INTRODUCTION — New daily persistent headache (NDPH) is a type of chronic daily headache that begins one day and typically does not remit. Many patients can pinpoint the exact date their headache started. New daily persistent headache was first described in 1986 as a benign form of chronic daily headache that improves over time without therapy. However, in other studies and in practice, NDPH can endure for many years or even decades and be completely refractory to treatment.
This topic will discuss NDPH. Other types of chronic daily headache are reviewed elsewhere. (See "Chronic daily headache: Associated syndromes, evaluation, and management".)
PATHOPHYSIOLOGY — The pathophysiology of NDPH is poorly understood. Some reports have related the specified time of onset of NDPH with an environmental or situational trigger. Triggering factors most commonly identified with NDPH include [1-3]:
●Stressful life events (10 to 20 percent)
●Respiratory infection (10 to 30 percent)
●Surgery (2 to 12 percent)
The observation that headache onset can occur in relation to infection or a flu-like illness has triggered interest in a possible microbial etiology. Several viral infections have been associated with NDPH in observational studies, including Epstein-Barr virus (EBV), herpes simplex virus (HSV), cytomegalovirus (CMV), and dengue virus [2,4,5]. As examples, a case-control study found evidence of active EBV infection in 27 of 32 patients (85 percent) with NDPH compared with 8 of 32 controls (25 percent) [6]. In a retrospective analysis of 18 NDPH cases, there was evidence of recent infection with HSV in six patients and CMV in two, but no evidence of EBV [4]. Of note, the positive cases for HSV or CMV had been seen within 60 days of headache onset. An activated autoimmune response that may lead to persistent neurogenic inflammation has been hypothesized to account for NDPH [7], but the potential causal role of viral or other infection in the pathogenesis remains to be determined.
Cases of NDPH that started with a single thunderclap headache have also been reported [8-10]. In one study, 12 out of 328 (3.6 percent) patients with NDPH had a thunderclap headache at onset [1]. It has been proposed that this syndrome might be precipitated by cerebral artery vasospasm, possibly based on a subform of reversible cerebral vasoconstriction syndrome (RCVS), although this remains unconfirmed [10].
The link between NDPH and potential risk factors or inciting events such as infection, trauma, or surgery is not firmly established. These factors probably do not cause the headache but rather may incite an underlying predisposition to headaches [11]. An unanswered question is why the headache persists so long, even after the inciting factor has resolved.
In several case series, no precipitating factor was identified in up to 80 percent of cases [3,12].
EPIDEMIOLOGY — A general population study of adults in Spain found that the prevalence of NDPH was 0.1 percent, while a larger general population study of adults 30 to 44 years of age in Norway found a prevalence of 0.03 percent [13,14]. When compared with other primary headache disorders, NDPH appears to be rare but widespread, as it has been described in multiple ethnic groups [2,12].
NDPH affects females more often than males. The female-to-male ratio of NDPH has ranged from 1.3 to 2.5 [1,2,12,15].
The age of onset for NDPH extends from the early teens to >80 years of age [1,2,12]. Out of 328 patients, the mean age of onset was 40.3 years in a United States study [1]. In a series from Japan of 30 patients with NDPH, the mean age of onset was 35 years [12]. In another report, the peak age of onset was earlier for females (the second and third decade) than for males (the fifth decade) [2]. Similarly, the first report describing NDPH found an earlier age of onset for females (16 to 35 years) than for males (26 to 45 years) [15].
Studies from headache clinics suggest that NDPH is more frequent in children than in adults. In a study of patients with chronic daily headache that included both adolescents (n = 170) and adults (n = 638), the frequency of NDPH was 21 and 11 percent, respectively, and the difference was statistically significant [16]. In reports from tertiary headache clinics of American children with chronic daily headache, the frequency of NDPH was 13 to 31 percent [11,17-19].
A seasonal pattern of onset has been described in children with NDPH. One retrospective study of 92 children in the United States found that the onset of NDPH was associated with months that children start or return to school (September and January) [20]. Another study of 42 children with NDPH seen in a headache center in Italy noted that 75 percent of cases began during the winter months (November to February) [21].
