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Abstract

Background

The occurrence of antiphospholipid antibodies (aPLs) and headache comorbidity in the presence or absence of underlying autoimmune diseases remains unclear.

Aim

The aim of this review was to summarize the relationship between headache and aPLs based on evidences from cohort studies and case reports, in addition to examining the treatment strategies that resolved headache in aPLs-positive individuals.

Methods

A comprehensive literature search was conducted through PubMed, ISI Web of Science and Google Scholar. A total of 559 articles were screened and the appropriate articles were selected based on quality and level of evidence.

Results

Cohort studies (n = 27) from Europe, North America and Asia demonstrated comorbidity of aPLs and headache in antiphospholipid syndrome, systemic lupus erythematosus (SLE) and neuropsychiatric SLE patients. Significantly higher association between migraine and aPLs was observed (n = 170/779; p < 0.0001) in individuals without any underlying diseases. Our analysis of shortlisted case reports (n = 17) showed that a higher frequency of anticardiolipin antibodies were present in subjects with different autoimmune disorders (70.6%). Corticosteroids were highly effective in resolving headache in aPLs-positive individuals.

Conclusion

Higher frequency of comorbidity between aPLs and headache was observed in healthy individuals and patient cases. Therefore, experimental studies are warranted to evaluate the aPLs-induced pathogenic mechanism of headache.

Keywords

Lupus anticoagulant anticardiolipin antibodies anti-β2GPI antibodies headache migraine

Introduction

Headache is one of the most common forms of nervous system disorder. It has been reported that up to 54.4% of the world population experience headache at some point in their lifetime (1), and headache disorders are denoted as the third highest major cause of disability worldwide (2). According to the International Headache Society (IHS), the majority of the headaches are primary headaches (i.e., not caused by any underlying diseases). Primary headaches are further classified into migraine, tension-type headache (TTH), trigeminal autonomic cephalalgias (TACs) and other primary headache disorders (3).

Different types of primary headaches, especially TTH and migraine, are among the most commonly reported neurologic manifestations in systemic autoimmune diseases including antiphospholipid syndrome (APS) (4) and systemic lupus erythematosus (SLE) (5). Based on the updated classification criteria (6), definite APS is characterized by the presence of antiphospholipid antibodies (aPLs) including lupus anticoagulant (LA), anticardiolipin (aCL) antibodies, and anti-β2-glycoprotein I (β2GPI) antibodies. The presence of aPLs was observed in 75.4% of pediatric (7) and 72% of adult SLE patients (8), and according to the recent SLICC classification criteria (9), aPLs positivity (LA, aCL, anti-β2GPI or false-positive rapid plasma reagin) is one of six of the immunological criteria for the diagnosis of SLE.

The objective of this review was to summarize and discuss the coexisting relationships between different types of headaches and aPLs in the presence or absence of underlying disease based on cohort studies and clinical evidence. Additionally, we summarize current treatment strategies that resolve headache in aPLs-positive individuals.

aPLs and the central nervous system

Interference in normal brain functions occur when aPLs transverse the blood-brain barrier (BBB) or are synthesized within the brain (10,11). In the brains of healthy individuals, the entrance of aPLs is inhibited by the physiological and astrocyte-mediated biochemical support of the BBB (12). Although the exact mechanism of aPLs’ entrance into the central nervous system in patients is unclear, some studies have suggested that aPLs may cause dysfunction of endothelial cells (13,14) followed by the disruption (15) or inflammation (16) of the BBB to allow access into the brain. Interestingly, neurological dysfunctions have been associated with aPLs-mediated pathophysiological mechanisms. For instance, an ex vivo study demonstrated that the anti-β2GPI antibody can bind directly to neurons and astrocytes, causing reduced viability of these cells (17).

Another experimental study with rat’s brain extract showed that aPLs can potentially disrupt neuronal function by exerting a direct action on nerve terminals (10). An in vivo study demonstrated that aPLs can directly interfere with the glutamatergic cerebellar granule cells of excitatory pathways, leading to neuronal dysfunction via over-activation of the N-methyl-D-aspartate glutamate receptor (18). Both neuronal toxicity and dysfunction have also been observed to occur via aPLs-mediated complement activation (19). Nevertheless, although the impact of aPLs on neurological dysfunction is notable, to date there is no experimental evidence exist that links the pathophysiological influence of aPLs with headache development.

