TriE PAiHOGENESIS OF AND DYSRAPHISf,i ABSTRACT

A review of the clinical and pathological findings in 30 patients with further defines the distinct pathological anatomy of diastematomYelia and further elucidates its association \'/ith a variety of other midline dysraphic anomalies. These definitions allow the formulation of an integrative, universal hypothesis on the origin of virtually all forms of spina bifida and dysraphism and cranium bifidum. The essence of the hypothesis is the formation, in early embryonic life (18-30 d.), of a sagittal cleft of the embryonic neuraxis which involves neuroectoderm, noto­ chord, and endoderm. Incorporation of a persistent neurenteric canal is invoked to explain the origin of the neuraxis cleft. Sequential events of cleft formation, cleft healing and faulty delayed closure of the are proposed as yielding a spectrum of dysraphic anomalies, ranging from combined anterior and posterior spina bifida through open myeloceles to myelodysplasia, spina bifida occulta, and certain midline developmental tumors. THE PATHOGENESIS OF SPINA BIFIDA AND DY S RA PHI S r·1: CLUES FROM DIASTEMATOMYELIA

EV

HENRY PAIGE TUTT, M. V.

A Thesis submitted to the Faculty of Graduate Studies and Research in partial fu1fi1lment of the requirements for the degree of Master of Science.

Department of Neurology and Montreal Neuro1ogica1 Institute, f1cGil1 University, r·1ontrea 1•

June 1973

® Henry paige Tutt 1973 To

Sandy, M,Lc.ha.e1 and Re.be.c.ca. THE PATHOGENESIS OF SPINA BIFIDA

AND DY S RA PHI S M: CLUE S F R0 f1 DIA STE MAT 0 MYE LIA TABLE OF CONTENTS

I. CLINICAL MATERIAL A. Introduction...... 1 Purpose. . . . • . . • . • . • . • • • . . 1 Historica1 Review of Diastematomye1ia ...... •. 2 B. f~ateria1s and r~ethods ...... •...... 3 C. Results...... 3 Inci dence • • . • . . . • 3 Symptoms ...... • . . • . . .4 Si gns . . . • ...... 5 Radio1ogy ...... •. 7 Operative Studies . . . .9 Operative experience .9 Operative findings. • . • • . . 11 Autopsy Study . . • . • • • • . . 13 D. Discussion of Resu1ts . . . 14 Revi e\'l of the Li terature . • . . . . . • 14 Summary of Resu1 ts • • . . • ...... • . .21 II. PRESENTATION OF THE HYPOTHESIS A. Pertinent Embryology • . • . . . . • • • . . • • •. .24 B. Previous Hypotheses •....•..•...... 26 Primary Medullary Plate Abnormality (Nonclosure) .• 27 Abnormal Notochord Induction .••....•.... 27 Disturbances of the Blastopore ..•••••..•. 28 Atresia of the Rhornbencephalic Roof. • • 29 C. Current Hypothes i s . • . • • • . • . • . . • • 30 D. Hypothetical Mechanisms • • . . . • • 32 Cranio-cervico-thoracic Lesions· • 32 Thoraco-lumbar Lesions ...... 34 Lumbo-sacro-coccygeal Lesions . • 39 Heal ing of Neuraxis Clefts • . • •. . ·39 E. Relationship to Previous Hypotheses • • • • . . ·42 F. Clefts of the Brain Primordium . . • . ·45 Chiari Deformit'ies • . • . • ·45 Dandy-Wa 1ker Syndrome ...... ·50 III. SUMMARY AND CONCLUSIONS· •.... 54 IV. BIBLIOGRAPHY AND ACKNOWLEDGEMENTS • 57 V. APPENDIX ••••....•••• 71 CLINICAL MATERIAL

l rMTROVUCfION

Pwr.pO.6e

There has been a tendency among clinicians to etiologically

link, under the broad categories of spina bifida and dysraphism, a \~ide variety of midline lesions of ectodermal, mesodermal and endodermal origin. It is the objective of the present study to advance an integ­ rative, universal hypothesis \lfhich relates a corrmon etiological factor in the teratogenesis of various lesions associated with spina bifida and dysraphism, including prevertebral lesions (alimentary fistulae, diverti­ culae, and ; mediastinal cysts), vertebral body anomalies, intra­ spinal neurenteric cysts, , cranium bifidum, , combined anterior and posterior spina bifida, diastematornyelia, spina bifida cystica and occulta, hydrornyelia and , various forrns of congenital , sorne developmental spinal tumors, and pilo­ nidal cysts and fistulae. The Chiari deforrnities and the Dandy-Walker syndrome, as well as other midline cranial malformations, are also explicable in terms of the hypothesis. It is submitted that a study of diastematomyelia, a lesion v/hich represents a most extreme form of dysraphism, offers valuable clues, in terms of its distinct pathological anatomy and in terms of its associations, to the understanding of the embryogenesis of all these conditions. The hypothesis is advanced primarily on the basis of clinical and pathological observations, although sorne experimental and embryological observations are cited in support. 2.

H,u:toJt-i..c.a1.. Re.v-Lew 06 V-é..M:te.matomyeLi.a.

The lesion in diastematomyelia is characterized by a sagittal cleft of the which extends over one or several segments. The term diastematomyeLia was introduced by Ollivier (1837) in a study of several congenital neuropathological 1esions. Various other terms

have been applied to the anomaly, such as dipLomyeLia~ dupLication and

redupLication~ but Lichtenstein (1940) and Benstead (1953) have clarified that the lesion represents a symmetrical halving of the spinal cord or its anlage, the neural plate or tube, rather than actual duplication of cord elements. Although the lesion was well knmm in pathological material, it vias not diagnosed during life until 1913, when encountered at operation for meningomyelocele (Zale\'/ska-Ploska, 1913). In the usual cases of surgi cal significance, the spinal cord cleft is bridged by a septum of , carti l age or fi brous ti ssue, \'/hi ch tethers the cord and prevents its ascent with later disproportionate grO\'ith bet\'/een the spinal column and spinal cord. The lesion was first diagnosed in its purer form at operation by Hamby (1936), who provided the first clear documentation of the beneficial effect of surgery. By 1950, an additional 5 cases had been reported in which a diagnosis had been made at operation and defini­ tive surgical therapy applied (Herren and Edwards, 1940; Harr and Uihlein, 1944; Walker, 1944; Maxwell and Bucy, 1946; Pickles, 1949). 1'1atson et al. (1950) first reported the condition diagnosed preoperatively and since their report, over 100 cases have appeared in the literature, mostly as smal1 series or isolated case reports, but clarifying the essential diagnostic features of the entity. These include cutaneous lesions, gait disturbance, foot deformity, sphincter dysfunction and focal neurological 3.

deficit of one or both lm'ler extremities. Halker, in 1944, first pointed Oüt the radiological finding in diastematomye1ia of a widened without erosion of pedicles, and later reports (Neuhauser, Wittenborg, and Dehlinger, 1950; Cow;e, 1951, 1952; Gryspeerdt, 1963) stressed such radio­ logica1 features as bony dysraphism, abnorrnally developed vertebrae, the presence of a mid1ine osseous spicule and the importance of tomography and mye10graphy in diagnosis.

MATERIALS AND METHOVS A relatively large group of patients \'1ith diastematomye1ia has provided a rare opportunity to elucidate the relative incidence of the clinical and radio1ogica1 features of this anoma1y and further define its patho1ogy. The c1inical records, operative reports, radio­ graphs, and patho1ogica1 specimens of 30 c1inical cases of diastemato­ mye1ia diagnosed during 1ife and seen at the t10ntreal Neuro1ogical Hospital since 1937 were reviewed and forrned the basis of the hypothesis advanced in this study. In addition, the records of a separate, morbid case of diastematomYelia were reviewed.

RESULTS

Inudenc.e

Fig. 1 demonstrates the age at diagnosis and sex distribution of the entire series. The patients fal1 into 2 distinct groups, a juvenile group comprising 25 patients ranging in age from 1 day to 12 11/12 years, and an adu1t group comprising 5 patients ranging in age from 19 6/ 12 years to 26 B/ 12 years. The average age of the juvenile group was 4 11/ 12 years.

The average age of the adult group was 22 3/ 12 years. Twenty-one (70%) of the patients were fema1es. A11 of the patients were Caucasian and of chiefly French Canadian descent, except for a single Negro fema1e chi1d. JUVENILE ADULT 4

..en Il Female C 3 .-..Q) ~Male C Q. ë5 2 VD~~ .a-Q) :;E 1 Z

1 3 5 7 9 11 13 19 21 23 25 27 Age at Diagnosis I-'igure 1. Age at diagnosis and sex distribution of 30 clinica1 cases of diastematomyelia. 4.

A significant family history \'/as obtained in 4 patients. The father of one patient had a hairy patch over the lumbar spine. A sister of one patient had a prominent hairy patch over the midline back. One patient had blo sibl ing cousins \'/ho had foot deformities present since early infancy, one of v/hom \'Ias also mentally retarded. A brother of one patient had undergone operation at the Montreal Neurological Hospital sorne years previously for cranium bifidum and encephaloceie.

S!f17lptOm6

Table l contrasts the chief complaints of the two groups of patients. vias the most frequent chief complaint of the juvenile group \'Iith compl aints rel ated to a disturbance of gait being next oost frequent. T\'IO patients \'Iere diagnosed as a resul t of investigation of a foot deformity. Three patients were diagnosed at sorne time in the course of investigation and treatment of spina bifida cystica and/or hydrocephalus. Back pain \'/as the most frequent chief complaint of the adult group, with complaints related to sphincter dysfunction comprising the remainder. The average duration of the chief complaint in the juvenile group was 4 3hz years; in the adult group, it \'Ias 7 months. Three adult patients had no symptoms prior to the development of the chief complaint. One of the adult patients had undergone correction of a foot deformity 16 years previously. Another had undergone repair of a lumbar meningocele in early infancy with subsequent seemingly static weakness and atrophy of a lower extremity and development of progressive scoliosis. This patient developed vesical sphincter dysfunction following a spinal fusion for chronic back pain and application of a spica cast. Chief Complaint No. of Chief Complaint No. of iuvenile patients Cases adult group Cases

ScoÎiosis i2 Back Pain 3 Limp 7 Constipation 1 Foot deformity 2 Urinary dysfunction 1 Spina Bifida' Cystica 2 Hydrocephalus 1 Cutaneous 1 ) Total 25 5

Table 1. Chief complaints of 30 patients with diastematomYelia. 5.

A history of stress \'1as elicited as a factor in the development of the chief complaint in 3 other adult patients. One developed back pain following a prolonged motorcycle ride; a student nurse developed back pain after lifting a patient; and a third patient related the development of back pain to posture assumed in her recent job in a garment factory. A history of stress could not be elicited in the adult patient who spontaneously developed constipation of a severe degree 9 months prior to admission. All principal symptoms given by the patients on admission are listed in Table II.

S-i.gM

The principal objective findings, juvenile and adult groups compared, are listed in Table III. The findings listed were established by physical examination and raàiological procedures other than plain films of the spine and myelography. The most frequent findings among the juvenile group were cutaneous lesions, gait disturbance, scoliosis, foc a1 \'/eakness and atrophy with refl ex changes in the 1m'1er extremit i es, and foot deformity. In the adult group, the most frequent findings were back tenderness, sphincter disturbance, weakness and atrophy in the lm'/er extremities, and focal sensory deficit in the 10\oJer extremities. Of the entire series, 24 patients had cutaneous lesions over the midline spine. These lesions consisted of areas of hypertrichosis, hemangiomas, hyperpigmentation, dimples, diffusely thickened subcutaneous fat pads, spina bifida cystica, or various combinations of these. The No. of Cases No. ~f Cases Symptom iuvenile adults Total Cutaneous 16 1 17 Scoliosis 13 1 14 Focal weakness leg 12 2 14 Sphincter Disturbance 7 4 11 Limp 9 0 9 Foot deformity 8 1 9 Baek pain 1 5 6 Shortiiess, ~e9 2 1• 3 Radiating leg 0 or trunk pain 3 3 Sensory loss 0 2 2

Table IL Principal symptoms of 30 patients with diastematomYelia. ~ .. \.~j \ "'" 1

Findings Juvenile Adult Total Concurrent Abnormalitiœs Juvenile Adult T.)tal

Cutaneous 22 2 24 Spinci Bifida Cystica 9 2 11 Limp 16 0 16 Underdeveloped Hip 5 0 5 Scoliosis 15 2 17 Hydrocephalus 5 0 5 Focal Weakness Legs 15 3 18 Arnold- 4 0 4 Absent KJ / AJ 14 2 16 Sprengel's Deformity Shoulder 3 0 3 Foot Deformity 13 1 14 Klippel-Feil Syndromo 2 0 2 Focal Atrophy Legs 13 3 16 Hyportelorism 2 0 2 Sphincter Involvement 9 4 13 Strabismus 2 0 2 Dim. KJ/AJ 9 2 11 Aqueductal Stenosis 2 0 2 Secondary Chest Deformity 6 0 6 Congenital Dislocation Hip 2 0 2 Focal Sensory Loss 6 3 9 Bilateral Inguinal 2 0 2 Pelvic Tilt 5 1 6 Bilateral Scrotal Hydrocoele 1 0 1 Absent Abdominals 4 0 4 Patent Ductus Arteriosus 1 0 1 Hyperreflexia Legs 4 1 5 Pectus Excavatum 1 0 1 Extensor Plantar Response 3 1 4 Esophageal Diverticulum 1 0 1 Proprioceptive Loss 1 2 3 Pilonidal Sinus 1 0 1 Back Tenderness 0 5 5 Cervical Rib 1 0 1 Limited Straight Lag Raising 0 2 2 Unilateral Weakness 1 0 1 Upper Extremity Table III. Principal Objective findings of 30 patients with diastematomYelia.

