Sage Journals: Discover world-class research

Abstract

Background Accumulating evidence suggests various specific triggers may lead to new daily persistent headache (NDPH)-like presentations, suggesting that new daily persistent headache is a heterogenous syndrome, and challenging the concept that new daily persistent headache is a primary headache disorder.

Method We searched the PubMed database up to August 2022 for keywords including persistent daily headache with both primary and secondary etiologies. We summarized the literature and provided a narrative review of the clinical presentation, diagnostic work-ups, possible pathophysiology, treatment response, and clinical outcomes.

Results and conclusion New daily persistent headache is a controversial but clinically important topic. New daily persistent headache is likely not a single entity but a syndrome with different etiologies. The issue with past studies of new daily persistent headache is that patients with different etiologies/subtypes were pooled together. Different studies may investigate distinct subsets of patients, which renders the inter-study comparison, both positive and negative results, difficult. The identification (and removal) of a specific trigger might provide the opportunity for clinical improvement in certain patients, even when the disease has lasted for months or years. Nonetheless, if there is a specific trigger, it remains unknown or unidentified for a great proportion of the patients. We need to continue to study this unique headache population to better understand underlying pathogenesis and, most importantly, to establish effective treatment strategies that hopefully resolve the continuous cycle of pain.

Keywords

NDPH post-infectious thunderclap chronic daily headache chronic migraine

History and evolution of the disease entity

New Daily Persistent Headache (NDPH) was first described by Dr Walter Vanast, in 1986, as a benign form of persistent headache after the onset (1). The diagnostic entity was not yet included in the first version of the International Classification of Headache Disorders (ICHD-1) in 1988 (2) but was first recognized in the “Silberstein-Lipton” (S-L) criteria for chronic daily headache (CDH) published in 1994 (3). The lack of a common classification system has led to a miscellany of diverse patients with various triggers and etiologies in early NDPH series, including those with secondary, usually infectious etiologies (4,5).

The clinical description of NDPH has also evolved over the years. Apart from the initial report by Vanast (1), NDPH, according to the S-L criteria, is not necessarily daily or persistent, while “daily” was defined as ≥15 days/month and “persistent” was defined as ≥4 hours/day (3). The pathognomonic features of daily and persistent were reinstated in the second version of ICHD (ICHD-2), published in 2004 (6). Additionally, for the first time, the clinical features were defined as exclusively tension-type headache (TTH)-like only, and migrainous features were not allowed, presumably in order to delineate NDPH from the most common type of CDH – chronic migraine. Notably, ICHD-2 clearly categorized NDPH under primary headache disorders, headache attributed to secondary etiologies must be excluded and can only be diagnosed as secondary headaches regardless of the clinical presentations (6).

After the introduction of ICHD-2, several large NDPH cohort studies demonstrated that headache features, being TTH-like or migrainous, do not differ greatly in the disease-associated disability, quality of life, treatment responses, or prognosis (7,8). Therefore, headache features are no longer restricted in the 3rd version of ICHD (ICHD-3) published in 2018 (9). Moreover, in this revision, the onset of NDPH was defined as pain becoming continuous and unremitting within 24 hours since onset, contrasting 72 hours in ICHD-2, reciprocating the fact that most patients can clearly pinpoint the date of onset (6,9). Secondary headaches must also be ruled out, like in the ICHD-2, reflecting the concept that NDPH is a primary headache disorder. Whether it is reasonable to categorize NDPH as a primary headache will be further discussed in this review.

Epidemiology

Population-based studies of NDPH are rare. Castillo et al. (10) identified two cases of NDPH using S-L criteria among 1883 subjects from the general population, corresponding to a one-year prevalence of 0.1%. Grande et al. (11) reported a one-year prevalence of NDPH of 0.03% in 30,000 persons aged 30–44 years. Notably, this study used the most restrictive ICHD-2 criteria – only patients with TTH features were allowed. The prevalence is expected to be two to three times higher when including those with migrainous features. Both studies suggest that the prevalence of NDPH in the general population is low.

NDPH is a subtype of CDH. CDH affects 4% of the general population (10,12), but CDH and its various subtypes present substantial management challenges in headache clinics. In tertiary headache centers (13), NDPH accounts for up to 35% of CDH in pediatric population (14,15) and 2.5–10.8% in the adult population (8,16). Some suspect, therefore, that the prevalence of NDPH among all CDH may be higher in pediatric populations. For NDPH, sex predisposition in women may not be as prominent as that seen with migraine and might differ in various populations. In European and North-American studies, the F:M ratio ranged from 1.79–2.57 (7,17 –20). In Asian studies, the F:M ratio is lower (0.75–1.35) and studies from India and Japan even showed a slight male predominance (8,21,22). NDPH affects all age groups, and the age of onset varies greatly among studies and may also differ based on sex and trigger (7,8,23)

Triggers of NDPH

Patients with NDPH (20% to 88%) may recall specific triggers before the onset of headache, but the inter-study variance is high (7,17,18,20 –22,24). Common triggers include infectious episodes or stressful life events (7,8). Besides, the onset of pediatric NDPH is concentrated in specific months or seasons, supporting a possible link between infectious episodes and the onset of NDPH (20,25); however, school related stressors may also be connected. Some triggers may provide hints to disease mechanisms and are worth further exploration; however, triggers, in general, are easily misattributed and may be affected by recall bias.

