Basal Ganglia Pathophysiology in Movement Disorders

Basal ganglia dysfunction can occur on many levels. There can be destructive lesions of specific nuclei (e.g., infarction, hemorrhage, metabolic disorders) that may result in specific movement disorders. There also can be injury to multiple nuclei that results in single or multiple movement disorders (e.g., hypoxia, carbon monoxide poisoning, metabolic disorders). Movement disorders also can be caused by loss of specific neuron types (e.g., Huntington’s disease, Parkinson’s disease), or by cellular dysfunction without neuronal death (e.g., DYT1 dystonia). As in other areas of neurology, lesion localization is important in movement disorders and may often provide important clues to guide an efficient evaluation and treatment plan.

Lesions in the striatum produce variable results that depend in part on the location of the lesion, in part on the lesion mechanism, and in part on what is measured. Lesions in the caudate nucleus most commonly cause behavioral disturbance, such as abulia, but may also cause chorea or dystonia. Lesions in the putamen are likely to produce movement deficits and typically cause dystonia (most common) or parkinsonism [Bhatia and Marsden, 1994].

A unilateral STN lesion is the classic cause of hemiballism, but smaller-amplitude chorea can also result from STN lesions [Carpenter and Carpenter, 1951]. When bilateral, STN lesions cause bilateral chorea or ballism. Most commonly, the chorea or hemiballism resulting from STN lesions involves the lower extremities more than the upper extremities, and can persist for days to months. The intensity of hemiballism usually diminishes over time. Globus pallidus lesions usually involve GPe and GPi, GPe and putamen, or GPi and SNpr. Such lesions can cause dystonia, parkinsonism, or both [Mink, 1996; Bhatia and Marsden, 1994; Heidenreich et al., 1988]. Chorea rarely accompanies globus pallidus lesions. Focal lesions of SNpr can cause involuntary eye movements [Hikosaka and Wurtz, 1985]. Lesions of SNpc dopamine neurons cause depletion of dopamine in the striatum, resulting in parkinsonism, dystonia, or both [Calne et al., 1997].

Focal basal ganglia lesions are uncommon in children. Movement disorders in children are more likely to result from global dysfunction of basal ganglia circuits. The model shown in Figure 68-3 has been used to explain the basis for hypokinetic and hyperkinetic movement disorders, but does not distinguish among the different hyperkinetic movement disorders. However, based on what is known about these disorders and the underlying neural circuitry, specific models have been proposed [Mink, 2003]. Diseases affecting the basal ganglia cause movement disorders that can be understood as failure to facilitate desired movements (e.g., Parkinson’s disease), failure to inhibit unwanted movements (e.g., chorea, dystonia, tics), or both [Albin et al., 1989; DeLong, 1990; Mink, 1996, 2003]. The involuntary movements of chorea, dystonia, and tics differ in important spatial and temporal characteristics that reflect important pathophysiologic differences. More extensive discussion of the neural basis of these disorder is contained in Mink [2003].

Huntington’s Disease

Huntington’s disease (HD) is transmitted as an autosomal-dominant trait, caused by a trinucleotide repeat expansion of the IT-15 gene on chromosome 4 [Li et al., 1993]. This disorder is characterized by a combination of dystonia, chorea, myoclonus, behavioral abnormalities, ataxia, and, ultimately, dementia. When HD begins in childhood, the typical presentation of the movement disorder is dystonia and rigidity, and not chorea. Seizures are not infrequently the first manifestation of HD in childhood. This has been referred to as the Westphal variant of HD [Quinn and Schrag, 1998; Topper et al., 1998]. The age of onset is earlier for children with a higher number of repeats [Langbehn et al., 2004]. There tends to be amplification of the number of repeats, particularly when it is transmitted from father to child, and therefore in most children with juvenile HD disease is inherited from the father and involves repeat lengths that are significantly higher than those seen in adults.

Diagnosis is based upon identification of the trinucleotide repeat sequence. Although at least 38 repeats are usually required for the occurrence of symptoms in adults, a larger number of repeats would be expected when symptoms present in childhood [Quinn and Schrag, 1998; Langbehn et al., 2004]. Magnetic resonance imaging (MRI) shows atrophy of the heads of the caudate nucleus and, in later stages, generalized cerebral and cerebellar atrophy.

In teenagers, the initial presentation of HD may be with psychiatric illness and, in particular, major depression [Tost et al., 2004]. Dystonia or chorea usually supervenes later. The pathology includes basal ganglia, cerebellar, and cortical degeneration [Vonsattel et al., 1985; de la Monte et al., 1988; Myers et al., 1988]. The origin of the chorea has been hypothesized to be a primary loss of medium spiny cells in the striatum that bear D2-like receptors [Deng et al., 2004]. In children, there may be a relatively symmetric loss of D1-bearing and D2-bearing medium spiny neurons, which could account for the primarily dystonic rather than choreic presentation [Augood et al., 1997; Albin et al., 1990].

Treatment of Huntington’s chorea in adults is typically based upon modification of the chorea or myoclonus. Since the chorea has been presumed to be due to loss of medium spiny neurons in the indirect pathway, neuroleptic medications have been most frequently used in adults [Bonelli and Hofmann, 2004; Bonelli et al., 2004]. Neuroleptics would be expected to compensate partially for early loss of indirect pathway neurons by blocking the inhibitory effects of dopamine and disinhibiting the remaining indirect pathway neurons. There is much less experience in children, for whom dystonia and rigidity may be greater contributors to disability. Other medications that have been used successfully in HD include tetrabenazine [Asher and Aminoff, 1981; Ondo et al., 2002], clonazepam [Thompson et al., 1994], and valproic acid [Grove et al., 2000]. There is currently no treatment that modifies the progression of the disease.

Prognosis is poor for childhood-onset HD, and the movement disorder is expected to worsen progressively over the years following diagnosis. Life expectancy depends upon the severity of symptoms and the number of repeats, but typically children will survive 10–15 years from the time of diagnosis.

Ataxia-Telangiectasia

Despite the name of this disorder, ataxia is not always the presenting finding, and ataxia may be a much less prominent early symptom than upper-extremity chorea. However, the chorea is usually less disabling than the ataxia. Other symptoms associated with ataxia-telangiectasia include dystonia, which is often proximal [Bodensteiner et al., 1980]. Ataxia-telangiectasia (Louis–Bar syndrome) is most commonly due to mutations in the ATM (ataxia-telangiectasia mutated) gene on 11q22–23 [Chun and Gatti, 2004; Coutinho et al., 2004; Gatti et al., 1988]. Mutation in this gene leads to decreased inhibition of cell cycling in the context of injury to nuclear DNA, and this leads to an accumulation of mutations at known “hot spots,” including translocations between regions on chromosome 7 and 14 known to be involved with immune function [Farina et al., 1994]. Therefore, one of the cardinal features of this disorder is a history of frequent sinopulmonary infections [Centerwall and Miller, 1958], which requires very close attention to pulmonary function and aggressive treatment of pulmonary infections at all ages. In later stages, hematologic malignancy may occur [Stankovic et al., 1998]. Children with ataxia-telangiectasia may be particularly vulnerable to injury from ionizing radiation and certain chemotherapy agents, and this must be taken into consideration in planning any treatment for malignancy.

The cause of the cerebellar degeneration is not known [Farina et al., 1994], but the pathology shows a characteristic loss of Purkinje cells, such that, by late stages in the disease, Purkinje cells are often completely absent. The cause of the chorea is not known, and basal ganglia pathology is minimal. Eye movement disorders are well described, and include an inability to suppress, as well as an inability to initiate, saccades [Lewis et al., 1999; Bundey, 1994]. The inability to initiate saccades leads to a characteristic finding of oculomotor apraxia, in which a child will use thrusts of the head in order to position the eyes on the target. Diagnosis is based upon laboratory testing, including decreased immunoglobulin (Ig) G2 and IgA, abnormalities in T-cell subsets, elevated α-fetoprotein, lymphocyte radiosensitivity, and decreased radiation-induced mitotic suppression [Stray-Pedersen et al., 2004]. Treatment of this disorder is primarily supportive, although there are isolated reports of dystonic symptoms responding to trihexyphenidyl or l-DOPA. The chorea generally is mild and does not require specific treatment. There is no known treatment for the ataxia.