CLINICAL FEATURES — Unique to NDPH is the fact that the headache begins one day and typically does not remit. Up to 80 percent of patients with NDPH can pinpoint the exact date their headache started [2]. Some patients awaken from sleep with the headache, while others note the onset while awake. The headache becomes continuous and unremitting within 24 hours of onset [22].
Headache phenotype — The phenotype of NDPH frequently resembles migraine or, less often, tension-type headache [2,4,12,15,18,23]. In a study of 162 adults with NDPH from the United Kingdom, headaches met criteria for chronic migraine in 90 percent and tension-type headache in 9 percent [23]. Among 53 children and adolescents at a headache clinic in the United States diagnosed with NDPH but not overusing medication, most headache days (average 18.5 per month) met criteria for migraine [18]. Headaches may be aggravated by stress, physical exertion, or bright light [2].
Other headache characteristics in NDPH include:
●Severity – The baseline average pain intensity associated with NDPH is typically moderate, although a significant proportion of patients experience severe pain all the time [2,19].
●Location – The headache of NDPH is bilateral in 64 to 91 percent [1,2,12,15]. The pain can be holocranial or localized to any head region, including occipital-nuchal, temporal, and retroorbital locations.
●Quality – The quality of the head pain is most often throbbing and/or pressure-like. Other common descriptions include stabbing, aching, dullness, tightness, burning, and searing [2].
The course may be either self-limited or refractory. (See 'Prognosis' below.)
Associated features — Nausea, vomiting, phonophobia, and photophobia may accompany the headache in NDPH [17]. In a series of 56 patients with NDPH from a referral center in the United States, associated migrainous symptoms were frequent and included nausea (68 percent), photophobia (66 percent), phonophobia (61 percent), lightheadedness (55 percent), sore/stiff neck (50 percent), blurred vision (43 percent), vomiting (23 percent), and vertigo (11 percent) [2].
Examination — The neurologic examination is typically normal in NDPH. Greater occipital nerve trigger point tenderness and evidence of cervical facet inflammation on neck extension and rotation maneuvers may be seen in some [2]. The significance of this finding is uncertain.
DIAGNOSIS — The diagnosis of NDPH is based upon the clinical features, fulfillment of diagnostic criteria (table 1), and exclusion of secondary causes of headache. Previous diagnostic criteria excluded many patients with predominant migrainous features, even though migrainous features are common in NDPH [24,25]. Subsequent revisions in diagnostic criteria, however, allow the diagnosis of NDPH even when migrainous features are present alone or in combination with tension-type features [22]. (See 'Diagnostic criteria' below.)
Secondary headache disorders must be ruled out before making a diagnosis of NDPH [26], even in the presence of a normal neurologic examination. (See 'Evaluation' below and 'Differential diagnosis' below.)
Diagnostic criteria — The International Classification of Headache Disorders, 3rd edition (ICHD-3), published in 2018, describes NDPH as a persistent and continuous headache with a clearly remembered onset [22]. The pain lacks characteristic features and may be migraine-like or tension type–like or have elements of both.
The following are the ICHD-3 diagnostic criteria for NDPH (table 1) [22]:
●(A) Persistent headache fulfilling criteria B and C
●(B) Distinct and clearly remembered onset, with pain becoming continuous and unremitting within 24 hours
●(C) Present for longer than three months
●(D) Not better accounted for by another ICHD-3 diagnosis
Evaluation — New headache onset in the absence of a headache history always warrants attention. Therefore, the initial evaluation of a new daily headache must exclude secondary causes of headache. We recommend neuroimaging for patients with acute (within the first few weeks from onset) headache suspicious for NDPH. Where available, we suggest brain magnetic resonance imaging (MRI) with gadolinium as the initial imaging study. Head computed tomography (CT) with contrast is an alternative for those who cannot have MRI because of intolerance, contraindications, or availability.
