Whittaker et al. BMC Neurology (2018) 18:161
https://doi.org/10.1186/s12883-018-1163-8

CASE REPORT

Open Access

Cerebral granulomatosis as a manifestation
of Crohn’s disease
Konrad Whittaker1* , Konstanze Guggenberger2, Nils Venhoff3, Soroush Doostkam4, Hans-Eckart Schaefer5
and Brita Fritsch1

Abstract
Background: Crohn’s disease (CD) is associated with a variety of extra-intestinal manifestations. Most commonly
these involve the eye, skin, joints, coagulation system and liver. Cerebral manifestations of CD have been reported
to a far lesser extent. The extensive detrimental impact of neurological symptoms on a patient’s quality of life
makes an early diagnosis and treatment particularly important. In previous case-reports, diagnosis of cerebral
manifestations in CD often relied upon magnetic resonance imaging (MRI) and computed tomography (CT) alone.
To our knowledge, only one case-report has documented a histologically confirmed case of cerebral lesions
associated with CD so far.
Case presentation: A 39-year-old right-handed woman with a history of CD was referred to our hospital with
etiologically unexplained Gadolinium (Gd)-enhancing cortical lesions, triggering epileptic seizures. A CT-scan of
the thorax and bronchoalveolar lavage found no signs of sarcoidosis. Lumbar punctures and laboratory testing
found no underlying infection or coincidental autoimmune disorders and MRI-scans showed progression of lesion load.
Consequently, the patient underwent stereotactic biopsy of a cortical lesion. Histological examination revealed a mixed
lympho-histiocytic and tuberculoid granulomatous inflammation surrounding small vessels and no signs for infection.
After exclusion of other granulomatous diseases and the typical histological findings we diagnosed a cerebral
granulomatosis as a manifestation of CD. The patient was initially started on azathioprine, which had to be
switched to corticosteroids and methotrexate because of an azathioprine related pancreatitis. The patient has
not suffered any further epileptic seizures to date.
Conclusion: Cerebral manifestation of CD is a possibly underreported entity that may respond well to immunosuppressive
treatment. In contrast to earlier reports of cerebral manifestations in CD, our patient showed no coincident gastrointestinal
symptoms indicating an activity of CD during the progression of cortical lesion load, suggesting that similar to
other extra-intestinal manifestations in CD, the activity of gastrointestinal symptoms does not necessarily reflect
the activity of CD associated cerebral vasculitis. Therefore, diagnosis and therapy of cerebral manifestation may
be delayed when focusing on gastrointestinal symptoms alone.
Keywords: Crohn’s disease, Cerebral vasculitis, Epilepsy, Central nervous system, Biopsy, Granulomatosis

Background
Crohn’s disease (CD) is an autoimmune disorder that
primarily affects the gastrointestinal tract, but manifests
itself in other organs as well [1]. The most common sites
of extra-intestinal manifestation are joints, skin, eyes,
coagulation system and liver. Cerebral manifestations of
CD have been reported to a far lesser extent, contrasting
* Correspondence: konrad.whittaker@uniklinik-freiburg.de
1
Department of Neurology and Neuroscience, Medical Center, University of
Freiburg, Breisacher Straße 64, D-79106 Freiburg, Germany
Full list of author information is available at the end of the article

the relatively high number of these reports in the context
of other inflammatory bowel diseases [2–4]. Most commonly, cerebral manifestations in CD are a consequence of
an affection of the coagulation system or a complication of
medication [1, 5]. The extensive detrimental impact of
neurological manifestations on a patient’s quality of life
makes early diagnosis and treatment particularly important.
In previous case-reports, diagnosis of cerebral manifestation in CD often relied upon MRI and CT alone
[6–10]. To our knowledge, only one case-report has

© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
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reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Whittaker et al. BMC Neurology (2018) 18:161

documented a histologically confirmed case of a cerebral manifestation in CD [11].

