Headache & Pain
Migraine: pathogenesis and pathophysiology
Nov. 18, 2022
At vero eos et accusamus et iusto odio dignissimos ducimus qui blanditiis praesentium voluptatum deleniti atque corrupti quos dolores et quas.
This article discusses the approach to headache when presenting in the context of solid organ or hematopoietic stem cell transplant patients, which can include both primary and secondary causes. In this article, the author outlines the epidemiology and etiologies of headache in the transplant population including pharmacotherapies, infection, vascular associations, and miscellaneous causes. Suggestions for management and possible pathophysiological mechanisms are discussed.
• Headache, which can significantly affect quality of life, is common in patients who have received transplants.
• As in the general population, the most common headaches seen in transplant patients are migraine and tension-type headache.
• The best characterized secondary cause of headache in patients who have received transplants is the usage of immunosuppressants such as cyclosporine and tacrolimus.
• Other most important differential diagnoses are infection and intracerebral hemorrhage.
Organ transplantation is 1 of the greatest therapeutic advancements of the second half of the 20th century. Transplants are defined as tissue, including an organ or group of cells, being transferred from a donor to a recipient. They can include solid organ transplantation like a liver or heart but can also include hematopoietic stem cell transplants often used in the treatment of cancer.
Organ transplantation was first referred to in Hindu texts around 3000 BC with skin autografting (25). The first successful human transplant was kidney transplantation between twins in 1954. In 1962, azathioprine started being used for immunosuppression, but over time due to persistent morbidity and mortality other agents were tried.
By 1983, the triple therapy of cyclosporine, azathioprine, and corticosteroids became the preferred therapy for allograft transplantation. Since that time, further innovations in immunosuppression have included agents such as tacrolimus, mycophenolate, sirolimus, and others.
The concept of headache in transplant patients does not have a clear history and in general is poorly documented in terms of clinical features. There are multiple etiologies that can be identified including many secondary causes. It is known that headache can significantly impact the quality of life in patients with history of transplant. The association between headaches and transplant patients is not well understood and more clinical studies are needed.
Headaches occurring in transplant patients are often poorly described in the literature. Many of the headaches have clinical features of migraine or tension-type headaches. Of headaches occurring in transplant patients, there are important secondary headache diagnoses to consider often related to immunosuppressant medications. However, even secondary headaches tend to have a phenotype consistent with a primary headache disorder such as migraine, or they may have red flag features like thunderclap onset or positional exacerbation.
The presentation of primary headache disorders can be reviewed in detail and associated articles and diagnostic criteria can be accessed at http://ichd-3.org, which contains internationally accepted criteria. Briefly, migraine criteria require at least 5 attacks of a headache lasting 4 to 72 hours if untreated. The characteristics should be at least 2 of unilateral, pulsatile quality, moderate to severe pain, and/or negatively affecting routine activity. Associated features required at least 1 of nausea (+/- vomiting) or the combination of photophobia plus phonophobia. Importantly, the criteria require that no better diagnosis is identified, as secondary headaches can present like migraine. It should be noted that aura is seen in one third of migraine, which includes most commonly visual aura, sensory aura, and language aura. A migraine lasting beyond 72 hours is considered status migrainosus.
Both tension-type headache and many secondary headaches may alternatively present with a headache lasting 30 minutes to 7 days with at least 2 of bilateral location, nonpulsatile pain, mild to moderate intensity, and not affecting routine activity. It should not have nausea, vomiting, or the combination of photophobia plus phonophobia. Again, this presentation requires secondary causes be considered.
The differential diagnoses that can be considered in the setting of transplant patients may include certain red flags that guide diagnosis; however, the immunosuppressed state itself is a red flag in these patients. An excellent mnemonic to consider when assessing these patients for differential diagnosis is the SNOOP4 approach (12):
S = Systemic symptoms and signs: consider constitutional symptoms like meningismus, fever, and chills, which can be seen in setting of certain drug toxicities and infection.
N = Neurologic symptoms and signs: new onset headache with associated neurologic deficits, seizures, or change in mental status warrant investigation for secondary causes.
O = Onset sudden: thunderclap headache is a 10/10 headache peaking from 0/10 in seconds. It raises concern for vascular etiologies like subarachnoid hemorrhage or reversible cerebral vasoconstriction syndrome.
