ICH After Thrombolysis in Granulomatosis with Polyangitis: Learning Through a Case with Review of Literature

Sir, Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is typified by small-vessel vasculitis and ANCA. Their spectrum includes granulomatosis with polyangiitis (GPA), microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (EGPA). They can rarely present with central nervous system (CNS) involvement like acute ischemic stroke (AIS).[1] Thrombolysis with intravenous (IV) tissue plasminogen activator (tPA) is the widely accepted modality for AIS. Vasculitis is not cited as a contraindication for thrombolysis.[2] We wish to illustrate a case of localised GPA who presented with AIS and developed ICH after thrombolysis and deliberate on the ramifications of thrombolysis in such patients. A 35 year-old male, hypertensive (well controlled), follow-up case of localised GPA, on immunomodulatory therapy (injection rituximab and tablet dexamethasone) from Department of Rheumatology presented to the emergency room at our hospital with complaints of sudden onset slurring of speech, deviation of angle of mouth and left-sided weakness for last 30 minutes. Six years back biopsy of a painful swelling in the right maxillary region revealed necrotising granuloma which was negative for Acid Fast Bacilli and Periodic Acid Schiff stain. Clinical and laboratory features were suggestive of AAV-GPA (ANCA negative). There was no previous history suggestive of any neurological involvement. Urgent magnetic resonance imaging (MRI) of the brain done for above mentioned acute symptoms revealed acute infarct in the right corona radiata and external capsule and lacunar infarct in right half of pons, evident as areas of diffusion restriction showing signal drop on apparent diffusion coefficient. [Figure 1a and b] Inflammatory markers (erythrocyte sedimentation rate and C-reactive protein) were normal one week prior to presentation (at the time of rituximab infusion). He was thrombolysed with 50 mg of IV tPA. After 1 h, he deteriorated and was shifted to intensive care unit (ICU). Non-contract computed tomography (NCCT) of head revealed focal area of hemorrhage with fluid level in right ganglio-capsular region, along with diffuse subarachnoid hemorrhage (SAH) and interventricular extension. [Figure 2a and b] He was managed conservatively with fresh frozen plasma transfusions, anti-edema measures, IV dexamathasone and comprehensive supportive treatment including ventilator support. Neurosurgical intervention was deferred in view of very low Glasgow coma scale score and diffuse SAH. On 14th day, he developed bradycardia and had a sudden cardiac arrest. CD19 level estimation was not done.Figure 1: (a) Magnetic resonance imaging axial section of diffusion weighted image showing diffusion restriction in right periventricular region, (b) Magnetic resonance imaging axial section of diffusion weighted image showing small diffusion restriction in right side of ponsFigure 2: (a) Noncontrast computed tomography of brain showing subarachnoid haemorrhage around pons in axial section, (b) Noncontrast computed tomography axial section showing right basal ganglia haemorrhage with intraventricular extension and extensive bilateral subarachnoid haemorrhageGPA is an uncommon necrotizing and granulomatous vasculitis characterized by involvement of the respiratory tract with or without renal and systemic involvement predominantly affecting small vessels.[1] GPA is usually characterised into two variants, generalised and localised. Localized GPA, seen in less than 5% patients has ANCA positivity of around 50% only.[3] On the other hand, 95% patients with generalized GPA demonstrate ANCA positivity.[3] Most common neurological involvement seen in GPA is peripheral neuropathy, occurring in about 50% cases.[4] Though, central nervous system (CNS) involvement is uncommon, still, infarction, intracranial bleed, meningitis and granulomatous space-occupying lesions are well-known manifestations of GPA. Nishino et al. showed that only 13 patients out of 324 patients of GPA developed cerebrovascular events.[1] The pathogenesis of AIS in GPA can be due to vasculitis (making the endothelial lining prothrombotic and proadhesive) or the necrotizing granuloma. Moreover, conventional brain angiography in these patients could be normal, because the small vessels (200500 μm diameter) typically affected cannot be detected on angiography.[1] Arterial wall damage in GPA may further result in aneurysms, which may explain the occurrence of haemorrhage. Numerous infarcts of varying ages in multiple arterial territories strongly signify vasulitis. Usually the ischemic stroke in vasculitis occurs during the earlier course of the illness or in poorly controlled drug naïve patients. Our patient had a localised GPA and was ANCA negative. Patient developed AIS involving anterior and posterior circulation on the right side (multiple territories) which was consistent with a vasculitic infarct. Moreover, he developed AIS while being on adequate immunosuppression and 6 years into his disease course, when the disease is expected to be quiescent. As thrombolysis is the standard of care treatment of AIS, our patient was immediately administered IV tPA. Subsequently, he developed extensive ICH although there was no evidence of coagulopathy or active vasculitis as patient was on adequate immunotherapy. Evidence, thus far reveals no reliable data on the use of IV tPA in patients with known vasculitis. It has not been mentioned as either absolute or relative contraindication for thrombolysis.[2] The cause of such extensive haemorrhage in our patient could be pre-existing fibrinoid necrosis of the vessel wall leading to its damage, or aneurysm formation. Similar views were reflected by Esfahani et al. and Fattahi et al. in their respective case reports.[5,6] [Table 1] Sairanen et al. highlighted a patient of vasculitis with AIS, who developed an expansive ICH without thrombolysis.[7] In the case report by Esfahani et al., the patient had ischemic stroke at the onset of the myriad of symptoms of GPA.[5] On the other hand, in the case report by Fattahi et al., the patient had EGPA and developed ischemic stroke 11 years into his illness and his vasculitic illness was poorly controlled.[6] In contrary to the above two case reports, our patient had well-controlled disease activity.Table 1: Summary of the clinical features of the case reports of IV tPA in AAV related acute ischemic strokeTo the best of our know-how, this is the only case write-up from India, highlighting two facts, a) though rare, stroke can occur in AAV and, b) the unfavourable outcome following thrombolysis in AAV associated AIS. This case provides a crucial medium to contemplate the pathophysiology of AIS in small vessel vasculitis along with its serious ramifications for thrombolysis. By presenting this case, we wish to highlight the probable hazards of IV thrombolysis in AAV associated AIS. One should be very cautious to offer thrombolysis in such patients. We further advocate that AAV associated AIS should be considered as a relative contraindication for use of thrombolysis. To conclude, AIS secondary to AAV has not been acknowledged as a contraindication to IV tPA. In view of high probability of haemorrhagic transformation, the value of thrombolysis is dubious and it should be considered as relative contraindication in such scenario. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.