Ataxia-oculomotor apraxia is an autosomal-recessive disorder with similar motor symptoms, caused in some cases by mutations in the aprataxin gene AOA-1 [Tranchant et al., 2003; Shimazaki et al., 2002; Moreira et al., 2001]. This disorder commonly presents with chorea, ataxia, and oculomotor apraxia [Sano et al., 2004]. It is most prevalent in Japan and Europe. AOA-1 does not seem to be involved with cell cycle regulation, and therefore the DNA breakage, immune abnormalities, and malignancies seen in ataxia-telangiectasia do not occur. These patients have hypoalbuminemia [Shimazaki et al., 2002]. AOA-2 is a similar autosomal-recessive disorder due to mutations in Senataxin (SETX). Like ATM, Senataxin is involved with DNA repair, although mutations are not associated with increased radiosensitivity [Suraweera et al., 2009]. Clinical features include ataxia, oculomotor apraxia, peripheral neuropathy, and, more rarely, chorea or dystonia [Criscuolo et al., 2006; Le Ber et al., 2004]. The long-term prognosis of AOA-1 and AOA-2 is considerably better than for ataxia-telangiectasia.

Other Genetic Choreas

Other genetic causes of chorea include familial benign hereditary chorea [Kleiner-Fisman et al., 2003; Breedveld et al., 2002a], which is an autosomal-dominant disorder that, in some cases, is due to mutations in the TITF-1 gene on chromosome 14 [Breedveld et al., 2002b]. Affected family members have normal or near-normal intelligence, and chorea is often the only complaint, although mild truncal dystonia and gait ataxia have been reported [Fernandez et al., 2001]. The severity of chorea can vary between different affected family members. It may be accompanied by hypothyroidism, pulmonary disease, or both in some family members with TITF-1 mutations. Symptomatic treatment may yield some mild benefit.

Neuroacanthocytosis is also a potential cause of chorea [Marson et al., 2003], although classification as a primary or secondary chorea is not universally agreed upon.

Sydenham’s Chorea

Of the secondary causes of childhood chorea, Sydenham’s chorea is the most common [Jordan and Singer, 2003; Jummani and Okun, 2001; Garvey and Swedo, 1997]. It has onset weeks or months after an acute infection with group A beta-hemolytic streptococcus (GABHS) and is one of the cardinal symptoms of rheumatic fever. Symptoms may persist for weeks or months, but chorea almost always resolves spontaneously within 6 months [Jordan and Singer, 2003]. There have been rare reported cases of continued or recurring symptoms [Faustino et al., 2003]. The chorea typically involves the distal musculature, initially of one hand and then of both, with a “piano-playing” pattern, but other forms of chorea, including ballism, have been observed. Large, generalized body movements in some patients previously inspired the term “St. Vitus’ dance.”

Anti-basal ganglia antibodies (ABGA) are found in some children [Church et al., 2002] and it has been hypothesized that production of these antibodies is triggered due to molecular mimicry by streptococcal antigens [Loiselle and Singer, 2001; Kirvan et al., 2003; Singer et al., 2003; Goldenberg et al., 1992]. ABGA can be detected in cerebrospinal fluid [Singer et al., 2003], and anti-streptolysin (ASLO) antibodies can be detected in serum. However, the high prevalence of positive ASLO titers in the general population means that both acute and convalescent ASLO titers must be measured in order to probe for an acute infection. The clinical situation often provides a strong indication for the diagnosis, but if other neurological symptoms are present or there is doubt about etiology, a more complete work-up may be needed, including tests for thyroid function, toxins, metabolic disorders, or encephalitis.

Sydenham’s chorea usually does not require treatment, although the acute streptococcal infection should be treated. All children diagnosed with Sydenham’s chorea, even in cases of isolated chorea, should be treated with penicillin, both acutely for treatment and long-term for prophylaxis, according to American Academy of Pediatrics guidelines [American Academy of Pediatrics, 2006].

Penicillin or an acceptable alternative is effective as secondary prevention of recurrent chorea, but more importantly reduces the likelihood that future GABHS infections will cause carditis and permanent valvular damage. Current recommendations in the United States are for prophylactic treatment until age 21 years, regardless of the age of chorea onset. Valproic acid, carbamazepine, or neuroleptics may have some symptomatic benefit in more severe or persistent cases [Pena et al., 2002; Genel et al., 2002; Kulkarni and Anees, 1996]. Treatment with immune suppressant medication, including corticosteroids or intravenous immunoglobulin preparations, has been studied, but the natural history, with spontaneous resolution of symptoms, makes interpretation of efficacy in open clinical trials difficult [Garvey and Swedo, 1997; Green, 1978; Cardoso et al., 2003]. One randomized, blinded, placebo-controlled study showed that a 4-week, 2-mg/kg daily oral dose of prednisone, followed by a taper, reduced duration of chorea and accelerated the reduction in symptoms. Weight gain was substantial by the end of 2 months, and long-term outcome including recurrence rates was not different between groups [Paz et al., 2006]. There are sometimes associated obsessive-compulsive or behavioral symptoms [Moore, 1996; Wilcox and Nasrallah, 1988], and these symptoms are often managed with selective serotonin reuptake inhibitors.

The prognosis for the movement disorder is excellent, and complete resolution occurs in most cases. Recurrence is rare and is sometimes associated with recurrence of other symptoms of rheumatic fever [Korn-Lubetzki et al., 2004]. There appears to be a higher risk of chorea gravidarum in women with a previous history of Sydenham’s chorea [Korn-Lubetzki et al., 2004].

The rapid onset of Sydenham’s chorea has raised the question of whether an autoimmune mechanism could be responsible for other acute-onset movement disorders. This has led to the hypothesis of pediatric autoimmune neuropsychiatric disorders associated with Streptococcus (PANDAS) [March, 2004; Trifiletti and Packard, 1999]. PANDAS is characterized by an abrupt or explosive onset of tics, obsessive-compulsive behavior, and a movement disorder (usually chorea) that is temporally associated with streptococcal infection [Snider and Swedo, 2004; Chmelik et al., 2004; Pavone et al., 2004; Swedo, 2002]. Symptoms may persist, with a relapsing and remitting course. The existence of this disorder has been debated [Singer and Loiselle, 2003] [Swedo et al., 2004; Kurlan and Kaplan, 2004; Kurlan, 2004], and ABGA have not been shown to be elevated [Singer et al., 2004]. It has not been possible to transmit the disorder passively to animals by inoculation with antibodies from affected humans [Loiselle et al., 2004]. Nevertheless, there have been an increasing number of case reports of explosive onset of neurobehavioral disorders, including tic disorders, chorea, and obsessive-compulsive disorder following streptococcal infections, and therefore the hypothesis merits further investigation. It is not clear that there is any specific treatment, although some authors advocate immune modulation, long-term antibiotics, or tonsillectomy [Green, 1978], [Araujo et al., 2002; Heubi and Shott, 2003; van Toorn et al., 2004; Leonard and Swedo, 2001; Gebremariam, 1999].

Medication-Induced Chorea

Chorea is frequently associated with administration of medications, and any child with chorea needs to be carefully examined for the possibility of iatrogenic causes. In particular, treatment of other movement disorders with anticholinergic medication, such as trihexyphenidyl, can precipitate chorea, even at relatively low doses [Nomoto et al., 1987]. Antiepileptic medications, including carbamazepine and phenytoin, have been associated with precipitation of chorea, and in children with diffuse brain injury, sedating medications can sometimes precipitate chorea.

Chorea can appear as a tardive symptom many months after being on a medication, or after discontinuing a medication. Tardive chorea is probably less common than tardive dystonia or dyskinesia, but it nevertheless does occur, and the onset of chorea, even many months or years after being treated with neuroleptic or anticholinergic medications, should raise suspicion of a tardive medication effect. There is a more complete description of tardive syndromes below.

