NEJMcpc2402484

The n e w e ng l a n d j o u r na l of m e dic i n e
Case Records of the Massachusetts General Hospital
Founded by Richard C. Cabot

Eric S. Rosenberg, M.D., Editor
David M. Dudzinski, M.D., Meridale V. Baggett, M.D., Kathy M. Tran, M.D.,
Dennis C. Sgroi, M.D., Jo‑Anne O. Shepard, M.D., Associate Editors
Emily K. McDonald, Tara Corpuz, Production Editors
Case 18-2024: A 64-Year-Old Woman

with the Worst Headache of Her Life
Jonathan A. Edlow, M.D., Aneesh B. Singhal, M.D., and Javier M. Romero, M.D.
Pr e sen tat ion of C a se

From the Department of Emergency Dr. Gabriella DiCarlo (Neurology): A 64-year-old woman was evaluated in the emer-
Medicine, Beth Israel Deaconess Medi‑ gency department of this hospital because of a sudden onset of the worst headache
cal Center and Harvard Medical School
(J.A.E.), and the Departments of Neurol‑ of her life.
ogy (A.B.S.) and Radiology ( J.M.R.), The patient had been in her usual state of health until the evening of the current
Massachusetts General Hospital and presentation, when she stood up to speak during a meeting for her condominium
Harvard Medical School — all in Boston.
association. Bilateral, frontal, pulsatile headache developed suddenly and reached
N Engl J Med 2024;390:2108-18. maximal intensity within seconds. The patient rated the pain at 10 (on a scale of
DOI: 10.1056/NEJMcpc2402484
Copyright © 2024 Massachusetts Medical Society. 0 to 10, with 10 indicating the most severe pain) and noted that it was the worst
headache pain that she had ever had. The pain was so severe that she could not
CME complete her sentence. She sat down, feeling as though she might faint because
of the severity of the pain. She repeatedly told her husband, “Something is really
wrong.” Nausea developed without emesis. When the symptoms did not abate after
30 minutes, emergency medical services were called, and the patient was trans-
ported to the emergency department of this hospital for evaluation.
On arrival at the emergency department, the patient reported ongoing headache
and nausea. Medical history included hypertension and cervical disk disease with
chronic neck pain. Medications included hydrochlorothiazide and oral conjugated
estrogens, which the patient took every 3 days for symptoms of menopause. She
had no known allergies. She was a lifelong nonsmoker, drank alcohol occasion-
ally, and did not use illicit drugs. She lived with her husband and worked as an
administrative assistant. Her mother had diabetes. There was no family history of
venous thromboembolism.
On examination, the temporal temperature was 36.3°C, the blood pressure
157/77 mm Hg, the heart rate 77 beats per minute, the respiratory rate 16 breaths
per minute, and the oxygen saturation 96% while the patient was breathing ambi-
ent air. The neck was supple. She was oriented to time, place, and person. Her
speech was fluent with intact naming, repetition, and comprehension. Cranial
nerve examination was normal. The visual fields were full on confrontation test-
ing. The visualized portions of the retina were normal in both eyes with normal-
appearing optic disks. Tests of motor strength and sensation showed normal
2108 n engl j med 390;22 nejm.org June 13, 2024
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Case Records of the Massachuset ts Gener al Hospital
results, as did tests of reflexes and cerebellar considering the differential diagnosis of thunder-
function. Blood levels of glucose and electrolytes clap headache, with particular attention to condi-
were normal, as were the complete blood count tions that can also cause convexal subarachnoid
with differential count and the results of tests of hemorrhage.
kidney function and coagulation. Imaging stud-
ies were obtained. Identifying Thunderclap Headache
Dr. Javier M. Romero: Two hours after the onset Two percent of all emergency department visits
of headache, computed tomography (CT) of the involve evaluation of headache,2 and 15% of
head, performed without the administration of those visits involve evaluation of thunderclap
intravenous contrast material (Fig. 1), revealed a headache.3 It is important that patients with
subarachnoid hemorrhage along the left superior thunderclap headache undergo immediate and
parietal lobule and paramedian parietal sulci. thorough evaluation for causes (Table 1), most
Dr. DiCarlo: Treatment with intravenous mor- notably intracerebral bleeding after rupture of a
phine and promethazine was administered. Nau- cerebral artery aneurysm, known as aneurysmal
sea resolved, and the headache pain abated. Four subarachnoid hemorrhage.4-6
hours after the onset of headache, the blood How can providers recognize thunderclap
pressure was 136/45 mm Hg. Additional labora- headache? In patients with preexisting primary
tory studies were obtained. The erythrocyte sedi- headache syndromes, thunderclap headache is al-
mentation rate was 8 mm per hour (reference most always different in character from previous
range, 0 to 20), the blood level of C-reactive episodes of headache. The International Headache
protein 2.7 mg per liter (reference value, <8.0), Society defines a thunderclap headache as a head-
and the blood level of troponin T 0.36 ng per ache that is severe in intensity, abrupt in onset
milliliter (reference value, <0.03). Electrocardi- (peaking in intensity in less than 1 minute), lasts
ography showed sinus rhythm with first-degree at least 5 minutes, and is not accounted for by
atrioventricular block and diffuse submillimeter another diagnosis.1 However, a rigid definition of
ST-segment depressions. thunderclap headache that is based on a time to
Additional testing was performed, and a diag-
nosis was made.
Differ en t i a l Di agnosis
Dr. Jonathan A. Edlow: This 64-year-old woman
had a sudden-onset, severe headache after stand-
ing up to speak at a public meeting. The severity
and tempo of her headache are compatible with
“thunderclap headache.”1 The neurologic exami-
nation and blood levels of inflammatory bio-
markers (platelet count, erythrocyte sedimenta-
tion rate, and C-reactive protein) were normal,
but the blood level of troponin was elevated. CT
of the head that was performed 2 hours after the
onset of headache revealed a convexal subarach-
noid hemorrhage (also known as a convexity
subarachnoid hemorrhage), in which the blood
is located high over the convexities of the cere-
bral cortex, as opposed to around the basal cis-
Figure 1. CT Scan of the Head, Obtained during the
terns — the typical pattern for aneurysmal
Initial Presentation.
subarachnoid hemorrhage. In developing a dif-
An axial image from CT of the head, obtained without
ferential diagnosis, three key elements of this the administration of intravenous contrast material,
case need to be explained: the thunderclap head- shows subarachnoid hemorrhage in the convexity of
ache, the convexal subarachnoid hemorrhage, the superior parietal lobule (arrow).
and the elevated troponin level. I will begin by
n engl j med 390;22 nejm.org June 13, 2024 2109

