EDUCATION PRACTICE
GUIDELINES
1
National Collaborating Centre for
Mental Health, Royal College of
Psychiatrists, London E1 8AA, UK
2
Sheffield Health and Social Care
NHS Foundation Trust, Sheffield
S10 3TH, UK
3
Psychiatry and Applied Psychology,
Faculty of Medicine and Health
Sciences, University of Nottingham,
Nottingham, UK
4
Department of Epidemiology,
Johns Hopkins Bloomberg School of
Public Health, Baltimore, MD, USA
5 airways disease, pneumonia, and unintentional injury.2
National Collaborating Centre for
Mental Health, University College
London, London, UK
6
Centre for Outcomes Research and
Effectiveness, University College
London, London, UK
Correspondence to: T Kendall
tim2.kendall@virgin.net
Cite this as: BMJ 2014;349:g5673
doi: 10.1136/bmj.g5673
This is one of a series of BMJ
summaries of new guidelines
based on the best available
evidence; they highlight important
recommendations for clinical
practice, especially where
uncertainty or controversy exists.
Further information about the
guidance, a list of members of the
guideline development group,
and the supporting evidence
statements are in the full version
on bmj.com.
32 27 September 2014 | the bmj
Assessment and management of bipolar disorder:
summary of updated NICE guidance
Tim Kendall,1 2 Richard Morriss,3 Evan Mayo-Wilson,4 Elena Marcus,5 6 on behalf of the
Guideline Development Group
Bipolar disorder is a complex, recurrent, and severe
mental illness that has an onset typically between 13
and 30 years of age and a lifetime prevalence of 1.4%.1
It is characterised by episodes of mania or hypomania
with elation, overactivity, and disinhibited behaviour, as
well as episodes of depression with profound loss of inter-
est and motivation, often with milder depressed mood
in between episodes. Bipolar disorder is associated with
an increased risk of suicide and physical illness, such as
ischaemic heart disease, diabetes, chronic obstructive
Around two thirds of people with bipolar disorder also
experience another mental disorder, usually anxiety dis-
orders, substance misuse disorders, or impulse control
disorders.1 The risk of recurrence in the year after a mood
episode is especially high (50% in one year and >70% at
four years) compared with other psychiatric disorders,3
and this has important implications for the long term
management of the disorder.
This article summarises the most recent recommen-
dations from the National Institute for Health and Care
Excellence (NICE) on assessing and managing bipolar
disorder in adults, children, and young people.4
Recommendations
NICE recommendations are based on systematic reviews
of the best available evidence and explicit consideration
of cost effectiveness. When minimal evidence is available,
recommendations are based on the Guideline Develop-
ment Group’s experience and opinion of what constitutes
good practice. Evidence levels for the recommendations
are in the full version of this article on bmj.com.
Care for adults, children, and young people across all
phases of bipolar disorder
•   Use this guideline in conjunction with the NICE
clinical guidance on service user experience in adult
mental health5 to improve the experience of care by:
––Promoting a positive recovery message from the
point of diagnosis and throughout care
––Building supportive and empathic relationships as
an essential part of care. (New recommendation.)
•    early as possible negotiate with the person with
As
bipolar disorder and his or her carers about how
information about the person will be shared. When
discussing rights to confidentiality, emphasise
the importance of sharing information about risks
and the need for carers to understand the person’s
perspective. Foster a collaborative approach that
supports people with bipolar disorder and their
carers and also respects their individual needs and
interdependence. (New recommendation.)
Key symptoms of mania and severe depression
Mania
Expansive, grandiose affect
Inflated self esteem
Increased talkativeness
Decreased need for sleep
Increase in impulsive risk taking behaviour
Depression
Depressed mood
Profound loss of interest in activities
Feelings of worthlessness
Weight loss or gain
Suicidal thoughts or actions
•   When using any psychotropic drugs for bipolar
disorder ensure that:
––People are given information that is suitable for
their developmental level about the purpose
and likely side effects of treatment, including
any monitoring that is needed, and give them an
opportunity to ask questions
––Drugs are chosen in collaboration with the person
with bipolar disorder, taking into account the
carer’s views if the person agrees
––The overall medication regimen is regularly
reviewed so that drugs that are not needed
after the acute episode are stopped. (New
recommendation.)
