Clinical manifestations

Presentation and course

Clinical manifestations, course, and outcome of acute hemiplegia vary depending on the etiology.

Stroke. Acute hemiplegia, a common presentation of arterial ischemic stroke (60; 39), appears suddenly in 50% of cases but is subacute (evolving over hours) in 35% and stuttering in onset in 15% (30). Arteriopathy in contrast to other causes of stroke almost always presents with hemiparesis as opposed to multifocal or bilateral symptoms (59). Subacute onset also suggests an underlying arteriopathy (13). Duration of hemiplegia varies from days to weeks; deficits can be permanent. Etiology and location of lesion determine outcome. Seizures and headache may precede, present with, or follow arterial ischemic stroke in as many as a third of patients or more (30; 18; 43; 01; 83) and may delay the proper diagnosis (82). Seizures are particularly common in children younger than 1 year of age who may or may not have an apparent hemiparesis (97). Other neurologic signs can co-occur with hemiplegia, eg, hemisensory or visual deficit, aphasia, or constructional apraxia, depending on the location and type of the lesion. When seen in cerebral venous sinus thrombosis with associated infarction, acute hemiparesis is often accompanied by altered consciousness, headache, and seizures. Predisposing conditions, eg, dehydration and systemic diseases, are common (27).

Hemorrhage. Hemorrhage can occur in the setting of stroke (arterial or venous), vascular malformations and aneurysm, neoplasms, congenital heart disease, head and neck trauma, and hematologic disorders. Hemiplegia is generally abrupt in onset, except when it occurs in the setting of hemorrhagic stroke. Headaches and seizures are common (57; 18). In younger children, the clinical presentation may be nonspecific, whereas in older children (over 6 years of age) a focal deficit or hemiplegia is the rule (57).

Hemiplegic migraine. Hemiplegic migraine usually has a slowly progressive onset evolving over 5 to 30 minutes, but in 5% to 10% of cases onset is abrupt, peaking in less than 1 minute (90). In about 15%, the hemiplegia shifts sides during an attack. Weakness lasts less than 1 hour in 51% of cases, 1 to 24 hours in a subsequent 41%, and more than 24 hours in an additional 8% (90). In hemiplegic migraine, positive symptoms (particularly paresthesias) often precede the hemiplegia (41), and more typical auras (visual, sensory, or dysphasic) often co-occur with the hemiplegia. Headache can precede or occur at the same time as the aura or follow it--generally within an hour. A structural lesion needs to be ruled out as both arterial ischemic stroke and cerebral venous sinus thrombosis occur in migraineurs, at least in adulthood, at a greater frequency than in the general population, and headache, especially in children, can occur at the onset of stroke. It is not known whether prolonged aura (more than 1 hour but less than 7 days) or persistent aura (more than 7 days) increases the risk for stroke. However, hemiplegic migraine does not specifically confer a greater risk of stroke than migraines with other auras (51).

Seizures: ictal and Todd postictal paralysis. Todd postictal paralysis is identified by its context; it occurs after a seizure. Duration ranges from minutes to days but in most instances is less than 30 minutes (38). Hemiplegia lasting more than 6 hours is unusual and should not be assumed to be a Todd paralysis (41). However, Todd himself reported episodes lasting for days (91). Rarely, focal weakness may be the only manifestation of a seizure (72; 71). A hemiconvulsion-hemiplegia-epilepsy syndrome has been described and is characterized by a prolonged clonic seizure with unilateral predominance occurring during a febrile illness and followed by hemiplegia (05). Mutations in sodium channel genes SCN1A and SCN2A are a predisposing factor for this syndrome. It is hypothesized that altered channel activity resulting from these mutations provokes both seizures and subsequent excitotoxic brain damage (80).

Demyelinating disorders. Onset of hemiplegia in disorders affecting white matter, such as acute disseminated encephalomyelitis and leukoencephalopathy due to toxin or medication side effects, is more often subacute than acute and is often associated with an encephalopathy.

Conversion disorder. In conversion disorder, the hemiplegia usually appears suddenly and is typically temporally related to a psychological stressor (04). Other psychiatric disorders (ie, depression and anxiety) may coexist.

Asthmatic amyotrophy. Sudden, flaccid paralysis of 1 or more limbs may occur during recovery from an asthmatic attack. It resembles poliomyelitis. The interval between the asthmatic attack and the paralysis is 1 to 11 days. Monoplegia frequently involving the arm occurs in 90% of cases whereas 10% have hemiplegia or diplegia. Sensation is intact but there is pain in the paralyzed limb in 50% of cases. Recovery is incomplete (56).

Diabetes mellitus. Acute transitory attacks occur in children with insulin-dependent diabetes mellitus. Attacks frequently occur during sleep. Hemiparesis is present on awakening and lasts for 3 to 24 hours. Weakness is greater in the face and arm. Headache is a constant feature. Recovery is complete (67).

