Moyamoya angiopathy unmasking systemic lupus erythematosus

Abstract

A 47-year-old woman with history of seizure disorder (semiology of seizure unknown), not well controlled with antiepileptic drugs since last 30 years presented with 1-year history of intermittent throbbing headache. On the day prior to admission, she experienced worst headache, followed by loss of consciousness. On regaining consciousness, she had neck pain without any focal neurological deficit, but examination was marked by positive meningeal signs. She had history of oral ulceration, photosensitivity and small joints pain for which no medical consultancy was sought until. Following relevant investigations, this case came out to be moyamoya angiopathy secondary to underlying systemic lupus erythematosus. She was put on immunosuppressive and immunomodulator as per recommendations. Among neurological symptoms, headache improved dramatically without any further seizure recurrence till the 6 months of follow-up.

Background

Moyamoya angiopathy (MMA) is an intracranial angiopathy of unknown aetiology, characterised by bilateral progressive steno-occlusive changes of the intracranial portion of the internal carotid arteries (ICA) and proximal portions of the anterior cerebral artery (ACA) and/or middle cerebral artery (MCA).¹ MMA can be divided into Moyamoya disease (those without any associated disorder and bilateral stenosis) and Moyamoya syndrome (MMS) or Quasi-Moyamoya or Akin-Moyamoya (those with a well recognised associated condition and angiographic evidence of uni/bilateral stenosis).² Quasi-Moyamoya has been described with several autoimmune diseases including thyroid disorders, systemic lupus erythematosus (SLE), antiphospholipid antibodies syndrome and Sjogren’s. Though its exact etiopathogenesis is yet to be deciphered, chronic inflammation inducing fibrosis or angiogenesis due to the disruption of the adaptative responses, leading to onset or progression of MMA has been considered.³ Here, we present a case of MMS which unmasked an underlying SLE. This is the first reported case to our best belief from India. Author’s intention is to review previously published cases of SLE and MMA, providing a comparative analysis of our findings with previous reports.

Case presentation

A 47-year-old woman, non-hypertensive, non-diabetic, known case of seizure disorder, having recurrent episodes since the age of 17 years, was put on antiepileptics without much evaluation, following which her seizure frequency decreased but did not cease entirely, one episode in the last 3 years. The patient also had a history of frequent migraine-like headache episodes for last 1 year which was minimally responsive to analgesics. However, the patient had a recent change in headache, characterised by acute, severe, holocranial throbbing headache associated with episodes of vomiting and one episode of generalised tonic-clonic seizure followed by prolonged altered sensorium for next 3 days. On regaining consciousness after 3 days, she denied any focal weakness, there was also no sensory symptoms, abnormal movements or cranial nerve symptoms. There was no associated fever, weight loss or other systemic symptoms. However, on further probing, the patient admitted history of photosensitivity, oral ulcers as well as symmetrical predominantly small joint pain of upper and lower limbs for which no medical consultancy was taken earlier.

On initial evaluation, the patient was drowsy, pupils were normal size, reactive to light. Examination was marked by the presence of meningeal signs. She was moving all four limbs, and plantar was bilaterally unresponsive.

Investigations

Complete blood count showed mild microcytic anaemia. Metabolic parameters, coagulation profile, chest radiography were normal. HIV antibody and hepatitis B and C testing were negative. ECG and echocardiography also did not reveal any significant abnormality. Non-contrast CT brain revealed right temporal bleed with intraventricular haemorrhage (IVH) (figure 1). MR angiography revealed stenosis of bilateral terminal ICA and MCA with collateral formation, without any evidence of vessel wall thickening or tortuosity (figure 2). Digital substraction angiography was done, which confirmed the above findings and a diagnosis of MMA was made (figure 3). MR vessel wall showed eccentric thickening bilaterally with enhancement. Antinuclear antibody (ANA) came to be positive 4(+) at 1:160 titre, coarse speckled pattern, anti-double stranded DNA (anti-dsDNA) was raised, Ribonucleoprotein (RNP) was positive, however, complement levels were normal. A diagnosis of SLE was made based on American college of Rheumatology (ACR) criteria with mucocutaneous and musculoskeletal involvement, high titres of anti-dsDNA, with ANA positivity.⁴ Further searching for organ involvement revealed macroalbuminuria, however, there was no evidence of urinary cast. The patient denied permission for renal biopsy. Direct comb test and antiphospholipid antibodies were negative. ANA was not detectable in cerebrospinal fluid (CSF) sample.

