on 02-Aug-2021 (Mon)

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Moyamoya disease is a unique cerebrovascular entity characterized by progressive large intracranial artery narrowing and the development of prominent small vessel collaterals. The latter produces a characteristic smoky appearance on angiography, hence the name "moyamoya," a Japanese word meaning puffy, obscure, or hazy, like a puff of smoke in the air [1,2].

Moyamoya disease was first described in Japan in 1957. Many similar cases have subsequently been reported, mainly in Japan and other Asian countries. The disease is found less frequently in North America and Europe.

The term "moyamoya" describes the specific angiographic findings of unilateral or bilateral stenosis or occlusion of the arteries around the circle of Willis with prominent arterial collateral circulation (image 1).

● Moyamoya disease (MMD) refers to patients with moyamoya angiographic findings who may have genetic susceptibilities but no associated conditions. This may also be called primary or idiopathic moyamoya disease as well as the descriptive "spontaneous occlusion of the circle of Willis" [3,4].

● Moyamoya syndrome (MMS) refers to patients with moyamoya angiographic findings who also have an associated medical condition as described below.

Although the mode of inheritance is not established, one study suggested that familial moyamoya is an autosomal dominant disease with incomplete penetrance [20].

A later genome-wide association study confirmed the relationship of MMD and a previously reported locus on chromosome 17q25 [21]. The study also identified 10 novel risk loci, including the genes regulating homocysteine metabolism, loci related to large vessel disease, and loci that are highly expressed in the immune system.

● Disease affecting arteries around the circle of Willis

• Atherosclerosis [22]

• Radiation therapy to the base of the brain [23] (see "Delayed complications of cranial irradiation", section on 'Cerebrovascular effects')

• Cranial trauma [24]

• Brain tumors [25-27]

• Meningitis [28]

• Other viral or bacterial infection (eg, Cutibacterium acnes, leptospirosis, HIV) [29-31]

● Hematologic conditions

• Sickle cell disease [32-34]

• Beta thalassemia [35]

• Fanconi anemia [36]

• Hereditary spherocytosis [37]

• Homocystinuria and hyperhomocysteinemia [38]

• Factor XII deficiency [39]

• Essential thrombocythemia [40]

• Protein S deficiency [41-43]

• Pyruvate kinase deficiency [44]

● Vasculitis and autoimmune and multisystem diseases

• Systemic lupus erythematosus [45]

• Polyarteritis nodosa and postinfectious vasculopathy [46]

• Graves disease and thyroiditis [47-50]

• Sneddon syndrome and the antiphospholipid antibody syndrome [51,52]

• Anti-Ro and anti-La antibodies [53]

• Type 1 diabetes mellitus [50]

• Pulmonary sarcoidosis [54,55]

● Genetic and developmental disorders

• Alagille syndrome [56,57]

• Down syndrome [58,59]

• Hypomelanosis of Ito [60]

• Marfan syndrome [61]

• Microcephalic osteodysplastic primordial dwarfism type 2 [62]

• Multisystem disorder with short stature, hypergonadotropic hypogonadism, and dysmorphism [63,64]

• Neurofibromatosis type 1 [65-67]

• Noonan syndrome [68-70]

• Phakomatosis pigmentovascularis type IIIb [71]

• Prader-Willi syndrome [72]

• Pseudoxanthoma elasticum [73]

• Sturge-Weber syndrome [74]

• Tuberous sclerosis [75]

• Turner syndrome [76]

• Williams syndrome [77]

• Morning glory optic disc anomaly (image 2), usually in conjunction with other craniofacial abnormalities [

...

● Other vasculopathies and extracranial cardiovascular diseases

• Coarctation of the aorta [81]

• Congenital heart disease [82]

• Fibromuscular dysplasia [83]

• Renal artery stenosis [84]

● Metabolic diseases

• Type I glycogenosis [85,86]

• Hyperphosphatasia [87]

• Primary oxalosis [88]

● Renal disorders

• Polycystic kidney disease [89-91]

• Wilms tumor [84,92-104]

Vascular changes in moyamoya are associated with evidence of increased angiogenesis-related factors, including endothelial colony-forming cells, various cytokines, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) [105-107].

