Dr Greg Rogers outlines how the NICE guideline on epilepsy will help clinicians to choose the most appropriate drug based on seizure type and syndrome
  • All people with a recent onset suspected seizure should be seen urgently by a specialist
  • A diagnosis of epilepsy should be established by a specialist
  • If possible, the chosen anti-epileptic drug should be offered on the basis of the presenting epilepsy syndrome; if the syndrome is not clear at presentation, the decision should be based on the presenting seizure type(s)
  • When prescribing sodium valproate to women and girls of present and future childbearing potential, the healthcare professional should discuss the possible risk of malformation and neurodevelopmental impairments in an unborn child, particularly at high doses or when using as part of polytherapy
  • Buccal midazolam should be administered as first-line treatment in children, young people, and adults with prolonged or repeated seizures in the community. Rectal diazepam can be administered if preferred or if buccal midazolam is not available.

NICE Clinical Guideline 137 on the diagnosis and management of epilepsy has been awarded the NHS Evidence Accreditation Mark.
This Mark identifies the most robustly produced guidance available. See evidence.nhs.uk/accreditation for further details.

In January 2012, the National Institute for Health and Care Excellence (NICE) updated the pharmacological recommendations in Clinical Guideline 137 on the diagnosis and management of epilepsy.1 This update is welcomed as it covers the newer anti-epileptic drugs (AEDs) that have emerged in UK clinical practice following publication of the original guidance in 2004.2 With the current uncertainty over whether these newer medicines bring any additional clinical benefits for their cost, this update offers clinicians valuable guidance on therapeutic choices for epilepsy. The guideline also expands on the advice for using a ketogenic diet in people aged younger than 16 years.1

Scope of the guideline

The NICE guideline provides recommendations on the management of children, young people, adults, and older people with a diagnosis of any type of epilepsy; treatments for neonates are not covered. The full guideline includes care algorithms for adults and children (see Figure 1, below).3 Many recommendations from the original 2004 guideline are unchanged as they are beyond the scope of this update (based on recently published research and clinical need). However, many of these key points are still as important now as they were then. This article discusses the updated advice on pharmacological management and key recommendations from the guideline. Although many of these points have not been revised in the 2012 update, they continue to be relevant to primary care, particularly as implementation of the 2004 guideline is varied and in many cases has not yet been fully implemented.4

The NICE guideline on epilepsy is of relevance to primary care because it is the most common serious neurological condition—epilepsy affects 382,000 people in England, equivalent to 1 in 131 people.5 Although the majority of people with active epilepsy can control recurrent seizures satisfactorily, this condition still affects many individuals needlessly. There are approximately 400 avoidable epilepsy related deaths per year in the UK and 69,000 people living with unnecessary seizures (i.e. seizures that could have been controlled with medicine, if identified).5 Rendering these children and adults seizure-free improves not only health outcomes, but minimises the detrimental social impact of epilepsy for those who have it.

Figure 1: Outline care algorithm for adults with epilepsy3

graph

*Refer to the full guideline for further information
National Institute for Health and Care Excellence (NICE) (2012) CG137. The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care. London: NICE. Available from www.nice.org.uk/guidance/CG137 Reproduced with permission.


Following a first seizure

People presenting at accident and emergency departments should be screened initially, with onward referral to a specialist when an epileptic seizure is suspected or if there is diagnostic doubt. It is important that protocols are in place to ensure proper assessment in the emergency setting. All people who have a suspected seizure should be seen as soon as possible (within 2 weeks) by a specialist in the management of the epilepsies.1

Diagnosis

A diagnosis of epilepsy should be established by a specialist medical practitioner with training and expertise in epilepsy. Patients and their families or carers should be given the opportunity to discuss the diagnosis. The decision as to whether an epileptic seizure has occurred should be based on a description of the attack and different symptoms. If, however, a diagnosis cannot be established, further investigations and/or referral to a tertiary specialist should be considered.1

Investigations

Electroencephalogram

Individuals requiring an electroencephalogram (EEG) should have the test performed soon after it is requested (within 4 weeks), and it should only be performed to support a diagnosis of epilepsy. An EEG may be used to help determine seizure type and epilepsy syndrome, and to assess risk of seizure recurrence with a first unprovoked seizure. Repeated standard EEGs may be helpful when the diagnosis of epilepsy or the syndrome is unclear. However, they should not be used in preference to sleep or sleep-deprived EEGs. Photic stimulation and hyperventilation should remain part of standard EEG assessment.1

An EEG should not be performed:1

  • in the case of probable syncope
  • to exclude a diagnosis of epilepsy
  • in isolation to make a diagnosis.

