Ischaemic stroke as the initial manifestation of systemic amyloidosis

Abstract

A previously healthy 54-year-old woman was admitted to the stroke unit with an acute ischaemic stroke attributed to atrial fibrillation newly diagnosed at the emergency room. Nevertheless, preliminary investigation on stroke aetiology revealed incidental hypoalbuminaemia in the context of nephrotic syndrome, while clinically, the patient developed progressive signs of cardiac failure raising the suspicion of an underlying disorder. Systemic amyloidosis was histologically confirmed a few weeks after hospital admission. The rare presentation and non-specific symptom constellation contributed to delayed institution of the appropriated treatment regimen at a point where multiorganic involvement was irreversible leading to death only 2 months after the first manifestation. The presented case reminds us of the importance of always keeping in mind this rarer cause of ischaemic stroke since an early diagnosis remains the key to a more hopeful prognosis.

Background

Stroke remains a leading cause of mortality and long-term disability worldwide. New advances from the past decade led to a better understanding of stroke mechanisms and aetiology, allowing for more effective management and prevention. However, in some cases, underdiagnosed and scarce information regarding clinical guidance and treatment persists mostly due to their rarity and lack of clinical suspicion.

Amyloidosis is an uncommon multiorganic disorder characterised by extracellular deposition of a type of insoluble fibril protein, known as amyloid, in tissues, leading to structural and functional changes at the involved organs. Immunoglobulin light chain (AL) amyloidosis is the the most common type of amyloidosis, accounting for about 85% of all newly diagnosed cases.¹ The multiorganic involvement results in non-specific signs and symptoms and heterogeneous clinical presentations making the high level of suspicion essential to make the diagnosis.

Cardiogenic ischaemic stroke (IS) is a rare complication of amyloidosis, resulting from myocardial amyloid deposition with subsequent changes in cardiac contractile function and electrical conduction that predisposes to thromboembolic events. Early recognition of the underlying disease remains the mainstay of treatment since patients with advanced disease are unsuitable candidates for effective treatment including autologous stem cell transplantation, and those who are treated present with more unsatisfactory results. The occurrence of stroke among patients with AL systemic amyloidosis has also been associated with worse outcomes.²

We present the case of a 54-year-old patient with the diagnosis of systemic amyloidosis through the diagnostic workup of a cardioembolic IS.

Case presentation

A 54-year-old woman presented to the emergency room (ER) with speech impairment and inability to move her right-side body, with unknown time of onset. Her medical and family history were unremarkable, without any particularly known risk factors for ischaemic stroke. The physical examination revealed right hemiplegia, right homonymous hemianopia and global aphasia, with an initial National Institutes of Health Stroke Scale (NIHSS) score of 21. During the cardiac monitoring at the ER, atrial fibrillation (AF) with controlled ventricular response was identified. Urgent non-enhanced CT of the brain was performed, revealing an extensive area of ischaemia at the left middle artery territory (MCA) with an Alberta Stroke Program early CT score (ASPECTS) of 4, and a hyperdense M1 segment of the referred vessel, suggesting the presence of an intraluminal thrombus (figure 1). Since the time of evolution was not known and she already had low ASPECTS at admission, no reperfusion treatments were performed and the patient was admitted to the neurology department.

Figure 1.

Initial brain CT scan showing an acute ischaemic lesion at the left middle cerebral artery territory with hyperdensity along the M1 segment of the referred vessel, suggesting arterial occlusion.

Additional investigation on aetiology of the embolic event included an ultrasonography of cervical and intracranial arteries, which did not reveal significant stenosis, a transoesophageal echocardiogram showing a left atrial appendage thrombus and initial routine laboratory tests that were normal except for the serum albumin which was significantly below the lower reference limit (table 1).

Table 1.

