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Review

Approaching Headaches—A Guide to Differential-Diagnostic Considerations and Causal Claims

by
Heiko Pohl
Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, 8091 Zurich, Switzerland
Clin. Transl. Neurosci. 2023, 7(3), 17; https://doi.org/10.3390/ctn7030017
Submission received: 13 May 2023 / Revised: 10 July 2023 / Accepted: 14 July 2023 / Published: 18 July 2023
(This article belongs to the Section Headache)
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Abstract

:
Headaches can be nociplastic, neuropathic, and nociceptive. Pain related to the latter two categories occurs in the presence of nerve lesions and nociceptive stimuli; attributing pain to the last category requires a list of potential causes and arguments supporting the causal claim. Taking a history and examining patients serves to assess diagnostic criteria and screen for disorders whose diagnosis requires additional examinations. Screening information occurs in two types: one indicates that patients have a headache due to another condition; the other suggests they are at risk. Aspiring to make causal claims for a headache is reasonable because if underlying disorders appear independently and randomly, it is probable that there is only one cause. Thus, having found a cause often implies having found the cause. The prerequisites for causal claims are temporal sequencing, correlation, and elimination of alternate causes. Mechanistic, manipulative, and probabilistic evidence supports the second criterion. The importance of headaches lies in their frequent appearance as an early symptom of an incipient disorder (“sentinel symptom”). Hence, they provide the opportunity to diagnose early diseases with potentially deleterious consequences. Thus, it is sensible to assess each attack carefully and systematically.

1. Introduction

Shortly after Carl von Linné proposed his botanic and zoological classifications in the 18th century, in 1763, Boissier du Sauvage published his attempt to classify diseases entitled “Nosologia methodica” [1]. Over the years, accruing knowledge of microbiology, histopathology, and physiology allowed refining their approaches. Today, classifications are an indispensable and widely used tool in medicine. They enable decisions on the next appropriate therapeutic steps and their urgency and help estimate a patient’s prognosis.
After several less well-known attempts at classifying headaches [2], the ad hoc classification was published in 1962, and the International Headache Classification, now available in its third edition (ICHD-3, published in 2018), followed in 1988 [3,4,5]. Still, doctors confronted with the symptom “headache” and charged with its classification often find themselves in trouble. Studies assessing the inter-rater agreement and the number of requested imaging studies document their hardship [6,7,8].
Various factors contribute to the challenge of diagnosing headaches. One is that pain does not quantify bodily dysfunction and carries little information regarding its origin and cause [9]. Additionally, the history is important, but patients may struggle to recall relevant symptoms. Likewise, physicians may struggle to gather and integrate the information [7]. Furthermore, the validity of the collected data is uncertain, and language may be generally unsuited to communicate the highly individual experience of pain.
Nevertheless, it makes sense to take headaches seriously because they are often among the earliest symptoms of an incipient disorder (“sentinel symptom”) [10,11]. Hence, considering differential diagnoses allows the early detection and treatment of diseases with potentially grave implications.
This narrative review aims to discuss the thought process behind diagnosing headaches.

2. Identification of Potential Causes of Headache

Current conceptualisation views pain as nociceptive, neuropathic, or nociplastic. Nociceptive pain is due to the activation of nociceptors by an adequate stimulus, and neuropathic pain is “caused by a lesion or disease of the somatosensory nervous system” [12]. Nociplastic pain is due to neither a sufficient stimulus nor a lesion; some authors hypothesise a central sensitisation [13,14].
The pain experienced during headaches can fall into all three categories [13]: (i) neuropathic pain presents, for example, as neuralgia and neuropathy and rarely as central post-stroke pain or central pain due to multiple sclerosis [15]; (ii) nociplastic headaches are referred to as primary headaches (e.g., migraine, cluster headache, and tension-type headache) and (iii) nociceptive headaches as secondary headaches.
Many patients with nociplastic, i.e., primary, headaches recall that specific factors flared their pain [16,17,18]. However, these factors—generally called triggers—do not activate nociceptors sufficiently to cause pain. Instead, at least some seem to modulate the pain threshold. Examples are sleep deprivation [19,20], oestrogen withdrawal [21], and fasting [22]. Furthermore, alcohol likely increases the pain threshold, suggesting that withdrawal could lower it [23].
A significant challenge for differential diagnostic reasoning is that we identify nociplastic headaches by the absence of a nociceptive stimulus and a neuropathy. Thus, overlooking a nociceptive stimulus or a lesion of the somatosensory networks would result in the erroneous diagnosis of a primary headache with a different therapeutic approach. Therefore, searching thoroughly for nociceptive stimuli and nerve lesions is essential. (As a side note, we cannot diagnose contemporaneous primary and secondary headaches because of this strategy).
A stimulus qualifies as a cause of a nociceptive headache if it activates nociceptors. Evidence supporting such an attribution can be probabilistic and mechanistic. However, on its own, each type is insufficient [24].
Probabilistic evidence indicates the observed strength of an association but does not exclude that it is due to a common cause or random co-occurrence. Table 1 lists the proportion of patients who report headaches for various disorders.
Mechanistic evidence, on the other hand, suggests a causal relationship but not its strength.
Note that there are controversies about the nature of mechanistic evidence and the strength of the probabilistic evidence required to accept a stimulus as a potential cause of pain [25].
The proportions of patients with a specific disorder listed in Table 1 are imprecise correlation estimators. One reason is that the likelihood of getting a headache is high even without an underlying illness [26]. Particularly in chronic conditions, e.g., Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), the observed number of persons with headaches likely exceeds the number of persons with headaches due to the disorder. Hence, the occurrence of headaches is overdetermined [25].
Table
Table 1. Prevalence of different disorders and proportions of affected persons reporting headaches; I—incidence, P—prevalence.
Table 1. Prevalence of different disorders and proportions of affected persons reporting headaches; I—incidence, P—prevalence.
DiagnosisEpidemiologyProportion with Headache
Acute rhinosinusitisI: 17540 per 100,000 persons per year [27]29% [28]
Bacterial meningitisI: 1.49 per 100,000 persons per year [29]84% to 90% [30,31,32]
Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)P: 1.32 to 1.98 definite cases per 100,000 adults [33,34]45% to 55% [35,36]
Cerebral ischaemic eventI: 156 per 100,000 persons per year [37]7% to 34% [38]
Cerebral venous thrombosisI: 1.32 to 1.75 per 100,000 persons per year [39,40]76% to 77% [41,42]
Cervical vertebral artery dissectionI: 0.97 per 100,000 persons per year [43]69% [44]
Chiari malformation type IP: 96 per 100,000 persons [45]43% to 81% [46,47,48,49]
Giant cell arteritisP: 51.74 per 100,000 persons over 50 years [50]86% to 87% [51,52]
HypothyroidismI: 226.2 per 100,000 persons per year [53]30% to 34% [54,55]
Idiopathic intracranial hypertensionI: 0.9 per 100,000 persons per year [56,57]75% to 92% [56,58,59,60]
Internal carotid artery dissectionI: 1.72 per 100,000 persons per year [43]68% [44]
Intracranial neoplasiaI: 14.8 per 100,000 persons per year [61]48% to 60% [62,63,64,65]
Mitochondrial Encephalopathy, Lactic Acidosis and Stroke-like episodes (MELAS)P: 0.18 per 100,000 persons in Japan [66]69% to 86% [67,68]
Moyamoya angiopathyP: 1.01, 16.1, and 6.03 per 100,000 in China [69] Korea [70], and Japan [71], respectively20% to 67% [72,73,74,75]
NeurosarcoidosisI: 11.5 per 100,000 persons per year are affected by Sarcoidosis [76], 0.2 per 100,000 persons per year for isolated Neurosarcoidosis [77]32% [78]
Non-traumatic intracranial haemorrhageI: 29.9 per 100,000 persons per year [79]26% [80]
Pituitary apoplexyI: 4.0 per 100,000 persons per year [37]82% to 100% [81,82,83]
Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestationsUnknown, probably exceedingly rare27% to 59% [84,85]
Reversible cerebral vasoconstriction syndrome (RCVS)I: 0.3 per 100,000 persons per year [86]95% to 100% [87]
Sleep apnoeaP: 3420 per 100,000 persons [88]12% to 18% [89,90,91]
Spontaneous intracranial hypotensionI: 3.7 per 100,000 persons per year [92]90% to 100% [92,93]
Transient ischemic attackI: 83 per 100,000 persons per year [94]26% to 36% [38]
Unruptured vascular malformationP: 18 per 100,000 adults for arterio-venous malformations [95], 500 per 100,000 [96] for cavernous malformations49% to 54% [97]
Viral meningitisI: 0.26 to 17 per 100,000 persons per year [98]99% [32]
The mechanisms through which specific disorders activate nociceptors are not always well known. Furthermore, even when they are known, it is uncertain if they are the only mechanisms. There are hypotheses about the mechanisms of pain for several types of headaches:
  • Several secondary headaches, including traumatic injuries to the head, whiplash, and craniotomy, likely result from the activation of nociceptors by tissue damage or distension. A similar mechanism may apply to the reversible cerebral vasoconstriction syndrome and subarachnoid haemorrhage. The latter could also lead to pain through a mechanism such as that of mass lesions (see below).
  • Inflammatory disorders are likely to share a common mechanism. Research on COVID-19 infections suggested that cytokine release—Interleukin 10 in particular—might be associated with headaches [99,100].
  • Mass lesions, e.g., brain tumours, might cause pain through pressure-induced traction of pain-sensitive structures due to their size, accompanying oedema, or hydrocephalus. Subsequently, sensitisation could increase the pain intensity [101].
  • Similarly, strokes could lead to pain by exerting pressure on pain-sensitive structures. However, pain also occurs in smaller ischemia suggesting additional mechanisms. The release of pro-inflammatory substances and perhaps the occurrence of a cortical spreading depression could contribute to the pain [38,102].
  • Different hypotheses attempt to explain headaches in patients affected by CADASIL. One is that they are more prone to pain induced by cortical spreading depression. Hypoperfusion might also be a mediating factor [103]. Another hypothesis is that damage to the periaqueductal grey could increase the likelihood of headaches [103].
  • Milhorat and co-workers suggest that the cause of headaches in patients with Chiari Type 1 malformation may be a reduced CSF volume that results in difficulty mitigating pressure changes [46,104]. Additionally, Williams observed a “craniospinal pressure dissociation” that comprised a steeply increased pressure in the cranial but not the spinal CSF [105]. In addition to the elevated pressure distending the meninges, the pressure gradient might result in a further herniation of the tonsils with subsequent straining of pain-sensitive structures, which might contribute to the pain [104].
  • Headache due to pituitary gland apoplexy may result from increased intrasellar pressure, which activates nociceptors [106].
  • The pathophysiology of morning headaches due to sleep apnoea is incompletely understood. While hypoxia is a relevant factor, elevated intracranial pressure is also involved [90,107].
  • Headache due to hypothyroidism could be linked to an increased pituitary gland volume, which leads to the activation of intrasellar nociceptors [55,106]. Another hypothesis postulates that thyroxine has antinociceptive properties [55,106].
  • Focal demyelination of the trigeminal nerve leads to hyperexcitable afferents, which can result in synchronised after-discharge activity [108]. The latter results in pain perception in trigeminal neuralgia.
Overall, the presence of both mechanistic and probabilistic evidence suggests that a disorder is a potential cause of headaches. Equipped with this list, the next step is to develop a search strategy for these disorders in patients with headaches.

