What is a new daily persistent headache (NDPH)?

New Daily Persistent Headache (NDPH) is a rare condition that causes continuous headaches that persist for months.¹ “New” refers to the abrupt onset of symptoms, which helps differentiate this condition from common headaches or migraines. “Daily Persistent Headache” describes how people affected with the condition experience headaches every day after the onset, for several months.

NDPH can affect anyone; however, children and teenagers without a history of headaches are affected more frequently than other age groups.² People who receive a diagnosis can normally report the exact time that the headache began, as well as what they were doing at the time of onset, making this one of the diagnostic criteria for the condition. Additionally, diagnosing NDPH requires the individual to be experiencing non-stop headaches for at least 3 months.¹ 

Symptoms of NDPH

Symptoms of NDPH can vary from person to person. People with an NDPH diagnosis report feeling pressure or a tightening sensation, which often presents on both sides of the head, but cases of one-sided or area-specific pain have been reported.³ While the pain can fluctuate from mild to severe, it does not go away completely. The general symptoms of NDPH include sleep problems, dizziness, and neck pain or stiffness. In some cases, NDPH symptoms may resemble those of migraines, including pulsing, throbbing pain, pain on one side of the head, sound or light sensitivity, visual auras, vertigo, and nausea.

While the exact cause of NDPH has not yet been defined, there is some evidence that it is triggered by viral and bacterial infections.⁴ Given that NDPH has no known causes, understanding which specific trigger may be causing the condition can significantly increase the chances of correct management and treatment options and ultimately help alleviate symptoms to improve everyday life.

How can infections lead to NDPH?

To understand how viral and bacterial infections are linked to NDPH, we must first explore how our body reacts to an infection and how this reaction may trigger conditions like NDPH.

When a virus or bacterium, generally referred to as a pathogen, enters the body, our immune system activates several mechanisms that are designed to protect our cells from the invasion. This is known as an immune response, and while its goal is to eliminate the threat, it can sometimes lead to other health complications. Factors that may lead to NDPH following an immune system response to an infection include:

• Immune system dysregulation: Inflammation is the normal outcome of an immune response after the release of infection-fighting cells, cytokines. Sometimes, even after the infection has been eradicated, cytokines remain active and inflammation persists. Prolonged inflammation can affect the tissue and nerves that surround the head and neck area, which play a key role in headaches. As a result, a “switch-on” headache may occur, where the pain doesn’t turn off after a few hours like a simple headache would⁵
• Nervous system dysregulation: Infections may sometimes change the way our bodies process pain and send out pain signals, and therefore cause our nervous system to become overly sensitive. This is a phenomenon called central sensitisation. When this happens, normal signals may be misread as pain and result in persistent headaches⁵
• Direct nervous system effect: Some viruses have the ability to directly target and affect the nervous system. Viral chemicals or proteins have been identified in parts of the brain or the blood vessels of people infected by the virus¹

New Daily Persistent Headache has been associated with a variety of viruses and bacterial infections, and is not directly linked to one pathogen. In addition, research suggests that systemic infections (those that affect the whole body, rather than localised infections) are responsible for NDPH in most cases.

Viral infections linked to NDPH

Historically, New Daily Persistent Headache (NDPH) has been linked to pandemics. The first reports of NDPH symptoms date back to the 1980s, which were a result of viral illness, while the term New Daily Persistent Headache was coined in 1986.⁶ These reports have helped scientists identify the possible triggers for this condition, which have predominantly been identified as viral infections.