Multiple areas of cerebral infarction and focal cortical atrophy are commonly found. Although large vessel stenosis and occlusion are the hallmark of this disease, extensive territorial infarction is uncommon. The brain infarcts are generally small and located in the basal ganglia, internal capsule, thalamus, and subcortical regions [113]

However, the cause of death in most autopsy cases is intracerebral hemorrhage [ 94]. The hemorrhage is commonly found in the basal ganglia, thalamus, hypothalamus, midbrain, and/or periventricular region. Bleeding into the intraventricular space is frequently observed.

Pathologic vascular lesions appear in the large vessels of the circle of Willis and in the small collateral vessels [95]. The terminal portions of the internal carotid arteries as well as the proximal middle and anterior cerebral arteries are most commonly involved [114]. Some patients may have unilateral stenosis at presentation, although progression to bilateral involvement may occur [115,116]. Less frequently, the posterior circulation is affected, especially the posterior cerebral artery.

One of the hallmarks of moyamoya is the presence of a collateral meshwork of overgrown and dilated small arteries, the moyamoya vessels, that branch from the circle of Willis (image 3).

Leptomeningeal vessels are another source of collaterals in moyamoya. As a result of intracranial internal carotid artery stenosis, leptomeningeal anastomoses may develop from the three main cerebral arteries (middle, anterior, and posterior). These collaterals result from dilatation of preexisting arteries and veins. In addition, transdural anastomoses, termed vault moyamoya, may develop from extracranial arteries such as the middle meningeal and superficial temporal arteries [96].

In patients with moyamoya disease, stenosis due to fibrocellular intimal thickening may also affect the extracranial and systemic arteries, including the cervical carotid, renal, pulmonary, and coronary vessels [92,103].

Involvement of the renal arteries has been most frequently reported. In one study of 86 patients with moyamoya disease, six had renal artery stenosis, two had associated renovascular hypertension, and one had a renal artery aneurysm [84]. Similarly, in a later study of 73 consecutive patients with moyamoya disease, four had renal artery stenosis [121].

There is a female predominance, with a female-to-male ratio of 1.9.

● A family history of MMD is present in 10 to 12 percent of patients.

● The prevalence of moyamoya is 3.2 to 10.5 per 100,000 population.

Data from a nationwide registry in Japan, with 2545 cases of MMD, showed a bimodal distribution in the age of onset, with one peak at approximately 10 years of age and a second broader peak at approximately 40 years of age [127]

The most common initial presentation of moyamoya is ischemic stroke [134-138]. Transient ischemic attack (TIA) is also a frequent initial presentation and may be recurrent [134,138].

In one retrospective series from the United States, 61 percent of 31 adults with moyamoya disease (MMD) or moyamoya syndrome (MMS) presented with ischemic symptoms; in those with stroke, the predominant pattern was a border zone pattern of infarction [137].

Patients with moyamoya present infrequently with seizures, often secondary to ischemic damage [145]. The rate of epilepsy may be more frequent in children than in adults [142].

Headache is common in patients with moyamoya [146]. In one cohort of patients, migraine symptoms were more common than tension-type headache symptoms [147].

There are case reports of patients with moyamoya who develop dystonia, chorea, or dyskinesia, but these appear to be uncommon manifestations [148-150].

Patterns of infarction may be suggestive of moyamoya, but these features are not specific for this condition. In a retrospective series of 32 adults with first-ever ischemic stroke, patients with early-stage MMD had ischemic lesions involving only deep subcortical structures, while those with advanced stage had predominantly cortical lesions [155].

Dilated collateral vessels in the basal ganglia or thalamus can be demonstrated as multiple punctate flow voids, a finding that is considered virtually diagnostic of moyamoya (image 6) [161].

The "ivy sign" refers to focal, tubular, or serpentine hyperintensities on fluid-attenuated inversion recovery (FLAIR) or contrast-enhanced T1 images in the subarachnoid spaces that represent slow, retrograde collateral flow through engorged pial vessels via leptomeningeal anastomoses (image 7) [162-164].

