VIEWS & REVIEWS OPEN ACCESS

Immunoglobulin G4-related hypertrophic

pachymeningitis
A case-oriented review
Michaël Levraut, MD, Mikaël Cohen, MD, Saskia Bresch, MD, Caroline Giordana, MD, Correspondence
Dr. Levraut
Fanny Burel-Vandenbos, MD, PhD, Lydiane Mondot, MD, Jacques Sedat, MD, Denys Fontaine, MD, PhD,
[email protected]
Véronique Bourg, MD, Nihal Martis, MD, and Christine Lebrun-Frenay, MD, PhD

Neurol Neuroimmunol Neuroinflamm 2019;6:e568. doi:10.1212/NXI.0000000000000568

Abstract
Objective
Meningeal involvement in Immunoglobulin G (IgG)-4-related disease is rare and only de-
scribed in case reports and series. Because a review into the disease is lacking, we present 2 cases
followed by a literature review of IgG4-related hypertrophic pachymeningitis (IgG4-HP).

Methods
Two IgG4-HP cases were reported, one involving the spinal cord and responding to surgical
management and a second involving the brain and responding to Rituximab therapy. We then
review clinical cases and case-series of histologically proven IgG4-HP that were published in the
PubMed-NCBI database.

Results
Forty-two case reports and 5 case-series were studied (60 patients, 20 women). The median age
was 53. Eighteen patients had systemic involvement and 24 had single-organ IgG4-HP. Fifty-
five percent of patients had an elevated serum IgG4. Treatment was surgical in 20/53 cases.
Steroid therapy and immunosuppressors were effective in 85% and more than 90% of the cases,
respectively. The rate of disease relapse was 42.1% after steroid therapy was discontinued.

Discussion/conclusion
IgG4-HP is characterized by the lack of extra-neurologic organ-involvement and systemic signs.
Histopathologic studies should be performed as it is crucial for diagnosis because serum
markers are rarely informative. 18F-FDG positon tomography can be useful to characterize
systemic forms. There is no specific CSF marker for IgG4-HP and the diagnostic value of CSF
IgG4 levels needs to be studied with larger samples. We provide a treatment algorithm for IgG4-
HP. Such treatment strategies rely on early surgery, steroids, and early immunosuppressive
therapy to prevent neurologic complications.

From the Service de Médecine Interne (M.L., N.M.), Hôpital l’Archet 1, Centre Hospitalier Universitaire de Nice, Université Côte d’Azur; Service de Cytologie Pathologique (F.B.-V.),
Hôpital l’Archet 1, Centre Hospitalier Universitaire de Nice, Université Côte d’Azur; and Service de Neurologie (M.C., S.B., C.G., V.B., C.L.-F.), Service de Radiologie (L.M.), Service de
Radiologie Interventionnelle (J.S.), and Service de Neurochirurgie (D.F.), Hôpital Pasteur 2, Centre Hospitalier Universitaire de Nice, Université Côte d’Azur, France.

Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.

The Article Processing Charge was funded by the authors.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading
and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 1
 Glossary
CYC = cyclophosphamide; GPA = granulomatosis with polyangeitis; HPF = high-power field; IgG4 = immunoglobulin G4;
IgG4-HP = IgG 4-related hypertrophic pachymeningitis; IgG4-RD = IgG 4-related disease; RI = Responder Index; RTX =
Rituximab; WBC = white blood cell.

