ORIGINAL PAPER

IgG4-related meningeal disease: clinico-pathological featuresand proposal for diagnostic criteria

Katherine M. Lindstrom • John B. Cousar •

M. Beatriz S. Lopes

Received: 25 June 2010 / Revised: 3 September 2010 / Accepted: 4 September 2010

� Springer-Verlag 2010

Abstract IgG4-related disease has evolved from origi-

nally being recognized as a form of pancreatitis to

encompass diseases of numerous organs including the

hypophysis and one reported case of dural involvement. A

search of the University of Virginia, Division of Neuro-

pathology files for 10 years identified ten cases of

unexplained lymphoplasmacytic meningeal inflammation

that we then evaluated using immunohistochemical stains

for IgG4 and IgG. Ten control cases including sarcoidosis

(4), tuberculosis (1), bacterial abscess (2), Langerhans cell

histiocytosis (2), and foreign body reaction (1) were also

examined. The number of IgG4-positive plasma cells was

counted in five high power fields (HPFs) and an average

per HPF was calculated. Cases that contained greater than

ten IgG4-positive cells/HPF were considered to be IgG4-

related. Five of the study cases met these criteria, including

one case of leptomeningeal inflammation. All cases

exhibited the typical histological features of IgG4-related

disease including lymphoplasmacytic inflammation, fibro-

sis, and phlebitis. The dural-based lesions appear to

represent a subset of the cases historically diagnosed as

idiopathic hypertrophic pachymeningitis. While the lepto-

meningeal process most closely resembles non-vasculitic

autoimmune inflammatory meningoencephalitis. Given

these findings, IgG4-related meningitis should be

considered in the differential diagnosis of meningeal

inflammatory lesions after stringent clinical and histologic

criteria are used to rule out other possible diagnoses.

Keywords IgG4-related sclerosing disease �IgG4-related pachymeningitis �Non-vasculitic autoimmune inflammatory

meningoencephalitis �Idiopathic hypertrophic pachymeningitis �Central nervous system

Introduction

Recently, there have been numerous reports about what is

currently termed ‘‘IgG4-related autoimmune/sclerosing

diseases.’’ IgG4 was first recognized as being associated

with sclerosing diseases in 2001 when Hamano et al. [23]

reported that patients with autoimmune pancreatitis (AIP)

had elevated serum levels of IgG4 in comparison to

patients with other causes of chronic pancreatitis. Soon

after this, examination of pancreatectomy specimens from

patients with AIP revealed that the pancreas, as well as the

surrounding tissues, was infiltrated by increased numbers

of IgG4-positive plasma cells [28]. Over the years, cases of

pancreatitis have been described in association with

Sjogren syndrome, sclerosing cholangitis, primary biliary

cirrhosis, and multifocal fibrosclerosis [16, 21, 35, 47], and

it did not take long before it was demonstrated that tissues

from these other organs also showed infiltration by IgG4-

positive plasma cells [24]. Kamisawa et al. [26] proposed

the concept of an IgG4-related autoimmune/sclerosing

disease that encompassed these conditions [27]. Since then,

IgG4 has been recognized to be associated with diseases

involving numerous organs (Table 1), and these diseases

K. M. Lindstrom � M. B. S. Lopes (&)

Division of Neuropathology, Department of Pathology,

University of Virginia School of Medicine, PO Box 800214,

1215 Lee St., Charlottesville, VA 22908-0214, USA

e-mail: msl2e@virginia.edu

J. B. Cousar

Division of Hematopathology, Department of Pathology,

University of Virginia School of Medicine, PO Box 800214,

1215 Lee St., Charlottesville, VA 22908-0214, USA

123

Acta Neuropathol

DOI 10.1007/s00401-010-0746-2

may occur in isolation, in various combinations, and in the

absence of AIP.

IgG4-related diseases occur predominantly in men and

are more common in the fifth to sixth decade. The patients

often have hypergammaglobulinemia, elevated serum IgG

[34], elevated serum IgG4 [36], and the presence of auto-

antibodies [56]. Histologic examination of involved tissue

reveals characteristic features that include lymphoplasma-

cytic inflammation, fibrosis, obliterative phlebitis, and

increased numbers of IgG4-positive plasma cells. Other

less commonly seen features are lymphoid follicles and

eosinophilic infiltrates. Clinically, IgG4-related sclerosing

diseases often present as a mass-like lesion that can be

confused with malignancy. However, these diseases, which

are believed to be autoimmune in nature, respond well to

corticosteroid therapy. It is important to recognize IgG4-

related conditions so that patients do not undergo unnec-

essary surgical procedures.