Case presentation
This 39-year-old right-handed female suffered from
epileptic seizures that began to develop in early 2014.
The epileptic seizures were initiated by dyscognitive
seizures and secondarily evolved into tonic-clonic
seizures. The patient was started on anticonvulsive
medication in August 2014 (Lamotrigin and Levetiracetam). Under this regimen, which was adapted regularly,
the frequency of seizures stabilized at about one seizure
every six months.
Some weeks prior to the first epileptic seizure, the
patient had complained of novel subacute bifrontal
headaches, which persisted intermittently over the
course of the following months and were not directly
correlated with the occurrence of epileptic seizures.
Additionally, she reported a subjectively progressive
impairment of her short-term memory. Her husband
reported a temporary change in his wife’s personality
during May 2015, which was accompanied by promiscuous behavior in social media and had not recurred since then.
Gastrointestinal symptoms (diarrhea, weight loss) had
occurred for the first time in 2003. The diagnosis of CD
was confirmed histologically via ileocolonoscopy in
2006. Symptoms were treated with a combination of
steroids and mesalazine (5-ASA) from 2006 to 2008
and with methotrexate (15 mg once per week) from
2008 to 2016. The patient reported lack of gastrointestinal symptoms since 2013. Apart from nicotine abuse
(25 pack-years) she reported no further comorbidities
and did not suffer from any allergies. There was no
family history of headaches, epilepsy, cancer and no exposure to toxic chemicals at home or at her workplace.
There were no signs for lymphomatoid granulomatosis
(no pulmonary and cutaneous lesions) or leukocyte oxidase deficiency (no recurrent infections). The patient
did not travel outside of Europe in her entire life.
Management and outcome
The first isolated dyscognitive seizure was interpreted
as a transient ischemic attack (aphasia) in early 2014
and the patient was started on aspirin 100 mg daily
after a cerebral hemorrhage was ruled out via computed tomography. In August 2014 the first secondarily
generalized seizure led to the initiation of a standard
MRI of the head, showing supratentorial Gd-enhancing
cortical lesions that were deemed ischemic or inflammatory
in nature. A lumbar puncture revealed an inflammatory
constellation (14 cells/μl, negative oligoclonal bands). Bronchoalveolar lavage (including CD4/CD8-ratio) and a CT of
the lungs were performed to test for (neuro-)sarcoidosis

Page 2 of 5

and provided normal results with no signs of perihilar
lymphadenopathy. Furthermore, laboratory tests showed
normal results for IL-2 receptor, ACE, neopterin, calcium,
as well as for anti-neutrophil cytoplasmic antibodies
(ANCA), anti-nuclear antibody (ANA) and anti-phospholipid-antibodies. An Interferon-gamma release
assay test (QuantiFERON®) remained negative. A second
MRI after two months (October 2014) showed further progression of the cortical lesions. Subsequently, the immunosuppressive therapy with methotrexate was complemented
with steroids (initially 80 mg prednisolone, gradual reduction to 5 mg daily). A subsequent MRI in February
2015 showed a stable lesion load. Epileptic seizures in
March, June and December 2015 as well as in March
2016 did not lead to adjustments of anticonvulsant or
immunosuppressive therapy or to additional diagnostic measures.
In April 2016 the patient was referred to our university
center for epilepsy. Here, the dosage of the anticonvulsive
medication was increased and another MRI was initiated
(August 2016), which showed an increase of lesions
with numerous bihemispheric, hemorrhagically imbibed
lesions of the cortex, basal ganglia, midbrain and pons.
Gadolinium-enhancing lesions were revealed in both
corpora amygdaloidea and cortically in both inferior
frontal gyri, the left frontal medial gyrus, the left postcentral gyrus as well as in temporo-occipital and occipital regions in both hemispheres. Additionally, the MRI
showed bilateral hippocampal atrophy and hyperintensity
(Fig. 1). A comparative assessment between the MRI-scans
was made difficult by their qualitative differences. A clear
progression of lesion load could therefore only be established in comparison to the MRI-scans from 2014. Another
lumbar puncture confirmed the previous pleocytosis (8
cells/μl, protein 508 mg/l) and now revealed positive oligoclonal bands in the cerebrospinal fluid (CSF). Antineural
(Hu, Yo, Ri, CV2/CRMP5, amphiphysin, Ma1, Ma2, SOX1,
GAD65, Tr(DNER), Zic4) and autoimmune encephalitis
antibodies (VGKC (LGI1, CASPR2), GABA B, NMDA,
AMPA1, AMPA2) remained negative in CSF and
serum in two independent laboratories. Serum analysis
of ANA, ANCA, phospholipid antibodies and rheumatoid factor remained negative as well. Complement
factors were at normal levels. A neuropsychological
test revealed depressive symptoms and potentially related impairments in attention, executive functions
and long-term memory.
In September 2016 the patient was referred to our
department of neurology via our colleagues at the university center for epilepsy in order to assess cerebral
vasculitis. We performed another lumbar puncture (3
cells/μl, protein 584 mg/l) including antibody-tests for
borrelia burgdorferi and treponema pallidum, polymerase
chain reaction (PCR) tests for Herpes simplex viruses 1