Immunoglobulin G (IgG)-4-related disease (IgG4-RD) is Treatment with IV corticosteroids (1 g per day for 5 days)
a polyclonal lymphoproliferative disorder affecting many resulted in partial regression of neurologic signs. Spinal cord
organs. Diagnosis is histologic and shows lymphoplasmocytic arteriography confirmed the diagnosis of a dural fistula that
infiltration with IgG4+ plasma cell proliferation, storiform was treated by embolization (figure 1, A). Three months later,
fibrosis, and obliterative phlebitis.1,2 The pancreas, salivary the MRI showed complete regression of spinal cord lesions.
glands, retroperitoneum, and lymph nodes are the most The patient was able to walk without limitation to the walking
commonly affected.3–7 Central neurologic manifestations are perimeter. Only mild proximal motor weakness and pro-
rare with reports of mostly hypertrophic pachymeningitis prioceptive ataxia of the lower limbs persisted.
(HP) and hypophysitis. Previous studies have found that
retrospective analyses of idiopathic HP were able to ultimately The same patient presented to our department 3 years later
identify IgG4-RD in several cases.4 Specific diagnostic criteria with similar neurologic features. The MRI of the spine found
have been defined for HP associated with IgG4-RD (IgG4- a posterior T1 isointense signal intensively enhanced with
HP), which rely on histopathologic analysis.7 Unfortunately, gadolinium and a T2 hypointense signal related to an intra-
because of its scarcity, only case reports and a few case series dural, extra-medullary, posterior, and compressive tumor-like
of IgG4-HP are available in the medical literature. No treat- lesion regarding T2-T3 surrounded with edema (figure 1, B).
ment algorithm is known for this uncommon location of Surgical subtotal resection of the lesion was performed and
IgG4-RD where relapsing occurs frequently. Because a better confirmed its extramedullary location, originating from the
understanding of the disease is needed, we report 2 cases and dura and highly adherent to the spinal cord pia mater. His-
a literature review of the clinical, biological, and treatment topathologic examination of the surgical specimen identified
specificities of IgG4-HP. a fibro-inflammatory lesion with dural thickening due to
a lymphoplasmocytic infiltrate, storiform fibrosis, and oblit-
erative vasculitis. Immunohistochemical analysis showed
Case reports a polyclonal lymphocytic infiltration (expression of both
kappa and lambda light chains) including 53 IgG4+ plasma
Case 1 cells per high-power field (HPF) and an IgG4+/IgG ratio
A 55-year-old Caucasian male with a history of genetic he- greater than 40% (figure e-1a, links.lww.com/NXI/A115).
mochromatosis, diabetes mellitus, and high blood pressure There was no evidence of malignant, meningiomatous, or
presented with a progressive walking difficulty over a 2-week histiocytic disease (negativity of epithelial markers cytokeratin
period. Clinical examination reported T2-T3 dorsalgia, severe and Epithelial Membrane Antigen, progesterone receptors,
paresis with pyramidal syndrome, decreased vibratory sensa- protein S100, CD1a, langherin, and Anaplastic Lymphoma
tion of the lower limbs, and bladder dysfunction. There was Kinase). Staining for microbial pathogens (Gram, Gomori-
no weight loss, asthenia, fever, or extra-neurologic abnor- Grocott and Ziehl) was negative. Plasma IgG4 levels were,
malities. Spinal cord MRI revealed many cervico-thoracic T2/ however, normal (59 mg/dL). There was neither eosinophilia
fluid attenuated inversion recovery hyper intense signals from nor complement consumption. [18F]-fluorodeoxyglucose
C3 to T3 that were all enhanced by gadolinium injection positron emission tomography (FDG PET) (PET-CT) did
revealing active inflammatory myelitis. Spinal venous di- not document other lesions. IgG4-HP was diagnosed based
latation of the cervico-thoracic junction suggestive of dural on histopathologic criteria.
fistula was also reported (figure 1, A). The brain MRI was
normal as were visual evoked potentials. Blood tests did not Near-complete clinical recovery was achieved 3 months after
reveal an inflammatory syndrome (the C-Reactive protein surgery. Bladder dysfunction had subsided and walking did not
level was below 5 mg/L and fibrinogenemia was 3.15 g/L). require help. Nevertheless, proprioceptive disorders of the
Immunologic and infectious assessment did not help the di- lower limbs persisted. The MRI did not find residual lesions.
agnosis. Anti-aquaporin 4 and myelin oligodendrocyte gly- Given the patient’s history of diabetes mellitus, steroids were
coprotein auto-antibodies were negative. Analysis of the CSF not initiated, and a close follow-up attitude was adopted.
revealed elevated protein levels (1.96 g/L) and lymphocytic
meningitis (69 white blood cells [WBCs]/mm3 with 95% Case 2
of lymphocytes). Viral PCR testing and CSF cytology were A 66-year-old Caucasian male with a history of high blood
not informative. The CSF IgG index was 0.53 despite a high pressure, dyslipidemia, and smoking presented to the emer-
level of CSF IgG (18.7 mg/dL) and there was no oligoclonal gency department for subacute onset of non-painful bilateral
band. CSF levels of Interleukin-6 were high at 1923 pg/mL. loss of vision. He had been suffering from chronic pulsatile

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Figure 1 MRI of both patients with IgG4-HP and spinal cord arteriography of the first patient

(A) Multiple T2 hyperintense signals (white arrows)

