Patient 1 was a 60-year old man, without any past medical history, admitted in the emergency room of a nearby hospital in September 2012 for progressively increasing headaches, fever and confusion. The CT scan revealed no parenchymal abnormality. The cerebrospinal fluid examination showed 400 white blood cells/mm3 (95% lymphocytes), with high protein amount (2.4 g/L), normoglycorachia, and xanthochromia.
Patient 2 was a 77-yo women with a past medical history of Grave's disease and pulmonary tuberculosis who was admitted in the emergency room in our hospital in January 2018 with a strikingly similar clinical presentation. CT scans showed no parenchymal abnormality. A lumbar puncture revealed 84 white blood cells (90% lymphocytes) with hyperproteinorachia (3.5 g/L), normoglycorachia, and xanthochromia.
Infectious meningoencephalitis was considered in both cases, and probabilistic antibiotic (Penicillin in patient 1, Penicillin, and Cephalosporin in patient 2) and antiviral (Acyclovir for both patients) treatments were started. Despite full dose treatment, cognitive alterations worsened in both patients, with the occurrence of major psychomotor slowing in patient 1 and of aphasia in patient 2.
Brain MRI was performed, respectively, at day 15 and day 12 after the first symptoms. None of the two patients had large white matter lesions on the FLAIR sequence. Conversely, high intensity signals were observed along cortical sulci in both cases. On T2* sequences, no microbleeds was detected in patient 1, 5 microbleeds were observed in patient 2. By contrast, multiple cortical and subcortical punctuate lesions on diffusion weighted imaging (DWI) sequences were present in both patients (Figure 1). There was no parenchymal or meningeal gadolinium enhancement. Angio-MRI was normal in both patients. Conventional angiography (in patient 1) and angio-CTscan (patient 2) did not show any large and medium-sized arteries alterations.
Endocarditis and other sources of cardiac emboli were ruled out with transthoracic and transesophageal echocardiography and blood cultures in both patients. Infections screening was negative both in the blood and in the cerebrospinal fluid. Autoimmune and neoplastic etiologies were ruled out by a complete work up, including antinuclear, anti-neutrophil cytoplasmic, anti-cardiolipid, and onconeuronal antibodies. Thoracoabdominopelvic CTscan was normal in both patients. In addition, Positron Emission Tomography scan with fluorodeoxyglucose, gastric endoscopy, skin and ophthalmologic exams were normal in patient 2. Repeated lumbar punctures showed the persistence of xanthochromia with aseptic pleiocytosis in both cases. The association of diffuse subarachnoid hemorrhage and multiple cortical and subcortical microinfarcts finally led to suspect vasculitis involving the small cerebral and meningeal vessels as the potential underlying cause. A brain biopsy was performed in the two patients.
Pathological examination showed vascular amyloid deposits in leptomeningeal and cortical vessels in both patients. In patient 1, a meningeal perivascular lymphocytic and macrophagic inflammation was observed in the close vicinity of amyloid deposits, leading to the diagnosis of CAA-RI (Figure 2). Cortical vessels were sparred by inflammation. Significant intramural or perivascular inflammation lacked in patient 2, but the tissue was sampled from an area relatively sparred by lesions as seen on MRI. Considering the negativity of the complete work-up, the diagnosis of CAA-RI was considered probable for patient 2.
Immunosuppressive treatment was started in both patients, with high-dose parenteral corticosteroids (Methylprednisolone cumulative dose of 3,000 and 1,500 mg for patient 1 and 2, respectively) followed by oral corticoids (1 mg/kg of Prednisone), associated with Cyclophosphamide (one infusion per month for 6 consecutive months). No new DWI lesion was noted on control MRI obtained, respectively, at 1 year after the end of treatment for patient 1 and at 1 month in patient 2. In contrast, on T2* sequences, a large number of microbleeds and several foci of cortical siderosis appeared in both cases as previously reported in cerebral amyloid angiopathy (Figure 3). Cerebrospinal fluid examination progressively normalized in both patients. After 2 months, cerebrospinal fluid was acellular and proteinorachia was at 0.5 g/L in patient 1 and 0.3 g/L in patient 2. Patient 1 remained demented with frontal symptoms, apraxia, and disorientation in time and space, whereas patient 2 significantly improved and recovered a full autonomy in daily life. Cognitive assessment obtained at 9 months in patient 2 showed a complete normalization of language but some persisting alterations of executive performances. In addition, Alzheimer's biomarkers were assessed in the cerebrospinal fluid in patient 2 and showed increased tau protein and reduced beta amyloid 1-42.