Special essay prize 7
Effect of Hydrocephalus on Neuronal Migration and Maturation Carole A. Sobkowiak
The course of the management of spina bifida and hydrocephalus has been a long and fascinating one and there are those "'ho will remember the re"olution in the management of hydrocephalus by the invention of the Holter ,'alve, Indeed one only has to look at children today in third world eountries, 01' e"en Eastern Europe to be reminded of the dreadful problems associated ,,'ith grossly enlarged heads, often too hea',!' for the carers let alone the child to hold up, The "alw "hichjolzn Holler im'ented changed the course for the management of hydrocephalus, 1991 saw a historie land mark with the resulLs of the \1,RC "itamin trial being disclosed, Although not a eure, the discovery will lead to decreasing numbers of children being born with spina bifida, There are many paradoxes in medicine ,,'here one condition replaces another, often with the tendency for the former to be fOt'gotten, It would be tragic if this were to be the case \\'ith spina bifida and hydrocephalus as so much expertise and talent has been born out of this mishap of nature. We must look very seriously at how the skiJls can be transferred to benefit others with neurological problems, For several years the Association for Spina Bifida and Hydrocephalus (ASBAH) has had considerable invoh'ement with tho e chiJdren who have hydrocephalus alone which may be congenital, as a result of peri\'entricular haemorrhage in the newborn period of pre-term infants 01' perhaps as a result of acquired hydrocephalus following meningitis, brain tumours or head injuries. The ensuing neurological problems seen in these children are akin to various degrees of cerebral palsy, ranging from those with profound handicap to those with minimallearning difficulties. 1 begin by discu ing the management of spina bifida and hydrocephalus when historicaJly the spina bifida was considered to be the prime condition and hydrocephalus presented as a secondary medical complication which wa treated later, To be heard to say in the 1960's that children "ith pina bifida also had cerebral palsy was almost considered a heresy. But cerebral palsy is "'hat they had albeit masked by lower limb paralysis, To coin a phrase from Gilbertson' erudite Presidential Address at the meeting of this Society in 1991, it required the "engineering of atlitudes" to promote the idea that spina bifida "'as not paraplegia, There have been se\'eral studies of upper ex, tremity dy function in children \\'ith myelomeningocele ,,'hich Ikcel\ed
Jul~
IH. IUU2
Eur ) I'ediatr Surg 2, Suppl I 11 U921 f 11 © Ilippokrates \erlag Stullg,II1 ,\\asson Editeul'l'aris
ha\'e shO\\'TI correlation between the presence of hyd rocephal us, disturbance of hand function and impaired mental abilities (2/, 3/, 38), There was never a consensus agreement in these and other stud ies as to whether the le\'el of le ion affected the u pper limb function, for example, Jlazl/r et al (37) reported a correlation with high thoraeie le ions" hilst JJill/lS et al (38) could not find a relationship bet" een the le\'el of le~ion and hand fune tion, In the study by ,\lillllS et al (38), detailed im estigations of neurological signs and hand praxis "ere undertaken in a group of children within the age range 6-8 years "'hich showed a marked depression of hand funetion "'hen eompared to a group of controls. In a later study by Ellioll and Sobkowiak (13) the authors ,,'ere interested to folio,,' the de\'elopment of upper Iimb function into the adolescent period and were surprised to find such paucity of kill in a group of young people with spina bifida and hydrocephalus in the age range 14-16 years. [t was observed that their level of motor competence was more in keeping with that of a much younger child. A breakdown analysis of these results shows difficulty with fixation of the proximal joint during tasks of rapid pronation and supination of the forearm i. e. disdiadokinesia. It was observed that some of the young people had not even developed the skill of supination. There were problems with individual finger sequencing, the persistence of mirror movements, tactile and shape discrimination, Perhaps one of the most striking features, especially during the timed tests, wa the slowness to start the ta k with an apparent unawareness of how to reach the end of the task within the deadline, At the time of the study in 1981 a hypothesis was put forward, based on the findings of Gadson et al (19) who had demonstrated in morphological studies that hydrocephalus affected myelination of the axons in the corpus callosum whilst the reduction of hydrocephalus restored the formation of myelin, This speculation that POOl' hand praxi was a result of inadequate myelination \\'as ,'iewed ,,'ith sceptici m by ome and the alternati\'e h~'Pothesis that lack of opportunity as a result of immobility was a more likely reason for POOl' use of the hands \\'as ad\'anced, In subsequent \\'ork the author has applied the same test balle ries to different groups of children: those with cerebral palsy, designated clumsy and e\'en h~'Peractive children, and similar results ha\'e been obtained, There are indications, therefore, that these are central problems. The question could then be raised, ho\\' do these central problems arise, and hO\\' does hydrocephalus affeet the developing cerebral cOttex?
