Idiopathic Hypertrophic Pachymeningitis: Does Earlier Treatment Improve Outcome?

Background/goal: Hypertrophic pachymeningitis is a rare chronic inflammatory disorder characterized by marked fibrous thickening of the cerebral and/or spinal dura mater. This condition has largely been reported in adults, but there are very few reports in children. Methods: We describe a 14-year-old boy with idiopathic hypertrophic pachymeningitis, who presented with deteriorating vision on a background of severe headache. We evaluated pediatric cases of hypertrophic pachymeningitis and compared treatments and their relation to outcomes. Results: There are only eleven pediatric cases of hypertrophic pachymeningitis reported in the literature. In the patients treated with steroids either at presentation or subsequent relapses, a good response was reported. In the cases with delayed initiation of steroid treatment, this was often related to an incomplete recovery. In our patient, this delay may have contributed to his poor visual outcome. Conclusions: Early initiation of steroid treatment in children with idiopathic hypertrophic pachymeningitis may improve outcomes.


Introduction
Hypertrophic pachymeningitis is a rare inflammatory disorder characterized by localized or diffuse thickening of the cranial or spinal dura mater, resulting in progressive neurological deficits. The etiology of the pachymeningitis is thought to be immune in nature or secondary to other possible causes of dural reaction, such as infectious conditions (neurosyphilis, tuberculosis, fungal infections, syphilis, Lyme's disease); collagen vascular disorders (granulomatosis with polyangiitis, rheumatoid arthritis, systemic lupus erythematosus, mixed connective tissue disease); neoplasia (dural carcinomatosis, meningioma en plaque, lymphoma) and miscellaneous disorders such as sarcoidosis, mucopolysaccharidosis, intracranial hypotension syndrome and intrathecal drug administration [1,2]. IgG4-related hypertrophic pachymeningitis (IgG4-RHP), a recently described entity, is an increasingly recognized manifestation of IgG4-related disease, a fibroinflammatory condition that can affect virtually any organ [3]. The present report describes a 14-year-old boy with idiopatic hypertrophic pachymeningitis, the course of his illness, his response to treatment and a comparison to the other cases reported in literature.

Case Study
A previously healthy 14-year-old boy presented with a several-week history of deteriorating vision on a background of experiencing headaches 9 months prior, which worsened over recent months. He reported double vision and progressive loss of vision in the right eye over the few weeks prior to presentation. There were no other constitutional symptoms like fever, night sweats or weight loss. The patient reported a non-specific insect bite 3 months prior, and there was no history of recent foreign travel.
The key finding on clinical examination was a fulminant right optic neuritis, where he could only perceive light, alongside right sided 4th and 6th cranial nerve palsy. There was no evidence of uveal disease. He had a full neurological examination, which did not reveal any abnormality. His systemic examination was normal and in particular there was no evidence of lymphadenopathy, organomegaly or cutaneous features of connective tissue disease.
Magnetic resonance imaging (MRI) identified widespread dural (pachymeningeal) thickening with contiguous involvement of the cavernous sinus on the right side ( Figure 1) with no evidence of brain parenchymal or white matter involvement.

Case Study
A previously healthy 14-year-old boy presented with a several-week history of deteriorating vision on a background of experiencing headaches 9 months prior, which worsened over recent months. He reported double vision and progressive loss of vision in the right eye over the few weeks prior to presentation. There were no other constitutional symptoms like fever, night sweats or weight loss. The patient reported a non-specific insect bite 3 months prior, and there was no history of recent foreign travel.
The key finding on clinical examination was a fulminant right optic neuritis, where he could only perceive light, alongside right sided 4th and 6th cranial nerve palsy. There was no evidence of uveal disease. He had a full neurological examination, which did not reveal any abnormality. His systemic examination was normal and in particular there was no evidence of lymphadenopathy, organomegaly or cutaneous features of connective tissue disease.
Magnetic resonance imaging (MRI) identified widespread dural (pachymeningeal) thickening with contiguous involvement of the cavernous sinus on the right side ( Figure  1) with no evidence of brain parenchymal or white matter involvement. Following consultation with the infectious diseases and rheumatology team, investigations were initiated which did not reveal an infective or immune etiology for the presumed pachymeningitis (Table 1). Following consultation with the infectious diseases and rheumatology team, investigations were initiated which did not reveal an infective or immune etiology for the presumed pachymeningitis (Table 1). High-dose pulsed intravenous methylprednisolone 30 mg/kg/day was administered for 3 consecutive days and his vision began to improve (counting fingers), along with a vast improvement in his headaches. He was converted to 60 mg prednisolone orally daily. Although dural biopsy was considered, a marked improvement in his imaging ( Figure 1) to a near resolution of the lesion did not present us with a biopsy target. Similarly, systemic imaging with a whole-body MRI also failed to identify a potential lesion to biopsy or any underlying systemic process.
He was reviewed in the outpatient clinic a month after discharge and was doing well. His headaches had resolved completely (timeline detailed in Figure 2). Ophthalmology assessment revealed an ongoing reduction of vision in the right eye with a central visual acuity of LogMAR 1.52 (2/60) and remaining limitation of abduction in the right eye to the mid-line. His optical coherence tomography showed retinal nerve fiber layer thinning in the right eye and a stable, normal retinal nerve fiber layer in the left eye.

