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.

Management

Hydrocephalus is present in 10–20 percent of patients with DWM and can be treated with placement of a ventriculoperitoneal shunt. In some cases, cystoperitoneal shunting may also be required. Other features are managed symptomatically.

Clinical Characteristics

Patients typically present at birth with difficulty feeding, with maintaining their airway, or with temperature regulation. Labor may be associated with failure to progress through the birth canal. Patients display global hypotonia with a reduced level of alertness. Brainstem features predominate and include difficulty with coordination of sucking and swallowing and with handling oral secretions. These may be a reflection of defects in brainstem circuitry from development or may represent progressive degeneration of these circuits. There are some clinical features that can help distinguish the various PCH subtypes, but in actuality it is difficult to distinguish precisely between these subtypes solely on clinical grounds, so molecular testing can be helpful (Table 24-3).

Brain MRI shows characteristic involvement of the cerebellum and brainstem, including pontine hypoplasia. PCH is the one structural brain anomaly in which the cerebellar hemispheres may be more severely affected than the midline vermis.

Pathophysiology

The genetic etiologies of several of the PCH subtypes recently have been identified. One of the genes for PCH1 (VRK1) encodes for vaccinia-related kinase 1, a serine-threonine kinase required for nuclear envelope formation [Renbaum et al., 2009]. Absence of VRK1 suggests the presence of a defect in cellular integrity of posterior fossa structures, as well as anterior horn cells, which causes this condition.

Using homozygosity mapping, several of the genes for other forms of PCH have been identified in three of the four subunits of the tRNA splicing endonuclease. These genes, TSEN2, TSEN34, and TSEN54, cause PCH2 and PCH4 when mutated [Budde et al., 2008]. An additional gene mutation in the RARSL gene, encoding a mitochondrial arginine tRNA synthase, is mutated in a severe form of PCH, termed PCH6 [Edvardson et al., 2007]. The function of the splicing endonuclease is to remove introns from pre-RNAs, including tRNAs. Since in humans there are several tRNAs that require splicing, these genes presumably help promote maturation of tRNAs that are essential for mitochondrial protein synthesis. These findings suggest that a defect in mitochondrial function underlies some forms of PCH. This has led to the suggestion that PCH represents a form of mitochondrial disorder, although there is yet no evidence of generalized mitochondrial disturbances or accumulation of metabolites typically associated with mitochondrial dysfunction. Furthermore, there is no clear evidence for alterations in muscle integrity or visual or hearing deficits that are often associated with mitochondrial disorders. This raises the possibility of unique functions of these genes in modifying mitochondrial function during brainstem and cerebellar development.

Differential Diagnosis

Diagnosis is based upon MRI review and clinical assessment. It is important to evaluate midline sagittal and axial images to appreciate the reduced size of the cerebellum, as well as the reduction in brainstem volume, best appreciated at the level of the pons, in order to exclude cerebellar hypoplasia from the differential diagnosis. Olivopontocerebellar hypoplasia is a term that recently has fallen out of favor. It was previously used to describe a severe and early lethal form of PCH, and is most similar to type 4 PCH. Certain other genetic mutations can show patterns reminiscent of PCH. For instance, mutations in the RELN gene can show reduced brainstem and cerebellar size but without imaging demonstration of progressive atrophy. In addition, the clinical course is not as severe as PCH.

Management

Once a diagnosis of PCH is established, it is important to anticipate life-threatening brainstem dysfunction that may be present at birth or appear later in life. Placement of a gastrostomy tube and airway control can prolong life, but PCH infants are extremely fragile and usually do not survive beyond 1 year of age.

Clinical Characteristics

The clinical characteristics of Rho are mild and nonspecific, and include signs of developmental delay, hypotonia, and ataxia [Kruer et al., 2009]. Most children can learn to walk and speak, but usually these skills develop between 3 and 6 years of age. There is no evidence of developmental regression and epilepsy is uncommon.

Pathophysiology

The basis of the disease is not established. There are no reported cases with recurrence in family members and there is no increased frequency among families with consanguinity, thus suggesting a sporadic disease. Although a few rare copy number variants have been reported, their pathogenicity remains to be determined.

In one series of 40 cases, Rho was always associated with other brain abnormalities, including Purkinje cell heterotopias, collicular and thalamic fusion, agenesis of the corpus callosum, lobar holoprosencephaly, and neural tube defects [Pasquier et al., 2009].

