Chronic Suppurative Otitis Media Patient Presenting With Hyperhomocysteinemia in Granulomatosis With Polyangiitis

Granulomatosis with Polyangiitis (GPA) can present with Cerebral Venous Sinus Thrombosis (CVST), Chronic Suppurative Otitis Media, and Lower Motor Neuron (LMN) Facial Palsy. However, an association between CVST and Hyperhomocysteinemia in GPA has not previously been reported. Here, we report a case of CVST and Hyperhomocysteinemia in Proteinase 3 anti-neutrophil cytoplasmic antibody (PR3-ANCA) positive GPA without renal involvement.


Introduction
Granulomatosis with Polyangiitis (GPA), formerly known as Wegner's granulomatosis, is characterized by necrotizing granulomatous inflammation, usually involving the upper and lower respiratory tracts with nodules, alveolar hemorrhage, and necrotizing glomerulonephritis. However, any organ system could be affected during disease progression [1][2][3]. Renal involvement is the most common at 18-77 %, Central Nervous System (CNS) involvement was 1-8 %, and Otitis Media was up to 25-44% % in GPA patients [4]. A recent case report has revealed an association between Cerebral Venous Sinus Thrombosis (CVST) and Hypertrophic Pachymeningitis (HP) in patients with Proteinase 3 anti-neutrophil cytoplasmic antibody (PR3-ANCA) positive GPA [5]. There is a clear relationship between CVST and Hyperhomocysteinemia [6]. A few studies have reported deep venous thrombosis (DVT) as venous involvement in GPA [7].

Case Presentation
A 34-year-old male presented to General Medicine Outpatient Department with c/o low-grade fever without chills for five months, gradually culminating in persistent severe dry cough in the last three months and started having blood in sputum in the last two weeks. He took antibiotics and antipyretics, but there was no relief. He had a history of hospitalization two years ago for severe headaches and a single seizure episode. He was diagnosed with Cerebral Venous Sinus Thrombosis on MRI Brain Venogram (Figure 1-3), and serum Homocysteine was 234.9 µmol/L (4.7 -14.8). After taking Acenocoumarol 2 mg every alternate day, he remained asymptomatic and stopped taking it after four weeks as he felt he was completely alright.

FIGURE 1: Contrast Enhanced MRI Brain -Cerebral Venous Sinus Thrombosis
A non-invasive diagnostic procedure that uses a combination of a large magnet, radio frequencies, and a computer to produce detailed images of organs and structures within the body without the use of damaging ionizing radiation.
There are filling defects within the superior sagittal sinus, left transverse & sigmoid sinuses, and the left jugular bulb. Filling defects are also seen in the right transverse and straight sinus and the Galen region's vein. Cortical veins draining into these sinuses appear engorged, suggesting thrombosis.

FIGURE 2: Contrast Enhanced MRI Brain -Cerebral Venous Sinus Thrombosis
A non-invasive diagnostic procedure that uses a combination of a large magnet, radio frequencies, and a computer to produce detailed images of organs and structures within the body without the use of damaging ionizing radiation.
There are filling defects within the superior sagittal sinus, left transverse & sigmoid sinuses, and the left jugular bulb. Filling defects are also seen in the right transverse and straight sinus and the Galen region's vein. Cortical veins draining into these sinuses appear engorged, suggesting thrombosis.

FIGURE 3: MRI Brain Venogram -Cerebral Venous Sinus Thrombosis
A non-invasive diagnostic procedure that uses a combination of a large magnet, radio frequencies, and a computer to produce detailed images of organs and structures within the body without the use of damaging ionizing radiation.
The mid and posterior parts of the superior sagittal sinus show no flow in venography. There is non-visualization of flow in the right transverse, sigmoid sinus, and jugular bulb. The proximal aspect of the left transverse sinus also shows partial loss of flow. No obvious flow was seen in Galen's straight sinus and vein-these findings suggest cerebral venous sinus thrombosis.
Three months ago, he complained of pain in his right ear with hearing loss and drooping of the right angle of his mouth. He was treated for Right Chronic Suppurative Otitis Media and Lower Motor Neuron Facial Palsy (Figure 4) with Antibiotics and Acyclovir for three weeks. Now he presented with difficulty breathing; on examination, there was pallor, right infra-scapular crepitations with bronchial breath sounds, and drooping of the right side of the mouth with the inability to close the right eye completely. Chest X-ray ( Figure 5) showed right lower zone consolidation and blood investigations revealed neutrophilic leukocytosis, mild liver dysfunction, urine and renal function was normal, serum homocysteine -43.6 µmol/L (4.7 -14.8), erythrocyte sedimentation rate (ESR) -120 mmHr (< 15), Vitamin B12 -192 pg/mL (239 -931), c-reactive protein (CRP) -16 mg/L (< 10), Folic Acid -8 ng/mL (3 -17), D-dimer -2170 ng/ml (< 250) and Mantoux Test were negative. Empirical antibiotic therapy and Vitamin B12 supplementation were started within three days of admission. Chest X-ray ( Figure 6) deteriorated, and the requirement for Oxygen increased. Considering clinical and radiological deterioration, CECT Thorax (Figure 7, 8) was done, which suggested -a large area of consolidation with cavitation in the right lower lobe and multiple cavitary nodules in bilateral lung fields in the mid and lower lobes.

CECT -Contrast Enhanced Computerized Tomography
It's a diagnostic imaging tool to create detailed images of internal organs, bones, soft tissue, and blood vessels. Intravenous contrast dye is ingested into the body, which helps provide a detailed view of the blood vessels.
A large area of consolidation with internal areas of breakdown and cavitation is seen in the right lower lobe with surrounding confluent nodular densities.
On day five of the presentation, our patient complained of hoarseness of voice. We suspected Pulmonary Tuberculosis, Autoimmune Disease, Systemic Vasculitis, Sarcoidosis, Bronchial Carcinoma, Lyme disease, and Nocardiosis. So, Bronchoscopy was performed, which showed severe inflammation of the mucosa, and the right vocal cord was thickened. TB PCR was negative, and a Bronchial Alveolar Lavage (BAL) cell block revealed no hemosiderin-laden macrophages and malignant cells. Bronchial biopsy suggested chronic inflammatory pathology (Figure 9). BAL Nocardia PCR, Serum angiotensin-converting enzyme (ACE) levels, and Lyme Borrelia Burgdorferi IgG were Negative. X-ray paranasal sinus (PNS) suggested Maxillary Sinusitis with Deviated Nasal Septum ( Figure 10). Antinuclear antibody (ANA) and the perinuclear form of antineutrophil cytoplasmic antibody (P-ANCA) were also negative, while PR3 by EIAc-ANCA Serum -200 U/mL (>=5). Considering our patient's clinical and radiological improvement ( Figure 11) from symptomatic treatment and BVAS (Birmingham Vasculitis Activity Score) of 38±3/63, he was initiated on oral Cyclophosphamide 2mg/Kg with oral steroids. The patient has been on follow-up for the last five months and will be tested for methylenetetrahydrofolate reductase (MTHFR) mutation in the next visit.
underrecognized diseases, and early diagnosis leads to a favorable prognosis. At this point, it can only be hypothesized that Hyperhomocysteinemia and etiopathogenesis of GPA have a direct relation, as no other cases have been reported yet. Also, further research is needed to study the relationship between the same.

BVAS -Birmingham Vasculitis Activity Score
It is designed to document new or worsening clinically active vasculitis that would be likely to require treatment, after exclusion of other causes such as infection, hypertension, etc.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.