Accepted Manuscript
Title: Frontal lobe dementia syndrome as a first manifestation
of primary angiitis of the central nervous system (PACNS)
Author: Marlene Bönstrup Katja Ott Markus Glatzel Tim
Magnus
PII:
DOI:
Reference:

S0303-8467(15)30103-7
http://dx.doi.org/doi:10.1016/j.clineuro.2015.12.016
CLINEU 4265

To appear in:

Clinical Neurology and Neurosurgery

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Revised date:
Accepted date:

2-6-2015
26-11-2015
25-12-2015

Please cite this article as: Bddotonstrup Marlene, Ott Katja, Glatzel Markus,
Magnus Tim.Frontal lobe dementia syndrome as a first manifestation of primary
angiitis of the central nervous system (PACNS).Clinical Neurology and Neurosurgery
http://dx.doi.org/10.1016/j.clineuro.2015.12.016
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FRONTAL LOBE DEMENTIA SYNDROME AS A FIRST MANIFESTATION OF
PRIMARY ANGIITIS OF THE CENTRAL NERVOUS SYSTEM (PACNS)

Marlene Bönstrup, Katja Ott, Markus Glatzel, Tim Magnus
Authors:
Dr. Marlene Bönstrup
DEPARTMENT OF NEUROLOGY, UNIVERSITY MEDICAL CENTER HAMBURG-EPPENDORF, Martinistraße 52, 20246
Hamburg, Germany, Tel.:+49-40- 74105 – 5531, Fax:+49-40- 74105 – 57391, m.boenstrup@uke.de
Katja Ott
DEPARTMENT OF PSYCHIATRY, UNIVERSITY MEDICAL CENTER HAMBURG-EPPENDORF, Martinistraße 52, 20246
Hamburg, Germany, k.ott@uke.de
Prof. Dr. Markus Glatzel
INSTITUTE OF NEUROPATHOLOGY, UNIVERSITY MEDICAL CENTER HAMBURG-EPPENDORF, Martinistraße 52, 20246
Hamburg, Germany, m.glatzel@uke.de
Prof. Dr. Tim Magnus
DEPARTMENT OF NEUROLOGY, UNIVERSITY MEDICAL CENTER HAMBURG-EPPENDORF, Martinistraße 52, 20246
Hamburg, Germany, t.magnus@uke.de
Corresponding author:
Dr. Marlene Bönstrup

Highlights




frontal lobe dysexecutive syndrome as a primary manifestation of PACNS
widespread cortical atrophy as the only pathological finding on imaging
indirect histopathological signs of vascular damage give the diagnosis

Abstract: This case presents a clinical course of a frontal lobe dysexecutive syndrome with
dementia caused by a Primary angiitis of the central nervous system (PACNS) of exclusively
very small vessels. Although the clinical manifestations are diverse, an isolated frontal lobe
dementia syndrome as a primary manifestation of PACNS has not been reported before. The
patient presented with a progressive cognitive decline with loss of memory, disinhibited
behavior, parathymic affect and frontal release signs. The diagnostic workup essentially
revealed a lymphocytic pleocytosis in the cerebrospinal fluid and a generalized cortical
atrophy without any vascular abnormalities. To grasp a diagnosis for this enigmatic clinical
picture of a frontal lobe syndrome with signs of inflammation we targeted a tissue-based
diagnosis. A brain biopsy gave the decisive hint towards a microvasculitis. Although the
histopathologic picture showed peculiarities, a destruction of the vascular bed of very small
vessels by lymphocytic infiltration was evident. Our case illustrates an uncommon clinical
picture of a PACNS and points to shortcomings of the current histopathologic criteria if only
very small vessels are involved.

Keywords: Primary angiitis of the central nervous system, cerebral vasculitis, frontal dysexecutive
syndrome

