Update in the understanding of New Daily Persistent Headache, 2023

[pattismith]

Update in the understanding of new daily persistent headache - Kuan-Po Peng, Todd D Rozen, 2023 (sagepub.com)




Triggers:

Common triggers include infectious episodes or stressful life events

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).

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).

 

[pattismith]

New daily persistent headache: a systematic review on an enigmatic disorder | SpringerLink 2019

this older paper is full of interesting things @sb4

Rozen et al. noticed that their NDPH patients had characteristics similar to patients with connective tissue disorders. They were thin, tall, had a long neck and on physical examination they had lax joints suggestive of underlying cervical spine and systemic joint hypermobility. Using Beightons score as a screening test for joint hypermobility in 12 NDPH patients, they revealed that 11 had cervical spine joint hypermobility and 10 had widespread joint hypermobility. Thus, they suggested a possible role for cervical spine joint hypermobility in the pathogenesis of NDPH [23].

In another study, all 9 post-surgical NDPH cases in Rozen’s material had endotracheal intubation. Thus, he suggested a cervicogenic origin to their headache caused by the cervical hyperextension during neck positioning for intubation

Treatments listed:

Methylprednisolone

In one study, Prakash and Shah observed treatment response to a course of 5-days high dose methylprednisolone in 9 post-infectious NDPH patients. Six of them also received oral steroids for 2–3 weeks following intravenous methylprednisolone. All patients reported improvement. Seven had almost full recovery within 2 weeks, while in two other patients complete pain relief occurred within 1.5 to 2 months after starting the treatment [25]. The weakness of this study is that 5 of 9 patients were treated just few weeks after the headache began while the ICHD diagnostic criteria required at least 3 months of headache for NDPH diagnosis. Thus, treatment with high dose IV corticosteroids may not be as favorable in some classic cases that fulfill ICHD-3 diagnostic criteria.

Tetracycline derivatives
Doxycycline is a drug recognized to inhibit TNF-α. In a small, open-label trial reported in an abstract by Rozen [26], four treatment refractory NDPH patients with high TNF-α levels in the CSF were given 100 mg doxycycline twice daily for 3 months. Three patients reported that their headache had been precipitated by an infection. All patients had improvement within 3 months of initiation of doxycycline. Complete relief of the pain occurred in two NDPH patients who had the highest CSF TNF-α levels, while one patients reported 80% decrease in pain intensity, and one experience more than 50% decrease in frequency of severe headache episodes with minor reduction in severity of daily headaches.

Rozen, has described some effects for montelukast (10 mg twice daily) when added to doxycycline or minocycline to treat NDPH. However, there is no evidence in the literature to support using montelukast in the treatment of NDPH [6].

Topiramate and gabapentine
Rozen presented 5 NDPH patients in an abstract with favorable response to either gabapentin or topiramate but again no good scientific evidence supports using these medications for treatment of NDPH [6].

Mexiletine
Marmura et al. in a retrospective study reported on patients with refractory chronic daily headache including 3 NDPH patients who had been treated with mexiletine. All 3 NDPH cases reported decrease in pain intensity, while only one had diminished headache frequency. Serious adverse effects were reported during the treatment [27].

Nerve blockade
Robbins et al. performed nerve blocks in painful areas with 0.5% bupivacaine in 23 NDPH patients. It provided 60% acute response, consistent with at least one-day decrease in pain intensity in patients with NDPH [15].

In a retrospective review, Hascalovici et al. reported treatment response of 67% with peripheral nerve blockade in 3 NDPH patients. They considered nerve blockade as a safe and efficient strategy to treat older NDPH patients [28].

Puledda et al. reported that improvement was seen in 13 of 22 (59%) children and adolescents with NDPH who received greater occipital nerve block using 1% lidocaine and methylprednisolone [29].

Onabotulinum toxin type a (BTX)
In a case report, Spears treated a 67-years-old NDPH patient with 3 rounds of BTX injection. He reported 8–12 weeks of absolute pain free periods after each treatment [30].

Trucco and Ruiz reported a 19-year-old woman with refractory NDPH who had partial relief after the first injection of BTX and almost complete response after the third cycle [31].

Tsakadze and Wilson reported pain relief of 75% in one and 100% in one patient with treatment refractory NDPH who were treated with BTX injection every 3 month [32].

Intravenous lidocaine
Marmura et al. in a retrospective study, studied 68 intractable cases with chronic daily headache including 12 NDPH patients were treated with IV lidocaine. 25.4% of subjects exhibited a complete response and 57.1% exhibited partial response. They suggested that patients with NDPH may benefit from IV lidocaine treatment [33].

Akbar reported a 16-year-old boy diagnosed as NDPH who was refractory to several aggressive inpatient therapies. He was treated with IV lidocaine infusion and reported that the headache fully resolved for 2 weeks and severity and frequency decreased for almost 3 months [34].

Intravenous dihydroergotamine (IV DHE)
Nagy et al. studied the effect of IV DHE in the treatment of refractory primary headache disorders. Two of 11 NDPH cases in their study reported only mild benefit from DHE therapy. Both had migranous features. Thus, they proposed that in contrast to the effect of IV DHE in the chronic migraine, the outcome for treatment of NDPH with IV DHE particularly those with non-migranous characteristics is less encouraging [35].

Intravenous ketamine
In a retrospective study, Pomeroy et al. treated 14 NDPH patients who had previously failed aggressive treatments with a sub-anesthetic dose ketamine infusion. Acute response was seen in 8 (57.1%) NDPH patients receiving ketamine, while half of them reported persistent effect of it. As it is well tolerated, a trial of ketamine might be considered reasonable in refractory NDPH cases [36].

