Neuro-Ophthalmologic Manifestations of Hypertrophic Pachymeningitis
Hypertrophic pachymeningitis (HP) is an inflammatory process that causes thickening of the cranial and/or spinal dura mater. HP can present with various neurological symptoms and signs including headache, cranial nerve palsies, papilledema, and intracranial hypertension.
HP can be secondary to various autoimmune, infectious, and neoplastic causes. When no underlying disease process is found, it is termed idiopathic HP.
Autoimmune processes are the most common causes of HP. The differential diagnosis for HP includes anti-neutrophil cytoplasmic antibody (ANCA)-related vasculitis (e.g., granulomatosis with polyangiitis (GPA)), sarcoidosis and other systemic granulomatous diseases, IgG4-related disease, rheumatoid arthritis, systemic lupus erythematosus, giant-cell arteritis, Behçet syndrome, and Sjögren syndrome. Infectious etiologies of HP include neurosyphilis, tuberculosis, fungal meningitis (Aspergillosis), and bacterial sinusitis.
Neoplastic disorders can involve the dura and mimic HP clinically and radiographically (e.g., dural metastases, meningiomas, lymphomas, and histiocytosis).
The dura mater, formed by dense connective tissue, is the outermost layer of the meninges and encases the brain, spinal cord, proximal portions of cranial nerves, cavernous sinus, and optic nerve sheath. Thickening of the dura and inflammation can lead to mechanical compression of nerves, resulting in functional and radiographic lesions. Moreover, dural thickening and inflammation can cause venous stasis, arterial compression, and direct inflammatory spread to the brain parenchyma.
The clinical manifestations of HP can vary widely depending on the location and extent of dural thickening. The most common initial symptom in these patients is chronic, nonspecific headaches. Cranial neuropathy affecting one or more cranial nerves but particularly II can lead to vision loss. Other ocular motor cranial nerve involvement (e.g., III, IV, and VI) can result in anisocoria, ophthalmoplegia, ptosis, and diplopia. Additional neurological signs can include seizures, ataxia, hemiparesis, cognitive impairment, and signs of increased intracranial pressure. Rarely, spinal cord compression may occur.
Other presenting symptoms may provide clues to the underlying pathology. Systemic symptoms such as fever, weight loss, and fatigue may indicate an infectious or autoimmune etiology. Profound weight loss may suggest a neoplastic process. Specific symptoms, such as chronic sinusitis in GPA, should be considered in the differential diagnosis.
A full neurological exam and vital signs assessment should be conducted. Given that visual loss and double vision are common initial symptoms, a comprehensive ophthalmologic workup is warranted in such cases. Neuroimaging is recommended for patients presenting with chronic, progressive headaches and symptoms of focal cranial nerve palsies. Brain and orbital magnetic resonance imaging (MRI) with and without contrast should be performed in suspected HP. Post contrast cranial MRI typically shows diffuse or focal thickening of the dura mater and homogenous contrast enhancement due to the inflammatory etiology. Thickening of the falx cerebri, tentorium cerebelli, and cavernous sinus is also commonly observed . MR venography (MRV) may reveal dural sinus stenosis or adjacent thrombosis. Chest imaging (e.g., chest x-ray or computed tomography (CT)) can evaluate for bilateral hilar lymphadenopathy suggestive of sarcoidosis. Further systemic imaging with CT or MRI may be necessary to assess for IgG4 or other neoplasia.
Laboratory studies may include non-specific inflammatory markers such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), which can be elevated in HP patients. For infectious etiologies, specific laboratory investigations may include rapid plasma reagin (RPR) titer, fluorescent treptonemal antibody-absorption (FTA-abs), tuberculosis (TB) testing, Bartonella, and Lyme antibodies. Autoimmune etiologies can be further investigated with antibodies including SSA, SSB, rheumatoid factor, antinuclear antibody (ANA), ANCA, and IgG4. Angiotensin-converting enzyme (ACE) levels can help evaluate the possibility of sarcoidosis.
When there is imaging evidence of dural thickening, lumbar puncture with cerebrospinal fluid (CSF) analysis is indicated to investigate the underlying cause. CSF analysis may include polymerase chain reaction (PCR), serology, and culture to definitively exclude infection. CSF should also be assessed for autoimmune antibodies and neoplastic etiologies. CSF cytology can reveal non-specific elevation in protein and mild pleocytosis.
If a typical clinical picture with corresponding serological markers is absent, a dural biopsy is the gold standard for a definitive diagnosis. Pathological analysis and immunohistochemistry with markers for lymphocytes, macrophages, and IgG4 should be performed. Healthy dura mater is characterized by dense fibrous tissue, while HP shows a pattern of storiform fibrosis. Histological findings of marked lymphocytic infiltration with an IgG4/IgG positive cell ratio >40% and IgG4-positive plasma cells >10 per high-power field are suggestive of IgG4-related disease.
Due to the variable signs and symptoms of HP, ruling out various etiologies and differential diagnoses is essential
- Primary CNS tumors
- Secondary dural metastases
- Langerhans and non-Langerhans histiocytosis
- IgG4-related disease
- Rheumatoid arthritis
- Systemic lupus erythematosus
- Giant-cell arteritis
- Behçet syndrome
- Sjögren syndrome
- Neuromyelitis Optica
- MOG optic neuritis
- Paraneoplastic etiologies
- Fungal meningitis (Aspergillosis)
- Bacterial sinusitis
- Venous sinus occlusion
- Giant cell arteritis (GCA)
- Intracranial hypotension
- Idiopathic hypertrophic pachymeningitis (when all other etiologies are ruled out)
The treatment of HP depends on the underlying etiology. It is essential to exclude infectious diseases before initiating any immunosuppressive therapy.
Autoimmune causes, such as GCA, GPA, sarcoidosis, and IgG4-related disease, are treated with corticosteroids, which have been shown to improve and maintain vision and control headaches in some patients. In cases of inadequate response or recurrence on steroids, other immunosuppressive therapies such as azathioprine, cyclophosphamide, methotrexate, rituximab, and infliximab may be used. 
Clinicians should be aware of the ophthalmic presentations of HP (e.g., visual loss, diplopia, papilledema). The distinctive radiographic finding of HP is thickening of the meninges with enhancement (especially on postcontrast MRI). A complete clinical, laboratory, and cerebrospinal fluid evaluation is recommended for autoimmune inflammatory granulomatous and non-granulomatous etiologies. Neoplastic disease (e.g., carcinomatous meningitis) should also be included in the differential diagnosis and may require systemic imaging, CSF cytology, or a dural biopsy to confirm the diagnosis.
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