Introduction
Reversible Cerebral Vasoconstriction Syndrome (RCVS) is a neurological syndrome characterized
by a severe acute headache, maximal at onset, associated with diffuse segmental constriction
of cerebral arteries. Relapsing headache is the main feature, often qualified as thunderclap
headache – severe pain reaching peak in less than one minute – and can be followed
by other acute neurological symptoms, particularly transient focal deficits and seizures.
Symptoms are usually self- limited and can last up to twelve weeks, but complications
such as ischemic lesions and intraparenchymal and subarachnoid hemorrhages can occur.
1
Most RCVS cases are triggered by an underlying condition or exposure, like complications
of postpartum and vasoactive drugs use; some of which particularly implicated are
antidepressants, illicit drugs, nasal decongestants and triptans, among many others.
1
Less commonly, the use of chemotherapeutic agents can precipitate RCVS and intrathecal
cytarabine has been reported as a rare causative agent in the pediatric population.2,
3, 4, 5, 6
Even though differential diagnosis is vast, including intracranial hemorrhage, cerebral
venous thrombosis, artery dissection, pituitary apoplexy and primary headaches, it
can usually be narrowed after neuroimaging and cerebral angiograms. As a self-limiting
condition, observation and symptomatic management might be reasonable in patients
without clinical deterioration, but follow-up must be warranted to identify early
signs of progression and persistence of vasospasm. Other therapeutic strategies that
can be considered to relieve arterial narrowing in specific cases include nimodipine,
verapamil and magnesium sulphate.
2
The aim of this study is to report a case of RCVS following intrathecal chemotherapy
with cytarabine in an adult patient and to review the literature concerning this topic.
Case presentation
A 28-year-old female diagnosed with primary mediastinal B-cell lymphoma (PMBL) subtype
of diffuse large B-cell lymphoma (DLBCL) in May 2017 after experiencing several months
of weight loss, fever and fatigue associated with a large anterior mediastinal mass
infiltrating the right lung and the sternum. Her past medical history was unremarkable.
Initial work-up showed metastatic lesions affecting the liver and kidneys and also
revealed chronic thrombosis of bilateral internal jugular veins and subclavian veins.
Systemic chemotherapy with CHOP-R (6 cycles every 21 days of rituximab 375 mg / m2,
cyclophosphamide 750 mg / m2, doxorubicin 50 mg / m2 and vincristine 2 mg) was initiated
and intrathecal (IT) chemoprophylaxis with cytarabine 40 mg, methotrexate 15 mg and
dexamethasone 4 mg was indicated, once the patient was considered at risk for central
nervous system (CNS) relapse.
After four hours of the first IT chemotherapy infusion, the patient presented with
severe headache, maximal at onset, described as a frontal and retro-orbital pressure,
which persisted despite optimized analgesia, she did not show any other concurrent
neurological signs or symptoms and her arterial blood pressure on admission was 110/70 mmHg.
Patient had received the last systemic chemotherapy 3 days before symptoms onset and
denied receiving any other vasoactive drugs. Head computed tomography (CT) did not
show any abnormalities, thus symptoms were initially attributed to post puncture headache.
As she persisted presenting recurrent headache in the following days, a brain magnetic
resonance imaging (MRI) and angiography was obtained 11 days after symptoms onset.
Images showed signs of diffuse arterial vasospasms consistent with RCVS (Fig. 1A)
with secondary subarachnoid hemorrhage (Figs. 1B and 1C). The patient was treated
symptomatically and experienced gradual improvement of the headache within three weeks.
Neuroimaging after twelve weeks showed complete resolution of the vascular findings
and the previous hemorrhage.
Fig. 1
Brain magnetic resonance and angiography images. A, Angiography MRI showing segmental
arterial constriction (red arrows). B, High intensity signal in the cortical sulcus
and gyrus of the right parieto-occipital convexity on T2/Flair (white arrowheads).
C, Slight impregnation of contrast in the leptomeningeal adjacent to the right parieto-occipital
convexity on T1-GD (white arrowheads).
Fig. 1
Discussion
RCVS is diagnosed by detecting diffuse cerebral vasospasm in the absence of aneurysmal
subarachnoid hemorrhage (SAH) and reversion of symptoms within 12 weeks.
1
We report a case of a 28-year-old woman diagnosed with RCVS, with typical clinical
and radiological findings, after receiving treatment with IT cytarabine. Brain MRI
identified SAH as a complication of RCVS, with no brain aneurysms. Neurotoxicity is
a common side effect of chemotherapy and symptoms differ according to drug class and
dosage. Cytarabine has been associated with an array of neurotoxic effects, including
myelopathy, peripheral neuropathy, seizures, encephalopathy and acute cerebellar syndrome,
7
but cerebral vasospasm is not a frequently reported complication. We identified, throughout
an extensive literature review in major medical databases (PubMed and LILACS), six
previously reported cases of RCVS following chemotherapy,2, 3, 4, 5, 6 all in children
with LLA. IT cytarabine was implicated as the probable causative agent in four of
the cases3, 4, 5; in one other case, patient had received IT cytarabine more than
three weeks before symptoms onset, therefore it was not held responsible for triggering
the event.