Downloaded by: National University of Singapore. Copyrighted material.
,\ \ernorial Ho pital, Darlington, L'K
Eur J Pedialr urg 2, Suppt I (/992)
l\'eural development As the neural crest forms, its cells delach from the edge of the neural ecloderm atlhe lime when lhe neurallube is closing, The cells migrate outwards lowards lhe peripher}' along well-defined path\\'ays and cell layers are laid down fir t in lhe deeper layers of the cortex, It was suggesled by Rakic (8) that the radial migralion of postmilolic neurones is guided by radially-orienlaled glial cells which exlend from the \'entricular to the pial surface, Thi has led to the proposal of a "radial unit h~'pothesis" (~9), \\'here the units pro\'ide a "proto-map" of future coliical areas \\'hich could become the basis of the columnar organisation of the adult cOliex, Inorder for the neu rone to make its appropriate connections, it must send axons to project to the correct target tissue and to select cells in that target \I'ith wh ich to form ynapses, These stages are deri\'ed from t\l'O groups of processes, Firslly there is determination, differentiation, proliferalion, cell migration, axonal outgro\lth, dendrite elabora tion, cell death and neuronal recognition, Secondly, the appropriate synaptic connections are finally organised by em'ironmental conditions, There has been much research about axon guidance and largel recognition, It would seem that a neurone can change the particular molecules it expresses as it de\'elops (J 0, 23), so that a its axon elongates into a new en\'ironment it can make further pecific choices aboul where to graw, for exam pIe, where axons graw ac ross the de\'eloping corpus callo um (35), Following im'estigation in the hydrocephalus H-Tx ral,Jones et al (29, 30) ha\'e concluded that lhe cortex i subject lo se\'ere thinning \\'ilh disruption of the laminar slruclure, palticularJy in the poslerior regions and lhatthe palhological con equences are more severe in the audilory and \'isual cOItices, The deeper cortical layers dosest lo lhe venlricles are more se\'erely affected than layers I lo III which are adjacenl to the pial sUI'face, The cortex also becomes slrelched longitudinally as weil as in other direction and in the lale slages of hydrocephalus lhere is a small increase in COltiCal volume and a decrease in cell densily, Finally, despile the e change, there i no overallloss of cell bodies (neurones and glia) allhough lhere is a loss of conneclions, Further work wilh the H-Tx ral by Bucknall el al (3) looked al sensory evoked potentials and found a ignificantly Ionger latency lhan in lhe conlrol group which uggesled thal the processing of lhe signal within lhe cortex wa affecled by lhe hydrocephalus, One reason given for lhi was lhal when seen under lhe light microscope the apical dendrites of the pyramidal cells in control rats were orienlated perpendicular lo lhe pial surface whereas in hydrocephalic rats the dendrites are disorienlated,
Caro/e A, obkowiak
