New daily persistent headache ( NDPH ) is an often-refractory headache which presents with sudden onset. The day on which the patient develops the headache is distinct, and the time of onset is clearly remembered by the patient, with the pain becoming continuous and unremitting within 24 h. Though a subset of children and adolescents with NDPH will respond quite nicely to treatment, unfortunately, many continue to experience daily headaches for years to come. Secondary etiologies must be excluded in patients in whom NDPH is suspected, as misdiagnosis can lead to inappropriate treatment and poor outcomes. Once a diagnosis is established, the importance of early intervention cannot be overemphasized. These daily headaches can lead to missed school and extracurricular activities, as well as anxiety, depression, and significant strain upon the family. The onus is often on the primary care provider, who typically has first contact with the child with NDPH, to diagnose appropriately and treat aggressively, or to refer the patient to a headache specialist.
To make an accurate diagnosis, it is critical that the provider recognize an abrupt onset headache which rapidly escalates to a continuous headache within 24 h. A thorough workup must also be performed to exclude secondary causes. NDPH typically occurs in patients without any significant prior headache history, though it can occur in those with preexisting tension-type headache or migraine. In those with prior headache history, there should be no report of an increase in headache days before the onset of daily headaches. If the patient has prior history of tension-type headache or migraine, the presence of medication overuse during, or following the development of their daily headaches excludes NDPH as the primary diagnosis. Acute traumatic headaches, headaches attributed to low cerebrospinal fluid pressure (such as spontaneous intracranial hypotension), and headaches attributed to high cerebrospinal fluid pressure (such as idiopathic intracranial hypertension) are considered secondary headaches and are not classified as NDPH. These conditions will need to be ruled out by appropriate diagnostic evaluation.
As defined in the third edition of the International Classification of Headache Disorders (ICHD-3), a
a ICHD-3 is published as the first issue of Cephalalgia in 2018. It is a systematic classification system for headache with explicit diagnostic criteria for each condition as agreed upon by the Classification Committee of the International Headache Society and supported by research.
patients with NDPH have unremitting headaches which occur daily, and last all day for at least 3 months. The patient is classified as having probable NDPH when the headaches have been present for less than 3 months, with all other diagnostic features identical to those seen in NDPH.The quality of pain reported by children with NDPH may be nondescript. The pain is commonly bilateral in location and moderate in intensity, though it can be seen on any aspect of the head and range in intensity from mild to severe. In some, there are overlapping migrainous features. These may include pulsing/throbbing quality, unilateral location, photophobia, phonophobia, nausea and/or vomiting, and worsening by physical activity. The slow progression of headache frequency in those with chronic tension-type headache or chronic migraine is sharply contrasted by the rapid onset of NDPH. Careful history-taking alone should differentiate NDPH from chronic tension-type headache, chronic migraine, and rare daily headache conditions such as hemicrania continua.
In our experience, early diagnosis and treatment often decreases functional disability and in some cases prevents it. It is critical that the provider listen attentively to patients and their families while taking the history and take care not to be dismissive of complaints of daily headaches regardless of how “well” the child may appear in front of the provider. This advice applies for all headache patients, regardless of diagnosis. Pain ratings are often difficult to obtain from younger patients using validated scales, and we find using impairment of activities (no impairment equating to mild, some impairment equating to moderate, and complete impairment indicating severe intensity) to be clinically useful measures. Creating a strong therapeutic alliance is instrumental in directing appropriate diagnostic workup and therapeutic management, which can at times be lengthy and taxing on patients as well as their families ( Table 1 ).
NDPH diagnostic criteria:
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Epidemiology
NDPH has higher prevalence in children and adolescents than in adults. Studies conducted at various tertiary headache centers throughout the United States and abroad have shown NDPH to be present in 13%–35% of children with chronic daily headache (defined as headache for at least 15 days in a period of 1 month, over at least a 3 month period, and with no secondary cause). In comparison, it is estimated that up to 10.8% of adult patients with chronic daily headache have NDPH. Kung et al. found that NDPH is more prevalent in girls compared to boys (with a female: male ratio of 1.8). In their study, which included patients aged 6–18 years with chronic daily headache, the mean age of onset of NDPH was 14.2 years. The majority of patients with NDPH described in both the pediatric and the adult literature are Caucasian, although this may reflect selection bias as to who gets to a headache clinic.
