Spinal myoclonus Spinal myoclonus is the result of abnormal discharges generated in the spi nal cord. In segmental myoclonus the jerks are usually rhythmic with a frequency varying from 1 to 20 0 per minute. Th e duration of the EMG bursts can be up to 1000 ms. With nerve stimulation EMG discharges are found with diff erent latencies, possibly refl ecting involvement of pol ysynaptic pathways. Propriospinal myoclonus (PSM) is characterized by both spon- taneous and stimulus-sensitive jerks of the trunk and abdominal muscles, oft en induced by lying down (23, 24). PSM is pr esumed to originate from a spinal generator that elicits activity spreading up and down the spinal cord via intrinsic propriospinal path- ways (24). Electrophysiological features inc lude a fi xed pattern of muscle activation, slow spinal cord conduction velocity (5 \200 \22315 m/s), EMG burst duration of less than 1000 ms, and synchronous activation of agonist and antagonist muscles, without involve- ment of facial muscles (91). Diff usion tensor im aging showed Diagnosis Th e diagnostic procedure in patients with myoclonus starts with history, physica l examination, and determination of the clinical syndrome classifi cation (20). History tak ing includes mode of myo- clonus, onset, presence of other neurological problems, history o f Table 25.3 Th e clinical and anatomical classi \201 cation of myoclonus Anatomical classi \201 cation Subcortical BM Cortical Spinal PM MD SM Clinical presentation Spontaneous + \206\221 + + \206\221 \200\223 \200\223 \206\221 + + + \200\223 + \200\223 + During activity Stimulus sensitivity Distribution Focal (multi)+ \200\223 \200\223 +/ \200\223 \200\223 \200\223 \200\223 + + +/ \200\223 + \200\223 \200\223 \200\223 \200\223 + + Segmental \200\223 + \200\223 Generalized Synchronous Temporal pattern Irregular + +/ \200\223* + + \200\223 \200\223 + \200\223 \200\223 +/ \200\223 \200\223 \200\223 + \200\223 \200\223 Rhythmic Negative myoclonus Th e table correlates the clinical and anatomical classi \201 cation of myoclonus. + , lik ely to be a feature; +/ \200\223 , can be a feature; \200\223 , not usually a feature; \206\221 , increase ; MD, myoclonus dystonia; BM, brainstem myoclonus; SM, segmental myoclo nus; PM, propriospinal myoclonus. Cortical tremor can clinically resemble a tremor (see text). CHAPTER 25 Myoclonus 265 seizures, current and past drug or toxin exposure, past or current medical problems, and fa mily history. During physical examina- tion the features described under clinical diagnosis (Table 25.3) are determined. Th e combination of history and physical examination leads to the anatomical classifi cation of myoclonus. a combination may be best (93). In general, polytherapy is more eff ective than monotherapy in cortical myoclonus (93). Subcortical myoclonus Treatment options for diff erent forms of subcortical myoclonus are l argely based on small observational studies and case reports. Standard antiepileptic medica tion is usually not eff ective in sub- cortical myoclonus. In MD, L-5-HTP (a serotonin prec ursor) was eff ective in a few patients at the maximum dosage, but its use is oft en limite d by side eff ects (14). Other small studies showed an eff ect of sodium oxybate, levodopa, or zolpidem on myoclonus. Clonazepam, piracetam, levetiracetam, and trihexyphenidyl are al so prescribed for MD, but their eff ect is limited (93). In severe cases deep brain stimula tion of the GPi can be considered, with a good eff ect reported for motor symptoms (see (Vi deo 25.3). In brainstem myoclonus clonazepam is usually an eff ective drug. Furthermore, L- 5-HTP may be eff ective, but is frequently not well tolerated. In hyperekplexia a double-bl ind placebo-controlled study has shown a favorable eff ect of clonazepam on the magnitude o f motor startle refl exes and stiff ness (97). Orthostatic myoclonus treatment options incl ude clonazepam and gabapentin. If the patient suff ers from an acute or subacute form and the aeti- ological category can be determined with a relatively high degree of diagnostic certainty, basic and focused addi tional testing can sub- sequently be performed. Basic ancillary testing