
==== Front
Neurol Neuroimmunol Neuroinflamm
Neurol Neuroimmunol Neuroinflamm
nnn
NEURIMMINFL
Neurology® Neuroimmunology & Neuroinflammation
2332-7812
Lippincott Williams & Wilkins Hagerstown, MD

39141887
NXI-2024-100211
10.1212/NXI.0000000000200300
3
120
134
Diagnostic & Treatment Challenges
A 73-Year-Old Woman With Confusion, Visual Field Disturbances, and Edematous White Matter Lesions
From the National Multiple Sclerosis Society Case Conference Proceedings
https://orcid.org/0000-0003-0233-3944
Rohm Zachery MD
https://orcid.org/0000-0002-5675-945X
Goldman Myla D. MD
https://orcid.org/0000-0002-2133-9607
Riley Claire MD
https://orcid.org/0000-0003-2720-9915
Zamvil Scott S. MD, PhD
Pawate Siddharama MD
From the Department of Neurology (Z.R., S.P.), Vanderbilt University Medical Center, Nashville, TN; Department of Neurology (M.D.G.), Virginia Commonwealth University, Richmond; Department of Neurology (C.R.), Columbia University; and Department of Neurology (S.S.Z.), University of California San Francisco.
Correspondence Dr. Rohm zachery.rohm@vumc.org
Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.

The Article Processing Charge was funded by The National Multiple Sclerosis Society.

Submitted and externally peer reviewed. The handling editor was Editor Josep O. Dalmau, MD, PhD, FAAN.

9 2024
14 8 2024
14 8 2024
11 5 e20030004 6 2024
27 6 2024
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
2024
American Academy of Neurology
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

We describe the case of a 73-year-old woman presenting with headaches, confusion, and vision disturbances. Brain MRI showed a large T2-hyperintense lesion in the right temporo-occipital region with vasogenic edema and leptomeningeal enhancement. A leptomeningeal biopsy was performed, which led to a definitive diagnosis.

OPEN-ACCESSTRUE
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pmcCase Presentation

A 73-year-old woman presented to the emergency department with 3 weeks of new-onset headaches, episodic confusion, and difficulty seeing objects on her left side. Her husband described daily events characterized by approximately 30 seconds of behavioral arrest, staring off into the distance, smacking her lips, and fumbling purposelessly with her hands. Each episode was followed by several minutes of disorientation. The patient was unaware of these occurrences. Headaches were holocephalic, throbbing, and constant. She seemed to be bumping into objects, such as furniture and doorframes, on her left side which contributed to several falls.

The patient had regular medical care and well-controlled hypertension and hypothyroidism. She had no personal history of headaches or migraines, seizures, or other neurologic conditions. Family history was notable for late-onset Alzheimer disease in her mother and brother. The patient lived with her husband and previously worked as an accountant. She rarely had alcohol and denied tobacco or illicit drug use. There was no significant travel history. Upon review of system questioning, her husband asserted that he had noticed a decline in her short-term memory over the past year, but he attributed this to normal aging. She performed all daily activities independently.

On the initial examination, her vital signs were normal. She was notably bradyphrenic and required nearly 30 seconds to process and respond to questions. There was a dense left homonymous hemianopia. Brisk reflexes in the left upper and lower extremities indicated pyramidal involvement; however, strength was preserved in the extremities. No other focal neurologic deficits were noted.

Diagnostic Studies

Brain MRI with and without contrast showed a relatively large T2-hyperintense lesion in the right temporo-occipital region with associated leptomeningeal enhancement (Figure 1). Neither acute infarction nor intracranial blood products were detected on diffusion-weighted imaging and susceptibility-weighted imaging, respectively.

Figure 1 Brain MRI

Axial fluid-attenuated inversion recovery MRI showed a confluent T2-hyperintense lesion involving the right temporo-occipital subcortical white matter with extension to the cortico-subcortical junction (A–C). There was a smaller region of T2-hyperintensity in the left temporal lobe (A, arrow). Axial T1-weighted MRI with contrast revealed vasogenic edema and leptomeningeal enhancement associated with the lesion (D, arrowhead). No abnormalities were detected on diffusion-weighted imaging or susceptibility-weighted imaging.

