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to a maximum of two cups per day. This level of intake also did not meet the criteria
for caffeine withdrawal headache.
Despite partial relief with these medications, the improvement was often incomplete. This, combined with the signicant impact of the headache on her quality of
life, making it the most distressing symptom during hemodialysis, highlights the
importance of further research and the development of more effective prophylactic
and abortive treatment strategies.
A. L. de LimaAntoniazzi and A. C. J. Santos
39.5 Characteristics ofDialysis Headache
The prevalence of hemodialysis-related headache ranges from 6.6% to 70% among
patients undergoing maintenance hemodialysis [5, 6, 13, 17–19, 22–25]. Older
studies reported higher prevalence rates, while recent research suggests a decline,
potentially due to advancements in dialysis technology and changes in diagnostic
criteria under the third edition of the International Classication of Headache
Disorders (ICHD-3). Over the past 5 years, prevalence rates have ranged from 8.7%
to 49% [6, 19, 26]. There does not appear to be a preferential involvement based on
sex, although some studies suggest a slightly higher prevalence in men [10].
Hemodialysis headache can also occur in children. In a 2017 study, Davidovits etal.
examined 60 children with CKD and found a prevalence of 43.3% [24].
Hemodialysis-related headache is typically of moderate-to-severe intensity, signicantly impacting quality of life. It begins during the dialysis session, most commonly occurring some hours after its initiation, usually after the third hour [19]. The
pain has no specic characteristics but is commonly located in the frontal and temporal regions bilaterally. It may also affect the occipital area or present unilaterally.
The headache may be pulsatile, pressure-like, or tightening in nature, resembling
tension-type or migraine-like headaches. In severe cases, nausea and vomiting may
accompany the headache [18, 19]. The duration of symptoms varies, lasting an average of 3–7 hours post-dialysis but sometimes persisting up to 72hours.
Interestingly, approximately 20–23% of affected patients have no prior history of
primary headache disorders [18, 27]. However, patients with pre-existing headache
disorders may experience exacerbations or alterations in their headache patterns
after starting hemodialysis. The causal link between hemodialysis and headache is
reinforced by observations that headaches often resolve or revert to pre-dialysis
characteristics following successful kidney transplantation [7].
39.6 ICHD-3 Diagnostic Criteria [28]
Headache with no specic characteristics, occurring during and caused by hemodialysis. It resolves spontaneously within 72hours after the hemodialysis session
has ended.
39 Dialysis Headache
375
39.6.1 Diagnostic Criteria
A. At least three episodes of acute headache fullling criterion C
B. The patient is on hemodialysis
C. Evidence of causation demonstrated by at least two of the following:
1. Each headache has developed during a session of hemodialysis
2. Either or both of the following:
(a) Each headache has worsened during the dialysis session
(b) Each headache has resolved within 72hours after the end of the dialy-
sis session
3. Headache episodes cease altogether after successful kidney transplantation
and termination of hemodialysis
D. Not better accounted for by another ICHD-3 diagnosis.
Note: Caffeine is rapidly removed by dialysis: 8.3.1 Caffeine-withdrawal head-
ache should be considered in patients who consume large quantities of caffeine.
39.7 Diagnostic Algorithm
Step 1: Identication of Headache in Hemodialysis Patients
• Presence of recurrent headache episodes during hemodialysis sessions.
Step 2: Identication of Differential Diagnoses
• Monitor blood pressure before, during, and after hemodialysis.
• Differentiate from hypertensive crisis headache without hypertensive encephalopathy (acute systolic BP ≥180mm Hg and/or diastolic BP ≥120mm Hg),
per ICHD-3 criteria 10.3.2.
• Ensure the patient does not consume excessive caffeine (dened as ≥6 cups
of coffee/day) [19, 29].
• If the patient presents with severe symptoms of dialysis disequilibrium syndrome, such as altered consciousness or seizures unexplained by electrolyte
disturbances, brain imaging is warranted.
Step 3: Conrmation of ICHD-3 Diagnostic Criteria
Step 4: Identication of Predisposing Factors
• Assess for signicant electrolyte imbalances (sodium, magnesium, urea, calcium) before and during hemodialysis.
• Monitor weight and hydration status pre- and post-hemodialysis, as large
uctuations predispose to headache.
376
• Observe blood pressure variability, as both pre-dialysis hypertension and
intradialytic hypotension are contributing factors.
