• Pathophysiology
• CNS disorders
• Treatment
• Pharmacotherapy
• Baclofen
• Diazepam
• Tizanidine
• Clonidine
• Dantrolene sodium
• Gabapentin
• Botulinum toxin
• 4-Aminopyridine
• Intrathecal baclofen
• Antiepileptic drugs
• Epilepsy and antispasticity drugs
• Central surgery procedures
• Peripheral surgery procedures
• References

The muscle spindle consists of several bundles of intrafusal muscle fibers surrounded by a connective tissue capsule. It represents the most complex sensory structure of the muscle and conveys information about muscle length. The central part of this specialized structure is composed of a noncontractile nuclear bag region. Spindles lie in parallel with extrafusal fibers, large muscle fibers that effect gross movement. Stretching the noncontractile bag region, or stretching the extrafusal fibers, constitutes the mechanical stimulus to fire the primary afferent or group Ia fiber. Group Ia afferents from the muscle spindle make synaptic contact with the cells of the dorsal nucleus of the spinal cord and with alpha motor neurons. Shortening of the extrafusal muscle fibers shortens the spindle and silences the Ia afferents. The intrafusal muscle fibers of the spindle complex are innervated by gamma motor neurons in the anterior horns of the spinal cord, which increase the tension of the intrafusal fiber when it is shortened. This resets the spindle after shortening, so that it is again sensitive to changes in muscle length.3

When the muscle is lengthened by tendon tap or stretch, Ia afferents produce excitatory postsynaptic potentials on agonist motoneurons. Although this monosynaptic connection plays a role in the reflex, most excitatory activity in the stretch reflex is mediated by oligosynaptic and polysynaptic pathways.2 Interneurons play a major role in the reflex arc. Antagonist muscle spindles also send Ia afferents to produce excitatory postsynaptic potentials on agonist inhibitory interneurons, which then evoke inhibitory postsynaptic potentials on motoneurons. The firing of the motoneuron depends on the summation of excitatory and inhibitory postsynaptic potentials. Additional inhibitory interneurons act on Ia afferents to inhibit the afferent signal presynaptically. Gamma-aminobutyric acid (GABA) is the neurotransmitter mediating this selective presynaptic inhibition.4

The spinal segmental reflexes require the participation of muscle spindles, fusimotor innervation (gamma motor neurons), Ia primary afferents, and alpha motor neurons, as well as Renshaw recurrent inhibition, disynaptic reciprocal inhibition, nonreciprocal autogenic Ib inhibition, presynaptic inhibition, and remote inhibition-excitation of alpha motor neurons.2 Spasticity results from prolonged disinhibition of components of this system, but the exact mechanism remains unclear.

Adapted from: Bassi V, Kita M, Feldman DS, and Devinsky O. Spasticity. In: Devinsky O and Westbrook LE, eds. Epilepsy and Developmental Disabilities. Boston: Butterworth-Heinemann; 2001;231–247.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised May 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Spasticity is a classic feature of cerebral palsy (CP), a persistent but dynamic disorder of movement and posture. CP is a symptom complex, not a specific disease. It results from brain lesions or anomalies arising in early development,8 including:

• in utero brain malformations or hemorrhagic-ischemic insults
• perinatal insults
• postnatal insults (e.g., meningitis, trauma, ischemia) before age 5 years9
• CP is more likely to result from antepartum causes than from birth asphyxia.10–13

CP is classified on the basis of the extremities affected (monoplegic, diplegic, triplegic, hemiplegic, and quadriplegic) and the predominant movement abnormality, including:

• Spasticity, which occurs in about two-thirds of CP patients and typically affects the lower more than the upper extremities. In the legs, flexors, adductors, and internal rotators are more prominently involved than are their antagonists.



• Dystonia, which occurs in 15–25% of patients with CP and begins at 3–5 years of age or older.14 It is characterized by sustained muscle contractions that result in twisting and repetitive movements or abnormal postures. Dystonia persists throughout life but, because it causes continuous motion, it rarely causes contractions or deformities (e.g., scoliosis).8



• Athetosis, which occurs in about 25% of CP patients, usually owing to basal ganglia injury in the full-term brain.15 It is a nonrhythmic, involuntary movement of the limbs, trunk, or vocal muscles, producing dysarthrias.



• Chorea, which is characterized by involuntary, abrupt, rapid, brief, unsustained, irregular movements. Choreiform movements in CP usually develop at between 3 and 5 years of age.8



• Ataxia



• Hypotonia



• Mixed forms

Dystonia, athetosis, and chorea are hyperkinetic movement disorders, also known as dyskinetic movements. In contrast, spasticity is a hypertonic but isokinetic movement disorder.

Epilepsy in patients with cerebral palsy

Epilepsy is commonly associated with CP and can further impair the individual’s quality of life. The risk of epilepsy varies in different subtypes of CP, being most frequent in quadriplegics (50%) and least frequent in diplegic patients (27%).16,17 Therefore, epilepsy is likely related to the type of brain lesion. The relationship between epilepsy and a specific type of brain lesion is not fully understood.

