What are transverse myelitis and monoclonal gammopathy of undetermined significance, and how are they diagnosed?

Transverse Myelitis and MGUS: Definitions and Diagnostic Approach

What is Transverse Myelitis?

Transverse myelitis is an acute inflammatory disease of the spinal cord characterized by rapid onset of bilateral neurological symptoms—weakness, sensory disturbance, and autonomic dysfunction—that evolve over hours to days, typically reaching maximal severity within 10 days. 1

Clinical Presentation

• Motor symptoms: At maximal clinical severity, approximately 50% of patients develop complete paraparesis with no volitional leg movements 1, 2
• Sensory symptoms: 80-94% experience numbness, paresthesias, or band-like dysesthesias 2
• Autonomic dysfunction: Nearly all patients develop bladder dysfunction 1, 2
• Onset pattern: Symptoms progress rapidly over hours to days, with most reaching peak severity within 10 days 1

Pathophysiology

• The underlying mechanism involves an immune-mediated process causing neural injury to the spinal cord 3
• Histopathologic features include perivascular monocytic and lymphocytic infiltration, demyelination, and axonal injury 2

Diagnostic Workup for Transverse Myelitis

MRI of the spine is the cornerstone diagnostic test, showing diffuse hyperintensity on T2-weighted images extending longitudinally through the spinal cord. 1, 4

Essential Imaging

• Spinal MRI: Demonstrates characteristic T2 hyperintensity, often extending over multiple vertebral segments in longitudinally extensive transverse myelitis (LETM) 1, 4
• Brain MRI: Should be performed to evaluate for multi-focal CNS disease such as multiple sclerosis 1, 3

Laboratory Evaluation

• Cerebrospinal fluid analysis: Interleukin-6 levels strongly correlate with and predict disability severity 2
• Serum testing: Complete metabolic panel, inflammatory markers, and autoimmune serologies to identify underlying etiologies 3
• Free light chain ratio: May be transiently abnormal during acute phase but typically normalizes with disease improvement 4

Etiologic Classification

Transverse myelitis can occur as:

• Idiopathic: Despite extensive workup, many cases remain without identified cause 1, 3
• Demyelinating conditions: Part of multiple sclerosis or other demyelinating diseases 3
• Collagen vascular disease: Associated with systemic lupus erythematosus and other autoimmune conditions 1
• Parainfectious: Following viral or bacterial infections 1

Prognosis

Recovery is divided roughly into thirds: one-third recover with minimal or no sequelae, one-third have moderate permanent disability, and one-third have severe disability 1, 2

---

What is MGUS?

Monoclonal gammopathy of undetermined significance (MGUS) is a pre-malignant plasma cell disorder defined by serum monoclonal protein <3 g/dL, clonal bone marrow plasma cells <10%, and absence of end-organ damage (no CRAB criteria). 5, 6, 7

Epidemiology and Natural History

• Prevalence: Affects approximately 5% of adults aged 50 years and older 8, 9
• Progression risk: Approximately 1% per year risk of progression to multiple myeloma or related malignancies, with no reduction in risk even after 25-35 years of follow-up 8, 6
• Mortality: MGUS patients have poorer survival than the general population, with excess mortality from hematologic malignancies, infections, heart disorders, renal disorders, and liver diseases 8

Associated Complications Beyond Malignant Progression

MGUS is not merely a benign precursor—the monoclonal protein itself can cause significant organ damage and systemic complications. 8

Thrombotic Risk

• Venous thrombosis: 2-3-fold increased risk of deep venous thrombosis and pulmonary embolism, particularly with IgG and IgA MGUS (not IgM) 8
• Arterial thrombosis: Increased risk of coronary artery disease and cerebrovascular disease 8

M-Protein Related Organ Damage

• AL amyloidosis: Misfolded light chains deposit as amyloid fibrils causing heart failure, hepatosplenomegaly, nephrotic syndrome, macroglossia, carpal tunnel syndrome, and neuropathy 8
• Peripheral neuropathy: Direct autoantibody activity or nerve damage from M-protein 8
• Cryoglobulinemia: Type I or II, causing Raynaud phenomenon, acrocyanosis, cold urticaria, peripheral neuropathy, renal failure, and skin vasculitis 8

Diagnostic Workup for MGUS

The initial diagnostic approach requires serum and urine protein electrophoresis with immunofixation, serum free light chain assay, and nephelometric quantification of immunoglobulins. 5, 6

Essential Laboratory Tests

• Serum protein electrophoresis (SPEP) with immunofixation: Identifies and characterizes the monoclonal protein, showing a sharp M-spike representing clonal expansion 5, 7
• 24-hour urine collection: For protein electrophoresis and immunofixation (not random sample) to detect Bence Jones proteinuria 5
• Nephelometric quantification: Measures IgG, IgA, and IgM levels 5, 6
• Serum free light chain (FLC) assay: With kappa/lambda ratio to assess clonal light chain production 5, 6

