Table 1.
Overview of case reports describing cerebrovascular CNS manifestations (CNS, TMA, and macrovascular CNS manifestations).
| Reference | Age onset/sex | Defect | Characteristics | Imaging/biopsy results | Specific therapy | Outcome |
|---|---|---|---|---|---|---|
| CNS TMA | ||||||
| (25) | 19 months/f | CFH-Polym | aHUS onset with fluctuating level of consciousness, prolonged, generalized, tonic–clonic seizures, hemiparesis; EEG showing diffuse slow-wave encephalopathy; In addition cardiovascular instability with poorly contractile left ventricle and a LV-EF of 30% | MRI: subtle bilateral parenchymal abnormalities | Eculizumab started within 12 h after diagnosis | Subtle weakness in right-thumb and finger otherwise age adequate neurologic investigations |
| (26) | 4 years/m | CFH/CFHR1 | Despite intense PT ESRD 8 months after onset; 1 month thereafter bilateral nephrectomy due to uncontrolled hypertension; 3 days after nephrectomy sudden onset of partial complex epileptic seizures without laboratory signs of aHUS recurrence and with normal blood pressure; 1 month thereafter recurrence of generalized seizures; 8 months later third episode of seizures with decreased hemoglobin, low haptoglobine, and moderate thrombocytopenia; persistent deep confusion and violent agitation over 2 days | First MRI (at onset of CNS symptoms): normal; Second MRI: normal; Third MRI: bilateral symmetrical hyperintensities on cerebral pedunculas, caudate nuclei, putamens, thalami, hippocampi, and insulae; fourth MRI (after initiation of PT): completely normal | After third episode of CNS symptoms with MRI lesions suggestive for TMA start with intense PE and after 4 weeks PE replaced by PI | Normal clinical examination except for high blood pressure |
| (27) | 50 years/f | n/a | During first disease flair (day three) unresponsive seizures; EEG: diffuse cerebral dysfunction | Initial CT: unremarkable, MRI 28 days after Eculizumab start: subacute right parietal lobe infarction with areas of hemorrhagic conversion; suspected tiny subacute infarct within the right cenrtum semiovale | Eculizumab started at day 6 after disease onset | Complete neurologic (and renal) recovery |
| (28) | 11 years/f | CFH-Polym, CFI-Mut. | Partial response to PI and PE; multiple tonic–clonic seizures despite ongoing PE therapy; 2 days after first seizures vision loss and severe confusion; laboratory investigations showed hemolysis and thrombocytopenia | First MRI: bilateral, symmetrical hyperintensities on the occipital and posterior parietal lobes and edema; second MRI (2 months therafter): normal | Prior to CNS manifestation PT; thereafter eculizumab in addition to levetiracetam | Complete neurologic recovery after 1 month; normalization of MRI |
| 6 years/f | MCP-Mut. | Initially response to PE and HD with a clear hematologic response after 5 days; on day six patient developed tonic–clonic seizures, followed by vision loss and nystagmus – in parallel worsening hemolysis and thrombocytopenia | MRI: bilateral, hyperintense white matter lesions in the occipital and posterior parietal regions | Eculizumab was initiated after MRI | Five weeks after first eculizumab dose complete neurologic, hematologic, and renal recovery | |
| (29) | 25 years/m | De novo TA-TMA | Ktx at 12 years of age due to FSGS; uneventful course till age of 25 years; at 25 years acute onset of left-sided weakness preceded by general fatigue and progressive forgetfulness in the previous 2 months. Lab at time of admission showed mild thrombopenia, with low normal hemoglobin, and LDH | First MRI/A: right-sided temporo-parietal and thalamic lesions; missing flow signal of the right middle cerebral artery; second MRI/A: additional ischemic lesions of the left-sided thalamus and both occipital regions; Brain biopsy: extensive necrosis and arteriolar hyalinosis; Post-mortem examination: disseminated TMA of brain, lungs, and renal allograft | Cyclosporin A, prednisolone, valsartan, and darbepoetin alpha at time of CNS manifestation; no specific TMA therapy | After first MRI/A the patient was discharges with ASS; 4 weeks later admission due to listlessness and mutism; 5 days thereafter bilateral blindness was discovered and Cyclosporin A was paused; second MRI/A was performed; development of severe arterial hypertension, rapidly declining platelets and slightly increased LDH; C3/C4 and CH50 normal, no further complement analyses |
| MACROVASCULAR CNS MANIFESTATIONS | ||||||
| (30) | 20 months/f | Fam. | At diagnosis development of gangrenous lesions of finger and toes with thromozytopenia, increased LDH, fragmentocytes, and creatinine; 90 days after aHUS onset seizures and acute hemiparesis | First MRI/A: ischemia of the right frontoparietal region and steno-occlusive lesions of both internal carotid arteries and patent vertebral arteries; no laboratory signs of TMA | After aHUS onset 16 PE sessions and four PI leading to aHUS recurrence | n/a |
| (31) | 4 years/f | Stx-HUS | Stx-HUS onset with ESRD and need for PD. 3 months after onset various neurologic complaints including tonic movements of the left limbs, transient vision loss, and intermittent dysarthria | MRI/A: acute infarction in the right middle cerebral artery territory with bilateral occlusions of the distal internal carotid arteries with multiple small collaterals similarly to moyamoya disease; C3, C4, CH50, and CFH concentration normal, no further complement studies performed | PD; revascularization surgery; | Planed for renal transplantation; after revascularization persistent mild hemiparesis |