Results of the blood diagnostic workup at admission and after 2 months (amyloidosis treatment initiation)

	Blood tests
	At admission	After 2 months (treatment initiation)	Reference value
Haemoglobin (g/L)	173	94	120–160
Haematocrit (%)	55.7	28.3	36–46
Leukocytes (×109/L)	10.2	11.3	4–10
Platelets (×109/L)	313	213	150–400
Glucose (mg/dL)	107	92	60–109
Albumin (g/dL)	1.9	2.2	3.2–5.2
Urea (mg/dL)	13.2	124	7.9–20.9
Creatinine (mg/dL)	0.53	5.67	0.55–1.02
AST (U/L)	19	84	<31
ALT (U/L)	22	90	<34
Total cholesterol	232	NA	NA
LDL-cholesterol	179	NA	NA
Anti-dsDNA antibodies	Negative	NA	NA
P-ANCA and c-ANCA	Negative	NA	NA
Anti-SSa60, SSb, Sm, RMP and Jo1 antibodies	Negative	NA	NA
Complement C3 (g/L)	1.56	NA	0.9–1.8
Complement C4 (g/L)	0.37	NA	0.1–0.4
Anticardiolipin antibodies	Negative	NA	NA
Crioglobulins	Negative	NA	NA

ALT, alanine aminotransferase; AST, aspartate aminotransferase; c-ANCA, cytoplasmic antineutrophil cytoplasmic antibody; dsDNA, double-stranded DNA; LDL, low-density lipoprotein; NA, not available; p-ANCA, perinuclear antineutrophil cytoplasmic antibody.

At the first week of hospitalisation, she maintained her global neurological status with slight signs of improvement, seeming to sporadically understand simple orders (NIHSS score of 18), despite the evidence of haemorrhagic transformation on follow-up brain CT.

The workup continued with a urine sample, confirming exceeding excretion of proteins followed by quantitative measurement of proteinuria at the 24 hours urine that was compatible with a nephrotic syndrome (table 2).

Table 2.

Results of the urine diagnostic workup at admission

	Urine tests
	At admission	Reference value
Glucose	Negative	NA
pH	8.5	5.0–8.0
Proteins	1000	0–20
Bilirubin	Negative	NA
Haemoglobin	1.0	0
Volume (mL/24 hours)	1800	NA
Creatinine (mg/24 hours)	977	600–1600
Proteins (mg/24 hours)	6815	50–80
Albumin (mg/24 hours)	4207	<30
Glucose (mg/24 hours)	0	<50

NA, not available.

A renal biopsy was performed with the sample presenting an apple-green birefringence under polarised light after staining with Congo red dye (figure 2). Serum immunofixation electrophoresis identified an abnormal ratio of lambda and kappa light chains. Those findings were diagnostic of an AL amyloidosis. Bone marrow biopsy revealed the presence of 10% clonal bone marrow plasma cells, producers of immunoglobulins.

Figure 2.

Renal biopsy with H&E (A) and Congo red (B) staining (×400), showing amyloid deposits involving the mesangial tissue. The deposits showed apple-green birefringence in polarised light.

For treatment decision, we performed cardiac MRI that revealed increased thickness of cardiac walls and a late diffuse subendocardial enhancement after gadolinium contrast injection, thus being positive for cardiac involvement (figure 3). A thoracoabdominopelvic CT scan was requested, showing hepatomegaly and pleural effusion but without any evidence of other structural damages.

Figure 3.

Cardiac MRI revealing bilateral pleural effusion and thickened left ventricle walls with an abnormal late diffuse gadolinium enhancement, suggesting amyloid deposition.

Seven weeks after hospital admission, the patient started to show signs of right ventricular failure with oedema and dyspnoea that were managed with intravenous human albumin reposition with transient effect. Since intracranial haemorrhage complication was solved, anticoagulant therapy with warfarin was initiated, reaching a stable international normalised ratio values between 2 and 3.

When amyloidosis treatment was started, the patient exhibited progressive signs of organic dysfunction developing anasarca and respiratory failure. The main laboratory findings at this point are presented in table 1. The selected therapy was a combination of bortezomib, cyclophosphamide and dexamethasone (CyBord protocol), in addition to the ongoing supportive measures.

Outcome and follow-up

Despite treatment initiation, the patient died 2 months after hospital admission due to a second ischaemic stroke.

Discussion

Amyloidosis is a clonal plasma cell dyscrasia, historically associated with a very poor prognosis, with nearly a third of all patients still dying within a few months after diagnosis.^{3 4}

AL amyloidosis is the most common type, affecting 1 per 100 000 person-years in Western countries.⁵ The definite diagnosis relays on histological confirmation of amyloid deposition in tissues. Kidneys and heart are the the most common targets, being involved in about 60% and 50% of the cases, respectively.⁴

Cardiac involvement accounts for 75% of deaths in patients with amyloidosis, remaining one of the main prognostic factors and the actual leading cause of mortality.³ The amyloid infiltration within the cardiac walls ultimately leads to contractile and conduction changes that affect the heart function.¹ Additionally, in 10% to 15% of patients, AF may be identified.^{6 7} At the advanced disease, intracardiac thrombi are frequently found.

