Leukoencephalopathy (white matter disease)

Damage to white matter may occur due to may conditions that can affect the brain. The clinical features, prognosis and treatment are related to the underlying condition

Clinical features:

There is a wide range of symptoms:

  • Rapidly progressive dementia/subacute encephalopathy, lower body parkinsonism/gait apraxia, behavioural changes, pseudobulbar speech and pseudobulbar affect may occur
  • Later on the patient is: akinetic mute, spastic quadraparesis
  • Earlier on focal signs may occur and give clues to the diagnosis e.g. peripheral neuropathy, occular movement abnormalities, seizures, myoclonus
  • Systemic features may give clues to the diagnosis: skin changes, systemic disease, e.g. significant hypertension, liver disease in Zellwegar disease,

Findings on Investigations:


  • Diffuse white matter involvement with or without grey matter involvement
  • May be symmetric, asymmetric, enhancing, nonenhancing, associated with hemorrhage or not, associated with DWI restriction or not,
  • May be anterior predominant, posterior predominant, involve or spare the U-fibers
  • May also involve the grey matter
  • In late stages atrophy occurs with gliosis
  • Helps guide DDx & further tests


Fazekas grade I, Mild: few small punctate lesions in the white matter.
Fazekas grade II, Moderate: larger white matter lesions that are beginning to become confluent.
Fazekas grade III, Severe: confluent T2 hyper intensity.

Investigations to consider: consider as appropriate

MRI: guides further tests
MRA, CTA, Catheter angiography: as necessary if vasculopathy/vasculitis/cerebral vasoconstriction syndrome is considered
Lumbar puncture for CSF analysis:

  • Cell count, protein, glucose, IgG index, oligoclonal bands, myelin basic protein
  • Microscopy and Cultures
  • Broad tests for infections and inflammation, including viral encephalitis and other encephalitis
  • Features of inflammatory disease (autoimmune encephalitis, multiple sclerosis, ADEM, infectious disease) vs. non-inflammatory profile

Urine toxicology: cocaine, heroin
Serum toxicology
Carboxyhemoglobin: high in CO poisoning
Testing for infections:

  • VDRL, syphilis testing, Lyme disease testing,
  • HSV testing, West Nile virus testing (grey matter involvement initially), CMV testing, HIV testing, see viral encephalitis,
  • Cryptococcus testing, coccidiodes testing

Vasculitis screen:

  • ESR, CRP, ANA screen, ENA panel (anti- dsDNA, anti-Sm, anti-RNP, SSA, SSB, anti-Jo-1, antitopoisomerase ‘formerly anti Scl-70’, antinucleolar, anticentromere), ANCA (c-ANCA, p-ANCA), Complement C3, C4 and CH50

Testing for autoimmune or paraneoplastic encephalitis/encephalopathy:

  • anti: Hu (ANNA-1), Yo/PCA1, Ri, MaTa, CV2/CRMP5, amphiphysin, LGI1, CASPR2, VGKC, NMDA (NR1) and GAD65
  • Anti-TPO antibodies

Testing for CADASIL, NOTCH3 mutation

  • May provide clues e.g. GPEDs in SSPE,

Tests for mitochondrial disease:

  • Muscle biopsy with biochemical and respiratory chain analysis and electron microscopy
  • Specific testing for individual mitochondrial disease e.g. MELAS, POLG mutation, etc

Selected testing for leukodystrophies:

  • X-linked adrenoleukodystrophy, Metachromatic leukodystrophy, Globoid-cell leukodystrophy (Krabbe’s disease)

Selected testing for perioxisomal disorders:

  • Zellweger disease,

Catheter angiography: if vasculitis is suspected
Brain biopsy

Causes of leukoencephalopathy (diffuse white matter disease):






Toxic and drug induced:




  • Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA. MR signal abnormalities at 1.5 T in Alzheimer’s dementia and normal aging. AJR Am J Roentgenol. 1987 Aug;149(2):351-6.

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