcement about the global convention, I mentioned ‘The Rock’ on which Manipal stands. That rock has been our foundation as we have built our lives and careers. So remember yesterday, remember the Rock, and remember Manipal. Join us, and help make the 1st Global Manipal Alumni Scientific Convention the roaring and impactful success it deserves to be.

See you in August!

Dr. Nirmal Singh
President MAAM

Diagnosis, Treatment and Management of Seizures


The management of patients with epilepsy is focused on three main goals: controlling seizures, avoiding treatment side effects, and maintaining or restoring quality of life. Physicians should assist in empowering patients with epilepsy to lead lifestyles consistent with their capabilities.

It is usually appropriate to refer the patient to a neurologist, when establishing a diagnosis and formulating a course of treatment. Referral to an epilepsy specialist may be necessary if there is doubt about the diagnosis and/or if the patient continues to have seizures.


When to start AED therapy — Immediate antiepileptic drug (AED) therapy is usually not necessary in individuals after a single seizure, particularly if a first seizure is provoked by factors that resolve. AED therapy should be started in patients who are at significant risk for recurrent seizures, such as those with remote symptomatic seizures. AED treatment is generally started after two or more unprovoked seizures, because the recurrence proves that the patient has a substantially increased risk for repeated seizures, well above 50 percent.

Choosing an AED — About half of patients with a new diagnosis of epilepsy will become seizure free with the first AED prescribed [39,40]. Tolerability of side effects is as important as efficacy in determining the overall effectiveness of treatment. No single AED is optimal for every patient or even most patients. The selection of a specific AED for treating seizures must be individualized considering:

  • Drug effectiveness for the seizure type or types
  • Potential adverse effects of the drug
  • Interactions with other medications
  • Comorbid medical conditions, especially but not limited to hepatic and renal disease
  • Age and gender, including childbearing plans
  • Lifestyle and patient preferences
  • Cost

In general, enzyme-inducing AEDs (eg, phenytoin, carbamazepine, phenobarbital, primidone; and less so, oxcarbazepine and topiramate) are the most problematic for drug interactions with warfarin and oral contraceptive therapy, as well as certain anti-cancer and anti-infective drugs

Combination therapy — When possible, it is preferable to maintain a patient on a single AED. This increases the probability of compliance, provides a wider therapeutic index, and is more cost-effective than combination drug treatment. Monotherapy is also associated with fewer idiosyncratic reactions and a lower incidence of teratogenic effects. Combination therapy can be associated with drug interactions between AEDs, making it difficult to dose and monitor patients.

Seizure remission is achieved with combination therapy in only a small percentage (10 to 15 percent) of patients who have failed monotherapy. While the chances of treatment success diminish incrementally with each successive drug trial, two studies suggest a value in pursuing further drug trials.

Side effects of therapy —  During the first six months of treatment, systemic toxicity and neurotoxicity cause AED failure to the same degree as lack of efficacy against seizures. Serum levels that are associated with neurotoxicity vary from patient to patient, and toxicity can occur even when measured levels are considered to be within the appropriate therapeutic range.

The usual strategy in patients experiencing peak-level side effects from a specific drug is to alter the medication regimen or treatment schedule to minimize side effects; one alteration may be to spread the medication over more doses throughout the day. The physician should attempt to correlate serum drug concentrations with the patient’s side effects before abandoning that medication. Specifically, levels should be obtained when a patient is experiencing side effects compared with levels when the patient is free from symptoms can be helpful in the management of some patients.

Specific adverse reactions — Many side effects of AEDs specific to individual medications are reviewed in detail separately. Some severe reactions that are common to more than one medication include the following:

  • Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) are rare but severe idiosyncratic reactions, characterized by fever and mucocutaneous lesions that have been associated with the use of carbamazepine, oxcarbazepine, phenytoin, phenobarbital, primidone, zonisamide, lamotrigine, and (less commonly) other AEDs.
  • Reduced vitamin levels have also been described in patients taking AEDs. In one study, subnormal folate levels were reported in 16 percent of patients on AEDs (primarily in patients taking carbamazepine,gabapentin, phenytoin, or primidone). While vitamin B12 levels were lower on average in patients taking AEDs (particularly in patients taking phenobarbital, pregabalin, primidone, or topiramate), the frequency of subnormal B12 levels was not significantly different in patients compared with controls. Vitamin supplementation yielded normal levels in patients with subnormal levels within three months.
  • Bone loss has also been described in patients receiving long-term AEDs.

