Leukoencephalopathy with Calcifications and Cysts

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67.1 Clinical Features

and Laboratory Investigations Leukoencephalopathy with calcifications and cysts (LCC) is a very rare leukoencephalopathy. Affected siblings have been reported, suggesting an autosomal recessive mode of inheritance. Onset varies between early infancy and adolescence. Some children display intrauterine growth retardation. The disease is slowly progressive with signs of spasticity, cerebellar ataxia, extrapyramidal movement abnormalities, epilepsy, and mental deterioration. In addition, the patients may develop focal neurological deficits and signs of increased intracranial pressure related to growing in- tracranial cysts which require neurosurgical treat- ment. Optic atrophy with deterioration of vision and blindness may occur. Some of the children have bilat- eral Coats retinopathy. Coats retinopathy is a congen- ital retinal telangiectatic disease, characterized by ab- normal retinal vascular permeability and telangiecta- sia, leading to a progressive exudative retinal detach- ment and blindness.

As with all newly described syndromes for which the basic defect is not yet known, it is difficult to de- fine the phenotype. Several patients have been re- ported who lack some of the features described above and have additional features not mentioned above. A few patients had additionally dyskeratosis congenita- like symptoms (sparse hair, dysplastic nails, pigmen- tation abnormalities of the skin) and Fanconi ane- mia-like features (thrombopenia and aplastic ane- mia). Other features reported include microcephaly, osteopenia, osteosclerosis with a tendency to frac- tures, and short stature.

Laboratory investigations are unrevealing. Blood calcium, phosphorus, and alkaline phosphatase are normal. Parathormone levels are normal. CSF is nor- mal.

67.2 Pathology

The most prominent finding in tissue obtained in neurosurgical interventions consists of angiomatous changes. Numerous small, tortuous blood vessels are found with normal endothelial lamina but an irregu- lar, often calcified wall. These vessels are surrounded by many whirled and irregular Rosenthal fibers, eosinophilic bodies, microcalcifications, and ferric

iron deposits. The white matter shows myelin loss, microcystic degeneration, and gliosis.

67.3 Pathogenetic Considerations

The disease probably has an autosomal recessive mode of inheritance. The basic defect is unknown. A genome-wide linkage study has been started.

The pathophysiology of the disease has not been elucidated, but it is clearly a proliferative angiopathy involving the vessels of the central nervous system and the retina. The genesis of the cysts is unclear.

67.4 Therapy

Growing cysts may require neurosurgical interven- tion to alleviate the elevated intracranial pressure.

Other than that, only supportive care is available. Pre- natal diagnosis is as yet not possible.

67.5 Magnetic Resonance Imaging

CT is very important in the diagnosis of LCC, readily demonstrating the presence of calcium depositions (Figs. 67.3 and 67.6). The calcium deposits are most often seen in the thalamus, basal ganglia, the deep white matter, the white matter–cortex border, cerebel- lar white matter, dentate nucleus, brain stem, and lin- ing of the cysts. They are not necessarily symmetrical.

They are progressive over time. The calcium deposits are different from those seen in Aicardi–Goutières syndrome. In the latter disease the calcium deposits are small and punctate, and even in patients with more confluent calcifications, smaller punctate calci- fications can still be seen. In LCC the calcium deposits are larger and bulky.

Calcifications are less easily seen on MRI. Gradi- ent-echo images can be used for that purpose (Fig. 67.1). MRI is, however, superior in depicting the abnormality of the white matter (Figs. 67.1, 67.2, 67.4, and 67.5). The cerebral white matter shows large areas of signal abnormality. The abnormal areas may have a mildly swollen aspect with broadening of gyri and stretching of the overlying cortex. The white matter abnormalities may be asymmetrical. They increase in extent over time.

Leukoencephalopathy with Calcifications and Cysts

Chapter 67

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In addition, growing cysts may be seen, most often located in the region of the basal ganglia and third and fourth ventricle (Figs. 67.1–67.6). They may be- come large and lead to compression of brain tissue or obstruct the normal CSF flow, leading to secondary hydrocephalus. Some of the cysts seem entirely intra- ventricular, whereas other cysts are evidently primar- ily intraparenchymal. It is important to stress that the cysts are not present in all patients, or not yet. Patients may be known for many years with calcium deposits and white matter abnormalities before they develop cysts.

The imaging pattern showing a combination of leukoencephalopathy and calcium deposits is remi- niscent of that seen in other disorders leading to

white matter abnormalities and calcium depositions.

However, the cysts are unique. In Aicardi–Goutières syndrome the calcium deposits are typically punc- tate. In Cockayne syndrome the calcium deposits tend to be larger and more confluent, but the white matter disease is symmetrical and there are no cysts.

CNS infections, in particular congenital cytomegalo- virus infection, may lead to calcium depositions and extensive white matter abnormalities, but the pattern of white matter abnormalities is typical and there are often anterior temporal subcortical cysts. In disor- ders involving parathormone, similar calcium de- posits may be seen but the white matter abnormali- ties and cysts are lacking.

Chapter 67 Leukoencephalopathy with Calcifications and Cysts 506

Fig. 67.1. A boy with LCC syndrome started to have increas- ing walking difficulties at the age of 9–10 years. The first MRI was obtained at the age of 10 years. Note the calcium deposits in the basal ganglia, thalami, dentate nuclei, and lining of the cysts in the deep frontal white matter on the left and the cere- bellum on the right, indicated by a low signal intensity on the gradient-echo (first row, left) and T2-weighted images.

The cerebral white matter abnormalities are more serious on the left; the cerebellar white matter abnormalities are more serious on the right. The abnormal white matter has a swollen aspect. We thank Dr. P.G. Barth, Department of Child Neu- rology, Academic Medical Center, Amsterdam, The Nether- lands, for referral of the patient

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67.5 Magnetic Resonance Imaging 507

Fig. 67.2. The same patient 1 year later. With surgical intervention, the cysts have become smaller

Fig. 67.3. The same patient, now 13 years old.There is a grow- ing cyst in the region of the thalamus on the right.The CT scan shows the calcium in the basal ganglia, thalami, and dentate

nuclei. There are multiple calcium deposits in the cortico-subcortical junction in the cerebral hemispheres

Fig. 67.4. The same boy, now 19 years old. There are large cysts in the region of the thalamus on both sides 067_Valk_Leukoencephalo 08.04.2005 16:25 Uhr Seite 507

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Chapter 67 Leukoencephalopathy with Calcifications and Cysts 508

Fig. 67.5.

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67.5 Magnetic Resonance Imaging 509

Fig. 67.6. CT scan at the age of 22 reveals the increase in calcium as compared to the first CT (Fig. 67.3)

Fig. 67.5. The same boy, now 22 years of age. The cysts in the region of the thalami have regressed without surgical intervention. The cysts in the left hemisphere have become very large and have led to a marked midline shift. The T1-weighted images without (third row) and with contrast (fourth row) re- veal enhancement in the areas of calcium deposits: the lining of cysts and the basal ganglia and thalami.

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