Physical and neurological exam
His blood pressure was 110/46 mm Hg, pulse was 80 and regular, and respiratory rate was 22, and he was afebrile. He was healthy, appearing with no rashes, a normal cardiac examination, and no carotid or cranial bruits. He was lethargic and irritable, unable to vocalize, but able to follow simple commands.
Fundoscopy, pupillary reactions, and extraocular movements were normal, including no gaze deviation. There was an obvious right-sided facial droop; however, tongue protrusion and uvula were midline. He was unable to lift his right arm off the bed (casted for prior fracture) and had only slight movement of the fi ngers of his right hand. His right leg was weak; he was able to move on the bed but not against gravity when stimulated. His deep tendon refl exes were diffi cult to elicit. His right plantar response was extensor. Sensory testing was not completely reliable, but his response to cold was intact bilaterally. There was no limb ataxia. Gait could not be tested due to inability to bear weight on the right leg.
Initial laboratory results
On arrival, Adam’s complete blood count,
electrolytes, blood glucose, and routine coagulation studies (prothrombin and activated partial thromboplastin times) were normal.
Radiographic results (for stroke diagnosis and arteriopathy)
1 Day 1 initial head CT scan normal
2 Day 1 magnetic resonance imaging (MRI) at 7 hours post-onset
• Fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted imaging showed infarction in the left basal ganglia, adjacent white-matter and peri-insular cortex conforming to lenticulostriate vascular territory (Figure 11.1).
• Magnetic resonance angiography (MRA) of intracranial vessels showed minimal irregularity of proximal segments of the left middle cerebral artery (MCA) (M1 and M2) (Figure 11.2).
• MRA of neck vessels showed no evidence of occlusion or dissection.
Acute management
Elapsed time from the onset of facial droop to arrival at a pediatric hospital was 5 hours, and to MRI scan
was 7 hours. From arrival, oxygen saturation, blood pressure, temperature, and blood glucose were monitored. Low molecular weight heparin (LMWH) was initiated 8 hours after admission after the diagnostic MRI scan, at a treatment dose of 1 mg/kg/
d subcutaneously every 12 hours. LMWH was titrated to a 4-hour post-dose anti-Xa level of 0.5–1.0 units. At 24 hours post-onset, Adam was mute and had severe hemiparesis.
Further studies
Over a period of 7 days, he had the following investigations, all of which were normal:
1 Hematological investigations – normal complete blood count (CBC) including platelets (for infection, anemia)
2 Prothrombotic investigations: protein C, protein S, antithrombin, plasminogen, homocysteine, lipoprotein (a), factor V Leiden, prothrombin gene (for prothrombotic abnormalities) 3 Vasculitis investigations: ESR, CH50, C-reactive
protein (for vasculitis); echocardiogram including agitated saline (“bubble”) study (for cardiac lesions including congenital heart disease or patent foramen ovale)
Day 3 conventional angiography revealed focal beaded irregularity consistent with the appearance of transient cerebral arteriopathy (TCA) involving the distal left internal carotid, proximal MCA, and proximal anterior cerebral arteries (Figure 11.3).
Chronic management
Antithrombotic treatment was changed to IV unfractionated heparin on the evening of day 2 in preparation for conventional angiography. Following angiography, he was switched to aspirin 5 mg/kg/d.
Aspirin was continued through the hospital stay and continued indefi nitely at 3–5 mg/kg/d. In the discussion with pediatric rheumatology, IV steroid therapy for possible central nervous system vasculitis was considered but not pursued. Conventional angiography was repeated at 2 months post-onset and revealed smooth stenotic narrowing of the M1 segment at the previously “beaded” segment. MRA at 6 months showed stenosis at sites of the prior abnormalities. Conventional angiography at 1 year showed no change. Follow-up angiography confi rmed the diagnosis of TCA.
Fig. 11.1 Initial magnetic resonance imaging.
(a) (b)
Neurological course and rehabilitation
During the initial 7 days, Adam had return of some right limb power. While at the acute care pediatric hospital, he and his family were linked with occupational therapy, physiotherapy, speech therapy, and the social worker. The clinical nurse specialist/
nurse practitioner was also an ongoing source of support and education about pediatric stroke and the need for multiple investigations as well as treatment planning. Adam was transferred to a specialized pediatric rehabilitation hospital at 7 days for further intensive therapy (occupational, physical, and speech therapy). By discharge, he was able to ambulate with assistance and lift his right arm against gravity, although no wrist or fi nger movements were present.