The percentage of CP patients with epilepsy and the time course for development of epilepsy differ according to the type of brain lesion. Okumura and colleagues18 studied the relationship between epilepsy in the first 5 years of life in patients with CP and the type of brain lesions found on magnetic resonance imaging (MRI). Of 130 patients, 14 had congenital anomaly and 116 had perinatal injury. Overall, 37 (31%) of the 130 patients had epilepsy, similar to other studies, in which epilepsy incidence ranges from 25% to 45%.16–19

Partial seizures occurred in 12 patients, infantile spasms in 20, and generalized seizures in 5. Patients with congenital anomaly had a significantly higher incidence and an earlier age of onset of epilepsy than those with perinatal injury. Among perinatal injury patients, those with term injury (with or without preterm injury) showed a higher incidence and a later onset of epilepsy than those with only preterm injury.18

Multiple sclerosis (MS)

Spasticity is a classic feature of MS, the most common demyelinating disease. MS is characterized by the dissemination of demyelinating events in time and space. After demyelination occurs, destroyed myelin is phagocytosed by macrophages, and gliosis ensues. In most patients, the course is characterized by exacerbations and remissions, but a pattern of steady or stepwise progression can occur.

In MS, spasticity results from plaques of demyelination in the upper motor neuron fibers (i.e., pyramidal tract) in the brain or spinal cord.4

Spinal cord seizures

Paroxysmal neurologic disturbances of spinal cord origin, so-called spinal cord seizures, can also result from demyelinating lesions and can be difficult to distinguish from spasticity. They have also been associated with intravenous dye placement, transverse myelitis, and traumatic spinal cord injury.5

These seizures are characterized by tonic spasm in the extremities, often accompanied by painful dysesthesia. They are transient, usually lasting no more than 2 minutes. They may occur spontaneously, but commonly are precipitated by tactile stimulation or movement of the extremity.

Clinical differentiation from spasticity is critical, because these seizures may respond to antiepileptic drugs such as carbamazepine.6 These seizures may limit the rehabilitation of patients with idiopathic transverse myelopathy unless they are recognized and appropriate drug therapy is initiated.7

Adapted from: Bassi V, Kita M, Feldman DS, and Devinsky O. Spasticity. In: Devinsky O and Westbrook LE, eds. Epilepsy and Developmental Disabilities. Boston: Butterworth-Heinemann; 2001;231–247.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised May 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Direct effects of muscle relaxation from physiotherapy often are short-lived and, for many patients, these conservative measures alone are insufficient to treat their symptoms. Most patients experience symptomatic improvement with physiotherapy in combination with one or more antispasticity agents.

Patients also should be evaluated for adaptive equipment such as ambulatory aids, reachers, and other devices and should be instructed in the appropriate use of these tools.

Patients whose condition is inadequately controlled by physical therapy and medication may respond to a variety of neurosurgical procedures, both central and peripheral. A practitioner’s understanding of the mechanisms of these therapies should aid in developing individualized regimens for patients.

Adapted from: Bassi V, Kita M, Feldman DS, and Devinsky O. Spasticity. In: Devinsky O and Westbrook LE, eds. Epilepsy and Developmental Disabilities. Boston: Butterworth-Heinemann; 2001;231–247.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised May 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Adapted from: Bassi V, Kita M, Feldman DS, and Devinsky O. Spasticity. In: Devinsky O and Westbrook LE, eds. Epilepsy and Developmental Disabilities. Boston: Butterworth-Heinemann; 2001;231–247. With permission from Elsevier (www.elsevier.com).

Reviewed and revised May 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Baclofen (Lioresal) is a structural analog of GABA and inhibits monosynaptic and polysynaptic spinal reflexes. It binds the GABA(B) receptor, which is coupled to calcium and potassium channels and occurs both pre- and postsynaptically:20

• Presynaptic binding hyperpolarizes the membrane, restricting calcium influx into presynaptic terminals and thereby decreasing neurotransmitter release in excitatory spinal pathways and decreasing alpha motor neuron activity.21
• Postsynaptic binding on the Ia afferent terminal increases potassium conductance and hyperpolarizes the membrane, thus enhancing presynaptic inhibition.

Activation of GABA(B) receptors may also inhibit gamma motor neuron activity and decrease muscle spindle sensitivity.22,23

Clinical findings

Studies in people with multiple sclerosis have found that baclofen effectively reduces spasticity, decreasing frequency and severity of sudden painful spasms and improving range of joint movement.24–26 Increased weakness was commonly reported, however.

In patients with spinal cord lesions, baclofen is very helpful in reducing flexor spasms.

For stroke patients, baclofen is less beneficial.27,28 Such patients often had a modest decrease in muscle tone that was interpreted subjectively as slightly reduced stiffness. No effect was noted on hyperreflexia or clonus.23,28

Diazepam is often used as an adjunct to baclofen in treating spasticity.

Pharmacokinetics and dosage

Baclofen is rapidly absorbed after oral administration, but central nervous system penetration is relatively limited. The mean half-life is short, averaging 3.5 hours. Because it is partially metabolized by the liver (15%) and excreted by the kidney, the dose should be decreased in patients with hepatic or renal impairment.

Doses often are initiated at 5 mg daily, increasing to three times daily as tolerated. Thereafter, doses can be increased slowly at increments of 5 mg per day as needed. It may be helpful to initiate doses and increases at night to minimize side effects. The highest recommended dosage is 80 mg daily in divided doses. For some patients, this dose may be insufficient to relieve symptoms. Higher doses may be attempted cautiously, as side effects are likely to be more prominent.23

Side effects

Side effects are related mainly to central nervous system depression and include:

• drowsiness
• fatigue
• weakness
• dizziness
• nausea

Early clinical studies suggested that baclofen might be a proconvulsant and could exacerbate epilepsy. However, two prospective studies found that baclofen neither increased seizure frequency in epilepsy patients109 nor provoked paroxysmal activity on electroencephalography.110 Therefore baclofen is not contraindicated in epilepsy patients, but it should be tapered gradually. Baclofen may suppress epileptiform activity in the hippocampus at concentrations below those that suppress normal synaptic transmission. Several reports suggest that baclofen may reduce myoclonus in epilepsy patients.111–113

Abrupt cessation of sustained treatment should be avoided, because sudden withdrawal of baclofen may cause hallucinations, psychosis, visual disturbances, and seizures.29,30

Intrathecal baclofen

Paients with severe limitations who are not helped by other therapies may respond to baclofen infused directly into the intrathecal space. (See Another option: Intrathecal baclofen.)