A. L. de LimaAntoniazzi and A. C. J. Santos
39.8 Management ofDialysis Headache
The management of dialysis headache primarily focuses on identifying and mitigating predisposing factors. Current recommendations include limiting excessive caffeine intake, maintaining appropriate uid balance, and optimizing blood pressure
and electrolyte levels. However, research on specic pharmacological treatments
remains limited [10].
Anecdotal reports suggest that caffeine may be benecial for alleviating acute
symptoms. However, a recent randomized controlled trial failed to demonstrate a
higher incidence of headache among caffeine consumers [30]. Additionally, there
are reports of symptomatic relief with dipyrone, a non-narcotic analgesic with antipyretic and antispasmodic properties. While dipyrone is widely used in Brazil, its
availability is restricted in several countries [17, 31].
The role of triptans in dialysis headache remains unexplored, as does the use of
nonsteroidal anti-inammatory drugs (NSAIDs), which are generally avoided in
patients with chronic kidney disease due to potential nephrotoxicity and cardiovascular risks. Although a case report described headache relief with dihydroergotamine [32], ergot alkaloids are contraindicated in this patient population due to the
risk of arteriovenous stula thrombosis.
Evidence regarding prophylactic treatment is similarly scarce. One report suggested potential benets from chlorpromazine and angiotensin-converting enzyme
inhibitors [33]. Additionally, anecdotal accounts describe the use of topiramate,
nortriptyline, and amitriptyline [31], though robust clinical data are lacking.
To date, CGRP-blocking monoclonal antibodies have not been investigated as a
prophylactic treatment for dialysis headache. Given their pathophysiological rationale, they represent a promising therapeutic option. Studies by Alessandri etal. [20]
and Gursoy etal. [21] have strongly implicated CGRP in dialysis-related headache,
providing a solid foundation for future clinical trials exploring anti-CGRP therapies
as a potential prophylactic strategy.
39.9 Conclusion
Dialysis headache remains a prevalent yet underrecognized complication of hemodialysis, with multifactorial pathophysiology and signicant implications for patient
quality of life. Although progress has been made in understanding its mechanisms,
further research is needed to optimize preventive and therapeutic strategies.
Enhanced recognition and targeted interventions can potentially improve the wellbeing of patients undergoing hemodialysis.
39 Dialysis Headache
377
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A. L. de LimaAntoniazzi and A. C. J. Santos
Chapter 40
Headache Attributed
toPheochromocytoma
ChristinaI.Deligianni andTheodorosMavridis
40.1 Introduction
Pheochromocytomas are rare neuroendocrine tumors that secrete catecholamines
and arise from the adrenal medulla, representing approximately 80–85% of such
neoplasms [1]. When these tumors originate instead from extra-adrenal chromafn
cells of the sympathetic or parasympathetic ganglia in the chest, abdomen, pelvis,
head, or neck, they are referred to as paragangliomas [2]. Τhey are responsible for
producing excessive amounts of catecholamines (adrenaline, noradrenaline, dopamine) and their metabolites (metanephrines, normetanephrines) These tumors,
though uncommon, are of signicant clinical importance due to their potential to
cause life-threatening hypertension and a wide range of systemic clinical manifestations, and because they represent a potentially treatable condition. Among the various symptoms, headache is a frequently reported complaint in patients with
pheochromocytoma [2]. This chapter provides an overview of the disease, exploring
the mechanisms underlying headache in pheochromocytoma individuals, its variant
clinical presentations, diagnosis assessment, and management strategies.
C. I. Deligianni (*)
Neurology Department, Athens Naval Hospital, Athens, Greece
1st Department of Neurology, Eginition Hospital, National and Kapodistrian University of
Athens, Athens, Greece
T. Mavridis
Neurology Department, Tallaght University Hospital, Dublin, Ireland
Switzerland AG 2026
D. Uludüz et al. (eds.), Rare Causes of Headache Disorders, Headache,
https://doi.org/10.1007/978-3-032-10242-3_40
379© The Author(s), under exclusive license to Springer Nature
380
C. I. Deligianni and T. Mavridis
40.2 Pathophysiology
ofPheochromocytoma-Related Headaches
The pathophysiology of headache induction in pheochromocytoma is not fully
understood. It is primarily related to the excessive secretion of catecholamines, such
as epinephrine and norepinephrine, particularly during paroxysmal episodes of hormone secretion, leading to vasoconstriction and an abrupt rise in blood pressure.
