An Unusual Cause of Intracerebral Hemorrhage: Clinical Pearls Regarding Primary Angiitis of the Central Nervous System View PDF

*Brandon Lucke-Wold
Department Of Neurosurgery, University Of Florida, United States

*Corresponding Author:
Brandon Lucke-Wold
Department Of Neurosurgery, University Of Florida, United States
Email:Brandon.Lucke-Wold@neurosurgery.ufl.edu

Published on: 2020-10-19

Abstract

Primary angiitis of the central nervous system (PACNS) is a rare form of vasculitis. It is a diagnosis of exclusion and often diagnosed post mortem on pathologic evaluation. Cerebral angiography can be suggestive, but biopsy is required. Symptoms can vary from headache to focal cranial nerve deficits. On the more severe spectrum, patients can present with ischemic and vary rarely hemorrhagic stroke. We present in this case report key clinical pearls regarding suspected diagnosis. Younger patients with cortical hemorrhages may have PACNS instead of the more common cerebral amyloid angiopathy. Early suspicion may aid in initiating effective treatment as we highlight in the discussion.

Keywords

Primary Angiitis of the Central Nervous, Intracerebral Hemorrhage, Refractory Intracranial Pressures

Introduction

Among central nervous system vasculitis presentations, primary angiitis of the central nervous system (PACNS) represents one of the rarest forms. A key defining feature of this inflammatory vascular disorder is its isolation to the brain and spinal cord without evidence of systemic involvement [1]. Although headache is the most common presentation of PACNS, it can present with an array of clinical manifestations including cognitive dysfunction, stroke, transient ischemic attack, aphasia, visual deficits, seizures, and motor deficits [2]. Due to this wide spectrum of presentations along with non-specific imaging and laboratory findings, PACNS can be difficult to diagnose as it becomes a diagnosis of exclusion among other CNS vascular inflammatory disorders. Modern imaging advancements have helped recognize findings earlier and solve some previous diagnostic mysteries. Unfortunately, there is no clear classic clinical presentation for the disease and missing an early diagnosis can have devastating outcomes [3]. One of the rarest associated symptoms of PACNS is intracerebral hemorrhage (ICH) with few reports in the literature [4]. Here we report our diagnosis and management of a unique manifestation of PACNS diagnosed following presentation with ICH.

Case Report

55-year-old male presented to trauma bay after being found down at home. He was intubated en route. He had past medical history of seizure, partial epilepsy, and a watershed infarct 12 years prior with some reported residual left arm weakness. Exam upon arrival: does not open eyes, right eye 2mm and reactive, left eye 5mm and non-reactive, positive cough, gag, and corneal reflexes. He extended left upper extremity and localized right upper extremity. He withdrew right lower extremity and had trace nonspecific movement to nailbed pressure in left lower extremity. A right frontotemporal intracerebral hemorrhage (49 ml) was noted on CT with intraventricular hemorrhage and midline shift (Figure 1). Intracerebral hemorrhage score was 3. Patient was emergently taken for right frontotemporal craniotomy for evacuation of intracerebral hemorrhage. Clot was evacuated successfully, dura closed, and intracranial pressure monitor placed.

He continued to have a poor neurologic exam post-surgery: opens eyes to noxious stimuli, PERRL, positive cough, gag, and corneal reflexes. Localized right upper extremity, withdrew right lower extremity, triple flex left lower extremity. His ICP spiked to mid-30s on post-operative day 2 and a left frontal external ventricular drain was placed. Patient continued to have refractory intracranial pressure despite maximum medical management and drainage of CSF. After discussion with family, he was taken back to surgery for right craniectomy, frontal and temporal lobectomy.  Patient was made pupil check only after surgery. EEG placed and readings showed maximum sedation effects. Surgical pathology obtained during second surgery demonstrated leptomeningeal and superficial cortical vessels to be involved by an active vasculitis showing a prominent granulomatous component, favoring PACNS (Figure 2). CD3 and CD20 stains showed a mixture of mature appearing T and B cells associated with the granulomas. Amyloid β was negative. Due to overall poor prognosis with associated diagnosis, patient’s family elected to proceed with comfort care.

Discussion

PACNS is a rare idiopathic vasculitis that is isolated to the vessels of the spinal cord, leptomeninges, and brain. It has an estimated incidence of 2.4 cases per 1,000,000 persons yearly [4]. In 1959, Cravioto H, et al. (1959) first described PACNS as a non-infectious, granulomatous angiitis of the CNS effecting small- and medium-sized vessels [5]. They likened it to giant-cell arteritis (GCA), which alternatively effects the large extracranial vessels preferentially.  Although it has been documented to occur across all ages, PACNS primarily occurs during the 4th and 5th decades in life and is equally distributed among genders [1].  