Recognising and managing bipolar disorder in adults in
primary care
•   When adults present in primary care with
depression, ask about previous periods of
overactivity or disinhibited behaviour. If the
overactivity or disinhibited behaviour has lasted for
four days or more, consider referral for a specialist
mental health assessment. Refer people urgently
for a specialist mental health assessment if mania
or severe depression is suspected (see box for key
symptoms or refer to the ICD-10 (international
classification of diseases, 10th revision) for
full diagnostic criteria6) or they are a danger to
themselves or others. (New recommendation.)
•   Monitor the physical health of people with bipolar
disorder when responsibility for monitoring is
transferred from secondary care, and then at least
annually. The health check should be comprehensive
and focus on physical health problems, such as
cardiovascular disease, diabetes, obesity, and
respiratory disease. A copy of the results should be
sent to the care coordinator and psychiatrist, and it

thebmj.com
Previous articles in this
series
ЖЖDiagnosis and
management of drug
allergy in adults, children
and young people:
summary of NICE guidance
(BMJ 2014;349:g4852)
ЖЖEarly identification and
management of chronic
kidney disease in adults:
summary of updated
NICE guidance
(BMJ 2014;349:g4507)
ЖЖLipid modification
and cardiovascular risk
assessment for the primary
and secondary prevention
of cardiovascular disease:
summary of updated NICE
guidance
(BMJ 2014;349:g4356)
ЖЖThe management of
atrial fibrillation: summary
of updated NICE guidance
(BMJ 2014;348:g3655)
ЖЖPrevention and
management of pressure
ulcers: summary of NICE
guidance
(BMJ 2014;348:g2592)
the bmj | 27 September 2014 33
should be put in the secondary care records. (New
recommendation.)
•   Offer people with rapid cycling bipolar disorder the
same interventions as people with other types of
bipolar disorder because there is currently no strong
evidence to suggest that people with rapid cycling
bipolar disorder should be treated differently. (New
recommendation.)
Managing mania or hypomania in adults in secondary
care
•   If a person develops mania or hypomania and is
not taking an antipsychotic or mood stabiliser, offer
haloperidol, olanzapine, quetiapine, or risperidone,
taking into account any advance statements, the
person’s preference, and clinical context (including
physical comorbidity, previous response to
treatment, and side effects). If the person is already
taking lithium, check plasma lithium levels to
optimise treatment and consider adding haloperidol,
olanzapine, quetiapine, or risperidone. Do not offer
lamotrigine to treat mania. (New recommendation.)
•   If a person develops mania or hypomania and is
taking an antidepressant (as defined by the BNF7) as
monotherapy:
––Consider stopping the antidepressant and
––Offer an antipsychotic regardless of whether the
antidepressant is stopped. (New recommendation.)
Managing bipolar depression in adults in secondary care
•   Offer adults with bipolar depression:
––A psychological intervention that has been
developed specifically for bipolar disorder and has
a published evidence based manual describing
how it should be delivered or
––A high intensity psychological intervention
(cognitive behavioural therapy, interpersonal
therapy, or behavioural couples therapy) in line
with the NICE clinical guideline on depression.8
Discuss the possible benefits and risks of psychologi-
cal interventions and the person’s preference. Monitor
mood for signs of mania or hypomania or deterioration
of the depressive symptoms. (New recommendation.)
•   If a person develops moderate or severe bipolar
depression and is not taking a drug to treat the
disorder, offer fluoxetine combined with olanzapine,
or quetiapine on its own, depending on the person’s
preference and previous response to treatment.
•   If the person prefers, consider either olanzapine
(without fluoxetine) or lamotrigine on its own.
