Abstract

Background:Leukoencephalopathy, Calcification, and Cyst (LCC) is a syndrome describing the rare concurrence of these three unusual radiographic findings. Here, we describe the neurosurgical management in a patient afflicted with LCC and review the existing literature on surgical indications and outcomes.

Case Description:A 24-year-old man presented with symptoms of progressive headache, gait imbalance and horizontal diplopia. Magnetic resonance imaging (MRI) showed radiographic findings typically associated with LCC, including a large pontine cyst with significant mass effect. The patient's symptoms resolved after open surgical cyst drainage. However, he suffered cyst re-accumulation 3 months after the initial procedure and ultimately underwent placement of a ventriculo-cysto-peritoneal shunt. At the 3-year follow-up, the patient remained symptom free with continued cyst decompression.

Conclusion:Our case report suggests that ventriculo-cysto-peritoneal shunting appeared an effective strategy in LCC patients in whom the cyst fenestration failed. We present this case report in the context of the first systematic review of literature on neurosurgical management strategies for patients afflicted with LCC.

Keywords: Cerebral calcifications, leukoencephalopathy, pontine cyst

INTRODUCTION

Leukoencephalopathy, Calcification, and Cyst (LCC) describes a syndrome consisting of rare concurrence of these three radiographic findings. The term was initially coined by Labrune et al., in 1996.[ 9 ] Since then, approximately 20 additional cases have been described.[ 7 ] These cases share in common radiographic findings of peri-ventricular white matter abnormalities, subcortical calcifications, and cerebral cystic abnormalities found in various locations.[ 1 2 4 5 7 8 10 13 14 16 ] Clinical presentations are largely related to seizure or focal neurologic deficits consequent to progressive calcification or cystic expansion.[ 1 2 4 5 7 8 10 13 14 16 ] The etiology of the disease remains unclear. Some authors have proposed that diffuse microangiopathy causes chronic hypoxia with resultant gliosis, calcium deposition, and cystic parenchymal degeneration.[ 1 2 4 5 7 8 10 13 14 16 ] Others suggest genetic predisposition to aberrant myelination as the etiology.[ 5 ] Still others propose that the syndrome arose secondary to multiple central nervous system insults or insults in the context of congenital abnormalities.[ 7 ]

Given the rarity of the disease, there is a paucity of information with regard to natural history or neurosurgical management strategies.[ 6 ] Here, we report a patient with LCC who presented with symptoms related to an expanding pontine cyst. The patient underwent open fenestration and biopsy of the cyst with symptomatic relief. However, 3 months after fenestration, the patient suffered symptomatic recurrence and underwent a ventriculo-cysto-peritoneal shunt. In the context of this unusual case, we present the first systematic review of literature with the goal of identifying the optimal neurosurgical management of LCC.

CASE REPORT

A 24-year-old man with no past medical history presented to the emergency ward with several weeks of progressive headache, gait imbalance and horizontal diplopia. Detailed history revealed no foreign travel or unusual diets. Neonatal history revealed that the patient was born 5 weeks prematurely, but was born of otherwise normal gestation and vaginal delivery. He recalled no family history of neurological or metabolic diseases. The neurologic examination was notable for a right internuclear ophthalmoplegia (INO) and altered sensation to light touch, pinprick, and temperature in the left arm. Neuro-ophthalmologic examination revealed no evidence of retinal telangiectasias. Computed tomography (CT) demonstrated dense calcifications in the left corona radiata and bilateral thalamus, a 3.7 × 2.4 × 2.5 cm pontine cyst with compression of the fourth ventricle, and ventriculomegaly. A 4-mm-thick mural enhancement was noted in the right anterior portion of the cyst. Magnetic resonance imaging (MRI) confirmed these findings and additionally revealed extensive peri-ventricular and peri-cyst fluid-attenuated inversion recovery (FLAIR) signal abnormalities [ Figure 1 ].