(A.a) all enhanced after gadolinium injection (A.b)
of the posterior half of the cervico-thoracic spinal
cord. T2 hypointense signal of the posterior sub-
arachnoid space from C5 to D3 suggesting a dural
fistula (red arrow) (A.c), confirmed by medullary
arteriography (A.d) with opacification of a venous
peloton opposite the meninge of the left lateral
part of the dural sheath corresponding to the
medullary veins visible on MRI. (B) Intra-ductal, in-
tra-dural, postero-median, polylobulated tumor
lesion, well-defined, in T1 isointense signal (B.a),
intensely and homogeneously enhanced after in-
jection of gadolinium (B.b), T2 hypointense signal
(B.c), next to D2-D3 realizing a mass effect on the
spinal cord. There is an extensive intramedullary
edema supra and under-lesion (B.d). (C) Bi-frontal
meningeal thickening enhanced by gadolinium in-
vading the sheaths of optic nerves and cavernous
sinuses (white arrows) (C.a and c). T2/FLAIR hy-
perintense signal of the left optic nerve testifying
to radiologic optic neuritis, white arrows (C.b d).
FLAIR = fluid attenuated inversion recovery.

headaches for many months. There was no fever or weight loss. The CSF opening pressure was normal and its analysis showed
Physical examination revealed ptosis and left reactive mydriasis protein levels of 0.99 g/L without pleocytosis (2 WBC/mm3)
with a decrease in bilateral visual acuity at 5/10 in the right eye or inflammatory markers (IgG index of 0.63 and CSF IgG-levels
and less than 1/20 (light perception) in the left eye. Neurologic at 6.29 mg/dL). Interleukins-6 and -10 levels were also normal.
and general somatic examinations were normal. Visual evoked Meningeal biopsy identified an inflammatory infiltrate rich in
potentials revealed a bilateral severe axomyelenic defect in both IgG4+ plasma cells with perivascular storiform fibrosis and
eyes. Funduscopic examination showed left temporal pale ret- obliterative phlebitis. Immunostaining showed more than 10
ina. A brain MRI found a gadolinium-enhanced, bi-frontal IgG4-positive plasma cells per HPF. The IgG4+/IgG ratio was
meningeal thickening invading the optic nerve sheaths and greater than 40% (figure e-1b, links.lww.com/NXI/A115).
cavernous sinuses (figure 1, C). Microbial analyses and the PET-CT did not show pathologic hypermetabolism. The di-
immunologic bioassay were not informative. There was no in- agnosis of IgG4-HP was made.
flammatory syndrome, eosinophilia, or complement consump-
tion. Hypogammaglobulinemia was found on electrophoresis of Corticosteroid therapy (1 mg/kg/d) after pulse IV methyl-
plasma proteins. Plasma IgG4 levels were normal (40.1 mg/dL). prednisolone for 5 days at 1 g q.d. was introduced, but it was