Patient education — Before treatment is initiated, the physician needs to begin a dialogue with the patient and family to increase their understanding of epilepsy and their ability to report necessary and relevant information. Epilepsy affects each patient in a unique way, and patients differ in their capacity to understand various aspects of the disorder. As a result, physicians must tailor discussions to clarify the impact of the condition on the specific patient’s quality of life and expectations of the treatment plan. These discussions will improve the likelihood that the patient will comply with the plan of treatment.

Seizure calendar — Patients and family members should be asked to record seizures and AED doses on a calendar or diary, which can then be brought or sent to the physician for review. Seizure triggers should be indicated. The patient and family should note on the calendar the hour at which any symptoms occur. Electronic seizure diaries are also available.

Alcohol intake — Alcohol consumption in small amounts (one to two drinks per day) may not affect seizure frequency or serum levels of AEDs in patients with well-controlled epilepsy.

In an effort to enable people with epilepsy to live as normal a life as possible, it may be reasonable to advise that limited alcohol intake is acceptable, provided there is no history of alcohol or substance abuse or a history of alcoholrelated seizures. However, patients should be aware that the data are not definitive at this time. Driving or other high-risk activities should be avoided for 24 to 48 hours after heavy alcohol intake due to the higher risk of seizures.

Noncompliance with AED therapy —Up to 50 percent of patients with epilepsy may fail to take their medications as directed; over one-half of those evaluated in emergency departments for recurrent seizures have been noncompliant.

Initiation of therapy

Choice of drug — There is an evergrowing list of newer antiepileptic drugs (AEDs) and nonpharmacologic therapies available to manage childhood epilepsy. Traditionally, the medications have been separated into “older” and “newer” groups based upon their historic regulatory approval and availability. Typically, when a medication is first approved for epilepsy, it receives an “onlabel indication” for add-on (adjunctive) therapy for partial-onset seizures in adults. Then, as experience grows and other studies are done, the use of the drug may expand to other seizure types and younger age groups.

Drug dose — The AED dose should be increased until seizures stop, unremitting adverse effects occur, or serum levels reach a high or supratherapeutic range without a significant impact upon seizure frequency. The recommended upper therapeutic serum levels of most of the AEDs can be exceeded if side effects are absent. This should be done with particular caution with phenytoin because of its nonlinear pharmacokinetics and with valproate because of dose-related thrombocytopenia. If side effects appear but are tolerable, the dose should remain stable for several weeks to determine if the symptoms remit. Dose increases can continue at a slower rate if side effects remit and seizures continue.

Drug-drug interactions — Many commonly used drugs can alter the metabolism of AEDs and vice versa. Hepatic enzyme inducers will lower the levels of drugs metabolized in the liver, and liver enzyme inhibitors will slow the metabolism of the same drugs. Cimetidine, propoxyphene, erythromycin, fluoxetine, and clarithromycin are examples of enzyme inhibitors used in children that may elevate the serum levels of some AEDs.

Serum levels — Serum levels should be used only as guides to therapy. The therapeutic range is different for each patient. Many will achieve seizure control at levels below the recommended range; others require higher levels. There is no reason to increase the dose if seizures stop when the serum level is “low” or “subtherapeutic.” If the level reaches the “therapeutic range,” yet seizures continue, the level should be increased as long as there are no adverse effects.

Compliance — Rates of non-adherence to prescribed AED therapy are difficult to measure, but are probably higher than is generally appreciated. One prospective observational study in 124 children (2 to 12 years old) with newly diagnosed epilepsy found that 58 percent demonstrated nonadherence during the first six months of treatment.