Follow-up at 3 months in the Pediatric Stroke Clinic showed moderate weakness with functional slowing in his right arm and a moderate speech
defi cit. At 5 months, he presented with new onset dystonia in the hemiparetic limbs, which worsened over the subsequent 6 months. With the emergence of dystonia, he was started on an anticholinergic with only minor improvement. When dystonia persisted despite oral medications, botulinum toxin injections of selected upper limb muscles was provided with modest improvement. This was repeated every 3 months.
At 4 years post-stroke, Adam’s speech was mildly abnormal, he had learning diffi culties, and his right arm dystonia remained severe. He ambulated with an ankle-foot orthosis. He has, however, learned to water ski and participates in most activities typical for a boy his age. Adam has had neuropsychological testing showing several areas of learning diffi culty related to his basal stroke. He has in-school assistance to complete his schoolwork.
(a) (b) (c)
Fig. 11.3 Initial and follow-up conventional angiography. Cerebral angiography (CA) performed at (a) 1 week (initial CA), (b) 2 months, and (c) 6 months post-stroke showing unilateral intracranial arteriopathy characteristic of “transient cerebral arteriopathy of childhood”
[15].
Discussion
This otherwise healthy boy presents with signs and symptoms of a focal brain lesion with acute onset over hours, consistent with stroke. Investigations confi rmed arterial ischemic stroke (AIS). Many phy- sicians are not familiar with stroke in childhood.
Pediatric stroke, however, is emerging as an impor- tant cause of neurological morbidity in children and ranks in the top 10 causes of death in infants [1,2].
Studies over the past two decades estimate an inci- dence of 2–8/100,000 children per year and, in neo- nates, 1 : 4,000 live births [3]. Healthcare costs during the year after stroke were recently estimated at $42,338 per child, excluding out-of-pocket and lost parental productivity costs [4]. Previously, chil- dren were thought to have better outcomes after focal brain injury, including stroke, than adults. This historical impression has been refuted in recent outcome studies that document a high rate of mor- bidity [5–7]. Thus, despite being relatively uncom- mon, disabling long-term sequelae from childhood stroke are likely to result in a larger burden on society than previously estimated. The impact per affected individual is greater for children, since with full life expectancy, the burden of illness is expected to manifest over many more decades than in a com- parably affected adult.
Initial stroke diagnosis
Adam was diagnosed with stroke 7 hours after onset when MRI was performed. Urgent diagnosis of AIS in children presents major challenges. A lack of public and physician awareness of pediatric stroke
probably accounts for the delays in arrival to the hospital, which averages to 1.7 hours [8]. At pediat- ric hospitals, acute stroke systems with provision of around-the-clock MRI imaging for suspected stroke are rarely available. Consequently, delays from arrival to initial neuroimaging average to 12.7 hours for children [8].
Adam presented with a rapidly progressive hemi- paresis starting in the face and accompanied by mutism. This same presentation in an adult would lead to a presumptive diagnosis of stroke. His initial CT was normal. A normal head CT in an adult at this early stage following stroke onset would then lead to diagnosis of ischemic stroke, hemorrhage and other stroke mimics having been ruled out as the cause. Treatment with tissue-type plasminogen activator might be provided. Although such a pre- sentation in children should also be considered as due to stroke until proven otherwise, the differential diagnosis for acute focal neurological defi cits in chil- dren is much wider and includes unwitnessed sei- zures with Todd’s paralysis, complicated migraine, demyelinating disorders, and meningoencephalitis [9]. When CT is normal, MRI with diffusion is nec- essary to confi rm the diagnosis of AIS. Further con- founding early diagnosis is that in young infants and newborns, clinical presentations of AIS are usually very nonspecifi c, frequently including only mental status change or seizures alone [10]. This is because focal lesions in the immature, unmyelinated brain occur in areas not yet functioning. Instead, as the affected brain area becomes important with devel- opment, the child will “grow into” defi cits. Thus, family doctors, pediatricians, and emergency physi-
Adam was a previously well child, and only upon vascular imaging was the mechanism of his stroke clarifi ed – a focal unilateral intracranial arteriopa- thy. Initial vascular imaging suggested, and follow- up imaging confi rmed, that he had TCA, a disorder that has been recognized in recent years among chil- dren with AIS [15]. This unilateral, intracranial, anterior circulation disorder is limited to the distal internal carotid artery and proximal middle and anterior cerebral arteries, and is associated with a large, deep AIS involving basal ganglia. TCA is a presumed infl ammatory disorder, and is self-limited with some initial stenosis during the acute period (several weeks to months), then stabilization or regression of the arteriopathic lesions after 6 months (Figures 11.2 and 11.3). Post-varicella angiopathy is radiographically indistinguishable from TCA but is preceded by a varicella infection by several weeks to months. The infl ammatory nature of post-varicella angiopathy has been established by postmortem his- topathology on multiple adult cases and one child- hood case. Vascular imaging shows stabilization from several months to 1 year – characteristic of TCA.