Figure 1.

NCCT brain showing hyperdensities in right temporal lobe (A), along with hyperdensities in the ventricles (B). Intracerebral haemorrhage with intraventricular extension. NCCT, non-contrast CT.

Figure 2.

MR angiography showing cut-off at the terminal portions of bilateral internal carotid artery with non-visualisation of bilateral middle cerebral artery and anterior cerebral artery with evidence of collaterals and intracerebral haemorrhage.

Figure 3.

DSA showing evidence of stenosis of terminal ICA along with formation of collaterals in different views, right ICA anteroposterior (A), Left ICA anteroposterior (B), right ICA lateral (C), left ICA lateral (D). DSA, digital substraction angiography; ICA, internal carotid artery.

Differential diagnosis

Long-standing history (30 years) of seizure, headache for last 1 year along with excruciating headache, followed by unconsciousness with neck stiffness just before admission give rise to following differential diagnosis.

1. Arteriovenous malformation (AVM) with recent-onset haemorrhage.

2. Aneurysm with recent-onset rupture and subarachnoid haemorrhage.

3. Space occupying lesion (SOL) with recent-onset haemorrhage.

4. Primary IVH.

5. Subarachnoid haemorrhage.

6. MMA with IVH.

Further analysing the history and clinical examination, a long-standing history of seizure might be due to some vascular anomaly like AVM and aneurysm, as can history of headache for 1 year, corroborative with vascular headache (since great vessels are pain sensitive), following rupture they can lead to either subarachnoid space or intraventricular extension leading to presentations of sudden unconsciousness and neck stiffness. SOL with recent haemorrhage can fit in with this case description, but odds being, usually a malignant SOL gives rise to haemorrhage and it is quite unusual that a malignant SOL which was the probable source of seizure, bled after 30 years. MMA may remain undiagnosed without meticulous evaluation particularly when presenting with non-paretic symptoms like seizure and headache and ultimately can give rise to IVH and subsequent unconsciousness and neck stiffness, particularly in adults, where there is increased chance of intracerebral haemorrhage as opposed to infarction in childhood, because of rupture of immature collaterals.²

1. On detailed enquiry, as there were history of small joint pain, oral ulceration and photosensitivity, further extension of differential diagnosis in terms of an underlying connective tissue disorder like SLE, rheumatoid arthritis and Behcet disease was made.

To correlate these systemic diseases with central nervous system (CNS) manifestations in this case, a possibility of secondary CNS vasculitis was considered. However, 30 years history of seizure, absence of cranial nerve involvement and absence of fluctuations in disease course were not fitting.

ANA, ANA profile, anti-dsDNA titers, complement levels, antiphospholipid antibodies, rheumatoid factor, anticitrullinated peptide antibodies and acute phase reactants (erythrocyte sedimentation rate and C reactive protein) were done to clinch the diagnosis. MR angiography revealed classical MMA. ANA was positive with coarse speckled pattern in association with high titres of anti-dsDNA. ACR criteria for diagnosing Lupus was fulfilled.⁴ Overall diagnosis of MMS secondary to underlying SLE presenting with lobar haemorrhage with intraventricular extension was made.

