What could be the cause of gradual onset left-sided weakness with a normal brain Magnetic Resonance Imaging (MRI)?

Gradual Onset Left-Sided Weakness with Normal Brain MRI: Differential Diagnosis

The most likely causes of gradual onset left-sided weakness with normal brain MRI include spinal cord pathology (requiring cervical/thoracic spine MRI), motor neuron disease (particularly ALS), peripheral nerve disorders, and functional neurological disorder, with the diagnostic approach prioritizing spinal imaging first followed by electromyography and nerve conduction studies. 1

Immediate Diagnostic Priorities

Spinal Cord Evaluation

• MRI of the cervical and thoracic spine without contrast is the critical next imaging study, as spinal cord lesions commonly present with unilateral weakness but will not appear on brain MRI 1
• The "snake eyes" appearance on T2/STIR sequences in the anterior horns may indicate motor neuron disease, though this finding appears later in disease course 1
• Spinal cord compression, demyelinating lesions, or intrinsic cord pathology can all present with gradual unilateral weakness 1

Motor Neuron Disease Consideration

• Amyotrophic lateral sclerosis (ALS) typically presents with gradual weakness and has normal or near-normal brain MRI 1
• ALS manifests with both upper motor neuron signs (hypertonicity, hyperreflexia) and lower motor neuron signs (fasciculations, muscle atrophy, weakness) 1
• Electromyography and nerve conduction velocity studies are the key diagnostic tests for ALS, as imaging is primarily used to exclude other conditions rather than confirm ALS 1
• The median survival is 3-4 years after symptom onset, making timely diagnosis critical for patient counseling and management 1

Metabolic and Systemic Causes

Wilson Disease

• Wilson disease can present with neurologic symptoms including motor abnormalities with dystonia, hypertonia, and rigidity, but brain MRI typically shows basal ganglia abnormalities 1
• However, significant brain imaging abnormalities may be present even before symptom onset in some individuals 1
• If Wilson disease is suspected despite normal brain MRI, obtain serum ceruloplasmin, 24-hour urine copper, and slit-lamp examination for Kayser-Fleischer rings 1
• Hepatic copper content >250 μg/g dry weight provides critical diagnostic information 1

Neurosyphilis

• Paretic neurosyphilis can present with progressive cognitive decline and focal neurological signs despite non-specific or normal brain imaging 2
• Obtain serum RPR and, if positive, cerebrospinal fluid VDRL testing 2
• This is a devastating but easily treatable condition that is frequently misdiagnosed 2

Peripheral Nervous System Disorders

Neuromuscular Weakness Evaluation

• The pattern of weakness (proximal vs. distal), tempo of progression, and associated symptoms guide localization 3
• Peripheral nerve disorders, neuromuscular junction disorders, and myopathies can all present with gradual unilateral weakness 3
• Electromyography and nerve conduction studies are essential to differentiate between neuropathic, myopathic, and neuromuscular junction pathology 3

Rare but Important Considerations

Ipsilateral Stroke Phenomenon

• In extremely rare cases, ipsilateral weakness can result from ipsilateral stroke due to functional reorganization of corticospinal tract pathways 4
• This typically occurs in patients with previous contralateral hemisphere or brainstem injury 4
• The ipsilateral corona radiata, internal capsule, basal ganglia, or thalamus are typically involved 4

Functional Neurological Disorder

• When all organic causes are excluded, functional neurological disorder should be considered 3
• This diagnosis requires positive clinical signs (Hoover's sign, give-way weakness) rather than being purely a diagnosis of exclusion 3

Critical Diagnostic Algorithm

1. Obtain MRI of cervical and thoracic spine without contrast immediately to exclude spinal cord pathology 1

2. Perform electromyography and nerve conduction studies to evaluate for motor neuron disease, peripheral neuropathy, or neuromuscular junction disorders 1, 3

3. Assess for upper and lower motor neuron signs on examination:

   • Upper motor neuron: hyperreflexia, spasticity, Babinski sign 1
   • Lower motor neuron: fasciculations, muscle atrophy, hyporeflexia 1

4. Screen for metabolic causes if clinical suspicion warrants:

   • Wilson disease: ceruloplasmin, 24-hour urine copper, slit-lamp exam 1
   • Neurosyphilis: RPR, CSF VDRL if indicated 2

5. Consider advanced brain imaging if initial workup is unrevealing:

   • High-resolution MRI with susceptibility-weighted sequences may detect subtle lesions 1
   • MRI spectroscopy or functional MRI are not routinely indicated 1

Common Pitfalls to Avoid

• Do not assume normal brain MRI excludes all neurological pathology - spinal cord lesions and motor neuron disease are common causes of unilateral weakness with normal brain imaging 1
• Do not delay spinal imaging - this is the most critical next diagnostic step 1
• Do not rely solely on imaging for motor neuron disease diagnosis - electrodiagnostic studies are essential 1
• Do not overlook treatable causes such as neurosyphilis or Wilson disease, which require specific laboratory testing 1, 2
• Recognize that "gradual onset" favors neurodegenerative, metabolic, or compressive etiologies over acute vascular events 1, 3