includes electrolytes, glucose, renal and hepatic function tests, t hyroid function, and, if history suggests it, a drug and toxin screen (20). An EEG is usefu l to identify both ictal and interictal patterns. Specifi c EEG spike patterns can point to wards specifi c diagnosis. Loss of a normal EEG background rhythm and abnormal slow waves s uggest diff use encephalopathy. Imaging of the brain or spinal cord can be performed if foc al lesions or metabolic disorders are suspected. If the myoclonus is more chronic or if the anatomical type of myo- clonus is unclear, clini cal neurophysiology testing can be performed to confi rm the anatomical classifi cation. Th is includes, based on the history and physical examination, an EMG to determine the dura- tion of the burst, an EEG, an EEG with back-averaging or coher- ence analysis, an SSEP, or a C-refl ex. Spinal myoclonus In spinal segmental myoclonus it is essential to treat the underlying caus e fi rst, before turning to symptomatic therapy. Clonazepam is considered the drug of choic e for segmental myoclonus, although the evidence is very limited. Alternatively, carbamazep ine, tetra- benazine, and botulinum toxin may also be benefi cial. For prop- riospinal myoc lonus, clonazepam is considered the drug of choice mainly based on clinical experience, whi le zonisamide may be an alternative (93). Advanced testing for rare and specifi c diagnoses should be guided by the most prominent cl inical features, age at onset, and the course of the myoclonic disorder (see \200\230Etiol ogy and genetics \200\231, p.258, and Table 25.1). Focused testing may comprise genetic tes ting, specifi c metabolic screening, lumbar puncture, and antibodies, including paraneoplas tic antibodies (20). Management Th erapy should fi rst focus on cure of the underlying disorder, such as removal of a medication or toxin or reversal of an acquired abnor- mal metabolic state (93). Unfor tunately, this approach is frequently impossible and symptomatic treatment is required. Th e treatment strategies for myoclonus are based on the anatomical classifi cation. In genera l, treatment is oft en diffi cult, and several drug trials are required to fi nd the best t herapy for an individual patient. Drugs are usually partially benefi cial and, because of t he frequent side eff ects, initial low dosages with slow increase are advised. Peripheral myoclonus Botulinum toxin is the therapy of choice for hemifacial spasm, based o n a randomized double-blind controlled trial in 11 patients (98) and on large observational studies with a good to excellent eff ect of botulinum toxin in most cases (93). Microsurgi cal vascular decompression is an alternative therapy, but the risk of complica- tions is hi gher. Botulinum toxin may also be eff ective in other types of peripheral myoclonus. Key advances Th e major breakthroughs in myoclonus over the last 10 years have come from ge netics. New genetic causes of myoclonus have been identifi ed, and the molecular basis of s everal conditions has been discovered (45). Genetic counseling is now available for some pa tients. Finding new genes enables us to defi ne and expand the phenotype of clinical syndro mes. New genes for several disorders with cortical myoclonus include Unverricht \200\223Lun dborg disease and myoclonic epilepsy with ragged red fi bres (45). Cortical myoclonus Th e treatment for cortical myoclonus is based on treatment strate- gies for myoclonic epilepsy (31, 94, 95). Treatment strategies spe- cifi c for cortical myoclon us are based on small observational studies and expert opinion as little evidence is availa ble. Some evidence can be found for piracetam (96), a well-tolerated drug, but the daily do se is high (up to 24 g/day). Levetiracetam (2000 \200\2233000 mg/day), an analog of piracet am, also has few side eff ects. Th e eff ect on epileptic myoclonus is positive, and the ev idence in non-epileptic cortical myoclonus is based on case series. Levetiracetam is con- s idered as the fi rst choice of treatment for cortical myoclonus (see (Video 25.1). Based on a long history of clinical experience, but without evidence in the literature, valproic ac id and