•   Consider the use of lamotrigine if there is no
response to fluoxetine combined with olanzapine or
to quetiapine on its own. (New recommendation.)
•   If a person develops moderate or severe bipolar
depression and is already taking lithium, check the
person’s plasma lithium level. If it is inadequate,
increase the dose of lithium; if it is at maximum
level, add either fluoxetine combined with
olanzapine or quetiapine on its own, depending on
the person’s preference and previous response to
treatment.
EDUCATION PRACTICE
•   If the person prefers, consider adding olanzapine
(without fluoxetine) or lamotrigine to lithium.
•   If there is no response to the addition of fluoxetine
combined with olanzapine or quetiapine on its own,
stop the additional treatment and consider adding
lamotrigine to lithium. (New recommendation.)
Managing bipolar disorder in adults in the longer term in
secondary care
•   After each episode of mania or bipolar depression,
discuss the longer term management of the disorder
with the person and the carers, if appropriate.
Discussion should aim to help people understand
that bipolar disorder is often a long term relapsing
and remitting condition that needs self management
and engagement with primary and secondary care
professionals and the involvement of carers. The
discussion should cover:
––The nature and variable course of bipolar disorder
––The role of psychological and pharmacological
interventions to prevent relapse and reduce
symptoms
––The risk of relapse after reducing or stopping drugs
for an acute episode
––The potential benefits and risks of long term drugs
and psychological interventions, and the need to
monitor mood and medication
––The potential benefits and risks of stopping drugs,
including for women who may wish to become
pregnant
––The person’s history of bipolar disorder, including:
–– The severity and frequency of episodes of
mania or bipolar depression, with a focus on
associated risks and adverse consequences
–– Previous response to treatment
–– Symptoms between episodes
–– Potential triggers for relapse, early warning
signs, and self management strategies
–– Possible duration of treatment, and when and
how often this should be reviewed.
Provide clear written information about bipolar dis-
order, including NICE’s information for the public,9 and
ensure there is enough time to discuss options and con-
cerns. (New recommendation.)
•   Offer a structured psychological intervention
(individual, group, or family), which has been
designed for bipolar disorder and has a published
evidence based manual describing how it should
be delivered, to prevent relapse or for people
who have some persisting symptoms between
episodes of mania or bipolar depression. (New
recommendation.)
•   When planning long term drug treatment to
prevent relapse, take into account drugs that have
been effective during episodes of mania or bipolar
depression. Discuss with people whether they prefer
to continue this treatment or switch to lithium,
and explain that lithium is the most effective
long term treatment for bipolar disorder. (New
recommendation.) Offer lithium as a first line long
term drug treatment for bipolar disorder and:
EDUCATION PRACTICE
––If lithium is ineffective, consider adding valproate
––If lithium is poorly tolerated or is not suitable (for
example, because the person does not agree to
routine blood monitoring), consider valproate
or olanzapine instead or, if it has been effective
during an episode of mania or bipolar depression,
quetiapine. (New recommendation.)
Promoting recovery and return to primary care
•   Offer people with bipolar disorder whose symptoms
have responded effectively to treatment and who
remain stable the option to return to primary care
for further management. If they wish to do this,
record it in their notes and coordinate transfer
of responsibilities through the care programme
approach. (New recommendation.)
Recognising and diagnosing bipolar disorder in children
and young people
•   If bipolar disorder is suspected in primary care in
children or young people aged under 14 years, refer
them to child and adolescent mental health services
(CAMHS). Refer young people aged 14 years or over
to a specialist early intervention in psychosis service
or a CAMHS team with expertise in the assessment
and management of bipolar disorder in line with
the recommendations in this guideline. (New
recommendation.)
•   The diagnosis of bipolar disorder should be
made only after a period of intensive, prospective
longitudinal monitoring by a healthcare professional
or multidisciplinary team trained and experienced in
the assessment, diagnosis, and management of bipolar
disorder in children and young people. This should be
done in collaboration with the child or young person’s
parents or carers. (New recommendation.)