Adding a second AED — The first AED fails in 20 to 40 percent of children with epilepsy; lack of efficacy and side effects contribute roughly equally to treatment failure. A second AED is added when seizures are resistant to the initial drug. If the initial drug was partially effective, it should be continued until reasonable levels of the new AED are achieved. Tapering the first drug can then be attempted if seizures are controlled. If the initial AED is ineffective, it can be tapered earlier, as the dose of the second drug is increased.

Monotherapy versus polytherapy — Single-drug therapy is the goal of epilepsy treatment. Monotherapy is associated with better compliance, fewer adverse effects, less potential for teratogenicity, and lower cost than is polytherapy. Drug interactions are avoided and pharmacokinetics are simplified. A second AED may also be considered in children with several different seizure types when monotherapy is not effective. In one practice, the clinicians found that children with status epilepticus, developmental disabilities, and multiple seizure types were more likely to require polytherapy than those without these features.

DRUGS THAT AFFECT VOLTAGEDEPENDENT SODIUM CHANNELS — Depolarization of neuronal membranes (such as by excitatory neurotransmitters at postsynaptic receptor sites) produces an influx of sodium ions from the extracellular space into the neuron through sodium channels along the neuronal membrane.

Carbamazepine — Carbamazepine (CBZ) has been used to treat partial and generalized seizures since being introduced in Switzerland and the United Kingdom over 35 years ago. It is also effective for the treatment of affective illnesses such as bipolar disorder and chronic pain syndromes such as trigeminal neuralgia.

Adverse events — Common systemic side effects of CBZ include nausea, vomiting, diarrhea, hyponatremia, rash, pruritus, and fluid retention.

Phenytoin — Phenytoin was introduced nearly 60 years ago for use in epilepsy and is still widely prescribed for partial and generalized seizures. Similar to carbamazepine, it blocks voltagedependent neuronal sodium channels. The major systemic side effects of phenytoin are gingival hypertrophy, body hair increase, rash, and lymphadenopathy

  • Phenytoin has been associated with the Stevens-Johnson syndrome and toxic epidermal necrolysis, particularly during the first eight weeks of therapy.
  • Folic acid supplementation 0.5 mg/ day was associated with a reduced incidence of gingival hyperplasia (21 versus 88 percent) after six months in a randomized trial of children (ages 6 to 15 years) who were recently started on phenytoin.

Lamotrigine — The cellular mechanism of action of lamotrigine (LTG) is not completely understood, and it may have multiple effects. In rodent brain preparations, LTG blocks the repetitive firing of neurons by inactivating voltagedependent sodium channels.

Oxcarbazepine — Oxcarbazepine is a compound with a similar chemical structure to carbamazepine and likely a similar mechanism of action (table 1A-C).

Metabolism of oxcarbazepine occurs in the liver, but only minimally affects the cytochrome P450 system. This represents a major advantage over carbamazepine, particularly in patients who require polytherapy

The most common side effects of oxcarbazepine are sedation, headache, dizziness, rash, vertigo, ataxia, nausea, hyponatremia, and diplopia.

Zonisamide – Zonisamide is a sulfonamide derivative that is chemically and structurally unrelated to other anticonvulsants. Its primary mechanism of action appears to be to blocking both voltage dependent sodium and T-type calcium channels.

Lacosamide — Lacosamide selectively enhances slow inactivation of voltagedependent sodium channels; this results in stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing.

Rufinamide — Rufinamide is structurally unrelated to other marketed AEDs. Rufinamide modulates the activity of sodium channels, prolonging the inactive state. This action is particularly effective in depolarized neurons.

DRUGS THAT AFFECT CALCIUM CURRENTS — There are three types of calcium channels in neurons, each of which is distinguished by its rate of reactivation and voltage dependency. Low-threshold T-type calcium currents inactivate quickly and have been described in experimental preparations of thalamic relay neurons.

Ethosuximide — Ethosuximide diminishes T-type calcium currents in thalamic neurons, which are further reduced as membrane potentials become more hyperpolarized.

