IgG4-related intracranial hypertrophic pachymeningitis with skull hyperostosis: a case report
Division of Neurosurgery, Department of Surgery, National Taiwan University College of Medicine and National Taiwan University Hospital
No. 7, Chung Shan S. Rd., 10002 Zhongzheng Dist., Taipei City
Division of Neurosurgery, Department of Surgery, Far Eastern Memorial Hospital
No. 21, Sec. 2, Nanya S. Rd., Banciao Dist., New Taipei City 220
Background: Immunoglobulin G4 (IgG4)-related disease is a systemic syndrome, characterized by sclerosing lesions and usually associated with a raised serum IgG4 level; the pancreas, salivary glands, and lacrimal glands are typically affected. Recently, it has been suggested that IgG4-related sclerosing disease represents a subset of cases previously diagnosed as idiopathic hypertrophic pachymeningitis. This rare inflammatory disorder causes localized or diffused thickening of intracranial dura mater. Headache, cranial nerve palsy, and ataxia are the most common clinical manifestations. Herein, we report the clinical and histopathological features of a rare case of IgG4-related intracranial hypertrophic pachymeningitis involving cranial hyperostosis. Case presentation: A 52-year-old man presented with refractory generalized tonic-clonic seizure. Magnetic resonance imaging revealed thickening of the meninges with enhancement near the superior sagittal sinus; skull bone defect was also noted. Extensive excision of affected skull bone and dura was performed, providing the diagnosis of IgG4-related pachymeningitis. After the surgery, the patient's seizure stopped and he was smoothly tapered off antiepileptic medication. Conclusion: To our knowledge, this is the first reported case of IgG4-related pachymeningitis with concomitant skull hyperostosis.
Immunoglobulin G4 (IgG4)-related disease is a systemic
syndrome, characterized by sclerosing lesions and usually
associated with a raised serum IgG4 level ; the pancreas,
salivary glands, and lacrimal glands are typically affected.
Recently, it has been suggested that IgG4-related sclerosing
disease represents a subset of cases previously diagnosed as
idiopathic hypertrophic pachymeningitis [2-4]. This rare
inflammatory disorder causes localized or diffused
thickening of intracranial dura mater . Headache, cranial
nerve palsy, and ataxia are the most common clinical
Herein, we report the clinical and histopathological
features of a rare case of IgG4-related intracranial
hypertrophic pachymeningitis involving cranial hyperostosis.
A 52-year-old man with a history of treated hypertension
and diabetes mellitus presented to our hospital following
a single seizure attack; he regained consciousness shortly
before arrival. Two weeks before this, he had a head
injury that resulted in some minor scalp abrasion and
bleeding. No obvious neurological deficit was noted at
that time, and he was discharged following a period of
observation without imaging. However, on the day after
the discharge, he experienced another seizure attack that
lasted for 56 minutes with subsequent loss of
consciousness. He was then admitted to our hospital.
Initially, the patient experienced generalized tonic-clonic
seizures twice daily. Persistent right calf paresthesia was
also noted; this presented as a focal seizure when
aggravated and often progressed to a generalized tonic-clonic
seizure. Under antiepileptic medications, focal seizures
remained persistent but progression to secondary
generalized seizures became rare.
On physical examination there were no clinical signs to
suggest other organ involvement, in particular there was
no glandular enlargement or orbital disease. Abdominal
ultrasound showed a normal liver, gallbladder, pancreas
Magnetic resonance imaging showed thickening of the
meninges with enhancement near the superior sagittal
sinus; skull bone defect was also noted (Figure 1A-D).
We initially suspected meningitis or skull metastasis
with dura invasion. Subsequently, lumbar puncture was
performed for cerebrospinal fluid (CSF) examination.
Sugar level was within normal limit compared to
peripheral blood sugar levels, and no visible leukocytes were
noted. Hemogram did not reveal leukocytosis, and
C-reactive protein level was also within the normal limit.
Thus, infection seemed unlikely. CSF cytology revealed
no malignant cells.
Left parietal skull and dural nodule excision were then
performed for both pathological diagnosis and symptomatic
relief (Figure 2A). Duroplasty was also performed with
autologous fascia, and the skull defect was covered with
Titanium mesh. Hyperostosis of the skull was noted, and
the overlying galea aponeurotica showed thickening and a
whitish color change (Figure 2B). Gliosis was noted along
the cortical vessels and gyrus just below the involved dura
area (Figure 2C).
Microscopically, sections of the dura and galea showed
mixed inflammatory cell infiltration, composed mainly of
lymphoplasma cells, in a stroiform fibrous background with
occasional eosionphils. Lymphoid follicles with germinal
center formations were also observed in the galeal tissue
sections (Figure 3A-C). Skull sections revealed focal fibrosis
and chronic inflammation in the marrow space.
Immunohistochemical analysis revealed some inflammatory cells
and spindle cells that were immunoreactive to S-100 stain.
We concluded that a chronic inflammatory process was
occurring, and a diagnosis of idiopathic hypertrophic cranial
pachymeningitis was subsequently considered.
Immunohistochemical analysis using the
avidin-biotincomplex (ABC) stain revealed an increased IgG4 (+) plasma
cell count, which accounted for more than 50% of the IgG
(+) cells with a mean more than 30 in 3 high power fields
(HPFs); this was assessed by counting 20 HPFs 
(Figure 3D & E). No evidence of spirochete infection was
observed. Autoimmune profiles were normal, including
findings for antinuclear antibody and rheumatoid factors.