Treatment

The patient was put on antiepileptics, levetiracetam 500 mg two times per day, initially intravenous later changed to oral form, along with other supportive management. Following the initial week, the patient was put on steroid, oral prednisolone 50 mg once daily owing to the evidence of chronic inflammation aggravating MMA. Oral hydroxychloroquine 200 mg once daily to account for mucocutaneous and musculoskeletal features attributed to SLE.⁵ Further CT perfusion study was done after 6 weeks, which did not reveal any evidence of significant ischaemia. Hence, it was planned to continue with the conservative management and consider revascularisation surgery following stabilisation. The oral prednisolone was continued at 50 mg/day for 6 weeks and then was gradually tapered to 15 mg/day at the end of 6 months with our aim to reduce it to 7.5 mg/day dosing on subsequent follow-ups to limit the side effects.

Outcome and follow-up

The patient has been under our follow-up for 6 months now and has had marked improvement in her symptoms of headache, there were no further episodes of seizures and no focal neurodeficits on examination. There was also improvement in systemic features of SLE, Systemic lupus erythematosus disease activity index (SLEDAI) score decreased to 4 from 22 at initial presentation.

Discussion

Cerebrovascular event (CVE) is one of the most severe form of neuropsychiatric manifestation of SLE, usually occurring close to the diagnosis of the disease. It is quite common with reported prevalence of 2%–19% in various studies. However, the attribution of a CVE in SLE is challenging. MMA is an uncommon cause of CVE in SLE.⁶ Only 17 reported cases (including our case) are documented in literature and have been summarised in table 1.

Table 1.

Summarisation of demography, clinical features, management and outcome of cases of SLE with MMA documented in literature

	Matsuki et al16	Vlad et al17	El Ramahi and Al Rayes18	Inoue et al19	Lee et al20	Jeong et al21
1. Demography	30 y, F, Japan	24 y, F, Korea	18 y, M, Saudi Arabia	17 y, F, Japan	13 y, F, Korea	18 y, F, Korea
2. First neurological symptom and age	Recurrent TIA (right homonymous hemianospia), 16y	Poor scholastic performance, 19 y	Right complete hemiparesis, 18 y	TIA, 17 y	Headache, vomiting, 13 y	Hemiparesis, 18 y
3. Neurological symptom leading to diagnosis of MMA and age	Recurrent TIA (Right homonymous hemianospia), 30 y	Hemiparesis, 19 y	Complete hemiparesis, Multiple cranial N palsy, alexia, anomia, opposite side hemiparesis, global aphasia, 18 y	TIA, 17 y	Headache, vomiting, 13 y	Hemiparesis, 18 y
4. Age at diagnosis of SLE	29 y	24 y	17 y	2 weeks after birth	12 y	17y
5. Organs involved in SLE	Renal, haematological, mucocutaneous, musculoskeletal	Renal, haematological, mucocutaneous, musculoskeletal, constitutional	Mucocutaneous, musculoskeletal	Neonatal lupus, cardiac-complete heart block	Renal, haematological, mucocutaneous, musculoskeletal	Renal, Mucocutaneous, Serositis
6. Other associated condition	Sjogren’s	None	None	Born to a mother with Ro/SS-A (+)	K/C/O Familial MMA	Later found have PNET
7. SLE disease activity	Active	Active	Inactive	Inactive	Inactive	Active
8. Ongoing immunosuppressive therapy when MMA was diagnosed	Yes	No	Not described	No	Yes	No
9. Radiological features	No acute event	Subcortical haemorrhage with IVH	Multiple, sequential Cortical infarcts	Ischaemia	Cortical infarct	Subcortical infarct
10. Angiographic findings	Unilateral (U/L)	B/L	B/L	B/L	B/L	B/L
11. Therapy received in the current event	Steroid, plasmapheresis, Imidazole nucleotide, aspirin	Steroid, shunting (underwent B/L revascularisation surgery(Sx), on aspirin for 5 y)	Steroid, anticoagulation (later discontinued), cyclophosphamide, B/L revascularisation Sx, aspirin,	Permanent pacemaker (dual chamber DDD mode), antihypertensive (later not required)	Aspirin, analgesic, supportive	Steroid, Apirin, anti-hypertensive, revascularisation Sx
12. SLE outcome	Not mentioned	Remission	Remission	Remission	Remission	Remission
13. Neurological outcome and follow-up period	Partial remission of symptoms of TIA (2 years)	Improved (5 months) though second episode after 5 y following revascularisation Sx	Improved (9 months)	Not described	Improved severity and frequency of headache (2 y)	Improved (2 months)

