Upper Cervical Myelopathy in Achondroplasia S. SAMUEL YANG, M.D., DAVID P. CORBETT, M.D., A. JOSEPH BROUGH, M.D., KATHLEEN P. HEIDELBERGER, M.D., AND JAY BERNSTEIN, M.D.
Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, Michigan; Departments of Radiology and Laboratory Medicine, Children's Hospital of Michigan and Wayne State University School of Medicine, Detroit, Michigan; Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
heterozygous type, according to current roentgenographic,13,24"26 and histopathologic criteria.10,19,21,32 Each baby had a small foramen magnum and pathologic evidence of severe damage to the corresponding segment of the upper cervical spinal cord. The first was a newborn who had respiratory failure; the second succumbed to cardiopulmonary complications at the age of 6 months. One can speculate that upper cervical spinal cord injury in newborns is often obscured by respiratory distress and that not all lesions are necessarily fatal in the newborn period. Sublethal injury may persist into later infancy and early childhood, and in such cases the patients may be salvageable by appropriate surgical intervention. 3
ALTHOUGH a small foramen magnum with compression of the upper cervical spinal cord and the caudal medulla has been recognized as a complication of achondroplasia for approximately three quarters of a century, 1,3-7 ' 12,18,20 the findings have been based upon relatively few cases with only gross examination, 4-6 which seems inadequate for the understanding of the problem. Furthermore, in the light of recent advances in the field of skeletal dysplasia and separation of many disorders confused with achondroplasia,17,26 redocumentation of this rare neurologic complication becomes desirable. We recently encountered two infants with achondroplasia, one each of the homozygous type and the
Report of Two Cases Case I. A 2,040-g, dwarfed male infant was delivered by cesarean section in the thirty-eighth week of gestation. The father was 28 years old and the mother 26 years old; both were achondroplastic dwarfs. The mother had been treated for diabetes during the pregnancy. Examination of the baby at birth showed a large head, frontal bossing, a flat nasal bridge, a constricted, bell-shaped thoracic cage, and marked rhizomelia. The baby was apneic, pale and cyanotic. Heart beats were inaudible. The baby was kept alive after resuscitation for 12 hours. Laboratory examination of the blood revealed: sugar 35 mg/dl; pH 6.95, Pco2 69 mm Hg, Po2 13 mm Hg; 0 2 saturation less than 53%. Postmortem roentgenograms showed a large head, a short cranial base, a small thoracic cage, severe platyspondyly with equal interpediculate distances throughout the lumbar spine, small iliac bones with scalloped lower margins, and extremely shortened appendicular (tubular) bones, especially the humeri
Received July 26, 1976; accepted for publication August 26, 1976. Presented as an abstract at the Twelfth Annual Meeting of the Pediatric Pathology Club, Boston, Massachusetts, March 20, 1976. Address reprint requests to Dr. Yang: Department of Anatomic Pathology, William Beaumont Hospital, 3601 West 13 Mile Road, Royal Oak, Michigan 48072. 68
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Yang, S. Samuel, Corbett, David P., Brough, A. Joseph, Heidelberger, Kathleen P., and Bernstein, Jay: Upper cervical myelopathy in achondroplasia. Am J Clin Pathol 68: 68-72, 1977. Two achondroplastic infants had small foramina magna with lethal compression of the corresponding upper cervical spinal cords. The damage was histologically comparable to the hyperextension type of spinal cord injury. An anterior displacement of the foramen magnum was demonstrated in one of the two cases. The displacement is considered worthy of future verification as it may be an additional factor in susceptibility to hyperextension injury to the spinal cord. The second patient survived 6 months, demonstrating that not all upper cervical spinal cord injuries are immediately fatal. Patients who have sublethal lesions are potentially salvageable by surgery. It is also speculated that there might be more cases of nonlethal upper cervical spinal-cord damage in achondroplasia, especially in early infancy when infants are unable to hold their heads erect. The true incidence of slight upper cervical spinal cord damage is not known, although it is considered rare at present. As a result of the findings in these two cases, it is suggested that hyperextension of the head be avoided, when possible. (Key words: Achondroplasia; Foramen magnum; Cervical myelopathy.)
