HP is a rare disease worldwide with relatively low prevalence but that is seriously debilitating or life-threatening. The existing studies of HP are usually based on small sample sizes, especially in China. To our knowledge, this is the largest HP study conducted in China with the aim of exploring the clinical features of people with HP and could be useful for clinicians in diagnosis and prognosis.
We found that the most common type of HP was idiopathic HP, followed by AAV-related HP, tuberculous-associated HP, viral-related HP and bacterial-related HP. No sex preference was identified in our study, which was not consistent with previous works[2-4]. The onset of the first symptoms mainly occurred at an age of 50±12 years, which was earlier than the patients in the US and Japan[2,5]. The definite time to diagnosis of HP ranged from 0.25 to 144 months (with an average of 22 months), among which the HP patients with bacterial meningitis had the shortest duration (0.6±0.4 months) and idiopathic HP patients had the longest (25±36 months). For idiopathic HP patients, many different types of examinations were needed to rule out multiple possible reasons before the final diagnosis, which may explain why idiopathic HP patients required a relatively long time for diagnosis.
4.2 Imaging features
In our results, idiopathic, AAV and viral HP showed “diffuse” enhancement patterns, which was also confirmed by Hahn et al in idiopathic HP patients. We found that all cases of tuberculous meningitis appeared with “focal” enhancement patterns, which was similar to the results reported from Portugal. The “roughness” of the enhancement patterns seems to be a distinguishing factor for idiopathic HP. An “irregular” pattern was common in idiopathic HP patients, while other HP patients were likely to present a “regular” pattern. However, Hahn et al holds a contrasting view that the majority of idiopathic HP patients in the US exhibited regular enhancement instead of an irregular pattern. The reasons for the different conclusions between the two studies is not clear. The question of whether race was taken into consideration will require more studies in the future.
Locations of the thickened dura matter differ among different causes. The posterior fossa was the most affected area in idiopathic HP and tuberculous meningitis HP according to our study, which was also reported in other studies[6,8,9]. It is notable that posterior fossa HP can cause acute noncommunicating hydrocephalus. In addition to the posterior fossa, thickened falx cerebri[10-14], anterior cranial fossa, cerebellar tentorium[10,16], frontal lobes[10,11,17], sphenoid wings, cavernous sinuses, and paranasal maxillary sinuses[19,20] were also involved in HP patients. With enhancements in the cerebral falx and tentorium cerebelli in coronal scanning, a typical “Eiffel Tower”[21,22] or “Benz” sign emerged. Enhancement in the cerebral falx or tentorium cerebelli can be mistakenly regarded as subarachnoid hemorrhage or superior sagittal sinus. Thus, attention must be paid to the signs in images to avoid misdiagnosis. Temporal or occipital enhancements may be secondary to suppurative otitis media. Granulation or effusion in the middle ear caused by small vasculitis may spread to the dural mater and lead to secondary HP. Therefore, patients with otitis media or concurrent multiple cranial nerve deficits should receive contrast-enhanced MRI to rule out HP. In addition, the involvement of the junction of the craniocervical area has been reported in several cases[8,24] and causes obstructive hydrocephalus along with cerebellar tonsillar herniation. Peripheral to the lesion, there is usually a circle of enhancement in images[18,25], which may be caused by a zone of active inflammation along with the border of the lesion. Enhancement of spinal HP is typically found within cervical and high thoracic regions. In our study, the lumbar and cervical dura were enhanced in several idiopathic HP patients. In a Japanese retrospective study, dura matter in the convexity was the most commonly thickened area in AAV-induced HP. These findings suggested the potential role of racial differences for differential diagnosis in dural enhancement patterns in HP.
4.3 Clinical manifestation
Headache was the most common clinical feature of HP, regardless of etiology and was also the case in our study. As an initial symptom of HP, headache can progress overtime. Thus, for patients with progressive chronic headache, enhanced MRI is of great importance. Locations of headache mainly coincided with the locations of enhanced dura matter in MRI, which suggested that headache might be associated with irritations caused by inflammation, stenosis of cerebral venous sinus resulting from fibrosis, and hydrocephalus and intracranial hypertension caused by difficulty reabsorbing CSF.
