Background   

Systemic capillary leak syndrome (SCLS), also known as Clarkson syndrome, is a rare disease with a potentially fatal outcome. The syndrome was first described by Dr Clarkson in 1960 in a patient with recurrent episodes of hypotension, subcutaneous swelling, anasarca and increasing haematocrit.1 Due to the central role of vascular leakage in the pathogenesis, the disease was named idiopathic SCLS (or Clarkson disease). Since then, more than 350 cases of SCLS have been described in the literature.2 3 However, the fundamental pathogenesis of this entity remains largely unresolved. The diagnosis is made based on the presence of a triad of hypotension (systolic blood pressure <90 mm Hg), haemoconcentration (haematocrit >49%–50% in men and 43%–45% in women) and hypoalbuminaemia (<3.0 g/dL).3 A characteristic of SCLS is the presence of paraprotein (M component) in blood, also known as gammopathy of unknown significance (MGUS), in the majority of patients, although it is not required for the diagnosis of SCLS.

Due to the rarity of the disease and a general lack of recognition by clinicians, SCLS is probably underdiagnosed. The disease is sporadic and has been described most commonly in middle-aged Caucasians with an equal sex distribution, although cases have been reported in ethnic groups from around the world. The typical acute SCLS episode presents as hypotensive shock with intravascular volume depletion and haemoconcentration. Most patients rapidly develop peripheral oedema (anasarca) and hypoalbuminaemia following resuscitation with intravenous fluids due to plasma extravasation. Renal failure can occur due to acute kidney injury (AKI) during this ‘leak’ phase. Pleural, pericardial effusion, ascites and oedema of the gastrointestinal tract are sometimes present. Forty-eight to 96 hours later, fluids are mobilised from peripheral tissues into plasma with renormalisation of circulation and diuresis.3 The severity of attacks varies, and patients with severe episodes may also experience separate milder attacks characterised by fatigue, weakness, mild oedema and muscle discomfort. Similarly, the frequency of attacks is highly individual/variable, ranging from several mild attacks per week to up to intervals of 5–10 years between flares.4 Complications of acute vascular leak in SCLS include acute renal failure, thrombosis/pulmonary embolism and compartment syndrome, which may lead to sensorimotor neuropathy, foot drop or amputation.

Case presentation

Here we describe a 52-year-old man admitted to the intensive care unit (ICU) of our university hospital in February 2016 after 2–3 days of diffuse abdominal pain, which increased in intensity 5–6 hours prior to collapse, unconsciousness and cardiac arrest. Medical history included evaluation in the haematology department, October 2014, for a 2-month history of headache and several days of pain and swelling in both calves, polycythemia, and a normal blood pressure; evaluation with ultrasound of the lower extremities, CT scan of thorax and abdomen and bone marrow histopathology (negative for JAK3 mutation) were negative. The following 1.5 years before the acute admission, the patient had experienced two episodes of moderate, unexplained swelling of legs or arms and complained of persistent headache; moreover, he was diagnosed with a mild depression and granted partial disability, allowing him to work fewer hours/week because of this (still undiagnosed) condition.

On admission to the ICU, the patient had cardiac arrest with pulseless electrical activity, hypotension, severe hypovolaemia and extreme hypoalbuminaemia (0.8 g/dL), increased haemoglobin (25.8 g/dL) and haematocrit (0.56), all of which normalised within 6 hours (table 1). Coronary angiography was performed, which revealed patent coronary arteries and no underlying cardiac pathology that could account for his presentation. CT scan of the thorax, abdomen and cerebrum was without pathology. No pericardial or pleural effusions were visible. Massive fluid extravasation causing swelling of both legs and a compartment syndrome developed, necessitating bilateral fasciotomies. Gastroscopy was performed and showed diffuse bleeding. Renal replacement therapy was initiated for AKI. Within the first 48 hours, inotropic support (milrinone), corticosteroids and broad-spectrum antibiotics (piperacillin/tazobactam) were administered empirically as the primary diagnosis remained cryptic. Because the patient presented with acute hypotension, shock and cardiac arrest during peak influenza season, the patient was tested for influenza A and B following our institutional guidelines and was found to be positive for influenza A by PCR. Accordingly, oseltamivir treatment was initiated. Lab tests revealed positive paraprotein (M component) with increased levels of kappa light chains, initially 100 mg/dL, (most recently 520 mg/dL, table 1). C-1 esterase inhibitor level was normal.

During the course of the episode, infection and necrosis of the anterior muscle of right lower leg at the fasciotomy site developed, necessitating debridement. As a result, long-term residual peroneal nerve paresis on right side persisted following the attack. During his prolonged hospitalisation, the infections (ventilator associated pneumonia and necrosis/infection of anterior extensor muscle compartment) eventually resolved, renal function was restored and the patient was discharged 41 days after admission.

Investigations

The most severe manifestations of SCLS are hypovolaemic shock and cardiac arrest. A history of localised oedema and increased haematocrit should alert the clinician and prompt further diagnostic. Serum albumin levels, haematocrit and blood pressure should be monitored frequently during an attack. M-component (blood and urine), complement C3/4, C1-esterase inhibitor levels and function must be measured, together with other parameters to exclude or confirm other diagnoses.

The patient was evaluated at the National Institutes of Health 18 months after the acute episode. Lab tests were repeated, including beta-2-microglobulin, C3/4, quantitative immunoglobulins and immunofixation electrophoresis (table 2). Cardiac MRI was normal.

Differential diagnosis

Polycythemia vera was considered 2 years prior to the major capillary leak event.

In the acute phase, other reasons for shock (septic, cardiogenic, bleeding and so on) must be ruled out. Other rare causes of hypotension may include neuroendocrine tumours, inferior vena cava syndrome or coagulopathy. Likewise, hereditary angio-oedema may share features with SCLS and should be excluded by measuring C1 esterase inhibitor levels. Infections with filoviruses (eg, Ebola and dengue) can also present with features of vascular leak similar to Clarkson disease.

Treatment

The patient was started on intravenous immunoglobulin (IVIG) (2 g/kg) at day 34 for the prevention of capillary leak syndrome. Since then, he has received a maintenance dose of IVIG 1 g/kg every 4 weeks with a trough level of IgG around 1500 mg/dL and peak levels the day after IVIG administration of around 3000 mg/dL. In accordance with the current guidelines, the patient receives no other prophylactic treatment.

Outcome and follow-up

Presently, 2 years after this major leak episode, the patient is in relatively good clinical condition and is receiving IVIG 1 g/kg every 4 weeks with a through level of IgG around 1500 mg/dL and peak levels of around 3000 mg/dL. He did, however, experience a few minor episodes of oedema/swelling of extremities interpreted as minor leaks despite prophylaxis with IVIG. Moreover, he has a remaining significant fatigue and mild cognitive disturbances and was diagnosed with mild depression. Another medical issue is that he also suffers from neuropathic pain in both legs and receives physiotherapy on a lifelong regular basis.

Finally, the patient is followed in the Department of Hematology with a diagnosis of MGUS. A bone marrow was performed without signs of malignancy. Paraprotein (M-component), Ig levels and other haematological parameters are measured every 3 months.