Evaluation In a typically developing child with tics and an otherwise normal neurological e xamination, ancillary studies such as EEG, nerve conduction studies (NCS) and EMG, and brai n MRI are usually normal, and thus are not recommended unless there is some doubt about the diagnosis, there are atypical features, or the onset is later in childhood than would be e xpected for primary tic disorders. However, given the high burden of co-morbid psychopathol ogy, particularly in TS, identifi cation of the presence of tics is an oppor- tunity to exp lore and address other diagnoses. Careful evaluation of academic performance, socialization , and mood is warranted. Patients with TS are at increased risk for non-OCD generalized anxiety disorder, panic diso rder, specifi c phobias, and mood dis- orders, including depression (72). Separation anxiet y is common among children with TS and may be exacerbated by use of neu- roleptic agents wh ich can cause a specifi c school phobia (73). Episodic rage is oft en provoked by unmet expectation or a change in plan, is out of propor tion to the inciting incident, is directed, is brief in duration (<30 min), and is followed by remorse and regret. Parents or siblings are the most common targets, and rage attacks o ccur almost exclusively at home (74). Many children feel out of control during attacks, but some are able to sense when a rage attack is impending, which may be a tool for behavioral thera- pies. Parents oft en describe the spells as being incongruent with the child \200 \231s personality and temperament between attacks. Stephens and Sandor (73) evaluated 33 co nsecutive medication-free children with TS and found that children with TS plus ADHD or OCD were at increased risk for aggressive behaviors compared with children with TS only. Child ren with TS alone were similar to controls in aggressive behavior profi le. ADHD and OCD, b ut not tic sever- ity, best correlate with aggression in TS. Similarly, children with TS on ly are comparable to controls in the occurrence of disrup- tive behaviors, which are more f requent in children with TS plus ADHD or ADHD alone (75). Treatment For many children with tics, identifi cation of the problem and education regardi ng tics, low likelihood of impairment, and nat- ural history are suffi cient. If tics are n ot functionally impairing, do not cause signifi cant social embarrassment or school dysfunc - tion, and are not bothersome to the patient, treatment may not be warranted. Treatment is symptomatic only; it is not clear that treatment of tics alters the natural history of the disorder. When symptomatic treatment is required, the most troublesome symp- tom should be established and targeted fi rst, which may be a symp- tom other than tics. Given the waxing and waning nature of tics, it may be challen- ging to decide when to initi ate treatment. If a patient presents with worsening tics at a time consistent with prior fl ares, such as at the beginning of the school year, a period of waiting and supportive mana gement may be appropriate. It is unlikely that tics will be com- pletely eliminated by a pa rticular treatment regimen, but signifi cant improvement can occur, with return to premorbi d functioning. Tics are oft en non-impairing, and certainly life-threatening tics are rare. When tics or a ssociated disorders and behaviors result in emergency room visits or hospitalizations, the syndrome may be categorized as malignant TS. In a review of 333 individuals with TS, 5.1% w ere considered to have malignant TS. Emergency visits typically relate to anger, violence, self-injurious behavior, or sui- cidality. Malignant TS, oft en refractory to standard trea tments, has been associated with more complex tic symptomatology, suicidal ideation, and a greater burden of co-morbid disorders, especially OCD (76). Self-abusive tics were reported to be present in 13% of one sample of 250 children with TS (64). Serious TS-related seque- lae reported in the literature include third-degree burns, pica, eye For children with problematic tics, alpha-2-adrenergic agonists, which are typically well t olerated, are reasonable fi rst-line agents, even though they demonstrate only moderate eff i cacy. Guanfacine may be preferred to clonidine because of its longer half-life, and thus fewer daily doses and lesser sedative eff ects. Both tics and ADHD may respond to intervent ion with alpha-2-adrenergic Oxford Textbook of Movement Disorders 252 agents. Guanfacine and clonidine should be tapered aft er prolonged use to