Changes

May 2024 — minor update. Other drugs known to lower blood pressure added to the interactions section for Baclofen in prescribing information, in line with the manufacturer's updated SPC.

Update

Goals

To support primary healthcare professionals to:

• Recognize if a person may have multiple sclerosis (MS) as early as possible.
• Facilitate an accurate diagnosis by prompt referral to a consultant neurologist.
• Manage symptoms and complications in conjunction with the MS multidisciplinary team.
• Refer to secondary care or other specialist services when appropriate.

Outcome measures

Audit criteria

QOF indicators

QIPP - Options for local implementation

NICE quality standards

The following are included in the National Institute for Health and Care Excellence (NICE) Quality Standards on Multiple sclerosis (QS108) [NICE, 2016]:

•  Statement 1. Adults with multiple sclerosis (MS) are given support at the time of diagnosis to understand the condition, its progression and the ways it can be managed, by the consultant neurologist making the diagnosis.
• Statement 2. Adults with MS are offered a face‑to‑face follow‑up appointment with a healthcare professional with expertise in MS, to take place within 6 weeks of diagnosis.
• Statement 3. Adults with MS have a single point of contact who coordinates access to care from a multidisciplinary team with expertise in MS.
• Statement 4. Adults with MS who have problems with mobility or fatigue are offered support to remain physically active.
• Statement 5. Adults with MS who have a relapse that would benefit from treatment are offered treatment as soon as possible and within 14 days of the onset of symptoms.
• Statement 6. Adults with MS are offered a comprehensive review at least once a year by healthcare professionals with expertise in MS.

What is it?

• Multiple sclerosis (MS) is an acquired, chronic, immune-mediated, inflammatory condition of the central nervous system (CNS) that can affect the brain, brainstem, and spinal cord.
  • The inflammatory process causes areas of demyelination (damage to white matter), gliosis (scarring), and neuronal damage throughout the CNS.
• Onset of MS is typically in young adulthood — neurological symptoms and signs vary widely and include visual and sensory disturbances, limb weakness, gait problems, and bladder and bowel symptoms.
• There are three main patterns of the disease:
  • Relapsing-remitting MS (RRMS).
    • RRMS is the most common pattern of disease — about 85% of people with MS have RRMS at onset.
    • Episodes or exacerbations of symptoms (relapses) are followed by recovery (remissions) and periods of stability.
  • Secondary progressive MS (SPMS).
    • SPMS occurs when there is a gradual accumulation of disability unrelated to relapses, which become less frequent or stop completely.
    •  About two thirds of people with RRMS progress to SPMS.
  • Primary progressive MS (PPMS).
    • In PPMS there is a steady progression and worsening of the disease from the onset, without remissions.
    • PPMS occurs in about 10–15% of people with MS.
• Relapse is defined as:
  • • Onset of new symptoms, or the worsening of pre-existing symptoms.
    • Attributable to demyelinating disease.
    • Lasting more than 24 hours.
    • In the absence of infection, or any other cause.
    • After a stable period of at least a month.

[Kalb, 2018; Montalban, 2018; Thompson, 2018; Eccles, 2019; BMJ Best Practice, 2021; NICE, 2022]

What causes it?

• The cause of multiple sclerosis (MS) is unknown — it is thought that acute then chronic immune-mediated inflammation is precipitated by an abnormal response to environmental triggers in people who are genetically predisposed.
  • Cells of the immune system, mainly T-cells, attack oligodendrocytes. This results in focal or diffuse areas of inflammation that is thought to cause secondary damage, primarily to axons.
  • Re-myelination of axons may occur in remissions, but may be partial or transient.
  • Progressive damage to affected cells in the nervous system leads to irreversible loss of function of affected nerves, resulting in permanent symptoms and signs.

[Thompson, 2018; BMJ Best Practice, 2021; Barrier, 2024]

What are the risk factors?