O = Onset after age 50 years: if a transplant patient is more than 50 years of age and has no history of preceding headache, further concern is raised for a secondary cause.
P1 = Progressive headache: if headache progresses from intermittent to loss of headache-free intervals, consider a progressive cause like a mass lesion.
P2 = Precipitated by Valsalva: if a headache is precipitated by Valsalva or cough, workup for a secondary cause is needed as there may be increased or decreased intracranial pressure.
P3 = Postural headache: a headache that worsens when supine is concerning for increased intracranial pressure. A headache that worsens when sitting or standing is concerning for intracranial hypotension typically from a CSF leak such as postlumbar puncture.
P4 = Papilledema: every single patient presenting with headache needs to be assessed for papilledema, which can signify increased intracranial pressure including the possibility of idiopathic intracranial hypertension. Other associated features to ask about include transient visual obscuration (vision suddenly darkens often on postural change), diplopia, tinnitus (especially pulsatile), visual blurring, and visual field defects.
Following transplant, patients may report an increased frequency or intensity of their headache, and new onset headache has variable incidence in the literature (49; 13). Kidney transplant and headache seem particularly associated with studies showing that 65.5% to 70% of pre-kidney transplant patients have headache (46; 47). One study of 110 kidney transplant patients were diagnosed pretransplant with migraine (38.2%) and dialysis headache (14.5%) with posttransplant changes of 27.3% with full resolution, 19.1% with improvement, and 7.2% with worsening (47). Another study of 50 patients found that 83% improved despite only 20% being related to dialysis headache; in particular, 52% had improvement and 15% had resolution (46). Of those patients with a new headache syndrome, the majority are consistent with a migraine phenotype (15; 45). Headache associated with calcineurin inhibitors like cyclosporin or tacrolimus are the most commonly described secondary headaches but the associated clinical description is variable. Migraine-like headaches may occur de novo or may be exacerbated with cyclosporine introduction or even years later (28). Some case series have even described associated aura (41). A study of allogeneic hematopoietic stem cell transplantation of 971 patients found that 13% had headache posttransplant (04). The majority of transplant patients with headache describe a mild to moderate course that is often transient, but one third of presentations are severe with significant disability (45; 40) Cases of calcineurin inhibitor toxicity can include symptoms and signs in addition to headache such as tremor, encephalopathy, posterior reversible encephalopathy syndrome, peripheral nerve presentation, and seizures, among other presentations (32).
Prognosis is dependent on the underlying etiology. Headache in this population can be mild and transient but may herald a life-threatening cause. In particular patients with infectious and vascular causes of headache can have poor and even fatal outcomes (04).
A 63-year-old female patient presented to a headache clinic 3 years after allograft liver transplant due to cryptogenic cirrhosis. Eight months prior to presentation, she developed headaches twice monthly. By the time of presentation, headaches were occurring daily. Half were preceded by a 1-hour visual aura with word finding difficulties on 2 occasions. The headache was often unilateral but could be holocephalic. It was throbbing, severe, worse with physical activity, and associated with nausea, photophobia, and phonophobia. Initially, it lasted hours but over time became continuous.
Two weeks prior to presentation in clinic, she described an abrupt onset of headache with mild aphasia requiring emergency room assessment and admission. MRI demonstrated no abnormalities. The severe headache resolved while she was in the hospital, but she was found to have polycythemia, chronic renal failure, and hypertension. Her max in-hospital blood pressure was 190/90. Her past medical history was significant for the transplant, which was complicated by upper gastrointestinal bleeding, intraparenchymal cerebral hemorrhage from coagulopathy, 2 episodes of dermatomal zoster, transplant rejection resolving with immunosuppressant modification, and idiopathic pruritus. She was on chronic anticoagulation for a celiac vascular plexus abnormality. Over 2 years, she had developed hypertension and left renal artery stenosis-induced chronic renal failure responsive to left renal artery angioplasty. Prior surgical history included hysterectomy and cholecystectomy. Family history was remarkable for migraine headaches in her brother, a son, and a daughter.
The patient had a prior history of headaches in her early adult years consistent with migraine. These headaches subsided in her 30s.