The earliest record of NDPH-like headache after an infectious episode can be traced back to 1890 after the Russian/Asiatic flu. Headache was a complaint in 75–83% of the patients during the acute stage, and some of the patients (the exact number unknown) developed a long time subsequent headache that mimics NDPH (26). Infectious episodes as triggers, such as Epstein-Barr virus or Salmonella/E. Coli infection has been mentioned in the early NDPH series before the introduction of the S-L Criteria when both primary and secondary causes were not differentiated (4,5). The infectious triggers are not restricted to specific pathogens. Bordini and Valença (27) reported three possible cases of NDPH in 450 patients with Dengue fever. More recently, approximately half of the patients infected with COVID-19 developed headaches during the acute stage (28). Some patients developed persistent headaches after the resolution of the acute episodes, (29,30), among which some fulfilled the ICHD-3 diagnostic criteria of NDPH (29). In most reported cases with an infectious episode as a trigger of NDPH, the infection is usually systemic and not localized. Some patients may also fulfill the diagnostic criteria of §9.2 – Headache attributed to systemic infection according to the ICHD-3 when the headache started during the acute stage of the infection (9). The demarcation of primary vs secondary headaches in the case of an infectious trigger sometimes can be blurred.

The second most reported trigger is stressful life events, up to 26% in some series (8). However, stress is even more often reported as a trigger for migraine attacks (31) and is highly unspecific and easily falsely attributed. On the contrary, some NDPH triggers are not common but highly specific and remain rarely reported in other headache disorders. These triggers suggest a possible link to the mechanism that triggers persistent headache. In a large NDPH-series (n = 97), Rozen (18) reported nine patients with NDPH-like headaches after surgical interventions that required intubation. Cervical spine joint hypermobility was reported in 11 of 12 NDPH patients in another earlier report (32). Both combined suggest a possible cervicogenic etiology in a subset of NDPH patients. Valsalva event as a trigger has been reported in another seven NDPH patients. None of them had papilledema, and four had a normal weight. Therefore, idiopathic intracranial hypertension is less likely, but idiopathic intracranial hypertension without papilledema can only be excluded with a proper cerebrospinal fluid (CSF) pressure monitor, while a single spinal tap may fall in the normal range (<25 cm CSF) in 40% of these patients (33). Typical treatment options for intracranial hypertension, such as acetazolamide, reduced the headache frequency by more than 90% in five of seven patients (34), suggesting an abnormal distribution or equilibrium of CSF may also link to typical NDPH phenotypes. All the distinct triggers, each accounting for a small proportion of NDPH patients, suggest that NDPH is probably a syndrome with various mechanisms, instead of a homogenous disease (see below).

Clinical characteristics

The most typical presentation of NDPH is the acute onset headache on a specific day which becomes persistent within 24 hours. Most NDPH patients can recall the day when their headaches started (7,17,24). Hence, in the latest version of the ICHD, clearly remembering the onset is listed as a diagnostic criterion (9). Headache features are not restricted, and migrainous features may be more common than TTH features (7,8,22,25,35), reflecting the evolution of the diagnostic criteria. Notably, despite the prominent migrainous features, most patients presented with bilateral headache that is commonly pressing/tightening (7,21,22,24). Previous headache disorders may exist in up to 29% of the patients with NDPH (7,8,17,22,24), but a chronification of preexisting headache disorders or de novo NDPH must be carefully differentiated based on the headache features changes, if any, and pre-NDPH headache frequency. Even though the headache features are not restricted in NDPH, patients with migrainous features, compared to those with TTH features, may have higher psychiatric co-morbidities, disability, and possibly worse clinical outcomes (8,22).

Traditionally, NDPH has been considered refractory to most treatment options. Robbins et al. identified a subset of patients (24%) who may have remitting/relapsing disease course, instead of persisting headaches in long-term follow-up (7). Two studies suggested early (within six or 12 months after disease onset, respectively) treatment with migraine prophylactic treatment may be associated with better clinical outcome (8,25), and the headache may still remit in more than 50% of the patients (25). Therefore, those with early treatment may be more likely to have a relapsing/remitting disease course compared to those with years of persistent headache. Whether the disease course may be modified with early treatment can only be answered in placebo-controlled studies with long-term follow-up. Such studies are difficult to conduct, especially considering the low prevalence of NDPH.

Psychiatric comorbidities are prevalent in patients with CDH and are associated with decreased quality of life or worse treatment response (36). Comorbid depression affects approximately half of the NDPH patients, and patients with prominent migrainous features were more commonly affected (7,8). A recent study from India used established psychiatric batteries to evaluate the psychiatric comorbidities in patients with NDPH, those with chronic back pain, and healthy controls. In this study, up to 85.5% of NDPH patients had psychiatric comorbidities, and the proportion is significantly higher than those with low back pain or healthy controls (37). Again, the presence of migrainous features was associated with an even higher depression score and pain catastrophizing behavior (37). Disease-associated disability and disease burden remain high in patients with NDPH (8) and not distinguishable from those with chronic migraine (38).

