Can amyloidosis cause encephalopathy in a treatment-naive older adult patient with myeloma?

Can Amyloidosis Cause Encephalopathy in Multiple Myeloma?

Yes, amyloidosis can cause encephalopathy in myeloma patients, though it is uncommon and typically occurs through specific mechanisms: AL amyloidosis affecting the peripheral and autonomic nervous systems (not typically causing direct encephalopathy), or indirectly through metabolic derangements from organ failure (renal, hepatic) caused by amyloid deposition. 1, 2, 3

Direct Neurologic Involvement

AL amyloidosis in multiple myeloma primarily affects the peripheral nervous system rather than causing encephalopathy. 1

• Peripheral neuropathy is the most common neurologic manifestation, presenting as slowly progressing, demyelinating, symmetrical sensory neuropathy affecting the feet initially. 1
• Autonomic neuropathy can occur with orthostatic hypotension, urinary retention, erectile dysfunction, and constipation. 1
• Amyloidosis occurs in approximately 12-15% of patients with multiple myeloma and most commonly affects kidneys, heart, liver, and peripheral nerves—not the central nervous system directly. 1, 3

Indirect Mechanisms of Encephalopathy

Encephalopathy in myeloma patients with amyloidosis typically results from secondary organ dysfunction rather than direct amyloid deposition in the brain:

Renal Failure-Related Encephalopathy

• Uremic encephalopathy from amyloid-induced renal failure is a recognized complication. 4
• Kidneys are among the most commonly involved organs in AL amyloidosis, and progressive renal dysfunction can lead to metabolic encephalopathy. 2, 3

Hepatic Encephalopathy

• Hepatomegaly without imaging abnormalities is a characteristic finding in amyloidosis and can progress to hepatic dysfunction. 3
• Liver involvement can contribute to metabolic encephalopathy through hepatic insufficiency. 3

Hyperammonemic Encephalopathy

• Multiple myeloma itself (independent of amyloidosis) can rarely cause hyperammonemic encephalopathy presenting as altered mental status. 5

Hypercytokinemia-Induced Encephalopathy

• In the context of treatment (particularly high-dose chemotherapy and stem cell transplantation), hypercytokinemia with elevated TNF levels can cause metabolic encephalopathy, especially in patients with renal failure. 4

Cardiac Amyloidosis Considerations

Cardiac involvement is critical to assess as it affects prognosis and treatment tolerance:

• Heart failure from cardiac amyloidosis can lead to hypoperfusion and secondary encephalopathy. 1, 2, 3
• Cardiac assessment with echocardiography, cardiac MRI, and biomarkers (NT-proBNP, troponins) should be performed when amyloidosis is suspected. 1
• 25% of patients with AL amyloidosis die within 6 months of diagnosis, often from cardiac involvement. 3

Diagnostic Approach in Treatment-Naive Patients

When evaluating encephalopathy in an older adult with myeloma and suspected amyloidosis:

1. Confirm amyloidosis diagnosis with fat aspirate and bone marrow biopsy evaluated with Congo red staining. 1
2. Assess organ involvement systematically:
   • Renal function: 24-hour proteinuria, eGFR 1, 2
   • Cardiac function: echocardiography, NT-proBNP, troponins 1, 2
   • Hepatic function: liver function tests 1
   • Neurologic evaluation: EMG/nerve conduction studies for peripheral neuropathy 1
3. Evaluate alternative causes of encephalopathy:
   • Hypercalcemia (common in myeloma) 6
   • Hyperammonemia 5
   • Uremia from renal failure 4, 2
   • Hyperviscosity syndrome 1
   • Medication effects 7

Treatment Implications

Treatment selection must account for organ dysfunction from amyloidosis:

• Patients with AL amyloidosis are more fragile than those with myeloma alone due to multiple organ dysfunctions. 1
• High-dose chemotherapy with autologous stem cell transplantation can be considered in patients under 60-65 years with no more than 2 organs involved and without severe heart involvement (NYHA class III-IV). 1
• Transplant-related mortality exceeds 20% even in experienced centers, requiring careful patient selection. 1
• For patients ineligible for transplant, melphalan plus high-dose dexamethasone achieves high response rates. 1
• Frailty assessment is critical in older patients to predict treatment toxicity. 6, 7

Critical Pitfalls to Avoid

• Do not attribute all encephalopathy to amyloidosis—systematically evaluate metabolic causes (uremia, hypercalcemia, hyperammonemia, hepatic dysfunction). 4, 5, 3
• Do not overlook cardiac involvement—it is the primary driver of early mortality and affects treatment tolerance. 2, 3
• Do not delay diagnosis—25% of AL amyloidosis patients die within 6 months, and ability to reverse organ dysfunction is limited with advanced disease. 2, 3
• Do not use medications that worsen autonomic dysfunction (tricyclic antidepressants) in patients with amyloid neuropathy and orthostatic hypotension. 1