Keywords:
Pachymeningitis - Granulomatosis with Polyangiitis - Immunoglobulin G4-Related Disease
- Sarcoidosis
Palavras-chave:
Paquimeningite - Granulomatose com Poliangiite - Doença Relacionada a Imunoglobulina
G4 - Sarcoidose
Hypertrophic pachymeningitis (HP) is an inflammatory process which causes thickening
of the cranial or spinal dura mater and is associated with variable neurological syndromes
such as cranial nerve palsy, stroke, venous thrombosis and intracranial hypertension.
The diagnosis of HP is suggested by magnetic resonance imaging (MRI), which discloses
dural thickening and contrast enhancement[1]. Several disorders such as infectious and autoimmune diseases may cause HP[1],[2],[3],[4]. The gold standard for HP etiological diagnosis is dural biopsy, but cerebrospinal
fluid (CSF) and blood tests, as well as other tissues analyses, lead to a correct
diagnosis. Quick diagnosis and treatment are crucial to avoid permanent symptoms.
However, the diagnostic workup is usually a complex process, which may delay the specific
treatment. This review aims to discuss the causes of HP and propose a practical approach
to the diagnosis and treatment of its inflammatory and autoimmune origins.
CONCEPT AND ANATOMY
The meninges comprise three layers of protective tissue enveloping the brain and spinal
cord. Dura mater is the outermost and thickest of the meninges and is formed by dense
connective tissue closely related to the inner table of the skull. The other layers,
pia mater and arachnoid, are much thinner and thus referred to as the leptomeninges.
The pia mater is a transparent layer directly adherent to the surface of the brain
and spinal cord. A complex network of reticular fibers located between the dura and
the pia mater constitutes the arachnoid[5].
Numerous pathological processes target the meninges, including neoplasms, infections,
and autoimmunity[3]. The term leptomeningitis indicates that the pia mater and/or the arachnoid are
affected, while pachymeningitis describes a disease of the dura[6]. Because the dura encases the proximal portion of cranial nerves, the cavernous
sinus, and the optic nerve sheath, pachymeningitis may damage these structures[7].
In 1893, Gowers provided the first detailed description of pachymeningitis and identified
two subtypes of the disorder. External pachymeningitis was related to a local phenomenon
provoked by trauma or infection. The internal subtype reflected a more diffuse process,
either hemorrhagic (likely corresponding to subdural hematoma) or purulent (likely
resulting from the spread of leptomeningeal tuberculosis or syphilis)[8]. Charcot's 1873 description of a case of cervical pachymeningitis, in which “the
neighboring leptomeninx (…) was firmly united to the dura” is closer to the definition
currently used in medical literature[9].
HP is defined macroscopically by the local or diffuse thickening of the cranial or
spinal dura mater, which often becomes adherent to the underlying leptomeninges. Two
types of cranial pachymeningitis may occur, depending on the location of the dural
thickening: one affects the parasellar and cavernous regions, involving the cavernous
and supraclinoidal segments of the internal carotid artery and optic nerves; the other
compromises the posterior third of the falx, tentorial, and clival dura mater[10]. Histological findings vary significantly according to the underlying disease[11].
CLINICAL FEATURES
HP has a variable clinical presentation depending on the etiology. Early symptoms
often include headache (in up to 92% of patients) and cranial nerve involvement[7]. Cranial nerves II and VII are predominantly affected due to nerve compression or
orbital pseudotumor (the optic nerve is often affected, sometimes bilaterally). The
involvement of cranial nerves III, IV, and VI can also lead to diplopia and ophthalmoplegia.
Other common neurological symptoms include intracranial hypertension, seizures, cerebral
venous thrombosis, hearing loss and gait ataxia. The clinical manifestation of HP
may vary depending on lesion location and dura mater thickness in brain imaging. The
parenchymal manifestations of HP include seizures, hemiparesis, tremors, cognitive
impairment, and localized brain edema with ”pseudotumor” presentation[7],[12],[13]. HP is a rare cause of spinal cord compression[14].
The pathophysiological mechanism underlying parenchymal involvement includes venous
congestion, ischemia resulting from compression of cortical vessels and inflammatory
infiltration into the brain parenchyma.
Extra-neurological or systemic manifestations of HP may help to define the etiology.
