Adult-Onset Leucoencephalopathy with Axonal Spheroids and Pigmented Glia: Report of Two Cases

Sir, Adult-onset leucoencephalopathy with axonal sphenoids and pigmented glia (ALSP) formerly known as hereditary diffuse leucoencephalopathy with spheroids (HDLS) is a white matter disease due to the CSF-1R gene mutation resulting in microglial dysfunction. Microglia are the macrophages of the central nervous system and their dysfunction results in neurodegenerative diseases. The colony stimulating factor- 1 receptor (CSF-1R) gene is necessary for microglial proliferation and differentiation.[1,2] A 22-year-old man who was apparently normal until the age of 20 years presented with gradual onset of difficulty in speech, right-sided body weakness, and progressive difficulty in walking over 2 years. His family history revealed the consanguineous marriage of his parents. The patient had lost his father at the age of 10 years and the reason for it could not be assessed. No imaging was done before. Neurological examination showed motor aphasia, gait disturbances, and cognitive impairment. Increased muscular tone, reduced power, and hyperreflexia were noted in bilateral lower limbs. The electroencephalogram was normal. The MRI of the brain was advised. There were bilateral T2 and FLAIR white matter hyperintensities [Figure 1a and b] with associated volume loss and ventricular enlargement. These white matter changes showed restricted diffusion [Figure 1c]. The thinning of the corpus callosum was also noticed [Figure 1d]. In suspicion of adult-onset leukodystrophy, a CT scan of the brain was performed for any calcification. It showed a stepping stone pattern of pericallosal calcifications [Figure 1e and f]. In view of clinical and imaging features, a possible diagnosis of adult-onset leukodystrophy with axonal spheroids and pigmented glia was made and genetic sequencing was advised. It confirmed CSF-1R gene mutation. The patient was counseled and symptomatic treatment was given. One year later, the patient became completely dependent and bed bound. As further hospitalization was not possible due to affordability, he succumbed to death.Figure 1: MRI T2-weighted (a), FLAIR (b), and DWI (c) axial images through the brain show white matter hyperintensities with restricted diffusion (white arrows) respectively. Sagittal MRI image through the brain (d) shows thinned out corpus callosum (white arrow). Non-contrast sagittal (e) and coronal (f) sections through the brain show pericallosal calcifications (white arrows)A 36-year-old female had a 9-month history of progressive difficulty in walking and slowness of movements, lack of interest, and irritability. There was a gradual decline in mental functioning with word-finding and language difficulties, poor attention, poor judgment, and problem-solving skills. She relies on a wheelchair to move around at present. There is no positive family history. The patient is married and has two young boys who are apparently normal. Neurological examination and imaging findings were similar to case 1. Periventricular T2 and FLAIR white matter changes showing diffusion restriction without any enhancement were noted along with thinned-out corpus callosum and brain atrophy [Figure 2a-f]. A gradient sequence that was done to look for any focus of blooming showed no hemorrhage or calcification/mineralization [Figure 2g]. MRI screening of the entire spinal cord showed no signal changes. CT was conclusive of the disease [Figure 2h]. A mutation in the CSF-1R gene was confirmed by genetic sequencing. The patient is on symptomatic treatment at present.Figure 2: MRI FLAIR (a) T1 post-contrast (b), DWI (c) and ADC (d) images through the brain show periventricular fronto-parietal white matter hyperintensities (white arrows) appearing hypointense without contrast enhancement on T1-weighted post-contrast images (white arrows) with diffusion restriction (white arrows). MRI coronal (e) and sagittal (f) images through the brain show T2 periventricular frontal hyperintensities with thinned-out corpus callosum (red arrows). Susceptibility-weighted image (g) shows no abnormality. Non-contrast CT sagittal section (h) through the brain shows a characteristic stepping stone pattern of calcification (white arrows)ALSP is an autosomal dominant adult-onset leukodystrophy occurring in adults aged 30 to 50 years. It is a rare inherited progressive white matter degenerative disease, also popularly known as hereditary diffuse leucoencephalopathy with spheroids (HDLS) with a prevalence of <1/1,000,000. Though the disorder has a high penetrance, sporadic variety is also known without any family history. ALSP is due to microglial dysfunction. Microglia are the macrophages of the central nervous system and their dysfunction results in neurodegeneration. Colony-stimulating factor-1 receptor (CSF-1R) gene is necessary for microglial proliferation and differentiation. Mutation in the CSF-1R gene has been described as the causative factor in ALSP. Clinically, ALSP presents with motor aphasia, acalculia, agraphia, apraxia, reduced memory, gait disturbances, cognitive impairment, seizures, and psychiatric disturbances including dementia and depression. Rare presentations include Parkinsonian signs, peripheral neuropathy, or stroke-like episodes which may clinically resemble CADASIL. Neurological examination shows upper motor signs such as hyperreflexia, spasticity, and extensor plantar response.