Chorea Associated with Brain Injury

Chorea is frequently seen in children with cerebral palsy on awakening or when drowsy. A common form of more persistent chorea that can last several months often follows encephalitis. In particular, children with encephalitis will, in many cases, develop a severe and persistent chorea within several weeks of recovery from the acute phase of the illness. This chorea will often last 6–12 months. It may respond to treatment with benzodiazepines, including clonazepam or valproic acid. It does not appear to respond to other antichorea treatments, such as neuroleptic medication or tetrabenazine. Whether treatment of the chorea hastens its improvement or in any way alters the natural course is not known, but treatment may be helpful in order to assist with feeding and rehabilitation.

A severe form of chorea or ballism can occur in children with cerebral palsy or other static brain injury following the onset of an otherwise unremarkable febrile illness. Often there is a combination of chorea and dystonia, and this syndrome is described below in the section on dystonic storm.

Chorea Associated with Systemic Illness

Hyperthyroidism can be a cause of chorea, and any child with unexplained acute or persistent chorea should have serum testing for thyroid function. The mechanism is unknown. It should be noted that the TITF-1 gene, responsible for benign hereditary chorea, is a transcription factor involved with both thyroid and basal ganglia development, although in this disorder thyroid function is reduced.

Autoimmune diseases, including lupus erythematosus and antiphospholipid antibody syndromes, can be a cause of chorea, possibly through an autoimmune mechanism. In such cases, treatment should be directed at the underlying autoimmune disorder. This class of disorders may be a relatively common cause of chorea in children, and it is particularly important due to the potential for response to treatment.

Ballism

Ballism is a high-amplitude, flinging movement, usually due to involuntary movements of proximal joints. Ballism is part of the spectrum of chorea and involves similar pathophysiological mechanisms [Albin et al., 1989; DeLong, 1990]. When ballism involves one side of the body, it is called hemiballism. Hemiballism is the classical manifestation of vascular events affecting the subthalamic nucleus, but can be associated with lesions in other parts of the basal ganglia.

Treatment of Chorea

Chorea is often difficult to treat. Secondary chorea may respond to a combination of clonazepam and valproic acid. Sedation may be helpful for short-term management. In some cases, tetrabenazine [Asher and Aminoff, 1981; Jankovic and Orman, 1988; Chatterjee and Frucht, 2003], reserpine, or neuroleptics may be helpful, but the use of neuroleptics requires caution, as chorea may mask the onset of tardive dyskinesia or tardive dystonia. If dystonia is present with chorea, then neuroleptics should be used only with great caution due to their ability to precipitate acute or tardive dystonia and the potential for worsening dystonia due to dopaminergic failure. Trihexyphenidyl, l-DOPA, carbamazepine, and phenytoin can worsen chorea, and should be avoided in most cases. Chorea that is due to global cerebral injury, such as following encephalitis, may worsen when the child is sleepy, and therefore sedating medications should be avoided if possible, although clonazepam is sometimes helpful. Some forms of chorea are time-limited and may only require brief treatment. It is possible that there may be a role for deep brain stimulation in some patients with chorea [Thompson et al., 2000]. Before any treatment for chorea, it is important to evaluate the child’s current medications to rule out an iatrogenic cause.

Classification

Dystonia is classified by etiology as either primary or secondary, and by location as focal, segmental, hemidystonia, multifocal, or generalized dystonia [Fahn et al., 1998]. Focal dystonia involves a single part of the body, such as a limb, the neck, or the face. Examples include blepharospasm (forceful eye closure), oromandibular dystonia (involving the jaw and/or mouth musculature), spasmodic dysphonia (vocal cord involvement), torticollis (twisting or tilting of the neck), or focal hand or foot dystonia. Segmental dystonia involves the muscles of two contiguous body parts. For example, cranial segmental dystonia involves multiple muscles of the face and neck, axial dystonia involves the neck and trunk, brachial dystonia involves the arm and trunk, and crural dystonia involves one or both legs and the trunk. Hemidystonia involves all or most muscles on one side of the body. Multifocal dystonia involves two or more noncontiguous body regions. Generalized dystonia involves multiple limbs on both sides of the body, including at least one leg.

In children, dystonia often starts distally, and it may initially involve only a hand or foot. Typical patterns include spooning deformity of the fingers, with forceful extension at the metacarpal-phalangeal and interphalangeal joints of the hand, or a combination of inversion (supination) and extension of the ankle. An upgoing “striatal toe” is a common finding that is often confused with the Babinski sign but which seems to be due to extrapyramidal dysfunction. Proximal forms of dystonia include opisthotonus (arching), truncal sway, side bending, twisting of the neck, and proximal fixed postures or random movements of the large muscles of the legs or arms. Orofacial movements include dysarthria, involuntary tongue protrusion, involuntary jaw opening or closing, blinking, and facial contortions.

Dystonia is considered primary when it is the predominant or only clinical feature. At least 17 different inherited phenotypes designated with the “DYT” genetic locus specification have been defined so far [Bressman, 2004; Misbahuddin and Warner, 2001; Nishiyama et al., 2000]. Most of these are quite rare. Only seven of the genes have been identified. Many of these disorders do not present in childhood. Many of these disorders represent “dystonia plus” syndromes that include dystonia as a primary feature but which also have other associated movement disorders. Examples of dystonia-plus syndromes include dopa-responsive dystonia (DRD), myoclonus dystonia, and rapid-onset dystonia-parkinsonism (RDP).

Diagnosis

Dystonia must be distinguished from other disorders, including spasticity, rigidity, tics, tremor, and ataxia, although in some cases this is difficult. Spasticity is associated with increased reflexes and frequently shows a spastic catch, whose position depends on the velocity of movement [Sanger et al., 2003; Jobin and Levin, 2000]. Rigidity does not tend to have a particular fixed posture; it has a “lead-pipe” quality and resists attempts at passive movement of the arm or leg, although the limb can be placed into an arbitrary posture by the examiner [Sanger et al., 2003]. Tics can be differentiated by their episodic and repeatable nature, and normal posture and function between tics [Sanger et al., 2010]. In addition, tics rarely have the same degree of motor disability, as is seen in dystonia. Dystonic tremor tends to be less rhythmic than regular tremor, and often exhibits a “null point,” in which there exists a particular joint angle at which the tremor decreases or is absent [Deuschl, 2003]. To one side of that joint angle, movement in one direction will cause the tremor to worsen, but often beating in a particular direction that is different from the direction that the tremor will beat in if the joint is moved to the opposite direction. Ataxia does not show characteristic postures, does not have overflow of muscle activity, and quality of movement may improve at slow speeds [Sanger et al., 2006; Paulson and Ammache, 2001].

Dystonic Storm

A particularly dramatic presentation of dystonia that is seen primarily in children with pre-existing motor abnormalities is dystonic storm [Opal et al., 2002; Dalvi et al., 1998]. Usually, this is seen in the context of an acute illness in a child with a previous history of dystonia, cerebral palsy, or other movement disorder. The child will become ill with an otherwise unremarkable disease, such as a respiratory illness, but then will rapidly develop severe and intractable hyperkinetic dystonia or chorea with ballistic or flinging movements of the arms, legs, or head. This can also be associated with severe limb extension or opisthotonic posturing, with dorsiflexion at the neck or trunk. In many cases, these symptoms will not have been seen previously. In some cases, this clinical picture is associated with encephalitis or other causes of acute striatal injury. Treatment is extremely difficult, and may require general anesthesia to abate the movement. Multiple medications have been tried, including benzodiazepines, l-DOPA, anticholinergic medications, tetrabenazine, reserpine, dantrolene, and baclofen. The combination of trihexyphenidyl and tetrabenazine is sometimes effective, but any causative or triggering disease must be treated aggressively, and hyperthermia, rhabdomyolysis, and myoglobinuria must be watched for and controlled. It is possible that intrathecal baclofen [Dalvi et al., 1998] or deep brain stimulation [Angelini et al., 2000] could be helpful in severe cases when medications are ineffective [Kyriagis et al., 2004]. Dystonic storm can continue for months and can be life-threatening, usually requiring intensive care monitoring. It can recur in the context of a subsequent illness.