Diagnostic work-up and the 3Ts model of NDPH

All patients who present with a daily headache from onset require neuroimaging. At baseline, a brain MRI with and without gadolinium and an MR venogram are required. This will rule out the majority of secondary mimics of NDPH, including intracranial hypotension, mass lesion, sphenoid sinusitis, hydrocephalus, and cerebral vein thrombosis. If there is any question of arterial issues, such as a daily headache with stroke-like spells or thunderclap-like headache, arterial imaging of both the intracranial and extracranial circulations is needed. In most instances, however, these imaging studies will be normal. Thus, the etiology of the patient’s daily headache from onset remains a mystery. One of the authors (TDR) has established the 3Ts model to help define NDPH subtypes, which then can lead to more distinct treatment options (39). The full model is presented elsewhere, but in essence, looks at: i) Triggering events with specific questions; ii) the response of the headache to the Trendelenburg position; iii) defining the temporal profile of the original headache (Thunderclap or non-thunderclap).

Secondary headaches that mimic NDPH

Certain secondary headaches may present with typical NDPH features but cannot be diagnosed as NDPH following the current ICHD-3 diagnostic system. Possible secondary causes that led to an NDPH-like headache involve different pathologies, both intracranial and extracranial (Table 1). Following are some reported examples:

Table 1.

Headache disorders that mimic new daily persistent headache.

		Clinical clues	Diagnostic work-ups	Treatment recommendation	Remarks
Primary headache disorders
	Chronic migraine/chronic tension-type headache	History of pre-existing headache disorder Frequency change before NDPH-like presentation	Clarify preexisting headache history	Treat underlying primary headache disorders
	Hemicrania continua	Side-locked headache Prominent cranial autonomic symptoms	Indomethacin trial	Indomethacin 150–225mg/daily	Side-locked headache up to 18% in NDPH (8)
Secondary headache disorders
	Meningitis (aseptic or chronic)	Typical signs in acute bacterial meningitis may not absent	Spinal tap with CSF analysis	Treat underlying disease
	Idiopathic intracranial hypertension	Presentation mimics CM or CTTH Worsened by Valsalva F > M, obesity Visual disturbance Papilledema	Spinal tap with CSF pressure measurement Fundoscopy to exclude papilledema	CSF pressure reduction treatment	Up to 5% of IIH patients without papilledema (74)
	Reversible cerebral vasoconstriction syndrome	Initially recurrent thunderclap headache Followed by persistent background headache Specific triggers in some patients	Multifocal intracranial vasoconstriction using cerebrovascular imaging modalities	Calcium channel blocks such as nimodipine
	Structural lesion of the cranial and cervical regions	Look for accompanied symptoms, e.g., nasal symptoms in sinusitis	Neuroimaging and structural imaging study for exclusion	Treat underlying disease	Involvement of cervical vessels (e.g., dissection) may lead to NDPH-like headaches
	Intracranial hypotension	Postural-related headache	Neuroimaging of the brain for low pressure changes or the spinal cord for evidence of CSF leakage	Conservative treatment Epidural blood patch

CM, chronic migraine; CSF, cerebrospinal fluid; CTTH, chronic tension-type headache; NDPH, new daily persistent headache.

Cranial pathologies

Aguiar de Sousa et al. (40) reported a young female patient with a typical NDPH clinical presentation. Brain MRI revealed multiple white matter hyperintensities without gadolinium enhancement, involving the corpus callosum, juxtacortical and periventricular. A repeated MRI two years later revealed new gadolinium-enhanced lesions in the subcortical white matter, and multiple sclerosis was subsequently diagnosed. Treatment with interferon-beta-1a improved the headache intensity, but the headache remained persistent (40). There have been several reports of NDPH-like headaches with thunderclap headache onset (41 –43). Brain MR angiography during the acute stage revealed typical features seen in those with reversible vasoconstriction syndrome (RCVS) – multifocal arterial vasoconstriction, and the patient responded well to nimodipine, the standard treatment for RCVS (41,43). These cases suggest a possible arterial origin of the daily persistent headache. Infection or inflammation in the cranial structure may also present with a typical NDPH headache. Lee et al. (44) reported two pediatric cases with sphenoid sinusitis with minimal nasal symptoms but typical NDPH presentations. Skull base metastasis may also mimic NDPH. In this patient, following radiosurgery, the intensity of pain improved greatly (10 to 2, 0–10 scale), but the headache remained daily and persistent (45).

Extracranial pathologies

Carotid and vertebral artery compression secondary to goiter may also present with typical NDPH symptoms, and the headache completely resolved after thyroidectomy (46). Low-pressure headache due to CSF-venous fistula may resemble typical NDPH presentations, and surgical ligation completely resolved the headache in this case (47). Even more rarely, two independent groups reported daily-persistent headaches secondary to nutcracker syndrome – aortomesenteric compression of the left renal vein (48,49). One patient had nearly complete resolution of headache symptoms after aortomesenteric decompression (48), and six out of eight patients had immediate pain resolution after CSF volume removal (49). Notably, none of these eight patients had elevated intracranial pressure at baseline. The authors suggest that renal vein compression may lead to retrograde flow through the lumbar vein, which subsequently perturbs the CSF pressure balance and causes headaches. (49). The miscellaneous mimics of NDPH suggest more than one mechanism may be involved in the generation of persistent headaches. Proper identification of potential mimics provides the opportunity for an accurate treatment and possibly headache resolution.