clonazepam are also good therapeutic options. Clonazepam must be given in high doses in most cases (up to 14 mg/day), resulting in side eff ects such as drowsiness and sedatio n. In patients with post-hypoxic cortical myoclonus, valproic acid and clonazepam are equal ly eff ective and For subcortical myoclonus the SGCE gene was discovered in MD. Genetic testing showed that 3 0% of patients with the MD pheno- type showed a mutation or deletion in the gene. A stricte r defi ni- tion of the phenotype increased this to 50% (35). A second gene GLYT2 has been d iscovered for hyperekplexia (58). In about 20% of cases this gene shows a recessive or comp ound heterozygous mutation and has proved to be the main gene in sporadic cases of hyperekp lexia. Oxford Textbook of Movement Disorders 266 Electrophysiological studies have always been of great value in defi ning the type and stud ying pathophysiological mechanisms in myoclonus. Th e major breakthroughs, such as EEG \200 \223EMG back-averaging and SSEP giant potentials for cortical myoclonus, were performed mor e than 10 years ago. More recent EMG, TMS, local fi eld potential registrations aft er DBS, and MEG studies in both cortical and subcortical myoclonus have increased our under- stand ing of the pathophysiology of myoclonus. aetiological diagnosis to be made. In patients with progressive myoclonus epilepsies, it is not always possible to make a defi nite diagnosis. Th e fi nding of new genes in the futur e will improve this. Treatment options are also based on the anatomical classifi - cation o f myoclonus. Polytherapy is oft en required, but the eff ects are still frequently disappoi nting. Current practice is mainly based on small observational studies and expert opinion. Double-blind randomized controlled trials in large homogeneous patient groups using a stric t classifi cation strategy are required to develop guide- lines for treating myoclonus. Recent electrophysiological and clinical studies in propriospinal myoclonus have shown that PSM has a psychogenic origin in many patients, shedding new light on this patient group (2 2, 99). Key points From pathological studies it is increasingly apparent that dis- eases of the cerebellum are particularly important in the genesis of myoclonus, although the precise mechanisms and or igin of myo- clonus in many situations remains uncertain. Cerebellar pathology has been det ected in patients with cortical refl ex myoclonus, such as FCMTE (100) and coeliac disease (47). However, MD patients with subcortical myoclonus also show alterations in the cerebell um (89), suggesting a common pathway in the mechanisms generating myoclonic jerks. Myoclonic jerks regularly occur in patients in combination with other movement disorders. \227\206 Classifi cation of the anatomical origin of myoclonus is based on clinical and electrophysi ological characteristics. \227\206 Th e etiology of myoclonus is diverse and in 70% of cases is symptomatic. \227\206 Always rule out drug-induced myoclonus. \227\206 Future developments Th e progress likely to be made in understanding and treating myo- clon us in the next few years will come from further discovery of genetic mutations and from fun ctional studies improving our understanding of neural networks. Eff ective treatment of myo - clonus is still limited, and the challenge to develop more therapeu- tic options specifi cally designed for myoclonus rather than those intended for other disorders lies ahead. \206\223 \206\224 A diagnosis of psychogenic myoclonus should be considered \200\230idiopathic \200\231 prop riospinal myoclonus. \227\206 Treatment of cortical myoclonus is usually with polytherapy. \227\206 References 1. Fahn S, Marsden CD, Van Woert MH. Defi nition and classifi cation of myoclonus . Adv Neurol 1986; 43 : 1 \200\2235 . 2. Rubboli G, Tassinari CA. Negative myoclonus: an overview of its clinical features, patho physiological mechanisms, and management . Neurophysiol Clin 2006; 36 : 337 \200\22343 . Genetic information will yield more specifi c information with regard to the neurochemical and molecular pathophysiology of myoclonus which, in turn, will allow development of more s pecifi c treatments. 