Differential Diagnosis

Cerebellotrigeminal-dermal dysplasia, also known as Gomez–Lopez–Hernandez (GLH) syndrome, displays Rho, and should be distinguished from isolated forms of this disorder. GLH represents a rare neurocutaneous syndrome of craniosynostosis, ataxia, trigeminal anesthesia, scalp alopecia, cerebellar anomalies, midface hypoplasia, corneal opacities, mental retardation, and short stature. Rho is the most consistent finding in GLH [Poretti et al., 2008a], but most frequently it is seen in isolation from these other findings.

Rho has also been reported in Vacterl-H syndrome [Pasquier et al., 2009], comprising a combination of vertebral, anal, cardiac, tracheoesophageal, renal, limb, and other anomalies, with associated hydrocephalus.

Management

Hydrocephalus occurs infrequently in patients with Rho and, if clinically symptomatic, may require surgical treatment. Affected children also may develop strabismus, and ophthalmological evaluation should be considered.

Clinical Characteristics

Patients with LDD present with ataxia, signs and symptoms of increased intracranial pressure, and seizures [Abel et al., 2005]. LDD is associated with the familial hamartoma-neoplasia syndrome, Cowden’s disease (CD), an inherited cancer/hamartoma syndrome involving breast, thyroid, and other organs. Both conditions are linked to germline heterozygous mutations in the PTEN gene on chromosome 10 [Backman et al., 2001; Kwon et al., 2001]. LDD is frequently associated with features of CD. In one series of 31 patients with PTEN mutations, approximately 10 percent met full criteria for CD; another 30 percent had thyroid disease [Abel et al., 2005].

Brain MRI shows a nonenhancing unilateral lesion in the cerebellum, with mass effect on surrounding structures. The lesion characteristically is hypointense on T1 and hyperintense on T2 images, with alternating parallel hyperintense and isointense stripes that correspond to the inner molecular and granular layers of the cerebellum (Figure 24-4).

Fig. 24-4 Magnetic resonance imaging appearance of Lhermitte–Duclos disease.

A and B, Right cerebellar hemisphere mass with characteristic striated pattern on T2- (left) and T1-weighted (right) images.

(Used by permission from Qian LJ et al. Neurological picture. Lhermitte–Duclos disease. J Neurol Neurosurg Psychiatry 2010;81:255–256.)

Pathophysiology

LDD is believed to be a hamartomatous overgrowth of hypertrophic ganglion cells that replace the granular and Purkinje cell layers of the cerebellum, resulting in global thickening of the cerebellar folia. Histopathologically, there is widening of the molecular layer with abnormal myelination that is occupied by abnormal ganglion cells, absence of the Purkinje cell layer, and hypertrophy of the granular cell layer.

Differential Diagnosis

Since LDD presents in previously healthy children with features of a unilateral cerebellar mass, the main consideration is that of a posterior fossa tumor and secondary hydrocephalus. The unique radiographic appearance of LDD and the association with CD-like features can help distinguish it from tumors.

Management

The typical course consists of an insidious expansion of a posterior fossa mass. Decompressive surgery for symptomatic patients has been successful in improving long-term survival but the lack of clear tumor margins makes resection challenging. Chemotherapy is ineffective in treating these hamartomatous-like lesions. Although surgical management and anticipation of other PTEN-associated symptoms are the mainstays of treatment, it is possible that use of mammalian target of rapamycin (mTOR) inhibitors (e.g., rapamycin) might be effective, as preliminary studies show hyperactivation of this pathway in LDD [Abel et al., 2005].

Clinical Characteristics

There are three typical clinical presentations reported within the spectrum of VGAM [Gold et al., 1964]. The neonatal presentation consists of severe cardiorespiratory failure, including hydrops fetalis and renal failure secondary to aortic flow reversal. Of the vast majority of patients presenting in the newborn period, most show high-output cardiac failure with severe pulmonary hypertension, which may be mistaken for congenital heart disease. The infantile form presents with smaller and less hemodynamically apparent cardiac involvement. These patients can present with increasing head circumference due to aqueductal compression by the dilated vein of Galen with resultant hydrocephalus, or can present with nonspecific developmental delay. Other features may include hypothalamic and hypophyseal dysfunction, intracranial or carotid bruit, dilated scalp veins, proptosis, or epistaxis. In the childhood form, the typical presentation is headaches and seizures caused by subarachnoid and intraparenchymal hemorrhages. Such patients usually have insignificant cardiac symptoms [Heuer et al., 2010].

