Clinical manifestations

Presentation and course

The mode of onset is the main distinguishing feature of new daily persistent headache. It is distinguished by the acute onset of a daily, unremitting headache that lasts for at least three months. The onset is usually memorable: in one large series, 42% of patients recalled the exact day of onset (57). Around 80% of patients recall the exact month and year of onset. Up to 15% of patients report thunderclap-onset (21; 37). It typically occurs in patients without a prior history of headache (34; 79).

The baseline level of pain is usually moderate-to-severe, and the pain location is usually bilateral, although unilateral pain is occasionally noted; however, the phenotype and clinical features of new daily persistent headache can be similar to either chronic migraine or chronic tension-type headache. The chronic migraine phenotype of new daily persistent headache is often severe in pain and more common. Multiple studies have demonstrated the presence of migrainous features, such as throbbing, nausea, photophobia, and phonophobia in some patients. Nausea was seen in 33% to 68% of patients (34; 57; 49; 35; 79; 21). Given its similarities with migraine and tension-type headache, new daily persistent headache may simply be the mode of onset of these headache types rather than its own disease entity (55; 37).

Typical aura symptoms may occur and, as in migraine, are usually visual (34; 57). A minority of patients may have cranial autonomic symptoms, such as lacrimation, ptosis, miosis, and rhinorrhea, associated with headache exacerbations, but these symptoms are usually not prominent. With exacerbations, bilateral facial flushing lasting for minutes has also been described (57). Cutaneous allodynia was found in a quarter of new daily persistent headache patients (57). It is more common in migraine subtypes (04). Vertigo and dizziness have been reported in about 7% and 8% of patients, respectively (21).

New daily persistent headache is associated with psychiatric comorbidities, such as somatoform disorder, anxiety, severe depression, and panic disorder. Having migrainous features was associated with more depressive symptoms (52; 79; 78). In a study of 55 patients, 65.5% and 40% of patients with new daily persistent headache had severe anxiety and severe depressive symptoms, respectively (79). However, the authors did not discern whether these symptoms preceded symptoms of new daily persistent headache.

Prognosis and complications

Per the ICHD-3, there are two subtypes of new daily persistent headache: self-limiting (resolving within several months) and refractory (28).

In Vanast’s initial description of new daily persistent headache, the prognosis was described as generally excellent, with headache resolution occurring in 68% of patients at six months, 80% at 12 months, and men faring better than women (80). Subsequent studies show a much more unfavorable headache resolution rate. In a study of 56 patients with new daily persistent headache, all patients’ headaches persisted over six months, and many headaches persisted over five years (34). One study of 30 patients with new daily persistent headache showed a mean duration of 3.3 years, ranging from 3 months to 27 years (75).

Associations with longer duration of headache included Caucasian race, comorbid anxiety and depression, and migraine features. The ability to recall the precise onset date did not impart any prognostic significance. Relapsing and remitting new daily persistent headache, in which periods of continuous daily headache are interspersed with pain-free remissions lasting weeks or months, usually remits for the first time within two years of onset (57).

Clinical vignette

A 52-year-old man presented to a headache center with an unremitting daily headache that started spontaneously on a particular day in November 2012; he had no history of frequent headache attacks or any clear antecedent symptoms. The pain typically was holocephalic, pressure-like or sharp in character, moderate-to-severe in intensity, and associated with nausea, osmophobia, and poor concentration but without any positional component. His medical history included hypertension and depression. His mother and maternal grandmother had migraine. Brain MRI without gadolinium was reported as normal several years ago. Dozens of past prophylactic and acute medication trials were ineffective, and he was taking morphine tablets, acetaminophen/aspirin/caffeine tablets, and metoclopramide on a near daily basis. His neurologic examination was unremarkable. He was referred for a brain MRI with gadolinium, which showed no abnormalities. After the diagnosis was explained and he was counseled on medication overuse, he was started on nortriptyline for prophylaxis and naratriptan for headache exacerbations. Over the subsequent three years, his headaches remained daily, but the baseline level of pain diminished to a very mild, tolerable level with infrequent monthly headache exacerbations.