Neuroimaging

Magnetic resonance imaging (MRI) is the imaging method of choice and is important for people:1

  • who develop epilepsy before the age of 2 years or in adulthood
  • who have a suggestion of focal onset
  • in whom seizures continue despite first-line medication.

Computed tomography should be used to identify underlying gross pathology if MRI is not available or if sedation for MRI is required.1


Other tests

The NICE guideline also provides advice on the use of other diagnostic tests for epilepsy:1

  • Appropriate blood tests may be considered in adults and children (at the discretion of specialist)
  • Measurement of serum prolactin is not recommended
  • A 12-lead electrocardiogram should be performed in adults with suspected epilepsy and in cases of diagnostic uncertainty for children and young people
  • Referral to a cardiologist should be considered in cases of diagnostic uncertainty.

Pharmacological treatment

The updated NICE guideline advises on which treatment options should be used according to epilepsy seizure type and if known, by epilepsy syndrome. A list of epilepsy syndromes that are most likely to be encountered in primary care is shown in Table 1 (see below).1 It is important to be aware that the NICE guideline includes recommendations on drugs that did not have a UK marketing authorisation for the mentioned indication and/or population at the time of publication; informed consent should be obtained and documented for any drugs that do not have a UK marketing authorisation for a particular indication.

Therapy with an AED should only begin with the recommendation of a specialist and once a diagnosis of epilepsy has been confirmed. The decision to start therapy should be made after a full discussion of treatment risks and benefits between the patient and the specialist.1

The guideline recommends that the patient has a consistent supply of a particular manufacturer’s AED preparation unless the prescriber, in consultation with the patient and their family and/or carers, as appropriate, considers that this is not a concern. Different preparations of some AEDs may vary in bioavailability or pharmacokinetic profiles and care needs to be taken to avoid reduced effect or excessive side-effects. The summary of product characteristics (SPC)6 and the British National Formulary (BNF)7 should be consulted for details on bioavailability and pharmacokinetic profiles of individual AEDs, but it should be noted that these do not provide information on relative bioavailability of different generic preparations.1

Prescribing anti-epileptic drugs

People with epilepsy should be treated with a single AED wherever possible. Carbamazepine should be offered as a controlled-release preparation. The possible risks of malformation and neurodevelopmental impairments should be discussed with women and girls of present and future childbearing potential when prescribing sodium valproate.1

Referral

Refer to a tertiary care paediatric epilepsy specialist if a child has or is suspected of having:1

 

  • infantile spasms
  • Dravet Syndrome
  • Lennox-Gastaut
  • continuous spike and wave during slow sleep
  • Landau–Kleffner syndrome
  • myoclonic-astatic epilepsy.

Patients with epilepsy should be referred to tertiary services for further assessment if seizures are not controlled and/or there is diagnostic uncertainty or treatment failure. The NICE guideline includes other criteria that should trigger referral.1


Table 1: Pharmacological treatment of epilepsy syndromes likely to be encountered in primary care*†1

Focal seizures
Carbamazepine or lamotrigine are first-line treatment options for newly diagnosed focal seizures. If these two drugs are unsuitable or not tolerated, levetiracetam (provided the acquisition cost of levetiracetam falls to at least 50% of June 2011 documented in the National Health Service Drug Tariff for England and Wales), oxcarbazepine, or sodium valproate can be offered. If the first AED is ineffective, an alternative option may be offered from these five AEDs. If a second well-tolerated AED is ineffective, adjunctive treatment should be considered.

Adjunctive treatment
Carbamazepine, clobazam, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, sodium valproate, or topiramate should be offered as adjunctive treatment for refractory focal seizures if first-line treatments are ineffective or not tolerated. If adjunctive treatment is ineffective or not tolerated, discuss with or refer to a tertiary epilepsy specialist who may consider the use of eslicarbazepine acetate, lacosamide, phenobarbital, phenytoin, pregabalin, tiagabine, vigabatrin, or zonisamide.

