LETTER TO THE EDITORS

Advantage of 11C-methionine positron emission tomographyfor assessing IgG4-related central nervous system lesions

Kodai Kume • Kazuyo Ikeda • Kazushi Deguchi •

Masaki Kamada • Masaki Okada • Takashi Tamiya •

Tetsuo Touge • Tsutomu Masaki

Received: 13 December 2013 / Revised: 23 January 2014 / Accepted: 28 January 2014 / Published online: 16 February 2014

� Springer-Verlag Berlin Heidelberg 2014

Dear Sirs,

Although IgG4-related central nervous system (CNS)

lesions are typified by infundibular hypophysitis [1],

hypertrophic pachymeningitis (HPM) and intracerebral

inflammatory pseudotumor (IIP) have been reported [2–9].

These lesions are usually assessed by MRI with contrast.18F-fluorodeoxy-glucose (FDG) or 11C-methionine (MET)

positron emission tomography (PET) has been described as

a promising modality for IgG4-related HPM [7, 9], but a

comparative study of FDG-PET and MET-PET in the same

patients has not been conducted. We describe an advantage

of MET over FDG in a patient with IgG4-related HPM and

IIP complicated by otitis media and mastoiditis.

A 70-year-old woman was admitted to our hospital in

July 2011 for the management of ataxic gait and brain

lesions on MRI. Thirteen months earlier, she had devel-

oped bilateral hearing loss. Five months earlier, steroid

therapy based on the diagnosis of autoimmune otitis media

was ineffective. Around that time, she wobbled a bit when

walking. Brain MRI showed a high-intensity lesion on

fluid-attenuated inversion recovery (FLAIR) imaging in the

left parieto-occipital region. On admission, she was afe-

brile; no abnormal findings in general physical examina-

tion. Neurological examinations revealed cerebellar ataxia.

Pure tone audiometry showed elevated threshold (right:

108.3 dB, left: 115 dB). Laboratory tests revealed a slight

elevation in serum total IgG (1,688 mg/dl) but not in IgG4

(67.5 mg/dl). The major autoantibodies and fungal markers

were all negative. Her CSF showed elevated protein

(79 mg/dl) without pleocytosis. ACE and sIL-2R in the

serum and CSF were normal. Brain MRI revealed paren-

chymal hyperintensities on FLAIR imaging in the right

cerebellar hemisphere and the left frontal and parieto-

occipital regions (Fig. 1). Thickening of the dura mater

adjacent to these lesions was suspected, but MRI with

contrast was contraindicated for her asthma. With a

64-slice PET/CT scanner (Biograph mCT; Siemens, Hoff-

man Estates, IL, USA) with a spatial resolution of

4.27 mm, MET-PET was obtained first, considering the

short half-life of 11C. FDG-PET was then performed on the

same day. Although the FDG accumulation was observed

corresponding to the suspected dura mater thickening on

MRI, it was not easy to differentiate the pathological

lesions from normal cortex. The uptake of MET in the dura

mater and bilateral mastoids was more clear and intense

than that of FDG. Neither FDG nor MET accumulated in

the parenchymal lesions (Fig. 1, Table 1). Biopsy of the

dura mater and left middle ear showed marked lymphocyte

infiltration and fibrosis. Infiltration of IgG4 ? plasma cells

was observed in the dura mater [ratio of IgG4 ?/

IgG ? cells (68 %) and IgG4 ? plasma cells counts (83/

high power field)] but not in the middle ear. According to

the IgG4-related disease diagnostic criteria, the diagnosis

K. Kume � K. Deguchi (&) � T. Masaki

Department of Gastroenterology and Neurology, Kagawa

University Faculty of Medicine, 1750-1 Ikenobe,

Miki-cho, Kita-gun, Kagawa, Japan

e-mail: kdeguchi@med.kagawa-u.ac.jp

K. Ikeda � M. Kamada

Department of Neurological Intractable Disease Research,

Kagawa University Faculty of Medicine, 1750-1 Ikenobe,

Miki-cho, Kita-gun, Kagawa, Japan

M. Okada � T. Tamiya

Department of Neurosurgery, Kagawa University Faculty of

Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, Japan

T. Touge

Department of Health Sciences, Kagawa University Faculty of

Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, Japan

123

J Neurol (2014) 261:625–627

DOI 10.1007/s00415-014-7269-z

of probable IgG4-related HPM was made [1]. She received

four courses of methylprednisolone (1,000 mg/day,

3 days), followed by oral prednisone of 30 mg/day. Two

months later, cerebellar ataxia resolved and her walking

became stable. Auditory acuity improved slightly only in

the right ear (71.7 dB). Abnormal findings on MRI and

MET-PET disappeared (Fig. 1).

The more obvious MET uptake compared to FDG in the

dura mater lesions facilitated the identification of the biopsy

site and evaluation of the therapeutic efficacy, consistent

with a previous report [9]. Although FDG-PET provides

useful metabolic information on brain lesions, an intense

uptake of FDG in normal gray mater tissue might hamper

the identification of lesions adjacent to gray mater, such as

tumors located in the cortex, basal ganglia, and brainstem

[10]. MET uptake, which reflects amino acid transport, is

low in normal brain tissue [9–11]. MET thus has an

advantage over FDG for evaluating IgG4-related HPM.