Biological basis

Etiology and pathogenesis

No clear etiology of new daily persistent headache has been established because the diagnosis is made only after the exclusion of secondary causes. The pathogenesis of new daily persistent headache is unknown, and the uncertainty is propelled by its underlying heterogeneity and by the paradox that an etiology is likely to assign it a different diagnosis. By definition, patients must be free of underlying entities, such as aseptic meningitis or minor head trauma, at headache onset. In patients who have a headache phenotype similar to chronic migraine or chronic tension-type headache, it is conceivable that new daily persistent headache represents the de novo onset of these conditions rather than their occurrence after evolution from their episodic forms. As such, new daily persistent headache may have overlapping pathophysiology with chronic migraine and chronic tension-type headache. Naegel and colleagues found that patients with new daily persistent headache had no grey matter changes of MRI compared with controls (44).

If new daily persistent headache results from an antecedent viral infection, an inflammatory pathogenesis may be plausible. One small study of 20 patients with new daily persistent headache, 16 patients with chronic migraine, and two patients with posttraumatic headache confirmed almost universally elevated tumor necrosis factor-alpha (TNF-alpha) levels in the cerebrospinal fluid compared to known laboratory controls, who may or may not have had headache disorders themselves (59). Although far from a validated association, these findings provide an intriguing link to an inflammatory pathogenesis.

Various triggers have been described in association with new daily persistent headache development in case series, most notably an antecedent infection – upper respiratory infection was noted in 22% of patients with new daily persistent headache (63). This is especially true in children (39).

The earliest known record of a new daily persistent headache-like headache after an infection was with the Russian/Asiatic flu in 1890 (50). The infectious agent most implicated in the development of new daily persistent headache is Epstein-Barr virus. One study noted that 84% of patients with new daily persistent headache had evidence of an active infection, compared with 25% of controls (14). However, in this series, 47% reported having a multitude of neurologic symptoms atypical of a primary headache disorder, and workups, including MRI and CSF analysis, were not well described. In one study, 23% of 40 children with new daily persistent headache had positive Epstein-Barr virus serology (39). The association between new daily persistent headache and Epstein-Barr virus remains of interest but is unproven. Other infectious etiologies, including herpes simplex virus, dengue fever, and cytomegalovirus, have been implicated (41; 13). Persistent headache after SARS-CoV-2 infection have been reported (42). There are several case reports of new daily persistent headache after recovery from SARS-CoV-2 infection (36; 58; 17). Two series observed a seasonal variation for the onset of new daily persistent headache, with peaks in the winter and fall (57; 35; 62). This may have implications for the infectious hypothesis in a subgroup of patients.

Aside from viral infections, other inciting factors, including stressful life events, have been reported in as many as 9% of patients (63), which can also cause the transformation of other forms of chronic daily headache from episodic headache (65). Other associations include extracranial surgery (34; 39; 41; 21), Valsalva event (63), athletic activity (59), childbirth (59), menarche (57), human papillomavirus vaccination (57), tapering of antidepressants (57), thyroid disease (20), sphenoiditis (33), as well as exposure to pesticide, hormonal manipulation with progesterone, massage treatment, and syncope (63). A case series noted that 53% of patients with new daily persistent headache denied a triggering factor at all (63). In children, 39% of new daily persistent headaches first began at the start of a new semester (25).

Other hypothesized etiologies in small series of patients include higher rates of hypothyroidism (06), cervical spine joint hypermobility (60), and defective internal jugular venous drainage (16). The diversity of potential etiologies underlies the presumed heterogeneity of the new daily persistent headache syndrome. Case reports have shown an association between new persistent daily headache and clival metastasis (47), multinodular goiter causing carotid and vertebral compression (20), and aortomesenteric compression (74). In each case, headache resolved after treatment of the respective associated disease. In addition, Uniyal and colleagues found that 70% of patients with new daily persistent headache had a history of somatic symptoms compared with 15% of patients with chronic migraine and 23% of patients with chronic tension-type headache (p< 0.001) (78). The authors suggested that given their history, somatization may factor into patients’ symptoms in new daily persistent headache.

