What is the diagnosis of leptomeningeal enhancement, multiple bleeding and white matter lesions? Clinical reasoning
The patient was a 81 year old woman who was treated for "1 weeks" of "persistent 30min consciousness decline, right facial prolapse and unclear speech." Past medical history included chronic obstructive pulmonary disease, dyslipidemia, orthostatic hypotension and 2 TIA episodes. 1 weeks before treatment, the patient fell once (presumably related to drowsiness). Physical examination showed no fever, heart rate was 81 times / min, blood pressure was 108/65 mm Hg, alertness was good, physical examination was coordinated, time and place orientation was poor, language examination was normal, cranial nerves, movement, coordination and sensory examination were normal, without any focal dysfunction. Assessments during one episode showed poor response, decreased speech, and right facial prolapse. There was no obvious abnormality in serological examination (whole blood cell count, electrolytes and renal function tests). Cranial CT showed bilateral subarachnoid hemorrhage.
1. what are the differential diagnoses?
2. what inspections should be carried out?
Differential diagnosis should include Meningitis, viral encephalitis, other infectious causes, poisoning or metabolic encephalopathy, seizures, cerebrovascular events, increased intracranial pressure, and neuritis / autoimmune diseases. And so on.
MRI scan showed a high T2 Flair high signal in the left occipital lobe and bilateral frontal lobe. Multiple punctate diffusion restricted lesions in the subcortical white matter, the tentorium and the cerebellum are consistent with acute infarction. Magnetic susceptibility imaging showed multifocal microbleeds and cortical superficial iron deposition. Lumbar puncture showed increased protein (623 mg/L), mild leukocytosis (47 / L), and cryptococcal cytology, culture and serology were negative; CSF, NMDAR, AMPA receptor and voltage-gated potassium channel antibody were negative; serum C reactive protein slightly increased (58 mg/mL), erythrocyte sedimentation rate (ESR) was normal (50 Mg/mL); antinuclear antibodies (ANA), antineutrophil cytoplasmic antibodies (ANCA) and extractable nuclear antigens were all negative; West Nile virus and syphilis serology were negative. Electroencephalogram examination showed that "local polymorphism may indicate recent seizures."
Fig. imaging and pathological findings
Fluid attenuated inversion recovery (FLAIR) (A), diffusion weighted imaging (DWI) (B) and multiplanar gradient return (MPGR) (C) axial images showed extensive asymmetric T2 FLAIR high signal lesions in the right frontal lobe and left occipital lobe, and abnormal signals extended to subcortical white matter. There are multiple scattered lesions in bilateral frontal lobe, left parietal lobe and right occipital lobe, which are consistent with microinfarction in multiple vascular regions. Gradient imaging showed multiple cortical superficial iron deposition and microbleeds. Left frontal cortex H & E / Luxol staining (D) showed a micro infarct in the cortex and its lower white matter. CD163 immunostaining (E) showed macrophage infiltration in the above areas. The high energy H & E view of intratumoral (F) and G vessels revealed that the whole blood vessel wall had amorphous eosinophilic substances. The vessels are round, with thickened and abnormal vascular wall structures and fibrinogen necrosis. Obvious reactive gliosis is seen around the vessels. (H) frontal amyloid protein sections of the amyloid protein immunoreactivity confirmed vascular amyloid deposition and vascular wall destruction.
1. how to correct differential diagnosis based on the results?
Cranial MRI showed PIA enhancement with multiple bleeding and superficial iron deposition, providing important guidance for the etiology of symptoms. The differential diagnosis of diffuse leptomeningeal enhancement includes infection (fungi and mycobacteria), tumor (melanoma, tumor metastasis and lymphoma) and inflammation (sarcoidosis and inflammatory amyloidosis).
Bleeding and iron deposition can be seen on the image. CSF protein is elevated without erythrocyte proliferation, suggesting that bleeding is a subacute or chronic process. CSF cytological examination and negative culture results in little possibility of tumor or infectious etiology. For this patient, elevated CSF protein and altered levels of consciousness, asymmetric white matter hyperintensity and superficial iron deposition suggest that inflammatory amyloid angiopathy, such as amyloid angiopathy (CAA) associated inflammation or beta amyloid (A beta) associated vasculitis (ABRA), may be involved.
1. how to manage the patient?
What are the histopathological features of 2.CAA and ABRA?
The history and imaging findings are highly suggestive of the diagnosis of inflammatory amyloidosis. At admission, patients received treatment with phenytoin and levetiracetam for suspected epilepsy. Their mental status fluctuated and inhalation pneumonia recurred repeatedly. Patients suspected of inflammatory amyloid angiopathy received steroid shock therapy. But the clinical condition was not improved. Reexamination of MRI showed that T2 high signal was aggravated with substantial edema, accompanied by sporadic acute infarction. The patient eventually died of multiple organ failure and died in intensive care unit.