Figure 1

Pre-operative imaging. (a) Axial FLAIR MR imaging demonstrating extensive peri-ventricular signal abnormalities. (b) CT (left), T1-weighted axial MR (center), and axial FLAIR MR imaging (right) demonstrating bilateral thalamic calcification with peri-calcification FLAIR signal abnormality. (c) Sagittal, axial, and coronal post-gadolinium T1-weighted and axial FLAIR imaging demonstrating a cystic lesion at the level of the pons effacing the fourth ventricle with peri-cystic FLAIR signal abnormality

Serologic study for cysticercosis was negative. The patient underwent bilateral suboccipital craniectomy and trans-vermeal cyst drainage and biopsy of the enhancing region of the cystic wall under stereotactic guidance. Intraoperatively, green cystic fluid was obtained upon cystic fenestration [ Figure 2 ]. Pathologic analysis of the green cystic fluid and the thickened cystic wall revealed no evidence of neoplastic processes. No angiomatous rearrangement of microvasculature or Rosenthal fibers was noted in the cyst wall. The patient's neurologic deficits resolved after the open fenestration procedure. Postoperative MRI revealed cyst decompression and an interval decrease in ventricular size [ Figure 3 ]. At the 1-month follow-up, the patient reported full resolution of his presenting symptoms.

Figure 2

Operative findings. (a) Fenestration through the posterior wall of the pontine cyst. The lower retractor was placed over the left cerebellum. The upper retractor was placed over the right cerebellum. Rostral cerebellum was toward the left of the image, and caudal cerebellum was toward the right of the image. Suction cannula in each of the panels is identified by a white arrow. (b) Encountering a transparent greenish fluid collection upon cyst fenestration (black arrow). (c) Visualizing the anterior wall of the pontine cyst. (d) Mural nodule of the cyst visualized and biopsied (blue arrow)

Figure 3

Postoperative imaging. Sagittal, axial, and coronal post-gadolinium T1-weighted MR imaging taken (a) prior to cyst fenestration and (b) post cyst fenestration

Three months after the initial procedure, the patient re-presented with complaints identical to the initial presentation. Neurologic examination again revealed a right INO and altered sensation of the left upper extremity. Imaging revealed expansion of the pontine cyst and associated ventriculomegaly. The patient underwent placement of a cysto-ventriculo-peritoneal shunt in which a cyst draining catheter is connected through a “T” connector to a right occipital ventriculo-peritoneal shunt at a point distal to the valve [ Figure 4 ]. The patient's symptoms again resolved postoperatively. Postoperative CT revealed good positioning of the ventricular and the cyst catheters as well as an interval decrease in the ventricular size. The patient remained symptom free at the 3-year follow-up. Imaging at that time revealed continued decompression of the pontine cyst.

Figure 4

Schematic of ventriculo-cysto-peritoneal shunting. The cyst catheter is T’ed into a right occipital peritoneal shunt at a site distal to the valve

DISCUSSION

LCC is an unusual entity defined radiographically by the co-existence of extensive peri-ventricular white matter changes, subcortical calcifications, and intracerebral cysts of variable locations.[ 1 2 4 5 7 8 10 13 14 16 ] The etiology of the entity remains elusive though several propositions have been espoused in the literature. Microangiopathy has been proposed as an etiology for LCC. Evidence in support of this hypothesis include the following: 1) pathologic analysis of specimens from some LCC patients revealed an abundance of small vessels associated with rearranged Rosenthal fibers, intense gliosis, and micro-calcifications;[ 4 5 7 8 10 14 16 ] 2) microangiopathy is associated with chronic hypoxia that predisposes to parenchymal degeneration with resultant calcium deposition and cyst degeneration;[ 4 5 7 8 10 13 14 16 ] and 3) other syndromic entities associated with vascular telangiectasias, including Coat's plus disease, share the common radiographic findings with LCC, including intracerebral calcifications and extensive white matter changes.[ 11 ] In this context, the syndromic entity of CerebroRetinal Microangiopathy with Calcification and Cyst (CRMCC) has been proposed to describe entities with lesions referable to microangiopathy.[ 1 4 10 ] Another proposed etiology invokes aberrant myelination secondary to defective Glial Fibrillary Acidic Protein (GFAP).[ 5 ] This proposal is based on the observation that the rearranged Rosenthal fibers observed in LCC are pathologically reminiscent of those observed in Alexander's disease, a leukodystrophy resulting from mutations in GFAP.[ 3 ] Of note, the P47L GFAP polymorphism has been reported in an LCC patient.[ 5 ]