The recommended dose of ethosuximide is 20 to 40 mg/kg per day in one to three divided doses. Blood levels should be checked initially after one to three weeks, with a goal therapeutic concentration of 40 to 100 mcg/mL.

DRUGS THAT AFFECT GABA ACTIVITY — Gamma-aminobutyric acid (GABA) is a neurotransmitter that is widely distributed throughout the central nervous system and exerts postsynaptic inhibition. The GABA(A) receptor complex has binding sites for GABA, benzodiazepines, and phenobarbital. Picrotoxin and other similar proconvulsants bind to the GABA(A) receptor and block chloride channels, thereby preventing postsynaptic inhibition.

Phenobarbital — Phenobarbital (PBOB) is among the oldest AEDs still in use. It is effective for the treatment of generalized and partial seizures. However, its clinical utility is limited by its sedating effects

Tiagabine — Tiagabine (TGB) is a second generation AED that is indicated as adjunctive treatment for partial seizures. It is a potent enhancer of GABA action via specific inhibition of GABA reuptake into presynaptic neurons and glia in vitro.

Vigabatrin — Vigabatrin (VGB) is an irreversible inhibitor of GABA-transaminase that raises the concentration of GABA in the central nervous system.

Benzodiazepines — Benzodiazepines enhance GABA inhibition by increasing the frequency of GABA-mediated chloride channel openings.

Clobazam — Clobazam is approved by the US FDA for as an adjunctive therapy in patients >2 years of age with LennoxGastaut syndrome (LGS).

Others — Clonazepam is most often used as an adjunctive therapy for myoclonic and atonic seizures. Clorazepate, diazepam, and lorazepam are effective for those seizure types as well as for partial and generalized tonic-clonic seizures.


Perampanel — Perampanel is an orally active, noncompetitive AMPA-type glutamate receptor antagonist. It appears to inhibit AMPA-induced increases in intracellular calcium, reducing neuronal excitability.

DRUGS WITH MULTIPLE MECHANISMS OF ACTION — A number of antiepileptic drugs (AEDs) have multiple mechanisms by which they prevent seizures.

Valproate — Valproate (valproic acid, VPA) is a broad-spectrum AED used alone and in combination for the treatment of generalized and partial seizures.

Felbamate — The mechanism of action of felbamate is not well understood. It blocks the channel at the N-methyl-Daspartate (NMDA) excitatory amino acid receptor and augments GABA function in rat hippocampal neuronal cultures.

Topiramate — Topiramate (TPM) also has multiple mechanisms of action. It blocks voltage-dependent sodium channels, enhances the activity of GABA at a nonbenzodiazepine site on GABA(A) receptors, and antagonizes an NMDA– glutamate receptor. It also weakly inhibits carbonic anhydrase in the central nervous system.


Gabapentin — Gabapentin binds to the auxiliary alpha-2-delta subunit of a voltage-dependent calcium channel, which may inhibit inward calcium currents and attenuate neurotransmitter release.

Levetiracetam — Levetiracetam (LEV) is a broad spectrum AED and is approved as adjunctive therapy to treat partialonset seizures in patients aged 4 years or older with epilepsy, as adjunctive therapy in treating myoclonic seizures in patients aged 12 years or older with juvenile myoclonic epilepsy, and as adjunctive therapy for primary generalized tonicclonic seizures in patients 6 years of age and older with idiopathic generalized epilepsy.

Pregabalin — Pregabalin also has multiple potential mechanisms of action. It binds to the alpha2-delta subunit of voltage-gated calcium channels and modulates calcium currents.

Ezogabine — Ezogabine or retigabine is believed to exert its antiepileptic effect by opening KCNQ2/3 voltagegated potassium channels, activating M-current, which regulates neuronal excitability and suppresses epileptic activity.


INITIAL APPROACH — Patients with generalized motor seizures that are frequent or separated by a period of significantly impaired consciousness or who are medically unstable require immediate assessment and treatment, which usually is accomplished in the setting of the emergency department.