Currently the pathogenesis of PACNS remains under debate, however a leading theory is that it is an autoimmune response secondary to viral infection. Specific viral candidates include varicella-zoster virus, cytomegalovirus, and Ebstein-Barr Virus due to their correlation in other vasculitis diseases [6]. The primary histopathological finding in PACNS is segmental infiltration by T-lymphocytes and activated macrophages into vessel walls, resulting in granulomatous differentiation with multinucleated giant-cells [1]. It is notable, however, that there are cases of atypical PACNS with non-granulomatous histopathological patterns that are lymphocytic infiltration predominant. These atypical presentations are fibrinoid necrosis predominant [7]. Amyloid β deposits have also been found on pathological analysis, particularly in the granulomatous variant [8]. This has been associated with a subset of patients who present with concurrent cerebral amyloid angiopathy (CAA) and PACNS [9]. These pathological variations, along with clinical presentation heterogeneity, has led many to speculate that PACNS may instead encompasses a range of disorders with sub-clinicopathological variants [6].  

Clinical presentation can vary widely with several cognitive and motor neurological symptoms depending on location of vessels involved.  Symptoms tend to be slowly progressive, although acute presentations can also occur. Headache is the most prominent presenting symptom (occurring in 63% of patients) with cognitive impairment being second (occurring in approximately 50% of patients) [1]. Focal neurological symptoms develop later in the course with stroke occurring in 40% of patients and contributing to the high mortality rates observed in the early reported cases of PACNS [2]. Our patient’s initial presentation was likely his ischemic stroke that he experienced several years prior. Intracerebral hemorrhage is one of the least frequent manifestations occurring in only 8% of patients and was the presenting symptom for the patient in our case [4].  A case series comparing PACNS patients with (n=115) and without ICH (n=16), found that ICH patients exhibited lower rates of cognitive deficits, focal deficits, and infarctions on MRI [4].  ICH was also significantly associated with necrotizing variant and not amyloid deposition.  This suggests that the cause of hemorrhage in these patients is due to the vessel wall inflammation rather than the weakening of the vessels secondary to amyloid deposition [8], as was found in our case.

Due to its low incidence and non-specific clinical, laboratory, and imaging characteristics, PACNS becomes exceedingly difficult to diagnose [9]. This is further convoluted by the histopathological variants that exist within the disease.  As a result, PACNS diagnosis becomes essentially a diagnosis of exclusion that requires exhaustive investigation and high clinical suspicion [10]. Biomarkers such as acute-phase reactants, anti-neutrophil cytoplasm antibody, and antinuclear antibodies are non-specific [10]. Only cerebrospinal fluid (CSF) has proven viable, as approximately 90% of patients with PACNS present with abnormal CSF findings of elevated leukocytes and total protein [1]. A diagnostic criterion has been proposed by Calabrese LH, et al. (1988) in which three parameters are met:

  • Presence of an acquired neurological deficit without clear cause following initial basic assessment,
  • Evidence of vasculitis through digital subtraction angiogram (DSA) or pathological biopsy, and
  • Lack of evidence of any systemic vasculitis involvement [11].

This criterion was further expanded upon by Birnbaum J, et al. (2009) who proposed that diagnosis could only be absolute though biopsy, whereas the use of DSA and CSF analysis that are consistent with PACNS would only provide probable diagnosis [12]. 

Although biopsy is the most effective diagnostic tool, it has limitations as it is highly invasive and has the potential for false negative due to the segmental nature of PACNS [7]. Most imaging modalities are non-specific and although a normal MRI can essentially rule out diagnosis, cases of PACNS with normal MRIs have been reported [13].  DSA can aid in confirming diagnosis in cases of high clinical suspicion where biopsy is not feasible, or negative biopsy results. DSA findings of alternating segments of stenosis with normal or dilated sections in between (string of beads appearance), occlusions, delayed arterial emptying, and anastomotic channels can all be indicative of vasculitis [1].  However, these findings are also non-specific as they can found in other disorders that are not associated with vasculitis.  A study examining the sensitivity of DSA in detecting PACNS reported it to be as low as 30% [9]. In cases of only small vessel involvement DSA may even appear normal [14]. As a result, DSA alone cannot provide definitive diagnosis. A complete picture of clinical, laboratory, imaging, and biopsy findings must be considered in order to make an accurate assessment of PACNS presence.

