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Primary central nervous system vasculitis with prominent leptomeningeal enhancementA subset with a benign outcome.

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ARTHRITIS & RHEUMATISM
Vol. 58, No. 2, February 2008, pp 595–603
DOI 10.1002/art.23300
© 2008, American College of Rheumatology
Primary Central Nervous System Vasculitis With
Prominent Leptomeningeal Enhancement
A Subset With a Benign Outcome
Carlo Salvarani,1 Robert D. Brown, Jr.,1 Kenneth T. Calamia,2 Teresa J. H. Christianson,1
John Huston, III,1 James F. Meschia,2 Caterina Giannini,1
Dylan V. Miller,1 and Gene G. Hunder1
deposits of ␤-amyloid peptide. All 8 patients had a
prompt response to therapy, with resolution of the MRI
meningeal enhancement. Although 3 of the 8 patients
had relapses during followup, the overall outcome was
favorable. Patients with meningeal enhancement, compared with patients without enhancement, more commonly had substantial abnormalities of cerebrospinal
fluid (100% versus 58%; P ⴝ 0.02) and amyloid angiopathy (50% versus 12%; P ⴝ 0.03).
Conclusion. Prominent gadolinium leptomeningeal enhancement on MRI may point to a distinct
subtype of PCNSV with small leptomeningeal artery
vasculitis and rapid response to therapy.
Objective. Primary central nervous system vasculitis (PCNSV) is an uncommon condition that affects
the brain and spinal cord. This study was undertaken to
evaluate the clinical features and outcomes among
patients with PCNSV who presented with prominent
gadolinium meningeal enhancement on magnetic resonance imaging (MRI).
Methods. Through retrospective review using the
Mayo Clinic medical records linkage system, we identified 101 consecutive patients with PCNSV based on
brain biopsy or conventional angiography (or both)
between January 1, 1983, and December 31, 2003. We
evaluated data on demographics, clinical findings, laboratory studies, imaging, biopsy of brain or spinal cord
(or both), treatment, and neurologic outcome.
Results. MRIs showed prominent leptomeningeal
enhancement in 8 of 101 patients with PCNSV. In 6 of
those 8, cerebral angiography or magnetic resonance
angiography results were normal, but biopsy of the
brain or spinal cord showed vasculitis in all 8. Granulomatous vascular inflammation was found in 6 specimens and was associated in 4 cases with vascular
Primary central nervous system vasculitis
(PCNSV) is an uncommon condition in which vascular
inflammatory lesions are limited to the brain and spinal
cord. PCNSV has been generally considered a progressive CNS disorder that has a fatal course unless treated
vigorously with glucocorticoids and immunosuppressive
drugs (1–3). However, Calabrese et al (4) described a
subset of patients who had a diagnosis based on angiography alone and who appeared to have a more benign
course. These patients were characterized by a rapid
onset of neurologic deficit, mild cerebrospinal fluid
(CSF) abnormalities, a good response to therapy, and a
favorable outcome. For these cases, the term “benign
angiopathy of the CNS” was subsequently proposed (5).
In a more recent retrospective study, however, Woolfenden et al (6) observed 10 similar patients whose
diagnosis was established with angiography and who did
not have a similar benign monophasic course or a
favorable neurologic outcome. The different results in
these studies indicate that further investigation is
Supported by a grant from the Mayo Foundation, Rochester,
Minnesota.
1
Carlo Salvarani, MD (current address: Arcispedale S. Maria
Nuova, Reggio Emilia, Italy), Robert D. Brown, Jr., MD, MPH, Teresa
J. H. Christianson, BS, John Huston, III, MD, Caterina Giannini, MD,
Dylan V. Miller, MD, Gene G. Hunder, MD: Mayo Clinic, Rochester,
Minnesota; 2Kenneth T. Calamia, MD, James F. Meschia, MD: Mayo
Clinic, Jacksonville, Florida.
Address correspondence and reprint requests to Robert D.