In the central nervous system, IgG4 has been described

in several cases of hypophysitis [53], and it has been

recently reported in a case of pachymeningitis. The report

by Chan et al. [10] proposes that a proportion of idiopathic

hypertrophic pachymeningitis (IHP) cases may be a part of

the IgG4-related disease spectrum.

Intraspinal IHP was first described by Charcot and

Joffroy [11] and intracranial disease was described by

Naffzinger [48]. This rare disease typically presents clini-

cally with pain or symptoms of compression of the spinal

cord, spinal nerves, and/or cranial nerves. On MRI, it is

characterized by a marked thickening of the dura that

enhances along its edges [44]. In the spine, the cervical and

thoracic cord are involved most commonly [5], and intra-

cranial disease is typically seen along the base of the

brain, although it less commonly involves the cerebral

convexities [17]. In general, the differential diagnosis of dural

lesions includes infections, systemic autoimmune/vasculitic

diseases, and neoplasms. These etiologies must be ruled out

before the diagnosis of IHP can be made. It has been previ-

ously postulated that these unexplained cases of hypertrophic

pachymeningitis may be part of a systemic disorder [2, 7].

Clinically and histologically IHP shares many similarities

with IgG4-related diseases. It predominantly affects older

men [41], and the thickened dura exhibits inflammatory

infiltrates composed of lymphocytes and plasma cells, with

occasional histiocytes, neutrophils, and eosinophils [52].

In this study, we retrospectively analyzed cases with

unexplained meningeal inflammation in order to (1)

identify additional cases exhibiting involvement by IgG4-

positive plasma cells, (2) determine whether or not IgG4-

related disease represents a distinct subtype of IHP, and (3)

determine the usefulness of IgG4 immunostaining in dis-

tinguishing IgG4-related disease from other etiologies.

Materials and methods

Case selection

Nine cases with dural inflammation and one case with lep-

tomeningeal inflammation were selected from the archives

of the Division of Neuropathology at the University of Vir-

ginia from the period between 1999 and 2009. Study cases

were identified by eliminating any specimens that contained

granulomas, had positive cultures, had a prior history of

neurosurgery in the area, or had any other specific CNS

pathology. All study cases were originally given descriptive

diagnoses after it was determined that there was no evidence

of malignancy, infection, or a specific autoimmune disease.

The cases consist of two resections and nine biopsies. One

case without sufficient tissue was left out of the study.

Ten additional cases were used as controls. These

included cases of sarcoidosis (4), tuberculosis (1), bacterial

abscess (2), Langerhans cell histiocytosis (2), and foreign

body reaction (1).

All available material from the ten study cases was

reviewed. Medical records were evaluated to establish

clinical presentation, laboratory and neuroimaging data,

treatment, and clinical follow-up. The University of

Virginia Institutional Review Board approved the study.

Immunohistochemistry

Immunostains were performed using an autostainer (Dako

Cytomation; Carpinteria, CA) per the manufacturer’s

instructions. Antibodies used were a mouse monoclonal

IgG4 antibody (clone HP6025; 1:4,000 dilution; Invitro-

gen, Carlsbad, CA) and a rabbit polyclonal IgG antibody

Table 1 IgG4-related sclerosing diseases

Organ Disease

Salivary gland Sclerosing sialadenitis [37], Mikulicz’s disease

[45, 61]

Lung Interstitial pneumonia [55, 73], inflammatory

pseudotumor [54, 69]

Kidney Tubulointerstitial nephritis [57, 64]

Liver Inflammatory pseudotumor [32, 67, 72],

sclerosing cholangitis [67]

Lacrimal gland Sclerosing dacryoadenitis [13]

Retroperitoneum Retroperitoneal fibrosis [24, 63, 74]

Cardiovascular Inflammatory aortic aneurysm [33]

Prostate Prostatitis [65]

Breast Inflammatory pseudotumor [68]

Thyroid Thyroiditis [40, 42]

Pituitary Autoimmune hypophysitis [53, 59, 62]

Lymph nodes Lymphadenopathy [14]

Acta Neuropathol

123

(dilution 1:3,200; Dako, Carpinteria, CA). Sections stained

with IgG4 were pretreated with antigen retrieval. Appro-

priate positive and negative controls were used. The IgG4-

positive control was an IgG4-rich peri-aortic lymph node

associated with an abdominal aortic aneurysm.