Pathophysiology

The vascular malformation itself is thought to originate around 2–3 months of gestation from the choroidal arteries. The high blood flow, coupled with dural sinus stenosis, causes the anterior segment of the median prosencephalic vein of Markowski (which normally regresses) to progressively enlarge instead, forming the aneurysmal component [Gailloud et al., 2005]. The subsequent left-to-right shunt causes a noncyanotic high-flow state with resultant heart failure and accompanying macrocephaly.

Differential Diagnosis

VGAM should be considered in any newborn evaluated for heart failure, especially in the presence of macrocephaly. Auscultation of a cranial bruit can suggest the diagnosis and brain imaging can confirm it.

Two types of arteriovenous connections have been recognized. The simplest (or “choroidal”) type consists of direct, high-flow shunts located within the wall of the venous aneurysm. The second (or “mural”) type involves the interposition of an arterial network between arterial feeders and the venous aneurysm itself. This network is usually located in the quadrigeminal cistern and results in less significant blood flow [Gailloud et al., 2005].

Management

Patients with neonatal-onset VGAM historically suffered from a poor prognosis, which has significantly improved with the recent development of standard endovascular embolization. Prenatal ultrasound can detect VGAMs, but MRI and MR angiography can better delineate the anatomic boundaries and blood flow. Conventional angiography is the gold standard for precise evaluation of VGAM architecture, including evaluation of arterial feeders and venous drainage (Figure 24-5). Following radiographic studies, the goal is to stabilize patients with medications until they are old enough to tolerate endovascular surgery. The complete removal of the lesion is rarely achieved because of hemodynamic instability of the infant and location of the lesion. As a result, surgical treatment is now reserved for the evacuation of intracranial hematomas and treatment of hydrocephalus. Embolization is achieved using embolic glue or microcoils. One of the goals is to prevent the development of cerebral venous hypertension, so stepwise embolization to allow for collateral formation is advised [Hoang et al., 2009]. Recently, a 21-point scale was developed to help guide therapy [Lasjaunias et al., 2006], and most children survive, frequently with some neuromotor sequelae.

Fig. 24-5 Vein of Galen malformation.

A and B, Magnetic resonance imaging shows a massively enlarged vein of Galen, straight sinus and torcula, associated with markedly enlarged posterior cerebral arteries on T2 (left) and T1 (right) weighted images. C, The angiogram shows a nidus of vessels in the region of the posterior third ventricle, with a large aneurysmal draining venous structure (arrows).

(Courtesy of http://www.med.uc.edu.)

Clinical and Radiographic Characteristics

In the case of CA, there are few unique MRI findings to establish a specific diagnosis, but clinical features can help differentiate various subtypes. These include those individuals with:

It can be difficult to separate CA from cerebellar hypoplasia, the former being characterized primarily by the full complement of folia, but with increases in the interfolial cerebrospinal fluid spaces, implying shrinkage of the parenchyma (Figure 24-6). Separation of CA from cerebellar hypoplasia is not always possible and the two can coexist in several different diseases, such as the CDGs.

Fig. 24-6 T1 Magnetic resonance imaging appearance of cerebellar atrophy.

This 10-year-old child presented with normal milestones, then progressive ataxia beginning at 6 years of age, without a clear underlying cause. A, The sagittal MRI shows normal folia but severe atrophy, with loss of cerebellar parenchyma and wide spaces between the cerebellar folia (arrowhead). The brainstem shows intact structure and appearance. B, Axial view shows prominent cerebrospinal fluid spaces between cerebellar folia.

Pathophysiology

While precise mechanisms are specific to each cause, CA is usually accompanied by some combination of degeneration of the Purkinje and granular cell layer, as well as some involvement of the cerebellar white matter. For instance, ataxia telangiectasia and spinocerebellar ataxias (see Chapter 67) are correlated with Purkinje cell degeneration, whereas in other conditions there is a predilection for the granular layer [Pascual-Castroviejo et al., 1994]. Purkinje cells are extremely vulnerable to various cytotoxic and metabolic derangements, and when these cells are damaged, the whole cerebellum can become atrophic.

Differential Diagnosis

The clinical presentation and appearance of the cerebellum on MRI may suggest the specific etiology of CA (Box 24-1). In some individuals there may be clinical findings to suggest a specific entity, such as the presence of oculocutaneous telangiectasias (e.g., ataxia telangiectasia), cataracts (Marinesco–Sjögren syndrome), progressive myoclonic seizures (neuronal ceroid-lipofuscinosis), or peripheral nerve involvement (infantile neural axonal dystrophy). However, in the majority of patients, such diagnostic findings are usually not present. When they are absent, it is wise to consider a broad differential to include serum albumin and α-fetoprotein (which can be abnormal in ataxia telangiectasia and ataxia-oculomotor apraxia), a lysosomal enzyme panel, liver enzymes, serum copper and ceruloplasmin levels, and a metabolic profile (including a chemistry profile, plasma amino acids, urine organic acids, and serum lactate, pyruvate, and ammonia levels).

