Opinion
Headache associated with non-cephalic infections: classification and mechanisms
Milena De Marinis1, KMA Welch2
La Sapienza University, Department of Neurological Sciences, Rome, Italy1 ; Henry Ford Hospital and Health Science Center, Department of Neurology, Detroit, USA2
The editor of this article was Dr Marcia Wilkinson in view of the editor of Cephalalgia being one of the authors. Cephalalgia
De Marinis M, Welch KMA. Headache associated with non-cephalic infections: classification and mechanisms. Cephalalgia 1992;12:197-201. Oslo. ISSN 0333-1024 A classification of headache associated with non-cephalic infections is proposed. The classification is supported by published case series and reports. The head pain can be explained by direct activation of pain producing mechanisms by microorganisms or can be secondary to fever or to a combination of both. • Fever, headache, infectious diseases Milena De Marinis, La Sapienza University, Department of Neurological Sciences, V. le dell' Università 30, 00185 Rome, Italy. Received 6 April 1992, accepted 12 May 1992
Headache commonly occurs with focal or systemic infections outside the head. The International Headache Society has coded "Headache associated with non-cephalic infection" to group 9 of the classification and has defined this headache as a "new form of headache" (including migraine, tension-type headache or cluster headache) in close temporal relation to a non-cephalic infection (1). The classification committee recognized that this form of headache was poorly understood and that the classification needed to be further developed. Although commonly reported in the medical history of patients suffering from infectious diseases, there is relatively little information concerning the nature of mechanisms of the headache. Most often, headache is reported without specific descriptive features as part of the "infectious disease syndrome" that includes fever, chills, malaise, myalgia, arthralgia and asthenia. The incidence of headache associated with any one infectious disease is generally unpredictable with wide variation in reported rates. We sought in this opinion paper to expand the classification of headache associated with non-cephalic infections on the basis of the available literature so that the mechanisms might be better understood and the clinical problem clarified. Clinical features
Headache associated with non-cephalic infection is usually bilateral and diffuse, but in certain cases, occipital, fronto-temporal or distinctive retroocular pain has been reported. The pain is of variable intensity, described as throbbing, pulsatile or steady and can be worsened by head movement, coughing or straining. Apart from symptoms particular to the infection, or specifically due to fever or both, there can be associated symptoms such as photophobia, sonophobia, conjunctival injection, neck guarding, nausea and vomiting. The pain may be acute or chronic, outlasting symptoms of active infection. Occasionally recurrent headaches are experienced. When other neurological symptoms develop, direct involvement of cerebral structures (e.g. meningitis, encephalitis, brain abscess) should be suspected. In the infectious diseases we reviewed, we noticed that headache commonly coexists with fever and is strictly dependent on it, but that headache can also occur in the absence of fever. Clearly, under different circumstances the pain may have different mechanisms. Thus it seemed important to us to use the presence or absence of fever in the differential classification of headache. This was reinforced by the lack of specific headache patterns for any infectious disease we reviewed. We therefore propose the following classification: 9.1. Headache associated with fever 9.1.1. Headache during fever 9.1.2. Headache persisting after fever 9.2. Headache not associated with fever 9.3. Delayed or recurrent headache 9.4. Headaches coded as for 1.1-7, 2.1-7 (migraine and tension-type) All headaches must have an appropriate temporal association with non-cephalic infection. In the discussion that follows our aim is to support the proposed classification with published case series and reports. The information, from which only
