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October 16, 2018; 91 (16) Article

Primary angiitis of the CNS and reversible cerebral vasoconstriction syndrome

A comparative study

Hubert de Boysson, Jean-Jacques Parienti, Jérôme Mawet, Caroline Arquizan, Grégoire Boulouis, Cécilia Burcin, Olivier Naggara, Mathieu Zuber, Emmanuel Touzé, Achille Aouba, Marie-Germaine Bousser, Christian Pagnoux, Anne Ducros
First published September 19, 2018, DOI: https://doi.org/10.1212/WNL.0000000000006367
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Abstract

Objectives To further improve the distinction between primary angiitis of the CNS (PACNS) and reversible cerebral vasoconstriction syndrome (RCVS).

Methods We compared 2 large French cohorts of patients with PACNS (n = 110, retrospectively and prospectively enrolled) and RCVS (n = 173, prospectively enrolled).

Results Patients with RCVS were predominantly female (p < 0.0001), with migraines (p < 0.0001), and were more often exposed to vasoactive substances (p < 0.0001) or postpartum (p = 0.002) than patients with PACNS. Headache, especially thunderclap headache, was more frequent in RCVS (both p < 0.0001). Thunderclap headache was absent in only 6% of patients with RCVS and was mainly recurrent (87%) and provoked (77%) mostly by sexual intercourse, exertion, or emotion. All other neurologic symptoms (motor deficit, seizure, cognitive disorder, or vigilance impairment, all p < 0.0001) were more frequent in PACNS. At admission, brain CT or MRI was abnormal in all patients with PACNS and in 31% of patients with RCVS (p < 0.0001). Acute ischemic stroke was more frequent in PACNS than in RCVS (p < 0.0001). Although intracerebral hemorrhage was more frequent in PACNS (p = 0.006), subarachnoid hemorrhage and vasogenic edema predominated in RCVS (p = 0.04 and p = 0.01, respectively). Multiple small deep infarcts, extensive deep white matter lesions, tumor-like lesions, or multiple gadolinium-enhanced lesions were observed only in PACNS, whereas cervical artery dissection was found only in RCVS.

Conclusions Our study confirms that careful analysis of clinical context, headache features, and patterns of brain lesions can distinguish PACNS and RCVS within the first few days of admission in most cases. However, diagnosis remains challenging in a few cases.

Glossary

CTA=
CT angiography;
CYC=
cyclophosphamide;
DSA=
digital subtraction angiography;
GC=
glucocorticoid;
MRA=
MR angiography;
mRS=
modified Rankin scale;
NPV=
negative predictive value;
PACNS=
primary angiitis of the CNS;
PPV=
positive predictive value;
RCVS=
reversible cerebral vasoconstriction syndrome;
SSRI=
selective serotonine recapture inhibitor;
TCH=
thunderclap headache

Distinguishing primary angiitis of the CNS (PACNS) and reversible cerebral vasoconstriction syndrome (RCVS) can be a challenge in clinical practice,1,–,4 although much progress has been made over the past decade in the early identification of the 2 diseases. Both conditions have polymorphic manifestations with many overlapping features including headaches, focal neurologic deficits, seizures, and strokes, but their natural history and outcomes completely differ.5,–,10 In the absence of prompt diagnosis and immunosuppressive therapy, progressive inflammation in PACNS results in an important morbidity and mortality.5,10,–,12 When brain biopsy is unavailable or negative, diagnosis of PACNS relies on the combination of clinical features, brain imaging, and cerebral angiography, together with the exclusion of other more common diseases affecting CNS vessels, such as systemic vasculitides or other vasculopathies, including mainly RCVS.4,13,14 In the past 10 years, this noninflammatory nonatheromatous self-limited vasculopathy has been recognized as the main differential diagnosis of PACNS. In RCVS, removal of precipitating vasoactive substances, rest, and empiric therapy with calcium channel blockers are associated in most patients with an excellent clinical outcome and a complete normalization of brain arteries within 3 months.6,–,9,15,16 However, steroids may be deleterious in RCVS, further underscoring the need for proper early distinction between RCVS and PACNS.17

Few data exist comparing these 2 diseases.1,–,3 In 2016, Singhal et al.3 compared 47 patients with PACNS and 159 patients with RCVS and showed that recurrent thunderclap headache (TCH) and single TCH combined with either normal brain imaging, border-zone cerebral infarcts, or vasogenic edema have a 100% positive predictive value (PPV) for the diagnosis of RCVS. With the exception of recurrent TCH, all other variables had a lower sensitivity for PACNS diagnosis. To challenge or confirm these findings, we conducted a comparative study of 2 large French cohorts of PACNS (n = 110) and RCVS (n = 173).