Pathogenesis

At present, there is no defined pathogenesis for NDPH. If we take the stance that NDPH is not a single entity, there cannot be a unified pathogenesis theory but multiple potential underlying causes. If, however, we group patients into specific subtypes, we may be able to define unique underlying pathogenesis for each subgroup. Patients within a distinct NDPH subgroup will probably have the same underlying etiology, but those between subgroups not. Some patients who fit into more than one subgroup may have mixed etiologies (18,39). For example, post-infectious NDPH patients who worsen in the Trendelenburg position may have both a headache caused by a pro-inflammatory response to a virus plus elevated CSF pressure possibly caused by the virus itself and/or the location they were infected (vacationing at a higher altitude) and/or from the inflammatory cascade to the infection. Alternatively, some triggers remain a universal experience to nearly all human beings, e.g., headaches associated with an acute infection. Another argument for the pathogenesis would be a failed off-switch to cease the headache (50). This hypothesis requires further exploration.

The author (T. Rozen) and colleagues have defined a unique subtype of NDPH caused by nutcracker physiology with secondary spinal lumbar vein dilation and subsequent spinal epidural venous congestion (49). This would be one of the first NDPH subtypes with a definable underlying etiology that can be specifically treated with the resolution of head pain. There have recently been published studies trying to define structural brain alterations which may be unique to the NDPH population. This is a substantial leap forward in studying this condition. So far in adults, no structural imaging changes have been noted; however, in a pediatric population with NDPH, there were unique alterations compared to age-matched controls, including a reduction in thickness in the left superior frontal gyrus, cortical thinning in the temporal and middle frontal gyrus, and altered functional connectivity between certain brain regions (51,52). The issue with these studies, however, is that they regard NDPH as a single homogenous entity which it is not; so, the study results have to be interpreted with some caution. It is like studying the functional imaging of headache patients and not teasing out who has migraine, cluster headache, TTH, etc. The results would be uninterpretable outside of denoting the functional imaging of head pain. It would be very instructive to repeat the anatomical and functional connectivity studies by NDPH subtypes. This could provide very useful information.

Treatment

NDPH has been considered refractory to treatment, and up to date, there has been no well-designed or controlled study evaluating the clinical response of specific medication in NDPH. Treatment strategy usually follows the established protocols in other CDHs. For example, patients with prominent migrainous features are treated with chronic migraine prophylactic treatment. The standard treatment regimen of CDH has been reviewed elsewhere (53). Notably, medication overuse headache (MOH), which develops after NDPH, is not a rare complication (35). A standard treatment regimen against MOH should be considered in these patients. Nonetheless, patients with NDPH were less likely to develop MOH than those with other CDH (54). The exact reason remains unknown, but the initial inefficacy of acute medication and the type of acute medication used may contribute to the relatively lower prevalence synergically. Besides the common treatment for CDHs, some specific treatment regimens for NDPH have been investigated in small-scaled open-label studies, as discussed below.

Nerve Block/Stimulation

Great occipital nerve block improved headaches in 33% of pediatric NDPH patients in a retrospective study (55). Nerve blocks remain a favorable option in treating pediatric patients because of the tolerable side effect profiles, even though the efficacy has not been well established (56). The long-term outcomes of occipital nerve stimulation have been recently investigated. After eight years of follow-up, only 11% of the patients still had favorable responses (57). The evidence to support the general use of nerve block/stimulation in the treatment of NDPH is low, even though some patients might still benefit from the treatment.

Anti-Tumor Necrosis Factor-alpha (TNF-α) treatment

Exclusive intrathecal elevation of TNF-α levels has been reported in patients with NDPH and chronic migraine, suggestive of a role of CNS inflammation in CDH, including NDPH (58). Doxycycline reduces the expression of TNF-α (59), and in an open-label trial, four out of four NDPH patients with high TNF-α levels in the CSF reported ≥50% improvement of headache after three months of doxycycline treatment, among which two patients reported complete relief of pain (60). Venlafaxine, a serotonin-norepinephrine reuptake inhibitor, may inhibit the upregulation of TNF-α (61). In one case report, an NDPH patient who had not responded to more than 20 different medical treatments, had a remarkable reduction in headache intensity (from 9 to 3, 0–10 scale) after three months of treatment. The headache recurred after discontinuation of venlafaxine but remitted again after treatment resumed (62).

Intravenous ketamine

In a retrospective study, 14 patients with refractory NDPH were treated with a subanesthetic dosage of ketamine, and eight of them (57.1%) had a reduction in headache intensity (≥1.5, 0–10 scale) (63). Ketamine is an N-methyl-D-aspartic acid (NMDA) receptor antagonist, and the role of NMDA in NDPH may be worth further investigation.

OnabotulinumtoxinA (BTX)

In a meeting abstract, Ali et al. treated 12 patients with NDPH with BTX following the PREEMPT protocol used in the treatment of chronic migraine (64,65). Six out of the 12 patients (50%) had a reduction in headache frequency after two sessions (six months) of BTX therapy, and the response rate increased to 63.6% after four sessions of BTX therapy (65). Other case reports of the clinical efficacy of BTX in the treatment of NDPH exist (66,67). The efficacy of BTX in NDPH has not been examined in controlled studies.