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The mother gave birth to a female neonate with similar lethal dwarfism two years later. The baby died of respiratory insufficiency 83 days after birth. A thoracoplasty to augment the thoracic capacity was not beneficial. Review of the autopsy failed to demonstrate pathologic changes in the sections of brain stem and spinal cord, perhaps because the lesion was not present or perhaps because the proper segments had not been taken for examination. Case 2. A white, male infant was the product of an uneventful full-term pregnancy. The birth weight was 3,460 g. The diagnosis of achondroplasia was made at birth. The father and mother were 35 and 32 years of age, respectively. Three older sisters and two older brothers were living and well. There was no family history of dwarfism. Apneic spells and seizures developed when the infant was 11 weeks old. The seizures were atonic, grand mal, and myoclonic in type. The baby had rhizomelia and a large head, with a circumference in the ninetieth percentile. His nasal bridge was depressed. Neurologic examination showed no evidence of increased intracranial pressure. No sensory deficiency was demonstrable. The patellar reflex was brisk. There were, however, poor grasp and muscular hypotonia. Two electroencephalograms were considered normal. Examination of the urine revealed a normal pattern of amino acids and no excretion of mucopolysaccharide. The roentgenographic changes of the skeletal system were very
similar to those in the first case: large cranium with short base and small foramen magnum, flat vertebral bodies, less prominent than in the first case, equal interpediculate distances throughout the lumbar vertebrae, small iliac bones, and proximal shortening of tubular bones with oval, radiolucent, proximal femoral metaphyses. Thefindingswere consistent with heterozygous achondroplasia. I3!M~2G Clinical examination revealed an arrhythmia that was characterized by alternating severe tachycardia and bradycardia, wandering pacemaker, and sinus node arrest. At the age of 3 months, right and left cardiac catheterization showed no hemodynamic abnormality. An epicardial pacemaker was inserted because of the clinical diagnosis of sick-sinus syndrome. However, episodes of apnea and seizures persisted. Electroencephalograms demonstrated grade I dysrhythmia in the posterior region. The subsequent clinical course was complicated by frequent pneumonia. The infant died at the age of 6 months, because of aspiration pneumonia followed by progressive respiratory failure and cor pulmonale. The postmortem examination recapitulated the clinical findings. The head was large, and the brain (830 g) was heavier than average (660 g). There was no hydrocephalus. The foramen magnum was markedly reduced in size, especially in the anteroposterior diameter (Fig. 3). The upper cervical cord and the caudal medulla oblongata were grossly unremarkable. Histologically, however, the upper cervical cord contained a very short segment with central cystic myelomalacia (Fig. 4). The abnormal segment was so short that only a few microscopic sections could be obtained. The affected area, which was more prominent posteriorly, encompassed both posterior horns and was surrounded by gliosis. Multinucleated astrocytes and ferruginated neurons were present. A few relatively preserved neurons were seen only in the anterior portions of the anterior horns. No definite evidence of hematomyelia was seen. There was slight demyelination in the posterior columns. Histologic examination of the remaining central nervous system was unremarkable. Examination of the skeletal system revealed considerable stunting of endochondral ossification. Columnization of chondrocytes was preserved in the physis. The findings were in general consistent with heterozygous achondroplasia,19-21 though some disorganization of chondrocytes was seen in the peripheral physis. Other pertinentfindingsincluded severe, hemorrhagic, aspiration pneumonia and biventricular cardiac hypertrophy, consistent with mild cor pulmonale. No cardiac abnormality was found to account for the arrhythmia. Discussion A small foramen magnum in achondroplasia has been thought to cause neonatal death by compressing the upper cervical spinal cord and caudal medulla oblongata. 1,3_7 ' 12 ' 18,20 To our knowledge, the histologic changes in the spinal cord have not been described. The lack of detailed study has probably stemmed from two factors: (1) the occurrence of most cases in the newborn without corresponding clinical neurologic studies; (2) the difficulty in obtaining well preserved upper cervical spinal cord through the unusually small foramen magnum, an area inaccessible to routine postmortem dissection. A more intensive study of injuries to the lower spinal cord due to small spinal canal and deformity in older patients with achondroplasia has been done. 28
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and femora. The findings were consistent with homozygous achondroplasia. ">'12 Postmortem body measurements were as follows: c?own-toheel length 39.5, crown-to-rump length 30.5, head circumference 34.5, chest circumference 23, abdominal circumference 27, and outstretched arm span 33 cm. The head was large because its circumference was much larger than the normal of crown-rump length plus 2.5 cm.3' The anterior fontanelle wasflatand measured 3 cm; the posterior fontanelle, 1 cm. The cranial sutures were widely separated and averaged 0.5 cm in width. The central nervous system was dissected and examined in situ after injection of formalin into the aorta and the carotid arteries and afterfixationof the whole body in formalin for a week. The posterior cranial fossa was shallow. The foramen magnum was very small, especially its anteroposterior diameter, which was 0.4 cm. The brain weighed 224 g (normal 281 ± 54 g for a newborn of this body weight), and there was no dilatation of ventricular system. Slight intraventricular hemorrhage with subarachnoid extension was present. The subarachnoid space was wider than usual. The gross configuration of the cerebrum and cerebellum was unremarkable. The brain stem, however, was located abnormally posterior to the foramen magnum. Consequently, the upper cervical cord and lower medulla oblongata were angulated anteriorly (Fig. 1), and a 0.5-cm segment was gray and soft. Histologic examination (Fig. 2) showed the involved area to be cervical cord with poor demarcation of the gray matter, which was the site of gliosis and slight vascular proliferation. Only a few pyknotic neurons were seen in the anterior portions of anterior horns. Hematomyelia was not seen. The white matter had undergone demyelination. Gliosis, slight vascular proliferation, and dystrophic axons were also present in the posterior columns. The surrounding meninges and dura were not fibrotic or hemorrhagic. The vessels within the meninges showed no abnormality. The remaining spinal cord below the lesion appeared unremarkable, although the spinal canal was small. Histologic examination of the skeletal system showed markedly retarded and disorganized endochondral ossification, consistent with homozygous achondroplasia.'0'32 The other postmortem findings included moderate pulmonary hypoplasia and diffuse atelectasis with hyaline membrane formation.