Adapted from: Bassi V, Kita M, Feldman DS, and Devinsky O. Spasticity. In: Devinsky O and Westbrook LE, eds. Epilepsy and Developmental Disabilities. Boston: Butterworth-Heinemann; 2001;231–247. With permission from Elsevier (www.elsevier.com).

Reviewed and revised May 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Benzodiazepines like diazepam (Valium) act by coupling to the benzodiazepine–GABA(A) receptor–chloride ionophore complex.31 Binding of benzodiazepine to the GABA(A) receptor increases chloride conductance, resulting in presynaptic inhibition in the spinal cord.32,33

Clinical findings

Diazepam is the most commonly used benzodiazepine in the treatment of spasticity, having efficacy in patients with spinal cord injury, hemiplegia, and multiple sclerosis (MS).34–37 It frequently is used as an adjunct to baclofen in treating spasticity.41 Diazepam is less commonly used as a single agent.

From and Heltberg38 studied 17 patients with MS in a double-blind crossover trial with baclofen and diazepam. Each patient received 4 weeks of therapy with each drug. No differences were seen in efficacy of reducing spasticity, clonus, and flexor spasms or improving gait or bladder function. Side effect profiles differed slightly, with more patients reporting sedation while on diazepam, but the severity of side effects was similar in both groups. When patients still masked to treatment assignment were asked which agent they preferred, baclofen was significantly favored.38

Other studies confirmed comparable antispasticity effects of baclofen and diazepam in reducing muscle tone and frequency of spasms, but baclofen was not necessarily favored over diazepam by these patients.39,40

Pharmacokinetics and dosage

Diazepam is well absorbed orally and reaches a peak level in approximately 1 hour. It is 98% protein-bound and is metabolized by the liver to active compounds nordiazepam and oxazepam. Total half-life can range between 20 and 80 hours.

Doses may be initiated at 2 mg twice daily and may be increased as needed to a desired effect. Alternatively, single 5-mg doses at night may be effective for nocturnal symptoms. In patients with hepatic dysfunction, doses should be titrated carefully.

Side effects

Side effects include sedation and cognitive impairment, and there is a potential for dependence. The benzodiazepine withdrawal syndrome is characterized by anxiety, dysphoria, tremor, and sympathetic activation.

Seizures can occur in susceptible patients (i.e., those with a low seizure threshold) or in those who undergo rapid withdrawal after chronic use.23

Adapted from: Bassi V, Kita M, Feldman DS, and Devinsky O. Spasticity. In: Devinsky O and Westbrook LE, eds. Epilepsy and Developmental Disabilities. Boston: Butterworth-Heinemann; 2001;231–247.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised May 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Tizanidine has potent muscle-relaxing properties in animal models of spasticity42 and, in spine-transected cats, suppresses polysynaptic reflexes.43,44

Tizanidine also enhances vibratory inhibition of the H-reflex in humans and reduces abnormal co-contraction, which may partly contribute to its antispasticity effects.45

Clinical findings

In placebo-controlled trials, tizanidine reduces muscle tone and frequency of muscle spasms in patients with multiple sclerosis (MS) and spinal cord injury.46–48 Similar efficacy was found in open-label trials for stroke patients.49

In MS, tizanidine reduced spasticity without altering muscle strength, but no consistent positive effect was noted on functional measures (e.g., timed ambulation, upper-extremity function, or movements necessary in activities of daily living).46

When compared to baclofen or diazepam in early trials, tizanidine demonstrated similar efficacy and better tolerability.44,47,50–57 No controlled trials have investigated tizanidine in combination with baclofen or tizanidine therapy in patients with cerebral palsy or developmental delay.

Pharmacokinetics and dosage

Tizanidine undergoes first-pass hepatic metabolism and subsequently is eliminated by the kidney. Its half-life is approximately 2.5 hours, and peak effect is seen 1 to 2 hours after dosage.

Doses are initiated at 2–4 mg daily and are increased every 3 days by 2–4 mg. Total dose should not exceed 36 mg per day in three divided doses. Little experience has been reported with single doses greater than 8 mg.

Side effects

Side effects—including dry mouth (45%), drowsiness (54%), and dizziness—are seen primarily when doses exceed 24 mg per day. Visual hallucinations (3%) and elevated liver function tests (5%) are reversible with dose reduction.46 Liver function tests should be performed at baseline; months 1, 3, and 6 of treatment; and periodically thereafter.

Insomnia and weakness have been found to be more frequent with tizanidine than with baclofen.50

Tizanidine does not affect blood pressure but, because central alpha-adrenergic agonists may cause hypotension, concomitant use of antihypertensive agents should be monitored closely, and clonidine should be avoided.23

Adapted from: Bassi V, Kita M, Feldman DS, and Devinsky O. Spasticity. In: Devinsky O and Westbrook LE, eds. Epilepsy and Developmental Disabilities. Boston: Butterworth-Heinemann; 2001;231–247.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised May 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Clonidine is a centrally acting alpha-adrenergic agonist. Central alpha activation reduces sympathetic outflow. Clonidine decreases the vibratory inhibition index in spinal cord patients58 and reduces muscle tone in brain-injured patients (stroke, trauma, hematoma, CP).59

Clinical findings

Clonidine is used mainly to treat hypertension. It also can reduce symptoms of opiate withdrawal, impulsivity in children, and other behavioral problems. It can be effective as a supplement to baclofen60 but rarely is used alone to treat spasticity.