Alternating hemiplegia of childhood. Onset is from birth to 18 months. Mild developmental delay and abnormal eye movements are initial features. Young infants have more dystonic features and older children have flaccid hemiplegia. Brief attacks of nystagmus accompany attacks. Duration of attacks varies from minutes to days. Hemiplegia may shift from side to side. Arm is generally more severely affected than leg. Hemiplegia disappears with sleep. Neurologic impairment occurs as the disease progresses (88). Adults with this disorder can have other manifestations, including parkinsonism (see MedLink Neurology article Alternating hemiplegia of childhood).

Meningitis/meningoencephalitis. The clinical manifestations of CNS infection differ between the meningitic form and the encephalitic form. Fever, headache, vomiting, and stiffness of the neck dominate the meningitic form and altered state of consciousness, focal neurologic signs (including hemiplegia), and seizures dominate the encephalitic form.

Reversible cerebral vasoconstriction syndrome. Reversible cerebral vasoconstriction syndrome is a clinical and radiographic syndrome that is characterized by thunderclap headache, seizures, and focal neurologic deficits. There is narrowing of the cerebral arteries on cerebrovascular imaging. This usually diminishes within 12 weeks after the onset of symptoms. Reversible cerebral vasoconstriction syndrome is associated with stroke (ischemic or hemorrhagic) in 10% of cases. It is frequently associated with ingestion of vasoactive drugs such as nasal decongestants (29).

Posterior reversible encephalopathy syndrome. Posterior reversible encephalopathy syndrome is an emerging neurologic disease characterized by headache, altered mental status, visual disturbance, seizures, and focal neurologic findings including hemiplegia. Hypertension, cytotoxic agents, and corticosteroids are well-identified triggers. When it is managed in a timely fashion, the prognosis is benign with complete recovery within days or weeks. Typical radiographic findings include vasogenic edema in posterior cerebral regions (75).

Metabolic or genetic disorders. Metabolic abnormalities such as hyper- and hypoglycemia and hypocalcemia result in inadequate energy supply to neurons. Inherited metabolic disorders can cause stroke-like episodes with hemiplegia, which are mediated by cellular energy failure, for example, in mitochondrial disorders like MELAS (mitochondrial encephalopathy and lactic acidosis syndrome) and organic acidemias. Disease-specific mechanisms for stroke have been documented in some genetic disorders (89; Testai and Gorelick 2010b; 68).

Prognosis and complications

Outcome after acute hemiplegia is highly variable and depends on the underlying cause. Pooled data from several studies of children with arterial ischemic stroke indicate that 30% were neurologically normal, 61% had motor or cognitive problems, and 9% died (58). Epilepsy develops in 10% to 15% of children with arterial ischemic stroke (25). Following intracerebral hemorrhage, 42% of children are normal and 32% have persistent deficits, with 25% mortality, and epilepsy in 11% (58). Imaging studies suggest that acute involvement of the descending corticospinal tract on diffusion-weighted imaging is a harbinger of poor motor outcome (28). AHE causes mild to severe cognitive problems. Almost all affected children have some level of developmental delay and intellectual disability (88). Prognosis of intracranial infections and acute demyelinating disorders is excellent if diagnosed and treated early. Most patients with reversible cerebral vasoconstriction syndrome show resolution of symptoms within days to weeks. Fifteen to twenty percent are left with residual deficits from stroke (47). Prognosis in posterior reversible encephalopathy syndrome is usually excellent. Symptoms are most often fully reversible after removal of the inciting factor and control of the blood pressure. Serious neurologic disability and death have also been reported (Raj et al 2013; 81). Rarely, some patients develop epilepsy after recovery. The prognosis is asthmatic amyotrophy is uniformly poor (56). Most of the patients later develop marked limb amyotrophy and remain handicapped. The outcome in hemiconvulsion hemiplegia epilepsy syndrome depends on the cause and immediate seizure control. Most patients develop epilepsy and attacks of status epilepticus. Cognitive deficits are the rule (05). In contrast, the outcomes in hemiplegic migraine, acute hemiplegia in diabetes mellitus, Todd postictal paralysis, and conversion disorder are generally excellent.