The series of investigations that were conducted in Adam are generally performed in children pre- senting with AIS. Frequently, multiple risk factors are discovered in individual children, with some, including prothrombotic disorders, playing a cians need to have a high index of suspicion for
stroke in children with an acute focal neurological defi cit. Although Adam had no preceding transient ischemic attacks, these occur often in children in the days and weeks preceding ischemic stroke and fre- quently represent missed opportunities to initiate preventive treatment.
Etiological diagnosis
The search for an etiology begins once a diagnosis of stroke is established in a child. Childhood AIS is not due to atherosclerosis, the predominant cause for stroke in adults. Common conditions causing childhood stroke include congenital cardiac malfor- mations, acquired cardiac conditions, and cerebral arteriopathies. A multitude of additional systemic and head and neck disorders can also cause child- hood stroke including conditions both acute (dehy- dration, head trauma) and chronic (iron defi ciency anemia, brain tumor). Prothrombotic disorders are frequent additional risk factors reported in 30–50%
[11]. Cardiac disorders are usually evident prior to stroke, and stroke may be a complication of cardiac catheterization or surgery [12].
Overall, arteriopathy is the most common mecha- nism for pediatric AIS [13]. In most children, arteriopathy is unsuspected at the time of stroke presentation, and detection requires vascular imaging. Arteriopathies range from mild, reversible disorders to severe and progressive types and include migraine, dissection, TCA or post-varicella arteri- opathy, vasculitis, Moyamoya, and others [14]
(Table 11.1). In contrast to the extracranial distribu- tion of atherosclerosis, childhood arteriopathies tend to be intracranial. Intracranial arteriopathies can be bilaterial, including progressive vasculitis or the Moyamoya syndrome (either sickle or non-sickle related) or unilateral, including TCA and post-varicella angiopathy. Progressive vasculitis usually involves multiple caliber anterior and posterior circulation arteries at onset. Aggressive treatment with steroids and cyclophosphamide is frequently used. Arterial dissection is frequently extracranial and, along with migraine, favors the posterior circulation in children. Close monitor- ing of unilateral intracranial arteriopathy over at least 1 year is warranted to ensure it does not evolve into bilateral Moyamoya or progressive vasculitis.
Table 11.1 Cerebral vasculopathies in children Cervicocephalic arterial dissections
Moyamoya disease and Moyamoya syndrome Fibromuscular dysplasia
Vasculitis
Transient cerebral arteriopathy Post-varicella angiopathy Migrainous infarction Ergotism
Traumatic cerebrovascular disease Radiation-induced arteriopathy
Tumoral encasement of cervicocephalic vessels Hypoplasia and agenesis of cervicocephalic vessels Congenital arterial fenestration
Cerebral Vasculopathies in Children from AHA Pediatric Stroke Guidelines from [17].
Adapted from Biller J, Mathews KD, Love BB. Stroke in Children and Young Adults. Boston: Butterworth-Heinemann, 1994, with permission from Elsevier.
predisposing role and others, including head or neck trauma and dissection, playing a triggering role. In particular, prothrombotic laboratory testing should be considered even if other stroke mechanisms are found, as they play an important additive role in initial and recurrent stroke [16]. The recent Ameri- can Heart Association (AHA) Guidelines on Pediat- ric Stroke indicate that “it is reasonable to evaluate for the more common prothrombotic states even when another stroke risk factor has been identifi ed (Class IIa, Level of Evidence C) [17]. Other hema- tological disorders that are common in children with stroke require consideration including sickle- cell disease, and iron defi ciency anemia which is associated with stroke through as yet unclear mech- anisms [18]. The AHA Pediatric Stroke Guidelines provide comprehensive lists of possible causes of childhood stroke and a discussion of investigations in addition to treatment guidelines [17].