Methods

The clinical and management evidence discussed in this review was obtained by implementing a systematic search strategy (see Appendix A). PubMed, ISI Web of Science and Google Scholar databases were used for the search by using different keywords combined with Boolean operators ‘AND’ and ‘OR’. Only English articles were eligible for inclusion, without search year restrictions, and the last date of search was 6 January 2017. All types of research articles, such as prospective, retrospective, case study, meta-analysis and in vivo studies, were included where the presence or absence of aPLs was assessed in migraine patients with or without autoimmune diseases such as APS and SLE. Articles were chosen through an independent, unbiased selection of articles by MAI and FA. A PRISMA flow diagram is presented in Figure 1 illustrating how the articles of interest were selected. Statistical comparison between the proportion of adults and pediatric migraineurs with aPLs compared with healthy controls was conducted using the chi-squared test, and differences were considered to be statistically significant for two-sided p < 0.05.

Figure 1.

PRISMA flow diagram on the study selection process.

Relationship between aPLs and migraine

Migraine is a primary type of headache disorder characterized by recurrences of headaches with moderate to severe intensities. Migraine can be with or without aura (brief episodes of visual disturbance) (3). Currently, migraine is known as an assembly of confounding neurological factors involving the brain and the connecting tissues as the key performers during a migraine attack. Cortical spreading depression, the contribution of neuronal ion channels, transporters for the cortical excitatory or inhibitory imbalance, as well as activation of the trigeminovascular system and its essential neuropeptides, can render migraineurs vulnerable to an attack (20).

According to the Euro-Phospholipid Project (n = 1,000) (21) and the Latin American study (n = 100) (22) on the adult APS population, migraine is a common clinical symptom presenting in 20.2% (with 36.3% LA and 81.7% aCL positivity) and 35.2% (with 40% LA and 88% aCL positivity), respectively. In the presence of aPLs (IgG aCL), the occurrence of migraine was significantly higher in women compared to men (10% vs. 0%, p = 0.01) (23). These findings are consistent with our re-analysis of 11 case-control studies published between 1991 and 2014 (24 –34), where the frequency of aPLs (LA, aCL and anti-β2GPI) in patients (n = 170/779; 21.8%) was significantly higher (p < 0.0001) compared to the frequency among the healthy controls (n = 63/741; 8.5%) (Table 1).

Table 1.

Prospective case-control studies evaluating the association between aPLs and adults or pediatric migraineurs compared to healthy controls.

No.	Type of participants	Migraineurs with aPLs (%)			Controls with aPLs (%)			p-value				Conclusion of the studies	Year, (References)
No.	Type of participants	LA	aCL	Anti-β2GPI	LA	aCL	Anti-β2GPI	LA	aCL	Anti-β2GPI	aPLs	Conclusion of the studies	Year, (References)
1	Adults¹	3.1	1.4	8.8	0.0	0.4	2.6	0.007	0.273	0.004	4 × 10⁻⁴	The levels of LA and anti-β2GPI were significantly different among migraineurs; migraine and aPLs may comorbid with each other.	2011, (25)
2	Adults	20.0	32.5	10.0	0.0	5.5	0.0	0.048	0.043	0.299	0.009	Migraineurs with positive aPLs presented with persistent headaches.	2007, (31)
3	Pediatrics²	NR	56.6	NR	NR	0.0	NR	NR	1 × 10⁻⁶	NR	1 × 10⁻⁶	Pediatric patients had significantly higher aCL levels.	2006, (34)
4	Adults	NR	NR	57.3	NR	NR	38.1	NR	NR	0.016	0.016	The frequency of migraine attack was positively correlated with the presence of anti-β2GPI.	2009, (30)
5	Adults	NR	8.5	NR	NR	0.0	NR	NR	0.030	NR	0.030	The presence of aCL is prominent in patients with migraine attacks, which may explain its pathogenesis.	1991, (29)
6	Adults	0.0	2.9	3.9	1.9	2.9	5.9	0.155	1.000	0.516	0.118	No significant difference in the presence of aPLs was observed.	2014, (28)
7	Pediatrics	5.7	15.3	9.6	6.5	11.4	6.5	1.000	0.541	0.730	0.367	The prevalence of aPLs did not differ significantly between migraineurs and non-migraineurs. However, their roles in contributing to pediatric migraine pathogenesis cannot be ruled out.	2004, (26)
8	Adults	20.0	NR	NR	0.0	NR	NR	0.224	NR	NR	0.224	The levels of LA in migraine patients may not be high enough to cause injury to the endothelial cells.	1991, (33)
9	Pediatrics	NR	10.0	NR	NR	7.5	NR	NR	1.000	NR	1.000	The presence of aCL does not have an implication on the pathogenesis of pediatric migraine.	2000, (27)
10	Adults	NR	0.0	NR	NR	0.0	NR	NR	NC	NR	NC	Although aCL level among migraineurs was within the normal range, a higher frequency of factor V Leiden mutation was observed.	2002, (32)
11	Pediatrics	NR	100.0	0.0	NR	0.0	0.0	NR	NC	NC	NC	The presence of aCL may play a major role in the pathogenesis of pediatric migraine.	2006, (24)

