To explore the clinical features and treatment approaches for leukoencephalopathy with calcifications and cysts (LCC). We retrospectively analyzed a 22-year-old male patient with genetically confirmed LCC admitted to Qingdao University Affiliated Hospital in April 2019. The patient's clinical presentation, imaging characteristics, treatment course, and outcomes were summarized alongside a comprehensive literature review. The patient underwent resection of bilateral frontal lobe cysts followed later by resection of a parietal lobe cyst. Postoperative pathology confirmed LCC with calcification and cystic changes. No severe postoperative complications occurred. Follow-up imaging demonstrated gradual cyst regression and symptom resolution. Genetic testing identified heterozygous SNORD118 variants (n.3C>T and n.74G>A). Surgical resection is an effective treatment for LCC cysts causing significant mass effect or neurological deficits, requiring regular follow-up. For smaller, asymptomatic cysts without mass effect, treatment with VEGF inhibitors (e.g., bevacizumab) may be beneficial. Management should be individualized.

Intracranial calcification (ICC) occurs in many neurologic disorders both acquired and genetic. In some inherited white matter disorders, it is a common or even invariable feature where the presence and pattern of calcification provides an important pointer to the specific diagnosis. This is particularly the case for the Aicardi-Goutières syndrome (AGS) and for Coats plus (CP) and leukoencephalopathy with calcifications and cysts (LCC), which are discussed in detail in this chapter. AGS is a genetic disorder of type 1 interferon regulation, caused by mutations in any of the nine genes identified to date. In its classic form, AGS has very characteristic clinical and neuroimaging features which will be discussed here. LCC is a purely neurologic disorder caused by mutations in the SNORD118 gene, whereas CP is a multisystem disorder of telomere function that may result from mutations in the CTC1, POT1, or STN genes. In spite of the different pathogenetic basis for LCC and CP, they share remarkably similar neuroimaging and neuropathologic features. Cockayne syndrome, in which ICC is usually present, is discussed elsewhere in this volume. ICC may occur as an occasional feature of many other white matter diseases, including Alexander disease, Krabbe disease, X-ALD, and occulodentodigital dysplasia.

We present the case of a patient with leukoencephalopathy with calcifications and cysts (LCC), who experienced progressive severe hemiparesis despite multiple neurosurgical interventions of a large contralateral cyst. Bevacizumab was proposed as an ultimate treatment option based on prior case reports. While awaiting reimbursement approval for bevacizumab, major improvement occurred in both clinical and radiological disease manifestations. The disease course of LCC is variable and unpredictable; neurosurgical treatment should be reserved for severe and progressive neurological deficits. Bevacizumab has been reported as a promising alternative treatment option. Importantly, in our case the observed clinical improvement would have been attributed to the effects of bevacizumab, if started when requested. Our case underscores the need for a natural history study for LCC and the necessity of validating treatment efficacy by systematic evaluation through appropriate clinical trials rather than relying on anecdotal evidence from published case reports.

NOTCH1-related leukoencephalopathy is a new diagnostic entity linked to heterozygous gain-of-function variants in NOTCH1 that neuroradiologically show some overlap with the inflammatory microangiopathy Aicardi-Goutières syndrome (AGS). To report a 16-year-old boy harbouring a novel NOTCH1 mutation who presented neuroradiological features suggestive of enhanced type I interferon signalling. We describe five years of follow-up and review the current literature on NOTCH1-related leukoencephalopathy. Clinical evaluation, standardised scales (SPRS, SARA, CBCL, CDI-2:P, WISCH-IV and VABS-2) and neuroradiological studies were performed, as well as blood DNA analysis. For the literature review, a search was performed on Pubmed, Scopus and Web of Science up to December 2023 using the following text word search strategy: (NOTCH1) AND (leukoencephalopathy). Our patient presents clinical features consistent with other reported cases with NOTCH1 mutations but is among the minority of patients with an onset after infancy. During the five-year follow-up, we observed an increase in the severity of spasticity and ataxia. However, at the age of 16 years, our proband is still ambulatory. As for other reported patients, he manifests psychiatric features ranging from hyperactivity during childhood to anxiety and depression during adolescence. The neuroradiological picture remained essentially stable over five years. In addition to the typical findings of leukoencephalopathy with cysts and calcifications already described, we report the presence of T2-hyperintensity and T1-hypotensity of the transverse pontine fibres, enhancement in the periventricular white matter after gadolinium administration and decreased NAA and Cho peaks in the periventricular white matter on MRS. We identified a novel heterozygous variant in NOTCH1 (c.4788_4799dup), a frame insertion located in extracellular negative regulatory region (NRR)-domain as in previously published cases. Blood interferon signalling was not elevated compared to controls. This case provides further data on a new diagnostic entity, i.e., NOTCH1-related leukoencephalopathy. By describing a standardised five-year follow-up in one case and reviewing the other patients described to date, we outline recommendations relating to monitoring in this illness, emphasising the importance of psychiatric and gastroenterological surveillance alongside neurological and neuropsychological management. Studies are needed to better understand the factors influencing disease onset and severity, which are heterogeneous.