Brown, Jr., MD, MPH, Department of Neurology, Mayo Clinic, 200
First Street SW, Rochester, MN 55905. E-mail: brown.robert@
mayo.edu.
Submitted for publication February 22, 2207; accepted in
revised form October 12, 2007.
595
596
SALVARANI ET AL
Table 1. Clinical features of the 101 patients with PCNSV, according to the presence or absence of
meningeal enhancement on MRI*
Sex
Male
Female
Age at diagnosis, median (range) years
Days from symptom onset to diagnosis,
median (range)
Headache
Cognitive disorder
Focal manifestations
Intracerebral hemorrhage
Systemic manifestations†
CSF abnormality
Protein ⱖ45 mg/dl or WBC count
ⱖ5 cells/mm3
Protein ⱖ70 mg/dl or WBC count
ⱖ10 cells/mm3
ESR, median (range) mm/hour
Cerebral angiography findings consistent
with vasculitis
CNS histologic specimens consistent
with vasculitis
CNS biopsy specimen with amyloid
angiopathy
Presence of meningeal
enhancement
(n ⫽ 8)
Absence of meningeal
enhancement
(n ⫽ 93)
6 (75)
2 (25)
58 (30–78)
37 (16–426)
37 (40)
56 (60)
46 (17–84)
43 (0–1,913)
6 (75)
6 (75)
8 (100)
1 (12)
2 (25)
58 (62)
45 (48)
90 (97)
7 (8)
14 (15)
8 (100)
48/66 (73)
8 (100)
38/65 (58)
7 (2–41)
0/4
10 (0–110)
76/83 (92)
8/8 (100)
23/41 (56)
4/8 (50)
5/41 (12)
* Except where indicated otherwise, values are the number (%). PCNSV ⫽ primary central nervous
system vasculitis; MRI ⫽ magnetic resonance imaging; CSF ⫽ cerebrospinal fluid; WBC ⫽ white blood
cell; ESR ⫽ erythrocyte sedimentation rate.
† Defined as the presence of at least 1 of the following: fatigue, anorexia, weight loss, or fever.
needed to clearly define subsets of PCNSV. Lack of a
criterion standard for diagnosis of PCNSV and case
selection bias are possible reasons for the differences
reported in these studies. In addition, as with most
vasculitic syndromes, PCNSV is probably heterogeneous
in disease severity and treatment requirements.
To determine the clinical features and spectrum
of PCNSV, we reviewed the medical records of all
patients with a possible diagnosis of CNS vasculitis seen
at the Mayo Clinic in Rochester over a 21-year period.
We identified 101 patients meeting the criteria for
diagnosis of PCNSV (7). In this report, we describe the
clinical characteristics of a subset of 8 patients with a
biopsy-proven diagnosis of PCNSV who were found to
have prominent gadolinium leptomeningeal enhancement on magnetic resonance imaging (MRI). These
patients had relatively mild symptoms at presentation, a
good response to therapy, and a favorable neurologic
outcome.
PATIENTS AND METHODS
Patients. Using the Mayo Clinic medical records linkage system, a list of all patients with a possible diagnosis of
CNS vasculitis between January 1, 1983, and December 31,
2003, was generated. To maximize case ascertainment, we
reviewed the records of all patients in whom there was
evidence of vasculitis involving the CNS. The Mayo Clinic
Institutional Review Board approved this study.
Patients were considered to have definite PCNSV if
brain or spinal cord biopsy showed vasculitis (intramural
destructive inflammation) or if angiograms showed changes
highly suggestive of vasculitis (e.g., segmental narrowing, dilatation, or occlusion affecting multiple cerebral arteries in the
absence of proximal vessel changes of atherosclerosis; a neuroradiologist’s opinion was also needed to indicate that the
findings were consistent with a diagnosis of vasculitis), provided there was no other condition present that could explain
the findings. We excluded patients with evidence of vasculitis
in organs other than the CNS, those with evidence of other
diseases such as connective tissue disorders (e.g., lupus erythematosus), and those with an underlying infection that might
be associated with vasculitis (such as varicella-zoster virus
infections) or that might mimic vasculitis. We also excluded
patients with other diseases that might mimic PCNSV, such as
tumors, and patients whose results suggested cerebral vasoconstriction syndromes (8). In cases in which the initial review of the diagnosis was uncertain, 2 rheumatologists (CS
and GGH) and 1 neurologist (RDB) adjudicated the case by
again reviewing the complete medical record and reaching a
consensus.