avoid rebound hy pertension. for tics (CBIT) consists of habit reversal training with tic aware- ness and competing resp onse components, relaxation training, and functional interventions to target environments a nd situations where tics worsen (92). Although benefi cial for targeting specifi c problema tic tics, barriers to implementation of CBIT include lack of access to trained providers an d commitment to practice on the part of the patient. Very young and/or highly inattentive c hildren may not be appropriate candidates for this behavioral intervention. Dopamine receptor antagonists demonstrate greater effi cacy, but use may be limited by side -eff ect profi le. If fi rst-line therapy is insuffi cient, addition or substitution of a d opamine receptor blocker is an appropriate next step. Haloperidol and pimozide are the only two neuroleptics approved by the FDA for treatment of TS. Th ree trials have demonstrated superiority of pimozide to placebo in the treatment of tics. Two studies found no signifi c ant diff er- ence between haloperidol and pimozide, while one study showed inferiority of p imozide. Pimozide may demonstrate better overall tolerability and fewer extrapyramidal side eff ects than haloperidol (79). Risperidone has also shown effi cacy in the management of tics (80). Tic suppression correlates with D2 receptor binding affi n- ity, and thus some a typical antipsychotics such as quetiapine show limited benefi t. No signifi cant diff erenc e was observed between ris- peridone and pimozide in a randomized clinical trial (81). Treatment with botulinum toxin can be a very eff ective therapy for specifi c tics that are confi ned to a focal anatomical region, such as cervical tics or very loud vocalizations. Botulinum toxin may reduce the frequency and severity of tic as well as diminishing the pre monitory urge (49, 93, 94). Consideration of an invasive or surgical approach for pediatric TS is a complex decision, g iven the natural history of improvement in tics in late adolescence or adulthood. However, some patients with severe TS fail to demonstrate such a trajectory of improve- ment and hav e life-threatening tics that are refractory to treatment. Another consideration is that qua lity of life may be determined to a greater degree by other factors than tics, even when th ey are severe. Th ere are reports of effi cacy with use of tetrabenazine (82 \200\22384), baclofen (85), a nd topiramate (86, 87), and in open-label trials of levetiracetam (88, 89). Of note, in bli nded randomized trials ver- sus placebo or clonidine, levetiracetam did not demonstrate ben efi t (90, 91). Tetrabenazine, in contrast with dopamine receptor antag- onists, does not c arry the risk of development of tardive dyskinesia. However, its use may be limited by the side eff ect of depression. In a series of 18 patients with long-standing refractory TS, all responded to bilateral tha lamic DBS with decreased tic severity and decreased medication requirement. However, 12 exp erienced tic recurrence, with signifi cant waning of initial benefi t aft er 3 \200\2236 mo nths in three subjects. Most required frequent reprogramming aft er 6 months to address sym ptom fl uctuation. Serious adverse events included poor wound healing related to compulsive touch- ing of the incision ( n = 1) and abdominal haematoma at the pulse generator site ( n = 1) (95). Th ree of fi ve patients who underwent Specifi c agents, doses, and common side eff ects are listed in Table 24.3. In a recent ran domized observer-blind trial of behav- ioural intervention versus supportive therapy and ed ucation, over 50% of those randomized to behavioral intervention dem- onstrated benefi t de scribed as \200\230very much improved \200\231 or \200\230much improved \200\231. Most co ntinued to demonstrate benefi t 6 months aft er the initial intervention. Comprehensive beh avioral intervention Table 24.3 Tic pharmacotherapy Class Medication : generic name Clonidine Starting dose Maintenance daily dose 0.05 \200\2230.5 mg/day Common side e \200 ects 2 -adrenergic agonist 2 -adrenergic agonist 0.025 \200\2230.05 mg bid \200\223tid Sedation, dizziness 0.5 mg qd 0.5 \200\2234 mg/day Sedation, headache, irritability, dry mouth, syncope Guanfacine Clonazepam Benzodiazepine 0.125 \200\2230.5 mg qd \200\223bid 0.5 \200\22310 mg/day Sedation Haloperidol* Dopamine receptor antagonist, typical antipsychotic 0.25 \200\2230.5 mg bid \200\223tid 0.5 \200\22320 mg/day Sedation, weight gain, metabolic syndrome, cardiac arrhythmias, school