At the time of presentation, medications included tacrolimus 2 mg orally twice daily, sirolimus 4 mg orally daily, amitriptyline 50 mg orally nightly, metoprolol 75 mg orally twice daily, amlodipine 10 mg orally daily, atorvastatin 10 mg orally daily, omeprazole 10 mg orally daily, warfarin daily for INR 3.5 to 4, docusate sodium 100 mg orally daily, and lamivudine 150 mg orally daily. Tacrolimus was started 2 years prior to presentation at 10 mg per day, and this dose was consistent until after the headaches began. Following the onset of headaches, tacrolimus was decreased gradually by the patient’s transplant specialist. Sirolimus had been introduced 1 month ago and increased to the present dose. Prior to presentation, the patient had previously taken cyclosporine, prednisone, and azathioprine without headaches.
Examination in the headache clinic demonstrated normal cognitive functioning and a normal neurologic examination.
Trough tacrolimus levels measured at the time of headache initiation were slightly high (15.3 ug/L, therapeutic range 5 to 15 ug/L). Tacrolimus was further weaned and discontinued 3 weeks later. Sirolimus was increased to 5 mg twice daily. Within 1 week of tacrolimus discontinuation, headaches fully resolved, and she remained headache-free.
Primary headache disorders
• Tension-type headache
• Other primary headache disorders
Secondary headache disorders
• Headache attributed to long-term use of nonheadache medication
- Most commonly described with cyclosporin, tacrolimus, and OKT3
• Caffeine-withdrawal headache
- Consideration especially in chronic kidney disease patients consuming large caffeine volumes prior to dialysis, which is then rapidly removed by dialysis
• Dialysis headache
- Consideration especially in chronic kidney disease patients pretransplant or those patients posttransplant needing hemodialysis
• Headache attributed to infection
- Infections are particularly common in this population due to immunosuppression, and may be associated with headache
• Headache attributed to nontraumatic intracranial hemorrhage
- Hemorrhages, including intracranial (parenchymal) hemorrhage, subarachnoid hemorrhage, and subdural hemorrhage have all been described in the posttransplant period. Causes vary but can include underlying coagulopathy.
- Posterior reversible encephalopathy syndrome has been extensively described in transplant patients in part due to hypertensive episodes and medications like the calcineurin inhibitors. Headache, often sudden, is a frequent component of the presentation.
- Idiopathic intracranial hypertension has been described at the case report level in particular with renal transplant. The reason for the association is not known.
- CSF leak/intracranial hypotension is occasionally mentioned in the literature. Given the frequency of lumbar punctures in this population, this etiology should be considered especially in positional headache and/or new onset subdural hematomas or hygromas (31).
- Reversible cerebral vasoconstriction syndrome has been described in the setting of transplant and may in part relate to certain medications like tacrolimus (24).
- Other syndromes can be seen in patients with history of transplantation of which headache may be 1 feature. These include immune reconstitution inflammatory syndrome, engraftment syndrome (in stem cell transplantation), zoster without rash, posttransplantation lymphoproliferative disorder, and graft-versus-host disease (33; 34).
- In patients with chronic pain on long-term analgesia, especially opioids, consider medication overuse headache as a contributing etiology.
Headache has been reported in 2% to 50% of patients after transplant (49; 13). This variability has not been well explained, though Zivkovic and colleagues did theorize that their population had higher rates due to high tacrolimus doses for intestinal transplant and history of chronic abdominal pain on long-term analgesia. The age of presentation is variable including childhood presentations (45). Systematic review suggests that headaches are more common with tacrolimus over cyclosporine with a relative risk of 1.23 (48).
In terms of the type of headache presentation, the etiologies are variable in the literature and often no clear diagnosis is provided. Many of the cases described have not been assessed by neurology. In those with clearer descriptions, a migraine-like presentation is seen in one to two thirds (15; 45; 46). In renal transplant patients, a bivariate analysis identified headaches, along with emotional or psychological problems, to have the largest impact on quality of life. When analyzed with a multivariate analysis, headache had the largest adverse quality-of-life effect (29).
Caution must be taken in the diagnosis and management of all transplant patients due to their immunosuppressed state. Appropriate microbial prophylaxis and workup is required as relevant to each case.
In those with a prior history of a primary headache disorder, consider prophylaxis optimization and clarify preceding baseline. In those on analgesia for chronic pain, weigh the pros and cons of frequent analgesia given the potential to develop medication overuse headache.
