Handbook of Clinical Neurology, Vol. 119 (3rd series) Neurologic Aspects of Systemic Disease Part I Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 36

Neurologic manifestations of achondroplasia JACQUELINE T. HECHT1, JOHN B. BODENSTEINER2, AND IAN J. BUTLER3* Department of Pediatrics and Pediatric Research Center, University of Texas Medical School, Houston, TX, USA

1

2 3

Department of Neurology, Mayo Clinic, Rochester, MN, USA

Division of Child and Adolescent Neurology, Department of Pediatrics, University of Texas Medical School, Houston, TX, USA

INTRODUCTION Achondroplasia is the best described and most common form of the congenital short-limbed dwarfing conditions. The disorder has been recognized for more than 5000 years and is well represented in art, for example, in Egyptian statues and Vela´squez paintings, and in the literature of Charles Dickens. Individuals with achondroplasia were gladiators in Roman times, court jesters in medieval times, and wrestlers or circus clowns in modern times (Scott, 1976; Horton et al., 2007). Achondroplasia is apparent at birth and has a birth prevalence of 1 in 20 000–30 000 live-born infants (Oberklaid et al., 1979; Orioli et al., 1986; Stoll et al., 1989). The clinical and radiographic findings are characteristic, allowing for diagnosis at all ages (Horton et al., 2007). Although DNA testing is rarely needed for diagnosis, it is easily performed and is commercially available. Achondroplasia is inherited as an autosomal dominant condition, although 80% of cases occur sporadically as new events in their families (Horton et al., 2007). There is a strong correlation with advanced paternal age for men over 35 years (Murdoch et al., 1970; Wilkin et al., 1998). This is thought to be a result of high mutation rate and/or a selective advantage of FGFR3 mutant sperm over sperm bearing normal FGFR3 receptor similar to that observed for conditions with FGFR2 (Tiemann-Boege et al., 2002; Goriely et al., 2005). Achondroplasia is caused, in virtually all of the cases, by a G380R mutation in fibroblast growth factor receptor 3 (FGFR3) (Shiang et al., 1994; Rousseau et al., 1996). This amino acid substitution is in the transmembrane domain of the receptor and causes constitutive

activation of the receptor (Bellus et al., 1995). The tyrosine kinase-mediated transmembrane receptor of FGFR3 is an important negative regulator of linear bone growth, acting mainly through the STAT1, MAPK-p38, and MAPK-ERK signaling pathways which function to inhibit chondrocyte proliferation and terminal differentiation in the growth plate. Thus, the G380R FGFR3 mutation acts by promoting or stabilizing the dimerization required for receptor activation, by directly activating kinase activity through conformational change of the receptor, and by slowing of receptor degradation (Cho et al., 2004; Laederich and Horton, 2010). Since achondroplasia is an autosomal dominant condition, there is a 50% chance with each pregnancy that the offspring will be affected. Homozygous achondroplasia, a severe and lethal form, occurs as a result of a union between two achondroplastic individuals and leads to the demise of the progeny prenatally or shortly after birth (Hall et al., 1969). Both heterozygous and homozygous forms are often diagnosed prenatally because of the frequent use of in utero ultrasonography in managing pregnancies (Bellus et al., 1994; Gooding et al., 2002). Clinicians (medical geneticists/ genetic counselors/obstetric geneticists) experienced in the assessment of achondroplasia should be involved in prenatal counseling and appropriate obstetric management can be carefully planned to avoid perinatal injury. Many achondroplastic babies are delivered by Caesarean section because of macrocephaly. This is particularly important for women with achondroplasia who have small pelvic outlets, which impedes vaginal delivery.

*Correspondence to: Ian J. Butler, MBBS, FRACP, Director, Division of Child and Adolescent Neurology, Department of Pediatrics, University of Texas Medical School, 6431 Fannin Street, MSB 3.020, Houston, TX 77030, USA. Tel: þ1-713-5005700, E-mail: [email protected]