peak intensity of less than 1 minute can result a normal neurologic examination, 5 to 7% have
in missing important diagnoses, including an- aneurysmal subarachnoid hemorrhage, which
eurysmal subarachnoid hemorrhage. Case series makes diagnostic imaging imperative.3,5,11
of persons presenting with thunderclap head- The first step in the evaluation for aneurysmal
ache suggest that approximately 15% of patients subarachnoid hemorrhage is CT of the head.4,12,13
who eventually receive a diagnosis of aneurys- If such imaging is performed within 6 hours
mal subarachnoid hemorrhage described head- after the onset of thunderclap headache, the
ache that peaked in intensity after 1 minute, and sensitivity of head CT to detect subarachnoid
in some instances, up to 60 minutes later.5,7 In hemorrhage approaches 100%14 but decreases
addition, patient recall about such small incre- with time owing to the brisk circulation of cere-
ments of time can be imprecise. In my practice, brospinal fluid. This patient’s head CT identified
I always ask about the onset of symptoms in a convexal subarachnoid hemorrhage. Although
patients presenting with headache, and I pro- subarachnoid hemorrhage from a ruptured ce-
ceed with an evaluation for causes of thunder- rebral aneurysm almost never causes convexal
clap headache in all patients with rapid-onset, subarachnoid hemorrhage, aneurysmal subarach-
severe headaches without using any specific time noid hemorrhage remains a possible diagnosis in
cutoff.4 this case and needs to be ruled out by CT angiog-
This patient’s headache pain decreased after raphy of the head.15 Most of the uncommon or
treatment with intravenous morphine and pro- rare causes of subarachnoid hemorrhage can be
methazine. However, successful pain relief should reasonably ruled out on the basis of clinical fac-
not preclude evaluation for serious causes of tors (Table 1). I will focus on causes of thunder-
thunderclap headache.8,9 Pain control is appropri- clap headache that are commonly associated with
ate to improve patient comfort. It can also help convexal subarachnoid hemorrhage, which is an
distinguish whether hypertension is driven pri- important diagnostic clue to focus the differential
marily by pain (in which case blood pressure diagnosis.
improves with pain control) or by autoregulation
to preserve cerebral blood flow in an injured or Reversible Cerebral Vasoconstriction
ischemic brain (in which case blood pressure Syndrome
does not improve with pain control). Still, evalu- Reversible cerebral vasoconstriction syndrome
ation for causes of thunderclap headache should (RCVS) is characterized by fluctuating and revers-
occur in parallel with pain control. ible narrowing of the intracranial arteries and
occurs more commonly in women than in men.
Aneurysmal Subarachnoid Hemorrhage Although RCVS is far less well known than aneu-
As an emergency physician evaluating a patient rysmal subarachnoid hemorrhage, reports suggest
with thunderclap headache, I focus on ruling out that it is the cause of thunderclap headache in
“cannot miss” diagnoses — those for which ef- approximately 8% of patients presenting to the
fective treatment exists and outcomes are worse emergency department for evaluation of such
without treatment.10 The most important “can- headache (personal communication: W. Kim).16,17
not miss” cause of thunderclap headache is an- The term thunderclap headache may actually even
eurysmal subarachnoid hemorrhage, a medical have a historical connection to RCVS. An early
emergency associated with high morbidity and case report described a woman who presented
mortality without timely treatment.4-6 with recurrent, sudden-onset, severe headache.
This patient had systolic hypertension on Cerebral angiography revealed diffuse vaso-
presentation, a finding that is also common spasm but also a carotid artery aneurysm that
among patients with aneurysmal subarachnoid was considered to have caused the headache and
hemorrhage. She did not have other symptoms was subsequently clipped; 1 month later, the
or signs associated with aneurysmal subarach- results of cerebral angiography were normal.18
noid hemorrhage, such as neck pain or menin- At the time of the case report, RCVS had not yet
gismus, although early in the course, the pres- been described. In retrospect, that patient al-
ence of meningismus would be unusual. However, most certainly had RCVS with an asymptomatic
headache may be an isolated finding. In patients carotid artery aneurysm.
who present with thunderclap headache and have Patients in whom RCVS has been diagnosed