The differential diagnosis must include primary and secondary headaches. The secondary causes will be discussed here including headache attributed to medication, vascular etiologies, infections, and other miscellaneous causes.
Headache attributed to long-term use of nonheadache medication. The diagnostic criteria for this headache disorder as available in the ICHD-3 are as follows:
(A) Headache present on ≥ 15 days/month (and meets criterion C)
1. Headache develops with start of medication use
(a) Headache worsens with increased dose
(D) Medication is a recognized cause of headache
Multiple medications used in the setting of transplant could meet these criteria but the best described are the calcineurin inhibitors cyclosporine and tacrolimus. These are medications that have also been associated with triggering other secondary causes of headache like posterior reversible encephalopathy syndrome. A monoclonal antibody, OKT3, has also been associated with headache as well as aseptic meningitis.
Cyclosporine. Cyclosporine is an immunosuppressive drug used frequently in patients with organ transplantation. The mechanism of action of cyclosporine is inhibition of T-cell mediated alloimmune and autoimmune response, as well as diminishment the total number of thymocytes and active T-cells (22). Migraine-like headaches may start or be exacerbated after introduction of cyclosporine (28). In particular, patients susceptible to migraine experience increased severity and frequency of headaches when using cyclosporine therapy (41; 39). Intractable cyclosporine-induced headache may necessitate reducing or even discontinuing the medication (38). Headache appearance may not be associated with elevated cyclosporin level. Cyclosporine-associated headache is often refractory to simple analgesia though there are case reports of response to various migraine prophylactic agents as well as sumatriptan (41).
Tacrolimus. Tacrolimus, another calcineurin inhibitor, is a well-documented cause of headache. Tacrolimus binds to FK 506-binding proteins (FKBP) to produce inhibition of activation of phosphatase calcineurin by calcium-calmodulin (27). Some studies suggest that tacrolimus is the more likely cause of headaches (48). Otherwise, the headache from calcineurin inhibitors is variable, can be new onset or worsening of previous headache, and can vary in disability. Headaches can appear with normal or low tacrolimus levels, though levels may better correlate with tacrolimus compared to cyclosporine (28; 23). A review of 7 studies found the rate of headache was similar between tacrolimus dosing as once daily versus twice daily (08).
Muromonab CD3 (also called OKT3). OKT3, which modulates the CD3 portion of T-cell antigen receptors, was the first monoclonal antibody for solid organ transplantation (16). It has been associated with headache in isolation or as part of a cytokine release syndrome seen within 1 hour of the first dose. It can last 4 to 6 hours with associated fever, shortness of breath, and nausea. Less commonly, it can present as an aseptic meningitis (38). Usually the presentation is mild, but life-threatening presentation can be seen with seizures, encephalopathy, and thrombotic events. Risk factors for a more severe presentation include fluid overload, diabetes, poor renal function, higher dose, neurologic disease, hyponatremia, and hypocalcemia (35). A case of syndrome of transient headache and neurologic deficits with cerebrospinal fluid lymphocytosis (HaNDL) has also been described (43).
Caffeine-withdrawal headache. Caffeine-withdrawal headache is usually seen 24 hours after last caffeine in a patient who ingests at least 200 mg of caffeine daily for more than 2 weeks. There is no specifically defined headache characteristic other than that it can continue for 7 days until withdrawal is over and usually responds to 100 mg of caffeine within 1 hour. Interestingly, in chronic kidney disease patients needing dialysis (pre- or post-transplant), caffeine is quickly cleared, which can cause a caffeine-withdrawal headache during or after dialysis. One study of 156 patients with headache middialysis did not find caffeine midsession to provide benefit over placebo. Overall, in this study, 35% of patients had headache.
Dialysis headache. This headache occurs in association with hemodialysis developing during the session and resolving within 72 hours. The headache should fully resolve on successful kidney transplant and cessation of dialysis. It is often associated with hypotension, dialysis disequilibrium syndrome, and/or caffeine withdrawal (ICHD-3). In particular, a decline in systolic blood pressure and/or an increase in urea was associated with a 7% increase risk of headache. Risk factors including variations in urea, sodium, magnesium, blood pressure, and body weight. Caffeine-withdrawal as described above can mimic this condition. One study of 100 hemodialysis patients found that 60% of patients had headache, with 41.6% being hemodialysis related, but in those using online hemodiafiltration technique, only 12.5% had dialysis headache (19). A complication of dialysis called dialysis disequilibrium syndrome is reported to have headache in 24.8% of cases (36).