ducing a chemotropic signal lhal acts on corticaJ axons ari ing from neurane in layer V of the anterior part of the rat cortex, The growth cones of lhe anleriorly siluated corticospinal lraet axons seem lo be able lo respond lo the cen'ical spinal cord attraclanl, whereas axons from the inlermediate area terminate in the lumbal' spinal grey maller, Tl is suggested that lhe cervical spinal grey malter could in principle conlain chemical factors \\'hich repulse "lumbar" corticospinallract axons,
i\luscle innen:a tion Rapid ad\'(lnces are also being made aboutlhe netTe supply to muscles, During the innen'ation of the limb of chicks it has been shO\m by Dahm and Landmesser (t), thallhe motor axons \\'ait outside de\'eloping muscles belOI'e growing in, \\'hich is in keeping \I ith the presence of local guidance cues, Ho\\'ewr, sensory axons seem to lag behind the motor axons as they enter the li mb (5-1), Hecently, Fredelte and Landme seI' (13) ha\'e in\'etigated the neural dependence of myogenesis and its relation to fibre-t~-pe differentiation in chick limb muscles anclthey ha\e found that the relatil'e quantities of fast and sJow myotubes are regulated independent of inner\'ation \I'hich is contrary to traditionally held beliefs that fibre-lype specialisation is determined b,l' inner\'ation, Other recent supportil'e \I ork by DweIlS and
Kullberg Hel) has examined synaptic current durations in lhe transplanted muscles of Xenopus tadpoles and found that once differentiation of muscle is complele, synaptic channel properties may be fixed for each type of mu c1e fibre, They ha\'e concluded thal the regulalion of acetylcholine receptors (AChR) open time in de\'eloping muscle does not depend on lhe identily of lhe molor nerve and thalthe kinds of acetylcholine receptor lo be expressed by muscle are specified \'ery early in developmenl, perhaps in lhe me odermal cells gi\-ing rise lo musde,
Nerve cell death The failure of neurones to oblain adequate amounts of larget-released growth factor provides an explanation for lhe death of exce s neurone which ha\'e to compete for a limited amount of factor available from the largets, It has been shown thal the eliminalion of excess inputs requires activi.ty in lhe muscle, lnitially lhe density of synaplic terminals rises and then falls (49) bullhe relative proportion of dendrilic synapses to soma increases (6), In \iew of the theory oflones el al (29, 30) as discussed previously it 1V0uld suggesllhat hydrocephalus has a delrimental effecl upon lhis process, The findings of Bennetl and Lavidis (2) suggesl that incorreclly projecling neurones are being eliminated to creale an ordered pallern of adult conneclions,
Spinal reflex pathways
Spinal cord It has been shO\m by Tessier-La. J '\europhysiol 11 (1980) I;) I- 1/2 15 Freclette Bj. Lallclmesser LT' A ree\'aluation of the role of innel'\'ation in primaf!' and secondaf!' myogenesis in de\'eloping chiek muscJe. Oe\' Biol 143 (1991) 19-35 1
Downloaded by: National University of Singapore. Copyrighted material.