Dosage

Clonidine does not have FDA approval as an antispasticity drug. It is available in 0.1-mg tablets, the usual starting dose. The usual dose for hypertension is 0.2 to 0.6 mg per day.

The Catapres patch (0.1 mg and 0.2 mg) is designed to deliver the specified dose daily and must be changed every 7 days.

Side effects

Side effects include bradycardia, hypotension, dry mouth, drowsiness, constipation, dizziness, and depression.23

Adapted from: Bassi V, Kita M, Feldman DS, and Devinsky O. Spasticity. In: Devinsky O and Westbrook LE, eds. Epilepsy and Developmental Disabilities. Boston: Butterworth-Heinemann; 2001;231–247.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised May 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Dantrolene sodium (Dantrium) is a hydantoin derivative. It acts directly on muscle contractile elements, decreasing the release of calcium from skeletal muscle sarcoplasmic reticulum and thereby interfering with the excitation-contraction coupling needed to contract muscles.61–63

The effect is most pronounced on extrafusal fibers, but a minor effect also is seen on intrafusal fibers. Whether this effect may alter spindle sensitivity is unclear.64

Dantrolene has a greater effect on fast-twitch fibers (those that produce rapid contraction and high tension but fatigue relatively easily) than on slow-twitch fibers (those that contract tonically, producing less tension, but are more resistant to fatigue).65

Clinical findings

Placebo-controlled trials of dantrolene demonstrated significant reduction of muscle tone and hyperreflexia.63,66–68 In a double-blind crossover design in 42 patients with multiple sclerosis (MS), both dantrolene and diazepam decreased spasticity, clonus, hyperreflexia, muscle stiffness, and cramping.69

In children with cerebral palsy70 and in patients with spasticity due to various cerebral and spinal disorders,71 studies found that spasticity was slightly better controlled and side effects more tolerable with dantrolene than with diazepam.

Pharmacokinetics and dosage

The half-life for oral dantrolene is approximately 15 hours, with peak concentrations occurring in 3 to 6 hours. It is metabolized mainly by the liver.

Dantrolene is initiated at 25 mg per day and should be increased slowly, in increments of 25 mg per day every 5 to 7 days. The recommended maximum dosage is 400 mg per day in divided doses.

Side effects

Because its site of action is peripheral, the most common side effect of dantrolene is weakness, the mechanism by which it mediates its antispasticity action. For this reason, dantrolene may be most appropriate for nonambulatory patients with severe spasticity. Other side effects include drowsiness, diarrhea, and malaise.

Hepatotoxicity—which can be irreversible—is the major concern with dantrolene sodium, so liver function tests should be evaluated before the initiation of therapy and every 3 months thereafter.23

Adapted from: Bassi V, Kita M, Feldman DS, and Devinsky O. Spasticity. In: Devinsky O and Westbrook LE, eds. Epilepsy and Developmental Disabilities. Boston: Butterworth-Heinemann; 2001;231–247.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised May 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Gabapentin (Neurontin) was first introduced in 1994 to treat partial epilepsy.72 It is structurally similar to GABA, possibly exerting GABA-ergic activity by binding to receptors in neocortex and hippocampus. However, it does not bind conventional GABA(A), GABA(B), glycine, glutamate, benzodiazepine, or N-methyl-D-aspartate (NMDA) receptors.73,74

Clinical findings

Preliminary reports suggested that gabapentin can reduce spasticity,75,76 but further studies are needed.23

Pharmacokinetics and dosage

It is well absorbed, reaching peak plasma concentrations in 2 to 3 hours, is not protein-bound, does not undergo metabolism, and is excreted unchanged in the urine.

Gabapentin is well tolerated in doses of 1,800 to 3,600 mg per day in divided doses.75

Side effects

For information about the side effects of gabapentin (Neurontin), please visit:

http://www.epilepsy.com/medications/p_neurontin_commonside.html

Adapted from: Bassi V, Kita M, Feldman DS, and Devinsky O. Spasticity. In: Devinsky O and Westbrook LE, eds. Epilepsy and Developmental Disabilities. Boston: Butterworth-Heinemann; 2001;231–247.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised May 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Botulinum toxin is a product of Clostridium botulinum, and ingestion of the organism or its spores results in botulism. Botulinum toxin blocks pre-synaptic release of acetylcholine from the nerve terminal. Seven immunologically distinct toxins (types A–G) have been purified. Local intramuscular injection of botulinum toxin A (Botox) was approved to treat strabismus and blepharospasm associated with dystonia. When injected, the agent spreads through muscle and fascia approximately 30 mm, binding presynaptic cholinergic nerve terminals and resulting in a chemical denervation. 23

Clinical findings

Botulinum toxin injection is off-label for treatment of spasticity, but it may be an appropriate option for selected patients with severe localized spasms. Injection effectively reduces muscle tone and spasms in patients with severe spasticity due to stroke, traumatic brain injury, and other causes.77–80

Botulinum toxin injection is promising therapy for the treatment of spasticity in children with cerebral palsy.82,83 Its judicious use can delay surgery until children reach a more suitable age.

In a randomized, crossover, double-blind study, Snow and colleagues81 studied botulinum toxin A in 9 wheelchair- or bed-bound patients with advanced multiple sclerosis (MS). Muscle tone, frequency of spasms, and hygiene and self-care scores were used to assess efficacy. Botulinum toxin injection significantly reduced spasticity and improved ease of nursing care, with no adverse effects.