PCNSV WITH LEPTOMENINGEAL ENHANCEMENT
597
Table 2. Clinical characteristics and MRI findings in the 8 patients with PCNSV with gadolinium meningeal enhancement on MRI*
Brain MRI
Patient/
age/sex
1/63/F
Confusion, cognitive decline,
headache, aphasia, visual field
defect
2/60/M
Aphasia with alexia
3/78/M
Decreased level of consciousness,
confusion, cognitive decline,
dizziness, fatigue, anorexia with
weight loss
Confusion, cognitive decline,
personality change, headache,
ataxia
Confusion, cognitive decline,
amnestic syndrome, aphasia,
headache, papilledema
Confusion, lower extremity
weakness and numbness,
bladder and stool incontinence,
headache, ataxia
Confusion, amnestic syndrome,
personality change, headache,
vomiting
Ataxia, headache, dysarthria,
vertigo, vomiting, fatigue
4/64/M
5/57/M
6/39/M
7/30/M
8/39/F
Leptomeningeal
enhancement
Clinical symptoms at presentation
Diffuse over the left cerebral
hemisphere and the right
frontal and temporal
regions
Mild diffuse (right to left
hemisphere)
Mild overlying the posterior
parietal and occipital lobes
Diffuse over both cerebral
hemispheres and the
cerebellum
Prominent linear over both
cerebral hemispheres,
basal ganglia, and pons
Diffuse over both cerebral
hemispheres and posterior
fossa
Other lesions
None
Intracerebral hemorrhage, confluent
T2 abnormality of the white
matter
None
Multiple infarcts, patchy T2
abnormality of the white matter
Confluent T2 abnormality of the
white matter
None
Diffuse
None
Prominent in the cerebellum
and brainstem
Intracerebral hemorrhages
* MRI ⫽ magnetic resonance imaging; PCNSV ⫽ primary central nervous system vasculitis.
Assessments. Between 1983 and 2003, a total of 101
patients who fulfilled the diagnostic criteria for PCNSV (7)
were seen at the Mayo Clinic in Rochester. A standard data
collection form was completed in all cases. The form included
information about clinical manifestations at presentation and
during followup visits, comorbid medical conditions, laboratory investigations, including CSF analysis, and radiologic
images (from computed tomography, MRI, magnetic resonance angiography [MRA], and cerebral angiography). Brain
or spinal cord biopsy results or autopsy results (or both) were
collected. In addition, information on treatment regimens,
response to treatment, presence and number of relapses,
followup functional status, and cause of death was noted when
available. In some instances, outcome information was obtained by correspondence after the patient’s last visit to the
Mayo Clinic. In the sense that all patients meeting the criteria
were included, the 101 patients form a consecutive series.
The modified Rankin scale (9) was used to evaluate the
functional status at presentation and at the last followup visit.
The modified Rankin scale is a standardized, commonly used
scale that measures disability or dependence in activities of
daily living in stroke victims. The scale consists of 6 possible
scores, from 0 to 5, in which 0 ⫽ no symptoms; 1 ⫽ no
significant disability, despite symptoms; 2 ⫽ slight disability;
3 ⫽ moderate disability; 4 ⫽ moderately severe disability; and
5 ⫽ severe disability.
CNS tissue was examined histologically for a diagnosis
in 49 of the 101 cases. Vasculitis was found in 29 of 47 biopsy
specimens (62%), and CNS tissue from 2 postmortem cases
showed vasculitis. Of the 29 positive biopsy specimens, 27 were
brain tissue and 2 were spinal cord tissue. Histologic patterns
in positive specimens varied: 18 had a granulomatous inflammatory pattern (accompanied by vascular deposits of ␤A4
amyloid peptide in 8), 8 had a lymphocytic pattern, and 5 had
an acute necrotizing pattern. All the biopsy and postmortem
specimens were reviewed by 2 pathologists (CG and DVM). To
assess the effect of treatment, we used the treating physician’s
overall opinion about the response to the therapy provided.