Calcitonin gene-related peptide (CGRP) antibodies

Antibodies against CGRP or its receptor are emerging treatment options in migraine (68). Their roles in NDPH remain unknown. A recent cohort study reported some benefits of CGRP antibodies in 112 adolescent patients with refractory CDH, two-thirds of whom had continuous headaches. Among them, 12 were diagnosed with NDPH, but no breakdown data on NDPH were provided (69). A clinical trial has been conducted but was early terminated due to COVID-19 (ClinicalTrials.gov Identifier: NCT04260087). No results have been published yet.

3Ts model-specific treatment

A more effective way to treat NDPH is by defining subtypes and then utilizing distinct treatments for each subtype based on the theorized underlying pathogenesis. These specific treatment options are summarized in Table 2. There is evidence from small case series that the treatment effect is more substantial when this is done.

Table 2.

New daily persistent headache with specific triggers and their corresponding treatment options.

NDPH subtype	Triggers	Possible mechanism	Treatment option	References
Post-infectious	Infection	Inflammatory cytokines	Methylprednisolone	Prakash and Shah 2010 (70)
		Elevated TNF- α expression	Doxycycline (Reduction of TNF- α expression)	Di Caprio et al. 2015 (59)
		Chronic infection?	Famiciclovir	Rozen 2019 (39)
Post-surgical/post-intubation	Cervical hyperextension	Cervical facet syndrome?	Muscle relaxantsAnti-inflammatory medicationsBTX injection targeting cervical regions	Rozen 2016 (18)
Postural-related	Trendelenburg positionValsalva manoeuvre	CSF pressure/volume/equilibrium disturbance	CSF pressure/volume lowering agents	Rozen 2019 (34)
Thunderclap headache onset	Vasoconstriction	Possibly related to RCVS	Nimodipine	Robbins and Evans 2012 (42)Evans and Turner 2021 (71)Lobo et al. 2021 (72)

BTX, Botulinumtoxin; CSF, Cerebrospinal fluid; NDPH, new daily persistent headache; RCVS, reversible cerebral vasoconstriction syndrome; TNF, Tumor necrosis factor.

Post-Infectious NDPH

Early-Onset Post-Infectious NDPH: Prakash and Shah (70) reported on the use of high-dose intravenous methylprednisolone. All patients improved, with some achieving complete pain freedom. The issue is that by treating early in the course of the headache, none of the patients met the ICHD criteria for NDPH. Thus, it is feasible that some or all of the patients would have remitted without treatment (70).

Chronic Post-Infectious NDPH: A small case series of six patients with highly elevated viral titers of either cytomegalovirus or parvovirus or both and who were deemed treatment refractory (failing at least three preventives) showed a very positive treatment effect with the use of famciclovir 125mg to 250mg two times per day. Improvement of 95% or greater in most responders (five out of six) and pain freedom in four out of five patients (39).

b. Post-surgical/post-procedure NDPH

This is typically an older subgroup of NDPH sufferers. Their headache is speculated to be the result of an exacerbation of an underlying upper cervical facet syndrome induced by the cervical hyperextension occurring during intubation and the neck positioning during surgery. Treatments directed at the high cervical spine irritation including medications (muscle relaxants combined with anti-inflammatories), BTX injections, and pain anesthesia procedures have shown positive efficacy in this patient population (18).

c. Treatment based on the Trendelenburg worsening

An immediate worsening of headache in the Trendelenburg position suggests a state of elevated CSF pressure/volume. The authors have defined subgroups of NDPH with this presentation, and most appear to respond to CSF pressure/volume lowering medications including acetazolamide, spironolactone, and/or indomethacin sustained release (34).

d. Thunderclap onset

There are now 20 plus published cases for this NDPH subtype. It is probably a sub-form of RCVS. In those studies, with treatment data, nimodipine appears very effective. The dose is typically much lower than that utilized in post-subarachnoid hemorrhage vasospasm (42,71,72).

Controversy in the diagnosis and personal opinions from the authors

Is NDPH a primary headache disorder?

The authors suspect that a great proportion of true NDPH, defined as a daily persistent headache lasting for more than three months in a patient who has no personal or family history of headache, may be a secondary headache. In some instances, we can define the underlying secondary etiology; in others, it is yet undefined or unidentified. Something must have happened to that individual to turn on the switch from no headache to a daily persistent intractable headache that is unremitting for months to years. If a triggering event can be denoted, such as post-viral or post-surgical, the patient could be labeled with a distinct established secondary ICHD classification. Nonetheless, the proportion of NDPH patients with identifiable secondary triggers remains unknown. Both primary and secondary NDPH may coexist. In that circumstance, a new ICHD classification should be created for secondary NDPH with subtypes by triggering event, Trendelenburg response, thunderclap onset, and/or current unknown etiology. Clinically, secondary etiologies were sometimes defined and identified years later, and more importantly, the removal of the triggers or treatment options that target the triggers provides rapid clinical improvement (41).

Is NDPH just a quick chronification of migraine or tension-type headache?