Clinical vignette

A 9-year-old girl presented with sudden onset right-sided weakness. She was previously healthy and had no history of recent trauma, infection, or vaccination. There was no family history of premature stroke, myocardial infarction, or deep venous thrombosis. The patient was afebrile and vital signs were normal. Blood pressure was 90/60 mmHg. On neurologic examination, she was fully conscious and cooperative. Cranial nerve examination revealed left central facial paralysis. Strength in the right upper and lower extremities was normal (5/5), but greatly diminished on the left (1/5). Deep tendon reflexes were hyperactive on the left and left plantar response was extensor. Skin examination revealed no café-au-lait spots, neurofibromas, or freckling of the groin or the axilla. The remainder of the physical examination was normal. Diffusion-weighted magnetic resonance imaging revealed diffusion restriction in the right putamen, nucleus caudatus, and posterior limb of the internal capsule consistent with acute infarction. Time of flight magnetic resonance angiography showed beading and decrease in caliber in the right supraclinoid segment of the carotid artery and middle cerebral artery. In the superior-anterior part of the M1 segment of the middle cerebral artery, there seemed to be a second lumen with a signal intensity lower than that of the primary lumen but higher than that of the parenchyma. These findings suggested dissection superimposed on fibromuscular dysplasia in the middle cerebral artery, which compromised the origin of the lenticulostriate arteries and led to striatocapsular infarct. Digital subtraction angiography performed 1 week after the MRA showed the typical “string of beads” appearance of fibromuscular dysplasia in the right supraclinoid segment of the carotid artery, M1 and M2 segment of middle cerebral artery, and A1 segment of anterior cerebral artery. Dissection, however, was not confirmed. It was assumed that the dissected intima had sealed during the interval between the MRA and the digital subtraction angiography or that the second lumen appearance resulted from motion artifacts. Abdominal magnetic resonance imaging of the patient was normal. Complete blood count, coagulation parameters, antiphospholipid antibodies, antithrombin III, protein C, protein S, and homocysteine were normal. Factor V Leiden, methylene tetra-hydrofolate reductase, and prothrombin G20210A mutations were negative. Serum cholesterol, triglycerides and low- and high-density lipoproteins (LDL, HDL) were 303 mg/dl (122-209), 122 mg/dl (35-114), 221 mg/dl (60-150), and 58 mg/dl (35-84), respectively. Cardiac examinations, including echocardiography and electrocardiography, were normal. The lipid profile of both parents also showed increased levels of cholesterol, triglycerides, and LDL. Familial combined hyperlipidemia was suggested, and a low-cholesterol, low-saturated fat diet was started. Aspirin at a dosage of 3 mg/kg/day was started for its antiplatelet effect and physical rehabilitation was instituted for hemiparesis. No further strokes appeared in the follow-up period of 6 months, and at present, she has mild hemiparesis and is able to walk independently.

Biological basis

Anatomic localization

The corticospinal tracts arise from somatotopically organized areas of primary motor cortex, lateral premotor cortex, and supplementary motor area as well as the primary sensory cortex in the postcentral gyrus, ie, the anterior paracentral gyrus, superior parietal lobule, and areas of the cingulate gyrus. The corticospinal tract descends in the corona radiata, the posterior limb of the internal capsule, the middle three fifths of the cerebral peduncle, the pons, and the medullary pyramids. Thus, lesions in any of these areas can result in hemiparesis of varying degree and distribution. Corticospinal neurons within the motor cortex are somatotopically organized in accordance with their functional importance; the size of the cortical representation in the motor homunculus varies with the functional importance of the body part represented. For example, isolated hand weakness of cortical origin may present with loss of thumb and finger movements and impaired hand flexion and extension, or it may occur with only partial involvement of a few digits. The corticospinal tract is also organized somatotopically in the posterior limb of the internal capsule with hand fibers lateral and slightly anterior to foot fibers, in the pons with fibers controlling the proximal muscles placed more dorsally than those controlling more distal muscles, and in the medullary pyramids with fibers of the lower extremities placed more laterally and decussating more rostrally than those of the upper extremities. Depending on the location of the lesion relative to the corticospinal tract pathway, a hemiparesis of vascular origin may predominantly involve the upper or lower extremity with or without other associated findings, except for the pure motor hemiparesis of pontine lesions where the deficit is equally arm and leg and spares the face (14). Cervical cord lesions can also cause hemiparesis secondary to compression of the corticospinal tracts.

Pathophysiology

Acute hemiplegia in childhood is caused by an alteration in cerebral metabolism in a brain region involved in contralateral motor function. The specific mechanism of this metabolic derangement varies depending on the underlying cause.

Stroke. The pathogenesis of childhood stroke is multifactorial and can be divided into several categories: cardiac, extracranial arteriopathies, intracranial arteriopathies, thrombophilia, sickle cell disease, and systemic causes. Cardioembolic stroke occurs as a result of congenital heart disease, acquired heart disease, and procedure-related events. The pathophysiology of stroke in children with cardiac disease is usually thromboembolic. Extracranial arteriopathies are usually caused by craniocervical arterial dissection. Dissection promotes platelet activation and activation of clotting cascade in the intimal layer of the artery. Dissection also causes aneurysmal dilatation of the affected artery. The most common cause of childhood stroke is intracranial arteriopathies. They are mainly divided into dissection and inflammatory types. Dissection type occurs in the anterior circulation, usually with trauma. Inflammatory type is a focal vasculitis. An infectious or parainfectious process leads to localized vessel inflammation and secondary thrombus formation. Progressive disease of the distal middle cerebral artery/proximal internal carotid artery is called moyamoya disease. Moyamoya disease is associated with 6% to 10% of childhood strokes and transient ischemic attacks. Thrombophilia leads to hypercoagulable states resulting from inherited or acquired conditions. In fact, protrombotic conditions may act as triggers for stroke in the presence of other risk factors. Systemic causes of childhood stroke include inflammatory causes and genetic/metabolic syndromes. Typical examples include primary angiitis of the central nervous system, systemic lupus erythematosus, and polyarteritis nodosa. Clues for inflammatory causes include proteinuria, presence of persistent serum inflammatory markers, frequent fevers, and livedo reticularis. Genetic and metabolic causes of stroke are rare. ACTA2 syndrome, COL4A1 mutations, and PHACE syndrome are specific syndromes. Stroke in mitochondrial disorders do not follow typical arterial distributions (32). Common causes of pediatric stroke are shown in Table 1.