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A.J.C.P. . July 1977
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FIG. 1. (tipper, left). Gross photograph of the head and neck, Case 1, showing anteriorly displaced small foramen magnum (arrow). The corresponding upper cervical cord is displaced anteriorly, resulting in anterior angulation. Some soft tissue of the foramen magnum was trimmed to show the spinal cord. FIG. 2 (lower, left). Photomicrograph of the upper cervical cord at the foraman magnum, Case 1. Notice the poorly demarcated gray matter with gliosis and slight vascular proliferation. A few pyknotic neurons are present in the anterior horn (arrow). Only vessels (curved arrow) and slight gliosis are present in the posterior horn region. Gliosis and vascular proliferation are also discernible in the posterior columns. The central canal is indicated at the arrowhead. V = ventromedialfissure;D = dorsomedial sulcus. Hematoxylin and eosin. x32. FIG. 3. (upper right). Small foramen magnum in Case 2. The anteroposterior diameter is markedly diminished. In normal individuals, the anteroposterior diameter is larger than the transverse diameter. C = clivus; P = petrous bone; O = occipital sinus. FIG. 4 (lower, right). Photomicrograph of the upper cervical cord at the foramen magnum, Case 2. Cystic myelomalacia involves the posterior portion of the gray matter and trie immediately adjacent white matter. The anterior horn region (arrow) has a barely demonstrable neuronophage. Curved arrow = posterior horn; arrowhead = central canal; V = ventromedial fissure; D = dorsomedial sulcus. Hematoxylin and eosin. x32.
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The segment of central nervous system at the foramen magnum in normal individuals is the lower part of the medulla oblongata. 27 The same segment in our two cases, however, had the histologic features of spinal cord, confirming several previous observations. 3,6 The brain stem appeared to be displaced upward. Wise and associates 30 reported an unusually high position of the basilar artery relative to a short clivus, providing additional support for that interpretation. Possible explanations are: (1) a relatively small shallow posterior fossa in a large cranium; (2) basilar impression of the skull.11,30 which was not seen in our two cases; (3) anterior displacement of the foramen magnum, which increases the distance from the midbrain (cerebral peduncle) to the foramen and results in upward displacement of the brain stem. The three factors might be operative in combination.
Gross examination in one case also showed anterior angulation of the upper cervical cord at the foramen magnum, which is interpreted as an antemortem abnormality because the tissue was fixed in situ with formalin prior to dissection. Other specimens, both normal and abnormal, dissected in the same way have
not shown similar abnormalities and have remained in orthodox configuration after fixation. The anterior angulation of upper cervical cord is interpreted, therefore, as due to the anterior displacement of the small foramen magnum and as an additional factor in traumatization of the cord. Even with the head held in a normal position, the upper cervical spinal cord was anteriorly displaced and angulated, equivalent to 57 degrees of hyperextension (the angle formed by axis of brain stem and spinal cord). The angulation would be greater in dorsiflexion of the head, thus increasing the risk of injury. The cord would then be vulnerable to any maneuver requiring hyperextension of the head, as in intubating the patient or in clearing the airway after delivery and during management of postnatal respiratory distress. The anterior displacement of foramen magnum in relation to the brain stem in our first case is not described in the literature. It might be explained by shortening of the cranial base, which arises from endochondral ossification and is affected in achondroplasia. The foramen magnum is located near the rear end of the chondrocranium, so that the foramen might move anteriorly should the chondrocranium become abnormally short. Since shortening of the cranial base is a common feature of achondroplasia, one suspects that the displacement of foramen might occur frequently. A recent study of cranial bones in chondrodystrophies 15 indicates that only the supraoccipital, exoccipital and basioccipital portions of the occipital bone are significantly affected in achondroplasia and in thanatophoric dwarfism, resulting in marked narrowing of the foramen magnum. Since the remaining cranial bones are not significantly affected, the posterior margin of the foramen is more anteriorly displaced than the anterior margin. 15 The frequency of upper cervical spinal cord damage should be considered very low at the present time, because only a few cases have been reported. 4 - 6 One might speculate, however, that there should be more nonlethal cases, since small foramen magnum is a regular feature of achondroplasia 17 ' 26 and since babies are constantly subjected to hyperextension of the head in early infancy. If the diagnosis is difficult in early infancy, as in our second case, then many milder, nonlethal lesions could have been overlooked in the past. It is commonly known that achondroplastic dwarfs are slow in development of motor milestones and are hypotonic in the first months of life,16,17 although they have normal intelligence in later life. Perhaps the early hypotonia might actually be a slight quadriparesis, due to slight compression of the cord at the foramen magnum. Asssuming this hypothesis is correct, dorsiflexion of the head should