Associated Movement Disorders

Athetosis literally means “not fixed,” which refers to the continuous writhing movements that characterize this disorder [Morris et al., 2002b]. Athetotic movements are often caused or worsened by attempts at voluntary movement. The use of term athetosis has diminished substantially in recent years. It has been argued that, in most cases, athetosis is actually a form of dystonia [Turny et al., 2004], although a recent consensus suggests that it can be defined as a separate entity [Sanger et al., 2006]. Currently, the term is used most commonly to describe a form of cerebral palsy (athetoid), but it is also employed in conjunction with the term chorea (choreoathetosis) to describe the apparent random and hyperkinetic quality of the movements [Morris et al., 2002a]. Pure athetosis may be rare in children.

Dystonia in children is frequently associated with bradykinesia [Nygaard and Duvoisin, 1986]. This may be due to the fact that both dystonia and bradykinesia can be caused by failure of dopamine transmission [Segawa et al., 1999; Riederer and Foley, 2002]. Bradykinesia may be a relatively common finding in children with hypertonic disorders, but it is likely to be under-reported since the slow movement may be attributed to the hypertonia rather than to the underlying bradykinesia.

Primary Dystonias

Secondary Dystonia

There is a long list of possible secondary causes for dystonia, as shown in Box 68-2. Here we will discuss several of the most important causes. Many of these disorders are discussed in other chapters.

Pantothenate Kinase-Associated Neurodegeneration

PKAN is a member of the group of diseases now referred to as neuronal brain iron accumulation [Bertrand, 2002a, b]. Symptoms of PKAN include progressive dystonia, dysarthria, rigidity, ballism, choreoathetosis, spasticity, dementia, and pigmentary retinal degeneration [Swaiman, 1991]. In its later stages, this disorder has characteristic ballistic flinging movements of arms and legs, as well as involuntary and repetitive tongue protrusion. The limb and tongue movements may lead to injury, requiring restraint of the arms and legs, and dental extraction [Sheehy et al., 1999]. There is a gradual progression over years, with loss of ambulation within 5–15 years of onset. The initial symptoms usually occur in either the childhood or the juvenile years.

PKAN has been divided into the characteristic type with presentation in the first decade (average onset at 3 years), and an atypical form with onset in the second decade, which seems to have slower progression and lower severity [Thomas et al., 2004]. Dystonia in PKAN usually starts in the leg, but sometimes the earliest presenting sign is visual loss. There is often associated bradykinesia. The rate of progression is more rapid with younger onset. The overall incidence is estimated to be approximately 3 cases per million population. The severity of dementia is variable and difficult to quantitate, as the severity of the movement disorder makes assessment of cognitive function in later stages difficult.

The atypical form generally starts later, between 10 and 30 years of age at onset, with a mean of 13 years. It has slower progression, and retinopathy is rare. The atypical form presents with dysarthria and psychiatric disturbances, which include emotional lability, depression, and sometimes aggressive or violent behavior. There are also freezing episodes similar to those seen in Parkinson’s disease.

The gene responsible for PKAN is pantothenate-kinase-2 (PANK-2) on chromosome 20P13-P12.3 [Zhou et al., 2001; Hayflick, 2003a]. Inheritance is autosomal-recessive. Pantothenate kinase is responsible for synthesis of coenzyme A, and the neurologic abnormalities may be due to a combination of factors, including accumulation of upstream metabolites causing iron chelation, as well as decreased availability of coenzyme A for fatty acid metabolism [Hayflick, 2003b; Gordon, 2002]. The pathology is characterized by rust-colored iron pigmentation of the globus pallidus and substantia nigra pars reticulata. Injury to the globus pallidus, with consequent abnormalities of outflow patterns, may be responsible for the movement disorder [Mink, 2001b]. In addition, there are axonal spheroids similar to those seen in neuroaxonal dystrophy [Gordon, 2002].

MRI shows a characteristic “eye of the tiger” sign. This sign consists of a dark globus pallidus internus on T2 imaging, with a bright region in the center of the globus pallidus that is thought to be due to central necrosis (Figure 68-4). The dark signal is due to iron accumulation [Hayflick et al., 2001], although deposition of iron may be secondary to other metabolic deficits rather than the primary cause of symptoms [Koeppen and Dickson, 2001]. When the full eye of the tiger sign is present in childhood, 100 percent of such cases have the PANK-2 mutation [Hayflick et al., 2003]. Similarly, 100 percent of children with PANK-2 mutations show the eye of the tiger sign at some point during the illness [Trimble, 2003]. Children with clinical features of PKAN but without the eye of the tiger sign only have a 50 percent chance of being positive for the PANK-2 mutation. Ophthalmologic examination and electroretinogram may detect presymptomatic retinopathic changes and early visual loss [Swaiman, 1991]. Acanthocytes are sometimes, but not always, present, and there may be a low level of prebetalipoprotein. This is similar to what is seen in the HARP syndrome (hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration). Some families with HARP syndrome have been shown to have the PANK-2 mutation, and therefore it is not known whether or not this is a separate disorder or a variant of PKAN [Houlden et al., 2003]. It is important to test for other disorders that can present with similar generalized dystonia in childhood, including HD, neuronal ceroid-lipofuscinosis, and hexosaminidase A deficiency (Tay–Sachs disease).

Fig. 68-4 T2-weighted magnetic resonance image of an 11-year-old patient with pantothenate kinase-associated neurodegeneration.

The image shows the characteristic “eye of the tiger” sign within the internal globus pallidus.

Treatment is symptomatic. Some children receive benefit from benzodiazepines, anticholinergic medications, botulinum toxin, baclofen, or intrathecal baclofen. It is unlikely that any of these treatments slows the progression of the underlying disease, but several case reports of treatment with pallidotomy or deep brain stimulation of the globus pallidus internus suggest possibility of symptomatic improvement [Umemura et al., 2004; Justesen et al., 1999]. The prognosis is universally poor, with death from medical complications usually within 10–20 years of the onset in the typical form; in the atypical form, survival may be longer.

Neuroacanthocytosis

Neuroacanthocytosis has also been referred to as chorea acanthocytosis or Levine–Critchley syndrome. It is characterized by spiky projections on erythrocytes (Figure 68-5), although such projections are often seen in non-neurologic disease, including hepatic disease. Acanthocytes are also seen in abetalipoproteinemia (Bassen–Kornzweig disease) [Bohlega et al., 1998], vitamin E deficiency, hypoprebetalipoproteinemia, HARP syndrome, and with abnormal Kell blood group antigens (McLeod’s syndrome) [Rampoldi et al., 2002; Danek et al., 2001; Mehndiratta et al., 2000; Dotti et al., 2000]. Onset is usually in the adult years, but onset as early as 8 years of age has been reported. Symptoms in childhood resemble juvenile HD, with dystonia and an akinetic-rigid syndrome, as well as a severe and progressive tic disorder [Kutcher et al., 1999; Yamamoto et al., 1982]. Presentation in adults is more typically with chorea or psychiatric illness [Dixit et al., 1993; Bruneau et al., 2003; Robinson et al., 2004]. There is frequent tongue protrusion and difficulty eating, and severe dysarthria is often a presenting feature. Some children and adults show areflexia, impulsive behavior, and, occasionally, mild dementia.

Fig. 68-5 Stressed blood smear showing acanthocytes.

Testing for this disease requires examination of a fixed smear of blood under the microscope, stressed by mixing 1:1 with normal saline, and this requires an experienced and knowledgeable technician. A level of more than 3 percent acanthocytes is diagnostic. MRI shows caudate atrophy [Kutcher et al., 1999; Okamoto et al., 1997]. PET scanning shows decreased fluoro-dopa uptake and decreased raclopride binding, suggesting both pre- and postsynaptic disorders of striatal function [Brooks et al., 1991; Peppard et al., 1990]. Treatment is symptomatic. Benzodiazepines are often helpful. When chorea is present, neuroleptics are helpful, but this is probably less useful in childhood. There has been an isolated report of improvement with calcium channel blockers.