Epidemiology

Few studies have addressed the population prevalence of new daily persistent headache. The prevalence of chronic daily headache is estimated to be 4% in the general population. Several studies have reported the prevalence of new daily persistent headache to range between 2.5% to 10.8% (51).

In the headache specialty care setting, patients with new daily persistent headache, particularly adolescents, are seen more commonly. Rates of new daily persistent headache among chronic daily headache patients in such settings range from 1.7% to 10.8% in adults and 13% to 36.1% in teenagers (23; 05; 31; 39; 41; 32; 73).

Most studies have shown that new daily persistent headache occurs more commonly in women, with female:male ratios ranging from 1.1:1 to 2.6:1 (80; 34; 39; 41; 67; 32; 57; 43; 49; 35; 54).

The age of onset is variable, with the most common incidence between the teenage years and 50 years of age, and mean age of onset is typically between 30 and 40 years of age. Studies examining gender-specific onset ages have been inconsistent, ranging from the third to the fifth decades in both men and women (34; 57; 43; 49; 35). Clinic-based studies of new daily persistent headache are limited as they usually do not encompass children and adults in the same sample.

Patients with new daily persistent headache have been identified in North America, South America, Europe, and Asia, including Caucasian, African-American, Hispanic, and Asian individuals (80; 34; 41; 75; 67; 24; 32; 57; 43; 49; 35; 54), but no clear racial predilection has been elucidated.

Prevention

There is no known way to prevent the development of new daily persistent headache.

Differential diagnosis

The differential diagnosis of new daily persistent headache includes both secondary and primary headache disorders. New daily persistent headache should not be diagnosed in the presence of any head trauma or clear systemic, autoimmune, or other illness, so disorders that only feature headache as a part of a clinical constellation of other extra-neurologic symptoms are not addressed. Even with a normal neurologic examination, most practitioners would not diagnose new daily persistent headache without performing neuroimaging to exclude any space-occupying lesion that can feature a daily headache (56).

Table 2. Differential Diagnosis of New Daily Persistent Headache

Secondary headache disorders. Vascular causes of headache can certainly feature a daily pattern, but often have an acute or abrupt onset. Cerebral venous thrombosis is a possibility in any patient who is at risk for having a hypercoagulable disorder and may feature a daily headache without any other symptoms (11) although persistence without a diagnosis for a 3-month period would be uncommon. Giant cell arteritis should be entertained as a diagnosis in any patient who is over 50 years of age and presents with a new daily persistent headache, and suspicion should increase as age advances. The headache of giant cell arteritis is extremely variable, and around half of patients with giant cell arteritis present with an unremitting, persistent headache although it is usually not bilateral (69; 29). The presence of other neurologic or ophthalmologic signs and symptoms as well as an elevated serum erythrocyte sedimentation rate and other laboratory derangements help to diagnose or exclude giant cell arteritis.

Reversible cerebral vasoconstriction syndrome is an acute disorder characterized by severe headache and often other neurologic symptoms, in the setting of multifocal segmental cerebral vasospasm that reverses over a few weeks (08). The hallmark of this condition is the presence of multiple thunderclap headaches at the onset or during the acute period of the disorder. Evidence has documented a persistent daily headache in a sizeable minority of patients (19; 27).

