Hypertrophic pachymeningitis (HP) is a rare disease characterized by diffuse or localized thickening and inflammation of the intracranial and/or spinal dura mater. HP presents with various neurological symptoms and signs such as headache, cranial nerve palsy, optic disc edema, and increased intracranial pressure, and its impact on the visual system is particularly important clinically.
The reported prevalence is approximately 0.949 per 100,000 people1). In a nationwide survey in Japan, the most common cause was ANCA-associated (30.2%), followed by IgG4-related (8.8%)8). Some reports indicate that idiopathic HP accounts for about half of all cases1).
HP is classified into intracranial HP and spinal HP depending on the lesion site. Intracranial HP primarily presents with headache and cranial nerve disorders, while spinal HP mainly presents with nerve root symptoms and spinal cord compression symptoms.
The prevalence is reported to be approximately 0.949 per 100,000 people, making it a very rare disease. Because the initial symptoms are nonspecific, delayed diagnosis or misdiagnosis is common.
The most common initial symptom in HP is chronic, nonspecific headache 1). The headache is often perceived as a persistent local pressure sensation and progressively worsens.
Other subjective symptoms include the following:
The neuro-ophthalmic findings in HP vary greatly depending on the location and extent of dural thickening and the affected neural structures.
Optic Neuropathy
Compressive optic neuropathy: Dural thickening at the orbital apex compresses the optic nerve, causing gradual unilateral visual loss and visual field defects (concentric constriction, paracentral scotoma).
Optic disc edema: Bilateral papilledema due to increased intracranial pressure. In severe cases, it may progress to optic atrophy.
Positive RAPD: Relative afferent pupillary defect reflecting unilateral optic nerve damage.
Ocular motility disorders
Abducens nerve palsy (CN VI): Most common cranial nerve disorder. Presents with esotropia and horizontal diplopia.
Oculomotor nerve palsy (CN III): Causes ptosis, anisocoria, and restricted eye movements.
Trochlear nerve palsy (CN IV): Cyclotropia due to superior oblique muscle palsy.
Ophthalmoplegia: In cavernous sinus lesions, multiple cranial nerves are affected simultaneously.
Causes of compressive optic neuropathy include hypertrophic pachymeningitis along with thyroid eye disease, rhinogenic optic neuropathy, hemangioma, lymphoma, and granulomatosis with polyangiitis (GPA). In cases of unilateral gradual vision loss, these differential diagnoses must always be considered.
Hypertrophic pachymeningitis is also an important cause of orbital apex syndrome (total ophthalmoplegia + sensory disturbance in the first division of the trigeminal nerve + optic neuropathy).
The optic nerve (CN II) is most commonly affected, followed by the abducens nerve (CN VI), vestibulocochlear nerve (CN VIII), oculomotor nerve (CN III), trochlear nerve (CN IV), and trigeminal nerve (CN V), in that order1).
The causes of HP are diverse and are broadly classified into autoimmune, infectious, neoplastic, and idiopathic categories.
If no underlying disease is identified, it is diagnosed as idiopathic HP (IHP). It has been reported that IHP accounts for about half of all HP cases 1). MOG antibody-associated disease has been reported as a cause of some IHP cases 1).
The diagnosis of HP requires a comprehensive evaluation combining clinical findings, imaging, blood tests, cerebrospinal fluid analysis, and dural biopsy.
Since decreased visual acuity and diplopia are common initial symptoms of HP, a comprehensive ophthalmic evaluation focusing on the optic nerve and cranial nerves is important. Visual acuity testing, visual field testing, fundus examination, ocular motility testing, and RAPD testing should be performed.
| Test Item | Evaluation Target |
|---|---|
| Erythrocyte Sedimentation Rate (ESR) and C-Reactive Protein (CRP) | Nonspecific inflammatory markers |
| Antineutrophil Cytoplasmic Antibodies (ANCA) (MPO and PR3) | ANCA-associated vasculitis |
| IgG4 | IgG4-related disease |
| ANA, RF, anti-SSA/SSB | Collagen disease screening |
| Angiotensin-converting enzyme (ACE) | Sarcoidosis |
| RPR・FTA-abs | Syphilis |
| T-SPOT・QuantiFERON | Tuberculosis |
When dural thickening is confirmed on imaging, lumbar puncture is performed to investigate the underlying disease. Nonspecific protein elevation and mild pleocytosis (lymphocyte predominance) are often observed1). PCR, culture, and serological tests are performed to rule out infection. Approximately 70% of patients show elevated intracranial pressure and increased CSF protein and white blood cells1).
