Hypertrophic pachymeningitis (HP) is a rare disorder of the central nervous system marked by inflammation and thickening of the dura mater, which may be localized or widespread. It may involve leptomeninges and tentorium as well. Incidence is approximately 0.949 per 100,000 individuals (1,2).   Etiopathologically, HP can be either idiopathic or secondary to chronic infections such as tuberculosis, malignancies such as lymphoma, autoimmune disorders such as rheumatoid arthritis, and other systemic diseases including IgG4-related disease. Idiopathic hypertrophic pachymeningitis is considered only when all alternative etiologies have been rigorously excluded. (3–5).  Pathophysiologically, Clinical manifestations results from venous congestion, ischemia from cortical vessel compression, and direct inflammatory infiltration of the brain parenchyma. Headache serves as the most common presenting symptom.  Cranial nerve palsies is the second most frequent manifestation followed by seizures, hearing loss, and movement disorders. Diagnosis primarily relies on neuroimaging findings, supplemented by histopathological confirmation (6–8).  IgG4-related hypertrophic pachymeningitis (IgG4-RHP) is a major secondary cause of this inflammatory disease (IgG4-RD) (5,9,10), in which the immune system drives a buildup of IgG4-positive plasma cells in affected tissues. Over time, this causes characteristic scarring in a whorl-like pattern called storiform fibrosis, and inflammation around veins causing obliterative phlebitis. (5,9,10).  Serum IgG4 is often elevated in 70%–90% of IgG4-related patients, but it can be normal or only mildly increased in isolated IgG4-related hypertrophic pachymeningitis (IgG4-RHP). Meningeal biopsy remains the gold standard for diagnosing IgG4-related hypertrophic pachymeningitis (IgG4-RHP) (9,10).  Management of HP is directed by the underlying cause. There are currently no consensus guidelines for the treatment of IgG-RHP and Idopathic hypertrophic pachymeningitis (IHP), although corticosteroids and other immunosuppressants have been used successfully in previous case reports and series (4,6–8). Some patients may require surgical decompression.  Rituximab, a B-cell–depleting therapy, is a useful steroid-sparing option in IgG4-related disease and has been shown to improve symptoms, reduce serum IgG4 levels, and control many systemic manifestations. (9,10). The authors intend to present this case series of six patients suffering from hypertrophic pachymeningitis (HP), emphasising the uniqueness of slow sequential neural axis affection and rarely suspected if not aware of this entity.

Methods: This is a descriptive case series of six patients diagnosed with HP at a tertiary care neurology center. Patients having clinical features suggestive of HP and MRI evidence of focal or diffuse pachymeningeal thickening with contrast enhancement, with or without leptomeningeal involvement were included. Demographic details, presenting symptoms, neurological examination findings, laboratory investigations (including inflammatory markers, autoimmune profile, serum ACE, serum IgG4, and relevant infectious work‑up), CSF analysis, neuroimaging findings, histopathology, etiological diagnosis, treatment protocols, and short-term clinical outcomes were retrieved from hospital records. Etiological classification into tubercular HP, IgG4-RHP, and IHP was based on clinical features, imaging, CSF and microbiological data (including CBNAAT), serology (including serum IgG4), systemic evaluation, and, where available, meningeal biopsy. 

Case summaries

Case 1: Tubercular hypertrophic pachymeningitis presenting with headache and proptosis

A 24-year-old woman presented with migrainous headache for 5 years that lasted for 10–12 hours. Over the last 2.5 years, it transformed into a continuous dull aching left hemicranial headache persisting throughout the day, associated with nausea, vomiting, and transient visual obscurations (TVOs) and aggravated by bending forward.  She also developed gradually worsening swelling of the left eye over the past 2.5 years. Later proptosis developed associated with pain on eye movements, watering, a gritty sensation, double vision, and near-complete loss of vision. Examination revealed complete ophthalmoplegia of the affected eye with fundus revealed Grade II disc edema bilaterally. Rest of the neurological examination including motor, sensory, and cerebellar was normal. Routine investigations showed (Table 1) raised ESR. Vitamin D3, vitamin B12, and folate levels were also low. MRI brain and orbit revealed asymmetric pachymeningeal thickening with multiple areas of venous sinus thrombosis, including left cavernous sinus thrombosis, suggestive of hypertrophic pachymeningitis, with old healed granulomatous lesions in the head of the right caudate nucleus and left medial frontal gyrus (Figure 1A). There was partially empty sella, crowding of the posterior fossa, and mild prominence of the perineural CSF space in the retro-ocular segment of both optic nerves. These findings were consistent with HP.  Evaluation for secondary causes of HP was negative, including serum IgG4 levels, viral markers, Antinuclear Antibody (ANA), Antineutrophil Cytoplasmic Antibody (ANCA), 24-hour urinary calcium, and serum Angiotensin-Converting Enzyme (ACE). CSF showed lymphomononuclear pleocytosis, low glucose, and borderline high protein; routine fungal and mycobacterial studies were negative, while CSF CBNAAT and the tuberculin skin test were positive. Based on these findings, a diagnosis of tubercular hypertrophic pachymeningitis was made.  She was managed with 3 days of intravenous pulse methylprednisolone (1 g/day), followed by oral steroids and antitubercular therapy, anticoagulation were added along with supplementation of vitamin B12 &vitamin D. She gradually improved at 1 month and 3 month follow up.