Table 1. Common Causes of Pediatric Stroke

Hemorrhage. Hemorrhage causes hemiplegia as a result of mass effect or by specific involvement of the corticospinal tracts. Hemorrhages can be caused by vascular malformations (about 50%), brain tumors (10%), cardiac disease, hematological disorders, and medical illnesses (25%) (57). In some cases, there is no definable cause. Intraparenchymal hemorrhages are generally due to vascular malformations or brain tumors (57). Saccular aneurysms are 3 times more likely to hemorrhage than fusiform aneurysms (44). Subdural hemorrhages generally occur in the setting of hematological disorders or cardiac surgery. Subarachnoid hemorrhage is not associated with specific risk factors (57). Sturge-Weber syndrome has been associated with spontaneous intracranial hemorrhages in some children (69).

Metabolic or genetic disorders. Metabolic abnormalities such as hyper- and hypoglycemia and hypocalcemia result in inadequate energy supply to neurons. Inherited metabolic disorders can cause stroke-like episodes with hemiplegia, which are mediated by cellular energy failure, for example, in mitochondrial disorders like MELAS and organic acidemias. Disease-specific mechanisms for stroke have been documented in some genetic disorders (89; Testai and Gorelick 2010b; 68).

Hemiplegic migraine. Migraine auras of all types are due to cortical spreading depression characterized by brief neuronal excitation, which initiates a depolarization wave that moves across the cortex at a rate of 3 to 5 mm/minute and is followed by a prolonged inhibition of neuronal activity. Whether hemiplegic migraine is qualitatively different from other migraines with aura is debatable. Mutations in 1 of 3 genes, ie, voltage-gated channels CACNA1A and SCN1A genes and the Na/K pump ATP1A2 gene, are responsible for 50% to 70% of familial hemiplegic migraine (79). These genes are inherited in an autosomal dominant pattern; the child of a parent with familial hemiplegic migraine has a 50% chance of inheriting the mutation.

Seizures: Todd postictal hemiplegia and ictal hemiplegia. “Neuronal exhaustion” is considered the most likely cause of Todd postictal hemiplegia. Todd believed in the context of his electrical theory of epilepsy that the hemiplegia resulted from undue exultation resulting in a state of depression or exhaustion (12). Excessive inhibition is another proposed mechanism. Epileptic activity in the supplementary motor area or somatosensory cortex (23) or temporoinsular area (94) has been implicated in epileptic hemiparesis. Periodic lateralizing epileptiform discharges on EEG may be disproportionately frequent during ictal hemiparesis. Although the pathophysiological mechanism of hemiconvulsion-hemiplegia-epilepsy syndrome is not known, there are several factors that are believed to contribute to the pathogenesis. The proposed mechanism is neuronal lesion induced by venous thrombosis and/or by neuronal toxicity. The role of cerebral malformation and/or cortical dysplasia has also been suggested. Inflammation and hyperthermia are known to worsen status epilepticus and prolonged status epilepticus damages the blood-brain barrier. The unilaterality may be due to regional maturation of the corpus callosum, focality of a neurotropic virus, and genetic predisposition (05). New research has identified missense mutations in sodium channel SCN1A and SCN2A that predispose children to encephalopathy with severe febrile seizures (88; 80).

Demyelinating disorders. Demyelination in the cerebral white matter or in the spinal cord results in hemiplegia primarily by slowing conduction through motor fibers.

Infection. Meningitis and encephalitis can cause hemiplegia via destruction of brain parenchyma, abscess formation, local inflammation, or vasculopathy (19).

Neoplasm. A tumor may cause hemiplegia through compression of brain or cervical cord structures responsible for motor control by the mass lesion itself or surrounding edema or hemorrhage.