For select patients with recent onset of headache suspicious for NDPH, additional studies may be warranted:
●Vascular imaging with magnetic resonance venography (MRV) is indicated in addition to brain MRI if there is suspicion for cerebral venous sinus thrombosis. A hypercoagulable state or signs of raised intracranial pressure (eg, papilledema) lower the threshold for obtaining MRV. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".)
●Arterial imaging with head and neck magnetic resonance angiography (MRA) or computed tomography angiography (CTA) is indicated if carotid and/or vertebral artery dissection is suspected. A side-locked headache, with or without Horner syndrome, particularly following head or neck trauma, should lower the threshold to obtain these studies. (See "Cerebral and cervical artery dissection: Clinical features and diagnosis".)
●Lumbar puncture is indicated if there is suspicion for central nervous system infection or idiopathic intracranial hypertension (IIH). Meningismus or fever lowers the threshold for a lumbar puncture. (See "Lumbar puncture: Technique, indications, contraindications, and complications in adults", section on 'Indications'.)
●Giant cell arteritis should be ruled out in patients over 50 years old [27]. (See "Diagnosis of giant cell arteritis".)
DIFFERENTIAL DIAGNOSIS — Several secondary and primary causes of headache may mimic NDPH.
Secondary headache disorders — Common secondary headache syndromes in the differential include the following [28]:
●Cerebral venous sinus thrombosis
●Headache due to spontaneous spinal cerebrospinal fluid leak
●Idiopathic intracranial hypertension (IIH)
●Giant cell arteritis
Other secondary causes that may also mimic NDPH include the following [29,30]:
●Arteriovenous malformation
●Brain tumor
●Chronic meningitis
●Chronic subdural hematoma
●Dissection of carotid or vertebral artery
●Dural arteriovenous fistula
●Leptomeningeal metastasis
●Post-meningitis headache
●Post-traumatic headache
●Sphenoid sinusitis
●Subarachnoid hemorrhage
Cerebral venous sinus thrombosis — In addition to headache, most patients with symptomatic cerebral venous sinus thrombosis will present with other manifestations, such as papilledema, seizures, focal deficits, encephalopathy, cranial nerve palsies, bilateral cortical signs, and/or cerebellar signs [31]. However, these may be absent even in the presence of thrombus [27], and a new daily headache may be the only symptom. In this setting, cerebral venous sinus thrombosis can be misdiagnosed as idiopathic intracranial hypertension or NDPH [31]. Brain MRI in combination with magnetic resonance venography (MRV) can help to demonstrate the thrombus and the occluded dural sinus or vein in a noninvasive manner. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".)
Spontaneous intracranial hypotension — It is crucial to consider headache secondary to spontaneous intracranial hypotension due to spinal cerebrospinal fluid (CSF) leak in the differential diagnosis of NDPH since the syndrome can usually be treated successfully with appropriate interventions. (See "Spontaneous intracranial hypotension: Pathophysiology, clinical features, and diagnosis" and "Spontaneous intracranial hypotension: Treatment and prognosis".)
As an example, some patients who met NDPH criteria in one report were later found to have a CSF leak [2]. In another case of apparent NDPH where a thorough evaluation was negative, a CSF leak secondary to a spinal CSF-venous fistula was eventually identified [32]. Treatment of the CSF leaks in these cases led to complete headache resolution.
In spontaneous intracranial hypotension, headaches typically resolve or are significantly alleviated while lying down but recur while upright. In a large series of patients with a leak due to CSF-venous fistula, however, an even greater percentage of patients reported Valsalva-induced headache exacerbation or precipitation compared with an orthostatic headache, headache features that should raise suspicion for an occult CSF-venous fistula [33]. Brain MRI frequently shows diffuse pachymeningeal gadolinium enhancement and/or descent of brain within the cranial vault. Opening CSF pressure on lumbar puncture may be low (≤60 mmH20) [33,34]. However, the orthostatic component and other key clinical and/or neuroimaging features are not always present, making CSF leaks hard to diagnose. (See "Spontaneous intracranial hypotension: Pathophysiology, clinical features, and diagnosis", section on 'Evaluation and diagnosis'.)