-1 6.

most frequent lesions were either pure hypertrichosis, sometimes luxuriant and arranged in a Iponytai1" fashion (fig. 2), or a combination of hyper­ trichosis and hemangioma. A depigmented area \·lith peripheral hypertrichosis was seen in the single Negro patient. In 13 patients, the cutaneous lesion directly overlay the level of the diastematomyelia. In 6 patients, the cutaneous abnormality was 1 or 2 segments adjacent to the level of the dividing septum and presumably within the confines of the spinal cord cleft. In 5 patients (16.6%), the cutaneous lesion was \'lidely removed from both the cleft cord and the dividing septum. The significance of these remote cutaneous les ions vlill become apparent in a later section of this study dealing with the teratogenesis of this anomaly. Further pertinent to the understanding of the teratogenesis of this condition is the high incidence of spina bifida cystica and other congenital abnormalities in the series. Over 1/3 of the patients had spina bifida cystica, this les ion usually having been previously treated. Five juvenile patients either had hydrocephalus in association with spina bifida cystica or had experienced transient hydrocephalus after previous repair of such a lesion. Of these patients, 4 had radiological evidence of sorne degree of the Chiari deformity and 2 of these were also demonstrated to have aqueductal stenosis, hypertelorism and strabismus. Three patients had the unusual anomaly of congenital elevation of the shoulder, two of whom also had the clinical and radiological stigmata of the Klippel-Feil syndrome. One patient \'lith diastematomyelia at Tll had an air-fi11ed structure projecting into the posterior mediastinum which was thought to represent an esophageal diverticulum. Figure 2. Hypertrichosis overlying the cord les ion in a patient with diastematomyelia. The typical scoliosis seen in these patients is well demonstrated.

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Figure 2. Hypertrichosis overlying the cord lesion in a patient with diastematomyelia. The typical scoliosis seen in these patients is well demonstrated. 7.

Ra.cüo.f.ogy

The principal spinal radiological features in the series are summarized in Table IV, which demonstrates the relative frequency of each feature. Sorne degree of scoliosis l'las radiologically demonstrated in 2/3 of all cases. A bony spicule or peg bridging the spinal canal at sorne level was visualized on plain films of the spine in 23 of the 30 patients, and this constituted the most frequent radiological feature. Of the 7 ptltients in which a spicule l'las not visualized, operation confirmed the presence of a cartilaginous septum in one, a fibrous septum in another, and an osseo-fibrous septum in another. Of the remaining 4 patients who did not undergo operation, myelography confirmed a cleft cord around a filling defect in 3 patients, and in one patient, the cleft cord l'las directly visualized through a thin myelocele covering. Other frequently noted abnormalities included anomalous vertebral bodies, a category which included large bodies, dysplastic bodies, asym­ metrically developed bodies, "butterfly vertebrae", and hemivertebrae; posterior bony of varying degrees, ranging from spina bifida occulta to virtually complete rachischisis of several segments; a widened spinal canal without erosion of pedicles; and vertebral fusion defects (black vertebrae). Less frequently noted were rib anomalies, errors in segmentation, and sacrococcygeal hypoplasia or agenesis. There are two points from Table IV l'ihich l'iarrant further consi­ deration for an embryologica1 interpretation of diastematomyelia. 1) Anomalous vertebral bodies were found in 21 patients (70%) and a widened spinal canal \"Jithout erosion of pedicles \'1as found in 22 patients (73%). If both these categories are combined and considered as representing evi­ dence of delayed union of separate cleft vertebral half centra (a split noto­ chord), then such evidence l'las radiologically demonstrated in 23 cases (93%). \! )

Case Humber Total Total Total Radiological Finding 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 2324 25 Juvenile Al A2 A3 A4 A5 Adult Cases Scoliosis x x x x x x x x x x x x x x x x 16 x x x x 4 20 Anomalous Vertebral Bodies ® ® x ® x x ® ® x ® ® ® x x® ® x x x 19 ® ® 2 21 Posterior Bony Rachischisis x ® ® ® ® x ® ® ® ® ® ® x x x x ® x 18 ® x ® ® 4 22 Widened Canal 20 2 22 Cervical x x x x (4) (0) (4) Thoracic ® x x x x® x x x x ® ® x ® ® (15) ® (1 ) (16) lumbosacral x ® ® ® ® ® x x® ® ® ® x® x (15) ® (1) (16) Visible Peg x x x x x x x x x x x x x x x x x x x x 20 x x x 3 23 Fusion Defects(block vertebrae) 12 5 17 Vertebral Body x x x® ® x (6) ® ® 2 (8) Apophyseal Joints x x x ® x x (6) 0 (6) Posterior Arches ® x ® ® ® (5) x ® ® 3 (8) Error in Segmentation x x x 3 x 1 4 Rib Anomalies x® x x x x x x x x ® 11 x 1 12 Sacrococcygeal Hypoplasia or Agenesis x x x x x x 6 x 1 7 Myelogram done x x x x x x x x x x x x x x x x x x x x 20 x x x x x 5 25 TI2 TI level of Septum T7 L2 LI L4 L4 L3 L3 LI Tn TI2 L3 LI L2 Ls L3 LI L2 TI2 Ts T6 L2 T9 T9 LI Tll TlQ L3 Til I+L2 TI2

Table IV. Spinal radiological findings in 30 patients with diastematon~elia. A circled radiolog1cal finding denotes that the feature corr'elated with the level of the dividing septum or cord cleft.

1 8.

It is conceivable that tomography might have demonstrated such evidence in all of the cases. 2) The table demonstrates that each of the radio- logical features, such as anomalous vertebral bodies, might frequently occur widely removed from the actual level of the spinal cord cleft. An example is seen in patient 6, \'/ho had diastematomyelia at L4 with a visible bony peg at that level, but with vertebral body anomalies and a widened spinal canal in the cervical and thoracic regions.

Diagnosis was confirmed by myelography in 25 patients. Charac­ teristically, splitting of the oil column occurred over several segments within t\'/o separate dural tubes around a midline calcareous or "emptyll defect (fig. 3). In sorne instances, the oil column would be broken up into several channels in the region of the defect, later judged at operation to represent the presence of adhesions at the level of the dividing septum. Diagnosis was confirmed at operation in 3 additional patients and, as earlier mentioned, a cleft cord was directly visualized through a thin myelocele covering in one patient. In only one patient was the diagnosis not confirmed by either myelography, operation or direct visualization. In this case, a dense spicule of bone was stereoscopically seen traversing the spinal canal at T6 in association with widened inter­ pedicular distances, adjacent posterior dysraphism, vertebral body ano­ malies and a hypoplastic and coccyx; serious sequelae of hydro­ cephalus precluded operation in this patient. The segmental distribution of the dividing septum over the spinal column for the entire series is indicated in Table IV and graphically depicted in fig. 4. In sorne instances, the septum was attached to t\'/O adjacent vertebral bodies and the vertebral body which was most involved is taken for purposes of demonstration. One patient Figure 3. Mye10gram of a patient with diastematomye1ia demonstrating sp1itting of the oi1 co1umn around a midline osseous septum traversing the spinal canal. Figure 3. t4yelogram of a patient with diastematomyelia demonstrating splitting of the oil column around a midline osseous septum traversing the spinal canal. 6

5

QI C 4 -C. QI V) o 3 -... .cQI E ;:) 2 Z

Tl T2 T3 T4 TS T6 T7 Ta T9 TlO Tll Tl2 Ll L2 L3 L4 Ls Segmental Level

Figure 4. Segmental distribution of the dividing septum in 30 patients with diastematomyelia. One patient had a dividing septum which extended from Tl - T12 and is represented by the darkly-hatched units. The cross­ hatched units represent the adult patients in the series. 9. had t\vO separate septae \'/ithin the confines of a cleft cord, one bony and radiological1y visualized at L2, the other fibrocartilaginoüs and operatively confirmed at T12; each septum is plotted separately in the histogram. In one patient, a bony septum extended from Tl to T12, \'/ith each hemicord enclosed \vithin its 0\'1n separate bony canal. The septae most commonly occurred at the thoracolumbar junction and upper lumbar region. The septae in adult patients occurred within the usual spectrum of distribution and all lay ab ove the level of the conus medul1aris with the hemicords reuniting below, except for one case in which a bony spicule at L3 divided the roots of the cauda equina. In the juvenile patients, the cord reunited below the septum in all but 3 cases.

Operative Experience Operations have been performed on 22 of the 30 patients. The patient \'Jith the long bony septum from Tl to T12 undenvent a wedge osteo­ tomy (Dwyer procedure) for scoliosis, with removal of the dividing septum of bone only at the level at which osteotomy was performed. The remaining 21 patients were subjected to laminectomy for removal of the dividing septum. The surgical technique is relatively simple and well described (Natson et al., 1950; t4eacham, 1967), consisting of careful laminectomy, definitive excision of the dividing septum and its dural sheath, and closure of the dorsal dura. Alexander (1972) has seen recurrence of a fibrous septum in one case and recommends closure of the ventral dura to prevent this event and to prevent the development of symptomatic adhesions in the operative site. Perret (1960) has emphasized the association of a short, taut with diastematomyelia and suggests its division 10. as a part of the operative procedure. In one operated case, extensive adhesions \'1ere seen binding the bony peg, dural sheath and divided hemicords in the region of the , and definitive removal \'/as not completed for fear of precipitating sphincter dysfunction and further neurological deficit. Four cases are possible candidates for future operation. One adult patient with acute back pain and minimal neurological deficit had a demonstrable bony peg dividing the cauda equina; she sho\'/ed marked improvement on a conservative regime and is being followed for evidence of recurrent symptoms. Three patients were deemed not treat­ able because of other severe abnormalities. In 15 cases undergoing operation, the spinal cord reunited imme­ diately below the dividing septum and dural sheath, and in sorne of these cases, the reunited cord was so tightly apposed to the peg and sheath in­ feriorly, that immediately on reuniting below, it took on a dis~orted IIhumped­ Upll appearance. In two cases, the cord was actually seen to ascend a few millimeters immediately after removal of the dividing septum and dural sheath. In 4 cases, the cord remained ununited for at least one segment below the divi­ ding septum, but there clearly were dense adhesions binding both hemicords to the dural sl1eath and septum. In another case, the hemicords did not reunite below the dividing septum but dense adhesions were found anchoring one of the hemicords to the dural sheath and bony peg. In another case, there were n10 small lipomata embedded in the dorsal surface of each hemicord, the hemi­ cords lying tightly bet\'leen the dividing bony spi cul e and the lateral wal1s of the spinal canal, with this process having a tethering effect on the spinal cord. In every instance undergoing operation then, the cord vias tethered, either because it reunited immediately below the septum or because of local adhesions. The presence of binding adhesions stresses that surgery is not contraindicated when myelography demonstrates that the division of the cord extends well below the level of the septum and dural sheath. 11.

No patient was made worse as a result of the operative procedure, although sorne transient sphincter dysfunction occurred postoperatively in sorne patients. Sorne patients demonstrated a dramatic early improvement in sphincter performance and deep tendon reflex activity. The three adults submitted to surgery showed early improvement of symptoms and revers al of recent preoperative neurological findings. Operation in growing children is important as a prophylactic procedure to prevent development or progres­ sion of neurological deficit and in sorne cases, definite improvement occurred in sphincter function, rnotor strength and deep tendon reflex activity.

Operative Findings A characteristic operative picture, represented by the composite diagram of fig. 5, emerged from study of the detailed operative reports available in 20 of these cases. A detailed summary of the findings in these 20 cases is reproduced in the Appendix. Typically, there was a thin fibrous stalk connecting a midline cutaneous lesion or dimple with the dorsal portion of a bony or fibrocarti­ laginous septum which bridged the cleft spinal cord. In one case, a tera­ tomatous inclusion was found within the fibrous stalk connecting the skin and the dividing septum (fig. 6). In another case, a derrnoid tumor lay adjacent to the dividing septum. In other cases, lipomata were found adjacent to the dividing septum. The dorsal portion of the dividing septum generally consisted of a large irregular mass of bone which was interposed between and fused to one or both laminae at a given segmental level, essen­ tially replacing the spinous process at that level. The dividing septum arose from the ventral surface of this mass of bone, traversed the cleft in the cord, and fused to the posterior surface of a vertebral body or interspace area. The septum was generally of greater diameter in its more 81 Il

Figure 5. A composite representation of the operative findings in 20 cases of diastematomYelia. The dorsal broken lines indicate the positicn of a fibrous stalk connecting the septum with an overlying cutaneûus lesion. The ventral broken lines emphasize the radiological evidence of a split notochord (delayed union of separate cleft vertebral half centra) in these cases. -/ ".. . ", 1

, . '\ -' ~" ..;(:

Figure 6. Section taken through a fibrous stalk which connected the overlying skin and the dividing septum in a case of diastematomYelia. Within the fibrous stalk was found a teratomatous inclusion containing cells of the three primary germ layers, including dorsal root ganglion cells (arrow). Figure 6. Section taken through a fibrous stalk which connected the overlying skin and the dividing septum in a case of diastematomyelia. Within the fibrous stalk was found a teratomatous inclusion containing cells of the three primary germ layers, including dorsal root ganglion cells (arrow). 12. dorsal portion, thinning considerably at its point of fusion with the vertebral body, perhaps indicating a more dorsai origin with an original grOl'lth direction from dorsal to ventral. Around this septum, each hemi­ cord was enclosed within its O\'1n sheath of dura. The bony mass comprising the dorsal portion of the dividing septum was umbi~icated in its center and contained several perforations from which arteries and nerves could be seen exiting. These could some­ times be traced to enter masses of midiine fat or anomalously situated midline muscle masses and on a fei'i occasions, stimulation of these exiting nerves caused contraction of the midline muscle. In addition to the usual lateral complement of nerve roots, there were seen dorsal roots, sometimes containing grossly identifiable dorsal root ganglia, arising from the mesial aspect of each hemicord and running to the region of the dural sheath and enclosed septum. Less commonly, sorne mesial rudimentary ventral roots viere identifi ed. In sorne instances, dentate ligaments were also identified connecting the mesial aspect of the hemicords to the region of the dural sheath (fig. 7). After removal of the dividing septum and its surrounding dural sheath, the specimens were serially sectioned and appropriately stained. Histologie examination of these specimens frequently revealed the presence of numerous clusters of dorsal root ganglion cells and bundles of myelinated nerve fibers intimately associated with the dural sheath, often admixed with fibrous tissue comprising the dural sheath (fig. 8). The relative frequency of these described findings in a retrospec­ tive study of operative repor'.:~ is s'Jmmarized in Table V. The most common findings were myelinated ner'/es in the dural sheath, dorsal root ganglion cells in the dural sheath, and mesially situated dorsal roots, all present in over half of the operative cases. Figure 7. Operative photograph of a case of diastematomYelia demonstrating the presence of dentate ligament (arrow) between the two hemi­ cards. The asseous septum and dural sheath have been excised.