Head or neck trauma. Head trauma can cause acute hemiplegia through a variety of mechanisms, including shearing injury; intraparenchymal, epidural, subdural, or subarachnoid hemorrhage; or ischemic injury, which can be a primary effect due to dissection or secondary to vasospasm following subarachnoid hemorrhage. Repeated head trauma, as occurs in the setting of contact sports, may increase the risk of brain ischemia over time due to long-term vascular and neuronal changes (15). Acute cervical cord compression causing hemiplegia may be spontaneous or the result of trauma (36).

Toxin or medication side effects. Toxic agents produce stroke via a range of mechanisms like vasculitis (eg, cocaine) or cause hemiplegia through myelin and axon loss, gliosis, and necrosis (eg, methotrexate leukoencephalopathy) (53).

Conversion disorders. Atypical activation in motor cortex, basal ganglia, and thalamus in response to paretic limb stimulation (55) and atypical connectivity between the amygdala and the supplementary motor area (95) as well as between the ventromedial and dorsolateral prefrontal cortex (24) are present in patients with conversion disorder. Motor mental imagery is impaired (16). Together these data suggest an atypical relationship between emotion and motor function (95).

Posterior reversible encephalopathy syndrome. Previous reports suggest that vasogenic rather than cytotoxic edema plays a more significant role in the pathophysiology. When hypertension exceeds cerebrovascular autoregulatory limits, it results in endothelial dysfunction and failure of compensatory vasoconstriction to prevent hyperperfusion and subsequent fluid extravasation. Because sympathetic innervation is relatively scant in the posterior circulation, parieto-occipital lobes are affected frequently. Antineoplastic and immunosuppressive drugs may also cause a direct toxic effect on the cerebrovascular endothelium (37).

Reversible cerebral vasoconstriction syndrome. The pathophysiology of the abrupt-onset headache and the prolonged-reversible vasoconstriction in RCVS is not known. An abnormality of the cerebrovascular tone is suggested. Cerebral vasoconstriction may result in ischemic stroke or hemorrhages in some cases (93).

Alternating hemiplegia of childhood. About 70% of cases are caused by mutations in ATP1A3 gene. Other genes which cause alternating hemiplegia of childhood or similar symptoms include the CACNA1A, SLC1A3, and ATP1A2. The ATP1A3 gene is responsible for the production of ATPase, Na+K+ transporting, that is required for the normal function of nerve cells in the brain. This protein plays a critical role in the transport of sodium and potassium ions across a channel that connects nerve cells which helps to regulate brain activity. Alternating hemiplegia of childhood is therefore a channelopathy (62).

Global perspective. A retrospective review of 25 children with acute hemiplegia admitted to the Neurology Unit of the Department of Pediatrics of University of Calabar Teaching Hospital in Nigeria showed that prolonged seizures, speech defect, cranial nerve deficit, and loss of consciousness were the most common clinical findings (31). Viral encephalitis was the most common etiology, followed by meningitis and sickle cell anemia. Only 16% of the patients recovered completely, 8% died, and 76% had varying degree of weakness.

Epidemiology

A prospective observational study carried out in the department of pediatrics of a tertiary care hospital of Western India from November 2010 to October 2012 showed that acute hemiparesis was seen in only 0.44 of all pediatric admissions during the study period, with a slight male predominance. Most of the children were between 1 and 5 years of age (21). Annual incidence rates of arterial ischemic stroke in infants and children range from 0.6 to 7.9/100,000 children per year (26).

Differential diagnosis

The differential diagnosis of acute hemiplegia is extremely broad, although stroke, migraine, and Todd postictal paralysis are the most common causes (Table 2).

Table 2. Differential Diagnosis of Acute Hemiplegia in Children

In the differential diagnosis of hemiplegia in children, the clinician should first distinguish between peripheral and central deficits. A competent neurologic examination is a key. Facial weakness, encephalopathy, and seizures should point the clinician to central nervous system. Increased tone and reflexes on the affected side are late signs in hemiplegia due to central deficits. Partial Bell palsy, sparing the upper face, can be mistaken for an ipsilateral upper motoneuron facial palsy. Facial palsy contralateral to the hemiplegia localizes the lesion to the pons. The signs in younger children are more diffuse and the clinician should be careful for asymmetry of movements, tone, posture, and reflexes. The immediate priority in the acute setting is to identify a neurosurgical emergency such as intracranial hemorrhage, malignant ischemic stroke, brain tumor, and hydrocephalus. An abrupt onset with headache and coma is suggestive for intracranial hemorrhage. Ischemic stroke may have a stuttering onset. Headache is common in hemiplegic migraine, central nervous system infections, and sinovenous thrombosis. Cases with hemiplegic migraine also have more typical auras (visual, sensory, or dysphasic) often cooccurring with the hemiplegia. Encephalopathy is common in central nervous system infections and acute demyelinating disorders and should be perceived as a warning sign in cases of arterial ischemic stroke who develop malignant middle cerebral artery syndrome. Thunderclap headache is common in cerebral vasoconstriction syndrome and subarachnoid hemorrhage. Children with moyamoya disease have transient ischemic attacks that are triggered by hyperventilation and dehydration. During attacks of alternating hemiplegia, paralysis alternates form 1 side of the body to the other. Symptoms completely disappear with sleep and reappear with awakening. Seizures are often the presenting manifestation associated with visual disturbances in posterior reversible encephalopathy syndrome (10).