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Infants with achondroplasia should be evaluated by a multidisciplinary team of clinicians including geneticists, neurologists, and orthopedists, since there are numerous skeletal and neurologic complications. The most severe complication results from craniocervical stenosis and medullary and upper spinal cord compression, which can have devastating and even lethal sequelae during early childhood. In subsequent decades, including adolescence, spinal cord and nerve compression are more prominent. Foramen magnum stenosis can be problematic at all ages, particularly following head and neck trauma because of odontoid abnormalities (retroflexed or bulbous). In adulthood, clinical manifestations of intermittent spinal cord claudication, bladder, bowel, and sexual dysfunction from conus medullaris and cauda equina compression are more likely and are related to associated age-related spondylosis and hypertrophic ligamentum flavum in the presence of congenital vertebral canal stenosis. Knowledge of age-related clinical complications has been useful in evaluating patients with achondroplasia for neurologic complications and to enable early and appropriate medical and surgical management (King et al., 2009). The neurologic complications of achondroplasia have been recognized in adults for more than a century and are attributed to bony defects, connective tissue structures, or both (Vogl and Osborne, 1949; Spillane, 1952; Vogl, 1962; Hall, 1988; Horton et al., 2007). Similar neurologic complications are now appreciated in infants, young children, and teenagers with achondroplasia (Reid et al., 1987; Nelson et al., 1988). Defective endochondral ossification leads to a small, abnormally shaped foramen magnum, short vertebral pedicles, and a narrow spinal canal (Langer et al., 1968). The narrowing of the spinal bony canal may be problematic at the cervical and lumbar regions and at the level of the cervical and lumbar spinal cord enlargements. Various foramina may be narrowed and compress vascular and neural structures passing through the bone. Small jugular foramina at the base of the skull may compress the internal jugular veins and exiting cranial nerves. Occasionally, defective vertebral column alignment leads to scoliosis, kyphoscoliosis, lumbar gibbus deformity, and severe lordosis that can compress the spinal cord and cauda equina (Blau and Logue, 1961). Defective connective tissue elements in achondroplasia frequently lead to ligamentous laxity, which can aggravate the complications associated with bony stenosis. Bony abnormalities are known to cause neurologic morbidity and lead to a shortened lifespan (Hecht et al., 1987; Wynn et al., 2007). Table 36.1 lists the neurologic complications associated with achondroplasia that are reviewed in this article and Figure 36.1 provides a recommended paradigm for the evaluation and management of these problems.

Table 36.1 Neurological complications of achondroplasia Complication

Clinical sign/symptom

Macrocephaly Hydrocephalus Communicating type Noncommunicating type Subdural hematoma Craniocervical junction anomalies Small foramen magnum Abnormal atlantoaxial joint Myelopathy Syringobulbia-myelia Hydrocephalus Developmental delay Macrocephaly Ligamentous laxity Myelopathy Vertebral canal stenosis Abnormal vertebral skeleton

Macrocephaly

Vertebral column malalignment Gibbus Scoliosis Kyphosis Lordosis Nerve compression Cranial nerve(s) Occipital nerve(s) Spinal nerve(s) Cauda equina

Sudden death, sleep apnea syndrome, disorders of respiration, reflex changes, ataxia, gait disturbance

Marked head lag, delayed motor milestones

Pain, claudication, bladder incontinence, bowel incontinence, sexual dysfunction Pain, claudication, bladder incontinence, bowel incontinence, sexual dysfunction

Neuralgia, paralysis, occipital headache, claudication

COMPLICATIONS ASSOCIATED WITH ACHONDROPLASIA Macrocephaly and hydrocephalus Macrocephaly or an enlarged head (Fig. 36.2) is an easily recognizable and common phenotypic feature of achondroplasia (Scott, 1976; Hall, 1988; Horton et al., 2007). The etiology of the head enlargement is of concern, particularly in achondroplastic children under 2 years of age with delayed motor development. Earlier studies suggested that hydrocephalus was the cause of the head enlargement (Spillane, 1952). Other studies have suggested that the enlarged head was due to a large brain (megalencephaly) and that the ventricles were normal or only mildly dilated (Dennis et al., 1961). Standard

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Management of achondroplasia

Clinical evaluation (genetic / neurologic / orthopedic)

Somatosensory and brainstem evoked potentials Polysomnogram (all night) Computed tomography / magnetic resonance imaging Developmental assessment

Normal

Abnormal

Follow-up every 6 months x 3 years then once a year

Asymptomatic

Symptomatic

Repeat studies 3 – 6 months

Deterioration

Surgery VP shunt Craniectomy Laminectomy Vertebral fusion

Fig. 36.1. Management of achondroplasia. (Reproduced from Hecht and Butler, 1990.)

Fig. 36.2. Sagittal T1 sequence magnetic resonance image showing macrocephaly and macrocranium (frontal bossing) with constriction of the spinal cord due to posterior compression at the craniocervical junction. (Figure supplied by Dr. Ian J. Butler.)

growth curves for achondroplasia are now available, including those for head circumference, height, and weight (Horton et al., 1977; Horton et al., 1978; Hoover-Fong et al., 2007). These growth curves show that head size in achondroplasia is larger than in the average population and they are used routinely to clinically assess growth, and particularly any variation in head

circumference, over a period of time that could suggest progressive hydrocephalus. Although hydrocephalus with dilated ventricles has been recognized for many decades in achondroplasia, the exact mechanism in any individual is not always certain and remains controversial (Pierre-Kahn et al., 1980). Ventricles in achondroplasia may be mildly dilated (Fig. 36.3) but may also show marked dilation. Noncommunicating hydrocephalus has been attributed to stenosis of the aqueduct of Sylvius (Cohen et al., 1967). Kinking of the aqueduct and compressive obliteration of the basal cisterns related to the small cranial base (basis cranii) have also been identified. Communicating hydrocephalus is seen more frequently in achondroplasia and is often diagnosed as hydrocephalus ex vacuo, without clinical evidence of brain atrophy. It may be difficult to distinguish the hydrocephalus ex vacuo from mild ventricular dilatation frequently observed in achondroplasia using computed tomography (CT) (Mueller, et al., 1977). Communicating hydrocephalus, including prominent subarachnoid spaces over the cortex (Fig. 36.3), has been attributed to impaired absorption of cerebrospinal fluid via the arachnoid villi of the superior sagittal sinus. Pressure in the venous drainage of the brain, including the sagittal sinus, can be elevated by constriction of the jugular veins in the jugular foramina at the hypoplastic base of the achondroplastic skull (Dennis et al., 1961; Yamada et al., 1981). Reversal of blood flow in the emissary veins connecting the intracranial and extracranial venous systems has been demonstrated in one study, suggesting