Adult patients’ age ≥ 18 years; ²Pediatric patients’ age < 18 years; aPLs: Antiphospholipid antibodies; LA: Lupus anticoagulant; aCL: Anticardiolipin antibody; β2GPI: β2-glycoprotein I; NR: Not reported; NC: Not calculable; significant p-values (p < 0.05) are emboldened.

However, nonexistent or weak association of aCL with migraine was observed in three case-control studies on migraineurs compared with non-healthy controls: (i) aCL positivity did not differ between migraineurs (n = 71) and the non-healthy control group (n = 32) (35); (ii) the frequency of aCL positivity of migraineurs with transient focal neurologic events (n = 1,015) was not significantly different from the control group (n = 366) (36); (3) weakly-elevated levels of aCL titer were observed in 56% of migraineurs (n = 25) (37). Similarly, a monozygotic twin study found no association of aPLs (IgG or IgM aCL and anti-β2GPI) with migraine positive twins compared with migraine negative twins (38). Nonetheless, the main limitation was acknowledged by the authors in terms of diagnosis of migraine in their monozygotic twin study, where the diagnosis was dependent on questionnaires and the validity of self-reporting can be unreliable for certain cases. Additionally, it was unclear whether the migraine-negative twins were healthy or free of underlying diseases.

Comorbidity of aPLs with cephalalgia in patients with antiphospholipid syndrome (APS)

Although headache is not included in the clinical criteria for the diagnosis of definite APS, it has been reported as one of the most commonly observed neurologic manifestations in APS patients. For instance, a recent retrospective review (2014) demonstrated that migraine was the most common (87%) clinical manifestation where APS co-existed with different types of autonomic disorders such as postural tachycardia syndrome, neurocardiogenic syncope and orthostatic hypotension (39). Based on the pediatric-APS registry, the frequency of migraine is reported to be only 7% in pediatric APS (age range: 1.0–17.9 years) population (40). Here, we summarize the supporting studies conducted on European, North American and Asian APS patients to evaluate the association of aPLs with headache.

Europe and North America

A 15-year (1987–2001) retrospective follow-up study (n = 128) was conducted on primary APS (PAPS) patients (APS without other autoimmune diseases) in four different hospitals across Spain, the United Kingdom and Mexico, where approximately 40% (n = 51 of 128) were reported to occur with migraine while the presence of both LA and aCL (IgG or IgM isotype) occurred in 65%, 86% and 39% of the patients, respectively (41). A similar trend of aPLs positivity was subsequently reproduced in a Spanish cohort (n = 30) of APS patients associated with dementia (42). In this study, migraine was the most common neurologic feature (23%) in the APS patients along with the presence of LA (72%) and high titer of aCL (83%). Later, in 2010, these findings were reflected in another 12-year prospective follow-up study on echocardiography involving Spanish APS patients (n = 53), where the frequency of migraine was significantly higher (p = 0.02) and the presence of LA and aCL was reported (43).

In 2005, headache was observed in 67% PAPS patients (n = 125) from Russia (44) in the presence of aPLs (LA and/or aCL). Similar findings were reported in an observational study on a Polish cohort involving APS patients with SLE (n = 53), where headache was observed in 37.9% of the population and the presence of aPLs was shown to be a strong contributor of neurologic manifestations including headache (45).