Generalised tonic–clonic seizures
Sodium valproate should be offered as the first-line treatment to individuals with newly diagnosed generalised tonic–clonic seizures. Lamotrigine can be offered if sodium valproate is unsuitable but it may exacerbate myoclonic seizures if the person has myoclonic seizures or is suspected of having juvenile myoclonic epilepsy. Carbamazepine, and oxcarbazepine can be considered but healthcare professionals should be aware of the risk of exacerbating myoclonic or absence seizures.

Adjunctive treatment
Clobazam, lamotrigine, levetiracetam, sodium valproate, or topiramate should be offered as adjunctive treatment options if first-line treatments are ineffective or not tolerated.

Do not offer: carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, tiagabine, or vigabatrin if there are absence or myoclonic seizures, or if juvenile myoclonic epilepsy is suspected.

Absence seizures
Ethosuximide or sodium valproate should be offered as first-line treatment for absence seizures; however if there is a high risk of generalised tonic–clonic seizures, sodium valproate should be offered first, unless it is unsuitable. Lamotrigine should be offered if ethosuximide and sodium valproate are unsuitable, ineffective, or not tolerated.

Adjunctive treatment
If the two first-line AEDs are ineffective, a combination of two of the following AEDs should be considered for adjunctive treatment: ethosuximide, lamotrigine, or sodium valproate. If these therapies are ineffective or not tolerated the clinician should discuss with, or refer to, a tertiary epilepsy specialist and consider the use of clobazam, clonazepam, levetiracetam, topiramate, or zonisamide as treatment options.

Do not offer: carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, tiagabine, or vigabatrin.

Myoclonic seizures
Sodium valproate is the first-line treatment for myoclonic seizures. Levetiracetam or topiramate should be considered if sodium valproate is unsuitable or not tolerated although topiramate has a less favourable side-effect profile compared with levetiracetam and sodium valproate.

Adjunctive treatment
Levetiracetam, sodium valproate, or topiramate should be offered for adjunctive treatment if first-line treatments are ineffective or not tolerated. If adjunctive treatment is ineffective or not tolerated, discuss with, or refer to, a tertiary epilepsy specialist and consider clobazam, clonazepam, piracetam, or zonisamide.

Do not offer: carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, tiagabine, or vigabatrin.

AED=anti-epileptic drug
*Refer to the full guideline for further information and recommendations on the use of pharmacological therapies.
†Certain drugs discussed in the NICE guideline on epilepsy did not have a UK marketing authorisation for the mentioned indication and/or population at the time of publication. Informed consent should be obtained and documented.
‡Clinicians should be aware of the teratogenic risks of sodium valproate.


Table 1: Pharmacological treatment of epilepsy syndromes likely to be encountered in primary care*† (continued)1

Tonic or atonic seizures
Sodium valproate should be offered as first-line treatment.

Adjunctive treatment
Lamotrigine should be offered if first-line treatment with sodium valproate is ineffective or not tolerated. Discuss with a tertiary epilepsy specialist if adjunctive treatment is ineffective or not tolerated (they may consider the use of rufinamide and topiramate as possible treatment options).

Do not offer: carbamazepine, gabapentin, oxcarbazepine, pregabalin, tiagabine, or vigabatrin.

Idiopathic generalised epilepsy
Sodium valproate is the first-line treatment for idiopathic generalised epilepsy. Lamotrigine can be offered if sodium valproate is unsuitable or not tolerated but be aware of the risk of exacerbation of myoclonic seizures. Topiramate can be considered but it has a less favourable side-effect profile than sodium valproate and lamotrigine.

Adjunctive treatment
Lamotrigine, levetiracetam, sodium valproate, or topiramate should be offered as adjunctive treatment options if first-line treatments are ineffective or not tolerated. If adjunctive treatment is ineffective or not tolerated, discuss with, or refer to, a tertiary epilepsy specialist and consider the use of clobazam, clonazepam, or zonisamide.

Do not offer: carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, tiagabine, or vigabatrin.