Discussion
Hypertrophic pachymeningitis was first described by Charcot and Joffroy in 1869 [4]. It is a rare chronic inflammatory disorder characterized by marked thickening of the cerebral and/or spinal dura matter. It has been described in association with infection, trauma, tumors and immune-mediated disease such as granulomatosis with polyangiitis,  Figure 1 Investigation See Table 1 Treatment 30 mg/kg/day methylprednisolone for 3 days 60 mg/day prednisolone (6 months weaning protocol)

Follow-up Headache resolved
Brain MRI See Figure 1  At 3 months from symptom presentation, while on a slow steroid taper (10 mg daily, 6 months weaning protocol), repeat imaging continues to demonstrate no active dural disease. At latest follow-up (10 months), he remains well clinically and his visual acuity has improved to LogMAR 0.50 (6/19) in the right eye. His eye movements also continue to improve, with only 25% limitation of right abduction and he has no esotropia or double vision when looking straight ahead. He continues to have a mild right relative afferent pupillary defect and a pale right optic disc.

Discussion
Hypertrophic pachymeningitis was first described by Charcot and Joffroy in 1869 [4]. It is a rare chronic inflammatory disorder characterized by marked thickening of the cerebral and/or spinal dura matter. It has been described in association with infection, trauma, tumors and immune-mediated disease such as granulomatosis with polyangiitis, neurosarcoidosis or IgG4 related disease [1][2][3]5]. In cases when no causative factors can be identified, the condition is referred to as 'idiopathic" [6].
The thickened dura causes progressive neurological impairment. Chronic headache and multiple cranial neuropathies are the most common clinical manifestations [5,6]. These may include ataxia, facial pain, cranial nerve involvement and neuro-ophthalmic complications such as papilledema and various neurological deficits [1,2].
The definitive diagnosis is based on MRI or brain biopsy of the thickened dura mater, which reveals interstitial fibrosis and inflammatory cell infiltration.
Among the twelve pediatric cases of hypertrophic pachymeningitis reported in the literature, three cases developed in association with tuberculosis [10,11,17], one was PR3-ANCA-associated [13], two developed in association with IgG4-RD [16,18] and six were regarded as idiopathic [7][8][9]12,14,15]. The clinical features, MRI findings, biopsy results, treatment and outcomes are summarized in Table 2.   In the patients treated with steroids either at presentation or subsequent relapses, a good response to steroids was reported (6 events; Case 2 relapse (R) 1; Case 3 presentation (P) and R1; Case 5 P; Case 7 R1; Case 9 P; Case 12 P and R1).
However, the course of the disease was chronic and relapsing in six of the 13 cases, necessitating more aggressive immune therapy such as methotrexate, cyclophosphamide, intraventricular cytarabine, azathriopine or rituximab (Cases 2, 3, 6, 7, 9 and 12).
Of the two patients (Cases 1 and 2) treated conservatively, one patient relapsed, who then responded to steroids (Case 2). Overall, all but one case (Case 6), had a satisfactory outcome (mRS 0-2). Residual visual deficits occurred in two cases and hypoglossal palsy in one case (Cases 3, 5 and 9); one chronically deteriorated neurologically into a chronic vegetative state (Case 6).
Although immunotherapy-responsive, the delay in initiating steroid treatment in our patient may have contributed to his poor visual outcome. In the reported cases with a lag in initiating steroid treatment, this was often related to an incomplete recovery (Case 2 initiating 21 months later at relapse; Case 3 6 months from prior episode managed as viral meningitis; Case 6 10 weeks).
In conclusion, idiopathic hypertrophic pachymeningitis can present in children and should be considered in cases of pachymeningitis and negative findings from diagnostic evaluation.
Early initiation of steroid treatment may improve the outcome.