10
Eur J Pedialr Surg 2, Suppl1 (1992)
Efficl ofHydrocephalus on Neuronal Migration ami "la/uralion
35 Liesi P, Silver j: Is astrocyle laminin in\'ol\'ed in axon guidance in the 36
31 38
39 10
11
12
13
11
15
-16 11
18 19
50 5\
52
53
5-1
55
mammalian CNS? Oe\' Biol 130 (1988) 77·1-785 iI1arlinjH, Ghez C: Task-related coding of stimulus and response in cat red nucJeus. Exp Brain Res 85 (199 I) 373-388 ,\lazur j.\l, ,\lenelaus ,\lB, Hudson I, Slil/well A: Hand function in pa, tienls with spina bifida cystica. J Pediatr OrLhop 6 (1986) 442-447 ,\limzs RA, Sobkowiak CA, SkardoulsouA, Dick K, Ellon RA, Bro' n}l{, Forfar jO. Upper limb function in spina bifida. Z I
Effect of Hydrocephalus on Neuronal Migration and Maturation Carole A. Sobkowiak
The course of the management of spina bifida and hydrocephalus has been a long and fascinating one and there are those "'ho will remember the re"olution in the management of hydrocephalus by the invention of the Holter ,'alve, Indeed one only has to look at children today in third world eountries, 01' e"en Eastern Europe to be reminded of the dreadful problems associated ,,'ith grossly enlarged heads, often too hea',!' for the carers let alone the child to hold up, The "alw "hichjolzn Holler im'ented changed the course for the management of hydrocephalus, 1991 saw a historie land mark with the resulLs of the \1,RC "itamin trial being disclosed, Although not a eure, the discovery will lead to decreasing numbers of children being born with spina bifida, There are many paradoxes in medicine ,,'here one condition replaces another, often with the tendency for the former to be fOt'gotten, It would be tragic if this were to be the case \\'ith spina bifida and hydrocephalus as so much expertise and talent has been born out of this mishap of nature. We must look very seriously at how the skiJls can be transferred to benefit others with neurological problems, For several years the Association for Spina Bifida and Hydrocephalus (ASBAH) has had considerable invoh'ement with tho e chiJdren who have hydrocephalus alone which may be congenital, as a result of peri\'entricular haemorrhage in the newborn period of pre-term infants 01' perhaps as a result of acquired hydrocephalus following meningitis, brain tumours or head injuries. The ensuing neurological problems seen in these children are akin to various degrees of cerebral palsy, ranging from those with profound handicap to those with minimallearning difficulties. 1 begin by discu ing the management of spina bifida and hydrocephalus when historicaJly the spina bifida was considered to be the prime condition and hydrocephalus presented as a secondary medical complication which wa treated later, To be heard to say in the 1960's that children "ith pina bifida also had cerebral palsy was almost considered a heresy. But cerebral palsy is "'hat they had albeit masked by lower limb paralysis, To coin a phrase from Gilbertson' erudite Presidential Address at the meeting of this Society in 1991, it required the "engineering of atlitudes" to promote the idea that spina bifida "'as not paraplegia, There have been se\'eral studies of upper ex, tremity dy function in children \\'ith myelomeningocele ,,'hich Ikcel\ed
Jul~
IH. IUU2
Eur ) I'ediatr Surg 2, Suppl I 11 U921 f 11 © Ilippokrates \erlag Stullg,II1 ,\\asson Editeul'l'aris
ha\'e shO\\'TI correlation between the presence of hyd rocephal us, disturbance of hand function and impaired mental abilities (2/, 3/, 38), There was never a consensus agreement in these and other stud ies as to whether the le\'el of le ion affected the u pper limb function, for example, Jlazl/r et al (37) reported a correlation with high thoraeie le ions" hilst JJill/lS et al (38) could not find a relationship bet" een the le\'el of le~ion and hand fune tion, In the study by ,\lillllS et al (38), detailed im estigations of neurological signs and hand praxis "ere undertaken in a group of children within the age range 6-8 years "'hich showed a marked depression of hand funetion "'hen eompared to a group of controls. In a later study by Ellioll and Sobkowiak (13) the authors ,,'ere interested to folio,,' the de\'elopment of upper Iimb function into the adolescent period and were surprised to find such paucity of kill in a group of young people with spina bifida and hydrocephalus in the age range 14-16 years. [t was observed that their level of motor competence was more in keeping with that of a much younger child. A breakdown analysis of these results shows difficulty with fixation of the proximal joint during tasks of rapid pronation and supination of the forearm i. e. disdiadokinesia. It was observed that some of the young people had not even developed the skill of supination. There were problems with individual finger sequencing, the persistence of mirror movements, tactile and shape discrimination, Perhaps one of the most striking features, especially during the timed tests, wa the slowness to start the ta k with an apparent unawareness of how to reach the end of the task within the deadline, At the time of the study in 1981 a hypothesis was put forward, based on the findings of Gadson et al (19) who had demonstrated in morphological studies that hydrocephalus affected myelination of the axons in the corpus callosum whilst the reduction of hydrocephalus restored the formation of myelin, This speculation that POOl' hand praxi was a result of inadequate myelination \\'as ,'iewed ,,'ith sceptici m by ome and the alternati\'e h~'Pothesis that lack of opportunity as a result of immobility was a more likely reason for POOl' use of the hands \\'as ad\'anced, In subsequent \\'ork the author has applied the same test balle ries to different groups of children: those with cerebral palsy, designated clumsy and e\'en h~'Peractive children, and similar results ha\'e been obtained, There are indications, therefore, that these are central problems. The question could then be raised, ho\\' do these central problems arise, and hO\\' does hydrocephalus affeet the developing cerebral cOttex?