Initial assessment — A brief physical examination should assess respiratory and circulatory status. A rapid neurologic examination should be performed to provide a preliminary classification of the type of SE. A history obtained from a parent or caregiver may help to determine the cause of the seizures.

An adequate airway should be established immediately if there is respiratory compromise, and supportive therapy (e.g., oxygen, mechanical ventilation) should be instituted as needed. A secure intravenous catheter should be placed for sampling of blood and administration of medications. Ongoing monitoring of vital signs should be initiated.

Pharmacologic agents: — There are four main categories of drugs used to treat status epilepticus: benzodiazepines, phenytoin (or fosphenytoin), barbiturates, and propofol.

Benzodiazepines — Benzodiazepines remain the first-line treatment for status epilepticus because they can rapidly control seizures.

Diazepam — Diazepam has a high lipid solubility and therefore an ability to rapidly cross the blood-brain barrier; it is highly effective in rapidly terminating seizures when administered at doses of 0.1 to 0.3 mg/intravenously.

Lorazepam — Although lorazepam is as effective as diazepam in terminating seizures, the time from its injection to its maximum effect against seizures is as long as two minutes. The clinical advantage of lorazepam is that the effective duration of action against seizures is as long as four to six hours because of its less pronounced redistribution into adipose tissue.

Midazolam — Like lorazepam and diazepam, midazolam is very effective in acutely terminating seizures (frequently in less than one minute), but it has a short half-life in the central nervous system.

Clobazam — Clobazam has been used to treat status epilepticus outside the United States in settings where intravenous formulations are available.

Phenytoin — Phenytoin is one of the most commonly used treatments for status epilepticus, despite the trial described above which showed that initial treatment of generalized convulsive status epilepticus with lorazepamalone was more effective than treatment with diazepam and phenytoin.

Fosphenytoin — Fosphenytoin is a prodrug of phenytoin that is hydrolyzed into phenytoin by serum phosphatases. Fosphenytoin is highly water soluble and therefore unlikely to precipitate during intravenous administration.

Barbiturates — Barbiturates are similar to benzodiazepines in that they also bind to the GABA(A) receptor, amplifying the actions of GABA by extending GABAmediated chloride channel openings.

Phenobarbital — Phenobarbital is an excellent anticonvulsant, especially in the acute management of seizures.

Pentobarbital — Pentobarbital is used primarily in the treatment of refractory status epilepticus, typically with a loading dose of 10 mg/kg infused at a rate of up to 100 mg/minute.

Thiopental — Some centers use thiopental instead of pentobarbital for refractory status epilepticus, but there are a number of problems with this approach.

Propofol — Propofol is a hindered phenolic compound with anticonvulsant properties. The drug is unrelated to any of the currently used barbiturate, opioid, benzodiazepine, arylcyclohexylamine, or imidazole intravenous anesthetic agents. Hypotension and respiratory depression may complicate its use.

Valproic acid — The use of intravenous (IV) valproic acid (Depacon) is increasingly used in the treatment of status epilepticus. (FDA) approved it only for slow infusion rates (up to 20 mg/min).

A Taste of the Convention

Leadership and Management in Clinical Education

Clinical leadership and management is the ability to motivate and direct those around us for them to achieve the best outcome for the patient by teaching, enabling them to learn; training them to be competent in the needed technical and communication skills and helping them to acquire the attitude and behavioral skills to provide safe and high quality clinical care. They should also develop an inquiring mind by research and audit. Research today is clinical practice tomorrow and audit helps to measure the quality of care we provide. In the current climate they should learn management and financial skills to deliver cost effective health care. Thus clinical education encompasses a multitude of skills. The General Medical Council defines the duties of a professional under ‘general’ and ‘specific’ characteristics. The described general characteristics are; care of one’s patient must be the first concern; every patient should be treated politely and considerately; patients’ dignity and privacy should be respected; patients views should be listened to and respected; information should be given to patients in a way they can understand and the rights of patients should be respected and they should be fully involved in decisions about their care (The ‘Picker principle’ – there is no decision about me without me’). The specific characteristics are; One should maintain their professional knowledge and skills up to date; one should recognise the limits of one’s professional competence; he/she should be honest and trustworthy; must respect and protect confidential information; one should make sure that their personal beliefs do not prejudice the patient’s care; one should avoid abusing their position as a professional; they should work with colleagues in ways that best serve patient’s interests; professionals should act quickly to protect patients from risk if one believes that you or a colleague may not be fit to practise.