[3,4] EEG is normal in patients without seizures. MRI is the commonest imaging modality used for diagnosing leukodystrophies. However, CT helps to narrow down the differential diagnoses. Like all adult-onset leukodystrophies, ALSP also shows white matter T2/FLAIR hyperintensities in all patients with fronto-parietal or frontal periventricular distribution. However, the hyperintensities show asymmetrical distribution. There is persistent diffusion restriction of these white matter hyperintensities, which are typically arranged in a linear pattern or have a punctate appearance paralleling the ependymal lining, predominantly distributed in the corona radiata. Fronto-parietal white matter abnormalities show no enhancement on contrast images. However, a breach in the blood–brain barrier results in enhancement of the lesion in a few patients.[5] Enlargement of cortical sulcal spaces and ventricles with white matter volume loss represents cerebral atrophy. Corpus callosal involvement is almost always present and is seen as severe thinning and signal changes on imaging.[6] There may be an involvement of the pyramidal tract. Deep gray nuclei are not commonly involved. Cavum septum pellucidum is commonly present in these patients; however, it may not be seen in all. Microhemorrhages are not seen. Gradient echo images do not show any calcifications. MR spectroscopy reveals reduced N-acetyl aspartate, increased choline, myoinositol, and lactate. Spinal cord involvement can occur in the form of T2 hyperintense cord signal changes with diffusion restriction.[5] However, no such changes were seen in our case. The most important finding of CT is calcification. Calcifications of ALSP on CT are typically punctate in appearance and are distributed in the bilateral frontal, periventricular, and pericallosal regions. This pattern of punctate calcification is seen as a stepping stone appearance and is specific for ALSP.[1,6] Toxoplasmosis, other (syphilis, varicella–zoster, parvovirus B19), Rubella, and Herpes infections (TORCH) infections and infective granulomas also show calcifications; however, the appearance and location of these differ from ALSP. Calcifications in TORCH infections are typically seen in children and calcifications in infective granulomas are commonly seen in the cortices. Differential diagnoses on imaging include leukoencephalopathy due to autosomal recessive mutations in the mitochondrial alanyl–transfer RNA (tRNA) synthetase 2 gene (AARS2-L), cerebral autosomal dominant arteriopathy with subcortical infarcts, and leucoencephalopathy (CADASIL) and primary progressive multiple sclerosis (PPMS). AARS2-L is a subtype of adult-onset leucoencephalopathy secondary to the mutation of the AARS2 gene. This neurodegenerative disorder resembles ALSP and cannot be differentiated clinically. On imaging, T2 and FLAIR hyperintensities in bilateral frontal and parietal periventricular hyperintensities with restricted diffusion are seen similar to ALSP. However, the white matter hyperintensities may be confluent. Unlike ALSP, there may be involvement of deep gray nuclei along with cerebellar atrophy. The severity of thinning of the corpus callosum is not as severe as that of ALSP. CT does not show any calcifications in this disease. However, microhaemorrhages are not uncommon.[2] CADASIL is a microvasculopathy seen in adults with autosomal dominant traits secondary to the mutation in the NOTCH3 gene. Confluent white matter T2/FLAIR hyperintensities that may involve deep gray nuclei and subacute infarcts, typically involving the anterior temporal lobe and external capsule are classical. The diffusion restriction subsides over time as the infarct ages. Microhemorrhages are common in CADASIL.[7] PPMS is a chronic inflammatory demyelinating disease of the brain and spinal cord. Clinically, patients present with ataxia, gait disturbances, cranial nerve involvement, diplopia, fatigue, or depression. Imaging criteria for MS include one or more T2 hyperintense lesions in the periventricular, juxtacortical, infratentorial, and spinal cord depicting dissemination in the space and simultaneous contrast-enhancing and non-enhancing lesions at any time depicting dissemination in time. No restricted diffusion or calcification is seen. The central vein sign, seen in gradient echo images as small hypointense dots, is one of the markers for MS.[8] There is no specific treatment available for ALSP at present. Patients are treated according to their symptoms. Hormonal and immunoglobulin therapies are being tried. ALSP is a progressive neurodegenerative disease. However, the rate of progression depends on the pathogenic variant running in the family. Cross-sectional imaging helps in narrowing the differential diagnoses. Patients may benefit from symptomatic treatment, though there is no definitive management for this condition. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.