Downloaded by: National University of Singapore. Copyrighted material.
,\ \ernorial Ho pital, Darlington, L'K
Eur J Pedialr urg 2, Suppt I (/992)
l\'eural development As the neural crest forms, its cells delach from the edge of the neural ecloderm atlhe lime when lhe neurallube is closing, The cells migrate outwards lowards lhe peripher}' along well-defined path\\'ays and cell layers are laid down fir t in lhe deeper layers of the cortex, It was suggesled by Rakic (8) that the radial migralion of postmilolic neurones is guided by radially-orienlaled glial cells which exlend from the \'entricular to the pial surface, Thi has led to the proposal of a "radial unit h~'pothesis" (~9), \\'here the units pro\'ide a "proto-map" of future coliical areas \\'hich could become the basis of the columnar organisation of the adult cOliex, Inorder for the neu rone to make its appropriate connections, it must send axons to project to the correct target tissue and to select cells in that target \I'ith wh ich to form ynapses, These stages are deri\'ed from t\l'O groups of processes, Firslly there is determination, differentiation, proliferalion, cell migration, axonal outgro\lth, dendrite elabora tion, cell death and neuronal recognition, Secondly, the appropriate synaptic connections are finally organised by em'ironmental conditions, There has been much research about axon guidance and largel recognition, It would seem that a neurone can change the particular molecules it expresses as it de\'elops (J 0, 23), so that a its axon elongates into a new en\'ironment it can make further pecific choices aboul where to graw, for exam pIe, where axons graw ac ross the de\'eloping corpus callo um (35), Following im'estigation in the hydrocephalus H-Tx ral,Jones et al (29, 30) ha\'e concluded that lhe cortex i subject lo se\'ere thinning \\'ilh disruption of the laminar slruclure, palticularJy in the poslerior regions and lhatthe palhological con equences are more severe in the audilory and \'isual cOItices, The deeper cortical layers dosest lo lhe venlricles are more se\'erely affected than layers I lo III which are adjacenl to the pial sUI'face, The cortex also becomes slrelched longitudinally as weil as in other direction and in the lale slages of hydrocephalus lhere is a small increase in COltiCal volume and a decrease in cell densily, Finally, despile the e change, there i no overallloss of cell bodies (neurones and glia) allhough lhere is a loss of conneclions, Further work wilh the H-Tx ral by Bucknall el al (3) looked al sensory evoked potentials and found a ignificantly Ionger latency lhan in lhe conlrol group which uggesled thal the processing of lhe signal within lhe cortex wa affecled by lhe hydrocephalus, One reason given for lhi was lhal when seen under lhe light microscope the apical dendrites of the pyramidal cells in control rats were orienlated perpendicular lo lhe pial surface whereas in hydrocephalic rats the dendrites are disorienlated,
Caro/e A, obkowiak
ducing a chemotropic signal lhal acts on corticaJ axons ari ing from neurane in layer V of the anterior part of the rat cortex, The growth cones of lhe anleriorly siluated corticospinal lraet axons seem lo be able lo respond lo the cen'ical spinal cord attraclanl, whereas axons from the inlermediate area terminate in the lumbal' spinal grey maller, Tl is suggested that lhe cervical spinal grey malter could in principle conlain chemical factors \\'hich repulse "lumbar" corticospinallract axons,