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Fig. 36.3. Coronal T2 sequence magnetic resonance image showing prominent subarachnoid fluid, mild enlargement of lateral ventricles, and constriction of the spinal cord at the craniocervical junction. (Figure supplied by Dr. Ian J. Butler.)

that this was due to raised venous pressure in the jugular veins (Mueller and Reinertson, 1980). Clinically, this increased venous pressure may appear as prominent scalp veins. Hydrocephalus in achondroplasia may not be obvious clinically and is frequently discovered during routine evaluation of macrocephaly or neurologic manifestations such as gait impairment or weakness of the limbs (paraparesis or quadriparesis). Often during the first year of life, hydrocephalus may be suspected because of a bulging anterior fontanel. Although CT will often demonstrate the degree of ventricular dilation, magnetic resonance brain imaging will show more detailed anatomy (e.g., aqueductal stenosis) and also the presence of subependymal fluid, indicating decompensation of the hydrocephalus and potential need for surgical shunting. Computed brain tomography can be used serially to monitor for mild to moderate communicating types of ventricular dilation and surgical diversion of cerebrospinal fluid can often be avoided (King et al., 2009). Neuropsychological testing and evaluation by a neurosurgeon are indicated before deciding to perform a shunting procedure for clinically significant ventricular dilation (Dennis et al., 1961). A few cases of ventricular dilation have been attributed to severe jugular venous outflow obstruction. In these cases, venous angiography with venous pressure gradient evaluations are necessary prior to venous graft anastomosis of an internal venous sinus to an external vein in order to improve collateral circulation

Fig. 36.4. Sagittal T1 sequence magnetic resonance image showing prominent subarachnoid fluid, spinal stenosis at the craniocervical junction, and a large subdural hematoma following mild injury (falling) to the occiput that subsequently required a craniotomy for clot evacuation. (Reproduced from Hecht and Butler, 1990.)

and decrease venous backflow pressure (Sainte-Rose et al., 1984). Raised jugular venous pressure may produce dilated ventricles in young children due to communicating hydrocephalus, whereas in older subjects, pseudotumor cerebri occurs, with small ventricles (Sainte-Rose et al., 1984). The ability of the skull to expand in the young child prior to fusion of the sutures may account for this difference in clinical manifestations and outcome. Subdural hematomas have been observed in several children with achondroplasia without a history of severe head trauma (Fig. 36.4). Spontaneous onset of a subdural hematoma could be a result of enlarged subarachnoid spaces commonly observed in achondroplasia. Excessive movement of the brain within the relatively large skull could lead to rupture of bridging veins within the subarachnoid and subdural spaces. Other causes are related to postoperative ventriculoperitoneal shunting or leakage from a posterior fossa decompression site, with decreased intracranial pressure and dynamic shifts of brain structures leading to rupture of bridging veins. Because of the relatively large volume of the skull, the subdural collections may have minimal initial neurologic effects. However, such collections may be a prelude to further bleeding and increase in head circumference, necessitating neurosurgical decompression.

Craniocervical junction anomalies The bones of the cranial base and neural arches grow and enlarge by endochondral ossification. Thus, anomalies of the craniocervical junction are frequent in

NEUROLOGIC MANIFESTATIONS OF ACHONDROPLASIA achondroplasia and result from defective endochondral ossification (Hecht et al., 1985, 1989; Reid et al., 1987). The various components of the craniocervical junction in achondroplasia that can lead to neurologic complications include foramen magnum stenosis, upper cervical vertebral canal stenosis (C1, C2), abnormal odontoid shape or position, ligamentous laxity, and jugular foramen stenosis. The reduced growth of the occipital bones produces a small abnormally shaped foramen magnum in achondroplasia with markedly reduced transverse and sagittal dimensions (Fig. 36.5) (Hecht et al., 1985, 1989; Wang et al., 1987). The disparity in size of the foramen magnum is present at birth and the foramen remains small, particularly in the transverse diameter. Growth in this area is greatly diminished in both dimensions, especially during the first 18 months of life, at a time when maximum growth is expected. Although symptomatic and asymptomatic individuals with achondroplasia had similar foramen magnum dimensions at birth, the symptomatic individuals showed a nonsignficant decreased mean rate of growth in both dimensions (Hecht et al., 1989). The average adult foramen magnum in achondroplasia was the size of that in average-stature newborns and 2-year-olds in the transverse and sagittal dimensions, respectively. The failure of foramen magnum growth has been attributed not only to the defect in bone development, but also to premature fusion and aberrant development of the posterior synchondroses. The posterior fusion defect may also contribute to the hypertrophied margin of the posterior aspect of the foramen magnum that appears as a bony shelf radiologically and surgically, and projects into the posterior brainstem

Fig. 36.5. Axial computed tomography image of the craniocervical junction with “keyhole” stenosis of the foramen magnum. (Figure supplied by Dr. Ian J. Butler.)

