What investigations are needed to rule out differential diagnoses for this patient?

Investigations to Rule Out Differential Diagnoses

For a patient presenting with suspected neuromuscular pathology, begin with creatine kinase (CK), aldolase, comprehensive metabolic panel, thyroid function tests, and inflammatory markers (ESR, CRP), followed by electromyography (EMG) and nerve conduction studies (NCS) to differentiate myopathic from neuropathic processes. 1

Initial Laboratory Testing

First-Line Blood Tests

• Muscle enzyme panel: CK is the most sensitive marker for muscle injury and should be ordered first 1. Include aldolase, AST/ALT, and LDH as they can be elevated in myopathies and provide complementary diagnostic information 1
• Complete blood count with differential to evaluate for underlying infection or malignancy 1
• Comprehensive metabolic panel including glucose, electrolytes, kidney and liver function 2, 1
• Thyroid function tests (TSH, free T4) to rule out thyroid-related myopathy 1
• Inflammatory markers (ESR and CRP) to assess for systemic inflammation 1
• Troponin to evaluate for potential myocardial involvement, which can be fatal if missed 1

Important Caveat for Enzyme Interpretation

• If aldolase is elevated but CK is normal, consider glycogen storage diseases (Types IIIa, IV, V, VII), mitochondrial myopathies, or dermatomyositis 3
• This pattern requires specific workup including assessment for dermatomyositis features, autoantibody testing, and potentially muscle biopsy 3

Autoimmune and Inflammatory Workup

Autoantibody Testing

• Myositis-specific antibodies (anti-Jo-1, anti-Mi2, anti-SRP) and anti-synthetase panel should be performed when inflammatory myopathy is suspected 3, 1
• For myasthenia gravis: AChR and antistriated muscle antibodies; if negative, consider MuSK and LRP4 antibodies 2
• Note that absence of antibodies does not rule out the syndrome 2

Electrophysiologic Studies

EMG and Nerve Conduction Studies

• EMG/NCS should be performed together except in unique situations, as NCS alone provides incomplete diagnostic information and can lead to missed diagnoses 4
• EMG confirms myopathic process through detection of polyphasic motor unit potentials of short duration and low amplitude 3
• NCS differentiates neuropathy from myopathy and can identify axonal versus demyelinating patterns 5, 4
• These studies are essential for diagnosing myopathy, radiculopathy, plexopathy, motor neuron disorders, and peripheral neuropathies 4

Specific Testing for Neuromuscular Junction Disorders

• Repetitive nerve stimulation can identify defects of neuromuscular junction transmission 5
• Pulmonary function assessment with negative inspiratory force (NIF) and vital capacity (VC) when myasthenia gravis is suspected 2

Neurologic Examination and Additional Testing

Physical Examination Priorities

• Test for parkinsonism: bradykinesia/akinesia, parkinsonian gait/posture, or rigidity 2
• Evaluate motor neuron signs and primitive reflexes such as grasp reflex 2
• Test smooth pursuit and saccadic eye movements for vertical eye-gaze palsy 2
• Assess for unilateral dystonia, myoclonus, cortical sensory deficits, ideomotor apraxia 2

Neurologic Testing for Diabetic Neuropathy (if applicable)

• Thermal sensitivity, pinprick sensation, vibration perception (128-Hz tuning fork), pressure sensation (10-g monofilament), and ankle reflexes are recommended for screening distal symmetric polyneuropathy 2

Advanced Imaging

MRI Studies

• MRI of affected muscles with T2-weighted/STIR sequences detects muscle inflammation and guides biopsy site selection 1
• MRI brain and/or spine depending on symptoms to rule out CNS involvement or alternative diagnoses 2
• MRI spine with/without contrast to rule out compressive lesions and evaluate for nerve root enhancement when radiculopathy is suspected 2

Cardiac Evaluation

• ECG and consider transthoracic echocardiography (TTE) and/or cardiac MRI to evaluate concomitant myocarditis, particularly in immune-related myopathies 2

Differential Diagnosis Considerations

Excluding Alternative Diagnoses

• Cervical and lumbar disease (nerve root compression, spinal stenosis) should be excluded with appropriate imaging 2
• Cerebral infarction, Guillain-Barré syndrome require specific evaluation 2
• Drug-induced myopathy: detailed medication history is essential, particularly for statins, chemotherapeutic agents, and immune checkpoint inhibitors 1
• Metabolic causes: evaluate for hypocalcemia, hypomagnesemia, and renal insufficiency-related neurotoxicity 2

For Guillain-Barré Syndrome Suspicion

• Cerebrospinal fluid examination to identify albumino-cytological dissociation (elevated protein with normal cell count) 2
• Note that protein levels are normal in 30-50% of patients in the first week, so normal CSF protein does not rule out GBS 2
• Marked pleocytosis (>50 cells/μl) suggests alternative diagnoses such as leptomeningeal malignancy or infectious/inflammatory disease 2

Muscle Biopsy Indications

• Consider muscle biopsy when: presentation is atypical, there is absence of rash in suspected inflammatory myopathy, or diagnosis remains uncertain after initial testing 1
• Biopsy should target a weak muscle, guided by EMG or MRI findings 1
• Gomori trichrome stain can identify ragged red fibers suggestive of mitochondrial myopathy 3

Special Populations

Pediatric Considerations

• In children with suspected multiple sclerosis, at least one black hole (hypointense T1 lesion) and at least one periventricular lesion help distinguish MS from monophasic demyelination 2

Patients Over 50 Years

• More stringent criteria should be applied, including a higher number of periventricular lesions abutting the lateral ventricles 2

Common Pitfalls to Avoid

• Do not rely solely on NCS without needle EMG, as this leads to incomplete diagnostic information and missed diagnoses 4
• Do not miss cardiac involvement, which requires troponin, ECG, and potentially advanced cardiac imaging 2, 1
• Do not overlook metabolic and endocrine causes of weakness 1
• Do not fail to distinguish true muscle weakness from pain-limited movement 1
• Do not wait for antibody results before initiating treatment when GBS or myasthenia gravis is strongly suspected 2