Pathogenesis of Spastic Cerebral Palsy

Spastic CP is the most common subtype of cerebral palsy. Spastic diplegia and spastic quadriplegia affect approximately 60% of patients, but spasticity may also occur with dyskinesia or ataxia, or both, in mixed subtypes of CP. Thus, in total, spasticity afflicts 80% to 90% of all patients with CP.^3,4 A distinctive epidemiologic feature of spastic CP—and spastic diplegia in particular—is its correlation with premature birth and low birth weight.^5–7 This relationship does not exist with other subtypes of the disease, such as athetoid or dyskinetic CP.

Periventricular leukomalacia (PVL) is the most common finding on brain magnetic resonance imaging (MRI) in children with spastic CP.^8,9 Histologically, PVL is characterized by ischemic necrosis of the periventricular and subcortical white matter (Fig. 227-1), areas that are predisposed to hypoperfusion during hypotension.¹⁰ Reperfusion injury resulting from oxygen free radicals, cytokines, and excitatory amino acids such as glutamate probably mediate PVL.¹⁰ The high incidence of spastic diplegia in infants with PVL has led many to speculate that PVL is the neuropathologic basis for spastic CP.¹¹ The neurological deficits in spastic CP may be explained in part by the topographic arrangements of projection fibers descending from the motor homunculus in the white matter. As seen in Figure 227-2, the leg fibers traverse the white matter closer to the ventricle than the arm fibers do. Thus, PVL is more likely to injure the leg fibers and spare the arm fibers. However, extensive leukomalacia will also injure other projection fibers and result in spastic quadriplegic CP.

FIGURE 227-1 Coronal section of the brain showing periventricular leukomalacia with markedly reduced white matter adjacent to the posterior lateral ventricle. A subcortical infarct is also seen.

FIGURE 227-2 Schematic drawing of projection fibers from the motor cortex in relation to the lateral ventricle. The topographic arrangement of the descending motor tracts, with the leg fibers located medially, explains the high incidence of spastic diplegia in the setting of periventricular leukomalacia.

Spinal cord ventral horn alpha motor neuron output is a primary determinant of muscle tone. The activity of alpha motor neurons is modulated by excitatory influences (e.g., Ia fibers from muscle spindles, descending input from the corticospinal and reticulospinal pathways) and inhibitory influences (e.g., descending GABAergic [γ-aminobutyric acid] pathways from the cerebellum and basal ganglia). Although the neural pathways involved in CP spasticity remain speculative, it is believed that spasticity results from an imbalance in these excitatory and inhibitory influences that creates hyperactive alpha and gamma neurons with exaggerated stretch reflex activity compounded by loss of inhibitory control (reviewed by Koman and colleagues¹²). Thus, excessive alpha motor neuron activity of the target muscles, coupled with decreased inhibition of antagonistic muscles, results in the co-contraction of agonist and antagonist muscle groups.¹³ Clinically, this results in a velocity-dependent, increased resistance to passive stretch.¹²

Deleterious Effects of Cerebral Palsy Spasticity

CP spasticity has harmful, long-term effects on growing children and thus requires optimal treatment at an early age. When untreated, inhibition of motor activity and limitation of voluntary movement result in decreased muscle and bone development, which ultimately causes deformities of the affected extremities.¹⁴ Long-lasting improvements in motor function are observed after SDR, thus supporting the argument for early intervention in the disease.¹⁵ Indeed, the spasticity-induced inhibition of motor activities does not abate if the spasticity is left untreated. Normally, longitudinal muscle growth proceeds as new myofilaments and sarcomeres are added to the ends of the muscle fibers.¹⁶ The greatest increase in sarcomere numbers occurs at an early age, with the increase taking place much more actively during development than after maturation. In parallel with the addition of sarcomeres, longitudinal muscle growth occurs rapidly during development. The increase in sarcomere number is not under neural control but is induced mainly by the amount of tension that the muscle is subjected to (i.e., repeated muscle stretch).^17,18 Thus, when muscles are immobilized, there is a rapid decrease in the number of already existing sarcomeres, as well as a decrease in the number of new sarcomeres that should increase with normal development.¹⁹ Because CP spasticity in developing children limits muscle stretch in daily activities, it could cause loss of sarcomeres and inhibition of longitudinal muscle growth. In fact, the effect of spasticity on muscle growth was clearly shown in an experimental study in which longitudinal muscle growth was reduced by 45% in spastic mice as compared with control animals.²⁰ The loss of sarcomeres accompanies a significant decrease in elasticity in the muscles²¹ and makes them resistant to passive stretch.²² Additionally, atrophy of type I and II muscle fibers compounds the slowed muscle growth.²³ Recent work has implicated both shorter muscle (decreased sarcomere length, myocyte length, and fascicle length)²⁴ and an increased extracellular elastic modulus²⁵ in the clinical finding of stiffness. These pathologic events in the muscle cells cause abnormally shortened muscles, long tendons, and muscle contracture (i.e., increased resistance of the muscle to passive stretch in the absence of muscle contraction).^22,26,27 The muscle contractures typically worsen as a child grows²⁶ and produce various bone and joint deformities in the extremities.¹⁴

Treatment of Spastic Cerebral Palsy

Spasticity is commonly treated with oral medications, including the GABA_B receptor agonist baclofen (Lioresal), benzodiazepines such as diazepam (Valium), the anticholinergic trihexyphenidyl, dantrolene, and tizanidine (Zanaflex).^28,29 In general, oral medications are moderately effective in treating spasticity but frequently have significant adverse effects (sedation, confusion, dependence).

Intramuscular injections of alcohol and phenol for chemodenervation have been performed for many years. The introduction of intramuscular injection of Botox was a major advance in the treatment of CP spasticity, with predictable benefits and fewer adverse effects.²⁹ Botox is injected directly into the affected muscle, and relaxation is generally seen within several days. Maximal benefit occurs approximately 4 weeks following injection, after which the effect declines and repeated injection is required in approximately 3 to 4 months.