Authors: Ala Torabi, Zahra Rezaei, Aria Setoodeh, Neda Pak, Elmira haji esmaeil memar, Fatemeh Zamani
Categories: Case Report, dyslipidemia, neuroimaging, pediatrics, intracranial xanthoma, intracranial hemorrhage
Source: BMC Pediatrics
Authors: Ala Torabi, Zahra Rezaei, Aria Setoodeh, Neda Pak, Elmira haji esmaeil memar, Fatemeh Zamani
Neurological manifestations are rare in hyperlipidemia; however, extreme hypertriglyceridemia may cause “milky” blood and cerebrospinal fluid (CSF) and may compromise the central nervous system. We report an infant with familial hyperlipidemia who presented with seizures and unusual neuroimaging findings, including fat deposition in the cerebral vasculature and intracranial xanthomas.
A 2-month-old boy, previously healthy, presented with fever, followed by a focal seizure. His parents are consanguineous. His perinatal history and early development are unremarkable. Physical examination revealed no abnormal findings. During phlebotomy, the blood appeared lipemic with a distinctive ‘salmon-colored’ hue. Laboratory work-up revealed severe hypertriglyceridemia with normal pancreatic enzymes; other metabolic, hematologic, and infectious evaluations were unremarkable. Non-contrast brain CT and MRI showed fat within the dural venous sinuses and cortical veins, along with two extra-axial, fat-containing intracranial lesions in the left parietal and right frontal regions. The patient was treated with anticonvulsant medications, antiplatelet therapy, and a specialized low-fat formula, resulting in significant improvement in lipid levels and clinical stabilization.
In severe hypertriglyceridemia causing visible lipemia of blood, blood viscosity increases and perfusion in the microcirculation can be impaired. Hyperviscosity and the toxic effect of lipid particles on the endothelium may lead to vascular injury in the brain. Accumulation of lipid in intracranial blood vessels can extravasate through the injured blood-brain barrier to CSF and brain parenchyma. Intracranial xanthoma, parenchymal hemorrhage and infarction are considered as the complications.
In infants presenting with seizures or stroke-like signs alongside lipemic blood, clinicians should consider hyperlipidemia-induced neurovascular injury. Neuroimaging signs such as fat-density vessels or lesions should prompt an evaluation for dyslipidemia.
Hyperlipidemia is defined by abnormally elevated levels of lipids in the bloodstream. It can be primary (familial), due to genetic defects in lipid metabolism, or secondary, resulting from acquired conditions (such as obesity, diabetes, or medications). Clinical manifestations of hyperlipidemia are usually related to chronic cardiovascular events. In and of itself, hyperlipidemia often remains silent, aside from features like eruptive or tendinous xanthomas in severe cases. Pancreatitis is a well-known acute complication of extreme hypertriglyceridemia, but neurologic complications are exceedingly rare [1].
Prior reports have documented ‘’milky’’ blood and “chylous” CSF in patients with severe hypertriglyceridemia, sometimes accompanied by elevated intracranial pressure or being misdiagnosed as infection [2]. Moreover, intracranial hemorrhages have been reported in the setting of hypertriglyceridemia, likely due to hyperviscosity and vascular injury from lipid-laden serum [2]. This pathophysiology can reasonably result in distinct and clinically relevant neuroimaging findings. We discuss the various unusal neuroimaging findings, diagnostic challenges and underlying pathophysiological insights and differential diagnoses pertinent to this case, with a brief review of the literature.
A 2-month-old male infant was brought to the emergency department with a one-day history of fever and vomiting. He was the third child of consanguineous parents, with two healthy older siblings. There were no complications in pregnancy or delivery, and the infant had been growing appropriately (with weight and head circumference between the 50th–75th percentiles). He could momentarily hold his head up, visually track objects, and had a social smile. About six hours after admission for dehydration management, the infant developed a focal clonic seizure involving the right leg, lasting two minutes and terminated without recurrence after administration of a loading dose of intravenous phenobarbital.
On physical examination, the infant appeared well-nourished and appropriately developed for age. No dysmorphic features, hepatosplenomegaly, or lipemia retinalis were observed. Neurological examination revealed brisk deep tendon reflexes but no focal deficits or meningeal signs. Notably, during phlebotomy, his blood was milky pink in appearance, described as “salmon-colored”. (Fig. 1) This unusual finding prompted immediate laboratory investigation and consideration of metabolic causes.