Increased serum IgG4 (939 mg/dl; normal ranges:
1140 mg/dl)  was noted. Based on the histopathological
and immunohistochemical findings, as well as the exclusion
Figure 1 Preoperative images. A. Anteroposterior view of skull
X-ray radiography shows left skull bone effacement near the vertex.
B-D. Magnetic resonance image shows an area of abnormal bony
marrow over left high convexity showing loss of normal fatty
marrow with moderate enhancement after contrast injection (arrow).
Mild subperiosteal soft tissue thickening and adjacent dura and
leptomeningeal thickening and enhancement (arrowhead) are
apparent. The left central and precentral sulci are filled with
abnormal enhancing lesion (white arrows).
Figure 2 Intraoperative images. A. The dura with nodule at the
central part (arrow). B. Galeal thickening. C. The secondary dural
change along the cortical vessels and gyrus is noted just below the
involved dura area (arrows).
Figure 3 Histopathological findings. A-D. Sections of the dura and galea show increasing inflammatory change (A, H&E, 40) composed of
mainly lymphoplasma cells in a storiform fibrous background with occasional eosinophils (B, H&E, 100; C, H&E, 200). Lymphoid follicles with
germinal center formation are also seen in a section of galeal tissues (D, H&E, 100). E&F. IgG4 (+) plasma cells account for more than 50% of
IgG (+) cells with a mean more than 30 in 3 higher power fields (ABC immunohistochemical stain, E, 100; F, 200).
of known causes of pachymeningitis, a diagnosis of
IgG4related hypertrophic intracranial pachymeningitis was
After total excision of the affected skull bone and
meninges, the patients seizures stopped; he was smoothly
tapered off antiepileptic medication. In addition, his serum
IgG4 levels returned to normal, and no obvious sequela
was noted after the operation. Follow-up imaging study
and physical examinations in 3 months later revealed that
the infiltration of the arachnoid membrane had vanished
and there was no involvement of other organs.
Hypertrophic pachymeningitis is a rare disorder that causes
localized or diffused thickening of the dura mater .
Numerous clinico-pathological entities cause thickening of
the pachymeninges, thus idiopathic hypertrophic pachy
meningitis is diagnosed by exclusion; a dural biopsy is
usually essential for a definitive diagnosis [5,7]. Pathological
findings consist of thick fibrous dura often associated with
chronic inflammation cell infiltrate consisting of
lymphocytes and plasma cells; compression of neural structures by
the thickened fibrous dura results in neurological defects.
Hypertrophic cranial pachymeningitis most commonly
presents with headache and cranial neuropathies . Other
associations include seizure, memory loss, ataxia,
TolosaHunt syndrome, and pituitary dysfunction [7,8]. The
condition has also been described in relation to specific
infections, including Lyme disease, syphilis,
Mycobacterium tuberculosis, fungal infections, cysticercosis, HTLV-1,
and malignant external necrotizing otitis due to
Pseudomonas. Similarly, it has been described in relation to
autoimmune disorders, such as Wegener granulomatosis,
rheumatoid arthritis, sarcoidosis, Behet disease, Sjgren
syndrome, and temporal arteritis. Finally, it can be related
to neoplasia, such as carcinomatosis, lymphoma, and
meningioma en plaque [5,9].
IgG4-related sclerosing disease was initially recognized
as a form of autoimmune pancreatitis. However, it is
now known that this disease can affect the bile duct,
gallbladder, salivary glands, retroperitoneum, kidneys,
lungs, and even, prostate. Pathologically, this disease is
characterized by extensive infiltration of IgG4-positive
cells in various organs . Clinically, it often presents
with mass-like lesions. Central nervous system
involvement is rarely reported; however, recently it has been
suggested that IgG4-related sclerosing disease represents
a subset of cases previously diagnosed as idiopathic
hypertrophic pachymeningitis [2-4]. IgG4-related
sclerosing pachymeningitis may present a diffuse infiltrative
pattern with or without mass formation [2-4]. To our
knowledge, this is the first reported case of localized
IgG4-related pachymeningitis with concomitant skull
hyperostosis. Noda D et al. previously reported a case of
idiopathic pachymeningitis with skull hyperostosis 
but without clarifying its possible etiology.
Meningeal biopsies are frequently performed for a
differential diagnosis of pachymeningitis, especially for
those with infectious etiology [5,7,9]. In our case, surgical
excision was performed to provide possible symptomatic
relief as well as for diagnosis. In our case, thickening of
the arachnoid membrane was left untouched to avoid
Although it has been reported that pachymeningitis
responds well to steroid treatment and other
immunosuppressants, we did not prescribe the above
medications owing to concerns about the adverse effects of
their long-term use [3,9,11,12]. In addition, this case
was found only to be involved locally in dura and skull
at admission, and without involvement of other organs,
such as: lacrimal glands, salivary glands, or pancreas
after detailed examinations.
The patients symptoms disappeared following surgical
treatment. Thus, surgical excision to decrease the affected
region may benefit patients with IgG4-related
pachymeningitis, especially for patients with a solitary mass and
without other organ involvement. Beyond our expectation,
the infiltrative pattern of the involved arachnoid membrane
disappeared following surgery. The self-limiting course may
be related to the decrease in systemic IgG4 levels. It will be
important to follow-up the patient for signs of recurrence
and further organ involvement in the future.
Despite its extremely rarity, IgG4-related sclerosing
disease may present as a solitary intracranial condition.
Surgical biopsy may be the only means of obtaining a
differential diagnosis. Extensive excision of the
intracranial lesion may be performed for symptomatic patients.
C.K.L: Collections of the clinical data of the case and writing of the
manuscript. D.M.L: Instructions and responsibility for the completion of this
manuscript. Both authors read and approved the final manuscript.