Juvenile myoclonic epilepsy
Sodium valproate is the first-line treatment for juvenile myoclonic epilepsy. Lamotrigine (may exacerbate myoclonic seizures), levetiracetam, or topiramate can be considered if sodium valproate is unsuitable or not tolerated.

Adjunctive treatment
Lamotrigine, levetiracetam, sodium valproate, or topiramate can be offered as adjunctive treatment if first-line treatments are ineffective or not tolerated. If adjunctive treatment is not effective or not tolerated, discuss with, or refer to, a tertiary epilepsy specialist and consider clobazam, clonazepam, or zonisamide.

Do not offer: carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, tiagabine, or vigabatrin.

Epilepsy with generalised tonic–clonic seizures only
Lamotrigine or sodium valproate should be offered as first-line treatment for people with generalised tonic–clonic seizures only. Carbamazepine and oxcarbazepine can also be considered but clinicians should be aware of the risk of exacerbating myoclonic or absence seizures.

Adjunctive treatment
Clobazam, lamotrigine, levetiracetam, sodium valproate, or topiramate can be used as adjunctive treatment if first-line treatments are ineffective or not tolerated.

Childhood absence epilepsy, juvenile absence epilepsy, or other absence epilepsy syndromes
Ethosuximide and sodium valproate are first-line treatment options for absence syndromes. Lamotrigine is a possible option if ethosuximide and sodium valproate are unsuitable, ineffective, or not tolerated.

Adjunctive treatment
If two first-line AEDs are ineffective, a combination of two of the following drugs should be considered for adjunctive treatment: ethosuximide, lamotrigine, or sodium valproate. If the patient fails to respond or is unable to tolerate adjunctive treatment, discuss or refer to a tertiary epilepsy specialist and consider clobazam, clonazepam, levetiracetam, topiramate, or zonisamide.

Do not offer: carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, tiagabine, or vigabatrin.

AED=anti-epileptic drug
*Refer to the full guideline for further information and recommendations on the use of pharmacological therapies.
†Some of the drugs discussed in the NICE guideline on epilepsy did not have a UK marketing authorisation for the mentioned indication and/or population at the time of publication. Informed consent should be obtained and documented.
‡Clinicians should be aware of the teratogenic risks of sodium valproate.


Refractory epilepsy

Children and young people with epilepsy whose seizures have not responded to appropriate AEDs should be referred to a tertiary paediatric epilepsy specialist for consideration of the use of a ketogenic diet.1 Vagus nerve stimulation is indicated as an adjunctive therapy in reducing the frequency of seizures in people who are refractory to antiepileptic medication but who are not suitable for resective surgery.1

Refractory epilepsy

Immediate emergency care and treatment should be provided to individuals who have prolonged or repeated convulsive seizures in the community. Buccal midazolam or rectal diazepam should only be prescribed to people who have had a previous episode of these types of seizures. If intravenous access has already been established and resuscitation facilities are available, intravenous lorazepam should be administered. An ambulance should be called depending on circumstances and particularly if:1

  • the seizure continues for 5 minutes after emergency medication has been administered
  • the person has a history of frequent episodes of serial seizures or has convulsive status epilepticus
  • there are concerns or difficulties monitoring the person’s airway, breathing, circulation, or other vital signs.

Women and girls

The discussion about pregnancy and contraception with women and girls with epilepsy can and should be started in primary care (particularly as this is an area that is included in the quality and outcomes framework8). However, if potential problems are identified that are beyond the GP’s knowledge of epilepsy, patients should be referred to a specialist.

Accurate tailored information and counselling about contraception, conception, pregnancy, caring for children, breastfeeding, and menopause should be provided to women and girls. The risk of malformations and possible neurodevelopmental impairments in an unborn child associated with AEDs should be discussed. It is important to be aware of the latest data on the risks to the unborn child associated with AED therapy when prescribing. All women and girls receiving AEDs should be offered 5 mg per day of folic acid before any possibility of pregnancy. The summary of product characteristics and the BNF should be consulted for individual drug advice on the interactions between AEDs and hormonal replacement and contraception.1

Contraception

Healthcare professionals should discuss:

  • possible interactions between oral contraceptives and AEDs and make an assessment as to the risks and benefits of treatment with individual drugs
  • the risks and benefits of different contraceptive methods, including hormone-releasing intrauterine devices.