Headache attributed to infection. Patients receiving organ transplantation are vulnerable to infection. These vary based on the type of transplant (solid organ vs. hematopoietic stem cell transplant) as well as the time since transplant. The timing of infectious and other complications posttransplantation is often divided into less than 1 month, 1 to 6 months, and more than 6 months (33; 34).
In the first month posttransplant, preceding chronic infections like mycobacteria or Strongyloides may be exacerbated by starting immunosuppressants (11). Viruses seen around this time include CMV or HHV-6 (32). Other early infections include those transmitted by the allograft or from routine bacterial infections (11). Within months 1 to 6 posttransplant infections start to include entities like aspergillosis, varicella, CMV, cryptococcus, and toxoplasmosis (33). Later in the course after 6 months, similar infections can occur along with progressive multifocal leukoencephalopathy, mucor, West Nile virus, and Epstein-Barr virus-associated posttransplant lymphoproliferative disorder (33; 34).
An acute presentation may have various causes, but listeria is 1 to consider. Other entities may have a subacute course like CMV or mycobacterium. Note that cryptococcal meningitis can have an indolent course in this population with cases described of headaches appearing weeks before other meningeal symptoms (32). Following an infection like cryptococcus, immune reconstitution inflammatory syndrome can occur due to rapid recovery of the host immune system. It can be associated with increased intracranial pressure and CSF may show pleocytosis (32). Infection may also present as a brain abscess such as with aspergillosis (11).
Headache can be associated with infection from COVID-19. Based on systematic review and meta-analysis, COVID-19 appears to occur at a similar rate in patients with a history of solid organ transplantation but has a worse prognosis and a mortality rate 8 times that of the general population (02). This study showed that headache and vomiting were seen in 10% to 20% of patients with COVID-19 in the context of a solid organ transplant.
When it comes to headache from infection, headache may be initially isolated or associated with other neurologic and systemic features. In general, the combination of headache, fever, and nausea suggest infection with higher sensitivity if there is lethargy and/or seizures (20). However, note that when neutropenic, features like fever may be absent (33). In the setting of headache attributed to infection there is either a new onset of headache in close temporal relationship or a preexisting that headache clearly worsens (20). The ICHD-3 has diagnostic criteria for headache in the setting of infection divided into those from an intracranial infection versus a systemic infection. The intracranial infections are further divided according to bacterial, viral, fungal/parasitic, and localized. Some of these are further divided in acute versus chronic, with 3 months being the division. A headache is considered “persistent” if a bacterial meningitis has resolved but headache persists (20).
The headache of an intracranial infection usually has a temporal relationship to the infection often associated with a holocephalic pain and neck stiffness. However, an abscess can have mass effect so it may have characteristics like gradual worsening over time, exacerbation by Valsalva, and ipsilateral pain (20).
Headache attributed to nontraumatic intracranial hemorrhage. Headache due to nontraumatic intracranial hemorrhage is sudden onset, sometimes thunderclap in nature, and may be associated with focal neurologic deficits. Generally, the headache improves parallel to other symptoms of the bleed. The headache is usually maximal on the day of onset. It may be localized to the site of hemorrhage.
These etiology warrant discussion in the setting of transplant as certain populations, particularly bone marrow transplant patients, can be susceptible to intracranial hemorrhage. Subdural hematoma, often bilateral, has been associated with myeloblastic leukemia with risk factors including recent lumbar puncture and prolonged thrombocytopenia (10; 33). An important note here, however, is that these patients get lumbar puncture or intrathecal chemotherapy so are at risk of CSF leak, which can also cause subdural hematoma. This etiology should also be considered in these patients.
Other types of intracranial hemorrhage may also be seen, often early in the transplant course. These are associated with coagulopathy though other causes seen may include infection, hypertension, posterior reversible encephalopathy syndrome, or reversible vasoconstriction syndrome (34; 32; 13).