Pharmacokinetics

Physicians who inject it should be trained in the use of Botox, with attention to relevant topical anatomy and kinesiology. Onset of focal muscle fiber paralysis begins in 24 to 72 hours, with a maximal effect seen at 5 to 14 days. The paralysis is transient, lasting 12 to 16 weeks.

To produce optimal effects, it may be necessary to localize specific muscles with electromyographic guidance.

Side effects

Injection site reactions can occur and antibodies may develop to specific immunologic strains, limiting efficacy.

Because the delivery of toxin is not entirely contained, the paralysis of muscles may not be exact. Excessive weakness (ultimately reversible) may result.23

Adapted from: Bassi V, Kita M, Feldman DS, and Devinsky O. Spasticity. In: Devinsky O and Westbrook LE, eds. Epilepsy and Developmental Disabilities. Boston: Butterworth-Heinemann; 2001;231–247.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised May 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

4-Aminopyridine (4-AP) is a voltage-gated, fast potassium channel blocker capable of improving axonal conduction by facilitating the propagation of action potentials in demyelinated nerve fibers.84

Clinical findings

Preclinical trials of orally administered 4-AP found transient improvements in neurologic function in patients with long-standing spinal cord injury.86 Administration of 4-AP led to marked and sustained reductions in upper- or lower-extremity spasticity due to cervical cord lesions. Other clinical benefits included:86

• reduced pain
• restored muscle strength
• improved sensation
• voluntary control of bowel function
• sustained penile tumescence
• improved hand function
• enhanced mobility in transfers and gait
• improved endurance and energy

Segal et al.84 studied long-term safety and efficacy of orally administrated, immediate-release 4-AP. They found that patients given 30 mg per day over a period of 3 months displayed improvement and recovery of sensory and motor function and diminished spasticity. (Patients receiving 6 mg per day did not benefit.)

Other investigations of 4-AP in patients with spinal cord injury report enhanced gait,87 improved motor control and sensory ability below the injury site, and reduction in chronic pain and spasticity.88

One study using intravenous 4-AP to treat pain and spasticity in spinal cord injury found that benefits did not outweigh adverse effects.89

Pharmacokinetics and dosage

4-AP is well absorbed and reaches peak concentrations in 2 to 4 hours.85

No recommended dosage has been set, since 4-AP is not approved by the U.S. Food and Drug Administration. A dosage of 10 mg two or three times daily has been used in studies.

Side effects

Oral 4-AP has been well tolerated during most studies.84 Side effects can include dizziness, nausea, restlessness and anxiety, paresthesias, abdominal pain, and obstipation.86

Experimental studies and clinical observations have documented epileptogenic effects. Application of 4-AP on hippocampal slices produced several patterns of epileptiform discharges and seizurelike events.90 In studies of 4-AP to treat spinal cord injury in rats, all animals that received a dose of 6 mg/kg had generalized seizures.7 New onset of seizures can complicate 4-AP therapy.91

Adapted from: Bassi V, Kita M, Feldman DS, and Devinsky O. Spasticity. In: Devinsky O and Westbrook LE, eds. Epilepsy and Developmental Disabilities. Boston: Butterworth-Heinemann; 2001;231–247.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised May 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Penn et al.92 conducted a double-blind, placebo-controlled 3-day crossover study in 20 patients—10 with MS and 10 with spinal cord injury. All patients had decreased muscle tone and frequency of spasms while being treated with baclofen. All patients were subsequently enrolled in a long-term open trial of continuous baclofen infusion, with a mean follow-up period of 19 months. Using a standardized scale to assess spasticity, these researchers found that all patients exhibited normal tone and that spasm frequency was diminished to the point that spasms no longer interfered with activities of daily living.93 In 7 of 8 patients, bladder function also improved.92

Other investigators have found equally dramatic results.94–96 Safety and efficacy on long-term follow-up was documented in patients for up to 84 months.97

Effect in cerebral palsy

In cerebral palsy (CP), intrathecal baclofen can effectively treat spasticity in two groups:

• Spastic diplegics or spastic quadriplegics who can ambulate with or without assistance but who have weak legs and use their spasticity to stand or walk. The ability to ambulate might be lost if spasticity were eliminated completely, but excessive spasticity limits ambulation because of underlying leg weakness. The goal of treatment for these patients is to allow them to walk with less effort.



• Nonambulatory patients with quadriplegia and severe spasticity. The goal of treatment is to facilitate their care and relieve discomfort.98

The efficacy and tolerability of continuous intrathecal infusion of baclofen can be tested by administering a trial bolus of baclofen by intrathecal injection.99,100 In studies of CP patients, intrathecal baclofen injections in the 25- to 100-µg range led to significant reductions in muscle tone within 2 hours. The effects persisted for 6 hours. Long-term follow-up in CP patients revealed that spasticity remains almost 50% improved after more than 3 years of continuous intrathecal baclofen therapy.101

Dosage

After a patient undergoes a trial of intrathecal baclofen to establish responsiveness, pump implantation can be considered. Starting doses are 25 µg per day, up to an average of 400–500 µg per day, although doses as high as 1,500 µg per day have been reported.105 The half-life of intrathecal baclofen is approximately 5 hours. Many patients require dose increases in the first 6 months, owing to tolerance.106,107

Side effects and complications

Most side effects tend to occur during the titration phase. They include drowsiness, headache, nausea, weakness, and hypotension. Overdose can produce reversible coma.108

Other complications may be due to mechanical problems (dislodgment, disconnection, kinking, blockage), pump failure, or infection.

