What are the possible causes of severe headaches in a patient with Interstitial Lung Disease (ILD) on nintedanib (BIBF 1120) with normal MRI brain and no other explanatory findings?

Severe Headaches in ILD Patient on Nintedanib: Differential Diagnosis

The most likely diagnosis is nintedanib-induced headache as a medication adverse effect, though spontaneous intracranial hypotension (SIH) with potential cerebral venous thrombosis (CVT) must be urgently excluded given the normal MRI but concerning clinical presentation.

Primary Consideration: Nintedanib-Related Headache

• Nintedanib commonly causes headaches as an adverse effect, though gastrointestinal symptoms (diarrhea in 62%, nausea, vomiting, abdominal pain) are more frequently reported 1, 2
• The "pulling and tightening" sensation described is consistent with tension-type headache patterns that can occur as medication side effects
• However, headache is not among the most prominently documented adverse effects in major trials, making this diagnosis one of exclusion 3, 1

Critical Alternative: Spontaneous Intracranial Hypotension with CVT Risk

Despite normal MRI, SIH remains a serious consideration that requires specific imaging protocols:

Why SIH Must Be Excluded:

• Non-orthostatic headaches can occur in SIH, contrary to classic teaching—the case presented describes "holocephalic non-orthostatic headaches" that were initially misdiagnosed as migraine 3
• Dural enhancement may be the only initial MRI finding in SIH, and can be subtle or missed on routine sequences 3
• SIH can precipitate life-threatening CVT, even with initially normal imaging 3

Specific Imaging to Request:

• Review the existing MRI specifically for:

  • Smooth, diffuse dural and leptomeningeal enhancement (may be present without "brain sag" or tonsillar herniation) 3
  • Ipsilateral dural thickening and enhancement, which may indicate isolated cortical vein thrombosis 3

• If dural enhancement is present or clinical suspicion remains high, obtain:

  • CT venography or MR venography to evaluate for CVT 3
  • T2-susceptibility-weighted gradient echo sequences to look for cortical vein signal loss (the "cord sign") 3

Red Flags Requiring Urgent Venographic Imaging:

• Rapid increase in headache frequency or severity 3
• New neurological symptoms (dizziness, coordination problems, numbness, tingling) 3
• Headaches awakening patient from sleep 3
• Any focal neurological deficits 3

Other Differential Considerations

Tension-Type Headache (Primary)

• The "pulling and tightening" description is classic for tension-type headache
• However, neuroimaging cannot be recommended or excluded based on insufficient evidence for tension-type headaches 3
• Given the recent onset and severity in a patient without prior headache history, this should be a diagnosis of exclusion

Medication Withdrawal or Interaction

• Consider if patient recently stopped any medications
• Evaluate for drug-drug interactions with nintedanib that might precipitate headaches

Recommended Diagnostic Algorithm

1. Immediate re-review of existing MRI by radiologist specifically looking for:

   • Dural enhancement patterns 3
   • Subtle signs of intracranial hypotension
   • Cortical vein abnormalities 3

2. If any dural enhancement or high clinical suspicion:

   • Obtain CT venography or MR venography urgently 3
   • Consider digital subtraction angiography if venographic studies inconclusive but suspicion remains high 3

3. If all imaging definitively normal:

   • Trial of nintedanib dose reduction (from 150mg to 100mg twice daily) to assess if headaches improve 1, 2
   • Monitor for 1-2 weeks with close follow-up

4. If headaches worsen or new symptoms develop:

   • Immediate repeat imaging with venographic study 3
   • Consider neurology consultation for lumbar puncture to measure opening pressure if SIH remains suspected

Critical Pitfall to Avoid

The most dangerous error would be attributing these headaches to benign medication side effects or tension-type headache without excluding SIH/CVT, as this combination can rapidly progress to life-threatening complications including intracranial hemorrhage, seizures, and death 3. The case literature demonstrates that initial normal CT scans and misdiagnosis as migraine can delay recognition of SIH-associated CVT until catastrophic complications occur 3.