Complete blood count and comprehensive metabolic panel were unremarkable. Serum markers of systemic inflammatory conditions were normal and included anti-nuclear antibody, rheumatoid factor, antineutrophil cytoplasmic antibody, erythrocyte sedimentation rate, and C-reactive protein. Serum rapid plasma reagin, HIV 1/2 antibody screen, and HIV p24 antigen were negative. CSF testing revealed normal white blood cells (0 cells/mm3), mildly elevated protein (71 mg/dL), and normal glucose (68 mg/dL). Polymerase chain reactions in the CSF for varicella zoster virus, herpes simplex virus, human herpesvirus 6, and mycobacterium tuberculosis were negative. Other pertinent negative CSF tests included an autoimmune encephalitis panel, bacterial and fungal cultures, cytology, and flow cytometry.

Final Diagnosis and Treatment

A leptomeningeal biopsy was performed. Histopathologic analysis showed transmural inflammation of amyloid-β (Aβ)-laden arterioles consistent with a diagnosis of Aβ-related angiitis (ABRA; Figure 2). The patient received IV methylprednisolone 1,000 mg daily for 5 days. Levetiracetam was started for the treatment of focal nonmotor seizures with impaired awareness. Upon hospital discharge, she was prescribed prednisone 60 mg daily tapered over 6 months and mycophenolate mofetil 1,000 mg twice daily.

Figure 2 Neuropathology

There was extensive immunohistochemical Aβ staining within leptomeningeal arterioles (A, arrow; 10× magnification). Hematoxylin and eosin staining showed vessel mural thickening with replacement of the vessel media with Aβ (B, arrowhead; 100× magnification). Transmural, angiodestructive inflammation with multinucleated giant cells was consistent with amyloid-β–related angiitis (C; 100× magnification).

Three months after hospital discharge, the patient's cognition and bradyphrenia had substantially improved. There were no further seizures. Her left homonymous hemianopia was unchanged. She had also developed visual release hallucinations in her left visual hemifields characterized by continuous streams of colors and light. Repeat brain MRI showed improvement in the right temporo-occipital T2-hyperintense lesion and resolution of leptomeningeal enhancement.

Discussion

Cerebral amyloid angiopathy (CAA) is a localized form of amyloidosis characterized by deposition of insoluble Aβ into small arterioles and capillaries of the cerebral cortex and leptomeninges, with a predilection for posterior cortical regions.1,2 Although the pathogenesis of CAA is incompletely understood, age-related impairment of cerebral perivascular drainage may result in Aβ accumulation in arteriole media and adventitia, thereby disrupting vessel integrity.1 The prevalence of CAA, estimated at 23% in the general elderly population and 47.5% in patients with Alzheimer disease (AD), is remarkably high and increases with age.3 The clinicoradiological spectrum of noninflammatory CAA encompasses spontaneous lobar intracranial hemorrhage and microhemorrhages, progressive cognitive impairment, transient focal neurologic episodes, acute convexity subarachnoid hemorrhage, and cortical superficial siderosis.3,4 Although definite CAA requires neuropathologic examination, the Boston criteria allows for the diagnosis of probable CAA based on a combination of clinical and MRI features.4

CAA provokes in select patients a cerebrovascular inflammatory response, which may be broadly defined as inflammatory CAA (iCAA).5 iCAA may be more common than originally believed, with 49% of patients with biopsy-proven CAA showing neuropathologic evidence of vascular inflammation.6 Two pathologic subtypes have been described: CAA-related inflammation (CAA-RI), characterized by perivascular inflammation without angiodestruction, and ABRA, designated by transmural, often granulomatous, and angiodestructive inflammation.6 There is significant clinical and radiographical overlap between CAA-RI and ABRA.6,7 Recent studies have found no impact by pathologic subtype on clinical presentation, imaging findings, and outcome.8 We will, therefore, use the broader term iCAA.