3. Searching for Potential Causes of Headaches

Central assumptions of disease classifications are that different entities are distinguishable and that identical disorders are listed as one entity (principle of unambiguousness) [1,109]. Consequently, if a patient suffers from a specific disorder, we should be able to detect symptoms or signs indicative of that underlying disorder. However, a crucial restriction complicates the diagnostic process.
Because of the high prevalence of headaches [110], additional examinations cannot be ordered for everyone. Yet, several diagnoses require more than a history and a physical examination. Thus, preselection and targeted testing are necessary. Consequently, one aspect of data collection is screening for underlying disorders whose diagnosis requires further investigations [111].
There are two types of information (provided by the history and clinical examination) that support the detection of a potential cause of a headache. These are information with diagnostic value and information with screening value.
  • Information with diagnostic value comprises all diagnostic criteria that patients may be aware of, i.e., phenotypes and several specific causes of headaches.
  • Phenotypes are relevant for the diagnosis of primary headaches. The causes that patients can be inquired about are trauma to the head, whiplash, craniotomy, medication overuse, exposure to a substance (nitric oxide [NO] donor, phosphodiesterase [PDE] inhibitor, alcohol, and cocaine), withdrawal (pain killers in the case of medication overuse headache and caffeine), high altitude, aeroplane travel, diving, dialysis, and fasting [5]. Moreover, many patients will know if they have a systemic or localised inflammation.
  • There are two types of information with screening value: One comprises symptoms and signs typical of a headache, whose diagnosis requires additional examinations [111]. The other includes risk factors indicating an increased likelihood of a secondary headache.
  • The difference between these two types lies in the provided temporal information: A risk factor implies that the patient may develop a specific headache eventually; however, it allows no conclusions about the pathophysiology of the current headache. On the other hand, a symptom of another disorder suggests that the patient is currently diseased [111]. The former does not provide temporal information; the latter does.
The following two subsections discuss these two types of information with screening value in further detail.

3.1. Screening Factors with Temporal Information

Screening factors that provide temporal information can be likened to screening tests [111]. Thus, they suggest but do not prove the presence of a specific disease. Screening factors for secondary headaches are called red flags [111,112].
Since secondary headaches often require more urgent measures than primary headaches, they should not be missed. Consequently, red flags need high sensitivity (i.e., few false negatives). However, specificity is important, too. If it is too low, the number of false positives will be high; the more unspecific red flags are being used, the more unnecessary additional tests will result (cf. multiple comparison problem) [111]. Thus, it makes sense to maximise specificity of individual red flags and aim for high specificity of their entirety. A recent study shows that the strategy can be successful, as a set of red flags had high sensitivity despite fairly low sensitivity of the individual red flags [113].
Table 2 provides an overview of red flags with temporal information. In addition to them, the Ottawa rule may help to screen for a subarachnoid haemorrhage [114]. Furthermore, trauma to the head, which itself may lead to pain, also indicates an increased risk of a traumatic haemorrhage that can cause headaches, too.

3.2. Screening Factors without Temporal Information (Risk Factors)

Several authors recommend including screening factors without temporal information, i.e., risk factors, in clinical reasoning [142]. However, basing decisions on data that does not provide temporal information may seem unreasonable, given that there is screening information that does (see Table 2). On the other hand, it is unknown if screening with temporal information alone allows for identifying every patient with a secondary headache at every stage of the underlying disorder. Hence, it makes sense to consider risk factors.
We distinguish two types of risk factors. One is a disease that can eventually lead to pain; the other is a disease that predisposes for another that can lead to pain. The latter can serve as the starting point for a hypothesis about the origin of the pain that can be corroborated.
  • Type 1 risk factors are chronic conditions that increase the long-term risk of a secondary headache. Examples listed in the ICHD-3 are MELAS, CADASIL, Chiari malformation type 1, vascular malformation, temporomandibular dysfunction, and Moyamoya disease [5].
  • Type 2 risk factors indicate an increased risk of developing or having a disorder that might lead to a secondary headache or neuralgia.
  • Examples are pregnancy (increased risk of hypertensive disorders, e.g., eclampsia) [143] and extracranial solid tumours (increased risk of headaches due to metastases) [144]. Furthermore, overweight females have an increased risk of idiopathic intracranial hypertension [145], and multiple sclerosis increases the risk of trigeminal neuralgia [146]. Moreover, polymyalgia rheumatica increases the risk of giant cell arteritis [147].
  • In addition, AV malformations, dural fistula, and Moyamoya disease that may lead to headaches themselves also predispose patients to a haemorrhage [148,149].
  • Additionally, exposure to several substances is a type 2 risk factor. Several chemotherapeutic agents, CHOP/R-CHOP regimens in particular, increase the risk of a posterior reversible encephalopathy syndrome (PRES) [150]. Cannabis and perhaps cocaine consumption could precipitate a reversible cerebral vasoconstriction syndrome (RCVS) [151]. Treatment with doxycycline and retinoids can increase intracranial pressure [152]; and eculizumab treatment predisposes meningitis [153]. Furthermore, treatment with oral contraception increases the risk of cerebral thromboses [154].
The disadvantage of Type 1 risk factors is that they could be blamed for every headache the patient has—irrespective of a “true” connection. The reason is that a causal relationship between an individual headache attack and these risk factors cannot be shown (see next section). An exception is Chiari malformation type 1, as it leads to headaches of a specific phenotype.
Conversely, the advantage of type 2 risk factors is that they provide a hypothesis about the origin of a headache that screening factors with temporal information and further diagnostic tests can corroborate. For example, papilledema provides temporal information and supports a causal claim in a patient treated with retinoids and complaining about headaches.
Figure 1 provides an overview of the different types of information discussed in the last section.
Should the information collected, as outlined above, indicate the presence of a secondary headache, further diagnostic tests should be ordered to confirm the suspicion. The pertinent examination depends on the suspected disorder.
  • Cerebral imaging is helpful when a haematoma, haemorrhage, ischemia, blood vessel malformation, tumour, hydrocephalus, and other causes of increased intracranial pressure or inflammation are suspected [155].
  • A spinal tap allows measuring the intracranial pressure and searching for inflammation, haemorrhage, and tumour cells.
  • An ophthalmic examination may help detect signs of raised intracranial or intraocular pressure, inflammation, including keratitis, and refractive errors [156].
  • An ear, nose, and throat specialist should be consulted when local inflammation (e.g., otitis or mastoiditis) and craniomandibular dysfunction are suspected [157].
  • Monitoring the blood oxygen levels during sleep can detect sleep apnoea.
  • Occasionally, myelography can help to detect a cerebrospinal fluid leak [158].
However, the presence of a potential cause of a headache does not prove it is the cause because most nociceptive stimuli and many lesions of the somatosensory system do not necessarily cause pain. Hence, strategies are required to support the assumption of causality on an individual level.

4. Causal Claims

Headaches are unspecific: they can be due to many different causes, and most potential causes do not always lead to pain (see Table 1). Thus, identifying a patient’s potential source of pain does not mean identifying the source. However, once a source of pain is identified, the (sole) source of pain is likely found.
As pain-causing disorders generally appear randomly, co-occurrence of two or more of them is unlikely—except if they are not independent events. Examples of headache diagnoses that increase the likelihood of another diagnosis that could lead to headaches, are headaches due to trauma to the head, AV malformations, dural fistula, and Moyamoya disease [148,149].
Identifying a disorder as the source of a patient’s pain implies making causal claims. Doing so is justified when the three conditions of causality are satisfied—temporal sequencing, correlation/non-spurious association, and elimination of alternate causes [159].
  • Temporal sequence: An essential requirement is that a cause must appear before its effect. However, in practice, that sequence may be difficult to evidence. Accordingly, the ICHD-3 relaxes that criterion for headaches due to acute disorders. It stipulates merely that the condition “has been diagnosed” [5]. Nevertheless, for every symptom supposedly due to an underlying disease, one should attempt to clarify the temporal sequence and note the onset time of each symptom.
  • For non-acute disorders that permanently increase the likelihood of a headache (see above, type 1 risk factors), it is sufficient to make it plausible that the disorder was present before the headaches.
  • Correlation: A spurious relationship seems unlikely when a disorder known to cause pain appears in close temporal association with pain. However, given how unspecific and prevalent headaches are, it is reasonable to consider the possibility of a random co-occurrence, especially when dealing with stimuli that weakly correlate with pain (see Table 1).
  • Evidence supporting the assumption of a non-spurious relationship can be mechanistic, manipulative, and probabilistic (see below).
  • Elimination of alternate causes: It is impossible to unequivocally eliminate all alternate causes of a headache, as there are no diagnostic tests for primary headaches, and the process of collecting information, as outlined above, does not necessarily detect all underlying conditions. Yet, for practical reasons, it makes sense to assume that this prerequisite is satisfied if clinical evidence does not suggest a yet-to-be-discovered secondary headache or neuralgia—provided that data were collected meticulously.
The following subsections discuss the different types of evidence for a non-spurious relationship between a nociceptive stimulus and a neuropathy in further detail. Note that all kinds of evidence are only relevant for stimuli identified as potential causes of headaches, as discussed in Section 1.
In primary headaches, there are no causes whose association with the pain could be shown. In that case, headaches must have an appropriate phenotype, and alternate reasons must be eliminated as much as possible.