High blood pressure results in endothelial damage, leading to alterations in cerebral
blood ow, which in turn may induce headaches [3]. Other potent vasodilator agents
secreted by the adrenal gland, such as adrenomedullin, which belongs to the calcitonin gene-related peptide (CGRP) superfamily of vasoactive peptide hormones
could induce headache, via the activation of the trigeminovascular system, which is
also activated by high levels of catecholamines (dopamine and norepinephrine) in
the synaptic dopaminergic and noradrenergic clefts of pain matrix pathways [4, 5].
40.3 Case Presentation
A 22-year-old non-smoker male with no previous medical history presented to the
emergency department with a severe, right-sided, throbbing headache lasting 76h.
The pain was rated as 10/10in intensity and accompanied by photophobia, phonophobia, and persistent nausea. He denied prior episodes of similar headaches. There
was no trauma, fever, or illicit drug use. His family history included his mother suffering from chronic migraine. He received oral sumatriptan 50mg and naproxen
500mg twice daily and metoclopramide 10mg four times daily for nausea over 4
days at home without meaningful relief. In the emergency department, pain
improved only slightly to 7–9/10. On examination, he was diaphoretic with a blood
pressure of 220/122mmHg, heart rate 95bpm, oxygen saturation (SpO₂) 99%, and
temperature 36.8°C.The neurological examination revealed only a ne tremor in
the upper limbs, with no focal neurological decits. Due to the absence of a headache history and the presence of red ag symptoms (neurological signs, systemic
involvement, and new headache), further evaluation was necessary. Routine blood
tests and magnetic resonance imaging (MRI) of the brain were unremarkable.
Despite symptomatic treatment with intravenous dexketoprofen and dexamethasone
(which reduced pain to 2/10), blood pressure remained elevated at 200/110mmHg.
Given the triad of headache, sustained hypertension, and diaphoresis, workup for
pheochromocytoma was initiated. A 24-hour urinary catecholamine prole revealed
elevated metanephrine (600 μg/24h) and normetanephrine (1200 μg/24h). Urine
norepinephrine, epinephrine, and dopamine were also elevated. Contrast-enhanced
computed tomography (CT) of the abdomen and pelvis showed a 5cm right adrenal
mass consistent with pheochromocytoma. Fludeoxyglucose-18-positron emission
tomography (FDG-PET) ruled out metastatic disease or extra-adrenal paragangliomas. Metoclopramide was promptly discontinued due to its potential to precipitate
catecholaminergic crises [6]. The patient was started on an α-blocker with doxazosin, followed by a β-blocker with metoprolol. Blood pressure gradually improved.
40 Headache Attributed toPheochromocytoma
After appropriate preoperative preparation, he underwent successful laparoscopic
adrenalectomy. Histopathology conrmed pheochromocytoma. Postoperatively, the
patient made a full recovery. Antihypertensive medications were tapered and discontinued. He has remained normotensive and free of headache episodes since.
Despite the absence of clinical features suggestive of a hereditary syndrome, genetic
testing for common mutations associated with pheochromocytoma/paraganglioma
(Von Hippel–Lindau [VHL], REarranged during Transfection/multiple endocrine
neoplasia [RET/MEN2], neurobromatosis type 1 [NF1]) was conducted and
returned negative [7].
381
40.4 Case Discussion
This case illustrates the necessity of following the criteria of the International
Classication of Headache Disorders (ICHD) for diagnosing headache syndromes,
particularly when a secondary cause is possible [8]. While migraine-like headaches
and migraine status are typically seen in patients with established migraine, their
occurrence in a patient without prior headache history should prompt evaluation for
secondary causes. The presence of SNNOOP10 red ags appropriately guided further workup [9]. Pheochromocytoma should be considered in patients with episodic
headache, especially when associated with hypertension and autonomic features
[10–12]. Metoclopramide, commonly used for migraine-associated nausea, can provoke hypertensive crises in this context and should be avoided [6]. Early diagnosis
and surgical resection of pheochromocytoma are curative in most cases [13].
Genetic testing remains essential for ruling out syndromic associations, even in
apparently sporadic presentations.
40.5 Headache Characteristics ofPheochromocytoma
Headaches in patients with Pheochromocytoma can vary in presentation. Typically,
these headaches are associated with other classic symptoms of catecholamine
excess, including hypertension, sweating, palpitations, anxiety/ panic-like symptoms, and ushing. It is the most common symptom (39.5%) [14]. It is predominantly characterized by it is paroxysmal manifestation in 51–80% of patients
suffering from pheochromocytoma [8]. Headache intensity is usually severe, the
location is frontal or occipital, and has pulsating or constant features. The duration
of the headache is distinctive, lasting less than 15min in 50% of patients, while in
70% lasts less than an hour. It could be accompanied by anxiety, tremor, visual disturbances, nausea, vomiting, abdominal/chest pain, ashing/blanching face, and
rarely by paresthesias [8]. These symptoms often occur in episodes, with periods of
remission between attacks. Nevertheless, some patients may experience more persistent, non-paroxysmal symptoms. A headache is present in close temporal relation
to a blood pressure rise and improves with normalization of the blood pressure.
