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Stem
A 71-year-old man is brought to the emergency department by his wife, who describes two weeks of progressive drowsiness, daily nosebleeds and blurred vision. He has known Waldenstrom macroglobulinaemia, diagnosed 18 months ago, but has declined systemic therapy. On examination he is drowsy (GCS 14), pale, with active epistaxis and gum oozing. Fundoscopy shows markedly dilated and tortuous ('sausage-string') retinal veins with scattered flame haemorrhages and blurred disc margins. There is no focal neurological deficit and no lymphadenopathy; the spleen is palpable 3 cm below the costal margin. Blood pressure 145/88, pulse 96, oxygen saturation 97 percent on room air. Bloods: haemoglobin 76 g/L (MCV 89), platelets 130, INR 1.0, creatinine 95 micromol/L, corrected calcium 2.35 mmol/L, total protein 128 g/L, albumin 32 g/L. Serum IgM 72 g/L; serum relative viscosity 6.4 (normal under 1.8).
Questions
a) What is the diagnosis of this acute presentation, and which four clinical features support it? (2 marks)
The diagnosis is hyperviscosity syndrome complicating Waldenstrom macroglobulinaemia. Four supportive features: (1) the hyperviscosity triad — mucosal bleeding (epistaxis, gum oozing), visual disturbance (blurred vision), and neurological symptoms (drowsiness); (2) the pathognomonic fundal finding of 'sausage-string' retinal veins with haemorrhages and papilloedema; (3) a markedly raised serum relative viscosity (6.4) and IgM (72 g/L); (4) the known diagnosis of IgM-secreting Waldenstrom.
b) Outline the IMMEDIATE management. (3 marks)
- Urgent therapeutic plasma exchange (plasmapheresis) — physically removes the intravascular IgM pentamer (about 80 percent of IgM is intravascular); exchange 1 to 1.5 plasma volumes, daily or alternate-day until symptoms resolve and viscosity falls.
- Do NOT transfuse first — red-cell transfusion worsens viscosity; if anaemia is severe, plasmapheresis first, then cautious slow transfusion.
- Maintain hydration, avoid over-diuresis and nephrotoxins; manage bleeding with local measures.
- Watch for citrate-induced hypocalcaemia during exchange (perioral tingling) and give calcium.
- Begin planning definitive Waldenstrom therapy (see part d) once the emergency is controlled.
c) Why is plasmapheresis so effective in IgM-mediated hyperviscosity compared with IgG myeloma? (2 marks)
IgM is a 970-kDa pentamer that is approximately 80 percent confined to the intravascular space (versus about half of IgG, which distributes extravascularly). Because most of the IgM is in the plasma compartment, one or two plasma exchanges lower the IgM by 30 to 60 percent and reverse symptoms within hours. IgG is smaller (150 kDa), largely extravascular, and rebounds from the extravascular compartment after exchange, so plasmapheresis is far less effective in IgG hyperviscosity.
d) Outline the definitive therapy for this patient once the acute presentation is controlled, and state TWO treatment-related pitfalls. (3 marks)
Definitive therapy for symptomatic Waldenstrom:
- Rituximab-based chemoimmunotherapy — BR (bendamustine + rituximab) for 4 to 6 cycles, or DRC (dexamethasone + rituximab + cyclophosphamide) for older/frailer patients.
- OR a BTK inhibitor — zanubrutinib 160 mg orally twice daily (preferred over ibrutinib after the ASPEN trial showed fewer atrial-fibrillation and bleeding events), taken continuously until progression.
- Supportive care — monitor cytopenias, infection prophylaxis, and arrange lifelong monitoring if disease becomes smouldering.
Two treatment-related pitfalls:
- The rituximab IgM flare — in a very high IgM (over 40 g/L), rituximab can transiently raise IgM 4 to 8 weeks after the first dose and precipitate hyperviscosity; delay rituximab or plasmapheresise first.
- BTK-inhibitor toxicities — bleeding (hold before procedures), atrial fibrillation (more with ibrutinib), hypertension, infection; plus the diagnostic pitfall of transfusing before plasmapheresis in hyperviscosity.