In a patient with a history of breast cancer who now has a new unilateral tongue deviation and a negative magnetic resonance angiogram, what is the most likely cause and what work‑up and management should be pursued?

Hypoglossal Nerve Palsy in Metastatic Breast Cancer with Negative MRA

In a breast cancer patient with new tongue deviation and negative MRA, immediately obtain contrast-enhanced brain and skull base MRI to evaluate for leptomeningeal disease, perineural tumor spread, or skull base metastases—the most likely causes in this oncologic context. 1, 2

Critical Diagnostic Approach

Immediate Imaging Requirements

• Obtain gadolinium-enhanced brain MRI focusing on the entire hypoglossal nerve pathway from medulla through skull base to sublingual space, as MRA only evaluates vascular structures and will miss the majority of pathology causing cranial neuropathy 1, 2

• Include dedicated skull base sequences with thin cuts through the hypoglossal canal, as metastatic breast cancer commonly involves the skull base and can cause isolated cranial nerve palsies through bone metastases or perineural invasion 3

• Evaluate for leptomeningeal disease with post-contrast FLAIR sequences, as breast cancer (particularly HER2-positive and triple-negative subtypes) has high propensity for leptomeningeal spread that can present with isolated cranial neuropathies 1

Anatomic Segmental Analysis

The hypoglossal nerve should be evaluated in five distinct segments, as each has different pathologic predilections 3:

• Medullary segment: Look for intraparenchymal brain metastases affecting the hypoglossal nucleus 3
• Cisternal segment: Assess for leptomeningeal disease coating the nerve 1, 3
• Skull base segment: Examine the hypoglossal canal for bone metastases or perineural tumor spread 3
• Nasopharyngeal/carotid space segment: Evaluate for nodal metastases or direct tumor extension 3
• Sublingual segment: Check for direct invasion from oral cavity or tongue base lesions 4, 3

Most Likely Etiologies in This Context

Primary Considerations

• Leptomeningeal carcinomatosis is the leading concern in metastatic breast cancer presenting with isolated cranial neuropathy, requiring CSF analysis and dedicated MRI sequences for diagnosis 1

• Skull base metastases involving the hypoglossal canal are common in breast cancer and may not be visible on standard brain imaging without dedicated skull base protocols 3

• Perineural tumor spread can occur even when the primary lesion is not evident on imaging, particularly with infiltrative metastatic patterns 4

Additional Workup Required

• Lumbar puncture with CSF cytology if leptomeningeal disease is suspected on imaging or if MRI remains negative despite high clinical suspicion 1

• PET-CT may identify occult metastatic disease along the nerve pathway when conventional MRI is negative, particularly for perineural invasion 4

• Examination under anesthesia with deep biopsy of the tongue base and oropharynx should be considered if imaging remains unrevealing, as infiltrative lesions may not be evident on MRI 4, 5

Management Algorithm

If Leptomeningeal Disease Confirmed

• Multidisciplinary discussion is mandatory as there is no accepted standard of care for leptomeningeal metastases 1

• Consider focal radiation therapy for circumscribed symptomatic lesions causing the cranial neuropathy 1

• Avoid combining intrathecal methotrexate with radiation due to increased neurotoxicity risk 1

If Skull Base Metastases Identified

• Stereotactic radiosurgery or fractionated radiation to the skull base lesion is typically the primary treatment 6, 1

• Continue systemic HER2-targeted therapy if extracranial disease is controlled and the patient has HER2-positive disease 1

If All Imaging Negative

• Idiopathic isolated hypoglossal nerve palsy remains a diagnosis of exclusion after comprehensive workup 5, 7

• Trial of corticosteroids and mecobalamin may be considered, though recovery is unpredictable (complete recovery possible in younger patients, less likely in older patients) 5

• Serial imaging every 2-4 months to monitor for emergence of previously occult disease 1

Critical Pitfalls to Avoid

• Never assume negative MRA excludes serious pathology—MRA only evaluates blood vessels and will miss parenchymal, leptomeningeal, and bony lesions that commonly cause cranial neuropathies in cancer patients 1, 2

• Do not delay CSF analysis when leptomeningeal disease is suspected, as MRI sensitivity for leptomeningeal carcinomatosis is imperfect and CSF cytology may be diagnostic 1

• Avoid attributing symptoms to "stroke" based on negative MRA alone—ischemic stroke does not cause isolated hypoglossal palsy without other brainstem signs 3

• Do not miss perineural invasion—this can occur with normal-appearing imaging and requires high index of suspicion with deep tissue biopsy if imaging is unrevealing 4