X-linked hydrocephalus (L1 syndrome) and its variants
- First described in 1949, linked to X chromosome in 1961: An X-linked syndrome characterized by congenital hydrocephalus, stenosis of the aqueduct, adducted thumbs, and spastic paraparesis was described in 1949 by Bickers and Adams (5) and in 1961 by Edwards (33). This syndrome was called “Bickers-Adams-Edwards syndrome” or “X-linked hydrocephalus.”
- Present in 25% of males with aqueductal stenosis: L1 syndrome is considered the most common genetic form of congenital hydrocephalus and occurs in about 1:30,000 births (33). Transmission of the disease is from mother to sons. It has been estimated that 25% of males with aqueductal stenosis have X-linked hydrocephalus (33).
- Severe hydrocephalus, mental retardation, spasticity, and adducted thumbs: Most males with L1 syndrome usually are born with severe hydrocephalus, adducted thumbs, and spasticity; intellectual disability is severe. In less severely affected males, hydrocephalus may be subclinically present and documented only because of developmental delay; intellectual disability ranges from mild (IQ of 50–70) to moderate (IQ of 30–50). Females may manifest minor features such as adducted thumbs and/or subnormal intelligence.
- Prenatal diagnosis possible: Hydrocephalus usually becomes apparent after 18–20 weeks’ gestation; adducted thumbs in the first trimester of pregnancy are highly suggestive of X-linked hydrocephalus (95). The diagnosis is confirmed by molecular identification of the mutation in the L1CAM gene by chorionic villus sampling and detection of asymptomatic female carriers.
- Other CNS malformations: Stenosis of the aqueduct was thought to be the primary cause of hydrocephalus; however, subsequent observations (64,116) suggested that the stenosis should be secondary to chronic compression from the lateral and third ventricles. The poor neurological outcome of patients with X-linked hydrocephalus reported in many series (86,88), despite early surgical intervention and good control of hydrocephalus, and the frequent association with other malformations, such as aplasia of the corpus callosum and of the pyramids in the medulla, are expressions of cortical malformation and poor differentiation and maturation of cortical neurons (32,33).
- MASA syndrome: Aside from X-linked hydrocephalus, the phenotypic spectrum of L1 syndrome also may include MASA syndrome (mental retardation, aphasia (delayed speech), spastic paraplegia (shuffling gait), adducted thumbs) (93).
- SPG1 (X-linked complicated hereditary spastic paraplegia type 1): In this syndrome spastic paraplegia, mild to moderate intellectual disability, and a normal MRI of the brain are seen in addition to the aqueductal stenosis (93).
- X-linked complicated corpus callosum agenesis: In this syndrome variable spastic paraplegia, mild to moderate intellectual disability, and corpus callosum anomalies such as dysplasia, hypoplasia, or aplasia appear in addition to the aqueductal stenosis (93).
Autosomal recessive hydrocephalus
- Autosomal recessive aqueductal stenosis: Aqueductal stenosis may rarely occur as an autosomal recessive trait that affects both sexes (13). The clasped thumbs, characteristic of X-linked hydrocephalus, are not generally present in this form of hydrocephalus. Also, in autosomal recessive hydrocephalus the role of aqueductal stenosis in inducting hydrocephalus is controversial (13). In both X-linked and autosomal recessive hydrocephalus, the age of onset may vary from child to child, even in the same family.
- Aqueductal stenosis unrelated to tumor: Nontumoral aqueductal stenosis may also be part of some inherited syndromes, such as neurofibromatosis (100). In the series of Pascual-Castroviejo et al. (81), aqueductal stenosis occurred in about 5% of children with NF1. However, most of these patients (60%) presented with associated optic pathway tumors and aqueductal stenosis.
- Bacterial infection: Bacterial meningitis, intrauterine or infantile, is the most common cause of acquired gliotic obstruction of the aqueduct; the lumen can be filled during the acute or subacute phase by a fibrinopurulent exudate that successively organizes. The stenosis can also develop gradually from proliferation and fusion of glial nodules in diffuse ependymitis (51).
- Parasitic infection: Toxoplasmosis is the most frequent intrauterine infection associated with aqueductal stenosis (57).
- Viral infection: Aqueductal stenosis may be a noninflammatory sequela of a previous viral infection of ependyma. This phenomenon was first demonstrated for infections with mumps virus (52), and then for CMV, lymphatic choriomeningitis, influenza A, and parainfluenza II infections (23, 51). Aqueductal stenosis was also reported in association with subacute sclerosing panencephalitis, mononucleosis (96), and inflammatory CNS disease, such as systemic lupus (8). The pathological features of viral-induced aqueductal stenosis are similar to those of simple stenosis (no associated gliosis) described by Russell (91), causing some authors to hypothesize a pathogenetic role of viral infection (in particular mumps infection) in inducing the forms of “unknown etiology” of aqueductal stenosis(23,51,52,90). Viruses may cause ependymitis and ependymal cell loss resulting in desquamation of the ependyma and subsequent aqueduct occlusion. Alternatively, viral particle bridges may cause a cross-linking between ependymal cells (115). At the level of the aqueduct this process is favored by the high concentration of particles that occur in the aqueduct, which is continously bathed by CSF into which virions are released.