Methods

Patients with PACNS

We included 110 patients with PACNS from the ongoing “COVAC” cohort (Cohort of Primary Cerebral Vasculitis [in French: “cohorte de vascularite cérébrale primitive”]), a multicentric French registry initiated in 2010. Most patients have been reported in previous publications.5,18,–,20 Data were retrospectively retrieved for patients diagnosed with PACNS before 2010 and prospectively collected after 2010. All patients satisfied the following 4 criteria: (1) clinical presentation suggestive of PACNS, with a combination of headache, focal deficits, seizures, or encephalopathy; (2) abnormalities of cerebral arteries evidenced on biopsy (n = 32), digital subtraction angiography (DSA; n = 68), or MR angiography (MRA; n = 10); (3) exclusion of other conditions and secondary CNS arteritis by a complete workup performed at diagnosis, including infective serologies (tuberculosis, HIV, hepatitis B virus, and hepatitis C virus), autoimmunity serologies (antinuclear antibodies and antineutrophil cytoplasmic antibodies), echocardiography, and whole-body imaging (CT and/or fluorodeoxyglucose-PET); and (4) a follow-up period of at least 6 months after diagnosis (unless the patient died before these 6 months from biopsy-proven PACNS) to exclude other differential diagnoses, such as RCVS, in which arterial abnormalities are expected to reverse within the first months, or atherosclerosis in which clinical and radiologic manifestations are not expected to improve under treatment. In all patients, repeat MRI and MRA were performed 4–6 months after induction treatment and at least once a year thereafter.

Before inclusion in the COVAC register, each case was reviewed by a multidisciplinary panel of experts, including neurologists, internal medicine physicians, and neuroradiologists.

Patients with RCVS

We prospectively included 173 patients with RCVS from the Lariboisière Hospital study in Paris, a monocentric cohort initiated in 2004, which recruited all consecutive patients meeting the following 3 criteria: (1) unusual, acute, and severe headaches with or without focal neurologic deficit and/or seizures; (2) cerebral vasoconstriction demonstrated on DSA, MRA, or CT angiography (CTA), with involvement of at least 2 different cerebral arteries; and (3) disappearance of arterial abnormalities within the first 3 months. From 2004 to 2011, 121 patients were recruited from the emergency headache clinic and 52 from the stroke unit. Previous publications about this cohort have described the first 89 patients6,21 and the 20 patients with RCVS associated with a cervical artery dissection.22 RCVS was qualified as secondary in the presence of a known potential precipitating factor.6,23 For the purpose of the present study, diagnosis of RCVS was retrospectively reassessed in each of the 173 patients by the same neurologist (A.D.). Reversibility of cerebral vasoconstriction was proven in 170 patients by at least 1 normalized investigation (DSA in 17 patients, MRA or CTA in 152 patients, and transcranial Doppler in 87 patients). The remaining 3 patients had purely cephalalgic RCVS with recurrent TCHs, normal brain MRI and angiographic narrowing and a self-limited clinical course in the absence of glucocorticoid (GC) or immunosuppressant treatment, and no recurrence during the long-term follow-up of 68, 115, and 152 months, respectively.

Standard protocol approvals, registrations, and patient consents

All patients were informed of their inclusion in the respective COVAC and RCVS Lariboisière registers with the possibility to decline the inclusion, resulting in a deletion of their data. The COVAC cohort was approved by the Paris-Cochin institutional review board (CPPRB) (No. 12541). All patients from the RCVS cohort signed written informed consent.

Study parameters and definitions

A data set was created for the purpose of this study, including all common information available in both databases. We thus extracted from the PACNS and RCVS databases the following findings in each patient: demographics, medical history (including the history of hypertension, tobacco use, diabetes mellitus, dyslipidemia, migraine, and depression), delivery within the month before clinical onset, use of vasoactive drugs or medications within the 15 days before clinical onset, clinical manifestations at onset, laboratory tests (including CSF analysis), brain CT and/or MRI and neurovascular imaging, results of CNS biopsy when performed, administered treatment, and outcomes.

CSF analysis was considered normal when showing a white blood cell count of <5/mm3 and/or a protein concentration of <0.45 g/L.

A TCH was defined as a headache reaching a maximum intensity above 7/10, on an 11-point scale from 0 (no pain) to 10 (worst possible pain), in less than 1 minute.

Functional status during follow-up was evaluated with the modified Rankin scale (mRS score, calculated on the basis of medical charts when the data were unavailable: 0 = no neurologic deficits; 1 = no important disability, despite symptoms; 2 = slight disability; 3 = moderate disability; 4 = moderately severe disability; 5 = severe disability; and 6 = death). The mRS score was recorded at different time points, especially at months 3, 6, and 12 and then every year until final follow-up.

Relapse of PACNS was defined as a new clinical CNS manifestation (e.g., focal deficit) associated with at least one new notable radiologic abnormality (cerebral infarct, extension of white matter lesion, appearance of gadolinium enhancements, and worsening of arterial stenosis), leading to intensification of treatment by the treating physician. Relapse of RCVS was defined as a new severe headache with new vasoconstriction on cerebral angiography.

