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Congenital hemiplegia Not only caused by presumed perinatal arterial stroke.

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ion fluxes associated with this molecular machinery
without degenerating. If so, this could provide an alternative strategy, in addition to protective approaches
that prevent axonal degeneration, that might slow the
progression of disability in MS.
16. Smith KJ, Bostock H, Hall SM. Saltatory conduction precedes
remyelination in axons demyelinated with lysophosphatidylcholine. J Neurol Sci 1982;54:13–31.
17. Waxman SG. Sodium channels and neuroprotection in MS:
current status. Nat Clin Pract Neurol (in press).
DOI: 10.1002/ana.21361
Stephen G. Waxman, MD, PhD
Department of Neurology and Center for Neuroscience
and Regeneration Research
Yale University School of Medicine
New Haven, CT
and VA Connecticut Healthcare
West Haven, CT
References
1. Waxman SG. Current concepts in neurology: membranes, myelin and the pathophysiology of multiple sclerosis. N Engl
J Med 1982;306:1529 –1533.
2. Stys PK, Waxman SG, Ransom BR. Ionic mechanisms of anoxic injury in mammalian CNS white matter: role of Na⫹
channels and Na⫹-Ca2⫹ exchanger. J Neurosci 1992;12:
430 – 439.
3. Waxman SG, Black JA, Stys PK, Ransom BR. Ultrastructural
concomitants of anoxic injury and early post-anoxic recovery in
rat optic nerve. Brain Res 1992;574:105–119.
4. Young EA, Fowler CD, Kidd GJ, et al. Imaging correlates of
decreased axonal Na⫹/K⫹ ATPase in chronic multiple sclerosis
lesions. Ann Neurol 2008;63;428 – 435.
5. Hirsch HE, Parks ME. Na⫹ and K⫹ dependent adenosine
triphosphatase changes in multiple sclerosis plaques. Ann Neurol 1983;13:658 – 663.
6. Craner MJ, Newcombe J, Black JA, et al. Molecular changes in
neurons in MS: altered axonal expression of Nav1.2 and Nav1.6
sodium channels and Na⫹ /Ca2⫹ exchanger. Proc Natl Acad
Sci USA 2004;101:8168 – 8173.
7. Black JA, Newcombe J, Trapp BD, Waxman SG. Sodium
channel expression within chronic MS plaques. J Neuropath
Exp Neurol 2007;66:828 – 838.
8. Coman J, Aigrot MS, Seilbean D, et al. Nodal, paranodal and
juxtaparanodal axonal proteins during demyelination and remyelination in multiple sclerosis. Brain 2006;129:3186 –3195.
9. Wolswijk G, Balesar R. changes in the expression and localization of the paranodal protein Caspr on axons in chronic multiple sclerosis. Brain 2003;126:1638 –1649.
10. Stys PK, Jiang Q. Calpain-dependent neurofilament breakdown
in anoxic and ischemic rat central axons. Neurosci Lett 2002;
328:150 –154.
11. Dutta R, McDonough J, Yin X, et al. Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann Neurol 2006;59:478 – 489.
12. Sontheimer H, Fernandez-Marques E, Ullrich N, et al. Astrocyte Na⫹ channels are required for maintenance of Na⫹/K⫹ATPase activity. J Neurosci 1994;14:2464 –2475.
13. Sontheimer H, Waxman SG. Ion channels in spinal cord astrocytes in vitro: II. Biophysical and pharmacological analysis of
two Na⫹ current types. J Neurophysiol 1992;68:1000 –1011.
14. Stys PK, Sontheimer H, Ransom BR, Waxman SG. Noninactivating, TTX-sensitive Na⫹ conductance in rat optic nerve
axons. Proc Natl Acad Sci USA 1993;90:6976 – 6980.
15. Hildebrand C, Waxman SG. Regional node-like membrane
specializations in non-myelinated axons of rat retinal nerve fiber
layer. Brain Res 1983;258:23–32.
Congenital Hemiplegia: Not
Only Caused by Presumed
Perinatal Arterial Stroke
In this issue of Annals, Kirton and colleagues1 report
on lesion patterns including periventricular venous infarction (PVI) of presumed antenatal onset, preceding
the postnatal development of hemiplegia. Until now,
stroke of presumed antenatal or perinatal timing has
been restricted to infants, who present with pathological handedness (hand preference earlier than 1 year
of age) and/or seizures at or after 2 months of age, or
occasionally with other neurological problems for
which brain imaging shows an ischemic, usually arterial territory stroke. In a recent population-based, case–control study,2 presumed perinatal ischemic stroke
(recently given the acronym PPIS) was present in 17
of 100,000 live births. Of the 38 cases, the majority
(n ⫽ 26; 68%) presented after 3 months from birth
with hemiparesis or seizures, and computed tomography or magnetic resonance imaging confirmed an established stroke in arterial distribution in all cases.
