What is the diagnosis and treatment for amyloidosis (a condition characterized by the deposition of amyloid, a protein, in various tissues) presenting with facial droop?

Amyloidosis Presenting with Facial Droop: Diagnosis and Treatment

Facial droop in the context of amyloidosis most likely represents AL (light chain) amyloidosis with soft tissue infiltration, and requires urgent tissue biopsy with Congo red staining plus mass spectrometry typing, followed by immediate plasma cell-directed chemotherapy with daratumumab-CyBorD as first-line treatment.

Clinical Recognition and Diagnostic Clues

Facial droop in amyloidosis is not a typical stroke presentation but rather represents soft tissue infiltration by amyloid deposits. The key clinical clues that should trigger evaluation for AL amyloidosis include:

• Macroglossia (enlarged tongue) - a hallmark feature that can cause facial asymmetry and droop 1
• Periorbital ecchymoses (periorbital purpura) - pathognomonic for AL amyloidosis and should prompt immediate evaluation 1, 2
• Submandibular gland enlargement - can contribute to facial asymmetry 2
• Peripheral or autonomic neuropathy - may cause true facial nerve involvement 3

The presence of macroglossia or periorbital ecchymoses mandates urgent evaluation for AL amyloidosis, as these are highly specific clinical signs 1.

Diagnostic Algorithm

Step 1: Confirm Amyloid Deposition

Tissue biopsy is mandatory and cannot be bypassed. Unlike ATTR cardiac amyloidosis which can be diagnosed non-invasively, AL amyloidosis requires both demonstration of tissue amyloid deposits AND evidence of plasma cell dyscrasia 1.

• Biopsy options (in order of invasiveness):

  • Abdominal fat pad aspiration (84% sensitivity for AL-CM, office-based procedure) 1
  • Gingival biopsy (particularly relevant given facial involvement) 1
  • Bone marrow biopsy (69% sensitivity for systemic AL) 1
  • Affected organ biopsy if surrogate sites are negative 1

• Congo red staining showing apple-green birefringence under polarized light confirms amyloid presence 1, 4

Step 2: Type the Amyloid Protein

Mass spectrometry (LC-MS/MS) is the gold standard for typing with 88% sensitivity and 96% specificity 1, 2, 5. This step is critical because:

• Over 10% of patients with monoclonal gammopathy can have ATTR deposits 1
• Treatment differs completely between AL and ATTR amyloidosis 2, 5
• Immunohistochemistry alone has limitations in specificity and sensitivity 4

Step 3: Confirm Plasma Cell Dyscrasia

All three tests must be performed simultaneously 2:

• Serum free light chain assay (sFLC) with kappa/lambda ratio 1, 2, 5
• Serum immunofixation electrophoresis (SIFE) 1, 2, 5
• Urine immunofixation electrophoresis (UIFE) 1, 2, 5

Critical pitfall: Standard protein electrophoresis (SPEP/UPEP) should NOT be used alone due to lower sensitivity 1, 2.

Bone marrow biopsy is required to demonstrate clonal proliferation of lambda or kappa-producing plasma cells 1, 2.

Step 4: Assess Organ Involvement

• Echocardiography - mandatory as cardiac involvement drives prognosis and mortality 1, 2, 5
• BNP/NT-proBNP levels - 93% sensitivity and 90% specificity for cardiac involvement 1
• Renal function and proteinuria assessment 2, 5
• Neurologic evaluation for peripheral and autonomic neuropathy 2, 3

Treatment Strategy

First-Line Treatment Selection

For transplant-eligible patients (age <60-65, adequate cardiac function, ≤2 organs involved):

• Daratumumab-CyBorD (daratumumab + cyclophosphamide + bortezomib + dexamethasone) as first-line therapy 2, 5
• Consider high-dose melphalan followed by autologous stem cell transplantation (ASCT) 2, 5

For transplant-ineligible patients:

• Daratumumab-CyBorD is the preferred first-line option 2, 5
• Alternative: CyBorD alone (cyclophosphamide, bortezomib, dexamethasone) 2, 5

Treatment Goal and Monitoring

The goal is to eradicate pathological plasma cells and remove affected light chains from circulation 2. This requires:

• Close collaboration between hematology, cardiology, and neurology given multisystem involvement 2, 5
• Monitoring for cardiac decompensation during therapy - essential as cardiac involvement is the main driver of mortality 2, 5
• Serial assessment of hematologic response using sFLC levels 2

Critical Medication Considerations

Daratumumab (anti-CD38 antibody):

• Recently FDA-approved for AL amyloidosis 2
• Cardiac toxicities include heart failure (12%), arrhythmias (8%), atrial fibrillation (6%) 2

Proteasome inhibitors (bortezomib, carfilzomib, ixazomib):

• Risk of Grade 3 heart failure, decreased LVEF, pulmonary hypertension 2

Corticosteroids (dexamethasone):

• Monitor for peripheral edema, pulmonary edema, fluid overload 2

Supportive Care for Facial/Soft Tissue Involvement

• Gastroenterology referral for macroglossia causing malnutrition, dysphagia, or weight loss 2, 6
• Avoid NSAIDs and IV contrast if renal involvement present 2
• Nutritional support as GI involvement is common with small intestine having greatest amyloid deposition 6

Critical Pitfalls to Avoid

1. Do not assume facial droop is a stroke - consider soft tissue infiltration from amyloidosis, especially with macroglossia or periorbital purpura 1, 2

2. Do not use SPEP/UPEP alone - requires all three tests (sFLC, SIFE, UIFE) simultaneously 1, 2

3. Do not skip amyloid typing - immunohistochemistry alone is insufficient; mass spectrometry is the gold standard 1, 4

4. Do not delay treatment - patients with AL amyloidosis are more fragile than multiple myeloma patients and at higher risk for treatment-related toxicity 2

5. There are no absolute contraindications to plasma cell-directed therapies based solely on ejection fraction or cardiac status in AL cardiac amyloidosis 2

6. Avoid standard heart failure medications that can be dangerous in amyloidosis:

   • Digoxin binds to amyloid fibrils causing toxicity even at normal levels 1
   • Calcium channel blockers bind to amyloid causing exaggerated hypotension 1
   • ACE inhibitors/ARBs should be used with extreme caution or avoided due to hypotension 1
   • Beta-blockers should be avoided when cardiac output is low with severe restrictive physiology 1

Prognosis

Cardiac involvement is the main driver of disease prognosis and mortality 2, 5. Deep hematologic responses correlate with improved organ function and survival 2. Early diagnosis and treatment are critical, as recent advances have improved survival from months to years 7, 8.