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Fig. 36.6. Sagittal reconstruction of computed tomography image of the craniocervical junction with foramen magnum constriction anteriorly by the odontoid process and posteriorly by fused occiput and uppermost cervical neural arch. (Figure supplied by Dr. Ian J. Butler.)

(Fig. 36.6). This hypertrophied margin has been implicated in severe angulation and pressure necrosis of the brainstem at the level of the foramen magnum. Neurologic complications such as myelopathy, apnea, and sudden death, resulting from cervicomedullary compression, are now appreciated and recognized. The two vertebrae making up the atlantoaxial complex also contribute to the narrowing of the vertebral canal in the upper cervical region. Furthermore, the posterior neural arch of the atlas may fuse with the posterior margin of the foramen magnum. Defects in the odontoid process can also contribute to the neurologic morbidity. The odontoid process tends to project posteriorly and superiorly into the small foramen magnum, and the medulla oblongata is anatomically draped over this protuberance (Fig. 36.6). In particular, projection of the odontoid process into the anterior aspects of the medulla can lead to compression necrosis affecting the corticospinal tracts and may damage the arterial supply (anterior spinal artery) to the medulla and cervical cord, leading to more widespread neurologic damage (Nelson et al., 1988). Moreover, a posteriorly dislocated bulbous odontoid process has been noted in a case presenting with intermittent quadriparesis. Presumably, both odontoid process size and shape and ligamentous laxity in this patient accounted for the neurologic disorder. Bony stenosis and instability at the craniocervical junction can compress the cervicomedullary cord and

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upper spinal nerve roots. Serious complications associated with damage of the spinal cord at this high level include sudden infant death, sleep apnea syndrome, disorders of respiration, myelopathy, syringobulbia-myelia, and hydrocephalus.

Sudden death in children Sudden unexpected death has been described in infants with achondroplasia. Thirteen such cases were found and described in a retrospective case ascertainment study (Pauli et al., 1984). A cohort study of 781 individuals with achondroplasia confirmed that sudden death was significantly increased (Hecht et al., 1987). The risk of dying suddenly for those less than 1 year of age was 7.5%, and 2.5% from 1 to 4 years of age, suggesting that sudden death in achondroplasia was different from that occurring in the general population. The overall rate of sudden death in children less than 5 years was fiftyfold greater than would be expected in the age-matched average stature population (Wynn et al., 2007). It is now well established that compression at the level of the foramen magnum interferes with the respiratory control centers, causing cessation of respiration that may result in death of the infant with achondroplasia (Stokes et al., 1983; Pauli et al., 1984; Nelson et al., 1988). Sudden death often occurs during sleep, since respiratory control centers are particularly sensitive either to postural effects at the craniocervical junction (neck flexion) or to blood carbon dioxide and oxygen level changes during sleep. A few younger children have had recurrent diurnal apneic episodes, some of which may be alarmingly prolonged and misdiagnosed as a seizure disorder (Stokes et al., 1983; Fremion et al., 1984; Pauli et al., 1984; Nelson et al., 1988). Gliosis, edema, and cystic myelomalacia at the level of the medulla as previously noted at postmortem examination can cause disordered respiratory control center functions (Pauli et al., 1984). Both acute and chronic compression of the spinal cord by constriction at the foramen magnum may also be the basis of these complications.

Sudden death in adults Sudden death in adulthood is also significantly increased, starting at age 25 years in both males and females (Hecht et al., 1987; Wynn et al., 2007). This was first appreciated in a historical cohort study of 801 individuals with achondroplasia and then confirmed in 20 year follow-up study of the same cohort (Hecht et al., 1987; Wynn et al., 2007). Cardiovascular disease-related mortality between ages 25 and 35 years was more than 10 times higher than the general population. Neurologic causes of death were also significantly increased in adults, suggesting that long-term neurologic complications are underappreciated. The high

death rate in the adult achondroplastic population illustrates the need for risk factor assessment to identify specific risk factors and to develop treatment interventions.