The "brush sign" refers to prominent hypointensity in medullary veins draining areas of impaired cerebral perfusion on susceptibility-weighted imaging (SWI), a high spatial resolution 3D-gradient echo MRI technique that accentuates paramagnetic properties of blood products such as deoxyhemoglobin

Like the ivy sign, the "brush sign" is not specific for moyamoya and has been identified in patients with subacute stroke from many causes [168].

The diagnosis of moyamoya disease (MMD) is made by identifying the characteristic angiographic appearance of bilateral stenoses affecting the distal internal carotid arteries and proximal circle of Willis vessels, along with the presence of prominent collateral vessels (image 5). Moyamoya syndrome (MMS) is diagnosed by identifying these characteristic angiographic features in the setting of an associated condition.

The possibility of MMD disease should be considered in:

● Children or young adults with repeated symptoms of ischemic attacks resulting from low perfusion in the same arterial territory.

● Patients who lack common factors for primary intracerebral hemorrhage (ICH) but present with intracerebral hemorrhage in brain regions supplied by small vessels that branch from the circle of Willis (eg, caudate, thalamus, or intraventricular hemorrhage within the lateral ventricles).

● Children or young adults with ischemic or hemorrhagic stroke who may lack common cerebrovascular risk factors. (See "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis", section on 'Differential diagnosis'.)

● Patients who undergo magnetic resonance imaging (MRI), particularly in the context of evaluation for cerebral ischemia, which shows associated findings such as dilated collateral vessels in the basal ganglia or thalamus, the "ivy sign," the "brush sign," or enhancement of the arterial wall (See 'Neuroimaging' above.)

Definitive diagnosis of moyamoya requires neurovascular imaging. Diagnostic criteria for MMD proposed by a Japanese research committee include the following major requirements [6]:

● Stenosis or occlusion at the terminal portion of the internal carotid artery and at the proximal portion of the anterior and middle cerebral arteries

● Abnormal vascular networks in the basal ganglia; these networks can also be diagnosed by the presence of multiple flow voids on brain MRI

● Angiographic findings are present bilaterally; cases with unilateral angiographic findings are considered probable

There are three clinically and genetically distinct forms of neurofibromatosis: neurofibromatosis types 1 and 2 (NF1 and NF2) and schwannomatosis. NF1, previously known as von Recklinghausen disease, is the most common type.

The condition is called segmental NF1 when clinical features are limited to one area of the body due to somatic mosaicism of a pathogenic variant in the NF1 gene.

The incidence of segmental NF1 is unknown, but the prevalence is estimated at 1:36,000 to 1:40,000 [3].

NF1 is an autosomal-dominant genetic disorder with an incidence of approximately 1:2600 to 3000 individuals [1]. Approximately one-half of the cases are familial (inherited) [1] The de novo mutations occur primarily in paternally derived chromosomes [2].

Pathogenic variants in the NF1 gene result in loss of production or reduced function of protein, causing the wide spectrum of clinical findings, including NF1-associated tumors [7]. Penetrance, or the likelihood that the individual carrying the variant will manifest the disorder, is complete

NF1 is highly variable in its expression, however (ie, the severity of and specific manifestations of the disorder vary among affected individuals within the same family and from one family to another) [ 8].

It is possible that haploinsufficiency (ie, heterozygosity for a pathogenic variant with an intact second allele) accounts for some aspects of the phenotype, such as neurocognitive problems.

The typical order of appearance of clinical manifestations is café-au-lait macules, axillary and/or inguinal freckling, Lisch nodules (iris hamartomas), and neurofibromas [14]. Osseous dysplasias, if present, usually appear during the patient's first year after birth, and symptomatic optic pathway glioma (OPG) usually occurs by the time the patient is three years of age (table 1).

Café-au-lait macules are flat, uniformly hyperpigmented macules that appear during the first year after birth and usually increase in number during early childhood (picture 1).

The number of café-au-lait macules then stabilizes over time. Up to 15 percent of the normal population has one to three café-au-lait macules; however, the presence of six or more café-au-lait macules is highly suggestive of NF1 [ 15,16].

