Pathophysiology

Although a number of theories as to the etiology of the Chiari I malformation have been suggested, no clear consensus has emerged. One popular theory that was dispelled was the idea that tethering of the spinal cord causes posterior fossa structures to be pulled into the spinal canal. Another theory gaining favor is that congenital hypoplasia of the posterior fossa occurs due to disrupted mesodermal development [Marin-Padilla and Marin-Padilla, 1981]. There is an increased risk of developing this malformation with growth hormone deficiency and bone defects like rickets. Female patients greatly outnumber male patients, and there is familial clustering, suggesting a genetic predisposition. Gene mutations of chromosomes 9 and 15 may contribute to development of this malformation [Boyles et al., 2006], and it also has recently been linked to Ehlers–Danlos syndrome [Castori et al., 2010]. In about 20 percent of individuals, there is identified trauma that precedes symptom onset.

Clinical Characteristics

Patients with Chiari I malformation may present with a variety of symptoms and signs, ranging from slight headache to severe myelopathy and brainstem compression. The most common presenting feature, in 80 percent of patients, is occipital pain, which increases upon Valsalva maneuver. The headache is described as a heavy, crushing sensation in the back of the head, which radiates to the vertex and to the neck and shoulders, and lacks a pounding quality. The major difference between the childhood and the adult presentation is the increased occurrence of sleep apnea and feeding problems in younger patients. Other common symptoms include pain in the shoulders, back, and limbs, sensory changes, clumsiness, and dysphagia, each observed in 10–50 percent of individuals at the time of presentation.

Initial clinical features largely depend on whether syringomyelia is present, since this defect tends to dominate the clinical picture. Symptoms from syringomyelia, present in 30–70 percent of adult Chiari I patients but in only 12 percent of children, depend on the location and size of the syrinx and can occur as a result of stretching and distention of the cord [Milhorat et al., 1999; Aitken et al., 2009]. Long-tract findings include hyperreflexia, urinary incontinence, muscle wasting, loss of proprioception, and arm numbness/tingling.

Management

Surgical decompression of the posterior fossa with duraplasty is the treatment of choice in selected cases. The purpose of this surgery is to enlarge the bony compartment. It is important to evaluate for coexistent hydrocephalus before any correction is attempted. In patients with a coexistent syrinx, there is a clear indication for surgery, and in a series of 49 children with Chiari-associated syringomyelia, just over half demonstrated clinical and radiographic improvement after hindbrain decompression [Attenello et al., 2008]. In these patients, decompression of the posterior fossa alone is often sufficient to reduce the syringomyelia without directly shunting the fluid collection. In patients without a syrinx but with >5 mm of caudal displacement or with progressive features, surgery may be offered. In some individuals, clinical symptoms and herniation may spontaneously improve, so a conservative approach is generally adopted in minimally affected patients [Novegno et al., 2008] and in those with <3 mm displacement.

Pathophysiology

The etiological basis of the cerebellar disorder predicts the pathophysiology, but generally follows some defect in cellular proliferation or differentiation of either the cerebellar Purkinje or granule cells. In the CDGs, as a result of insufficient protein glycosylation, there is probably an activation of the unfolded protein response, leading to an effect on the cerebellum (see Chapter 35). Likewise, teratogenic exposure to alcohol in animal models can affect neuronal migration by altering established pathways [Jiang et al., 2008].

Clinical Characteristics

An important distinction between the clinical characteristics of cerebellar hypoplasia and atrophy is the striking presence of neonatal hypotonia in the former, and ataxia in the latter. It is important to remember that the cerebellum controls muscle tone in the first few years of life, since the learned motor plans requiring the cerebellum are not in place at that time. After the first few years of life, however, the cerebellum takes on important roles in motor planning, so diseases affecting circuitry predominantly present with prominent features of ataxia, such as tremor and nystagmus, including possible loss of milestones.

Differential Diagnosis

It is critical to evaluate individuals with cerebellar hypoplasia for syndromic forms of this malformation, as well as to consider the various genetic etiologies (Table 24-2). Like most developmental brain anomalies, fetal infections, and toxic exposures, recessive and dominant inherited forms, as well as alterations in genetic copy number (using comparative genomic hybridization), should be considered. Normal transferrin isoelectric focusing can help exclude CDGs. Normal family history may help exclude genetic causes. Baseline laboratory tests, including creatine phosphokinase (CPK), vitamin E levels, and TORCH (toxoplasmosis, other infections, rubella, cytomegalovirus, and herpes simplex virus) titers, looking for prenatal viral infection, can help exclude muscle-eye-brain disease, vitamin E deficiency, and congenital infections. Mitochondrial disorders should be considered, especially in the setting of features such as growth retardation, hearing loss, acidosis, and respiratory or multi-organ involvement.