Statistical analysis. Differences between the groups
with and without meningeal enhancement were tested using
Wilcoxon’s 2-sample rank sum test for numeric characteristics
and Fisher’s exact test for categorical characteristics. For
hypothesis testing, P values less than 0.05 were considered
significant.
RESULTS
Demographic and clinical features and associated conditions. Eight of the 101 patients (7.9%) had
evidence of prominent gadolinium meningeal enhancement on MRI at diagnosis. Table 1 lists the demographic
characteristics, clinical manifestations, and other findings in these 8 and the 93 other patients. Six of the 8
were male. The median age at diagnosis was 58 years
(range 30–78 years). The time from onset of symptoms
598
SALVARANI ET AL
Table 3. Laboratory and pathology results in the 8 patients with PCNSV with gadolinium meningeal enhancement on MRI*
CSF
Patient
WBC count, cells/mm3
Protein, mg/dl
1
68
573
2
2
105
3
17
190
4
23
97
5
61
161
6
230
265
7
446
271
8
59
296
Pathology findings
Open brain biopsy: granulomatous, leptomeningeal, and
intraparenchymal, marked angiocentric inflammation;
presence of ␤-amyloid deposits
First open brain biopsy: granulomatous, leptomeningeal, and
intraparenchymal, marked angiocentric inflammation;
presence of ␤-amyloid deposits
Second open brain biopsy: same findings as in the first
Open brain biopsy: lymphocytic, leptomeningeal, marked
angiocentric inflammation
Open brain biopsy: granulomatous, leptomeningeal, and
intraparenchymal, marked angiocentric inflammation;
presence of ␤-amyloid deposits and infarct
Open brain biopsy: granulomatous, leptomeningeal, and
intraparenchymal, marked angiocentric inflammation;
presence of ␤-amyloid deposits
Open brain biopsy: granulomatous, leptomeningeal, and
intraparenchymal, marked angiocentric inflammation
Open brain biopsy: granulomatous, leptomeningeal, marked
angiocentric inflammation
Open brain biopsy: infarct, no evidence of vasculitis
Cauda equina biopsy: necrotizing, marked angiocentric
inflammation, infarct
* See Table 1 for definitions.
to diagnosis was ⱕ1 month in 4 of the 8 patients, with a
median of 37 days (range 16–426 days). Table 2 describes the manifestations and MRI findings in each of
the 8 patients. Cognitive disorder, headache, and focal
manifestations were the most common symptoms at
presentation. Constitutional symptoms were present in 2
patients (anorexia with weight loss and fatigue in patient
3 and fatigue in patient 8). Symptoms related to spinal
cord involvement were documented in 2 patients: patient 6 had spinal cord and cerebral symptoms at presentation, and patient 8 had spinal cord disease 8
months after the development of symptomatic brain
involvement. Other significant medical disorders were
noted in 4 patients, including 1 with hypothyroidism, 1
with diabetes, 1 with B cell chronic lymphocytic
leukemia/small lymphocytic lymphoma, and 1 with
Crohn’s disease.
Laboratory investigations and CSF results. Table 3 shows the details of the CSF examination findings
obtained at diagnosis. Results of the CSF examination
were abnormal in all 8 patients; the median CSF protein
level was 227.5 mg/dl (range 97–573), and the median
CSF white blood cell (WBC) count was 60 cells/mm3
(range 2–446). Lumbar puncture was performed after
the brain MRI in 4 patients (median 1 day; range 1–8
days) and before the brain MRI in the other 4 (median
7 days; range 4–12 days).
Radiology results. Conventional cerebral angiography was performed in 4 of the 8 patients. Brain MRA
was performed in 2 of these 4 and in 2 other patients.