"~~ '. ',.:'~:~, . -~--- _., -..... --«.--- .. :~~iJr:\:.·.;J·-~~~~ , ; • - , ~ 1 _t;': ." " ...... -.. ,

Figure 8. Photomicrograph of the dural sheath in a case of diastematomYelia, demonstrating a cluster of dorsal root ganglion cells. Case Operative and Pathological Findings Total 1 2 3 4 5 6 7 8 910 1112 13 14 15 16 17 18 19 20 Fibrous stalk x x x x 4 Oermoid, x x 2 , abnormal fat collections x x x x 4 Midline muscle x x x x x x 6

Mesial dorsal roots x x x x x x x x x x x x 12 Mesial ventral roots x x 2 Mesial dentate ligaments x x x 3

Mesial dorsal root ganglia, x x x x x x x x x x x x gross or microscopie 12 Myelinated nerves in durai sheath x x x x x x x x x x x x x x 14

Table V. Relative frequency of pathological findings in 20 operative cases of diastematomyelia. 13.

Au:to pO y S:tudy

A separate case of diastematomyelia which had r.ot been diagnosed during life has been studied at autopsy. The patient was a 54 year old female v/ho succumbed to a generalized tuberculous infection. She had been known to have a right hemiparesis since birth and had suffered frequent focal cerebral seizures. In addition, examination had revealed atrophy, focal weakness and areflexia of the lower limbs as well as bilateral club foot deformities. x-rays demonstrated left hemiatrophy of the cranial vault and x-rays of the spine revealed increased interpedicular distances without erosion of pedicles at T12 and Ll and block vertebrae at Tll and T12. Neuropathological examination revealed left cerebral hemi­ atrophy, presumably on the basis of birth trauma. In addition, there

~ias diastematomyelia of cord segments L1-L5, with the hemicords re­ uniting below the cleft to form a grossly normal conus medullaris (fig. 9). There was reduplication of the spinous processes from T12 to L4 with spina bifida occulta from Ll to L3. The dura was thickened over the lumbar cord segments but there was no cleft of the dura and no dividing septum. In sections rostral to the cord cleft (fig. 10), there \'las gross hydromyelia extending over several segments. Sections taken through the region of the cleft cord (fig. 11) revealed the presence of dorsal root gangl ion cells bet\'leen the hemicords. Each hemicord contained its own ependymal canal. Caudal to the cleft (fig. 12), the reunited cord con­ tained two distinct ependymal canals for several segments and a cluster of dorsal root ganglion cells could still be seen lying on the dorsal cord surface. - ~,'

~ ."~ .' • • l. _ _ .- .~ .' '. ,., ." .~~ ::-:::,.. , - . -.."., ,,-,~- ,..,., ,. ,_\~~ = _~~ __ . '9' ,< " '. "~-'- .-', ", - ,,>'. ~. -_.'<",,' .

INTREAl NEUROlOGICAl INSTITUTE 5 6 7 8 q 10 11 12 13 14 1~

Figure 9. Gross specimen of a case of diastematomyelia discovered incidentally at autopsy demonstrating a cleft of cord segments Ll - L5. !NTRfAL NfUROLor,ICAL INSTITUTE ) D ; ü 0 10 11 12 13 14 1~

Fi gu ,e 9. G,oss specimen of a case of diaster:latOfi1yel ia discovered inc~dental1y at autopsv defi10nstrcting a cleft of cord segments L1 - L5. Figure 10. Section taken rostral to the level of the cord cleft of fig. 9, demonstrating gross hydromyelia which extended over several segments. Figure 11. Section taken at the 1evel of the cord cleft of fig. 9, demonstrating the presence of dorsal root ganglion ce1ls between the hemicords, the presence of an ependyma1 canal in each hemicord, and the symmetrical halving of the central gray. •

Figure 11. Section taken at the level of the co rd cleft of fig. 9, demonstrating the presence of dorsal root ganglion cells between the hemicords, the presence of an ependymal canal in each hemicord, and the symmetrical halving of the central gray. Figure 12. Section taken caudal to the level of the cord cleft of fig. 9, demonstrating the persistence of two separate ependymal canals in the reunited cord. Note the continued presence of dorsal root ganglion cells, now visible on the dorsal surface of the reunited cord. 14.

vrSCUSSION OF RESULïS

Re.v-Lew on :the. U;tvc.a;tU/Le.

This ana1ysis of the findings in a series of patients with diastematomyelia indicates that there are two distinct clinical presen­ tations of the disease. The clinical manifestations of those patients presenting in juvenile age groups are wel1 recognized, usual1y consisting of gait disturbances due to focal atrophy and v/eakness of the lov/er limbs and foot deformity in association with sphincter dysfunction and midline back cutaneous lesions (f.1atson et al., 1950; il1atson, 1969; Perret, 1957, 1960). In those patients presenting in adult life, sorne degree of neuro­ logica1 deficit may have existed for many years before presentation, but the patients generally present as relatively acute painful back syndromes, with back tenderness, limited straight leg raising and sphincter dys­ function. These cases might easiiy be confused vJith intervertebral disc disease or other afflictions of the lower spine seen in adult life. English and Maltby (1967) reported two cases in adults and reviewed five others, including one of the patients in the present series. They emphasized the importance of a stressful event as a factor in the onset of presenting symptoms. They also emphasized the low level of the dividing septum and the fact that, in most cases, the spinal cord did not reunite below the level of the septum; they felt that this was an important factor in the delay of onset of symptoms in adults. In all of the adult cases in the present study, except the case in which the cauda equina was transfixed, the cord reunited below the level of the septum. Dale (1969) has described an additional case of a 59 year old patient \'1ith a bony spicule at T5-6 who had evidence of long-standing neurological defi~it and in whom the cord clearly reunited below the spicule. Another patient reported by Freeman (1961) had a spur at L3 with the conus reuniting below 15. the bony lesion. In the 13 adult cases nO\'i under consideration, relatively acute symptoms dominated the clinical picture, al­ though 7 patients did have evidence of sorne degree of long-standing neurological deficit preceding the development of the acute symptoms. The location of the bridging septum in these adult patients appears to conform to the general distribution of location seen in all patients with the disoy'der. It is submitted that the chief factor dis­ tinguishing the adult patients is the degree of tethering of the spinal cord. The cord, if reunited belo\'I the septum, probably originally reunited well below, allowing sorne cephaled migration of the cord in early life. This allows a precariously balanced functional situation to ensue, either because of a slightly tethered cord or the development of binding adhesions, which is brought to attention under the influence of seemingly benign stress. Herren and Edwards (1940) reviewed 43 cases of diastematomyelia, only two of which had been diagnosed during life, and concluded that the lesion \'Jas equal1y distributed bet\'/een the sexes. Dale (1969) revi€.Wed 39 cases of diastematomyelia \'Jhich \'/ere diagnosed during life, added 10 new cases, and noted that females constituted 71% of the cases, a figure almost identical to that of the present series. A significant family history was found in 4 of the present cases. Kapsalakis (1964) and Gardner (1964) have both described the occurrence of the anomaly in siblings and a familial tendency in spina bifida has been emphasized oy many authors (Ingraham et al., 1944; Record and McKemm, 1950; Lorber, 1965). Previous descriptions of diastematomyelia in children have stressed the usual presenting symptoms of limp and focal weakness of a lower limb. Scoliosis was the most frequent presenting complaint 16. of the juvenile cases in the present series. In 1962, one of the patients of the present series, who had a progressive scoiiosis, developed an acute sphinc­ ter disturbance following a spinal fusion for chronic back pain and spica cast application. Her acute symptoms were promptly relieved by excision of a dividing bony spur. Since that time, patients vJith scoliosis have been routinely seen in referral from the ~1ontreal Shriners 1 Hospital for Crippled Children prior to surgi cal correction of scoliosis, and many of the present eases have been diagnosed from that large group of sco1iotie ehildren. That 12 patients have been received from this source during the past 10 years would indicate that diastematomyelia is not a rare finding in scoliotic children. Shorey (1955) first described the asso- ciation of kyphoseoliosis and diastematomYelia in a child who became para­ plegie. ηlany of these patients have precariously balanced neurological function and it is felt imperative that a diagnosis of diastematomYelia be excluded or definitive treatment for the diastematomyelia be done prior to surgi cal correction of scoliosis. Radiological analysis of these cases indieates that the scoliosis is due to bony anomalies rather than any degree of muscle imbalance. t·lany of the pathological features seen in the present cases have been noted, at least in part, by previous authors. Perret (1960) and Natson (1969), among others, have noted a s imi 1ar frequency of mi dl ine cutaneous lesions overlying the spine in diastematomyelia. A fibrous band or stalk linking the overlying skin with the cord les ion has been described (Moes and Hendrick, 1963; Dale, 1969). Hamby (1936) described a case of diastematomyelia in which a pilonida1 connected the region of the cleft 17.

cord with the overlying hypertrichotic skin. CO\'1ie (1951) described a case in which a previous1y discharging midline fistula or. the back com­ municated with an underlying thoracic cleft cord. He remarked that in this case there \'1as, at the point of union of the bony septum to the vertebral body, a round hole, or fistu1a, passing through the antero­ posterior diameter of the vertebral body. r~atson et al. (1950) described tvlO cases of diastematomyelia in which smal1 dermoid inclusion cysts were found within the spinal canal at levels adjacent to the cleft cord; in one of these cases, the inclusion was contained within a fibrous tract which connected an overlying skin dimple to the region of the cord 1esion. Cowie (1952), in another case, described the presence of an intraspina1 dermoid tumor 1ying adjacent to a cleft cord. Arcomano, Sengstacken and

Wunder1ich (1962) reported a case of diastematomye1ia in \'/hich a small epi­ dermoid tumor \'1as found in the extraspina1 tissues overlying the cord lesion. Ritchie and F1anagan (1969), reporting 8 cases of diastematomyelia, des­ cribe 1 case in which a small intradural dermoid tumor lay adjacent to the dividing bony septum and another case in which a large intradura1 teratoma was entangled in the cord in the region of the dividing bony septum. Lipo­ mata in association with diastematomye1ia, at anatomic locations comparable to the dermoids and teratomata described, have been reported by several authors (Kahn and Lemmen, 1950; t·1atson et al., 1950; Perret, 1957; Dale, 1969). Emery and Lendon (1969), in a pathological study of a randorn series of 100 children dying from hydrocephalus and meningomyeloce1e, found 6 instances of diastematomye1ia associated with both intradural and extradural lipomata. 18.

The presence of dorsal and ventral roots arising from the mesial aspect of the hemlcords ','ias first noted by Herren and Edi'Jards (1940), 1tiho described them as rudimentary in development. Saunders (1943), in a meticulous morbid study of an infant i'lith what he termed combined anterior and posterior spina bifida, described a fecal-discharging, fistulous com­ munication between the large bowel and the midline lumbar skin \'1hich passed between a c1eft 1umbar cord. He demonstrated roots \'1ith well formed spinal ganglia situated in the region of the cleft and arising from the left half of the divided cord. Kapsenberg and Van Lookeren Campagne (1949) also described ectopic spinal ganglia lying between two hemicords in diastemato­ myelia. Nore recently, Lourie and Bierny (1970) have provided clear micro­ scopic documentation of the presence of cells of neural crest origin in association \'1ith the dural sheath around the dividing bony septum. Herren and Ed\'/ards (1940) have reported the finding of a dentate ligament arising from the mesial aspect of each hemicord and attaching to the dural sheath around the dividing septum. A review of the literature did not reveal a description of an innervated midline muscle mass such as described in the present series, but Perret (1957) describes a case of diastematomyelia in which an overlying bony defect was covered by a large mass of adipose tissue which was intermingled with striated muscle. In this case, there was also a dermal sinus surrounded by hypertrichosis, which connected to the region of the cleft cord. Dale (1969) has described a case ir. which a subcutaneous mass over1ay a cleft cord and contained glial tissue, arachnoid, cartilage and muscle; a fibrous band extended ventrally from this mass, passed between the hemicords and attached to the posterior surface of a vertebral body. 19.

Over one-third of the patients in the present series had sorne degree of spina bifida cystica. The association of spina bifida cystica with diastematomye1ia is we11 documented in various isolated reports (Weil and l'-Iatthews, 1935; Herren and Edwards. 1940; Kapsenberg and Van Lookeren Campagne, 1949; Perret, 1957, 1960; Cohen and Sledge, 1960; Matson, 1969; Ritchie and Flanagan, 1969), but the relatively high frequency of its association has not been general1y appreciated. Herren and Edwards (1940) in their revie~'! of 43 cases of diastematomyelia, all but 2 of which rep­ resented post mortem material, noted 9 instances of spina bifida cystica. t·ioes and Hendrick (1963) described 14 cases of diastematomyelia and reported 5 instances of spina bifida cystica out of 7 of those cases which had been studied at autopsy. Conversely, Cameron (1957) found diastematomyelia in about half of 26 consecutive cases of spina bifida cystica studied at autopsy. Emery (cited by Duckworth et al., 1968) has encountered diaste­ matomyelia in 50% of his cases of spina bifida cystica coming to post mortem. Doran and Guthkelch (1961), in a study of 307 consecutive clinical cases of spina bifida cystica, report finding diastematomYelia only 8 times in a total of 197 cases submitted to surgery; they stress, however, that many instances of diastematomyelia might have been missed because of incomplete exploration of the spinal canal and because many cases with grosser degrees of deformity had been rejected for surgery. Of further interest is the report by James and Lassman (1964), who found 24 instances of diastemato­ mYelia in 60 cases of spina bifida occulta submitted to laminectomy because of neurological deficit. Till (1969) similarly found 45 instances of dias­ tematomyelia at operation in a series of 112 children \'1ith spinal dysraphism, a diverse group of patients primarily characterized Dy a variety of cutaneous lesions and sorne degree of neurological deficit. 20.