The curriculum is developed based on these principles and the standards of competence stated above. The format and design of the overall assessment system and its methods are made appropriate to what is being tested and are grouped into: Clinical skills; Knowledge and decisionmaking; Interpersonal (communication) skills; and Competence in particular technical areas. Generally this is achieved by theoretical examinations and work place based assessment tools. The commonly available tools fall into four main groups; Assessment of technical skills – OSATS; Evaluation of a clinical encounter – Mini CEX; Case based discussion – CBD; Peer rating tools/multi source feedback – Team Observation (TO) 1 & TO2 – also called 360*appraisal. It is a challenge for the leadership managers in clinical education to achieve all these. They face many hurdles; what is the baseline? Was training high quality pre European working time directive? What objective measures do we have?

New curricula have generally shortened training time and they focus more on specialty skills rather than acute care skills. Acquiring explicit competencies, require supervision and assessment. Risk of reduction in daytime shifts is increased number of night-time shifts. Poorly planned shifts risk for patients and staff; it reduces trainer/trainee contact time. We need increased time for consultant supervision, assessments, completion of logbooks etc.

To face these challenges the management style should distinguish the fine line between ‘Decisive’ but not ‘Bossy’; ‘Visible’ but not ‘Controlling’. Effective leader should be able to communicate tasks & responsibilities; balance legal responsibility/develop situational leadership; involve appropriate resources and communicate expected ‘norms’ and model appropriate behavior (NASA Tech report 1995). They should be able to effectively manage resources and organize effective leadership – teamworking communication & decisionmaking skills to achieve the goals. Appropriate task management starts with determining the goals, deciding on what resources are required, providing the needed information, determining the personnel and equipment needed to carry out the task and instituting an evaluation mechanism. These are not constants and hence situational leadership will help one to be aware of the progress and the ability to balance the needs of: the particular task, the team’s ability as a whole to deliver and the capability of the Individual members of the team to perform. Situational analysis consists of continuous monitoring of the environment and detecting any changes needed to bring about the results to achieve good training. Effective leaders must also have a high emotional quotient i.e. know their own emotions and manage them to motivate themselves but also recognize & understand others’ emotions and manage relationships – i.e. manage others’ emotions (Goleman 1998). Leadership and management in clinical education have been in existence for centuries in different formats. But the leadership skill is becoming more of a challenge with modern inventions in medicine and technology, reduced working hours, more informed patient population with internet and higher expectations in health care.

Management of Dengue – What lies ahead?

Dengue, a mosquito-borne viral infection, is a major international public health concern, with nearly half of the world’s population, an estimated 2.5 billion people in over 100 countries, at risk. The incidence of dengue has increased 30- fold over the last 50 years, but the true magnitude of the disease burden is not well established.

Dengue viruses are single-stranded RNA viruses belonging to the family Flaviviridae. The 4 closely related but antigenically distinct virus serotypes (1, 2, 3 and 4) are transmitted primarily by Aedes aegyptii mosquitoes

Dengue infection is a systemic and dynamic disease. It has a wide clinical spectrum that includes both severe and non-severe clinical manifestations

There is no specific treatment for dengue disease. The management of DF is supportive with rest, control of fever and pain with antipyretics/analgesics, and adequate fluid intake. Treatment of DHF generally needs correction of fluid loss, correction of electrolyte and metabolic disturbances. Supportive intensive care and fluid management are the mainstays of therapy for severe disease. The case fatality rate (CFR) of DSS may be as high as 50% without supportive therapy, but in most centers with an intensive care unit and therapeutic experience, the CFR is < 1%. Yet due to significant increases in the size of the population the absolute number of fatalities remains high. The total number of dengue fatalities in Asia is 29 times higher than in the Americas (Shepard, 2012 submitted) and the incidence of severe dengue is 18 times higher. (Halstead, 2006) The public health burden on many societies in Asia due to dengue remains very large.