Managing bipolar disorder in children and young people
•   To treat mania or hypomania in young people
see NICE’s technology appraisal guidance on
aripiprazole for treating moderate to severe manic
episodes in adolescents with bipolar I disorder,10 and
also consider the recommendations for adults. In
children, refer to the BNF for Children to modify drug
treatments,11 be aware of the increased potential for
a range of side effects, and do not routinely continue
antipsychotic treatment for longer than 12 weeks.
(New recommendation.)
•   Do not offer valproate to girls or young women of
childbearing potential. (New recommendation.)
•   Offer a structured psychological intervention
(individual cognitive behavioural therapy or
interpersonal therapy) to young people with bipolar
depression. The intervention should last for at least
three months and have a published evidence based
manual that describes how it should be delivered.
(New recommendation.)
Overcoming barriers
There is a perception that because bipolar disorder has
important genetic and biological influences it must be
34 27 September 2014 | the bmj
treated with drugs, and the drug of choice for bipolar
depression for many professionals is an antidepressant.12
This misconception is challenged by this guideline, which
finds that psychological treatments are effective in the
treatment of bipolar depression in primary and secondary
care and in preventing recurrence. Psychological treat-
ments are also important for young people, both because
young people may benefit from them and because they
are at greater risk of harm with drug treatment.13 However
access to psychological therapies is currently insufficient
for adults and young people with bipolar disorder. For
adults, this guideline also finds that some antipsychot-
ics are effective in the treatment of bipolar depression,
but lithium (rather than antipsychotics) should be the
first line drug to prevent relapse. A major driver for these
changes will be the establishment of quality networks
and national audit. In adults, many mental health work-
ers have taken the view that smoking, not taking exercise,
and having a poor diet are unimportant compared with
the enormous impact of a bipolar illness.14 These beliefs
have contributed to people with bipolar disorder dying
from preventable diseases much earlier than others.2
This guideline emphasises the importance of maintain-
ing good physical health for people with severe mental
health problems, such as bipolar disorder, and we hope
it will contribute to a change in professional attitudes and
practice.
There has been much controversy over the diagnosis
and treatment of children and young people with pos-
sible bipolar disorder. In the United States, children as
young as 4 or 5 years are being treated with drugs,15 using
criteria for diagnosis that would not be accepted in the
NHS. Thus, increasing numbers of children and young
people are taking antipsychotics,16 which are associated
with serious adverse events, including increased prolac-
tin levels, rapid weight gain, and increased risk of diabe-
tes.10 The previous NICE guideline rejected the extension
of bipolar disorder into childhood and suggested that
clinicians apply stricter criteria to adolescents,17 but the
diagnosis and treatment of children and adolescents has
continued, mostly in the US.16 This is despite evidence
that symptoms are not stable over time18 and despite lim-
ited evidence that young people benefit from the treat-
ments commonly used in adults. Importantly, trials in the
US show that many children under 13 years diagnosed as
having bipolar disorder also have attention-deficit/hyper-
activity disorder,15  19 which might be a more appropriate
diagnosis. The updated guideline reinforces the findings
of the last guideline and finds that extensive use of this
diagnosis in children could cause more harm than good.
Contributors: All authors contributed to the conception and drafting of this
article and revised it critically. They have all approved this version. TK is
guarantor.
Competing interests: We have read and understood BMJ policy on
declaration of interests and declare the following interests: TK, EM-W,
and EM had support from the National Collaborating Centre for Mental
Health, which was in receipt of funding from NICE, for the submitted work;
RM received support from the National Institute for Health Research
Collaboration for Leadership in Applied Health Research and Care East
Midlands. The authors’ full statements can be viewed at: www.bmj.com/
content/bmj/349/bmj.g5673/related#datasupp.
Provenance and peer review: Commissioned; not externally peer reviewed.
References are in the version on thebmj.com.
