Leukoencephalopathy with brain calcifications and cysts (Labrune syndrome) case report: diagnosis and management of a rare neurological disease

The diagnosis of LCC is challenging given the diversity of ages at presentation and its rareness. Neuroimaging features commonly described include diffuse bilateral cerebral white matter T2 hyperintensity, particularly surrounding cysts [21]. Relative sparing of the corpus callosum and subcortical U-fibres has been reported while the posterior fossa white matter is variably affected [22, 23]. Cerebral calcifications are commonly asymmetrically scattered within the cerebral white matter or deep gray nuclei, rarely in the cerebellum, either as small punctate foci or larger confluent areas [11]. Cysts are likewise unevenly distributed throughout the brain parenchyma, most commonly supratentorial but as our case illustrates, may also affect the posterior fossa. Enhancement of the cyst wall and mass effect are common features whereas intracystic hemorrhage has been rarely reported [22]. Diffusion weighted imaging has suggested increased water content within abnormal appearing white matter and MR spectroscopy has suggested energy failure in the cyst wall parenchyma [21, 22]. Together, these findings suggest disruption of the blood brain barrier and white matter edema are features of LCC rather than demyelination, consistent with a microangiopathic pathogenesis [2, 11, 21, 22]. Although the radiologic differential may include various infectious or metabolic disease previously discussed, the triad of diffuse white matter T2 hyperintensity, cerebral calcifications, and parenchymal cysts without retinal or extra-CNS manifestations should suggest the diagnosis of LCC. Exceptionally, systemic involvement has been reported in a genetically confirmed case [23].

Biopsy has been commonly performed in suspected cases of LCC [1‐11, 18, 21, 22, 24‐40], likely owing to the broad differential diagnosis and the frequent need for neurosurgical intervention to treat mass effect. A pathologically confirmed diagnosis would also obviate the need for empiric antimicrobial or immunomodulatory agents that may be considered while genetic testing is being performed. Previous reports have suggested that biopsy of a cyst wall may carry the highest diagnostic yield [28], but this has simply been the most common site chosen for biopsy and systematic comparison to other sites is lacking. Our case and others illustrate that radiologically abnormal white matter can also yield a diagnostic result [3, 11]. Descriptions of the pathological changes of LCC in genetically confirmed cases are rare, as most reports pre-date the discovery of SNORD118 mutations [2, 40]. Nevertheless, in clinically and radiologically well-characterized cases, previous authors have described a similar spectrum of microangiopathic changes to our case, with sclerotic and hyalinized vessels occasionally showing fibrinoid deposition, gliosis with Rosenthal fiber formation, chronic microhemorrhage, and parenchymal calcification [1‐3, 7, 11, 22, 27, 38, 39]. In contrast, a commonly reported finding we did not observe were “angiomatous” proliferations of thin walled vessels, which have been either the main finding or were present in association with hyaline-sclerosing changes [1, 2, 4‐6, 8, 15, 21, 22, 27, 34‐40]. This pathologic variability seen in LCC remains to be addressed and may relate to regional variability and location of biopsy, as the cyst wall and more distant white matter may represent different components of the disease. Given the spectrum of microangiopathic change, one could hypothesize that this represents a temporal sequence, with vascular sclerosis, obliteration, ischemia, and cyst formation as the final steps. Conceivably, the angiomatous changes represent a subsequent reaction to hypoxia and would be commonly found in the cyst wall but not more distant white matter. In contrast to the vascular pathology, one consistent finding has been the lack of bona fide demyelination. While several authors have described pallor on myelin staining, there have no reports of active inflammatory demyelination with relative preservation of axons [1, 11, 18, 26, 27, 34, 37]. For the first time, we show that myelin pallor is accompanied by axonal loss, which supports an ischemic rather than demyelinating pathogenesis, consistent with prior radiologic studies. The main pathological substrate for LCC has been consistently shown to be microangiopathy. Hence, leukoencephalopathy may be a misnomer as the white matter changes are likely secondary.