	Yeung et al22	Mok and Poon23	Tomiyama et al14	Wang et al24	Troedson et al25
1. Demography	20 y, F, China	20 y, F, Chinya	54 y, F, Japan	24 y, F, China	18 m, F, Australia (Maltese background)
2. First neurological symptom and age	Headache, 15 y	Headache, 15 y	Cataplexy, 53.5y	Hemiparesis, seizure, 23.5 y	Gait disturbance, 3 y
3. Neurological symptom leading to diagnosis of MMA and age	Hemiplegia, 20 y	Hemiplegia, 20 y	Cataplexy, 54 y	Hemiparesis, seizure, 23.5 y	Focal seizure, 4 y
4. Age at diagnosis of SLE	10 y	10 y	34 y	22.5 y	2.5 y
5. Organs involved in SLE	Renal, haematological, mucocutaneous, musculoskeletal, serositis	Renal, mucocutaneous, musculoskeletal	Not described	Renal, aaematological	Mucocutaneous, constitutional, vasculitis (Chillbains)
6. Other associated condition	None	None	Hypothyroidism	None	Aicardi Goutieres Syndrome, C1q deficiency
7. SLE disease activity	Inactive	Active	Not described	Active	Active
8. Ongoing immunosuppressive therapy when MMA was diagnosed	Yes	Not described	Yes	No (self-withdrawn)	Yes
9. Radiological features	Acute watershed infarct, old cortical infarct	Right cerebral and left frontal hypoperfusion	Watershed infarct	Capsuloganglionic bleed	Cortical infarct
10. Angiographic findings	B/L	B/L	U/L	B/L	B/L
11. Therapy received in the current event	Steroid, IVIg, planned for revascularisation surgery	Steroid, anticoagulation, cyclophosphamide followed by azathioprine, scheduled for revascularisation Sx	Antiplatelet, cilostazol, U/L revascularisation Sx	Steroid, tacrolimus	Steroid, azathioprine(later replaced by MMF), B/L revascularisation Sx, cyclophosphamide, FFP transfusion
12. SLE outcome	Remission	Remission	Not described	death	Remission
13. Nurological outcome	Improved	Improved	Improved	Repeat ICH 1.5 month later, death	Progression(1y)

	Lee et al15	Zhou et al26	Lee et al27	Tanaka et al13	Our case
1. Demography	17 y, F, Korea	22 y, F, China	3Y, M, Korea (another sibling-8 Y, F)	29 y, F, Japan	47 y, F, India
2. First neurological symptom and age	Complete hemiparesis, 17	Complete hemiparesis, hemianesthesia, 22 y	Recurrent TIA (mono/hemiplegia), 3 y	Headache, LOC (29 y)	?Seizure, 17 y Headache, 46 y
3. Neurological symptom leading to diagnosis of MMA and age	Complete hemiparesis, 17 y	Left complete hemiparesis, hemianesthesia, 22 y	Recurrent TIA (mono/hemiplegia), 3 y, (Sibling-8 y)	Headache, LOC (29 y)	Headache, Seizure, LOC,47 y
4. Age at diagnosis of SLE	15 y	22 y (3 weeks prior)	6 y (Sibling-11 y)	29 y (1 month before)	47 y
5. Organs involved in SLE	Renal, haematological	Renal, haematological, mucocutaneous, constitutional	Renal, haematological, constitutional, vasculopathy	Renal, haematological	Renal, mucocutaneous, musculoskeletal
6. Other associated condition	None	None	Spondyloenchondroplasia, immunodysregulation	Pregnancy	None
7. SLE disease activity	Inactive	Active	Not described	Active	Inactive
8. Ongoing immunosuppressive therapy when MMA was diagnosed	Yes	No	No	Yes	No
9. Radiological features	No infarct	Cortical infarct	Ischaemia with cerebromalacia	Lobar haemorrhage	Lobar bleed with secondary IVH
10. Angiographic findings	B/L	B/L	B/L	B/L	B/L
11. Therapy received in the current event	Aspirin, U/L revascularisation Sx	Steroid, aspirin	B/L revascularisation Sx at 3 y age	Steroid, Tacrolimus, HCQS, Aspirin, Anticoagulation (later withdrawn)	Steroid, HCQS, antiepileptic
12. SLE outcome	Remission	Remission	Not described	Remission	Remission
13. Neurological outcome	Improved (14 month)	Improved (2 y)	Progressed (recurrent TIA, choreoathetoid movements, headache)	Improved (5 months)	Improved (6 months)