Introduction
Primary angiitis of the central nervous system (PACNS) is characterized by inflammation and
destruction of the walls of small- to medium sized parenchymal or leptomeningeal blood
vessels. It is a rare disease (2.4/1,000,000 inhabitants) limited to the brain and/or spinal cord
that is often lately diagnosed due to nonspecificity of bio- or imaging markers, mostly
unknown risk factors, and diverse symptomatology [1].
The diagnostic criteria, formulated by Callabrese and Mallek on the basis of clinical experience,
require i) an acquired neurological deficit of unknown origin after a thorough initial basic
assessment, ii) a cerebral angiogram with classic features of vasculitis or a biopsy showing
vasculitis and iii) no evidence of systemic vasculitis or any other disorder to which such a
finding could be secondary [2].
Most patients initially present with chronic and slowly progressive symptoms such as
headache, motor weakness, recurrent seizures or aphasia [1, 3] as focal neurologic signs.
Although frequently accompanied by cognitive deficits they rarely present the single or initial
manifestation of PACNS and are not further described in the literature. This article presents
an unusual case of a frontal lobe dysexecutive syndrome with dementia which turned out to
be the primary and isolated manifestation of a PACNS.
Case presentation
A 47-year old, previously well man presented with cognitive deficits progressing for one year.
On examination, he showed an atactic gait, a bilateral hand tremor with myoclonus,
dysfunctional fine motor skills, symmetric hyperreflexia and a positive glabbelar and
palmomental reflex as frontal release signs. Paraphasia and a cerebellar dysarthria marked his
speech. In social interaction he displayed inappropriate affect, a foolish attitude, deficits in
spatial reasoning, an erratic formal thought and subtle loss of memory. Most impressively was
his disinhibited behavior. All of which was preceded by an unintended weight loss of 20 kg.
Initial diagnostic work-up found an increased cell count in the cerebrospinal fluid (CSF) with
slightly elevated protein (43 cells/µl, 650 mg/l protein). Cells were predominantly of
lymphocytic type and showed no signs of malignancy. Infectious origin was excluded targeting
herpes simplex virus, varicella-zoster virus, cytomegalovirus, human immunodeficiency virus,
Hepatitis B/C, Listeria monocytogenes, Trophyerma whippeli and tuberculosis. A neoplastic
malignancy was suspected but excluded based on basic laboratory tests, tumor markers,
paraneoplastic antibodies (anti-Hu, -Ri, -Yo, -Tr, -Ma, -CV2.1, -Amphiphysin, AMPA, GABA-B,
CASPR2, LGI1), abdominal and thoracic CT, colo- and gastroscopy as well as a PET (positron
emission tomography)-CT. Tests for oligoclonal bands and proteins indicative of
neurodegeneration (protein 14-3-3-, amyloid beta 1-42, 1-40, total CSF tau protein and
phospho-tau, neuron specific enolase) were repeatedly negative. Antineuronal antibodies in
serum and liquor were repeatedly undetectable.

Interestingly, the first cMRI (1.5 Tesla), about 6-9 months after symptom onset, showed no
abnormalities. 6 months later however, for the first time and in subsequent studies, a
disproportionate cerebral atrophy was evident (figure 1). Contrast enhanced MR-angiograms
(CE-MRA) showed no vascular irregularities. The patient’s symptoms of a slowly progressive
decline of cognitive functions, mainly manifesting as apraxia and dementia, were
accompanied by some episodes of fever and elevated C-reactive protein (CRP).
Ultimately a brain biopsy gave the decisive hint towards the underlying disease: We detected
deposition of hemosiderin around small blood vessels using Prussian blue staining and a
rarefaction of elastic fibers in the Elastic Van Gieson stain (figure 2). This, together with
perivascular accumulation of inflammatory T-cells (CD3, CD8 > CD4), highly suggested the
diagnosis of an isolated vasculitis of small cerebral vessels, although the current principal
histopathological criteria were not fully met [4, 3]. In the bioptic sample we found
intraneuronal Aβ accumulations but no extracellular, especially vascular Aβ deposits.
After the diagnosis was made and almost 2 years after symptom onset, the patient was started
on immunosuppressive therapy with an initial bolus of intravenous methylprednisolone (3
days, 1g/d), six monthly administrations of cyclophosphamide at a dose of 750 mg/m2 BSA and
a maintenance therapy of weekly methotrexate 20 mg. This stabilized the course of the
disease.
Discussion
The presented case depicts the diagnostic challenges associated with PACNS due to an
uncommon clinical picture: Our patient presented with a relatively fast progressive frontal
dysexecutive syndrome as the main manifestation as well as constitutional symptoms
preceding cognitive decline. In first line the symptomatology was suggestive for a
neurodegenerative course like behavioral variant frontotemporal dementia or, due to the
presence of constitutional symptoms, which present only in 8% of PACNS patients [3], a
paraneoplastic origin. Finally, the repeatedly elevated cell count in CSF together with
abnormalities on cMRI led us to the assumption of an inflammatory origin . Diagnostic criteria
rely upon brain biopsy or cerebral angiogram which both have a limited sensitivity and
specificity in PACNs. Although the bioptic diagnosis is considered the gold standard, the
cerebral angiogram is increasingly conducted. It gives, however, only indirect signs of vasculitic
changes like symmetric narrowing of vessels, areas of dilation, beaded-vessel appearance
and/or displacement or occlusion of vessels of rather large to medium-sized vessels. These
signs can be mimicked by several entities including reversible vasospasms and atherosclerosis,
thus having a specificity as low as 30%. The biopsy however has a low sensitivity due to focal
and segmental changes and peripheral sampling, it may yield negative results in about 40% of
cases. It is often omitted because of its invasiveness. The sensitivity of either approach thus
differs in relation to the different vascular beds that are involved (overall sensitivity of biopsy
~62 % vs. angiography 73%, [5]). Our patient showed widespread cortical atrophy whereas the
CE-MRA showed no vascular abnormalities. This suggested involvement of small vessel in
which the diagnostic yield of biopsy over angiogram is higher due to the peripheral sampling.