Effect on dystonia

Intrathecal baclofen may improve medically refractory dystonia. Continuous intrathecal baclofen infusion was used with modest success in a case of hereditary generalized dystonia refractory to multiple medications and thalamotomy.102 After pump implantation, baclofen dosage was gradually increased to 450 µg per day. The patient displayed significant improvement on the right side of her body and moderate improvement on the left side.

On an average daily dose of 575 µg per day of intrathecal baclofen, 10 of 12 patients with generalized dystonia had significant reduction in scores for overall dystonia and dystonia in the extremities, trunk, and cervical regions.103 One-year follow-up studies of dystonic patients support the long-term efficacy of intrathecal baclofen for dystonia.104

Adapted from: Bassi V, Kita M, Feldman DS, and Devinsky O. Spasticity. In: Devinsky O and Westbrook LE, eds. Epilepsy and Developmental Disabilities. Boston: Butterworth-Heinemann; 2001;231–247.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised May 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

In therapeutic doses, antiepileptic drugs (AEDs) do not worsen spasticity. Several (in addition to gabapentin, covered elsewhere) have been shown to reduce spasticity, sometimes in combination with other medications:

Phenytoin

Phenytoin (Dilantin, Phenytek) and chlorpromazine (Thorazine) were preliminarily investigated in open and controlled studies to treat spasticity. In both types of studies, most patients exhibited both objective and subjective improvement with each drug.114 Tone was reduced in spastic muscles, and functional status was improved. (Phenytoin toxicity can worsen spasticity, however.115) The combination of phenytoin and chlorpromazine was most effective. Lethargy and somnolence were the most common side effects.

These drugs may exert their action by suppressing fusimotor efferent and afferent discharges from muscle spindles.113

Tiagabine

Tiagabine (Gabitril), a GABA uptake inhibitor developed as an AED, may reduce spasticity. In an open-label study, 14 children with congenital or acquired spastic quadriplegia and intractable epilepsy were treated with tiagabine. The dosage gradually was titrated upward until seizures ceased, adverse effects supervened, or the maximum dose of 1.1 mg/kg daily was reached. The mean improvement in motor function was approximately 50%. Other findings included improved muscle tone, strength, coordination, range of motion, and relaxation of extremities, with less ataxia and wobbling.116

Valproate

In one patient, baclofen and sodium valproate (Depakote, Depakene) were used successfully to relieve writer’s cramp. Writer’s cramp may result from striatal dopaminergic hyperactivity. Both sodium valproate and baclofen can increase GABA-ergic activity.117 The two drugs may act synergistically to reduce activity in the nigrostriatal dopaminergic pathway and inhibit release of dopamine in the striatum.118

Carbamazepine

Combined therapy with baclofen and carbamazepine (Tegretol, Carbatrol) can reduce spasticity and improve muscle tone, range of motion, and coordination in patients with brainstem and other supraspinal injuries.119

Oxcarbazepine

Bittencourt and Silvado120 observed that in several epilepsy patients who also exhibited spasticity, oxcarbazepine (Trileptal) reduced both seizure frequency and spasticity throughout the study. Minor side effects included nausea and dizziness. These authors subsequently assessed two patients with MS and one with transverse myelitis, who had lower-extremity spasticity. The antispastic effect of oxcarbazepine occurred at doses between 600 and 1,200 mg daily, usually below the dose that produced nausea, dizziness, and somnolence.121

Clonazepam

Clonazepam (Klonopin), alone or in combination with baclofen, may successfully treat spasticity. Cendrowski and Sobzcyk122 studied 25 patients with MS and other spastic disorders, 33 MS patients without other spastic disorders, and 10 control patients, all of whom were given clonazepam, baclofen, or placebo. Both clonazepam and baclofen were significantly more effective than placebo for spasticity. They were equally effective, but trends suggested that clonazepam was more effective in patients with slight muscle hypertonia mainly of cerebral origin and that baclofen was better suited to patients with severe spinal spasticity. The combination of both drugs was most effective in treating some MS patients.122

Adapted from: Bassi V, Kita M, Feldman DS, and Devinsky O. Spasticity. In: Devinsky O and Westbrook LE, eds. Epilepsy and Developmental Disabilities. Boston: Butterworth-Heinemann; 2001;231–247.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised May 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

No chemical interactions between antispasticity drugs and antiepileptic drugs (AEDs) are well documented. In vitro studies of cytochrome P450 isoenzymes suggest that hepatic metabolism of AEDs (or other drugs) will not be affected by any of the well known oral antispasticity agents or their metabolites. Thus, spasticity drugs do not interact pharmacokinetically with AEDs and should not interfere with epilepsy therapy.

Nor do any of the drugs used to treat spasticity lower the seizure threshold. Rapid withdrawal or abrupt discontinuation of baclofen or benzodiazepines should be avoided, however, as these changes could provoke seizures.

Adapted from: Bassi V, Kita M, Feldman DS, and Devinsky O. Spasticity. In: Devinsky O and Westbrook LE, eds. Epilepsy and Developmental Disabilities. Boston: Butterworth-Heinemann; 2001;231–247. With permission from Elsevier (www.elsevier.com).

Reviewed and revised May 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

The spinal stretch reflex arc can be interrupted at the level of the spinal cord. McCarty and Kiefer123 first described the cordotomy procedure in 1949. Because this radical procedure often had undesirable effects such as sensory loss and worsened bladder function, it is no longer preformed to treat spasticity.