Freckling in the axillary or inguinal regions (Crowe sign) is a diagnostic criterion distinct from café-au-lait macules. The freckles are smaller in size than café-au-lait macules, appear later, and usually occur in clusters in skin folds rather than randomly (picture 2 and picture 3).

Freckling occurs mostly in regions of skin apposition, especially the axillary and inguinal areas. Freckling usually is not apparent at birth but often appears by age three to five years, typically first in the inguinal region [15]. Freckling may also occur in other intertriginous areas, such as the neckline or inframammary areas in women. In some individuals, freckling may occur elsewhere on the body and may be diffuse. One or two small freckles or the presence of a café-au-lait macule in a skin fold does not fulfill the diagnostic criterion for skin fold freckling.

Lisch nodules are raised, tan-colored hamartomas of the iris and represent a specific finding for NF1. They do not affect vision in any manner. Lisch nodules are useful both in establishing a diagnosis of NF1 in a child and determining whether a parent is affected. These lesions are detected in fewer than 10 percent of affected children younger than six years of age but are seen in greater than 90 percent of adults [19,20].

They may be seen with a direct ophthalmoscope if the nodules are large or numerous and the iris is light in color, but the slit lamp is a more reliable way to distinguish Lisch nodules from iris nevi, which are not associated with NF1 ( picture 4) [21].

Persons with NF1 develop both benign and malignant tumors at increased frequency throughout life [22]. Neurofibromas are the most common type of benign tumor that develops in persons with NF1. OPGs are the predominant type of intracranial neoplasms, but other central nervous system (CNS) and non-CNS tumors can occur.

Discrete cutaneous neurofibromas are the most common type. They consist of soft, fleshy, sessile or pedunculated tumors [31]. They move with the skin on examination and are not tender. Some are located within the dermis and can be palpated as a soft spot in the skin, often with an overlying violaceous discoloration. These cutaneous lesions usually begin to appear just before or during adolescence, although small lesions can be seen in younger children, especially if the skin is viewed with side lighting. They tend to increase in size and number with age and vary in number from just a few to thousands, with the highest density occurring over the trunk.

Nodular neurofibromas are discrete lesions that may grow under the skin, where they appear as firm, rubbery masses that may be tender, or occur deeper inside the body (image 1). Some can enlarge to the point where they compress surrounding structures or cause pain, but they do not tend to invade surrounding tissues like plexiform neurofibromas. They may take up 18-fluorodeoxyglucose, as occurs in MPNST [36], and may have pathologic features including nuclear atypia, some mitotic activity, and dense cellularity, referred to as "atypical neurofibroma" or "atypical neurofibromatous neoplasms of uncertain biologic potential" (ANNUBP) [37].

Plexiform neurofibromas may be located superficially and associated with overgrowth of skin and soft tissues (picture 5), may be located deep inside the body, or may have both superficial and deep components. Cutaneous involvement tends to be diffuse, with no discernible nerve fibers, although small plaques of cutaneous plexiform tumors may have palpable cords of thickened nerves. Deeper plexiform neurofibromas tend to appear as thickened nerves and can grow into a complex mass consisting of a network of enlarged nerves.

OPGs occur in approximately 15 percent of children younger than six years of age with NF1 [41]. They rarely occur in older children and adults [42,43]. OPGs are typically low-grade pilocytic astrocytomas [42,43]. They can arise anywhere along the anterior visual pathway to the optic radiations and involve the optic nerves, chiasm, and postchiasmal optic tracts (image 2).

Detecting precocious puberty early in patients with NF1 is important because it may indicate the presence of a clinically significant OPG, although abnormal puberty can occur in the absence of OPG. In addition, treatment can minimize the complications of accelerated linear bone growth and premature development of secondary sexual characteristics. One of the earliest signs of precocious puberty is accelerated linear growth, which highlights the importance of maintaining accurate growth charts using standards for children with NF1

In addition to OPGs, individuals with NF1 are at an increased risk for developing other CNS neoplasms, particularly low-grade astrocytomas and brainstem gliomas [23,42,55-58]. The most frequent clinical presentation is that of increased intracranial pressure, although lesions are often asymptomatic and are noted as incidental findings if brain imaging is performed. Patients with symptoms are more likely to progress and require treatment [58].