Statistics

Categorical variables are expressed as numbers (%) and quantitative variables as medians (range). Categorical variables were analyzed using the χ2 or Fisher exact test and quantitative variables using the Wilcoxon rank-sum test. The repetitive mRS score over time among the same patients was compared using Wilcoxon matched-pairs signed-rank test for quantitative variables.

With the aim of a validation study, we calculated in our cohorts the diagnostic sensitivity, specificity, PPV, and negative predictive value (NPV) of the variables that were found significantly different between RCVS and PACNS in the study by Singhal et al.3

Statistical analyses were computed using JMP 9.0.1 (SAS Institute Inc., Cary, NC). p < 0.05 defined statistical significance.

Data availability

Anonymized data not published within this article will be made available by request from any qualified investigator.

Results

Demographics, medical history, and precipitating factors

Compared with patients with PACNS, patients with RCVS were more likely to be women (71% vs 47% in patients with PACNS, p < 0.0001) with a history of migraine (32% vs 7%, p < 0.0001) (table 1). At least one precipitating factor was identified in 121 patients with RCVS (70%) including early postpartum in 14 women, and current exposure to 1 or several vasoactive substances in 85 patients, the 3 commonest being cannabis (in 35), selective serotonine recapture inhibitors (SSRIs in 23), and nasal decongestants (in 16), followed by binge alcohol drinking (8), steroids (7), ergots (6), triptans (5), cocaine (5), nicotine patches (4), noradrenergic and selective serotonergic antidepressants (3), epinephrine (3), interferon alpha (2), cyclosporine (1), and sulprostone (1).

View this table:
Table 1

Anamnestic and clinical characteristics at diagnosis of patients with PACNS and RCVS

Conversely, none of the patients with PACNS was in the postpartum period. Twelve patients with PACNS had a long history of vasoactive substance use (cannabis in 3, SSRI in 8, and cannabis and SSRI in 1). Among these 12 patients, PACNS diagnosis was biopsy proven in 2. The 10 other patients presented with headaches (not thunderclap) and motor deficits associated with vigilance impairment in 3 and seizures in 3. MRI showed fluid-attenuated inversion recovery white matter hyperintensities and multiple acute infarctions in all, gadolinium enhancements in 5, intracerebral hemorrhage in 1, and subarachnoid hemorrhage in 2. All had elevated CSF protein levels >1.1 g/L and narrowings of at least 2 different arterial territories on DSA. Control angiography at >6 months after onset showed persistent abnormalities in all of them. Despite treatment with GCs in all, combined with cyclophosphamide (CYC) in 8, they had heavy sequelae with an mRS at 3 (2–5) and 2 (1–5) at months 6 and 12, respectively.

Clinical manifestations

Table 1 shows the different clinical manifestations at diagnosis between the 2 groups. Higher systolic and diastolic pressures were observed in patients with RCVS at admission (both p < 0.0001).

Headaches were more frequent in RCVS (99% vs 54% in patients with PACNS, p < 0.0001), especially TCHs (81% vs 3% in patients with PACNS, p < 0.0001). All neurologic symptoms (neurologic deficits, speech disorders, seizures, cognitive disorder, vigilance impairment, and cerebellar ataxia), except vision disorders, were significantly more frequent in PACNS (all with a p value < 0.0001).

Headache was present at onset in 171 patients with RCVS (99%), including 140 (81%) whose first headache was a TCH. Within the first week, 163 patients with RCVS (94%) experienced at least one TCH (median number 4, range 1–18) and 151 patients (87%) had recurrent TCHs. At least 1 headache had an immediate trigger in 77% of the patients with RCVS, mostly sexual intercourse (in 46), exertion (in 38), and acute emotional stress (in 32). The 2 patients with RCVS without headache at onset presented initially with seizures and focal deficits and developed headaches within the following 48 hours. RCVS started after a surgical procedure with traumatic tracheal intubation in 1 and in the setting of cannabis consumption in the other. Both had strokes and diffuse arterial narrowing on DSA, combined with a self-limited clinical course and a complete normalization of arteries on control angiography at 3 months in the absence of GC and immunosuppressant treatment. They both recovered completely.

Fifty-nine patients with PACNS (54%) experienced headaches at onset. None of the patients with PACNS had recurrent TCHs. Three patients had a single TCH at onset, revealing a convexity subarachnoid hemorrhage in 2 and a parenchymal hemorrhage in one. One had a biopsy-proven diagnosis. The other 2 showed abnormal angiography with bilateral arterial narrowing, neurologic deficits, multiple brain infarctions, and abnormal CSF, combined with a partial recovery under treatment with GC and CYC. They eventually relapsed with new ischemic lesions on control MRI and persistence of arterial irregularities at 8 and 15 months after diagnosis.