The occurrence of hydromye1ia above and be10w a c1eft cord has been regülarly demonstrated in the few patho1ogica1 descriptions of diastematomye1ia (Herren and Edwards, 1940; Lichtenstein, 1940; Ogryz10, 1942; vJa1ker, 1944; Kapsenberg and Van Lookeren Campagne, 1949; Benstead, 1953; Cameron, 1957; Gardner, 1964). The occurrence of t\'lO separate central canals extending for a considerable distance above or be10w a c1eft cord has not received comment. Benda (1959) demonstrates a section, taken rostral te a cleft cord, in \'Ihich there was duplication of the with both of these central canals being hydromye1ic. Severa 1 authors (Wei 1 and Matthe\'ls, 1935; Benda, 1959; Perret, 1960) have reported cases in which diastematomye1ia, hydromye1ia and spina bifida cystica were a11 present over different segments, and in sorne of these cases the Arno1d-Chiari malformation and hydrocepha1us were present

as we 11 • i~any other authors have a11 uded to the occurrence of the Arno 1d­ Chiari malformation and hydrocepha1us in association with c1inica1 cases of diastematomye1ia, a11 of which apparent1y had spina bifida cystica as well (Kapsenberg and Van Lookeren Campagne, 1949; Neuhauser, Hittenborg and Deh1inger, 1950; Benstead, 1953; Cameron, 1957; Perret, 1957,1960; Benda, 1959; Noes and Hendrick, 1963; Matson, 1969). Rhaney and Barclay (1959) described a case which had vertebral defects, an enteric cyst, a short , the Arno1d-Chiari malformation and meningocele in association with diastematomyelia. An association of the K1ippel-Fei1 syndrome \'/ith diastematomye1ia has not, apparently, been previous1y reported, but Gardner (1964) described 3 siblings, 2 of whom had diastematomye1ia and 1 of whom had inie~cepha1us, a 1esion which he considers an extreme form of the K1ippel-Fei1 syndrome. The association of congenital elevation of the shoulder with the Klippe1-Fei1 syndrome is well known. Vertebral anomalies in diastematomyelia as demonstrated by radio- 21.

graphy have been reported (vJa1 ker, 1944; i~euhauser, Wittenborg and Dehlinger, 1950; Cm'fie, 1951, 1952; Gryspeerdt, 1963), but relative frequencies were not given. Instances of rib anomalies (Marr and Uih1ein, 1944; Benstead, 1953; Perret, 1957, 1960; Cohen and Sledge, 1960) and hip dysp1asia and dislocation (Davies, Jennett and Hoskins, 1957; B1igh, 1961) have a1so been mentioned in association \'lÎth diastematomye1ia.

SummaJty On Re6uf.:t6

This ana1ysis of the findings in 30 c1inica1 cases and one morbid case of diastematomye1ia further defines the c1inica1, radio10- gica1 and pathological features of the anomaly. There are two clinical presentations of the disease. The juvenile cases present with progressive symptoms from birth of scoliosis, gait dis­ turban ce and focal weakness and atrophy of the 10wer extremities in associa­ tion with sphincter dysfunction, foot deformity and midline back cutaneous lesions. Diastematomyelia is not a rare finding in chi1dren with scoliosis and should be exc1uded prior to any surgical correction of scoliosis. The adult cases generally present as acute painfu1 back syndromes superimposed on a background of long-standing, mild neurologica1 deficit. In adult patients, the location of the bridging septum, relative to the spinal col­ umn, conforms to the general distribution of location seen in all patients with the anomaly. The spinal cord reunited below the bridging septum in 4 out of 5 adult cases. Tethering of the spinal cord was demonstrated in al1 cases undergoing operation. The chief factor distinguishing the adult cases is the less severe degree of tethering of the spinal cord. This re­ ·flects the presumption that the spinal cord of adult patients, if reuniting below the septum, originally reunited well below, a1lowing sorne cephalad migration of the cord in early life. 22.

Radiological features of the entity include a visible bony septum, vertebral body anomalies, posterior bony rachischisis, a \'Jidened spinal canal \'lÎthout erosion of pedicles, vertebral fusion defects, and errors in segmentation. Evidence of a split notochord was present in 93% of cases. Vertebral anomalies, as \'/ell as cutaneous lesions, frequently occur widely removed from the actual level of the spinal cord cleft. Certain pathological features of the les ion are elucidated, including: 1) the presence of dorsal root ganglion cells between the hemicords and intimately related to the dividing septum and its sur­ rounding dural sheath, 2) the origin of dentate ligament and dorsal and ventral roots from the mesial aspect of each hemicord and running to the region of the dividing septum and dural sheath, 3) the presence of anomalous midline muscle masses overlying the spinal canal at the level of the cord cleft and innervated by nerves exiting from the center of the dividing septum, 4) the occasional occurrence of dermoid inclu­ sions, teratomata, lipomata and fibrous stalks in the tissues between a midline cutaneous lesion and the cleft cord, and 5) the occurrence of hydromyelia and duplicated central canals in segments rostral or caudal to a cleft cord. Diastematomyelia is regularly associated with other congenital abnormalities, including spina bifida cystica (37% in the present series) and occulta, hydrocephalus, Chiari deformities, aqueductal stenosis, the Klippel-Feil syndrome, hydromyelia, lesions of foregut origin, sacro­ coccygeal hypoplasia and agenesis, rib and hip anomalies and congenital elevation of the shoulder. 23.

It is apparent that various defects, derived from all primary genn layers, regularly occur in association \'/ith diastematomyelia, in­ dicating a common embryological origin of these diverse defects. It is further apparent that although foregut diverticulae and cysts, vertebral body anomalies, the Klippel-Feil syndrome, the Chiari deformities, aque­ ductal stenosis, spina bifida cystica and occulta, hydromyelia, sorne rnid­ line developmental tumors and pilonidal lesions all occur as separate entities, diastematomyelia is the single entity with \'lhich they all are regularly associated. It is therefore felt that any attempt to explain the embryogenesis of diastematomyelia must also explain the embryogenesis of these, and perhaps other, anomalies. PRESENTATION OF THE HYPOTHESIS 24.

PERTINEfff EMBRYOLOGY

A discussion of the origin of spina bifida and dysraphism necessitates an account of the normal embryological phenomena occurring during the period of neurulation in early embryonic life. At the end of the second week of embryonic life, the pear-shaped embryonic disc consists of only two layers, ectoderm and endoderm, and is interposed between the yolk sac cavity, which is destined to become the gut, and the amniotic cavity. Axiation occurs on the sixteenth day, with formation of the primitive streak (Willis, 1962), at what is destined to become the caudal end of the embryo. Hensen's node, or the primitive knot~ appears at the most rostral end of the primitive streak (fig. 13A), and stages at 17 days possess a small evaginated area just rostral to Hensen's node, the head process. Hensen's node and the primitive streak are the origin of cells i'/hich contribute to further embryonic development and germ layer differentiation, analogous to the dorsal and ventral lips of the blastopore in primitive fonns (Patten, 1953a). From these areas, lateral streams of neuroectodermal and notochordal tissue proli­ ferate forward and fuse in the midline rostral to Hensen's node. On the 17th day, notochordal tissue invaginates from Hensen's node and proliferates fOl"V/ard in the midline, intervening bet\'1een the endoderm and ectoderm. This tissue becomes tunneled by a notochordaZ canaZ; on the 18th day, the floor of this canal disappears, establishing a tempo­ rary communication, the neurenteric canaZ~ between the yolk sac and amniotic cavities (fig. 13B). An embryo of 19 days completes the pre­ somite stage. A

amnionic cavity

B

reunited

Figur2 13. Diagrammatic dorsal ViE~ (A) and midsagittal section (8) of an 18 d. human embryo. Streams of neuroectoderm and notochord proliferate forward from either side of Hensen's node, forming the neural plate (A}. The neurenteric canal connects archent~ron and amnion and is formed when the floor of the notochordal canal disappears (8). The line AB represents the plane of cross-section for fig. 14A. 25.

The somite stage of development begins on about the 20th day and the full number of somites are achieved on about the 30th day. The neurenteric canal is thought normally to close after about 6 pairs of somites are formed (Bartelmez and Evans, 1926), closing in a ventro­ dorsal direction (Willis, 1962) and leaving an invagination in Hensen's node (primitive pit) throughout further somite development to mark its previ ous existence. Others (Hamil ton, Boyd and [\lossman, 1962), however, have indicated that the neurenteric canal might remain patent throughout most of somite deve10pment, connecting hindgut and amnion in 1ater stages just as foregut and amnion were connected in ear1ier stages. As more and more neural plate is laid down rostral1y, Hensen's node gradua11y retreats cauda11y, eventua11y combining with the ever-shortening primi- tive streak to form the end or taU bud:> from \'/hich the most caudal segments of the spinal cord and fi1um terminale are formed (Kunitomo, 1918). The neural tube begins to close at about the 7 somite stage \'/ith the latera1 margins of the neural plate meeting and fusing in the mid1 ine in the region of the 4th, 5th and 6th somites, \'/ith subsequent closure proceeding rostrally and caudally in a zipper-1ike fashion. i~hen c10sure of the neural tube begins, the rostral two-thirds of existing neural plate is the primordium of the brain, and the caudal one-third is the primordium of the upper cervical cord (Hamilton, Boyd and ~jossman,

1962); the primordium of the lo\'/er cord segments has yet to be formed at this stage. The rostral opening in the neural tube (anterior neuropore) closes at about the 20 somite stage; the caudal opening (posterior neuro­ pore) closes at about the 25 somite stage. 26~

Immediately subsequent to neural tube closure, the specialized columns of tissue (ne~Z crest) at the junction of neuroectoderm and somatic ectoderm meet along the dorsal aspect of the neural tube and shortly thereafter migrate ventrolaterally, coming to lie along the dorso­ lateral aspect of the neural tube (Hamilton, Boyd and ~lossman, 1962). Paraxial mesoderm segments during somite development, and the ventromedial portions of each somite, the scZerotomes~ meet in the midline and encircle the notochord, separating this structure from the neural tube and gut. From this midline union the vertebral bodies, and later their arches, are derived. The notochord segments between the vertebral bodies and contri­ butes to formation of the intervertebral discs. Table VI demonstrates the relative time sequences of the events involved in neural tube formation. These events antedate the establish­ ment of flow by several l'/eeks. The primary events in the formation of the entire neural tube occur between the l8th and 30th days of embryonic life when the embryo measures in length from .5 to 5 mm.

PREVr GUS HYPOTHESES

Several hypotheses, seemingly disparate, have been advanced to explain the origin of diastematomyelia and other forms of spina bifida and dysraphism. It is \'lOrthwhile to revie\'/ these proposals in order to trace the development of thought in this field and to appreciate the integrative aspects of the present hypothesis. Neurenteric canal ------_. Som ite formation

Neural ''Jbe closure

Ant. neuropore clos ure x

Post. neuropore closure x

Neural crest migration

Choroid plexus appearance x

CSF production

Rhombic roof perforation 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 18 20 22 24 26 28 30 4 8 12 16 ~------~.~.------~ Days Weeks Table VI. Relative time sequences of the events involved in neura1 tube formation and the events related to the establishment of cerebrospinal fluid flow. 27.

P!UmCVUJ Medui..e.CVUj p.ta;te. AbnOJLmaüty (NonW6Wl.e.J

Herren and Edwards (1940), noting that the ccrd deve10ped in embryonlc life long before the spinal column, considered the lesion in diastematomyelia as representing a primary alteration in the neural

ll plate, perhaps representing a IIslight degree of twinning • Lichtenstein (1940) considered the lesion an expression of improper closure of the neural tube. Kapsenberg and Van Lookeren Campagne (1949) felt that non­ closure of the neural tube led to the phenomena seen in their case. Patten (1953b) provided impetus to the concept of nonclosure as the origin of both diastematomYelia and mYeloschisis by demonstrating evidence of local overgrmvth of the neural plate in embryos with dorsal mYeloschisis, postulating that this local overgrowth prevented proper closure. Neural tube nonclosure as the etiology of most forms of dysraphism probably remains the most widely accepted concept among embryologists, and various mechanisms involving primary germ layer interaction have been invùked to explain this view (Killén, 1968).

AbnoJunal No:tochoJtd Indu.c:Uon

Feller and Sternberg (1929) had focused earlier attention on the split notochord as the primary defect, especially in cases with combined anterior and posterior spina bifida, proposing that the notochord became cleft by persistence in the midline of a cell rest from Hensen's node. Nore recently, Bentley and Smith (1960) and Burrows and Sutcliffe (1968) have extended this hypothesis to embody a wide variety of midline anomalies. Saunders (1943) agreed that a cleft notochord underlay the anomal y in instances of combined anterior and posterior spina bifida, but he modified the views of Feller and Sternberg by suggesting the 28.

development of endodermal-ectodermal adhesions between the cleft noto­ chord, with subsequent necrosis of these adhesions leading to a "neur­ enteric connectionl/. The term neurentepic was thereby introduced without any relation to the neurenteric canal and later applied to the description of \'>/hat is now known as neurenteric cysts. Various modifications of Saunders· view have subsequently been proposed to explain lesions of foregut origin associated with vertebral and neural anomalies, all sharing in common a concept involvi~g faulty embryonic differentiation of the three primary genn layers seaondcœy to a c1eft notochord (Veeneklaas, 1952; [~c­ Letchie, Purves and Saunders, 1954; Fallon, Gordon and Lendrum, 1954; Beardmore and Wiglesworth, 1958; Harriman, 1958; Nathan, 1959; Rhaney and Barclay, 1959; Gleeson and Stovin, 1961; Levin and Antin, 1964; Dorsey and Tabrisky, 1966).

V,utwz.banc.eo On :the BwtopoJr.e

In 1892, Hertwig described the production in amphibian embryos of duplication of axial structures and nonc10sure of the neural tube in experiments designed to prevent nonna1 deve10pment in the region of the blastopore. He regarded the cleft as representing incomp1ete fusion of the 1atera1 blastopore lips. Adelman (1920) considered these observations applicable to mamma1s, with the neurenteric canal and the region of Hensen·s node ana1ogous to the amphibian blastopore, and proposed that anoma10us connections between gut and neural tube might represent a persistent neurenteric canal. Dodds (1941), in a study of 2 fetuses with anterior and posterior rachischisis, suggested that an unusually large neurenteric canal or one that persisted too long might prevent 29.

union of the paired notochordal and neüral stieams as they proliferate forward from Hensen's node, resu1ting in two spinal cords or to a mal­ formed cord. Bremer (1952), in a remarkab1e discussion of dorsal intestinal fistu1ae associated with diastematomye1ia, proposed that "accessory" neurenteric canals under1ay the observed abnorma1ities. Cameron (1957) proposed that inhibition of c10sure of the blastopore was the cause of diastematomyeiia and that myelocele and other forms of spina bifida might result from a shorter de1ay in c10sure of the blastopore with lateral expansion of the growing caudal end of the neural plate.

