Based on PubMed | Is muscle weakness a known side effect of melanoma treatments such as immune checkpoint inhibitors or BRAF/MEK inhibitors, and how should it be evaluated and managed if it develops?

Muscle weakness can occur with several melanoma treatments, including immune checkpoint inhibitors and BRAF/MEK inhibitors, and it deserves prompt evaluation because causes and urgency vary. Immune checkpoint inhibitors can trigger immune-related inflammation of muscle (myositis), nerve (neuropathy), or the neuromuscular junction (myasthenia gravis), which may range from mild to life‑threatening. ^[1] Immune checkpoint inhibitors are also linked to musculoskeletal symptoms like myalgia and arthralgia, and in some cases true myositis. ^[2] BRAF/MEK inhibitors more commonly cause fatigue, myalgia, and arthralgia; frank immune‑mediated neuromuscular syndromes are less typical, but significant weakness still warrants assessment and may require dose modification. ^[3]

How treatments cause weakness

• Immune checkpoint inhibitors (e.g., nivolumab, pembrolizumab, ipilimumab, durvalumab): These can unleash the immune system, sometimes attacking muscle fibers (myositis), nerves (Guillain–Barré–like neuropathy, optic neuritis), or the neuromuscular junction (myasthenia gravis), leading to rapid-onset proximal weakness, ocular/ptosis symptoms, swallowing problems, or diffuse neuropathic weakness. ^{[1] [4]} Severe cases have been reported across different regimens and may appear even after treatment stops. ^[5]
• BRAF/MEK inhibitors (e.g., encorafenib/binimetinib, dabrafenib/trametinib, vemurafenib/cobimetinib): These more often cause myalgia, arthralgia, fatigue, headache, fever syndromes, and gastrointestinal side effects, with weakness usually secondary to these symptoms rather than immune‑mediated myositis. ^[3] When toxicity is significant, dose interruption or reduction may be used. ^[6]

Red flags that need urgent attention

• New trouble breathing, swallowing, drooping eyelids or double vision, or rapidly progressive weakness suggest myasthenia gravis or severe myositis and require urgent evaluation. ^[1]
• Dark urine, severe muscle pain, very high fatigue, or chest symptoms may indicate myositis with rhabdomyolysis or myocarditis, which can be life‑threatening. ^[7]
• Ascending weakness, numbness, or reduced reflexes can indicate an acute inflammatory neuropathy. ^[1]

Initial evaluation steps

• Clinical exam: Document pattern (proximal vs distal), symmetry, cranial nerve involvement (ptosis, diplopia), reflexes, and respiratory/ bulbar function. Proximal symmetric weakness with myalgia suggests myositis; ocular/bulbar signs suggest myasthenia; areflexia/ascending weakness suggests neuropathy. ^[1]
• Labs: Creatine kinase (CK), aldolase, AST/ALT, troponin (screen for concurrent myocarditis), and thyroid tests (thyroid dysfunction is common with checkpoint inhibitors and can contribute to weakness). Markedly elevated CK supports myositis; normal CK does not rule out neuropathy or myasthenia. ^{[1] [2]}
• Electrodiagnostics: EMG/NCS to distinguish myopathic vs neuropathic patterns; repetitive nerve stimulation or single‑fiber EMG for myasthenia. ^[1]
• Autoantibodies: AChR and MuSK antibodies for suspected myasthenia gravis. Myositis-specific antibodies can be considered, though checkpoint inhibitor–related myositis may be seronegative. ^[1]
• Imaging/biopsy: Muscle MRI can show edema/inflammation; muscle biopsy helps confirm myositis when diagnosis is uncertain. ^[1]
• Medication review: Identify current melanoma regimen and timing; immune toxicities often present within weeks of initiating checkpoint inhibitors. ^[5]
• Cardiac and pulmonary assessment: If chest symptoms or dyspnea, screen for myocarditis or pneumonitis, which may accompany neuromuscular irAEs. ^[5]