In many instances, if we look at the headache phenotype of NDPH patients and disregard the temporal profile of onset, we can diagnose chronic migraine or TTH in the majority. The question arises: can migraine or TTH start daily from the onset, especially if that individual never experienced any prior headaches or had a very minimal personal and family history of headaches? The typical scenario for headache chronification is a slow and steady increase in headache frequency unless there is a secondary lesion (like a brain neoplasm). The judgment for a rapid chronification vs de novo onset depends on the patients’ interpretation of their daily headaches. If they feel it is their prior headache just chronified, most likely they are correct in that assumption, especially if testing for secondary conditions is negative. However, if they feel it is a new distinct entity or their first-ever headache, then in that instance, NDPH should be the diagnosis. The demographics and headache phenotype are somewhat different when comparing chronic migraine to NDPH with a migrainous phenotype (7,73), suggesting that both might be divergent conditions. Treatment responses provide additional clues. As we often see in NDPH, both with and without migraine features, the treatment response rate to typical migraine preventives is quite low, suggesting against this being just an offshoot of the primary headache syndrome.

Conclusion

NDPH is a controversial but clinically important topic. It sometimes is just a quick chronification of an already pre-existent primary headache disorder, rarely a manifestation of an underlying psychiatric disorder, and perhaps frequently secondary to something as the number of documented secondary etiologies of NDPH keeps increasing in the literature. The heterogeneity of NDPH renders interstudy comparison difficult and inconclusive when specific subgroups are not separately studied. What is important is that the patients who develop a daily headache out of the blue in many instances have a life-changing event. We need to continue to study this unique headache population to better understand underlying pathogenesis and, most importantly, to establish effective treatment strategies that hopefully resolve the continuous cycle of pain.

Clinical implications

NDPH is a syndrome that encompasses different etiologies/subtypes.

The identification of a specific trigger provides the opportunity for specific treatment options.

Accumulating evidence suggests that a least some patients have a secondary etiology, which challenges the current diagnosis of NDPH as a primary headache.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Kuan-Po Peng

Todd D Rozen

References

Vanast

New daily persistent headaches: definition of a benign syndrome. Headache 1986; 26: 317.

Headache Classification Committee of the International Headache Society. Classification and Diagnostic Criteria for Headache Disorders, Cranial Neuralgias and Facial Pain. Cephalalgia 1988; 8: 1–96.

Silberstein

Lipton

Solomon

, et al. Classification of Daily and Near-Daily Headaches: Proposed Revisions to the IHS Criteria. Headache 1994; 34: 1–7.

Santoni

Santoni-Williams

CJ.

Headache and painful lymphadenopathy in extracranial or systemic infection: etiology of new daily persistant headaches.

Intern Med 1993; 32: 530–532.

Diaz-Mitoma

Vanast

Tyrrell

DLJ.

Increased frequency of Epstein-Barr virus excretion in patients with new daily persistent headaches. The Lancet 1987; 329: 411–415.

Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 2004; 24: 9–160.

Robbins

Grosberg

Napchan

, et al. Clinical and prognostic subforms of new daily-persistent headache. Neurology 2010; 74: 1358–1364.

Peng

K-P

Fuh

J-L

Yuan

H-K

, et al. New daily persistent headache: Should migrainous features be incorporated? Cephalalgia 2011; 31: 1561–1569.

Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition. Cephalalgia 2018; 38: 1–211.

10.

Castillo

Muñoz

Guitera

, et al. Kaplan Award 1998. Epidemiology of chronic daily headache in the general population. Headache 1999; 39: 190–196.

11.

Grande

Aaseth

Lundqvist

, et al. Prevalence of new daily persistent headache in the general population. The Akershus study of chronic headache. Cephalalgia 2009; 29: 1149–1155.

12.

Scher

Stewart

Liberman

, et al. Prevalence of frequent headache in a population sample. Headache 1998; 38: 497–506.

13.

Goadsby

Boes

Chronic daily headache. J Neurol Neurosurg Psychiatry 2002; 72: ii2–ii5.

14.

Baron

Rothner

AD.

New daily persistent headache in children and adolescents. Curr Neurol Neurosci Rep 2010; 10: 127–132.

15.

Koenig

Gladstein

McCarter

, et al. Chronic daily headache in children and adolescents presenting to tertiary headache clinics. Headache 2002; 42: 491–500.

16.

Bigal

Sheftell

Rapoport

, et al. Chronic daily headache in a tertiary care population: correlation between the International Headache Society diagnostic criteria and proposed revisions of criteria for chronic daily headache. Cephalalgia 2002; 22: 432–438.

17.

Rozen

TD.

The clinical characteristics of new daily persistent headache. Cephalalgia 2002; 22: 66–69.

18.

Rozen

TD.

Triggering events and new daily persistent headache: age and gender differences and insights on pathogenesis-a clinic-based study. Headache 2016; 56: 164–173.

19.

Kung

Tepper

Rapoport

, et al. New daily persistent headache in the paediatric population. Cephalalgia 2009; 29: 17–22.

20.

Mack

KJ.

What incites new daily persistent headache in children?

Pediatr Neurol 2004; 31: 122–125.

21.

Takase

Nakano

Tatsumi

, et al. Clinical features, effectiveness of drug-based treatment, and prognosis of new daily persistent headache (NDPH): 30 cases in Japan. Cephalalgia 2004; 24: 955–959.

22.

Uniyal

Paliwal

Tripathi

Psychiatric comorbidity in new daily persistent headache: A cross-sectional study. Eur J Pain 2017; 21: 1031–1038.