A combination of risk factors may contribute to triggering an autoimmune response and development of multiple sclerosis (MS), these include:

• Genetics – the genetics of MS is complex; over 200 alleles have been identified as contributing small risk effects.
  • 32 variants are located in the human leukocyte antigen (HLA) region. 
  • The concordance rate for MS in monozygotic twins is about 18–30% compared with about 5% in dizygotic twins.
  • The risk of a first-degree relative of a person with MS developing MS is about 1 in 40 for non-twin siblings, and about 1 in 50 for a child (compared with about 1 in 330 risk for the general population).
• Vitamin D deficiency — vitamin D may have an immuno-modulatory role that helps to prevent MS but the mechanism for this is not clear.
• Cigarette smoking — risk associated with smoking increases with duration and pack years and is greater in men than in women. Smoking may adversely affect disease course.
• Diet and obesity in early life — associated with two-fold increase in risk. The mechanism is unclear but may be partly due to lower vitamin D levels in obesity.
• Latitude — in general, the prevalence of MS increases the greater the distance north or south from the equator.
  • One theory for this is that lower levels of sunlight exposure in more distant latitudes results in lower average levels of vitamin D.
  • It is also thought that the increased genetic risk for MS in Northern Europeans was brought about due to migration of steppe pastoralist populations approximately 5000 years ago. 
• The Epstein–Barr virus (EBV) — infection with EBV is common in the general population but some studies suggest it is more common in people with MS than in people without MS, and it may have a disease-triggering role in susceptible people.
• Female gender — MS is 2–3 times more common in women than in men.

Risk factors for relapses:

• Although it is impossible to predict when a relapse will occur, known possible triggers include infection, stress, and the postpartum period.

[Hassan-Smith and Douglas, 2011; Lucas, 2011; Weinstock-Guttman, 2012; O'Gorman, 2013; Harrison, 2014; Galea, 2015; Reich, 2018; Thompson, 2018; Wallin, 2019; Barrier, 2024]

How common is it?

• Multiple sclerosis (MS) is the most common non-traumatic cause of significant neurological disability in people under 40 years of age [BMJ Best Practice, 2021]:
  • In 2016, an estimated 2.3 million people worldwide and 100,000 people in the UK were living with MS [Thompson, 2018; Wallin, 2019; Solari, 2020; NICE, 2022]. 
  • Age-standardized prevalence has increased by around 10% since 1990 [Wallin, 2019].
• Onset is usually in young adulthood between the ages of 20 and 50 years — mean age at diagnosis is approximately 30 years [Montalban, 2018; Wallin, 2019].
  • Disease onset is rare under the age of 10 years and over the age of 60 years [Hassan-Smith and Douglas, 2011].
  • Relapsing-remitting MS is the most common pattern of disease affecting about 85% of people with MS at onset [NICE, 2022].
  • Primary progressive MS accounts for about 15% of people with MS overall and is disproportionately more common in people with disease onset over the age of 40 years [Hassan-Smith and Douglas, 2011].
• MS affects 2–3 times more women than men [Montalban, 2018].
• Prevalence and incidence rates vary in different parts of the UK, in general, becoming progressively higher in more northerly populations.
  • The admixture of different populations with varying genetic risk is considered to have resulted in a north-south gradient in MS prevalence [Barrier, 2024]. 
  • The MS Trust estimates the prevalence rates of MS to be:
    • 290 per 100,000 in Scotland (about 15,750 people) — prevalence in the north of Scotland is particularly high.
    • 258 per 100,000 in Northern Ireland (about 4830 people).
    • 190 per 100,000 in England (around 105,450 people).
    • 179 per 100,000 in Wales (about 5600 people).
• A study by Public Health England using a sample of anonymized primary care records from 385 primary care practices in the UK (the Health Improvement Network dataset) found [PHE, 2020]:
  • That MS is more than twice as common in females than in males.
  • Females in the 50–59 years age group are three times more likely than males of a similar age to have MS.
  • The highest prevalence for MS occurs in the 60–69 years age group for both sexes.
  • 75% of males and females with MS are aged between 40–74 years of age.
  • Smoking rates among males with MS are likely to be higher than those in the general population and people with MS are more likely to be ex-smokers than the general population.