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 ineffective. IV Rituximab (RTX) was started 12 months later bibliographical references is provided in the supplemental
(1 g day 1 and day 15) and was followed by maintenance data online document.
treatment (M8). Fifteen months later, clinical and radiologic
improvement was observed with partial regression of head- Patients’ characteristics
aches and recovery of visual acuity at 10/10 in the right eye Brain involvement was mostly reported (49/60 cases). Spinal
and less than 1/20 (movements of the hand perceived at 50 cord lesions were described in 16 cases, of which 9 were
cm) in the left eye. At follow-up 1 year later, a brain MRI cervical. Thoracic and lumbar spinal cord lesions were de-
showed the complete regression of meningeal thickening. scribed respectively in 8 and 5 cases. The disease affected both
the brain and the spine in 5 patients. Systemic IgG4-RD was
noted in 18 cases and mostly accompanied cranial manifes-
A systematic review tations of IgG4-HP. The extra-meningeal manifestations are
reported in figure 2. Isolated meningeal damage was identified
Methods and definitions in 25 patients of whom 24 had single-organ IgG4-HP. Sev-
We reviewed clinical cases and case-series of cerebral and spinal enteen patients could not be classified because of a lack of
cord HP with histologically proven IgG4-RD that were published data.
between January 2008 and September 2017 in the PubMed-
NCBI database. The key words used in the search were The demographics, clinical, pathology, and blood work-ups
“Pachymeningitis,” “IgG4-related disease,” “HP,” “IgG4-HP,” are shown in table 1. Patients with IgG4-HP were mostly
“IgG4 neurologic impairment,” and “IgG4 CNS.” Demographics, males with a male-to-female ratio of 2. Median age was 53
clinical and biological data, pathology features, and treatment years (range: 19–82). Headache was common in cases of
strategies were collected for each patient, when available. cerebral IgG4-HP. Visual impairment and cranial nerve palsy
were each present in less than one-third of cases.
Diagnostic criteria are those of the Japan College of
Rheumatology8: Plasma IgG4 levels of more than 135 mg/dL were found in 20
of the 36 patients for whom this information was available.
1. A clinical study showed characteristic diffuse/localized The median level of plasma IgG4 levels was higher in patients
swelling or masses in single or multiple organs with systemic IgG4-RD, whereas meningeal IgG4 infiltration
2. A hematologic study showed elevated levels of serum was higher in isolated IgG4-HP. A biological inflammatory
IgG4 (135 mg/dL or higher) syndrome was inconsistently present (10/27 cases) and was
3. A histopathologic study showed the following 2 findings: more frequently found with systemic involvement. Eosino-
c Histologic findings: marked lymphocyte and plasmo- philia was only reported in the case of a patient who also
cytic infiltration and fibrosis presented with eosinophilic granulomatosis with polyangiitis.
c IgG4-positive plasma cell infiltration: ratio of IgG4/
IgG positive cell >40% and IgG4-positive plasma cells/ CSF analysis
HPF >10 CSF findings are presented in table 2. Aseptic lymphocyte
meningitis was identified in more than half of the specimens
When (1) + (2) + (3) are fulfilled, it is definite. with median CSF protein levels of 0.91 g/L and a median CSF
white blood count of 19.5/mm3. The CSF profile was gen-
When (1) + (3) are fulfilled, it is probable. erally oligoclonal (5 cases). Intrathecal IgG synthesis was
found in 11/13 patients. CSF IgG4 levels were only available
When (1) + (2) are fulfilled, it is possible. for 4 patients, but they were significantly increased with
a median value of 5.225 mg/dL—which is more than 10 times
Isolated IgG4-HP was characterized by the absence of extra- the upper limit of the normal range (0.32 mg/dL).
meningeal organ-involvement (including the pituitary gland).
Mutually exclusive lesions of the brain or spinal cord defined Treatment
“single-organ pachymeningitis.” When extra-meningeal in- Treatment strategies are presented for 53 patients in table 3.
volvement was reported, IgG4-HP was defined as systemic Nearly all patients received systemic steroids (48/53), of
IgG4-RD. Non-specified IgG4-HP was retained when data which 20 received pulse steroid therapy. Relapse occurred
was lacking for classification. in 16 cases and was less frequent in the “pulse therapy”
group (13/23 patients vs 3/15 patients). Relapse occurred
Data availability less frequently when the steroid dose was greater than 49
The authors confirm that the data supporting the findings of this mg/d (relapse rate was 52.6%, whereas it was 100% with
study are available within the article and its supplementary lower dosages). In the same way, the occurrence of relapse
materials (e-references e1-e47, links.lww.com/NXI/A115). was lower when steroid therapy was followed over a longer
period of time (100% relapse for less than 6 months of
Findings steroid therapy vs 42.9% when steroids were continued over
We report findings from 60 patients that were taken from 42 a year). All the steroid treatment specific data are available
case reports and 5 case-series. The complete list of in table e-1, links.lww.com/NXI/A115.

4 Neurology: Neuroimmunology & Neuroinflammation | Volume 6, Number 4 | July 2019 Neurology.org/NN

Figure 2 Classification of IgG4-HP

a–c
Other locations of IgG4-RD involvement by patients: a1. Orbital pseudotumor, kidney and lung. 2. Pancreas. 3. Lymph nodes, submandibular glands and
lung. 4. Retroperitoneal fibrosis. 5. Mastoid. 6. Retroperitoneal fibrosis. 7. Aortitis. 8. Episcleritis. 9. Hypophysitis. 10. Lacrymal and submandibular glands. 11. Orbital
pseudotumor. 12. Maxillary pseudotumor. 13. Episcleritis. b1. Orbitory pseudotumor. 2. Pulmonary pseudo-tumor and hypophysitis. 3. Orbitary pseudotumor. 4.
Retroperitoneal fibrosis. c1. Submandibular gland. IgG4-HP = IgG 4-related hypertrophic pachymeningitis; IgG4-RD = IgG 4-related disease; NS = non-specified.

Twenty patients were treated surgically, mostly in cases of cere- surgery was done (33% vs 44% without surgery). Surgical treat-
bral involvement. Only 3 patients with systemic IgG4-RD re- ment was in itself sufficient to achieve disease remission within 6
quired surgical treatment. Relapse occurred less often when months (range: 3–12 months) in 4 cases of isolated IgG4-HP.