 EDUCATION PRACTICE

1
Department of Haematology,
Oxford University Hospitals NHS
Trust, Oxford, UK
2
Oxford University Clinical Medical
School, Oxford, UK
Correspondence to: T Littlewood
tim.littlewood@orh.nhs.uk
Cite this as: BMJ 2014;349:g5340
doi: 10.1136/bmj.g5340
This series of occasional articles
provides an update on the best
use of key diagnostic tests in the
initial investigation of common or
important clinical presentations.
The series advisers are Steve
Atkin, professor of medicine, Weill
Cornell Medical College Qatar;
and Eric Kilpatrick, honorary
professor, department of clinical
biochemistry, Hull Royal Infirmary,
Hull York Medical School. To
suggest a topic for this series,
please email us at practice@bmj.
com.
RATIONAL TESTING
Neutropenia in primary care
Deborah Hay,1 Matilda Hill,2 Tim Littlewood1
A mild neutropenia of 1.2×109/L is detected in a 69 year
old man who presents with a short history of fatigue. He
takes no regular drugs. The rest of his blood count is nor-
mal, as is his physical examination.
Is further investigation needed?
Neutropenia is defined as an absolute neutrophil count of
less than 1.5×109/L. It is important for two reasons. Firstly, it
may indicate an underlying systemic or haematological dis-
ease. Secondly, it reflects an increased risk of life threatening
bacterial infection—risk increases once the count is less than
1.0×109/L and becomes even greater in severe neutropenia
(box).1  2
The General Practice Research Database suggests that
1:100 000 patients per year receive an ICD (International
Classification of Diseases) code for neutropenia or agranulo-
cytosis.3 Although data are limited, we can assume that many
more have transient or mild neutropenia. The more severe
the neutropenia, the more likely it is that further investigation
will be initiated, although no strict guidelines exist for this.
Table 1 highlights important causes of isolated neutropenia.
Severity of neutropenia
Mild: 1.0-1.5×109 neutrophils/L
Moderate: 0.5-0.9×109 neutrophils/L
Severe: <0.5×109 neutrophils/L
genuinely abnormal. Benign ethnic neutropenia affects
25-50% of people of African or Afro-Caribbean ancestry,
as well as some of Arabic-Middle Eastern origin, and has
no clinical significance.4 Normal ranges specific to ethnic
groups are not reported; however, a population study
from Uganda suggests that the mean neutrophil count
for healthy black African adults is lower than that seen
in white people, at 1.8×109/L (90% confidence interval
0.84 to 3.37).5 Similar findings were reported in a study of
four ethnic groups in the United Kingdom,6 with a mean
neutrophil count of 2.6×109/L (1.1 to 6.1) being reported
for black Africans. The average neutrophil count for white
people was 3.6×109/L (1.7-7.5). In patients of African or
Afro-Caribbean ancestry, we therefore recommend inves-
tigating neutropenia only in those who have counts persis-
tently less than 1.0×109/L.

Consider ethnicity Review the drug history

Before embarking on further investigation, however, it is The underlying cause of neutropenia is often evident from the
necessary to determine whether the neutrophil count is history. The incidence of drug induced severe neutropenia or
agranulocytosis is 2.4-15.4 per million population per year,7
LEARNING POINTS and, although a temporal association with drug treatment is
Isolated neutropenia is a common incidental finding in primary care. It is most often typical, delayed neutropenia can occur in patients who have
drug induced or caused by acute viral infection been taking a stable dose of a drug for years (table 2).8
Benign ethnic neutropenia is common in people of black African and Afro-Caribbean A systematic review of more than 900 published reports
ethnicity of agranulocytosis identified 125 “definite or probable”
It is rare for primary haematological malignancy to present with isolated neutropenia causative agents and highlighted a 10% mortality rate in
because other haemopoietic cells lines are usually also affected patients with a neutrophil nadir of less than 0.1×109/L.9 In
The initial investigation of persistent isolated neutropenia should include a peripheral such severe cases, the drug usually needs to be discontinued
blood film, haematinics, and chronic viral serology and granulocyte colony stimulating factor is often needed
to speed neutrophil recovery. Drug induced neutropenia is
No formal diagnosis can be reached in many adults with isolated neutropenia
more often mild or moderate, however, and a clinical deci-
Referral for haematological assessment is warranted if anaemia or thrombocytopenia is
sion must be made regarding the relative benefits of drug
also evident, or when persistent neutropenia is moderate or severe (<1×109/L)
treatment and the risks of neutropenic sepsis. If a decision
is made to continue treatment, the neutrophil count should
Table 1 | Important causes of acquired neutropenia be carefully monitored.