23.

Rozen

TD.

New daily persistent headache: A lack of an association with white matter abnormalities on neuroimaging. Cephalalgia 2016; 36: 987–992.

24.

Prakash

New daily persistent headache: disease or syndrome?

Headache 2013; 53: 678–679.

25.

Papetti

Sforza

Tarantino

, et al. Features and management of new daily persistent headache in developmental-age patients. Diagnostics 2021; 11: 385.

26.

Rozen

TD.

Daily persistent headache after a viral illness during a worldwide pandemic may not be a new occurrence: Lessons from the 1890 Russian/Asiatic flu. Cephalalgia 2020; 40: 1406–1409.

27.

Bordini

Valença

MM.

Post-Dengue new daily persistent headache. Headache 2017; 57: 1449–1450.

28.

Fernández-de-Las-Peñas

Navarro-Santana

Gómez-Mayordomo

, et al. Headache as an acute and post-COVID-19 symptom in COVID-19 survivors: A meta-analysis of the current literature. Eur J Neurol 2021; 28: 3820–3825.

29.

Caronna

Ballvé

Llauradó

, et al. Headache: A striking prodromal and persistent symptom, predictive of COVID-19 clinical evolution. Cephalalgia 2020; 40: 1410–1421.

30.

Sampaio Rocha-Filho

Voss

Persistent headache and persistent anosmia associated with COVID-19. Headache 2020; 60: 1797–1799.

31.

Peroutka

SJ.

What turns on a migraine? A systematic review of migraine precipitating factors. Curr Pain Headache Rep 2014; 18: 454.

32.

Rozen

Roth

Denenberg

Cervical spine joint hypermobility: a possible predisposing factor for new daily persistent headache. Cephalalgia 2006; 26: 1182–1185.

33.

Torbey

Geocadin

Razumovsky

, et al. Utility of CSF pressure monitoring to identify idiopathic intracranial hypertension without papilledema in patients with chronic daily headache. Cephalalgia 2004; 24: 495–502.

34.

Rozen

TD.

New daily persistent headache (NDPH) triggered by a single Valsalva event: A case series. Cephalalgia 2019; 39: 785–791.

35.

Strong

Pierce

Langdon

, et al. New daily persistent headache in a pediatric population. J Child Neurol 2021; 36: 888–893.

36.

Pompili

Di Cosimo

Innamorati

, et al. Psychiatric comorbidity in patients with chronic daily headache and migraine: a selective overview including personality traits and suicide risk. J Headache Pain 2009; 10: 283–290.

37.

Paliwal

Uniyal

Aneez

, et al. Do paroxysmal hemicrania and hemicrania continua represent different headaches? A retrospective study. Neurol Sci 2019; 40: 2371–2376.

38.

Reidy

Riddle

Powers

, et al. Clinic-based characterization of continuous headache in children and adolescents: Comparing youth with chronic migraine to those with new daily persistent headache. Cephalalgia 2020; 40: 1063–1069.

39.

Rozen

TD.

The Three T’s of NDPH (How clinical observations have led to improved treatment outcomes).

Headache 2019; 59: 1401–1406.

40.

Aguiar de Sousa

Geraldes

Gil-Gouveia

, et al. New daily persistent headache and radiologically isolated syndrome. J Neurol 2013; 260: 2179–2181.

41.

Jamali

Rozen

TD.

An RCVS spectrum disorder? New daily persistent headache starting as a single thunderclap headache (3 new cases). Headache 2019; 59: 789–794.

42.

Robbins

Evans

RW.

The heterogeneity of new daily persistent headache. Headache 2012; 52: 1579–1589.

43.

Rozen

Beams

JL.

New daily persistent headache with a thunderclap headache onset and complete response to Nimodipine (A new distinct subtype of NDPH).

J Headache Pain 2013; 14: 100.

44.

Lee

Rhee

Suh

ES.

New daily persistent headache with isolated sphenoiditis in children. Korean J Pediatr 2015; 58: 73.

45.

Ogunlaja

Zhang

New daily persistent headache syndrome secondary to clival metastasis within an osseous hemangioma. Headache 2019; 59: 1609–1610.

46.

Evans

Timm

JS.

New daily persistent headache caused by a multinodular goiter and headaches associated with thyroid disease. Headache 2017; 57: 285–289.

47.

Duvall

Robertson

Whealy

, et al. Clinical reasoning: An underrecognized etiology of new daily persistent headache. Neurology 2020; 94: e114–e120.

48.

Stubberud

Cheema

Tronvik

, et al. Nutcracker syndrome mimicking new daily persistent headache: A case report. Cephalalgia 2020; 40: 1008–1011.

49.

Rozen

Devcic

Toskich

, et al. Nutcracker phenomenon with a daily persistent headache as the primary symptom: Case series and a proposed pathogenesis model based on a novel MRI technique to evaluate for spinal epidural venous congestion. J Neurol Sci 2022; 434: 120170.

50.

Young

WB.

New daily persistent headache: controversy in the diagnostic criteria. Curr Pain Headache Rep 2011; 15: 47–50.

51.

Naegel

Zeller

Hougard

, et al. No structural brain alterations in new daily persistent headache – a cross sectional VBM/SBM study. Cephalalgia 2022; 42: 335–344.