6
The clinical characteristics of the six reported cases as well as the present case
are summarized in Table 1.
Table 1
Summary of RCVS cases after chemotherapy.
Table 1
Case 1 Pound et al.
Case 2 Yoon et al.
Case 3 Sankhe et al.
Case 4 Tibussek et al.
Case 5 Tibussek et al.
Case 6 Aoki et al.
Case 7 This report
Age at onset
7 y
3 y
13 y
3 y
5 y
7 y
28 y
Hematologic diagnosis
ALL
ALL
ALL
ALL
ALL
ALL
DLCBL
Chemotherapy protocol
COG AALL 0331
Not started
N.D.a
COG AALL 0932
COG AALL 0932
JPLSG ALL-B12
CHOP-R
IT cytarabine Dose
Yes 70mg
Yes 70mg
N.D.
Yes 70mg
Yes 70mg
Yesb
Yes 40 mg
Symptom onset after infusion
3 d
10 d
4 d
4 d
11 d
6 db
4 h
Associated
Aphasia,
Headache,
Seizures
Limb
Headache,
Headache
Headache
Symptoms
visual
visual loss,
weakness
hemiplegia,
hallucinations,
hemiparesis
gaze deviation,
hemiparesis
speech arrest
Complications
AIS
AIS
PRES
AIS
AIS
None
SAH
Neurologic Outcomes
Full recovery
Full recovery
Full recovery
Full recovery
Persistent hemiplegia
Full recovery
Full recovery
ALL: Acute Lymphocytic Leukemia; DLCBL: Diffuse Large B-cell Lymphoma; COG: Children’s
Oncology Group; JPLSG: Japanese Pediatric Leukemia/Lymphoma Study Group; N.D._ Not
described; AIS: Acute Ischemic Stroke; PRES: Posterior Reversible Encephalopathy Syndrome;
SAH: Subarachnoid Hemorrhage.
a
Protocol not described. Patient received daunorubicin, vincristine and steroids before
symptoms onset.
b
Patient received IT cytarabine more than 3 weeks before symptoms onset (dose not described)
and it was not implicated by the authors as the triggering factor.
We could not find other reports of RCVS after chemotherapy with cytarabine in the
adult population in current literature; although, comparable cases of posterior reversible
encephalopathy syndrome (PRES) following treatment with cytarabine have been described
in older adults.8, 9 A recent study by Sun et al.
10
used transcranial Doppler ultrasound to evaluate signs of subclinical cerebral vasospasm
in a subset of children with hematologic malignancies who receive intrathecal cytarabine.
Among the 18 enrolled subjects, four (22%) met the criteria for subclinical vasospasm
within four days of IT cytarabine administration, suggesting that this complication
may not be as rare as once thought and that it is probably underdiagnosed. Unlike
the aforementioned reports, the majority of patients in this study with cerebral vasospasm
(three of the four) had acute myeloid leukemia (AML) and only one had ALL.
Other chemotherapeutic agents have been implicated as triggers for RCVS. The patient
in question had also been exposed to rituximab, cyclophosphamide, doxorubicin, vincristine,
and methotrexate. There are reports of other chemotherapy drugs possibly implicated
with RCVS, including methotrexate,
11
cyclophosphamide,
12
daunorubicin and vincristine.
2
Rituximab is most often related to paresthesia, dizziness, and anxiety. Cyclophosphamide
is most often related to encephalopathy, seizures, dizziness, peripheral neuropathy,
and myelopathy. Doxorubicin is implicated with cerebrovascular disease peripheral
neurotoxicity. Vincristine tends to have dose-dependent neurological effects, which
are mainly peripheral symptoms and cranial neuropathy, but can also be associated
with seizures, cerebellar dysfunction, and movement disorders. Methotrexate can be
related to several types of neurotoxicity, specially leukoencephalopathy and chemical
meningitis.
13
In the present case, the patient did not show any symptoms after exposure to the other
chemotherapeutic agents and presented the symptoms with an intimate temporal relationship
to the exposure to cytarabine, not presenting any complaints after continuing therapy
with methotrexate alone. Thus, we consider that the patient's symptoms were caused
by diffuse cerebral vasospasm probably after IT cytarabine.
As the mechanism of chemotherapy-associated neurotoxicity is not well known, specific
therapeutic and prevention strategies are a challenge and have not yet been developed.
Conclusions
Previous studies strongly suggest a true association between RCVS and IT cytarabine;
however, it may be underdiagnosed. This seem to be the first reported case in the
adult population and further research is needed to confirm this association.
The knowledge and early recognition of RCVS in patients undergoing chemotherapy is
important for all neurologists, hematologists, and emergency physicians once it could
potentially prevent subtle and severe neurologic consequences.
Conflicts of interest
The authors declare no conflicts of interest.