general conclusions should be drawn, must be viewed with caution because publications are limited in number and scope. Also, we believe that this headache type, being a secondary complaint of a common primary disorder, is too complex to lend itself easily to epidemiological study. Working with these limitations, we have nevertheless attempted to identify diseases with characteristic headache patterns. Undoubtedly in clinical experience there are many infectious diseases in which a specific headache pattern cannot be predicted. 9.1. Headache associated with fever 9.1.1. Headache during fever To classify this headache type, the fever must be considered to be the cause of pain and headache must accordingly be closely time-locked with the presence of fever. In viral influenza, headache coexists with fever with incidence ranging from 68 to 100%. A distinctive retroorbital pain has been described in 26% of patients (2). In a case series of epidemic adenovirus infection, headache had an incidence of 83% and associated conjunctival injection of 51% (3). A reported epidemic of Oropouche virus illness (4) was characterized by headache, retroorbital pain and photophobia in the presence of fever. Retroorbital pain, photophobia, nausea, vomiting, skin rash, and severe headache have been reported in dengue fever (5-7). In infections due to Rickettsiae, the pathogenic agents of Ehrlichia canis, Mediterranean spotted fever, Rocky Mountain spotted fever, and Q fever, headache occurs in a high percentage of patients and closely parallels fever, i.e. severe headache occurs with high temperature (8-10). In Ehrlichia canis infection, headache, fever and fatigue were reported in 94% of patients (8). A lower prevalence of headache (69%) has been reported in Mediterranean spotted fever (9). Severe retroorbital headache has also been described in association with fever to 104°F in this illness (11). In Legionella pneumophila and Mycoplasma pneumoniae, headache coexists with fever, fatigue, arthralgia, myalgia, cough, and breathlessness (12, 13). In Leptospirosis, which also presents with severe kidney and liver damage sometimes associated with meningeal involvement, headache occurs in 97% of cases and fever in 70% (14). Gastrointestinal infectious diseases may also be associated with headache, although less predictably. Besides diarrhea and abdominal cramps, which are the most prominent symptoms, coexisting fever and headache are of variable incidence ( 15 - 17). There are a number of diseases in which, although headache is coincident with fever, the incidence is of low order. For example, headache accompanies Brucellosis (18) in 23% of cases, much lower than the incidence of fever (91%) (19). Similarly, a headache incidence of just under 10% has been reported in typhoid fever (20). 9.1.2. Headache persisting after fever In the acute stage of malaria, fever has been found in 94% of patients and in 33.5% severe headache (21). However, shivering and headache are the main symptoms in the chronic phases of this disease (22, 23). A persistent headache which lasted after the acute fever has been described in Semliki Forest infection (24). Headache is closely associated with erythema and fever in 88% of patients suffering from Borreliosis in the acute stages (25). Radicular pain and cranial neuritis also have been observed in 58% of the cases within two weeks and up to four months from the onset. Headache duration of about three weeks beyond fever has been reported (26). 9.2. Headache without fever There are only a few reports of this category to be found in the literature. In Trypanosomiasis, headache does not coexist with fever. A long-lasting headache (about three months) was found in 73-75% of patients, whereas fever was present in only 30-36% (27, 28). Other authors have described a shorter duration of headache (one week) in this disease (29). Chronic headaches have been described in Xylohypha bantiana infection (23). The fact that this fungal disease was followed later by fever and hemiparesis, however, raises the possibility that the initial headache might have been caused by direct involvement of the CNS (30). 9.3. Delayed or recurrent headache Meningeal involvement associated with headache is generally present in patients suffering from septicemia (31). But, the development of severe headache which recurs after a high fever is over may be the early expression of a delayed septicemia (32). Among the viral illnesses, Herpes Simplex and Epstein3/4Barr seem particularly related to the occurrence of delayed or recurrent headaches. For example, chronic headache is the prominent symptom of herpes simplex-induced chronic fatigue syndrome (33). Moreover, an increased frequency of Epstein3/4Barr virus excretion has been found in patients with daily persistent headache (34) so that some authors recommended search for Epstein-Barr virus infection in patients with what they termed chronic benign daily headache (35). 9.4. Headaches coded as for 1.1-7 to 2.1-7 This category is to be used for the occurrence of migraine and tension-type headache when they are