Bone Marrow Examination

• Not routinely required for IgG MGUS if serum M-protein ≤15 g/L without end-organ damage 8, 5
• Mandatory for all IgA and IgM M-proteins to assess plasma cell percentage and perform cytogenetic studies 8, 5
• CD138 staining: Should be performed to accurately quantify plasma cell percentage when bone marrow is examined 5

Imaging Considerations

• Not routinely recommended for IgG M-protein ≤15 g/L or IgA M-protein ≤10 g/L without bone pain 8
• Should be considered for higher M-protein levels: skeletal survey for non-IgM MGUS; CT chest/abdomen/pelvis for IgM MGUS 8
• Low-dose whole-body CT: May be superior to conventional radiography for detecting bone lesions 8

Exclusion of End-Organ Damage (CRAB Criteria)

To confirm MGUS diagnosis, the following must be absent 5:

• C (Calcium): Serum calcium >11.5 mg/dL
• R (Renal): Creatinine >2 mg/dL or clearance <40 mL/min
• A (Anemia): Hemoglobin <10 g/dL or ≥2 g/dL below lower limit of normal
• B (Bone): Lytic lesions, severe osteopenia, or pathologic fractures

Risk Stratification

The Mayo Clinic risk stratification model uses three factors—M-protein size (≥15 g/L), non-IgG isotype, and abnormal FLC ratio—to predict progression risk. 8, 6

Risk Categories and 20-Year Progression Rates

• Low risk (0 factors): 5% progression at 20 years 8, 6
• Low-intermediate risk (1 factor): 21% progression at 20 years 8
• High-intermediate risk (2 factors): 37% progression at 20 years 8
• High risk (3 factors): 58% progression at 20 years 8

Additional Prognostic Factors

• Bone marrow plasma cell percentage: ≥5% associated with higher risk 8
• Polyclonal immunoglobulin suppression: Reduction of uninvolved immunoglobulins predicts progression 8
• Evolving M-protein: Progressive increase over time significantly increases risk (55% vs 10% at 10 years for evolving vs non-evolving) 8

Monitoring Strategy

Low-risk MGUS patients should be monitored with SPEP at 6 months, then every 2-3 years for life, while intermediate/high-risk patients require SPEP and CBC at 6 months, then annually. 8, 6

Low-Risk MGUS Follow-Up

• SPEP at 6 months after diagnosis 6
• Then every 2-3 years for life or when symptoms arise 6
• No routine bone marrow biopsy or imaging required 8

Intermediate/High-Risk MGUS Follow-Up

• SPEP and complete blood count at 6 months 6
• Then annually for life 6
• Consider baseline bone marrow biopsy 6
• Imaging if M-protein levels exceed thresholds or symptoms develop 8

Treatment Approach

No treatment is indicated for MGUS—management consists solely of risk-stratified monitoring to detect progression before serious complications develop. 8, 6

• No therapy has demonstrated benefit in preventing progression to malignancy 6
• Treatment should only be initiated when symptomatic disease (multiple myeloma, AL amyloidosis, or other malignancy) develops 8
• Exception: Bisphosphonates (alendronate or zoledronic acid) are indicated for MGUS patients with osteopenia/osteoporosis or osteoporotic fractures 8

Critical Distinction: MGUS vs Smoldering Multiple Myeloma vs Multiple Myeloma

Smoldering multiple myeloma (SMM) represents an intermediate stage with M-protein ≥3 g/dL and/or bone marrow plasma cells ≥10%, but without end-organ damage, carrying a 10% annual progression risk for the first 5 years. 5, 6, 7

• MGUS: M-protein <3 g/dL, BM plasma cells <10%, no CRAB criteria, 1% annual progression risk 6, 7
• SMM: M-protein ≥3 g/dL and/or BM plasma cells ≥10%, no CRAB criteria, 10% annual progression risk (first 5 years) 5, 6
• Multiple Myeloma: BM plasma cells ≥10% or plasmacytoma, PLUS CRAB criteria or myeloma-defining biomarkers, requires immediate treatment 5, 6

---

Connection Between Transverse Myelitis and MGUS

An unusual association has been reported where acute transverse myelitis can present with transiently abnormal free light chain ratios and M-peaks that normalize as the neurologic disease improves, though the pathophysiologic link remains unclear. 4

• A pediatric case demonstrated longitudinally extensive transverse myelitis with abnormal serum M-peak and urine FLC ratio during acute phase 4
• The κ/λ ratio returned to normal range as the patient's neurologic status improved with treatment 4
• This suggests a potential transient monoclonal response during acute inflammatory states, though further studies are needed to clarify the association 4

Clinical Implication

When evaluating patients with transverse myelitis who have abnormal protein electrophoresis or FLC ratios, repeat testing after acute phase resolution is essential to distinguish true MGUS from transient inflammatory changes 4