Posterior reversible encephalopathy syndrome (PRES). Posterior reversible encephalopathy syndrome, also known as reversible posterior leukoencephalopathy syndrome (RPLS), is a diagnosis that can be seen in the transplant population (21). Patients typically present with abrupt onset of headache, nausea, vomiting, confusion, seizures, and cortical blindness (17). Blood pressure surge is common. The course can be benign with resolution of neuroimaging findings, but more severe presentation do occur. The exact mechanism is not clear, but there is an association with immunosuppressants (21).
Idiopathic intracranial hypertension. Idiopathic intracranial hypertension, also known as pseudotumor cerebri, has been described at the case series level in renal transplant. In pediatric patients undergoing renal transplantation, the prevalence of pseudotumor cerebri was 4.4%, and may be related to concomitant medications in some cases, such as nitrofurantoin and minocycline, and weight gain in other cases (18). The key feature in this presentation is headache with papilledema. The headache may be positional (worse supine).
CSF leak/intracranial hypotension. CSF leak/intracranial hypotension is a consideration given the frequent lumbar punctures. Consider this diagnosis if positional headache (better supine). It can present with subdural hematomas or hygromas as noted above. Other imaging signs can be seen on MRI brain or spine.
Reversible cerebral vasoconstriction syndrome. Reversible cerebral vasoconstriction syndrome has been described in the setting of transplant potentially related to immunosuppressants like tacrolimus (24). Consider if recurrent thunderclap headache is present and there is evidence of vasospasm on neuroimaging. It can self-resolve but may cause focal ischemia or subarachnoid hemorrhage.
Immune reconstitution inflammatory syndrome (IRIS). Immune reconstitution inflammatory syndrome is a potential complication often seen after an infection like cryptococcal meningitis. It is due to a proinflammatory response often seen with reduction of immunosuppressants in association with infection and can lead to rejection. A CNS presentation should be considered if neuroimaging shows new or worsening inflammatory signs, symptoms despite appropriate microbial treatment, and the infectious workup is negative or stable. Potential neuroimaging signs include leptomeningeal enhancement, mass lesion, and signs of increased intracranial pressure. CSF may show a pleocytosis and/or raised opening pressure (32). Headache may be a feature.
Engraftment syndrome. Engraftment syndrome is a potential complication of stem cell transplantation with rash, fever, and headache occurring in the first month posttransplantation. Other etiologies like posttransplant acute limbic encephalitis (PALE) should be ruled out (33).
Zoster without rash. Zoster without rash, including trigeminal distribution, can occur in this population but dermatomal rash with risk of postherpetic neuralgia is more common. Other zoster complications can include infarction. Pain from zoster is usually neuralgiform and dermatomal in nature (33).
Graft-versus-host disease (GVHD). Graft-versus-host disease can be acute or chronic, with the difference being a 100-day cutoff point. CNS presentations are rare and normally from the chronic form of graft-versus-host disease. It should respond to immunosuppression. Forms include a vasculitis, focal encephalitis, and acute disseminated encephalomyelitis (33). Headache may accompany these presentations.
Posttransplant lymphoproliferative disorders. Posttransplant lymphoproliferative disorders can present with headache. They range from reactive polyclonal lesions to frank lymphomas and have a close relationship with Epstein-Barr virus (03).
Medication overuse headache. Consider medication overuse headache in patients on chronic analgesia for more than 3 months (20). There is often an underlying primary headache disorder like migraine as well.
Headache can present in the context of solid organ or hematopoietic stem cell transplantation from a wide range of primary or secondary headache disorders as described above.
MRI brain. MRI should be considered in all transplant patients with new onset or clear change in headache.
MRI with MRA may help with the diagnosis of an intracranial hemorrhage, though an acute presentation warrants CT imaging for faster results.
Primary headache disorder. The MRI of the brain should be normal but may have nonspecific findings like white matter hyperintensities.
Headache attributed to calcineurin inhibitors. Headache attributed to calcineurin inhibitors will have a normal MRI unless they develop cyclosporine- or tacrolimus-induced encephalopathy. In that case, MRI may demonstrate multiple bilateral focal hyperintensity regions, suggesting focal brain edema (42; 23). Infratentorial structures are often involved (44). Imaging can also be normal in these more severe cases, however (30).