The longitudinal myelotomy was introduced in 1951 by Bischof.124 To avoid damaging descending motor pathways, he later modified this procedure from a lateral to a dorsal longitudinal myelotomy.125 Laitinen et al.126 used this procedure in patients with spinal cord injury, cerebral palsy (CP), and multiple sclerosis (MS). Spasticity was relieved in 8 of 9 patients but recurred over time. Transient bladder dysfunction and permanent sensory deficits also occurred. Moyes127 reported that 19 of 21 patients who underwent longitudinal myelotomy had good results. This procedure has been recommended for patients with severe spinal cord injuries or diseases with severe intractable, bilateral, lower-extremity spasticity.128

In 1986, Sindou et al.129 modified the selective dorsal rhizotomy such that afferent fibers were divided as they entered the spinal cord in the dorsal root entry zone (DREZ). This DREZotomy consists of a 3-mm–deep microsurgical incision directed at a 45-degree angle in the posterolateral sulcus at the involved spinal levels. This incision destroys nociceptive and myotatic fibers but spares the lemniscal fibers, thus interrupting the spinal reflex arc and nociceptive pathways. Although originally performed in adult hemiplegic patients with severe upper-extremity spasticity, favorable results were reported in 121 patients treated with microsurgical DREZotomy for lower-extremity spasticity.128,130

Stereotactic procedures

Such stereotactic procedures as pallidotomy, pulvinolysis, and ventrolateral thalamotomy are used to treat extrapyramidal disorders characterized by involuntary movements and fluctuations in tone. The basal ganglia modulate motor activity, forming the center of a looping circuit between cortical motor areas and thalamus. Basal ganglia diseases may release inhibition and thereby result in abnormal movements. Stereotactic thalamotomy can reduce unilateral tremor, athetosis, and chorea, but it is not effective for spasticity.128,131–133

Interrupting outflow from the dentate nucleus (dentatomy) by stereotactic cerebellar lesions can diminish muscle tone by reducing the unbalanced facilitatory influences on the ventral horn cells. Gornall et al.133 reported improvement in 5 of 6 children with spastic CP who underwent stereotactic dentatomy. However, Guidetti and Fraioli134 reported a series of dentatomies in 47 patients and noted some improvement in dystonias but little effect on spasticity. Siegfried et al.135 observed that dentatomy may reduce spasticity in some cases. Overall, stereotactic procedures have not proven very effective in spastic conditions.128

Implanted stimulators

Chronic cerebellar stimulation was initially reported by Cooper et al.136 in 1976 to increase inhibitory outflow on the ventral motor neurons. Cooper’s group implanted a subdural electrical stimulator on the surface of the cerebellum as a “pacemaker” to decrease the extensor hypertonia in patients with spastic CP. In 1980, Davis et al.137 reported on a series of 262 patients, 230 of whom had spastic CP and underwent chronic cerebellar stimulator implantation. The primary effect was a lowering of spastic muscle tone in 90% of patients. Six months postoperatively, 25 patients were out of their wheelchairs and another 47 had improved ambulation. Davis’s group138 later conducted a double-blind trial in 33 patients, of whom 75% enjoyed qualitative improvement in spasticity and function. Other groups, however, could not demonstrate consistent successful reductions in spasticity with chronic cerebellar stimulation.136,138–141 Harris et al.142 reported a series of 13 children with CP with up to 14 years of follow-up and concluded that cerebellar stimulation was initially effective in reducing hypertonicity but that effectiveness decreased significantly after 3 to 5 years. Although some groups still advocate chronic cerebellar stimulation,143,144 this procedure rarely is used to manage spasticity.128

Dorsal spinal cord stimulation was introduced to treat chronic pain disorders but was found also to improve motor function in a patient with MS and to reduce painful spasticity in a patient with metastatic spinal disease.145 Subsequent experience with chronic epidural spinal cord stimulation varies. Quantitative measures of spasticity improved in one series of 48 patients with spinal cord injury.146 In another series of 17 patients, however, only 1 patient gained long-term relief of spasticity.147 Cervical spinal cord stimulation can reduce spasticity on functional, neurophysiologic, and subjective measures,148,149 but its rare use suggests that clinically significant benefits are uncommon.

Adapted from: Bassi V, Kita M, Feldman DS, and Devinsky O. Spasticity. In: Devinsky O and Westbrook LE, eds. Epilepsy and Developmental Disabilities. Boston: Butterworth-Heinemann; 2001;231–247. With permission from Elsevier (www.elsevier.com).

Reviewed and revised May 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Dorsal rhizotomy was performed first by Abbe in the late nineteenth century to relieve pain,150 and Sherrington151 pioneered the use of this procedure to improve spasticity in decerebrate cats. In 1913, Foerster152 reported decreased spasticity and improvement in posture and function after the division of complete dorsal nerve roots in 159 patients, 88 of whom had congenital spastic paraplegia. Foerster152 divided the entire dorsal nerve roots from L2 to S2, sparing L4 to preserve knee extension for standing. He used intraoperative electrical stimulation to identify the nerve roots associated with knee extension and to distinguish between ventral and dorsal roots. Because this procedure caused disabling sensory deficits, it was modified such that only four-fifths of the dorsal lumbosacral nerve rootlets were sectioned, but it still caused troublesome sensorimotor deficits.