There is currently no licensed vaccine to prevent dengue infection and no specific treatment exists. Preventive measures presently rely on vector control and personal protection measures, which are difficult to enforce and maintain and can be expensive.

The most effective way to control this disease in the future will be through the use of a safe and effective vaccine. Recently the results from Sanofi Pasteur’s lead candidate dengue vaccine efficacy study, a very first of its kind, went public. These data show for the first time that a safe and efficacious vaccine against dengue is possible. This candidate vaccine was immunogenic for all four serotypes and protected against three of the four serotypes (1, 3, and 4) in the range of 60 to 90%. Results of this study in context of the wider Sanofi Pasteur dengue vaccine development will be discussed along with other vaccine candidates.

Current Approaches and Future Challenges in Prenatal and Bone Marrow Cytogenetics

Chromosome aneuploidies and structural rearrangements such as translocations, inversions and copy number variations can cause congenital anomalies and cancer. Specific gene disruption or abnormal gene expression arises from such rearrangements forms a causative link between the observed phenotype and the underlying genetic cause. Owing to the complexity of the human genome, finding the genetic causes for patients with these conditions can be challenging and time-consuming and this often leaves the patients and families with limited access to genetic diagnosis or accurate genetic information.

For several decades, traditional karyotyping which allows microscopic visualization of the entire genome has been extensively used as a diagnostic tool for a number of clinical syndromes in prenatal and bone marrow cytogenetics. The conventional cytogenetic analysis has been very useful in finding both balanced and unbalanced chromosomal anomalies associated with congenital disorders and cancer. This method has shown that the clinical and biological diversity of certain genetic disorders such as leukemia are attributed to distinct chromosome aberrations which are now routinely used for diagnosis, prognostics and treatment responses. Unfortunately, subtle chromosomal imbalances (<5 Mb) are invisible in karyotyping, therefore additional molecular cytogenetic techniques such as FISH and chromosomal microarray are required for solving diagnostic dilemma.

Since its introduction in 1970s, fluorescence in situ hybridization (FISH) has emerged as an indispensable tool for clinical diagnostics in prenatal and cancer cytogenetics. This technique enables a specific detection of targeted sequences, chromosomal regions or entire chromosomes in both cultured and uncultured cells using fluorescent labelled DNA probes. In prenatal diagnosis, interphase cells obtained from amniotic fluid are used for rapid detection of chromosomes 13, 18, 21, X and Y aneuploidies. In addition, FISH also plays a leading role in providing crucial information regarding genetic variations in malignant cells and evaluation of copy number variations and chromosomal rearrangements of clinically important biomarkers such as Her-2/neu, N-MYC and ALK for targeted molecular therapy in cancer patients. While this technology can identify smaller chromosomal gains and losses, FISH is biased toward selected regions of the genome and it requires a priori knowledge of the selected regions, therefore it is unsuitable for scanning the whole genome.

The advent and application of chromosomal microarray, particularly array comparative genomic hybridization (array CGH) has transformed cytogenetics from ‘morphology’ into a massively robust ‘molecular’ space. Chromosomal microarray (CMA) can achieve a resolution less than 100kb and provides analysis of the entire genome without a priori knowledge of the genomic region involved. This platform has greatly improved the mapping efficiency of clinically relevant chromosomal imbalances in known syndromes. In recent years, CMA has become the firsttier diagnostic test for postnatal testing in individuals with intellectual disabilities and other childhood syndromes, and now its application has also increased substantially in prenatal. Despite its ability to detect genomic imbalances at a higher resolution than the conventional methods, it carries a potential risk for finding uncertain clinical significance which may result in patient anxiety and challenging in genetic counselling.

