She had headaches for many years. She visited multiple doctors, including her primary care physician, a neurologist, a pain clinic, and even a headache specialist, but she was unable to find an effective treatment. Over time she developed additional symptoms, including unexplained rashes and abdominal pain. When a close family member was diagnosed with an autoinflammatory disease, she was referred to my clinic to see if she, too, had one of these rare illnesses.
Autoinflammatory diseases are a group of illnesses that cause recurrent episodes of fevers and other symptoms such as joint pain, rash, stomach ache, and fatigue. Until recently, I didn’t fully appreciate the extent to which these protean illnesses may also cause headaches and other neurological symptoms.
Autoinflammatory diseases cause an inappropriate release of chemicals into the bloodstream (including IL-1β in several conditions) that produce their many symptoms. These same chemicals are usually released by the body–in a very controlled fashion–whenever it encounters an infection. However, in patients with autoinflammatory diseases, the release of these chemicals is uncontrolled and leads to the manifestations of the disease. Because the same chemicals get released during an infection and as part of an autoinflammatory disease, it is often challenging to distinguish between the two conditions; many patients with autoinflammatory diseases are commonly diagnosed with recurrent infections before the diagnosis of autoinflammatory disease is made.
In some autoinflammatory diseases, like cryopyrin-associated periodic syndrome (CAPS), cells within the brain and spinal cord are made to produce these chemicals, causing a powerful inflammatory reaction and recruiting white blood cells into the fluid that surrounds the brain, similar to what happens in patients with meningitis. No wonder patients with CAPS complain of headaches!
In fact, many autoinflammatory diseases have been shown to cause headaches including mevalonate kinase deficiency (HIDS), TNF receptor-associated periodic syndrome (TRAPS), familial Mediterranean fever, and even periodic fevers, aphthous stomatitis, pharyngitis, and adenitis (PFAPA). In the study discussed here, we showed that a third of children with PFAPA experience headaches during fever flares.
But it’s not just headaches. Autoinflammatory diseases may affect the brain in a multitude of ways. Patients with deficiency of adenosine deaminase 2 (DADA2) can develop strokes at an early age, in addition to periodic fevers, rashes, and vasculopathy. Those with macrophage activation syndrome (or hemophagocytic lymphohistiocytosis) may develop a variety of neurological complications including lethargy, seizures, irritability, confusion, and even coma.
Also, there is a group of illnesses within the autoinflammatory family called “interferonopathies” that cause even more devastating neurological problems. Like other autoinflammatory illnesses, the interferonopathies cause an uncontrolled release of chemicals into the blood (in this case, the chemical is interferon) that cause inflammation throughout the body, especially within the brain. The most well-known interferonopathy is called Aicardi-Goutières syndrome (AGS), which affects children shortly after birth. It causes irritability, fevers, loss of skills, poor feeding, seizures, and even blindness. Treatment remains challenging, but it is no longer accurate to say there are no potentially effective treatments. Specialist care may include targeted therapies such as JAK inhibitors; responses and risks vary, and existing neurologic injury may not be reversible. The EULAR/ACR interferonopathy guidance discusses the evidence and its limitations.
My patient improved after starting a medication for her autoinflammatory disease. She still has headaches, although not as severe as they were previously. Unfortunately, her story is not unique; although we’ve made tremendous progress in understanding these rare illnesses, there is still an unmet need for more effective treatments for patients with autoinflammatory diseases. Also, she experienced a long delay in the diagnosis of her condition; the article described research on leveraging wearable thermometers to help physicians make more timely and accurate diagnoses.
Putting headaches in context
Headaches are common and usually have explanations other than a rare autoinflammatory disease. The broader history and examination determine whether further evaluation is appropriate. A sudden severe headache, new weakness, confusion or other acute neurologic change needs urgent medical assessment.
Clinical context updated September 30, 2026; the patient story is preserved.