4.1. Mechanistic Evidence

A high degree of certainty can be reached if the mechanism through which the stimulus causes pain is substantiated directly or indirectly.
Direct evidence is evidence of the underlying pathophysiologic mechanism. For example, in a patient in whom a brain tumour caused pain by increasing the intracranial pressure, the confirmation of increased intracranial pressure is direct mechanistic evidence.
On the other hand, indirect evidence comprises further (and potentially less specific) consequences of the suspected pathophysiology. For example, indirect mechanistic evidence in said patient would be another effect of intracranial pressure, such as papilledema and vomiting—Table 3 lists additional suggestions for evidencing the mechanism of pain.
If the mechanism cannot be observed or is unknown, another, albeit weaker, mechanistic approach to finding a causal relationship may be to search for other symptoms of the suspected stimulus. For example, a tumour responsible for a focal-neurological deficit may be more likely to cause headaches than a completely asymptomatic lesion. The rationale for this strategy is that headaches are often among the first symptoms of an underlying disorder [10,11]. Thus, if a condition can produce symptoms, headaches are likely one of them.

4.2. Manipulative Evidence

If the most likely mechanism of pain is known, interventions may impede it. Observing changes in a symptom by manipulating its alleged cause provides manipulative evidence for a causal relationship [163].
There are two types of manipulative evidence concerning headaches. The first type comprises the treatment of the underlying cause. Examples are the removal of a tumour, treatment of hypothyroidism, withdrawal in medication overuse, and closing of a CSF leakage in intracranial hypotension.
The second type modifies the mechanism without attempting to abolish it. For example, relieving pain in a patient with increased intracranial pressure due to communicating hydrocephalus by lowering the pressure supports a causal claim [164]. A further example would be to relieve pain by reducing the inflammatory response without treating the cause of the inflammation.
However, some debate surrounds the value of this evidence type [163]. For example, if an intervention fails to provide mechanical evidence by relieving pain, a causal relationship is still not excluded because other mechanisms might sustain the pain. For instance, the pain of idiopathic intracranial hypertension may exacerbate following lumbar puncture despite a decrease in intracranial pressure [165]. In addition, pain caused by inflammation occasionally persists for long periods despite the end of detectable inflammatory activity [166].

4.3. Probabilistic Evidence

The assumption that a specific cause and a headache are associated can be supported when their occurrence is highly correlated (see Table 1 for correlation estimates). However, an exception is type 1 risk factors. They are unreliable even if there is a high correlation, as they indicate a generally increased likelihood of pain; their relationship with the current headache cannot be shown. (As discussed above, Chiari malformation type 1 is an exception, as it leads to a specific kind of pain.)
Occasionally, it may be acceptable to consider probabilistic evidence collected individually: patients who report regularly responding with a headache to a specific stimulus provide an inductive argument for a causal relationship. Note that these stimuli must satisfy the criteria for potential causes of pain, as discussed in Section 1.
Whenever possible, probabilistic evidence should be complemented by mechanistic or interventional evidence. The reason is that no cut-off value indicates when the correlation between disease and the symptom of pain is sufficiently strong to support the hypothesis of a causal connection.

5. Conclusions

Headaches are unspecific, and classifying them correctly is challenging. However, attempting to make a correct diagnosis makes sense, as causes, treatments, and prognoses differ vastly among different entities.
When approaching a patient with a headache, disposing of a list of potential causes is essential. These are characterised by the presence of both mechanistic and probabilistic evidence of their capability to cause pain.
In the next step, we collect information that helps to identify these disorders. However, as we cannot order additional examinations for every patient, but some diagnoses cannot be made without them, the collected information serves two purposes: besides making a diagnosis, it helps to decide about ordering additional tests.
Once an underlying disorder is identified, we must show that the co-occurrence of the headache and the condition was not due to chance. Ideally, there is mechanistic or manipulative evidence supporting that assumption. Should there be no underlying disorder, we may assume the presence of a primary headache.
In summary, diagnosing a headache requires theoretical knowledge and the systematic collection of relevant information.

Funding

H.P. was funded by the Werner Dessauer Stiftung.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The author declares no conflict of interest.