Much later, intraoperative electrical stimulation and electromyography allowed rootlets innervating functionally important muscles to be spared and rootlets innervating the most dysfunctional muscle groups (e.g., hip adductors and flexors) to be cut.153,154

Selective dorsal lumbosacral rhizotomy

During the 1970s, Fasano et al.155 found that certain dorsal rootlets displayed an abnormal response to stimulation in spastic patients. In a selective dorsal lumbosacral rhizotomy, rootlets that responded to electrical stimulation with expected brief muscular contraction were spared, whereas those that evoked abnormally prolonged contractions that often spread to adjacent muscle groups were divided.155 This Fasano procedure then was modified to identify better the sacral nerve roots involved in sphincter control. By performing a more caudal laminectomy, the surgeon can better expose the cauda equina and roots exiting the neural foramina, improving verification of nerve root levels and ventral versus dorsal rootlets. On completion of an L2 through S1 laminectomy, the dorsal nerve rootlets between L2 and S2 are electrically stimulated and selectively divided on the basis of intraoperative electromyography and visual observation and palpation of muscle responses. Between 25% and 50% of rootlets usually are divided, but more may be divided in severely affected individuals. Care must be taken to ensure that not all rootlets of a particular level are divided.128

Selective dorsal rhizotomy improves spasticity only and is indicated for patients in whom spasticity is the main physical handicap.

Clinical evaluation focuses on:

• muscle tone
• tendon reflexes
• range of motion
• movement patterns
• posture
• gait
• functional capacity

The muscle disturbance must be due to spasticity, not dystonia or athetosis. The ideal patient is a spastic diplegic child without significant weakness or fixed contractures who ambulates independently with a scissoring gait, flexed hips and knees, and an equinus foot posture.156,157

Potential neurosurgical complications include increased weakness, sensory loss, sexual dysfunction, and spinal instability or deformity. Other adverse effects include wound infection, urinary tract infection or cystitis, hemorrhage, cerebrospinal fluid leakage, and respiratory complications.

Dorsal cervical rhizotomy

Dorsal cervical rhizotomy is rarely used, being reserved primarily for severe upper-extremity spasticity, dyskinesis, or athetosis. McCouch et al.158 found that the afferent endings for tonic neck reflexes were in the joints between the occiput, atlas, and axis. By performing complete dorsal rhizotomies of the C1 through C3 nerve roots, Kottke159 reported functional improvement in the upper extremities and more coordinated facial movement; in addition, reflex grimacing and symmetric and asymmetric tonic neck reflexes were abolished. Other groups, however, have reported reduced upper-extremity spasticity but limited functional improvement.160–162

Anterior rhizotomy

In 1945, Munro163 described the technique of anterior rhizotomy to relieve painful spasticity in 10 patients with complete spinal cord injuries. The procedure is no longer performed owing to flaccid paralysis and atrophy that resulted.

Smyth and Peacock128 performed anterior rhizotomy on three patients with incapacitating upper-extremity choreoathetoid movements. Intraoperative electrical stimulation and electromyography identified the ventral rootlets of the fifth through seventh cervical nerves. These rootlets were divided, paralyzing the abductors of the shoulder and flexors and extensors of the elbows but preserving distal sensorimotor function. The violent arm movements ceased, but only partial function was preserved.128

Peripheral neurectomy

Peripheral neurectomy involves sectioning the peripheral nerve or motor nerve branch to reduce overactivity of a muscle or muscle group. Because peripheral nerves contain motor and sensory fibers, division can cause sensory loss, weakness, and atrophy.

In the upper extremities, neurectomy of the musculocutaneous nerve can relieve spastic elbow flexion.164 Microneurosurgical ablation of fascicles in 52 spastic patients produced complete relief for 63% and some degree of improvement for 37%.165

Selective peripheral neurectomy of collateral motor branches of the brachial plexus has been shown to relieve spasticity in the shoulder in five patients.166

Peripheral neurectomies in the lower limbs can improve spastic calf muscles. Feve et al.167 noted clinical and electrophysiologic improvement in spasticity. They also reported abolition of ankle clonus and improved ankle angular variations in a large series of patients undergoing posterior tibial nerve collateral branch neurectomy. Tibial neurectomy improved gait significantly in some patients.168 However, Berard et al.169 found that symptoms recurred in 8 (61%) of 13 children with spastic hemiplegia who underwent unilateral tibial neurectomy.

Peripheral nerve and motor point block

Motor points are well-defined areas of the muscle that produce maximum contraction when the motor nerve branch passing through the muscle is stimulated. To relieve spasticity, motor blocks can be performed by injection of anesthetic agents or phenol into the peripheral nerve or muscle belly near the motor point and may last up to 6 months.167,170,171 Alcohol blocks provide a shorter duration of relief of spasticity, lasting 1 to 6 weeks, and may be helpful in evaluating responses in spastic children without fixed contractures before more permanent procedures are undertaken.172

Common injection sites include:128

• the median and ulnar nerves for wrist and finger spasticity
• the musculocutaneous nerve for elbow spasticity
• the obturator nerve for scissoring
• the posterior tibial nerve for relief of equinus deformity

A needle electrode is used to inject phenol and alcohol into the muscle belly after the motor point has been initially defined with a surface electrode. The peripheral nerve can also be injected either interneurally or perineurally. Both procedures present a risk of damage to afferent pathways.

Complications include causalgia and dysesthesias, cardiac arrhythmias, and permanent neurologic deficits.173

Adapted from: Bassi V, Kita M, Feldman DS, and Devinsky O. Spasticity. In: Devinsky O and Westbrook LE, eds. Epilepsy and Developmental Disabilities. Boston: Butterworth-Heinemann; 2001;231–247.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised May 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

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From: Bassi V, Kita M, Feldman DS, and Devinsky O. Spasticity. In: Devinsky O and Westbrook LE, eds. Epilepsy and Developmental Disabilities. Boston: Butterworth-Heinemann; 2001;231–247.
With permission from Elsevier (www.elsevier.com).

Reviewed May 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.