The differential diagnosis also includes spontaneous intracranial hypotension and idiopathic intracranial hypertension, which are classically associated with postural-related headaches. Headache that worsens with upright posture and improves with lying down is typical of spontaneous intracranial hypotension. This headache type is also associated with Valsalva-induced headaches, neck pain, tinnitus, imbalance, and mental fogginess. MRI of the brain with contrast is recommended for workup, which may reveal subdural fluid collections, pachymeningeal enhancement, engorgement of venous structures, pituitary hyperemia, and sagging of the brain (18). Idiopathic intracranial hypertension is a disorder of elevated intracranial pressure and is often associated with symptoms of pulsatile tinnitus, transient visual obscurations, and papilledema. It is commonly seen in obese young females.

Infectious causes are a potential mimic of new daily persistent headache but are largely an unknown entity. Bacterial meningitis itself is not a cause of chronic headache, but chronic postbacterial meningitis is a well-described entity (07; 28). However, as patients with viral meningitis may not always present to emergency or inpatient care, it may be an underdiagnosed entity, and postviral meningitis headache could ensue after clearance of the viral pathogen (46). Acute human immunodeficiency virus infection commonly presents with a generalized headache (reminiscent of new daily persistent headache) along with upper respiratory symptoms that can resolve subacutely (12). An isolated daily headache could be the initial manifestation of an undiagnosed inflammatory disease, such as Behçet disease (81).

Primary headache disorders. New daily persistent headache can be difficult to discern from chronic migraine, chronic tension-type headache, and hemicrania continua. New daily persistent headache should not be diagnosed in the setting of an episodic primary headache disorder that has been increasing in frequency prior to daily headache onset; however, there are no strictly defined cutoffs of maximum episodic attack frequency prior to diagnosing new daily persistent headache. Patients with new daily persistent headache should not describe onset of headache associated with medication overuse to treat prior headache to avoid confusion with medication overuse headache (28).

It is possible for patients to meet ICHD criteria for chronic migraine or chronic tension-type headache and meet criteria for new daily persistent headache. Should both criteria be met, the default diagnosis is new daily persistent headache. If patients meet criteria for both new daily persistent headache and hemicrania continua, then the diagnosis of hemicrania continua is upheld (28).

Chronic migraine develops in persons who already have a history of episodic migraine, in the setting of escalating attack frequency (28), and the process of clinical transformation takes place over several weeks, months, or years (03). This gradual transition may be the singular distinguishing characteristic between chronic migraine and new daily persistent headache. It is possible that many patients with new daily persistent headache simply have chronic migraine, with similar underlying biology yet an abrupt onset.

Like chronic migraine, chronic tension-type headache may develop in a minority of tension-type headache patients in the context of an escalating tension-type headache attack frequency (10). As with migraine, the diagnosis of new daily persistent headache may be misapplied to patients who truly have chronic tension-type headache because of underestimation or under-recognition of the preexisting tension-type headache attack frequency, which may be high or escalating.

Hemicrania continua is a unique form of chronic daily headache that is characterized by continuous, unilateral headache that features ipsilateral cranial autonomic signs during headache exacerbations, with a definitive response to indomethacin (28). Like new daily persistent headache, hemicrania continua is daily and continuous from its onset. Unlike new daily persistent headache, which usually presents with bilateral head pain and no or mild cranial autonomic symptoms (57), hemicrania continua almost always features unilateral headache with ipsilateral autonomic signs. However, bilateral hemicrania continua is a known entity (48; 70; 26; 71), and an indomethacin trial may be warranted in any patient with chronic daily headache, even bilateral chronic daily headache, that does not respond to standard therapies (70).

Diagnostic workup

By definition, new daily persistent headache starts acutely, and if presented to medical care early, the future chronicity of the syndrome would not be known. Therefore, the diagnostic workup would be similar to any acute headache, which emphasizes identifying “red flags” and ruling out secondary causes of headache that may carry high rates of morbidity and mortality if the underlying disorder remains untreated (15).