- Acute or chronic obstruction: In case of intraventricular hemorrhage, aqueductal stenosis may develop in the acute phase, secondary to direct obstruction of the aqueduct by blood, or in a chronic phase, secondary to the organization of clots (7).
- Germinal matrix hemorrhage in infants: Prematurity-related germinal matrix hemorrhage is the most common hemorrhage causing aqueductal stenosis in infants.
- Aneurysmal hemorrhage in adults: Rupture of an intracranial aneurysm is the most common cause in adults.
- Experimental models raise possibility: In experimental models many substances, such as trypan blue, salicylate and cuprizone, administered to the mother in early gestation, induced aqueductal stenosis (104). Similar lesions were induced in rabbits by vitamin A deficiency and in rats born from mothers fed with a diet deficient in vitamin B or folic acid (51).
- Abnormal midbrain development: Chiari malformation types 1 and 2 and spina bifida may be associated with aqueductal stenosis (22, 51).
- Other malformations: Occipital encephalocele as well as retrocerebellar and supracollicular cysts can be associated with aqueductal stenosis (22, 51).
- Posterior fossa masses: In cases of space-occupying lesions in the posterior fossa, transtentorial upward displacement of the cerebellum with compression of the quadrigeminal plate may explain the aqueductal stenosis. It may become irreversible because of secondary modifications of the ependyma and gliosis (22). In particular, in the case of Dandy-Walker malformation (22), aqueductal stenosis may be secondary to herniation of vermis or cyst through the tentorial hiatus.
- Vein of Galen malformations in children: Aqueductal stenosis caused by vascular malformations is a rare occurrence (51). The quadrigeminal plate may be displaced by a vein of Galen aneurysmal malformation or by abnormal draining veins of midbrain arteriovenous malformations (91).
- Aneurysms in adults: In adults aqueductal stenosis may be due to giant fusiform aneurysms of the basilar artery (51).
- Pathophysiology of rotation vermis with aqueductal compression: Raimondi et al. (84, 85) observed, in cases of a pressure gradient between the supratentorial and infratentorial compartments (such as Dandy-Walker malformation or overfunctioning supratentorial shunt drainage), an anterior rotation of the upper vermis with aqueduct obstruction. They named this condition “functional aqueductal stenosis.”
- Isolated fourth ventricle: In cases of postmeningitic or posthemorrhagic hydrocephalus, this phenomenon may isolate the fourth ventricle (79,101). Raimondi et al. (85) observed that decreasing the gradient pressure may result in re-opening of the aqueduct. However, isolated fourth ventricle is not always a reversible condition, but it often results from irreversible changes subsequent to meningitis, hemorrhage, or posterior fossa operation (101).
- Communicating hydrocephalus: A functional mechanism might contribute to an evolution in the type of hydrocephalus in patients with communicating hydrocephalus initially: progressive enlargement of the lateral and third ventricles that leads to a distortion of the brainstem with kinking of the aqueduct (77, 84). In shunted patients with initially communicating hydrocephalus, the continuous diversion of CSF from the lateral ventricle may cause an acquired aqueductal stenosis with a “functional” mechanism. This phenomenon, together with the re-expansion of CSF spaces around the brain promoted by the shunt, increases the chance of a ETV being successful when shunt malfunction occurs (78).
- Late-onset idiopathic aqueductal stenosis: Aqueductal stenosis may present later in life with a more chronic form of obstructive hydrocephalus termed LIAS (37). Younger patients tend to experience symptoms related to intracranial hypertension, but older patients tend to have NPH–like symptoms (ataxia, cognitive impairment, and incontinence) (2). Bateman (2) observed that patients with LIAS experience reduced venous compliance and an elevation in venous collateral flow, suggesting that an elevation in venous pressure may be associated with this disease process. According to Bateman, venous hypertension should be considered as the most crucial factor in the pathophysiology of LIAS. As in normal pressure hydrocephalus and idiopathic intracranial hypertension, increased pressure in the venous system (particularly in the sagittal sinus) results in a decrease in brain compliance and a consequent aqueductal blockage with ventricular dilation.
- Tectal plate gliomas: Small subependymal tectal tumors can cause progressive aqueductal stenosis. Gliomas of the tectal plate usually are particularly indolent, often remaining stable in size for many years (82). These tumors characteristically present with hydrocephalus secondary to late onset aqueductal stenosis, often without associated brainstem signs. The management of hydrocephalus usually warrants a favorable long-term prognosis (82).
- Other midbrain tumors: High-grade tumors can occur in the periaqueductal region, and thus atypical behavior radiographically or clinically should raise suspicion.