382
C. I. Deligianni and T. Mavridis
However, there are cases reported with atypical clinical manifestations of headache
type, mimicking other types of headaches, especially when other systemic symptoms do not accompany them.
40.5.1 Diagnostic Algorithm
Step 1: Clinical Suspicion
• Apply a detailed clinical evaluation including patient’s history, general physical examination, neurological examination, fundoscopy [15]
• Identify Key Symptoms:
– Arterial hypertension, palpitation, anxiety, sweating, ashing/blanching
face during the attack
– Family history of hereditary syndromes: multiple endocrine neoplasia
(MEN) type 2, Von Hippel–Lindau (VHL) syndrome, and neurobromatosis type 1 (NF1)
Step 2: Initial Diagnostic Workup
• Perform brain computed tomography (CT)
– Exclude other causes of thunderclap headache, for example, subarachnoid
hemorrhage (SAH), other intracranial hemorrhages, cerebral venous
thrombosis (CVT), brain tumor, central nervous system (CNS) infections,
posterior reversible encephalopathy syndrome (PRES)
• Perform lumbar puncture (LP)
– If brain CT is not diagnostic
– Measure opening pressure, cell count, protein, glucose, inspect visually
xanthochromia, test for CNS infections
• Perform contrast-enhanced brain magnetic resonance imaging (MRI) and
noninvasive vascular imaging of the head and neck (e.g., magnetic resonance
angiography [MRA], CT angiography [CTA]).
– If brain CT and LP are not diagnostic
– Exclude other diagnoses
Step 3: Biochemical Testing
• Measure plasma or 24-hour urine metanephrine levels [16]
– It is the gold standard for the diagnosis of pheochromocytoma
Step 4: Additional Diagnostic Evaluations
• Perform either contrast enhanced CT or MRI for the initial anatomical localization of the tumor
40 Headache Attributed toPheochromocytoma
383
– Abdomen and pelvis imaging is most commonly used
• Perform functional imaging to clearly establish the diagnosis [17]
– If the tumor is extra-adrenal, additional imaging with
123I- metaiodobenzylguanidine (MIBG) scintigraphy may be helpful for
locating tumors outside of the adrenal glands.
– 18F-FDG PET scan is the most accessible tracer and is playing an increas-
ingly important role in PCC/ PGL imaging [17].
Step 5: Apply ICHD-3 Diagnostic Criteria [8]
A. Recurrent discrete short-lasting headache episodes fullling criterion C
B. Pheochromocytoma has been demonstrated
C. Evidence of causation demonstrated by at least two of the following:
1. Headache episodes in temporal relation to development of the pheochromocytoma, or led to its discovery
2. Either or both of the following:
(a) Individual headache episodes develop in temporal relation to abrupt
rises in blood pressure
(b) Individual headache episodes remit in temporal relation to normaliza-
tion of blood pressure
3. Headache is accompanied by at least one of the following:
(a) Sweating
(b) Palpitations
(c) Anxiety
(d) Pallor
4. Headache episodes remit entirely after removal of the
pheochromocytoma
D. Exclude more suitable diagnoses according to ICHD-3 criteria
Step 6: Conrm Diagnosis
• Combination of clinical suspicion, application of ICHD-3 criteria, biochemical testing, and imaging studies.
Other investigations: Genetic testing may be indicated in certain cases, particularly in patients with familial syndromes, such as multiple endocrine neoplasia
(MEN) type 2. Pheochromocytomas are also associated with mutations in genes
locations: SDHB (succinate dehydrogenase subunit B or complex II of the mitochondrial respiratory chain), SDHC (subunit C), SDHD (subunit D), VHL (Von
Hippel-Lindau), RET (REarranged during Transfection), and NF1 (neurobromatosis type 1), and the very recently reported susceptibility genes SDHAF2 (succinate
dehydrogenase complex assembly factor 2, also called SDH5), TMEM127 (transmembrane protein 127), SDHA (subunit A), and MAX (MYC associated factor X).