All of the studies conducted on the European population with APS showed the co-existence of headache with LA and/or aCL, except for the study in a group of Serbian APS patients (n = 374) (46). In the Serbian cohort study, migraine was observed in 26.9% patients with PAPS (n = 260), while 32.5% of APS (n = 114) was associated with other diseases. In addition, a significant relationship between migraine and the absence of LA (p = 0.014) was observed, although the presence of IgM aCL was significantly associated with PAPS migraineurs (p = 0.017). The reason behind the absence of LA association with migraineurs in the Serbian cohort was unclear, however the difference in the proportion of migraineurs positive or negative for LA was not remarkable, 23.3% (n = 44 of 107) vs. 34.1% (n = 63 of 107), respectively.

Asia

In Singapore, a cohort of confirmed APS patients (n = 59; the majority (68.2%) were of Chinese ethnicity) were reviewed retrospectively for two years (2004–2005), where headache was observed in 25.4% and LA, IgG and IgM aCL were ≥ 2 times positive in 27.6%, 35.8% and 2.2% of those patients, respectively (47). Later, in 2014, a six-year (2008–2013) a multi-centre retrospective study on the Chinese APS population (n = 51) demonstrated that in the presence of LA (18.7%), aCL (75%) and anti-β2GPI (37.5%), the frequency of headache was significantly higher (p = 0.02) in neurological APS (50%) compared with rheumatology APS (20%) (48). We conclude that the presence of headache was significantly associated with the presence of aPLs in Asian populations, particularly those of Chinese ethnicity or descendants.

Comorbidity of aPLs with cephalalgia in patients with systemic lupus erythematosus (SLE)

According to the latest SLE classification criteria (9), one of the laboratory diagnostic criteria of definite SLE is the presence of aPLs (LA, aCL or anti-β2GPI). Although headache is not a clinical feature in diagnosing SLE, it is one of the most common clinical features of SLE patients (49). Here we discuss the existing clinical evidence supporting the frequent occurrence of aPLs and headache comorbidity in SLE patients.

North America

In 1998, a prospective follow-up study was conducted on American SLE patients (n = 27) for 34 months, where 67% of the patients had a prominent history of migraine-like headache. LA was positive in 72%, and a high titer of IgG aCL ( > 100 GPL) was observed in all of the patients (50). Later, in 2004, aCL was also found as a comorbid antibody in Mexican SLE patients with headache. In this cross-sectional study with a higher number of SLE patients (n = 81), 33 (41%) presented with different types of cephalalgias including migraine with aura (18%), migraine without aura (7%), episodic TTH (7%), chronic TTH (4%) and mixed headache (5%). In these SLE patients with headache, a higher titer of IgA (7%), IgG (7%) and IgM (50%) aCL (OR = 2.7, 95% CI: 0.2–32.2, p = 0.17) or significantly higher titer of IgA (30%), IgG (3%) and IgM (10%) anti-β2GPI (OR = 4.5, 95% CI: 1.2–16.2, p = 0.01) were observed compared to non-headache SLE subjects (51). Another observational study in a large number of Canadian SLE patients (n = 391) coexisting with Raynaud’s syndrome showed that anti-β2GPI was frequently present in SLE headache sufferers. In this study, headache was observed in 46.1% of the SLE patients in addition to a strong association with anti-β2GPI (OR = 5.6, 95% CI: 1.8–16.9) and a moderate association with LA (OR = 1.3, 95% CI: 0.6–2.6) and aCL (OR = 1.2, 95% CI: 0.8–1.9) (52).

Based on the studies on the North American SLE population, the frequency of headache is distinctively higher in the presence of LA, aCL and anti-β2GPI. Nevertheless, none of the studies completely evaluated the presence of all of the three aPLs in SLE patients with headache.

Europe

In 1998, a pioneer study involved screening Dutch SLE patients (n = 175), where 10% of them had migraine. According to the laboratory profiles, 33% of the migraineurs were LA-positive and 66.6% had elevated titer of aCL (53). These findings were similar to those derived from a Romanian cohort of SLE patients (n = 167) with headache, where headache was reported as the most frequent clinical phenomenon (61%) that significantly coexisted with aPLs (LA and/or aCL) (54).