Thus, 6 of the 8 (75%) underwent cerebral angiography
or brain MRA (or both) at presentation, but none of the
findings were suggestive of vasculitis.
Brain MRI at presentation showed prominent
leptomeningeal contrast enhancement in all 8 patients
(Figure 1 and Table 2). In 5 of them it was diffuse; in 3,
it was more localized. In 1 patient (patient 5), linear
enhancement was distributed over both cerebral hemispheres, basal ganglia, and pons; in a second (patient 8),
the enhancement was prominent in the cerebellum and
brainstem. In 4 patients, leptomeningeal enhancement
was the only MRI finding; in 4 others, there were
associated parenchymal abnormalities such as multiple
infarcts, intracerebral hemorrhages, and patchy or confluent white matter T2 abnormalities.
Biopsy results. Table 3 also shows the pathology
results. Nine open brain biopsies and 1 cauda equina
biopsy were performed. All 8 patients underwent at least
1 open brain biopsy; 1 patient (patient 2) underwent 2
brain biopsies (the second was performed 3 years after
the first), and 1 patient underwent both brain and cauda
equina biopsies (patient 8). Open brain biopsy showed
evidence of vasculitis in 7 patients. The inflammatory
infiltration was granulomatous (Figure 2) in 6 of these 7
PCNSV WITH LEPTOMENINGEAL ENHANCEMENT
599
Figure 1. Magnetic resonance images (MRIs) showing prominent leptomeningeal contrast enhancement. A, MRI at symptom onset showed diffuse,
asymmetric, nodular, and linear leptomeningeal enhancement, with minimal involvement of the dura. B, Fluid-attenuated inversion recovery
(FLAIR) MRI showed scattered areas of increased T2 signal within the white matter bilaterally, with abnormal FLAIR T2 signal apparent in the
sulci. C, MRI after treatment showed resolution of the abnormal contrast enhancement and abnormal T2 signal within the sulci. D, FLAIR T2 image
showed development of mild generalized cerebral atrophy.
600
SALVARANI ET AL
Figure 2. Histologic findings in a patient with leptomeningeal granulomatous vasculitis. A,
Destructive vasculitis with well-formed granulomas involved the small vessels of the leptomeninges
(hematoxylin and eosin stained; original magnification ⫻ 200). B, Enlarged view. Arrows indicate
multinucleated giant cells (original magnification ⫻ 400).
patients and lymphocytic in 1. In the other patient
(patient 8), findings from the open brain biopsy did not
include evidence of vasculitis, but necrotizing angiitis
was seen in the biopsy specimen from the cauda equina.
The inflammation was markedly angiocentric in
all patients. In 5 of the 7 with abnormal brain biopsy
results, both leptomeningeal and parenchymal involvement were observed, but 2 had only leptomeningeal
involvement. Four patients had vascular deposits of
amyloid with deposition of ␤-amyloid peptide. Both
brain biopsies from patient 2 showed similar findings.
Evidence of ischemic changes and infarct was seen in 3
biopsies from 2 patients (patients 4 and 8).
Treatment and outcome. Table 4 shows the details of treatment, followup MRI, and status of the
patients at the last followup visit. The median duration
of followup was 24 months (range 1–87 months). Treatment of all patients included prednisone. The median
starting dosage of oral prednisone was 60 mg/day (range
30–80 mg/day). In 4 patients, oral prednisone therapy
was preceded by a course of methylprednisolone pulse
therapy (1 gm/day for 4–6 days). The median duration of
oral prednisone therapy was 5 months (range 1–45
months).
In 4 patients (patients 1, 3, 5, and 8), therapy was
started with prednisone alone and in the other 4, therapy
was started with prednisone plus cyclophosphamide.
Patient 8 was treated with prednisone and cyclophosphamide for a recurrence 3 months after stopping
prednisone treatment. Thus, 4 patients received monthly
pulse intravenous injections of cyclophosphamide, and a
fifth received daily oral cyclophosphamide. The median
duration of treatment with cyclophosphamide was 12
months (range 1–17 months).