Table 1 Demographic, clinical, histologic, and blood work-up data

Total IgG4-HP Systemic IgG4-HP Isolated IgG4-HP Non-specified IgG4-HP

n 60 n 18 n 25 n 17

Median age, ya 60 53 (19–82) 18 48 (32–70) 25 52 (35–71) 17 55 (19–82)

Sex ratio (M/F) 60 2 (40/20) 18 1.6 (11/7) 25 2.1 (17/8) 17 2.4 (12/5)

Single brain involvement 60 44 (73.3%) 18 13 (72.2%) 25 20 (80%) 17 11 (64.7%)

Single spine involvement 11 (18.3%) 1 (5.6%) 4 (16%) 6 (35.3%)

Both brain and spine involvement 5 (8.3%) 4 (22.2%) 1 (4%) 0

Headaches 55 36 (65.4%) 17 15 (88.2%) 25 15 (60%) 13 6 (46.2%)

Visual acuity lost 55 16 (29.1%) 17 6 (35.3%) 25 6 (24%) 13 4 (30.8%)

Cranial nerve palsy 55 16 (29.1%) 17 9 (52.9%) 25 6 (24%) 13 1 (7.7%)

Epilepsy 55 7 (12.7%) 17 2 (11.8%) 25 5 (20%) 13 0

Motor weakness (limbs) 55 16 (29.1%) 17 3 (17.6%) 25 6 (24%) 13 7 (53.8%)

Sensory loss (limbs) 51 9 (16.4%) 17 2 (11.8%) 24 3 (12.5%) 10 4 (40%)

Serum IgG4 > 135 mg/L 36 20 (55.6%) 12 9 (75%) 19 7 (36.8%) 5 4 (80%)

a
Median serum IgG4 (mg/L) 29 155 (40.1–939) 11 165 (54–260) 15 97 (47–939) 3 162 (155–182)

Blood inflammatory syndrome 27 10 (37%) 7 5 (71.4%) 12 3 (25%) 8 2 (25%)

Eosinophils >500/mm3 22 1 (4.5%) 4 1 (25%) 11 0 7 0

a
Median IgG4+/IgG ratio 35 50.5 (40–94) 9 49.5 (40–70) 15 58 (40–94) 11 50 (40–73.3)

a
Median IgG4+/HPF 39 50 (10–310) 7 51.7 (10–310) 18 63 (10–200) 14 40.05 (10–140)

Abbreviations: HPF = high-power field; IgG4 = immunoglobulin G4; IgG4-HP = IgG 4-related hypertrophic pachymeningitis; n = number of patients with
available data.
a
Range.

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 Table 2 Cerebrospinal fluid data
Total IgG4-HP Systemic IgG4-HP Isolated IgG4-HP Non-specified IgG4-HP

n 60 n 18 n 25 n 17

Protein >0,4 G/L 28 21 (75%) 9 7 (77.8%) 15 11 (73.3%) 4 3 (75%)

Median protein level (g/L)a 20 0.925 (0.22–4.17) 7 0.83 (0.44–1.68) 11 0.99 (0.22–4.17) 2 0.72 (0.44–1)

3
WBC >5/mm 30 18 (60%) 11 7 (63.6%) 15 7 (46.7%) 4 4 (100%)

3 a
Median WBC (/mm ) 20 19.5 (0–150) 8 23.5 (1–112) 9 14 (0–150) 3 17 (10–21)

Median lymphocytes count (%)a 18 91.5 (0–100) 8 91.5 (85–100) 8 94.5 (0–100) 2 65.5 (51–80)

IgG >8 mg/dL 13 11 (84.6%) 3 3 (100%) 8 6 (75%) 2 2 (100%)

a
Median IgG count (mg/dL) 10 14.3 (6.29–38.1) 3 14.3 (8.7–18.8) 5 13.03 (6.29–38.1) 2 23.8 (13.3–34.3)

Median IgG indexa 6 0.965 (0.53–1.84) 2 1.82 (1.8–1.84) 3 0.63 (0.53–0.84) 1 1.09

Profile 8 Oligoclonal (5) 2 Oligoclonal (2) 5 Oligoclonal (2) 1 Oligoclonal (1)

Transudate (2) Transudate (2)

Normal (1) Normal (1)

Oligoclonal bands 10 7 (70%) 4 3 (75%) 6 4 (66.7%) 0 —

IgG4 > 0.32 mg/dL 4 4 (100%) 2 2 (100%) 2 2 (100%) 0 —

a
Median IgG4 (mg/dL) 4 5.225 (4.94–8.5) 2 5.05 (4.94–5.1) 2 6.925 (5.35–8.5) 0 —

Abbreviations: IgG4 = immunoglobulin G4; IgG4-HP = IgG 4-related hypertrophic pachymeningitis; n = number of patients with available data; WBC: white
blood cells.
a
Range.

