History
In 1965, Suzuki, Kowada, Asahi, and Takaku [1] came across the angiograms of many patients with strange blood artery cluster near the base of the brain which resembled a net and termed it as Moya-Moya Disease, a Japanese description for “puff of cigarette smoke”. Moya-Moya disease is considered to be a recurrent cerebral vascular illness marked by increasing stenosis of the Willis circle and the internal carotid artery. The majority of cases reported with Moya-Moya disease have an unknown origin [2], recent advances in neuroimaging and genetics have given a clearer understanding. It is believed to result from either idiopathic, environmental, genetic, or an interaction of these factors. RNF213 gene, namely Arg4810Lys variant, has been associated in genetic investigations as the likely implicated gene. The disease manifests as ischemic stroke or transient ischemic attack in juvenile patients. The first signs of Moya-Moya disease in younger people are typically brief episodes of hemiparesis. [2]. In children, convulsions, migraines, and intellectual disabilities are rather common [2]. Additionally, epilepsy may be present (Solomon et al., 1970). Adults frequently report experiencing headaches and losing consciousness.
Incidence and Prevalence
Asians are considered to have more chances of acquiring the disease that Americans. This is evident from the nationwide epidemiological studies done in Japan, which showed that there was a nearly twofold increase in the overall number of individuals diagnosed with moya-moya disease, from 3,900 to 7700. Studies from other Asian countries like South Korea demonstrated the existence of 8,154 patients with moya-moya disease in 2011 by a population-based nationwide survey. The incidence also rose from 1.7 to 2.3 cases per 100,000 people during a time period of 2007 to 2011 [3]. A study in 2009 [4] reported that the Japanese population has the highest frequency, impacting three people per 100,000 people, whereas Americans have the lowest incidence, 0.086 per 100,000 people. These findings are supported by the evidences from genetics testing which revealed that Asians are more likely than Whites to have the disease as White people have a less common "non-Arg4810Lys" form of the gene [5].
Age Distribution
There appears to be no age limit to the disease [2]. However, there are enough studies that suggest the presence of a peak age of occurrence in different topological regions. Shang et al in 2020 reported that moya-moya disease shows a “bimodal age distribution” with the first peak at 6–15 years and second peak at 31–40 years of age. This was in support of the study done in Japan [6] revealing that the two peak age groups observed are between 10-19 years and 40-49 years and Miao et al in 2010 in china with peaks around 5-9 years in paediatric group and 40-44 in adults.
Sex factors
Early investigations revealed that young Japanese females are more susceptible to acquire Moya-Moya disease [2] However, the epidemiological surveys conducted in other parts of world exhibited different values. Studies on Chinese individuals [7]. reported a female to male ratio of 1:1 and 1.5:1 respectively. In contrast, there was a high incidence in European individuals which accounted for a female to male ratio of 4.25:1. These studies suggest that occurrence of Moya-Moya disease can be highly influenced by race and region.
Pathophysiology of Moya-Moya disease
Although Moya Moya disease is considered to occur as a primary pathology, certain other diseases or conditions make the individual susceptible to developing MMD, such as sickle cell disease, Neurofibromatosis-1, Down’s syndrome and exposure to cerebral radiotherapy.
A cluster of pathological manifestations in Moya Moya diseases starts with arterial stenosis. The stenosis or occlusion of arteries such as internal carotid artery (ICA), middle cerebral artery (MCA), and anterior cerebral artery (ACA) is considered for the diagnosis [8]. It is classified into six stages, known as Suzuki staging, of which the first stage is isolated stenosis, which manifests early and is characterised by the absence of collateral channel creation and the sixth stage with a complete occlusion of proximal ACA and MCA. The abnormal occlusion results in reduced blood flow in the major vessels, thus paving the way for alternate small vessel connections to maintain the circulation termed collateral circulation.
The majority of Moya Moya disease patients show a vessel malformation or stenosis in the bilateral anterior circulation pathways of the brain, majorly affecting the supra clinoid internal carotid artery (ICA) and its branches [9]. Despite this, there have been cases of posterior cerebral circulation involvement in 1/3 of the paediatric and adult patients diagnosed with the disease. Zhao et al. (2017) [10] conducted a study in 574 patients, including both paediatric and adult participants, to understand the posterior circulation involvement in them. He concluded that children are more vulnerable to having posterior cerebral artery lesions compared to adults. Occlusion in the posterior region is considered an unpropitious prognostic factor. However, until the late stages, the ischemic events are uncommon in the posterior circulation area. The rare occurrence of posterior lesions suggests an embryological predisposition for the arterial vessels to develop Moya moya disease.