Management principles

• Grade severity (Common Terminology Criteria for Adverse Events) and act promptly; withhold the suspected agent for moderate to severe weakness while evaluating. ^[5]
• Immune checkpoint inhibitor‑related myositis/neuropathy/myasthenia:
  • Mild (Grade 1): Consider close monitoring, NSAIDs/acetaminophen for myalgia; some cases may need low‑dose corticosteroids. ^[8]
  • Moderate to severe (Grade ≥2): Start systemic corticosteroids (e.g., prednisone 0.5–1 mg/kg/day or equivalent), escalate to IV methylprednisolone for severe or rapidly progressive weakness, and consult neurology. Hold immunotherapy; resume only after substantial improvement and steroid taper, if at all. ^{[5] [1]}
  • Myasthenia gravis features: Add pyridostigmine, and for severe cases or respiratory/bulbar involvement, use IVIG or plasma exchange and consider ICU monitoring. Early aggressive therapy improves outcomes. ^[9]
  • Neuropathy (e.g., Guillain–Barré–like): IVIG or plasma exchange are commonly used along with corticosteroids, guided by neurology. ^[9]
  • Steroid‑refractory cases: Consider additional immunosuppression (e.g., IVIG for myositis; rituximab or other agents under specialist guidance). Close follow‑up is essential. ^{[10] [11] [12]}
• BRAF/MEK inhibitor‑related weakness:
  • Supportive care for myalgia/arthralgia (acetaminophen, cautious NSAIDs). Assess for dehydration, fever syndrome, and thyroid dysfunction. ^[3]
  • If weakness is significant or persistent, dose interruption or reduction may be appropriate, with reassessment on rechallenge. ^[6]
  • If features suggest immune‑mediated disease (ocular symptoms, severe CK elevation), re‑evaluate for alternative causes and consider switching therapy, since this pattern is atypical for BRAF/MEK and may indicate another process. ^[3]

Practical monitoring and prevention

• Before and during checkpoint inhibitor therapy, educate on early symptoms of myositis, myasthenia, and neuropathy, and encourage prompt reporting. These events can be serious but are treatable when caught early. ^{[5] [1]}
• Baseline and periodic CK and thyroid tests may be considered in higher‑risk or symptomatic individuals; tailor frequency to clinical context. Neurologic review is warranted for new focal deficits or cranial nerve involvement. ^[1]
• For BRAF/MEK combinations, anticipate myalgia/arthralgia and fatigue, and discuss fever syndrome management and when to pause therapy. Most side effects are manageable with supportive care or dose adjustments. ^{[3] [6]}

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Summary table: Typical neuromuscular issues by therapy

Therapy class	Common neuromuscular symptoms	Serious immune-related syndromes	First-line management approach
Immune checkpoint inhibitors	Myalgia, arthralgia, fatigue	Myositis, myasthenia gravis, Guillain–Barré–like neuropathy, optic neuritis	Withhold drug for moderate–severe weakness; start corticosteroids; add IVIG/plasma exchange for severe or MG/GBS; neurology consult; cautious rechallenge if fully resolved
BRAF/MEK inhibitors	Myalgia, arthralgia, fatigue, headache; fever syndromes	Rare immune‑mediated myositis/MG; consider alternate causes if present	Supportive care; evaluate CK/thyroid; dose interruption/reduction; resume when improved; investigate atypical features

Immune checkpoint inhibitors have well‑recognized musculoskeletal and neurological toxicities that can cause true weakness and require timely corticosteroids and sometimes IVIG or plasma exchange, often with treatment interruption. ^[1] Arthralgia and myalgia are common and may be managed conservatively when mild, but escalation is needed when weakness is moderate to severe or involves ocular or bulbar muscles. ^[8] BRAF/MEK inhibitors more often produce myalgia and fatigue; significant weakness should prompt evaluation and may require dose modification. ^[3] Dose interruption or reduction for BRAF/MEK‑related toxicity is an accepted strategy when adverse reactions arise. ^[6]