Alexander disease

Alexander disease (AD) also known as fibrinoid leukodystrophy is a rare fatal leukodystrophy, which usually becomes clinically evident in the infantile period, although neonatal, juvenile and even adult variants are recognised. As with many other diseases with variable age of presentation, the earlier it manifests the more fulminant the clinical course. 

There are 3 clinical forms:

1. infantile / childhood onset
2. juvenile onset 
3. adult onset (AOAD)

Childhood onset AD

Childhood onset Alexander disease is sporadic and typically presents with macrocephaly, rapid neuorological deterioration, seizures and spasticity, and retarded psychomotor development.

In some cases the gene for glial fibrillary acidic protein (GFAP): mapped to chromosome 17q21: has been implicated. Histologically the disease is characterised by the accumulation of large numbers of Rosenthal fibres and eosinophilic granular bodies (large accumulations aglomerations of astrocytic processes) in the degenerated (demyelinated) white matter which is a product of GFAP. This is on its own a non-specific finidng, as they are also seen in slow growing or benign astrocytomas (e.g. pilocytic astrocytomas).

Pathology

Most of the cases are sporadic, however familial disease has also been reported. A heterozygous mutation in the coding region of GFAP, an astrocyte specific intermediate filament protein, are associated with most cases of infantile sporadic onset.

Histologic examination reveals Rosenthal fibres in brain, ependyma and pia. Intracellular deposition of these fibres may cause abnormal functioning of the oligodendrocytes.

Clinical presentation

It generally presents in infants and adolescents. Macrocephaly is typically present and other clinical features include progressive quadreparesis and intellectual failure.

Radiographic features

The disease begins in frontal region and extends posteriorly. Subcortical u-fibresU-fibers are initially spared but affected later in course of disease. End stage disease is characterised by contrast enhancing cystic leukomalacia. 

MRI

• T2 - increased signal in
  • bifrontal white matter which tends to be symmetrical 
  • caudate head > globus pallidus > thalamus > brain stem
  • periventricular rim
• C + (Gd) - enhancement may seen in the same areas
• obstructive hydrocephalus secondary to periaqueductal involvement and swelling of basal ganglia.

Juvenile / adult onset Alexander disease (AOAD)

Adult onset Alexander disease (AOAD) only recognised with any frequency after GFAP was recognised as the mutation has markedly different imaging findings and presentation. It has been described as autosomally inherited in some pedigrees, presenting with prominent bulbar symptoms (dysphagia, dysphonia or dysarthria), sleep distrurbance and impairment of autonomic function.

Radiographic features

MRI

• T2 - increased T2 signal (demyelination)  and atrophy of the
  • medulla and upper cervical cord
  • occasional involvement of inferior cerebellar peduncles
  • pons, middle and superior cerebellar peduncles (rare)
  • supratentorial (typically periventricular) may be seen in patients < 40 years of age
• C+ (Gd) - patchy enhancement uncommonly seen in adult patients