For example, the involvement of salivary glands, lymph nodes, the pancreas, and the
retroperitoneum suggest IgG4-related disease (IgG4-RD); pulmonary, renal and paranasal
sinus involvement may suggest granulomatosis with polyangiitis (GPA), formerly known
as Wegener's granulomatosis; hypothalamic involvement suggests IgG4-RD, sarcoidosis
or histiocytosis; and coexistence with neoplasia may suggest meningeal carcinomatosis[7],[12].
NEUROIMAGING
MRI in patients with HP demonstrates thickening of the dura mater, which may be diffuse
or focal. The sinus cavernous and orbital apex are commonly affected[3],[15]. Most of the patients present diffuse and asymmetric thickening of the dura mater.
The inflammatory process and increased vessel permeability cause a marked contrast
enhancement in HP. Contrast enhancement usually decreases with immunotherapy, and
MRI is relevant for the follow-up. Sinus occlusion may occur due to the thickening
of the dura, and thrombosis may occur because of hemodynamic changes[3],[15]. [Figure 1] shows typical thickening of the dura mater in HP and similar findings in autoimmune
causes and infections. In addition, a hyperintense signal of the dura mater may occur
as a result of intracranial hypotension, as a compensatory edema of the meninges caused
by a decreased volume of cerebrospinal fluid[3]. Additionally, other non-inflammatory conditions such as en plaque meningioma, post-surgical change, and chronic subdural hematoma may lead to a similar appearance
of thickened dura mimicking HP.
Figure 1 (A) patient with granulomatosis and polyangiitis presenting focal hypertrophic pachymeningitis
(arrow); (B) patient with sarcoidosis presenting asymmetric thickening of the dura
mater in the cerebellar tentorium (arrow); (C) patient with IgG4-related hypertrophic
pachymeningitis presenting a focal thickening of the dura mater in the right cavernous
sinus (arrow); (D) patient with neurosyphilis presenting asymmetric thickening of
the dura mater mimicking hypertrophic pachymeningitis (arrow); (E) patient with neurotuberculosis
presenting anterior thickening of the dura mater mimicking hypertrophic pachymeningitis
(arrows); (F) patient with intracranial hypotension after lumbar puncture mimicking
hypertrophic pachymeningitis, with hyperintense signal of the dura mater (arrows).
MRI features are relevant in differentiating idiopathic hypertrophic pachymeningitis
(IHP) from secondary HP. The characterization of MRI features in HP should include:
1) location — supratentorial, infra-tentorial, diffuse, and spinal canal; 2) configuration
— linear and nodular; 3) signal intensity — hyperintense, iso-intense or hypointen-se[15].
The essential MRI sequencing to evaluate and identify HP is the post-contrast T1-weighted
sequence, which demonstrates a marked hyperintense signal caused by contrast enhancement[15],[16]. The secondary HP group significantly has dural mater thickening at the anterior
and middle cranial fossae when compared with IHP patients. Most of the latter have
homogeneous contrast enhan-cement. Finally, imaging features presenting as hypointense
in T2 sequences, and central T2 hyperintense signal with hypointense rim (T2-rim pattern)
suggest HP[16].
CAUSES
[Table 1] shows the many causes of HP. The most common are discussed separately below:
Table 1
Main causes of hypertrophic pachymeningitis.
|
Inflammatory
|
Infectious
|
|
IgG4-related disease
|
Tuberculosis
|
|
Granulomatosis with polyangiitis
|
Syphilis
|
|
Sarcoidosis
|
Fungal infections
|
|
Idiopathic
|
Sinusitis complication
|
|
Rheumatoid arthritis
|
Neoplastic
|
|
Sjögren syndrome
|
Lymphoma
|
|
Systemic lupus erythematosus
|
En plaque meningioma
|
|
Giant-cell arteritis
|
Carcinomatous meningitis
|
|
Behçet's syndrome
|
Histiocytosis
|
|
Relapsing polychondritis
|
Other
|
|
Previous surgical procedure
|
|
Cerebrospinal fluid hypotension
|
Granulomatosis with polyangiitis
GPA is an anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, a group
of diseases associated with antibodies against neutrophil cytoplasmic structures[17]. It is characterized by the involvement of the respiratory tract and kidney[18],[19]. Its serologic marker is the PR3-ANCA (c-ANCA), but some cases could exhibit MPO-ANCA
(p-ANCA)[20]. The nervous system impairment is composed of peripheral nerve symptoms (especially
mononeuritis multiplex), HP, central nervous system vasculitis, cranial neuropathy,
myelopathy, and pituitary involvement[21],[22]. HP is mostly associated with the localized phenotype of GPA and MPO-ANCA positivity.