Whittaker et al. BMC Neurology (2018) 18:161

Page 3 of 5

A

B

C

D

E

F

Fig. 1 MRI-imaging reveals progressive atrophy of the temporal structures (a, b) and a new signal increase of the corpora amygdaloidea and
hippocampi in FLAIR weighted sequences (c) over the course of time. Several spots of cortical hyperintensities are present in FLAIR weighted
imaging (d). A faint contrast enhancement can be detected in the bihemsipheric cortex (e) and the corpora amygdaloidea (c). Mesencephalic
and cortical hemorrhage (f) suggest an inflammatory process with microvascular vasculitis or an infectious or granulomatous genesis as possible
differential diagnoses

and 2, Varicella-zoster virus, tropheryma whipplei and a
HIV-test, which remained negative. An ultrasonography
of the extra- and intracranial arteries of the neck and brain
showed no signs of a vasculitis of the large vessels. The
biomarkers for sarcoidosis (IL2-receptor, ACE, beta-2-microglobulin, lysozyme, neopterin) remained negative, as
did proteinase3 antineutrophil cytoplasmic antibodies
(PR3-ANCA), perinuclear anti-neutrophil cytoplasmic
antibodies (p-ANCA) and blood cultures. There were
no abnormalities in the differential blood count and in
the immunoglobulins. A fluorescein angiography of the
retina was performed in the department of Neuro-ophthalmology to test for a small-vessel vasculitis and Susac’s syndrome and revealed normal results.
After completion of above-mentioned diagnostics,
an interdisciplinary consent was reached to perform
a stereotactic biopsy of one of the cortical lesions.
Histology revealed leptomeningeal mixed mononuclear round cell infiltrates and multifocal mixed
lympho-histiocytic and tuberculoid granulomatous lesions surrounding small vessels confirming the diagnosis of a cerebral granulomatosis (Fig. 2a-h).
Histological, enzyme- and immunohistochemical
examination showed no signs of infection with

toxoplasmosis, mycobacteria or other bacteria or
fungi as well as no signs for Amyloid-Beta Related
Angiitis of the Central Nervous System (ABRA).
There were no caseating and no geographical
necroses.
On the basis of the histological analysis and negative
tests for infectious causes we diagnosed a cerebral granulomatosis as a manifestation of Crohn’s disease in the
central nervous system and began immunosuppressive
treatment with azathioprine, which had to be switched
to methotrexate and corticosteroids because of an azathioprine related pancreatitis. To date, the patient has
not suffered any further epileptic seizures and revealed
no signs of cognitive deterioration in the outpatient
follow-ups.