Table 24-2 Causes of Cerebellar Hypoplasia

Management

The important consideration in individuals with cerebellar hypoplasia is that clinical features usually do not worsen over time. With physiotherapy and nervous system maturation, the clinical features generally diminish. If specific causes can be identified, there is the potential for intervening, e.g., in patients with nutritional deficiencies or specific metabolic disorders.

Clinical Characteristics

The MTS is the result of cerebellar vermis hypoplasia, thick and maloriented superior cerebellar peduncles, and an abnormally deep interpeduncular fossa, which together give the appearance of a tooth. JS is the best-known and probably most common syndrome associated with the MTS. JS is notable for both intrafamilial and interfamilial phenotypic variability. Even in the original pedigree of four affected siblings, two had hypoplasia of the posterior inferior cerebellar vermis and two had complete agenesis of the cerebellar vermis [Joubert et al., 1968].

Clinical features are highly variable for patients with the MTS. Many patients with JS present in the newborn period with an unusual pattern of intermittent respiration, displaying alternating hyperpnea and apnea. In JS, there is no specific lung pathology to explain this respiratory abnormality. Instead, it likely relates to dysfunction of the respiratory centers located in the brainstem or cerebellum [Xu and Fraser, 2002]. Because some neonates have died from apnea, it is critical to institute careful respiratory care until this feature of JS passes, usually by 1 year of age. Some patients will have relatively mild disease, with congenital ataxia that lessens with age, and a delay in the ability to walk until age 4–5 years, but are otherwise healthy. Other patients will display congenital blindness and renal failure requiring dialysis or renal transplantation. It is important to differentiate the type of JSRD at the time of presentation, and then to monitor the patient periodically for development of any extra-central nervous system signs. If patients do not develop retinal or renal involvement by age 10–15 years, they are unlikely to do so.

The disorders related to JS include cerebellar vermis hypo/aplasia-oligophrenia-ataxia-ocular coloboma-hepatic fibrosis (COACH syndrome), cerebello-oculo-renal syndrome (CORS), and oro-facio-digital syndrome type VI (OFD-VI), all of which share the MTS, but additionally display features that distinguish them from JS [Zaki et al., 2008]. Diagnostic criteria can help distinguish each of the four major clinical entities within the JSRD spectrum.

Pathophysiology

JSRDs fall within the “ciliopathy” spectrum of conditions, which are due to alterations in development or signaling within the cellular primary cilium. Motile cilia are well known for their roles in certain tissues, such as the sperm, where they propel cells, but there is another class of cilia, termed primary cilia, which are nonmotile, typically lacking the central pair of microtubules and outer dynein arms necessary for movement. Several genes associated with JS have now been established, and protein products of these genes are found specifically at the primary cilium in most cells throughout the body. Thus, JS is now included with other ciliopathies, including Bardet–Biedl syndrome, nephronophthisis, Leber congenital amaurosis, congenital hepatic fibrosis, Jeune asphyxiating thoracic dystrophy, and Ellis–van Creveld syndrome, as a disorder of the primary cilium [Tobin and Beales, 2009].

For some of these disorders, like Leber congenital amaurosis (congenital retinal blindness), the relation between primary cilia and pathogenesis is readily apparent, given the fact that the entire photoreceptor outer segment is a modified primary cilium. Within the developing cerebellum, primary cilia have been shown to be essential for reception of the cell signaling ligand sonic hedgehog, which in turn is essential for proliferation of cerebellar granule neurons [Chizhikov et al., 2007; Spassky et al., 2008]. Thus, it is postulated that reduced granule neuron production is the central aspect of the cerebellar hypoplasia.

Differential Diagnosis

JSRDs can be distinguished by the presence of the MTS, which can be detected prenatally and used for diagnosis [Saleem and Zaki, 2010]. In the absence of the MTS, other cerebellar malformations must be considered. In some families, there can be one child with JS and a second child with either a more severe disorder like Meckel–Gruber syndrome, or a less severe disease like Bardet–Biedl syndrome. This heterogeneity cannot be clearly explained by genetics alone, since even identical twins can show divergent severity [Raynes et al., 1999]. It is important to evaluate the whole family to determine if children with such divergent disease might share the same underlying genetic cause.

Management

The management of JSRD can be aided by anticipation of typical problems and the use of genetic testing to help determine prognosis. Patients identified in the neonatal intensive care unit should be monitored closely for apnea. Treatment with caffeine may help promote respiratory drive and an apnea monitor may be required for the first year of life. Because of the heterogeneity of these conditions, it is recommended that patients be evaluated by a geneticist and undergo screening for coexisting medical problems, including brain MRI, polysomnogram, echocardiogram, careful dysmorphology and retinal evaluation, and annual monitoring with liver function testing and renal ultrasound examinations [Parisi and Dobyns, 2003].