typically report multiple thunderclap headaches Posterior Reversible Encephalopathy

that occur over a period of a few days to weeks. Syndrome
There is usually an emotional, physical, medical, Posterior reversible encephalopathy syndrome
or pharmacologic trigger (Table 2). If this pa- (PRES) is another uncommon cause of thunder-
tient was unaccustomed to public speaking, it is clap headache that can also cause convexal sub-
plausible that addressing her condominium as- arachnoid hemorrhage.22,28 However, headache
sociation could have provoked anxiety and sym- that occurs in patients with PRES usually devel-
pathetic hyperactivity that would be sufficient to ops gradually and is not abrupt in onset. In ad-
trigger RCVS. In addition, roughly 35% of pa- dition, seizures, vision symptoms, and altered
tients with RCVS have convexal subarachnoid mentation are common features associated with
hemorrhage.19-21 In fact, among patients without PRES, and this patient did not have any such
head trauma, RCVS is one of the most common symptoms.32,33 Overall, PRES is unlikely to ex-
causes of convexal subarachnoid hemorrhage.22-25 plain this patient’s presentation.
A diagnosis of RCVS could explain both thun-
derclap headache and convexal subarachnoid Accounting for the Troublesome Troponin
hemorrhage in this patient. My suspicion for Level
RCVS would be even higher if she had presented Aortic dissection and myocardial infarction are
with recurrent thunderclap headaches. However, rare causes of thunderclap headache but are im-
it is important to keep in mind that every second portant considerations in this patient who had a
or third headache must have been preceded by troponin level that is 10 times the upper limit of
a first one. the normal range. “Painless” aortic dissection is
uncommon. Without the presence of chest or
Cerebral Venous Sinus Thrombosis back pain or clinical or laboratory evidence of
Thunderclap headache is a presenting symptom brain, gut, kidney, or limb ischemia, it is highly
in 15% of patients with cerebral venous sinus unlikely (albeit still possible) that this patient
thrombosis (CVST).26,27 CVST is a possible diag- has aortic dissection.34
nosis in this patient, since it could also account Is this patient having a myocardial infarction?
for the finding of convexal subarachnoid hemor- Electrocardiography showed borderline first-
rhage.22,28 In addition, although the patient did degree atrioventricular block and diffuse sub-
not have a family history of venous thromboem- millimeter ST-segment depressions, but there
bolism, her use of conjugated estrogens is a risk were no findings that would be diagnostic of a
factor for CVST.29 myocardial infarction. I would obtain serial elec-
trocardiograms and troponin levels. However,
Arterial Dissection neither aortic dissection nor myocardial infarc-
Arterial dissection is an uncommon cause of tion would explain the patient’s convexal sub-
thunderclap headache, but it is an important arachnoid hemorrhage.
consideration in this patient because arterial dis- The most likely explanation for the elevated
section can also cause convexal subarachnoid troponin level in this patient is takotsubo car-
hemorrhage.30 However, convexal subarachnoid diomyopathy; this condition has been associated
hemorrhage due to arterial dissection is report- with RCVS, which suggests that vasoconstriction
ed primarily in postpartum persons and in per- in patients with RCVS may not be limited to the
sons with dissection that has caused ischemic cerebral arteries.35,36 This patient fits the typical
stroke, neither of which fit with this patient’s epidemiologic profile of takotsubo cardiomyopa-
presentation.19,30 In addition, thunderclap head- thy. In an international registry of 1750 patients
ache is not a typical manifestation of arterial with takotsubo cardiomyopathy, 90% were wom-
dissection. In a case series that included 970 en and the mean age was 67 years.37
patients with arterial dissection, only 3.6% of RCVS with takotsubo cardiomyopathy is the
the patients with carotid artery dissection and most likely diagnosis that would explain thun-