Brain imaging and CSF analysis

Characteristics of imaging are shown in table 2. All patients underwent a brain imaging by CT or MRI at admission, which was abnormal in all patients with PACNS and in 53 patients with RCVS (31%, p < 0.0001). Repeated brain imaging in the following days still showed normal images in 107 patients with RCVS (62%) and demonstrated new lesions in 13 patients (8%) who initially had a normal brain scan. Acute ischemic stroke was more frequent in PACNS than in RCVS (76% vs 8%, respectively, p < 0.0001). Although intracerebral hemorrhage was more frequent in PACNS (20% in PACNS vs 9% in RCVS, p = 0.006), subarachnoid hemorrhage (27% in RCVS vs 16% in PACNS, p = 0.04) and reversible vasogenic edema (8% in RCVS vs 1% in PACNS, p = 0.01) predominated in RCVS. Some brain lesions were observed only in patients with PACNS, namely multiple diffuse small deep infarcts (in 36 patients), extensive deep white matter lesions (in 66 patients), tumor-like lesions (in 11 patients), or multiple gadolinium-enhanced lesions (in 44 of 91 patients who underwent gadolinium injection).

View this table:
Table 2

Paraclinical characteristics at diagnosis of patients with PACNS and RCVS

Cervical artery dissection was found in 12% of the patients with RCVS but not in patients with PACNS.

Regarding CSF analysis, higher white blood cell count and protein levels were observed in patients with PACNS (p < 0.0001 for both). A strictly normal CSF analysis (white blood cell count <5/mm3 and protein level <0.45 g/L) was more common in patients with RCVS than in patients with PACNS (66% vs 32%, p < 0.0001). Moreover, striking CSF abnormalities with a white blood cell count of >35 mm3 and a protein level of >1.1 g/L were found in 37 patients with PACNS (36%) but in none of the patients with RCVS. No brain biopsy was performed in patients with RCVS.

Comparison of subgroups of PACNS and RCVS

Table 3 shows the comparison of the 78 patients with angiography-diagnosed PACNS with the 173 patients with RCVS. Significantly more neurologic symptoms (neurologic deficits, speech disorder, seizures, cognitive disorder, vigilance impairment, and cerebellar ataxia), higher inflammation levels in CSF, and more ischemic and hemorrhagic parenchymal strokes were observed in patients with angiography-diagnosed PACNS. Conversely, more migraine, headaches, especially TCHs, and subarachnoid hemorrhage were observed in patients with RCVS.

View this table:
Table 3

Characteristics of patients with PACNS diagnosed on neurovascular imaging and RCVS

Table 4 compares the 32 patients with biopsy-proven PACNS with the 173 patients with RCVS. The same differences previously described were observed between the 2 groups, except rates of hypertension, transient neurologic deficits and subarachnoid hemorrhage on CNS imaging were no longer significantly different in the 2 groups.

View this table:
Table 4

Characteristics of biopsy-proven PACNS and RCVS

Tables 5 and 6 compared the 110 patients with PACNS with the 53 patients with RCVS with abnormal brain imaging at diagnosis. The same differences were observed, regarding precipitating factors, clinical manifestations, and imaging abnormalities.

View this table:
Table 5

Anamnestic and clinical characteristics at diagnosis of patients with PACNS and RCVS with abnormal imaging at initial presentation

View this table:
Table 6

Paraclinical characteristics at diagnosis of patients with PACNS and RCVS with abnormal imaging at initial presentation

Treatment and outcomes

Two patients with RCVS received GC: one presented with TCHs, motor deficit, multiple brain infarctions, and abnormal CSF analysis and received 3 months of GC; the other presented with TCHs without additional neurologic symptoms but abnormal CSF analysis and received a 1-month course of GC. Both had a complete reversal of arterial narrowing on control angiography. No patient with RCVS received immunosuppressant therapy. Conversely, 107 patients with PACNS (97%) received GC, combined with immunosuppressant in 91 (85%). The 3 patients who did not receive GC were administered IV CYC.

Calcium channel blockers were administered to 165 patients with RCVS (95%) for a median of 40 (1–100) days. Most patients with RCVS (11 of 13) who initially presented with a normal brain scan and showed further deterioration in the few first days were discharged from other institutions with a misdiagnosis of benign headache and were only started on calcium channel blockers when they presented to the emergency headache center.

At month 3, 11/105 surviving patients with PACNS (10%) and 167/173 patients with RCVS (97%) had an mRS score of ≤1. At months 6 and 12, the rates were 28% vs 97% and 31% vs 98%, respectively (p < 0.0001 at months 3, 6, and 12).

Reversibility of cerebral vasoconstriction was proven in 170 of the 173 patients with RCVS by at least one follow-up neurovascular assessment. The 3 other patients with RCVS made a complete clinical recovery without relapse. Among the 84 patients with PACNS who initially had abnormal MRA or DSA, 72 underwent a follow-up neurovascular assessment that showed fewer lesions in 64 patients, worsened lesions in 5, and disappearance of narrowings in 3.

