Ischemic Stroke as a Consequence of Granulomatosis With Polyangiitis

Michelle Kurian Solik, MS, MD
Laurel Fick, MD
Volume 57 - Issue 2 - February 2017

In August 2015, a 51-year-old woman presented to the emergency department after having been evaluated by her primary care physician. Upon presentation, the patient explained that she had been unwell for nearly 3 months; she reported that since May she had experienced significant fatigue and a 25-lb unintentional weight loss, as well as intermittent fevers, chills, and night sweats.

She had recently completed a course of antibiotics for treatment of streptococcal pharyngitis and a case of methicillin-resistant Staphylococcus aureus cellulitis with ulceration involving her right inner thigh and buttocks. The patient described having some hoarseness and ear fullness (which she associated with her recent throat infection) along with occasional nasal discharge, areas of ulceration along the inside of her mouth, and a cough that produced phlegm with occasional specks of blood. A few days prior to presentation, the patient had noted the development of areas of dark discoloration under her fingernails, as well as point tenderness along the joints in her hands and feet.

Given these findings, she was admitted to the inpatient general medicine service with a concern for possible endocarditis, and she was started on broad-spectrum antibiotics after blood culture samples were collected.

History. The patient had no history of recent travel or known toxic exposures. She had a 30 pack-year smoking history but had quit 4 years prior. She denied any use of alcohol or illicit drugs. Her family history was noncontributory. Her past medical history included genital herpes, hypertension, depression, and idiopathic hypothyroidism. Her medications were acyclovir, estradiol, hydrochlorothiazide, pregabalin, fluoxetine, and levothyroxine.

Physical examination. The patient was afebrile, with normal vital signs. She had generalized edema of her nasal turbinates, with no signs of bleeding or drainage. Her oropharynx appeared nonerythematous and without obvious exudates or ulcers. A cardiovascular examination did not reveal any murmurs. Her lungs were clear bilaterally.

Skin examination revealed a small area of superficial skin breakdown without erythema or warmth at the upper margin of the right buttocks, as well as an area of well-healing ulceration along the right medial thigh. Additionally, examination of the fingertips revealed a small, 1-cm, dark macular lesion underneath the third fingertip of her right hand, and a similar lesion of smaller size on the fourth fingertip of her left hand. No other rashes were observed, and both hands were tender to palpation but without evidence of nodules or joint swelling.

Her lower extremities were nonedematous, without any obvious asymmetry or calf tenderness. She had no appreciable lymphadenopathy, and neurologic examination findings were nonfocal.

Diagnostic tests. Pertinent laboratory data on admission included a white blood cell count of 21,100/µL, a hemoglobin level of 8.6 g/dL, a platelet count of 891 × 103/µL, and an erythrocyte sedimentation rate (ESR) of 106 mm/h. Her creatinine level was elevated at 1.81 mg/dL. Levels of electrolytes were otherwise within normal limits. Urinalysis revealed both hematuria and non-nephrotic–range proteinuria. Blood culture results remained negative for pathogens throughout the patient’s hospital course.

The patient had undergone computed tomography (CT) scans of the head and neck without contrast on admission, the results of which were negative for abnormalities. Initial chest radiography on admission revealed possible pneumonitis without evidence of focal consolidation, masses, or infiltrate. Results of renal ultrasonography were normal. A transthoracic echocardiogram (TTE) with Doppler revealed an ejection fraction of 60% to 65%, without evidence of intracardiac shunt, vegetation, or valve abnormalities.

Given the patient’s negative blood culture results and negative TTE results, other etiologies for her symptoms were considered, including the possibility of an autoimmune or vascular disease. In light of the chest radiography findings, a CT scan of the chest without contrast was performed on hospital day 2; it revealed evidence of widespread peribronchovascular ground-glass changes that were concerning for diffuse alveolar hemorrhage. Simultaneously, results from the initial autoimmune panel that had been submitted at the time of admission returned positive for cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA). It should be noted that complement levels and the antistreptolysin O (ASO) titers were normal, and test results were negative for antinuclear antibodies and antiglomerular basement membrane antibodies.

Diagnosis. In light of the patient’s constellation of symptoms involving the upper airway and the laboratory data and imaging findings indicating lung and kidney involvement, the patient was given a presumptive diagnosis of granulomatosis with polyangiitis (GPA). Antibiotics were discontinued, and treatment with oral prednisone and intravenous cyclophosphamide, as well as oral trimethoprim-sulfamethoxazole for Pneumocystis jirovecii pneumonia prophylaxis, was initiated on hospital day 3.