Besides the comorbidity of the common aPLs (LA, aCL and anti-β2GPI) with headache, a case-control study on Turkish SLE patients (n = 59) established an association of migraine with an unusual aPL (antiphosphatidylserine antibody (aPS)). In this study, a significant association was observed between migraine and the presence of IgA or IgM aPS (p < 0.01) and also with IgA (p < 0.001) or IgM (p < 0.01) aCL (55).

A recent case-control study (2015) with a German SLE cohort (n = 57) showed that headache was the most prevalent manifestation (n = 22/57) in addition to having an independent association with IgM anti-β2GPI (OR = 5.6, 95% CI: 1.17–26.88, p < 0.05) when compared to healthy controls (56). From these observations, we can conclude that in a European cohort of SLE patients, headache may be associated with LA, aCL, anti-β2GPI and aPS.

Asia

According to a 16-year follow-up (1984–2000) of a retrospective study on Chinese SLE subjects (n = 518), only 21 (4%) of the patients experienced headache (57). Although the investigators did not evaluate the association between headache and aPLs in those SLE patients (57), neuropsychiatric manifestations were significantly associated with LA (p = 0.001) and IgG aCL (p = 0.01), suggesting an association between cephalalgia and the presence of aPLs. In another 13-year retrospective study involving Chinese SLE and cerebral venous sinus thrombosis patients (n = 17), the association of headache with aPLs was investigated and persistent headache was found to be the most frequently reported clinical manifestation (n = 15/17; 88.2%) along with significantly higher (p = 0.04) incidence of aPLs (n = 7; 41.2%) (58).

Similar findings were established by another 14-year retrospective investigation from Korea. Although the study was conducted in a small cohort of SLE patients (n = 8) with idiopathic intracranial hypertension, all of the patients experienced headache, with 25% exhibiting co-occurrence with aPLs (59). These findings were comparable with another four-year retrospective study on a Saudi Arabian SLE population (n = 46), where headache was reported as the most frequent neurologic manifestations (28.3%) and 17.4% of the patients presented with LA and aCL (60). Nevertheless, the possibility that none of the patients with neurological presentations was positive for LA or aCL cannot be ruled out.

From the above observations, although a comorbid association of headache with LA and aCL is noticeable in the Asian populations, none of the studies evaluated the comorbid association of headache with anti-β2GPI, indicating that more studies in these areas are necessary.

Comorbidity of aPLs with cephalalgia in patients with neuropsychiatric systemic lupus erythematosus (NPSLE)

Headache is a common phenomenon among the neurological manifestations exhibited by SLE patients. “lupus headache” is a specific proposed term for the headaches experienced by patients with neuropsychiatric systemic lupus erythematosus (NPSLE) (5). A few retrospective studies were conducted to evaluate the association between headache and aPLs in NPSLE subjects.

Europe

Two British studies assessed the comorbidity of headache and aPLs in NPSLE patients. In 2003, the first retrospective study on a large cohort of the British SLE population (n = 323) investigated the prevalence of neuropsychiatric manifestations and their association with aPLs. Headache was reported as the most frequent manifestation among NPSLE patients (42.1%), as well as among SLE patients (24%) (61). According to the findings of this study, although high frequency of headache (32.3%) was significantly (p = 0.01) present in aPLs positive subjects (n = 127), the incidence of headache was moderately associated with LA (p = 0.06) and was not associated with IgM aCL (p = 0.55). The second retrospective study (2015) in a smaller cohort of British NPSLE patients (n = 108) showed similar findings where headache was the most frequently observed (28.5%) clinical manifestation and aPLs were positive in 39.8% of them (LA: 21.5%, IgG aCL: 30.1% and IgM aCL: 12.9%) (62).

We observed another two retrospective studies on Italian NPSLE subjects evaluating the comorbidity of headache and aPLs. According to the pioneer multicentre retrospective study on an Italian cohort (n = 326), headache was the most frequent neurologic event in patients with NPSLE (31.5%), where 67.3% had at least one of the three aPLs (LA: 39.3%, aCL: 54.9% and anti-β2GPI: 21.8%) (63). Comparable results were shown by another retrospective study (1999–2008) on Italian NPSLE patients (n = 152) where headache (migraine and TTH) was the most commonly observed neurologic manifestation (32.6%) in the presence of significantly higher levels (p < 0.05) of LA (27.5%) and aPLs (47.7%) (64) compared with non-headache NPSLE patients. Based on these European cohort studies on NPSLE, it is notable that headache co-exists with aPLs.