induced by non-cephalic infections, most probably the fever, in patients who have an established history of these disorders. Note that an association of Herpes Simplex and, possibly, Epstein-Barr virus has been drawn with the occurrence of cluster headache. The association between Epstein-Barr virus and cluster headache is uncertain, however, and must await further case reports. The relationship between Herpes Simplex and cluster headache seems more established (36, 37). Under these circumstances this headache may tentatively be coded for cephalic infections, since the herpes simplex virus most likely invaded the trigeminal or autonomic system supplying the periorbital structures. Mechanisms of headache
The mechanisms causing headache associated with non-cephalic infection can be considered direct or indirect. In the former, headache mechanisms are dependent on intrinsic characteristics of microorganisms and in the latter headache depends on mechanisms induced by fever. Fever related headache. The headache of non-cephalic infectious disease is most commonly coincident with fever. Fever can be stimulated exogenously by pyrogens, such as inflammatory mediators and toxins, or directly, by microorganisms or fragments of microorganisms which act through intermediary compounds or endogenous pyrogens (38, 39). For example, endogenously produced antigen-antibody complexes, complement components and some lymphocyte products induce fever. Endogenous pyrogens release additional pyrogens from stimulated leukocytes or induce interleukin-1, a-interferon and tumor-necrosis factor (TNF). Interleukin-1 is also produced by monocytes and macrophages and its targets include neutrophils, fibroblasts, striated muscle cells and hepatocytes. The intravenous administration of inter-leukin and a-interferon to patients directly induces headache (40-44). Interleukin is known to activate the serotonergic brainstem nuclei responsible for the sleep disturbances of fever which is the same brain-stem system implicated in headache induction. Inter-leukin also mobilizes amino acids from muscle (via PGE1) to induce the myalgias which accompany fever and which could contribute a tension-type component of the headache directly caused by fever. Pyrogens also induce increases in arachidonic acid metabolites such as the cyclooxygenase derived prostaglandins, prostacyclin and thromboxane. Prostaglandin E2 (PGE2) acts directly on the hypothalamus and can also initiate fever independent of endogenous pyrogen production (39). PGE2 has vaso-active properties and could be indirectly implicated in any vascular component of headache. Dynamic changes in CBF can be produced by shifts in pCO2 as the respiratory centers participate in the thermoregulatory reflexes of fever. Headache can be secondary to either increase or decrease in CBF, most commonly the former produced by high pCO2. Hypotension due to shock can induce a decrease in CBF and sometimes account for headache. Directly caused by microorganisms. Some infective agents have a particular tropism for the CNS. They may invade brainstem nuclei such as locus coeruleus, trigeminal nuclei and raphe nuclei where the release of toxins or the toxic properties of cellular fragments activate headache mechanisms (45, 46). Microorganism infected cells, particularly activated macrophages, release interleukin, and a-interferon (47, 48). As discussed above, besides acting as pyrogens and mediating inflammatory responses, interleukin and a-interferon directly induce headache (40-44). The inflammatory response induced by infected cells is also potentiated by these compounds. Activation of the enzymes cyclooxygenase and lipoxygenase leads to the further generation and release of pain sensitizing vasoactive compounds such as prostaglandins, peptides and amines. Plasma protein extravasation and painful vasodilation are induced in the arteries, veins and meninges supplied by the trigeminal system. Some microorganisms, particularly gram negative bacteria, provoke platelet activation and degranulation (32). The release of compounds from platelets, e.g. serotonin, has been implicated in the pathogenesis of headache (49-53) although some consider this an epiphenomenon. The same mechanisms directly caused by microorganisms may, of course, be active during fever, but cannot be distinguished from those indirectly due to fever. Summary
In summation, we have proposed a new classification of headache associated with non-cephalic infections, taking into account the occurrence of fever in each infectious disorder. The head pain can be attributed to direct activation of pain producing mechanisms by microorganisms or can be secondary to fever or to a combination of both. Prospective studies, rigorously controlled and statistically designed are required to test the opinions derived from our retrospective analysis of the literature. References