When PR3-ANCA antibodies are present, HP is associated with systemic features and
parenchymal brain lesions[20],[23].
Sarcoidosis
Sarcoidosis is a systemic granulomatous disease characterized by the presence of noncaseating
granulomas[24]. It can appear in practically any organ, in acute or chronic form. The most frequent
site of disease activity is the lung, affected in 80–90%[24],[25] of cases, with symptoms like cough, wheezing, and stridor[25].
The nervous system is affected in 3–10% of the cases, with variable manifestations[26],[27]. The most remarkable features are facial nerve neuropathy, optic neuritis, meningitis
(including HP), parenchymal lesions, hypophysitis, peripheral neuropathy, and myelopathy[26]. Other disease-associated symptoms are fatigue, depression, and cognitive impairment[24]. Sarcoidosis can also affect the skin (lupus pernio, papules, infiltrated scars,
and nodular skin thickening at tattoos), muscles, eyes (uveitis and conjunctival granulomas),
and the exocrine glands (salivary and lacrimal glands)[24].
IgG4-related disease
IgG4-RD is a systemic fibroinflammatory disease that can affect any organ, the most
frequent of which are the lacrimal and salivary glands, the pancreas and biliary tree,
the retroperitoneal space[12],[28],[29]. Neurological impairment is rare and frequently occurs without systemic disease[12]. The meningeal involvement is restricted to the dura and causes headaches as a result
of its traction, as well as irritation of trigeminal nerves and higher cervical roots[12]. The extension of the inflammation to the cavernous sinus, superior orbital fissure
or orbit produces ophthalmoparesis, proptosis, and ocular pain[12]. IgG4-RD can extend to the pituitary gland and stalk, causing hypophysitis; the
endocrinological abnormalities cause diabetes insipidus, hypogonadism, and hypothyroidism[30].
Idiopathic hypertrophic pachymeningitis
IHP is diagnosed after the exclusion of other possible causes of pachymeningitis and
a negative biopsy[7]. This disorder is restricted to the pachymeninges, and its most typical symptoms
are headaches, visual symptoms (due to the optic and oculomotor nerve impairment),
and ataxia.
Other inflammatory causes
Other inflammatory diseases can trigger HP. Rheumatoid arthritis is an autoimmune
arthropathy that presents with pachymeningitis, generally combined with leptomeningitis.
The clinical presentation is acute, with stroke-like events and seizures[31],[32],[33]. There are reported cases of systemic lupus erythematosus, giant-cell arteritis,
relapsing polychondritis, Behçet syndrome, and Sjögren syndrome presenting with HP[34],[35],[36],[37],[38].
DIAGNOSIS
The etiological diagnosis of HP through clinical, laboratory and imaging workup remains
a challenge, and final diagnosis is usually performed with tissue biopsy. It is essential
to rule out infectious diseases (tuberculosis, syphilis, fungal infections), autoimmune,
or inflammatory diseases (GPA, sarcoidosis and IgG4-RD) and malignancies, especially
lymphoma[39]. [Table 2] shows a diagnostic workup for patients with HP.
Table 2
Diagnostic workup of patients with hypertrophic pachymeningitis.
|
Initial evaluation
|
Etiology investigation
|
Search for biopsy site
|
|
MRI with contrast CSF analysis — cytology, flow cytometry, biochemistry, opening pressure,
cultures for bacteria, mycobacteria and fungus, PCR for mycobacterium tuberculosis,
VDRL
|
Serum IgG4
ANCA
Sinus CT
Thorax CT
Abdominal MRI
Cervical US
ANA
Serum VDRL
Rheumatoid factor
HIV serology
Galactomannan (patients with risk for Aspergillus infection)
Long bones radiography
Hypophysis survey (hormones)
|
Check systemic survey tests, if there are no sites for biopsy other than CNS, consider
F18-FDG-PET-CT before final decision.
|
MRI: magnetic resonance imaging; CSF: cerebrospinal fluid; PCR: polymerase chain reaction;
VDRL: venereal disease research laboratory; CT: computerized tomography; US: ultrasound;
ANA: antinuclear antibody; 18FDG-PET: positron emission tomography with 18-fluorodeoxyglucose.
