New Daily Persistent Headache

New daily persistent headache (NDPH) is among the most underrecognized and undertreated headache disorders. The International Classification of Headache Disorders, 3rd edition (ICHD-3) defines NDPH by its distinct onset, which becomes constant and unremitting within a day (Table 1).¹ Many people with NDPH have a self-limiting disorder that resolves in less than 1 year. Many others, however—especially those seeking neurologic care—have NDPH that is resistant to therapy and persists much longer.² Although headache onset in NDPH is abrupt, resolution is not inevitable, and improvement tends to be gradual.³

Clinical Features

The headache features of NDPH vary among individuals and may be indistinguishable from more common primary headache disorders. Most individuals with NDPH can specify the exact date, or least month, of headache onset. Although most do not remember the exact time of onset, a minority describe a sudden or “thunderclap” onset. Most have continuous pain, and some experience exacerbations, whereas others have a relatively constant pain that rarely fluctuates. The headache is usually bilateral, and an occipital location is more common than ocular, temporal, or more diffuse pain.⁴

Migraine features are common in people with NDPH presenting for treatment in neurology or headache clinics.⁵ Previous editions of the ICHD excluded headaches with migrainous features from an NDPH diagnosis,^6,7 which changed with the recognition of several different NDPH phenotypes. In tertiary headache centers, most patients with NDPH present with more severe headache phenotypes (eg, chronic migraine, including symptoms such as nausea, light or sound sensitivity, and vertigo or imbalance). Individuals with a personal or family history of migraine may be more likely to have migrainous features with NDPH. It is unclear if these different clinical presentations are because of different etiologies or reflect biologic differences among individuals in response to the same stimulus. Although some people with NDPH have a family history of notable headache, NDPH has no known genetic basis and most affected individuals are not able to identify family members with the disorder. Several other symptoms that commonly coexist with NDPH include light-headedness, blurry vision, insomnia, paresthesias, and fatigue. Mood disorders, in particular anxiety disorders, are very common, and in a case series, the majority of participants with NDPH had severe anxiety.⁸

Epidemiology

The prevalence of NDPH in the general population is approximately 0.1% although this may have increased owing to less restrictive diagnostic criteria. Women are more likely to develop NDPH than men, but the ratio is more equal than that of migraine. Some studies suggest a relatively even ratio of men and women with NDPH.⁹ The mean age of onset for NDPH onset is the fourth decade of life, although men tend to have later onset than women. NDPH is more common in children with daily headache compared with adults.¹⁰ In our tertiary headache center, we have diagnosed over 1,500 individuals with NDPH over the past 20 years. Although some individuals already knew they had NDPH, the majority were unaware of their diagnosis at their initial visit.

Precipitating Factors

NDPH is considered a primary headache disorder, and the majority of persons with NDPH do not identify precipitating events. The diagnosis of NDPH does not include proven causes of secondary headache (eg, cerebrospinal fluid [CSF] hypertension or hypotension, vascular or traumatic brain injury, or central nervous system [CNS] infection). Of those who do report an inciting factor for NDPH, an infection or flu-like illness is the most common cause mentioned. NDPH may start during the acute illness or within the next month. Several studies have evaluated persons with NDPH for potential viral etiologies.¹¹ Acute or chronic Epstein-Barr virus (EBV) infection may be associated with NDPH,¹² as may several other infections (eg, recent herpes simplex virus, cytomegalovirus, herpes zoster, adenoviruses, arboviruses, and streptococcal infection). More recently, there have been several reports of headache after COVID-19 persisting well beyond the initial illness in otherwise healthy individuals (see also Headache in Dysautonomia & “Long COVID”/PASC in this issue).¹³

Memorable or stressful life occurrences, including trauma or surgery, Valsalva events,¹⁴ medications, or withdrawal from medications can precipitate NDPH. Life events such as menarche or a postpartum state are other reported precipitating factors for NDPH. In children, NDPH is most common at the start of a new school year.¹⁵

Pathophysiology

The biologic causes of NDPH may be similar to other primary headache disorders (eg, migraine), considering symptoms can be fairly similar with the exception of onset. Many comorbid conditions occur with NDPH (eg, mood disorders, asthma, and allergies) that are identical to those occurring with migraine.¹⁶ The relationship of several viruses with NPDH supports the concept of NDPH as a postinfectious immune-mediated disorder, which is also supported by elevated markers of CNS inflammation (eg, tumor necrosis factor α).¹⁷

Diagnostic Test & Ruling Out Secondary Headaches

Numerous secondary disorders can precipitate NDPH, although it is a primary headache disorder as well. Because diagnostic criteria for NDPH include persistence for at least 3 months, most catastrophic etiologies that cause sudden-onset headache (eg, large stroke or brain cancer) are likely to be observed much earlier and are, thus, less likely to present in the outpatient setting.