Twenty-five patients received an immunosuppressive drug, cancerous, allergic, and autoimmune disorders.6,9,10 The speci-
either as a steroid sparing agent (11/25) or after failure to ficity and positive predictive value of the serum IgG4 for IgG4-
achieve disease control (19/25). RTX was the most used RD are 60 and 34% respectively.11
immunosuppressant as first-line (10/25 patients) and second-
line therapy (6/7 patients). The clinical response was repor- Meningeal involvement of IgG4-RD is rare and was first de-
ted for all patients with the first immunosuppressive therapy. scribed in 2009.12 Its prevalence is estimated to be slightly
The clinical response data for patients who received more above 2% of overall clinical manifestations, based on data
than 1 immunosuppressant were available for 7 of the 8 from recent series.5,6,13–15
patients. The overall clinical remission was obtained for 24
patients; 11 had isolated IgG4-HP, 11 had systemic IgG4-RD, To the best of our knowledge, we have presented the first case
and 2 had non-specified IgG4-HP. RTX (14 patients) and of an arteriovenous dural fistula in IgG4-HP, suggesting it
cyclophosphamide (CYC) (5 patients) were associated with could develop after a local precipitating factor, if ever
the best response rate in comparison to other drugs. One identified.
patient died of an infection with RTX therapy.
Synchronous pachymeningitis of the brain and spinal cord is
less common. Clinical manifestations of the disease are sub-
ject to localization or complications due to compression and/
Discussion or infiltration of neurologic and/or vascular adjacent
IgG4-RD has been described as a multisystemic, fibro- structures.
inflammatory, and lymphoproliferative disease that is char-
acterized as a polyclonal IgG4-infiltration, leading to storiform IgG4-HP is isolated in more than half of the overall cases
fibrosis and oblitering phlebitis.1 Histopathologic studies are contrasting with the preferential multisystemic involvement
essential for diagnosis and allow infectious, neoplastic, and/or reported by other authors.13,14,16
other inflammatory diseases to be eliminated.
Serum IgG4 levels were increased in 55.5% of the studied
The 2011 Japan College of Rheumatology classification criteria population. Stone et al. and Zhang et al. identified a preva-
for IgG4-RD are the most commonly used.8 Serum IgG4 levels lence rate ranging from 70% to 94.1%, respectively.1,5 How-
are not specific markers for IgG4-RD, as they also increase in ever, using the serum IgG4 level as a diagnostic criteria for

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Table 3 Treatment and relapse characteristics

Total IgG4-HP Systemic IgG4-HP Isolated IgG4-HP Non-specified IgG4-HP

n 60 n 18 n 25 n 17

Surgical excision 53 20 (37.7%) 16 3 (18.8%) 25 10 (40%) 12 7 (58.3%)

Steroid therapy 53 48 (90.6%) 16 16 (100%) 25 21 (84%) 12 11 (91.7%)

Neurology: Neuroimmunology & Neuroinflammation | Volume 6, Number 4 | July 2019

Steroid efficacy 53 41 (77.4%) 15 14 (93.3%) 22 17 (77.3%) 10 9 (90%)

IV pulse steroid therapy 39 20 (41.7%) 12 8 (66.7%) 23 10 (43.5%) 4 2 (50%)

IV pulse steroid efficacy 20 15 (75%) 8 7 (87.5%) 10 6 (60%) 4 2 (50%)

Relapse after steroids 38 16 (42.1%) 11 5 (45.4%) 19 8 (42.1%) 8 3 (37.5%)

Relapse after IV pulse steroids 15 3 (20%) 7 2 (28.6%) 6 1 (16.7%) 2 0

IS 49 25 (51%) 15 11 (73.3%) 22 12 (54.5%) 12 2 (16.7%)

Efficacy with first line IS 25 17 (68%) 11 (4 RTX, 3 AZA, 2 MTX, 1 CYC, 1 CSA) (5 RTX, 4 MTX, 2 CYC, 1 MMF) (1 RTX, 1 CYC)

9 (81.8%) 6 (50%)

(4 RTX, 2 AZA, 1 MTX, 1 CYC, 1 CSA) 12 (3 RTX, 2 CYC, 1 MTX) 2 2 (100%)

Efficacy with further line IS 8 7 (87.5%) 2 2 (100%) 5 5 (100%) — —

(2 RTX) (3 RTX, 1 itRTX, 1 CYC)