The recent advancement of high throughput next generation sequencing provides a more comprehensive genomic coverage than array-based methods. This technology currently offers the best resolution, resulting in discovery of novel mutations and unexpected complex rearrangements as well as identification of fusion genes leading to new therapeutic targets. As the sequencing cost continue to decline, it is likely that next generation sequencing may supercede array-based testing and conventional methods. The future cytogenetic laboratory will have more sequencers than microscopes, and more technologists with molecular training and bioinformatics knowledge than ever before.

Dr. Saira Bahnu bte Mohamed Yousoof
Molecular Geneticist
Departments of Cytogenetics and Molecular Diagnostics
Subang Jaya Medical Centre, Malaysia

Ovarian Cancer: Unmasking the great pretender.

Despite considerable investment into early diagnosis and treatment, the cure rate for ovarian cancer has remained stagnant over the last four decades and it is the 5th most common cause of cancer-related death in women. This is because about 90% of the deaths from ovarian cancer are from high-grade serous (HGSC) and related high grade subtypes, which are often diagnosed in advanced stages. So far, all screening programs have failed spectacularly in diagnosing HGSC inn early stage, while it is still confined to the ovary. The pilot phase of our ongoing study, Diagnosing Ovarian cancer Early (DOvE), shed some light on why the screening trials failed. In the DOvE pilot, women with symptoms associated with ovarian cancer were given open access to fast-track diagnostic testing using serial CA125, and TVUS, with a low threshold for follow up with CT and MRI scans to try and achieve early stage diagnosis. To our surprise, we found that most “ovarian” HGSC actually originated from the fallopian tube epithelium and had disseminated into the abdomen while the ovaries were normal. Although the tubes had been pinpointed as the source of HGSC in patients with BRCA mutation, the ovary remained the focus of diagnostic tests for ovarian cancer in the general population. However, with HGSC starting in the fallopian tube, it can disseminate into the peritoneal cavity early in the course of the disease. By the time the ovary has become involved to the extent of appearing abnormal on transvaginal ultrasound scan, the abdominal cavity is already involved by disseminated tumour nodules. If we are to diagnose HGSC early, we have to focus on HGSC and the fallopian tube.

Lucy Gilbert, MD, MSc, FROCG
Director of Gynecologic Oncology
McGill University

Hand Surgery: Minimal Invasive & Reconstructive Procedures

Minimal invasive surgical procedures which used to be a trend in the past is currently considered to be a gold standard of treatment in many disciplines. In hand surgery, wrist arthroscopy has made it possible to diagnose and treat wrist ligament injuries which is often missed even with MRI.

Carpal tunnel syndrome, a common hand problem, is traditionally treated with Open carpal tunnel release when conservative management has failed. This procedure usually relieves the patient’s symptoms but can prevent the use of his hand for a few weeks. This procedure can now be done through a minimal invasive technique -Endoscopic Carpal Tunnel Release. In addition to a cosmetically smaller and better scar it allows earlier use of the hand post surgery.

Brachial plexus injury in adults is commonly due to motor vehicle accidents and this can also present at birth (Brachial Plexus Birth Palsy). In the past, treatment of Brachial Plexus injury was said to be a wasted effort as surgical exploration and repair of Brachial Plexus had poor functional outcome.

With advances in surgical technique and better understanding of nerve physiology, improved outcomes can now be achieved. Surgery is indicated in all patients with no recovery within 6 months. In adults, neurotization (nerve transfer) procedures have shown to produce the best results. In Birth palsy, reconstruction of the brachial plexus with nerve grafts is performed if nerve roots are available (not avulsed). Early microsurgical repair plays the most important role as it gives the patient the unique opportunity to recover at his best…. especially total paralysis. Secondary surgery is an important contribution for improving the functional result after primary surgery and also for patients who presented late where nerve transfer could not be done.

We now have the ability to obtain something in someone who started with nothing.

Dr. Ravindran Thuraisingham
Consultant Hand & Microsurgeon
Sunway Medical Centre