Possible causes Comments
Drug related May be expected (for example, cytotoxics) or idiopathic (for example, What is the next investigation?
immune mechanism)
Acute infection, usually viral Typically transient; clinical history and blood film are likely to help
Ask for a blood film
Chronic viral infection (HIV, hepatitis B and C) Clinical history, risk factors, and viral serology are likely to be diagnostic
For moderate or severe unexplained neutropenia, inspection
Autoimmune diseases (such as systemic Additional clinical features will be expected; drug treatment may have of a blood film is an important investigation. Figures 1 and
lupus erythematosus, Sjögren’s syndrome, confounding effects 2 highlight some of the abnormalities that may be detected.
rheumatoid arthritis) The presence of reactive T cells may suggest acute viral
Haematinic deficiency Rarely affects neutrophils alone; red cell indices and blood film will infection. Neutropenia is seen in 50% of cases of infectious
probably hold clues
mononucleosis10 and may also be seen in acute cytomeg-
Primary immune neutropenia Rare in adults; usually diagnosed in early childhood and
spontaneously remitting alovirus infection and toxoplasmosis. A suitable history
Marrow infiltration (for example, metastases) Clinical history and blood film likely to be suggestive; >1 cell line (perhaps including fever, sore throat, or general malaise)
typically affected and the blood film shown in fig 1 should prompt a monos-
Haematological malignancy Most affect multiple cell lines; blood film likely to be supportive. pot test or specific viral serology. Neutropenia in this con-
Chronic idiopathic neutropenia Diagnosis of exclusion; some cases have an immunological cause text usually resolves in three to four weeks.

the bmj | 27 September 2014 35

 EDUCATION PRACTICE
Table 2 | Non-cytotoxic drugs that can cause neutropenia
Category Drugs
Antibiotics Ampicillin, cephalosporins, trimethoprim-sulfamethoxazole, erythromycin, nitrofurantoin
Anticonvulsants Carbamazepine, phenytoin
Anti-inflammatory drugs Ibuprofen, diclofenac, indometacin
Anti-rheumatic drugs Gold, penicillamine, infliximab
Anti-thyroid drugs Carbimazole, propylthiouracil
Cardiovascular agents Spironolactone, angiotensin converting enzyme inhibitors, propranolol, clopidogrel
Psychotropic agents Clozapine, olanzapine, chlorpromazine, fluoxetine
Other Allopurinol, omeprazole
Large granular lymphocytes, similar to those in fig 1,
are also seen in many autoimmune or reactive condi-
tions. Less commonly, a persistent lymphocytosis sug-
gests an underlying lymphoproliferative disease, with
the rare T cell disorder large granular lymphocytic
leukaemia manifesting as an isolated neutropenia in
60-85% of cases.11
A myelodysplastic syndrome may be suggested by
typical blood film findings (fig 2), although these are
observer dependent and usually extend to cell lines other
than granulocytes.12
Occasionally, the blood film suggests haematinic defi-
ciency. Vitamin B12 and folate deficiency are often cited
as possible causes of isolated neutropenia,13  14 although
few if any cases of neutropenia in the absence of anae-
mia or macrocytosis are reported. Iron deficiency may
also rarely cause neutropenia.15  16 Because haematinic
deficiency is readily testable and easily remedied, vita-
min B12, folate, and ferritin assays are justifiable in the
investigation of patients presenting with unexplained
neutropenia. Other nutritional deficiencies are also
worth considering: neutropenia caused by deficiencies of
trace elements (such as copper) has also been described,
although other haemopoietic cell lines are usually
affected.17 Extreme energy restriction—in patients with
anorexia nervosa, for example—can also cause neutro-
penia, partly due to haematinic deficiencies and partly
through serous atrophy of the marrow.
