Medicine

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Clinical Case Report

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Medial medullary infarction caused
by antineutrophil cytoplasmic
antibody-related vasculitis
Case report and review of the literature
∗

Kumi Yanagiha, MDa, Kazuhiro Ishii, MD, PhDa, , Tomoyuki Ueno, MDb, Aiki Marushima, MD, PhDc,
Akira Tamaoka, MD, PhDa
Abstract
Rationale: Medial medullary infarction accounts for less than 1% of brain infarctions, and medial medullary infarctions is very rarely

caused by antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.
Patient concerns: We report the case of a 76-year-old man at low risk of arteriosclerosis who presented with disorders on the left
side including gaze-evoked nystagmus, paralysis of the extremities, pyramidal signs, sensory disturbance, and dysesthesia. Brain
magnetic resonance imaging also showed right medial medullary infarction.
Diagnoses: Medial medullary infarction caused by ANCA-related vasculitis was diagnosed based on mild renal dysfunction and
high levels of blood leukocytes, C-reactive protein (CRP), and myeloperoxidase (MPO)-ANCA.
Interventions and outcomes: He underwent two 3-day courses of steroid pulse therapy involving daily 1000 mg doses of
methylpredonine. He then received 30 mg/day (0.5 mg/kg/day) of prednisolone (PSL) without other immunosuppressants. Levels of
MPO-ANCA and the inflammatory marker CRP decreased rapidly a month after admission. Once MPO-ANCA became
undetectable, the PSL dose was carefully reduced to 10 mg/day. To treat his paralysis, we provided rehabilitation with a Hybrid
Assistive Limb five times starting at a month post-onset. His Barthel index score rose from 45 to 70 points.
Lessons: Medullary infarction is mostly caused by arteriosclerosis and vertebral arterial dissection. When systemic inflammatory
findings are obtained, ANCA-associated vasculitis should be considered a potential cause, and steroid pulse therapy should be
promptly administered.
Abbreviations: ANCA = antineutrophil cytoplasmic antibody, CRP = C-reactive protein, CT = computed tomography, MPO =

myeloperoxidase, MRI = magnetic resonance imaging, PSL = prednisolone, s-IL2R = interleukin-2 receptor.

Keywords: ANCA-related vasculitis, hybrid assistive limb, medial medullary infarction, MPO-ANCA

brain infarctions), artery dissection (15%), small-vessel infarction (13%), cardiac thrombosis (5%), and Moyamoya disease
(<1%).[2] In rare cases of antineutrophil cytoplasmic antibody
(ANCA)-associated vasculitis, the initial symptoms are those of
cerebral infarction, which is difficult to distinguish from
atherothrombotic cerebral infarction, leading to possible treatment delays. We report a case of medial medullary infarction
caused by ANCA-associated vasculitis that was effectively treated
with steroid pulse therapy.

1. Introduction
Medial medullary infarction accounts for <1% of brain
infarctions[1] and is usually caused by atherothrombotic brain
infarction. Other causes include large-vessel infarction (50% of
Editor: Raouf Hajji.
This study was supported by Grants-in-Aid for Scientific Research from the
Japanese Ministry of Health, Labour and Welfare’s Industrial Disease Clinical
Research Grants (14060101-01).
The authors report no conflicts of interest.

2. Case report

a

Department of Neurology, b Department of Rehabilitation Medicine, University of
Tsukuba Hospital, c Department of Emergency and Critical Care Medicine,
Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba,
Ibaraki, Japan.

A 76-year-old man noticed bilateral edema in his lower legs and
livedo reticularis and a weight gain of 4 kg 1 month before being
transferred to our hospital. Eleven days before the transfer, he
suddenly felt dizzy at work and became unable to walk. Because
weakness in the left extremities and dysarthria occurred
simultaneously, he visited a nearby hospital and was diagnosed
with a brainstem infarction using brain magnetic resonance
imaging (MRI). Because hypertension was noticed in a medical
appointment earlier in the year, he had been receiving oral
amlodipine (2.5 mg/day), and his blood pressure was favorably
controlled. Although he received antiplatelet therapy (intravenous infusion of ozagrel [160 mg/day], aspirin [100 mg/day], and
cilostazol [100 mg/day]), left limb paralysis and dysarthria
progressed. In addition, his renal function deteriorated (creati-

∗

Correspondence: Kazuhiro Ishii, Department of Neurology, Division of Clinical
Medicine, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennoudai,
Tsukuba-shi, Ibaraki 305-8575, Japan (e-mail: kazishii@md.tsukuba.ac.jp).

Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc.
This is an open access article distributed under the terms of the Creative
Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NCND), where it is permissible to download and share the work provided it is
properly cited. The work cannot be changed in any way or used commercially
without permission from the journal.
Medicine (2017) 96:33(e7722)
Received: 18 April 2017 / Received in final form: 14 July 2017 / Accepted: 17
July 2017
http://dx.doi.org/10.1097/MD.0000000000007722

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nine [Cre]: 1.3 mg/dL), and a myeloperoxidase (MPO)-ANCA
test result was highly positive. Because cerebral infarction
associated with the vasculitis was suspected, he was therefore
transferred to our hospital,
In a physical examination on admission, he was alert, had mild
hypertension (146/84 mmHg), and had a regular pulse (81 beats/
min). In a neurologic examination, he exhibited gaze-evoked
nystagmus when looking to the left. He had dysarthria,
dysphagia, and an impaired gag reflex. He had bilateral Babinski
and Chaddock signs during extension, dysesthesia, and left-side
extremity disorders including paresis, enhanced tendon reflexes,
and impaired positional and tactile senses. He could sit upright
but could not stand or walk independently. Neither cerebellar
ataxia nor autonomic system dysfunction was observed.
Laboratory tests showed 20 to 99 red blood cells per high
power field and 5 to 9 granular casts per whole field in the urinary
sediment, leading us to suspect nephritis. We therefore ran
various serological tests to assess the likelihood of nephritis. The
white blood cell count was high (11,000 cells/mL), and anemia
was observed (hemoglobin: 8.6 g/dL). A coagulation test showed
a prolonged activated partial thromboplastin time (43.6 s). Mild
hepatic dysfunction was observed. Glucose tolerance was
normal. Elevating C-reactive protein (CRP: 6.93 mg/dL) and
normal procalcitonin (0.10 mg/dL) showed systemic inflammation without any bacterial infections. The immunoglobulin levels
in the g-globulin fraction and among complement proteins were
normal. Antinuclear antibodies were not detected. Blood analysis
revealed reduced levels of anti-DNA antibodies (<4 IU/mL) and
anti-proteinase 3-ANCA (<1.0 U/mL) and a high level of MPOANCA (130.0 U/mL). The soluble interleukin-2 receptor (s-IL2R)
level was 981 U/mL, and the rheumatoid factor level was 6 U/mL.
Neither anti-Anti-Sjögren-syndrome-related antigen A nor antigen B antibodies were detected, and complement protein levels
were within the normal range. Tumor marker levels were normal.
The absence of serological abnormalities disproved our suspicion
of nephritis and made us instead suspect a hepatitis B or C
infection. We next ran several tests to assess the likelihood of
hepatitis infection. The lack of any observed abnormalities led us
to reject the possibility of a hepatitis infection.
An analysis of cerebrospinal fluid showed a cell count of 0 cells/
mL, a protein concentration of 46 mg/dL, a glucose concentration
of 62 mg/dL (simultaneous blood glucose: 116 mg/dL), and an sIL2R concentration of <50.0 U/mL, all within normal ranges. No
abnormalities were observed in electrocardiograms or chest and
abdominal x-rays.
Brain MRI at 2 weeks after onset showed medial medullary
infarction in diffusion-weighted imaging and T2-weighted
imaging. When compared with MRI scans from the previous
hospital, there was no obvious infarct enlargement or new infarct
development (Fig. 1).
A carotid ultrasound did not show any clear plaque lesions on
either side. Contrast-enhanced chest computed tomography (CT)
did not show thickening or irregular width of the aortic vascular
wall. Although minor pleural effusion was detected, chest CT
revealed no lesion suggestive of vasculitis. From these findings,
we denied suspicion of the large-vessel and/or medium-vessel
vasculitis.
A bilateral limb nerve conduction study found no abnormalities. A neurological examination revealed left-dominant paresis
of all four extremities, dysarthria, dysphagia, and enhanced
tendon reflexes of the left extremities and MRI revealed right-side
medial medullary infarction. Based on the detection of MPOANCA and systemic inflammation that was not attributable to

Figure 1. Brain magnetic resonance imaging at 2 weeks after onset showed a
hyperintensity lesion in the right medial medulla oblongata on diffusionweighted imaging and T2-weighted imaging. No clear infarct enlargement or
suspicious new infarcts were observed in comparison with MRI scans taken at
the previous hospital. We observed nonspecific high-signal intensity lesions in
the deep white matter on T2-WI.