When new daily persistent headache is diagnosed, it has become chronic (persisting for 3 months or more), so the workup at that stage may vary according to the clinical suspicion of possible disorders in the differential diagnosis. A fundoscopic exam is warranted to look for papilledema. At the minimum, a non-contrast-enhanced brain MRI should be performed to rule out any intracranial space-occupying lesion. A contrast-enhanced study may increase the diagnostic yield when spontaneous intracranial hypotension or neoplasm is considered as well as in the presence of a systemic disorder or symptoms. Particularly, if the headache had an abrupt onset, vascular neuroimaging, such as magnetic resonance angiography and venography, would be appropriate. Depending on age and a review of systems, laboratory tests, including a sedimentation rate, Lyme titer, and thyroid function tests, may also be indicated. Lumbar puncture may be necessary to rule out derangements of intracranial pressure, particularly idiopathic intracranial hypertension, if the patient is obese or has visual symptoms as well as spontaneous intracranial hypotension in the presence of an orthostatic headache.

Management

The management of new daily persistent headache is largely symptomatic, and headache and related symptomatology are treated according to the chronic daily headache phenotype. If new daily persistent headache resembles chronic tension-type headache (aside from its onset), prophylaxis with a tricyclic antidepressant may be considered first. If the headache phenotype resembles chronic migraine, the armamentarium for migraine should be employed, including preventive treatments, such as topiramate or onabotulinumtoxinA.

Specific data regarding the pharmacologic treatment of new daily persistent headache are lacking. A sizeable proportion of new daily persistent headache patients may be responsive to acute therapies, such as triptans and nerve blocks (01; 57; 22; 09). A case series demonstrated success in treating refractory new daily persistent headache with occipital and auriculotemporal nerve blocks, once weekly for four weeks followed by once a month for three months (09). Intravenous therapies have reportedly been successful in small groups of patients administered dihydroergotamine (particularly if a migraine phenotype is present) (45), methylprednisolone, valproate (54), haloperidol (38), and magnesium sulfate (59). For patients with postinfectious new daily persistent headache, high doses of corticosteroids are particularly recommended to decrease the inflammatory response provoked by the infection (17). Physical therapy, osteopathic manipulations, and cervical blocks have been shown to be helpful in patients, particularly with cervical hypermobility or postsurgical-onset new daily persistent headache (63; 02).

Reported preventive therapies that have generated success in small observational or retrospective series include amitriptyline (41; 75; 54), flunarizine, sodium valproate (41; 75), fluvoxamine, paroxetine, baclofen (75), nortriptyline, topiramate (57), onabotulinumtoxinA (72), mexiletine (40), and clonazepam (77). Newer reports have noted improvement or resolution with mirtazapine (particularly for new daily persistent headache-associated nausea) (68), intravenous ketamine (53), and nimodipine (when presenting with thunderclap onset) (64; 30). Based on possible elevations of TNF-alpha levels in the cerebrospinal fluid (59), there have been several case reports that have shown improvement in new daily persistent headache using TNF-alpha inhibitors, doxycycline, and venlafaxine (61; 76). One case series of patients with new daily persistent headache onset after a single Valsalva event showed that five out of seven patients achieved over 90% improvement in headache frequency after cerebrospinal volume-lowering medication, such as acetazolamide (62). Given the possibility of new daily persistent headache mimicking hemicrania continua, an indomethacin trial may be warranted in any patient with chronic daily headache, even bilateral chronic daily headache, that does not respond to standard therapies (70).

As with other forms of chronic daily headache, a comprehensive treatment approach is likely to be the most successful. Aside from acute and prophylactic medications, analgesic overuse should be avoided, as it may develop in up to half of all patients with new daily persistent headache (57). Nonpharmacologic strategies (eg, trigger avoidance, biofeedback) and treatment of comorbidities (eg, depression, anxiety) should be employed.

Special considerations

Pregnancy

The effect of pregnancy on preexisting new daily persistent headache is not known; however, some cases of new daily persistent headache have been reported with an onset during pregnancy (59). Symptomatic treatment considerations of new daily persistent headache in pregnancy would be similar to that of chronic migraine or chronic tension-type headache in pregnancy.

Anesthesia

There is no known interaction between this syndrome and anesthesia.