Idiopathic intracranial hypertension — IIH typically presents with headache upon waking that lessens in severity as the day goes on. It is generally worse with recumbency. In addition, visual obscurations and pulsatile tinnitus may be reported. The diagnosis of IIH should be considered particularly in females with obesity, who account for most cases [31]. (See "Idiopathic intracranial hypertension (pseudotumor cerebri): Clinical features and diagnosis".)
When papilledema is present, the diagnosis of IIH is straightforward [35]. A neuroimaging study is required to exclude other causes of elevated intracranial pressure. Brain MRI with and without contrast and postcontrast MRV is the imaging study of choice. Lumbar puncture should follow MRI unless a source of elevated intracranial pressure is clearly delineated. An opening pressure greater than 250 mmH2O taken with the patient lying on the side with legs extended confirms elevated intracranial pressure. Pressures between 200 and 250 mmH2O are considered equivocal. (See "Idiopathic intracranial hypertension (pseudotumor cerebri): Clinical features and diagnosis", section on 'Diagnosis'.)
Giant cell arteritis — The diagnosis of giant cell (temporal) arteritis should be ruled out in patients over 50 years old who have any combination of headache, abrupt onset of visual disturbances, symptoms of polymyalgia rheumatica, unexplained fever or anemia, and elevated erythrocyte sedimentation rate and/or serum C-reactive protein. Temporal artery biopsy is the gold standard for confirming the diagnosis. (See "Clinical manifestations of giant cell arteritis" and "Diagnosis of giant cell arteritis".)
Primary headache disorders — Primary headache disorders may mimic NDPH [18,23]. Although clinical features of NDPH may be similar to chronic migraine or chronic tension-type headache, NDPH is unique in that headache is daily and unremitting from, or almost from, the moment of onset, typically in individuals without a prior headache history. A clear recall of such an onset is necessary for the diagnosis of NDPH [26]. If strictly unilateral, hemicrania continua may be a more likely diagnosis than NDPH. A trial of indomethacin can be both diagnostic and therapeutic in this setting. (See "Hemicrania continua".)
The combination of daily headaches in the setting of medication overuse may create diagnostic uncertainty. In this situation, one needs to ask about the temporal relationship between headache onset and the development of daily headache.
●In NDPH, the headache is daily and unremitting from onset in a patient who is not yet overusing analgesics. Unlike medication overuse headache, the overuse in NDPH begins after the onset of daily headache.
●In contrast, some patients with ongoing episodic migraine or tension-type headache progressively consume analgesics in an attempt to fight the gradually increasing headache frequency [27]. The medication overuse begins before the onset of daily headache.
Nevertheless, many NDPH sufferers are overusing analgesics by the time they are seen in clinic [27]. In a series of 245 children with NDPH, approximately one-third were also diagnosed with medication overuse headache [17].
PROGNOSIS — New daily persistent headache appears to have two subtypes [22,27,36]:
●A self-limited form (nonpersisting) that typically resolves without therapy within several months
●A refractory form (persisting) that is resistant to aggressive treatment regimens
Very likely, the refractory form is the one seen in the clinician's office. Self-limited forms may not reach medical attention.
The original report describing NDPH with 45 patients (19 male, 26 female) found that, at two years from onset, 16 males (84 percent) and 19 females (73 percent) were headache-free without treatment [15]. In a later series of 18 cases, the number of patients pain-free at two years after headache onset was 12 (66 percent) [4].
However, in other studies and in practice, NDPH can endure for many years or even decades and be completely refractory to treatment [12,27]. In a series of 56 patients, all patients at study entry had NDPH for at least six months, many had headache for more than five years, and a few had headache for more than 10 years [2]. In a retrospective series of 328 patients, the median duration of NDPH at last visit was 1.9 years, and prognostic types were persisting/refractory in 93.0 percent, relapsing-remitting in 2.7 percent, and remitting or self-limited in 4.3 percent [1].
The true long-term prognosis of refractory NDPH is unknown [7].
TREATMENT — As noted above, the phenotype of NDPH often resembles primary chronic tension-type headache or chronic migraine. Although evidence is lacking, it is intuitive to treat NDPH based on the phenotype [37]. (See 'Headache phenotype' above.)