If a woman or girl taking enzyme-inducing AEDs chooses to take the combined oral contraceptive pill, guidance about dosage should be sought from the SPC and the BNF. The progestogen-only pill and progestogen implant are not recommended as reliable contraceptive methods in those taking enzyme-inducing AEDs. The use of additional barrier methods should be discussed with women taking enzyme-inducing AEDs and oral contraception or having depot injections of progestogen. If emergency contraception is needed, the type and dose should be in line with the SPC and the BNF.1

Women who are taking lamotrigine should be informed that the simultaneous use of any oestrogen-based contraceptive can result in a significant reduction of lamotrigine levels and lead to loss of seizure control. The dose of lamotrigine may need to be adjusted when a woman or girl starts or stops taking these contraceptives.1

Pregnancy

Seizure freedom should be aimed for before conception and during pregnancy but this goal should take into account the risk of adverse effects of AEDs, use of the lowest effective dose of each AED, and avoidance of polytherapy if possible. Levels of AEDs do not need to be monitored routinely during pregnancy, but it may be useful when making dose adjustments if seizures increase or are likely to increase.1


Considerations for other patient groups

People with epilepsy who have learning disabilities should be enabled to take an active part in developing a personalised care plan. Adequate time should be allocated in consultations to ensure that effective management is achieved. It is important to avoid discrimination and offer the same services, investigations, and therapies as would be provided for the general population.1

The physical, psychological, and social needs of young people should always be considered. A named clinician should assume responsibility for the ongoing management of the young person and ensure smooth transition of care to adult services during adolescence.1

Older people should be offered the same services, investigations, and therapies as would be provided for the general population. Particular attention should be directed to pharmacokinetic and pharmacodynamic issues with polypharmacy and co-morbidity in older people with epilepsy. Lower doses of AEDs should be considered along with controlled-release preparations of carbamazepine if prescribing this drug.

Implementation tools

NICE has developed the following tools to support implementation of Clinical Guideline 137 on The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care. The tools are now available to download from the NICE website: www.nice.org.uk/CG137

Baseline assessment tool Audit

The baseline assessment tool is an Excel spreadsheet that can be used by organisations to identify if they are in line with practice recommended in NICE guidance and to help them plan activity that will help them meet the recommendations.

Clinical audit tools Audit

Audit tools aim to assist organisations with the audit process, thereby helping to ensure that practice is in line with the NICE recommendations. They consist of audit criteria and data collection tool(s) and can be edited or adapted for local use.

Clinical case scenarios Education and learning

Clinical case scenarios are an educational and learning resource designed to improve and assess users' knowledge of the epilepsies and its application in primary and secondary care.

Costing statement commissioning icon

The costing statement estimates the financial impact to the NHS of implementing this clinical guideline. This statement focuses on the financial impact of the recommendations that require most change in resources to implement in England.

Electronic audit tool Audit

Electronic audit tools are developed to assist organisations with clinical audit and to ensure that practice is in line with the NICE recommendations.

Slide set Education and learning

The slides provide a framework for discussing the NICE guideline with a variety of audiences and can assist in local dissemination. This information does not supersede or replace the guidance itself.

Pharmacological treatment table Education and learning

The table provides a summary reference guide to pharmacological treatment for epilepsy.

Key to NICE implementation icons
commissioning icon NICE support for commissioners
  • Support package for commissioners and others for quality standards
  • NICE guide for commissioners
  • NICE cost impact support for guidance (selection from national report/local template/costing statement, dependent on topic)
Audit NICE support for service improvement systems and audit
  • Forward planner
  • ‘How to’ guides (generic advice on processes)
  • Local government briefings (with Centre for Public Health Excellence)
  • Baseline assessment tool for guidance
  • Audit support including electronic data collection tools
  • E-learning modules (commissioned)
Education and learning NICE support for education and learning
  • Clinical case scenarios
  • Learning packages including slide sets
  • Podcasts
  • Shared learning and other local best practice examples