Three patients (38%) had a relapse or recurrence. Patient 1 had a recurrence characterized by
headache, confusion, and expressive aphasia 6 years
after the suspension of initial therapy. At the time of the
recurrence, brain MRI revealed the reappearance of
meningeal enhancement. The patient was treated again
with prednisone alone, resulting in complete remission
of neurologic and MRI findings. Patient 6 had 2 relapses
characterized by the presence of mild headache and
confusion, MRI evidence of meningeal enhancement,
and CSF abnormalities similar to those found at first
diagnosis. With treatment, there was an improvement of
symptoms and complete resolution of meningeal enhancement and CSF abnormalities that persisted to the
last visit 31 months later. Patient 8 had a recurrence
involving the spinal cord 3 months after stopping prednisone therapy but improved within days when therapy
was restarted.
In summary, all 8 patients responded to therapy
with glucocorticoids or to glucocorticoids plus immunosuppressive therapy, generally within the first 2–3 weeks.
However, in 1 patient, a delayed response was observed,
with response noted only after 3 months of therapy. A
rapid response to therapy was also noted in patients with
relapses as described above. Four patients underwent
followup brain MRIs and had a complete resolution of
meningeal enhancement by a median of 12 weeks (range
2–24 weeks) after initiation of treatment. The outcome
PCNSV WITH LEPTOMENINGEAL ENHANCEMENT
601
Table 4. Treatment, outcome, and followup duration among the 8 patients with PCNSV with gadolinium meningeal enhancement on MRI*
Patient
Treatment
1
2
Prednisone for 13 months
Prednisone for 7 months; oral cyclophosphamide
for 12 months
Methylprednisolone pulse, 1 gm/day for 5 days;
prednisone for 1 month
Prednisone for 2 months; cyclophosphamide
for 14 months (1.7 gm/month IV)
Prednisone for 19 months
Methylprednisolone pulse for 4 days (1 gm/day);
prednisone for 45 months; cyclophosphamide
for 17 months (1 gm/month IV);
mycophenolate mofetil for 12 months;
etanercept for 31 months
Methylprednisolone pulse for 4 days (1 gm/day);
prednisone for 1 month; cyclophosphamide
for 1 month (1 gm/month IV)
Methylprednisolone pulse for 6 days (1 gm/day);
prednisone for 3 months; cyclophosphamide
for 1 month (1 gm/month IV), started for a
recurrence 3 months after stopping the first
course of prednisone therapy
3
4
5
6
7
8
Findings at last
followup visit
Followup MRI findings for
leptomeningeal
enhancement
Status
Modified
Rankin score†
Followup duration,
months‡
Resolution
Not available
Improved
Improved
1
0
87
37
Not available
Improved
3
2
Resolution
Improved
1
15
Resolution
Resolution
Improved
Improved
1
2
33
61
Not available
Improved
1
1
Not available
Improved
3
14
* PCNSV ⫽ primary central nervous system vasculitis; MRI ⫽ magnetic resonance imaging; IV ⫽ intravenous.
† Modified Rankin scale ranges from 0 to 5, with scores as follows: 0 ⫽ no symptoms; 1 ⫽ no significant disability, despite symptoms; 2 ⫽ slight
disability; 3 ⫽ moderate disability; 4 ⫽ moderately severe disability; and 5 ⫽ severe disability.
‡ After the onset of symptoms.
during followup was favorable among all patients. None
had permanent major neurologic dysfunction at the last
visit. Five patients had total recovery, and 3 had recovery
with residual slight or moderate disability. The median
Rankin score at the last visit was 1 (range 0–3), compared with a median score of 2 (range 1–4) at presentation. None of the 8 patients died during the followup
period. However, patient 5 died suddenly subsequent to
his last followup visit. The circumstances and cause of
death were unknown.
