Acute disseminated encephalomyelitis differential diagnosis: Difference between revisions

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{{Acute disseminated encephalomyelitis}}
[[Image:Home_logo1.png|right|250px|link=https://www.wikidoc.org/index.php/Acute_disseminated_encephalomyelitis]]
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{{CMG}}; {{AE}} {{Sujaya}}


==Overview==  
==Overview==
No one test established the diagnosis of ADEM.  Supporting features include an appropriate viral or vaccination history, an appropriate acute neurologic illness, and consistent features on CNS imaging.
The [[differential]] diagnoses of [[Acute disseminated encephalomyelitis]] include:
== Differential Diagnosis ==
* [[Viral]] [[encephalitis]]
* '''Acute infectious encephalitis'''
* [[HIV]] [[encephalopathy]]
*:* Herpes simplex virus
* [[Multiple sclerosis]]
*:*:* Most common and treatable form of infectious encephalitis
* [[Antiphospholipid antibody syndrome]]
*:*:* Usually due to Human herpesvirus 1 (HSV-1), though HSV-2 accounts for 5%
 
*:*:* One-third occur during primary infection
==Differential Diagnosis==
*:*:* Most commonly involves the temporal and frontal lobes;  speech disorders, bizarre behaviors, and gustatory and olfactory hallucinations are common
{| class="wikitable"
*:*:* Fever present in 90%.  Altered state of consciousness present in most.
|+
*:*:* Associated with scattered hemorrhages, CSF red cells
!Disease
*:*:* Treated with acyclovir 10 mg/kg IV q8h; reduces mortality and morbidity if started early enough.  Untreated mortality is 70%.
!Clinical manifestations
*:* Epstein-Barr virus
!Para-clinical findings
*:* Lyme disease
!Gold standard
*:* Arborviruses
!Additional findings
*:*:* Viruses transmitted by arthropods, mosquitos and tick
|-
*:*:* Most common in the summer and fall (in contrast to winter and spring presentations of measles, mumps and VZV).
|'''[[Viral]] [[encephalitis]]''' <ref name="pmid14978145">{{cite journal| author=Kennedy PG| title=Viral encephalitis: causes, differential diagnosis, and management. | journal=J Neurol Neurosurg Psychiatry | year= 2004 | volume= 75 Suppl 1 | issue=  | pages= i10-5 | pmid=14978145 | doi=10.1136/jnnp.2003.034280 | pmc=1765650 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14978145  }}</ref>
*:*:* Present with:
|Can occur in any age characterised by [[fever]] and occasional [[prodromal]] [[illness]]
*:*:*:* Fever
|[[Leukocytosis]] in [[blood]]; T2-weighted [[MRI]] shows multiple diffuse [[hyperintensities]] overlying the [[grey matter]] and [[white matter]] of bilateral [[cerebral]] [[cortices]], and to a lesser extent the [[basal ganglia]], [[brainstem]] and [[cerebellum]]; [[lymphocytic]] [[pleocytosis]] with elevated [[protein]] and normal [[glucose]] in [[CSF]].
*:*:*:* Headache
|[[CSF]] analysis for [[viral]] [[cultures]] and [[serological]] assays
*:*:*:* Gastrointestinal symptoms
|History of recent travel, animal bites ([[Lyme]] disease/[[rabies]]), contact with childhood [[exanthema]] and [[polio]], high-risk occupations and drug abuse; skin [[rashes]] ([[VZV]],[[Measles]], [[Rickettsia]]). [[HSV]] may cause [[fronto-temporal]] signs, [[aphasia]], personality changes and focal [[seizures]] while [[myelitis]] is seen in [[polio]] [[infection]].
*:*:*:* Neurologic disease typically presents day 2 or 3
|-
*:*:*:* CSF typically shows elevated protein, a few hundred white blood cells, normal glucose
|'''[[HIV]] [[encephalopathy]]'''<ref name="pmid32310354">{{cite journal| author=| title=StatPearls | journal= | year= 2022 | volume=  | issue=  | pages=  | pmid=32310354 | doi= | pmc= | url= }}</ref>
*:*:*:* No specific treatment
|Waxing and waning pattern of [[psychomotor]] [[retardation]], decreased [[memory]], concentration and attention span. [[Tremor]], [[ataxia]], [[hyperreflexia]], [[hypertonia]], progressive decline in [[MMSE]] scores<ref name="pmid23362139">{{cite journal| author=Nir TM, Jahanshad N, Busovaca E, Wendelken L, Nicolas K, Thompson PM | display-authors=etal| title=Mapping white matter integrity in elderly people with HIV. | journal=Hum Brain Mapp | year= 2014 | volume= 35 | issue= 3 | pages= 975-92 | pmid=23362139 | doi=10.1002/hbm.22228 | pmc=3775847 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23362139  }}</ref>. Typical absence of [[cortical]] [[signs]] and [[symptoms]]
*:* Eastern equine encephalitis
|Increase in CSF protein, cell count; multiple symmetric, hyperintense, non-enhancing subcortical foci on T2-weighted MRI<ref name="pmid21921226">{{cite journal| author=Valcour V, Paul R, Chiao S, Wendelken LA, Miller B| title=Screening for cognitive impairment in human immunodeficiency virus. | journal=Clin Infect Dis | year= 2011 | volume= 53 | issue= 8 | pages= 836-42 | pmid=21921226 | doi=10.1093/cid/cir524 | pmc=3174098 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21921226  }}</ref>.
