Vanishing white matter disease

Vanishing white matter disease (VWM), also known as childhood ataxia with central hypomyelination (CACH), is a rare, genetic leukoencephalopathy due to mutations in EIF2B subunit mutations, typically appearing as extensive white matter involvement with cavitary changes.

Epidemiology

Most cases are encountered in young patients with onset in early childhood or adolescence being typical ¹. A number of adult patients have, however, been described ⁴.

Presentation is preceded by minor head trauma or infection resulting in episodic deterioration followed by incomplete and slow recovery ¹. With repeated episodes, patients accumulate neurological impairment eventually succumbing to the disease ¹.

Clinical presentation

Currently, the diagnosis is made on the basis of clinical and MRI appearances, as no established diagnostic laboratory tests exist ¹. 

Diagnostic criteria have been proposed ³:

1. psychomotor development is normal or near normal initially
2. onset of neurologic deterioration is episodic with chronic progressive course, and occurs in childhood
3. neurologic signs typically include:
   • cerebellar ataxia
   • spasticity
   • optic atrophy (not always)
   • epilepsy (not always)
   • motor functions disproportionately affected
4. imaging (MRI) bilateral and symmetric cerebral hemispheric white matter signal intensity similar to CSF

For the diagnosis to be made, all four criteria should be identified ³.

There is some evidence that vanishing white matter disease is an autosomal recessive condition, and it is believed that the culprit gene resides on chromosome 3q27 ⁴.

Pathology

Vanishing white matter disease is a leukodystrophy characterized by astrocytic dysfunction ⁵.

Microscopic appearance

Histology reveals the following ¹:

• rarefaction of the white matter (more severe in the deeper white matter)
• microcystic change in the periventricular white matter
• spongiform change in the arcuate fibers and the corpus callosum
• neuronal loss is not present

Genetics

Vanishing white matter disease is caused by mutations in any of the genes EIF2B 1 through 5 that encode the 5 subunits of the eukaryotic translation initiation factor 2B (eIF2B) ⁵.

Radiographic features

MRI

MRI is the modality of choice for assessing cases of possible vanishing white matter disease and other white matter diseases.

White matter is diffusely involved with T2-FLAIR hyperintensity, extending from periventricular white matter to the subcortical arcuate fibers. Over time, the white matter vanishes replaced by near-CSF intensity fluid (i.e. it attenuates on FLAIR) ¹.

Cerebellar atrophy is variably present and ranges from severe to mild and typically involves the vermis ³.

MRS is useful. In affected white matter, only lactate and glucose peaks remain. In unaffected grey matter, the trace is near-normal with small glucose and lactate peaks ¹.

Treatment and prognosis

Although the disease is spontaneously remitting, each episode results in accumulation of further injury. No treatment has been identified and death usually occurs within months to years (range: few months to 14 years) ¹.

Differential diagnosis

When a potential case is encountered, it is unusual for the reading radiologist to have had any significant personal experience with the disease, and as such a differential needs to be entertained, including ³:

• leukodystrophies, especially: Alexander's disease
  • deterioration is not episodic
  • patients are usually macrocephalic
  • white matter is affected in a fronto-occipital gradient
  • histology: Rosenthal fibers are present