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Headache associated with non-cephalic infections: classification and mechanisms
Milena De Marinis1, KMA Welch2
La Sapienza University, Department of Neurological Sciences, Rome, Italy1 ; Henry Ford Hospital and Health Science Center, Department of Neurology, Detroit, USA2
The editor of this article was Dr Marcia Wilkinson in view of the editor of Cephalalgia being one of the authors. Cephalalgia
De Marinis M, Welch KMA. Headache associated with non-cephalic infections: classification and mechanisms. Cephalalgia 1992;12:197-201. Oslo. ISSN 0333-1024 A classification of headache associated with non-cephalic infections is proposed. The classification is supported by published case series and reports. The head pain can be explained by direct activation of pain producing mechanisms by microorganisms or can be secondary to fever or to a combination of both. • Fever, headache, infectious diseases Milena De Marinis, La Sapienza University, Department of Neurological Sciences, V. le dell' Università 30, 00185 Rome, Italy. Received 6 April 1992, accepted 12 May 1992
Headache commonly occurs with focal or systemic infections outside the head. The International Headache Society has coded "Headache associated with non-cephalic infection" to group 9 of the classification and has defined this headache as a "new form of headache" (including migraine, tension-type headache or cluster headache) in close temporal relation to a non-cephalic infection (1). The classification committee recognized that this form of headache was poorly understood and that the classification needed to be further developed. Although commonly reported in the medical history of patients suffering from infectious diseases, there is relatively little information concerning the nature of mechanisms of the headache. Most often, headache is reported without specific descriptive features as part of the "infectious disease syndrome" that includes fever, chills, malaise, myalgia, arthralgia and asthenia. The incidence of headache associated with any one infectious disease is generally unpredictable with wide variation in reported rates. We sought in this opinion paper to expand the classification of headache associated with non-cephalic infections on the basis of the available literature so that the mechanisms might be better understood and the clinical problem clarified. Clinical features
Headache associated with non-cephalic infection is usually bilateral and diffuse, but in certain cases, occipital, fronto-temporal or distinctive retroocular pain has been reported. The pain is of variable intensity, described as throbbing, pulsatile or steady and can be worsened by head movement, coughing or straining. Apart from symptoms particular to the infection, or specifically due to fever or both, there can be associated symptoms such as photophobia, sonophobia, conjunctival injection, neck guarding, nausea and vomiting. The pain may be acute or chronic, outlasting symptoms of active infection. Occasionally recurrent headaches are experienced. When other neurological symptoms develop, direct involvement of cerebral structures (e.g. meningitis, encephalitis, brain abscess) should be suspected. In the infectious diseases we reviewed, we noticed that headache commonly coexists with fever and is strictly dependent on it, but that headache can also occur in the absence of fever. Clearly, under different circumstances the pain may have different mechanisms. Thus it seemed important to us to use the presence or absence of fever in the differential classification of headache. This was reinforced by the lack of specific headache patterns for any infectious disease we reviewed. We therefore propose the following classification: 9.1. Headache associated with fever 9.1.1. Headache during fever 9.1.2. Headache persisting after fever 9.2. Headache not associated with fever 9.3. Delayed or recurrent headache 9.4. Headaches coded as for 1.1-7, 2.1-7 (migraine and tension-type) All headaches must have an appropriate temporal association with non-cephalic infection. In the discussion that follows our aim is to support the proposed classification with published case series and reports. The information, from which only