F, female; HCQS, Hydroxychloroquine; IVH, intraventricular haemorrhage; IVIg, intravenous Ig; LOC, Loss of consciousness; M, male; MMA, Moyamoya angiopathy; MMF, Mycophenolate Mofetil; PNET, Primitive neuroectodermal tumor; Ro/SS-A, Anti-Sjögren's-syndrome-related antigen A autoantibodies; SLE, systemic lupus erythematosu; TIA, transient ischaemic attack; y, years.

The distribution of cases of MMA with SLE was predominantly Eastern Asia. Fourteen of 17 cases occurred from this region, consistent with the higher prevalence of MMA in this population.⁷ This is the first case to be reported from India, where recent studies have shown that it may not be so uncommon.²

There was a striking female preponderance among the reported cases, 15 out of 17 cases were female, compatible with both MMA and SLE wherein a female predilection is noted.^{2 8}

The diagnosis of SLE preceded the detection of MMA in 12 of the 17 cases, simultaneous diagnosis was made in two other cases. Among the reported cases before ours, except for one, SLE was diagnosed within the third decade of life. Our case had a later presentation of SLE, diagnosis was made at the age of 47 years, although symptoms of SLE were present 2 years prior to the diagnosis.

Among the cases in which SLE preceded the diagnosis of MMA, it was found that MMA occurred within 2 years of diagnosis of SLE in majority of the cases (9 out of 12). Even among the cases where SLE was diagnosed later to MMA, one case had features of SLE 1 year prior to the development of MMA which remained undetected.

The presence of transient neurological manifestations (headache, transient ischaemic attack (TIA), seizure) at onset are often neglected. In majority, alleviation of this initial manifestations with symptomatic therapy were satisfactory outcome to both patient’s kin and treating physician without pursuing further investigations to reach the actual underlying grave diagnosis due to reasons related to socio-economic burden and absence of robust healthcare system in countries like India. The presence of seizure followed by headache as the initial symptom led to the maximum latency in diagnosing MMA in such patients.² In 6 of 17 cases, the onset of neurological manifestation preceded the diagnosis of MMA. The predominant initial neurological manifestation included TIA or headache. Because of the subtle and benign nature of such symptoms, it is often ignored and there is scope of even inadequate elicitation of such events from history on the part of the treating physician unless aware of its possible significance. Severe headache often ineffective to anaesthetic drug therapy has been considered as an important clinical symptom in patient of SLE with MMA and would warrant a thorough investigation.⁹ Three of the 17 patients (including our case) had a history of headache onset much earlier to the actual neurological symptom leading to its diagnosis. This underscores the necessity of thorough probing of subtle neurological symptoms by a trained neurologist in SLE patients, which may precede the catastrophic neurological symptom leading to its diagnosis eventually and thus can act as an early pointer and aid in early diagnosis with possible prevention of calamitous outcome.

However, the presence of overlapping spectrum of neurological symptoms of NPSLE and MMA poses a great diagnostic dilemma among the neurologists and rheumatologists alike in the attribution of the symptom to the specific disease process.