Recent cases have pointed towards various infections that commonly affect people:

Epstein-barr virus (EBV)

Epstein-Barr virus (EBV) is a very common infection that is responsible for causing mononucleosis (commonly known as mono). Numerous cases of individuals who get diagnosed with NDPH are reported to have an active EBV infection or to have been infected with EBV sometime before experiencing NDPH symptoms.¹

Although the precise mechanism that leads this virus to cause NDPH is unclear, EBV creates a strong immune response and is therefore likely to trigger NDPH by prolonged inflammation.⁷ Epstein-Barr virus causes systemic symptoms and may also affect the nervous system. For this reason, it is reported as the most frequent viral trigger for NDPH.⁶

Herpes virus

Herpes type viruses are neurotropic, meaning that they have the ability to infect nerve tissue and directly affect the central nervous system (CNS).⁸ There is concrete evidence that individuals who have been infected by different herpes viruses have later developed NDPH.^9,1 The herpesvirus types that have been linked to NDPH are:

• Herpes Simplex Virus (HSV): Can cause oral or genital herpes, depending on the virus type
• Varicella Zoster Virus (VZV): Responsible for chickenpox (varicella) and shingles (herpes zoster)
• Cytomegalovirus (CMV): Can cause a range of mild symptoms and serious conditions, including mononucleosis, pneumonia, and hepatitis

SARS-CoV-2 (COVID-19)

The recent COVID-19 pandemic has shown significant evidence of association between the virus and New Daily Persistent Headache instances.¹⁰ Epidemiology reports strongly suggest the onset of NDPH following infection with the virus responsible for COVID-19, SARS-CoV-2, as infected or recovering individuals experienced symptoms that fulfil the diagnostic criteria for NDPH.¹⁰

While COVID-19 is recent and therefore further research is required, it is suspected that the link between the virus and NDPH onset occurs through neurological factors. Additionally, the virus is known to invade the nerves through the olfactory pathway, suggesting direct nervous system targeting by SARS-CoV-2.¹¹

Bacterial infections linked to NDPH

While viral infections have a clearer association with NDPH, increasing evidence shows that bacterial infections are also responsible for the syndrome.

Salmonella

Infection with Salmonella usually leads to gastrointestinal symptoms, which in turn cause systemic inflammation. In some cases, Salmonella may affect the nervous system and cause other conditions, such as meningitis or encephalopathy.^12,13 There is limited evidence of direct Salmonella-NDPH association. However, the mechanisms that Salmonella bacteria use to invade the body and the reported cases show a potential link.¹

E. coli

Urinary tract infections (UTIs) are primarily caused by the bacterium Escherichia coli (E. coli). While direct association between E. coli and NDPH is limited, infection with this pathogen can lead to mild or life-threatening symptoms that can be systemic or affect the nervous system.

Why identifying infectious triggers matters

Given that NDPH is a rare condition, with poorly understood underlying causes that can be connected to several different triggers, it is very important to investigate the exact cause of onset for each specific case. Understanding the link between infections and New Daily Persistent Headache can significantly help:

• Improve diagnostic accuracy: Increasing evidence suggests that the majority of NDPH cases present in a post-infection manner, where the individual has presented with either a viral or bacterial infection sometime prior to NDPH onset. Examining all the factors that could contribute to NDPH helps rule out other headache-related conditions with similar, generic symptoms, while also providing an accurate diagnosis early on
• Guide treatment approach: Dealing with daily headaches for several months, with no response to treatment, is frustrating, but identifying the trigger that is responsible for the condition can drastically increase how effective treatment can be. Viruses and bacteria can be targeted through entirely different treatment options, and therefore, cause-specific therapy is essential
• Future biomarker development: Immune system disorders rely on tests that measure inflammation-related products, such as proteins and chemicals, called biomarkers. If healthcare providers can identify the specific infection that led to NDPH, they can look for specific biomarkers (i.e., cytokines) in the fluid that surrounds the brain and spinal cord or use bioimaging to detect inflammation. If an individual presents with NDPH symptoms and a history of infection, specialised biomarkers can confirm chronic inflammation and ultimately achieve early intervention

Summary

New Daily Persistent Headache is a rare condition with poorly understood underlying mechanisms. Despite being linked to various risk factors, no direct cause has been identified, making effective, targeted treatment complicated. However, increasing evidence points towards viruses and bacterial infections as infectious triggers for this condition. Understanding the way these infections may predispose individuals to NDPH is crucial in optimising treatment outcomes and making New Daily Persistent Headache more manageable.