Malignant peripheral nerve sheath tumors — MPNSTs, previously called neurofibrosarcomas, usually arise within preexisting plexiform or nodular neurofibromas. The primary care provider should be alert to the possibility of this highly malignant tumor, particularly in teenagers and young adults. The first presentation of malignant transformation often is development of significant and constant pain, change in consistency from soft to hard, or rapid growth of a nodule within an existing plexiform neurofibroma [60,61].

Rhabdomyosarcoma — RMS is encountered more frequently in persons with NF1 than in the general population [68]. RMS in association with NF1 tends to present at an early age, often arises in a genitourinary site, and is usually of the embryonal histologic subtype [68].

Gastrointestinal stromal tumors — Persons with NF1 are also at an increased risk of developing soft tissue sarcomas that arise within the stromal compartment of the gastrointestinal tract, termed gastrointestinal stromal tumors (GISTs) [69-72]. In the setting of NF1, GISTs frequently occur in the small intestine (more than 70 percent), are often multiple, and have a different molecular pathology from sporadic GISTs in persons who do not have NF1.

Glomus tumors — Glomus tumors arise in the tips of the fingers and toes under the nail bed (image 3) and present with pain, tenderness, and sensitivity to cold. They are associated with NF1 [73] and are important to recognize because the pain is readily relieved by surgical removal of the tumor.

Other tumors — NF1 patients have an increased risk of certain other malignancies, such as juvenile myelomonocytic leukemia and pheochromocytoma, although genetic etiologies other than NF1 are more common causes of these malignancies.

Bone abnormalities in NF1 include pseudoarthrosis and bone dysplasia, which are part of the United States National Institutes of Health (NIH) Consensus Conference criteria for the disease, as well as short stature, scoliosis, nonossifying fibromas, sphenoid dysplasia, and osteoporosis [76,77].

Other bone lesions — Other skeletal lesions include vertebral defects, such as scalloping caused by dural ectasia, nonossifying fibromas within long bones, and sphenoid wing dysplasia, which may present as facial asymmetry. Rarely, a bone defect can occur in the lambdoidal suture, which is easily palpable [80,81].

Scoliosis occurs in 10 to 25 percent of persons with NF1 [78,84,85]. This condition frequently becomes apparent at 6 to 10 years of age or in early adolescence. Scoliosis in children with NF1 most commonly affects the thoracic spine and tends to be sharply angulated and dystrophic. Sometimes there is an associated paraspinal plexiform neurofibroma.

Osteoporosis — Persons with NF1 have lower bone density per age compared with general population controls [76]. The severity of decreased bone density can range from osteopenia to osteoporosis. The etiology of this decrease in bone density is unknown.

Neurologic disorders include cognitive deficits, learning disabilities, headaches, and seizures. Gross and fine motor developmental delays are also seen. Macrocephaly is a common feature. Dural ectasia along the spine can result in symptoms such as pain resulting from nerve root compression [87].

The diagnostic criteria developed by the United States National Institutes of Health (NIH) Consensus Conference in 1987 [152] and updated in 1997 [153] are based upon specific clinical features of NF1 (table 2). According to these criteria, at least two of the following clinical features must be present to make the diagnosis of NF1:

● Six or more café-au-lait macules >5 mm in diameter in prepubertal and >15 mm in diameter in postpubertal individuals. For each lesion, the longest diameter is measured. Ordinary room light (not a Wood's lamp) is used.

● Two or more neurofibromas of any type or one plexiform neurofibroma (picture 6).

● Freckling in the axillary or inguinal regions.

● Optic glioma.

● Two or more Lisch nodules (iris hamartomas).

● A distinctive bony lesion, such as sphenoid dysplasia or thickening of the long bone cortex with or without pseudoarthrosis.

● A first-degree relative (parent, sibling, or offspring) with NF1 based upon the above criteria.