The median follow-up period was 55 (0–192) months in PACNS (4 patients with biopsy-proven PACNS died within the first 6 months) and 72 (2–154) months in RCVS. A relapse occurred in 34 patients with PACNS (31%) at 16 (5–145) months from diagnosis, whereas 1 patient with RCVS had an angiographically proven relapse with isolated headache. Altogether, 8 patients with PACNS died, whereas none of the patients with RCVS died.

Improving the distinction between RCVS and PACNS

We calculated the diagnostic sensitivity, specificity, PPV, and NPV of the variables that were found significantly different between RCVS and PACNS in the comparative study by Singhal et al.3 Results are shown in table 7. We found that recurrent TCH, or the combination of single TCH with normal brain imaging or cortical-only infarctions or vasogenic edema, reached a PPV of 100% for the diagnosis of RCVS. In patients with abnormal angiogram and without TCH, the combination of deep cerebral infarctions and abnormal CSF analysis had a PPV of 98% for the diagnosis of PACNS.

View this table:
Table 7

Distinction of RCVS from PACNS using the criteria from Singhal et al.3

Discussion

Only 2 comparative studies between RCVS and PACNS have been published so far, the first comparing 13 patients with RCVS with 8 patients with PACNS, and the second, 159 patients with RCVS with 47 patients with PACNS.2,3 The present study, comparing 173 patients with RCVS enrolled in a single center with 110 patients with PACNS enrolled in a multicenter register, is thus the largest reported so far.

In all our patients with PACNS, a complete workup excluded other conditions that may affect CNS vessels. In patients with angiography-proven PACNS, confidence in the vasculitis diagnosis was strengthened by the long follow-up (>6 months in all and 5 years in median) without complete clinical and radiologic reversibility. In addition, the initial presence of white matter lesions on brain MRI in 96% of patients along with multiple deep ischemic lesions in >80% of patients with angiography-proven PACNS is more likely secondary to vasculitis rather than RCVS or other vasculopathies. In addition, as each patient with a PACNS diagnosis enrolled in the register has a longitudinal follow-up, we only kept in the register patients with a definite diagnosis of PACNS.

Our comparative study found several clinical and radiologic features that help distinguish RCVS and PACNS within the first few days of presentation, especially in patients with challenging presentations such as multiple strokes on imaging, and strengthens the results previously reported by Singhal et al.3 First, patients with RCVS were more commonly women and migrainers. Precipitating factors such as vasoactive drug exposure, emotional stress, or postpartum were found by careful questioning in more than two-third of patients with RCVS but were very rarely seen in patients with PACNS. Second, headache was almost twice as common in RCVS than in PACNS, with distinctive features. TCHs were rare (3%) and never recurrent in our patients with PACNS. Conversely, they were almost omnipresent in patients with RCVS, of whom >85% had the characteristic pattern of recurrent TCH over 1–2 weeks. Third, focal neurologic deficits were found in >85% of patients with PACNS often associated with multiple bilateral and deep ischemic lesions, whereas in RCVS, focal deficits affected only a quarter of patients and were secondary to acute infarctions in less than 10%. Three-fourths of patients with PACNS had a motor deficit compared with only 6% of patients with RCVS. The rate of focal deficits in our patients with RCVS is lower than the 43% observed in the American RCVS cohort, which were linked to brain infarction in 39%.3 The frequency of focal deficits in a series of RCVS is known to vary according to patterns of recruitment.6,–,8,24 Our large RCVS recruitment through an emergency headache center probably favored inclusion of purely cephalalgic RCVS cases, whereas a multicentric recruitment through stroke centers would have increased the proportion of severe RCVS cases with strokes, as in the American cohort.3,7 However, whatever the reported cohorts, multiple focal neurologic deficits are the rule in PACNS and affect twice more patients than in RCVS. Fourth, the first brain imaging performed at hospital admission was constantly abnormal in PACNS, while 69% of patients with RCVS showed no lesion on first imaging and 62% still had normal neuroimaging a few days later. However, a significant minority of patients with RCVS (8% in our cohort) can present with isolated headaches and initial normal brain scan and show a neurologic and radiologic deterioration within the first few days, while already treated with calcium channel blockers. This stepwise evolution of RCVS has already been described7 and should not lead to GC treatment initiation, which might be deleterious.17 Among patients with RCVS with abnormal imaging, cortical subarachnoid hemorrhage was the most frequent finding. Several studies have shown that in patients combining cortical subarachnoid hemorrhage, TCHs, and arterial irregularities on cerebral angiography, RCVS is the most likely diagnosis.21,25 However, we reported in this study 3 patients with PACNS showing TCHs, associated with cortical subarachnoid hemorrhage and abnormal angiography in 2. Such patients with overlapping diseases have been reported before3 and represent a diagnostic and therapeutic challenge as GC should be started as soon as possible in PACNS and might be avoided in RCVS. These cases also remind that cortical subarachnoid hemorrhage is a major cause of TCHs, independently of RCVS. Fifth, we found distinct CSF results in our comparative study with inflammatory features in the setting of PACNS. A CSF protein level above 1.1 g/L should exclude RCVS.

