Case report: Spontaneous improvement and treatment considerations in leukoencephalopathy with calcifications and cysts

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. Bev-acizumab 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.


Introduction
Leukoencephalopathy with calcifications and cysts (LCC), also known as Labrune syndrome, is a rare cerebral microangiopathy caused by biallelic pathogenic variants in the SNORD118 gene, encoding the box C/D small nucleolar RNA (snoRNA) U8 [1,2].The disease can manifest at any age, spanning from early infancy to late adulthood.Patients typically develop progressive neurological deficits, with a combination of motor and cognitive impairment, seizures, language and speech problems, visual impairments, behavioral and psychiatric symptoms, and headaches [1,3].No study documenting the natural disease course in a substantial number of patients is available.
The diagnosis of LCC primarily relies on brain imaging, revealing a triad of frequently asymmetrical white matter abnormalities, calcifications in white and gray matter structures, and cysts [4].
Currently, there are no specific therapies for LCC and management is primarily symptomatic, including surgical drainage of symptomatic cysts and antiepileptic medications [5].Previous case studies have suggested that bevacizumab could be an effective treatment modality to alleviate the clinical and MRI features of the disease.This effect is attributed to its inhibition of vascular endothelial growth factor (VEGF)-mediated signaling pathways, thereby impeding angiogenesis and reducing vascular leakage related to the underlying microangiopathy [6][7][8].However, the efficacy of bevacizumab has not been confirmed by clinical trials.
We report a single case of LCC illustrative of the therapy dilemmas occurring in this disease.This study was approved by the local Institutional Review Board (protocol number: 2018.300), and written consent was obtained according to the Declaration of Helsinki.

Case report
The patient, a 60-year-old female, had an unremarkable medical history until age 20 years, when she developed diplopia, balance difficulties, and vomiting.She underwent neurosurgery for an intracranial tumor of unknown pathology, in hindsight most likely a cyst related to LCC, and insertion of an Ommaya reservoir in a right frontal cyst.
Twenty-eight years later, she experienced balance and coordination problems.Brain MRI revealed multiple cysts in the left brachium pontis, right thalamus and both cerebral hemispheres, multiple calcifications, and extensive cerebral white matter abnormalities, right more than left (Fig. 1A-H).No intervention was performed.The balance problems persisted.
Ten years later, she experienced motor decline with loss of function of her left arm and impaired function of her left leg, necessitating the use of a cane, along with speech and swallowing difficulties, and urinary and fecal incontinence.MRI revealed an increase in size of the right frontal cyst with surrounding edema of the white matter (Fig. 1I-L).The old Ommaya reservoir was located just below the cyst (Fig. 1L).One month later, the cyst size and extent of the white matter edema were reduced spontaneously (Fig. 1M), without clinical improvement.After 3 weeks, however, the cyst was enlarged again (Fig. 1N).It was decided to puncture the cyst, which was associated with a significant, though shortlived, improvement in her clinical condition.Six weeks later, an MRI was performed due to the recurrence of the left-sided hemiparesis, revealing that the cyst had enlarged to its prior size and that the perifocal edema was worse than before (Fig. 1O).A second Ommaya reservoir was inserted, but the hemiparesis increased in severity and CT suggested that the Ommaya reservoir was not inside the cyst.A new Ommaya reservoir was placed using navigation.Repeated punctures over the next 2 months resulted in a decrease in cyst size, some blood in the cyst, and severely increased perifocal white matter edema in the right hemisphere (Fig. 1P).The patient experienced at most minimal short-term improvements after punctures, with an overall decline over time.Her left hand became completely paralytic and she also developed tremors of her left hand.EEG showed no epileptic abnormalities.Treatment with Keppra improved the tremors.No further intervention was undertaken.
At that time, she was referred to the Amsterdam Leukodystrophy Center.She could walk with a cane, but had almost complete loss of function of her left hand.Neurological examination revealed a partial central facial palsy on the left side.Speech was mildly dysarthric.She had a mild hypertonia of the left arm and leg, with hyperreflexia and a Babinski sign on the left.There was weakness and severely impaired dexterity of the left arm and hand.Her gait was unsteady, with circumduction and dragging of the left foot.
Based on previous MRI and CT images, the diagnosis of LCC was suspected.Genetic testing confirmed previously published pathogenic variants in SNORD118: n.24 C > T and n.*5 C > G [3]. Considering that the disease course had been progressive over the last year and anticipating irreversible, invalidating neurological impairment without treatment, we proposed bevacizumab.While awaiting reimbursement approval in the following months, the patient's left hemiparesis significantly improved.A new MRI 6 months later revealed a notable decrease in the extension of the white matter abnormalities and swelling in the right hemisphere (Fig. 1Q and R).The cysts were small.The motor function of her left arm and leg had further improved.Neurological examination 12 months after the referral revealed a slight central facial paresis, a slight left-sided pronator drift, a mild remaining impairment of dexterity and minor intention tremor of the left hand.Signs of slight pyramidal dysfunction of the left leg were also noted.Her balance had recovered to pre-deterioration level.MRI confirmed a slight further decrease in cyst size, edema, and white matter abnormalities (Fig. 1S  and T).A summarized graphical timeline of clinical status, neurosurgical interventions, and associated MRI results is presented in Fig. 1U.