Treatments for Dystonia

Because DRD can mimic cerebral palsy, it has been recommended that all children with unexplained dystonia or cerebral palsy be given a trial of l-DOPA [Nygaard et al., 1988; Jan, 2004]. l-DOPA may be helpful in some children, even with secondary dystonia [Brunstrom et al., 2000]. The required dose of l-DOPA is very low in DRD (typically 50–100 mg per day), but may be much higher in juvenile Parkinson’s disease and secondary causes of dystonia, including cerebral palsy. Dosages as high as 10 mg/kg/day divided three times per day are sometimes needed. Common side effects of l-DOPA include nausea, vomiting, and diarrhea. Orthostatic hypotension occurs rarely in children. l-DOPA must be combined with a peripheral decarboxylase inhibitor, such as carbidopa, in order to increase central uptake and decrease peripheral side effects. Commercial preparations with a ratio of l-DOPA to carbidopa of 4:1 are typically used. Peripheral side effects can often be reduced by an additional dose of the peripheral decarboxylase inhibitor given one half-hour before the l-DOPA dose. l-DOPA competes for absorption with neutral amino acids, and therefore absorption will be slowed and the peak effect will be less when it is taken with a protein meal. Conversely, absorption rate is increased, the peak effect is greatest, and the side effects may be greatest when it is taken with carbohydrates. l-DOPA and anticholinergic medications are frequently used together. The appropriate dose of l-DOPA is difficult to determine, and it needs to be titrated gradually over a period of 2 weeks to 2 months. Rapid titration is possible, but the purpose of gradual titration is to find the optimal dose. Excessive doses of l-DOPA will usually cause dyskinesias or worsen dystonia, and often an intermediate dose is most effective. Rapid withdrawal can lead to worsening of dystonia and there are rare reports of symptoms similar to neuroleptic malignant syndrome following rapid withdrawal in adults.

Anticholinergic medication is very effective in acute dystonic reactions, as described above. It is partly effective in a subset of children with chronic dystonia [Hoon et al., 2001], and trihexyphenidyl remains the best studied centrally active antidystonia medication [Burke et al., 1986; Burke and Fahn, 1983; Greene et al., 1988]. Its mechanism of action for dystonia is not known, although it is presumed to have an effect on the large cholinergic interneurons of the striatum. Its anticholinergic effects would be expected to be widespread throughout basal ganglia and cortex [Fahn, 1987]. It is often necessary to proceed to very high doses: 1 mg/kg/day and, in some cases, higher [Fahn, 1983a, b]. In younger children, lower doses may be sufficient, but children will tolerate the high doses better than adults. In particular, adults and older children are more likely to develop confusion or behavior changes on high doses. The effectiveness may be greater in young children, and speech and hand function seems to improve the most [Hoon et al., 2001]. The dose must be increased gradually, and it may often take 3–4 months to achieve an appropriate dosage. Appropriate initial dosage is 0.05–0.1 mg/kg/day or less. The medication is usually divided three times per day and given during the day. Side effects are similar to those of other anticholinergic medications. Behavior changes are not uncommon, and deficits in attention have been reported in adult trials. Anticholinergic medications can worsen chorea and possibly choreoathetosis. The benefit on dystonia is often delayed, and there may be no apparent benefit for several months after starting the medication. At high doses, abrupt withdrawal could potentially be dangerous, and there are rare reports of neuroleptic malignant syndrome following abrupt withdrawal of high doses of trihexyphenidyl in adults. Other anticholinergic medications may work as well, but have not been extensively tested.

Diazepam and other benzodiazepines or sedative medications can occasionally be helpful. Orthopedic procedures may not have expected outcomes in children with dystonia, as there is a tendency for dystonia to transfer to other muscles following an orthopedic procedure. Restraint of a dystonic limb, casting, or braces may make the dystonia worse, and there is a tendency for the dystonia to “fight against” any restraining force. This needs to be considered very carefully when planning prolonged casting of the lower extremities, such as following hip surgery, since the dystonia may worsen significantly following removal of the cast. Selective dorsal rhizotomy has been reported to have very poor outcome in dystonia, and it is therefore essential to exclude dystonia when selecting cases for this intervention.

When dystonia is associated with increased tone, botulinum toxin has been shown to be very effective [Boyd et al., 2001; Graham et al., 2003]. It may be effective in directly reducing the tone in the hypertonic muscles, but may also be effective in changing the overall pattern of dystonia. In particular, it is sometimes observed that botulinum toxin injection into one muscle will relax other muscles of the same limb. Injection is often performed with electromyographic guidance, and although some practitioners will use general anesthesia and electrical stimulation for localization, many have now chosen to inject with only local anesthesia. The procedure should not be performed more frequently than every 3 months, due to the risk of build-up of neutralizing antibodies. In some cases, repeated doses of botulinum toxin every 3 months are needed but, in other cases, short-term treatment can be effective. Phenol or alcohol nerve blocks and dantrolene have not been commonly used in dystonia.

Baclofen has been used and may be effective in some cases, although its mechanism of effectiveness in dystonia is not known. Intrathecal baclofen can reduce tone in generalized dystonia if the catheter is placed at cervical levels [Albright et al., 1996, 1998, 2001; Butler and Campbell, 2000; Ford et al., 1998]. There is a high rate of complications, up to 35 percent in some series [Campbell et al., 2002]. Complications can be serious, and can include meningitis. Overdoses are rare, but pump failure or catheter disconnection with acute and possibly life-threatening baclofen withdrawal can occur. Withdrawal needs to be treated with a combination of oral baclofen and intravenous diazepam, as well as surgical reimplantation of the catheter as soon as possible. For this reason, many clinicians recommend that children with intrathecal baclofen pumps remain within 30 minutes of an appropriately experienced emergency room at all times.

Neurosurgical intervention is reserved for the most severe cases, but the possibility that earlier surgical intervention may slow progression of the disease or lead to a longer disease-free interval has been raised. Pallidotomy and thalamotomy have been in use for many years, with some success [Gros et al., 1976a, b; Vercueil, 2003]. More recently, deep brain stimulation has become available, and multiple targets have been attempted, including the ventrolateral thalamus [Thompson et al., 2000; Ghika et al., 2002], internal globus pallidus [Coubes et al., 2000; Tronnier and Fogel, 2000; Vercueil et al., 2001], and, most recently, subthalamic nucleus [Deep-brain stimulation for Parkinson’s Disease Study Group, 2001; Benabid et al., 2001]. The advantage of deep brain stimulation is the ability to control the current delivery and the ability to select one or a combination of up to four electrodes through an external programmer. The stimulation wire is implanted using a combination of stereotactic neurosurgical techniques and usually microelectrode recording for precise localization. The lead is connected to a pacemaker implanted in the chest. For generalized dystonia, usually both sides need to be implanted. The full effect of ablative surgery or stimulation implantation is often not seen for many months, and there are reports of continued improvement up to 1 year or longer after pallidotomy [Lin et al., 2001]. Surgical procedures in the globus pallidus internus seem to be particularly effective in DYT-1 and other primary dystonias [Eltahawy et al., 2004; Coubes et al., 2004], [Vercueil et al., 2002; Ford, 2004; Vitek et al., 1998; Lozano et al., 1997], and these are cases in which earlier intervention may be most effective [Coubes et al., 2000]. The secondary causes of dystonia may also respond [Ghika et al., 2002; Rakocevic et al., 2004], but surgery seems to be less effective for secondary dystonia [Cif et al., 2003], [Coubes et al., 2002; Krack and Vercueil, 2001; Teive et al., 2001]. The largest case series suggests up to 50 percent effectiveness in children with secondary dystonia, but up to 80 percent effectiveness in children with primary dystonia. Complications are essentially those of the implantation procedure. Infections do occur, but these are rare outside of the immediate perioperative period. Batteries will need to be replaced every 3–5 years, and this requires a much simpler surgical procedure. The long-term efficacy of deep brain stimulation is not known. Whether there is a difference in programming parameters between children and adults is likewise not known.