Case 2: IgG4 Related Hypertrophic Pachymeningitis responding to Rituximab therapy

A 50-year-old woman presented with bilateral progressive hearing loss of three years duartion along with headache, and bulbar palsy over next one year.  Examination revealed bilateral facial, eighth, and ninth cranial nerve palsies suggesting polyneuritis cranialis. Her inflammatory markers (CRP) was elevated and serum IgG4 was markedly raised (65.30 g/dL). MRI showed diffuse sheet-like pachymeningeal thickening and enhancement in the posterior fossa extending to C2, with mass effect on posterior fossa structures, hydrocephalus (Figure1B).  A diagnosis of IgG4-related hypertrophic pachymeningitis was made and meningeal biopsy demonstrated storiform fibrosis with lymphocytic infiltrates.  She was started on intravenous steroids and rituximab. Two doses of rituximab 1 g were administered 14 days apart, after which her headache completely resolved. During the 6 months follow up, she has showed improvement in headache frequency and severity and marked resolution of craniopathy.

Case 3: Idiopathic hypertrophic pachymeningitis presenting with headache and seizure responding to steroids

A 27-year-old woman presented with acute onset frontal headache for 1 month. The headache was throbbing and moderate in intensity, lasting more than 3 hours with infrequent vomiting, photophobia, and phonophobia and some relief on sleeping. She also reported low grade fever for 1 month, with evening rise of temperature, 2 episodes of tonic clonic seizures 1 week apart. MRI brain performed was suggestive of hypertrophic pachymeningitis, with thick sheet like diffuse and asymmetrical leptomeningeal enhancement over the bilateral temporal convexities and tentorium cerebelli with compression of posterior fossa structures (Figure 2A). A previously ongoing inflammatory process was suspected. Ophthalmology evaluation was normal. Investigation revealed normal IgG4 level, non-reactive VDRL, ACE and negative autoimmune work- up. CSF analysis was also normal. She was managed with intravenous pulse methylprednisolone therapy for 5 days followed by Oral steroids and azathioprine were then started for long term immunosuppression.  Meningeal biopsy could not be performed due to technical reasons. Based on MRI findings, negative etiological work-up, and response to steroids, a diagnosis of idiopathic hypertrophic pachymeningitis was concluded.

Case 4: Tubercular hypertrophic pachymeningitis treated with antitubercular therapy and steroids

A 45-year-old man presented with moderate intensity, migrainous type headache for 2 years duration and later developed right eye painful ophthalmoplegia featuring drooping of the right eyelid, pain and restricted eye movements associated with fever. Neurological examination showed right fourth and sixth cranial nerve palsies. There was 5^th sensory impairement on right side over V1, V2 distribution. Other neuraxis examinations were normal. The patient was evaluated for infectious, inflammatory, and neoplastic causes. Investigations revealed elevated ESR and CRP.  HRCT thorax showed fibro- atelectatic and fibro-calcific changes involving both upper lobes suggestive of tuberculosis. Mantoux test was strongly positive (22 mm at 48 hours).  A guarded lumbar puncture and CSF analysis showed mild pleocytosis with lymphocytic predominance, elevated protein, and low CSF glucose relative to blood glucose. MRI brain done outside showed diffuse, irregular dural thickening and enhancement in basal cisterns and the suprasellar region, non-enhancing FLAIR hyperintense signal in the right temporal, parietal, and genu of corpus callosum regions, and encasement of the right optic nerve with involvement of the right orbital canal (Figure 2B). MRI brain with contrast and MR spectroscopy favored granulomatous etiology, with no choline peak. Total serum IgG4 level was normal. The combination of positive Mantoux test, HRCT thorax findings, CSF hypoglycorrhia and high protein with positive CBNAAT and clinical presentation favored tuberculosis.  He was managed with anti-edema measures (intravenous mannitol, oral spironolactone) and supportive care. A final diagnosis of tubercular hypertrophic pachymeningitis was made, and antitubercular drugs added with dexamethasone steroid tapered over 8 weeks.