infection, we strongly suspected ANCA-associated vasculitis, but
we could not perform a renal biopsy. We diagnosed cerebral
lesion-limited ANCA-associated vasculitis with medullary infarction as an initial symptom. In screening for risk factors,
carotid ultrasound imaging revealed no arteriosclerotic lesions,
and we considered atherothrombotic brain infarction highly
unlikely to be a risk factor, so the patient’s favorably controlled
hypertension was the only risk factor.
Because there was no adequate evidence to perform immunotherapy in patients with advanced age or in cases, such as ours,
without lesions in other organs, we referred to Japanese
guidelines,[3] and chose steroid pulse therapy. We performed 2
courses of steroid pulse therapy on post-onset day 12 and
prescribed 30 mg of orally administered prednisolone (PSL) for
posttreatment. The inflammatory response (CRP >6 mg/dL)
rapidly declined, and the MPO-ANCA level gradually decreased.
PSL was continued at 30 mg/day until the MPO-ANCA and CRP
level decreased to <10 U/mL and <0.03 mg/dL, respectively. On
post-onset day 43, both MPO-ANCA and CRP levels had
decreased.
Activities of daily living improved through rehabilitation. We
performed gait training with a hybrid assistive limb (HAL) 5
times beginning a month after onset.[4] The patient’s Barthel
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Table 1
Reported cases of the ANCA-related vasculitis that presented medullary infarction.
Reports

Age/sex

Lesion

Affected organ

72 M

Medial medullary

Renal; renal biopsy (+)

Tarachenko et al[9]

41 M

Medial medullary

Renal; renal biopsy (+)

Ozkul et al[10]

55 F

Lateral medullary

Bares et al[11]

52 F

Lateral medullary

Auditory nerve, retina,
lung; Nerve biopsy (+)
Renal; renal biopsy (+)

Fauset et al[12]

49 M

Lateral medullary

Present case

76 M

Medial medullary

Chen et al

[8]

Lung, renal, peripheral
nerve
Renal

Onset of medullary infarction
One month before renal
dysfunction
One week before renal
dysfunction
One day before fever
Three month before renal
dysfunction
One month after peripheral neurologic
symptoms
Presenting symptom

ANCA antibody titer

Therapy

P-ANCA; 788 U/mL

PE 4 times, Steroid
pulse Tx + IVCY
PE 5 times, Steroid
pulse Tx + IVCY
Steroid pulse Tx,
PSL 80 mg + IVCY
PSL + IVCY

C-ANCA; 100 U/mL
P-ANCA; 87.5 U/mL
C-ANCA; 320 times
C-ANCA; 160 times
P-ANCA; 130 U/mL

Steroid pulse Tx,
PSL 125 mg + IVCY
Steroid pulse Tx,
PSL 30mg

P-ANCA (= MPO-ANCA) = perinuclear antineutrophil cytoplasm autoantibodies, C-ANCA(= PR3-ANCA) = cytoplasmic antineutrophil cytoplasm autoantibodies, PE = plasma exchange, PSL = prednisolone,
IVCY = intermittent pulse intravenous cyclophosphamide therapy.

symptoms, including sinusitis or otitis media, and vasculitis lesions
on chest CT; therefore, granulomatosis with polyangiitis was
excluded, too. Finally, because he does not have asthma, allergic
rhinitis, eosinophilia, or IgE elevation until now, a diagnosis of
eosinophilic granulomatosis with polyangitis was unlikely.
Because CRP and MPO-ANCA titer moved parallel to the
disease activity, and skin lesions associated with livedo reticulata
and renal dysfunction were observed, we diagnosed this case as
cerebral lesion-limited ANCA-associated vasculitis with the
exclusion of other possible vasculitis.
There are some limitations about the diagnosis of our case.
First, the diagnosis was not confirmed pathologically; second, no
abnormalities were found in main target organs, such as the
kidneys or lungs.
Medullary infarction is less common than cerebral infarction.
Lateral medullary infarction accounts for no >2.5% of all
reported cerebral infarction cases, and medial medullary
infarction accounts for no >1%.[1] In addition, Toyoda et al[7]
reported observing 11 cases (0.52%) of medullary infarction
among 2130 brain infarction cases. The risk factors for medial
medullary syndrome (MMS) and lateral medullary syndrome
(LMS)[1,2] include hypertension (seen in 64%–89% of MMS
patients and 75% of LMS patients, respectively), diabetes
(25%–27% and 37%, respectively), recent smoking history
(6.8%–25% and 25%, respectively), and dyslipidemia (20% and
12%, respectively). Vasculitis is an extremely rare cause.
Only 5 cases of ANCA-associated vasculitis with medullary
infarction have been previously reported (Table 1).[8–12] The
patients in these cases were slightly younger (range: 41–72 years)
than ours. The lesion sites included the medial (n = 2) and lateral
(n = 3) parts of the medulla oblongata. Except for nonspecific
symptoms such as fever, medullary infarction was the initial
symptom in most cases, as in ours. In all the patients with renal
dysfunction symptoms, these occurred or rapidly progressed after
the infarction developed. All patients received strong immunotherapy combined with steroid and cyclophosphamide (CY)
treatment, which resulted in favorable outcomes for all except
one with severe renal dysfunction.
Methotrexate or mycophenolate mofetil with glucocorticoid is
recommended as the standard therapies for ANCA-associated
vasculitis.[13] As shown in the Table 1, CY and plasma exchange
were combined with steroids in cases of medullary infarction
caused by ANCA-associated vasculitis with previous renal and/or