Sleep apnea syndrome Various sleep apnea syndromes have been recognized in achondroplasia (Reid et al., 1984; Nelson et al., 1988). Commonly, children with achondroplasia have a history of excessive snoring at night and this symptom, together with excessive head retraction at rest, may be a valuable clinical clue as to the need for further studies of respiration. Recurrent apneic episodes during sleep can cause multiple arousals, sleepwalking, and enuresis. Lack of nocturnal sleep in these children can present with excessive daytime somnolence, excessive weight gain, poor linear growth, body fluid retention, headaches, behavior changes, and dyspnea. Many of these clinical problems are due to cor pulmonale with carbon dioxide retention during the apneic episodes, with reactive constriction of pulmonary vasculature. Sleep apnea syndromes in achondroplasia had previously been considered secondary to obstruction of the airway due to enlarged tonsils, glossoptosis, and pharyngolaryngeal wall laxity and redundancy. Recent studies have shown that there is a neural basis for some cases of sleep apnea (Reid et al., 1984; Nelson et al., 1988). Polysomnography has demonstrated the presence of obstructive, central, and mixed (obstructive and central) forms of apnea during sleep. Improvement in apnea, both obstructive and central types, has been observed following surgical enlargement of the foramen magnum and decompression of the medulla oblongata. Similar mixed polysomnographic findings have been observed in other neurologic conditions having clinically significant obstructive apnea, such as syringomyelia, poliomyelitis, and lateral medullary syndrome (Haponik et al., 1983). Presumably, foramen magnum stenosis causes damage to the medulla oblongata, impairing respiratory control mechanisms and leading to apnea during either wakefulness or sleep (Fremion et al., 1984; Nelson et al., 1988). In addition, apnea can result from injury to the motor nuclei of the brainstem that control reflex movements of the larynx and pharynx during respiration, such that discoordinated movements of the upper airway muscle wall during inspiration can cause severe airway obstruction. Awareness that obstructive apnea in achondroplasia may be due to a central brainstem etiology is important in management and may require surgical decompression of the foramen magnum and assisted methods of respiration.

Disorders of respiration Respiratory dysfunction is estimated to occur in up to 85% of achondroplastic children (Stokes et al., 1983;

NEUROLOGIC MANIFESTATIONS OF ACHONDROPLASIA Reid et al., 1984; Nelson et al., 1988). A number of factors have been implicated as having an etiologic role in impaired respiration and dyspnea in achondroplasia. A small chest circumference could restrict respirations; however, this does not appear to be a factor in the sleep apnea syndromes (Nelson et al., 1988; Bellus et al., 1995). Chest circumference is small in achondroplasia, but catch-up growth in the first 2 years of life usually leads to a normal chest circumference. Chest size was not found to correlate with respiratory dysfunction in children less than 2 years of age (Reid et al., 1984). Following progressive cervical myelopathy or as a complication after surgical decompression of the cervical cord, there may be impairment of phrenic nerve control of the diaphragm or spinal tracts to the intercostal nerves. The effect on respiration would depend on the degree of cord involvement and, in particular, whether there was unilateral or bilateral spinal cord injury. Two children presented with central respiratory abnormalities and marked foramen magnum compression initially had relief of respiratory problems following suboccipital decompression. Subsequently they developed mixed obstructive and central apnea on polysomnography and cor pulmonale. Response to treatment with continuous positive airway pressure (CPAP) at night with resolution of all symptoms suggested that central respiratory drive abnormalities were presenting as obstructive apnea (I.J. Butler, unpublished observations).

Myelopathy

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Fig. 36.7. Axial computed tomography (CT) image of the craniocervical junction showing a double calcified syrinx (double-barreled shotgun appearance) and a single calcified syrinx that is also demonstrated on sagittal CT reconstruction. (Reproduced from Hecht and Butler, 1990.)

Traumatic myelopathy of the medulla due to foramen magnum stenosis is a well-recognized complication in achondroplasia occurring at all ages, although in our experience it is more frequently recognized in infancy or younger children. Clinically, there may be extreme hypotonia in the infant, progressing to hypertonia with increased reflexes and extensor plantar responses. Older children may have impaired dorsal column sensation with a positive Romberg sign and gait disturbances progressing to quadriparesis.

traumatic cystic necrosis of the spinal cord, since similar findings have been observed in a child with achondroplasia who died suddenly (Pauli et al., 1984). A glioma and subependymal glioma associated with a syrinx were identified at postmortem examination in the brainstems of two children with achondroplasia (Fremion et al., 1984; Hecht et al., 1984). The association of cystic myelomalacia from chronic foramen magnum stenosis and tumor formation suggests an etiologic relationship.

Syringobulbia-myelia

Developmental delay

Syringomyelia as a consequence of progression of the cystic myelomalacia has been observed and this also appears to be on the basis of local compression of the spinal cord by the constricted foramen magnum (Yang et al., 1977; Hecht et al., 1987). Single, double (doublebarreled shotgun appearance), and elongated central calcified lesions were found in three individuals. These cystic lesions were observed as an incidental finding on CT and sagittal reconstruction to evaluate the size of the foramen magnum (Fig. 36.7) (Hecht et al., 1987). The cystic changes appear to be secondary to

Psychomotor delays in infants with achondroplasia have been frequently observed (Scott, 1976; Todorov et al., 1981; Hecht et al., 1991). Such delays in development have been attributed to a relatively large head compared to body size causing head lag, skeletal abnormalities, and ligamentous laxity at various joints. Although these explanations are generally accepted to explain failure to walk until age 2 years, neurologic factors may be present and hypotonia may be on a basis of myelopathy rather than solely due to ligamentous laxity. Children with achondroplasia usually have normal intelligence