This patient was a young adult woman with no hypertension, hyperlipidaemia or other known vascular risk factors, presented at the emergency room with an ischaemic stroke. In young patients with cerebrovascular events of an unknown aetiopathogenic cause, screening for rare diseases should be considered.⁸ In this patient, further diagnostic workup led to the diagnosis of AF. She also exhibited symptoms of right ventricular failure (oedema, dyspnoea and hepatomegaly) which prompted suspicion for an underlying disorder compromising the heart function, although, the initial echocardiogram did not reveal any structural changes. The cardiac MRI, later performed, ended up recognising the cardiac involvement by showing the typical late subendocardial enhancement after gadolinium contrast injection, emphasising that a normal echocardiogram may not exclude the cardiac involvement if amyloidosis is suspected.⁷

As a consequence of cardiac dysfunction, patients with amyloidosis are at increased risk of developing thromboembolic events. AF and blood stasis, associated with the underlying hypercoagulable state, may result in ischaemic stroke, generally at an advanced disease.¹

In a retrospective study from the Mayo Clinic, 40 patients with confirmed AL amyloidosis and stroke, evaluated between January 2000 and July 2006 were included, with ischaemic stroke occurring in 32.5% of the cases as first presentation. Seventy per cent of all patients had a cardioembolic stroke, a high frequency compared with the 20% usually reported on the general population. The mean time from the stroke event to diagnosis was 9.6 months. Those patients with initial stroke presentation had the worst outcome with an average survival of 6.9 months after diagnosis. 37.5% of the patients had multiple strokes.^{2 9}

In this case, the patient had a cardioembolic stroke as amyloidosis first presentation followed by other two embolic events who led to premature death only 2 months after hospital admission, reinforcing the low average survival time of this disease.

Although specific orientations for embolic ischaemic stroke prevention among patients with amyloidosis does not exist, anticoagulation therapy has strongly been recommended in patients with atrial fibrillation because of the associated high risk, despite the haemorrhage tendency secondary to the blood dyscrasia.¹⁰ The specific drug choice, frequency and dose still need to be addressed and the actual practice remains empirical. The same applies to the management of the hyperacute phase of ischaemic stroke among these patients, with one case report, suggesting that intravenous alteplase (rt-PA) thrombolysis therapy may be safe and effective.⁹ Our patient did not perform any recanalisation therapy, nevertheless, she developed a haemorrhagic complication. The spontaneous recanalisation of the MCA, presumed by the absence of stenosis and occlusions at the ultrasonography may have resulted in cerebral hyperperfusion and subsequent bleeding. Since amyloidosis itself relates to increased risk of haemorrhage, additional data are necessary to evaluate the application and safety of the reperfusion procedures in amyloidosis patients with ischaemic stroke.^{11 12}

Without specific treatment, the disease has a progressive and fatal course due to uncontrolled organ damage.⁵ The selected approach should target the underlying plasma cell dyscrasia with the aim of rapidly reducing the production of amyloidogenic light chains limiting the organ damage, ultimately leading to function preservation and improved survival.^13–15

Autologous stem cell transplantation remains the most effective treatment available, although it is usually reserved for patients with early and low-risk disease.^{3 15} For those with more advanced disease, not eligible for transplant, treatment comprises chemotherapy agents and symptomatic support, as was the case of this patient.

Learning points.

• In patients presenting with stroke or transient ischaemic attack of unknown aetiopathogenic causes, especially those with young age at onset or positive family history, screening for rare diseases should be performed.

• Primary systemic amyloidosis constitutes a rare yet not negligible cause of single or recurrent ischaemic stroke.

• Early diagnosis remains the mainstay for effective treatment and improved survival, although the clinical presentation is unspecific delaying recognition of this disease.

• The occurrence of ischaemic stroke as a complication of primary systemic amyloidosis is associated with worse outcomes.

• A thorough search for cardiac disease should be performed in all patients with stroke and low risk of cerebrovascular diseases.