Discussion
While LCC in general follows a progressive trajectory, it exhibits notable variability in its course, with patients experiencing fluctuations in symptom severity.This variability is reflected in the dynamic nature of the cysts, which may enlarge, increase in number, but also diminish or resolve over time.Similarly, white matter abnormalities demonstrate diverse patterns of progression and regression [9][10][11].The case presented here exemplifies this variability, already clear before any intervention was undertaken.Multiple therapeutic neurosurgical interventions for progressive hemiparesis related to a large cyst led to short lasting improvements.Overall, her condition continued to deteriorate, despite in the end a lasting reduction in size of the cyst, but with severe signal abnormalities and swelling of the white matter of the right hemisphere.During a subsequent period without any specific treatment, she experienced a spontaneous clinical and radiological improvement.
There is no study of the natural disease course of LCC, documenting clinical signs and neuroimaging findings in a substantial number of patients over a prolonged period of time.It is our personal experience that neurological dysfunction, size and number of cysts and extent of the white matter abnormalities may vary without interventions.This disease course of the current case confirms this.Surgical treatment should be reserved for cases, in which severe and progressive neurological deficits necessitate urgent intervention.Especially clinical signs of increased intracranial pressure in the presence of a space-occupying lesion may require neurosurgical treatment.Otherwise, a watchful waiting approach helps avoid unnecessary surgeries.We felt that the chronic progressive severe decline of the patient justified treatment with bevacizumab, but considering the subsequent spontaneous improvement it is essential to acknowledge the potential for misinterpretation of treatment effects outside controlled trials.

Conclusion
If bevacizumab would have been started, the clinical improvement observed in our case would have been mistakenly attributed to the effects of bevacizumab.Thus, verifying treatment efficacy through a clinical trial is essential rather than relying solely on anecdotal evidence from published case reports.

Fig. 1 .
Fig. 1.Neuroimaging evolution in the patient with leukoencephalopathy withcalcifications and cysts (LCC) and association with clinical status and neurosurgical interventions.First and second rows display the MRI obtained at the moment of neurological decline at 48 years of age.Axial T2-weighted images (A-D) reveal white matter abnormalities and cysts in both cerebral hemispheres, right more than left (A and B), along with a cystic lesion in the right thalamus (C) and the left brachium pontis (D).Axial gradient echo images (E-G) show multiple calcifications, in the right centrum semiovale (E) and thalamus (F) as well as the dentate nucleus on both sides (G).A sagittal T1-weighted image (H) exhibits multiple cystic lesions and extensive cerebral white matter abnormalities in the right cerebral and cerebellar hemispheres.The third row displays the MRI at the moment of neurological decline at 58 years of age.Axial T2-weighted images (I and J) and sagittal T1-weighted images (K and L) show a significant increase in the right frontal cyst with surrounding edema of the white matter.The old Ommaya reservoir is visible just below the cyst (L).The fourth row shows MRIs during a period with multiple therapeutic neurosurgical interventions for progressive hemiparesis.The sagittal T1-weighted image (M) demonstrates spontaneous reduction in cyst size and extent of white matter edema one month after the previous MRI displayed in the third row.Axial CT image (N) reveals re-enlargement of the cyst 3 weeks later.Sagittal T1-weighted image (O), six weeks after a cyst puncture, shows that the cyst has enlarged to its prior size, with worsened perifocal edema.Sagittal T1 image (P), after repeated punctures over the next 2 months, shows a decrease in cyst size, presence of blood within the cyst, and severely increased white matter edema of the white matter of the right hemisphere.The fifth row depicts MRIs during spontaneous clinical and radiological improvement.Axial T2-(Q) and sagittal T1-weighted images (R) reveal stable cyst size and a decrease in the extension of the white matter abnormalities and swelling in the right hemisphere 6 months after the previous MRI (P).Axial T2-(S) and sagittal T1-weighted images (T), another 6 months later, show a slight further decrease in cyst size, edema, and white matter abnormalities.(U) Timeline illustrating the clinical status, neurosurgical interventions, and associated MRI scans, beginning with the first episode of neurological decline at age 20.