Diagnostic workup

History and clinical examination provide crucial clues about the cause of hemiplegia. Both family and personal history are relevant. Funduscopic examination may reveal signs of retinal hemorrhage, suggesting cerebral trauma, as well as signs of a genetic disorder like Lisch nodules or cataracts. Examination of the oropharynx and neck may reveal evidence of injury or inflammation. Examination of the heart facilitates the diagnosis of cardiac disease. Delayed or diminished femoral pulses suggest coarctation of the aorta, which has been associated with moyamoya disease. Examination of the skin may reveal lesions of varicella or herpes infection, abnormalities of Ehlers-Danlos syndrome or other connective tissue disorder, stigmata of neurocutaneous disorders, or lesions of conjunctivae and skin, suggesting Kawasaki or Behçet disease.

Neuroimaging. Neuroimaging is essential in the evaluation of a child with acute hemiplegia. Computed tomography (CT) is rapid and appropriate for emergent evaluation, but it is inadequate, except for perfusion-weighted imaging, to detect early stroke or accurately distinguish the many mimickers of ischemic stroke in children (82; 01; 83). Magnetic resonance imaging (MRI) with diffusion-weighted imaging sequences with apparent diffusion coefficient maps is the most sensitive test for arterial ischemic stroke (03). Diffusion- and perfusion-weighted imaging can detect ischemia within minutes. Gradient echo imaging detects blood. Specific patterns on MRI may aid in defining etiology, especially in mitochondrial disorders. Stroke-like lesions that do not conform to vascular territories, which are bilateral, and the presence/absence of basal ganglia signal abnormalities may be clues to an underlying mitochondrial disorder. Subsequent MR spectroscopy is useful to aid in identifying certain mitochondrial disorders by evaluating for lactate peaks in noninfarcted areas (54). Typical findings of PRES are bilateral areas of white matter edema in the posterior cerebral hemispheres but variations do occur.

MRI can also provide some information about the presence of vasculopathies. Axial T1 MRI of the neck with fat saturation should be performed along with magnetic resonance angiography to evaluate for arterial dissection or other vasculopathy. Moyamoya disease can be diagnosed on MRI based on its dilated, tortuous enhancing signal voids in the basal ganglia and the severe stenosis of the distal internal carotid artery (06).

In hemorrhagic stroke, CT may not identify underlying vascular abnormalities such as arteriovenous malformations and cavernomas, and it may poorly differentiate tumor from secondary hemorrhage. Therefore, MRI of the brain with gadolinium should be obtained. Multiple areas of hemorrhagic infarction suggest emboli. Tumor, demyelination, leukoencephalopathy, and evidence of trauma are best detected using MRI. Diffusion-weighted MRI can be similar in leukoencephalopathy and arterial ischemic stroke. However, in leukoencephalopathy the changes may not be confined to specific vascular territories (07); abnormalities can be present in subcortical or deep periventricular white matter, corpus callosum, cortex, cerebellum, and thalamus (78; 34). Diffusion-weighted imaging changes may represent reversible cerebral dysfunction with associated cytotoxic edema and metabolic derangement rather than ischemic structural injury (78). Transient abnormalities have been described on MRI with both migraine and seizures. Longitudinal follow-up of a case of prolonged hemiplegic attack using MRI, DWI, MR spectroscopy, and single-photon emission computed tomography (SPECT) provided supportive evidence for primary neuronal dysfunction (92). The MRI revealed progressive signal alterations in the hemisphere affected. The magnetic resonance spectroscopy demonstrated neuronal loss (decreased N-acetylaspartate) without cerebral ischemia, and single photon emission computed tomography (SPECT) exhibited reversible impairment of neuronal function.

MRA is probably equivalent to standard angiography for carotid and middle cerebral artery angiopathies, but it is less sensitive for small vessel disease and distal angiopathy (13). In some cases, cerebral angiography may be required to better delineate suspected arterial dissection, moyamoya disease, fibromuscular dysplasia, or vasculitis (77). MRA can actually overestimate the length and severity of stenosis. MRA can also identify aneurysms larger than 3 mm. A 3-D CT angiography may have value in the evaluation of arterial ischemic stroke and arteriopathies, but the amount of radiation is relatively high, and its utility in pediatric cases is not well studied. Abnormal cerebral angiography is the primary diagnostic feature of reversible vasoconstriction syndrome. Smooth, tapered narrowing followed by dilated segments of second and third order of cerebral arteries, resulting in a “sausage on a string” appearance, is the most characteristic abnormality (64).