Early reports of PACNS were primarily found postmortem, as a result it was thought to have an exceedingly poor prognosis [5]. Currently however, with single glucocorticoid treatment or combination therapy with cyclophosphamide, patients have exhibited favorable outlooks and improved Rankin outcome scale scores [15].  Although no formal randomized clinical trials exist for PACNS treatment, current treatment paradigms center around the use of successful treatment modalities of other vascular inflammatory disorders. This has led to the use of immunomodulating therapies such as rituximab, TNFα blockers, and mycophenolate; particularly in rapidly progressive cases that are resistant to glucocorticoid therapy [16].  Current evidence suggests that different variants of PACNS may require separate tailored therapies in order to adequately slow down disease progression [17].

References

  1. Salvarani C, Brown Jr RD, Hunder GG (2012) Adult primary central nervous system vasculitis. Lancet 380: 767-777. https://doi.org/10.1016/S0140-6736(12)60069-5
  2. Alba MA, Espigol-Frigole G, Prieto-Gonzalez S, Tavera-Bahillo I, Garcia-Martinez A, et al. (2011) Central nervous system vasculitis: still more questions than answers. Curr Neuropharmacol 9: 437-448. https://doi.org/10.2174/157015911796557920
  3. Hajj-Ali RA, Calabrese LH (2020) Central nervous system vasculitis: advances in diagnosis. Curr Opin Rheumatol 32: 41-46. https://doi.org/10.1097/BOR.0000000000000676
  4. Salvarani C, Brown Jr RD, Calamia KT, Christianson TJ, Huston III J, et al. (2011) Primary central nervous system vasculitis presenting with intracranial hemorrhage. Arthritis Rheum 63: 3598-3606. https://doi.org/10.1002/art.30594
  5. Cravioto H, Feigin I (1959) Noninfectious granulomatous angiitis with a predilection for the nervous system. Neurology 9: 599-609. https://doi.org/10.1212/WNL.9.9.599
  6. Scolding NJ, Jayne DR, Zajicek JP, Meyer PA, Wraight EP, et al. (1997) Cerebral vasculitis--recognition, diagnosis and management. QJM 90: 61-73. https://doi.org/10.1093/qjmed/90.1.61
  7. Baker D, Hankey DJ (2003) Gene therapy in autoimmune, demyelinating disease of the central nervous system. Gene Ther 10: 844-853. https://doi.org/10.1038/sj.gt.3302025
  8. Danve A, Grafe M, Deodhar A (2014) Amyloid beta-related angiitis--a case report and comprehensive review of literature of 94 cases. Semin Arthritis Rheum 44: 86-92. https://doi.org/10.1016/j.semarthrit.2014.02.001
  9. Shiner EA, Zagami AS (2014) An illustrative case of primary angiitis of the central nervous system. SAGE Open Med Case Rep 2: 2050313X14559638. https://doi.org/10.1177/2050313X14559638
  10. Deb-Chatterji M, Schuster S, Haeussler V, Gerloff C, Thomalla G, et al. (2019) Primary angiitis of the central nervous system: new potential imaging techniques and biomarkers in blood and cerebrospinal fluid. Front Neurol 10: 568. https://doi.org/10.3389/fneur.2019.00568
  11. Calabrese LH, Mallek JA (1988) Primary angiitis of the central nervous system. Report of 8 new cases, review of the literature, and proposal for diagnostic criteria. Medicine 67: 20-39.
  12. Birnbaum J, Hellmann DB (2009) Primary angiitis of the central nervous system. Arch Neurol 66: 704-709. https://doi.org/10.1001/archneurol.2009.76
  13. Niu L, Wang L, Yin X, Li XF, Wang F (2017) Role of magnetic resonance imaging in the diagnosis of primary central nervous system angiitis. Exp Ther Med 14: 555-560. https://doi.org/10.3892/etm.2017.4572
  14. Salvarani C, Brown RD, Calamia KT, Christianson TJ, Huston III J, et al. (2008) Angiography-negative primary central nervous system vasculitis: a syndrome involving small cerebral vessels. Medicine 87: 264-271. https://doi.org/10.1097/MD.0b013e31818896e1
  15. Salvarani C, Brown Jr RD, Calamia KT, Christianson TJ, Weigand SD, et al. (2007) Primary central nervous system vasculitis: analysis of 101 patients. Ann Neurol 62: 442-451. https://doi.org/10.1002/ana.21226
  16. Salvarani C, Brown Jr RD, Calamia KT, Huston III J, Meschia JF, et al. (2008) Efficacy of tumor necrosis factor alpha blockade in primary central nervous system vasculitis resistant to immunosuppressive treatment. Arthritis Rheum 59: 291-296. https://doi.org/10.1002/art.23337
  17. Rosati A, Cosi A, Basile M, Brambilla A, Guerrini R, et al. (2017) Mycophenolate mofetil as induction and long-term maintaining treatment in childhood: Primary angiitis of the central nervous system. Joint Bone Spine 84: 353-356. https://doi.org/10.1016/j.jbspin.2016.12.004
scroll up