The number of IgG4-positive and IgG-positive plasma

cells was counted in five high power fields (HPFs) (109

eyepiece, 409 lens) containing the highest concentration of

inflammation. An average number of positive cells per HPF

was calculated. Cases that contained greater ten IgG4-

positive plasma cells/HPF were considered to be IgG4-

related according to consensus criteria that have been

established for diagnosing AIP [12, 51].

Tissue artifact made the IgG stain uninterpretable in one

study case (case 5) and one control case (case D). A second

control case (case H) did not have sufficient remaining tissue

to perform IgG staining. The percentage of IgG4-positive

cells to IgG-positive cells was calculated in the other cases.

In situ hybridization

In situ hybridization of j- and k-light chains was previ-

ously performed on three of the study cases (cases 1, 2, 3)

during the initial workup of the specimens. Stains were

carried out using an autostainer (BenchMark XT, Ventana

Medical Systems, Tucson, AZ), as per the manufacturer’s

instructions. Specific probes for j- and k-light chains were

obtained from Ventana Medical Systems.

PCR

Three of the study cases (cases 2, 3, 6) were also previously

evaluated for immunoglobulin heavy chain clonality using

IgH receptor DNA that was extracted from the formalin-

fixed paraffin-embedded tissue using a modified version

of the QIAGEN QIAamp DNA purification protocol.

InVivoScribe Technologies developed the primer sets

utilized for PCR of the immunoglobulin heavy chain. The

performance of these primers in the detection of clonal

lymphoid proliferations was validated by the BIOMED-2

Concerted Action Group [58]. After PCR, amplicon anal-

ysis was by capillary electrophoresis on the ABI 310

instrument. Validation of this method in the molecular

diagnostics laboratory at the University of Virginia has

confirmed the technical performance of the assay with a

detection rate from formalin-fixed paraffin-embedded tis-

sues of 94% for B cell lymphomas. The assay is also able

to detect a 1% clonal population in a polyclonal back-

ground under ideal conditions.

Statistical analysis

Statistical analysis was performed using the t test. A

probability of P \ 0.05 was considered statistically

significant.

Results

Five of the ten study cases (cases 1–5; Table 2), including

the case of leptomeningeal inflammation, demonstrated

elevated levels of IgG4-positive plasma cells (Table 2;

Fig. 1). The mean number of IgG4-positive cells/HPF

in these cases was 36.2 (11.8–54.2). The five non-IgG4-

related cases (cases 6–10; Table 2) had an average of

0.6 IgG4-positive cells/HPF (0–2.2). The percentage of

IgG4/IgG-positive plasma cells was calculated in the cases

Table 2 Study cases: pathologic features

Case # Lymphoplasmacytic infiltrationa Fibrosisa Phebitisa IgG4? cells/HPF IgG4?/IgG? Molecular profile

1 Severe; giant cells present Minimal Moderate 54.2 54% j/k ISH: polytypic

2 Severe Severe Severe 46.6 60% j/k ISH: polytypic

IgH PCR: polyclonal B

3 Severe Severe Moderate 41.6 24% j/k ISH: polytypic

IgH PCR: polyclonal B

4 Severe Moderate Minimal 11.8 30% ND

5 Severe; lymphoid follicles; giant cells present Severe Moderate 26.8 – ND

6 Moderate None None 0.4 1% IgH PCR: polyclonal B

7 Minimal Severe None 0 0 ND

8 Minimal Severe None 0 0 ND

9 Moderate; lymphoid follicles Moderate None 2.2 8% ND

10 Moderate None None 0.2 1% ND

j/k ISH j- and k-light chains in situ hybridization, IgH PCR PCR for immunoglobulin heavy chain clonalitya Intensity: severe, moderate, minimal

Acta Neuropathol

123

that had interpretable immunostaining for IgG. The average

percentage in the IgG4-related cases was 42% (24–60%),

and it was 3% (1–8%) in the non-IgG4 cases. Statistical

analysis showed a significant difference between these two

sets of cases (Table 3) by both mean IgG4 cells/HPF and

IgG4/IgG ratio.