Among the 17 cases reported, 15 of them had described the organ involvement of SLE. It was found that the most common systems involved included renal, mucocutaneous and haematological systems occurring in 12, 10 and 9 out of the 15 patients, respectively. Thus, there might be possible predilection for neurological involvement in the presence of this organ involvement in SLE or this observation may simply be a part of general disease activity.

MMA usually presents with two peaks of incidence, children who are approximately 5 years of age and adults in their mid-40s, Indians might have an earlier peak though. The paediatric population has a tendency for ischaemic presentation, while adults have an increased tendency for haemorrhage. However, in adults also, it has been seen in Indian and Western population, haemorrhagic presentation is much lower compared with East Asian cohort.2 7 10 11 However, only three cases including ours had haemorrhagic manifestation leading to diagnosis.

MMS has been associated in higher incidence with syndromes like Down, neurofibromatosis type I, sickle cell disease and MELAS (mitochondrial encephalopathy, lactic acidosis and stroke-like episodes).¹² As a part of our institutional experience dealing with MMA, out of the 98 consecutive patients, we have had 20 cases of MMS, the most common secondary cause being atherosclerosis. This was the first case of MMA to be associated with SLE.

MMA is postulated to be induced by immune reactivity vasculitis, as evidenced by presence of positive immunohistochemical reaction staining with deposition of IgG, IgM and C3 in the intima of MMA vessels and the infiltration of macrophages and T-lymphocytes of SMC, finally leading to intimal hyperplasia following aberrant cytokine regulation and interaction.⁹

Quasi-moyamoya in association with autoimmune disorder is postulated to occur by two mechanisms, one leads to onset of MMA in response to increased inflammatory cytokine that influence RNF 213. Second mechanism involves influence of anti-inflammatory cytokines leading to acceleration or acute aggravation of MMA. This has been applied to disease process of quasi-moyamoya related to hyperthyroidism.³ However, its extrapolation to other autoimmune disorder with MMA may not be a big leap.

Out of 17 cases, eight were in active stage of SLE, six were inactive (three cases did not mention activity of SLE). This probably favours the fact that chronic inflammation in an autoimmune disorder in itself can lead to slow accumulation of pathological changes of intracranial vessel walls of ICA, even in the phases of low disease activity, eventually leading to MMA. Also among the 17 cases, 11 cases with concomitant immunosuppressive therapy achieved remission of neurological symptoms, of which two cases were already on immunosuppression from earlier. Such observation might warrant the use of immunosuppression to achieve remission of symptoms of MMA with autoimmune disorder.¹³

Deciding on the therapy in a patient of SLE with MMA is often difficult, however, the role of immunosuppressive cannot be understated and might be essential in prevention or attenuating the rate of development of MMA. Revascularisation therapy should also be considered after assessment of cerebrovascular reserve and leptomeningeal collaterals to prevent further attacks, also an initial cerebrovascular evaluation might be helpful.^{14 15}

Patient’s perspective.

I can only remember the worst headache after which I got admitted in hospital by my family members. I have been told that I remained unconscious for 3 days. After that, I regained consciousness but neck pain and heaviness over head were there for 10 days. I had small joints pain and intermittent oral ulceration and photosensitivity which I ignored previously but at the time of discharge, I have been told by group of doctors that there may be some association of these symptoms with worst headache and unconsciousness. I have been told to keep track in Neurology and Rheumatology department on monthly basis with some blood reports before visit.

Learning points.

• Headache and seizure are the two most important non-paretic symptoms for which diagnosis of Moyamoya angiopathy (MMA) may get delayed.

• Role of immunosuppression and immunomodulation in MMA secondary to connective tissue disorders remains debatable.

• Acute-onset severe headache with neck stiffness indicates haemorrhage either in subarachnoid space or within the ventricles. Meningeal signs stem from chemical meningitis due to blood in subarachnoid space.

• Lobar haemorrhage in young needs meticulous evaluation for underlying pathology.