Introduction to moyamoya disease

Moyamoya disease (MMD) is a rare, progressive cerebrovascular disorder characterised by stenosis (narrowing) or occlusion (blockage) of the terminal portions of the internal carotid arteries and their proximal branches.^1,2 The name "moyamoya" means "puff of smoke" in Japanese, referring to the appearance of tiny collateral vessels that develop at the base of the brain to compensate for the blocked arteries.¹ MMD  has a higher incidence in East Asian countries, especially Japan, Korea, and China.³ It primarily affects children, though it can also occur in adults.¹ The two peak age distributions for the condition are 5–9 years and 45–49 years.² 

The exact cause of MMD  is unknown, but several risk factors have been identified, such as having:² 

• Asian heritage
• Female gender (slightly higher incidence)
• Genetic factors (30-40 times higher risk in those with family history)
• Associated medical conditions like neurofibromatosis type 1, sickle cell disease, and Down’s syndrome

Cognitive impairment in moyamoya disease

Cognitive impairment is a common and significant result of MMD . Studies have shown that a substantial proportion of both children and adults with MMD experience cognitive deficits. In children, the median percentage with impaired cognition is around 30%, while in adults, it's approximately 31%.⁴ These cognitive effects can significantly impact patients' quality of life, daily functioning, and independence.

Types of cognitive deficits

Executive function

Executive function deficits are commonly reported in MMD patients. This includes difficulties with planning, problem-solving, decision-making, and cognitive flexibility.

Memory

Memory impairment is observed in MMD, with a median z-score of -0.39 for memory function in children.⁴ Both short-term and long-term memory can be affected.

Attention and processing speed

Deficits in attention and processing speed are frequently reported. In children, the median z-score for processing speed is -0.43.⁴ These impairments can affect a patient's ability to focus and quickly process information.

Language

Language deficits can occur in MMD, although they may be less prominent than in other cognitive domains. This can include difficulties with verbal fluency and comprehension.

Factors influencing cognitive impairment severity 

Several factors can influence the severity of cognitive impairment in MMD:

• Age of onset: Early age of onset and longer disease duration have been associated with more severe cognitive impairment⁴ 
• The extent of vascular involvement: The degree of stenosis and the number of affected vessels may impact cognitive function
• Presence of stroke or silent infarcts: Overt or silent brain infarcts can contribute to cognitive deficits
• Chronic hypoperfusion: Even in the absence of stroke, chronic hypoperfusion (cerebral blood flow reduction) can lead to cognitive impairment⁴

Mechanisms linking moyamoya to cognitive impairment

Ischemic events and brain damage

Strokes and transient ischemic attacks (TIAs) in MMD can cause direct damage to brain tissue, leading to cognitive deficits. Both overt and silent infarcts contribute to cognitive impairment.

Chronic hypoperfusion

The progressive narrowing of cerebral arteries in MMD leads to chronic hypoperfusion, which can affect cognitive function even in the absence of stroke. This reduced blood flow can impair neuronal function and contribute to cognitive decline over time.⁴ 

Microstructural brain changes

MMD can cause subtle changes in brain structure, including white matter abnormalities and alterations in grey matter volume. These microstructural changes may contribute to cognitive impairment, even in patients without visible lesions on conventional imaging.⁴

Symptoms and signs

Cognitive symptoms in MMD can include:⁵ 

• Difficulty with concentration and attention
• Memory problems
• Slowed thinking and processing speed
• Challenges with problem-solving and planning
• Language difficulties, such as word-finding problems

Impact on academic and occupational performance:

Cognitive impairment in MMD can significantly affect patients' academic and occupational functioning. In children, it may lead to learning difficulties and poor school performance. In adults, it can impact job performance and lead to difficulties maintaining employment or advancing in their careers.⁵ 

The cognitive effects of MMD can be subtle and may not always be apparent in routine clinical examinations. Therefore, comprehensive neuropsychological testing is often necessary to fully assess the extent of cognitive impairment in MMD patients.

Mechanisms of cognitive impairment in moyamoya 

Chronic cerebral hypoperfusion

Chronic hypoperfusion is a primary mechanism leading to cognitive impairment in MMD. The progressive narrowing of cerebral arteries results in reduced blood flow to the brain, which can impair neuronal function even in the absence of overt stroke.⁶ This chronic reduction in blood supply can affect various cognitive areas over time.⁴ 

Silent infarcts and microbleeds

MMD can cause both overt and silent infarcts, as well as microbleeds, which contribute to cognitive deficits.⁴ These small areas of brain damage, even when not clinically apparent, can accumulate over time and impact cognitive function. Silent infarcts may occur in areas critical for cognition without causing obvious neurological symptoms.