References

  1. Federspil, G.; Giaretta, P.; Rguarli, C.; Scandarelli, C.; Serra, P. Filosofia Della Medicina; Rafaello Cortina Editore: Milano, Italy, 2008. [Google Scholar]
  2. Isler, H. Headache classification prior to the Ad Hoc criteria. Cephalalgia 1993, 13 (Suppl. S12), 9–10. [Google Scholar] [CrossRef] [PubMed]
  3. Friedman, A.P.; Finley, K.H.; Graham, J.R.; Kunkle, E.C.; Ostfeld, A.M.; Wolff, H.G. A classification of headache: Ad Hoc Committee on Classification of Headache. Neurology 1962, 12, 378. [Google Scholar] [CrossRef]
  4. Anonymous. Classification. Cephalalgia 1988, 8, 13–17. [Google Scholar] [CrossRef]
  5. Headache Classification Committee of the International Headache Society (IHS). Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia 2018, 38, 1–211. [Google Scholar] [CrossRef] [PubMed]
  6. Granella, F.; D’Alessandro, R.; Manzoni, G.C.; Cerbo, R.; Colucci D’Amato, C.; Pini, L.A.; Savi, L.; Zanferrari, C.; Nappi, G. International Headache Society Classification: Interobserver Reliability in the Diagnosis of Primary Headaches. Cephalalgia 1994, 14, 16–20. [Google Scholar] [CrossRef]
  7. Neumeier, M.S.; Stattmann, M.; Wegener, S.; Gantenbein, A.R.; Pohl, H. Interrater agreement in headache diagnoses. Cephalalgia Rep. 2022, 5, 1–6. [Google Scholar] [CrossRef]
  8. Tsushima, Y.; Endo, K. MR Imaging in the Evaluation of Chronic or Recurrent Headache. Radiology 2005, 235, 575–579. [Google Scholar] [CrossRef]
  9. Sciascia, A.D.; Jacobs, C.A.; Morris, B.J.; Kibler, W.B. The degree of tissue injury in the shoulder does not correlate with pain perception. J. Shoulder Elb. Surg. 2017, 26, e151–e152. [Google Scholar] [CrossRef]
  10. Linn, F.H.; Rinkel, G.J.; Algra, A.; van Gijn, J. Headache characteristics in subarachnoid haemorrhage and benign thunderclap headache. J. Neurol. Neurosurg. Psychiatry 1998, 65, 791–793. [Google Scholar] [CrossRef] [Green Version]
  11. Zhu, Q.; Liang, Y.; Fan, Z.; Liu, Y.; Zhou, C.; Zhang, H.; Li, T.; Zhou, Y.; Yang, J.; Wang, Y.; et al. Ischemic Infarction of Pituitary Apoplexy: A Retrospective Study of 46 Cases From a Single Tertiary Center. Front. Neurosci. 2021, 15, 808111. [Google Scholar] [CrossRef]
  12. International Association for the Study of Pain IASP Taxonomy. Pain Terms. Neuropathic Pain. Available online: www.iasp-pain.org/Taxonomy#Neuropathicpain (accessed on 5 July 2023).
  13. Steinberg, D.F.; Argoff, C. Understanding Pain. Pract. Neurol. 2021. [Google Scholar]
  14. Nijs, J.; Lahousse, A.; Kapreli, E.; Bilika, P.; Saraçoğlu, I.; Malfliet, A.; Coppieters, I.; De Baets, L.; Leysen, L.; Roose, E.; et al. Nociplastic Pain Criteria or Recognition of Central Sensitization? Pain Phenotyping in the Past, Present and Future. J. Clin. Med. 2021, 10, 3203. [Google Scholar] [CrossRef]
  15. Wasner, G. Central Pain Syndromes. Curr. Pain Headache Rep. 2010, 14, 489–496. [Google Scholar] [CrossRef]
  16. Chabriat, H.; Danchot, J.; Michel, P.; Joire, J.E.; Henry, P. Precipitating Factors of Headache. A Prospective Study in a National Control-Matched Survey in Migraineurs and Nonmigraineurs. Headache 1999, 39, 335–338. [Google Scholar] [CrossRef]
  17. Peroutka, S.J. What Turns on a Migraine? A Systematic Review of Migraine Precipitating Factors. Curr. Pain Headache Rep. 2014, 18, 454. [Google Scholar] [CrossRef] [PubMed]
  18. Park, J.-W.; Chu, M.K.; Kim, J.-M.; Park, S.-G.; Cho, S.-J. Analysis of Trigger Factors in Episodic Migraineurs Using a Smartphone Headache Diary Applications. PLoS ONE 2016, 11, e0149577. [Google Scholar] [CrossRef] [PubMed]
  19. Kundermann, B.; Krieg, J.-C.; Schreiber, W.; Lautenbacher, S. The Effect of Sleep Deprivation on Pain. Pain Res. Manag. 2004, 9, 25–32. [Google Scholar] [CrossRef] [Green Version]
  20. Schuh-Hofer, S.; Wodarski, R.; Pfau, D.B.; Caspani, O.; Magerl, W.; Kennedy, J.D.; Treede, R.-D. One night of total sleep deprivation promotes a state of generalized hyperalgesia: A surrogate pain model to study the relationship of insomnia and pain. Pain 2013, 154, 1613–1621. [Google Scholar] [CrossRef]
  21. Ma, B.; Yu, L.-H.; Fan, J.; Cong, B.; He, P.; Ni, X.; Burnstock, G. Estrogen modulation of peripheral pain signal transduction: Involvement of P2X3 receptors. Purinergic Signal. 2011, 7, 73–83. [Google Scholar] [CrossRef] [Green Version]
  22. Kumar, M.; Saxena, I.; Verma, A. Pain response during fasting and postprandial conditions in healthy young Indian males. Int. J. Clin. Exp. Physiol. 2014, 1, 262. [Google Scholar] [CrossRef]
  23. Horn-Hofmann, C.; Büscher, P.; Lautenbacher, S.; Wolstein, J. The effect of nonrecurring alcohol administration on pain perception in humans: A systematic review. J. Pain Res. 2015, 8, 175–187. [Google Scholar] [CrossRef] [Green Version]
  24. Russo, F.; Williamson, J. Interpreting Causality in the Health Sciences. Int. Stud. Philos. Sci. 2007, 21, 157–170. [Google Scholar] [CrossRef]
  25. Williamson, J. Establishing Causal Claims in Medicine. Int. Stud. Philos. Sci. 2019, 32, 33–61. [Google Scholar] [CrossRef] [Green Version]
  26. Stovner, L.J.; Hagen, K.; Linde, M.; Steiner, T.J. The global prevalence of headache: An update, with analysis of the influences of methodological factors on prevalence estimates. J. Headache Pain 2022, 23, 34. [Google Scholar] [CrossRef]
  27. Hoffmans, R.; Wagemakers, A.; van Drunen, C.; Hellings, P.; Fokkens, W. Acute and chronic rhinosinusitis and allergic rhinitis in relation to comorbidity, ethnicity and environment. PLoS ONE 2018, 13, e0192330. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  28. Clifton, N.J.; Jones, N.S. Prevalence of facial pain in 108 consecutive patients with paranasal mucopurulent discharge at endoscopy. J. Laryngol. Otol. 2007, 121, 345–348. [Google Scholar] [CrossRef]
  29. Subbarao, S.; Ribeiro, S.; Campbell, H.; Okike, I.; Ramsay, M.E.; Ladhani, S. Trends in Laboratory-Confirmed Bacterial Meningitis (2012–2019): National Observational Study, England. SSRN Electron. J. 2021. [Google Scholar] [CrossRef]
  30. Hasbun, R. Progress and Challenges in Bacterial Meningitis: A Review. JAMA 2022, 328, 2147–2154. [Google Scholar] [CrossRef]
  31. Sharifi-Mood, B.; Khajeh, A.; Metanat, M.; Rasouli, A. Epidemiology of Meningitis Studied at a University Hospital in Zahedan, South-Eastern Iran. Int. J. Infect. 2015, 2. [Google Scholar] [CrossRef]
  32. McGill, F.; Griffiths, M.J.; Bonnett, L.J.; Geretti, A.M.; Michael, B.D.; Beeching, N.J.; McKee, D.; Scarlett, P.; Hart, I.J.; Mutton, K.J.; et al. Incidence, aetiology, and sequelae of viral meningitis in UK adults: A multicentre prospective observational cohort study. Lancet Infect. Dis. 2018, 18, 992–1003. [Google Scholar] [CrossRef] [PubMed]
  33. Razvi, S.S.; Davidson, R.; Bone, I.; Muir, K.W. The prevalence of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) in the west of Scotland. J. Neurol. Neurosurg. Psychiatry 2005, 76, 739–741. [Google Scholar] [CrossRef] [Green Version]
  34. Narayan, S.K.; Gorman, G.; Kalaria, R.N.; Ford, G.A.; Chinnery, P.F. The minimum prevalence of CADASIL in northeast England. Neurology 2012, 78, 1025–1027. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Choi, J.C.; Song, S.-K.; Lee, J.S.; Kang, S.-Y.; Kang, J.-H. Headache among CADASIL patients with R544C mutation: Prevalence, characteristics, and associations. Cephalalgia 2014, 34, 22–28. [Google Scholar] [CrossRef]
  36. Guey, S.; Mawet, J.; Hervé, D.; Duering, M.; Godin, O.; Jouvent, E.; Opherk, C.; Alili, N.; Dichgans, M.; Chabriat, H. Prevalence and characteristics of migraine in CADASIL. Cephalalgia 2016, 36, 1038–1047. [Google Scholar] [CrossRef]
  37. Saini, V.; Guada, L.; Yavagal, D.R. Global Epidemiology of Stroke and Access to Acute Ischemic Stroke Interventions. Neurology 2021, 97, S6–S16. [Google Scholar] [CrossRef]
  38. Oliveira, F.A.A.; Sampaio Rocha-Filho, P.A. Headaches Attributed to Ischemic Stroke and Transient Ischemic Attack. Headache 2019, 59, 469–476. [Google Scholar] [CrossRef]
  39. Coutinho, J.M.; Zuurbier, S.M.; Aramideh, M.; Stam, J. The Incidence of Cerebral Venous Thrombosis: A cross-sectional study. Stroke 2012, 43, 3375–3377. [Google Scholar] [CrossRef] [Green Version]
  40. Kristoffersen, E.S.; Harper, C.E.; Vetvik, K.G.; Zarnovicky, S.; Hansen, J.M.; Faiz, K.W. Incidence and Mortality of Cerebral Venous Thrombosis in a Norwegian Population. Stroke 2020, 51, 3023–3029. [Google Scholar] [CrossRef]
  41. Wasay, M.; Bakshi, R.; Bobustuc, G.; Kojan, S.; Sheikh, Z.; Dai, A.; Cheema, Z. Cerebral Venous Thrombosis: Analysis of a Multicenter Cohort From the United States. J. Stroke Cerebrovasc. Dis. 2008, 17, 49–54. [Google Scholar] [CrossRef]