9.2% of those with vertebral artery dissection derclap headache, convexal subarachnoid hem-
had presented with thunderclap headache.31 Al- orrhage, and an elevated blood level of troponin
though unlikely, arterial dissection remains a in this patient. However, aneurysmal subarach-
possible diagnosis in this patient. noid hemorrhage must still be ruled out. I would

Table 1. Differential Diagnosis of Thunderclap Headache.
Condition Clinical Considerations in This Patient Standard Diagnostic Testing

Common causes
Aneurysmal subarachnoid Evidence to support diagnosis: hypertension CT of the head (if ≤6 hr after
hemorrhage Evidence against diagnosis: no neck pain, meningismus, transient onset of headache); lumbar
loss of consciousness, vomiting, or retinal hemorrhage puncture or CT angiography
(if CT was performed >6 hr
after onset of headache and
showed no abnormalities)
Reversible cerebral vasocon‑ Evidence to support diagnosis: headache often preceded by a vaso‑ CT angiography or magnetic
striction syndrome constrictive trigger resonance angiography (re‑
Evidence against diagnosis: a single headache at the time of sults may be falsely normal
presentation (multiple thunderclap headaches over a period early in the course of revers‑
of days to weeks is pathognomonic) ible cerebral vasoconstriction
syndrome)
Uncommon causes
Cerebral venous sinus Evidence to support diagnosis: estrogen use causing possible CT venography or magnetic
thrombosis hypercoagulable state resonance venography
Evidence against diagnosis: no papilledema (although CT angiography
usually shows the venous
sinuses)
Arterial dissection Evidence against diagnosis: no preceding head or neck trauma CT angiography or magnetic
and no Horner’s syndrome resonance angiography
Posterior reversible encepha‑ Evidence to support diagnosis: hypertension MRI
lopathy syndrome Evidence against diagnosis: no seizure or vision symptoms and
no other coexisting medical conditions
Eclampsia or preeclampsia Evidence against diagnosis: not pregnant Clinical evaluation including
context plus MRI
Pituitary apoplexy Evidence against diagnosis: no history of pituitary adenoma and no MRI with dedicated cuts of the
ptosis, ophthalmoplegia, decreased vision, or visual-field deficits sella turcica
Acute sphenoid sinusitis Evidence against diagnosis: no preceding respiratory infection or CT
fever and no findings of sinusitis on CT of the head
Spontaneous intracranial Evidence against diagnosis: headache not positional (typically worse Lumbar puncture with recording
hypotension on standing up, resolves with lying down); no tinnitus, sound of opening pressure; MRI
distortion, dizziness, or sixth cranial nerve palsy with gadolinium enhance‑
ment
Acute posterior circulation Evidence against diagnosis: no neurologic symptoms of stroke MRI (although misses 20% of
stroke hyperacute stroke manifest‑
ing as isolated dizziness)
Rare causes
Meningitis or encephalitis Evidence against diagnosis: no fever or neck pain or stiffness; normal Lumbar puncture; MRI in some
levels of inflammatory markers (platelet count, erythrocyte sedi‑ cases
mentation rate, and C-reactive protein); no abnormal mental
status that would suggest encephalitis
Symptomatic unruptured Evidence against diagnosis: convexal subarachnoid hemorrhage; CT angiography
aneurysm no third cranial nerve palsy
Colloid cyst of the third Evidence against diagnosis: no hydrocephalus on CT of the head CT (may show hydrocephalus)
ventricle and no vomiting, dizziness, vision symptoms, or transient loss
of consciousness; headache not paroxysmal and positional
Retroclival hematoma Evidence against diagnosis: no cranial neuropathy or CT findings CT
of hematoma
Giant-cell arteritis Evidence to support diagnosis: older than 50 yr of age Temporal artery biopsy; temporal
Evidence against diagnosis: no vision symptoms; normal levels of artery ultrasonography may show
inflammatory markers (platelet count, erythrocyte sedimentation a “halo sign”
rate, and C-reactive protein); no description of temporal artery
swelling or tenderness