What are the complications and associated conditions?

• Multiple sclerosis (MS) is the commonest cause of serious physical disability in adults of working age — it has a significant detrimental effect on quality of life for people living with it and their families/carers.
• As lesions can develop almost anywhere in the brain or spinal cord of a person with MS, a large range of complications may develop including:
  • Fatigue — affects more than 80% of people with MS and can occur at any stage of disease; it may precede onset by several years.
  • Spasticity — affects up to 80% of people with MS and varies widely in severity, for example from a feeling of tightness or stiffness in a limb that causes mild mobility problems to widespread tightening of the muscles so severe that the person cannot move voluntarily and is confined to a wheelchair or bed.
    • If left unmanaged in the severe stage, secondary complications of muscle shortening, permanent contractures, and pain can develop.
    • Many people with MS also experience spasms, which are sudden, involuntary, often painful movements that can affect any part of the body.
  • Ataxia and tremor — ataxia and tremor are common in MS and can lead to marked problems with mobility and other activities of daily living such as dressing, toileting, and eating.
    • A survey of people with MS (n = 552) found the estimated prevalence of tremor to be about 45%, with severe disabling tremor affecting about 6% [Rinker, 2015].
  • Visual problems — various visual problems are associated with MS including optic neuritis, intranuclear ophthalmoplegia, nystagmus, and diplopia:
    • Optic neuritis is a common initial presentation in MS and often remits but may recur later in the disease course. It is the result of an acute inflammatory lesion in the optic nerve and typically presents with visual impairment and pain on eye movements.
    • Oscillopsia is the subjective sensation of horizontal and/or vertical movement of the visual field that is unexplained by movement of the observer or environment. In people with MS, oscillopsia is usually due to nystagmus.
  • Reduced mobility — 85% of people with MS report a gait disturbance as their main complaint.
    • Causes of reduced mobility include muscle weakness, spasticity, disordered balance, poor coordination, and visual problems.
  • Pain — estimates of the prevalence of MS-related pain vary widely from 29–86%. Pain can be neuropathic or musculoskeletal in origin.
    • Neuropathic pain is likely due to nervous system damage caused by MS lesions and may present as dysesthetic extremity pain (abnormal sensations such as burning or prickling), painful tonic spasms, Lhermitte's sign (a shock-like sensation radiating down the spine induced by neck flexion), trigeminal neuralgia, headaches, or low back pain.
    • Musculoskeletal pain is usually secondary to problems with mobility and posture.
  • Bladder problems — present in over 90% of patients with progressive MS and includes difficulty with storage control (urinary frequency, urgency, and incontinence) as a result of neurogenic detrusor overactivity.
    • One survey of people with MS (n = 309) reported that urinary urgency was the most common urinary symptom (62%), followed by frequency (50.4%), urge incontinence (44.7%), and nocturia (33%) [Akkoc, 2015].
  • Sexual dysfunction — a significant, but often underestimated or overlooked, complication of MS, affecting 50–90% of men and 40–80% of women with MS at some stage in their disease process.
  • Mental health problems:
    • Depression and anxiety — common in MS with reported lifetime prevalence rates up to 50%.
    • Emotional lability (pseudobulbar affect) — people with emotional lability may laugh or cry without any apparent trigger. Once this starts it cannot easily be controlled, may occur at inappropriate times, and can be very distressing.
    • Cognitive impairment — affects 43–70% of people with MS during the course of their illness and can lead to reduced engagement in social activities, employment difficulties, problems carrying out routine household tasks, and reduced quality of life for the person and their family/carer(s).

