A 40-year-old man with a history of episodic cluster headache (CH) was referred to the headache clinic for intractable headache that has been persistent for the past year without remission. His initial diagnosis of CH (obtained 2 years previously) was based on a 3-week episode of daily, severe, unilateral headache attacks in and above the right eye twice per day for 45 min associated with conjunctival injection, tearing, and rhinorrhea. This was successfully treated with subcutaneous sumatriptan (6 mg) and 100 % oxygen at 15 l/min via rebreathing mask for acute episodes and verapamil preventively (titrated up to 360 mg daily). All medicines were discontinued 5 weeks after the cluster period started.

He was pain-free for 1 year and subsequently began to experience severe unilateral head pain again. On this occasion, his head pain occurred three to four times a day and lasted up to 90 min per episode. The pain was always right sided, periorbital, knifelike, and excruciating with an intensity of 10/10 and consistently associated with ipsilateral conjunctival injection, tearing, miosis, ptosis, and rhinorrhea. He was again treated with subcutaneous sumatriptan and high flow oxygen therapy, which provided symptomatic benefit only 25 % of the time. He was started on verapamil (titrated up to 480 mg daily) for preventive treatment. However, he continued to have recurrent pain daily even after 2 months of treatment. High-dose corticosteroids were added with a 2-week taper but without efficacy. Due to lack of response, lithium (900 mg daily) and topiramate (up to 300 mg/day) were tried, each for 6 weeks, without efficacy. He was switched to intranasal zolmitriptan with some efficacy but continued to experience three attacks of head pain daily. He was hospitalized for 1 week both for severe pain and suicidal ideation.

He was otherwise healthy with no significant past history. He did not take any other prescription medications and reported no allergies to medication. He was smoking one pack of cigarettes per day for 15 years. He stopped drinking alcohol 2 years previously after receiving a diagnosis of cluster headache. His mother suffered from migraine. He had no family history of cluster headache.

At the time of the neurological exam, he was pain-free, and his exam was normal with the exception of slight ptosis on the right.

This patient has a history of CH. While it is possible for episodic CH to transform into chronic cluster headache (CCH), any significant change in headache characteristic and duration warrants further investigation. Differential diagnosis for CCH must include other primary headache disorders with autonomic features, such as chronic migraine and other trigeminal autonomic cephalalgias (TACs). In addition, secondary headache conditions can occasionally mimic symptoms of chronic CH, especially lesions in the parasellar area or dissection of a carotid artery.

CCH can be differentiated from chronic migraine by the unilateral and ipsilateral nature of its accompanying autonomic symptoms and especially by its timing (short duration and frequent episodes daily). In comparison, migraine patients are much more likely to describe bilateral lacrimation, conjunctival injection, periorbital edema, ptosis, and rhinorrhea, although unilateral symptoms can occur. Migraineurs also have much longer duration of attacks with more associated symptoms such as nausea, photo- and phonophobia, and worsening with exertion. While other TACs can also cause head pain with ipsilateral autonomic symptoms, they can be distinguished from CH most readily based on their duration and frequency. CH can be distinguished from hemicrania continua by its short, more intense painful attacks with predictable interictal pain-free periods and its circadian or circannual periodicity.

Vascular abnormalities such as carotid dissection, aneurysms, venous sinus thrombosis, and cavernous sinus dural arterial-venous (AV) fistulas as well as structural disease of the sellar and parasellar structures have all been reported to mimic treatment-resistant CH. There have also been rare reports of multiple sclerosis lesions in the pontomedullary trigeminal nuclei presenting as unrelenting cluster-like head pain. Therefore, when a patient, even one with a prior history of CH, presents with intractable severe headache different from the prior CH episode, a thorough updated history as well as a general and neurological examination must be performed. Consideration should also be given to a repeat MRI, as a new lesion may not be detectable by history and neurological exam alone. On exam, visual field deficits may be suggestive of a sellar mass such as a prolactinoma. Cranial nerve palsies with severe unilateral retro-orbital pain may be suggestive of Tolosa-Hunt syndrome or other structural abnormalities in the cavernous sinus. Focal weakness, numbness, or vision changes, especially interictally, may suggest structural lesions, vascular abnormalities, or multiple sclerosis.