Table 1. (Continued.)
Condition Clinical Considerations in This Patient Standard Diagnostic Testing

Transient global amnesia Evidence against diagnosis: no acute amnesia at onset of headache Clinical presentation; MRI
(typically clears over a period of 6 to 12 hr) (usually normal results early
in course)
Painless aortic dissection Evidence to support diagnosis: hypertension CT angiography of the chest
Evidence against diagnosis: no chest or back pain and no clinical
or laboratory evidence of brain, gut, kidney, or limb ischemia
Acute myocardial infarction Evidence to support diagnosis: elevated troponin level Electrocardiography and mea‑
Evidence against diagnosis: no cardiopulmonary symptoms surement of troponin T level
recommend CT angiography of the head to si- Table 2. RCVS2 Scoring System.*

multaneously rule out aneurysmal subarachnoid
Criterion Score
hemorrhage and look for multifocal vasocon-
striction of the intracranial arteries that would Recurrent or single thunderclap headache
be consistent with RCVS, while recognizing that Present 5
the results of CT angiography of the head can be Absent 0
falsely normal early in the course of RCVS. I Carotid artery (intracranial)
would ask the radiologist to use a CT angiogra-
Affected −2
phy protocol to also assess the venous sinuses
Not affected 0
for CVST, since multidetector CT angiography of
the head usually allows for visualization of the Vasoconstrictive trigger†
cerebral venous sinuses even without the use of Present 3
dedicated venography.38 Finally, I would obtain Absent 0
an echocardiogram, which I expect would show Sex
wall-motion abnormalities, including apical bal- Female 1
looning that is consistent with takotsubo cardio-
Male 0
myopathy.
Subarachnoid hemorrhage
Present 1
Dr . Jonath a n A . Edl ow ’s
Di agnosis Absent 0
* Patients with new cerebral arteriopathy can be evaluated for the presence
Reversible cerebral vasoconstriction syndrome of reversible cerebral vasoconstriction syndrome (RCVS) with the use of the
with takotsubo cardiomyopathy. RCVS2 scoring system. Scores of 5 or higher have 99% specificity and 90%
sensitivity for diagnosing RCVS. Scores of 2 or lower have 100% specificity and
85% sensitivity for ruling out RCVS. Scores of 3 and 4 indicate an uncertain
Im aging S t udie s diagnosis, and a bedside clinical approach is recommended.
† Vasoconstrictive triggers can be categorized into five classes: pregnancy-
Dr. Romero: CT angiography of the head, per- related, headache disorder, physiologic, substances, and procedure-related.
Pregnancy-related triggers occur during the third trimester and postpartum
formed before and after the administration of period and include eclampsia and preeclampsia (including postpartum occur‑
intravenous contrast material (Fig. 2), revealed rence). Headache disorders include migraine, primary thunderclap headache,
subtle diffuse segmental narrowing of multiple benign headache associated with exertion, benign headache associated with
sexual activity, and primary headache associated with cough. Physiologic
distal arterial branches of the intracranial ves- triggers include high altitude, cold and heat exposure, reaction to grief, and
sels. There was no evidence of aneurysm or a typhoons. Substances include sympathomimetic and serotonergic agents,
nidus that would indicate arteriovenous malfor- immunosuppressant and immunomodulating drugs, hormone-related medi‑
cations (e.g., oral contraceptives, ovarian stimulation, and levonorgestrel),
mation. recreational drugs (e.g., cocaine, ecstasy, amphetamines, marijuana, and
Magnetic resonance imaging (MRI) of the lysergic acid diethylamide), and vaccines against coronavirus disease 2019.
head, performed before and after the adminis- Procedure-related triggers include carotid artery surgery or stenting, open
neurosurgical procedures, tonsillectomy, dural puncture, and transcranial
tration of intravenous contrast material, showed magnetic stimulation. Note that this is not a comprehensive list of triggers.
no acute brain infarct or mass lesion. Subarach- RCVS has also been associated with many miscellaneous conditions, includ‑
noid hemorrhage was present in the left parietal ing takotsubo cardiomyopathy, transient global amnesia, thyrotoxicosis, and
unruptured cerebral aneurysm.
lobe and the left occipital lobe.