Asia

A number of studies evaluated the association of IgG aCL with headache in Asian NPSLE patients: (i) In a pediatric cohort of Indian NPSLE and SLE patients (n = 53), headache was the commonest neurologic manifestation (39.6%) in NPSLE patients (n = 27) with high frequency of IgG aCL (52.6%) (65) and (ii) In an Egyptian cohort of NPSLE patients (n = 16), a significant IgG aCL positivity (p = 0.001) was observed in severe NPSLE patients (66). Although LA was not found to be significantly present in NPSLE patients with headache in the Indian cohort, elevated levels of LA were detected in the Egyptian severe NPLSE cohort (p = 0.04). According to a recent (2015) cross-sectional comparative study (67) with Saudi Arabian NPSLE patients (n = 97), frequency of headache was higher in patients presenting with aPLs (32%) compared with patients without aPLs (23%).

Apart from the comorbid evidence of aPLs and headache from European and Asian clinical studies on NPSLE patients, a recent meta-analysis (2016) has also shed some light on the comorbid association. This meta-analysis, comprising a total of 1,383 NPSLE patients (in 28 published articles) found that headache was significantly associated with the presence of aPLs (OR = 2.05, 95% CI: 1.22–3.43, p = 0.007), aCL (OR = 1.89, 95% CI: 1.07–3.33, p = 0.029) and LA (OR = 1.81, 95% CI: 1.01–3.24, p = 0.046). In terms of anti-β2GPI, a moderate association was observed (OR = 2.70, 95% CI: 0.91–8.05, p = 0.075) in NPSLE patients (68). In the context of the comorbid association of headache with anti-β2GPI, only one study found to be associated with anti-β2GPI was selected in this meta-analysis. Therefore the conclusion of insignificant association of anti-β2GPI with headache remains undefined, as the odds ratio was 2.70 with the higher range of 95% confidence interval.

Other autoimmune diseases

In rheumatoid arthritis patients from Mexico (n = 29), headache (including migraine with and without aura) was observed in 34% of the patients (17% headache and 17% migraine) with elevated titer of aCL and anti-β2GPI (51). Headache was observed in 38% of the patients with Sjögren’s syndrome, where LA and aCL were positive among headache sufferers (54). In a group of multiple sclerosis patients (n = 20) with persistently elevated levels of IgG aCL (mean 38.8 ± 28.2 GPL), migraine-type headache was observed as the dominant (40%) clinical symptom, which is not a common feature of multiple sclerosis (69).

Comorbidity evidence from case reports published between 2000 and 2015

In addition to the clinical studies discussed above, we found 17 case reports (70 -86) demonstrating the co-existence of aPLs with headache in different autoimmune disorders including APS, APS associated with other diseases, SLE, patients with cerebral thrombosis, rhupus and arteritis (Table 2). Approximately 76.5% of the 17 case reports examined involved females with a mean age of 30.7 ± 14.5 years old. Seven of the studies reported were from Asia, six were from Europe, two were from South America and another two were of African-American descent. Among the case reports, aCL was the most common aPLs (70.6%), followed by LA (29.4%) and anti-β2GPI (17.6%) to coexist with headache. The association of aPLs positivity comorbid with cephalalgia is similar to that observed in the prospective or retrospective cohort studies, as discussed previously.

Table 2.

Summary of case reports presenting cephalalgia in the presence of aPLs.