Another study from the Canadian Pediatric Ischemic
Stroke Registry identified 22 infants with PPIS.3
A few children with hemiplegia, with presumed antenatal or perinatal onset of a unilateral parenchymal hemorrhage (known as “venous infarction” in the preterm
infant), were recently reported and referred to as perinatal venous infarction (PVI).4,5 This type of hemorrhage
with subsequent evolution into a porencephalic cyst is a
condition that is seen in 5 to 8% of very low-birthweight infants and is considered to be caused by impaired venous drainage from the medullary veins in the
periventricular white matter.6 A hemiplegia will result if
the region of the trigone is involved, and appropriate
and symmetric myelination of the internal capsule is not
achieved by term-equivalent age.7 The incidence of this
type of lesion increases with decreasing gestational age,
and the diagnosis is mostly made after birth in preterm
infants born before the gestational age of 30 completed
© 2008 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
413
Fig. Preterm infant (gestational age, 32 weeks) with neonatal onset of lateral lenticulostriate artery infarcts (LLSs), shown at the echogenic (day 10) and cystic stage (6 weeks). A cyst is also seen in the periventricular white matter, either because of periventricular venous
infarction (PVI) or LLSs with associated involvement of the distal perforators. Magnetic resonance imaging performed at 7 years of age
(coronal inversion recovery sequence [left]), T2 spin-echo (middle), and axial fluid-attenuated inversion recovery sequence (right) confirm the neonatal ultrasound findings and show an LLS with the tip of the triangle pointing in a caudal direction with a line of prolonged T2-weighting crossing the anterior portion of the posterior limb of the internal capsule. Another lesion, a PVI, is also seen on
the ipsilateral site.
weeks. In contrast with cystic white matter disease, the
incidence has remained stable over the past decade.8
Kirton and colleagues1 extracted all cases from their
SickKids Children’s Stroke Program in Toronto who
met the criteria of PPIS and classified them into six
groups, with five related to an arterial ischemic stroke
in the distribution of the middle cerebral artery and
the sixth group related to PVI. In the 59 infants that
they identified, proximal M1 arterial territory infarction was the most common (n ⫽ 19; 35%) lesion
found, and PVI turned out to be the second most
common (n ⫽ 12; 22%) lesion, accounting for 75% of
subcortical injuries.
Distinction between the different PPIS patterns
was possible with a high intraclass correlation coefficient (0.975 [0.958 – 0.985]). PVI was diagnosed on
magnetic resonance imaging when focal encephalomalacia (typical of a porencephalic cyst known to follow
PVI identified in preterm born infants) was present in
the periventricular white matter, the cortex was
spared, the basal ganglia were relatively spared, when
prolongation of signal in the posterior limb of the
internal capsule was present on a T2-weighted spinecho sequence, and when hemosiderin was present
adjacent to the lateral ventricle or in the germinal matrix. Hemosiderin was not present in all and depended on the sequences used and the age when the
414
Annals of Neurology
Vol 63
No 4
April 2008
magnetic resonance imaging was done. The main distinction between PVI and lateral lenticulostriate artery infarcts (LLSs) was based on the direction of the
triangle that could be visualized, being caudal in the
PVI and cranial in those with LLSs. One could argue
about the direction of the triangle. The tip of the
triangle of the LLS usually points caudally, as is
shown in the figure, and an observer would therefore
be inclined to use caudal rather than cranial for LLS.
Whereas interrater reliability was high, disagreement
occurred in two PVI or LLS cases. In my view, disagreement also exists for one of the images in Figure
2 where their involvement of the basal ganglia does
suggest an LLS. Overlap may occur between PVI and
LLS as a small area of the caudate body and the posterior putamen drain into the medullary venous system. When sequential imaging, starting soon after the
onset of the lesion, is not available, a definite diagnosis cannot always be made and a combination of involvement of the two sites, resulting in two “triangles,” may also occur, as has been previously shown in
a preterm infant who would meet most of the diagnostic criteria of LLS, as well as PVI (Fig).
Subsequent neurodevelopmental outcome was better for those with PVI, because they were less often
affected by cognitive problems or epilepsy, presumably because of sparing of the cortex concordant with
what is known about preterm with PVI.6 Risk factors
were not analyzed, and it would be of interest to
study these as well. Antenatal (mild) trauma, coagulopathy, and especially neonatal alloimmune thrombocytopenia have been identified as underlying causative factors in case reports or small series of
cases.9 –11 Familial porencephaly should also be considered, a dominant disorder with a mutation in
COL4A1 on chromosome 13q34.12,13
This article expands the spectrum of PPIS and illustrates that hemiplegia, diagnosed in infancy in children
thought well at birth, may also follow antenatal PVI.