Atlteôla. 06 :the. Rhombe.nc.e.pheLUc. Ro06

l~ore recently, the views of Gardner (1960,1961,1964,1968) have had considerable influence on clinical thought in 1esions of spina bifida and dysraphism. Basica11y, he proposed that physio10gic embryonic hydro­ cepha10mye1ia causes, with failure of the rhombencephalic roof to perforate, a further distension of the central canal with rupture of some portion of the neural tube. If the rupture occurred dorsally, a mYeloce1e or meningo­ cele might result, whereas if the rupture simultaneously occurred dorsally and ventrally, diastematomye1ia would resu1t. 30.

CURRENT HYPOTHESIS

It is submitted that retarded closure of the neurenteric canal is not only responsible for the lesion in diastematomyelia but also for a vlide variety of midline lesions, a modification of the view of Cameron (1957). Unlike Bremer (1952), it is felt unnecessary to invoke the development of "accessory" neurenteric canals ta explain the various defects. This hypothesis encompasses all of the anomalies described under the entity of the split notochord syndrome {sorne enteric IIduplications ll or diverticulae; prevertebral, mediastinal and mesenteric cysts; vertebral body anomalies; spinal and cranial cysts; postvertebral

IIteratomatous ll or derrnoid cysts and sinuses; dorsal intestinal fistulae; and combined anterior and posterior spina bifida (Bentley and Smith, i960)} and proposes a more logica1 explanation for the split notochord. It is further felt that all forrns of cranium bifidum and spina bifida cystica and occulta and their associated distant neuroanatomic malforma­ tions are easily explicable in terms of the hypothesis. That the above congenital defects are all pathogenetically related is attested to by the frequent concomitant occurrence of several of the anomalies in individual cases, their frequent hereditary asso­ ciation, the cornmon sharing of certain rnesoderrnal defects between the various anomalies (most notably, vertebral body defects), and by the experirnental observations that many of the anomalies are seen as separate

sequelae )~ marnmalian offspring exposed to various teratogenic agents during a critical period of pregnancy. 3l.

The composite cross-sectional diagram of fig. 5 indicates the previous existence of an lIabsolute midline ll fistula in diastema­ tomyelia along i'lhich derivatives of a11 three embryonic germ layers have met. In the present series of cases, the residuum of this fistula passes from the ventral surface of the vertebral body to the midline cutaneous region, reminiscent of the embryonic neurenteric canal which connected archenteron and amnion. Although these cases have net demonstrated an actual enteric connection with the cord anomaly, one case did have a probable posterior mediastinal esopha- geal diverticulum in association with diastematomyelia at a corres­ ponding segmental level (T11). Other authors (Keen and Cop1in, 1906; Saunders, 1943; Bent1ey and Smith, 1960; Burrows and Sutc1iffe, 1968) have described cases of dorsal enteric fistulae \'/hich connected sorne portion of the gut with the skin of the back bet\'/een a cleft cord or the nerve roots of the cauda equina. If again one considers the regiona1 distribution of the les ion in the present series of cases of diastematomye1ia (fig. 4), a longitudinal view of the 1esion is obtained. It is apparent that instances of prevertebral cysts and diverticu1ae, neurenteric cysts, the Klippe1-Feil syndrome and combined anterior and posterior spina bifida have a regional distribution rostral to that seen in diastematomYe1ia; instances of spina bifida cystica generally para11el the regiona1 distribution of diastematomYelia; and instances of dermoids, teratomata, lipomata and pilonidal cysts and sinuses gene­ ra11y have a regiona1 distribution which lies caudal to that of diaste­ matomyelia. This longitudinal vie\'1 a1so suggests a corranon origin of the various anomalies with either different time sequences involved, or different embryologico-anatomical mechanisws operating at the three 1eve1s. 32.

HYPOTHETI CAL MECHANISj\{$

CJta.tU.o - c.eJt v-i..c.o -thoJz.a.uc. Leh-toYL6

Consider first those lesions seen in the cranio-cervico- thoracic regions. Wh en the neurenteric canal first makes its appearance, it passes through what is destined to become the cranio-cervical region (Heuser, 1932) and by the usual time of closure, it has probably extended through sorne upper thoracic segmental anlagen as well. The canal is directed in a ventrorostrai direction, running frorl Hensen's node dorsally to perforations in the endoderm more rostra11y and ventra11y, under1ying a portion of the head process in its most rostral extent (fig. 138). The neuroectoderm direct1y over1ying this ob1ique1y directed canal is not c1eft as is the neuroectoderm an1age strearning forward from either side of Hen­ senls node. Notochordal tissue encirc1es the notochorda1 canal and when the f100r of this canal disappears to forrn the archenteron-amnion communi­ cation, the notochord becomes virtua11y c1eft with strearns of notochorda1 tissue 1ying on either side of the neurenteric canal and a unice11u1ar notochorda1 layer forming the roof of the canal (fig. 14A). Any break in this unice11u1ar roof at this point wou1d estab1ish a complete1y c1eft notochord (fig. 14B). The stimulus which initiates disappearance of the floor of the notochorda1 canal is, of course, unknown; it is conceivab1e that the notochorda1 tissue might sometimes respond to this stimulus by the disappearance of ce11s in the roof of the notochorda1 canal as we11. There would then be estab1ished an open communication in the most rostral somite regions extending from the archenteron to a site just ventral to the esta­ b1ished neuroectoderm. If this communication shou1d remain patent, a patho1ogica1 basis is estab1ished for the development of the c1inica1 enti­ ties of foregut diverticu1ae and cysts, the K1ippel-Feil syndrome, and rendoderm

B 111\l\\\UlII\\IIIUU\\U\Il 1\\\l\llm\l\\\UIlIllIIIIIII\IIlIUIIl~ \l .A •

~ .11.• ii11. , ~~l.liti. ~-.,

Figure 14. A. Cross section of fig. 13B, indicated by the 1ine AB of that figure. When the f100r of the notochorda1 canal disappears, forming the neurenteric canal, the roof of the neurenteric canal consists of a unicellu1ar notochorda1 layer. B. Any break in this unice11u1ar roof would estab1ish a comp1etely c1eft notochord, a110wing endodermal diverticulae to extend dorsa11y to a point just ventral to the established neuroectoderm.

-- 33. neurenteric cysts, all of which demonstrate considerable clinical overlap, lie ventral to the spinai cord, and share in common evidence of a previous notochordal cleft (abnormal vertebral bodies) with intact neuroectoderm (spinal cord). Alternatively, these rostrally-situated lesions are expli­ cable by the development of a complete fistulous communication between archenteron and a~nion with subsequent complete healing of the neuroectoderm.

A complete fistulous communication bet\~een archenteron and amnion, as is se en in instances of combined anterior and posterior spina bifida, would result if the entire neurenteric canal were to remain patent and be incorporated between the neuroectodermal and notochordal streams proliferating forward from Hensen's node. Were the canal to remain entirely patent through­ out further somite formation, preventing union of the notochordal and neuro­ ectodermal streams, it is easy to appreciate the process by which occasional instances of combined anterior and posterior spina bifida with diastemato­ myelia could be seen at any point along the neuraxis. In a review of 37 cases of combined anterior and posterior spina bifida, Saunders (1943) demonstrated that in the majority of cases, the cleft involved either the cervico-thoracic region in varying degrees, or else extended throughout the whole length of the . He further demonstrated, by graphing the site of alimentary involvement relative to spinal involvement, that the portions of the alimentary tract most commonly affected were derivatives of the fore- or midgut, not surprising when one considers that the foregut primordium directly underlies the early established neurenteric canal. Healing of the neural plate and notochordal clefts of these com­ bined defects, with subsequent nonclosure of the neural tube, would provide a pathological basis for cervical myelocele (spina bifida aperta); anen­ cephaly and iniencephaly (cranium bifidum aperta) would result from more rostrally situated neural-notochordal clefts. The possible mechanism of 34.

rostral clefts vlhich involve the brain primordium is discussed in a later section of this study. Healing of a cleft with nonclosure of the neural tube appears to be demonstrated by a totally dysraphic human embryo of 14 somites (2.75 mm C-R length) studied by Dekaban (1963). The neural tube of the embryo was open throughout its extent, except for the most rostral portion, which normally has no underlying notochord. The cells of the notochord in this embryo were noted to be more loosely arranged than normal (1 healing of a cleft notochord), and the cells constituting the neural crest were slightly decreased in number and also loosely arranged. There is no notochordal tissue beneath the most rostral portion of the neural tube, a region which includes the optic vesicle anlage. This region would not become cleft by the events related to the neurenteric canal and this might explain why the eyes and frontal regions usually develop normally in anencephalic monsters, a point to vlhich Dekaban alluded. Instances of en­ cephalocele, which are usually occipital in location (Lorber, 1967), and instances of cervical meningocele and spina bifida occulta would represent a continuum from the above-mentioned lesions, with healing of the neural plate cleft and subsequent varying degrees of closure of the neural tube. Perhaps the commonly seen occipito-cervical midline hemangioma, sometimes associated with spina bifida occulta, in normal individuals represents the most completely healed clinical stigmata marking the previous site of the neurenteric canal.

ThoJta.C.o-.twnba/r.. Leo-i..ol1.6

Consider now those lesions seen in the thoraco-lumbar regions. The mechanism of diastematomyelia is essentially that as outlined for combined anterior and posterior spina bifida, with a cleft of the neural plate and notochord resulting from incorporation of a persistent neurenteric canal in a portion of the subsequently formed thoraco-lumbar neuraxis. 35.

In this entity, there is an attempt at closure of the neural material vlÏthout healing of the neural plate cleft, and in the Il'!::.jority of cases, there occurs variable healing of portions of the neurenteric fistula. The neuroectodermal streams, separated by the incorporated neurenteric canal, would form 2 separate hemicords, each with its own central canal. The lateral sclerotome masses \'lould eventually encompass the separated notochordal streams and form anomalous vertebral bodies, often associated with thin disc spaces and/or a segmentally widened canal, features which were almost invariably found in the present series of cases. In the presence of a cleft neural plate, neural crest tissue could migrate between the separated neuroectodermal streams, resulting in the clusters of ganglion cells interposed between the eventual hemicords of the cases in the present series. The migratory potential of neural crest tissue is \'Iell known, and sorne have ascribed to it the capability of contributing to the body'mesenchyme (Horstadius, 1950; Kallén, 1968). Gruenwald (1941) has studied a 20 mm human embryo with thoracic diastematomyelia, thoraco­ lumbar myeloschisis and sacrococcygeal foci of dystopic tissue composed of cartilage, primitive mesenchyme and renal tissue. On the basis of the intimate relationship of these dystopic tissue masses to ectopic neural crest tissue, he concluded that the dystopic abnormalities were of neural crest origin. His observations suggest that ectopic midline neural crest tissue might contribute to or induce midline abnormal development, such as anomalous muscle, fibrous stalks, teratomata, lipomata and bony septae seen in diastematomyeîia and other dysraphic anomalies. The cutaneous pigmentary changes overlying diastematomyelia and other dysraphic lesions, as well as the finding of cells of neural crest origin in association with a teratoma in one of the present cases, glve credence to the view that the neural crest plays an important role in the embryogenesis of these anomalies. 36.

With these mechanisms in mind, it is proposed that the les ion in spina bifida cystica represents an attempt ta heal a neural plate cleft, a further development of the early phenomena proposed in the mechanisms of combined anterior and posterior spina bifida and diastematomyelia. Variable delayed closure of the neural tube would yield a spectrum ranging from open myeloceles to simple meningoceles and spina bifida occulta. There is strong clinical evidence that diastematomyelia and spina bifida cystica are developmental1y closely related. 1) They have essentially the same regional distribution and are frequently associated. 2) The two 1esions, when occurring separately, are associated \'/ith the same mesoderma1 anomalies (Doran and Guthkelch, 1961; 1'1atson, 1969). 3) As earlier men­ tioned, flat myeloceles are sometimes seen to be split in the midline. Duckworth et al. (1968) have described instances of hemimYelocele, which might be more properly termed diastematomyeZoceZe> in which one half of the cord was represented by f1at neural plate and the other ha1f was better formed, both under1ying a typica1 cystic mye10ce1e appearance. 4) Tal­ walker and Dastur (1970) have demonstrated tissue from all three germ 1ayers, including mucin-secreting endodermal tissue, lying dorsal to the bulk of the neural lesion, indicative of the proposed previous cleft and fistula. B1undell (1972) confirms the presence of endodermal tissue lying dorsal to the neural 1esion as a finding in sorne of his instances of mye1o­ meningoce1e. 5) Ectopic dorsal root ganglion cells are associated with both diastematomyelia and spina bifida cystica. Doran and Guthkelch (1961) have mentioned a type of cervico-thoracic spina bifida cystica, sornetimes termed a syringoceZe> in which the cystic protrusion is composed of 2 sacs, the inner of which protrudes from the mid1ine dorsum of the cord, is epen­ dyma1-1ined, and contains ganglion ce11s in its wal1s. It can on1y be 37.

concluded that these ganglion cells became associated with ependymal cells during a period \'1hen the neural plate was cleft. Talwalker and Dastur (1970) also demonstrated ectopie ganglion cells associated \'1ith a case of myelomeningocele, and others (Gilman, Gilbert and Gilman, 1948; Harkany, Wilson and Geiger, 1958; Lendon, 1968) have reported the presence of mid­ line masses of dorsal root ganglion cells in association with trypan blue experimentally-produced myeloceles in rat embryos. 6) Both diastemato­ myelia and spina bifida cystica are associated with enteric fistulae, remi­ niscent of the neurenteric canal. Lucksch (1903) described a stillborn infant in which the stomach and intestines opened at several points along the floor of a large myelomeningocele and another in which the floor of a fiat myelocele was connected to the esophagus by an open fistula. j~usca­ tello (1394) also described a stillborn infant with a broad connection between the pharynx and esophagus and a large, flat cervico-thoracic myelocele.