Electroencephalography (EEG). EEG distinguishes between an ictal and postictal basis for hemiplegia. In moyamoya disease, hyperventilation can produce bursts of high-amplitude delta. Following cessation of hyperventilation, the delta activity can resolve and spontaneously recur, called "re-build up phenomenon" (52). Prolonged video EEG monitoring may be high yield in arterial ischemic stroke, cerebral venous sinus thrombosis, or hemiplegic stroke as the reported incidence of non-convulsive seizures, including status epilepticus, in those who presented with seizure at the time of stroke ranges from 14% to 23% (01; 83).

Complete blood count is required to evaluate for infection and hematologic disorders. Blood cultures are necessary for diagnosing bacterial endocarditis. Erythrocyte sedimentation rate, prothrombin time, and partial thromboplastin time may also suggest an etiology in some cases. Serum chemistries may help distinguish neurologic complications of hyperglycemia or hypoglycemia from stroke, whereas urine drug screen for cocaine and amphetamines may identify a toxicological cause of stroke. Routine urinalysis provides information about possible renal disease and dehydration. Pregnancy tests should be performed in adolescent females. When embolic disease is suspected, chest x-ray and echocardiography are essential to evaluate for possible cardiac disease. Cardiac rhythm monitoring can identify arrhythmias as a source of emboli. When an acute or chronic meningitis or encephalitis is suspected, lumbar puncture is indicated. Children without evidence to suggest common causes of hemiplegia should undergo more extensive evaluation, such as a search for underlying prothrombotic state (49). A genetic workup should be undertaken in cases with familial hemiplegic migraine and alternating hemiplegia of childhood. Metabolic stroke is usually the result of metabolic defects that cause energy failure and intoxication. Serum and cerebrospinal fluid lactate is usually elevated in mitochondrial disorders. Serum amino acids and urine organic acids are helpful at the time of clinical deterioration. Genetic testing for common mitochondrial mutations and measurement of respiratory chain activities in muscle are required to establish the diagnosis of mitochondrial encephalomyopathies (10).

Prevention

Risk factors for stroke in children differ significantly from those in adults. Widespread vaccination against Haemophilus influenzae and Streptococcus pneumoniae has decreased the incidence of bacterial meningitis and its complications, including stroke. Similarly, vaccination against varicella may have decreased the frequency of post-varicella focal cerebral arteriopathy. Children with metabolic and genetic disorders underlying stroke may benefit from treatment of their underlying condition, including possible gene therapy. Medication management to prevent migraine and seizure presumably decreases the frequency of hemiplegic migraine and Todd paralysis. Primary prevention for stroke in children has been accomplished in sickle cell disease and intracardiac thrombus. Blood transfusion therapy decreases recurrence risk in sickle cell disease and anticoagulation or surgery prevents stroke in children with intracardiac thrombus. Aside from these high-risk situations, stroke prevention has not been achieved in pediatric patients. It is important to establish healthy behaviors in childhood to reduce the risk of obesity and sedentary lifestyle (32).

Management

Management depends on the cause of hemiplegia and differs significantly after stroke, hemorrhage, epilepsy, migraine, and infection as well as demyelinating, metabolic disease and genetic disease.

Stroke. Several consensus guidelines for the management of different types of stroke have been published. Treatment of hypertension, hypotension, fever, hyperglycemia, and seizures is essential. Decompressive hemicraniectomy should be considered for large strokes associated with mass effect and deterioration of consciousness (85). Early heparinization is reasonable pending evaluation for the cause of the stroke because the likelihood of arterial dissection, undiagnosed cardiac disease, and coagulopathy is fairly high in children. Once these etiologies are ruled out, anticoagulation can be stopped and aspirin substituted for secondary stroke prevention. The duration of aspirin therapy depends on the underlying condition. Most children are treated for 2 years to cover the time window when the vast majority of recurrent strokes occur. If arterial ischemic stroke is due to cardiac embolism, extracranial arterial dissection, or hypercoagulable state, long-term anticoagulation is recommended. In sickle cell disease, acute exchange transfusion followed by long-term transfusion therapy is standard care. Revascularization surgery is recommended for moyamoya disease if symptoms of ischemia increase or if cerebral perfusion is compromised (77). With strokes due to cerebral venous sinus thrombosis, the precipitating illness and seizures and elevated intracranial pressure, if present, require treatment (77). Anticoagulation both acutely and chronically is recommended (3 to 6 months) (66; 77), particularly given the fact that thrombus propagation may occur in over one third of untreated children (65). Treatment of stroke due to genetic and metabolic conditions varies by disorder (77).

Arterial recanalization therapy, including intravenous tissue type plasminogen activator (tPA) and intraarterial tPA or endovascular thrombectomy for childhood arterial ischemic stroke, remains controversial. They can be used in children with persistent disabling neurologic deficits (pediatric NIH score ≥ 6 at the time of intervention), radiographically confirmed cerebral large artery occlusion, and larger children. Treatment decision should be made with neurologists and endovascular surgeons with experience in treating children (32).