Case 5: Idiopathic hypertrophic pachymeningitis responding to azathioprine

A 50-year-old man presented with holocranial, dullaching headache for 3 months with constitutional features in form of loss of appetite, weight loss.  The general physical and neurological examinations was normal.  MRI brain with contrast revealed marked diffuse dural and leptomeningeal thickening and enhancement, with a small subependymal cystic lesion with mild surrounding edema and enhancement in the left anterior temporal lobe (Figure 3). Differential diagnoses of infectious, neoplastic, and autoimmune etiologies were considered. Routine investigation- Complete Blood counts (CBC) showed normocytic normochromic anemia suggesting chronic course. ESR was raised, Tumor markers were nnormal, ANA and ANCA, Rheumatoid factor were negative. CSF analysis including autoimmune panel, Serum IgG4 levels were within normal limits. CECT abdomen and thorax were normal. Patients underwent Meningeal biopsy from the left fronto-parietal region that showed thickened dura with focal areas of meningothelial cell proliferation adjacent to the thickened dura and focal aggregates of lymphomononuclear cells, consistent with chronic inflammatory pachymeningitis without a definitive secondary cause. A probable diagnosis of chronic granulomatous meningitis was kept and patient managed as Idiopathic HP with   intravenous dexamethasone and symptoms responded and immunosuppressive agent- azathioprine was added.

Case 6: Young female with IgG4 related hypertrophic pachymeningitis treated with rituximab

A 19-year-old woman with encephalitis illness and seizures 3 years earlier presented with

 chronic daily holocranial headache and one episode of seizure. She had TVOs also.

Examination revealed Cushingoid facies, right eye RAPD (relative afferent pupillary defect)

And bilateral disc edema. Rest of the neurological examination was normal. Her MRI Brain with contrast revealed meningeal thickening diffusely, lytic bone lesions in frontal bone and ethmoid sinus involvement (image not shown).  ENT consultation was obtained; nasal swabs for malignant cells and fungal pathology were negative. Routine investigations including vasculitic and viral markers were normal. CSF revealed high pressures (24 cm H₂O) with all cytobiochemical parameters normal, CSF was negative for malignant cytology, fungal including cryptococcal antigen, CBNAAT. Sarcoid workup was also negative. Bone marrow aspiration and biopsy were also negative. Skeletal survey was normal. Serum protein electrophoresis, CT chest, and CT abdomen showed no evidence of disseminated infection, sarcoidosis, or malignancy. Serum IgG4 level was elevated (2.69 g/L).  Meningeal biopsy showed brain parenchyma with scattered neurons in a dense fibrillary neuroglial matrix, with edema and meningeal congestion, without granulomas or malignancy. As her IgG4 levels were raised and she was partially responsive to steroids, so immunosuppressive therapy with intravenous rituximab was initiated to which she responded dramatically over next 6 months.

Figure 1A: (Case 1) MRI Brain T1 post contrast coronal section showing asymmetrical pachymeningeal thickening at multifocal area in (a)right frontoparietal and (b)temporal region

Figure 1B: (Case 2) MRI Brain T1 sagittal section with contrast Thick sheet like pachymeningeal thickening & enhancement in posterior fossa (A), extending into upper cervical spine region.

Figure 2A: Case 3: MRI Brain T1 contrast axial view showing Thick sheet like diffuse and asymmetrical leptomeningeal enhancement in bilateral temporal convexities (A, B), tentorium cerebelli (C)with contrast enhancement and compression over posterior fossa structures.

Figure 2B: Case 4 MRI Brain T1 contrast axial view showing (A, B) Diffuse, irregular thickening and dural enhancement in basal, suprasellar cisterns.

Figure 3: (Case 5)-MRI brain T1 contrast axial view (A, B, C arrows) shows Diffuse dural and leptomeningeal thickening with enhancement.

Table 1-Summary of Cases