  42. Iurlaro, S.; Beghi, E.; Massetto, N.; Guccione, A.; Autunno, M.; Colombo, B.; Di Monda, T.; Gionco, M.; Cortelli, P.; Perini, F.; et al. Does headache represent a clinical marker in early diagnosis of cerebral venous thrombosis? A prospective multicentric study. Neurol. Sci. 2004, 25 (Suppl. S3), s298–s299. [Google Scholar] [CrossRef]
  43. Lee, V.H.; Brown, R.D., Jr.; Mandrekar, J.N.; Mokri, B. Incidence and outcome of cervical artery dissection: A population-based study. Neurology 2006, 67, 1809–1812. [Google Scholar] [CrossRef] [PubMed]
  44. Silbert, P.L.; Mokri, B.; Schievink, W.I. Headache and neck pain in spontaneous internal carotid and vertebral artery dissections. Neurology 1995, 45, 1517–1522. [Google Scholar] [CrossRef] [PubMed]
  45. Passias, P.G.; Pyne, A.; Horn, S.R.; Poorman, G.W.; Janjua, M.B.; Vasquez-Montes, D.; Bortz, C.A.; Segreto, F.A.; Frangella, N.J.; Siow, M.Y.; et al. Developments in the treatment of Chiari type 1 malformations over the past decade. J. Spine Surg. 2018, 4, 45–54. [Google Scholar] [CrossRef]
  46. Milhorat, T.H.; Chou, M.W.; Trinidad, E.M.; Kula, R.W.; Mandell, M.; Wolpert, C.; Speer, M.C. Chiari I Malformation Redefined: Clinical and Radiographic Findings for 364 Symptomatic Patients. Neurosurgery 1999, 44, 1005–1017. [Google Scholar] [CrossRef] [Green Version]
  47. Stovner, L.J. Headache Associated With the Chiari Type I Malformation. Headache 1993, 33, 175–181. [Google Scholar] [CrossRef]
  48. Wu, Y.W.; Chin, C.T.; Chan, K.M.; Barkovich, A.J.; Ferriero, D.M. Pediatric Chiari I malformations: Do clinical and radiologic features correlate? Neurology 1999, 53, 1271–1276. [Google Scholar] [CrossRef]
  49. Aitken, L.A.; Lindan, C.E.; Sidney, S.; Gupta, N.; Barkovich, A.J.; Sorel, M.; Wu, Y.W. Chiari Type I Malformation in a Pediatric Population. Pediatr. Neurol. 2009, 40, 449–454. [Google Scholar] [CrossRef] [Green Version]
  50. Li, K.J.; Semenov, D.; Turk, M.; Pope, J. A meta-analysis of the epidemiology of giant cell arteritis across time and space. Arthritis Res. Ther. 2021, 23, 82. [Google Scholar] [CrossRef]
  51. Vincenten, S.C.C.; Mulleners, W.M. The quest for a headache pattern in giant cell arteritis: A cohort study. Cephalalgia Rep. 2021, 4. [Google Scholar] [CrossRef]
  52. Gonzalez-Gay, M.A.; Barros, S.; Lopez-Diaz, M.J.; Garcia-Porrua, C.; Sanchez-Andrade, A.; Llorca, J. Giant Cell Arteritis: Disease patterns of clinical presentation in a series of 240 patients. Medicine 2005, 84, 269–276. [Google Scholar] [CrossRef]
  53. Garmendia Madariaga, A.; Santos Palacios, S.; Guillén-Grima, F.; Galofré, J.C. The Incidence and Prevalence of Thyroid Dysfunction in Europe: A Meta-Analysis. J. Clin. Endocrinol. Metab. 2014, 99, 923–931. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Moreau, T.; Manceau, E.; Giroud-Baleydier, F.; Dumas, R.; Giroud, M. Headache in hypothyroidism. Prevalence and outcome under thyroid hormone therapy. Cephalalgia 1998, 18, 687–689. [Google Scholar] [CrossRef] [PubMed]
  55. Lima Carvalho, M.F.; de Medeiros, J.S.; Valença, M.M. Headache in recent onset hypothyroidism: Prevalence, characteristics and outcome after treatment with levothyroxine. Cephalalgia 2017, 37, 938–946. [Google Scholar] [CrossRef] [Green Version]
  56. Durcan, F.J.; Corbett, J.J.; Wall, M. The Incidence of Pseudotumor Cerebri. Population studies in Iowa and Louisiana. Arch. Neurol. 1988, 45, 875–877. [Google Scholar] [CrossRef]
  57. Radhakrishnan, K.; Ahlskog, J.E.; Cross, S.A.; Kurland, L.T.; O’Fallon, W.M. Idiopathic Intracranial Hypertension (Pseudotumor Cerebri). Descriptive epidemiology in Rochester, Minn, 1976 to 1990. Arch. Neurol. 1993, 50, 78–80. [Google Scholar] [CrossRef]
  58. Wall, M.; George, D. Idiopathic intracranial hypertension: A prospective study of 50 patients. Brain 1991, 114, 155–180. [Google Scholar] [CrossRef]
  59. Friedman, D.I.; Quiros, P.A.; Subramanian, P.S.; Mejico, L.J.; Gao, S.; McDermott, M.; Wall, M.; the NORDIC IIHTT Study Group. Headache in Idiopathic Intracranial Hypertension: Findings From the Idiopathic Intracranial Hypertension Treatment Trial. Headache 2017, 57, 1195–1205. [Google Scholar] [CrossRef]
  60. D′Amico, D.A.; Curone, M.; Ciasca, P.; Cammarata, G.; Melzi, L.; Bussone, G.; Bianchi Marzoli, S. Headache prevalence and clinical features in patients with idiopathic intracranial hypertension (IIH). Neurol. Sci. 2013, 34 (Suppl. S1), S147–S149. [Google Scholar] [CrossRef] [Green Version]
  61. Bondy, M.L.; Scheurer, M.E.; Malmer, B.; Barnholtz-Sloan, J.S.; Davis, F.G.; Il’Yasova, D.; Kruchko, C.; McCarthy, B.J.; Rajaraman, P.; Schwartzbaum, J.A.; et al. Brain tumor epidemiology: Consensus from the Brain Tumor Epidemiology Consortium. Cancer 2008, 113, 1953–1968. [Google Scholar] [CrossRef] [Green Version]
  62. Pfund, Z.; Szapáry, L.; Jászberényi, O.; Nagy, F.; Czopf, J. Headache in Intracranial Tumors. Cephalalgia 1999, 19, 787–790, discussion 765. [Google Scholar] [CrossRef]
  63. Forsyth, P.A.; Posner, J.B. Headaches in patients with brain tumors: A study of 111 patients. Neurology 1993, 43, 1678–1683. [Google Scholar] [CrossRef] [PubMed]
  64. Valentinis, L.; Tuniz, F.; Valent, F.; Mucchiut, M.; Little, D.; Skrap, M.; Bergonzi, P.; Zanchin, G. Headache attributed to intracranial tumours: A prospective cohort study. Cephalalgia 2010, 30, 389–398. [Google Scholar] [CrossRef] [PubMed]
  65. Schankin, C.J.; Ferrari, U.; Reinisch, V.M.; Birnbaum, T.; Goldbrunner, R.; Straube, A. Characteristics of Brain Tumour-Associated Headache. Cephalalgia 2007, 27, 904–911. [Google Scholar] [CrossRef] [PubMed]
  66. Yatsuga, S.; Povalko, N.; Nishioka, J.; Katayama, K.; Kakimoto, N.; Matsuishi, T.; Kakuma, T.; Koga, Y.; Taro Matsuoka for MELAS Study Group in Japan. MELAS: A nationwide prospective cohort study of 96 patients in Japan. Biochim. Biophys. Acta 2012, 1820, 619–624. [Google Scholar] [CrossRef]
  67. Tiehuis, L.H.; Koene, S.; Saris, C.G.J.; Janssen, M.C.H. Mitochondrial migraine; a prevalence, impact and treatment efficacy cohort study. Mitochondrion 2020, 53, 128–132. [Google Scholar] [CrossRef]
  68. Kraya, T.; Deschauer, M.; Joshi, P.R.; Zierz, S.; Gaul, C. Prevalence of Headache in Patients With Mitochondrial Disease: A Cross-Sectional Study. Headache J. Head Face Pain 2018, 58, 45–52. [Google Scholar] [CrossRef]
  69. Sun, Y.; Zhou, G.; Feng, J.; Chen, L.; Liu, G.; Wang, J.; Wang, Q.; Yu, J.; Yang, X.; Yang, Z.; et al. Incidence and prevalence of moyamoya disease in urban China: A nationwide retrospective cohort study. Stroke Vasc. Neurol. 2021, 6, 615–623. [Google Scholar] [CrossRef]
  70. Ahn, I.M.; Park, D.-H.; Hann, H.J.; Kim, K.H.; Kim, H.J.; Ahn, H.S. Incidence, Prevalence, and Survival of Moyamoya Disease in Korea: A nationwide, population-based study. Stroke 2014, 45, 1090–1095. [Google Scholar] [CrossRef] [Green Version]
  71. Kuriyama, S.; Kusaka, Y.; Fujimura, M.; Wakai, K.; Tamakoshi, A.; Hashimoto, S.; Tsuji, I.; Inaba, Y.; Yoshimoto, T. Prevalence and Clinicoepidemiological Features of Moyamoya Disease in Japan: Findings from a nationwide epidemiological survey. Stroke 2008, 39, 42–47. [Google Scholar] [CrossRef] [Green Version]
  72. Seol, H.J.; Wang, K.-C.; Kim, S.-K.; Hwang, Y.-S.; Kim, K.J.; Cho, B.-K. Headache in pediatric moyamoya disease: Review of 204 consecutive cases. J. Neurosurg. 2005, 103, 439–442. [Google Scholar] [CrossRef]
  73. Battistella, P.A.; Carollo, C. Clinical and neuroradiological findings of Moyamoya disease in Italy. Clin. Neurol. Neurosurg. 1997, 99 (Suppl. S2), S54–S57. [Google Scholar] [CrossRef]
  74. Kraemer, M.; Lee, S.-I.; Ayzenberg, I.; Schwitalla, J.C.; Diehl, R.R.; Berlit, P.; Bosche, B.; Katsarava, Z.; Obermann, M. Headache in Caucasian patients with Moyamoya angiopathy—A systematic cohort study. Cephalalgia 2017, 37, 496–500. [Google Scholar] [CrossRef]
  75. Hishikawa, T.; Sugiu, K.; Date, I. Moyamoya Disease: A Review of Clinical Research. Acta Med. Okayama 2016, 70, 229–236. [Google Scholar] [CrossRef]
  76. Arkema, E.V.; Grunewald, J.; Kullberg, S.; Eklund, A.; Askling, J. Sarcoidosis incidence and prevalence: A nationwide register-based assessment in Sweden. Eur. Respir. J. 2016, 48, 1690–1699. [Google Scholar] [CrossRef] [Green Version]
  77. Nowak, D.A.; Widenka, D.C. Neurosarcoidosis: A review of its intracranial manifestation. J. Neurol. 2001, 248, 363–372. [Google Scholar] [CrossRef]