The mean age at iCAA presentation is 65–70 years of age with no sex predilection.2,8,9 Symptoms generally develop in an acute or subacute time course. In order of frequency, clinical manifestations include cognitive dysfunction (48%–76%), focal neurologic deficits (24%–51%), headaches (35%–41%), and seizures (31–37%).2,8-10

Brain MRI is the most sensitive diagnostic tool, with 98% of patients with iCAA having an abnormal MRI.2 Because iCAA requires the presence of CAA, MRI evidence of CAA is the most important neuroimaging criterion.11 Nearly 90% of patients with iCAA have imaging findings consistent with CAA.2,10 White matter hyperintensities on T2-weighted MRI are present in 83% of cases, frequently involve the cortico-subcortical interface, are often asymmetric, and may have associated vasogenic edema with sulcal effacement.10,12 Leptomeningeal enhancement is present in 63%–70% of cases and useful for distinguishing iCAA from noninflammatory CAA with a likelihood ratio of 9.5.7,10 Because small caliber vessels are primarily affected, angiography (CT, MR, and digital subtraction) is usually normal.2,9 Nearly 85% of patients have at least 1 CSF abnormality, either pleocytosis (44–68% of cases) or elevated protein (61–71% of cases).2,8,9 Although not a widely available test, CSF anti-Aβ autoantibodies are elevated during the acute phase of iCAA and return to normal after clinicoradiological remission.13 The ApoE e4/e4 genotype is expressed in 71% of patients with iCAA compared with 4% of patients with noninflammatory CAA.14

Primary angiitis of the CNS (PACNS), on the differential diagnosis of iCAA, has a distinct clinical and radiologic signature. Compared with iCAA, PACNS is associated with a younger age at onset (mean 44–47 years), more frequent headaches, less frequent MRI leptomeningeal enhancement, and more cerebral infarctions.6,9 Treatment outcomes between iCAA and PACNS are similar.6

Biopsy directed at the leptomeninges or the gray-white junction is the diagnostic gold standard.7 Neuropathologic examination shows Aβ-laden arterioles colocalized with perivascular and/or transmural inflammation.9 Diagnostic criteria proposed in 2011 and validated in 2016 allow for the diagnosis of probable iCAA using a combination of typical clinical and radiologic features with a sensitivity of 82% and specificity of 97%, which may obviate the need for an invasive biopsy (Table).10,15

Table iCAA Diagnostic Criteria

Diagnosis	Criteria	
Possible iCAA	• Age >40 y
• > 1 of the following symptoms (not attributable to an acute ICH)
 ◦ Cognitive dysfunction
 ◦ Focal neurologic deficits
 ◦ Headaches
 ◦ Seizures
• Evidence of CAA on susceptibility-weighted MRI sequences
 ◦ Corticosubcortical hemorrhagic lesions
 ◦ Cerebral macrobleeds
 ◦ Cerebral microbleeds
 ◦ Cortical superficial siderosis
• WMH that extend to the immediately subcortical white matter
• Absence of neoplastic, infectious, or other causes	
Probable iCAA	• Meets all criteria for possible iCAA
• WMH must be asymmetric	
Definite iCAA	• Meets all criteria for probable iCAA
• Neuropathology shows
 ◦ Aβ deposition within vessels of affected areas
 ◦ Perivascular, transmural, and/or intramural inflammation	
Abbreviations: Aβ = amyloid-β; iCAA = inflammatory cerebral amyloid angiopathy; ICH = intracranial hemorrhage; WMH = white matter hyperintensity.

Adapted from Chung et al. 201110 and Auriel et al. 2016.15

iCAA responds favorably to immunotherapy. Although cases of self-limiting iCAA that resolve without treatment have been described, early immunosuppressive therapy is associated with substantially improved clinical and radiographic outcomes in 94% and 86% of patients, respectively.16 A variety of immunosuppressive therapies have been successfully used, including corticosteroids, cyclophosphamide, mycophenolate, methotrexate, and azathioprine.2,6,8,16 Initial high-dose corticosteroids followed by a prolonged taper over several months until radiologic remission may be sufficient to prevent subsequent relapses.12 The optimal duration of therapy is unknown. In one observational study, 71% of untreated patients with iCAA relapsed over a 2.7-year follow-up period, which suggests a need for longer term therapy with steroid-sparing agents.16 A reasonable treatment approach is to prescribe high-dose corticosteroids initially tapered over several months with concurrent initiation of a steroid-sparing oral medication. Clinicians may consider weaning immunotherapy after 2–3 years of clinical and radiologic stability.