A retrospective review published by Grengs and Mack in 2016 evaluated the temporal onset of NDPH in school-aged children seen at a tertiary care center. Interestingly, there was a statistically significant increase in headache onset in the months of September and January, months traditionally associated with return to school following a break at the end of the prior semester. The authors postulate that the action of returning to school may trigger the onset of NDPH. We suspect that this correlates with a significant stress trigger.
In adults, mood disorders have been shown to have higher prevalence in NDPH patients compared to healthy subjects. A cross-sectional study conducted in India looked at the prevalence of depression, anxiety, pain somatization, and catastrophizing in NDPH patients. Among these adult NDPH patients, severe anxiety was evident in 65.5%, and severe depression was present in 40%. Though few pediatric studies have explored this association, in our clinical experience, mood disorders appear highly prevalent in pediatric NDPH patients. Baron and Rothner reported straight-A report cards and excessive extracurricular activities as possible risk factors for NDPH chronification. However, this reflects co-morbidity but not causality.
Pathogenesis
Unfortunately, little is known about the pathogenesis of NDPH. There is a paucity of data regarding this condition, especially in the pediatric population. Thus the etiology of these headaches is largely speculative. Some authors have theorized that NDPH results from glial cell activation precipitated by prior viral illness or infection, psychological stress, invasive surgical procedure, mild to moderate head injury, or other provoking events. These events could lead to the continuous production of cytokines, triggering a chronic inflammatory response and the production of pain. In an abstract from 2004, the authors found that in 34 children and adolescents with NDPH, 15% (5 patients) developed NDPH following an infection, 15% (5 patients) had a history of preceding mild to moderate head injury, and 12% (4 patients) had significant psychosocial stressors.
A number of researchers have explored whether an infectious trigger exists for NDPH. Diaz-Mitoma and colleagues hypothesized that activation of latent Epstein-Barr virus (EBV) may play a role in the development of NDPH. In their study, 84% of 32 NDPH patients had evidence of an active EBV infection compared to only 25% of 32 age- and gender- matched controls. In a retrospective chart review by Li and Rozen, EBV antibody titers were positive for past infection in 5 of 7 patients (71%) tested, though there was no evidence of active infection. Others have found no evidence of past or prior EBV infection in their NDPH patients, but have identified evidence of other infections, including herpes simplex virus (HSV) and cytomegalovirus (CMV). Additional proposed infectious triggers include Salmonella , adenovirus, toxoplasmosis, herpes zoster virus, and Escherichia coli urinary tract infections.
A temporal relationship between NDPH and exposure to pesticides, certain medications (including antibiotics, terbinafine, and progesterone), and massage treatment has also been observed in adults. Rozen and colleagues also suspect that cervical joint hypermobility may play a role. Hypothetically, irritation of the cervical facet and atlanto-axial region, as well as stimulation of the C1-C3 cervical nerve roots in individuals with hypermobility could bring on daily head pain through activation of the trigemino-cervical complex. This may be especially relevant in cases of NDPH following surgical procedures due to extension of the neck with intubation. Additionally, defective internal jugular venous drainage has been suggested as a potential trigger.
Interestingly, Rozen and Swidan found elevated levels of TNF alpha in the CSF samples of 19 out of 20 NDPH patients from an inpatient headache unit, lending support to the role of pro-inflammatory cytokines in the pathogenesis of NDPH. TNF alpha can activate the production of calcitonin gene-related peptide, a protein that is known to play a major role in the pathogenesis of other headache disorders, including migraine and cluster headache. Though the implications of elevated levels of TNF alpha in the CSF of NDPH patients remain entirely theoretical, these findings may suggest that NDPH is not a consequence of a specific infectious agent, but instead results from a nonspecific inflammatory response to illness, physical or emotional stress, or other significant change in the environment.