When typical clinical findings and serological markers do not confirm the diagnosis, dural biopsy is the gold standard for definitive diagnosis. Pathologically, it is characterized by infiltration of lymphocytes and macrophages and interstitial fibrosis. In IgG4-related disease, diagnostic criteria include storiform fibrosis, obliterative phlebitis, an IgG4/IgG-positive cell ratio >40%, and >10 IgG4-positive plasma cells per high-power field 7).
Gadolinium-enhanced MRI is the most useful. Contrast-enhanced MRI shows diffuse or localized thickening and enhancement of the dura. Non-contrast MRI or CT may not detect inflammatory dural thickening, so contrast-enhanced imaging is essential.
Treatment of HP is based on addressing the underlying disease. Before starting immunosuppressive therapy, it is essential to rule out infection.
The first-line treatment for compressive optic neuropathy is steroid pulse or half-pulse therapy. After 1 to 3 courses, switch to oral steroids. Avoid rapid tapering as it may cause recurrence of optic neuropathy.
Steroid therapy is highly effective for autoimmune HP; in a Japanese report, 87.2% of 94 patients showed significant symptom improvement with steroids 1). Steroids are effective for improving and maintaining vision and controlling headaches.
If response to steroids is insufficient or if recurrence occurs, the following immunosuppressants are used.
With the addition of immunosuppressive drugs, symptom improvement is achieved in approximately 92.6% of cases 1).
When conservative treatment is ineffective or in urgent situations such as spinal cord compression or non-communicating hydrocephalus, surgical intervention is necessary 5). Partial resection of the dural lesion and decompression are performed.
The dura mater is the outermost layer of the meninges, composed of dense connective tissue, and envelops the brain, spinal cord, proximal cranial nerves, cavernous sinus, and optic nerve sheath.
Thickening and inflammation of the dura mater cause neurological deficits through the following mechanisms:
Multiple cytokine pathways are involved in dural fibrosis in HP4).
IgG4-related HP and ANCA-related HP have been considered distinct diseases, but cases with features of both have been reported8)9). As a mechanism for ANCA positivity in IgG4-related disease, it has been proposed that T follicular helper cells polarize toward the Tfh2 subtype, promoting differentiation into IgG4-producing plasma cells9). In patients with granulomatosis with polyangiitis, ANCA mainly belongs to the IgG1 and IgG4 subclasses, and repeated exposure to antigens via a Th2-type immune response may induce a shift toward IgG49).
Kikuchi et al. (2024) reported a case of intracranial HP associated with MDS4). It has been hypothesized that immune abnormalities in MDS lead to infiltration of inflammatory cytokines such as TNF-α and IFN-γ into the cerebrospinal fluid, triggering an inflammatory response in the dura mater. It has also been noted that the cytokine profile of VEXAS syndrome (an inflammatory syndrome with cytopenia due to somatic mutations in the UBA1 gene) is similar to that of HP.
Xia and Li (2022) analyzed 10 cases (3 of their own plus 7 from the literature) of IgG4-HP with positive ANCA, reconfirming the existence of HP as an overlap syndrome of IgG4-related disease and ANCA-associated vasculitis9). Of the 10 cases, 8 were MPO-ANCA positive and 2 were PR3-ANCA positive. Response to immunosuppressive therapy was generally good, with clinical and imaging improvement in 6 cases.
Lin et al. (2023) reported a case in which en plaque meningioma presented as infiltrative optic neuropathy and HP 2). In this case, extensive serological and cerebrospinal fluid tests did not lead to a diagnosis, and finally, a transsphenoidal biopsy confirmed WHO grade 1 meningioma (meningothelial type). This highlights the importance of considering neoplastic lesions in the differential diagnosis of HP.