Review of the reported LCC cases[ 1 2 4 – 10 13 14 16 ] further suggests heterogeneity in natural history. In LCC patients with early onset disease, the patients suffer progressive neurologic decline with poor prognosis despite aggressive neurological and neurosurgical management.[ 9 10 13 ] In contrast, there is accumulating evidence that some LCC patients, like the one described here, maintain good neurologic status upon neurosurgical management of the cystic lesions.[ 6 ] This heterogeneity in natural history suggests that LCC may constitute an umbrella term encapsulating distinct disease entities, including microangiopathy,[ 4 5 7 8 10 13 14 16 ] aberrant myelination,[ 6 ] or multiple central nervous system injuries or insults in the context of congenital abnormalities.[ 7 ]

A systemic review of the existing literature on the neurosurgical management of LCC revealed a wide spectrum of management strategies [ Table 1 ] with varied outcome. There are two central questions with regard to neurosurgical management of LCC. The first involves the issue of diagnosis. In patients with radiographic findings of LCC and exhaustive medical work-up without definitive diagnosis, should biopsy be performed for tissue diagnosis? To the extent that parasitic infections and neoplastic processes[ 1 ] cannot be excluded, we would favor surgical maneuvers for tissue diagnosis.[ 7 8 ] Based on the existing literature, the highest yield of diagnosis likely involves draining of the cyst and biopsy of the cyst wall.[ 4 13 ] Most previous reports of angiomatous changes in LCC originate from tissue surrounding the cyst wall.[ 1 2 4 – 10 13 14 16 ] The regions of encephalopathy were biopsied in one report[ 7 8 ] and also yielded specimens with angiomatous changes. Repeated biopsy did not enhance the diagnostic yield[ 7 ] and should be undertaken only in extreme situations. The utility of biopsying regions of calcification remains unclear, as there are no current reports addressing this issue.

Table 1

Neurosurgical management of cyst formation in documented cases of patients diagnosed with calcifications, and Cysts

The second neurosurgical issue involves the optimal treatment strategy in cases of symptomatic cyst expansion. Table 1 shows a synopsis of an exhaustive review of the reported LCC patients who underwent neurosurgery. From this review, it appears that therapeutic efficacy can be derived from resection of the cystic lesion in surgically accessible regions.[ 1 6 7 14 ] For deeper lesions, stereotactic drainage and biopsy,[ 1 13 ] open drainage,[ 4 ] and shunting[ 9 ] have all been reported with good clinical outcome. In our case, we favored an open cyst fenestration strategy because 1) the lesion was located in a surgically accessible region, 2) the procedure afforded ample tissue acquisition for exclusion of neoplastic or infectious processes, and 3) the procedure avoided implant of foreign materials and shunt dependency. The patient experienced immediate symptomatic relief, but suffered recurrence 3 months after the procedure. Given that approximately one-third of LCC cysts recur after open fenestration [ Table 1 ], a cysto-ventriculo-peritoneal shunt was placed. The maneuver harbored two inherent advantages. First, the ventricular shunt serves as a “back up” drainage mechanism to prevent hydrocephalus should the cyst catheter become obstructed. Second, the cerebrospinal fluid (CSF) drainage from the ventricular system may serve to dilute the proteinaceous material in the cystic fluid so as to minimize the risk of catheter obstruction or shunt malfunction. Similar strategies have been employed in the treatment of arachnoid cysts and Dandy–Walker cysts.[ 12 15 ]

CONCLUSION

We treated an unusual case of LCC requiring neurosurgical intervention and present the first systematic review of the literature in terms of surgical indications and outcomes. Given the inherent complexity of LCC, it is difficult to add to the pathophysiology of LCC through this single case report. However, by conducting the first systematic review of the literature in terms of the surgical indications and outcomes for LCC patients, we provide therapeutic insights to aid neurosurgical practitioners in the management of LCC. In general, tissue diagnosis is warranted in cases of diagnostic uncertainty, though repeated biopsies should generally be avoided. The highest diagnostic yield is achieved by biopsy of the cyst wall or mural nodule. Resection of cystic lesions has been performed in surgically accessible areas with good neurologic outcome. When cysts are located in the deep gray matter or the brainstem, fenestration and shunting have both been described as treatment for symptomatic cyst expansion. Ventriculo-cysto-peritoneal shunting appeared effective in a patient in whom the cyst fenestration failed.

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