An ultrasound-guided kidney biopsy was pursued on hospital day 4, which subsequently revealed evidence of focal segmental necrotizing and crescentic glomerulonephritis with c-ANCA and antiproteinase 3 antibody (anti-PR3) positivity, confirming the diagnosis of GPA. Immediately following initiation of treatment, the patient had reported subjective improvement in her symptoms and had been doing well.

Outcome of the case. On hospital day 6, the patient acutely developed aphasia, left-sided hemiplegia with neglect, and unequal pupil reactivity. She was emergently intubated and moved to the intensive care unit.

CT scans of the head revealed a new left posterior frontal hypodensity that was suspicious for an acute ischemic infarction. CT angiogram of the head and neck revealed a complete occlusion of the right internal carotid artery 2 cm from the origin, as well as complete occlusion of the right anterior cerebral artery, the majority of the right middle cerebral artery, and the distal inferior branch of the left middle cerebral artery. The patient underwent emergent mechanical thrombectomy of the internal carotid and associated vessels, with favorable intraoperative angiographic results.

Postprocedural imaging of the head by CT scan revealed extensive cerebral edema with evidence of a new hyperdensity concerning for intracerebral hemorrhagic transformation on the right side with extension. The patient was observed neurologically to have absent brainstem reflexes and decorticate posturing. Given her poor prognosis and poor neurologic function, she was felt to not be appropriate for surgical decompression. The patient’s family elected to pursue comfort-care measures on hospital day 7, and the patient died later that day.

Discussion

GPA, formerly known as Wegener granulomatosis, is a systemic disease of unknown etiology characterized by necrotizing granulomatous inflammation and variable degrees of vasculitis in small and medium-sized blood vessels.1 GPA is often suspected in patients who present with progressive sinus symptoms or upper airway disease, as well as evidence of lung or kidney involvement.1,2

First described in 1931, its incidence is approximately 3 in 100,000 people, and it is most commonly observed among the white population, especially persons of Northern European descent.1,3 The average age of patients at diagnosis is between 40 and 50 years, and there does not appear to be an epidemiologic gender bias.

Presentation

The classic triad of clinical symptoms associated with GPA includes upper airway symptoms, lung involvement, and kidney involvement. Most patients present with fever, fatigue, weight loss, sinusitis, epistaxis, oral ulcers, hearing loss, saddle nose deformity, hoarseness, cough, hemoptysis, hematuria, myalgias, splinter hemorrhages, and digital infarctions.1,3 Hoarseness may be the first sign of the tracheal inflammation that occurs in patients with GPA and that can lead to tracheal stenosis and respiratory failure in severe cases.

Approximately 85% of cases of GPA will have pulmonary involvement on presentation.1,3,4 Ground-glass opacities from peribronchovascular infiltrates on imaging are often indicative of diffuse alveolar hemorrhage, which is characteristically observed in cases of GPA.1-3 

Less than 20% of cases will have renal involvement on presentation, but ultimately most patients with GPA develop glomerulonephritis over time.1 Urinalysis will reveal microscopic hematuria and non-nephrotic–range proteinuria.2,3 More severe cases of GPA ultimately may lead to renal failure; therefore, rapid recognition of this disease process and initiation of treatment are imperative.

Patients with GPA also may exhibit ocular symptoms consistent with keratitis or conjunctivitis. Cases have been reported of patients experiencing vision loss or symptoms consistent with optic neuritis during the progression of GPA.1,3 More than two-thirds of patients develop myalgias and arthralgias,1 and more than half develop skin lesions.1,3,4 Skin changes can include the development of subcutaneous nodules (sometimes mimicking those observed in rheumatoid arthritis), as well as evidence of digital infarctions or gangrene/splinter hemorrhages in the nail beds.1,2,4 Rarely (8% of cases), neurologic manifestations such as mononeuritis multiplex can be observed.5,6