general conclusions should be drawn, must be viewed with caution because publications are limited in number and scope. Also, we believe that this headache type, being a secondary complaint of a common primary disorder, is too complex to lend itself easily to epidemiological study. Working with these limitations, we have nevertheless attempted to identify diseases with characteristic headache patterns. Undoubtedly in clinical experience there are many infectious diseases in which a specific headache pattern cannot be predicted. 9.1. Headache associated with fever 9.1.1. Headache during fever To classify this headache type, the fever must be considered to be the cause of pain and headache must accordingly be closely time-locked with the presence of fever. In viral influenza, headache coexists with fever with incidence ranging from 68 to 100%. A distinctive retroorbital pain has been described in 26% of patients (2). In a case series of epidemic adenovirus infection, headache had an incidence of 83% and associated conjunctival injection of 51% (3). A reported epidemic of Oropouche virus illness (4) was characterized by headache, retroorbital pain and photophobia in the presence of fever. Retroorbital pain, photophobia, nausea, vomiting, skin rash, and severe headache have been reported in dengue fever (5-7). In infections due to Rickettsiae, the pathogenic agents of Ehrlichia canis, Mediterranean spotted fever, Rocky Mountain spotted fever, and Q fever, headache occurs in a high percentage of patients and closely parallels fever, i.e. severe headache occurs with high temperature (8-10). In Ehrlichia canis infection, headache, fever and fatigue were reported in 94% of patients (8). A lower prevalence of headache (69%) has been reported in Mediterranean spotted fever (9). Severe retroorbital headache has also been described in association with fever to 104°F in this illness (11). In Legionella pneumophila and Mycoplasma pneumoniae, headache coexists with fever, fatigue, arthralgia, myalgia, cough, and breathlessness (12, 13). In Leptospirosis, which also presents with severe kidney and liver damage sometimes associated with meningeal involvement, headache occurs in 97% of cases and fever in 70% (14). Gastrointestinal infectious diseases may also be associated with headache, although less predictably. Besides diarrhea and abdominal cramps, which are the most prominent symptoms, coexisting fever and headache are of variable incidence ( 15 - 17). There are a number of diseases in which, although headache is coincident with fever, the incidence is of low order. For example, headache accompanies Brucellosis (18) in 23% of cases, much lower than the incidence of fever (91%) (19). Similarly, a headache incidence of just under 10% has been reported in typhoid fever (20). 9.1.2. Headache persisting after fever In the acute stage of malaria, fever has been found in 94% of patients and in 33.5% severe headache (21). However, shivering and headache are the main symptoms in the chronic phases of this disease (22, 23). A persistent headache which lasted after the acute fever has been described in Semliki Forest infection (24). Headache is closely associated with erythema and fever in 88% of patients suffering from Borreliosis in the acute stages (25). Radicular pain and cranial neuritis also have been observed in 58% of the cases within two weeks and up to four months from the onset. Headache duration of about three weeks beyond fever has been reported (26). 9.2. Headache without fever There are only a few reports of this category to be found in the literature. In Trypanosomiasis, headache does not coexist with fever. A long-lasting headache (about three months) was found in 73-75% of patients, whereas fever was present in only 30-36% (27, 28). Other authors have described a shorter duration of headache (one week) in this disease (29). Chronic headaches have been described in Xylohypha bantiana infection (23). The fact that this fungal disease was followed later by fever and hemiparesis, however, raises the possibility that the initial headache might have been caused by direct involvement of the CNS (30). 9.3. Delayed or recurrent headache Meningeal involvement associated with headache is generally present in patients suffering from septicemia (31). But, the development of severe headache which recurs after a high fever is over may be the early expression of a delayed septicemia (32). Among the viral illnesses, Herpes Simplex and Epstein3/4Barr seem particularly related to the occurrence of delayed or recurrent headaches. For example, chronic headache is the prominent symptom of herpes simplex-induced chronic fatigue syndrome (33). Moreover, an increased frequency of Epstein3/4Barr virus excretion has been found in patients with daily persistent headache (34) so that some authors recommended search for Epstein-Barr virus infection in patients with what they termed chronic benign daily headache (35). 9.4. Headaches coded as for 1.1-7 to 2.1-7 This category is to be used for the occurrence of migraine and tension-type headache when they are