White matter changes

MMD can lead to microstructural brain changes, including white matter abnormalities.⁵ These changes in white matter integrity can disrupt the connectivity between different brain regions, which would affect cognitive processes such as executive function, processing speed, and memory.

Neurovascular uncoupling

Neurovascular uncoupling (the relationship between local neural activity and changes to cerebral blood flow) is likely a contributing factor to cognitive impairment in MMD. The disease affects the normal relationship between neuronal activity and blood flow, potentially leading to a mismatch between metabolic demands and blood supply in active brain regions.^7,8 

Assessment of cognitive function in moyamoya patients

Neuropsychological testing

An essential part of evaluating cognitive function in individuals with MMD  is neuropsychological testing. These assessments assess different cognitive domains:⁹

• Intelligence Quotient (IQ): Used to assess overall cognitive ability
• Memory: Including prospective memory (PM), immediate memory (IM) and retrospective memory (RM)
• Executive function: Including Wisconsin Card Sorting Test and stroop test
• Attention: Such as the Continuous Performance Test (CPT)
• Processing speed:Including Trail-Making Test Part A (TMT-A), verbal fluency (VF) and visual perception

Neuroimaging techniques

Structural MRI

Structural MRI is used to assess brain anatomy and detect any structural changes associated with MMD. It can identify silent infarcts, microbleeds, and white matter changes that may contribute to cognitive impairment.¹⁰ 

Functional MRI (fMRI)

fMRI is employed to evaluate brain activity patterns and neurovascular coupling in MMD patients. It can help identify areas of impaired brain function and assess the impact of chronic hypoperfusion on cognitive processes.⁹ 

PET and SPECT

Positron Emission Tomography (PET) and Single-Photon Emission Computed Tomography (SPECT) are valuable tools for assessing cerebral blood flow and metabolism in MMD patients. These techniques can provide insights into the relationship between hypoperfusion and cognitive impairment.¹⁰ 

Treatment approaches for cognitive impairment in moyamoya

Surgical interventions

Revascularization surgery

This is considered the primary treatment approach for MMD  and may help improve cognitive function.⁴ The main types include:¹¹

• Direct revascularisation: Usually involves anastomosis between the superficial temporal artery and a cortical branch of the middle cerebral artery 
• Indirect revascularisation: Various techniques using different connective tissues to promote angiogenesis 
• Combined direct and indirect techniques: This approach has shown benefits, though its specific impact on cognitive parameters needs further study 

Mixed outcomes after revascularization

A study on adult MMD patients with ischemic presentation showed varied cognitive changes after direct revascularisation surgery:¹²

• 31% of patients showed cognitive improvement
• 44% of patients showed cognitive decline
• These changes were observed 2 months after surgery

The goal of these surgical interventions is to augment intracranial blood flow using the external carotid system, which can improve resting cerebral blood flow and vascular reserve capacity.

Multiple burr hole surgery 

Multiple burr hole surgery is mentioned as an alternative to revascularisation surgery or rescue surgery option.¹¹ 

Medical management

Pharmacotherapy 

Acetylcholinesterase inhibitors have been suggested for treating cognitive symptoms in moyamoya  patients.⁵ Specifically mentioned are:

• Donepezil 
• Galantamine
• Rivastigmine

Summary 

Moyamoya disease (MMD) is a rare cerebrovascular disorder characterised by progressive stenosis of intracranial arteries, primarily affecting East Asian populations. It can lead to significant cognitive impairment in both children and adults, impacting executive function, memory, attention, processing speed, and language.

The mechanisms underlying cognitive impairment in MMD include chronic cerebral hypoperfusion, silent infarcts, microbleeds, white matter changes, and neurovascular uncoupling. These factors can affect brain function even without overt stroke.

Assessment of cognitive function in MMD patients involves neuropsychological testing and advanced neuroimaging techniques such as MRI, fMRI, PET, and SPECT. These methods help identify specific cognitive deficits and understand the relationship between cerebrovascular abnormalities and cognitive impairment.Treatment approaches primarily focus on surgical interventions, particularly revascularisation procedures, to improve cerebral blood flow. Medical management with acetylcholinesterase inhibitors has also been suggested. However, outcomes can be variable, with some patients showing improvement and others experiencing decline post-treatment. Factors influencing cognitive impairment severity include age of onset, extent of vascular involvement, presence of stroke or silent infarcts, and chronic hypoperfusion. The cognitive effects of MMD can significantly impact patients' quality of life, academic performance, and occupational functioning.