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) z Video 25.2 Th e video shows a patient with myoclonus \200\223dystonia (with a mutation in the SGCE gene). Th e typical features of \200\230twitching \200\231 jerks mainly in the u pper part of the body are seen. Th e myoclonus is more prominent during voluntary action. I n addition, mild cervical dystonia may be noted. Tijssen MAJ and Tijssen CC. Myoclonus. In: Parkinsonism and related disorders. Wolters E Ch, van Laar T, Berendse HW (eds). 2008. VU University Press. ISBN 9789086591503 Symptomatic myoclonus Storage disease Lafora body disease Sialidosis Lipidosis (GM1 and GM2 gangliosidosis, Krabbe disease) Tay \200\223Sachs disease Neuronal ceroid-lipofuscinose Spinocerebellar degeneration Unverricht \200\223Lundborg disease Ataxia telangiectasia Friedreich \200\231s ataxia Spino cerebellar ataxias Degeneration basal ganglia Multiple system atrophy Progressive supranuclear palsy Parkinson \200\231s disease Huntingt on \200\231s disease Corticobasal degeneration DRPLA Wilson disease Dystonia Pantothenate-k inase-associated neurodegeneration 2 Mitochondrial encephalopathy MERFF Dementia Creutzfeldt \200\223Jakob disease Alzheimer \200\231s disease Lewy body dementia Frontotemp oral dementia z Video 25.3 Th e video shows a patient with myoclonus \200\223dystonia (with a mutation in the SGCE gene). Th e patient has myclonic jerks in the upper part of the body, but also pr ominent disabling dystonic features. Th e patient was treated with stereotactic surgery (bi lateral globus pallidus interna stimulation) with good e \200 ect. Th e second part of the video shows the patient several months after surgery. Malabsorption syndrome Whipple \200\231s disease Coeliac disease Infectious or postinfectious SSPE Encephalitis lethargica Postinfectious encephalitis Arbovirus or herpes simplex virus encephalitis AIDS transmembrane proteins (39), but little is known about its func- tion in the brain. SGCE is highly homologous to -sarcoglycan, but no muscle or myocardial muscle abnormalities hav e been identifi ed in MD patients (40). Epileptic myoclonus Several forms of epilepsy can be accompanied by myoclonic jerks, such a s isolated epileptic myoclonic jerks, photosensitive myo- clonus, and myoclonic absences wi th petit mal (see Table 25.1). Th e EEG changes associated with epileptic myoclonus are usu ally spikes, polyspikes, and spike and slow-wave complexes. Movement disorders are the main issue of this book, and therefore epileptic Metabolic encephalopathy Hepatic failure Hyperthyroidism Renal failure Hypoglycaemia Hyponatraemia Vitamin E de \201 ciency (Continued) Oxford Textbook of Movement Disorders 260 Table 25.1 (Continued) includes Lafora body disease, myoclonus epilepsy with ragged red fi bres (MERRF), lipofusci nosis (Kuf \200\231s disease), sialidosis, and dentatorubral-pallidoluysian atrophy (DRPLA ). New genes for several of these progressive myoclonus epilepsy syndromes, includ- ing MER FF, DRPLA, sialidosis, and neuronal ceroid lipofuscinosis, have been discovered in the last few years (44, 45) (see Table 25.2). Th e progressive nature of the illness and cognitive decline diff eren- tiate progressive myoclonic encephalopathy diagnoses from more benign ep ileptic myoclonic syndromes. Toxic and drug induced (25, 59) Physical encephalopathy Paraneoplastic encephalopathy Focal CNS lesions Post-hypoxic Without a prominent cognitive decline, but with epilepsy or ataxia, the course of the progr ession of myoclonic encephalopa- thy is usually slower. Clinically, patients exhibit a comb ination of action myoclonus, epilepsy, and ataxia. Depending on the most prominent feature other than myoclonus, two subgroups (43) can be recognized: progressive myoclonus epilepsy and progres- sive myoclonus ataxia. Th e cause of progressive myoclonus epi- lepsy is in mo st cases Unverricht \200\223Lundberg (UL) disease, which usually manifests in the fi rst ye ars of life with action-induced and stimulus-sensitive multifocal myoclonus. Ataxia is usua lly mild. Th e associated generalized tonic \200\223clonic seizures can be diffi cult to tr eat. Recently, the CSTB gene cystatin B has been implicated in UL (44, 45) (see Table 25.2) . Modi \201 ed from Caviness and Brown (20). myoclonus in epilepsy syndromes will not be discussed further (for a review of epileptic my oclonic jerks and their treatment options, see ref. 31). Familial cortical myoclonic tremor and epilepsy (FCMTE) is an example of a syndrome overlap ping with movement dis- orders and should be discriminated from essential tremor. FCMTE pre sents with tremor-like myoclonus and epilepsy (41). It is a rare autosomal dominant inherit ed disorder characterized by late-onset intention-like tremor and distal myoclonus, myo- cl onic and generalized seizures, moderately progressive course, and good response to antiepil eptic drugs. Electrophysiological studies reveal features of cortical reflex myoclonus, inc luding giant somatosensory evoked potentials (gSSEP) and enhanced cortical reflexes (C-refl exes). Coherence analysis shows strong cortical and intermuscular coherence in the 8 \200 \22330 Hz range (9). EEG may show polyspike \200\223wave complexes. Genetic studies have re vealed linkage to three loci (chromosomes 8q23.3-q24.1, 2p11.1-q12.2, and 5p15.31-p15) (42) , but no gene has been identified yet. In patients with progressive myoclonus ataxia, unsteadiness of gait is one of the most prom inent signs next to the multifocal action-induced