OVERVIEW

What is hereditary multi-infarct dementia?

Hereditary multi-infarct dementia, also known as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

This disease is a hereditary cerebrovascular disorder that manifests in adulthood, with patients primarily experiencing recurrent strokes and chronic progressive cognitive decline. It is a genetic condition with limited treatment options, mostly focusing on symptomatic support.

Is hereditary multi-infarct dementia common?

This disease is considered rare and often shows familial clustering. Rough data indicate a carrier rate of the pathogenic gene mutation at 0.8 to 5 per 100,000 people.

SYMPTOMS

What are the manifestations of hereditary multi-infarct dementia?

• Hereditary multi-infarct dementia has a clear familial genetic tendency. Typical patients often experience migraines with aura in their 20s–30s, recurrent transient ischemic attacks or ischemic strokes in their 40s–50s, dementia in their 50s–60s, and death around age 65.

• About 30% of patients with hereditary multi-infarct dementia may experience migraines with aura in their 20s–30s, characterized by recurrent unilateral or bilateral throbbing headaches, often preceded by aura symptoms such as visual disturbances (e.g., visual distortions, flashes, or streaks). The pain typically lasts 4–72 hours before gradually subsiding.

• The most common clinical manifestation is recurrent transient ischemic attacks or cerebral infarctions, usually beginning in middle age. Infarctions primarily occur in subcortical regions, with small "lacunar" lesions. Clinical presentations include various lacunar syndromes, such as pure motor hemiparesis, ataxic hemiparesis, dysarthria-clumsy hand syndrome, pure sensory stroke, or sensorimotor stroke. In severe cases, it may lead to significant disability, manifesting as gait disturbances, urinary incontinence, and pseudobulbar palsy.

• Repeated strokes and chronic cerebral ischemia can lead to cognitive impairment.

  • Cognitive dysfunction in this disease primarily involves frontal lobe functions, presenting as apathy, decreased attention, slowed movements, and delayed reactions, along with short-term memory decline (e.g., forgetting recent events or failing to recognize familiar people) and visuospatial impairments (e.g., disorientation or difficulty recognizing familiar places).
  • Cognitive decline occurs in a stepwise manner, with each stroke potentially causing a significant deterioration, eventually progressing to subcortical vascular dementia.

• Additionally, about 20% of patients may exhibit psychiatric abnormalities, such as severe depression, mania, or even suicidal tendencies. In rare cases, behavioral and personality disorders, delusions, hallucinations, or schizophrenia may occur. Only 1.2%–8.9% of patients present with psychiatric symptoms as the initial manifestation.

• Some patients may also develop epilepsy, spinal cord injury, sensorineural hearing loss, cerebral hemorrhage, acute encephalitis-like coma, or coronary heart disease.

What severe consequences can hereditary multi-infarct dementia cause?

Hereditary multi-infarct dementia can lead to various neurological deficits due to recurrent cerebral infarctions, potentially resulting in severe difficulties with eating or complete paralysis. Additionally, severe dementia may gradually cause loss of independent living ability and a mute state.

What conditions should hereditary multi-infarct dementia be differentiated from?

Hereditary multi-infarct dementia should be distinguished from subcortical arteriosclerotic leukoencephalopathy, cerebral amyloid angiopathy, multiple sclerosis, and other hereditary vascular dementias (e.g., coagulopathies, dyslipidemia, Fabry disease, CARASIL, homocystinuria, and mitochondrial encephalomyopathy).

CAUSES

What is the cause of hereditary multi-infarct dementia?

Current research suggests that hereditary multi-infarct dementia is associated with mutations in exon 4 of the autosomal Notch3 gene, and this disease follows an autosomal dominant inheritance pattern.

The Notch3 gene encodes a transmembrane protein with both receptor and signaling functions, primarily expressed in vascular smooth muscle cells and pericytes. Gene mutations lead to abnormal protein structure, causing degeneration of vascular smooth muscle cells. This results in impaired local cerebrovascular regulation, leading to lacunar infarcts and chronic ischemic changes. The former may manifest as recurrent stroke episodes, while the latter gradually affects cognitive function, ultimately causing dementia.

DIAGNOSIS

How is hereditary multi-infarct dementia diagnosed?

When middle-aged patients present with recurrent cerebral infarctions, cognitive decline, and a family history, especially with a previous history of migraines, this condition should be considered. Further diagnostic workup includes brain MRI, skin biopsy, and genetic testing to confirm the diagnosis. It should be noted that not every patient has a family history.

What tests are required for patients with hereditary multi-infarct dementia, and why are these tests necessary?

• Brain MRI: MRI can detect multiple subcortical lacunar infarcts and may also reveal white matter demyelination.

• Skin biopsy: Skin biopsy may identify GOM deposits or Notch3 protein accumulation in peripheral small arteries, which is a sensitive diagnostic method for this condition.

• Genetic testing: Genetic testing is the gold standard for diagnosing this disease.

TREATMENT

Which department should I visit for hereditary multi-infarct dementia?

Neurology.

Can hereditary multi-infarct dementia heal on its own?

No.

Does hereditary multi-infarct dementia require hospitalization?

Hospitalization is necessary for diagnosis and during stroke episodes.

How is hereditary multi-infarct dementia treated?

As a genetic disorder, hereditary multi-infarct dementia currently has no cure. Treatment focuses on managing vascular risk factors, anti-dementia therapy, and symptomatic relief.

• Although evidence is limited, antiplatelet drugs like aspirin or clopidogrel are recommended to prevent cerebral infarction.

• Strict control of cerebrovascular risk factors such as hypertension, diabetes, and hyperlipidemia is essential.

• For cognitive impairment, limited evidence suggests donepezil may improve executive function in dementia.

• Rehabilitation therapy is beneficial for patients with neurological deficits to aid functional recovery.

• For those with migraines or mood instability, migraine prophylaxis or antidepressants may be considered.

• Asymptomatic family members of diagnosed patients without clear family history should undergo brain imaging and genetic testing.

DIET & LIFESTYLE

What should patients with hereditary multi-infarct dementia pay attention to in their diet?

Patients should follow a low-salt and low-fat diet, ensure adequate water intake to reduce blood viscosity, and appropriately increase the consumption of fruits, vegetables, and low-fat dairy products. Quit smoking, limit alcohol, and control body weight.

What should patients with hereditary multi-infarct dementia pay attention to in daily life?

Due to recurrent strokes, patients may experience limb paralysis and should engage in appropriate rehabilitation training while avoiding accidents such as falls. They may also experience choking or difficulty swallowing, so eating and drinking should be done carefully to prevent aspiration pneumonia. Nasogastric feeding may be necessary in some cases.

For bedridden patients, enhanced nursing care is required to prevent complications like pressure sores and deep vein thrombosis. In later stages, severe cognitive impairment may occur, requiring family members to provide close supervision to prevent wandering accidents. Patients should be encouraged to stay active and maintain social functions.

Does hereditary multi-infarct dementia require follow-up examinations? How?

Yes, outpatient follow-ups and repeat head MRI scans are necessary.

PREVENTION

Can hereditary multi-infarct dementia be prevented?

This disease is a genetic disorder. For families with similar cases, prenatal screening and diagnosis can be performed during pregnancy to help achieve eugenics and better birth outcomes.