Altogether, our study confirms the findings observed by Singhal et al.3 on the high PPV for RCVS diagnosis of recurrent TCH or of the combination of single TCH with either normal brain imaging or cortical-only infarctions or vasogenic edema. Conversely, we also confirm that the combination of abnormal angiogram in a patient without TCH but with deep brain infarctions and abnormal CSF is highly predictive of PACNS. However, this combination showed either poor sensitivity or poor specificity.

The present comparison between these 2 conditions is limited by 2 important points. First, PACNS is not a homogeneous condition, and its presentation is widely variable. Different disease subgroups have been identified, some of them linked to the size of involved vessels.18,26,–,28 As compared with patients with large-vessel PACNS, patients with small-vessel PACNS often show more encephalopathic presentation, smaller acute brain infarctions on imaging, and more abnormal CSF. Angiography is more likely negative in these patients, but biopsy often leads to diagnosis. In these patients, the diagnosis of RCVS is not evoked. Conversely, large-vessel PACNS is more often responsible for large and multiple brain infarctions leading to focal neurologic deficits associated with angiographic abnormalities.18,26 In these patients, RCVS must be ruled out. It has been shown in these patients that biopsy is less frequently useful, often providing negative results.29,30 The present study offers new insights to distinguish PACNS from RCVS, in the absence of histology, by careful analysis of anamnestic characteristics, clinical and radiologic findings, and outcomes. Second, the important differences we observed among our cohorts have to be downplayed by the less severe presentation of our patients with RCVS. In the study by Singhal et al.,3 patients with RCVS presented with nearly twice as many neurologic symptoms as ours (43% vs 24% in our cohort), and 17% of them underwent brain biopsy. As a result, half the patients also received GCs. Distinction between PACNS and RCVS is thus probably more challenging in cases of severe RCVS. However, in the comparative study of Singhal et al.,3 similar distinctions regarding clinical and radiologic presentations were demonstrated.

Some other limitations have to be highlighted. First, the retrospective design of our study limits complete data retrieval. However, we made sure to include in the database of the present study only data available in both cohorts. Second, as previously stated, our 2 cohorts showed some differences with other published series, limiting the extrapolation of our results. Further comparative works with other non-French cohorts are required to confirm our findings. Third, our study does not reflect real-life practice, as reported patients were selected. Physicians from an emergency headache center are probably more prone to diagnose RCVS earlier than other physicians from general emergency departments. This may also explain why none of the patients with RCVS in our study underwent biopsy or was treated by immunosuppressive drugs. Finally, the initial demonstration of multiple and bilateral abnormalities on angiographic imaging does not help distinguish both diseases. However, Singhal et al.3 observed some differences on vascular morphology. Patients with RCVS were more likely to develop symmetric, concentric, and smooth taper lesions, with segmental dilation, than patients with PACNS. Conversely, the later may show more eccentric narrowings than patients with RCVS. We did not conduct similar analyzes in our study precluding any confirmation, but further studies are planned. A future prospective study including and analyzing all consecutive patients with neurovascular abnormalities is thus required. A few small studies have suggested that MR vessel wall imaging might help differentiate PACNS and RCVS, but the sensitivity and specificity of this imaging technique have not been studied.31,–,34

Finally, our study confirms that careful analysis of clinical context, headache features, and patterns of brain lesions can distinguish PACNS and RCVS within the first few days of admission in most cases. However, diagnosis remains challenging in a few cases.

Author contributions

H. de Boysson: concepted the study, acquired and interpreted data, and drafted the manuscript. J.-J. Parienti: interpreted data, performed statistical analysis, and read the manuscript. J. Mawet, C. Arquizan, G. Boulouis, C. Burcin, O. Naggara, M. Zuber, E. Touzé, A. Aouba, M.-G. Bousser, and C. Pagnoux: acquired data and revised the manuscript. A. Ducros: concepted the study, acquired and interpreted data, and drafted the manuscript.

Study funding

No targeted funding reported.

Disclosure

H. de Boysson, J.-J. Parienti, J. Mawet, C. Arquizan, G. Boulouis, C. Burcin, O. Naggara, M. Zuber, E. Touzé, A. Aouba, and M.-G. Bousser report no disclosures relevant to the manuscript. C. Pagnoux reports having received speaker fees from Roche. A. Ducros reports no disclosures relevant to the manuscript. Go to Neurology.org/N for full disclosures.

Publication history

Received by Neurology April 24, 2018. Accepted in final form July 13, 2018.

Footnotes

  • Received April 24, 2018.
  • Accepted in final form July 13, 2018.