Treatment of Dyskinesia and Hyperkinetic Dystonia

Hyperkinetic disorders are more difficult to treat and, although they represent a positive symptom, it is often difficult to remove the effects of dyskinetic movements through botulinum toxin due to the likely need to paralyze the affected muscle completely. Trihexyphenidyl can often make dyskinesia worse, as can l-DOPA. There is some effectiveness of clonazepam and valproate. Tetrabenazine [Jankovic and Orman, 1988; Jankovic and Beach, 1997], reserpine, and amantadine have been tried, but there are no consistent reports of benefit. Whether hyperkinetic dystonia and dyskinesia respond to pallidotomy or deep brain stimulation is not currently known. In Parkinson’s disease, pallidotomy does seem to improve dyskinesias, but the mechanism of dyskinesia in this case may be very different from the hyperkinetic symptoms seen in children, and there are not yet adequate data to guide therapy.

Classification of Tremor

Tremor has been described as “a rhythmical, involuntary, oscillatory movement of a body part” [Deuschl et al., 1998]. It can be classified based on the time of greatest severity as rest, postural, action, or intention tremor. Rest tremor is defined as tremor involving a body part that is inactive and supported against gravity. It may improve during movement. Rest tremor is most commonly associated with other signs of parkinsonism, but may occur in isolation. Postural tremor is worse when a child attempts to sustain a posture against gravity, such as with the arms outstretched in front or with the hands near the nose. It may improve with movement or with rest supported against gravity. Action tremor is worse during active movement, but postural or rest components may be present as well. Intention tremor is a specific form of tremor associated with cerebellar disorders, in which the tremor becomes worse as the arm approaches an endpoint or target, and there is great difficulty achieving target accuracy. Tremor can affect the head [DiMario, 2000], extremities, trunk, or voice.

Tremor can be described in terms of its frequency. Tremor associated with Parkinson’s disease or parkinsonism is between 4 and 6 Hz [Findley et al., 1981], while essential tremor is more likely at 5–8 Hz [Elble, 2000], and physiologic tremor has two components at 8–12 Hz and at 20–25 Hz [Makabe and Sakamoto, 2002; Takanokura et al., 2002]. In diagnosing tremor, it is important to distinguish it from dystonic tremor and myoclonus. Dystonic tremor, as described above, tends to be less regular, and often exhibits a null point. Myoclonus can be rhythmic and can be a form of tremor, but the rapid shocklike quality distinguishes it from tremor. Electromyography may be helpful in distinguishing myoclonic-type tremor from other forms of tremor, due to the short bursts of less than 50 milliseconds and correlation with scalp potentials that are often seen with myoclonus [Shibasaki et al., 1986; Shibasaki, 2000]. Myoclonic tremor is also more likely to have a burst-and-release (saw-tooth) pattern rather than a symmetric back-and-forth reciprocal pattern [Sanger et al., 2010].

Causes of tremor in childhood are summarized in Box 68-3.

Box 68-3 Causes of Tremor in Childhood

Benign Disorders

Enhanced physiologic tremor

Shaking/shuddering spells

Spasmus nutans

Static Injury/Structural Disorders

Stroke (particularly in the midbrain or cerebellum)

Multiple sclerosis

Hereditary/Degenerative Disorders

Familial essential tremor

Juvenile parkinsonism (tremor is rare)

Pallidonigral degeneration

Wilson’s disease

Huntington’s disease

Metabolic Disorders

Hyperthyroidism

Hyperadrenergic state (including pheochromocytoma and neuroblastoma)

Hypomagnesemia

Hypocalcemia

Hypoglycemia

Hepatic encephalopathy

Vitamin B₁₂ deficiency

Drugs/Toxins

Valproate

Lithium

Tricyclic antidepressants

Stimulants (cocaine, amphetamine, caffeine, thyroxine, bronchodilators)

Neuroleptics

Cyclosporine

Toluene

Mercury

Thallium

Amiodarone

Nicotine

Lead

Manganese

Arsenic

Cyanide

Naphthalene

Ethanol

Lindane

Serotonin reuptake inhibitors

Other Causes of Tremor

Peripheral neuropathy

Cerebellar disease or malformation

Anxiety

Psychogenic tremor

Primary Tremor

Etiologies of primary tremor are shown in Box 68-3. Familial essential tremor is an autosomal-dominant disorder with variable penetrance and severity. It can present in childhood and often is slowly progressive over many years [Jankovic et al., 2004; Louis et al., 2001; Paulson, 1976]. It is rarely disabling in childhood, except in extreme cases. Tremor is primarily postural, but can also be worsened with action. Tremor with holding a cup or handwriting are often some of the earliest complaints, but head, trunk, and voice can be affected [Jankovic, 2000]. There is no specific treatment. In adults, there may be a statistical association between essential tremor and Parkinson’s disease [Yahr et al., 2003].

Task-specific tremor is rare in children; when it does occur, it most often seems to involve handwriting. Whether task-specific tremors are a variant of dystonic tremor with task specificity, or whether this is a form of essential tremor is not known [Rosenbaum and Jankovic, 1988]. It is important to examine the child for other evidence of dystonia either in the affected limb or elsewhere. Medical treatment is usually ineffective, but occupational therapy may be helpful to develop compensatory strategies.

Physiological tremor is normally present and becomes particularly noticeable when a muscle is exerting high levels of force [Makabe and Sakamoto, 2002; Takanokura et al., 2002]. The distinguishing characteristic of physiologic tremor is that it occurs or worsens only when the child is carrying a heavy object or otherwise needs to contract the muscle against high resistance. Some children have an enhanced physiologic tremor that can become noticeable but is only rarely bothersome. There is no effective treatment for enhanced physiological tremor, but progression is probably rare.

Tremor is a frequent manifestation seen in psychogenic movement disorders. As noted in the section on psychogenic dystonia, psychogenic tremor likely represents a conversion reaction, and may reflect relatively serious psychopathology with consequent poor prognosis [Miyasaki et al., 2003; Kim et al., 1999]. Psychogenic tremor can often be distinguished from organic bases of tremor by entrainment (i.e., synchronization) to the examiner. In particular, when a child is asked to make a rhythmic movement with the unaffected hand or foot at a rhythm different from the tremor, often the tremor will entrain to the rhythmic movement, or the rhythmic movement will entrain to the tremor, such that either the tremor becomes irregular during accurate performance of the rhythmic movement, or performance of the rhythmic movement is impossible in the apparently unaffected limb [Zeuner et al., 2003]. Similarly, distraction using mathematical tasks or other difficult cognitive tasks can often change the nature or frequency of a physiologic tremor, but this would not be expected to occur for an organic tremor. However, the severity (but usually not the frequency) of an organic tremor can worsen in the context of a cognitive performance task if it is worsened by stress.

Other causes of tremor include Parkinson’s disease, although the tremor-dominant form is much more common in adults than children. HD can cause tremor, although other symptoms usually dominate. Spasmus nutans is an unusual tremor-like disorder seen in infants, usually starting as early as 4 months of age and lasting several years. Shaking and shuddering spells are rarely observed in the clinic and diagnosis rests on parental description of the typical episodes. These are a benign phenomenon, and are described in a separate section.

Secondary Tremor

There are a large number of secondary causes of tremor, and many of these are listed in Box 68-3. It is important to exclude Wilson’s disease. This disorder is characterized by a wing-beating tremor that often involves the adductors of the arm, and is shown when the child is asked to abduct the arms with elbows bent [Stremmel et al., 1991; Saito, 1987]. The tremor is primarily postural but may occur at rest. Other forms of tremor may occur in individuals with Wilson’s disease. Other symptoms include dystonia, rigidity, dysarthria, and psychiatric disorders. The defect is due to a mutation in the ATP7B copper-transport atp-ase gene on 13q14.3, which leads to reduced biliary excretion of copper and consequent accumulation of copper in multiple tissues. Symptom onset is between 6 and 45 years of age. Diagnosis of Wilson’s disease is made by noting a low serum ceruloplasmin and elevated excretion of copper in a 24-hour urine collection with measurement of the copper to creatinine ratio. In patients with neurological symptoms, slit-lamp examination almost always reveals Kayser–Fleischer rings. Overt or occult liver disease is often, but not always, present. Because Wilson’s disease is treatable, it is very important to assess patients with tremor for this disorder. Common treatments include zinc acetate, trientine, or penicillamine, although if disease is not detected early, then liver transplantation may be needed [Roberts and Schilsky, 2003].