Infectious etiologies. MRI can be normal, have hyperintensities, and show meningeal or lesion enhancement, mass lesion(s), invasive lesions, hemorrhage, and signs of increased intracranial pressure. Arterial imaging may show other features such a mycotic aneurysm or vasculitis. Especially now with the COVID-19 pandemic, ensure COVID-19 testing in transplant patients with new onset headache (06).
Posterior reversible encephalopathy syndrome. Posterior reversible encephalopathy syndrome is usually associated with posterior predominant hyperintensities due to vasogenic edema though other areas including infratentorial can be involved (05).
Elevated intracranial pressure. MRI in the setting of idiopathic intracranial hypertension may be normal but there are classic signs to look for including the empty sella sign, slit-like ventricles, flattening of the posterior globe, protrusion of optic nerve head, distension of optic nerve sheath, and tortuosity of the optic nerve. The most reliable of these signs in 1 study was flattening of the posterior globe (01). These patients should always also have an MR venogram performed to rule out venous sinus thrombosis (07).
CT head. CT head should be performed in the setting of any thunderclap headache. Vascular imaging should be included.
Lumbar puncture. Lumbar puncture is most important to perform in the transplant patient when red flags are present that may suggest infection. Neurologic deficits with headache may also be an indication to evaluate on an individual basis. Particularly in the hematopoietic stem cell population, cytology is also important to rule out CNS involvement. Pleocytosis may be seen in many conditions including immune reconstitution inflammatory syndrome and posttransplant acute limbic encephalitis. Lumbar punctures should include an extensive microbiology panel performed with guidance from an infectious disease consultant. Consider doing opening pressure as idiopathic intracranial hypertension and many infections will have elevations. Note that the opening pressure can be low or normal in a CSF leak. In patients presenting with COVID-19 and new headache, CSF studies are typically negative for SARS-CoV-2, especially if no concurrent evidence of encephalitis (14).
Bloodwork. Bloodwork should include standard testing in the setting of headache with additional testing done on an individual basis. If on a calcineurin inhibitor, consider level testing though headache can still occur if normal or low. Also, testing for COVID-19 via PCR in the setting of new onset headache should be considered, especially if concurrent infectious symptoms or new onset anosmia (37).
Neurologic exam. A full neurologic exam including fundoscopy is required and is the most important part of the workup.
Caffeine-withdrawal. Screen patients for caffeine amount and timing of use. Caffeine should be less than 200 mg per day. In patients still on dialysis, ask about predialysis consumption.
Dialysis headache. Ensure to screen for hypotension and signs of dialysis disequilibrium syndrome. Alterations in dialysate with attention to blood pressure, urea, magnesium, and sodium change may affect the headache. In particular, look for low blood pressure and high urea.
The options for the treatment of migraine are extensive, and discussed elsewhere. Prophylactic treatment can be considered when there are 4 to 8 headache days per month or significant disability. There are many oral and nonoral drug treatments as well as neuromodulation devices. Careful selection is required, especially with oral medications for adverse effect profile and drug-drug interactions. Good nonoral options that do not interact with medications include onabotulinumtoxin A injections for those with headaches at least 15 days a month. There are also the new monoclonal antibodies to consider, though they have not been specifically tested in an immunosuppressed population. The neuromodulation devices are safe but should not been used in those with other devices like pacemakers.
All patients with headache should have an abortive treatment, which may include an antiemetic as needed. Abortive medications should not be used more than 10 days per month, even if analgesia is used for other indications, to avoid development of medication overuse headache. Note that the standard option is triptans, but in many transplant patients like heart transplants these may not be an option due to vasoconstriction. NSAIDs are often not an option as well, but if no contraindication can be considered. Acetaminophen can be used but sparingly in liver transplantation, and can be combined with an antiemetic like prochlorperazine. Devices may alternatively be used for rescue treatment. Opioids are not recommended in the treatment of headache.
Lifestyle management should also be considered by optimizing hydration, diet, exercise, and caffeine intake. Stress and mood disorder management are important as well. Consider nonpharmacologic treatment strategies like biofeedback, cognitive behavioral therapy, and mindfulness.
If headache is persistent, has red flags, and/or is severe consider neurologic consultation.