Management
Age-specifi c considerations underlying pediatric stroke treatment
As in adult stroke, the treatment of pediatric AIS is largely etiology-driven. Antithrombotic treatment aims to prevent initial or recurrent stroke. Although randomized trials in children are lacking, anti- thrombotic drugs during the acute stroke period are frequently used due to the high risk of early recur- rent stroke. Up to 50% of children not treated with aspirin or anticoagulants have recurrent strokes [19]. The risk of recurrent stroke in children is maximal in the fi rst days and weeks after index stroke [19]. Antithrombotic treatment generally consists of either antiplatelet (aspirin) or anticoagu- lant (heparin or LMWH) medication. The challenge facing clinicians is whether to select an antiplatelet drug or an anticoagulant. In adults, anticoagulants have not been shown to be of any benefi t in the acute period. Treatment decisions in children are based on the likelihood of recurrence and the presumed bio- logical basis of the thrombus in an individual child.
The etiology largely determines whether thrombus is predominantly fi brin based or platelet based, although most clots are apt to be composed of a combination of the two thrombotic systems.
Children clearly differ from adults in the cause for stroke and risks of treatment. Childhood AIS is not
due to atherosclerosis; the predominant cause for adult stroke and the etiology is frequently arterial dissection or structural cardiac disease with embo- lism. Combined, these two etiologies are found in approximately one-third of children with AIS [13].
Prothrombotic risk factors, present in 30–50% of children with AIS, increase the risk of stroke recur- rence [11,16].
The fi rst institutional protocols for the manage- ment of pediatric stroke were published in 1997 [20]. In the past 4 years, three consensus-based guidelines for pediatric stroke have been published.
Each assigns levels of evidence for individual recom- mendations [20–23]. Tables 11.2 and 11.3 compare the treatment recommendations from these three sources for the acute and chronic treatment of sub- types of childhood AIS. The original guidelines also provide additional recommendations for other stroke subtypes, including neonatal stroke and cere- bral sinovenous thrombosis. The participation of hematologists in clinical management decisions, pediatric stroke research, and clinical guideline developments has played critical roles in expanding our understanding of non-atherogenic cerebral artery thrombosis. Experience gleaned from the management of children with systemic arterial thrombosis and expertise in the safe use of aspirin and anticoagulants has benefi ted pediatric neurolo- gists, the primary treating physicians for children with acute stroke.
The “UK” guidelines published in 2004 by the Royal College of Physicians of London are compre- hensive consensus guidelines including general care, medicinal and nonmedical treatment, and rehabili- tation [22]. They also provide an educational hand- book for children with stroke and their parents. For the fi rst time in 2004, the American College of Chest Physicians Antithrombotic Guidelines included a chapter devoted to pediatric stroke. These were updated in 2008 [21]. Most recently, the “Manage- ment of stroke in infants and children, a scientifi c statement from a Special Writing Group of the AHA Stroke Council and the Council on Cardiovascular Disease in the Young” was published [18]. These are very comprehensive guidelines encompassing diag- nosis and medical, surgical, and rehabilitative treat- ments for all subtypes of pediatric stroke. Given the absence of randomized controlled trials in pediatric stroke, the evidence supporting individual recom-
Table 11.2 Comparison of the American Heart Association (AHA) and other childhood stroke guidelines: acute treatment
Acute treatment of childhood arterial ischemic stroke by subtype
UK guidelines 2004 Chest guidelines 2008 AHA 2008
Recommendation Recommendation Recommendation
Subtype G S G S G S
Acute supportive measures
Maintain normal temperature and oxygen saturation
D 4 Not addressed Control fever, maintain
normal oxygenation, control systemic hypertension, and normalize serum glucose
1-C 1
General ASA 5 mg/kg WPC 1 UFH or LMWH or ASA
1–5 mg/kg/d until cardioembolic and dissection excluded
1B 1 UFH or LMWH (1 mg/kg/12 hours) up to 1 week until cause determined
2b-C 3
Sickle-cell disease
Exchange transfusion to HbS
≤30%
WPC 1 IV hydration and exchange transfusion to HbS <30%
1B 1 Exchange transfusion to HbS
<30%
2a-B 2
Cardiac Anticoagulation should be discussed by senior pediatric neurologist and pediatric cardiologist
WPC 1 LMWH 6+ weeks 2C 3 For cardiac embolism unrelated to patent foramen ovale, and judged to have high recurrence risk:
UFH or LMWH as a bridge to oral anticoagulation
2a-B Alternative: UFH or LMWH
as a bridge to maintenance LMWH
2a-C 2
Dissection Anticoagulation for extracranial dissection with no hemorrhage
WPC 1 LMWH 6+ weeks 2C 3 UFH or LMWH as a bridge
to oral anticoagulation
2a-C 2
tPA Not recommended 1 Not recommended 1B 1 Not recommended 3-C 1
tPA in teens Not addressed Not addressed No consensus on use
Childhood defi ned as 28 days to 18 years (Chest), 1 month to 16 years (UK).