*:*:* Presents with flu-like symptoms, fever, headache, vomiting, seizures, and progressive neurologic disease
|Identification of [[HIV]] [[RNA]] in [[CSF]]
*:*:* Seen mostly along the east coast of the U.S.
|[[Bowel]] and/or [[bladder]] complaints
*:*:* Mosquito and bird vectors
|-
*:*:* Most common in those <15 or >55 years of age
|'''[[Multiple sclerosis]]'''
*:*:* Most virulent of arborviruses:  70% mortality
|[[Sensory]] disturbances, walking difficulties, [[dizziness]], [[vision]] problems, [[intestinal]], [[urinary]] and [[sexual]] dysfunction, [[cognitive]] and emotional impairment<ref name="pmid24507522">{{cite journal| author=Gelfand JM| title=Multiple sclerosis: diagnosis, differential diagnosis, and clinical presentation. | journal=Handb Clin Neurol | year= 2014 | volume= 122 | issue=  | pages= 269-90 | pmid=24507522 | doi=10.1016/B978-0-444-52001-2.00011-X | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24507522  }}</ref>
*:* [[Western equine encephalitis]]
|[[MRI]] of the [[brain]] and [[spinal cord]] showing new [[lesions]], both [[enhancing]] and [[non-enhancing]], disseminated in space and time<ref name="pmid12566545">{{cite journal| author=Garg RK| title=Acute disseminated encephalomyelitis. | journal=Postgrad Med J | year= 2003 | volume= 79 | issue= 927 | pages= 11-7 | pmid=12566545 | doi=10.1136/pmj.79.927.11 | pmc=1742586 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12566545  }}</ref>; [[evoked potentials]] test demonstrate [[demyelination]] in the [[optic]] [[nerve]] and [[CNS]]<ref name="pmid10802774">{{cite journal| author=Gronseth GS, Ashman EJ| title=Practice parameter: the usefulness of evoked potentials in identifying clinically silent lesions in patients with suspected multiple sclerosis (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. | journal=Neurology | year= 2000 | volume= 54 | issue= 9 | pages= 1720-5 | pmid=10802774 | doi=10.1212/wnl.54.9.1720 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10802774  }}</ref>; [[Myelin]] basic [[protein]] and [[IgG]] [[oligoclonal]] bands on [[CSF]] analysis<ref name="pmid22904139">{{cite journal| author=Greene DN, Schmidt RL, Wilson AR, Freedman MS, Grenache DG| title=Cerebrospinal fluid myelin basic protein is frequently ordered but has little value: a test utilization study. | journal=Am J Clin Pathol | year= 2012 | volume= 138 | issue= 2 | pages= 262-72 | pmid=22904139 | doi=10.1309/AJCPCYCH96QYPHJM | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22904139 }}</ref>; [[vitamin]] [[deficiencies]] in [[blood]] sample<ref name="pmid21569549">{{cite journal| author=Shah I, James R, Barker J, Petroczi A, Naughton DP| title=Misleading measures in Vitamin D analysis: a novel LC-MS/MS assay to account for epimers and isobars. | journal=Nutr J | year= 2011 | volume= 10 | issue= | pages= 46 | pmid=21569549 | doi=10.1186/1475-2891-10-46 | pmc=3114718 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21569549 }}</ref>.
*:*:* Mosquito vector
|[[T2-weighted MRI]] of the [[brain]] and [[spinal cord]] showing new patchy [[lesions]], both [[enhancing]] and [[non-enhancing]], disseminated in space and time<ref name="pmid12566545" />
*:*:* Young children
|[[Urinary tract infections]], [[depression]], social, vocational and psychological complications<ref name="pmid245075222">{{cite journal| author=Gelfand JM| title=Multiple sclerosis: diagnosis, differential diagnosis, and clinical presentation. | journal=Handb Clin Neurol | year= 2014 | volume= 122 | issue= | pages= 269-90 | pmid=24507522 | doi=10.1016/B978-0-444-52001-2.00011-X | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24507522  }}</ref>
*:*:* Often asymptomatic
|-
*:*:* Western U.S.
|'''[[Antiphospholipid antibody syndrome]]'''<ref name="pmid10670410">{{cite journal| author=Cuadrado MJ, Khamashta MA, Ballesteros A, Godfrey T, Simon MJ, Hughes GR| title=Can neurologic manifestations of Hughes (antiphospholipid) syndrome be distinguished from multiple sclerosis? Analysis of 27 patients and review of the literature. | journal=Medicine (Baltimore) | year= 2000 | volume= 79 | issue= 1 | pages= 57-68 | pmid=10670410 | doi=10.1097/00005792-200001000-00006 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10670410  }}</ref>
*:* California encephalitis
|[[Arterial]] [[thrombosis]] ([[TIA]], [[stroke]]), [[venous]] [[thrombosis]] leading to [[pulmonary]] [[embolism]] and [[pulmonary]] [[hypertension]], [[fetal]] loss, [[livedo reticularis]], response to [[anticoagulant]] therapy