Histologic review of the IgG4-related pachymeningitis

cases revealed lymphoplasmacytic inflammation infiltrat-

ing the dense connective tissue of the dura with varying

amounts of sclerosis (Fig. 2). The one case with leptome-

ningeal inflammation had a similar lymphoplasmacytic

inflammatory infiltrate but less prominent sclerosis

(Fig. 3). The inflammation tended to be perivascular in

location, and phlebitis was present. However, obliterative

phlebitis was not seen. Infiltrating macrophages were

present in most cases, and rare giant cells were seen in two

cases (cases 1, 5). There were occasional granulocytes in

the majority of cases. One of the larger resection specimens

contained several lymphoid follicles (case 5). The sample

size was limited in all but two of the cases (cases 2, 5) as

small biopsies were taken for diagnostic purposes only.

Crush artifact distorted several of the cases and limited the

evaluation of IgG in one study case.

Overall, the IgG4-related cases had a higher degree of

lymphoplasmacytic infiltration (Table 2). The degree of

fibrosis was comparable between IgG4-related and non-

IgG4 cases, in particular in the cases of dural involvement.

The only histological feature that appears to be predomi-

nantly seen in the IgG4-related cases was phlebitis. In none

of the non-IgG4 cases was phlebitis observed (Table 2).

In situ hybridization of j- and k-light chains revealed a

polyclonal population of plasma cells in the three studied

Fig. 1 Immunohistochemistry

demonstrates an increased

percentage of IgG4-positive

plasma cells. The inflammation

is often focal, predominantly in

a perivascular location. a IgG-

IHC 4009, b IgG4-IHC 4009,

c IgG4-IHC 2009

Table 3 Comparison of IgG4-related and non-IgG4-related cases

IgG4-related (n = 5) Non-IgG4-related (n = 5) P

IgG-positive plasma cells/HPF 97.3 (39.8–71.4) 17.6 (0–40.2) 0.001

IgG4-positive plasma cells/HPF 36.2 (11.8–54.2) 0.6 (0–2.2) 0.02

IgG4/IgG-positive plasma cell ratio (%) 42 (24–60) 3 (0–8) 0.01

Acta Neuropathol

123

cases. The three cases analyzed by PCR revealed no evi-

dence of a clonal IgH-receptor gene rearrangement.

A summary of the clinical data of the ten study cases is

shown in Table 4. The cases with increased levels of IgG4

(cases 1–5) included two women and three men with ages

ranging from 53 to 74 years. The non-IgG4 cases (cases

6–10) included four women and one man with an age range

31–57 years. None of the patients have had the diagnosis

of systemic or localized IgG4-related sclerosing disease

(Table 1). The majority of the ten patients presented with

clinical signs and symptoms due to either cord compression

or pain. There were no significant differences between

IgG4-related cases and non-IgG4-related cases regarding

previous or concomitant systemic immunologic diseases.

In fact, other than two patients (cases 1, 6) with a history of

rheumatoid arthritis and one patient (case 4) with history of

Chron’s disease, the majority of the patients had no con-

tributory previous diseases.

Laboratory data was remarkable for CSF abnormalities

in five out of ten patients with a variable increase of protein

levels and pleocytosis. However, there was no distinction

between IgG4-related cases (cases 1, 2) and non-IgG4-

related cases (cases 6, 8, 10). Since the diagnosis of an

IgG4-related disorder was not contemplated at the time of

presentation, none of the patients had serum or CSF IgG4

levels performed.

Other than one patient (case 4) in which clinical follow-

up was lost immediately after surgery, all patients have

been followed by a median of 16 months (10–115 months).

These nine patients were treated with steroids after surgery,

and two out of four IgG4-related cases were still receiving

steroids at their last clinical visit. One patient (case 2) has

stopped steroids since receiving radiation therapy for his

spinal cord lesion for disease control.

Two of the control cases had elevated numbers of

IgG4-positive cells (Table 5; Fig. 4). One case consisted

of tuberculous meningitis with positive cultures for

M. tuberculosis, and the second was a lumbar abscess that

was culture positive for S. aureus.

Discussion

In this study we identified five cases of meningitis (four

dural, one leptomeningeal) that demonstrated increased

numbers of IgG4-positive plasma cells. All of these cases

exhibited the characteristic lymphoplasmacytic inflamma-

tion and fibrosis of IgG4-related sclerosing diseases.