Fig. 1Gross appearance of the patient’s blood samples showing marked lipemia due to severe hypertriglyceridemia. A Fresh blood in an EDTA tube demonstrates a thick milky supernatant layer overlying a small column of packed red blood cells. B Another sample reveals a salmon-pink, opaque appearance consistent with extreme chylomicronemia
Laboratory tests revealed an abnormal lipid profile (LDL = 440 mg/dL, HDL = 280 mg/dL, total cholesterol = 1320 mg/dL, triglycerides = 10720 mg/dL) with normal pancreatic function. Other metabolic, hematologic, coagulation, renal, hepatic, and thyroid functions were unremarkable. Electroencephalography and echocardiography were normal. Non-contrast brain CT scan demonstrated diffuse hypoattenuation of the dural venous sinuses, including the superior sagittal sinus and transverse sinuses, as well as the cortical veins. The measured density in the sagittal sinus was in the range of fat (negative Hounsfield units). In addition, linear streaks of fat density were observed in the deep frontal white matter bilaterally, corresponding to the medullary veins. These findings suggested that the venous blood was extraordinarily lipid-rich. No hemorrhagic lesions were seen on CT. However, two non-enhancing fat-density intracranial masses were one extra-axial lesion over the cortical surface of the left parietal lobe with mild peripheral edema and another smaller lesion in the right frontal parasagittal region. No hydrocephalus or developmental brain anomalies were present (Fig. 2). Following subsequent MRI, the findings were further characterized. On T1-weighted sequences, the venous sinuses and cortical veins lacked the normal flow void and instead appeared hyperintense, which suppressed in fat-saturation sequences, confirming the presence of fat or chylous content within the venous blood. Diffusion-weighted imaging (DWI) revealed restricted diffusion in the cortex and subcortical white matter underlying the larger left parietal extra-axial lesion, consistent with an acute or subacute venous infarction in that region. The left parietal lesion itself was heterogeneous on MRI: it had a rim of T1 hyperintensity and internal regions of mixed signal with partial enhancement, suggesting that it contained fat as well as blood-breakdown products. The smaller right frontal lesion showed predominantly lipid components without significant edema. Both lesions were located extra-axially. No evidence of purulent meningitis or empyema was present. Magnetic resonance venography was performed and showed absence of flow in the anterior superior sagittal sinus (Fig. 3). Overall, the imaging findings suggested that the extremely high serum lipids had led to intravascular fat deposition in the cerebral veins and extravasation of lipids into the CSF spaces, causing formation of intracranial xanthomas as well as secondary brain injury.
Fig. 2Axial non-contrast brain CT image shows negative Hounsfield unit as fat density in sagittal sinus (white arrow), superficial cortical veins and deep medullary veins (black arrows) associated intracranial fat containing masses (yellow arrows)
Fig. 3Axial non-contrast T1-W (A-B) images shows absent signal void and high T1-w signal intensity at superior sagittal and transverse sinuses (black arrows), cortical and deep medullary veins (white arrows). There are extra-axial fat containing lesions (xanthomas) on cortical surface of left parietal and right frontal lobes, with adjacent parenchymal edema in T2-W images (white arrows in B-D) and restriction in DWI (E) and ADC (F) images. MRV demonstrate non visualization of superior sagittal sinuses (G)
Anti-seizure medication (phenobarbital, 1–3 mg/kg/day in 1–2 divided doses) and anti- platelet therapy (enoxaparin, 1.5 mg/kg subcutaneous every 12 h) were prescribed for 10 days and resulted in clinical stabilization, with no recurrent episodes of seizure or new neurological symptoms. Breastfeeding was replaced with Kanso-Lipano formula. A significant reduction of lipid profile values as well as a red normal- colored blood sample, was achieved after one week. The patient was discharged with close follow -up visits. Genetic testing was done and the results were positive for familial lipoprotein lipase (LPL) variant (Chr8: 19813385 G > A, c.809G > A. p.Arg270His / homozygote contributed to Combined familial hyperlipidemia and Lipoprotein lipase deficiency) and Dual oxidase (DUOX2)variants ( Chr15: 45400272 C > T, c.1547G > A. p. Arg516His / homozygote contributed to thyroid dys-horomonogenesis but of uncertain significance).
Plans were made for close follow-up with pediatric neurology, endocrinology/metabolism, and nutrition specialists. The infant’s parents and siblings were also advised to undergo lipid screening given the hereditary nature of the disorder, but genetic testing was not performed due to their financial problems.
In summary, we report a 2-month-old male infant with severe hypertriglyceridemia (> 11,000 mg/dL) presenting with fever and focal seizures. Neuroimaging revealed extensive intravascular fat deposition in cerebral veins, resultant ischemic infarction and extra-axial xanthomas. The patient responded well to anticonvulsants, antiplatelet therapy, and low-fat formula with clinical stabilization.
