It seems that certain neurological symptoms can lead to or worsen headache, many studies have claimed the association of primary headaches with major neurological diseases, including Parkinson’s disease (PD) [22, 23], multiple sclerosis [24, 25] and myasthenia gravis [26].

Headache is not generally considered a symptom of ALS. The studies delineating the occurrence of headaches in ALS patients have only highlighted secondary headaches as one of the clinical manifestations of respiratory muscle weakness and subsequent respiratory failure which is the leading cause of death in ALS.

In fact, several studies have concluded that ALS isn't restricted to the motor system. Showing that, there is a marked affection of hypothalamus [27] and somatosensory cortex in ALS [28,29,30]. Moreover, recent studies claims that ALS pathophysiology is affected by the calcitonin gene-related peptide (CGRP) [31]; which is expressed physiologically in the spinal cord [32, 33]. However, it was found to be pathologically accumulated in both the anterior and posterior spinal horns of patients with familial ALS [34]. In addition, CGRP high expression levels were associated with higher levels of motor neuron degeneration [35] which could potentially link ALS and primary headaches.

Our study reveals that Headaches are common in ALS. Not only secondary headache attributed to hypercapnea, which represented 12% of patients, but also Primary headaches, constituting 62% of studied patients; with tension-type headache being the most common (46%), followed by migraine (16%).

As regards the general characteristics of ALS patients, we found a significant correlation between headache severity and severity of ALS symptoms and its stage, as well as with female gender, fALS, and younger age of disease onset. To the best of our knowledge, there are no previous studies describing different types of headaches in ALS patients and their relation with disease parameters. However, there are many studies analyzing headaches in other neurodegenerative diseases as PD [22, 23] a recent meta analysis about primary headaches in PD stated that they commonly occur with PD. However, the correlations between PD parameters and headache have not been verified [36].

A systematic review involving over 300 studies found that the global prevalence of migraine was 11.6% worldwide, of which 10.4% in Africa [37]. An Egyptian study showed that the most common headache type was episodic tension type headache (ETTH) (24.5%), followed by migraine (17.3%) [38]. We believe that the high frequency of TTH and Migraine in our cohort is totally imaginable considering their wide prevalence worldwide; the estimated global prevalence of migraine 14% and of TTH 26% [7].

Moreover, the relatively younger age of ALS patients in our cohort; mean age of onset was 40.03 ± (14.8 years) coincides with the timing primary headaches usually peak, as a systemic review stated about migraine being highest during the productive and formative periods of patient's lives, mostly between age 25 and 55 years [39].

As well as an Egyptian study which found that both TTH and migraine peaked in mid-life and dropped to its lowest level above 55 years [38].

It's widely reported that females remain the most vulnerable population for primary headaches worldwide [6] as well as in the Arab countries [40, 41]. Women in different countries were found to be two to three times more prone to migraines [42, 43].

On the other hand, ALS is known to be more predominant in males [44], which was reported in a recent Egyptian study [45].

In our study there is an increased male to female ratio (M: F = 2.5:1); 80% of male ALS patients and 75% of female patients suffered from Headache. Female gender was found to be associated with increased severity of headache in our patients. Moreover, analyzing gender across each type of headache individually further elucidated our findings, As for TTH, it was reported in 17% of female patients (5 out of 28 total female patients) and 57% of male patients (41 out of 72 male patients). Meanwhile, migraine was reported in a total of 16 ALS patients; 35% of female patients (10 out of 28) and 8% of male patients (6 out of 72), which in doubtfully points to increased migraine in our female patients.

Additionally, single marital status correlated with increased headache severity in our cohort; which goes in line with previous studies investigating factors affecting headache intensity [46]. Thus, indicating the role of partner support; which is excessively needed in ALS patients.

When we search for ALS-associated headache, the most considered type so far was headache secondary to respiratory insufficiency. Our study showed that 15 patients suffered secondary headaches; 12 of whom had Headache attributed to hypoxia or hypercapnia, and 3 patients had headaches related to their Riluzole treatment; the role of ALS treatments in exacerbating preexisting headaches and triggering de novo headache syndromes hasn't been studied. Headache wasn’t among the reported side effect in the Riluzole clinical trial [47].

Also, 2 patients had non specific headache but both of them were suffering from neck muscles weakness and progressive head dropping, which added difficulty to their classification.

On a different note, this should lead us to expand our interview with ALS patients in order to include different disease related parameters that can precipitate headache or aggravate it.

There was a reported case of headache in bed ridden ALS patient secondary to brain abscess [48]. That’s why, we shouldn’t overlook other causes of secondary headaches that could be related to advanced disease stages and prolonged recumbence.

ALS is an incurable disease thus management is directed mainly for relieving symptoms in order to improve quality of life (QoL) [49].

The headache triggers most frequently reported among our patients were in accordance with the usually described triggers [50, 51]. However, as regard ALS motor symptoms, neck muscles spasms or pains should be viewed cautiously as a trigger, since it can be related to progressive neck muscle weakness and subsequent head dropping that could be associated with ALS.

HIT scale showed us that 24% of interviewed ALS patients reported substantial (17 patients) and sever impact of headache (7 patients). Yet, Only 15% (12 out of 79 patients) sought medical help for their headache. Patients attributed their reluctance to seek help for their headache to being in part able to withstand the pain with analgesics, trying not to over burden their caregivers with added physician visits, and finally because they thought their headache wouldn't show considerable improvement with medications, as they attributed it to their ALS; believing it's an integral symptom of their condition. Hence, it's critical to consider and screen ALS patients for both primary and secondary headaches and include it in their management plan.

Our main limitation would be attributed to recall bias and selection bias. A recall bias may have been present because patients with more severe symptoms may not have paid as much attention to their headache, on the other hand, ALS patients have an average diagnostic delay of one year [45], which means that patients in the very early stages of disease are less represented, as well as those in very advanced stages; who have marked communication limitations, cognitive impairments, and less frequent follow up visits to the clinic, hence the selection bias. Also, the cross-sectional design which hinders the ability to obtain causal relationship, relatively small sample size, younger age of patients, and hospital-based recruitment could limit our results generalization.

That’s why; future research is needed with long term studies and larger number of patients; that can help in depth interpretation of headache types and triggers along different ALS stages. As well as, assess patient's response to different lines of headache management. Moreover, it could be beneficial to study MRI brain findings in those patients, and their genotypes to detect whether certain ALS genetic mutations are more prone to headaches.