Comparison of patients with and those without
meningeal enhancement. Table 1 compares the 8 cases
of PCNSV with prominent meningeal enhancement and
those of the other 93 without enhancement for whom
information was available. Histologic evidence of vasculitis and of amyloid angiopathy was significantly more
frequent in the 8 patients with meningeal enhancement
than in the other 41 patients without enhancement who
underwent biopsies (P ⫽ 0.02 and P ⫽ 0.03, respectively). The frequency of cerebral angiography showing
evidence of vasculitis was significantly higher in the 83
patients without meningeal enhancement who had this
test performed (P ⬍ 0.001). CSF abnormalities (protein
ⱖ70 mg/dl or WBC count ⱖ10 cells/mm3) were signifi-
cantly more frequent in the 8 patients with meningeal
enhancement than in the other 65 patients without
enhancement who had CSF results available (P ⫽ 0.02).
Patients with meningeal enhancement were older at
diagnosis, were more frequently male, had a more acute
clinical onset with a shorter median period from onset of
symptoms to diagnosis, and more frequently had a
cognitive disorder as the presenting finding; however,
these differences were not significant.
At presentation, the Rankin scores were ⱖ4 in 2 of
the 8 patients (25%) with leptomeningeal enhancement
and 20 of the 93 (22%) without prominent enhancement.
At the last visit, the Rankin scores were ⱖ4 in none of the
8 patients with leptomeningeal enhancement but in 13 of
the 93 patients (14%) without enhancement. At the last
followup, 1 of the 8 patients (12%) with leptomeningeal
enhancement and 16 of the 93 (17%) without enhancement had died. When the 8 patients with meningeal
enhancement were compared with the other 23 patients
who had positive CNS biopsy findings but no prominent
enhancement, no significant clinical differences were
found. The median Rankin score at presentation was 2 in
the 8 patients with meningeal enhancement and in the
other 23 with positive CNS biopsy results; at the last visit, it
602
SALVARANI ET AL
was 1 in the 8 patients with meningeal enhancement and
remained at 2 in the 23 with positive CNS biopsy findings
but no prominent enhancement.
DISCUSSION
As part of an analysis of 101 consecutive patients
with PCNSV seen at our institution over a 21-year
period (7), we noted that in 8 patients MRI examination
showed prominent gadolinium enhancement of the meninges. After review of the clinical features of the 8
patients, it became apparent that, although not identical
in all respects, they exhibited several similar features,
including a male predominance, a rapid clinical onset,
the frequent presence of cognitive dysfunction at presentation, and the absence of findings of vasculitis on
cerebral angiography or brain MRA (or both). Brain or
spinal cord biopsy showed evidence of small-vessel vasculitis in all involved parenchyma or leptomeninges (or
both), and it was frequently granulomatous in appearance. Half of the patients had vascular amyloid deposits
with ␤A4 amyloid peptide. The median age of the 8
patients at diagnosis was older than that of those without
meningeal enhancement. CSF abnormalities were
present in all patients at diagnosis, whereas the ESR was
normal in all but 1. All patients had a good clinical
response to corticosteroid therapy (alone or combined
with immunosuppressive agents, most commonly cyclophosphamide), with resolution of MRI enhancement
and an overall favorable course. A trend toward better
outcomes in the 8 patients at last visit was not significant,
perhaps because of the small number of patients. When
the 8 patients were compared with the 23 whose CNS
biopsies were positive, a small trend toward less disability at last visit in the 8 patients was not significant.
The typical MRI findings in PCNSV are multiple
bilateral T2 and fluid-attenuated inversion recovery
high-signal abnormalities in the cortex and deep white
matter (10). Rarely, findings on conventional MRI may
be normal (11). Leptomeningeal enhancement may represent diffuse inflammation and vasculitis in these structures. Leptomeningeal enhancement has been reported
previously in 4 patients as the most prominent initial
MRI abnormality, which was isolated or associated with
parenchymal lesions (12–15). The characteristics of
these patients were similar to the characteristics of our
patients, including normal angiographic findings but
pathologic evidence of granulomatous angiitis affecting
mainly the small leptomeningeal vessels. Acute onset of
mental status changes was the predominant presenting
finding, and the neurologic status and MRI findings in
these patients normalized or improved markedly with
aggressive treatment (corticosteroids plus cyclophosphamide).