As new evidence-based rehabilitational interventions,
such as constraint-induced movement therapy,14 is increasingly being used, it will be important to classify
carefully the type of lesion underlying the deficits before starting any intervention. Kirton and colleagues1
have shown that antenatal PVI also needs to be considered when classifying children presenting with congenital hemiplegia.
Linda S. de Vries, MD, PhD
Professor in Neonatal Neurology
Department of Neonatology
University Medical Center, University of Utrecht
Utrecht, the Netherlands
References
1. Kirton A, deVeber G, Pontigon A, et al. Presumed perinatal
ischemic stroke: vascular classification predicts outcomes. Ann
Neurol 2008;63:436 – 443.
2. Wu YW, March WM, Croen LA, et al. Perinatal stroke in children with motor impairment: a population-based study. Pediatrics 2004;114:612– 619.
3. Golomb MR, MacGregor DL, Domi T, et al. Presumed pre- or
perinatal arterial ischemic stroke: risk factors and outcomes.
Ann Neurol 2001;50:163–168.
4. Takanashi J, Barkovich AJ, Ferriero DM, et al. Widening spectrum of congenital hemiplegia: periventricular venous infarction
in term neonates. Neurology 2003;61:531–533.
5. Takanashi J, Tada H, Barkovich AJ, Kohno Y. Magnetic resonance imaging confirms periventricular venous infarction in a
term-born child with congenital hemiplegia. Dev Med Child
Neurol 2005;47:706 –708.
6. De Vries LS, Van Haastert IL, Rademaker KJ, et al. Ultrasound
abnormalities preceding cerebral palsy in high-risk preterm infants. J Pediatr 2004;144:815– 820.
7. De Vries LS, Groenendaal F, Eken P, et al. Asymmetrical
myelination of the posterior limb of the internal capsule: an
early predictor of hemiplegia. Neuropediatrics 1999;30:
314 –319.
8. Hamrick SE, Miller SP, Leonard C, et al. Trends in severe
brain injury and neurodevelopmental outcome in premature
newborn infants: the role of cystic periventricular leukomalacia. J Pediatr 2004;145:593–599.
9. Ozduman K, Pober BR, Barnes P, et al. Fetal stroke. Pediatr
Neurol 2004;30:151–162.
10. Ghi T, Simonazzi G, Perolo A, et al. Outcome of antenatally
diagnosed intracranial hemorrhage: case series and review of the
literature. Ultrasound Obstet Gynecol 2003;22:121–130.
11. Dale ST, Coleman LT. Neonatal alloimmune thrombocytopenia:
antenatal and postnatal imaging findings in the pediatric brain.
AJNR Am J Neuroradiol 2002;23:1457–1465.
12. Gould DB, Phalan FC, Breedveld GJ, et al. Mutations in
Col4a1 cause perinatal cerebral hemorrhage and porencephaly.
Science 2005;308:1167–1171.
13. Breedveld G, de Coo IF, Lequin MH, et al. Novel mutations in
three families confirm a major role of COL4A1 in hereditary
porencephaly. J Med Genet 2006;43:490 – 495.
14. Juenger H, Linder-Lucht M, Walther M, et al. Cortical neuromodulation by constraint-induced movement therapy in congenital hemiparesis: an FMRI study. Neuropediatrics 2007;38:
130 –136.
DOI: 10.1002/ana.21374
Rapamycin and Tuberous
Sclerosis Complex: From
Easter Island to Epilepsy
The Dutch explorer Jacob Roggoveen discovered Easter
Island on Easter Sunday 1722.1 Easter Island was given
its Polynesian name, Rapa Nui, in the 1800s by French
Polynesian immigrants, who observed that Rapa Nui
was geographically similar to their homeland of Rapa
Iti in the Bass Islands. A startling finding on Rapa Nui
was the mysterious “moai” statues or Easter Island
Heads, believed to have been constructed between
1000 and 1500 CE. These unique and enormous
monoliths were carved out of volcanic ash indigenous
to Rapa Nui and placed ceremoniously on platforms or
“ahus” at the perimeter of Rapa Nui. At first analysis,
the moai were believed to represent deified ancestors
impassively surveying their lands. Further studies by
anthropologists have led to more intriguing questions.
Why were the moai built? How were these massive
statues moved around the island? Who did the imperious faces represent?
Some 250 years later in the 1970s, a macrolide antibiotic was discovered as a product of the bacterium
Streptomyces hygroscopicus in a soil sample from Rapa
Nui by Dr Suren Sehgal and so named “rapa”-mycin
(rapamycin).2 In addition to its effects as an antifungal
agent, rapamycin has been shown to have important
regulatory effects on cell growth, proliferation, and inflammation via its inhibitory action on a key protein,
mammalian target of rapamycin (mTOR). In the
brain, mTOR has been shown to play a role in longterm potentiation, dendritic arborization, local protein
synthesis in dendrites, and synaptic connectivity.3 Two
major regulatory proteins that also negatively modulate
© 2008 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
415
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