phobia, hepatotoxici ty Pimozide* Dopamine receptor antagonist, typical antipsychotic 0.5 \200\2231 mg bid 0.5 \200\22310 mg/day Sedation, weight gain, metabolic syndrome, cardiac arrhythmias**, school phobia, hepatotoxi city Risperidone Dopamine receptor antagonist, atypical antipsychotic 0.25 \200\2230.5 mg qd 0.5 \200\22316 mg/day Sedation, weight gain, metabolic syndrome, cardiac arrhythmias** Aripiprazole Dopamine receptor antagonist, atypical antipsychotic 2 \200\2235 mg qd 5 \200\22330 mg/day Sedation, weight gain, metabolic syndrome Tetrabenazine Dopamine depletor, dopamine receptor antagonist GABA B agonist Carbonic anhydrase inhibitor , antiepileptic 12.5 \200\22325 mg qd 25 \200\223200 mg/day Depression, sedation 5 \200\22310 mg bid \200\223tid 10 \200\223120 mg/day Sedation Baclofen Topiramate 15 \200\22325 mg qd \200\223bid 25 \200\223400 mg/day Sedation, cognitive slowing, nephrolithiasis, dizziness qd, once daily; bid, twice daily; tid, three times daily. FDA approved for treatment of tics. **Consider baseline and serial ECGs to monitor for prol ongation of the QT interval. CHAPTER 24 Tic Disorders and Stereotypies 253 bilateral thalamic DBS achieved marked improvement in tics, as measured by tic count and qu ality of life. Th ere were non-signifi cant trends towards improvement in anxiety, depressi on, and OC behav- iours. Unilateral stimulation did not produce an eff ect on tic fre- quen cy or severity (96). Others have achieved similar results with bilateral thalamic stimulati on (97). Until further data are available, surgical interventions are currently reserved fo r medically refrac- tory cases, ideally in adults. 20. Temudo T, Santos M, Ramos E, et al. Rett syndrome with and without detected MECP2 mutat ions: an attempt to redefi ne phenotypes . Brain Dev 2011; 33 : 69 \200\22376 . 21. Temudo T, Oliveira P, Santos M, et al. Stereotypies in Rett syndrome: analysis of 83 pa tients with and without detected MECP2 mutations . 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Deep brain stimulation in a Chinese Tourette \200\231s syndrome patient . Hong Kong Med J 2011; 17 : 147 \200\22350 . This page intentionally left blank CHAPTER 25 Myoclonus Marina A. J. Tijssen Summary Myoclonus is characterized by quick and involuntary jerks and clas- sifi ed as one of the hyperkinetic movement disorders. Myoclonus can be caused by muscle contractions (pos itive myoclonus) or by interruptions of tonic muscle (negative myoclonus). Th e main clas- sifi cation of myoclonus is based on the anatomical origin of the myoclonic jerks: cortical , subcortical, spinal, and peripheral myo- clonus, each with distinctive physiological mech anisms. Clinical characteristics, etiology, and treatment options are related to the anatom ical classifi cation of myoclonus. increases with muscle activation, while motor tics almost never interact with motor activit y. Furthermore, in contrast with tics, myoclonus is a non-suppressible and simple movement, not pre- ceded by an urge to move, and without relief aft er the movement. In contrast wit h tremor, myoclonus is generally arrhythmic. Th is can sometimes be diffi cult to discrimin ate in clinical practice and EMG registration might be required (9, 10). In dystonic jerks, the posture can oft en be infl uenced by a geste antagonistique , which is not seen in myo clonus. In chorea the individual movements can be myoclonic but the overall movements are m ore continuous and in a constant fl ow. Psychogenic movements can be a diffi cult diagnosis in jerky patients and will be discussed elsewhere in this chapter (see \200\230Etiology a nd genetics \200\231, p.258). In general, it should be appreciated that myoclonic jerks reg ularly occur in combination with other movement disorders (1). Th e epidemiology of myoclonus is poorly documented, as myo- clonus has many diff erent cau ses and a spectrum of clinical presen- tations. A single study showed a lifetime prevalence of 8.6 cases per 100 000. Th e etiology of myoclonus is diverse and in 70% of cases is sym ptomatic. Over the last 10 years new genes have been dis- covered for several myoclonic dis orders. Recent pathophysiological studies illustrate an important role for the cerebellum i n generat- ing both cortical and subcortical myoclonus, but further stud- ies addressing th e precise mechanism of myoclonus are required. Th erapy is usually symptomatic, as treatmen t of an underlying cause is oft en impossible or ineff ective. Th erapeutic options are mai nly based on a low level of