Discussion and conclusions
Cerebral manifestation of CD is a possibly underreported entity [5, 12, 13], which may respond well to
immunosuppressive treatment [11]. In contrast to
earlier reports of similar cases, our patient showed no
clinical signs of an activity of CD during the progression of
cortical lesion load. Similarly to other extra-intestinal manifestations in CD [14], the activity of gastrointestinal

Whittaker et al. BMC Neurology (2018) 18:161

Page 4 of 5

Fig. 2 a, b Early granuloma formation, surrounding small blood vessels marked by asterics (*). a Immunohistochemical staining for CD3+
T-lymphocytes (brown staining). Serial sections (not depicted here) disclose an identical distribution of predominating CD4+ T-helper cells.
b Serial section of the same vessel as shown in (a) at a higher magnification with CD68+ macrophages gathering at subintimal and
adventitial spaces. c, d Full-blown granulomas. c Haematoxylin-Eosin staining displays a dense plasmocytic infiltrate at the left upper
corner. The right lower corner encompasses a tuberculoid granuloma dominated by epithelioid cells and multinucleated Langhans-type
giant cells. d A large granulomatous complex is embedded into sharply confined neuropil, highlighted by immunohistochemical staining
for glial fibrillary acidic protein (brown colour). e-h Miscellaneous aspects of granuloma histiocytes. e Enzyme-histochemical staining for
tartrate-resistant acid phosphatase (red colour) discloses a high activity of this particular isoenzyme of acid phosphatase, typically upregulated in
mature macrophages involved in chronic lysosomal lipid degradation. f Periodic acid Schiff staining (PAS, red colour). A centrally placed foam cell contains
translucent lipid vacuoles and few PAS+ ceroid-like granules. Additional smaller-sized macrophages are storing ceroid-like granules exclusively, whithout
visible lipid vauoles. At the periphery of the graph, there are several gemistocytic astrocytes with large swollen PAS-negative cytoplasm. g Clustering PAS+
ceroid-storing macrophages fuse to multinucleated giant cells, partially of Touton-type (Tt). h On Giemsa-staining, some giant macrophages adopt a
phenotype of sea-blue histiocytes

symptoms does not seem to be a reliable parameter in
assessing the activity of cerebral granulomatosis.
Therefore, diagnosis and therapy in CD may be delayed when the diagnostic focus lies on gastrointestinal symptoms alone. In our patient, time between

symptom onset and diagnosis was two and a half
years. To reduce progress of morbidity, an early
stereotactic biopsy may be indicated in cases, in which
MRI-scans are not sufficient for confidently assessing
the etiology of progressive cerebral lesions.

Whittaker et al. BMC Neurology (2018) 18:161

Page 5 of 5

Abbreviations
5-ASA: Mesalazine; ABRA: Amyloid-Beta Related Angiitis of the Central
Nervous System; ACE: Angiotensin-converting enzyme; ANA: Anti-nuclear
antibody; ANCA: Anti-neutrophil cytoplasmic antibody; CD: Crohn’s disease;
CSF: Cerebrospinal fluid; CT: Computed tomography; CT: Computed
tomography; Gd: Gadolinium; HIV: Human immunodeficiency virus;
MRI: Magnetic resonance imaging; p-ANCA: Perinuclear Anti-Neutrophil Cytoplasmic Antibodies; PCR: Polymerase chain reaction; PR3-ANCA : Proteinase-3
antineutrophil cytoplasmic antibodies

5.

Acknowledgements
The authors would like to thank their patient for participation in this study
and Dr. Schneider for supplying to us the original colon biopsy.

8.

6.

7.

9.
Funding
The article processing charge was funded by the German Research Foundation
(DFG) and the University of Freiburg in the funding programme Open Access
Publishing.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated
or analyzed during the current study.

10.

11.

12.
Authors’ contributions
All authors have read and approved the manuscript and contributed
significantly to the submitted work: KW, NV and BF treated the case-patient
at the Freiburg center and drafted the manuscript, KG analyzed the MRI and
SD and HS analyzed the histological samples.

13.
14.

Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient 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.
Competing interests
The authors declare that they have no competing interests.

Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Author details
1
Department of Neurology and Neuroscience, Medical Center, University of
Freiburg, Breisacher Straße 64, D-79106 Freiburg, Germany. 2Department of
Neuroradiology, University of Freiburg, Breisacher Straße 64, D-79106
Freiburg, Germany. 3Department of Rheumatology and Clinical Immunology,
University of Freiburg, Breisacher Straße 64, D-79106 Freiburg, Germany.
4
Department of Neuropathology, University of Freiburg, Breisacher Straße 64,
D-79106 Freiburg, Germany. 5Department of Clinical Pathology, University of
Freiburg, Breisacher Straße 64, D-79106 Freiburg, Germany.
Received: 29 January 2018 Accepted: 24 September 2018

Bibliography
1. Casella G, Tontini GE, Bassotti G, Pastorelli L, Villanacci V, Spina L, et al.
Neurological disorders and inflammatory bowel diseases. World J
Gastroenterol. 2014;20(27):8764–82.
2. Unnikrishnan A, Azodi S, Ansari N, Brown M, Kamnetz J, Uchiyama RC.
PR3ANCA related cerebral Vasculitis in ulcerative colitis presenting with
orbital involvement: a case report with review of literature. Case Rep
Rheumatol. 2014;2014:582094.
3. Bonrath EM, Rijcken E, Dziewas R, Vieth V, Bettenworth D, Senninger N,
Brüwer M. Cerebral Vasculitis as rare Extraintestinal manifestation in
ulcerative colitis: Review of the Literature and Case Report. Zentralbl Chir.
2010;135(4):350–3.
4. Scheid R, Teich N. Neurologic manifestations of ulcerative colitis. Eur J
Neurol. 2007;14(5):483–93.

Katsanos AH, Kosmidou M, Giannopoulos S, Katsanos KH, Tsivgoulis G, Kyritsis
AP, et al. Cerebral arterial infarction in inflammatory bowel diseases. Eur J
Intern Med European Federation of Internal Medicine. 2014;25(1):37–44.
Ullrich S, Schinke S, Both M, Knop KC, Kirkiles-Smith NC, Gross WL, et al.
Refractory central nervous system Vasculitis and gastrocnemius myalgia
syndrome in Crohn’s disease successfully treated with anti-tumor necrosis
factor-α antibody. Semin Arthritis Rheum Elsevier Inc. 2009;38(5):337–47.
Schluter A, Krasnianski M, Krivokuca M, Spielmann RP, Neudecker S, Hirsch
W. Magnetic resonance angiography in a patient with Crohn’s disease
associated cerebral vasculitis. Clin Neurol Neurosurg. 2004;106(2):110–3.
Holzer K, Esposito L, Stimmer H, Hemmer B, Poppert H. Cerebral vasculitis
mimicking migraine with aura in a patient with Crohn's disease. Acta Neurol
Belg. 2009;109(1):44–8.
Brohee P, Violon P, Mavroudakis N, Pirotte B, Brotchi J, Zegers de Beyl D, et
al. Central nervous system lesions associated with Crohn’s disease. J
Neuroimaging. 1997;7(3):195–8.
Garge SS, Vyas PD, Modi PD, Ghatge S. Crohns disease with central nervous
system vasculitis causing subarachnoid hemorrhage due to aneurysm and
cerebral ischemic stroke. Ann Indian Acad Neurol. 2014;17(4):444–7.
Gekka M, Sugiyama T, Nomura M, Kato Y, Nishihara H, Asaoka K.
Histologically confirmed case of cerebral vasculitis associated with Crohn’s
disease -a case report. BMC Neurol. 2015;15:169.
Zikou AK, Kosmidou M, Astrakas LG, Tzarouchi LC, Tsianos E, Argyropoulou
MI. Brain involvement in patients with inflammatory bowel disease: a voxelbased morphometry and diffusion tensor imaging study. Eur Radiol.
2014;24(10):2499–506.
Lossos A, River Y, Eliakim A, Steiner I. Neurologic aspects of inflammatory
bowel disease. Neurology. 1995;45(3 Pt 1):416–21.
Levine J, Burakoff R. Extraintestinal manifestations of inflammatory bowel
disease. Gastroenterol Hepatol. 2011;7(4):235–41.