discharge. Approximately 2% of patients with

RCVS have progressive vasoconstriction or other
complications that result in death.35
An increasing number of clinical observa-
tions suggest a relationship between RCVS and
conditions associated with vasospasm, such as
takotsubo cardiomyopathy, transient global am-
nesia, and PRES.35 Primary or benign thunderclap
headache and headache associated with sexual
activity, cough, or exertion are included within
the spectrum of RCVS if cerebral angiography
shows abnormalities.35,41
Recent U.S. observational studies in which
cases of RCVS were identified on the basis of
diagnosis codes listed in the International Classifi-
cation of Diseases, 10th Revision (ICD-10) have esti-
Figure 2. CT Angiogram of the Head, Obtained during
mated an incidence of RCVS of 2.7 cases per
the Initial Presentation.
million adults42 and 0.02 cases per 100,000 in-
A sagittal maximum-intensity-projection image from
CT angiography of the head shows segmental narrow‑ patients.43 However, the true incidence is much
ing of the intracranial arteries (arrow). higher, given ongoing underdiagnosis, misdiag-
nosis, and inadequate medical coding and the
fact that overlapping conditions such as PRES
Discussion of M a nagemen t and primary thunderclap headache are not in-
cluded. The mean age of patients with RCVS in
Dr. Aneesh B. Singhal: RCVS is a clinical syndrome cohort studies has ranged from 42 to 51 years,
that predominantly affects women. It is heralded but children also can be affected.35
by thunderclap headaches that usually recur over Several triggers of RCVS have been proposed
a period of a few days and is characterized by on the basis of their vasoconstrictive effects and
fluctuating and reversible narrowing and dilata- temporal relationships (Table 2). The patho-
tion of the intracranial arteries.19,20,35,39,40 physiology of this disorder is attributed to over-
Initial head imaging results can be normal, stimulation of the central serotonergic system
but follow-up studies show abnormalities in 30 and possibly the sympathetic nervous system,
to 70% of patients who are hospitalized with given the actions of the various associated trig-
RCVS. Imaging abnormalities include convexal gers. Cerebral autoregulation dysfunction has
subarachnoid hemorrhage, intracerebral hemor- been correlated with reversible brain edema re-
rhage, ischemic strokes in arterial watershed sulting from disruption of the blood–brain bar-
areas, and reversible brain edema. Hemorrhagic rier.44 Oxidative stress, circulating microRNAs,
lesions occur earlier in the clinical course than and endothelial dysfunction also have been im-
ischemic lesions and are attributed to dynamic, plicated.45 Evaluation of the anatomical patho-
centripetally progressing vasoconstriction and logical characteristics of RCVS has not identified
vasodilatation, which results in ischemia–reper- inflammation.35
fusion injury.21 Infarctions result from reduced Common diagnostic errors include the misdi-
cerebral perfusion. agnosis of thunderclap headache as migraine,
Self-limited generalized tonic–clonic seizures which leads to the administration of triptans
develop in up to 20% of patients with RCVS, and and other antimigraine agents — medications
neurologic deficits such as cortical vision loss, that can worsen vasoconstriction. The main fea-
encephalopathy, aphasia, hemiparesis, and atax- tures of RCVS — headache, strokes, and abnor-
ia develop in up to two thirds of affected pa- mal findings on cerebral angiography — can
tients. Despite these clinical and imaging abnor- mimic those of cerebral arteriopathies such as
malities, outcomes are excellent, with 90 to 95% primary angiitis of the central nervous system
of patients with RCVS having complete recovery (PACNS).39 The presence of these overlapping
or only mild disability by the time of hospital features may result in invasive diagnostic proce-