Diagnosis

The diagnosis of GPA is based on clinical suspicion, findings of a thorough history and physical examination, and supporting laboratory data. In the presence of the triad of airway symptoms, lung involvement, and kidney involvement, GPA should be highly suspected. Laboratory abnormalities may include anemia, thrombocytosis, an elevated ESR, active urine sediment, and an increase in creatinine.1,3 Positive test results for c-ANCA/anti-PR3 are highly suggestive of GPA, with more than 90% sensitivity and specificity.1-3 However, c-ANCA positivity is not the sole criterion for confirming the diagnosis of GPA; tissue biopsy is necessary as a confirmatory test. The choice of tissue sample with highest yield is most commonly obtained from the kidney or the lung, achieved with ultrasound-guided percutaneous kidney biopsy or an open vs thorascopic biopsy of pulmonary parenchymal lesions, respectively.1-4

Treatment

Treatment of GPA is achieved through a combination of a glucocorticoid (namely, prednisone) with an alkylating agent (namely, cyclophosphamide). Studies have shown that this combination induced complete remission in more than 75% of patients.1-3 At least half of patients who achieve remission have a relapse, however.1,3 Additionally, significant toxicities are associated with cyclophosphamide that have contributed to morbidity among patients with GPA.

Long-term treatment regimens are based on the severity of disease. Transition of cyclophosphamide to less-toxic agents such as methotrexate or azathioprine, as well as the use of tumor necrosis factor α inhibitors (rituximab) to maintain remission states, continue to be investigated.1,7 Most recently, the RAVE (Rituximab for ANCA-Associated Vasculitis)8,9 and RITUXVAS (Rituximab vs Cyclophosphamide in ANCA-Associated Renal Vasculitis)10 trials found that the use of rituximab with glucocorticoids for remission induction among patients with severe cases of GPA was noninferior to the use of cyclophosphamide. Additionally, the RAVE trial was able to demonstrate superiority of rituximab among patients presenting with severe disease relapses and those who were clearly identified by c-ANCA/anti-PR3 positivity.8,11

Some authors have acknowledged the value of the observations made in the RAVE trial but cautioned that the evidence for the use of rituximab among newly diagnosed patients with GPA requires further confirmation, and that the extensive evidence behind cyclophosphamide-based induction therapy supports its continued use as first-line treatment.12,13 It should be noted that in the RAVE trial, no differences were observed in the adverse events associated with rituximab vs those of cyclophosphamide. The major causes of death in GPA identified in past investigations include renal and respiratory failure, infection, malignancy, and heart failure or myocardial infarction. Interestingly, stroke has rarely been identified among them.

An Unforeseen Complication

Our patient demonstrated many of the symptoms concerning for GPA: a history recent streptococcal pharyngitis (although this was of questionable significance given that her outpatient ASO titers were negative); evidence of nasal turbinate edema; a history of scant hemoptysis; a significant unintentional weight loss with fever; hoarseness; oral ulcers; and skin changes, including evidence of splinter hemorrhages. She had c-ANCA/anti-PR3 positivity with positive findings on kidney biopsy consistent with GPA. She was appropriately started on prednisone and cyclophosphamide and seemed to be making clinical improvement in the days following initiation.

Unfortunately, our patient sustained an unforeseen complication that is not commonly encountered in cases of GPA: ischemic stroke. The question arises: Was this patient’s underlying disease a predisposing factor to the development of this deadly complication? Most sources agree that there is a high risk of thrombotic events among patients with GPA.1-3,14 Our patient was hypercoagulable for many reasons: She demonstrated thrombocytosis on admission that steadily increased during her hospital course until corticosteroids were initiated; she was continued on her home estrogen regimen; and she had not been receiving pharmacologic deep venous thrombosis (DVT) prophylaxis in light of concerns about active alveolar hemorrhage.

Although the patient had risk factors for stroke, including hypertension and a history of smoking, blood pressure control prior to and during her hospitalization had been achieved with use of a single agent, and she had maintained abstinence from smoking for several years (although we acknowledge that the effects of her past cigarette use had likely already taken effect). Because no signs or symptoms concerning for stroke were present during her initial presentation and admission, evaluation of the patient’s vasculature by ultrasonography was not pursued. We, therefore, acknowledge the possibility that the patient was already predisposed to the development of ischemic stroke, but that the subacute development of GPA along with her hypercoagulable state ultimately compounded her individual risk for stroke and led to this poor outcome.