Since parenchymal lesions associated with HPM consist

of microglia proliferation and lymphocyte perivascular

infiltration and are curable by steroid therapy [5], it is

likely that HPM causes IIP involving nearby brain paren-

chyma. In our patient, however, MET uptake was not

observed in the parenchymal lesions. The discrepancy of

MET uptake between the dura mater and parenchyma

might reflect the difference of inflammatory cell density

Table 1 The standardized

uptake values (SUV) in the

FDG and MET-PET before

steroid therapy

The maximum standardized

uptake values (SUVmax) were

measured in the hypermetabolic

and/or MRI lesions. The

SUVmax/SUVmean ratio was

defined as the lesion-to-mean

normal cortex uptake ratio

Dura mater Left

mastoid

Right

mastoid

Parenchyma

Lt.

frontal

Lt.

p-occipital

Rt.

cerebellum

Lt.

frontal

Lt.

p-occipital

Rt.

cerebellum

FDG

SUVmax 16.74 16.57 12.56 10.26 9.65 6.74 3.23 10.08

SUVmax/

SUVmean

1.51 1.49 1.22 0.93 0.87 0.61 0.29 0.98

MET

SUVmax 8.16 7.28 7.44 7.06 6.42 1.58 0.71 1.68

SUVmax/

SUVmean

5.07 4.52 4.54 4.39 3.99 0.98 0.44 1.02

Fig. 1 MR and coregistered MR and PET images before steroid

therapy (a–c) and after steroid therapy (d–f). a, d Axial FLAIR

images. b, e Coregistered MR and FDG-PET axial images. c,

f Coregistered MR and MET-PET axial images. The FLAIR image

before treatment showed thickening dura mater (arrows) and

parenchymal lesions in the right cerebellar hemisphere and the left

frontal and parieto-occipital regions. The uptake of MET in the dura

mater and bilateral mastoids (arrows) was more clear and intense than

that of FDG. These lesions disappeared rapidly with steroid treatment

626 J Neurol (2014) 261:625–627

123

[11]. To clarify the relationship between HPM and IIP,

PET using [11C](R)-PK11195 as a marker of activated

microglia should have been performed for the assessment

of neuroinflammation [12].

The intense MET uptake in our patient’s bilateral mas-

toids disappeared in parallel with the disappearance of

MET accumulation in the dura mater following the suffi-

cient doses of steroid therapy. In addition, auditory acuity

in the right ear showed a slight but significant improve-

ment, as in a previous report of IgG4-related disease [4].

These findings suggest that MET uptake in the mastoids

might represent mastoiditis due to extension of steroid-

responsive otitis media. Although an infiltration of

IgG4 ? plasma cells was not confirmed in the left middle

ear, otitis media due to IgG4-related disease remains a

possibility.

In conclusion, MET-PET has considerable potential for

the diagnosis, characterization, and monitoring of the dis-

ease activity of IgG4-related CNS lesions.

Conflicts of interest The authors declare that they have no conflicts

of interest.

Ethical standard This study describes activities performed in

patients during the course of appropriate diagnostic examinations and

therapy in clinical practice. It is not a clinical study or trial and

therefore did not require submission to an Ethics Committee. All

activities were performed in accordance with the ethical standards

laid down in the 1964 Declaration of Helsinki. The authors hereby

declare that the research documented in the submitted manuscript has

been carried out in accordance with the above stated ethical standards.

References

1. Umehara H, Okazaki K, Masaki Y et al (2012) Comprehensive

diagnostic criteria for IgG4-related disease (IgG4-RD), 2011.

Mod Rheumatol 22:21–30

2. Chan S-K, Cheuk W, Chan K-T, Chan JKC (2009) IgG4-related

sclerosing pachymeningitis: a previously unrecognized form of

central nervous system involvement in IgG4-related sclerosing

disease. Am J Surg Pathol 33:1249–1252

3. Choi S-H, Lee SH, Khang SK, Jeon SR (2010) IgG4-related

sclerosing pachymeningitis causing spinal cord compression.

Neurology 75:1388–1390

4. Kosakai A, Ito D, Yamada S et al (2010) A case of definite IgG4-

related pachymeningitis. Neurology 75:1390–1392

5. Kim EH, Kim SH, Cho JM et al (2011) Immunoglobulin G4-

related hypertrophic pachymeningitis involving cerebral paren-

chyma. J Neurosurg 115:1242–1247

6. Yamashita H, Takahashi Y, Ishiura H et al (2012) Hypertrophic

pachymeningitis and tracheobronchial stenosis in IgG4-related

disease: case presentation and literature review. Intern Med

51:935–941

7. Della Torre E, Bozzolo EP, Passerini G et al (2012) IgG4-related

pachymeningitis: evidence of intrathecal IgG4 on cerebrospinal

fluid analysis. Ann Intern Med 156:401–403

8. Shapiro KA, Bove RM, Volpicelli ER et al (2012) Relapsing

course of immunoglobulin G4-related pachymeningitis. Neurol-

ogy 79:604–606

9. Norikane T, Yamamoto Y, Okada M et al (2012) Hypertrophic

cranial pachymeningitis with IgG4-positive plasma cells detected

by C-11 methionine PET. Clin Nucl Med 37:108–109

10. Pirotte B, Goldman S, Massager N et al (2004) Combined use of

18F-fluorodeoxyglucose and 11C-methionine in 45 positron

emission tomography-guided stereotactic brain biopsies. J Neu-

rosurg 101:476–483

11. Okita Y, Kinoshita M, Goto T et al (2010) (11)C-methionine

uptake correlates with tumor cell density rather than with

microvessel density in glioma: a stereotactic image-histology

comparison. Neuroimage 49:2977–2982

12. Banati RB, Goerres GW, Myers R et al (1999) [11C](R)-

PK11195 positron emission tomography imaging of activated

microglia in vivo in Rasmussen’s encephalitis. Neurology

53:2199–2203

J Neurol (2014) 261:625–627 627

123