MRI evidence of meningeal enhancement has
also been reported in patients with antineutrophil cytoplasmic autoantibody–positive vasculitis, particularly in
Wegener’s granulomatosis (16–18). However, these patients usually have a pachymeningeal pattern of meningeal enhancement, and leptomeningeal enhancement
has been reported to occur infrequently (16,17). Neurosarcoidosis and infections are also causes of meningeal
enhancement (19–21). The findings required to make a
diagnosis of neurosarcoidosis are the presence of the
disease in another organ, involvement of the cranial
nerves (in particular, the optic nerve), and histologic
confirmation with evidence of granulomas and absence
of the classic changes of vasculitis in the CNS (19,20). A
diagnosis of Wegener’s granulomatosis, infection, or
neurosarcoidosis was excluded in our patients on the
basis of isolated CNS involvement, clinical, laboratory,
and radiologic findings, and histologic characteristics.
Four of our patients had associated cerebral
amyloid angiopathy (CAA). In our entire clinical series
of 101 patients with PCNSV (8), CAA was significantly
more frequent in patients with meningeal enhancement
than in those without. Although PCNSV and CAA are
generally considered to be unrelated, cases with granulomatous CNS vasculitis and CAA have been described
(22–25). This association is unlikely to be fortuitous, and
it has been proposed to represent a distinct entity that is
a variant of PCNSV (24). As in our patients, angiographic evidence of vasculitis was not found in the few
patients previously described in the literature with CAA/
PCNSV who underwent angiography (22–24). Furthermore, as noted in the cases presented here, some
patients with CAA/PCNSV had MRI evidence of prominent meningeal enhancement, which, when diffuse,
raised concerns about carcinomatous or inflammatory
meningitis (21,23). The earlier patients, similarly to ours,
had a sustained and rapid clinical improvement and
resolution of radiologic lesions with therapy. Therefore,
patients presenting with CAA/PCNSV and meningeal
enhancement seem to have a less progressive disease,
which is responsive to treatment, with a prognosis that is
apparently unaffected by the presence of amyloid angiopathy.
Our patients were different from the cases described by Calabrese and colleagues (4,26) as a subset of
PCNSV with a favorable course (benign angiopathy of
the CNS). Ours were pathologically documented as
having PCNSV, but available angiographic and MRA
PCNSV WITH LEPTOMENINGEAL ENHANCEMENT
findings were negative. All of our patients had CSF
abnormalities, and the course was not monophasic as
described in the series reported by Calabrese and colleagues. All of our patients had true vasculitis, whereas
“benign angiopathy of the CNS” is a heterogeneous
disorder that, in many patients, could be the result of a
reversible vasoconstriction without underlying vasculitis.
The medical literature on PCNSV is limited and
difficult to analyze since much of the current understanding comes from small case series, individual case
reports, and retrospective reviews of the literature. The
strength of the present study is the identification of a
clinical subset of patients who appear to have a less
progressive disease in the context of the largest cohort of
consecutive patients with PCNSV studied to date, with
well-defined and uniform case ascertainment and clinical followup.
ACKNOWLEDGMENT
Editing, proofreading, and reference verification were
provided by the Section of Scientific Publications at the Mayo
Clinic.
AUTHOR CONTRIBUTIONS
Dr. Brown had full access to all of the data in the study and
takes responsibility for the integrity of the data and the accuracy of the
data analysis.
Study design. Salvarani, Brown, Meschia, Giannini, Hunder.
Acquisition of data. Salvarani, Brown, Christianson, Meschia, Giannini, Miller, Hunder.
Analysis and interpretation of data. Salvarani, Brown, Calamia, Christianson, Huston, Meschia, Giannini, Miller, Hunder.
Manuscript preparation. Salvarani, Brown, Calamia, Christianson,
Huston, Meschia, Hunder.
Statistical analysis. Brown, Christianson.
Funding assistance. Brown, Calamia.
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