ASA, aspirin; G, grade of evidence/recommendation; HbS, sickle hemoglobin; LMWH, low molecular weight heparin; S, strength of evidence/recommendation; tPA, tissue-type plasminogen activator; UFH, unfractionated heparin; WPC, working-party consensus.
mendations in all three sets of guidelines is sparse.
They represent consensus opinions, based primarily on experience or intuition, or, in some cases, case- control or cohort study data, rather than random- ized controlled trials. In many cases, evidence from adult treatment trials has been selectively extrapo- lated, keeping in mind that the major mechanism in adults, atherosclerosis, does not play a role in the causation of pediatric stroke.
Primary prevention was not an option in Adam.
But treatment aimed at preventing a fi rst stroke is highly desirable, and is available in certain subgroups of children at signifi cant risk for AIS. For children with sickle-cell disease, regular transfusions can prevent a fi rst stroke based on a randomized con- trolled trial [24]. Vaso-occlusive stroke complicates 1 in 185 cardiac surgeries in children, and reopera- tion is a risk factor for stroke. It should therefore be
Table 11.3Comparison of the American Heart Association (AHA) and other childhood stroke guidelines: chronic treatment Chronic treatment of childhood arterial ischemic stroke UK guidelines 2004Chest guidelines 2008AHA 2008 RecommendationRecommendationRecommendation SubtypeGSGSGS GeneralASA 1–5 mg/kg/dWPC1Once dissection and cardioembolism are excluded, ASA 1–5 mg/kg/d, 2+ years 1B1ASA 3–5 mg/kg/d2a-C3 DissectionConsider anticoagulation until evidence of vessel healing or up to 6 monthsWPC1LMWH ongoing depending on radiographic results2C3Intracranial dissection or associated subarachnoid hemorrhage: anticoagulation not recommended
3-C1 Extracranial dissection: LMWH or warfarin 3–6 months ASA may be substituted
2a-C ASA beyond 6 months2a-C Cardiogenic embolism Consider anticoagulation after discussion with the cardiologist managing the patient
WPC1LMWH ongoing depending on radiographic results2C3LMWH or warfarin ≥1 year2a-B2 Prothrombotic statesRefer patient to a hematologistWPC1Not addressedWarfarin long term for selected hypercoagulable states2a-C2 VasculopathyVasculopathy ASA 1–3 mg/kg/dWPC1Not addressedNot addressed MoyamoyaRevascularization surgeryD3Revascularization surgery1B1Revascularization surgery1-B1 Sickle-cell diseaseBlood transfusion every 3–6 weeks to HbS 30%C3Long-term transfusion program1B1Regular transfusion program1-B1 After 3 years, aim for HbS <50%C3Not addressedNot addressed If no transfusion, hydroxyureaC3Not addressedIf no transfusion, hydroxyurea2b-B2 Consider bone-marrow transplantB2Not addressedConsider bone-marrow transplant2b-C3 Recurrent stroke on ASAConsider anticoagulationWPC1Change to clopidogrel or anticoagulation2C3Not addressed RehabilitationRehabilitation developmentally relevant and appropriate to home, community, and school environment D4Not addressedAge-appropriate rehabilitation and psychological assessment of cognitive and language defi cits
1-C Preventing atherosclerosisAdvise re: preventable risk factors, smoking, exercise, and dietD4Not addressedAdvise re: diet, exercise, and tobacco 2a-C Child defi ned as 28 days to 18 years (Chest), 1 month to 16 years (UK). ASA, aspirin; G, grade of evidence/recommendation; LMWH, low molecular weight heparin; S, strength of evidence/recommendation; WPC, working-party consensus.