Individuals who have signs or symptoms suggesting serious secondary headache (Table 2) should have a prompt reevaluation of their NDPH diagnosis. Presentations of serious secondary headaches include fever, papilledema, progressive headache, confusion, severe medical disease, and focal neurologic findings on examination. The initial history should focus on potential secondary causes, including changes in the headache with positional changes or a history of sudden “thunderclap” onset.

The workup for secondary causes of NDPH should be thorough and focus on common causes of NDPH that would potentially change medical management. Brain MRI is usually worthwhile, especially in those with neurologic deficits, abnormal exam findings (eg, papilledema), or suspecting disorders of intracranial hypertension or hypotension. MRI findings, however, are usually nonspecific and white matter changes may be less frequent than what is seen in chronic migraine.¹⁸ Lumbar puncture and CSF analysis is indicated in persons who are immunosuppressed, have suspected increased intracranial pressure or chronic meningitis, or have headache refractory to treatment. Occasionally secondary disorders (eg, sinusitis or “contact point” headache), or primary headache disorders (eg, hemicrania continua or primary trochlear headache) will present as NDPH.¹⁹

Treatment

Because there is a lack of evidence for any specific treatment for NDPH, management of the disorder remains challenging. Medications that are effective for migraine are not always effective for NDPH, and no pharmacologic treatment of NDPH had a greater than 50% response rate in case series.¹¹ Analgesics and migraine-specific therapies (eg, triptans) are usually ineffective. A trial-and-error approach may be necessary, as well as combination therapy (see Rational Polypharmacy for Migraine in this issue), considering the refractory nature of NDPH. Most clinicians treat NDPH based on its phenotype, and 2 basic strategies are the following: 1) long-term preventive therapies including pharmacologic, behavioral, or neuromodulation modalities; and 2) short-term interventions to “break the cycle” of continuous headache and improve long-term outcomes (Table 3).

Several conventional preventive drugs for migraine have proven effective in selected persons with NDPH. These include onabotulinumtoxinA,²⁰ gabapentin, topiramate, tricyclic antidepressants and mexiletine.²¹ Medications that lower intracranial pressure such as indomethacin or acetazolamide can be considered, especially in those with clinical features, MRI abnormalities, or CSF findings suggesting these could be beneficial. Case reports have suggested the use of therapies that target inflammation or glial activation such as doxycycline, montelukast, and low-dose naltrexone.²²

Attempts to “break the cycle” of constant pain, potentially making the disorder more responsive to treatment, have included the use of steroids and antiseizure medications. A study showed the use of methylprednisolone and sodium valproate followed by preventive therapy for at least 3 months was effective.²³ Intravenous therapies used for migraine (eg, dihydroergotamine) may be less effective in NDPH.²⁴ Other therapies such as intravenous lidocaine²⁵ or ketamine²⁶ have been reported to successfully treat NDPH. Peripheral nerve blocks (eg, occipital nerve blocks) may provide immediate relief but are not likely to provide long-term improvement.

Clinical Controversies

The importance of making an NDPH diagnosis is unclear, especially in those with migraine features or who have a personal or family history of significant headache. Over time, symptoms of NDPH usually become indistinguishable from migraine or chronic tension-type headache. It is certainly possible that NDPH is simply migraine with unusual onset, and that environmental factors that trigger migraine to start (eg, viruses) may be underecognized.²⁷ A clinic-based study in a pediatric headache center failed to demonstrate differences between children with chronic migraine and NDPH. There are no approved treatments for NDPH and for most individuals, pharmacologic management is identical to other headache disorders. In our experience, however, making an NDPH diagnosis is worthwhile. An accurate diagnosis increases patients’ confidence in their providers and acceptance of their disease as well as informing the need for further diagnostic testing.

Although testing for secondary headache is routine for NDPH, the yield of such diagnostic testing is relatively low. When abnormal test results are found, they may represent incidental findings unlikely to cause NDPH. The initial cause of NDPH may have little relevance to the choice of therapies. A reasonable approach would be to focus on the most likely secondary causes based on individual risk factors and clinical characteristics, with a particular focus on testing that could change medical management.

Conclusion

Migraine often begins in childhood or in young adults, often in those with a strong family history of headache. This allows many with migraine time to develop exceptional coping strategies for managing their disease. These adaptations may include lifestyle routines or strategies to manage migraine at work or home. In contrast, most people with NDPH do not have a history of bothersome headache and find the experience quite distressing.^8,28 High rates of pain catastrophizing and acute medication overuse reflect the considerable distress that many people with NDPH experience. In the management of NDPH, it is important to explain NDPH, emphasize your experience in treating the disorder, show empathy, and promise to work together to improve outcomes.