dures, such as brain biopsy, or the initiation of often administered to counter vasoconstriction,
corticosteroid therapy. Treatment with cortico- although evidence of their effectiveness is lacking.
steroids is relatively contraindicated in patients On the first hospital day, echocardiography
with RCVS, given their association with clinical showed normal left ventricular volume and sys-
and angiographic progression, which is presum- tolic function; segmental left ventricular wall-
ably due to mineralocorticoid actions.46 motion abnormalities were present in the
To help make an accurate diagnosis of RCVS midanteroseptal and inferoseptal walls. Trace
and rule out mimics, the RCVS2 or RCVS-TCH regurgitation of the mitral, tricuspid, and pul-
scoring system can be used (Table 2). This pa- monary valves was also noted. A diagnosis of
tient’s RCVS2 score was 10, which was based on takotsubo cardiomyopathy was made, and out-
the presence of thunderclap headache, triggers patient cardiology follow-up was arranged. The
(underlying stress during public speaking and patient remained asymptomatic and was dis-
estrogen use), female sex, and imaging findings charged home on the second hospital day.
of convexal subarachnoid hemorrhage (Table 2). Two days after discharge from the hospital,
An RCVS2 score of 10 is consistent with a diag- the patient had headache pain that she rated at 8;
nosis of RCVS and virtually rules out PACNS.39 the pain was accompanied by nausea. Emergency
In addition, CT angiography showed narrowing medical services were called, and the patient was
and dilatation of the intracranial arteries. Some transported to the emergency department of this
physicians rely on an improvement in arterial hospital for evaluation.
caliber in response to intraarterial vasodilator The patient reported ongoing headache that
infusions to rule out PACNS. However, this inva- was decreasing in severity. She stated that her
sive procedure carries the risk of reperfusion hands and feet felt different when she touched
injury, which can be fatal.47 Invasive procedures them together. On examination, the temporal
for diagnosis of RCVS cannot be justified, given temperature was 36.3°C, the blood pressure
the reliability of clinical- and imaging-based 131/48 mm Hg, the heart rate 74 beats per min-
bedside diagnosis and scoring systems and the ute, the respiratory rate 16 breaths per minute,
benign natural history of the disorder. and the oxygen saturation 100% while she was
Treatment of headache with analgesic agents breathing ambient air. She appeared uncomfort-
or even opioids is warranted, and this patient able and was clutching the left side of her fore-
received morphine for headache pain. It is im- head. There was a loss of sensation of pain,
portant to avoid exposure to triggers (including temperature, light touch, and vibration on the
illicit substances), as well as physical exertion left side of the face and in the distal right arm
(including sexual activity), until recurrent thun- and distal right leg. The remainder of the ex-
derclap headaches subside — usually over a pe- amination was normal. Imaging studies were
riod of days to weeks. The Valsalva maneuver obtained.
can exacerbate thunderclap headache, so stool Dr. Romero: CT angiography of the head, per-
softeners were recommended in this case. formed before and after the administration of
Many patients with RCVS have wide fluctua- intravenous contrast material (Fig. 3A and 3B),
tions in blood pressure that result from auto- revealed an increase in convexal subarachnoid
regulation or severe pain exacerbations. Pharma- hemorrhage as compared with the previous im-
cologic blood pressure modulation should be aging study, as well as multifocal arterial seg-
avoided when possible. Medications that are used ments of stenosis and beading of the distal an-
to raise the blood pressure can promote further terior, middle, and posterior cerebral arteries
vasoconstriction. Medications that are used to that had also progressed since the previous study.
lower the blood pressure can lead to relative hy- MRI of the head, performed without the admin-
potension and exacerbate cerebral ischemia. No istration of intravenous contrast material (Fig. 3C),
oral or intravenous antihypertensive medications revealed lesions of restricted diffusion in the
were used in this patient because her systolic posterior corpus collosum, which probably indi-
blood pressure did not exceed 180 mm Hg. cates acute infarction. Arterial spin labeling MRI
In addition to morphine for headache pain, showed areas of low perfusion in the bilateral
the patient received oral nimodipine. Calcium- posterior and middle cerebral arterial watershed
channel blockers or intravenous magnesium are areas.