In many cases, however, the blood film provides no
clues to the underlying cause. For these patients, further
testing is determined on a case by case basis.
Fig 1 | Large granular lymphocytes with azurophilic granules
may be seen in viral infection. More rarely, they are seen in the
T cell chronic lymphoproliferative disorder, large granulocytic
leukaemia
36 27 September 2014 | the bmj
Chronic viral serology (HIV, hepatitis B and C)
Neutropenia has been described in 50% of patients with
HIV, and is seen in 5-10% of asymptomatic patients with
early infection.18  19 It may also be seen in treatment naive
patients with hepatitis C, with a minority of cases being
severe.20 A prospective study of patients undergoing a
structured investigation in primary care for isolated neu-
tropenia identified chronic hepatitis in 6% of patients,16
confirming chronic viral serology as a useful test in the
investigation of persistent unexplained neutropenia.
Antinuclear antibodies (ANA) and rheumatoid factor
Autoimmune spectrum disorders are often associated with
neutropenia. Although most cases of severe neutropenia in
systemic lupus erythematosus are caused by drug induced
myelosuppression,21 one study reports that 50% of patients
with this condition have mild to moderate neutropenia, usu-
ally with an immunological pathophysiology.22 Fewer data
are available on neutropenia in rheumatoid arthritis (except
for the well described, but rare, Felty’s syndrome), Sjögren’s
syndrome, or mixed connective tissue disorders.
Other articles in this series have discussed the limited sensi-
tivity of ANA testing for the diagnosis of systemic lupus erythe-
matosus.23 Systematic studies are lacking, but pragmatically
we support testing for ANA, rheumatoid factor, or antibodies
to extractable nuclear antigens only when there are additional
features consistent with these disorders. For isolated neutrope-
nia in an otherwise well person, a positive ANA or rheumatoid
factor result is unlikely to inform diagnosis or management.
Antineutrophil antibodies
Primary immune neutropenia in the absence of any systemic
immunological disease is also well described. In infancy and
early childhood, this is the most common cause of acquired
neutropenia, with antineutrophil antibodies being detected
in more than 98% of cases.24 However, it is less clear whether
adults with neutropenia should be tested for these antibodies
because the correlation between a positive test and clinically
detectable neutropenia in adults is poor.25  26 This makes it
difficult to assess the prevalence of primary immune neutro-
penia in primary care; testing for antineutrophil antibodies
is not recommended in this setting.
Fig 2 | “Pelger form” neutrophil (top right), and a hypogranular,
poorly segmented neutrophil (bottom left), both with typical
dysplastic features; some variation in red cell size and shape
is also seen
 EDUCATION PRACTICE

thebmj.com When to refer?
Previous articles in this Primary care doctors are perhaps most worried that
series patients with isolated neutropenia may have an under-
ЖЖOrdering and lying haematological malignancy. However, this is a rela-
interpreting ear swabs in tively unusual explanation. One study in primary care
that reported the results of a panel of investigations,
otitis externa
including bone marrow examination, in 97 patients with
(BMJ 2014;349:g5259)
isolated neutropenia detected a clonal haematological
ЖЖDiagnosis of
disorder in only seven (three cases of myelodysplastic
immediate food allergy syndrome and four chronic B cell lymphoproliferative
(BMJ 2014;349:g3695) disorders).16 Of note, a potentially helpful inspection of
ЖЖInvestigation of the peripheral blood film was not mentioned as part of
suspected urinary tract the diagnostic investigation of these patients.
infection in older people Referral to secondary care is warranted whenever there
(BMJ 2014;349:g4070) is suspicion of progressive or serious disease of any kind.