Iatrogenic iCAA has been described in the field of AD immunotherapy. In 2002, a phase II trial of Aβ42 vaccination in patients with AD was terminated early due to several cases of subacute meningoencephalitis in those receiving the active vaccine.17 Autopsies of these patients showed meningeal and perivascular inflammation concentrated around Aβ-laden vessels, similar to the neuropathologic findings in patients with iCAA.14,18 More recently, anti-Aβ monoclonal antibody therapy has been associated with vascular abnormalities detectable by MRI called Aβ-related imaging abnormalities (ARIAs). A subset of ARIAs called ARIA-edema (ARIA-E) is characterized by cortico-subcortical hyperintense lesions and vasogenic edema on T2-weighted MRI, closely resembling the MRI findings of iCAA.19 The clinical features of ARIA-E may also mirror those of iCAA. Although most patients with ARIA-E are asymptomatic, some patients develop headaches, confusion, and neuropsychiatric symptoms.19 For both Aβ vaccine-induced meningoencephalitis and ARIA-E, it has been speculated that mobilization of Aβ from neuritic plaques overwhelms the perivascular drainage pathways resulting in increased Aβ deposition in vessel walls, immune-mediated inflammation, and increased vascular permeability.20 ARIA-E may, therefore, be an iatrogenic, albeit attenuated, form of iCAA.20

Conclusion

We present a case of ABRA, a subset of iCAA characterized by transmural, angiodestructive inflammation in response to Aβ deposition in cerebral arterioles. The clinical syndrome is characterized by a combination of acute or subacute cognitive decline, headaches, focal neurologic deficits, and/or seizures in patients older than 60 years who have underlying CAA. MRI, which usually shows signs of CAA on susceptibility-weighted MRI and T2-hyperintense white matter lesions in the cortico-subcortical regions with variable contrast enhancement, is the most important diagnostic tool. However, as in this case, iCAA may occur absent MRI evidence of CAA in a minority of patients. Although leptomeningeal biopsy remains the diagnostic gold standard, clinicians may avoid the need for invasive biopsies by using validated diagnostic criteria that incorporate typical clinical and radiologic features.10,15 iCAA responds favorably to immunosuppressive therapy, which highlights the importance of prompt diagnosis and treatment. Neurologists should expect to encounter iCAA more frequently because not only the incidences of CAA and AD increase with the aging population but also the number of iatrogenic iCAA cases rise from more widespread use of anti-Aβ monoclonal antibodies.

Study Funding

The authors report no targeted funding.

Disclosure

The authors report no relevant disclosures. Go to Neurology.org/NN for full disclosures.

Appendix Authors

Name	Location	Contribution	
Zachery Rohm, MD	Department of Neurology, Vanderbilt University Medical Center, Nashville, TN	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design	
Myla D. Goldman, MD	Department of Neurology, Virginia Commonwealth University, Richmond	Drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data	
Claire Rile, MD	Department of Neurology, Columbia University, New York, NY	Drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data	
Scott S. Zamvil, MD, PhD	Department of Neurology, University of California San Francisco	Drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data	
Siddharama Pawate, MD	Department of Neurology, Vanderbilt University Medical Center, Nashville, TN	Drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data	

Glossary

Aβ amyloid-β

ABRA Aβ-related angiitis

AD Alzheimer disease

ARIA Aβ-related imaging abnormalities

ARIA-E ARIA-edema

CAA cerebral amyloid angiopathy

CAA-RI CAA-related inflammation

iCAA inflammatory CAA

PACNS primary angiitis of the CNS
==== Refs
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