References

  1. 1.↵
    1. Hammad TA,
    2. Hajj-Ali RA
    . Primary angiitis of the central nervous system and reversible cerebral vasoconstriction syndrome. Curr Atheroscler Rep 2013;15:346.
    OpenUrlCrossRefPubMed
  2. 2.↵
    1. Néel A,
    2. Auffray-Calvier E,
    3. Guillon B, et al
    . Challenging the diagnosis of primary angiitis of the central nervous system: a single-center retrospective study. J Rheumatol 2012;39:1026–1034.
    OpenUrlAbstract/FREE Full Text
  3. 3.↵
    1. Singhal AB,
    2. Topcuoglu MA,
    3. Fok JW, et al
    . Reversible cerebral vasoconstriction syndromes and primary angiitis of the central nervous system: clinical, imaging, and angiographic comparison. Ann Neurol 2016;79:882–894.
    OpenUrlCrossRefPubMed
  4. 4.↵
    1. Birnbaum J,
    2. Hellmann DB
    . Primary angiitis of the central nervous system. Arch Neurol 2009;66:704–709.
    OpenUrlCrossRefPubMed
  5. 5.↵
    1. de Boysson H,
    2. Zuber M,
    3. Naggara O, et al
    . Primary angiitis of the central nervous system: description of the first fifty-two adults enrolled in the French cohort of patients with primary vasculitis of the central nervous system. Arthritis Rheumatol 2014;66:1315–1326.
    OpenUrl
  6. 6.↵
    1. Ducros A,
    2. Boukobza M,
    3. Porcher R,
    4. Sarov M,
    5. Valade D,
    6. Bousser MG
    . The clinical and radiological spectrum of reversible cerebral vasoconstriction syndrome: a prospective series of 67 patients. Brain 2007;130:3091–3101.
    OpenUrlCrossRefPubMed
  7. 7.↵
    1. Singhal AB,
    2. Hajj-Ali RA,
    3. Topcuoglu MA, et al
    . Reversible cerebral vasoconstriction syndromes: analysis of 139 cases. Arch Neurol 2011;68:1005–1012.
    OpenUrlCrossRefPubMed
  8. 8.↵
    1. Chen SP,
    2. Fuh JL,
    3. Lirng JF,
    4. Wang YF,
    5. Wang SJ
    . Recurrence of reversible cerebral vasoconstriction syndrome: a long-term follow-up study. Neurology 2015;84:1552–1558.
    OpenUrlAbstract/FREE Full Text
  9. 9.↵
    1. John S,
    2. Singhal AB,
    3. Calabrese L, et al
    . Long-term outcomes after reversible cerebral vasoconstriction syndrome. Cephalalgia 2016;36:387–394.
    OpenUrlCrossRefPubMed
  10. 10.↵
    1. Salvarani C,
    2. Brown RD Jr.,
    3. Christianson TJ, et al
    . Adult primary central nervous system vasculitis treatment and course: analysis of one hundred sixty-three patients. Arthritis Rheumatol 2015;67:1637–1645.
    OpenUrl
  11. 11.↵
    1. Benseler SM,
    2. Silverman E,
    3. Aviv RI, et al
    . Primary central nervous system vasculitis in children. Arthritis Rheumatol 2006;54:1291–1297.
    OpenUrl
  12. 12.↵
    1. Calabrese LH,
    2. Mallek JA
    . Primary angiitis of the central nervous system: report of 8 new cases, review of the literature, and proposal for diagnostic criteria. Medicine 1988;67:20–39.
    OpenUrlCrossRefPubMed
  13. 13.↵
    1. Hajj-Ali RA,
    2. Singhal AB,
    3. Benseler S,
    4. Molloy E,
    5. Calabrese LH
    . Primary angiitis of the CNS. Lancet Neurol 2011;10:561–572.
    OpenUrlCrossRefPubMed
  14. 14.↵
    1. Salvarani C,
    2. Brown RD Jr.,
    3. Hunder GG
    . Adult primary central nervous system vasculitis. Lancet 2012;380:767–777.
    OpenUrlCrossRefPubMed
  15. 15.↵
    1. Ducros A
    . Reversible cerebral vasoconstriction syndrome. Lancet Neurol 2012;11:906–917.
    OpenUrlCrossRefPubMed
  16. 16.↵
    1. Ducros A,
    2. Hajj-Ali RA,
    3. Singhal AB,
    4. Wang SJ
    . Reversible cerebral vasoconstriction syndrome. JAMA Neurol 2014;71:368.
    OpenUrl
  17. 17.↵
    1. Singhal AB,
    2. Topcuoglu MA
    . Glucocorticoid-associated worsening in reversible cerebral vasoconstriction syndrome. Neurology 2017;88:228–236.
    OpenUrlAbstract/FREE Full Text
  18. 18.↵
    1. de Boysson H,
    2. Boulouis G,
    3. Aouba A, et al
    . Adult primary angiitis of the central nervous system: isolated small-vessel vasculitis represents distinct disease pattern. Rheumatology 2017;56:439–444.
    OpenUrlCrossRefPubMed
  19. 19.↵
    1. de Boysson H,
    2. Boulouis G,