Osteopathic manipulation treatment
Alexander reported a 15-year-old girl with NDPH who had pain relief after osteopathic manipulation treatment. He proposed that osteopathic manipulation treatment might be helpful in treatment resistant NDPH cases [37].

Nimodipin
Rozen et al. presented a 46-year-old woman with NDPH started as thunderclap headache followed by 13 month of daily headache from onset along with acalculia. All symptoms resolved rapidly and completely with nimodipin 30 mg administered twice daily. He proposed this case as a distinct subtype of NDPH caused by continuous cerebral artery vasospasm due to rapid increase in CSF TNF-α levels. This is the only report of efficacy of nimodipin in NDPH [38].

Combination of various drugs
Prakash et al. treated 37 NDPH patients with a combination therapy of IV methylprednisolone, IV sodium valproate, anti-depressant (amitriptyline or dothiepin) and naproxene for at least 3–6 months. After a median follow-up of 9 months, the clinical response was “excellent” (no or less than 1 headache per month) in 37% and “good” (50% reduction in headache frequency or days per month) in 30% of NDPH patients [16].

In summary, ketamine infusion, onabotulinum toxin type A, intravenous (IV) lidocaine, IV methylprednisolone and nerve blockade are possible treatment options for patients who do not respond to common prophylactic drugs.

A few reports have suggested a better response when adequate treatment of NDPH administered early in the course of the disease (within 3–12 months of NDPH onset) [16, 39]. However, this association has not been established in all studies [10]

 

[sb4]

Thanks for the tag, I find it very interesting.

I recently took doxycyclin at 50mg per day, as oppose to that papers 200mg per day, along with some other inhibitors of MMPs (Q10, Mg, and 2 other supplements I can't remember) but unfortunately didn't notice much.

I have had more success going cold turkey on the nicotine lozengers and bromocriptine. I read that nicotine inhibits neuroinflammation but you get a rebound where there is more glial activation / inflammation. This is consistent with my experience where you feel better for 20 mins or so (headache also lessens) then you feel worse than baseline for the next hour.

Despite stopping those things my neck is still quite fragile. I have to be very careful with my posture and have noticed things like typing on the keyboard too long cause shoulder and neck pain.

I am currently trialing rapamycin so I will see how that fairs in modulating the immune system / inflammation. I am also going to see what applying deep heat spray to the neck does.

That methylprednisolone helps is interesting. Perhaps it is lowering inflammation caused by viruses?

I recently checked for a sacral dimple and found I have one at the top of my butt crack. This area used to bleed when I did situps. That and my feet bleeding easily with friction from the floor leads me to believe I had mild connective tissue problems even before this illness started.

 

[pattismith]

That methylprednisolone helps is interesting. Perhaps it is lowering inflammation caused by viruses?
.

Methylprednisolone may helps, but not sure it works on the long run.

Some of their treatments might be interesting for ME/CFS with associated headache.

Here another paper where Lithium successfuly cured the chronic headache

Case report: Therapeutic response for new daily persistent headache by a tumor necrosis factor alpha antagonist, lithium (sagepub.com)

 

[heapsreal]

I'm suprised they weren't pushing medication overuse headache syndrome. My 4 day headache and vomiting episode in hospital everytime I saw a new Dr, the first thing out of their mouth was medication overuse headache syndrome. When I eventually got an mri done the report came back saying possible benign increased intracranial hypertension. They didn't do much other than say to me to find a neurologist.

Long story short. Working with my gp, the combination of lyrica and toprimate is helping alot more than lyrica alone. Very similar to the above post of Gabapentin and topiramate. I recently read an article and saw that toprimate is a drug used for intracranial hypertension. Should have saved the article.

 

[pattismith]

Long story short. Working with my gp, the combination of lyrica and toprimate is helping alot more than lyrica alone. Very similar to the above post of Gabapentin and topiramate. I recently read an article and saw that toprimate is a drug used for intracranial hypertension. Should have saved the article.

@heapsreal , you puzzle me again with your knowledge!

Topiramate is more effective than acetazolamide at lowering intracranial pressure - PMC (nih.gov)

 

[lenora]

Hello everyone.... I'll check into Topiramate for intracranial pressure.....I don't think anyone knows what to do with me. If something works for you, then go ahead and use it. Also, give things a chance before you drop them...plenty of people do that after 2 days, if that. It takes time and start with a low dose and go up from there if needed. We have a lot of choices today compared to years ago...but that doesn't mean they work on everyone. Lenora

 

[heapsreal]

@heapsreal , you puzzle me again with your knowledge!

Topiramate is more effective than acetazolamide at lowering intracranial pressure - PMC (nih.gov)

Just learn by by glueing my broken parts back together 🤣😉

 

[heapsreal]

Hello everyone.... I'll check into Topiramate for intracranial pressure.....I don't think anyone knows what to do with me. If something works for you, then go ahead and use it. Also, give things a chance before you drop them...plenty of people do that after 2 days, if that. It takes time and start with a low dose and go up from there if needed. We have a lot of choices today compared to years ago...but that doesn't mean they work on everyone. Lenora

Agree. Medication especially in cfsers seem very individual on if they work and side effects. Very much trial and error. Toprimate can change your taste buds especially cola type soft drink which taste awful as well as beer, not that I drink alot of beer but when I do, I usually enjoy it, but I prefer not to have headaches.

 

[kangaSue]

Left renal vein compression whether it causes symptoms (renal Nutcracker Syndrome) or not (Nutcracker Phenomenon) can be another little known of cause of sudden onset persisting headaches in some cases too, and interestingly, those with EDS are a fairly prevalent cohort among those with renal Nutcracker Syndrome.

https://pubmed.ncbi.nlm.nih.gov/35093724/
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 (2022);