evidence, as randomized controlled trials are not available. Th e identifi cation and classifi cation of myoclonus is important, with three generally ac cepted classifi cations: according to anatomi- cal origin, based on clinical signs, and bas ed on etiology (1, 5, 11). Th e three classifi cation systems are interrelated. In this cha pter, the anatomical classifi cation will be discussed fi rst as it forms the basis of the approach towards the patient with myoclonus. Anatomical classi \201 cation Myoclonus can originate from the cortex, subcortical areas ( includ- ing brainstem), spinal cord, or peripheral nerves. Classifi cation of the anatomica l origin of myoclonus is based on electrophysiologi- cal characteristics and is additionall y guided by clinical signs and the aetiological classifi cation. It should be noted that di ff erent types of myoclonus can occur in a single patient. Here, a short overview will be g iven. Essential background Myoclonus literally means \200\230a quick movement of muscle \200\231 and is clinically defi ned by sudden, brief, and shock-like involuntary movements caused b y muscle contractions (positive myoclonus) or muscle inhibition (negative myoclonus) (1, 2) . Th e term para- myoclonus multiplex for the sudden jerks was introduced in 1881 by Friedr eich in a patient with essential myoclonus (3). In 1963, Lance and Adams fi rst described n egative myoclonus in patients with post-hypoxic myoclonus (4). Cortical myoclonus originates from the cortex as a result of abnor- mal fi ring of the sens orimotor cortex (12). Body parts with the larg- est cortical representation, such as the ha nds and the mouth, are the most frequently involved (12, 13) (Video 25.1). Th e jerks are u sually (multi)focal and are exacerbated by voluntary movements. Continuous frequent focal s pontaneous jerks are also described as \200\230epilepsia partialis continua \200\231. Refl ex myoclonus is common; for example, the jerks can be elicited by touching the aff ected l imb (12, 14). Electromyographic examination shows short bursts (usually <50 ms) (15). With EEG \200\223EMG back-averaging a time-locked cor- tical spike preceding the jerk in the con tralateral hemisphere can Clinically, myoclonus is quite distinct. In most cases the diag- nosis can be established o n clinical grounds with a relatively high degree of diagnostic certainty. Alternative diagn oses include tics, tremor, dystonia, chorea, simple partial seizures, and psychogenic jerks . Clinical clues help to diff erentiate it from other movement disorders (5 \200\2238). For example, stimulus sensitivity can be present in patients with myoclonus, but is rare in ot her movement disor- ders. Myoclonus oft en interferes with voluntary movements and Oxford Textbook of Movement Disorders 258 can be triggered by voluntary movement and the burst duration varies (26). Epidemiology Epidemiological studies of myoclonus are scarce. Th e main prob- lem is that m yoclonus has many diff erent causes and a spectrum of clinical presentations, while epidemi ological studies have mainly been performed for specifi c diagnoses. Th ere is one study in a defi ned population in Olmsted County, Minnesota, showing that persistent and pathologic al myoclonus has a lifetime preva- lence of 8.6 cases per 100 000 (27). In that study the m ost com- mon etiology for myoclonus was symptomatic (72%), followed by epileptic (17%) and then essential myoclonus (11%) (27). In a study in patients in the emergency room because o f a move- ment disorder, 27.6% exhibited myoclonus, including patients with transient myocl onus (e.g. drug-induced) (28). Overall, myoclonus appears to be a relatively frequent cause of abnormal movement control. z Video 25.1 Th e video shows a patient with cortical myoclonus. Th e body parts with the l argest cortical representation, such as the hands and the mouth, are involved. Th e jerks a re multifocal and are exacerbated due to voluntary movements. Tapping the \201 ngers illu strates stimulus sensitivity. Etiology and genetics Marsden was the fi rst to classify myoclonus by etiology, comprising four main groups (1, 5). Th e fi rst group is physiological myoclonus, with examples such a s sleep jerks and hiccoughs, which are com- mon in healthy individuals. A second group is f ormed by \200\230essen- tial \200\231 myoclonus, or myoclonus dystonia, which is usually h ereditary (29, 30). Epileptic myoclonus forms the third group, dominated by epileptic seizu res (31). Th e last group, symptomatic myoclonus, is by far the