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The distribution of the pathologic changes in the spinal cords of our two cases is very similar to the "traumatic central spinal cord syndrome" following hyperextension injury,2,22 in which the damage is mainly in the central gray matter and the white matter is usually preserved. The location of the lesion, which was most prominent in the posterior gray matter of the cord in our two cases, also appears identical to that of the experimental spinal-cord injury induced in monkeys by impact trauma on the posterior surface of the cord. 29 This form of injury, which is mediated through the extremely vulnerable microvasculature of grey matter, is analogous to hyperextension, which also produces impact trauma. Backward displacement of the cervical spine with compression of the corresponding spinal cord has also been described to occur in hyperextension injuries,14 but the same mechanism does not apply to our patients since no backward shearing force was involved. The damage in each of our cases was located in a very short segment. Were the changes secondary to arterial insufficiency rather than impact trauma, we would expect to find lesions more distally, several neural segments below the site of compression. 23 The pathologic changes were, however, exactly at the site of compression, and distant lesions attributable to vascular insufficiency were not found. Compression of the anterior spinal artery in spinal injury of achondroplasia was considered by Vogl and Osborne, 28 but its validity was questioned by Duvoisin and Yahr. 8
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be avoided in achondroplastic newsborns and infants. Should progressive neurologic signs be manifested, a suboccipital craniectomy and upper cervical laminectomy may be indicated. Cohen and colleagues 3 have reported a case of successful surgical decompression. A 5-year-old child was treated by suboccipital craniectomy and upper cervical laminectomy because of paraparesis, difficulty in walking, weakness of the right arm, and absent proprioception in the arms and legs. Our second patient might have been helped by a similar procedure, but a precise neurologic diagnosis was not achieved, perhaps because of the difficulty in evaluating such a young patient. The signs of progressive upper cervical spinal-cord damage include quadriparesis, paraparesis, seizures, apneic spells, and probably cardiac arrhythmia. 9
1. Bergstrom K, Laurent U, Lundberg PO: Neurological symptoms in achondroplasia. Acta Neurol Scand 47:59-70, 1971 2. Bosch A, Stauffer ES, Nickel VL: Incomplete traumatic quadriplegia: A ten-year review. JAMA 216:473-478, 1971 3. Cohen ME, Rosenthal AD, Matson DD: Neurological abnormalities in achondroplastic children. J Pediatr 17:367376, 1967 4. Cohn S, Weinberg A: Identical hydrocephalic achondroplastic twins; subsequent delivery of single sibling with the same abnormalities. Am J Obstet Gynecol 72:1346-1348, 1956 5. Collmann B: Beitrag zur Kenntniss der Chondrodystrophia foetalis. Virchows Arch Pathol Anat 166:1-12, 1901 6. Dennis JP, Rosenberg HS, Alvord EC: Megalencephaly, internal hydrocephalus and other neurological aspects of achondroplasia. Brain 84:427-445, 1961 7. Draps MH: Hydrocephalic congenitale et achondroplasie. Bull Fed Soc Gynecol Obstet Franc 4:903-910, 1952 8. Duvoisin RC, Yahr MD: Compressive spinal cord and root syndromes in achondroplastic dwarfs. Neurology 12:202207, 1962 9. Frankel HL, Mathias CJ. Splading JMK: Mechanisms of reflex cardiac arrest in tetraplegic patients. Lancet 2:1183, 1975 10. Hall JG, Dorst JP, Taybi H, et al: Two probable cases of homozygosity for the achondroplasia gene. Birth Defects 5:24-34, 1969 11. Hancock DO, Phillips DG: Spinal compression in achondroplasia. Paraplegia 3:23-33, 1965
12. Jansen M: The causation of the condition known as achondroplasia. J Anat 47:360-362, 1912 13. Langer LO Jr, Baumann PA, Gorlin RJ: Achondroplasia. Am J Roentgenol Radium Ther Nucl Med 100:12-26, 1967 14. Marar BC: Hyperextension injuries of the cervical spine. J Bone Joint Surg 56-A: 1655-1662, 1974 15. Marin-Padilla M, Marin-Padilla TM: Malformation of the occipital bone in human chondrodystrophies (abstr). Am J Pathol 82:4a, Feb 1976 (accepted for publication, Hum Pathol) 16. Maroteaux P, Lamy M: Achondroplasia in man and animals. Clin Orthop 33:91-103, 1964 17. McKusick VA: Heritable Disorder of Connective Tissue. Fourth edition. St. Louis, C. V. Mosby, 1972, pp 750759 18. Nelson MA: Orthopedic aspects of the chondrodystrophies. Ann R Coll Surg Engl 47:185-210, 1970 19. Ponseti IV: Skeletal growth in achondroplasia. J Bone Joint Surg52-A:701-716, 1970 20. Potter EL, Coverstone VA: Chondrodystrophy fetalis. Am J Obstet Gynecol 56:790-793, 1948 21. Rimoin DL, Hughes GNF, Kaufman RL, et al. Endocrondral ossification in achondroplastic dwarfism. N Engl J Med 283:728-735, 1970 22. Schneider RC, Cherry G, Pantek H: The syndrome of acute central cervical spinal cord injury. J Neurosurg 11:546-577, 1954 23. Schneider RC, Schemm GW: Vertebral artery insufficiency in acute and chronic spinal trauma. J Neurosurg 18:348-360, 1961 24. Silverman FN, Briinner S: Errors in the diagnosis of achondroplasia. Acta Radiol 6:305-321, 1967 25. Silverman FN; A