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Because of the intermittent nature of these movement disorders, diagnosis is usua lly made from clinical and family history. Recent advances in genetics have identifi ed cau sative mutations for many of these disorders. lowers attack threshold. Many PKD patients describe a non-specifi c and variable aura allow ing them to minimize attack severity by stopping contributory movements (6). PKD attacks generally last less than 30 \200\22360 seconds but can occur over 20 times dail y. Episode phenomenology is dystonia in over half of cases; mixed hyperkinesias are present in another third. Chorea and ballism alone occur rarely. Involved limbs may be unilateral or bilateral. When unilateral, the aff ected limbs may be consistently on one side or varia ble (6). Almost all PKD patients have their fi rst attack before age 20 and 90% have episodes prior to age 15. Episodes stop or decrease in the majority of PKD patients in their twenties. Whi le various antiepileptic drugs (AEDs) have been tried, 86% of PKD patients requiring medica tion responded to carbamazepine or phenytoin in one series (6). Similar benefi ts are seen in other PKD studies (7, 8). Oxcarbazepine may also be eff ective and has advantages given its diff erent side-eff ect profi le (9). Paroxysmal dyskinesias Paroxysmal dyskinesias are rare disorders characterized by attacks o f choreoathetosis, dystonia, and ballismus. Although phenome- nology is diverse, six have r eceived DYT designations (Table 26.1). Various clinical classifi cation schemes have been p roposed and revised over time, with four main subtypes \200\224paroxysmal kinesi- genic dys kinesia (PKD), paroxysmal non-kinesigenic dyskinesia (PNKD), paroxysmal exercise-induced dy skinesia (PED), and paroxysmal hypnogenic dyskinesia \200\224each with idiopathic and sec- ondary causes (1). Mixed forms are also described (2 \200\2234) with the suggestion that an additional classifi cation of \200\230paroxysmal dyski- nesias, mixed type \200\231 be co nsidered (3). Th ese categorizations based on clinically observed patterns are being furthe r refi ned as genetic causes are identifi ed. Familial PKD is more common than sporadic PKD, but clin- ical characteristics are similar ( 6). A small subset of familial PKD cases has an infantile-onset movement disorder with a mi ldly dif- ferent phenotype (6). Patients with familial PKD are more likely to have a person al and family history of infantile convulsions. Th is is unsurprising given that the loci f or benign infantile familial con- vulsions and paroxysmal choreoathetosis (ICCA) overlap wi th those for PKD (6, 7, 10). Adolescent- and adult-onset epilepsy (8, 10), migraine (6), an d writer \200\231s cramp (6) are also described in PKD patients and families. It remains un clear if these relate to the same underlying pathophysiology. Familial PKD shows autosomal dominant (AD) inheritance, but an associated gene has yet to b e identifi ed. Multiple studies link familial PKD to chromosome 16. Two diff erent loci (EK D1 and EKD2) are known, with others still suspected (7, 8, 10, 11). Despite these linkages, screening for abnormal genes has been unsuccessful (12, 13). It is generally assumed that PKD is related to an ion-channel mutation, but this is yet to be shown. With no avai lable genetic testing, diagnosis is based on clinical criteria (Box 26.1) supplemented by normal neurological examination, imaging, and electroencephalography (EEG). Paroxysmal kinesigenic dyskinesia PKD is the most common of the paroxysmal dyskinesias with an estimated prevalence of 1 in 150 000 (5). A series of 121 aff ected individuals evaluat ed in 2004 established the diagnostic criteria (Box 26.1) (6). Individuals aff ected by PKD have a normal interic- tal neurological examination. Dyskinetic episodes are triggered by activities such as standing up, walking, and running. Less com- mon triggers include startl e or focal movements such as stretch- ing. Uncommon triggers include caff eine and fatigue. Anxiety oft en Oxford Textbook of Movement Disorders 270 Table 26.1 Paroxysmal dyskinesias assigned a DYT designation