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unless there are neurologic complications related to hydrocephalus, head injury, or impaired respiratory function such as sleep apnea with hypoxemia (Scott, 1976; Todorov et al., 1981). Studies using formal psychometric testing found intelligence quotients (IQs) of less than 80 in 10–16% of individuals with achondroplasia (Morris and MacGillivray, 1953; Rogers et al., 1979; Priestley and Lorber, 1981). One study suggested that individuals with severe ventricular dilation had decreased intelligence (Wassman et al., 1982). However, this impression was not confirmed with formal psychometric testing. One study using Bayley scales on achondroplastic children less than 40 months of age found a mean mental developmental index of 96 and mean motor developmental index of 65 (Hecht et al., 1991). The latter quotient reflects the severe motor delay characteristic of achondroplasia. Three children in this group with mental developmental indices of 85 (Hecht et al., 1991) had severe, chronic respiratory problems by history and polysomnography. The decreased mental developmental index was significantly correlated with respiratory dysfunction (p < 0.05). Frontal horn size did not correlate with decreased mental developmental index, suggesting that increased ventricular size was not the cause of mental retardation in this group. However, hydrocephalus resulting from aqueductal stenosis, although occurring rarely in achondroplasia, was the probable cause of mental retardation (IQs, 50 and 68) in two teenagers. Developmental charts for achondroplasia are available and should be used to monitor motor development. Hearing impairment may result from repeated otitis media and may significantly impact normal speech development. Articulation problems may be related to midface hypoplasia causing small maxillae and dental crowding or to lower cranial nerve or medullary dysfunction. Tongue thrusting is common, often requiring speech therapy.

Vertebral canal stenosis Vertebrae of the spinal canal are also involved because they are derived from endochondral bone ossification. Although there are defects of the vertebral bodies, including wedged vertebrae and posterior central bony spurring, most of the neurologic problems are secondary to the short pedicles and narrowing of the interpedicular distances (Fig. 36.8). Spinal canal stenosis occurs at all levels of the vertebral column. Bony narrowing of the lumbar vertebrae can potentially compress the spinal cord and nerve roots of the cauda equina and can be further exaggerated in individuals with excessive lordosis. Lumbar stenosis appears most commonly in early adulthood and is aggravated by excessive weight.

Fig. 36.8. Axial computed tomography image showing severe stenosis of the lumbar vertebral canal due to short pedicles and narrowing of the interpedicular distances. (Figure supplied by Dr. Ian J. Butler.)

Clinical symptoms and signs will depend on the level of spinal cord involvement and range from quadriparesis or quadriplegia from cervical cord stenosis to paraparesis or paraplegia from thoracolumbar region stenosis. Gradual impairment of gait and excessive falling from ataxia and spasticity are often the first symptoms. Temporary deterioration in spinal cord function is often closely related to minor closed trauma such as a blow to the spine, tripping and falling, or suddenly sitting down on the buttocks (Benglis and Sandberg, 2007). Deterioration in bladder or bowel function in patients with achondroplasia should be evaluated for spinal cord compression. Evaluation of bladder and bowel dysfunction in young children can be problematic but clinically important. Symptoms of intermittent claudication of the conus medullaris and cauda equina are frequently associated with lower spinal compression (Blau and Logue, 1961). Commonly, patients complain of pain radiating from the buttocks down one or both legs and associated with back pain. Pain, paresthesias, or dysesthesias are often apparent after exercise such as walking a short distance. Persistent pain with weakness of the legs and falling occurs unless the individual with achondroplasia sits down and rests or assumes a squatting position with their back to a vertical support such as a wall. These postures are thought to improve impaired blood supply to the conus medullaris and cauda equina by reducing the lumbar lordosis and decompressing the spinal cord

NEUROLOGIC MANIFESTATIONS OF ACHONDROPLASIA and nerve roots. This clinical feature is often dramatic and an indication of potentially progressive permanent loss of motor, sensory, bladder, and bowel functions of the lower spinal cord. Clinical examination may establish the extent and level of myelopathy. Dorsal column compression may affect vibration and proprioception sensations; however, in young children, demonstration of posterior cord compression may require laboratory evaluation using somatosensory evoked responses with stimulation of both of upper and of lower limbs (Nelson et al., 1984). Pain and electrical sensations up and down the cervical spinal cord (Lhermitte sign) can occur with neck flexion in the presence of cervical cord stenosis and may be a presenting manifestation after minor trauma such as a whiplash injury. Absent, depressed, or inverted deeptendon reflexes particularly in the upper arms, are often indicative of cervical or lumbar radiculopathy. Evaluation for suspected myelopathy in achondroplasia depends on the combination of CT to determine the level of bone compression and magnetic resonance imaging (MRI) to observe the level of cord compression as demonstrated by spinal cord narrowing, gliosis, or cystic changes (Fig. 36.7). Previously, myelography was performed; however, this is usually technically difficult because of the generalized spinal canal stenosis with severe and persistent back pain observed after myelography.