[Kessler, 2009; Brola, 2014; Seixas, 2014; Drulovic, 2015; Alberta Health and the Alberta Medical Association, 2015; Veauthier, 2016; Aharony, 2017; Kalb, 2018; Thompson, 2018; Solari, 2020; BMJ Best Practice, 2021; NICE, 2022]

What is the prognosis?

• At present there is no cure for multiple sclerosis (MS) — prognosis varies widely, but for most people, neurological disability gradually accumulates over time.
• Relapsing-remitting MS:
  • Most people (85–90%) have a relapsing course from onset characterized by relapse and remission of neurological symptoms.
  • Severity and frequency of relapses vary greatly from person to person, as can the time it takes to progress to the secondary progressive phase of the disease and to significant permanent disability — it is difficult to give individual estimates of disease course and likely outcome.
  • Treatment of a relapse with steroids may shorten the length and severity of the relapse, but does not alter the overall course or prognosis of the disease.
  • In pregnancy, relapse frequency typically reduces but some MS symptoms (such as fatigue, balance, and bladder symptoms may worsen, particularly in later pregnancy). Around a quarter of women will experience a relapse during the first 3 months postpartum.
  • In general, 10–20 years after onset on relapsing-remitting MS, over half of people develop progressive disease (secondary progressive MS).
• Primary-progressive MS:
  • Approximately 10–15% of patients have a progressive clinical course from onset of MS.
  • Progression to disability is, on average, more rapid with PPMS than with RRMS. One study (n = 216) reported a median time from disease onset to needing a walking aid (Expanded Disability Status Score 6) of 8 years [Cottrell, 1999].
• Clinical factors that have been associated with poorer prognosis include:
  • Male sex.
  • Older age at onset.
  • Multifocal presentation.
  • Involvement of pyramidal and cerebellar systems.
  • Partial recovery from relapses.
  • High relapse rate during the first 2 years following onset.
  • Higher lesion burden on magnetic resonance imaging.
• Prompt diagnosis is important — early intervention with disease-modifying drugs may reduce risk of relapse and delay disability progression.

[Mowry, 2009; Filippini, 2013; Scalfari, 2014; Gallo, 2015; Palace et al, 2015; Scolding, 2015; Montalban, 2018; Rae-Grant, 2018; Reich, 2018; Thompson, 2018; Dobson, 2019a; Wallin, 2019; Solari, 2020; BMJ Best Practice, 2021] 

When should I suspect that a person has multiple sclerosis?

• Be aware that:
  • Multiple sclerosis (MS) typically presents between 20–50 years of age. 
    • About 0.5% of adults with MS first develop symptoms aged 60 years or older — older age at onset is associated with a progressive course.
  • The person may have:
    • A history of previous neurological symptoms.
    • Symptoms that evolve over more than 24 hours, may persist over several days or weeks and then improve.
• MS can affect nearly any part of the central nervous system. 
  • Presenting symptoms and signs can vary greatly and may include:
    • Loss or reduction of vision in one eye with painful eye movements.
    • Diplopia.
    • Ascending sensory disturbance and/or weakness.
    • Balance or gait problems, unsteadiness, or clumsiness.
    • Altered sensation radiating down the back and sometimes into the limbs on neck flexion (Lhermitte's symptom).
• The most common initial presentations are:
  • Optic neuritis — inflammation of the optic nerve.
    • Optic neuritis is the initial presentation in about 20–30% of people with MS.
    • The person may describe partial or total unilateral visual loss developing over a few days, pain behind the eye (in particular on eye movement) and/or loss of colour discrimination (particularly reds).
    • Fundoscopy is often normal but the disc may appear pale or swollen. There may be paradoxical dilation of the pupil when light is rapidly shifted from the unaffected eye to the affected eye (relative afferent pupillary defect).
    • Optic neuritis may be bilateral, but if this occurs extra vigilance is needed to rule out neuromyelitis optica which is often confused with MS and needs urgent treatment.
  • Transverse myelitis — focal inflammation within the spinal cord.
    • May present with sensory symptoms (such as paraesthesia) or motor symptoms (such as weakness) below the level of the inflammation that typically develop over hours or days.
    • Some people describe a tight band sensation around the trunk at the level of the inflammation, or a shock-like sensation radiating down the spine induced by neck flexion (Lhermitte’s phenomena).
    • There may be urinary symptoms such as urgency, frequency, or retention.
    • Examination may reveal focal muscle weakness and reduced sensation below the affected spinal level. Muscle tone is initially reduced.
    • Symptoms and signs may be symmetrical or asymmetrical, and tend to reflect a partial myelitis that only affects a part of the spinal cord — symptoms and signs similar to a full spinal cord transection are rare.
  • Cerebellar-related symptoms.
    • These may include ataxia, vertigo, clumsiness, and dysmetria (as demonstrated by abnormalities with finger-to-nose testing and walking heel to toe).
  • Brainstem syndromes — these may result in:
    • Ataxia.
    • Eye movement abnormalities that can cause diplopia, oscillopsia (a sensation of movement of the vision), nystagmus, and internuclear ophthalmoplegia (inability to adduct one eye and nystagmus in the abducting eye on oculomotor examination).
    • Bulbar muscle problems resulting in dysarthria or dysphagia.
• Do not routinely suspect MS if:
  • The person's main symptoms are fatigue, depression, or dizziness unless they have a history or evidence of focal neurological symptoms or signs.