ЖЖInvestigating This takes account of features beyond the blood count
hypophosphataemia alone, but the development of anaemia or thrombocyto-
(BMJ 2014;348:g3172) penia in a patient with previously isolated neutropenia
ЖЖInterpreting raised may suggest a primary bone marrow disorder and is a
serum prolactin results strong indication for a referral for haematological opin-
(BMJ 2014;348:g3207) ion. More severe neutropenia is also more likely to prompt
referral, particularly if a downward trend in the absolute
neutrophil count is also seen. Although evidence based
clinical guidelines are lacking, these are the patients in
whom a bone marrow examination is likely to be per-
formed. Any patient with unexplained neutropenia con-
sistently less than 1×109/L warrants a discussion with
the haematology service to establish the utility of further
investigation in secondary care.
In one prospective study, no cause was found in a third
of patients with isolated neutropenia, even after compre-
hensive investigation.16  27 However, doctors in primary
and secondary care should be aware that disease specific
symptoms may become apparent with time and periodic
re-evaluation may be needed.
Patient outcome
A blood film from the patient showed occasional dysplas-
tic neutrophils. Although his haemoglobin was preserved,
abnormalities in red cell size and shape (anisopoikilocy-
tosis) were noted. A repeat full blood count was arranged
for three months later.
At this point, the blood count showed a moderate neu-
tropenia of 0.8×109/L, and a mild macrocytic anaemia had
developed. No haematinic deficiency was present, and
serology for HIV, hepatitis B, and hepatitis C was nega-
tive. A bone marrow aspirate showed hypercellularity with
dysplastic changes in more than 10% of the granulocytic
and erythroid lineages, suggesting a myelodysplastic syn-
drome. Long term ongoing management was shared with
the haematology department.
Contributors: DH, MH, and TJL all contributed to the conception of this article,
and were all involved in the drafting and critical revision of the work. All agreed
the final version and are accountable for its content. TL is guarantor.
Competing interests: We have read and understood BMJ policy on
declaration of interests and declare the following interests: none.
Provenance and peer review: Commissioned; externally peer reviewed.
Patient consent not required (patient anonymised, dead, or hypothetical).
References are in the version on thebmj.com.

ANSWERS TO ENDGAMES, p 38
For long answers go to the Education channel on thebmj.com

ANATOMY QUIZ PICTURE QUIZ

Lateral radiograph of
the ankle
A: Base of fifth metatarsal
B: Navicular bone
C: Head of talus
D. Medial malleolus
E. Lateral malleolus
STATISTICAL
QUESTION
Randomised
controlled trials:
balance in baseline
characteristics
Statements a, b, and c are
true, whereas d is false.
A man with absolute dysphagia after eating a steak
1 A lateral soft tissue radiograph of the neck.
2 An opacity consistent with soft tissue in the upper oesophagus measuring about
2 cm in width, lying anterior to the C5-C6 vertebrae with air below. There is also
mild loss of lordosis.
3 Soft food bolus in the proximal oesophagus.
4 Keep the patient nil by mouth and secure intravenous access. Routine blood
tests may be indicated if perforation is suspected, although they may not provide
any new information. Provide intravenous fluids and analgesia if needed. The
patient should be given intravenous or intramuscular hyoscine butylbromide
20 mg unless contraindicated and referred to the ear, nose, and throat (ENT)
surgeons.
5 Initial review by the ENT team, who may perform a flexible nasoendoscopy.
Observe the patient and give further intravenous hyoscine butylbromide
or glucagon. If symptoms do not resolve, the patient will need pharyngo-
oesophagoscopy or oesophagogastroduodenoscopy so that the food bolus
can be removed under direct vision. Rigid oesophagoscopy is the first line
choice if the bolus is thought to be in the proximal oesophagus and flexible
oesophagoscopy if it appears to be more distal. This is because of the higher risk
of perforation when using a rigid oesophagoscope in the distal oesophagus.

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