i\luscle innen:a tion Rapid ad\'(lnces are also being made aboutlhe netTe supply to muscles, During the innen'ation of the limb of chicks it has been shO\m by Dahm and Landmesser (t), thallhe motor axons \\'ait outside de\'eloping muscles belOI'e growing in, \\'hich is in keeping \I ith the presence of local guidance cues, Ho\\'ewr, sensory axons seem to lag behind the motor axons as they enter the li mb (5-1), Hecently, Fredelte and Landme seI' (13) ha\'e in\'etigated the neural dependence of myogenesis and its relation to fibre-t~-pe differentiation in chick limb muscles anclthey ha\e found that the relatil'e quantities of fast and sJow myotubes are regulated independent of inner\'ation \I'hich is contrary to traditionally held beliefs that fibre-lype specialisation is determined b,l' inner\'ation, Other recent supportil'e \I ork by DweIlS and
Kullberg Hel) has examined synaptic current durations in lhe transplanted muscles of Xenopus tadpoles and found that once differentiation of muscle is complele, synaptic channel properties may be fixed for each type of mu c1e fibre, They ha\'e concluded thal the regulalion of acetylcholine receptors (AChR) open time in de\'eloping muscle does not depend on lhe identily of lhe molor nerve and thalthe kinds of acetylcholine receptor lo be expressed by muscle are specified \'ery early in developmenl, perhaps in lhe me odermal cells gi\-ing rise lo musde,
Nerve cell death The failure of neurones to oblain adequate amounts of larget-released growth factor provides an explanation for lhe death of exce s neurone which ha\'e to compete for a limited amount of factor available from the largets, It has been shown thal the eliminalion of excess inputs requires activi.ty in lhe muscle, lnitially lhe density of synaplic terminals rises and then falls (49) bullhe relative proportion of dendrilic synapses to soma increases (6), In \iew of the theory oflones el al (29, 30) as discussed previously it 1V0uld suggesllhat hydrocephalus has a delrimental effecl upon lhis process, The findings of Bennetl and Lavidis (2) suggesl that incorreclly projecling neurones are being eliminated to creale an ordered pallern of adult conneclions,
Spinal reflex pathways
Spinal cord It has been shO\m by Tessier-La. J '\europhysiol 11 (1980) I;) I- 1/2 15 Freclette Bj. Lallclmesser LT' A ree\'aluation of the role of innel'\'ation in primaf!' and secondaf!' myogenesis in de\'eloping chiek muscJe. Oe\' Biol 143 (1991) 19-35 1
Downloaded by: National University of Singapore. Copyrighted material.
10
Eur J Pedialr Surg 2, Suppl1 (1992)
Efficl ofHydrocephalus on Neuronal Migration ami "la/uralion
35 Liesi P, Silver j: Is astrocyle laminin in\'ol\'ed in axon guidance in the 36
31 38
39 10
11
12
13
11
15
-16 11
18 19
50 5\
52
53
5-1
55
mammalian CNS? Oe\' Biol 130 (1988) 77·1-785 iI1arlinjH, Ghez C: Task-related coding of stimulus and response in cat red nucJeus. Exp Brain Res 85 (199 I) 373-388 ,\lazur j.\l, ,\lenelaus ,\lB, Hudson I, Slil/well A: Hand function in pa, tienls with spina bifida cystica. J Pediatr OrLhop 6 (1986) 442-447 ,\limzs RA, Sobkowiak CA, SkardoulsouA, Dick K, Ellon RA, Bro' n}l{, Forfar jO. Upper limb function in spina bifida. Z I