differential diagnosis of achondroplasia. Radiol Clin North Am 6:223-237, 1968 26. Silverman FN: Achondroplasia. Prog Pediatr Radiol 4:94-124, 1973 27. Vakili H: The Spinal Cord. New York, International Medical Book Corporation, 1967, p 5 28. VogI A, Osborne RL: Lesions of the spinal cord (transverse myelopathy) in achondroplasia. Arch Neurol Psychiat 61:644-662, 1949 29. White RJ: Pathology of spinal cord injury in experimental lesions. Clin Orthop 12:16-26, 1975 30. Wise BL, Sondheimer F, Kaufman S: Achondroplasia and hydrocephalus. Neuropediatrie 3:106-113, 1971 31. Yang S-S, Chen Y-C, Brough AJ, et al: Correlation of head circumference and crown-rump length in newborn infants. Biol Neonate 27:308-317, 1975 32. Yang S-S, Heidelberger KP, Brough AJ, et al: Lethal shortlimbed chondrodysplasia in early infancy, Perspectives in Pediatric Pathology. Volume 3. Edited by Rosenberg HS, Bolande RP. Chicago, Year Book Medical Publishers, Inc., 1976, pp 1-40
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References
A.J.C.P. . July 1977
Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, Michigan; Departments of Radiology and Laboratory Medicine, Children's Hospital of Michigan and Wayne State University School of Medicine, Detroit, Michigan; Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
heterozygous type, according to current roentgenographic,13,24"26 and histopathologic criteria.10,19,21,32 Each baby had a small foramen magnum and pathologic evidence of severe damage to the corresponding segment of the upper cervical spinal cord. The first was a newborn who had respiratory failure; the second succumbed to cardiopulmonary complications at the age of 6 months. One can speculate that upper cervical spinal cord injury in newborns is often obscured by respiratory distress and that not all lesions are necessarily fatal in the newborn period. Sublethal injury may persist into later infancy and early childhood, and in such cases the patients may be salvageable by appropriate surgical intervention. 3
ALTHOUGH a small foramen magnum with compression of the upper cervical spinal cord and the caudal medulla has been recognized as a complication of achondroplasia for approximately three quarters of a century, 1,3-7 ' 12,18,20 the findings have been based upon relatively few cases with only gross examination, 4-6 which seems inadequate for the understanding of the problem. Furthermore, in the light of recent advances in the field of skeletal dysplasia and separation of many disorders confused with achondroplasia,17,26 redocumentation of this rare neurologic complication becomes desirable. We recently encountered two infants with achondroplasia, one each of the homozygous type and the
Report of Two Cases Case I. A 2,040-g, dwarfed male infant was delivered by cesarean section in the thirty-eighth week of gestation. The father was 28 years old and the mother 26 years old; both were achondroplastic dwarfs. The mother had been treated for diabetes during the pregnancy. Examination of the baby at birth showed a large head, frontal bossing, a flat nasal bridge, a constricted, bell-shaped thoracic cage, and marked rhizomelia. The baby was apneic, pale and cyanotic. Heart beats were inaudible. The baby was kept alive after resuscitation for 12 hours. Laboratory examination of the blood revealed: sugar 35 mg/dl; pH 6.95, Pco2 69 mm Hg, Po2 13 mm Hg; 0 2 saturation less than 53%. Postmortem roentgenograms showed a large head, a short cranial base, a small thoracic cage, severe platyspondyly with equal interpediculate distances throughout the lumbar spine, small iliac bones with scalloped lower margins, and extremely shortened appendicular (tubular) bones, especially the humeri
Received July 26, 1976; accepted for publication August 26, 1976. Presented as an abstract at the Twelfth Annual Meeting of the Pediatric Pathology Club, Boston, Massachusetts, March 20, 1976. Address reprint requests to Dr. Yang: Department of Anatomic Pathology, William Beaumont Hospital, 3601 West 13 Mile Road, Royal Oak, Michigan 48072. 68
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Yang, S. Samuel, Corbett, David P., Brough, A. Joseph, Heidelberger, Kathleen P., and Bernstein, Jay: Upper cervical myelopathy in achondroplasia. Am J Clin Pathol 68: 68-72, 1977. Two achondroplastic infants had small foramina magna with lethal compression of the corresponding upper cervical spinal cords. The damage was histologically comparable to the hyperextension type of spinal cord injury. An anterior displacement of the foramen magnum was demonstrated in one of the two cases. The displacement is considered worthy of future verification as it may be an additional factor in susceptibility to hyperextension injury to the spinal cord. The second patient survived 6 months, demonstrating that not all upper cervical spinal cord injuries are immediately fatal. Patients who have sublethal lesions are potentially salvageable by surgery. It is also speculated that there might be more cases of nonlethal upper cervical spinal-cord damage in achondroplasia, especially in early infancy when infants are unable to hold their heads erect. The true incidence of slight upper cervical spinal cord damage is not known, although it is considered rare at present. As a result of the findings in these two cases, it is suggested that hyperextension of the head be avoided, when possible. (Key words: Achondroplasia; Foramen magnum; Cervical myelopathy.)