Vertebral column malalignment A gibbus deformity of the thoracolumbar vertebrae is common in achondroplastic infants and should be investigated by lateral radiographs of the involved vertebrae. Anterior wedging of one or more vertebral bodies is important, since angulation at this level can compress the conus medullaris and cauda equina. In younger children, wedging of the vertebrae should be carefully followed radiologically since angulation may be progressive. Usually, the gibbus deformity resolves with ambulation and onset of exaggerated lumbar lordosis. Bracing for residual L1 wedging in childhood may be effective in some children. Occasionally in the older patient, angulation becomes established and neurologic symptoms of paraparesis or intermittent claudication of the cauda equina are manifest. A combined orthopedic approach of laminectomy and angle reduction may be necessary to correct this thoracolumbar deformity. Scoliosis and kyphosis are infrequent in achondroplasia and usually do not contribute to the neurologic problems. However, lumbar lordosis and thoracolumbar gibbus formation cause neurologic morbidity. Marked angulation of the sacrum (Fig. 36.9) is a common malformation of the spine in achondroplasia and the degree of

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Fig. 36.9. Sagittal T1 sequence magnetic resonance image of the lumbosacral junction with severe lordosis and angulation of the sacrum and coccyx. (Figure supplied by Dr. Ian J. Butler.)

lordosis increases with age (Spillane, 1952). The causes of the sacral angulation to almost a right angle to the lumbar vertebrae are not well established but contribute to compression of nerve roots of the cauda equina. Occasionally lumbosacral lordosis is complicated by vertebral subluxation, which causes marked angulation and compression of the spinal cord (Fig. 36.10). Claudication of the cauda equina is most pronounced while standing or walking upright with maximum tendency to lumbosacral lordosis. Often, symptoms of intermittent claudication of the cauda equina are relieved by squatting and resting against a firm surface. These measures reduce the degree of lordosis at the lumbosacral junction.

Nerve root compression Compression of the nerve roots as they exit the spinal cord is a common problem in achondroplasia. Both the abnormal shortening of the pedicles of the vertebrae and small neural foramina are contributory. Narrowing of neural foramina can occur at multiple levels but is usually clinically significant in the cervical and lumbar regions. Patients complain of distal dysesthesias and paresthesias in the upper and lower limbs, with loss of tendon reflexes and focal muscle wasting on examination. Depressed triceps reflex unilaterally or bilaterally with an inverted reflex (flexion at the elbow) is an early sign of nerve root compression in the arms. Occipital neuralgia is not uncommon in achondroplasia and is caused by compression of the occipital nerve or

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Fig. 36.10. Sagittal T2 magnetic resonance image of the lumbosacral junction showing severe lordosis complicated by vertebral body anterior subluxation and vertebral body anterior wedging that caused vertebral “gibbus” deformity and subsequent compression of the conus medullaris and cauda equina. (Reproduced from Hecht and Butler, 1990.)

nerves exiting through the posterior atlanto-occipital membrane. Presumably, the nerve is entrapped by the fibrous membrane or by proximity to the posterior lip of the foramen magnum and posterior arch of the atlas (which may be fused in achondroplasia) (Fig. 36.6). Complaints of paresthesias or headache in the occipital region of the scalp or an area of anesthesia in the distribution of the occipital nerves should suggest occipital neuralgia. However, these symptoms may be difficult to distinguish clinically from those due to narrowing of the foramen magnum with compression of the cervicomedullary junction. Electromyographic examination of specific muscle groups will assist localization of particular nerve roots that are functionally compressed. Often, following surgical enlargement of the neural foramina either at the time of laminectomy or laminoplasty (Yoshii and Traynelis, 2009), or occasionally as an isolated procedure at one or more foramina, there is improved motor and sensory function. Occipital neuralgia can be treated by occipital neurectomy provided that significant craniocervical junction compression has been excluded by neuroimaging.

HOMOZYGOUS ACHONDROPLASIA Homozygous achondroplasia will occur in a quarter of offspring produced from a union between two individuals with heterozygous achondroplasia (Scott, 1976; Hall, 1988; Horton et al., 2007). Most homozygous

infants die at birth or in the early months of life as a result of respiratory complications (Hall, 1969; Pauli et al., 1983). Initially, respiratory complications, including cor pulmonale, were attributed to the extremely small chest size and restrictive pulmonary disease (Hall et al., 1969). However, the severe bone dysplasia affects not only the long bones but also the bones of the vertebral column and the foramen magnum, which is extremely small (Hecht et al., 1986). As a result of stenosis at the craniocervical junction, there may be marked compression of the medullary respiratory centers and neural outflow pathways with subsequent apnea and respiratory insufficiency. The recognition that some of the respiratory complications could be related to medullary and cervical spinal cord compression has led to a more aggressive approach to treatment, with prolonged survival (Pauli et al., 1983; Hecht et al., 1986; Moskowitz et al., 1989). However, long-term survival has not been demonstrated, and the requirement for prolonged respiratory support raises ethical and clinical questions as to the efficacy of this surgical intervention. Motor delay and hypotonic quadriparesis or quadriplegia are neurologic complications of homozygous achondroplasia. Hydrocephalus may be evident on neuroimaging studies and require shunting procedures. The physical characteristics of these infants with homozygous achondroplasia are qualitatively similar to, but quantitatively much more severe than, those in heterozygous achondroplasia (Shiang et al., 1994).