Cranial nerve deficits, the second most common symptom of HP, might be caused by oppressive ischemia, thickened meninges encroachment, or epineurium inflammatory infiltration. Cranial nerve deficits can be divided into two types according to the location of the thickened dura matter. Cranial nerve II to VI deficit might be associated with thickened meninges from the cavernous sinus to the superior orbital fissure. Thickened meninges from the cerebral falx and tentorium cerebelli to the posterior cranial fossa may lead to cranial nerve IX to XII dysfunction. Cranial nerves II and VIII were the most affected cranial nerves in HP, which was in agreement with our study.
Other common symptoms in HP patients in our study included psychiatric disorders[12,18], ataxia, and seizures, which were in accordance with previous studies. Venous sinus thrombosis[32-34] and venous sinus stenosis[35-37]were reported in some western countries but have not been identified in China, including in our study.
IHSP mainly affects the cervical and thoracic spine (86%) and, in rare situations, involves the entire spine (7%). Only a few cases of the craniospinal form of idiopathic HP have been reported[24,39]. Generally, the ventral spine canal dura was more susceptible than the dorsal spine canal dura. The most common symptom, paralysis, occurred in 71% of the HSP patients. Other symptoms include numbness (64%), bladder and rectal dysfunction (43%), back pain, and nerve root or spinal cord compression.
4.4 Laboratory findings
In a retrospective study of 12 Chinese patients, elevated CRP and ESR were reported, which is in accordance with our results, revealing an inflammatory nature of HP. In a retrospective study of 22 Chinese patients diagnosed with HP, 17 patients had abnormal cerebrospinal fluid (CSF) and/or abnormal biochemical tests, such as increased CSF pressure, elevated CSF protein levels and immunoglobulins, which was also in line with our study. Blood-CSF barrier damage caused by adjacent inflammation, such as necrotizing vasculitis at the arachnoid, enabled inflammatory cell infiltration and increased immunoglobulin levels in the CSF. Excessive proteins may be synthesized by intrathecal plasma cells due to a fibroinflammatory immune reaction to stabilize the CSF internal environment. The arachnoid is involved in idiopathic HP, and a proportion of immunoglobulins may originate from the blood because of damage to the blood–CSF barrier at the arachnoid.
According to a large-scale national epidemiological survey of 159 cases that was conducted in Japan, the majority of HP cases were idiopathic (44%). The prevalence rates of ANCA-related HP and IgG4/multifocal fibrosclerosis (MFS)-related HP were 34.0% and 8.8%, respectively. In our study, the highest proportion was idiopathic HP, followed by AAV-related HP and infection-related HP. No cases of IgG4-related HP were confirmed in our study since few of them underwent biopsies.
Immune-related HP included HP caused by AAV, IgG4-related disorder, rheumatoid arthritis, sarcoidosis, Behcet disease, and Sjogren syndrome. In a retrospective study in Japan, 7 of the 39 patients with AAV presented with HP. ANCA-associated vasculitis (AAV) include granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). GPA, characterized by necrotizing granulomatous vasculitis in small-to-medium vessels, mainly affects the respiratory tract, pulmonary capillaries, and kidneys. Additionally, central nervous system involvement has been reported in 22%-54% of GPA cases[43,44]. MPA is a systemic vasculitis of small- to-medium-sized vessels that is associated with antibodies directed against the target antigen myeloperoxidase (MPO). GPA is the most common form of AAV-related HP, followed by MPA. In a recently published article, the HP incidence was significantly higher in patients with GPA than in those with MPA (60.2 versus 3.3 persons per 1000 person-years, respectively). The reasons why AAV-related disorders affect the CNS may include the following: (1) granulomatosis tissue extends directly to the intracranial nervous system from adjacent lesions in the orbit or the paranasal cavity; (2) granulomatosis tissue transfers to the intracranial nervous system from the respiratory tract; and (3) vasculitis affects intracranial vessels. In addition, IgG4-related disorder (IgG4-RD) is a newly recognized immune-mediated fibro-inflammatory disease that affects multiple systems. Induced by overactivity of T2-helper cells, stimulating plasma cells can produce excessive IgG4, resulting in lesions in virtually every system, including the meninges. The histopathological features of IgG4-related HP include lymphoplasmacytic infiltration of IgG4-positive plasma cells, storiform fibrosis, and obliterative phlebitis. Diagnosis may be challenging, given that serum IgG4 concentrations were neither specific nor sensitive and biopsy samples stained for IgG4+ plasma cells were difficult to obtain.