Workup
Diagnostic workup should include laboratory studies to exclude metabolic derangements and inflammatory disorders as secondary causes. Blood work should include complete blood count with differential, comprehensive metabolic panel, thyroid studies, and sedimentation rate. In our practice, we additionally check vitamin D and vitamin B12 levels, as well as antinuclear antibodies (ANA) with reflex. Obtaining EBV IgG and IgM titers is reasonable, though the significance of elevated EBV titers when identified is unknown. Some headache specialists advocate for having titers drawn for CMV, human herpesvirus 6, and parvovirus, and others consider testing for West Nile and Lyme disease potentially useful. Although there is no targeted treatment for most of these illnesses, identifying a potential causative agent as a trigger can be reassuring for families.
Regarding neuroimaging, we recommend a gadolinium-enhanced MRI of the brain with MRV in all NDPH or probable NDPH patients to exclude spontaneous CSF leak, cerebral venous sinus thrombosis, inflammatory processes, and other potential intracranial pathology that can mimic the presentation of NDPH. In treatment-refractory patients, a lumbar puncture may be necessary to exclude a high-pressure headache without papilledema, low pressure headache, or a CNS inflammatory disorder.
Treatment
We recommend that the provider tailor the treatment approach to the patient’s level of functional disability, which is measured by frequency of missed school and social events, and impairment of daily activities. The spectrum of disability observed in the NDPH patient population is quite wide. The patient without disability remains in school without impairment of their day-to-day routine, while other patients are so significantly disabled that they have withdrawn from traditional school programs entirely. The goal of therapy is to allow the patient to return to (or remain in) a state of normal function.
For the patient without disability, we recommend initiating treatment with a course of oral steroids 5–7 days in duration. Though the literature regarding the use of steroids in NDPH is sparse, with only rare findings of patient improvement with cycled intravenous steroids , in our clinical experience, a relatively short steroid pulse provides significant clinical benefit to a small subset of patients.
Any of the daily medications used for migraine and tension headache may be of potential benefit for the patient with NDPH, including neuromodulators such as topiramate or valproic acid; tricyclic antidepressants such as amitriptyline or nortriptyline; or beta blockers such as propranolol. If there is no clinical improvement within 6–8 weeks on a given daily enteral medication, we recommend transitioning to a medication with a different mechanism of action. If there is partial response, we recommend continuing therapy, titrating further, or adding another agent.
Selection of an oral preventive should be directed by the semiology of the headache (i.e., higher consideration of topiramate if more migrainous in character, versus a tricyclic antidepressant if more tension-type), while also taking the potential side-effect profile of the medication into consideration. Again, though this approach has proven helpful in our clinical experience, there is very limited data to support the selection of one oral medication over another.
We have found nerve blocks to be quite beneficial as well, and these are commonly used by pediatric headache specialists to treat patients with NDPH. In our practice, we use a combination of lidocaine and bupivacaine. Other specialists may use bupivacaine alone or in combination with steroids. We often offer these in conjunction with titration of daily medications. If the response is poor, we then consider cycling intravenous medication in an inpatient setting. For refractory cases, Botox (onabotulinumtoxinA) injections, a prolonged course of steroids, leukotriene inhibitors, or perhaps anticalcitonin gene-related peptide monoclonal antibodies may be of benefit. Biofeedback, relaxation therapy, or acupuncture may also be helpful.
