Pract Neurol: first published as 10.1136/practneurol-2017-001846 on 15 February 2018. Downloaded from http://pn.bmj.com/ on 16 December 2018 by hosam azmy.
Protected by copyright.
Editorial
1
Royal Gwent Hospital,
Department of Neurology,
Newport, UK
2
Spire Cardiff Hospital, Cardiff,
UK
Correspondence to
Dr Fady Georges Joseph,
Department of Neurology, Royal
Gwent Hospital, Newport NP20
2UB, UK; f​ ady.​joseph@​wales.​
nhs.u​ k, ​fadygjoseph@​gmail.​com
Accepted 31 January 2018
Published Online First
15 February 2018
►► http://​dx.​doi.​org/​10.​1136/​
practneurol-​2017-​001824
To cite: Joseph FG,
Habboush HW. Pract Neurol
2018;18:82–83.
82
The antiphospholipid syndrome and
its ‘non-criteria’ manifestations
Fady Georges Joseph,1 Husni W Habboush2
The antiphospholipid syndrome is char-
acterised by thrombotic and/or recurrent
fetal loss/pregnancy morbidity associated
with persistent antiphospholipid anti-
bodies, namely lupus anticoagulant,
anticardiolipin antibodies or anti-ß2
glycoprotein-1 antibodies. It is defined
as primary when occurring without any
underlying autoimmune disorder or
secondary when associated with chronic
inflammatory conditions, such as systemic
lupus erythematosus, Sjögren’s syndrome
and rheumatoid arthritis.
Although persistent antiphospholipid
antibodies are associated with many other
clinical manifestations, these are not
considered diagnostic for the antiphos-
pholipid syndrome. The most commonly
associated neurological disorders are
stroke, transient ischaemic attacks and
migraine, but also sometimes epilepsy,
transverse myelitis, multiple sclerosis-like
presentations, ocular symptoms, Guil-
lain-Barré syndrome, cognitive impair-
ment, dementia and very rarely chorea.
Neurologists frequently see patients
who test positive for antiphospholipid
antibody or lupus anticoagulant. These
might be only mildly elevated, present
transiently or have no discernible clin-
ical relationship, and we therefore often
appropriately dismiss them. Indeed, up
to 5% of the normal population test posi-
tive for these antibodies. However, when
significantly elevated and clinically rele-
vant, they raise the suspicion of antiphos-
pholipid syndrome.
The updated international Sydney
consensus diagnostic criteria1 for definite
antiphospholipid syndrome are useful for
scientific research, but clinicians should
be cautious about adhering rigidly to
such criteria in clinical practice to avoid
excluding patients with genuine mani-
festations of antiphospholipid syndrome.
So when should we take these antibodies
seriously and what importance should we
Joseph FG, Habboush HW. Pract Neurol 2018;18:82–83. doi:10.1136/practneurol-2017-001846
place on the diagnostic guidelines in this
context?
Zhang and Pereira’s report of ‘Oroman-
dibular chorea in antiphospholipid anti-
body syndrome’ in this edition of Practical
Neurology is an important and fasci-
nating case in point. The authors report
on an elderly woman with headache and
right-sided chorea, progressing to more
significant oromandibular choreiform
movements, speech arrest and feeding
problems. She responded dramatically to
anticoagulation therapy.
Her blood tests were positive for lupus
anticoagulant. The authors had planned
to repeat the test at 12 weeks (which if
still positive would have satisfied the
laboratory diagnostic requirements
for the syndrome), but the patient was
admitted with worsening chorea at just
over 8 weeks. Her lupus anticoagulant
was confirmed positive once again and
she started on anticoagulation. However,
she had no history of pregnancy failure
or recurrent thromboembolic events, and
so did not meet the clinical diagnostic
criteria; her anticardiolipin antibodies
were only in the low range and anti-ß2
glycoprotein-1 was absent. Nonetheless,
having excluded other potentially revers-
ible causes of chorea (toxic, infectious,
metabolic, drug related and the MR scan
of brain was normal), it was reasonably
assumed that this represented an anti-
phospholipid syndrome-induced chorea.