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The mother gave birth to a female neonate with similar lethal dwarfism two years later. The baby died of respiratory insufficiency 83 days after birth. A thoracoplasty to augment the thoracic capacity was not beneficial. Review of the autopsy failed to demonstrate pathologic changes in the sections of brain stem and spinal cord, perhaps because the lesion was not present or perhaps because the proper segments had not been taken for examination. Case 2. A white, male infant was the product of an uneventful full-term pregnancy. The birth weight was 3,460 g. The diagnosis of achondroplasia was made at birth. The father and mother were 35 and 32 years of age, respectively. Three older sisters and two older brothers were living and well. There was no family history of dwarfism. Apneic spells and seizures developed when the infant was 11 weeks old. The seizures were atonic, grand mal, and myoclonic in type. The baby had rhizomelia and a large head, with a circumference in the ninetieth percentile. His nasal bridge was depressed. Neurologic examination showed no evidence of increased intracranial pressure. No sensory deficiency was demonstrable. The patellar reflex was brisk. There were, however, poor grasp and muscular hypotonia. Two electroencephalograms were considered normal. Examination of the urine revealed a normal pattern of amino acids and no excretion of mucopolysaccharide. The roentgenographic changes of the skeletal system were very
similar to those in the first case: large cranium with short base and small foramen magnum, flat vertebral bodies, less prominent than in the first case, equal interpediculate distances throughout the lumbar vertebrae, small iliac bones, and proximal shortening of tubular bones with oval, radiolucent, proximal femoral metaphyses. Thefindingswere consistent with heterozygous achondroplasia. I3!M~2G Clinical examination revealed an arrhythmia that was characterized by alternating severe tachycardia and bradycardia, wandering pacemaker, and sinus node arrest. At the age of 3 months, right and left cardiac catheterization showed no hemodynamic abnormality. An epicardial pacemaker was inserted because of the clinical diagnosis of sick-sinus syndrome. However, episodes of apnea and seizures persisted. Electroencephalograms demonstrated grade I dysrhythmia in the posterior region. The subsequent clinical course was complicated by frequent pneumonia. The infant died at the age of 6 months, because of aspiration pneumonia followed by progressive respiratory failure and cor pulmonale. The postmortem examination recapitulated the clinical findings. The head was large, and the brain (830 g) was heavier than average (660 g). There was no hydrocephalus. The foramen magnum was markedly reduced in size, especially in the anteroposterior diameter (Fig. 3). The upper cervical cord and the caudal medulla oblongata were grossly unremarkable. Histologically, however, the upper cervical cord contained a very short segment with central cystic myelomalacia (Fig. 4). The abnormal segment was so short that only a few microscopic sections could be obtained. The affected area, which was more prominent posteriorly, encompassed both posterior horns and was surrounded by gliosis. Multinucleated astrocytes and ferruginated neurons were present. A few relatively preserved neurons were seen only in the anterior portions of the anterior horns. No definite evidence of hematomyelia was seen. There was slight demyelination in the posterior columns. Histologic examination of the remaining central nervous system was unremarkable. Examination of the skeletal system revealed considerable stunting of endochondral ossification. Columnization of chondrocytes was preserved in the physis. The findings were in general consistent with heterozygous achondroplasia,19-21 though some disorganization of chondrocytes was seen in the peripheral physis. Other pertinentfindingsincluded severe, hemorrhagic, aspiration pneumonia and biventricular cardiac hypertrophy, consistent with mild cor pulmonale. No cardiac abnormality was found to account for the arrhythmia. Discussion A small foramen magnum in achondroplasia has been thought to cause neonatal death by compressing the upper cervical spinal cord and caudal medulla oblongata. 1,3_7 ' 12 ' 18,20 To our knowledge, the histologic changes in the spinal cord have not been described. The lack of detailed study has probably stemmed from two factors: (1) the occurrence of most cases in the newborn without corresponding clinical neurologic studies; (2) the difficulty in obtaining well preserved upper cervical spinal cord through the unusually small foramen magnum, an area inaccessible to routine postmortem dissection. A more intensive study of injuries to the lower spinal cord due to small spinal canal and deformity in older patients with achondroplasia has been done. 28
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and femora. The findings were consistent with homozygous achondroplasia. ">'12 Postmortem body measurements were as follows: c?own-toheel length 39.5, crown-to-rump length 30.5, head circumference 34.5, chest circumference 23, abdominal circumference 27, and outstretched arm span 33 cm. The head was large because its circumference was much larger than the normal of crown-rump length plus 2.5 cm.3' The anterior fontanelle wasflatand measured 3 cm; the posterior fontanelle, 1 cm. The cranial sutures were widely separated and averaged 0.5 cm in width. The central nervous system was dissected and examined in situ after injection of formalin into the aorta and the carotid arteries and afterfixationof the whole body in formalin for a week. The posterior cranial fossa was shallow. The foramen magnum was very small, especially its anteroposterior diameter, which was 0.4 cm. The brain weighed 224 g (normal 281 ± 54 g for a newborn of this body weight), and there was no dilatation of ventricular system. Slight intraventricular hemorrhage with subarachnoid extension was present. The subarachnoid space was wider than usual. The gross configuration of the cerebrum and cerebellum was unremarkable. The brain stem, however, was located abnormally posterior to the foramen magnum. Consequently, the upper cervical cord and lower medulla oblongata were angulated anteriorly (Fig. 1), and a 0.5-cm segment was gray and soft. Histologic examination (Fig. 2) showed the involved area to be cervical cord with poor demarcation of the gray matter, which was the site of gliosis and slight vascular proliferation. Only a few pyknotic neurons were seen in the anterior portions of anterior horns. Hematomyelia was not seen. The white matter had undergone demyelination. Gliosis, slight vascular proliferation, and dystrophic axons were also present in the posterior columns. The surrounding meninges and dura were not fibrotic or hemorrhagic. The vessels within the meninges showed no abnormality. The remaining spinal cord below the lesion appeared unremarkable, although the spinal canal was small. Histologic examination of the skeletal system showed markedly retarded and disorganized endochondral ossification, consistent with homozygous achondroplasia.'0'32 The other postmortem findings included moderate pulmonary hypoplasia and diffuse atelectasis with hyaline membrane formation.
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YANG ET AL.
