Clinical Reasoning: A 73-year-old man with recurrent aphasia, headaches, and confusion

Section 1

A 73-year-old man presented with sudden right-sided weakness, aphasia, and low-grade headache. Medical history was pertinent for obstructive sleep apnea, hypertension, diabetes, and dyslipidemia, for which he was appropriately treated, in addition to taking aspirin for primary prevention. Initial bloodwork, head CT, and vessel imaging were normal. MRI showed a nonenhancing, nonrestricting T2 hyperintensity in the left temporal lobe, in addition to multiple microhemorrhages (figure 1, A and B). Symptoms resolved within 24 hours and he was discharged on a second antiplatelet agent (clopidogrel). Three weeks later, a second episode of aphasia and right-sided weakness occurred, resolving within hours. He returned to the hospital the following day as symptoms recurred again. He had had been continually complaining of headaches, and his family had noted a gradual cognitive decline over the past month. Repeat bloodwork and erythrocyte sedimentation rate were normal. MRI demonstrated persistent microhemorrhages and superficial siderosis, worsening of the left temporal lobe subcortical changes, as well as diffuse leptomeningeal enhancement.

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Figure 1 MRI characteristic of β-amyloid–related angiitis

(A) T2 fluid-attenuated inversion recovery image showing left temporal lobe hyperintensity (arrow). (B) Susceptibility-weighted image showing microhemorrhages and superficial siderosis (arrows). (C) Six-month gadolinium-enhanced T2 fluid-attenuated inversion recovery showing leptomeningeal enhancement (arrows).

Section 2

The differential included TIA, although lack of diffusion restriction on MRI and stereotyped events despite normal vessel imaging made this less likely. An echocardiogram and 72-hour Holter monitor were done and also normal. Recurrent events are typical of focal seizures, and given the increasing temporal lobe hyperintensity, a low-grade glioma was a potential cause and levetiracetam was initiated. A routine 1-hour EEG was performed and did not capture any clinical events or epileptic abnormalities; however, the medication was continued. The patient's age, headaches, and focal neurologic symptoms prompted investigation for giant cell arteritis, though erythrocyte sedimentation rate was normal.

The leptomeningeal enhancement was investigated with CSF analysis, which showed marked elevation in protein at 1.87 g/L; however, there were zero total nucleated or red blood cells/μL, gram stain was negative, CSF glucose was normal, no oligoclonal bands were detected, and flow cytometry and cytology testing were negative for malignancy. No opening pressure was obtained. Given the absence of total nucleated cells, and lack of fever, herpes simplex virus was not sent despite the temporal lobe abnormality on MRI. The elevated protein was suggestive of an inflammatory etiology, yet vessel imaging did no show changes suspected for primary angiitis of the CNS (PACNS), and a chest CT was performed that did not show hilar lymphadenopathy that can be seen in sarcoidosis. Despite a negative CSF cytology and flow cytometry, lymphoma was still a potential differential and a CT abdomen and pelvis was performed without abnormality.

The clinical course of recurrent neurologic symptoms, headache, and cognitive decline, presence of multiple microhemorrhages with superficial siderosis and leptomeningeal enhancement, and inflammatory CSF analysis was suggestive of β-amyloid-related angiitis (ABRA).

Section 3

Treatment for the presumed diagnosis of ABRA was initiated with a 5-day course of IV methylprednisolone 1,000 mg daily followed by oral prednisone 50 mg per day, and clopidogrel was discontinued. Brain biopsy and cyclophosphamide were recommended, but the headaches, neurologic examination, and leptomeningeal enhancement improved. Consequently, the patient and his family deferred brain biopsy with sampling of parenchyma and meninges, the gold standard test for ABRA. The patient's cognitive testing initially improved from a Montreal Cognitive Assessment of 20/30 to 24/30 after 1 month of therapy, but he remained fatigued, attributed to steroid use, and weaned to 40 mg daily 1 month postdischarge. Two months postdischarge, methotrexate was added to prednisone to reduce risk of ABRA recurrence. Despite these adjustments, the patient's fatigue worsened and his cognition progressively declined.

Six months postdischarge, the confusion had progressed, headaches worsened, and the patient developed gait difficulty prompting return to hospital. Bloodwork including absolute neutrophil count, thyroid, liver, and renal function, and serum inflammatory markers including erythrocyte sedimentation rate, antinuclear antibody, and antineutrophil cytoplasmic antibody were normal. An infectious workup for HIV, syphilis, and Lyme borreliosis was negative. Repeat CSF analysis yielded protein elevation at 1.06 g/L, slightly less than previously; and again, zero total nucleated cells or red blood cells were detected, cytology was negative, CSF glucose was normal, and gram stain, fungal culture, and mycobacterium culture were negative. Opening CSF pressure was not obtained. Creutzfeldt-Jakob disease testing with CSF 14-3-3, tau, and endpoint quaking-induced conversion assay were negative. Both serum and CSF paraneoplastic and autoimmune antibody panels were negative. Repeat CT chest, abdomen, and pelvis were negative. MRI showed resolution of the previously observed left temporal hyperintensity, but development of a new left parietal infarct with petechial hemorrhages, as well as worsening leptomeningeal enhancement (figure 1C).

Section 4

Due to concern for ABRA recurrence, a course of IV immunoglobulin G 2 g/kg over 5 days followed by IV methylprednisolone 1,000 mg daily for 5 days was delivered. Brain biopsy and cyclophosphamide were again recommended; however, as the patient's cognitive status and expected quality of life were guarded, after discussion with the family, no further diagnostic investigations or treatments were pursued. The patient died and autopsy was performed.

Neuropathologic examination revealed significantly thickened arachnoid and a 4 × 2.5 × 3.5 cm subacute left parietal infarct. At microscopy throughout the cerebral hemispheres, β-amyloid accumulation was found within intracortical and arachnoidal artery and arteriole walls, at times fragmented (figure 2A), and focally surrounded by mononuclear inflammatory cells. Focal hemosiderin was noted in the arachnoid. In addition to this first process, the arachnoid was filled with granulomas (figure 2B) with halo-surrounded budding organisms in keeping with Cryptococcus sp yeast (figure 2C). The arachnoid near to the infarct was especially involved, and the arteries showed obliterating endarteritis, likely causing the infarct.

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Figure 2 Microscopic examination postmortem demonstrating findings of β-amyloid (Aβ)–related angiitis and cryptococcal meningoencephalitis

(A) Aβ antibody staining showing Aβ accumulation within cortical arterioles, occasionally with irregular interruptions due to previous amyloid phagocytosis. (B) Granulomatous inflammation of arachnoid (hematoxylin & eosin). (C) Arachnoid with mucin carmine showing Cryptococcus species organisms. Size bar indicates 100 µm.