Abbreviations: CSA = cyclosporine A; CYC = cyclophosphamide; IgG4 = immunoglobulin G4; IgG4-HP = IgG 4-related hypertrophic pachymeningitis; IS = immunosuppressants; itRTX = intrathecal rituximab; MMF =
mycophenolate mofetil; MTX = methotrexate; n = number of patients with available data; RTX = rituximab.
7
 IgG4-RD remains debatable because IgG4 levels are closely meningitis and a moderate increase in CSF proteins with
related to disease activity and the extent of organ intrathecal synthesis of IgG with oligoclonal bands. Further-
damage.6,10,17 It appears that IgG4-HP is infrequently asso- more, Della-Corte et al.22 reported that an increase in in-
ciated with systemic disease and explains normal-to-low se- trathecal IgG4 levels could be a surrogate marker for
rum IgG4 levels and the lack of inflammatory markers. This is neurologic IgG4-RD when tissue biopsies could not be
further illustrated by a recent study showing that an increase performed.
in serum IgG4 is usually associated with lymph node in-
volvement, pancreatic, biliary, and/or ENT features.18 On the IgG4-HP closely follows granulomatosis with polyangeitis
other hand, skin, prostate, and/or retroperitoneum in- (GPA) as a leading cause of inflammatory HP.23 Other di-
volvement is associated with lower levels of serum IgG4.18 As agnoses to consider are lymphoma, sarcoidosis, tuberculosis,
supported by our review, IgG4-HP is also associated with rheumatoid arthritis and Langerhans-cell histiocytosis.24,25
lower IgG4 plasmatic levels, inflammatory syndrome, eosin- Interestingly, increases in plasma IgG4 levels have also been
ophilia, and complement consumption. It is thus essential to observed in cases of GPA. Therefore, histopathologic studies
ascertain extra-neurologic organ-involvement in patients with have to be an integral part of the diagnostic workup. To
IgG4-HP presenting with high serum IgG4 levels and elevated complicate matters, overlapping syndromes of IgG4-RD and
plasma inflammatory markers. In such circumstances, PET- antineutrophil cytoplasmic antibodies-related vasculitides
CT has been shown to be of diagnostic value.19–21 have been described in a French cohort of 18 cases.26

CSF alone is not a reliable parameter for the diagnosis of There is no specific treatment protocol for meningeal forms of
IgG4-HP. It is, however, common to find lymphocytic IgG4-RD. Steroids remain the first-line treatment,27 though

Figure 3 Treatment algorithm for IgG4-HP

* Oral steroid therapy should be reduced over a period of 1-year minimum. AZA = azathioprine; CYC = cyclophosphamide; IgG4-HP = IgG 4-related
hypertrophic pachymeningitis; MMF = mycofenolate mofetil; MTX = methotrexate.

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several other studies also report the efficacy of immunosup- immunosuppressive therapy (such as RTX) to prevent neu-
pressive agents such as RTX.28,29 Short-term response to rologic complications.
surgery in single-organ IgG4-HP is good and, in some cases,
may be sufficient to achieve remission. Systemic steroids are Study funding
prescribed for most patients and appear to reduce relapse rate. No targeted funding.
Patients with early relapse—most often than not—had not
received steroid pulse therapy. In addition, relapse is less Disclosure
frequent when oral steroids are prescribed at a minimal dose M. Levraut reports no disclosures; M. Cohen received honoraria
of 50 mg/d and are maintained for a minimum of one year for advisory board participation from Biogen, Novartis, Roche
period. Because steroids should be continued over a year, and Ad Scientam; S. Bresch reports no disclosures; C. Giordana
immunosuppressive drug use as steroid sparing agent should received honoraria from Abbvie; F. Burel-Vandenbos reports no
be considered early on. Though used in half of the patients, disclosures; J. Sedat reports no disclosures; D. Fontaine is
immunosuppressive therapy is best suited to multisystem a consultant for Medtronic, St Jude-Abott, Autonomic Tech-
organ-involvement. The clinical response rates are particu- nologies, Renishaw; V. Bourg reports no disclosures; N. Martis
larly good in patients treated with RTX or CYC. One report reports no disclosures; C. Lebrun-Frenay received honoraria for
even described the efficacy of intrathecal RTX in the event of expertise and presentations at meetings from Teva, Biogen,
treatment failure from other immunosuppressors.30 Car- Merck, Roche, Novartis. Go to Neurology.org/NN for full
ruthers et al.31 published in 2015, a prospective clinical trial of disclosures.
30 patients, studying the efficacy of RTX in IgG4-RD. Re-
mission, obtained in 77% of patients, was calculated from Publication history
a combined score, the Responding Index. The data of our Received by Neurology: Neuroimmunology & Neuroinflammation January
review concord with the literature designating RTX as the 24, 2019. Accepted in final form March 12, 2019.
immunosuppressive drug of choice for IgG4-RD and
IgG4-HP.