*:*:* Worldwide
|[[Mitral]] and [[aortic]] [[valvular]] involvement<ref name="pmid10220649">{{cite journal| author=Espínola-Zavaleta N, Vargas-Barrón J, Colmenares-Galvis T, Cruz-Cruz F, Romero-Cárdenas A, Keirns C | display-authors=etal| title=Echocardiographic evaluation of patients with primary antiphospholipid syndrome. | journal=Am Heart J | year= 1999 | volume= 137 | issue= 5 | pages= 973-8 | pmid=10220649 | doi=10.1016/s0002-8703(99)70424-2 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10220649 }}</ref>, [[hypertension]], abnormal localisation of [[lesion]] on [[MRI]], positive [[Coombs]] test, [[proteinuria]], [[renal]] failure
*:*:* Most common in school-age children
|[[Clinical]] criteria plus presence of [[lupus anti-coagulant]] or moderate titres of [[IgG]] or [[IgM]] [[anti-cardiolipin]] or [[anti-beta-2-glycoprotein-I]] [[antibodies]] on two samples at least 12 weeks apart <ref name="pmid16420554">{{cite journal| author=Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R | display-authors=etal| title=International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). | journal=J Thromb Haemost | year= 2006 | volume= 4 | issue= 2 | pages= 295-306 | pmid=16420554 | doi=10.1111/j.1538-7836.2006.01753.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16420554 }}</ref>
*:*:* Mosquito vector
|[[Skin]] [[ulcerations]], [[thrombocytopenia]]<ref name="pmid11953980">{{cite journal| author=Cervera R, Piette JC, Font J, Khamashta MA, Shoenfeld Y, Camps MT | display-authors=etal| title=Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. | journal=Arthritis Rheum | year= 2002 | volume= 46 | issue= 4 | pages= 1019-27 | pmid=11953980 | doi=10.1002/art.10187 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11953980 }}</ref>, [[hemolytic]] [[anemia]], sudden [[visual]] loss/ [[deafness]]
*:*:* Gastrointestinal (GI) symptoms common
|}
*:* St. Louis encephalitis
*:*:* Wild bird reservoir
*:*:* Wild bird – mosquito cycle
*:*:* Throughout U.S.
*:* Japanese encephalitis
*:*:* Flavivirus endemic in Southeast Asia from India to Japan
*:*:* Mosquito transmission
*:*:* Vaccine available
*:* Mycoplasma infection
*:* Cytomegalovirus infection
*:* Ehrlichiosis
*:* Measles
*:* VZV/chickenpox
*:* Mumps encephalitis
*:*:* CNS features present in ~1% of cases
*:*:* Not all patients have parotitis
*:*:* Most common in winter and spring
*:*:* Most patients recover completely, but some patients left with deafness, seizure, and mental retardation
*:*:* Confirmed via culture or serology
*:* Mycoplasma
*:* Bacterial meningoencephalitis
*:* Other infectious encephalitidies
* '''Acute multiple sclerosis (MS)'''
*:* MS may not be possible to exclude, and to some extent depends upon the natural history of the patient’s disease; MS is typically a chronic disease with a recurrent or progressive course, and ADEM is usually an acute monophasic disease.  Both diseases are characterized by demyelination; it is acute in ADEM, and sustained or progressive in MS.  It is sometimes best to refer to the illness as an “acute demyelinating disease”, until the disease course declares itself.   
*:* Simultaneous optic nerve, brain and spinal cord involvement, as well as meningismus, drowsiness, coma and seizures, are features suggestive of ADEM instead of MS. 
*:* Optic nerve involvement is typically bilateral in ADEM, and unilateral in MS.  Transverse myelopathy is usually complete in ADEM, and partial in MS. 
*:* CSF protein is usually elevated in ADEM, and is often normal in MS.  CSF lymphocyte counts >50, and CSF polys are also uncommon in MS.
*:* In ADEM in contrast to MS, most MRI lesions enhance with gadolinium, suggestive that all lesions are active, and that the disease is therefore monophasic.
* '''Hypoxic encephalopathy'''
* '''Cerebrovascular disease'''
* '''CNS vasculitis'''
* '''Lupus cerebritis'''
* '''Toxin effect'''
* '''Acute toxic hepatoencephalopathy – Reye’s syndrome'''
*:* Acute liver and CNS disease in children under 15 years of age, characterized by progressive liver and CNS disease, commonly in association with the use of salicylates.   
*:* Often follows a viral infection, especially chickenpox or influenza.
*:* Patients often present with vomiting and progressive neurologic disease. Hypoglycemia is common. Jaundice is usually not a prominent feature.   
*:* The liver is enlarged and evidence of liver disease includes elevated transaminases, prothrombin time, and ammonia, hypoglycemia, and metabolic acidosis. Cerebral edema and brain neuronal degeneration occurs.
*:* Mitochondria dysfunction occurs in the liver, brain and muscle.  Liver cells show microvacuolization, as do renal tubules. 
*:* Mortality approaches 50%.