No.	Associated diseases/features	Type of cephalalgia experienced	Age (years)	Sex	Ethnicity/ nationality	Positivity of aPLs	Year, (Reference)
APS and APS associated with other diseases
1	Primary APS	Migraine	28	F	French	LA, aCL and anti-β2GPI	2000, (70)
2	APS with SLE	Severe headache	20	F	Iranian	LA and aCL	2012, (71)
3	Catastrophic APS with SLE	Headache	22	F	African-American	LA and aCL	2015, (72)
4	APS with SLE and Raynaud’s phenomenon	Migraine	35	F	Argentine	LA, aCL (IgM) and anti-β2GPI (IgM)	2000, (73)
5	APS with SLE and meningitis	Severe headache	21	F	Israeli	aCL (IgG and IgM)	2000, (74)
6	APS with autoimmune intrahepatic cholangiopathy	Headache	26	F	Italian	At least one of the aPLs positive	2007, (75)
7	APS with probable HELLP syndrome	Severe headache	37	F	Spanish	At least one of the aPLs positive	2014, (76)
8	APS with hemangioblastoma	Migraine	27	M	British	At least one of the aPLs positive	2014, (77)
SLE
1	SLE with hypereosinophilic syndrome	Headache	34	F	Iranian	aCL	2009, (78)
2	SLE with HIV	Daily headache	39	F	African-American	aCL (IgG)	2001, (79)
3	SLE with unruptured middle cerebral artery aneurysm	Severe headache	22	F	Iranian	At least one of the aPLs positive	2012, (80)
Patients with cerebral thrombosis
1	Cerebral thrombosis	Headache	30	M	Brazilian	LA	2015, (81)
2	Sinus thrombosis	Headache	7	F	Indian	aCL	2005, (82)
3	Intracerebral venous thrombosis	Throbbing headache	40	M	Japanese	aCL	2000, (83)
Rhupus and arteritis
1	Rheumatoid arthritis and SLE	Headache	38	F	Israeli	aCL and anti-β2GPI	2015, (84)
2	Rheumatoid arthritis and SLE	Severe headache	21	F	Indian	aCL	2008, (85)
3	Temporal arteritis	Throbbing headaches	76	M	Taiwanese	aCL (IgG)	2005, (86)

APS: Antiphospholipid syndrome; aPLs: Antiphospholipid antibodies; F: Female; M: Male; SLE: Systemic lupus erythematosus; LA: Lupus anticoagulant; aCL: Anticardiolipin antibody; anti-β2GPI: Anti-β2-glycoprotein I; HELLP: Hemolysis, elevated liver enzymes, low platelet count; HIV: Human immunodeficiency virus.

Treatment strategies to resolve aPLs-positive cephalalgia

The optimal treatment strategy to resolve headache in the presence of aPLs is still unclear, since the association of aPLs with headache remains controversial. However, we observed a few studies addressing different treatment strategies to minimize headache in aPLs-positive patients with APS, SLE and NPSLE (Figure 2). From our observation, administration of corticosteroids either alone (87,88) or in combination with antithrombotic regimens (89), anticoagulants and immunosuppressive drugs (90) have been the most commonly used or successful treatment regimens in resolving headache (and other symptoms) in patients with APS, SLE, APS associated with SLE, and NPSLE (Figure 2).

Figure 2.

Summary of successful therapeutic strategies used in minimizing migraine or headache with elevated antiphospholipid antibodies.

Future implications and conclusion

From the prospective studies, retrospective studies and case reports discussed above, the coexistence of aPLs and headache is a notable phenomenon in patients with APS, SLE, APS associated with SLE and NPSLE or subjects without any underlying autoimmune diseases (Table 1). To date, there is no firm molecular pathogenic evidence of aPLs-induced headache, and whether aPLs contribute to headache pathogenesis represents an avenue for further research.

In terms of coexistence of APS with aPLs and headache, none of the studies (41 –47) actually evaluated the presence of anti-β2GPI (except for the most recent study (48)), although some studies (43,45 –47) were published following the availability of the updated APS criteria (6). Unlike the former Sapporo classification criteria (91), the updated APS classification criteria included anti-β2GPI as one of the laboratory parameters (besides LA and aCL). Therefore, for future investigations into APS with headache, establishing its association with anti-β2GPI in addition to LA and aCL is recommended. Moreover, prolonged follow-up prospective cohort studies with headache patients co-existing with aPLs would be interesting, to investigate whether they develop APS later in life.

Although IgA anti-β2GPI is neither included in the definite laboratory criteria of APS (6) nor that of SLE (9), interestingly IgA anti-β2GPI were reported to be present in 30% of the Mexican SLE patients with headache (51). Further clinical studies are required to clarify whether IgA anti-β2GPI is another factor contributing to the pathogenesis of headache in SLE patients. Additionally, since all of the reported findings on SLE are based on retrospective studies, the findings of prospective cohort studies may firmly conclude the comorbid tendency of cephalalgias and aPLs. Meta-analyses with the existing case-control studies are also required to determine whether aPLs are significantly associated with headache sufferers.