Rubral tremor describes a large-amplitude, rhythmic, but partly ballistic movement that often affects the arms and can be unilateral. It is associated with attempts at movement and is therefore an action tremor. In some cases, it can be difficult to distinguish chorea from rubral tremor, although rubral tremor is much less common. It is associated with lesions in the thalamus [Tan et al., 2001], midbrain [Leung et al., 1999], pons, or cerebellar peduncles, and not necessarily the red nucleus, despite its name. Rubral tremor is usually nonprogressive but can be severely disabling.

It is important, in the work-up of a tremor, to exclude hyperthyroid states, and they either can be a primary cause of tremor or can worsen a pre-existing tremor. Hyperadrenergic states can cause tremor, and may occur in the presence of tumors that secrete epinephrine, such as pheochromocytoma or neuroblastoma; they can also occur in the context of severe anxiety disorders. Tremor can accompany electrolyte or glucose abnormalities, and vitamin B₁₂ deficiency, and may occur in response to medication, including valproate, lithium, tricyclic antidepressants, and stimulant medication such as methylphenidate.

Treatment of Tremor

The first goal in treatment of tremor is to exclude other possible causes of rhythmic movement, including myoclonus, dystonia, seizures, or cerebellar dysfunction. Any underlying metabolic or hormonal cause must be corrected. Essential tremor is treated with propranolol, primidone, benzodiazepines (clonazepam may be particularly effective), or gabapentin [Jankovic et al., 2004; Paulson, 1976; Rajput et al., 2004; Gironell et al., 1999]. If tremor is caused or worsened by anxiety, benzodiazepines or a serotonin reuptake inhibitor may be helpful. Tremor due to “stage-fright,” social phobia, or panic disorder often responds to propranolol.

These same medications can be tried in other forms of tremor, but usually there is minimal responsiveness. Rubral tremor is notoriously refractory to all attempts at intervention, although some cases will respond to l-DOPA [Yuill, 1980; Findley and Gresty, 1980], clonazepam [Jacob and Pratap Chand, 1998], or thalamic deep brain stimulation [Nikkhah et al., 2004].

Parkinson’s Disease

Primary causes of parkinsonism in children are rare [Pranzatelli et al., 1994]. DRD may be a relatively common cause compared to others, and has been described above. Juvenile Parkinson’s disease presents with leg dystonia in younger children, and bradykinesia and rigidity in older children. It rarely demonstrates tremor. It most commonly presents in young adults, and childhood or juvenile onset is rare. Many cases are due to mutations in the Parkin gene, labeled PARK-2, on chromosome 6Q25.2–27 [Ruiz-Linares, 2004; Huynh et al., 2003]. This is autosomal-recessive, and can be contrasted with the autosomal-dominant inheritance of some forms of adult parkinsonism associated with mutations in the alpha-synuclein gene. The autosomal-dominant form does not appear to occur in childhood. Other genes have been identified in specific families [Bentivoglio et al., 2001; DeStefano et al., 2002; Valente et al., 2002; West et al., 2002a, b, 2003]. The pathology of Parkin-associated Parkinson’s disease does not show Lewy bodies, although there is neuronal loss and neurofibrillary tangles. Fluoro-dopa PET scanning can show decreased uptake, suggesting a presynaptic abnormality consistent with degeneration of the nigro-striatal pathways, rather than a metabolic defect in the synthesis of dopamine, as seen in DRD [Khan et al., 2002; Pal et al., 2002].

Juvenile Parkinson’s disease is l-DOPA-responsive in the early years. It will also respond to anticholinergic medication, dopamine agonists, and inhibitors of dopamine breakdown. However, escalating doses are required, and children eventually will develop dyskinesias similar to those seen in adults on chronic dopaminergic therapy. It is important to differentiate this disorder from dopamine-responsive dystonia, as well as other disorders that may respond to dopaminergic medication, since the prognosis is different, and since it may be helpful to consider treatment with dopamine-sparing medications, including dopamine agonists or inhibitors of dopamine breakdown, in order to prolong the efficacy and delay the onset of dyskinesias.

Etiologies of parkinsonism are summarized in Box 68-4.

Box 68-4 Causes of Parkinsonism

Static Injury/Structural Disorders

Basal ganglia infarcts

Brain tumor

Hydrocephalus

Hereditary/Degenerative Disorders

Juvenile Parkinson’s disease

Spinocerebellar ataxia

Huntington’s disease (Westphal variant)

Pantothenate kinase-associated neurodegeneration (PKAN)

Rett’s syndrome

Pelizaeus–Merzbacher disease

Machado–Joseph disease (spinocerebellar ataxia type 3)

Ceroid-lipofuscinoses

Neuronal intranuclear inclusion body disease

Metabolic Disorders

Dopa-responsive dystonia

Tyrosine hydroxylase deficiency and other abnormalities of bioamine metabolism

Abnormalities of folate metabolism

Wilson’s disease

Basal ganglia calcification (Fahr’s disease, hypoparathyroidism)

Infectious/Para-Infectious Disorders

Encephalitis lethargica (Von Economo’s disease)

Viral encephalitis

Acute demyelinating encephalomyelitis

Drugs/Toxins

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) poisoning

Rotenone

Tetrabenazine

Reserpine

Methyldopa

Sedatives

Neuroleptics

Antiemetics

Calcium channel blockers

Isoniazid

Serotonin reuptake inhibitors (sertraline, fluoxetine)

Meperidine

Disorders that Mimic Parkinsonism

Catatonia

Spasticity

Hypothyroidism

Depression (with psychomotor retardation)

Secondary Parkinsonism

Secondary causes of parkinsonism are shown in Box 68-4. These include infarcts, particularly in the striatum or pallidum, as well as the ceroid-lipofuscinoses, in which a combination of bradykinesia and visual loss leads to a very striking hesitancy of gait [Nijssen et al., 2002]. PKAN, as described above, can cause bradykinesia. Similarly, spinocerebellar ataxia, Rett’s syndrome, HD, and Wilson’s disease can be causes of bradykinesia. Parkinsonism can be associated with acute encephalitis or postencephalitic parkinsonism. The widespread epidemic of encephalitic parkinsonism (von Economo’s disease) that occurred between 1916 and 1930 has not recurred, and the term encephalitis lethargica should probably be reserved for patients who were victims of that epidemic. There are reported cases of a similar syndrome following streptococcal illness [Vincent, 2004; Dale et al., 2004; Kiley and Esiri, 2001]. Whether or not the original epidemic of encephalitis lethargica was due to influenza virus remains in question [Lo et al., 2003; Jellinger, 2001].

Several medications and toxins are known to cause parkinsonism [Pranzatelli et al., 1994]. This is a common side effect of tetrabenazine and reserpine, and can be seen with neuroleptic treatment as well. The chemical MPTP, which is a synthetic methamphetamine derivative used for illicit recreational purposes, led to several cases of very rapid onset of irreversible parkinsonism, but also has become very important in research into the pathogenesis and treatment of parkinsonian syndromes [Eldridge and Rocca, 1985; Burns et al., 1985].

Treatment of Parkinsonism

Bradykinesia is the primary symptom that is responsive to treatment in childhood parkinsonism. It is usually assumed to be due to dopamine deficiency, and therefore is treated with l-DOPA or dopamine agonists. l-DOPA is combined with a peripheral decarboxylase inhibitor, such as carbidopa, in order to reduce side effects and increase delivery to the brain. Treatment is often initiated with a single dose of l-DOPA 1 mg/kg (or 50–100 mg total) given in the morning to evaluate for potential side effects, including nausea or postural hypotension. If this dose is tolerated for 3–4 days, then therapeutic treatment can be initiated three times per day. Unless symptoms are present at night, the doses are usually given during the daytime to maximize effect. Dosage can be increased to a maximum of 10–15 mg/kg/day (divided into three doses), depending on effectiveness. In addition to nausea and hypotension, common side effects can include dystonia, agitation, sleeplessness, and behavior changes. The dosage must be adjusted gradually in order to find the optimal dose, and the optimal dose may change as the child grows. Additional carbidopa may be given to decrease nausea.