Headache attributed to long-term use of nonheadache medication. If headache is attributed to cyclosporine consider a dose decrease or switch to another agent. If headache is attributed to parenteral tacrolimus, try an oral formulation. If headache is attributed to oral tacrolimus, try to decrease dose or switch to a different agent (38). Switching between cyclosporine and tacrolimus may work, however, in the literature as successful cases often switch to an alternative agent like sirolimus. If unable to switch, migraine prophylactic agents have been tried with variable success in the literature, and if there are no contraindications to triptans sumatriptan could be tried for abortive treatment. If disabling or frequent, consider neurology consultation.
In the setting of headache from OKT3, case report level evidence suggests some benefit if pretreating with hydrocortisone and an antihistamine (38).
Caffeine-withdrawal headache. Keep caffeine use to less than 200 mg per day and avoid prior to dialysis for chronic kidney patients on dialysis.
Dialysis headache. Dialysis headache by definition should resolve upon kidney transplantation and/or cessation of dialysis. A retrospective study of chronic kidney disease patients on dialysis prior to transplant, of which 14.5% had dialysis headache, noted that overall greater than 50% of patients improved posttransplantation (47). Medications noted to be beneficial for both migraine and dialysis headache subgroups in this study were steroids, beta blockers, and calcium channel blockers.
Headache attributed to infection. Infectious disease should be consulted, and appropriate management provided empirically and then based on the underlying infectious etiology. Headache can also occur as a postinfection presentation, which has been described with COVID-19 during the recent pandemic, with one systematic review and meta-analysis of long COVID presentation identifying headache in 44% (26). If persistent headache, agents used for the treatment of migraine can be tried and neurologic consultation considered.
Headache attributed to nontraumatic intracranial hemorrhage. Consult neurology and/or neurosurgery. If evidence of raised intracranial pressure, manage acutely as needed. Persistent headache beyond the acute/subacute time period can be treated with prophylactic agents with neurology’s assistance.
If there are subdural hematomas with previous lumbar puncture or intrathecal chemotherapy assess for the possibility of a CSF leak, especially if considering surgical management of subdural hematoma.
Posterior reversible encephalopathy syndrome (PRES). Neurology consult is recommended. Review medications like calcineurin inhibitors for possible discontinuation, though no clear guidelines for management exist. Optimize blood pressure. Exclude other causes and precipitants.
Idiopathic intracranial hypertension. Consult neurology and rule out a secondary cause. The primary goal of treatment is prevention of vision loss. Drug treatments may include acetazolamide (07). Identify precipitants. Weight loss can be beneficial if felt to be safe. Refractory cases may need surgical management.
CSF leak/intracranial hypotension/postlumbar puncture headache. It can be self-limited. Lying supine often improves the pain. If able, increase hydration, salt intake and caffeine.
Persistent postlumbar puncture can be treated with an epidural blood patch if there are no contraindications. Other surgical techniques can be considered if warranted. If subdural hematoma is present, these typically improve with treatment of the CSF leak.
Reversible cerebral vasoconstriction syndrome. Consult neurology and consider a calcium channel blocker like nimodipine (09). Medications like triptans, which are vasoactive, should be avoided in this setting.
As a general approach, persistent headache can be managed with migraine treatment on an individual basis. These patients should be referred to neurology for assistance in management and to ensure secondary causes have been ruled out.
The outcomes of headache in transplant patients are likely dependent on the causes. For patients with headache due to medications, there is usually resolution after discontinuation of the offending agents, if possible. For serious conditions, early diagnosis and treatment are mandatory. This is particularly true for transplant patients with infection caused by bacteria, fungus, and, rarely, viruses susceptible to antibiotics and antiviral agents.
Jennifer Robblee MD MSc FRCPC
Dr. Robblee of Barrow Neurological Institute received research support from Eli Lilly and AbbVie as principle investigator.See Profile
Shuu-Jiun Wang MD
Dr. Wang of the Brain Research Center, National Yang-Ming University, and the Neurological Institute, Taipei Veterans General Hospital, has no relevant financial relationships to disclose.See Profile
Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.
Headache & Pain
Nov. 18, 2022
Headache & Pain
Nov. 01, 2022
Headache & Pain
Oct. 31, 2022
Headache & Pain
Oct. 31, 2022
Oct. 18, 2022
Oct. 18, 2022
Neuro-Ophthalmology & Neuro-Otology
Sep. 16, 2022
Sep. 07, 2022