Thus, our suggested approach is to first classify the phenotype of NDPH as most similar to either migraine or chronic tension-type headache and then treat with appropriate preventive headache therapy accordingly [35]. (See "Preventive treatment of episodic migraine in adults" and "Tension-type headache in adults: Preventive treatment" and "Acute treatment of migraine in children" and "Tension-type headache in children".)
NDPH can continue for years or even decades after onset and can be very disabling. Even with aggressive treatment, including medications from multiple classes of abortives and prophylactics, many patients do not improve [27]. Many headache specialists consider NDPH to be the most treatment refractory of all headache disorders.
Data regarding the effectiveness of specific treatments for primary NDPH are limited to small series and case reports.
●In one report, 30 patients with NDPH were treated for five years, beginning with muscle relaxants (tizanidine or baclofen) [12]. Patients who did not respond were subsequently treated with amitriptyline, serotonin-specific reuptake inhibitors (fluvoxamine or paroxetine), and/or valproic acid. By self-assessment, the outcome was considered very effective, moderately effective, mildly effective, and not effective in 27, 3, 20, and 50 percent, respectively [12].
●Some headache experts have reported successful therapy of NDPH with a variety of agents, including amitriptyline, nortriptyline, propranolol, atenolol, gabapentin, topiramate, valproate, and peripheral nerve blocks [27,35,38-40].
●Other authors have anecdotally seen benefit using nonsteroidal antiinflammatory drugs combined with muscle relaxants and neck physical therapy [7].
Some reports suggest the response rate to pharmacologic treatment is better early in the course of NDPH (eg, during the first year) compared with late (eg, at 10 to 20 years) [27]. However, this relationship has not been demonstrated in all studies [12].
Analgesic overuse should be stopped if concurrent with NDPH, even though available evidence suggests that medication withdrawal typically does not help relieve the pain in NDPH [27]. This contrasts with the improvement that often occurs with drug withdrawal in patients who have background migraine and medication overuse headache. (See "Medication overuse headache: Treatment and prognosis".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Migraine and other primary headache disorders".)
SUMMARY AND RECOMMENDATIONS
●Definition and epidemiology – New daily persistent headache (NDPH) is a primary headache disorder in which headache begins one day and does not remit, usually in an individual without a headache history. NDPH appears to be rare, with a general population prevalence that is likely less than 0.1 percent. Available evidence suggests that NDPH is more frequent in children than in adults and affects females more often than males. (See 'Epidemiology' above.)
●Clinical features – A characteristic feature of NDPH is that the headache starts rather abruptly and is daily and unremitting from, or almost from, the moment of onset. Considerable variability is seen in the clinical features. The pain in NDPH lacks specific features and may be migraine-like, tension type–like, or have elements of both. (See 'Clinical features' above.)
●Diagnosis and evaluation – The diagnosis of NDPH is clinical (table 1) and requires ruling out secondary causes of headache, even in the presence of a normal neurologic examination. (See 'Diagnosis' above.)
For patients with recent onset of suspected NDPH, we recommend neuroimaging upon presentation. For select patients, additional studies may be warranted. A lumbar puncture is indicated if clinical features suggest a possible central nervous system infection or idiopathic intracranial hypertension. (See 'Evaluation' above.)
●Differential diagnosis – The differential diagnosis of NDPH includes several secondary and primary causes of headache. It is particularly important to consider cerebral venous sinus thrombosis, headache secondary to spontaneous spinal cerebrospinal fluid leaks, idiopathic intracranial hypertension (pseudotumor cerebri), and giant cell arteritis. (See 'Differential diagnosis' above.)
●Prognosis – New daily persistent headache may take either of two subtypes: a self-limited one or a persistent form, which can last years or decades and is challenging to treat. (See 'Prognosis' above.)
●Treatment – For patients with primary NDPH, we suggest first classifying the phenotype of NDPH as most similar to either migraine or tension-type headache and then treating with appropriate preventive headache therapy accordingly (Grade 2C). (See 'Treatment' above.)