The first step of the diagnostic approach is clinical characterization. An investigation
of respiratory and systemic symptoms is essential. The respiratory system is affected
frequently by granulomatosis with polyangiitis, neurosarcoidosis, and tuberculosis;
complaints like shortness of breath, nasal discharge, and cough can occur under these
circumstances[24],[40],[41]. The next step of the investigation is MRI (see Neuroimaging) and CSF analysis.
The latter is a valuable tool to exclude infections; the execution of molecular assays
(e.g., polymerase chain reaction), serologies, and cultures are essential to rule
out tuberculosis, syphilis, and fungal infections[41],[42]. Another possible technique to exclude infections is CSF metagenomics[43]. Cytological and biochemical analyses in HP cases are unspecific, varying from normal
parameters to mild pleocytosis and elevated protein levels[21],[26]. Angiotensin-converting enzyme (ACE) levels in CSF have limited value for the diagnosis
of NS, as they are raised in other inflammatory diseases[44].
The blood workup should include markers for autoimmune disorders (especially antinuclear
antibody — ANA, rheumatoid factor, ANCA, and IgG4 levels), HIV serology, venereal
disease research laboratory — VDRL, galactomannan (in patients at risk of fungal infections),
and pituitary hormones. To confirm the diagnosis of certain diseases, e.g. GPA, the
typical clinical picture in the presence of the serological marker might be sufficient,
but IHP, NS, and IgG4-RD diagnoses depend on biopsy findings[7],[12],[22],[27].
The systemic survey for other organs affected by the disease is crucial, since it
helps to characterize it and might disclose other possible biopsy sites. This survey
should include neck, sinus, thorax, abdomen, and pelvis images. Imaging modality varies,
and a possible approach includes cervical ultrasound (US), sinus computerized tomography
(CT), thoracic CT, abdominal MRI, and pelvic MRI[24],[26],[45],[46]. A possible alternative after a negative systemic survey is to perform a whole-body
Positron Emission Tomography (PET) with 18-fluorodeoxyglucose (FDG) CT; this might
reveal a hypermetabolic lesion that was not observed with the conventional imaging
techniques[47],[48].
The biopsy of these lesions is safer than a central nervous system (CNS) procedure
and might disclose the disease's primary process. If it is restricted to the CNS,
meningeal biopsy is necessary for a final diagnosis[17],[49],[50]. It is imperative to perform the conventional pathological analysis and immunohistochemistry
with markers for lymphocytes, macrophages, and IgG4.
DIFFERENTIAL DIAGNOSIS
Infectious diseases
Syphilis may present with HP as a meningovascular form. Serologic evaluation is essential
to rule out this type of syphilis[6]. Tuberculosis is also associated with leptomeningitis and HP, generally with cognitive
behavioral disorders, and systemic symptoms[41]. Typical CSF may guide the diagnosis, although advanced techniques (molecular analysis
— polymerase chain reaction — PCR, and biopsy) are paramount[41]. Moreover, complicated bacterial sinusitis or otitis may present with meningeal
involvement and cause HP of the dura adjacent to the infectious process[51]. Fungal meningitis causes dural thickening with similar features of other etiologies
of HP; the main related specimen is Aspergillus flavus
[52].
Neoplastic diseases
Different neoplastic disorders may cause meningeal involvement mimicking HP. Secondary
dural metastasis may be similar to HP, and the most frequent associated tumors are
lung cancer (small-cell carcinoma and adenocarcinoma), breast cancer, prostate and
gastrointestinal tract tumors[53]. En plaque meningiomas have a similar appearance to HP on MRI and the differential is based
on biopsy characteristics[54]. Hematological malignancies can present with dural masses and effusion, mainly lymphomas
(Hodgkin and non-Hodgkin). Another group of neoplasm related to HP is histiocytosis.
There are two main types, Langerhans and non-Langerhans, and both can present with
pachymeningeal infiltration[55]. The clues for the diagnosis are systemic impairment (bones, skin, pituitary, spleen,
and lungs); biopsy provides the diagnosis with markers for macrophages (CD1a, S100,
and CD68)[55].