In this case, a bioptic diagnosis should be aimed and it should target abnormalities close to
the leptomeninges to increase the sensitivity [3].
Of specific interest in the present case is the fact that the biopsy clearly suggested a
microvasculitic origin although the current histopathological criteria were not fully met. These
require a vasculocentric transmural inflammation marked by lymphocytic infiltration and
damage, with or without fibrinoid necrosis. Not mandatory, but often, granuloma formation
through the vascular wall is found or extracellular amyloid deposition in the vessel walls. Since
secondary involvement of vessels to an encephalitic or infectious process is common, a clear
dominance of vascular to parenchymal infiltration is required for differentiation [4]. In our
patient, since only very small vessels were involved, a transmural inflammation was not
directly traceable. We found however indirect signs, clearly pointing to a destruction of the
vascular integrity: leaky vessels, a decay of the vascular wall and perivascular infiltrations of
inflammatory T-cells (CD3, CD8 > CD4). The presence of vascular damage in areas of only little
parenchymal affection was decisive for the interpretation of a causal influence of vascular
destruction to parenchymal loss. In the context of a reduction in working memory capacities
in our patient we looked for distinguishing signs to a neurodegenerative process like in
Alzheimer’s disease. In fact neither extracellular plaque formation nor tau deposition was
detected so that we don’t attribute a pathophysiological role of this intracellular Aβ to the
clinical presentation of our patient.
Conclusion
Taken together a lot can be learnt from our case. In particular the unusual clinical presentation
highlights the protean manifestations of PACNS and teaches clinicians to consider PACNS even
if acute onset and vascular abnormalities in neuroimaging are lacking. This case calls for an
early tissue based diagnosis if involvement of small vessels is highly suspected.
Conflicts of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
Ethical standards and Consent
Written informed consent was obtained from the patients’ guardian for publication of this
Case report and any accompanying images. A copy of the written consent is available for
review by the Editor of this journal.
Authors' contributions
MB: clinical course, writing the manuscript
KO: clinical course
MG: neuropathologic diagnosis
TM: clinical course, writing the manuscript

References
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2. Calabrese LH, Mallek JA. Primary angiitis of the central nervous system. Report of 8 new
cases, review of the literature, and proposal for diagnostic criteria. Medicine (Baltimore).
1988;67(1):20-39.
3. Giannini C, Salvarani C, Hunder G, Brown RD. Primary central nervous system vasculitis:
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Figure legend

Figure 1 Axial T1 weighted cMRI 9 months after symptom onset (A) compared to 33 months
after symptom onset demonstrating widespread, generalized cortical atrophy especially at the
insular cortex, opercula with ventricular widening but also detectable at the frontal and
parietal lobes.

Figure 2 Pathologic features of microvasculitis. Hematoxylin and eosin (A) and Prussian blue
(C) staining showing hemosiderin around small blood vessels indicative of leaky vessels.
Perivascular and sparsely intramural accumulation of inflammatory T-cells (D, CD3) in the
absence of parenchymal inflammation. Rarefication of elastic fibers in the Elastic Van Gieson
stain (B).