According to the individual studies, significant association of anti-β2GPI antibodies was observed in Western SLE patients with headache (51,56). Some studies assessed the presence of anti-β2GPI antibodies in neuropsychiatric APS (48) and SLE (63) patients, where headache was the most common neurologic manifestation; however, no comorbid association was reported. There appears to be a lack of studies on Asian SLE and Western non-SLE patients assessing the association of anti-β2GPI and migraine or headache.

A significant association of IgM aCL was observed in Turkish SLE (55) and Serbian PAPS (46) patients with migraine. A few studies on the Spanish (41,43), British (41,62), Mexican (41) and Singaporean (47) populations reported headache or migraine as the most common neurologic manifestations of APS. Although the presence of IgM aCL was reported in these studies, none of them assessed the comorbid association between IgM aCL and cephalalgia. A study of British NPSLE subjects (61) demonstrated a lack of association between the presence of IgM aCL and migraine. To the best of our knowledge, no study has been conducted on APS-associated SLE patients with migraine evaluating aCL antibody; future studies are thus warranted in this area.

Randomized controlled trials (RCTs) are warranted to evaluate the effects of conventional anti-migraine drugs or drugs for headache among patients with cephalalgia and positive aPLs. RCTs can be designed to determine whether steroids or immunosuppressive drugs can successfully resolve headache in the presence of elevated aPLs levels compared to the use of anti-migraine drugs alone.

Among the above-mentioned clinical studies, a major discrepancy was observed in terms of the cut-off levels of aPLs. Although there is a qualitative (medium to high titer) for SLE (9) and quantitative guidelines for APS confirmation (6), a more appropriate guideline (with cut-off values) is required to confirm positive aPLs in headache patients either in the presence or absence of systemic autoimmune diseases. In addition, the majority of studies on APS and SLE do not define the type of headache the patients suffered from (i.e. migraine (with or without aura), TTH and TACs). Therefore, for future association studies on aPLs and headache among APS or SLE patients, the types of existing headache should be precisely defined based on the latest headache classification criteria as set by the IHS (3).

Experimental studies (in vitro, in vivo and ex vivo) are required to examine whether aPLs are a contributory factor to the pathogenesis of headache in either the presence or absence of other autoimmune diseases. A firm knowledge of this association may allow early detection of different types of systemic, neurologic and autoimmune disorders including APS, SLE and cerebrovascular events, which may further prevent fatal complications. Therefore, headache and migraine in the presence of aPLs should not be neglected as a common symptomatic phenomenon by the patients, since this subgroup may require distinct therapeutic regimens to effectively resolve the disease and its clinical presentations.

Article highlights

The presence of antiphospholipid antibodies (aPLs) was significantly (p < 0.0001) high among migraineurs compared to healthy controls.

There is a strong co-existing tendency for aPLs and headache in patients with antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE).

Corticosteroids alone or in combination with other drugs (i.e. immunosuppressive regimens) could be noteworthy treatment options in treating aPLs-positive individuals with headache.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the Research University grant (1001/PPSP/813054), Universiti Sains Malaysia (USM). We would also like to acknowledge the USM Vice-Chancellor Award (2015/2016) and the USM Global Fellowship (2014/2015) awarded to Md. Asiful Islam and Fahmida Alam, respectively, to pursue their PhD degrees.

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Coexistence of antiphospholipid antibodies and cephalalgia

Abstract

Background

Aim

Methods

Results

Conclusion

Keywords

Introduction

aPLs and the central nervous system

Methods

Relationship between aPLs and migraine

Comorbidity of aPLs with cephalalgia in patients with antiphospholipid syndrome (APS)

Europe and North America

Asia

Comorbidity of aPLs with cephalalgia in patients with systemic lupus erythematosus (SLE)

North America

Europe

Asia

Comorbidity of aPLs with cephalalgia in patients with neuropsychiatric systemic lupus erythematosus (NPSLE)

Europe

Asia

Other autoimmune diseases

Comorbidity evidence from case reports published between 2000 and 2015

Treatment strategies to resolve aPLs-positive cephalalgia

Future implications and conclusion

Article highlights

Footnotes

Declaration of conflicting interests

Funding

References

Supplementary Material