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Leucoencephalopathy with brain stem and spinal cord involvement and raised lactate (LBSL) is a white matter disease that has recently been described based on typical magnetic resonance imaging (MRI) findings.1,2 These include widespread, homogeneous or inhomogeneous white matter abnormalities, corpus callosum involvement, and selective involvement of certain brain stem and spinal cord tracts. Increased white matter lactate levels are usually found on magnetic resonance spectroscopy (MRS). Clinically, the condition is characterised by a childhood onset slowly progressive course. Here we report two patients who presented with adult onset LBSL and normal lactate on MRS.
A 23 year old woman and her 25 year old brother were referred to our department because of a slowly progressive gait disorder. At the age of 20 (in the female patient) and 23 years (in the male patient), the siblings had first noted an unsteady gait, stiffness in both legs, and bilateral clumsiness. They had both had normal development, and their former medical history was unremarkable. They had achieved unsupported walking at ages of 14 months (female patient) and 15 months (male patient). Both had been examined during early adolescence, with normal neurological findings. They were the only affected members in their family, and their parents were non‐consanguineous.
Neurological examination on admission revealed mild spastic tetraparesis (affecting the legs more than the arms), generalised ataxia, saccadic smooth pursuit, saccadic dysmetria, and horizontal, gaze evoked nystagmus. Both patients had hyperreflexia, and plantar reflexes were extensor. Sensory testing was remarkable for a distal symmetrical decrease in position and vibration sense. Neuropsychological testing (Wechsler Memory Scale Revised, Rey‐Osterrieth Complex Figure Test, logical reasoning, dual task paradigm, Multiple Choice Vocabulary Test B) revealed that they were of average intelligence and did not show signs of cognitive decline. The following laboratory investigations were normal: routine blood chemistry, ammonia, creatine kinase, vitamins E and B‐12, folic acid, thyroid function, antinuclear antibodies, lactate, pyruvate, very long chain fatty acids, phytanic acid, copper, caeruloplasmin, lysosomal enzymes (arylsulphatase‐A, galactocerebrosidase, β‐galactosidase, hexosaminidase‐A), and routine cerebrospinal fluid indices (including lactate). Central motor and somatosensory evoked potentials were delayed. Sensory and motor nerve conduction velocities were normal. MRI (1.5 Tesla) of the brain revealed a non‐enhancing, inhomogeneous (“spotty”) appearance, that was hypointense on T1 weighted and hyperintense on T2 weighted images. Most signal changes were seen within the deep and periventricular cerebral white matter (fig 11,, panels A to C), completely sparing the U fibres. The signal changes were also observed in the posterior limb of the internal capsule (fig 1C1C)) and in the posterior part of the corpus callosum. Infratentorial changes were seen in the cerebellar white matter, pyramidal tracts, medial lemniscus, superior and inferior cerebellar peduncles, and in the intraparenchymal trajectories of the trigeminal nerves (fig 11,, panels D to F). On spinal MRI, abnormalities were detected in the dorsal columns and lateral corticospinal tracts (fig 1G1G).). Repeated MRS with short (STEAM, TR=1500 ms, TE=20 ms) and long (PRESS, TR=1500 ms, TE=135 ms) echo time of the affected white matter revealed mildly decreased N‐acetylaspartate and increased choline levels, but normal lactate levels (fig 1H1H).). The patients were started on a low dose of baclofen and have shown a moderate improvement in spasticity over time.
The two patients reported here presented with slowly progressive pyramidal and cerebellar signs and a mild concomitant dorsal column dysfunction. MRI revealed “spotty” cerebral white matter changes, abnormality of the pyramidal and sensory tracts over their entire length, and a remarkably selective involvement of cerebellar and trigeminal tracts. As in the majority of all reported cases,1,2,3 no cognitive decline was detectable by standard neuropsychological testing. Thus these patients have the clinical characteristics and distinct MRI pattern of LBSL,1,2 which is different from those seen in all other known leucoencephalopathies.3 However, despite repeated examinations and the full blown disease pattern on MRI in our patients, we did not detect increased lactate levels on MRS and in serum and cerebrospinal fluid, although we detected decreased N‐acetylaspartate and increased choline levels, as previously described for LBSL.1
Besides the MRI changes, increased lactate on MRS has been considered the only consistently abnormal finding among all indices tested.4 Moreover, in most patients described to date, motor deterioration started relatively early (5±4 years), with some patients showing delayed development from birth onwards.1,2 Our cases show that LBSL may begin in adulthood in some instances, and that increased lactate levels on MRS may be missing even at advanced disease stages. Furthermore, as we report here the third pair of affected siblings with LBSL, an autosomal recessive mode of inheritance becomes increasingly likely. With 20 patients now reported since the first description of the disorder,1 LBSL seems to comprise a relatively large subgroup among patients with leucoencephalopathy of unknown origin. Moreover, cases with late onset and atypical findings on MRI and MRS may become increasingly known, as clinicians become aware of this novel disease entity, and a more appropriate name may be coined once the underlying genetic abnormality and the full clinical spectrum have been identified.
These cases may help to better define the clinical spectrum of this novel disease. Moreover, our findings suggest that until a critical number of informative families has been collected for a genetic linkage study and genetic testing ultimately becomes available, the diagnosis of LBSL is based on the suggestive MRI findings and the exclusion of other leucoencephalopathies by a complete metabolic screen.
Competing interests: none declared