index score improved from 35 at admission to 45 points before
HAL training and 70 points after completion of the training.
Although the patient still experienced distal-dominant muscle
weakness, impaired sensation (impaired deep sensation and
mildly impaired superficial sensation), and left femur-dominant
dysesthesia, he became able to walk independently using a walker
and was transferred to another hospital for further rehabilitation.
Our case report was waived from the ethical approval or
institutional review board of University of Tsukuba hospital,
based upon their policy to review all intervention and
observational study except for a case report. Written informed
consent was obtained from both patients for the publication of
this manuscript and accompanying images.

3. Discussion
Primary vasculitis is classified into large-vessel, medium-vessel,
and small-vessel types. In small-vessel vasculitis, lesions are
present in the intraparenchymal small vessels such as small
arteries, arterioles, capillaries, and venulae. Cases are classified
into immune complex-mediated and nonimmune complexmediated groups. Nonimmune complex-mediated vasculitis
includes ANCA-associated vasculitis, a disease group so-called
because they share ANCAs as common disease markers. In 2012,
the Chapel Hill Consensus Conference[5] renamed and reclassified the subclasses of ANCA-associated vasculitis into microscopic polyangiitis, granulomatosis with polyangiitis, and
eosinophilic granulomatosis with polyangiitis. Although the
common sites and mechanisms of cerebral infarction caused by
ANCA-associated vasculitis have not been fully elucidated,
Reichart et al,[6] working before microscopic polyangiitis was
established as a disease concept, observed infarcts in the deep
white matter of the perforator region near a lacunar infarct in
patients with polyarteritis nodosa.
Concerning the differential diagnoses of our case, we could
exclude the diagnoses of IgA vasculitis and secondary vasculitis
associated with collagen disease from the patient’s medical
history and blood findings, including autoantibodies. A diagnosis
of polyarteritis nodosa was unlikely because there the patient
presented no myalgia or arthralgia, and was ANCA-positive.
Because there were no eye manifestations, erythema nodosum,
oral aphtha, or pubic region ulcer, Behcet disease was excluded.
PR3-ANCA was not detected, and there were no nose and ear
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[5] Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel
Hill Consensus Conference Nomenclature of Vasculitides. Arthritis
Rheum 2013;65:1–11.
[6] Reichart MD, Bogousslavsky J, Janzer RC. Early lacunar strokes
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[8] Chen NC, Lai PH, Fang HC, et al. Microscopic polyangiitis with
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[9] Taraschenko OD, Amory CF, Waldman J, et al. Lateral medullary stroke
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[10] Ozkul A, Tataroglu C, Kiylioglu N, et al. Microscopic polyangiitis
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[11] Bares M, Muchová M, Dufek M, et al. Wegener’s granulomatosis:
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[12] Faust J, Visbeck A, Fitzek S, et al. Vasculitic Wallenberg syndrome with
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involvement. Nephrol Dial Transplant 2000;15:893–6.
[13] Yates M, Watts RA, Bajema IM, et al. EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis. Ann
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[14] Wakisaka K, Hagiwara N, Kanazawa Y, et al. Case of CNS-limited
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[15] Ito Y, Suzuki K, Yamazaki T, et al. ANCA-associated vasculitis (AAV)
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lung involvement. However, there are 2 reports of ANCAassociated vasculitis causing an isolated (without previous renal
and/or lung involvement) cerebrovascular lesion, which was
treated with steroid therapy alone.[14,15] As our patient was an
elderly patient lacking severe lesions in other organs, we followed
the Japanese guidelines[3] and administered steroids alone, thus
obtaining a successful outcome.

4. Conclusion
When systemic inflammation is observed in cases of medullary
infarction, ANCA-associated vasculitis should be considered a
potential cause, and steroid pulse therapy should be promptly
administered.

Acknowledgement
To the authors thank Editage (www.editage.jp) for English
language editing.

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[3] Arimura Y, Maruyama S, Honma S. ANCA-related vasculitis, Practice
guideline 2017 [in Japanese]. 2017;Shindan to Chiryo sha Co., Ltd,
Tokyo, Japan:135–136.
[4] Watanabe H, Goto R, Tanaka N, et al. Effects of gait training using the
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