Case Report

Erdheim–Chester Disease: An Unusual Cause of Intracranial
Vasculitis and Progressive Leukoencephalopathy
Sharmila Sagnier, MD,*† Sabrina Debruxelles, MD,* Sébastien Lepreux, MD, PhD,†‡
and Igor Sibon, MD, PhD*†

Erdheim–Chester disease (ECD) is a non-Langerhans histiocytosis affecting multiple organs. Stroke as symptom onset of ECD with intracranial vasculitis is unusual.
We report the case of a 64-year-old man who presented with an acute ischemic
stroke associated with a moderate leukoencephalopathy and intracranial arteries
stenosis. Four years later, he developed movement disorders with dysarthria and
cognitive impairment. Neuroradiological findings demonstrated a rapidly progressive and diffuse leukoencephalopathy associated with brain atrophy and
infiltration of the intracranial vertebral artery wall. Brain postmortem evaluation
confirmed the diagnosis of ECD. This diagnosis should be evoked in patients with
cryptogenic stroke, progressive leukoencephalopathy, and infiltration of the arterial wall. Key Words: Erdheim–Chester disease—stroke—diffuse progressive
leukoencephalopathy—brain atrophy—vasculitis.
© 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.

From the *Unité Neuro-vasculaire, CHU de Bordeaux, Bordeaux,
France; †Université Bordeaux Segalen, CHU de Bordeaux, Bordeaux, France; and ‡Laboratoire d’Anatomo-Pathologie, CHU de
Bordeaux, Bordeaux, France.
Received November 9, 2015; revision received January 25, 2016;
accepted January 29, 2016.
Authors’ contributions: Dr. Sagnier: drafting and redaction of the
manuscript, critical revision, final approval, and agreement to be accountable for all aspects of the work; Dr. Debruxelles: acquisition
of data, revision, final approval, and agreement to be accountable
for all aspects of the work; Dr. Lepreux: acquisition, interpretation
of anatomopathological data, critical revision, final approval, and
agreement to be accountable for all aspects of the work; Dr. Sibon:
conception and design of the work, critical revision, final approval,
and agreement to be accountable for all aspects of the work.
Address correspondence to Igor Sibon, MD, PhD, Unité Neurovasculaire, Pôle de Neurosciences Cliniques, Hôpital Pellegrin, CHU
Bordeaux, Université Bordeaux Segalen, 33076 Bordeaux, France.
E-mail: igor.sibon@chu-bordeaux.fr.
1052-3057/$ - see front matter
© 2016 National Stroke Association. Published by Elsevier Inc. All
rights reserved.
http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2016.01.042

Introduction
Erdheim–Chester disease (ECD) is a non-Langerhans
histiocytosis due to a clonal and inflammatory disorder
most frequently related to BRAFV600E mutation1 and exceptionally revealed by a stroke and brain vasculitis. The
diagnosis of this rare disorder is frequently delayed, from
9 months to 12 years.2 History of diffuse long bone pain
and diabetes insipidus should lead clinicians to suspect
the diagnosis of ECD,1,2 but all organs can be affected,
contributing to nonspecific symptoms such as asthenia
or fever. The prognosis is reported to be poor but can
vary according to the organs involved.

Observation
A 64-year-old man was admitted for sudden aphasia
and paresis of the right arm and face (National Institutes of Health Stroke Scale score = 7). He only had history
of chronic hypertension. Brain magnetic resonance imaging

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S. SAGNIER ET AL.

Figure 1. Evolution of brain MRI and brain postmortem histopathological findings. Axial DWI sequence (A) demonstrates the infarct lesion in the left
deep middle cerebral artery territory. Axial FLAIR sequences show the rapid progressive leukoencephalopathy and brain atrophy (B) after 3 (C) and 4 (D)
years of evolution. TOF reconstructions of the polygon of Willis (E) demonstrates stenosis of the intracranial portion of the left vertebral artery associated
with stenosis of the left middle and anterior cerebral arteries. Axial T1-weighted imaging shows intracranial periarterial sheathing of the vertebral arteries
with gadolinium enhancement (F). Fusion between MRI and 18FDG–PET imaging illustrates radiotracer uptake in the vertebral artery wall (G). Brain
postmortem evaluation demonstrates fibrosis and infiltration of the vertebral artery wall by foamy histiocytes and giant cells (Hematoxylin Eosin Saffron
[HES]) (H) that express CD68 (immunohistochemistry) (I). Immunohistochemistry with anti-CD68 antibody reveals also small foci of positive histiocytes
in the splenium corpus callosum (J). In addition, periventricular white matter showed myelin and axonal loss, astrogliosis, interstitial edema, and microscopic infarctions. Abbreviations: DWI, diffusion-weighted imaging; 18FDG-PET, 18-fluoro-deoxyglucose positron emission tomography; FLAIR, fluidattenuated inversion recovery; MRI, magnetic resonance imaging; TOF, time of flight.

