What is the differential diagnosis for a 42-year-old female with uncontrolled diabetes (DM), throbbing unilateral headache on the left side, left eye ptosis, and reduced vision in the left eye, with a normal MRI brain scan?

Differential Diagnosis for Unilateral Ptosis with Headache and Vision Loss in Diabetic Patient

Most Likely Diagnosis: Diabetic Third Nerve Palsy (Superior Division)

The most likely diagnosis is diabetic oculomotor nerve palsy affecting the superior division, which characteristically presents with isolated ptosis and can occur without diplopia or pupillary involvement in patients with uncontrolled diabetes. 1

Key Diagnostic Features Supporting This Diagnosis:

• Isolated ptosis as sole manifestation: Diabetic third nerve palsy can present with acute ptosis as the only finding, particularly when affecting the superior division that innervates the levator palpebrae superioris 1
• Uncontrolled diabetes: This is the most common etiologic subset of oculomotor nerve palsy in adults, with long-standing poorly controlled type 2 diabetes being the primary risk factor 2
• Normal MRI: Diabetic microvascular ischemic neuropathy typically does not show abnormalities on standard brain MRI, as the pathology is at the microvascular level 1, 2

Critical Differential Diagnoses to Exclude

1. Pupil-Involving Third Nerve Palsy (Compressive Lesion)

• Urgent evaluation required: If pupillary involvement is present (anisocoria, dilated pupil), this represents a neurosurgical emergency requiring immediate neuroimaging with MRI or CTA to exclude posterior communicating artery aneurysm 3, 4
• Clinical examination: Carefully assess for anisocoria in both bright and dim illumination 3, 4
• Pitfall to avoid: Failing to recognize pupil-involving third nerve palsy can have life-threatening consequences 3, 4

2. Myasthenia Gravis

• Variable, fatigable ptosis: Worsens with prolonged upgaze or throughout the day 3, 4
• Ice test: Apply ice pack over closed eye for 2 minutes; reduction of ptosis by ≥2mm is highly specific for myasthenia gravis 4
• No pupillary abnormalities: Unlike third nerve palsy, pupils remain normal 5
• Consider even with negative antibodies: Single-fiber EMG may be needed if seronegativity occurs 3

3. Horner's Syndrome

• Mild ptosis with miosis: Disruption of sympathetic pathway causes milder ptosis (1-2mm) compared to third nerve palsy, accompanied by pupillary miosis and anhidrosis 5
• Requires evaluation: For sympathetic pathway disruption from carotid dissection, tumor, or stroke 4, 5

4. Brainstem Stroke

• Red nucleus infarction: Can cause isolated complete ptosis without extraocular movement deficits in patients with cardiovascular risk factors 6
• Consider with other neurological symptoms: Brainstem lesions affecting the central caudal nucleus or fascicles may present with ptosis and associated neurological deficits 3, 5
• MRI indication: If accompanied by other neurological symptoms, obtain MRI head and orbits with contrast 3, 5

5. Orbital/Mechanical Causes

• Orbital inflammatory conditions: Thyroid eye disease, IgG4-related disease, or idiopathic orbital inflammatory syndrome can present with unilateral ptosis 3
• Proptosis: If present, obtain MRI orbits without and with contrast to evaluate for mass lesion 3, 4
• Floppy eyelid syndrome: Upper eyelid easily everted with edema 3

Diagnostic Algorithm

Immediate Assessment:

1. Pupillary examination: Check for anisocoria in bright and dim light to exclude compressive third nerve palsy 3, 4
2. Extraocular movements: Assess for diplopia, ophthalmoplegia, or strabismus 3
3. Fundoscopic examination: Evaluate for papilledema, optic atrophy, or diabetic retinopathy 3, 7
4. Fatigability testing: Perform ice test or rest test if myasthenia gravis suspected 3, 4

Imaging Considerations:

• Normal MRI does NOT exclude diabetic third nerve palsy: Microvascular ischemia typically shows no abnormalities on standard imaging 1, 2
• Isolated ptosis without pupillary involvement or other neurological symptoms typically does not warrant advanced neuroimaging as first-line investigation 3, 5
• MRI with contrast indicated if: Pupillary involvement, ophthalmoplegia, proptosis, or other neurological deficits present 3, 4, 5

Management Approach for Diabetic Third Nerve Palsy

• Aggressive glucose control: Initiate or intensify insulin therapy to achieve glycemic control 1
• Expected recovery: Partial improvement may occur within one week with improved hyperglycemia control, though complete resolution typically takes 3-6 months 1, 2
• Symptomatic management: Alternating monocular occlusion or prisms for diplopia if present 2
• Monitor for diabetic retinopathy: 56% of patients with diabetic oculomotor palsy have concurrent diabetic retinopathy 2

Common Pitfalls to Avoid

• Missing pupil-involving third nerve palsy: Always assess pupils carefully, as this represents a neurosurgical emergency 3, 4
• Assuming normal MRI excludes all pathology: Diabetic microvascular neuropathy does not show on standard imaging 1, 2
• Overlooking myasthenia gravis: Variable presentation requires high index of suspicion and ice test even with negative initial antibodies 3, 4
• Failing to control hyperglycemia aggressively: This is the primary treatment for diabetic third nerve palsy 1