The definitive diagnosis of ABRA requires neuropathological examination through brain biopsy or autopsy. The patient's macroscopic autopsy revealed swelling of the brain, obvious leptomeningeal opacity, and multiple cerebral infarction. Microscopically, there were multiple subacute and distal microinfarctions throughout the cortex (map), and white matter showed infiltration of CD163 immunoreactive macrophages with different degrees. There are a large number of granulomatous inflammation and fibrinous necrosis in the vessels of the superficial brain parenchyma and the pia mater (Fig.), accompanied by a large number of multinucleated giant cells and glial degeneration. A beta immunohistochemistry confirmed that there was amyloid protein deposition in the involved vessels. Overall, these findings can be diagnosed as ABRA.
In the past forty years, CAA has been reported in the literature with perivascular inflammation or granulomatous vasculitis. The clinical and pathological features of this disease are different from those of isolated central nervous system primary vasculitis or CAA. The latter two are deficient in amyloid deposits and inflammation. The presence of CAA and perivascular inflammation is defined as CAA associated inflammation (CAA-RI). When there is obvious inflammation of the blood vessel wall and fibrin like death (as shown in this case), it is called ABRA. [1,2] 。
The average age of onset of CAA-RI and ABRA was 50 years old, older than that of primary vasculitis of the central nervous system, but younger than CAA. [3,4] 。 The clinical manifestations of patients vary widely, but usually include one or more of the subacute cognitive impairment or cognitive impairment in several months, new onset seizures, recurrent or persistent headache, hallucinations, sensory impairment, visual impairment or hemiplegia. [1,3,5] 。 Similar to non inflammatory CAA patients, cerebral hemorrhage caused by rupture of blood vessel walls can lead to more acute clinical manifestations.  。 Imaging examination and biochemical examination of suspected ABRA patients are essential for timely and accurate diagnosis of the disease. In general, serum tests for ANA and ANCA were negative. Most patients had normal ESR (although some patients were elevated); CSF analysis showed elevated protein (> 70 mg/dL) and lymphocyte predominantly leucocytosis (>10 /mm3). [3,5-7] 。 It is worth noting that compared with non inflammatory CAA, APOE e 4/ E 4 genotype is more common in inflammatory vascular disease, suggesting the role of genetic (and downstream immunological) factors in the occurrence or maintenance of disease.  。
Recent advances in imaging pathology have suggested clinical and imaging features that can replace invasive brain biopsy.  。 Previous studies have reported possible clinical imaging criteria for CAA-RI, but the diagnostic value of these criteria for ABRA remains to be further verified. These criteria included (1) age over 40 years of age; (2) headache, decreased consciousness, behavioral changes, focal neurological symptoms or seizures; (3) single or multiple white matter lesions, asymmetrical and extended to adjacent subcortical white matter; (4) presence of one or more types of skin or subcortical hemorrhage, massive hemorrhage or slight hemorrhage or superficial iron deposition; (5) Exclude other reasons. In a study involving 17 cases of CAA-RI confirmed by pathology, the sensitivity and specificity of these criteria were 82% and 97%, respectively.  。 Similar CAA-RI diagnostic criteria, such as lowering the admission criteria for white matter lesions, did not increase sensitivity and significantly reduced specificity (82% and 68%, respectively).  。
ABRA is more sensitive to immunosuppressive therapy in imaging and clinical aspects than CAA, although some patients relapse and therefore have poor prognosis. [5,9] 。 The main treatment is corticosteroid therapy, usually including a course of oral prednisone or intravenous methylprednisolone. Other drugs include cyclophosphamide, methotrexate, azathioprine, mycophenolate mofetil and intravenous immunoglobulin. [4,7] 。 Most patients can complete or almost completely relieve symptoms within weeks or months, but a published study shows that about 18% of patients relapse after withdrawal.  。 In some cases, these relapsed patients responded well to the second immunosuppressive therapy. [5,7] 。
The neuropathological features of this case are similar to those reported in ABRA cases, including the vascularity of amyloid protein and its surrounding PIA and parenchymal meningitis. Lymphocytes, macrophages and giant cells (vasculitis) are found. A beta 40 and A beta 42 both exist. The former is predominant, and the blood vessels are divided, fibrinous necrosis and thrombosis, sometimes accompanied by recanalization. Bleeding and parenchymal infarction were common in different age groups.  。 These findings suggest that the imaging pathology of ABRA is due to the immune response induced by A beta deposits in the brain. The hypothesis is supported by animal and human experiments.  。