ALERD - Acute Leukoencephalopathy with Restricted Diffusion

What is ALERD?

ALERD stands for Acute Leukoencephalopathy with Restricted Diffusion. It is a distinct clinico-radiological syndrome - a viral (or toxic)-associated encephalopathy seen predominantly in children, described mainly from the Asian continent. It is characterized by acute onset encephalopathy with restricted diffusion on MRI DWI affecting subcortical white matter (and sometimes grey matter), while routine MRI sequences (T1, T2, FLAIR) may be entirely normal.

Etiology

ALERD is broadly divided into:

Type	Cause
Infectious ALERD	Viral triggers (Influenza A/B, HHV-6, dengue, RSV, adenovirus), bacterial (CA-MRSA reported)
Toxic ALERD	Cranial irradiation, methotrexate, 5-FU, CO poisoning, drugs of abuse, environmental toxins

Clinical Presentation

The classic presentation is biphasic (especially the central-sparing subtype):

Phase 1 (Days 1-2): Fever + prolonged febrile seizure (>30 min) → followed by apparent improvement
Phase 2 (Days 3-6): Cluster of seizures, altered sensorium, encephalopathy - this is when MRI changes appear

Diffuse ALERD may present more severely as monophasic rapid deterioration with coma within 24 hours, with multi-organ involvement (MODS, DIC, shock, hepatic failure, metabolic acidosis).

MRI - The Diagnostic Cornerstone

DWI (Diffusion-Weighted Imaging) is the key sequence - often the only abnormal finding
T1, T2, and FLAIR can be completely normal
Characteristic pattern: symmetric restricted diffusion in periventricular and deep white matter, corpus callosum, posterior limb of internal capsule ("bright tree appearance")
MRI may be normal in the first 2-3 days - if clinical suspicion is high, repeat MRI after Day 4-5
Always request DWI with ADC maps; inform the radiologist of clinical suspicion

Two Subtypes by MRI Pattern:

Feature	Diffuse ALERD	Central-Sparing ALERD (= AESD)
Clinical course	Monophasic, rapid severe deterioration	Biphasic (seizure → improvement → late seizures)
MRI	Widespread bilateral white matter restriction	Restriction with perisylvian/primary sensorimotor cortex sparing
Systemic features	MODS, DIC, shock, elevated liver enzymes, CK	Mild or absent
Prognosis	Worse (5-10% mortality)	No reported deaths

Pathophysiology

ALERD is thought to result from glutamate-induced astrocytic swelling and cytotoxic oedema - not vasogenic oedema or demyelination. This explains why ADC values are reduced (cytotoxic) rather than elevated (vasogenic). No autoantibodies have been identified.

Differential Diagnosis

Condition	Distinguishing Feature
ADEM	T2/FLAIR lesions prominent; vasogenic (high ADC); asymmetric
PRES	Posterior-predominant; vasogenic oedema
Viral encephalitis	CSF pleocytosis; temporal lobe involvement (HSV)
ANE (Acute Necrotizing Encephalopathy)	Bilateral thalamic swelling/necrosis/haemorrhage
MERS	Restricted diffusion limited to corpus callosum splenium
FIRES	MRI initially normal; mesial temporal changes later
Ischaemic stroke	Vascular territory; typically unilateral

Workup

MRI brain with DWI + ADC maps (mandatory)
Serum liver enzymes, CK, blood glucose, metabolic panel
CSF - usually normal or mildly abnormal (no pleocytosis)
Viral PCR panel (blood + nasopharyngeal swab)
Toxicology screen if toxic aetiology suspected

Treatment

Treatment is largely supportive. Based on published case reports and series:

Prompt seizure management (anti-epileptics)
Steroids (methylprednisolone)
IVIG (intravenous immunoglobulin)
Anti-glutamate agents (to address cytotoxic oedema mechanism)
Supportive care for MODS in severe/diffuse cases
Follow-up MRI at 2-4 weeks to assess for cerebral atrophy or gliosis

Prognosis

Diffuse ALERD: 5-10% mortality; >2/3 develop sequelae (post-encephalopathic epilepsy ~1/4, cognitive impairment, hyperactivity, language delay, spasticity, dyskinesias, hemiparesis)
Central-sparing ALERD (AESD): No reported deaths; better outcomes

Key Pearls

Do not miss it on MRI - always include DWI; T1/T2/FLAIR can be normal
Repeat MRI if initial scan is negative but clinical suspicion persists (after Day 4-5)
The condition is increasingly recognized due to wider availability of MRI with DWI
Reporting has risen in recent years - recent cases include associations with dengue fever (PMID: 39737281) and CA-MRSA (PMID: 39730172)

Sources: PMC review on ALERD (PMID: 30111927); Child-Neurology.Org ALERD overview; recent case series (PMID: 34116345, 39737281, 39730172)

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