  78. Fritz, D.; van de Beek, D.; Brouwer, M.C. Clinical features, treatment and outcome in neurosarcoidosis: Systematic review and meta-analysis. BMC Neurol. 2016, 16, 220. [Google Scholar] [CrossRef] [Green Version]
  79. Wang, S.; Zou, X.-L.; Wu, L.-X.; Zhou, H.-F.; Xiao, L.; Yao, T.; Zhang, Y.; Ma, J.; Zeng, Y.; Zhang, L. Epidemiology of intracerebral hemorrhage: A systematic review and meta-analysis. Front. Neurol. 2022, 13, 915813. [Google Scholar] [CrossRef]
  80. Ljubisavljevic, S.; Ignjatovic, A.; Ljubisavljevic, M. Headache secondary to nontraumatic brain hemorrhage: A single-center, retrospective clinical study. Arch. Med. Sci. 2019. [Google Scholar] [CrossRef]
  81. Falhammar, H.; Tornvall, S.; Höybye, C. Pituitary Apoplexy: A Retrospective Study of 33 Cases From a Single Center. Front. Endocrinol. 2021, 12, 656950. [Google Scholar] [CrossRef]
  82. Biousse, V.; Newman, N.J.; Oyesiku, N.M. Precipitating factors in pituitary apoplexy. J. Neurol. Neurosurg. Psychiatry 2001, 71, 542–545. [Google Scholar] [CrossRef] [Green Version]
  83. Briet, C.; Salenave, S.; Bonneville, J.-F.; Laws, E.R.; Chanson, P. Pituitary Apoplexy. Endocr. Rev. 2015, 36, 622–645. [Google Scholar] [CrossRef] [PubMed]
  84. Stam, A.H.; Kothari, P.H.; Shaikh, A.; Gschwendter, A.; Jen, J.C.; Hodgkinson, S.; Hardy, T.A.; Hayes, M.; Kempster, P.A.; Kotschet, K.E.; et al. Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations. Brain 2016, 139, 2909–2922. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Pelzer, N.; Hoogeveen, E.S.; Haan, J.; Bunnik, R.; Poot, C.C.; Van Zwet, E.W.; Inderson, A.; Fogteloo, A.J.; Reinders, M.E.J.; Middelkoop, H.A.M.; et al. Systemic features of retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations: A monogenic small vessel disease. J. Intern. Med. 2019, 285, 317–332. [Google Scholar] [CrossRef] [PubMed]
  86. Magid-Bernstein, J.; Omran, S.S.; Parikh, N.S.; Merkler, A.E.; Navi, B.; Kamel, H. RCVS: Symptoms, Incidence, and Resource Utilization in a Population-Based US Cohort. Neurology 2021, 97, e248–e253. [Google Scholar] [CrossRef] [PubMed]
  87. Wolff, V.; Ducros, A. Reversible Cerebral Vasoconstriction Syndrome Without Typical Thunderclap Headache. Headache 2016, 56, 674–687. [Google Scholar] [CrossRef]
  88. Acquavella, J.; Mehra, R.; Bron, M.; Suomi, J.M.; Hess, G.P. Prevalence of narcolepsy and other sleep disorders and frequency of diagnostic tests from 2013–2016 in insured patients actively seeking care. J. Clin. Sleep Med. 2020, 16, 1255–1263. [Google Scholar] [CrossRef]
  89. Russell, M.B.; Kristiansen, H.A.; Kværner, K.J. Headache in sleep apnea syndrome: Epidemiology and pathophysiology. Cephalalgia 2014, 34, 752–755. [Google Scholar] [CrossRef]
  90. Kristiansen, H.A.; Kværner, K.J.; Akre, H.; Øverland, B.; Sandvik, L.; Russell, M.B. Sleep apnoea headache in the general population. Cephalalgia 2012, 32, 451–458. [Google Scholar] [CrossRef]
  91. Suzuki, K.; Miyamoto, M.; Miyamoto, T.; Numao, A.; Suzuki, S.; Sakuta, H.; Iwasaki, A.; Watanabe, Y.; Fujita, H.; Hirata, K. Sleep apnoea headache in obstructive sleep apnoea syndrome patients presenting with morning headache: Comparison of the ICHD-2 and ICHD-3 beta criteria. J. Headache Pain 2015, 16, 56. [Google Scholar] [CrossRef] [Green Version]
  92. Schievink, W.I.; Maya, M.M.; Moser, F.G.; Simon, P.; Nuño, M. Incidence of spontaneous intracranial hypotension in a community: Beverly Hills, California, 2006–2020. Cephalalgia 2022, 42, 312–316. [Google Scholar] [CrossRef]
  93. Schievink, W.I.; Maya, M.M.; Moser, F.; Tourje, J.; Torbati, S. Frequency of spontaneous intracranial hypotension in the emergency department. J. Headache Pain 2007, 8, 325–328. [Google Scholar] [CrossRef] [Green Version]
  94. Kleindorfer, D.; Panagos, P.; Pancioli, A.; Khoury, J.; Kissela, B.; Woo, D.; Schneider, A.; Alwell, K.; Jauch, E.; Miller, R.; et al. Incidence and Short-Term Prognosis of Transient Ischemic Attack in a Population-Based Study. Stroke 2005, 36, 720–723. [Google Scholar] [CrossRef]
  95. Al-Shahi, R.; Fang, J.S.; Lewis, S.C.; Warlow, C.P. Prevalence of adults with brain arteriovenous malformations: A community based study in Scotland using capture-recapture analysis. J. Neurol. Neurosurg. Psychiatry 2002, 73, 547–551. [Google Scholar] [CrossRef] [Green Version]
  96. Flemming, K.D. Incidence, Prevalence, and Clinical Presentation of Cerebral Cavernous Malformations. Methods Mol. Biol. 2020, 2152, 27–33. [Google Scholar] [CrossRef]
  97. Mohr, J.P.; Parides, M.K.; Stapf, C.; Moquete, E.; Moy, C.S.; Overbey, J.R.; Al-Shahi Salman, R.; Vicaut, E.; Young, W.L.; Houdart, E.; et al. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): A multicentre, non-blinded, randomised trial. Lancet 2014, 383, 614–621. [Google Scholar] [CrossRef] [Green Version]
  98. McGill, F.; Griffiths, M.J.; Solomon, T. Viral meningitis: Current issues in diagnosis and treatment. Curr. Opin. Infect. Dis. 2017, 30, 248–256. [Google Scholar] [CrossRef]
  99. Trigo, J.; García-Azorín, D.; Sierra-Mencía, A.; Tamayo-Velasco, A.; Martínez-Paz, P.; Tamayo, E.; Guerrero, A.L.; Gonzalo-Benito, H. Cytokine and interleukin profile in patients with headache and COVID-19: A pilot, CASE-control, study on 104 patients. J. Headache Pain 2021, 22, 51. [Google Scholar] [CrossRef]
  100. Bobker, S.M.; Robbins, M.S. COVID-19 and Headache: A Primer for Trainees. Headache 2020, 60, 1806–1811. [Google Scholar] [CrossRef]
  101. Goffaux, P.; Fortin, D. Brain Tumor Headaches: From bedside to bench. Neurosurgery 2010, 67, 459–466. [Google Scholar] [CrossRef]
  102. Leira, R.; Dávalos, A.; Aneiros, A.; Serena, J.; Pumar, J.M.; Castillo, J. Headache as A Surrogate Marker of the Molecular Mechanisms Implicated in Progressing Stroke. Cephalalgia 2002, 22, 303–308. [Google Scholar] [CrossRef]
  103. Liem, M.K.; Oberstein, S.A.; Van Der Grond, J.; Ferrari, M.D.; Haan, J. CADASIL and migraine: A narrative review. Cephalalgia 2010, 30, 1284–1289. [Google Scholar] [CrossRef] [PubMed]
  104. Taylor, F.R.; Larkins, M.V. Headache and Chiari I malformation: Clinical presentation, diagnosis, and controversies in management. Curr. Pain Headache Rep. 2002, 6, 331–337. [Google Scholar] [CrossRef] [PubMed]
  105. Williams, B. Cough Headache due to Craniospinal Pressure Dissociation. Arch. Neurol. 1980, 37, 226–230. [Google Scholar] [CrossRef] [PubMed]
  106. Arafah, B.M.; Prunty, D.; Ybarra, J.; Hlavin, M.L.; Selman, W.R. The Dominant Role of Increased Intrasellar Pressure in the Pathogenesis of Hypopituitarism, Hyperprolactinemia, and Headaches in Patients with Pituitary Adenomas. J. Clin. Endocrinol. Metab. 2000, 85, 1789–1793. [Google Scholar] [CrossRef] [Green Version]
  107. Jennum, P.; Børgesen, S.E. Intracranial Pressure and Obstructive Sleep Apnea. Chest 1989, 95, 279–283. [Google Scholar] [CrossRef]
  108. Devor, M.; Amir, R.; Rappaport, Z.H. Pathophysiology of Trigeminal Neuralgia: The Ignition Hypothesis. Clin. J. Pain 2002, 18, 4–13. [Google Scholar] [CrossRef]
  109. Hucklenbroich, P. “Disease Entity” as the Key Theoretical Concept of Medicine. J. Med. Philos. 2014, 39, 609–633. [Google Scholar] [CrossRef] [Green Version]
  110. Stovner, L.J.; Nichols, E.; Steiner, T.J.; Abd-Allah, F.; Abdelalim, A.; Al-Raddadi, R.M.; Ansha, M.G.; Barac, A.; Bensenor, I.M.; Doan, L.P.; et al. Global, regional, and national burden of migraine and tension-type headache, 1990–2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2018, 17, 954–976. [Google Scholar] [CrossRef] [Green Version]
  111. Pohl, H. Red flags in headache care. Headache 2022, 62, 534–535. [Google Scholar] [CrossRef]
  112. Pohl, H.; Do, T.P.; García-Azorín, D.; Hansen, J.M.; Kristoffersen, E.S.; Nelson, S.E.; Obermann, M.; Sandor, P.S.; Schankin, C.J.; Schytz, H.W.; et al. Green Flags and headache: A concept study using the Delphi method. Headache 2021, 61, 300–309. [Google Scholar] [CrossRef]
  113. García-Azorín, D.; Abelaira-Freire, J.; González-García, N.; Rodriguez-Adrada, E.; Schytz, H.W.; Barloese, M.; Guerrero, A.L.; Porta-Etessam, J.; Martín-Sánchez, F.J. Sensitivity of the SNNOOP10 list in the high-risk secondary headache detection. Cephalalgia 2022, 42, 1521–1531. [Google Scholar] [CrossRef]
  114. Perry, J.J.; Sivilotti, M.L.A.; Sutherland, J.; Hohl, C.M.; Émond, M.; Calder, L.A.; Vaillancourt, C.; Thiruganasambandamoorthy, V.; Lesiuk, H.; Wells, G.A.; et al. Validation of the Ottawa Subarachnoid Hemorrhage Rule in patients with acute headache. Can. Med. Assoc. J. 2017, 189, E1379–E1385. [Google Scholar] [CrossRef] [Green Version]