induced by non-cephalic infections, most probably the fever, in patients who have an established history of these disorders. Note that an association of Herpes Simplex and, possibly, Epstein-Barr virus has been drawn with the occurrence of cluster headache. The association between Epstein-Barr virus and cluster headache is uncertain, however, and must await further case reports. The relationship between Herpes Simplex and cluster headache seems more established (36, 37). Under these circumstances this headache may tentatively be coded for cephalic infections, since the herpes simplex virus most likely invaded the trigeminal or autonomic system supplying the periorbital structures. Mechanisms of headache
The mechanisms causing headache associated with non-cephalic infection can be considered direct or indirect. In the former, headache mechanisms are dependent on intrinsic characteristics of microorganisms and in the latter headache depends on mechanisms induced by fever. Fever related headache. The headache of non-cephalic infectious disease is most commonly coincident with fever. Fever can be stimulated exogenously by pyrogens, such as inflammatory mediators and toxins, or directly, by microorganisms or fragments of microorganisms which act through intermediary compounds or endogenous pyrogens (38, 39). For example, endogenously produced antigen-antibody complexes, complement components and some lymphocyte products induce fever. Endogenous pyrogens release additional pyrogens from stimulated leukocytes or induce interleukin-1, a-interferon and tumor-necrosis factor (TNF). Interleukin-1 is also produced by monocytes and macrophages and its targets include neutrophils, fibroblasts, striated muscle cells and hepatocytes. The intravenous administration of inter-leukin and a-interferon to patients directly induces headache (40-44). Interleukin is known to activate the serotonergic brainstem nuclei responsible for the sleep disturbances of fever which is the same brain-stem system implicated in headache induction. Inter-leukin also mobilizes amino acids from muscle (via PGE1) to induce the myalgias which accompany fever and which could contribute a tension-type component of the headache directly caused by fever. Pyrogens also induce increases in arachidonic acid metabolites such as the cyclooxygenase derived prostaglandins, prostacyclin and thromboxane. Prostaglandin E2 (PGE2) acts directly on the hypothalamus and can also initiate fever independent of endogenous pyrogen production (39). PGE2 has vaso-active properties and could be indirectly implicated in any vascular component of headache. Dynamic changes in CBF can be produced by shifts in pCO2 as the respiratory centers participate in the thermoregulatory reflexes of fever. Headache can be secondary to either increase or decrease in CBF, most commonly the former produced by high pCO2. Hypotension due to shock can induce a decrease in CBF and sometimes account for headache. Directly caused by microorganisms. Some infective agents have a particular tropism for the CNS. They may invade brainstem nuclei such as locus coeruleus, trigeminal nuclei and raphe nuclei where the release of toxins or the toxic properties of cellular fragments activate headache mechanisms (45, 46). Microorganism infected cells, particularly activated macrophages, release interleukin, and a-interferon (47, 48). As discussed above, besides acting as pyrogens and mediating inflammatory responses, interleukin and a-interferon directly induce headache (40-44). The inflammatory response induced by infected cells is also potentiated by these compounds. Activation of the enzymes cyclooxygenase and lipoxygenase leads to the further generation and release of pain sensitizing vasoactive compounds such as prostaglandins, peptides and amines. Plasma protein extravasation and painful vasodilation are induced in the arteries, veins and meninges supplied by the trigeminal system. Some microorganisms, particularly gram negative bacteria, provoke platelet activation and degranulation (32). The release of compounds from platelets, e.g. serotonin, has been implicated in the pathogenesis of headache (49-53) although some consider this an epiphenomenon. The same mechanisms directly caused by microorganisms may, of course, be active during fever, but cannot be distinguished from those indirectly due to fever. Summary
In summation, we have proposed a new classification of headache associated with non-cephalic infections, taking into account the occurrence of fever in each infectious disorder. The head pain can be attributed to direct activation of pain producing mechanisms by microorganisms or can be secondary to fever or to a combination of both. Prospective studies, rigorously controlled and statistically designed are required to test the opinions derived from our retrospective analysis of the literature. References
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