The disease-activity score or Responder Index (RI) has been Appendix Authors
proposed by some authors.31 Patients were categorized into
Name Location Role Contribution
high- or low-risk groups for relapse based on serum IgG4
levels, the extent of organ involvement, and organ failure. Michaël Université Côte Author Major role in acquisition of
Levraut, MD d’Azur, Hôpital data; drafted the
IgG4-HP is rarely associated with other organ-involvement, l’Archet 1 manuscript
but it is known to relapse despite steroid therapy in nearly half
Mikaël Université Côte Author Revised the manuscript for
of cases, regardless of the type of meningeal involvement. The Cohen, MD d’Azur, Hôpital intellectual content
RI does not seem to reflect this risk of relapse in cases of Pasteur 2
isolated IgG4-HP. Because systemic involvement is less fre- Saskia Université Côte Author Revised the manuscript for
quent in IgG4-HP, serum markers such as CD19+, CD27+, Bresch, MD d’Azur, Hôpital intellectual content
CD20−,and CD38(hi) cells, IgG4 and IgE levels,32–34 may be Pasteur 2

less reliable than in IgG4-RD with multi-organ involvement Caroline Université Côte Author Revised the manuscript for
for predicting relapse. On the other hand, CSF IgG4 levels Giordana, d’Azur, Hôpital intellectual content
MD Pasteur 2
may better reflect disease activity in IgG4-HP but would also
require regular spinal taps—limiting its use to specific sit- Fanny Burel- Université Cote Author Interpreted the data,
Vandenbos, d’Azur, Hôpital revised the manuscript for
uations (i.e., treatment resistance, initiation of immunosup- MD, PhD Pasteur 1 intellectual content
pressive therapy).
Lydiane Université Côte Author Revised the manuscript for
Mondot, MD d’Azur, Hôpital intellectual content
Based on our experience and the available data from previous Pasteur 2
studies, a treatment algorithm for IgG4-HP is presented in Jacques Université Côte Author Revised the manuscript for
figure 3. Sedat, MD d’Azur, Hôpital intellectual content
Pasteur 2

Denys Université Côte Author Revised the manuscript for

Fontaine, d’Azur, Hôpital intellectual content
Conclusion MD, PhD Pasteur 2

IgG4-HP is an uncommon form of IgG4-RD and is one of the Véronique Université Côte Author Revised the manuscript for
Bourg, MD d’Azur, Hôpital intellectual content
leading causes of meningeal inflammatory disease. It is mainly Pasteur 2
characterized by the lack of extra-neurologic organ-
Nihal Martis, Université Côte Author Designed and
involvement and systemic signs. Histopathologic studies MD d’Azur, Hôpital conceptualized the study;
should, when possible, be performed as it is crucial for di- l’Archet 1 revised the manuscript for
intellectual content
agnosis because serum markers are rarely informative.
Treatment strategies rely on early surgery, steroids, and early Continued

Neurology.org/NN Neurology: Neuroimmunology & Neuroinflammation | Volume 6, Number 4 | July 2019 9

 15. Lin W, Lu S, Chen H, et al. Clinical characteristics of immunoglobulin G4-related disease:
a prospective study of 118 Chinese patients. Rheumatology (Oxford) 2015;54:1982–1990.
Appendix (continued)
16. Chen Y, Zhao JZ, Feng RE, et al. Types of organ involvement in patients with
immunoglobulin G4-related disease. Chin Med J 2016;129:1525–1532.
Name Location Role Contribution
17. Tabata T, Kamisawa T, Takuma K, et al. Serial changes of elevated serum IgG4 levels
in IgG4-related systemic disease. Intern Med 2011;50:69–75.
Christine Université Côte Author Designed and 18. Umehara H, Okazaki K, Nakamura T, et al. Current approach to the diagnosis of
Lebrun- d’Azur, Hôpital conceptualized the study; IgG4-related disease–combination of comprehensive diagnostic and organ-specific
Frenay, MD, Pasteur 2 revised the manuscript criteria. Mod Rheumatol 2017;27:381–391.
PhD 19. Takahashi H, Yamashita H, Morooka M, et al. The utility of FDG-PET/CT and other
imaging techniques in the evaluation of IgG4-related disease. Joint Bone Spine 2014;
81:331–336.
20. Lee J, Hyun SH, Kim S, et al. Utility of FDG PET/CT for differential diagnosis of
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10 Neurology: Neuroimmunology & Neuroinflammation | Volume 6, Number 4 | July 2019 Neurology.org/NN

 Immunoglobulin G4-related hypertrophic pachymeningitis: A case-oriented review
Michaël Levraut, Mikaël Cohen, Saskia Bresch, et al.
Neurol Neuroimmunol Neuroinflamm 2019;6;
DOI 10.1212/NXI.0000000000000568

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