How should I confirm a diagnosis of multiple sclerosis?

• If a person has symptoms and signs suggestive of multiple sclerosis (MS):
  • Refer promptly to a consultant neurologist — early diagnosis and treatment may improve prognosis.
  • Only a consultant neurologist should make a diagnosis of MS.
  • Speak to a specialist directly if you think the person needs to be seen urgently, for example they present with sudden onset visual loss (to exclude neuromyelitis optica).
• Arrange further tests to help exclude alternative diagnoses, based on the individual's presenting symptoms.
• Urgent referral should not be delayed while awaiting results of the tests.

What else might it be?

• No symptom or sign that may occur with multiple sclerosis (MS) is unique to MS — other conditions often need to be ruled out, especially in early stages of the disease such as:
• Other demyelinating diseases:
• Neuromyelitis optica — a rare disorder that causes demyelination in the optic nerves and spinal cord and is often misdiagnosed as MS. It has a high mortality rate if not diagnosed and treated quickly and appropriately with immunosuppressive treatments.
• Idiopathic transverse myelitis — spinal cord inflammation that may have a post-infectious aetiology.
• Acute disseminated encephalomyelitis — often post-infectious causing diffuse areas of central nervous system (CNS) demyelination, fever, and encephalopathy.
• Metabolic disorders:
• Vitamin B12 deficiency — classically, dorsal column abnormalities may develop. It can cause cognitive changes. For more information, see the CKS topic on Anaemia - B12 and folate deficiency.
• Diabetic peripheral neuropathy, hypocalcaemia, and hypothyroidism can cause sensory symptoms similar to MS.
• Copper deficiency — can cause symptoms similar to vitamin B12 deficiency. Zinc toxicity — can cause an acquired copper deficiency.
• Adult-onset leukodystrophies — can cause progressive neurological symptoms. A family history is often present.
• Infections:
• Lyme disease — can cause various neurological signs. There is often a history of tick bites, arthralgia, and rashes. For more information, see the CKS topic on Lyme disease.
• Tertiary syphilis — classically, dorsal column abnormalities with dementia. For more information, see the CKS topic on Syphilis.
• HIV — can cause encephalopathy and myelopathy. For more information, see the CKS topic on HIV infection and AIDS.
• Tropical spastic paraparesis — caused by infection with human T-lymphotropic virus. It is mainly seen in tropical countries and causes a slowly progressive myelopathy.
• Vascular disorders:
• Primary CNS vasculitis.
• Ischaemic stroke.
• Systemic inflammatory disorders:
• Systemic lupus erythematosus — can cause stroke-like episodes.
• Behcet's syndrome — typically presents with a history of oral and genital ulcers, and uveitis. High risk of thrombotic events including cerebral thrombosis.
• Sarcoidosis — a multi-systemic granulomatous disease that can affect various parts of the body.
• Neoplasia:
• Primary or metastatic neoplastic brain lesions — can cause progressive neurological symptoms and signs.
• Paraneoplastic syndromes — may cause cerebellar ataxia and other neurological symptoms and signs.