Paediatric Symptomatology
Headache or fatigue is exhibited as the primary symptom, which may be misdiagnosed as suffering from hypochondriasis or developmental deficits. Alternatively, they may be unfairly dismissed as exhibiting laziness (Fox et al., 2021). The symptoms shown by children can be grouped into two: those caused by cerebral ischemia, such as stroke, transient ischemic attacks and seizures and those occurring due to the compensatory mechanism undertaken due to the occlusion of blood flow, such as headache and haemorrhage. However, the degree of arterial involvement, area of ischemic lesions, stenosis progression and the response to the decreased blood flow decide the manifestation of the symptoms in the affected individuals [11] The primary indications of MMD encompass cognitive impairment, aphasia, dysarthria, and hemiparesis. Further symptoms comprise syncope, visual impairments, seizures, and alterations in personality. Typical childhood behaviours, such as crying accompanied by hyperventilation, could potentially trigger a stroke or transient ischemic attack (TIA). Intracranial haemorrhage, a common occurrence among adult patients with Moyamoya disease (MMD), is likewise prevalent in paediatric MMD cases. Such haemorrhages typically manifest within the subarachnoid space, ventricular system, and brain parenchyma, often affecting the basal ganglia region. Historically, intracranial haemorrhage has been attributed to the rupture of delicate collateral vessels associated with Moyamoya disease, arising from the progressive stenosis of the internal carotid artery (ICA). Another possible cause of haemorrhage in these patients might be the fluctuating blood flow patterns at the base of the brain, which have been linked to the formation of intracranial aneurysms. These aneurysms are generally found at the apex of the basilar artery or in the posterior cerebral artery (PCA), which are frequent locations of elevated shear stress in Moyamoya disease (MMD). Enlarged moyamoya-related collateral vessels in the basal ganglia may be linked to the onset of choreiform movements in paediatric patients with moyamoya disease (MMD)
Cognitive Characters
Cognitive impairments in moyamoya disease constitute a substantial component of the overall clinical presentation, markedly diminishing the quality of life for affected individuals. The gradual deterioration of cerebral blood supply can lead to cognitive, emotional, and behavioural impairments, frequently accompanied by severe neurological deficits in affected individuals.
It is postulated that mild cognitive impairment, resulting from cerebral hypoperfusion, would correlate with decreased regional cerebral blood flow (rCBF) in certain regions of brain, however, their results indicated that the average intellectual capacity was not reduced in pediatric MMD patients. Furthermore, they discovered no link between poor cognitive performance and the angiographic severity of the disease, ischemic symptoms, family history, or the patient's age at disease onset.
A study [12], was carried out to understand the neurocognitive dysfunction in adult patients diagnosed with MMD. The cognitive domains examined were memory, attention, processing speed, verbal memory, visuospatial, language, and executive functions. Along with cognitive functions, manual strength and dexterity, as well as depressive symptoms, were also assessed. A significant proportion of patients exhibited marked cognitive dysfunction in tests of processing speed (29%), verbal memory (31%), verbal fluency (26%), and executive function (25%). Additionally, many patients showed impairment in manual strength and dexterity, with deficits observed in 36–58% of cases.
According to an imaging study conducted by Haas et al in 2022, there is a correlation between the degree of cognitive impairment and the degree of hypoperfusion. Chronic hypoperfusion causes ischemic changes and alterations in brain chemistry, both of which affect cognition. Nonetheless, regardless of their history of stroke, MMD patients' cognitive ability stays comparatively steady over the long run following the initial phase of cognitive deterioration.
Speech Characters
The scarce literature documenting the speech and language skills of paediatric individuals affected with MMD suggests that more research is required to establish the general speech and language characteristics of MMD. A study conducted on the impact of MMD on written and oral language performance suggested that those affected with MMD can have issues with working memory, phonological awareness skills and difficulty in accessing the mental lexicon. If the lesion occurs particularly in the frontal lobe, it can result in attention, memory and planning deficits. A lesion in the temporal lobe would compromise auditory comprehension and perception and higher-order visual processing. Damage to the left parietal lobe can lead to difficulties in writing and thinking mathematically (dysgraphia and dyscalculia), confusion about the left and right, and abnormal perception of objects (dysgnosia). Damage to the right parietal lobe can lead to impairments that impair independence in activities of daily living (ADL) and interfere with the person's ability to care for their body, including bathing and clothing. The integration of visual attention and motor efficiency is disrupted by bilateral lesions, leading to symptoms associated with dyspraxia, impairments in formal drawing and writing tasks, difficulties constructing angles, and difficulties integrating lines. There can be conditions of acquired childhood aphasia in the pediatric population. [10,11]. Dysarthria and aphasia occurring as a consequence of MMD can have a major impact on the quality of life of the child. Dysarthria can lead to weakness in oral structures leading to articulation errors during speech production, drooling and swallowing difficulties. On the other hand, aphasia can hinder the learning ability of the child due to reduced expression or comprehension abilities. The motor weakness or hemiparesis, a consequence of stroke in MMD, can affect the writing skills of the child as well as carrying out limb movements for daily activities.
Conclusions
The current study was undertaken with the aim of introducing the vivid deficits associated with Moya-Moya disease. Moya-Moya disease is considered to be a syndrome as there is a multitude of problems associated with this condition. The condition results in progressive stenosis or narrowing of blood vessels leading to stroke. This condition is the leading cause of childhood aphasia or aphasia in children. Children who are as young of 5-6 years can be affected with this condition and children of both genders are susceptible to Moya-Moya disease. The symptom manifestation is dependent on the region of interest or the arteries occluded as a consequence of Moya-Moya disease. Cognitive deficits and Speech language deficits are common in this condition. The current study documents the holistic details about Moya-Moya disease