| (32, 33) | 3 years/f | CFH-mut; fam. | Acute onset of aHUS proceeding to ESRD – first Ktx with aHUS recurrence and subsequent graft loss on day 3; nephrectomy was performed; with 12 years second Ktx under prophylactic pre and post-transplant PE. Eight weeks later creatinine increase and intense TMA lesions on biopsy, despite intensive PE graft loss and patient on HD. With 15 years episodic sensory and motor symptoms – first MRI; with 17 years third Ktx under prophylactic pre and post-transplant PE; postoperatively infarction in the right frontoparietal region with left-sided hemiparesis, focal seizures, and impaired consciousness. Thereafter progressive neurologic recovery without additional events under PE. Later on PE was switched to Eculizumab | First MRI/A: severe stenosis in proximal segments of the middle and anterior cerebral arteries; Further imaging: infarcts in the right frontal and frontoparietal regions | Prophylactic PE and later on due to allergic reactions Eculizumab | Progressive recovery of neurologic symptoms under PE |
| (34) | 1 month/f | CFB-mut. | aHUS with ESRD at 4 months; due to severe arterial hypertension bilateral nephrectomy at the age of 1 year. Ktx at the age of 19 months; 15 days thereafter hematologic recurrence, treated with PE and IVIG. With 6 years again HD dependent, nephrectomy of the graft; with 10 years episodes of bilateral hemiparesis and loss of consciousness. Imaging studies showed multiple and intense stenoocclusive vascular lesions cerebral, pulmonal cardial and peripheral | MRI/A: bilateral stenosis of intracranial carotid arteries and left subclavian and vertebral arteries; CT-Angiography and cardiac catheterization: stenosis of all branches of pulmonary arteries, moderate pulmonary arterial hypertension and stenosis of distal anterior interventricular, right and marginal coronary arteries, right humeral artery, celiac trunk and splenic artery | Initially HD and nephrectomy. Recurrence after 1st transplant treated with IVIG and PE. After graft loss nephrectomy and again HD. After onset of cerebrovascular symptoms attempt of carotid siphon angioplasty | Attempt of carotid siphon angioplasty, complicated by dissection and massive infarction leading to death |
| (35) | 2 month/m | C3-mut. | Ten months after recovery of aHUS fulminant recurrence with ESRD despite PE. After 4.5 years PD and poor blood pressure control sudden onset of convulsions involving the right hand and face, followed by hemiparesis and aphasia (at that time normal RR and normal lab); MRI/A revealed stenoocclusive lesions; symptoms resolved completely without specific therapy; 1 year thereafter Ktx under prophylactic eculizumab therapy. At day four seizures of the right hand and face and aphasia; death at day 9 after transplantation | MRI/A: stenosis of the left internal carotid artery and bilateral collaterals of the middle cerebral arteries; signs of subacute stroke in the territory of the left middle cerebral artery. CT after renal Tx: massive ischemic lesions in the region of the middle cerebral arteries | PE after first recurrence – ESRD – PD – transplantation under prophylactic eculizumab | Development of severe stroke on day 4 after Ktx leading do death within 5 days despite eculizumab therapy |
| (36) | 17 months/f | CFB and CFI mut. in addition to CFH-polym | Despite intensive PE ESRD 3 month after aHUS onset; with 3 years Ktx under prophylactic post-transplant PE and PI and nephrectomy of native kidneys. Despite prophylactic PT three aHUS recurrences leading to malignant hypertension and generalized seizures with transient focal neurologic symptoms (normal CT); with 4 years transplant nephrectomy and HD, PT was terminated. Seven years later, despite normal laboratory parameters development of a transient ischemic attack with severe neurological symptoms including vomiting, headache, aphasia, ataxia, confusion and weakness in both arms; measurement of C3 and C3dg showed ongoing complement activation and eculizumab was initiated under the suspicion of complement-mediated TMA like vasculopathy; Ktx 11 months after the TIA episode | CT at onset of CNS symptoms: normal, MRI/A at second severs CNS manifestation: total occlusion of the right carotid artery and near-occlusion of the left carotid artery. Repeated imaging over a period of one year showed no progression of vascular occlusions under eculizumab therapy | Eculizumab was started after severe TIA episode | Repeated imaging over a period of one year showed no progression of vascular occlusions under eculizumab therapy. The patient was successfully re-transplanted under eculizumab |
aHUS, atypical hemolytic-uremic syndrome; CFB, complement factor B; CFH, complement factor H; CFHR, CFH related protein; CFI, complement factor I; CNS, central nerve system; CT, computer tomography; EEG, electroencephalogram; ESRD, end stage renal disease; f, female; fam., familial; FSGS, focal segmental glomerulosclerosis; HD, hemodialysis; IVIG, intravenous immunoglobulins; Ktx, kidney transplantation; LDH, lactate dehydrogenase; LV-EF, left ventricular ejection fraction; m, male; MCP, membrane-cofactor protein; MRI, magnetic resonance imaging; MRI/A, MRI angiography; Mut., mutation; n/a, not available; PD, peritoneal dialysis; PE, plasma exchange; PI, plasma infusion; Polym., polymorphism; PT, plasma therapy (PE and/or PI); Stx, shigatoxin, TIA, transient ischemic attack; TMA, thrombotic microangiopathy.