Finally, secondary headaches from infections or other local diseases of ophthalmological, nasal, dental, or sinus origins can cause headache pain together with symptoms of lacrimation, conjunctival injection, or rhinorrhea. Patients suffering from these secondary headaches tend to have more associated symptoms, such as fever, chills, and cough. In addition, they tend to suffer from continued pain instead of the episodic pain and interictal pain-free periods characterizing CH.

Screening laboratory studies including white blood cell count (WBC), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) can help to identify an infectious or inflammatory etiology that may be causing or contributing to the head pain. In addition, serum melatonin levels can be obtained, as decreased nocturnal melatonin secretion with low melatonin levels has been linked with CH, and may provide a source of therapy when abnormality is identified. To definitively rule out secondary causes of severe, unilateral cluster-like headache, imaging studies must be performed. Magnetic resonance imaging (MRI) of the brain with and without contrast and magnetic resonance studies focusing on the arteries and veins in the brain and the neck (MRA and MRV) are the preferred initial imaging studies. A head CT may be able to identify certain mass lesions and vascular lesions but is much less sensitive than MRI. If the suspicion is high clinically for chronic sinusitis as the etiology or as a contributing factor for the headache (i.e., background pain outside of cluster attacks, pain upon palpation of the maxillary sinuses, bad smelling or tasting post nasal drip, etc.), a CT scan of the paranasal sinuses is the best study. If vascular malformation or aneurysm is suspected or suggested by MRA or MRV, further vessel imaging with contrasted CT scan, CT angiography, or even more invasive (and more sensitive) cerebral angiography may be necessary.

This patient’s neurological exam revealed right-sided ptosis. While it is possible for CH sufferers to have persistent ipsilateral ptosis and/or pupil changes even interictally, given the change in the treatment responsiveness of his headache, an MRI of the brain with and without contrast was performed. This was found to be normal. In addition, MRA of his head and neck and MRV of his head were performed with contrast, and they were also normal. His basic laboratory studies were unremarkable. With these normal results, secondary causes of his headache were effectively ruled out.

By the time he presented to the headache clinic, he had already tried and failed several pharmacologic options for CH at appropriate doses. He had also been hospitalized once for suicidal ideation, which further attested to the devastating impact CH had on this patient. Occipital nerve block was performed ipsilaterally, without significant benefit. After confirming a normal EKG and no history of coronary artery disease or arrhythmias, he was started on methylergonovine maleate (0.2 mg three times a day) for prevention over the next 3 months. He was concurrently referred for greater occipital nerve stimulation (ONS). He received ipsilateral placement of an occipital nerve stimulator and was set on continuous stimulation. He continued to use high flow oxygen for acute pain. At 3-month follow up, his headache frequency had decreased by 75 %, and his headache intensity decreased by 50 %. Methylergonovine maleate was stopped after 3 months of use to decrease the risk of fibrosis, and he was able to maintain the decreased frequency and intensity of the headache on ONS.

Our patient had an initial diagnosis of episodic CH and transformed into CCH. While his symptoms (unilateral severe pain with associated ipsilateral autonomic dysfunction occurring with predictable periodicity) fulfilled the diagnostic criteria for CH, the change in the treatment responsiveness of his head pain and the shift to chronic cluster with its unrelenting pain were red flags that something else might have been going on. This led to further brain and vessel imaging to rule out secondary causes of cluster-like headache pain.

Interventional treatment options are available for those with CCH in which pharmacologic therapies have been found ineffective or insufficient. Further, a high prevalence of depression and self-inflicted injuries have been reported in the population of active and CCH sufferers, and clinicians must take great care to identify those at risk. (The patient in this case was hospitalized for suicidal ideation.)

CH is a devastating headache disorder characterized by its unilateral severe nature and its associated ipsilateral cranial autonomic symptoms, and it is defined in particular by its short duration and its circadian and circannual periodicity. CH is considered chronic when there have been no pain-free periods over the course of 1 year, or if a pain-free period lasts less than 1 month.

CH is one of the more common TACs, but is still relatively rare compared to migraine or tension-type headache. The lifetime prevalence of cluster headache is about 124/100,000. There is a 5–18-fold increased risk of developing CH for first-degree relatives of patients with CH. About one in six CH patients suffers from the chronic form. Men are three to four times more likely than women to suffer from CH and are more likely to have chronic CH.