Sudden unexpected death in epilepsy

Clinical discussions should be tailored to provide information and open discussion on a person’s relative risk of sudden unexpected death in epilepsy (SUDEP). The risk of SUDEP can be minimised by optimising seizure control and being aware of the potential consequences of nocturnal seizures. Healthcare professionals should offer their condolences and referral to bereavement counselling to families and carers who have been affected by SUDEP.1

Role of primary care

General practitioners should remain alert to the possible diagnosis of epilepsy and suspected cases should be referred to a specialist urgently. Ideally, details of the attack should be mentioned in the referral letter, with as much information as possible. For individuals who have a confirmed diagnosis of epilepsy, the GP is in a key position to support them not only for medical conditions but also in terms of the potential psychological and social impact arising from their illness.

Seizure freedom is the gold standard and if someone is experiencing ongoing seizures, it is important to explore the reasons why and if needed, to refer to specialist care. Achieving seizure freedom reduces a person’s mortality and morbidity risk similar to that of the general population.

Commissioning effective care of epilepsy will help to reduce unscheduled admissions, which will be of benefit to all.

Implementation

If the new guideline recommendations and indeed the retained sections of the 2004 guideline are effectively implemented, the care of epilepsy will improve, as indeed would the outlook for people with epilepsy. NICE is currently developing a quality standard on epilepsy to help ensure that this takes place, and a review of commissioned services would be both timely and recommended to help people affected by this condition.

Conclusion

The NICE guideline offers a practical and useful resource for diagnosis and management of epilepsy and should equip healthcare professionals to offer the best treatment and advice for the people they are supporting. A range of implementation tools are available. The treatment gap for people who could be rendered seizure-free but who are not currently, will hopefully close further as a result of this practical guideline.

For further information and to access support tools for primary care, please visit: www.nice.org.uk/CG137

View the Guidelines summary of the NICE guideline on The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care at: egln.co.uk/link/34875

  • The NICE guideline provides clear algorithms that can be built into local care pathways by commissioners and local specialists
  • Commissioners should ensure rapid access to first fit assessment clinics (within 2 weeks)
  • Pharmacotherapy for epilepsy is led by specialists but commissioners should ensure use of cost-effective drugs from local formularies as agreed between specialists and primary care
  • Commissioners should ensure that primary care and urgent-care services are aware of and follow NICE guidance for management of emergency fits and status epilepticus
  • Primary care is incentivised to perform annual review of people with epilepsy and offer pre-conceptual and pre-pregnancy advice through the quality and outcomes framework
  • Tariff prices for neurology outpatients:a
    • adult first (non-mandatory) = £225 (new), £130 (follow up)
    • child first (non-mandatory) = £401 (new), £228 (follow up).
  1. National Institute for Health and Care Excellence. The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care. Clinical Guideline 137. London: NICE, 2012. Available at: www.nice.org.uk/guidance/CG137 nhs_accreditation
  2. National Institute for Health and Care Excellence. The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care. Clinical Guideline 20. London: NICE, 2004.
  3. National Clinical Guideline Centre. The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care. London: NCGC, Royal College of Physicians, 2012. Available at: www.nice.org.uk/guidance/CG137 nhs_accreditation
  4. Epilepsy Action. Epilepsy in England: time for change. A study of epilepsy service provision in England by Epilepsy Action. Epilepsy Action: Leeds, 2008. Available at: www.epilepsy.org.uk/sites/epilepsy/files/images/campaigns/Epilepsy_in_England_-_Time_for_change_report.pdf
  5. All Party Parliamentary Group on Epilepsy. The human and economic cost of epilepsy in England. Joint Epilepsy Council: Leeds, 2007. Available at: www.epilepsy.org.uk/sites/epilepsy/files/images/campaigns/arygrouponepilepsy_wasted_money_wasted_lives.pdf
  6. Electronic Medicines Compendium website. www.medicines.org.uk/emc/
  7. British Medical Association, Royal Pharmaceutical Society. British National Formulary website. www.bnf.org
  8. British Medical Association. NHS Employers. Quality and outcomes framework 2012/13. London: BMA, NHS Employers, 2012. Available at: www.bma.org.uk/employmentandcontracts/independent_contractors/quality_outcomes_framework/qofchanges2012.jsp#.T4bMoe1LKyG nhs_accreditation G