A.J.C.P. . July 1977
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FIG. 1. (tipper, left). Gross photograph of the head and neck, Case 1, showing anteriorly displaced small foramen magnum (arrow). The corresponding upper cervical cord is displaced anteriorly, resulting in anterior angulation. Some soft tissue of the foramen magnum was trimmed to show the spinal cord. FIG. 2 (lower, left). Photomicrograph of the upper cervical cord at the foraman magnum, Case 1. Notice the poorly demarcated gray matter with gliosis and slight vascular proliferation. A few pyknotic neurons are present in the anterior horn (arrow). Only vessels (curved arrow) and slight gliosis are present in the posterior horn region. Gliosis and vascular proliferation are also discernible in the posterior columns. The central canal is indicated at the arrowhead. V = ventromedialfissure;D = dorsomedial sulcus. Hematoxylin and eosin. x32. FIG. 3. (upper right). Small foramen magnum in Case 2. The anteroposterior diameter is markedly diminished. In normal individuals, the anteroposterior diameter is larger than the transverse diameter. C = clivus; P = petrous bone; O = occipital sinus. FIG. 4 (lower, right). Photomicrograph of the upper cervical cord at the foramen magnum, Case 2. Cystic myelomalacia involves the posterior portion of the gray matter and trie immediately adjacent white matter. The anterior horn region (arrow) has a barely demonstrable neuronophage. Curved arrow = posterior horn; arrowhead = central canal; V = ventromedial fissure; D = dorsomedial sulcus. Hematoxylin and eosin. x32.
Vol. 68 • No. I
ACHONDROPLASIA AND CERVICAL MYELOPATHY
The segment of central nervous system at the foramen magnum in normal individuals is the lower part of the medulla oblongata. 27 The same segment in our two cases, however, had the histologic features of spinal cord, confirming several previous observations. 3,6 The brain stem appeared to be displaced upward. Wise and associates 30 reported an unusually high position of the basilar artery relative to a short clivus, providing additional support for that interpretation. Possible explanations are: (1) a relatively small shallow posterior fossa in a large cranium; (2) basilar impression of the skull.11,30 which was not seen in our two cases; (3) anterior displacement of the foramen magnum, which increases the distance from the midbrain (cerebral peduncle) to the foramen and results in upward displacement of the brain stem. The three factors might be operative in combination.
Gross examination in one case also showed anterior angulation of the upper cervical cord at the foramen magnum, which is interpreted as an antemortem abnormality because the tissue was fixed in situ with formalin prior to dissection. Other specimens, both normal and abnormal, dissected in the same way have
not shown similar abnormalities and have remained in orthodox configuration after fixation. The anterior angulation of upper cervical cord is interpreted, therefore, as due to the anterior displacement of the small foramen magnum and as an additional factor in traumatization of the cord. Even with the head held in a normal position, the upper cervical spinal cord was anteriorly displaced and angulated, equivalent to 57 degrees of hyperextension (the angle formed by axis of brain stem and spinal cord). The angulation would be greater in dorsiflexion of the head, thus increasing the risk of injury. The cord would then be vulnerable to any maneuver requiring hyperextension of the head, as in intubating the patient or in clearing the airway after delivery and during management of postnatal respiratory distress. The anterior displacement of foramen magnum in relation to the brain stem in our first case is not described in the literature. It might be explained by shortening of the cranial base, which arises from endochondral ossification and is affected in achondroplasia. The foramen magnum is located near the rear end of the chondrocranium, so that the foramen might move anteriorly should the chondrocranium become abnormally short. Since shortening of the cranial base is a common feature of achondroplasia, one suspects that the displacement of foramen might occur frequently. A recent study of cranial bones in chondrodystrophies 15 indicates that only the supraoccipital, exoccipital and basioccipital portions of the occipital bone are significantly affected in achondroplasia and in thanatophoric dwarfism, resulting in marked narrowing of the foramen magnum. Since the remaining cranial bones are not significantly affected, the posterior margin of the foramen is more anteriorly displaced than the anterior margin. 15 The frequency of upper cervical spinal cord damage should be considered very low at the present time, because only a few cases have been reported. 4 - 6 One might speculate, however, that there should be more nonlethal cases, since small foramen magnum is a regular feature of achondroplasia 17 ' 26 and since babies are constantly subjected to hyperextension of the head in early infancy. If the diagnosis is difficult in early infancy, as in our second case, then many milder, nonlethal lesions could have been overlooked in the past. It is commonly known that achondroplastic dwarfs are slow in development of motor milestones and are hypotonic in the first months of life,16,17 although they have normal intelligence in later life. Perhaps the early hypotonia might actually be a slight quadriparesis, due to slight compression of the cord at the foramen magnum. Asssuming this hypothesis is correct, dorsiflexion of the head should