How do I know my patient is having a relapse?

• Diagnosis of a relapse is largely clinical in a person known to have relapsing-remitting multiple sclerosis (RRMS):
  • Symptoms and signs vary widely but are similar to those that can occur when multiple sclerosis (MS) first presents.
  • Severity of each relapse can vary markedly — neurological deficits may involve one site (monofocal) or multiple sites (multifocal) in the central nervous system (CNS). About 7 in 10 are monofocal.
  • A relapse typically develops over hours or days until a plateau is reached, which may then last for days, weeks, or months, followed by complete or partial recovery (remission).
  • It is sometimes difficult to differentiate between a single relapse that affects two or more sites in the CNS, and multiple relapses that occur in quick succession. If in doubt, seek specialist advice.
• Diagnose a relapse of MS if the person:
  • Develops new symptoms or existing symptoms have worsened, and
  • These last for more than 24 hours in the absence of infection or any other cause after a stable period of at least 1 month.
• Before diagnosing a relapse of MS:
  • Rule out infection, in particular, urinary tract and respiratory infections.
  • Discriminate between the relapse and fluctuations in disease or progression.
  • Consider other conditions unrelated to MS that may present with similar clinical features.
• Do not routinely diagnose a relapse of MS if symptoms are present for more than 3 months — discuss with a specialist if unsure.

Scenario: General management

From age 18 years onwards.

Scenario: Managing a relapse

From age 18 years onwards.

Scenario: Managing the major symptoms and complications of multiple sclerosis

From age 18 years onwards.

Corticosteroids

• For detailed prescribing information on oral corticosteroids, see the CKS topic on Corticosteroids - oral.

Baclofen

Gabapentin

• The use of gabapentin for spasticity and for oscillopsia in people with multiple sclerosis is off-label.
  • Gabapentin is a Class C controlled substance (under the Misuse of Drugs Act 1971):
    • Careful evaluation for a history of drug abuse is required before prescribing — monitor for development of signs of abuse and dependence [MHRA, 2019; NICE, 2020b].
  • For general prescribing information, see the section on gabapentin in the CKS topic on Neuropathic pain - drug treatment.

Amitriptyline

• The use of amitriptyline for emotional lability in people with multiple sclerosis is off-label.
• For prescribing information, see the section on Amitriptyline in the CKS topic on Neuropathic pain - drug treatment.

Search strategy

Scope of search

A literature search was conducted for guidelines and systematic reviews on primary care management of multiple sclerosis.

Search dates

June 2015 - July 2022

Key search terms

The terms listed below are the core search terms that were used for EBSCOhost MEDLINE (searched 20th July 2020). These were combined with filters to identify guidelines, systematic reviews and primary care relevant literature in EBSCOhost MEDLINE. The strategy was adapted for The Cochrane Library databases.   

S3 S1 OR S2 
S2 AB multiple sclerosis OR TI multiple sclerosis 
S1 (MH "Multiple Sclerosis+")  

Sources of guidelines

• National Institute for Health and Care Excellence (NICE)
• Scottish Intercollegiate Guidelines Network (SIGN)
• Royal College of Physicians
• Royal College of General Practitioners
• Royal College of Nursing
• NICE Evidence
• World Health Organization
• Guidelines International Network
• TRIP database
• Agency for Healthcare Research and Quality
• National Health and Medical Research Council (Australia)
• Royal Australian College of General Practitioners
• British Columbia Medical Association
• Canadian Medical Association
• Alberta Medical Association
• Michigan Quality Improvement Consortium
• Singapore Ministry of Health
• National Resource for Infection Control
• RefHELP NHS Lothian Referral Guidelines
• Medline (with guideline filter)
• Driver and Vehicle Licensing Agency
• NHS Health at Work (occupational health practice)