Designation DYT8 Dystonia type Paroxysmal non-kinesigenic dyskinesia (PNKD1) Mode of inheritance AD Gene locus 2q35 Gene Myo \201 brillogenesis regulator 1 ( MR1 ) Unknown OMIM number 118800 DYT9 Paroxysmal choreoathetosis with episodic ataxia and spasticity AD 1p 601042 DYT10 Paroxysmal kinesigenic dyskinesia (PKD) AD 16p11.2-q12.1 Unknown 128200 DYT18 Paroxysmal exertion-induced dyskinesia (PED) with or without epilepsy and/or haemolytic ane mia AD 1p35-p31.3 Glucose transporter SLC2A1 612126 DYT19 Episodic kinesigenic dyskinesia 2 (EKD2) or PKD2 AD 16q13-q22.1 Unknown 611031 DYT20 Paroxysmal non-kinesigenic dyskinesia 2 (PNKD2) AD 2q31 Unknown 611147 AD, autosomal dominant; OMIM, Online Mendelian Inheritance of Man. Adapted from http://www.ncbi.nlm.nih.gov/omim. PNKD associated with MR- 1 mutations (DYT-8) Th e PNKD phenotype is consistent across eight kindreds with diff erent MR- 1 mutations. Attacks start at age 4 years on average (range 3 months to 12 years). PNKD attacks are superimposed on a normal baseline neurological exami nation. Positive and nega- tive emotions can lower attack threshold. Caff eine and alcohol are almost universal triggers. Less common triggers include heat, exercise, fatigue, menstr uation, and hunger. Sleep is commonly benefi cial (22). Most patients experience attacks at least weekly, though rare attacks are also described. Typical attacks last from 10 minutes to 1 hour, ranging from several minutes to 12 hours (22). Aura occurs in approximately 40% of patients and may involve focal limb numbness, stiff ening, or general anxiety. Attack p he- nomenology combines chorea and dystonia and can vary within an individual over time and between members of the same fam- ily. Less commonly reported phenomenology includes blepha ros- pasm, risus sardonicus, and diplopia. Speech involvement occurs in just under half of patients. Attacks tend to decrease in frequency with age, although natural history varies ( 22). Headache and migraine are commonly reported in PNKD families (22). Based on these clin ical fi ndings and comparison with gene-negative PNKD patients (see further discussion in t he next section), clini- cal diagnostic criteria for MR- 1 mutation PNKD have been pro- pos ed (Box 26.2) (22). Numerous reports hypothesize secondary causes for PKD pres- entations including cerebral pa lsy (14), peripheral trauma (2, 15), subcortical white matter ischaemia (16), cervical cord compression (17), primary central nervous system lymphoma (18), HIV (19), voltage-gated po tassium channel (VGKC) complex protein anti- body encephalitis (20), and hyperglycaemia (21 ). Whether these observations represent true causal links is unclear. Interestingly, severa l of these cases also respond to carbamazepine (2, 15, 17, 18). Phenytoin (14) and benzodia zepines (19) are benefi cial in other cases. In the patient with VGKC-complex protein antib ody encephalitis, PKD symptoms decreased aft er intravenous immu- noglobulin infusions (20) . Paroxysmal non-kinesigenic dyskinesia Attacks in PNKD are spontaneous rather than triggered by sud- den movements as in PKD. PNKD attacks also tend to be longer (lasting minutes to h ours) than those seen in PKD. With identi- fication of causative mutations in the myofibril logenesis regula- tor 1 ( MR- 1 ) gene, PNKD families are further divided into true PNKD (w ith the mutation) and \200\230PNKD-like \200\231 conditions without an identified mutation (22). Box 26.1 Clinical diagnostic criteria for paroxysmal kinesigenic dyskinesia (PKD) Non-benzodiazepine anticonvulsants are generally unsuccess- ful in preventing PNKD attacks. However, in a series of PNKD patients, 34 of 35 patients who tried benzodiazepines for eit her pre- ventive or abortive therapy responded favorably (22). While ben- zodiazepines are the mainstay of treatment, individual PNKD cases improved with valproate (22), levetiraceta m (23), oxcarbazepine (24), haloperidol (22), acetazolamide (22), and levodopa (22). 1. Dyskinetic attacks triggered by sudden movements. 2. Short duration attacks (<1 min). 3. No loss of consciousness or pain during attacks. 4. Antiepileptic drug responsiveness (particularly carbamazepine