Prenatal diagnosis may be approached in one of several ways. JS is one of the disorders that may be encountered when cerebellar hypoplasia is detected on prenatal ultrasound. In this case, an ultrasonographer may observe nonspecific hypoplasia, and then will seek fetal brain MRI for more specific diagnosis. JS may diagnosed on brain MRI, based on the presence of the MTS [Saleem and Zaki, 2010]. Alternatively, prenatal diagnosis can be made genetically, especially in certain populations with founder mutations [Valente et al., 2010].

Genetic testing can predict disease severity, based upon established genotype–phenotype correlations. Mutations in certain genes for JS, such as AHI1, INPP5E, CC2D2A, and ARL13B, can be detected in patients with MTS who do not have involvement of other organs, or they can be detected in patients with MTS together with retinal blindness. Mutations in TMEM216 and RPGRIP1L genes are often encountered in those patients with MTS and renal involvement. Mutations in CEP290 are encountered in half of patients with MTS together with retinal blindness and renal involvement. Mutations in TMEM67 are the most common cause of MTS with liver involvement [Brancati et al., 2009]. Thus, the specific gene mutation identified in a patient can help predict the range of organ involvement.

Clinical Characteristics

The clinical spectrum associated with DWM is extremely broad, ranging from asymptomatic to severe mental retardation. Half of the patients have normal cognition, whereas others never achieve normal intellectual function, even when hydrocephalus is treated effectively. The vermis anatomy in DWM is statistically correlated with neurological and intellectual outcome [Klein et al., 2003]. Systemic malformations associated with DWM may include cardiac anomalies (ventriculoseptal defects, patent ductus arteriosus, transposition of the great arteries), urogenital anomalies (hydroceles, vesico-ureteral reflux, abnormal kidney shape), and other abnormalities (duodenal atresia, cleft palate, malformed limbs), and occur collectively in about half of patients [Sasaki-Adams et al., 2008]. Those with isolated DWM can have normal development.

Pathophysiology

An insult that leads to developmental arrest in the formation of the hindbrain, with lack of fusion of the cerebellum in the midline, can be localized temporally between the 7th and 19th gestational weeks. Historically, medial fusion failure was proposed to lead to persistence of the anterior membranous area/roof plate, which could then extend and herniate posteriorly, resulting in a large fourth ventricle. Because DWM represents a fluid accumulation of the fourth ventricle, both Dandy and Walker considered that the defect resulted from atresia of the foramina of Magendie and Luschka, the outflow foramina of the fourth ventricle. However, the finding of normal foramina in DWM, together with new genetic studies, points to defects in the early development of the cerebellum or in the surrounding parenchyma.

The low empiric recurrence risk of approximately 1–2 percent for nonsyndromic DWM suggested that a simple mode of inheritance was unlikely [Murray et al., 1985], and the frequent association with chromosomal anomalies supported this hypothesis. Accumulating evidence suggests that many cases represent de novo alterations in genomic integrity, with focus on chromosome 3q2 and 6p25.3 associated with the Axenfeld–Rieger syndrome [Aldinger et al., 2009]. Additionally, a dominant form has been linked to chromosome 2q36.1 in association with occipital encephalocele.

The genes ZIC1, ZIC4, and FOXC1 when deleted can result in DWM. The ZIC1 [Grinberg et al., 2004; Aldinger et al., 2009] and ZIC4 genes are produced in cerebellar primordial cells, whereas the FOXC1 gene is produced by the developing mesenchyme, which gives rise to the meninges and posterior skull, overlying the developing cerebellum. This suggests at least two different mechanisms of disease, one in which some regulatory genes are required in the developing cerebellum itself, and others in the adjacent mesenchyme, with DWM a result of either defect. Because all genes identified to date are transcription factors, DWM is presumably a disorder associated with altered cellular programming during development; however, further research is required to delineate these mechanisms.

Differential Diagnosis

To distinguish DWM from other cerebellar malformations, it is important to acquire both midline sagittal and axial MRIs in order to evaluate for the unique features of DWM. Although some of the older literature attempted to link DWM with Meckel’s syndrome, JS, polydactyly, or kidney disease, these previous papers did not specifically evaluate for the MTS. Thus, these patients would probably now better fit within the JS spectrum.

Previous literature also used the term Dandy–Walker variant, which included any of the various cerebellar hypoplasias; this should be dropped in favor of more specific terminology. It is important to consider mega cisterna magna, retrocerebellar cysts, and Blake’s pouch cyst in the differential diagnoses [Nelson et al., 2004]. In each of these disorders, there is a fluid collection in the posterior fossa adjacent to the cerebellum, but not within the fourth ventricle, without elevation of the torcula; they thus do not meet the criteria for DWM. Additionally, in these three conditions, which are often found incidentally, the prognosis is usually excellent. In some cases, imaging findings are intermediate between one of these conditions and DWM, and expert review might be necessary to arrive at a precise diagnosis. As mentioned, the association with hydrocephalus, congenital heart disease, urogenital anomalies, and cleft lip/palate can support the diagnosis of DWM.