Sources of systematic reviews and meta-analyses

• The Cochrane Library:
  • Systematic reviews
  • Protocols
  • Database of Abstracts of Reviews of Effects
• Medline (with systematic review filter)
• EMBASE (with systematic review filter)

Sources of health technology assessments and economic appraisals

• NIHR Health Technology Assessment programme
• The Cochrane Library:
  • NHS Economic Evaluations
  • Health Technology Assessments
• Canadian Agency for Drugs and Technologies in Health
• International Network of Agencies for Health Technology Assessment

Sources of randomized controlled trials

• The Cochrane Library:
  • Central Register of Controlled Trials
• Medline (with randomized controlled trial filter)
• EMBASE (with randomized controlled trial filter)

Sources of evidence based reviews and evidence summaries

• Drug and Therapeutics Bulletin
• TRIP database
• Central Services Agency COMPASS Therapeutic Notes

Sources of national policy

• Department of Health
• Health Management Information Consortium (HMIC)

Patient experiences

• Healthtalk
• BMJ - Patient Journeys

Sources of medicines information

The following sources are used by CKS pharmacists and are not necessarily searched by CKS information specialists for all topics. Some of these resources are not freely available and require subscriptions to access content.

• British National Formulary (BNF)
• electronic Medicines Compendium (eMC)
• European Medicines Agency (EMEA)
• Medicines and Healthcare products Regulatory Agency (MHRA)
• REPROTOX
• Scottish Medicines Consortium
• Stockley's Drug Interactions
• TERIS
• TOXBASE
• Micromedex
• UK Medicines Information

Stakeholder engagement

Our policy

The external review process is an essential part of CKS topic development. Consultation with a wide range of stakeholders provides quality assurance of the topic in terms of:

• Clinical accuracy.
• Consistency with other providers of clinical knowledge for primary care.
• Accuracy of implementation of national guidance (in particular NICE guidelines).
• Usability.

Principles of the consultation process

• The process is inclusive and any individual may participate.
• To participate, an individual must declare whether they have any competing interests or not. If they do not declare whether or not they have competing interests, their comments will not be considered.
• Comments received after the deadline will be considered, but they may not be acted upon before the clinical topic is issued onto the website.
• Comments are accepted in any format that is convenient to the reviewer, although an electronic format is encouraged.
• External reviewers are not paid for commenting on the draft topics.
• Discussion with an individual or an organization about the CKS response to their comments is only undertaken in exceptional circumstances (at the discretion of the Clinical Editor or Editorial Steering Group).
• All reviewers are thanked and offered a letter acknowledging their contribution for the purposes of appraisal/revalidation.
• All reviewers are invited to be acknowledged on the website. All reviewers are given the opportunity to feedback about the external review process, enabling improvements to be made where appropriate.

Stakeholders

• Key stakeholders identified by the CKS team are invited to comment on draft CKS topics. Individuals and organizations can also register an interest to feedback on a specific topic, or topics in a particular clinical area, through the Getting involved section of the Clarity Informatics website.
• Stakeholders identified from the following groups are invited to review draft topics:
  • Experts in the topic area.
  • Professional organizations and societies (for example, Royal Colleges).
  • Patient organizations, Clarity has established close links with groups such as Age UK and the Alzheimer’s Society specifically for their input into new topic development, review of current topic content and advice on relevant areas of expert knowledge.
  • Guideline development groups where the topic is an implementation of a guideline.
  • The British National Formulary team.
  • The editorial team that develop MeReC Publications.
• Reviewers are provided with clear instructions about what to review, what comments are particularly helpful, how to submit comments, and declaring interests.