52.

Szabo

Chang

Shulman

, et al. Alterations in the structure and function of the brain in adolescents with new daily persistent headache: A pilot MRI study. Headache 2022; 62: 858–869.

53.

May

Schulte

LH.

Chronic migraine: risk factors, mechanisms and treatment. Nat Rev Neurol 2016; 12: 455–464.

54.

Palacios-Ceña

Talavera

Gómez-Mayordomo

, et al. The day my life changed: A qualitative study of the experiences of patients with new daily persistent headache. Headache 2020; 60: 124–140.

55.

Gelfand

Reider

Goadsby

PJ.

Outcomes of greater occipital nerve injections in pediatric patients with chronic primary headache disorders. Pediatr Neurol 2014; 50: 135–139.

56.

Szperka

Gelfand

Hershey

AD.

Patterns of use of peripheral nerve blocks and trigger point injections for pediatric headache: Results of a survey of the American Headache Society Pediatric and Adolescent Section. Headache 2016; 56: 1597–1607.

57.

Lagrata

Cheema

Watkins

, et al. Long‐term outcomes of occipital nerve stimulation for new daily persistent headache with migrainous features. Neuromodulation Technol Neural Interface 2020; ner.13282.

58.

Rozen

Swidan

SZ.

Elevation of CSF tumor necrosis factor? Levels in new daily persistent headache and treatment refractory chronic migraine. Headache 2007; 47: 1050–1055.

59.

Di Caprio

Lembo

Di Costanzo

, et al. Anti-inflammatory properties of low and high doxycycline doses: an in vitro study. Mediators Inflamm 2015; 2015: 329418.

60.

Rozen

TD.

Doxycycline for treatment resistant new daily persistent headache. Headache 2008; 48: S49.

61.

Chen

, et al. Venlafaxine inhibits the upregulation of plasma tumor necrosis factor-alpha (TNF-α) in the Chinese patients with major depressive disorder: A prospective longitudinal study. Psychoneuroendocrinology 2013; 38: 107–114.

62.

Tariq

Board

Eftimiades

, et al. Resolution of new daily persistent headache by a tumor necrosis factor alpha antagonist, Venlafaxine. SAGE Open Med Case Rep 2019; 7: 2050313X1984780.

63.

Pomeroy

Marmura

Nahas

, et al. Ketamine infusions for treatment refractory headache. Headache 2017; 57: 276–282.

64.

Aurora

Dodick

Turkel

, et al. OnabotulinumtoxinA for treatment of chronic migraine: Results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial. Cephalalgia 2010; 30: 793–803.

65.

Ali

Kriegler

Tepper

, et al. New daily persistent headache and onabotulinumtoxina therapy. Clin Neuropharmacol 2019; 42: 1–3.

66.

Spears

RC.

Efficacy of botulinum toxin type A in new daily persistent headache. J Headache Pain 2008; 9: 405–406.

67.

Trucco

Ruiz

P009. A case of new daily persistent headache treated with botulinum toxin type A. J Headache Pain 2015; 16: A119.

68.

Edvinsson

Haanes

Warfvinge

, et al. CGRP as the target of new migraine therapies — successful translation from bench to clinic. Nat Rev Neurol 2018; 14: 338–350.

69.

Greene

Gentile

Szperka

, et al. Calcitonin gene–related peptide monoclonal antibody use for the preventive treatment of refractory headache disorders in adolescents. Pediatr Neurol 2021; 114: 62–67.

70.

Prakash

Shah

ND.

Post-infectious new daily persistent headache may respond to intravenous methylprednisolone. J Headache Pain 2010; 11: 59–66.

71.

Evans

Turner

DP.

Clinical features of new daily persistent headache: A retrospective chart review of 328 cases. Headache 2021; 61: 1529–1538.

72.

Lobo

Wang

Lobo

, et al. Time to retire ‘New daily persistent headache’: Mode of onset of chronic migraine and tension-type headache. Cephalalgia 2021; 033310242110444.

73.

Nagaraj

Wei

Puledda

, et al. Comparison and predictors of chronic migraine vs. new daily persistent headache presenting with a chronic migraine phenotype. Headache 2022; 62: 828–838.

74.

Mollan

Ali

Hassan-Smith

, et al. Evolving evidence in adult idiopathic intracranial hypertension: pathophysiology and management. J Neurol Neurosurg Psychiatry 2016; 87: 982–992.

Update in the understanding of new daily persistent headache

Abstract

Keywords

History and evolution of the disease entity

Epidemiology

Triggers of NDPH

Clinical characteristics

Diagnostic work-up and the 3Ts model of NDPH

Secondary headaches that mimic NDPH

Cranial pathologies

Extracranial pathologies

Pathogenesis

Treatment

Nerve Block/Stimulation

Anti-Tumor Necrosis Factor-alpha (TNF-α) treatment

Intravenous ketamine

OnabotulinumtoxinA (BTX)

Calcitonin gene-related peptide (CGRP) antibodies

3Ts model-specific treatment

Controversy in the diagnosis and personal opinions from the authors

Is NDPH a primary headache disorder?

Is NDPH just a quick chronification of migraine or tension-type headache?

Conclusion

Clinical implications

Footnotes

Declaration of conflicting interests

Funding

ORCID iDs

References