==References==
==References==
{{Reflist|2}}
{{Reflist|2}}




[[Category:Disease]]
[[Category:Infectious disease]]
[[Category:Neurological disorders]]
[[Category:Neurology]]
[[Category:Neurology]]
{{WS}}
{{WH}}

Latest revision as of 11:50, 10 November 2022

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sujaya Chattopadhyay, M.D.[2]

Overview

The differential diagnoses of Acute disseminated encephalomyelitis include:

Differential Diagnosis

Disease Clinical manifestations Para-clinical findings Gold standard Additional findings
Viral encephalitis [1] Can occur in any age characterised by fever and occasional prodromal illness Leukocytosis in blood; T2-weighted MRI shows multiple diffuse hyperintensities overlying the grey matter and white matter of bilateral cerebral cortices, and to a lesser extent the basal ganglia, brainstem and cerebellum; lymphocytic pleocytosis with elevated protein and normal glucose in CSF. CSF analysis for viral cultures and serological assays History of recent travel, animal bites (Lyme disease/rabies), contact with childhood exanthema and polio, high-risk occupations and drug abuse; skin rashes (VZV,Measles, Rickettsia). HSV may cause fronto-temporal signs, aphasia, personality changes and focal seizures while myelitis is seen in polio infection.
HIV encephalopathy[2] Waxing and waning pattern of psychomotor retardation, decreased memory, concentration and attention span. Tremor, ataxia, hyperreflexia, hypertonia, progressive decline in MMSE scores[3]. Typical absence of cortical signs and symptoms Increase in CSF protein, cell count; multiple symmetric, hyperintense, non-enhancing subcortical foci on T2-weighted MRI[4]. Identification of HIV RNA in CSF Bowel and/or bladder complaints
Multiple sclerosis Sensory disturbances, walking difficulties, dizziness, vision problems, intestinal, urinary and sexual dysfunction, cognitive and emotional impairment[5] MRI of the brain and spinal cord showing new lesions, both enhancing and non-enhancing, disseminated in space and time[6]; evoked potentials test demonstrate demyelination in the optic nerve and CNS[7]; Myelin basic protein and IgG oligoclonal bands on CSF analysis[8]; vitamin deficiencies in blood sample[9]. T2-weighted MRI of the brain and spinal cord showing new patchy lesions, both enhancing and non-enhancing, disseminated in space and time[6] Urinary tract infections, depression, social, vocational and psychological complications[10]
Antiphospholipid antibody syndrome[11] Arterial thrombosis (TIA, stroke), venous thrombosis leading to pulmonary embolism and pulmonary hypertension, fetal loss, livedo reticularis, response to anticoagulant therapy Mitral and aortic valvular involvement[12], hypertension, abnormal localisation of lesion on MRI, positive Coombs test, proteinuria, renal failure Clinical criteria plus presence of lupus anti-coagulant or moderate titres of IgG or IgM anti-cardiolipin or anti-beta-2-glycoprotein-I antibodies on two samples at least 12 weeks apart [13] Skin ulcerations, thrombocytopenia[14], hemolytic anemia, sudden visual loss/ deafness