~Iyelodysplasia, meningocele, spina bifida occulta and sorne instances of syringomyelia would result from subsequent delayed closure of the healed neural plate. Of course, faulty closure of the neural tube alone may explain sorne instances of these anomalies, but the frequent finding of associated vertebral body anomalies and other remote mesodermal anomalies certainly indicates the previous existence of a neural-notochordal cleft in these cases. Schlesinger (1902), for example, noted anomalous develop­ ment of the vertebral column in one-third of his cases of syringomyelia. Myeloceles and myelomeningoceles are seen more frequently than simple meningoceles, at a ratio approaching 4:1 (~oran and Guthkelch, 1961), per­ haps indicating the difficulty involved in healing cf a cor:!pletely cleft neural plate. Instances of simple meningocele, the sac by definition con­ taining no neural elements, are sometimes associated with neurological 38.

deficit and foot deformity (status dysraphiaus); in these cases, a local "myei odyspl asia" i s postul ated as the cause. It is pl"oposed that these cases always represent either an underlying diastematomyelia or a less extreme dysraphic anomaly, the healed residua of a previously cleft neural plate. Matson (1969) mentioned the frequent finding of cleft cords or cystic cords in cases of meningocele. Certainly the posterior dural and bony araphia, termed by Lichtenstein (1940) the sine qua non of all forms of spina bifida cystica, is explicabl~ in terms of a previous midline fistula \'/hich prevented or delayed midline mesodermal union. The concept of a cleft with subsequent healing embodies those lesions described under the term of spinaZ dysraphism (Benda, 1959; Matson, 1969; Till, 1969; James and Lassman, 1972), including instances of spina bifida occulta associated with hypertrichosis, dimple, dermoid and fatty tumors, and other mesodermal anomalies. Spina bifida occulta, mani­ fest only by a dorsal bony lesion, would represent the most completely healed clinical form of an early embryonic neural-notochord cleft. Ependymomas and ependymal cysts of the cord might also have their origin in the process of healing of neural clefts. Ependymal cell rests are often demonstrated in association with various dysraphic anomalies and ependymomas occur most frequently in those segments where myeloschisis has been most frequently demonstrated. Of the three cases of ependymal cysts of the cord thus far reported (Wisoff and Ghatak, 1971), two were associated with widened spinal canals witl10ut erosion of pedicles, anomalous vertebral bodies and vertebral fusion defects. 39.

With regard to the 1umbo-sacro-coccygea1 les ions seen c1inically, the same mechanisms of neurenteric canal persistence and incorporation are invoked, but two embryologico-anatomical differences exist in this region which wou1d influence these mechanisms: 1) The most caudal portion of the neural tube under­ goes atrophy or dedifferentiation (Kuni tomo , 1918), forming the filum terminale, and sorne lesions in this region ...,ould represent primary interaction along the proposed amnion-archenteron fistu1a . between mesoderm, endoderm and somatia ectoderm. 2) This region is the final resting place of the cell mass derived from the union of Hensen's node and the primitive streak (end or taiZ oud) , and this multipotentia1 cell mass might be expected to yield dermoids, teratornata, lipomata, and pilonidal lesions, perhaps in relation to ectopie neural crest tissue. A tight filum terminale might also result from these interacting mechanisms. Abnormal notochordal phenomena have been observed in embryos in this region where the tail bud "plays outil (Kunitomo, 1918), perhaps leading to the con­ centrated occurrence of chordomas in this region.

The mechanisms proposed for spina bifida formation are based, then, on healing of a cleft neural plate in instances of mYeloce1e with subsequent faulty, delayed neural tube closure in instances of meningocele, syringornye1ia, spinal dysraphism, mye1o­ dysplas;a and spina bifida occulta. Healing of the neural plate 40.

would occur first, with closure of the neural tube being a subsequent development. In diastematomyeiia and combined anterior and posterior spina bifida, attempted closure of the neural material occurs without healing of the neural plate cleft. In a remarkable embryological demonstration, Padget (1968, 1970) has recently defined the entity which she terms neurosahisis as "abnormal neural clefts which may completely divide any part of the neural plate or neural tube". Her study was based on 100 embryos àemon• strating neuroschisis from the collection of the C&rnegie Institute of Washington. She concluded that the condition might be common since almost two-thirds of the embryos had been obtained from tubal pregnancies, hysterectomy, or surgi cal or self-induced abortion and had not necessarily been sent te the Carnegie Institute because of the presence of myelo- schisis. She felt that abnormal neural clefts had their origin in various noxious stimuli from without the embryo, with opening of a neural tube or plate previously closed. It is proposed, however, that a neural plate cleft is the basic defect. This seems illustrated by the fact that neural plate clefts were more frequently seen in her younger embryos, whereas neural tube clefts occurred in older embryos. Furthermore, the most severe degrees oT cleft were seen in earlier stage embryos, whereas clefts in older embryos were generally more benign appearing, indicating the natural course of healing of a neural cleft. In one embryo, less than 3 mm in C-R length, a cleft notochord as well as a cleft neural plate was demonstrated. Padget documented the healing of neural clefts and described three basic types of healing. A sequel te neural clefts was an abnormal folding of the neural tube wall with an increase in neural volume (Pattenls overgrowth) and increased mitotic activity in neural tissue, phenomena which could be 41.

interpreted as processes involved in the healing of clefts. This indicates that overgrovJth 1s secondary to a neural cleft rather than its cause, as Fowler (1953) concluded after observing neural tube overgrowth as a component of mechanically-produced mYelo­ schisis in chick embryos. In the present case studied at autopsy, as well as in numerous other pathological studies (Lichtenstein, 1940; Gruenwald, 1941; Ogryzl0, 1942; Kapsenberg and Van Lookeren Campagne, 1949; Benstead, 1953; Cameron, 1957; Daniel and Strich, 1958; Benda, 1959), hydromyelia, ependymal cell rests, midline raphe gliosis, deepened dorsal and ventral fissures and duplicated central canals have been regularly demonstrated in segments just rostral to and caudal to a cleft cord, indicating in the se instances that healing of the neural cleft had occurred above and below the clinical les ion and that the cleft had originally extended over many more segments. In one of the cases demonstrated by Benda (1959), extensive central shaft gliosis was found around a central canal in a section taken rostral to a cord cleft. A considerable body of clinical evidence also exists to support the concept of healing of long neural clefts. As earlier described, vertebral defects and cutaneous lesions frequently occur widely removed from the cord lesion in diastematomyelia. The early embryo described by Oekaban (1963) vividly illustrates a cleft extending over the entire neuraxis, as does one of the present cases described in which the cord was cleft from approximately C7 distalwards. Bailey (1971) has described an infant with two separate meningoceles, one situated in the upper thoracic region and the other at lumbosacral levels. 42.

Another case on record at the ~10ntreal Neurological Hospital (8ertrand~ 1972) had an occipital encephaioceie as weii as a iumbo-sacrai myeiomeningo­ cele (fig. 15). rlackenzie and Emery (1971) have reported cervical cord deformities, including hydro- and syringomyelia, diastematomyelia, v/inged cords, and dorsal slits in 96 of a series of 100 children who had died with myelomeningocele. 81aauw (1971) has demonstrated a defect in the posterior arch of the atlas in 70 percent of a series of 30 children who had died with a myeiomeningoceie at iower neuraxis levels. It is necessary, then, to visualize the healing of neural clefts in both a horizontal and a vertical plane, with the final clini- cal manifestation representing the efficacy of the healing process.

Padget (1968) has illustrated an embryo with IImu ltiple clefts" along its neuraxis; in the terms of the present concept, this embryo is inter­

preted as showing "multiple areas of healing ll of an extensive neuraxis cleft. The view of Padget (1968, 1970) is supported that clefts of the developing embryonic neuraxis probably occur frequently, with such effective healing that only a relatively small number of such clefts

become clinic~lly apparent. In support of this view is the study by Zappert (cited by Riley, 1930); he investigated several hundred spinal cords in young, normal individuals and found many anatomical variations of the central canal, including divel"ticulae, hydromyelia, surrounding gliosis and other anomalies.

RELATIONSHIP TO PREVIOUS HYPOTHESES

The proposed hypothesis provides an orderly scheme for vie\'lÎng the entire spectrum of spina bifida and dysraphism. The hypothesis rests on the occurrence, in early embryonic life, of clefts involving the neural plate. The neurenteric canal is invoked to explain these clefts because · . - .. - _.------'1'--

f •

Figure 15. An infant with an occipital encephaloce1e and a iumbo-sacral mYe1omeningocele. A case such as this suggests that the embryonic neural plate was c1eft over many segments, with effective hea1ing of the neural plate c1eft and closure of the neural tube occurring between the two 1esions. Figure 15. An infant with an occipital and a 1umbo-sacral myelomeningocele. A case such as this suggests that the embryonic neural plate \'/aS cleft over many segments. \'iith effective healing of the neural plate cleft and closure of the neural tu~e o~:urring between the two lesions. 43.

it is the only normally-occurring structure through which amnion and archenteron can be linked and clinical evidence suggests that such a link has been present at sorne time in the embryogenesis of these defects. The hypothesis embodies those entities included in the split notochord hypothesis, proposes a different mechanism for the split notochord, and adds several other entities. iionclosure of the neural tube is included in the mechanisms of the hypothesis to explain certain anomalies, but simple non-closure, as previously proposed, would not explain the pre­ vertebral mesodermal and endodermal defects seen in diastematomyelia and other forms of spina bifida and dysraphism. Overgrowth of the neural tube is viewed as a component of the healing of clefts rather th an their cause. The hypothesis is at v, ~~nce chiefly with the hydromyelic hypo­ thesis and several points mitigate against this concept: 1) Several embryos with mye10schisis have been described in very early stages (Patten, 1953b; Dekaban, 1963; Lemire, Shepard and Alvord, 1965; Padget, 1970), ",lell before CSF formation by the choroid plexus or perforation of the rhombic roof are known to occur. It is difficu1t to imagine the high protein f1uid said to be secreted by the neural tube epithelium (Weed, 1917; Gardner, 1968) as sufficient in pressure to rupture the neural tube. Furthermore, the very early embryos demonstrating myeloschisis (Dekaban, 1963; Padget, 1970) have not reached the stage of posterior neuropore c10sure and consis­ tently demonstrate microencepha1y. 2) 8y the same token, the presence of midline clusters of dorsal root ganglion cells between the hemicords in the present series of cases and in the syringoce1e mentioned by Doran and Guthkelch (1961) dates the neural cleft to at least the period of neural crest organization and migration, a time a1so antedating CSF production and rhombic roof perforation. 3) Hith regard to the proposed hydromyelic 44.

mechanism of diastematomyelia, it is difficult to conceive that both dorsal and ventral rupture of a c10sed neural tube could occur; after dorsal rupture (Gardnerls structura11y weak area), intramYelic pressure i'lOu1d be relieved and ventral rupture would not be expected. It also does not seem tenable, even if ventral rupture shou1d occur, that escaping f1uid could split the sma11 , dense rest of notochorda1 tissue lying ventral to the cord, a mechanism invoked by Gardner to explain

the vertebral c1eft defects seen in diastematomYe1ia. 8y the ti~~ hydro­ myelic rupture is proposed (8 weeks), the notochord is enc10sed by sc1e­ rotome and vertebral body formation is we11 unden'Jay. It should a1so be reca11ed that a c1eft notochord has been demonstrated in sorne pre-neuro­ pore c10sure embryos. 4) There seems to be no exp1anation in the hydro­ mye1ic hypothesis for the demonstration of two separate ependyma1 canals above and be10w the lesion in diastematomyelia. 5) Fina1ly, simple meningoce1es and instances of mYe1odysp1asia are not explicable in terms of dorsal rupture of the neural tube un1ess subsequent dorsal hea1ing is postu1ated as we11. One wou1d have to agree with Gardner, however, IIthat any theory that attempts to explain the origin of mye1omeningoce1e, of necessity, must exp1ain the hydrocephalomye1ia and the deformity of the hindbrain that accompany itll (Gardner, 1960). This statement is applicable not on1y to the Arno1d-Chiari malformation (Chiari Type II) accompanying mye­ lomeningoce1e, but a1so to the other Chiari deformities (l, III) and the Dandy-Wa1ker syndrome, \'/hich a1so are associated with spina bifida and dysraphism. The fo11owing account is an attempt to extend the present hypothesis to exp1ain these entities. 45.