Box 24-1 Types of Cerebellar Atrophy

Pure Cerebellar Atrophy

Ataxia telangiectasia

Ataxia telangiectasia-like disorders

Late GM₂ gangliosidosis

Ataxia-oculomotor apraxia

Cerebellar Atrophy and Hypomyelination

Pelizaeus–Merzbacher disease

Pelizaeus–Merzbacher-like diseases

Salla disease

Leukoencephalopathy with ataxia, hypotonia, and hypomyelination

Hypomyelination and atrophy of basal ganglia and cerebellum

Cerebellar Atrophy and Progressive White-Matter Abnormalities

Neuronal ceroid-lipofuscinosis

Niemann–Pick type C disease

Dentatorubral-pallidoluysian atrophy

Vanishing white-matter disease

Cerebellar Atrophy and Cerebellar Cortex T2 Hyperintenisty

Infantile neuroaxonal dystrophy

Marinesco–Sjögren syndrome

Mitochondrial disorders

Cerebellar Atrophy and Basal Ganglia Involvement

Kerns–Sayre and other mitochondrial disorders

Cockayne’s syndrome

Hypomyelination with atrophy of basal ganglia and cerebellum

Wilson’s disease

Specific considerations for CA include diseases such as toxic exposures to phenytoin or lithium (which are unusual in childhood), postinfectious cerebellar ataxia (usually presents with acute rather than chronic ataxia), and many autosomal-dominant and recessive genetic disorders, as reviewed in Chapter 67. Relatively recently recognized syndromes include cerebellar ataxia with mental retardation, optic atrophy, and skin abnormalities (CAMOS) syndrome, due to mutations in the ZNF592 gene [Nicolas et al., 2010], and ataxia oculomotor apraxia (AOA) syndrome, which presents very similarly to ataxia telangiectasia (e.g. with progressive ataxia) but backs telangectasias, increased risk for infections, leukemias and lymphomas seen in ataxia telangectasia. Mutations in the APTX and SETX genes have emerged as the major causes.

CA also may be seen in later stages of Friedreich’s ataxia (FA), one of the most common forms of autosomal-recessive ataxia (reviewed in detail in Chapter 67). It usually presents before adolescence with generalized ataxia and absent tendon reflexes, Babinski signs, impaired position and vibration sense, and scoliosis. The triad of hypoactive knee and ankle reflexes and ataxia in childhood is generally sufficient for diagnosis. In FA, it is important to recognize the clinically significant hypertrophic cardiomyopathy and diabetes, as well as the causative trinucleotide expansion in the FXN gene, which is involved in mitochondrial function and iron homeostasis. Treatments are emerging for many of the anticipated problems of FA, specifically targeted at underlying pathogenic mechanisms [Schmucker and Puccio, 2010].

Also reviewed in Chapter 67, the various autosomal-dominant forms of spinocerebellar ataxia (SCA) are a cause of CA in children. Although most SCAs present post adolescence, there are a number that can manifest at earlier ages, including SCA13, SCA17, SCA21, SCA25, and the related disorder known as juvenile Huntington’s disease. Many of the SCAs are due to CAG trinucleotide repeat expansions within the coding sequence of their respective genes; because the CAG tract encodes for glutamine, such disorders have also been called polyglutamine disorders. Due to the mutability of these expansions, the dominant forms display anticipation, referring to earlier onset and increasing severity of disease in subsequent generations of a family. SCA13 displays childhood onset associated with mild mental retardation and short stature, and is one of the rare dominant SCAs not associated with repeat expansion. SCA17 displays childhood or adult onset associated with mental deterioration, occasional chorea, dystonia, myoclonus, and epilepsy. The other forms of SCA listed above have been observed only in single publications.

Management

Except for vitamin E therapy for ataxia with vitamin E deficiency (AVED) (see Chapter 103) and some on-going but as yet inconclusive trials in FA, there are no specific treatments available for the conditions causing CA. Aggravating medications should be avoided. Physical medicine management is helpful (e.g., physical, occupational, and speech therapy; use of canes, walkers, writing instruments, or weights to minimize tremor) and can improve the activities of daily living (see Chapter 105).