Interestingly, the patient was found to have a superficial femoral DVT on her left lower extremity on the day that she decompensated. One would have to consider the possibility of this causing a paradoxical embolus secondary to an intracardiac or intrapulmonary shunt. Given her normal TTE with Doppler results, however, this scenario is less likely, and so we believe that the finding of the left lower extremity DVT was incidental and was not responsible for the ischemic event. We propose that the vascular inflammatory process underlying this disease process is such that it led to a secondary thrombosis that precipitated the ischemic event. Ischemic stroke has been identified as a presenting symptom rather than a consequence among patients with GPA.4-6,15 Similarly, this diffuse inflammatory state with hypercoagulable risk factors predisposed this patient to having a poor outcome. Further investigations are necessary to elucidate the mechanism of action of this secondary process.

THe Take-Home Message

GPA is a systemic disease that has widespread manifestations involving the lungs and kidneys. However, possible neurologic complications associated with GPA, including risk of ischemic stroke, require further consideration and investigation. It is important that clinicians be aware of the highly inflammatory state observed in GPA and the potential for deadly thrombotic events in these very ill patients.

Michelle Kurian Solik, MS, MD, is chief resident in the Department of Internal Medicine at St. Vincent Hospital in Indianapolis, Indiana.

Laurel Fick, MD, is associate director of the Internal Medicine Residency Program and director of the Transitional Year and Preliminary Medicine Program at St. Vincent Hospital in Indianapolis, Indiana.

References:

  1. Mubashir E, Ahmed MM, Hayat S, Latif S, Heldmann M, Berney SM. Wegener granulomatosis: a case report and update. South Med J. 2006;99(9):​977-988.
  2. Langord CA. Update on Wegener granulomatosis. Cleve Clin J Med. 2005;​72(8):​689-697.
  3. Reinhold-Keller E, Beuge N, Latza U, et al. An interdisciplinary approach to the care of patients with Wegener’s granulomatosis: long-term outcome in 155 patients. Arthritis Rheum. 2001;43(5):1021-1032.
  4. Bares M, Muchová M, Dufek M, Litzman J, Krupa P, Rektor I. Wegener’s granulomatosis: ischemic stroke as the first clinical manifestation (case study). J Neurol. 2002;249(11):1593-1594.
  5. Nishino H, Rubino FA, Parisi JE. The spectrum of neurologic involvement in Wegener’s granulomatosis. Neurology. 1993;43(7):1334-1337.
  6. Moore PM, Cupps TR. Neurological complications of vasculitis. Ann Neurol. 1983;14(2):155-167.
  7. Bartolucci P, Ramanoelina J, Cohen P, et al. Efficacy of the anti-TNF-α antibody infliximab against refractory systemic vasculitides: an open pilot study on 10 patients. Rheumatology (Oxford). 2002;41(10):1126-1132.
  8. Stone JH, Merkel PA, Spiera R, et al; RAVE-ITN Research Group. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363(3):221-232.
  9. Jones RB, Tervaert JWC, Hauser T, et al; European Vasculitis Study Group. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med. 2010;363(3):211-220.
  10. Geetha D, Specks U, Stone JH, et al; Rituximab for ANCA-Associated Vasculitis Immune Tolerance Network Research Group. Rituximab versus cyclophosphamide for ANCA-associated vasculitis with renal involvement. J Am Soc Nephrol. 2015;26(4):976-985.
  11. Unizony S, Villarreal M, Miloslavsky EM, et al; RAVE-ITN Research Group. Clinical outcomes of treatment of anti-neutrophil cytoplasmic antibody (ANCA)-​associated vasculitis based on ANCA type. Ann Rheum Dis. 2016;​75(6):1166-1169.
  12. Kronbichler A, Jayne DRW. Con: should all patients with anti-neutrophil cytoplasmic antibody-associated vasculitis be primarily treated with rituximab? Nephrol Dial Transplant. 2015;30(7):1075-1081.
  13. Langford CA. Update on the treatment of granulomatosis with polyangiitis (Wegener’s). Curr Treat Options Cardiovasc Med. 2012;14(2):164-176.
  14. Faurschou M, Obel N, Baslund B. High risk of pulmonary embolism and deep venous thrombosis but not of stroke in granulomatosis with polyangiitis (Wegener’s). Arthritis Care Res (Hoboken). 2014;66(12):1910-1914.
  15. Jethava A, Ali S. Ischemic stroke as a presenting feature of Wegener’s granulomatosis. Conn Med. 2013;77(9):535-555.