Case report: Monoclonal antibodies as an alternative treatment for new daily persistent headache

Abstract

Background:

New Daily Persistent Headache (NDPH) is a disabling daily headache that causes huge frustration for patients and headache specialists. Elevated TNF-alpha levels, that elevate CGRP levels, on the CSF of NDPH patients has been described as a possible cause of this disease. TNF-alpha inhibitors like doxycycline, venlafaxine, montelukast and lithium have been used in the past to treat NDPH patients, with relatively good success as described from case reports.

Conclusion:

We report three NDPH patients that improved with the administration of Anti CGRP monoclonal antibodies (mAbs), after trying multiple treatments. We propose this class of drugs, as a therapeutic option for NDPH.

Introduction

New daily persistent headache (NDPH) is a disabling chronic daily headache that causes huge disability in patients and a problem to solve, for headache specialists. It was defined as a daily headache, unremitting, continuous headache for 3 months or longer that is not attributable to any other secondary or primary headache. ¹ Different treatments have been tried for years and still today this disorder has no known specific treatment. It was described by Vanast in 1986 as benign syndrome ^2,3 combining phenotypic features of migraine and tension-type headache, that occurs daily from the first day the headache begins.

Known triggering events associated to the initiation of NPDH have been described: cervical injury, Surgery, Epstein-Barr virus infection or a stressful life event. The hallmark is that the patient remembers the day that, when and how, the headache started. Although it has a low 1-year population prevalence of 0.03–0.1%, ⁴ patients who suffer this condition have a poor quality of life.

Elevated TNF-alpha levels on CSF (cerebrospinal fluid) of NDPH patients, that elevated CGRP (Calcitonin gene related protein) levels as a possible cause of this disease, has been postulated. ⁵ Treatment with TNF-alpha inhibitors like doxycycline, venlafaxine, montelukast and lithium have been used in the past to treat NDPH patients, with relatively good success as described from case reports.

Monoclonal anti CGRP antibodies (mAbs) is a new class of drugs targeted to block CGRP, one of the neuropeptides involved in migraine. ⁶ Effectiveness of mAbs in episodic and chronic migraine has been well established in several randomized placebo-controlled studies. ^{7 –9}

We present three cases of patients diagnosed with NDPH, with failure to previous treatments, who improved with mAbs.

Case report 1

This is a 53-year-old right-handed female patient, from Lima-Peru, with a history of daily headaches from the start, with no known triggering factors for the last 30 years. She had no past history of headaches. The patient describes her headaches as throbbing and holocraneal, with no nausea nor photo/phonophobia. No cranial autonomic symptoms were described. On her work up, she had two MRIs with contrast with no significant findings, brain sagging was not seen nor meningeal enhancement. MRI angiography was reported as normal. Blood tests were normal. Fundoscopy showed no papilledema. No lumbar puncture was performed. She was diagnosed with episodic migraine and posteriorly as chronic migraine, and treated with Topiramate, Valproate, Propranolol for several cycles during all these years, with poor results. Patient had daily analgesic use and was detoxified without any change to daily headache. Patient did not receive onabotulinum toxin type A as treatment, preferring the monoclonal antibody option.

After all these treatment failures, she was diagnosed with NDPH and started venlafaxine 50 mg QD, Lithium 300 mg tid. ¹⁰ A week later, her headaches were still daily but less intense during the morning, with increasing intensity in the afternoons. Six weeks later she had 50% of her daily headaches of low intensity (3/10).

Four months later she came back and had discontinued Lithium (which she lowered to twice daily) because she felt it was not helping. Her headache intensity was 5/10. She was started on Montelukast 10 mg as add on therapy to venlafaxine which we increased to 100 mg daily. Ketorolac 40 mg or Eletriptan 40 mg was used if pain increased over 5/10 in intensity, not more than twice a week any of them.

Five months later, she was once again with intense daily headaches 8–10/10. We decided to try Erenumab 140 mg on a monthly basis, which was added to Desvenlafaxine 100 mg. One month later, her pain intensity had lowered, although still caused disability. After her second dose, the patient referred that the pain started when she woke up and dropped in the next 60 minutes. She lowered the use of analgesics to six tabs of ketolorac 40 mg and no Eletriptan that month.