  115. Sempere, A.P.; Porta-Etessam, J.; Medrano, V.; Garcia-Morales, I.; Concepción, L.; Ramos, A.; Florencio, I.; Bermejo, F.; Botella, C. Neuroimaging in the Evaluation of Patients with Non-Acute Headache. Cephalalgia 2005, 25, 30–35. [Google Scholar] [CrossRef]
  116. Wan, W.H.; Ang, B.T.; Wang, E. The Cushing Response: A case for a review of its role as a physiological reflex. J. Clin. Neurosci. 2008, 15, 223–228. [Google Scholar] [CrossRef]
  117. Pascual, J.; Iglesias, F.; Oterino, A.; Vazquez-Barquero, A.; Berciano, J. Cough, exertional, and sexual headaches: An analysis of 72 benign and symptomatic cases. Neurology 1996, 46, 1520–1524. [Google Scholar] [CrossRef]
  118. Cordenier, A.; De Hertogh, W.; De Keyser, J.; Versijpt, J. Headache associated with cough: A review. J. Headache Pain 2013, 14, 42. [Google Scholar] [CrossRef] [Green Version]
  119. García-Azorín, D.; Do, T.P.; Gantenbein, A.R.; Hansen, J.M.; Souza, M.N.P.; Obermann, M.; Pohl, H.; Schankin, C.J.; Schytz, H.W.; Sinclair, A.; et al. Delayed headache after COVID-19 vaccination: A red flag for vaccine induced cerebral venous thrombosis. J. Headache Pain 2021, 22, 108. [Google Scholar] [CrossRef]
  120. Peral-Cagigal, B.; Perez-Villar, A.; Redondo-Gonzalez, L.M.; Garcia-Sierra, C.; Morante-Silva, M.; Madrigal-Rubiales, B.; Verrier-Hernandez, A. Temporal headache and jaw claudication may be the key for the diagnosis of giant cell arteritis. Med. Oral Patol. Oral Cir. Bucal. 2018, 23, e290–e294. [Google Scholar] [CrossRef]
  121. Saper, J.R.; Da Silva, A.N. Medication Overuse Headache: History, Features, Prevention and Management Strategies. CNS Drugs 2013, 27, 867–877. [Google Scholar] [CrossRef]
  122. van de Beek, D.; de Gans, J.; Spanjaard, L.; Weisfelt, M.; Reitsma, J.B.; Vermeulen, M. Clinical Features and Prognostic Factors in Adults with Bacterial Meningitis. N. Engl. J. Med. 2004, 351, 1849–1859. [Google Scholar] [CrossRef] [Green Version]
  123. Linn, F.H.; Wijdicks, E.F.; van der Graaf, Y.; Weerdesteyn-van Vliet, F.A.; Bartelds, A.I.; van Gijn, J. Prospective study of sentinel headache in aneurysmal subarachnoid haemorrhage. Lancet 1994, 344, 590–593. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  124. Munoz-Cerón, J.; Díaz-Forero, F.; Buitrago, A.; Chinchilla, S. Secondary cluster headache and numb chin syndrome as initial manifestation of high-grade B-lymphoma: A case report. J. Med. Case Rep. 2021, 15, 468. [Google Scholar] [CrossRef] [PubMed]
  125. Xie, J.S.; Donaldson, L.; Margolin, E. Papilledema: A review of etiology, pathophysiology, diagnosis, and management. Surv. Ophthalmol. 2022, 67, 1135–1159. [Google Scholar] [CrossRef] [PubMed]
  126. Schievink, W.I. Spontaneous Spinal Cerebrospinal Fluid Leaks and Intracranial Hypotension. JAMA 2006, 295, 2286–2296. [Google Scholar] [CrossRef]
  127. Hofmann, E.; Behr, R.; Neumann-Haefelin, T.; Schwager, K. Pulsatile Tinnitus: Imaging and differential diagnosis. Dtsch. Arztebl. Int. 2013, 110, 451–458. [Google Scholar] [CrossRef] [Green Version]
  128. Figatner, J.G. Diagnosis of Night Sweats. JAMA J. Am. Med. Assoc. 1993, 270, 2502. [Google Scholar] [CrossRef]
  129. Pohl, H.; Tarnutzer, A.A. Acute Angle-Closure Glaucoma. N. Engl. J. Med. 2018, 378, e14. [Google Scholar] [CrossRef]
  130. Hsu, C.-C.; Tsai, S.-H.; Wang, J.-C.; Kao, H.-W.; Hsu, C.-W.; Liu, W.-H.; Chen, S.-J. Swollen and bloodshot eye following headache. Am. J. Emerg. Med. 2019, 37, 378.e7–378.e9. [Google Scholar] [CrossRef]
  131. Sakaida, H.; Kobayashi, M.; Ito, A.; Takeuchi, K. Cavernous sinus thrombosis: Linking a swollen red eye and headache. Lancet 2014, 384, 928. [Google Scholar] [CrossRef]
  132. Bravo Petersen, S.M.; Vardaxis, V.G. The flexion–rotation test performed actively and passively: A comparison of range of motion in patients with cervicogenic headache. J. Man. Manip. Ther. 2015, 23, 61–67. [Google Scholar] [CrossRef] [Green Version]
  133. Tabak, F.; Murtezaoglu, A.; Tabak, O.; Ozaras, R.; Mete, B.; Kutlubay, Z.; Mert, A.; Ozturk, R. Clinical Features and Etiology of Adult Patients with Fever and Rash. Ann. Dermatol. 2012, 24, 420–425. [Google Scholar] [CrossRef] [Green Version]
  134. Tsai, J.; Nagel, M.A.; Gilden, D. Skin rash in meningitis and meningoencephalitis. Neurology 2013, 80, 1808–1811. [Google Scholar] [CrossRef]
  135. Grooters, G.S.; Sluzewski, M.; Tijssen, C.C. How Often Is Thunderclap Headache Caused by the Reversible Cerebral Vasoconstriction Syndrome? Headache 2014, 54, 732–735. [Google Scholar] [CrossRef]
  136. Cheng, Y.-C.; Kuo, K.-H.; Lai, T.-H. A common cause of sudden and thunderclap headaches: Reversible cerebral vasoconstriction syndrome. J. Headache Pain 2014, 15, 13. [Google Scholar] [CrossRef] [Green Version]
  137. Schwedt, T.J. Thunderclap Headache. Contin. Lifelong Learn. Neurol. 2015, 21, 1058–1071. [Google Scholar] [CrossRef]
  138. Suri, H.; Dougherty, C. Presentation and Management of Headache in Pituitary Apoplexy. Curr. Pain Headache Rep. 2019, 23, 61. [Google Scholar] [CrossRef]
  139. Vinod, K.V.; Reddy, P.; Pillai, V.M. Scalloped tongue: A rare finding in nocturnal bruxism. Natl. Med. J. India 2017, 30, 296. [Google Scholar] [CrossRef]
  140. Weiss, T.M.; Atanasov, S.; Calhoun, K.H. The Association of Tongue Scalloping With Obstructive Sleep Apnea and Related Sleep Pathology. Otolaryngol. Head Neck Surg. Off. J. Am. Acad. Otolaryngol. Head Neck Surg. 2005, 133, 966–971. [Google Scholar] [CrossRef]
  141. Giuseffi, V.; Wall, M.; Siegel, P.Z.; Rojas, P.B. Symptoms and disease associations in idiopathic intracranial hypertension (pseudotumor cerebri): A case-control study. Neurology 1991, 41, 239–244. [Google Scholar] [CrossRef]
  142. Do, T.P.; Remmers, A.; Schytz, H.W.; Schankin, C.; Nelson, S.E.; Obermann, M.; Hansen, J.M.; Sinclair, A.J.; Gantenbein, A.R.; Schoonman, G.G. Red and orange flags for secondary headaches in clinical practice: SNNOOP10 list. Neurology 2019, 92, 134–144. [Google Scholar] [CrossRef]
  143. Robbins, M.S.; Farmakidis, C.; Dayal, A.K.; Lipton, R.B. Acute headache diagnosis in pregnant women: A hospital-based study. Neurology 2015, 85, 1024–1030. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  144. Argyriou, A.A.; Chroni, E.; Polychronopoulos, P.; Argyriou, K.; Papapetropoulos, S.; Corcondilas, M.; Lepoura, N.; Heras, P. Headache characteristics and brain metastases prediction in cancer patients. Eur. J. Cancer Care 2006, 15, 90–95. [Google Scholar] [CrossRef] [PubMed]
  145. Chen, J.; Wall, M. Epidemiology and Risk Factors for Idiopathic Intracranial Hypertension. Int. Ophthalmol. Clin. 2014, 54, 1–11. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  146. Fallata, A.; Salter, A.; Tyry, T.; Cutter, G.R.; Marrie, R.A. Trigeminal Neuralgia Commonly Precedes the Diagnosis of Multiple Sclerosis. Int. J. MS Care 2017, 19, 240–246. [Google Scholar] [CrossRef] [Green Version]
  147. Weyand, C.M.; Goronzy, J.J. Clinical practice. Giant-Cell Arteritis and Polymyalgia Rheumatica. N. Engl. J. Med. 2014, 371, 50–57. [Google Scholar] [CrossRef] [Green Version]
  148. Crawford, P.M.; West, C.R.; Chadwick, D.W.; Shaw, M.D. Arteriovenous malformations of the brain: Natural history in unoperated patients. J. Neurol. Neurosurg. Psychiatry 1986, 49, 1–10. [Google Scholar] [CrossRef] [Green Version]
  149. Gross, B.A.; Du, R. The natural history of Moyamoya in a North American adult cohort. J. Clin. Neurosci. 2013, 20, 44–48. [Google Scholar] [CrossRef]
  150. How, J.; Blattner, M.; Fowler, S.; Wang-Gillam, A.; Schindler, S.E. Chemotherapy-associated Posterior Reversible Encephalopathy Syndrome: A Case Report and Review of the Literature. Neurologist 2016, 21, 112–117. [Google Scholar] [CrossRef]
  151. Short, K.; Emsley, H.C.A. Illicit Drugs and Reversible Cerebral Vasoconstriction Syndrome. Neurohospitalist 2021, 11, 40–44. [Google Scholar] [CrossRef]
  152. Friedman, D.I. Medication-Induced Intracranial Hypertension in Dermatology. Am. J. Clin. Dermatol. 2005, 6, 29–37. [Google Scholar] [CrossRef]
  153. Matsumura, Y. Risk Analysis of Eculizumab-Related Meningococcal Disease in Japan Using the Japanese Adverse Drug Event Report Database. Drug Healthc. Patient Saf. 2020, 12, 207–215. [Google Scholar] [CrossRef]
  154. Amoozegar, F.; Ronksley, P.E.; Sauve, R.; Menon, B.K. Hormonal Contraceptives and Cerebral Venous Thrombosis Risk: A Systematic Review and Meta-Analysis. Front. Neurol. 2015, 6, 7. [Google Scholar] [CrossRef] [Green Version]
  155. Holle, D.; Obermann, M. The role of neuroimaging in the diagnosis of headache disorders. Ther. Adv. Neurol. Disord. 2013, 6, 369–374. [Google Scholar] [CrossRef] [Green Version]