CLEFTS OF THE BRA.IN PRIMORDIUM

The CIUaJü IJe6oJz.mU,i.u

Several hypotheses have been advanced to explain the Arnold­ Chiari malformation. Sorne have proposed that tethering of the cord by mYe1omeningocele is responsible for the hindbrain deformity (Penfield and Coburn, 1938; Lichtenstein, 1942). Points which mitigate against this hypothesis include: 1) the peculiar buckling of the cervico­ medullary junction, 2) the occurrence of Type 1 deformity in the absence of overt spina bifida cystica, 3) the conclusion of Barry, Patten and Ste\'Iart (1957) from a study of the angulation of spinal nerves in embryos and fetuses that traction is not dissipated beyond 4 segments rostral to the rnyeloschisis, and 4) the inability of Gold­ stein and Kepes (1966) to produce a hindbrain defonnity by surgical tethering of the spinal core in newborn opossums. Barry, Patten and

Stewart (1957), \'/ho felt that overgrm'/th \'Ias responsible for neural tube nonclosure and subsequent myeloschisis, postulated that similar overgrowth phenomena separately affected the hindbrain, with hypertrophy of hindbrain structures overcrowding the posterior fossa and herniating its contents. Subsequent studies, however, have demonstrated in this condition that the posterior fossa is small, the tentorium is situated lower than normal, and the neural tissue is hypoplastic or of approxi­ mately normal volume (Cameron, 1957; Daniel and Strich, 1958; van Hoytema and van den Berg, 1966). There remain only those hypotheses based on altered fourth ventricle pressure relationships. Gardner (1960) proposed that physiologie hydrocephalus, with failure of the rhombic roof to perforate, causes herniation of the hindbrain. Cameron (1957) pro­ posed that the hindbrain malformation results from leakage of CSF into 46.

the amniotic cavity from the exposed central canal of an embryonic myeloschistic lesion, with herniation of the hindbrain occurring as a consequence to both the decompressive effect of the leak and the altered intraventricular-amniotic pressure relationships. These theories have sought primarily to explain the variable caudal herniation of hindbrain contents in the anomaly. The anomaly consists, however, of much more th an simple herniation of the hindbrain. Other features described include anomalies of the aqueduct, thickening of the massa intermedia, hypoplasia of the falx, partial obliteration of the great longitudinal fissure of the cerebrum, heterotopic nodules of cerebral gray matter projecting into the lateral ventricles, hetero­ topic folia formation in the roof of the fourth ventricle, anomalies of the septum pellucidum, cleft-like spaces in the inferior , fusion of the corpora quadrigemina into a single midline mass, craniolacunia, and cysts in the region of the foramen ~lagendie (Lich­ tenstein, 1942; Ingraham and Scott, 1943; Russell, 1949; Crome, 1952; Feigin, 1956; Cameron, 1957; Peach, 1964,1965). Cameron (1957) pointed out the frequent association of the Arnold-Chiari malformation vlÏth diastematomyelia and hydromyelia and Peach (1965) described a 20 percent incidence of hemivertebrae in his cases of the Arnold-Chiari malformation. It is submitted that all of these essentially midline features indicate that in the Arnold-Chi ari ma lformati on the embryoni c neuraxi s vias involved by a midline neural plate cleft as earlier proposed for other anomalies, the cleft extending rostrally into the brain primordium. Healing of the neural plate cleft and subsequent faulty closure of the neural tube began in the more rostral portions of the neuraxis, leaving the above-mentioned pathological features as sequelae of the cleft. 47.

In the more caudal portions of the neuraxis, healing of the neural plate occurred, but incomplete closure of the neural tube resulted in an overt spina bifida aperta. The fact that the vermis is primarily herniated in Type II might indicate that sorne herniation occurred in these cases whi1e that part of the neural tube comprising the caudal hindbrain was still cpen, i.e., before the paired cerebellar anlagen had fused in the mid1ine. The previous existence of a cleft of the neural plate or neural tube of the brain primordium, however, does not explain the most publicized feature of the anomaly, i.e., the hindbrain herniation. It is proposed that this dramatic feature of the anomaly is the result of altered pressure relationships in the manner proposed by Cameron (1957) and supported by the studi es of van Hoytema and van den Berg (1966) and \~i 11 i ams (1971). The altered pressure relationships \'Iould be mediated via the persisting dorsal opening of the caudal neural tube, the cystic spina bifida 1esion. Under the terms of this concept, leakage of CSF into the amniotic cavity from a myeloschistic les ion would alter the normal static equilibrium exis­ ting between a closed embryonic ventricular system and the amniotic cavity, vlith the net effect being a relative1y increased amniotic pressure acting on the developing embryonic cranium and causing herniation of hindbrain contents (fig. 16). There seems litt1e doubt that continuity exists be­ tween the embryonic ventricular system and the amniotic cavity in myelo­ schistic lesions. Exposure of an open central canal to the amnion is well documented in the descriptions of several embryos and fetuses (Gruenwald, 1941; Patten, 1953b). Andersson, Carlsson and Rosengren (1967) have radio­ logically demonstrated communication between the ventricles and amnion via A

Figure 16. A. Normal static pressure equi1ibrium existing between the embryonic ventricu1ar system and the amniotic cavity. B. With a mye10schistic defect, this equi1ibrium is a1tered; the net effect is a re1atively increased amniotic pressure due to the transfer of arterial pulsations from the choroid plexus, this pressure acting on the deve10ping embryonic cranium and causing herniation of hindbrain contents. Microencephaly wou1d be expected in association with an open mYeloschistic 1esion. 48.

the central canal in a stillborn infant with myelomeningocele. Jacobs, Landing and ïhomas (i961) have demonstrated the presence of amniotic epithelium in the central canal of infants \'lÏth spina bifida. Further­ more, there is a high incidence of hydramnios in al1 pregnancies in which the infant is born with spina bifida, hydrocephalus or anencephaly (Stevenson, 1960; Comerford, 1965) and hypertrophy of the choroid plexus has been demonstrated in instances of anencephaly (Scott and Paterson, 1966) and the Arnoid-Chiari malformation (Cameron, 1957). Peach (1965) has offered a va1id criticism of Cameronls proposal, invoking Pascalls 1a\" and stating that "any increase in intra-amniotic tension wou1d be transmitted equa11y to the region of the spinal defect as to the sku11, and theoretica11y, no fluid wou1d leak out of the ventric1es under such conditions". This criticism ignores, howevei, the pump effect of the transfer of arterial pulsations from the choroid plexus to the CSF (Bering, 1955) and the possibility of a ba11-valve effect at the site of the myeloschisis, as offered by the demonstration of adherent amnion and somatic ectoderm in the region of the defect (Padget, 1970). Assuming Cameronls mechanisms for the development of the hind­ , small ventricles would be expected in association with an open mYeloschistic lesion. Padget (1970) reported the finding of micrencephaly in the majority of her 100 embryos with neuroschisis, micrencepha1y invariably being present in the most severe cases of neuro­ schisis. Warkany, Wilson and Geiger (1958) also reported that hydrocephalus could not be demonstrated in instances of experimenta11y-produced mYelo­ schisis, whereas 1itter mates without myeloschisis did have hydrocephalus. 49.

They further demonstrated that hindbrain herniation was absent in feta1 rats with mye10schisis up to 17 days, whereas it was present in sorne feta1 rats older than 17 days; this suggests that after 17 days, suffi­ cient leakage had occurred to cause hindbrain herniation. This feta1 micrencepha1y may account for the cortical microgyria in the Arno1d- Chiari malformation; the diminished size of the posterior fossa and low tentorium would represent later mesoderma1 response. That the degree of hindbrain herniation is dependent upon the duration and extent of the CSF leak provides a scheme for understanding a progression in the Chiari deformities. In the Type l deformities, i.e., those cases consisting of minimal (tonsillar) hindbrain herniation in the absence of spina bifida aperta, healing of the myeloschistic defect (delayed closure of the neural tube) would have occurred early, preventing the severe herniation accom­ panying a persistent spina bifida aperta. These cases also lack the associated cerebral anomalies seen in Chiari Type II deformities, indi­ cating that the original neural plate cleft which caused the transient myeloschistic defect had probably not extended rostrally into the brain primordium. It is conceivable that the timing of healing of the myelo­ schisis in relation to rhombic roof perforation could explain sorne instances of congenital communicating hydrocephalus. If healing were 50 tirned that the rhombic roof perforated but intraventricular pressure was inadequate for normal dissection of the subarachnoid spaces and arachnoid villi, then a communicating type of hydrocephalus would resu1t. Support for this concept is offered by the clinical study of Lorber and Bassi (1965) who found in 67 cases of congenital hydrocephalus without spina bifida cystica that in 26 cases there were either other neuraxis malformations including myelodys­ plasia, vertebral anomalies, and or else a family history of 50.

CNS ma1formations, including anencephaly, spina bifida cystica and hydrocephalus. The Chiari Type III deformity, consisting of dO\llnward displacement of the medulla with herniation of the into a high cervical meningocele, reflects the dramatic hydrodynamic effect of a large and persistent, rostrally-situated mYeloschistic lesion.

The. Oa.ndy-(tJalkeJl. Syn.dll.ome.

The Dandy-Walker syndrome, although originally described as atresia of the foramen i1agendie (Dandy and Blackfan, 1914; Dandy, 1921; Taggart and Walker, 1942), has subsequently been shoi'in to be a highly complex developmental anomaly. Benda (1954) noted as essential patho­ logical features of the anomaly a sac formation at the caudal end of the cerebellum and posterior roof of the fourth ventricle, variable separation of the cerebellar hemispheres, and underdevelopment of the caudal portion of the vermis. He further noted that the posterior medul­ lary velum lacked its normal regressive changes and persisted as a thick membrane, that the dentate nuclei were elongated in a saggital direction, and that the roof nuclei were rudimentary. Brodal and Hauglie-Hanssen (1959) felt that underdevelopment of the cerebellar vermis, particularly in its caudal portions, and anomalies in the roof of the dilated fourth ventricle were the essential features of the anomaly. D1Agost;no, Kernohan and BrO\'1n (1963) aga;n pointed out that the more rostral parts of the vermis were better preserved, and noted that the foramen Ï'lagendie \'1as not necessarily occluded. In a discussion of their 10 cases, they directed attention to other associated cerebral anomalies seen in the syndrome, including agenesis of the corpus callosum, anomalies of the aqueduct, alterations in the ependyma of the aqueduct and fourth ventricle , 51.

heterotopic glial tissue in the subarachnoid space, and in one case, fusion of the nuciei of the third craniai nerve into a midiine mass. In another case, they described ectopic ganglion cells in the region of a lateral recess and lying beneath the ependyma. Again apparent in these descriptions are midline features indicative of the previous existence of a midline neural cleft. Benda (1954), in fact, felt that the main pathology was a midline cerebellar rachischisis and termed the anomaiy the :lDandy-Waiker Syndrome" to direct attention away from atresia of the foramen Magendie as the etiology of the condition. The bulbar abnormalities seen in the anomaly indicate, however, that a midline cleft originally involved the neural plate and that healing of the cleft occurred, with subsequent delayed closure of the neural tube. Unlike the Chiari deformities, where the original neural plate cleft primarily involves the lower' embryonic neur­ , perhaps extending into the brain primordium, the Dandy-\~alker syndrome represents the sequelae of a cleft which primarily affects the brain primordium, perhaps extending into the lov.Jer neuraxis. Hindbrain herniation would not be expected with CSF leakage from a rostrally­ situated neural tube cleft. That caudal extension of a cleft has existed in instances of the Dandy-Halker syndrome is apparent from a later report by Benda (1959) in which he presented pathological evidence of occult neural dysraphism, hydromyelia and even central canal duplication, in instances of the anomaly which had no overt spina bifida. Baker and Rydell (1971) have also directed attention to the association of syringo­ myelia with the Dandy-Halker syndrome. 52.

It is proposed that there exist three varieties of congenital cord cavitation related to the centrai canal. The term hydromyeZia should be reserved for those instances in \'/hich an active communication exists viith the ventricular system via the central canal. The key to understanding progression in these cases must lie in the degree of obstruction to fourth ventricle outflow. This variety is commoniy associated \'iith the Chiari Type l anomalies, the Dandy-~~alker syndrome and adhes ions in the regi on of the foramen Nagendi e (Gardner, 1965;

App1eby et al., 1969; NevJton, 1969; Bertrand, 1973). SyringorrryeZia~ as ear1ier proposed, \o,Jou1d result from faulty, delayed closure of the neural tube; in this variety, there is not necessarily a communication \o,Jith the ventricular system and it occurs at more caudal levels of the neuraxis. Another variety of syringomyelia results from a diverticulum of a hydro­ mye1ic process vihich loses its original connection with the ventricular system. The mechanisms proposed for the Chiari deformities and the Dandy­ Walker syndrome are independent of the controversy of whether perforation of the rhombic roof occurs in response to embryonic intraventricu1ar pressure (Weed, 1917; Gardner, 1960) or occurs as a normal midline deve10pmental process (Brock1ehurst, 1969). In those cases where atresia of the foramen [·1agendie exists, the atres ia wou1d represent a consequence of fau1ty, de1ayed c10sure of the neural tube in that region.

Ignoring the hindbrain herniation of t~e Chiari deformities and considering on1y those features indicating the previous existence of a mid1ine cleft, it shou1d be apparent that there exists an intimate patho­ genetic re1ationship between the Chiari deformities and the Dandy-Wa1ker anoma1y, the two anomalies representing variations in the severity and longitudinal extent of the original neural plate cleft and in the timing of hea1ing of these c1efts and subsequent de1ayed c10sure of the neural tube. 53.

Similarly apparent is the close pathogenetic relationship between these entities and anencephaly, iniencephaly, and cervical myelocele. It is further submitted that many other midline cranial abnormalities, including of the corpus callosum, aqueductal anomalies, agenesis of the cerebellum, familial agenesis of the cerebellar vermis (Joubert et al., 1969), intracranial leptomeningeal cysts, sorne forms of chronic cystic arachnoiditis, and sorne intracranial dermoid and epidermoid tumors also have their origin in the faulty healing of neural clefts involving the brain primordium. In an earlier section of this communication, it was proposed that the development of a neural plate cleft of the spinal neuraxis was related to the incorporation of a persistent neurenteric canal by the developing neurai piate. ïhe mechanism whereby a neural plate cleft involves the brain primordium, i.e., that portion of the neural plate rostral to the usual site of appearance of the neurenteric canal, seems less clear. A plausible explanation is offered by the fact that only a few embryological specimens have been studied with a view towards esta­ blishing the site of appearance of the neurenteric canal and although it is generally thought to appear in the upper cervical anlage (Heuser, 1932), it could well be that in sorne individuals it has a more rostral site of appearance. Cranium bifidum occurs less commonly than spina bifida, at an approximate ratio of 1:5, perhaps indicating that in approximately 20 per cent of normal individuals, the neurenteric canal appears in more rostral (brain primordium) neural plate segments. An alternative possi­ bility is that an established neural plate cleft is extended rostrally by mechanical forces. A diagrammatic representation of the basic mechanisms of the proposed hypothesis, applicable to various levels of the neuraxis, is depicted in fi g. 17. NORMAL SOMITE EMBRYO

notochord neuroectoderm •1

~~SOMITE EMBRYD with PERSISTENT NEURENTERIC CANAL 1IIt.

~ifôPERSISTENT NEURENTERIC CANAL combined êI1t. & post spina blfida .$;. # ~ PERSISmrr IlEURAl PLATE cmT dlastematomyefra , dorsal intestinal fistula

lEAlED NEURAL PLATE; NOHCLOSURE of NEURAL TUBE spina bifida aperta, lanellcephalY,iniencephaly! DELAYED CLDSURE of NEURAL TUBE

spina bifida occulta, hyllromyelia, rœnin~cceie IDANDY-WALKER syadroaIe,CIWI dIforaitiaj

Figure 17. Diagrammatic representation of the basic mechanisms of the proposed hypothesis, applicable to various levels of the neuraxis. s ur~ r~ A RY AND CON CLUS ION S 54.