However, obliterative phlebitis was not appreciated. This is

likely related to the limited sampling size of the specimens.

Previous studies of AIP and retroperitoneal fibrosis also

had difficulty finding evidence of obliterative phlebitis in

biopsy specimens [66, 70, 74]. A slight male predominance

(M:F 3:2) and older age (mean 61 years) was seen in the

IgG4-related group in comparison to the non-IgG4 cases

(1:4, 46 years). This is typical of IgG4-related diseases

[31].

Clinically, the four patients with IgG4-related pachy-

meningitis presented with pain or compressive symptoms,

which lead to the identification of an enhancing mass or

Fig. 2 The five IgG4-related

cases all showed similar

histological features including

fibrosis with lymphoplasmacytic

inflammation (a, b) and

phlebitis (c). One case involving

the spine had extension of the

inflammation into the

surrounding soft tissue (d).

H&E 409, 2009, 1009, 2009

Acta Neuropathol

123

dural thickening. Two of the cases were intracranial and

two were intraspinal. The intracranial cases were biopsied

for diagnosis and the intraspinal cases were resected due to

spinal cord compression. Clinically, all of these cases fit

the diagnosis of IHP. IHP has always been a diagnosis of

exclusion. Before making this diagnosis infection, neo-

plasia, and autoimmune/vasculitic diseases must be ruled

out. Surgical resection was historically recommended as

the only means of treatment for IHP [5, 22], but some cases

have been shown to respond to immunosuppression [41,

52]. Current treatment recommendations are for biopsy

followed by high dose corticosteroid therapy and decom-

pressive surgery if emergently required [20]. Response to

corticosteroid therapy is generally variable [20, 41, 52],

and IgG4-related cases may represent part of the steroid-

responsive subset of this disease.

We are also reporting one case of IgG4-related lepto-

meningitis, a manifestation that has not been previously

described. The patient (case 1) presented with cognitive

decline and gait instability and was found to have

leptomeningeal enhancement. Dural, meningeal, and cor-

tical biopsies showed lymphoplasmacytic inflammation

involving the leptomeninges and Virchow–Robin spaces

(Fig. 3). There was no dural inflammation, no evidence of

infection, and no vasculitis identified. Similar presentations

and pathologic findings have been described in patients

with autoimmune diseases such as Hashimoto’s thyroiditis

[9] and Sjogren syndrome [3], and in patients described as

having non-vasculitic autoimmune inflammatory menin-

goencephalitis (NAIM) [8]. It is important to recognize

patients with encephalopathy caused by autoimmune dis-

eases because the dementia is often reversible with steroid

treatment [43]. Our study indicates that it may be important

to recognize IgG4-related disease as a cause of reversible

dementia.

In the present study, cases that were considered IgG4-

related demonstrated an increased number of IgG4-positive

cells ranging from 11.8 to 54.2 cells/HPF. AIP is the first

and probably the best studied of the IgG4-related diseases.

Early studies evaluating AIP tended to consider IgG4-

positive cell counts ranging from [10 cells/HPF to [30

cells/HPF to be sufficient for diagnosis [18, 30, 39, 75]. By

the current Asian diagnostic criteria [51] and the Mayo

Clinic’s histology, imaging, serology, other organ

involvement and response to therapy (HISORt) criteria

[12], finding C10 IgG4-positive plasma cells/HPF in the

setting of a characteristic histopathology is considered

sufficient to support the diagnosis of AIP. However, addi-

tional clinical and radiologic evidence is required to

definitively make the diagnosis.

No consensus criteria have been established thus far for

extra-pancreatic disease. Some studies in organs such as

lung, lymph nodes, and salivary glands advocate using the

ratio of IgG4/IgG-positive cells to establish diagnostic

cutoff levels [14, 37, 45, 73]. Ratios ranging from 30 to

50% have been applied for diagnosing cases of extra-

pancreatic IgG4-related disease; however, there are no

established international criteria and most of the diagnostic

breakpoints are established by internal controls in a given

series [14, 45, 73, 74]. For example, in a large series of

IgG4-related lymphadenopathy, the IgG4/IgG cutoff ratio

of 40% was used because the control reactive lymphade-

nitis cases had levels up to 30%. As demonstrated in

Table 3, the mean IgG4/IgG-positive plasma cell ratio in

our cases shows a statistically significant difference

between our IgG4-related and non-IgG4-related cases.