With the third dose, she had woken up that day with pain that improved in severity within minutes after administration. Used two tablets of Ketorolac in the whole month.

On her fifth month on mAbs, she woke up with pain intensity of 4/10 that dropped to 2/10 in minutes. Did not need to take non-steroidal anti-inflammatory drugs (NSAIDs) nor Eletriptan and was doing a normal life. The patient has a daily minor intensity headache, receiving Erenumab 140 mg monthly, now in her 12th dose.

Case report 2

A 44-year-old woman from Medellin, Colombia, with a history of daily headaches (that began on July 14, 2015) with no pain-free days, without triggering factors, came to our outpatient clinic. It was initially treated as chronic migraine with no results. Medication Overuse Headache was not present. She had no history of headaches. Her headache had an intensity of 7/10 and with two peaks of 10/10 per week, pain was pulsatile, with nausea, phono and photophobia, she had no pain-free hours during the day. No comorbidities found. No endocrinological disease found.

Secondary causes were ruled out with lumbar puncture, contrast brain magnetic resonance with angiography, laboratories: renal and hepatic function, erythrocyte sedimentation rate, complete blood count, electrolytes, HIV, were all normal.

She was diagnosed as NDPH and started multiple treatments, that included over time Desvenlafaxine 100 mg, gabapentin 600 mg, topiramate 50 mg, propranolol 40 mg, (according to usual daily prescription) melatonin 3 mg, pericranial blocks. After 5 years of preventive medicines, onabotulinum toxin type A 200U was started (for 2 years), with a 30% improvement in intensity, but not in pain frequency.

Due to the presence of adverse effects, topiramate and gabapentin were discontinued, and management was continued with onabotulinum toxin type A 200U, venlafaxine 150 mg QD and propranolol 40 mg QD due to comorbidity with depression and panic disorder. Pain crisis were managed with ketorolac 30 mg and sumatriptan 100 mg, with a 30–50% reduction in pain intensity. After 2 years of management with onabotulinum toxin type A, there was a loss of effect with a resumption of daily pain intensity 8–9/10 and so, it was discontinued.

We decided to start management with galcanezumab with a loading dose of 240 mg and maintenance with 120 mg as add on therapy to venlafaxine 150 mg and propranolol 40 mg.

After the first month, the intensity was reduced to 6/10. Six months after treatment started, pain intensity had reduced to 2/10 and this intensity has been maintained until its current 10th dose, to date. She does not require the use of ketorolac or sumatriptan and achieves 15 pain-free days a month to date.

Case report 3

A 65-year-old female patient, from Buenos Aires Argentina, with a history of 8 months of daily headache from the beginning, no triggering event identified, with migraine features of nauseas, phono and phonophobia with no cranial autonomic features, came to our outpatient clinic. The patient describes her attacks with an intensity of 8/10 and with two peaks of 10/10 per week. She had no history of headaches or migraine. Her neurological exam was normal. MRI with contrast, LP, EEG, were all normal. Labs were not relevant and ruled out endocrinological disease.

She was diagnosed and treated as chronic migraine with amitriptyline 75 mg daily, Topiramate 100 mg daily and Valproate 500 mg bid with no response to any of these treatments after 6 months. She did not receive onabotulinum toxin type A. She had no Medication Overuse Headache.

The patient was diagnosed with NDPH due to the frequency of attacks, no previous history of migraine and no response to previous mentioned treatments.

Erenumab 140 mg on a monthly basis was started, due to the impact in pain intensity, frequency and quality of life in this patient. One week after she started Erenumab, she reported on a phone call visit, that the intensity of her attacks had lowered. Six weeks after she started Erenumab, she presents two episodes per week with an intensity of 2/10 that now responds to NSAIDs. On a follow up visit, the patient returned (1 week prior to her third Erenumab dose) to daily headaches, although with lower intensity

To date, she has been treated for 7 months and has gone back to work.