Patient engagement

Clarity Informatics has enlisted the support and involvement of patients and lay persons at all stages in the process of creating the content which include:

• Topic selection
• Scoping of topic
• Selection of clinical scenarios
• First draft internal review
• Second draft internal review
• External review
• Final draft and pre-publication

Our lay and patient involvement includes membership on the editorial steering group, contacting expert patient groups, organizations and individuals.

Evidence exclusion criteria

Our policy

Scoping a literature search, and reviewing the evidence for CKS is a methodical and systematic process that is carried out by the lead clinical author for each topic. Relevant evidence is gathered in order that the clinical author can make fully informed decisions and recommendations. It is important to note that some evidence may be excluded for a variety of reasons. These reasons may be applied across all CKS topics or may be specific to a given topic.

Studies identified during literature searches are reviewed to identify the most appropriate information to author a CKS topic, ensuring any recommendations are based on the best evidence. We use the principles of the GRADE and PICOT approaches to assess the quality of published research. We use the principles of AGREE II to assess the quality of published guidelines.

Standard exclusions for scoping literature:

• Animal studies
• Original research is not written in English

Possible exclusions for reviewed literature:

• Sample size too small or study underpowered
• Bias evident or promotional literature
• Population not relevant
• Intervention/treatment not relevant
• Outcomes not relevant
• Outcomes have no clear evidence of clinical effectiveness
• Setting not relevant
• Not relevant to UK
• Incorrect study type
• Review article
• Duplicate reference

Organizational, behavioural and financial barriers

Our policy

The CKS literature searches take into consideration the following concepts, which are discussed at the initial scoping of the topic.

• Feasibility
  • Studies are selected depending on whether the intervention under investigation is available in the NHS and can be practically and safely undertaken in primary care.
• Organizational and Financial Impact Analysis
• Studies are selected and evaluated on whether the intervention under investigations may have an impact on local clinical service provision or national impact on cost for the NHS. The principles of clinical budget impact analysis are adhered to, evaluated and recorded by the author. The following factors are considered when making this assessment and analysis.
  • Eligible population
  • Current interventions
  • Likely uptake of new intervention or recommendation
  • Cost of the current or new intervention mix
  • Impact on other costs
  • Condition-related costs
  • In-direct costs and service impacts
  • Time dependencies
• Cost-effectiveness or cost-benefit analysis studies are identified where available. 

We also evaluate and include evidence from NICE accredited sources which provide economic evaluations of recommendations, such as NICE guidelines. When a recommended action may not be possible because of resource constraints, this is explicitly indicated to healthcare professionals by the wording of the CKS recommendation.

Declarations of interest

Our policy

Clarity Informatics requests that all those involved in the writing and reviewing of topics, and those involved in the external review process to declare any competing interests. Signed copies are securely held by Clarity Informatics and are available on request with the permission of the individual. A copy of the declaration of interest form which participants are asked to complete annually is also available on request. A brief outline of the declarations of interest policy is described here and full details of the policy is available on the Clarity Informatics website. Declarations of interests of the authors are not routinely published, however competing interests of all those involved in the topic update or development are listed below. Competing interests include:

• Personal financial interests
• Personal family interest
• Personal non-financial interest
• Non-personal financial gain or benefit

Although particular attention is given to interests that could result in financial gains or losses for the individual, competing interests may also arise from academic competition or for political, personal, religious, and reputational reasons. An individual is not obliged to seek out knowledge of work done for, or on behalf of, the healthcare industry within the departments for which they are responsible if they would not normally expect to be informed.

Who should declare competing interests?

Any individual (or organization) involved in developing, reviewing, or commenting on clinical content, particularly the recommendations should declare competing interests. This includes the authoring team members, expert advisers, external reviewers of draft topics, individuals providing feedback on published topics, and Editorial Steering Group members. Declarations of interest are completed annually for authoring team and editorial steering group members, and are completed at the start of the topic update and development process for external stakeholders.

Competing interests declared for this topic:

None.