Traditional rehabilitation is appropriate for hemiplegia of any cause. Both unimanual constraint therapy and bimanual therapy have been adapted for children and appear to improve function of the hemiparetic hand (42). Motor imagery training appears to enhance recovery of hemiplegia (86). The use of daily inhibitory, low frequency, repetitive transcranial magnetic stimulation to the unaffected M1 region may improve motor function in children with chronic subcortical arterial ischemic stroke by rebalancing cortical inhibition of the contralateral motor cortex (50).

Hemorrhage. In the acute setting, children with cerebral hemorrhage should be stabilized medically. Surgical or endovascular intervention may be indicated in cases of large hemorrhage and arteriovenous malformations or aneurysm (09).

Seizures. Appropriate EEG monitoring and choice of antiepileptic medication therapy is crucial to seizure control.

Alternating hemiplegia of childhood. Flunarizine, a calcium channel blocker, has been shown to reduce duration, severity, and frequency of episodes of alternating hemiplegia, but has no abortive effects (63). Theoretically, flunarizine works because alternating hemiplegia is a channelopathy involving CACNA1A and ATP1A2 (20). However, flunarizine has not been shown to have a significant effect on the overall developmental outcome. Glutamate and N-methyl-D-aspartate (NMDA) receptors are thought to also be involved in the induction of attacks. Amantadine, an NMDA receptor antagonist, and topiramate are drugs that modulate ion channels and inhibit non-NMDA excitatory neurotransmission, and have been investigated as add-on agents (20). Seizures are a rare side effect of amantadine (87).

Hemiplegic migraine. Flunarizine, valproate, and steroids have been used to treat prolonged auras acutely (96). Intranasal ketamine has been used to treat hemiplegic aura (48). Calcium channel blockers and valproate are the most commonly used as preventative agents in hemiplegic migraine (96; 74). Beta blockers and triptans should be avoided (51; 41).

Demyelinating disorders. Acute disseminated encephalomyelitis generally responds to treatment with corticosteroids or intravenous immunoglobulins (22). Plasma exchange is suggested in cases who fail to respond steroids and intravenous immunoglobulins.

Conversion disorder. Physical therapy is an important part of treatment for conversion paralysis along with appropriate pharmacotherapy and psychotherapy to address the related psychological stressors and any comorbid psychiatric disorder (eg, depression, anxiety) (70).

Reversible cerebral vasoconstriction syndrome. There is no established therapy for RCVS. Most patients fully recover with time. It is reasonable to admit patients for observation, pain control, and supportive care. Calcium channel blockers such as nimodipine and verapamil, serotonin antagonists, dantrolene, and brief courses of magnesium sulfate have been helpful in some studies (29).

Posterior reversible encephalopathy syndrome. PRES should be promptly recognized because it is usually reversible with appropriate treatment. Gradual blood pressure lowering will often improve the patients dramatically. Overaggressive blood pressure lowering can lead to complications. Seizures are treated with antiseizure drugs. Reduction drug dose or prompt removal of the cytotoxic or immunosuppressive drug is recommended (35).

Pregnancy

Pregnancy is by definition a proinflammatory and hypercoagulable state. Postnatal infection, migraine, thrombophilias, lupus, heart disease, preeclampsia, smoking, obesity, older age, bed rest more than 4 days, and surgical delivery are specific risk factors (33). Migraine frequency can increase or decrease during pregnancy; and migraine can also increase the risk of stroke during pregnancy (17). Seizure control can be an issue during pregnancy.

Anesthesia

Specific anesthetic management is required in children who are at high risk for stroke due to moyamoya (08) or sickle cell disease (61).

Outcomes

There are no clinical trials evaluating the best treatment for childhood arterial ischemic stroke (anticoagulant or antiplatelet medication). It is well known that absence of antithrombotic therapy increases the risk of recurrent stroke by 1.5- to 2-fold. The use of anticoagulation is relatively safe in children with arterial ischemic stroke, with a 4% risk of intracerebral hemorrhage. Safety and efficacy data for hyperacute stroke therapies in children are lacking. Hemicraniectomy is a potentially lifesaving option in children with large supratentorial stroke. Decompressive craniotomy results in decreased mortality and improved outcomes in patients with large cerebellar infarctions (32). Flunarizine is associated with more than 50% reduction in attack frequency in 85% of pediatric hemiplegic migraine (74). Flunarizine can also reduce severity, frequency, and duration of dystonic and hemiplegic attacks in acute hemiplegia in childhood. The effect of flunarizine on long-term prognosis of disease is unknown (76). There is no proven therapy for RCVS and PRES. The clinical outcome is benign in 90% of cases with supportive care. Most patients with demyelinating disorder of central nervous system make a full but slow recovery with steroids over 4 to 6 weeks.