In addition te further defining the clinical and radiological features of diastematomyelia, it is ascertained in the present study that the lesion in diastematomyelia has a distinct pathological anatomy, hitherto incompletely elucidated. The characteristic anatomical features include: 1) the presence of dorsal root ganglion cells, dentate ligament and dorsal and ventral roots in the area between the hemicords and their dividing septum and dural sheath, 2) the presence of innervated, anomalous midline muscle overlying the spinal canal at the level of the lesion, 3) the occasional occurrence of dermoids, teratomata, lipomata and fibrous stalks in the tissues between a midline cutaneous lesion and the cleft cord, and 4) the occurrence of hydromyelia and duplicated central canals in segments rostral or caudal to a cleft cord. It is further ascertained that diastematomyelia is regularly asso­ ciated with certain other midline developmental anomalies, including spina bifida cystica and occulta, scoliosis and other vertebral column anomalies, Chiari deformities, hydrocephalus, aqueductal stenosis, the Klippel-Feil syndrome, lesions of foregut origin, sacrococcygeal hypoplasia and agenesis, rib and hip anomalies, and congenital elevation of the shoulder. It is submitted that any attempt to explain the embryogenesis of diastematomyelia must also explain the embryogenesis of these, and perhaps other, anomalies. The association of these anomalies with diastematomyelia, as well as the pathological features of the lesion in diastematomyelia, provides clues \'1hich allow the formulation of a universal hypothesis on the origin of all forms of spina bifida and dysraphism and their associated malformations. 55.

The essence of the hypothesis is the formation, in early embryonic

iife 08-30 d.), of a sagittal cleft of the embryonic neuraxis \~hich involves neuroectoderm (neural plate), notochord, and endoderm. Incorporation of a persistent neurenteric canal in the developing embryonic neuraxis is invoked to explain the origin of the neuraxis clefts; this is the only structure which, at sorne period of embryonic development, connects archenteron and amnion, and clinical observations indicate that such a connection must have been present in the formation of these clefts. Sequential events of cleft formation, cleft healing, and faulty delayed closure of the neural tube are proposed as yielding a spectrum of dysraphic anomalies, ranging from open myeloceles (spina bifida aperta) to syringomyelia, myelodysplasia, meningoceles, spina bifida occulta and certain midline developmental tumors. Anencephaly and iniencephaly are considered analogous ta myelocele, occurring as a consequence to clefts invol­ ving the more rostral levels of the neuraxis. Instances of combined anterior and posterior spina bifida and dorsal intestinal fistulae represent examples of extreme persistence of the original neuraxis clefts. Diastematomyelia is viewed as an attempt at closure of the neural tube without prior healing of the neural plate cleft. Alternative mechanisms, involving a notochordal cleft vlithout a neuroectodermal cleft, are postulated to explain cervico-thoracic prevertebral lesions, the Klippel-Feil syndrome and intraspinal neurenteric cysts. Numerous midline cranial malformations, including the Dandy-Walker syndrome, certain manifestations of the Chiari deformities, agenesis of the cerebellar vermis, absence of the corpus callosum, lipomas of the corpus callosum, anomalies of the aqueduct, and intracranial dermoids and epidermoids are considered to be intimately, pathogenetically related and represent resi­ dua of clefts which involve the brain primordium. A hydrodynamic mechanism, mediated via a caudal myeloschisis, is supported to explain the hindbrain herniation of the Chiari deformities. 56.

The proposed developmental hypothesis appears to integrate most previous views on the origin of various forms of spina bifida and dysraphism, being at variance chiefly with the recently revived hydromyelic concept. Clefts of the developing neuraxis probably occur frequently, with such effective healing that only a relatively small number of such clefts become clinically apparent. BIBLIOGRAPHY

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The author is indebted to Dr. Theodore Rasmussen and Dr. William H. Feindel for the opportunity to train and study at the j~ontreal Neurological Institute. A great debt is further acknowledged to Dr. Gi11es Bertrand, under v/hose care t\o/enty-three of the patients comprising this study were admitted. His keen observations at the bedside and operating table made this study possible. Gratitude is also expressed to Dr. Theodore Rasmussen, Dr. William H. Feindel, Dr. J. Preston Robb, Dr. Phanor Perot, and Dr. Henry Garretson for permission to include in this study patients who \'Jere admitted under their ski1lful care. Dr. Jean L. Vezina and Dr. Denis Melançon gave assistance in radiological interpretation and Dr. Stirling Carpenter assisted in reviewing the pathological material. Especial gratitude is acknowledged to Dr. Gilles Bertrand, Dr. Stephen L. Nutik, and Dr. Eduardo J. Garcia-Flores for entering into lively discussion and encouraging the ideas formulated in the hypothesis of this communication. The artistic merits of j·:lrs. Margaret Hherry of the Department of j'1edical Arts, Royal Victoria Hospital, and the technical and photo­ graphie talents of r~r. Charles P. Hodge, j'1iss Judith Little and Nr. Garreth Gauthier of the Department of Photography, Montreal Neurological Institute, are gratefully appreciated.

i'1rs. Marina Boski and j~rs. Claudia Ugolik of the Library staff of the f1lontreal Neurological Institute readily provided aid in the review of the literature. i1iss Cathie Sabbath and i~rs. Marie Clark provided invaluable assistance in preparation of the manuscript. APPENDIX 'DETAILEV OPERATIVE AND PAHfOLOGICAL FINVINGS IN 20 CASES OF DIASTEMATOMYELIA

Ca.M. Levd Sep.tum Op~a.tive F~ndLng~ Pa.thotogü~.ltt F.i.ncüng~ ------1) 1-1. B. 1 T 7 Fibrous stalk connected overlying telangiectatic skin with Tissue from 3 germ layers in stalk dorsal surface, or head, of bony septum; nodule in ventral nodule, including ciliated columnar portion of stalk. Fusion of T6 & T7 laminae on Left. Head epithelium and dorsal root ganglion of septum was an irregular umbilicated mass of bone re­ cells. Myelinated nerve fibers and placing spinous process of T7' fused to T7 laminae. Small dorsal root ganglion cells seen in meningocele at Ts• "Adhesions" betvJeen dural sheath and dural sheath. bony septum.

2) ~1.B.2 T12 & Lz Cord split T11-L3 4. Cartilaginous mass replaced spinous Myelinated nerve fibers, dorsal root process at T1Z , f~om ventral surface of which a fibrous ganglion cells, fat cells and muscle septum divided spinal canal at Lz, representing head of fibers seen in fibrous septum at T1Z bony septum. Artery and small nerve seen exiting from mass and in dural sheath at L2 level. of bone. Rudimentary dorsal rootlets seen arising from mesial aspect of hemicords at T1Z level, running to dural sheath with grossly identifiable dorsal root ganglion. Ano­ malous dentate ligament seen on Right side of fibrous septum at T1Z , between septum and hemicord. 3) K.H. Lz Irregular, umbilicated bony mass formed by fusion of Lz No specimen. laminae, representing head of bony septum traversing spinal canal at Lz.

4) C.NcC. L 1 Irregular bony mass, representing head of bony septum traver­ Myelinated nerve fibers identified sin~ spinal canal at L1' attached to L1 laminae by fibrous in soft tissue core of septum and structures. Bony mass contained core of soft tissue with in dural sheath. blood vessels emerging. Dorsal nerve rootlets seen arising from mesial aspect of hemicords running to dural sheath. 5) M.J. Lit Fusion of Lz & L3 laminae on Left. Umbilicated bony mass rep­ Dorsal root ganglion cells and myeli­ resenting head of bony septum traversing spinal canal at Lit, nated nerve fibers identified in formed by fusion of Lit laminae. Arteries and nerves seen exit­ dural sheath. ing from umbilicated center of mass, with nerves innervating small midline muscle mass overlying bony mass inferiorly; stimu­ lation of nerves caused contraction of muscle mass. Nerve '1 rootlets seen arising from mesial aspect of hemicords and -' running to dural sheath. 6) S.T. Lit Pitted, umbi1icated bony mass, representing head of bony septum Dermoid, abnormal fat, striated traversing canal at Lit, formed by fusion of Lit laminae. Channe1s muscle fibers and myelinated nerve of soft tissue in septum. Fibrous tissue connected inferior por­ fibers identified in tissue be10w tion of bony mass ta sma11 tumor containing ye110w caseous materia1 bony mass. Myelinated nerve fibers and blond hairs. Mid1ine muscle fibers and nodules of fat lying and dorsal root ganglion cells seen below tumor. Nerve root1ets seen running from mesial aspect of in dural sheath. hemicords ta dural sheath. Well formed dentate ligament between right hemicord and dura1 sheath. Anterior spinal artery seen on each hemicord. 7) C.G. L3 Umbi1icated mass of bone, representing head of bony septum, traver- r'1yelinated nerve fibers and dorsal sing spinal canal at L3' fused ta Left L3 lamina. Artery exiting root ganglion ce1ls identified in from umbilicated center of bony mass. Nerve root1ets and "adhesions" dural sheath. seen running from mesial aspect of hemicords ta dura1 sheath. 8) B.B. L3 Thin fibrous stalk connected dimple in overlying telangiectatic, Single fascic1e of mye1inated hypertrichotic skin ta umbilicated center of bony mass, representing nerve fibers identified in dura1 head of bony septum traversing spinal canal at L3, which was fused sheath. between the laminae of L3. Structures resemb1ing dentate ligaments seen lying between hemicords and dural sheath. 9) J.U. Ll Umbilicated bony mass, representing head of bony septum traversing Abundant mye1inated nerve fibers spinal canal at Ll , fused to laminae of Ll. Bony septum contained identified in dural sheath. soft tissue channels with identifiable arteries and nerves exiting. Nerve root1ets seen running from mesial aspect of hemicords ta dural sheath. Small lipomata embedded on the dorsal surface of each hemicord.

10) N.G. T 11 Laminae of T10 & Tll scrambled into single large umbilicated bony Dorsal root ganglion cells and mass from ventral surface of which a bony septum traversed spinal myelinated nerve fibers identified canal at Tll . Single artery seen ex;ting from umbi1icated center of in dural sheath. li bony mass. Hemicords bound ta dural sleeve by tough lIadhesions •

11) K.O. T 12 Laminae of Tl2 over1apped and fused, with thin bony septum arising Numerous dorsal root ganglion ce11s from undersurface and traversing spinal canal. identified in dural sheath.

...... N 12) S.J. L3 Large bony mass, representing head of bony septum, traversing spinal Myelinated nerve fibers and muscle canal at La, fused between laminae of L3. Rootlets seen arising identified in dural sheath. from mesial aspect of each hemicord and running to dural sheath. 13) C.L. LI Large umbilicated mass of bone, representing head of bony septum Artery and myelinated nerve bundle traversing spinal canal at LI' fused to Left lamina of LI and in soft tissue of bony septum. attached to Right lamina of LI by thin line of cartilage. Arteries Myelinated nerve fibers seen in and nerves seen exiting from center of bony mass. Nodule of fat dural sheath. lying at inferior edge of bony mass. Dorsal nerve rootlets with grossly identifiable dorsal root ganglia running from mesial aspect of hemicords to dural sheath; possibly sorne rnesial rudimentary ventral filaments present.

14) A.D. L 2 Mass of bone, representing head of bony septum traversing spinal No specimen. canal at L2' fused between laminae of L2. Dense "adhesions" beb/een hemicords, dural sheath and bony mass and proximity of the lesion to conus medullaris prevented further dissection and removal of the dividing bony septum. 15) B.R. L5 Fibrous stalk connected overlying hypertrichotic skin with ab normal 'o1yel i nated nerve fibers and many mass of bone, representing head of cartilaginous septum traversing dorsal root ganglion cells identi­ 5pinal canal at L5. Mass of bone \'/aS interposed between, but not fied in dural sheath. fused to the laminae of L5. Roof of sacrum was covered by thin layer of bone over which lay an anomalous mass of midline muscle. Dorsal rootlets seen running from dorsolateral (usual) aspect of hemicords to region of dural sheath. 16) R.L.D. L3 Fibrous stalk (.4 cm diameter) arose from under thickened skin at Clusters of dorsal root ganglion La level, entered spinal canal between spinous processes of L3 and cells identified in intradural L4 , pierced dura and attached to dorsal surface of La body. Cord, portion of stalk. but not dura, bifid around fibrous stalk. Cord reuniting below stalk was tethered. 17) J.T. LI Large, flat thoracolumbar mYelocele covered by tissue paper thin Dorsal root ganglion cells identi­ skin. At inferior portion of mYelocele, flattened cord was bifid fied in dural sheath. around a spicule of bone which was fused ta the Right lamina of Ll. The spicule of bone was invested in a sheath of dura...... w

( 18) J.M. Ll Well formed anomalous mass of midline muscle overlay spinal canal Myelinated nerve fibers seen in at L1 -L 4 • Muscle mass attached to inferior portion of underlying dural sheath. umbilicated mass of bone, representing head of bony septum tra­ versing spinal canal at Ll , which was fused to laminae of Ll' Blood vessels and nerves seen exiting from mass of bone to supply midline muscle mass. Dorsal and ventral rootlets seen running from mesial aspect of hemicords to dural sheath.

19) D.G. T11 Irregular umbilicated mass of bone, superior portion of which re­ r~ye li nated nerve fi bers i dent i fi ed presented head of bony septum traversing spinal canal at T 11' formed in dural sheath. roof of spinal canal from Tll-L 1 and was fused to adjacent laminae. Nerves and arteri es seen exiti ng from umbil i cated center of bony mass. Nerve rootlets with grossly identifiable dorsal root ganglia running from mesial aspect of hemicords to dural sheath. "Adhesions" between dural sheath and bony septum. Anterior spinal artery seen duplicated.

20) C.H. T 10 Laminae of T10 and Tll fused into an irregular mass of bone, from No neural elements identified in ventral surface of which a fibro-osseous septum arose and traversed dural sheath. spinal canal at T10 ' Nerve rootlets seen running from mesial aspect of hemicords to dural sheath.

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