Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia

Introduction

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), also known ashereditary diffuse leukoencephalopathy with spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD), refers to a rare inherited autosomal dominant disease characterized by an adult-onset leukoncephalopathy disease that usually leads to death in around 5-7 years. It is considered to belong to the microgliopathies.

Terminology

For many years HDLS and POLD were considered two seperate hereditary leukoencephalopathies. Sometimes HDLS was also called neuroaxonal leukodystrophy. The striking similarities in clinical presentation and histology suggested a link between the two diseases for a long time. HDLS and POLD are now considered to be part of the same disease spectrum, which researchers have recommended calling ALSP¹.

ImagingEpidemiology

ALSP is considered a rare disease. Its prevalence is unkown. It typically manifests between the age of 30 and 50 years. The regions affecteddisease has been previously been mistaken for many other diseases and it might be underdiagnosed currently.

While it is usually an inherited disease there exist case reports of proven de-novo mutations and mutation carriers without clinical symptoms currently up to the age of above 70 years².

Clinical presentation

Patients with ALSP can have a wide variety of symptoms, that usually show a rapid progression and lead to death within a couple years due progressive motor impairment.

Typical symptoms are:

• depression, which might preceed the other symptoms
• neuropsychiatric symptoms, progressing to dementia
• motor impairment, with extra-pyramidal and pyramidal symptoms that usually lead to tetraparesis
• apraxia and rarely ataxia
• epilepsy

Pathology

ALSP is caused by autosomal-dominantly inherited mutations in the colony stimulating factor 1 receptor (CSF1R) gene. The mutations can be proven by a genetic testing of blood samples. Before the identification of the underlying genetic cause of the disease brain biopsy was needed to confirm the disease. Neuropathologic findings usually show gliosis, white matter destruction with pigmented glia and/or axonal spheroids and macrophages.

Radiographic features

MRI

Presymptomatic mutation carriers

Mutation carriers usually show unspecific T2 hyperintens lesions of the white matter that are pronounced for the age of the patient. MR spectroscopy in these lesions is usually normal without characteristic findings.

Symptomatic patients

Characterised by bilateral, asymetric patchy or confluent areas of subcortical and deep white matter signal change, usually most pronounced in the frontal lobe followed by the parietal lobe with a relative sparing of the temporal lobe. The corticospinal tract is usually affected late in the disease course. Progression leads to a severe atrophy of the supratentorial white matter. The cerebellum and anterior corpus callosumbrainstem is usually spared^3,4.

On CT the

• T1: affected areas are low in signal
• T1 C+ (Gd): no enhancement is visible
• T2/FLAIR: hyperintense
• DWI: small spots of diffusion restriction, that can be visible over months have been described as a characteristic finding³
• MR Spectroscopy: (in symptomatic patients)
  • reduced N-acetylasparatate
  • increased choline
  • increased myo-inositol
  • increased lactate

CT

Small periventricular calcifications, often only seen on thin sagittal reconstructions with a bone kernel are a typical imaging finding. Affected areas show a low attenuation.

On MRI the affected areas return low signal on T1-weighted images and high signal on T2-weighted images.

There is no mass effect or contrast enhancement.

Diagnosis

Requires neuropathological confirmation. Lysosomal enzyme studiesTreatment and serum very long chain fatty acid studies are normal. CSF analysis is unremarkable. Normal blood countprognosis

Currently their exists no accepted causal therapy

TreatmentDifferential diagnosis

None.General imaging differential considerations include^2-,6:

Progressive neurological deterioration and death.

• Alzheimer's disease
• Frontotemporal dementia
• Atypical parkinsonism