found a recent infarct in the left deep middle cerebral
artery territory and a moderate leukoencephalopathy (Fig 1,
A). Computed tomography angiography showed a not
significant stenosis of the left middle and anterior cerebral arteries (M1 and A1). A diagnosis of stroke related
to intracranial artery stenosis probably due to atherosclerosis was evoked. Three years later, he presented a
vertebral-basilar transient ischemic attack with a slight
progression of the leukoencephalopathy (Fig 1, C). One
year later, his neurological status rapidly worsened, including dystonia, gait disturbances, dysarthria and cognitive

impairment. Brain magnetic resonance imaging demonstrated an extension of the leukoencephalopathy with brain
atrophy, but without stroke recurrence. We observed the
previously known intracranial stenosis together with a
stenosis of the intracranial segment of the vertebral arteries, which were sheathed by a contrast-enhanced
perivascular sleeve (Fig 1, E,F). Abdominal computed tomography demonstrated periaortic sheathing, infiltration
of mesenteric and perirenal fat with a typical “hairy
kidney” appearance, and technetium 99m bone
scan showed moderate radiotracer uptake in the

ECD CAUSES INTRACRANIAL VASCULITIS AND LEUKOENCEPHALOPATHY

metaphyseal area of the tibias. 18-Fluoro-deoxyglucose
positron emission tomography scan revealed a hypermetabolism of the aortic and vertebral artery walls (Fig 1,
G). A leukocyte infiltrate with CD68-positive histiocytes
was observed on perirenal fat biopsy. BRAFV600E sporadic mutation was positive.
Two cures of infliximab (5 mg/kg), a tumor necrosis
factor alpha inhibitor, were administered intravenously
at a 15-day interval without any significant improvement. The patient’s condition rapidly became worse until
he finally succumbed to his disease. Brain postmortem
examination identified typical foamy histiocytes that expressed CD68 (Fig 1, H-J) but not S100 protein nor CD1a
in the arterial wall of intracranial arteries and, to a lesser
extent, in the brain parenchyma, confirming the diagnosis of ECD.

Discussion
Central nervous system (CNS) manifestations of ECD
are usually related to the infiltration of the brain parenchyma by abnormal cells, with a predominance of lesions
occurring in the posterior fossa.1,3,4 Stroke is an uncommon presentation and has never been described to our
knowledge. In the present case, stroke was due to an intracranial periarterial infiltration, which is a rare and most
often asymptomatic presentation in ECD.3 While intracranial localization is unusual, other periarterial infiltrations
are more typical, such as sheathing of the thoracic and
abdominal aortas described in up to 60% of the patients.1
We also observed a diffuse and progressive leukoencephalopathy probably due to a chronic hypoperfusion
related to intracranial vasculitis rather than to an infiltration of foamy histiocytes that prevailed in the splenium
corpus callosum. Leukoencephalopathy-like patterns involving periventricular white matter with brain atrophy
are known lesions in Langerhans cell histiocytosis and
are usually associated with poor outcome.5 Similarly, our
patient had rapid neurological deterioration. This is in
accordance with previous studies that reported a poor
prognosis in ECD patients with involvement of the CNS
and the cardiovascular system.1,2,6 In a large series of 53
patients, 14 patients died after a median follow-up of 55.9
months from disease onset, and four of them died from
rapid or slow CNS involvement.6
To date, only interferon-α has been described to be a
major predictor of survival,6 and infliximab is consid-

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ered as a second-line therapy. Vemurafenib, a BRAF
inhibitor actually in clinical trial, showed efficacy in patients with multisystemic and refractory ECD harboring
the BRAFV600E mutation.7,8 Unfortunately, this treatment was not started due to the rapid clinical worsening
of the patient.
Finally, although stroke with brain vasculitis is uncommon in ECD, the more typical extraneurological signs
found in our patient, including periaortic sheathing, hairy
kidney appearance, and infiltration of the tibias metaphysis, allowed the diagnosis. Such signs should alert the
stroke clinician.

Conclusion
This observation illustrates the variability of neurological involvement in ECD and reminds clinicians of the
need to pursue etiologic investigations in the case of atypical stroke presentation.

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