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The distribution of the pathologic changes in the spinal cords of our two cases is very similar to the "traumatic central spinal cord syndrome" following hyperextension injury,2,22 in which the damage is mainly in the central gray matter and the white matter is usually preserved. The location of the lesion, which was most prominent in the posterior gray matter of the cord in our two cases, also appears identical to that of the experimental spinal-cord injury induced in monkeys by impact trauma on the posterior surface of the cord. 29 This form of injury, which is mediated through the extremely vulnerable microvasculature of grey matter, is analogous to hyperextension, which also produces impact trauma. Backward displacement of the cervical spine with compression of the corresponding spinal cord has also been described to occur in hyperextension injuries,14 but the same mechanism does not apply to our patients since no backward shearing force was involved. The damage in each of our cases was located in a very short segment. Were the changes secondary to arterial insufficiency rather than impact trauma, we would expect to find lesions more distally, several neural segments below the site of compression. 23 The pathologic changes were, however, exactly at the site of compression, and distant lesions attributable to vascular insufficiency were not found. Compression of the anterior spinal artery in spinal injury of achondroplasia was considered by Vogl and Osborne, 28 but its validity was questioned by Duvoisin and Yahr. 8
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be avoided in achondroplastic newsborns and infants. Should progressive neurologic signs be manifested, a suboccipital craniectomy and upper cervical laminectomy may be indicated. Cohen and colleagues 3 have reported a case of successful surgical decompression. A 5-year-old child was treated by suboccipital craniectomy and upper cervical laminectomy because of paraparesis, difficulty in walking, weakness of the right arm, and absent proprioception in the arms and legs. Our second patient might have been helped by a similar procedure, but a precise neurologic diagnosis was not achieved, perhaps because of the difficulty in evaluating such a young patient. The signs of progressive upper cervical spinal-cord damage include quadriparesis, paraparesis, seizures, apneic spells, and probably cardiac arrhythmia. 9
1. Bergstrom K, Laurent U, Lundberg PO: Neurological symptoms in achondroplasia. Acta Neurol Scand 47:59-70, 1971 2. Bosch A, Stauffer ES, Nickel VL: Incomplete traumatic quadriplegia: A ten-year review. JAMA 216:473-478, 1971 3. Cohen ME, Rosenthal AD, Matson DD: Neurological abnormalities in achondroplastic children. J Pediatr 17:367376, 1967 4. Cohn S, Weinberg A: Identical hydrocephalic achondroplastic twins; subsequent delivery of single sibling with the same abnormalities. Am J Obstet Gynecol 72:1346-1348, 1956 5. Collmann B: Beitrag zur Kenntniss der Chondrodystrophia foetalis. Virchows Arch Pathol Anat 166:1-12, 1901 6. Dennis JP, Rosenberg HS, Alvord EC: Megalencephaly, internal hydrocephalus and other neurological aspects of achondroplasia. Brain 84:427-445, 1961 7. Draps MH: Hydrocephalic congenitale et achondroplasie. Bull Fed Soc Gynecol Obstet Franc 4:903-910, 1952 8. Duvoisin RC, Yahr MD: Compressive spinal cord and root syndromes in achondroplastic dwarfs. Neurology 12:202207, 1962 9. Frankel HL, Mathias CJ. Splading JMK: Mechanisms of reflex cardiac arrest in tetraplegic patients. Lancet 2:1183, 1975 10. Hall JG, Dorst JP, Taybi H, et al: Two probable cases of homozygosity for the achondroplasia gene. Birth Defects 5:24-34, 1969 11. Hancock DO, Phillips DG: Spinal compression in achondroplasia. Paraplegia 3:23-33, 1965
12. Jansen M: The causation of the condition known as achondroplasia. J Anat 47:360-362, 1912 13. Langer LO Jr, Baumann PA, Gorlin RJ: Achondroplasia. Am J Roentgenol Radium Ther Nucl Med 100:12-26, 1967 14. Marar BC: Hyperextension injuries of the cervical spine. J Bone Joint Surg 56-A: 1655-1662, 1974 15. Marin-Padilla M, Marin-Padilla TM: Malformation of the occipital bone in human chondrodystrophies (abstr). Am J Pathol 82:4a, Feb 1976 (accepted for publication, Hum Pathol) 16. Maroteaux P, Lamy M: Achondroplasia in man and animals. Clin Orthop 33:91-103, 1964 17. McKusick VA: Heritable Disorder of Connective Tissue. Fourth edition. St. Louis, C. V. Mosby, 1972, pp 750759 18. Nelson MA: Orthopedic aspects of the chondrodystrophies. Ann R Coll Surg Engl 47:185-210, 1970 19. Ponseti IV: Skeletal growth in achondroplasia. J Bone Joint Surg52-A:701-716, 1970 20. Potter EL, Coverstone VA: Chondrodystrophy fetalis. Am J Obstet Gynecol 56:790-793, 1948 21. Rimoin DL, Hughes GNF, Kaufman RL, et al. Endocrondral ossification in achondroplastic dwarfism. N Engl J Med 283:728-735, 1970 22. Schneider RC, Cherry G, Pantek H: The syndrome of acute central cervical spinal cord injury. J Neurosurg 11:546-577, 1954 23. Schneider RC, Schemm GW: Vertebral artery insufficiency in acute and chronic spinal trauma. J Neurosurg 18:348-360, 1961 24. Silverman FN, Briinner S: Errors in the diagnosis of achondroplasia. Acta Radiol 6:305-321, 1967 25. Silverman FN; A differential diagnosis of achondroplasia. Radiol Clin North Am 6:223-237, 1968 26. Silverman FN: Achondroplasia. Prog Pediatr Radiol 4:94-124, 1973 27. Vakili H: The Spinal Cord. New York, International Medical Book Corporation, 1967, p 5 28. VogI A, Osborne RL: Lesions of the spinal cord (transverse myelopathy) in achondroplasia. Arch Neurol Psychiat 61:644-662, 1949 29. White RJ: Pathology of spinal cord injury in experimental lesions. Clin Orthop 12:16-26, 1975 30. Wise BL, Sondheimer F, Kaufman S: Achondroplasia and hydrocephalus. Neuropediatrie 3:106-113, 1971 31. Yang S-S, Chen Y-C, Brough AJ, et al: Correlation of head circumference and crown-rump length in newborn infants. Biol Neonate 27:308-317, 1975 32. Yang S-S, Heidelberger KP, Brough AJ, et al: Lethal shortlimbed chondrodysplasia in early infancy, Perspectives in Pediatric Pathology. Volume 3. Edited by Rosenberg HS, Bolande RP. Chicago, Year Book Medical Publishers, Inc., 1976, pp 1-40
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References
A.J.C.P. . July 1977