Infection-related HP usually originates from peri-cranial infections, such as paranasal sinusitis, otitis media or mastoid process inflammation. Common pathogens include Mycobacterium tuberculosis, Treponema pallidum, and EB virus. Uncommon infections, including Lyme disease, cysticercosis, and human T-cell lymphotropic virus, are also involved in the pathogenesis of HP. However, it has also been reported that untreated HP is a predisposing factor for bacterial meningitis (BM) due to Streptococcus pneumoniae. More efforts should be made to draw a cause-effect conclusion.
The histopathology of HP shows infiltration of small mature lymphocytes, plasma cells, and epithelioid histiocytes at the surface of the dura mater. Dense fibrosis occurs, mainly consisting of collagen fibers associated with hyaline degeneration, arranged in a concentric-circle-like manner. This can be explained by a theory that inflammatory infiltrate activates fibroblasts and induces collagen deposition, leading to tissue hypertrophy and increased dural thickness. Necrotizing vasculitis of small arteries located in the dura and cerebral surfaces has also been reported. In our study, only one patient underwent a biopsy, which was mainly conducted to confirm the diagnosis of IgG4-RD[48-50]. In fact, the biopsy rates were low both in China and other countries because of the potential risks of the procedure. Empiric treatment was usually administered when there was sufficient clinical evidence without biopsy results[4,23].
Etiological treatments, including antibiotic, antifungal, and antituberculosis drugs, are essential in HP patients. Glucocorticoids are considered the first-line therapy after the exclusion of infection. However, consensus on the course and dose of glucocorticoid treatment has not been reached. Classical treatment for HP patients in the active stage is methylprednisolone pulse therapy (500 mg/d for 3 days) followed by maintenance treatment with oral prednisone. The maintenance is also important, since disease recurrence occurred when prednisone was reduced to 10-30 mg/d; the condition can also sometimes cause progressive deterioration and death.
Disease recurrence is one of the major concerns in treatment. Approximately 50% of HP patients are reported to have disease relapse. In our study, three idiopathic HP patients relapsed on a 30-50 mg prednisone daily dose, and an ANCA-related HP patient suffered relapse at a dose of 30 mg of prednisone, suggesting that the corticosteroid should be tapered off extremely slowly in case of recurrence. For refractory HP patients, long-term steroid monotherapy may lead to potential adverse effects as well as disease recurrences. Immunosuppression therapies, including azathioprine[52,53], cyclophosphamide[52,54], rituximab or combined therapies, are often therapeutic options or adjuvant treatments for steroids. Rituximab (RTX), a monoclonal antibody targeting CD20 on the surface of pan-B cells, selectively suppresses B-cell-associated autoimmunity. RTX treatments for HP with IgG4-RD suppress the reciprocal activation of T2-helper cells to relieve the systemic inflammation. Three steroid-refractory HP patients treated with RTX for four weeks showed clinical improvements and exhibited prominent decreases in dural thickness. Thus, RTX has been suggested to be a second-line therapy for steroid-refractory HP, especially for IgG4-RD[56-60].
If conservative treatments are ineffective, surgery for decompression should be considered, especially for HSP[61-64]. Decompressive surgery, such as laminectomy or laminoplasty, and excision of the thickened dura were recommended[60,65,66]. In cases of chronic compressive myelopathy caused by dural hypertrophic change, decompressive surgery and postoperative steroid therapy may be helpful. Surgery serves not only as a purpose by achieving immediate decompression of the spinal cord but also as a means to diagnose some complicated cases. Extensive laminectomies may be an effective therapeutic option but may result in chronic discomfort. Once HP invades the brainstem, it may progress rapidly and even lead to death. Endoscopic third ventriculostomy (ETV) can be effective in resolving clinical deterioration and avoiding complications of ventriculoperitoneal shunt for HP-related hydrocephalus. With the application of ETV, immunosuppressive therapy can be postponed.