It seems that either IgG4-positive cell numbers or IgG4/

IgG-positive cell ratios could potentially be used in prac-

tice for diagnosis. However, based on the literature

experience, we favor the use of the cutoff of C10 IgG4-

positive cells/HPF recommended by the Asian and Mayo

Clinic’s guidelines for AIP due to the recognized evidence

basis of these criteria [12, 51]. Moreover, our study cases

Fig. 3 The case with leptomeningeal disease showed similar histo-

logical features with infiltration of IgG4-positive plasma cells into the

cortex and the Virchow-Robin spaces. a H&E 1009, b IgG4-IHC

2009

Acta Neuropathol

123

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Acta Neuropathol

123

demonstrate a distinct and significant breakpoint between

the cases with IgG4-positive cells and those without.

Yet, the total number of plasma cells in our cases is

much lower than what has been reported in many of the

studies of IgG4-related diseases involving extra-pancreatic

tissues [14, 37, 45]. We postulate that the relatively low

numbers of plasma cells in our specimens may be due to

the relatively hypocellular, dense collagenous nature of the

dura mater in comparison to tissues like lung, lymph nodes,

and salivary gland. Studies of other normally hypocellular,

fibrotic tissues, such as the retroperitoneum, have also

shown lower cell counts in comparison to other organs

examined in the same studies [60, 63]. Additionally, most

of our cases were diagnosed by biopsy alone and had rel-

atively small sample sizes. IgG4-related diseases have been

shown to be heterogeneous processes with variable cellu-

larity. Inflammation is often concentrated around ducts and

vessels and may be scarce in highly sclerotic areas [38, 66,

75]. This could create difficulties when trying to diagnose

the disease with a biopsy alone. In fact, studies have typ-

ically shown lower numbers of IgG4-positive cells in

biopsies when compared to resections [18, 69, 75].

Therefore, we believe that the higher cutoff values used by

some researchers may not be entirely appropriate in the

setting of meningeal disease, and perhaps different criteria

need to be applied in different organs and in biopsies

versus resections.

Two of the control cases in this study showed increased

numbers of IgG4-positive cells close to or above our cutoff

value. However, these cases could easily be distinguished

from IgG4-related disease based on the histology alone

(Fig. 4). One case (case A) was culture positive for

M. tuberculosis and contained necrotizing granulomatous

inflammation. The second case (case C) that met the

diagnostic criteria was a lumbar abscess that was culture

positive for S. aureus. The biopsy exhibited abundant acute

inflammation and necrosis. IgG4-related disease would not

have entered into the histologic differential in either of

these cases, and they would likely not have been immu-

nostained during the course of a normal diagnostic workup.

Overlap of IgG4 staining and serum levels with non-IgG4-

related diseases, such as pancreatic cancer and Rosai–

Dorfman disease, has been well documented [29, 54].

Table 5 Control cases: clinical data and immunohistochemistry

Control # Age Sex IgG4? cells/HPF IgG4?/IgG? Diagnosis

A 36 M 10.4 19% Miliary tuberculosis

B 48 M 0 0% Sarcoidosis

C 34 F 11.2 33% Lumbar S. aureus abscess

D 60 F 3.4 – Post-surgical abscess

E 32 M 4.8 4% Foreign body reaction

F 48 F 0 0% Sarcoidosis

G 56 F 2.4 14% Langerhans cell histiocytosis

H 10 F 2.6 – Langerhans cell histiocytosis

I 27 M 0.2 3% Sarcoidosis

J 18 F 0 0% Sarcoidosis

Fig. 4 Two control cases exhibited elevated levels of IgG4-positive

plasma cells but did not have the histology of IgG4-related disease.

One was a case of M. Tuberculosis (a) and the other was an S. aureusabscess (b). H&E 1009, 2009

Acta Neuropathol

123

As the criteria established for AIP suggest, the diagnosis

of an IgG4-related disease should not be made solely on the

basis of IgG4 immunostains. In addition to the histopa-

thology, the clinical picture, including IgG4 serum studies

and radiology, should be considered, and a combination of

findings should be used to make the diagnosis. Some cases,

that fit the histologic and clinical criteria of an IgG4-related

disease, can have borderline numbers of IgG4-positive

plasma cells in tissue, particularly in biopsies [18, 75].