In adults and children with Parkinson’s disease, long-term treatment with dopamine will eventually lead to dyskinesias and freezing episodes that can limit its use. Some authors have advocated “dopamine-sparing” strategies that involve the early use of dopamine agonists, such as pergolide, pramipexole, or ropinirole, or of dopamine breakdown inhibitors, such as entacapone or selegiline [Jenner, 2003]. This approach has not been studied in children.

Amantadine may be used to treat dyskinesias associated with acute or chronic use of l-DOPA [Furukawa et al., 2004b], and it has some antiparkinsonian effects as well [Paci et al., 2001; Crosby et al., 2003]. Anticholinergic medication will improve parkinsonism, but it is more commonly used to treat associated dystonia. Deep brain stimulation in the internal globus pallidus or subthalamic nucleus has met with success in ameliorating symptoms of adult Parkinson’s disease [Peppe et al., 2004; Germano et al., 2004]. Whether similar neurosurgical procedures would be effective in juvenile parkinsonism is not known.

Failure of dopaminergic transmission can be divided into presynaptic and postsynaptic forms. In presynaptic failure, there is reduced production or release of dopamine at nigrostriatal nerve terminals. This is typical in juvenile Parkinson’s disease and DRD. In postsynaptic failure, there is injury to the striatal targets. This is typical following encephalitis or hypoxic injury. Treatment with dopaminergic medication is most successful when there is presynaptic failure. If injury is primarily postsynaptic, there may be some mild benefit from dopaminergic medication, but the effect will be limited.

Classification of Myoclonus

Several different schemes have been used to classify myoclonus, using clinical, anatomical, or etiological criteria. Perhaps the simplest classification is based upon when the myoclonus occurs. Thus, myoclonus may occur at rest, with action, or in response to a sensory stimulus (reflex myoclonus). In adults, it is helpful to classify based on presumed neuroanatomical location, e.g., cerebral cortex, thalamus, brainstem, or spinal cord. The neurophysiology of myoclonus has been reviewed elsewhere [Caviness and Brown, 2004; Shibasaki and Hallett, 2004]. In children, etiological classification is the most useful, as summarized in Box 68-5.

Box 68-5 Etiologic Classification of Myoclonus

Physiologic

Hiccups

Hypnic jerks (sleep starts)

Nocturnal (sleep) myoclonus

Developmental

Benign neonatal sleep myoclonus

Benign myoclonus of early infancy

Myoclonus with fever

Essential

Familial myoclonus dystonia syndrome

Psychogenic

Symptomatic

Storage diseases

Juvenile Gaucher’s disease (type III)

Sialidosis type 1 (cherry-red spot–myoclonus)

GM₁ gangliosidosis

Neuronal ceroid-lipofuscinosis (late infantile juvenile)

Degenerative Conditions

Dentato-rubro-pallido-luysian atrophy (DRPLA)

Huntington’s disease

Progressive myoclonus ataxia

Ramsay–Hunt syndrome

Dementias

Bovine spongiform encephalopathy

Creutzfeldt–Jakob disease

Infectious and Postinfectious

Meningitis (viral or bacterial)

Encephalitis

Epstein–Barr virus (EBV)

Coxsackie virus

Influenza

Human immunodeficiency virus (HIV)

Acute disseminated encephalomyelitis (ADEM)

Metabolic

Uremia

Hepatic failure

Electrolyte disturbances

Hypo- or hyperglycemia

Aminoacidurias

Organic acidurias

Urea cycle disorders

Myoclonic epilepsy with ragged red fibers (MERRF)

Mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS)

Biotinidase deficiency (usually epileptic)

Cobalamin deficiency (infantile)

Opsoclonus-myoclonus syndrome (myoclonic encephalopathy of infancy)

Toxic

Psychotropic medications (tricyclic antidepressants, lithium, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, neuroleptics)

Antibiotics (penicillin, cephalosporins, quinolones)

Antiepileptics (phenytoin, carbamazepine, lamotrigine, gabapentin, benzodiazepines [in infants], vigabatrin)

Opioids

General anesthetics

Antineoplastic drugs

Strychnine, toluene, lead, carbon monoxide, mercury

Hypoxia

(Lance–Adams syndrome)

Physiologic and Developmental Myoclonus

Physiologic myoclonus is that which occurs in normal individuals in specific settings. It includes such entities as hiccups, sleep starts, and sleep myoclonus. Sleep starts, also known as hypnic or hypnagogic myoclonus, occur with sleep initiation [Montagna, 2004]. They are often accompanied by a sense of falling. Sleep starts are normal physiologic phenomena and no treatment is required. Sleep myoclonus (nocturnal myoclonus) is also a part of normal sleep physiology. It is thought to result from paradoxical excitation during rapid eye movement (REM) sleep, due to transient failure of brainstem inhibition [Montagna, 2004]. Sleep myoclonus in older children is more fragmentary than neonatal sleep myoclonus and tends to persist throughout life. No treatment is required.

Benign myoclonus may occur in association with specific developmental stages. Benign neonatal sleep myoclonus and benign myoclonus of early infancy are discussed in the section entitled “Transient Developmental Movement Disorders,” below. Myoclonus can also occur with fever in otherwise normal children [Dooley and Hayden, 2004]. The myoclonic jerks may be quite frequent, but they are self-limited, ceasing when the fever resolves. Febrile myoclonus may be more common in younger children. No treatment is required.

Essential Myoclonus

Essential myoclonus is a relatively mild condition, starting in the first or second decade. It is inherited as an autosomal-dominant trait with incomplete penetrance [Quinn, 1996; Fahn and Sjaastad, 1991]. It is usually slowly progressive for a few years after onset and then stabilizes. The myoclonus may fluctuate slightly over the years, or may show mild spontaneous improvement. The myoclonus usually responds to ethanol, but the magnitude of benefit varies across individuals, and ethanol is not useful as a long-term treatment. The most common mutation identified is in the epsilon-sarcoglycan gene (7q21–q31). Mutations in this gene have also been associated with myoclonus-dystonia syndrome (see above). Many patients with essential myoclonus also have dystonia, and it appears that the two clinical syndromes may have the same underlying genetic basis [Nygaard et al., 1999; Quinn, 1996]. Some family members may have only myoclonus, and others may have only dystonia, while yet others may have both myoclonus and dystonia. Essential myoclonus may respond to benzodiazepines, primidone, or propranolol.

Symptomatic Myoclonus

Myoclonus can by symptomatic of many disorders, as listed in Box 68-5. Many of these conditions are discussed elsewhere in this text. In this section, we discuss specific conditions in which myoclonus can be the primary feature.

Treatment of Myoclonus

Myoclonus is often refractory to medical treatment. Cortical myoclonus may respond to benzodiazepines and is commonly treated with clonazepam (although sleep myoclonus may worsen [Reggin and Johnson, 1989]). Valproic acid is sometimes helpful, but it must be used with caution due to the ability to cause tremor as a side effect, with consequent confusion of symptoms. Piracetam has been used for many years to treat myoclonus, with good efficacy. Levetiracetam is a piracetam analog, but does not seem to have equivalent efficacy to piracetam for treatment of myoclonus. There are reports of efficacy with zonisamide in some forms of myoclonus [Kyllerman and Ben-Menachem, 1998; Wallace, 1998]. Posthypoxic myoclonus seems to be particularly responsive to serotonergic medications, including selective serotonin reuptake inhibitors and oral administration of 5-hydroxytryptophan or 5-hydroxytryptamine. Baclofen has been occasionally used, but the mechanism of action is not clear. Carbamazepine can worsen myoclonus.