Dr. Singhal: The appropriate timing of dis- combination with the conversion of initially nor-
charge of patients with RCVS whose condition is mal results on MRI of the head to MRI showing
clinically stable remains uncertain. As with this new lesions is characteristic of RCVS.
patient, readmission owing to recurrent thun- Intraarterial vasodilator therapy carries risk
derclap headache is not uncommon.48 Indeed, and therefore should be administered only in
the pattern of recurrent thunderclap headache in patients with a clearly progressive clinical course.
A B
PCAs
C D
Figure 3. Imaging Studies of the Head, Obtained during the Second Admission.
Postprocessed images from CT angiography show segmental narrowing of the right superior cerebellar artery
(Panel A, arrow) and segmental and focal narrowing of the posterior cerebral artery (PCA) (Panel B, arrow). An axial
image from MRI, obtained at the level of the lateral ventricles, shows lesions of restricted diffusion in the corpus
callosum that most likely indicate acute infarction (Panel C, arrow). A susceptibility‑weighted image from MRI shows
susceptibility blooming within the subarachnoid space of the interhemispheric fissure that most likely corresponds to
extensive subarachnoid hemorrhage, predominantly within the cingulate sulcus (Panel D, arrow).

On the basis of this patient’s clinical and imag- deficits, findings that were concordant with the
ing progression, she underwent digital subtrac- corpus callosum infarction, as well as mild sen-
tion angiography with intraarterial verapamil sory loss in the distal right arm. Follow-up head
injection, which resulted in amelioration of the CT angiography and head MRI showed resolu-
vasoconstriction. Follow-up MRI of the head tion of cerebral arterial stenoses and convexal
revealed evolution of corpus callosum infarction subarachnoid hemorrhage, and no new parenchy-
with new postischemic hemorrhage, findings mal lesions were detected. The patient was reas-
that suggested mild reperfusion injury. Never- sured that there are no known genetic underpin-
theless, the patient’s condition improved clini- nings of RCVS and that recurrence of an episode
cally, and she had only mild disability by the of RCVS with complications such as stroke is
time of discharge on day 8 of the second hospital virtually unknown. She has not had any addi-
admission. Standard secondary stroke preven- tional thunderclap headaches.
tion that includes antiplatelet agents, anticoag-
ulant agents, and cholesterol-lowering medica- Fina l Di agnosis
tions is not indicated in patients with stroke due
to RCVS. Reversible cerebral vasoconstriction syndrome
After hospital discharge, the patient had a with takotsubo cardiomyopathy.
cardiac stress test, which showed normal re-
This case was presented at Neurology Grand Rounds.
sults. Six months after discharge, neurologic Disclosure forms provided by the authors are available with
examination showed mild attention and memory the full text of this article at NEJM.org.
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The n e w e ng l a n d j o u r na l of m e dic i n e

Case Records of the Massachusetts General Hospital

Founded by Richard C. Cabot

Case 18-2024: A 64-Year-Old Woman

Pr e sen tat ion of C a se

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n engl j med 390;22 nejm.org June 13, 2024 2109

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typically report multiple thunderclap headaches Posterior Reversible Encephalopathy

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Table 1. Differential Diagnosis of Thunderclap Headache.

Condition Clinical Considerations in This Patient Standard Diagnostic Testing

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Condition Clinical Considerations in This Patient Standard Diagnostic Testing

recommend CT angiography of the head to si- Table 2. RCVS2 Scoring System.*

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discharge. Approximately 2% of patients with

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