References

  1. ↑ Kennedy PG (2004). "Viral encephalitis: causes, differential diagnosis, and management". J Neurol Neurosurg Psychiatry. 75 Suppl 1: i10–5. doi:10.1136/jnnp.2003.034280. PMC 1765650. PMID 14978145.
  2. ↑ "StatPearls". 2022. PMID 32310354 Check |pmid= value (help).
  3. ↑ Nir TM, Jahanshad N, Busovaca E, Wendelken L, Nicolas K, Thompson PM; et al. (2014). "Mapping white matter integrity in elderly people with HIV". Hum Brain Mapp. 35 (3): 975–92. doi:10.1002/hbm.22228. PMC 3775847. PMID 23362139.
  4. ↑ Valcour V, Paul R, Chiao S, Wendelken LA, Miller B (2011). "Screening for cognitive impairment in human immunodeficiency virus". Clin Infect Dis. 53 (8): 836–42. doi:10.1093/cid/cir524. PMC 3174098. PMID 21921226.
  5. ↑ Gelfand JM (2014). "Multiple sclerosis: diagnosis, differential diagnosis, and clinical presentation". Handb Clin Neurol. 122: 269–90. doi:10.1016/B978-0-444-52001-2.00011-X. PMID 24507522.
  6. ↑ 6.0 6.1 Garg RK (2003). "Acute disseminated encephalomyelitis". Postgrad Med J. 79 (927): 11–7. doi:10.1136/pmj.79.927.11. PMC 1742586. PMID 12566545.
  7. ↑ Gronseth GS, Ashman EJ (2000). "Practice parameter: the usefulness of evoked potentials in identifying clinically silent lesions in patients with suspected multiple sclerosis (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology". Neurology. 54 (9): 1720–5. doi:10.1212/wnl.54.9.1720. PMID 10802774.
  8. ↑ Greene DN, Schmidt RL, Wilson AR, Freedman MS, Grenache DG (2012). "Cerebrospinal fluid myelin basic protein is frequently ordered but has little value: a test utilization study". Am J Clin Pathol. 138 (2): 262–72. doi:10.1309/AJCPCYCH96QYPHJM. PMID 22904139.
  9. ↑ Shah I, James R, Barker J, Petroczi A, Naughton DP (2011). "Misleading measures in Vitamin D analysis: a novel LC-MS/MS assay to account for epimers and isobars". Nutr J. 10: 46. doi:10.1186/1475-2891-10-46. PMC 3114718. PMID 21569549.
  10. ↑ Gelfand JM (2014). "Multiple sclerosis: diagnosis, differential diagnosis, and clinical presentation". Handb Clin Neurol. 122: 269–90. doi:10.1016/B978-0-444-52001-2.00011-X. PMID 24507522.
  11. ↑ Cuadrado MJ, Khamashta MA, Ballesteros A, Godfrey T, Simon MJ, Hughes GR (2000). "Can neurologic manifestations of Hughes (antiphospholipid) syndrome be distinguished from multiple sclerosis? Analysis of 27 patients and review of the literature". Medicine (Baltimore). 79 (1): 57–68. doi:10.1097/00005792-200001000-00006. PMID 10670410.
  12. ↑ Espínola-Zavaleta N, Vargas-Barrón J, Colmenares-Galvis T, Cruz-Cruz F, Romero-Cárdenas A, Keirns C; et al. (1999). "Echocardiographic evaluation of patients with primary antiphospholipid syndrome". Am Heart J. 137 (5): 973–8. doi:10.1016/s0002-8703(99)70424-2. PMID 10220649.
  13. ↑ Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R; et al. (2006). "International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS)". J Thromb Haemost. 4 (2): 295–306. doi:10.1111/j.1538-7836.2006.01753.x. PMID 16420554.
  14. ↑ Cervera R, Piette JC, Font J, Khamashta MA, Shoenfeld Y, Camps MT; et al. (2002). "Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients". Arthritis Rheum. 46 (4): 1019–27. doi:10.1002/art.10187. PMID 11953980.

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