Other causes
CSF hypotension is another cause of hyperintense signal of the dura mater masquerading
as HP, occurring secondary to idiopathic hypotension, lumbar puncture or excessive
CSF drainage by derivation devices. The headache pattern helps raise suspicion of
this etiology (worse when the patient is in vertical position), and the opening pressure
of the CSF is diagnostic[56].
TREATMENT
Specific treatment depends on the etiology, although some patients have a presumptive
diagnosis. A rigorous exclusion of infectious causes is mandatory to introduce immunotherapy
for inflammatory causes. [Figure 2] summarizes the first-line treatments of the most common causes; each of them is
discussed in detail below.
Figure 2 A guide showing clinical and pathological features of main disease presenting with
HP and its first-line therapy.
Idiopathic hypertrophic pachymeningitis
The first line of treatment of idiopathic HP is corticosteroids (prednisone with an
initial dose of 1 mg/kg/day). If the patient does not improve or recurs during corticosteroids
use, adding immunosuppressive agents such as azathioprine (AZA) (2–3 mg/kg/day), cyclophosphamide
(CYC) (initial dose of 500–750 mg/m2 each four weeks, with dose adjustment according to lymphocytes nadir — 10 to 14 days)
methotrexate (MTX) (20–25 mg/week), and rituximab, is a viable option[57],[58],[59].
Granulomatosis with polyangiitis
In GPA, CNS involvement is considered an organ-threatening manifestation, so the corticosteroid
(pulse therapy with methylprednisolone 1,000 mg/day for three to five days followed
by prednisone 1 mg/kg) is combined with CYC (initial dose of 500–750 mg/m2 each four weeks, with dose adjustment according to lymphocytes nadir — 10 to 14 days)
as first-line induction therapy. The switching to maintenance remission phase can
be done with oral MTX (20–25 mg/week), AZA (2-3 mg/kg), or mycophenolate mofetil (MMF)
(500–2,000 mg/day)[23]. Some literature evidence shows that in refractory GPA with severe systemic manifestations
rituximab is an effective alternative[59].
Neurosarcoidosis
NS treatment is initiated with 1 mg/kg/day prednisone-equivalent[60]. If the patient does not respond or has a rapidly progressive disease, pulse therapy
of methylprednisolone at 1,000 mg/d for three to five days should be considered. After
disease control, a gradual tapering can be done within four to eight weeks[61]. Neurosarcoidosis usually requires at least six to 12 months of corticoid therapy[60]. For patients who do not tolerate the adverse effects of corticosteroids and have
relapses during the tapering, immunosuppressive agents are required as second-line
therapy[62]. MTX has the most extensive efficacy data for NS, with doses ranging from 10 to
25 mg per week, and less adverse effects by the concomitant use of folic acid[62]. Other options are CYC, MMF, AZA, and thalidomide[26],[63]. Infliximab is effective in glucocorticoid and immunosuppressive refractory NS.
IgG4-Related Disease
Corticosteroids are the cornerstone of treatment for IgG4-RD[64]. The corticosteroid (prednisone 0.6 mg/kg) is almost always used alone or in combination
with conventional disease-modifying antirheumatic drugs (DMARDs) (AZA, MMF, MTX, leflunomide,
and CYC)[46]. The treatment is divided into two phases: induction, in which glucocorticoids are
discontinued within three to six months, and maintenance therapy, since the disease
is prone to recurrence. The maintenance strategy is individualized according to the
patient's disease features, such as the extent of disease-related damage, comorbidities,
and previous treatment responses[65]. Biological agents that promote B-cell depletion, such as rituximab (two intravenous
doses of 1 g, separated by two weeks, repeated at six-month intervals) in combination
with prednisone (40-60 mg/d for a month and tapering to discontinuation over two to
three months), are used in the initial treatment in patients with severe neurological
disease and multiorgan IgG4-RD. CNS imaging should be repeated three months later
to check response[12].
CONCLUSION
HP is a highly complex disorder with variable etiologies and heterogeneous clinical
presentation. Etiology of HP is a challenge, despite a thorough clinical, laboratory
and imaging investigation. Tissue biopsy remains the gold standard for final diagnosis.
Early clinical and etiological diagnosis is relevant in order to decide about therapy.
This review may serve as a guide to general neurologists by helping the diagnostic
workup and management of the several different forms of HP.