MANAGEMENT OF ACHONDROPLASIA Management of achondroplasia utilizes a multidisciplinary approach to follow and evaluate patients and is agedependent (Fig. 36.1). Diagnosis is generally made by a geneticist based on clinical, genetic, and radiographic findings (Langer et al., 1968; Scott, 1976). Following diagnosis, complete neurologic assessment by a neurologist experienced in evaluating patients with achondroplasia at all ages should be performed with special attention to developmental milestones, degree of hypotonia, and ligamentous laxity. Head size should be carefully monitored on a monthly basis during the first year of life and annually thereafter. Any deviation from normal head growth for achondroplasia should be an indication for further study. Hypotonia and delayed motor development should not be assumed to be related only to ligamentous laxity, since impaired motor skills may well be an early manifestation of spinal cord paralysis. After 3 months of age, we have found that somatosensory evoked responses in both upper and lower limbs may be helpful in evaluating the dorsal columns, since neurologic assessment of spinal cord functions can be difficult in a child younger than 5 years (Nelson et al., 1984).

NEUROLOGIC MANIFESTATIONS OF ACHONDROPLASIA Furthermore, somatosensory evoked responses can be assessed serially and also before, during, and after surgical decompression of the spinal cord (Sciubba et al., 2007). Abnormalities of somatosensory evoked responses and transcranial electrical stimulation-induced motor evoked potentials may also have localizing value in assessing the level of cord dysfunction, since the neurologic examination and neuroimaging may not be informative, particularly if there is diffuse canal stenosis. CT with particular attention to the posterior fossa was initially utilized to study neurologic complications in patients with achondroplasia. CT permits evaluation of the brain and ventricles in addition to the foramen magnum size and growth centers. General population and achondroplastic foramen magnum values are available (Hecht et al., 1985, 1989). Sagittal reconstruction of the posterior fossa and upper cervical canal permits more detailed assessment of the relationship of the bones of the craniocervical junction, and soft-tissue structures can also be evaluated. Sagittal views enable visualization of the odontoid process as well as the posterior neural arches of the atlas and axis and may indicate multiple levels of cord compression, in addition to the small foramen magnum. Similar studies can be performed at the cervical and lumbar levels to demonstrate canal stenosis at these potentially significant sites. Currently, MRI of the brain and spinal cord is used to define the anatomic level of hydrocephalus and degree of ventricular compensation (e.g., presence or absence of subependymal cerebrospinal fluid extravasation) or compression of the spinal cord (Fig. 36.11). Spinal cord gliosis, edema, and narrowing are more readily apparent on MR imaging of the cord, and an area of cystic necrosis or syringomyelia can be readily visualized at the level of compression. MRI and venography and even dynamic MR imaging (in flexion and extension) can be performed on achondroplastic individuals of all ages and has largely supplanted CT scanning in assessing neurologic complications in achondroplasia (Danielpour et al., 2007). Children with clinical respiratory problems must be assessed in order to define the relative contribution of peripheral (small chest cage, enlarged tonsils) and central (neurologic) mechanisms producing stridor, apnea, snoring, repeated pneumonia, or respiratory distress. In addition to chest radiographs and direct visualization of the upper airways, polysomnography has been used to investigate the nature of the respiratory disorder and, particularly, whether sleep apnea is present. Achondroplastic individuals with abnormal polysomnograms may need further evaluation for cor pulmonale, including an electrocardiogram and echocardiogram. Intensive study of achondroplasia in the last several decades has led to a greater understanding of the neurologic morbidity associated with the bony abnormalities of the

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Fig. 36.11. Sagittal T2 sequence magnetic resonance image of the craniocervical junction, cervical and upper thoracic spinal cord and showing stenosis of the foramen magnum with decreased subarachnoid fluid indicating widespread vertebral canal stenosis. (Figure supplied by Dr. Ian J. Butler.)

condition. Studies suggest that the associated complications, such as myelopathy, apnea, respiratory drive abnormalities, and sudden death are not uncommon. Careful attention should be paid to children with achondroplasia in order to identify those at high risk for these complications. Identification and correction of these problems in childhood and adulthood will assist in averting long-term and possibly irreversible neurologic complications and may increase longevity and the quality of life of subjects with achondroplasia of all ages.

ACKNOWLEDGMENTS We are indebted to Dr Charles I. Scott, Jr., who suggested more than 30 years ago, based on his clinical observations, that there were serious neurologic complications in achondroplasia.

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