This case highlights a rare “lipid encephalopathy” caused by extremely high circulating lipids. In hypertriglyceridemia severe enough to cause visible lipemia of the blood, blood viscosity increases and perfusion in the microcirculation can be impaired. Hyperviscosity and the toxic effect of lipid particles on the endothelium may lead to vascular injury. Animal studies have shown that triglyceride-rich lipoproteins can cross the blood-brain barrier and deposit in brain tissues. In humans, when serum triglyceride levels rise above a critical threshold (often > 1000 mg/dL), chylomicrons may leak into CSF, especially if there is any inflammation or disruption of the blood-brain barrier [1, 2]. Our patient’s presentation – with milky blood and neurological symptoms – is in line with these phenomena. Similar pediatric cases have been described including diffuse fat accumulation in cerebral venous structures, parenchymal damage, and white matter encephalopathy associated with lipid deposition [3–5]. Chen et al. reported milky cerebrospinal fluid and serum in a patient with hypertriglyceridemia, highlighting the potential for misdiagnosis as infection due to turbid CSF appearance [2]. Koral et al. described abnormal density and signal intensity of blood on neuroimaging in a neonate with lipoprotein lipase deficiency, demonstrating that lipemic blood can produce unusual imaging characteristics that may confound radiological interpretation [3]. A case of cerebral venous thrombophlebitis associated with chylomicronemia has been described by Onci-Es-Saad et al., which supports the role of hyperviscosity and vascular compromise [6]. Kalanj et al. reported an infant with familial chylomicronemia syndrome presenting with encephalopathy and intracranial lipid deposition mimicking an epidermoid cyst [7].
In our case, the presence of DWI restriction and edema suggests that lipid extravasation led to local tissue injury – likely through a mechanism of venous ischemia or hemorrhagic insult. As the lipid-laden blood stagnates in venous channels, it may cause local thrombosis or reduced oxygen delivery, resulting in infarction. Hypertriglyceridemia-induced hyperviscosity is considered a major mechanism leading to impaired microcirculation, endothelial dysfunction, and subsequent ischemic or thrombotic complications [8, 9]. Additionally, leakage of lipid into the subarachnoid space can incite a granulomatous inflammatory reaction, analogous to the formation of xanthomas [1, 10].
Intracranial Xanthomas are extremely rare fat-containing benign tumor-like lesions composed of lipid-engorged macrophages. Association with familial hyperlipidemia (especially Type II hyperlipoproteinemia) have been reported [3, 11]. Intracranial xanthomas, though rare, have been documented in patients with chronic hyperlipidemia. Argie et al. presented a case of bilateral frontal intracranial xanthomas in a patient with type II hyperlipidemia [4] They are usually extra-axial and can occur anywhere in the cranial cavity, with a predilection for regions like the cranial base, temporal bone, or cerebral convexities. The proximity of the xanthomas to the lipid-filled cortical veins (as seen in the left parietal region) further suggests a pathogenesis where fat escaped from the intravascular space and deposited in adjacent subarachnoid tissue. This phenomenon is analogous to superficial siderosis following chronic hemorrhage, except that lipid deposition triggers the inflammatory response. Over time, such deposits could enlarge and even become symptomatic [3, 4, 10]. Notably, intracranial xanthomas themselves can bleed or cause mass effect; however, in infants, the rapid recognition and treatment of the underlying hyperlipidemia may allow these lesions to regress or remain stable [5]. No biopsy was performed in our case due to the risks in an infant, but the radiologic appearance and clinical setting make the xanthoma explanation very likely.
Dermoid cyst rupture is the main differential diagnosis, appearing as floating globules of fat on MRI and hypodense foci on CT. However, dermoid cyst usually occurs sporadically (not in a diffuse vascular pattern) and often triggers aseptic meningitis (headache, meningeal signs), which our patient did not have [12].
In our patient, whole-exome sequencing revealed a homozygous pathogenic variant in the LPL gene (p.Arg270His), confirming the diagnosis of LPL deficiency, a rare autosomal recessive disorder. This condition impairs triglyceride hydrolysis, leading to severe hypertriglyceridemia, chylomicronemia, and related complications such as recurrent pancreatitis, lipemic serum, and, as highlighted in our case, neurovascular injury with unusual imaging findings [9, 13]. Additionally, a homozygous variant of uncertain significance (VUS) in DUOX2 was detected, which may contribute to congenital hypothyroidism through thyroid dyshormonogenesis. Although the pathogenicity of this DUOX2 variant remains uncertain [14]. The coexistence of LPL deficiency and a DUOX2 variant underscores the complexity of genetic contributions to this case, emphasizing the importance of genomic testing in elucidating the etiology and guiding both management and family counseling. Our patients’ parents did not perform genetic testing which is a limitation of our report.
This case illustrates that extreme hyperlipidemia can directly affect the brain, causing distinctive imaging findings and even infarction or hemorrhage due to lipid deposition in cerebral vessels. Recognition of this phenomenon is crucial for prompt treatment. In infants presenting with seizures or stroke-like signs alongside lipemic blood, clinicians should consider hyperlipidemia-induced neurovascular injury. Neuroimaging signs such as fat-density vessels or lesions should prompt a lipid evaluation.