largest, with approximately 70% of cases. In this group myoclonus is a manifestation of an underlying disorder, with n eu- rodegenerative disorders, hypoxia, drug-induced myoclonus, and toxic \200\223metabolic myoclonus as the main causes (28, 32). be found (16). Examination of the somatosensory evoked potential (SSEP) shows an enlarged ( giant) cortical amplitude (17). In subcortical myoclonus the source of discharges leading to myo- clonus is localized betwe en the cortex and the spinal cord. Th e clin- ical and electrophysiological characteristics are variable between the diff erent subtypes. In general, no signs of cortical hyperexcit- ability on EEG \200\223EMG or SSEP can be detected. Essential myoclonus or myoclonus \200\223dystonia (MD) (see \200\230Etiology and genetics \200\231, p.258, for more details) clinically consists of myoclonic jerks in the upper body oft en combined with mild to moderate dys- tonia. Th e myoclonus is not stimulus sensitive , but does increase with voluntary activity. On electrophysiology, no signs of cortical exc itability can be detected and EMG studies show short bursts (25 \200\223256 ms) (18, 19). T h e exact origin of the myoclonus is unknown but is considered to be subcortical. Physiological myoclonus Physiological myoclonus occurs in the normal population under certa in circumstances. Sleep jerks are the most frequent manifesta- tions, but hiccoughs are als o well known. Brainstem myoclonus represents generalized, synchronized, and especially axial jerks and is very sensitive to external stimuli (12, 20). EMG polymyography shows simultanous rostral a nd caudal activation of muscles (12, 21). Essential myoclonus In essential myoclonus or myoclonus \200\223dystonia (M D) , myoclonic jerks in the upper body are oft en combined with mild to moderate dystonia. Th e myoclonus is multifocal, with \200\230twitching \200\231 jerks of var- iable amplitude and intensity increasing with action, and tends to be responsive to alcohol (18, 19) (Videos 25.2 and 25 .3). Psychiatric symptoms such as depressed mood, anxiety or obsessive \200\223com- pulsive disorder are frequently observed (33). In most patients, symptoms occur within the fi rst two decades. MD is autosomal dominantly inherited, and a mutation in the epsilon-sarcoglyca n gene ( SGCE ) on chromosome 7q21 ( DYT11 ) is present in 30% of patients (34). If strict clinical criteria are applied, this number signifi cantly increases up to 50% (35). Penetra nce of MD is highly dependent on the parental origin of the disease allele, resulting from maternal imprinting (36). As DYT11 mutations are absent in up to 50% of patients with the M D phenotype, the involve- ment of other genes or environmental factors is suggested (35). A second locus has been reported in one large MD family (DYT15, 18p11), but no gene has yet been identifi ed (37, 38). SGCE is part of the sarcoglycan family which consists of N -glyc osylated Spinal myoclonus is the result of abnormal discharges generated in the spinal cord and can be subdivided into segmental and prop- riospinal myoclonus. Segmental myoclonus is a very rare disorder, inducing myoclonic jerks in muscles innervated by one or two contiguous spinal seg- ments. Th e jerks are continuous, rhythmic, unaff ect ed by voluntary movement or sensory stimulation, and oft en persist during sleep (22). On E MG recordings the frequency ranges from 1 to 200 per minute, with burst durations of up to 1000 ms. Propriospinal myoclonus is characterized by generalized axial muscle contractions, oft en i nduced by lying down, without involvement of the facial muscles (23, 24). Jerks can be spon tane- ous and stimulus sensitive (23, 25). Polymyography shows a slow spreading of activity with repetitive bursts of EMG activity (fre- quency 1 \200\2237 Hz) and a long duration (u p to several hudred mil- liseconds) (25). Peripheral myoclonus is very rare and is limited to one segment of the body, usually the pr oximal part of a limb or the trunk. Bursts CHAPTER 25 Myoclonus 259 Table 25.1 Causes of myoclonus Physiological myoclonus Essential myoclonus Sleep jerks, hiccoughs Myoclonus dystonia Epileptic myoclonus Parts of epilepsy Epileptic myoclonic jerks Photosensitive myoclonus Myoclonic absences with petit mal Epilep sia partialis continua Benign \200\230myoclonus of infancy \200\231 Infantile spasms Lenno x \200\223Gastaut epilepsy Cryptogenic myoclonic epilepsy Childhood myoclonic epilepsy Benign familial myoclonic epilepsy Familial cortical myoclonic tremor and epilepsy (FCMTE)