There is insufficient evidence on
the management of antiphospholipid
syndrome-associated movement disor-
ders and no superiority of one drug
over another. Some favour anticoagula-
tion, possibly combining symptomatic
management with neuroleptics. Immuno-
suppression with corticosteroids, azathi-
oprine and cyclophosphamide may also
be considered. There are isolated case
reports supporting the use of intrave-
nous immunoglobulins, plasma exchange

and monoclonal antibody therapy such as rituximab.
Although there is good evidence for anticoagulation in
typical thrombotic complications of antiphospholipid
syndrome, there is no consensus on the benefit of anti-
coagulation versus immunosuppression in non-throm-
botic complications.
In this case, the patient’s chorea radically improved
with warfarin therapy. In the absence of any relevant
macroscopic vascular thrombotic lesions on cerebral
imaging, one might naturally wonder why anticoagu-
lation therapy was successful. The pathophysiology of
antiphospholipid syndrome-induced movement disor-
ders, including chorea, remains poorly understood,
but neurological involvement in this condition may
be a biphasic process. There is likely a direct neuro-
toxic effect of antiphospholipid antibodies leading to
impaired basal ganglia cell function and development
of neuroinflammation. Antiphospholipid antibody
binding to brain endothelium may cause endothelial
dysfunction and probably also lead to microthrom-
bosis and blood vessel inflammation. This therefore
provides a logical explanation as to why either anti-
coagulation or immunosuppression therapy can be
an effective treatment.
The term ‘pre-antiphospholipid antibody syndrome’
was coined to express the incomplete features of
this disease. A recent task force2 critically analysed
the non-criteria manifestations of antiphospholipid
syndrome and recommended including chorea and
transverse myelitis in its classification criteria. Chorea
occurs in less than 2%3 of cases of antiphospholipid
syndrome and less than 4% of those with systemic
lupus erythematosus, but a prompt diagnosis is essen-
tial given the significant risk of further complications
such as transient ischaemic attack or stroke in these
patients.4 This process is also currently hindered by
Joseph FG, Habboush HW. Pract Neurol 2018;18:82–83. doi:10.1136/practneurol-2017-001846
Pract Neurol: first published as 10.1136/practneurol-2017-001846 on 15 February 2018. Downloaded from http://pn.bmj.com/ on 16 December 2018 by hosam azmy. Protected by copyright.
Editorial
the 12-week designated interval between antibody
tests. We therefore expect a change in the clinical
and laboratory criteria for this condition in the near
future, especially when confronted with ‘non-criteria’
manifestations.
This case emphasises the importance of suspecting
a rare disease process in the face of diagnostic uncer-
tainty and in having the confidence to offer treatment
when the benefit outweighs the risk. In this case, it
proved to be a positively transformative experience
for the patient and may therefore serve as a useful
reminder to us when signing off our next anticardio-
lipin antibody test result in the office.
Competing interests  None declared.
Provenance and peer review  Commissioned; internally peer
reviewed.
© Article author(s) (or their employer(s) unless otherwise stated
in the text of the article) 2018. All rights reserved. No commercial
use is permitted unless otherwise expressly granted.
References
1. Miyakis S, Lockshin MD, Atsumi T, et al. International
consensus statement on an update of the classification criteria
for definite antiphospholipid syndrome (APS). J Thromb
Haemost 2006;4:295–306.
2. Abreu MM, Danowski A, Wahl DG, et al. The relevance
of “non-criteria” clinical manifestations of antiphospholipid
syndrome: 14th International Congress on Antiphospholipid
Antibodies Technical Task Force Report on Antiphospholipid
Syndrome Clinical Features. Autoimmun Rev 2015;14:401–14.
3. Cervera R, Boffa MC, Khamashta MA, et al. The Euro-
Phospholipid project: epidemiology of the antiphospholipid
syndrome in Europe. Lupus 2009;18:889–93.
4. Asherson RA, Derksen RH, Harris EN, et al. Chorea in systemic
lupus erythematosus and “lupus-like” disease: association
with antiphospholipid antibodies. Semin Arthritis Rheum
1987;16:253–9.
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