For those with significant disability, we have found that early admission to the hospital for cycled intravenous medication is beneficial. Rather than prolonging school absences and potentially increasing patient deconditioning by waiting weeks for daily enteral meds to show effect, inpatient admission allows for a potentially rapid return to function. We recommend starting with serial intravenous infusions of diphenhydramine, prochlorperazine, and ketorolac, with transition to intravenous dihydroergotamine if poor response within 24–48 h. If these measures are ineffective, we recommend serial infusions of magnesium or valproate sodium. In our practice, typical duration of such inpatient admissions is 3–4 days, with discharge at that point if no response. Preventive enteral medication including neuromodulators, tricyclic antidepressants, and antihypertensives, among others, can be initiated prior to discharge to help prevent headache recurrence. If inpatient therapy fails to bring benefit, we recommend proceeding with nerve blocks, Botox (onabotulinumtoxinA) injections, or a trial of a prolonged course of steroids in the outpatient setting.
Prognosis
Despite aggressive treatment measures, NDPH is often quite treatment-refractory. This can be tremendously frustrating for the patient, the family, as well as the provider. It has been postulated that there may be two types of NDPH: (1) a form which can resolve spontaneously within several months; and (2) a form which is refractory to even the most aggressive forms of treatment. In our clinical practice, the latter form is by far more prevalent. In a small cohort study of 28 children and adolescents with NDPH by Wintrich and Rothner, 20 patients (71%) reported headaches 6 months to 2 years later, and only 8 patients (29%) were headache-free. Despite these high statistics regarding persistent headache, it is encouraging that 79% of these 28 patients had Migraine Disability Assessment (MIDAS) scores that indicated normal function.
NDPH: What families need to know
New daily persistent headache (NDPH) is a headache that develops on a given day and persists all day, every day from that time onward. To you and your child, these headaches may have seemed to come “out of the blue” and just won’t go away. Your child will likely recall where they were and what they were doing when the headache first started. For many, headache onset occurs during unremarkable circumstances, such as while sitting at home playing video games, socializing with friends at a birthday party, or concentrating at school during a math test.
Usually, the child who develops NDPH did not complain of frequent or severe headaches before the start of their daily headaches. NDPH is sometimes diagnosed in patients who already have another type of headache, such as migraine headache or tension-type headache, but then develop new headaches without any increase or significant change in the prior headache pattern.
Typically, over the counter and oral prescription medications for headache do not provide relief from these daily headaches. For many, even infusions of medication into the vein do not alleviate the pain. In other words, these headaches are often quite resistant to treatment. These headaches and their significant impact on day-to-day function can be alarming to families. For many, the mind often jumps to the worst-case scenario: brain tumor, brain bleed, severe infection, or other life-threatening conditions.
Fortunately, patients with NDPH do not suffer from any of the above. Testing is always ordered to exclude potential medical causes. Your provider may want to obtain a scan of your child’s brain (MRI), as well as laboratory (blood sample) studies. In some cases, your provider may even want to have a small amount of spinal fluid drawn (a procedure called a “spinal tap”) to check the pressure around the brain and look for markers of inflammation. Some providers will also order special blood tests to look for evidence of recent infection. If any of the tests for infection return positive, it is possible that a virus could have contributed to the development of your child’s headache. In patients with NDPH, this testing frequently comes back normal.
We still do not know the exact cause of NDPH. Of the few studies exploring this question, there have been some findings to support that a viral illness could have played a role, at least in some cases. Others suspect that mild head trauma or recent surgery on a part of the body besides the brain (such as having the appendix removed) may trigger these headaches. However, for many patients, no specific trigger is identified.
Your child may be prescribed medications including steroids, antidepressants, antiseizure medications, and blood pressure medications, among others. Other treatments include learning relaxation techniques through biofeedback, or participating in other types of therapy. In some cases, patients are admitted to the hospital for several days to receive cycled intravenous medications. The goal of treatment is not only to reduce or eliminate your child’s headaches, but also to allow your child to remain in school, enjoy daily activities, and return to normal function.
Though this type of headache is difficult to treat in most cases, and some patients continue to experience daily headaches despite therapy, many do see good improvement. It is crucial that you be an advocate for your child, and that you establish a partnership with a provider who is experienced in caring for children with NDPH. By creating a solid relationship with your provider and working through the challenges of diagnosis and treatment, one step at a time, it is possible to gain significant improvement and control of your child’s headaches so that your child can lead a normal life.
References
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