Similarly, patients that meet diagnostic criteria in tissue

may have normal serum IgG4 levels [12]. Since our study

was a retrospective analysis, many of the important clinical

data on the patient population could not be obtained.

Comparison of the two groups of IgG4-related and non-

IgG4-related disease did not reveal substantial differences

in terms of clinical presentation and laboratory data. This

makes future prospective studies of autoimmune meningi-

tis invaluable in validating the concept of IgG4-related

meningeal disease.

It is still not entirely understood how IgG4 is related to

the pathogenesis of sclerosing diseases. IgG4 is the least

common subclass of IgG, representing \5% of IgG in

serum. High serum levels are found in a limited number of

conditions including atopic dermatitis, parasitic diseases,

asthma, and pemphigus [1, 23]. Unlike the other forms of

IgG, IgG4 does not fix complement. It also consists of

effectively monovalent antibodies that have reduced path-

ologic potential and primarily function by interfering with

immune-mediated inflammation. Given this, it has been

suggested that the elevated levels of IgG4 in sclerosing

diseases may actually be a consequence of the disease

rather than a cause [1].

Studies of sclerosing diseases have suggested that they

are autoimmune in nature based on their strong association

with other autoimmune diseases, the presence of antinu-

clear antibodies, and their steroid sensitivity. Thus far a

definitive autoantibody has not been identified, but immune

complexes have been documented in the kidney and pan-

creas of AIP patients, and serum studies have suggested the

presence of IgG4 autoantibodies [4, 19]. The lymphoplas-

macytic infiltrates are composed mostly of a mixture of

CD4- and CD8-positive T cells, and different studies have

demonstrated a predominantly Th1-type reaction in the

peripheral blood and a predominantly Th2-type reaction in

the tissues of AIP patients [27, 50, 71]. A recent study of

the peripheral blood of patients with AIP revealed an

increase in CD25-high-expressing regulatory T cells and a

decrease in naıve regulatory T cells [46]. Based on these

studies, it has been suggested that the pathogenesis of the

sclerosing diseases may be a two phase process that has

both Th1 and Th2 responses. An initial Th1 response may

be a result of a reaction to a self-antigen in the presence of

a decreased number of naıve regulatory T cells. This initial

response could then switch to a Th2 response as disease

progresses. The Th2 response subsequently drives the dif-

ferentiation of B cells into IgG4 plasma cells [6, 46].

Nevertheless, IgG4-related diseases in all locations

respond well to corticosteroid therapy. There is a decrease

in the serum IgG4 level following treatment and imaging

has shown a reduction in the size of mass lesions [23, 69].

Histologic resolution of the inflammatory infiltrates has

even been demonstrated in cases of IgG4-related tubulo-

interstitial nephritis and retroperitoneal fibrosis [49, 57].

Initial responses are often good, but relapses may occur

after cessation of steroids. Alternative immunosuppressive

agents may be used in those requiring long-term therapy

[15]. One case with long-term follow-up exhibited a

relapsing–remitting course with development of IgG4-

related diseases in four organs over a 14-year time period

[25]. Four of the IgG4-related disease patients in our series

needed long-term corticosteroid treatment for control of the

disease. One patient has had radiation therapy as well for

control of the disease. This highlights the need to recognize

these diseases, as patients are prone to requiring long-

standing treatment and may develop disease in multiple

locations.

In conclusion, this study presents four additional cases

of IgG4-related pachymeningitis and one likely case of

IgG4-related leptomeningitis. It is important to consider

these entities in the differential diagnosis of meningeal

thickening and/or enhancement as they are medically

treatable conditions. Due to the lack of international stan-

dards for the histological diagnosis of extra-pancreatic

IgG4-related disease, we recommend the use of the con-

sensus criteria for AIP of C10 IgG4-positive cells/HPF as

minimum criteria for the diagnosis [12, 51]. We should

emphasize, however, that clinical and laboratorial data are

essential in making the definitive diagnosis of IgG4-related

meningeal disease. Biopsy can be used to rule out other

conditions and confirm the diagnosis, so that corticosteroid

therapy can be initiated.

Acknowledgments We would like to thank Michael W. Cruise,

M.D., Ph.D. for working up the IgG4 antibody in our laboratory.

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