  156. Friedman, D.I. Headache and the eye. Curr. Pain Headache Rep. 2008, 12, 296–304. [Google Scholar] [CrossRef]
  157. Felisati, G.; Lozza, P.; Maccari, A.; Scotti, A.; Leone, M.; Bussone, G. The role of the ear, nose and throat specialist in diagnosing headaches. Neurol. Sci. 2005, 26 (Suppl. S2), s83–s86. [Google Scholar] [CrossRef]
  158. Kranz, P.G.; Luetmer, P.H.; Diehn, F.E.; Amrhein, T.J.; Tanpitukpongse, T.P.; Gray, L. Myelographic Techniques for the Detection of Spinal CSF Leaks in Spontaneous Intracranial Hypotension. AJR Am. J. Roentgenol. 2016, 206, 8–19. [Google Scholar] [CrossRef]
  159. Antonakis, J.; Bendahan, S.; Jacquart, P.; Lalive, R. On making causal claims: A review and recommendations. Leadersh. Q. 2010, 21, 1086–1120. [Google Scholar] [CrossRef] [Green Version]
  160. Michali-Stolarska, M.; Bladowska, J.; Stolarski, M.; Sąsiadek, M.J. Diagnostic Imaging and Clinical Features of Intracranial Hypotension–Review of Literature. Pol. J. Radiol. 2017, 82, 842–849. [Google Scholar] [CrossRef] [Green Version]
  161. Maurya, V.; Sreedhar, C.M.; Khera, A.; Bhatia, M.; Sharma, V. Trigeminal neuralgia: When does neurovascular contact turn into a conflict? Med. J. Armed Forces India 2019, 75, 134–139. [Google Scholar] [CrossRef]
  162. Stuginski-Barbosa, J.; Murayama, R.A.; Conti, P.C.; Speciali, J.G. Refractory facial pain attributed to auriculotemporal neuralgia. J. Headache Pain 2012, 13, 415–417. [Google Scholar] [CrossRef] [Green Version]
  163. Campaner, R.; Cerri, M. Manipulative evidence and medical interventions: Some qualifications. Hist. Philos. Life Sci. 2020, 42, 15. [Google Scholar] [CrossRef] [PubMed]
  164. Foltz, E.L.; Ward, A.A., Jr. Communicating Hydrocephalus from Subarachnoid Bleeding. J. Neurosurg. 1956, 13, 546–566. [Google Scholar] [CrossRef] [PubMed]
  165. Yiangou, A.; Mitchell, J.; Markey, K.A.; Scotton, W.; Nightingale, P.; Botfield, H.; Ottridge, R.; Mollan, S.P.; Sinclair, A.J. Therapeutic lumbar puncture for headache in idiopathic intracranial hypertension: Minimal gain, is it worth the pain? Cephalalgia 2019, 39, 245–253. [Google Scholar] [CrossRef] [PubMed]
  166. Rozen, T.D. Daily persistent headache after a viral illness during a worldwide pandemic may not be a new occurrence: Lessons from the 1890 Russian/Asiatic flu. Cephalalgia 2020, 40, 1406–1409. [Google Scholar] [CrossRef]
Ctn 07 00017 g001 550
Figure 1. Overview of the pieces of information obtained through history and physical examination that are relevant to differential diagnostic reasoning; MELAS—Mitochondrial Encephalopathy, Lactic Acidosis and Stroke-like episodes, CADASIL—Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy.
Figure 1. Overview of the pieces of information obtained through history and physical examination that are relevant to differential diagnostic reasoning; MELAS—Mitochondrial Encephalopathy, Lactic Acidosis and Stroke-like episodes, CADASIL—Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy.
Ctn 07 00017 g001
Table
Table 2. Overview of red flags with temporal information screening for secondary headaches.
Table 2. Overview of red flags with temporal information screening for secondary headaches.
Red FlagAssociated Condition
Abnormal neurologic examinationHeadaches with different aetiologies including mass lesion, hydrocephalus, and dural fistula [115]
Arterial hypertensionPheochromocytoma, hypertensive crisis, pre-eclampsia and eclampsia, acute pressure response to an exogenous agent, and acute increase in intracranial pressure (Cushing response) [116]
Cough headacheChiari malformation type 1 [117] and posterior fossa lesion [118]
Delayed headache after COVID-19 vaccinationSinus thrombosis [119]
Exertional headacheSubarachnoid haemorrhage, sinusitis, and brain metastases [117]
FeverSystemic infection, meningitis, and encephalitis
Headache associated with sexual activitySubarachnoid haemorrhage [117]
Jaw claudicationTemporal arteritis, temporomandibular joint dysfunction, and myofascial pain [120]
Morning headacheBrain tumour [101], medication overuse headache [121], and sleep apnoea [89]
Neck stiffnessMeningitis [122] and intracranial haemorrhage [123]
Numb chinMetastatic tumour (infrequently associated with pain) [124]
PapilledemaRaised intracranial pressure [125]
Positional headacheIntracranial hypertension and intracranial hypotension [126]
Pulsatile tinnitusIntracranial hypertension, arterio-venous malformation, and arterio-venous fistula [127]
Recent unwanted weight loss, night sweatSystemic disorders including infection, malignancy (e.g., lymphoma), autoimmune (e.g., polymyalgia rheumatica), and endocrinologic disorders (e.g., carcinoid syndrome) [128]
Reddening of one eyeGlaucoma [129], carotid-cavernous fistula [130], and cavernous sinus thrombosis [131]
Reduced range of motion in the flexion-rotation testCervicogenic headache [132]
Skin rashSystemic infection, meningitis, meningoencephalitis due to, e.g., measles, Mediterranean spotted fever, Syphilis, Neisseria meningitides, varicella zoster virus, and West Nile virus [133,134]
Tenderness upon palpation of the temporal and masseter musclesTemporal-mandibular dysfunction and temporal arteritis [120]
Thunderclap headacheSubarachnoid haemorrhage [10], reversible cerebral vascular constriction syndrome (RCVS) [135,136], cervical artery dissection, cerebral venous sinus thrombosis, spontaneous intracranial hypotension [137], and pituitary apoplexy [138]
Tongue ScallopingBruxism [139] and sleep apnoea [140]
Transient visual obscurationIntracranial hypertension [141]
Table
Table 3. Examples of evidence of the mechanisms through which certain stimuli cause headache; IIH—idiopathic intracranial hypertension; SAH—subarachnoid haemorrhage; RCVS—reversible cerebral vascular constriction syndrome.
Table 3. Examples of evidence of the mechanisms through which certain stimuli cause headache; IIH—idiopathic intracranial hypertension; SAH—subarachnoid haemorrhage; RCVS—reversible cerebral vascular constriction syndrome.
MechanismAssociated ConditionsDirect Mechanistic EvidenceIndirect Mechanistic Evidence
Craniospinal pressure dissociationChiari malformation type 1Measurement of the pressure gradient [105]Headache attacks from coughing [47]
Decreased intracranial pressureSpontaneous CSF leakage and postdural headacheInvasive evidence of a pressure gradientMRI signs of reduced intracranial pressure [160] and positional headaches [126]
Focal demyelination of the trigeminal nerveNeuralgia-MR evidence of nerve vessel conflict with thinning, grooving, or distortion of the nerve [161], presence of a trigger point or a trigger zone, or pain restricted to a skin area innervated by a specific sensory nerve [5,162]
InflammationSystemic or localised inflammation-Elevated inflammatory parameters, skin rash
Medication overuseMedication overuse headache-Medication overuse and presence of morning headaches [121]
Raised intracranial pressureIIH and brain tumourMeasurement of the pressurePapilledema in fundoscopy, MRI signs of raised intracranial pressure, vomiting, impaired consciousness, bradycardia, hypertension (Cushing response) [116], and positional headaches [101]
Sleep-related hypoxiaSleep apnoeaReduced oxygen saturation during sleepMorning headaches [89]
Stimulation of arterial nociceptorsSAH and RCVS-Thunderclap headache [10,135,136] and imaging evidence of a bleeding or vasospasm
Traumatic stimulation of nociceptorsTrauma to the head, whiplash, and craniotomyWitness of the impactTraces of the trauma, e.g., scars
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Pohl, H. Approaching Headaches—A Guide to Differential-Diagnostic Considerations and Causal Claims. Clin. Transl. Neurosci. 2023, 7, 17. https://doi.org/10.3390/ctn7030017

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Pohl H. Approaching Headaches—A Guide to Differential-Diagnostic Considerations and Causal Claims. Clinical and Translational Neuroscience. 2023; 7(3):17. https://doi.org/10.3390/ctn7030017

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Pohl, Heiko. 2023. "Approaching Headaches—A Guide to Differential-Diagnostic Considerations and Causal Claims" Clinical and Translational Neuroscience 7, no. 3: 17. https://doi.org/10.3390/ctn7030017

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Pohl, H. (2023). Approaching Headaches—A Guide to Differential-Diagnostic Considerations and Causal Claims. Clinical and Translational Neuroscience, 7(3), 17. https://doi.org/10.3390/ctn7030017

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