    3. Dequatre N, et al
    . Tumor-like presentation of primary angiitis of the central nervous system. Stroke 2016;47:2401–2404.
    OpenUrlAbstract/FREE Full Text
  20. 20.↵
    1. de Boysson H,
    2. Parienti JJ,
    3. Arquizan C, et al
    . Maintenance therapy is associated with better long-term outcomes in adult patients with primary angiitis of the central nervous system. Rheumatology 2017;56:1684–1693.
    OpenUrl
  21. 21.↵
    1. Ducros A,
    2. Fiedler U,
    3. Porcher R,
    4. Boukobza M,
    5. Stapf C,
    6. Bousser MG
    . Hemorrhagic manifestations of reversible cerebral vasoconstriction syndrome: frequency, features, and risk factors. Stroke 2010;41:2505–2511.
    OpenUrlAbstract/FREE Full Text
  22. 22.↵
    1. Mawet J,
    2. Boukobza M,
    3. Franc J, et al
    . Reversible cerebral vasoconstriction syndrome and cervical artery dissection in 20 patients. Neurology 2013;81:821–824.
    OpenUrlAbstract/FREE Full Text
  23. 23.↵
    1. Choi HA,
    2. Lee MJ,
    3. Choi H,
    4. Chung CS
    . Characteristics and demographics of reversible cerebral vasoconstriction syndrome: a large prospective series of Korean patients. Cephalalgia 2017;38:765–775.
    OpenUrl
  24. 24.↵
    1. Chen SP,
    2. Fuh JL,
    3. Wang SJ, et al
    . Magnetic resonance angiography in reversible cerebral vasoconstriction syndromes. Ann Neurol 2010;67:648–656.
    OpenUrlCrossRefPubMed
  25. 25.↵
    1. Muehlschlegel S,
    2. Kursun O,
    3. Topcuoglu MA,
    4. Fok J,
    5. Singhal AB
    . Differentiating reversible cerebral vasoconstriction syndrome with subarachnoid hemorrhage from other causes of subarachnoid hemorrhage. JAMA Neurol 2013;70:1254–1260.
    OpenUrl
  26. 26.↵
    1. Schuster S,
    2. Bachmann H,
    3. Thom V, et al
    . Subtypes of primary angiitis of the CNS identified by MRI patterns reflect the size of affected vessels. J Neurol Neurosurg Psychiatry 2017;88:749–755.
    OpenUrlAbstract/FREE Full Text
  27. 27.↵
    1. Cellucci T,
    2. Tyrrell PN,
    3. Sheikh S,
    4. Benseler SM
    . Childhood primary angiitis of the central nervous system: identifying disease trajectories and early risk factors for persistently higher disease activity. Arthritis Rheumatol 2012;64:1665–1672.
    OpenUrl
  28. 28.↵
    1. Salvarani C,
    2. Brown RD Jr.,
    3. Calamia KT, et al
    . Angiography-negative primary central nervous system vasculitis: a syndrome involving small cerebral vessels. Medicine 2008;87:264–271.
    OpenUrlCrossRefPubMed
  29. 29.↵
    1. de Boysson H,
    2. Pagnoux C
    . Letter by de Boysson and Pagnoux regarding article, “Diagnostic yield and safety of brain biopsy for suspected primary central nervous system angiitis”. Stroke 2016;47:e256.
    OpenUrlFREE Full Text
  30. 30.↵
    1. Torres J,
    2. Loomis C,
    3. Cucchiara B,
    4. Smith M,
    5. Messe S
    . Diagnostic yield and safety of brain biopsy for suspected primary central nervous system angiitis. Stroke 2016;47:2127–2129.
    OpenUrlAbstract/FREE Full Text
  31. 31.↵
    1. Chen SP,
    2. Fuh JL,
    3. Lirng JF,
    4. Wang SJ
    . Hyperintense vessels on flair imaging in reversible cerebral vasoconstriction syndrome. Cephalalgia 2012;32:271–278.
    OpenUrlCrossRefPubMed
  32. 32.↵
    1. Chen SP,
    2. Wang SJ
    . Hyperintense vessels: an early MRI marker of reversible cerebral vasoconstriction syndrome? Cephalalgia 2014;34:1038–1039.
    OpenUrlCrossRefPubMed
  33. 33.↵
    1. Mandell DM,
    2. Matouk CC,
    3. Farb RI, et al
    . Vessel wall MRI to differentiate between reversible cerebral vasoconstriction syndrome and central nervous system vasculitis: preliminary results. Stroke 2012;43:860–862.
    OpenUrlAbstract/FREE Full Text
  34. 34.↵
    1. Mossa-Basha M,
    2. Shibata DK,
    3. Hallam DK, et al
    . Added value of vessel wall magnetic resonance imaging for differentiation of nonocclusive intracranial vasculopathies. Stroke 2017;48:3026–3033.
    OpenUrlAbstract/FREE Full Text

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