Discussion

Described by Vanast ² as a Daily Headache with migraine and tension-type headache features, NDPH is an under-recognized and heterogenous disorder of Chronic Daily Headache. It is frequently confused with Chronic Migraine situation which delays the diagnosis, causing frustration for patients and physicians. Its exact pathogenesis remains unknown having been associated to a series of diseases like Epstein-Barr virus infection, Surgery, Trauma and recently, COVID infections. ¹¹ There is a 50% of cases with no association at all.

We present three difficult-to-treat NDPH cases with migraine phenotype. Although an off label indication, since all three patients had migraine phenotype, we decided to try mAbs on these patients due to other treatment failure. When treatment started with mAbs their headache frequency, and specially headache intensity, dropped and permitted them to go back to normal life.

Two of our cases, showed a good response after the second month of mAbs use, having had years of daily headaches with different treatments, and no response. It is to notice, that although these two patients still have today daily headaches, the low intensity permits them to go back to a normal life, not needing to attend ERs anymore and having a very low NSAIDs or Triptans intake. The third case, had a quicker response with pain-free days after her second dose.

Although a placebo response could have been the cause of the positive treatment effect, being a sustained response for several months on our three cases, makes it improbable.

The role of TNF-alpha levels as a cause of NDPH has been described. This proinflammatory cytokine, increases CGRP levels, which in turn may result in chronic headaches. On the other hand, CGRP is involved in nociceptive transmission (migraine, TTH, Cluster Headache) so we could assume it could also be involved in NPDH pathogenesis. It is because of this link between TNF-alpha and CGRP, and the fact that our patients had migraine phenotype, so we decided to try mAbs on them.

Goadsby postulated that there could be secondary causes for NDPH ¹² named, Low volume CSF Headache, Raised CSF Pressure Headaches or Post Traumatic Headache, in a vast definition that includes not only a blow to the head but LP for infectious diseases, carotid dissection, SAH or Intracranial surgery. All of these were ruled out with neurological exam that included fundoscopy, neuroimages, lumbar puncture (in one case) and past medical history.

NDPH is described as bilateral in location although it can occur anywhere in the head with mild to severe intensity (moderate intensity in most cases). The pain is constant and lacks special characteristic features although migrainous and tension-type like symptoms are described. ^13,14 Our three cases share these migraine characteristics.

The spectrum of Chronic Daily Headaches, and more those with daily pain, can sometimes make it difficult to differentiate NDPH from Chronic Migraine, but it is not frequent in those cases that Headaches are Daily de novo or that patient remember the exact date of onset of pain. However, the clinical phenotype of migraine symptoms may overlap in the two entities.

Thus, we have the hypothesis that the improvement in our three patients of the associated migraine symptoms in the NDPH spectrum of symptoms is the result of the action of the treatment with the CGRP blockade.

Özkan et al. ¹⁵ presents a case of a patient with daily post COVID headaches that responded mAbs. This patient with 2 months of headaches, did not fulfill the IHS classification for NDPH. ¹⁶ Aside of this case, we have not found reports of CGRP mAbs use in NPDH patients in our literature search.

Limitations

We present three cases with a prospective follow up, in three different countries in Latin America, who underwent different previous treatments with poor results.

We are conscious that it is a small sample with a short follow up, (around 12 months) and that there is a chance that there could be a placebo effect.

We believe not to include QoL or MIDAS questionnaires, is a limitation to pain intensity follow up, but they were not done at the beginning of the treatment.

Conclusion

We propose the use of CGRP mAbs as a treatment option for difficult-to-treat cases of NDPH. These three case reports could open the field to future larger studies on the use of mAbs in NDPH, that should also aim to compare response in migraine versus tension-type phenotype of NDPH.

Clinical implications

New daily persistent headache (NDPH) is an uncommon, treatment-resistant primary headache disorder.

Elevated TNF-alpha and CGRP levels in NDPH patients as a possible cause of this disease.

NPDH patients have migraine and tension-type headaches characteristics.

We report three NDPH patients that improved to the administration of CGRP mAbs after trying multiple treatments.