myoclonus. Occasional seizures can be wel l treated with antiepileptic drugs. Progressive myoclonic ataxia is usually sporadic, with age at onset ranging from childhood to age 70 years. Diff erential diagnosis includes Ramsa y-Hunt syndrome, mito- chondrial disorders (e.g. MERFF, POLG1), vitamin E defi ciency, and coeliac disease (46, 47). If combined with nephropathy, action myoclonus renal failure synd rome (AMRFS) should be consid- ered. AMRFS starts in the second or third decade with progre ssive action myoclonus associated with occasional seizures, cerebellar ataxia, and preserve d cognition (48). Mutations in the gene cod- ing for the lysosomal protein SCARB2 have been found in AMRFS (49). Th e combination of prominent ataxia and myoclonus together with othe r features can also point towards a spinocerebellar ataxia (SCA) (50). Th e myoclonus in SC As can be cortical or subcortical (50, 51). Symptomatic myoclonus Symptomatic myoclonic jerks are usually multifocal, occur spontaneous ly, and can be increased by action and external stimuli. In an attempt to help in clinical decision-making, symptomatic cases are divided according to their anatomical origin. Mental status abnormalities, seizures, ataxia, and other movement disorders are common clinical a ssociations in symp- tomatic myoclonic syndromes. The various causes are outlined in Table 25.1. If dementia or parkinsonism is the most prominent sign in patients with progressive myoclon ic encephalopathy who are not suff ering from epilepsy, the diff erential diagnosis include s mainly late-onset neurodegenerative disorders. Examples include Alzheimer \200\231s disea se, Parkinson \200\231s disease, and multiple system atrophy. Patients usually have irregul ar small jerks of the hand muscles ( \200\230poly-mini-myoclonus \200\231). Cortical myoclo nus can also occur in other neurodegenerative disorders such as Lewy body dementia and Hunt ington \200\231s disease. A characteristic type of myoclonus may be seen in corticobasal sy ndrome. Th e aff ected limb, especially the distal arm, shows irregular continuous jerks in creasing with movement. Additional causes of severe cortical myoclonus include Creutzfeldt \200\223Jakob disease, where the gener- alized myoclonus is commonly sensitive to sound. If the myo- clonus is acute or subacute and accompanied by epilepsy and altered mental status , herpes simplex encephalitis and subacute sclerosing panencephalitis (SSPE), or NMDA encep halitis should be considered. Metabolic disorders, such as liver and kidney problems, usual ly lead to both positive and negative myoclonus (asterixis). Cortical Cortical myoclonus forms the largest group within symptomatic myoclonus and can be subdivided into progressive myoclonic and static myoclonic encephalopathies. Progressive myoclonic encephalopathy Clinically, patients with progressive myoclonic enceph alopathy suff er from action-induced stimulus-sensitive multifocal and gen- eralized myoclo nus. In general, it is oft en diffi cult to make the exact diagnosis. Further subgroups bas ed on associated neurologi- cal symptoms, such as the presence or absence of epilepsy and/o r dementia, help with classifi cation (43). If combined with both prominent epilepsy and dementia, the course is oft en progressive. Pa tients have intractable general- ized tonic \200\223clonic seizures and progressive dementi a. Th e age at onset of these disorders is usually in early childhood, but occa- sionally l ate onset has been described. Th e diff erential diagnosis CHAPTER 25 Myoclonus 261 Table 25.2 Genetic abnormalities of progressive myoclonus epilepsies (45) Inheritance Disea se AR UL Chromosome 21q22.3 Gene CSTB EPM2A MTTK NEU1 DRPLA Protein Cystatin B Lafora AR 6q24 Laforin MERRF Mat. mtDNA tRNALys Sialidosis types 1 & 2 AR 6p21.3 & 20 Sialidase 1 DRPLA AD 12p13.31 Atrophin 1 NCL Late infantile AR 11p15 TPP1 CLN3 CLN5 CLN6 Tripeptidyl peptidase 1 Juvenile AR 6p Late infantile (Finnish) AR 13q21 \200\223q32 Variant late infantile AR 15q21 \200\22323 UL, Unverricht \200\223Lundborg disease; MERRF, myoclonic epilepsy with ragged red \201 b res; DRPLA, dentatorubral-pallidoluysian atrophy; NCL, neuronal ceroid lipofuscinosis; AR, autosomal recessive; AD, autosomal dominant; CSTB, cystatin based on refs 44 and 45. Drug-induced myoclonus (DIM) is frequent in clinical practice, and all drugs should be chec ked as potential culprits. DIM is con- sidered to be cortical, but detailed electrophysiolo gy is scarce. In lithium-induced myoclonus the origin is believed to be cortical as there a re diff erent clinical symptoms of motor cortex hyperexcit- ability (12), but some argue in favor of a subcortical origin as EEG recordings do not always show jerk-related abnormalit ies in DIM. In general, the jerks are usually reversible with discontinuation of the off en ding drug. Psychiatric medication is most commonly responsible, but a number of drugs can c ause myoclonus, including anticonvulsants and propofol (20, 52). brainstem myoclonus with generalized jerks. Acute PHM occurs shortly aft er a hypoxic episo de with mainly generalized myoclonic jerks and has a poor prognosis. Subcortical Generalized reticular brainstem myoclonus can be caused by post-hypoxic encepha lopathy, brainstem encephalitis, and meta- bolic disorders such as uraemia. Excessive startle refl exes can be part of hyperekplexia, a heredi- tary mainly autosomal d ominant disorder (54, 55). Patients with hyperekplexia also suff er from stiff ness induced by the startle refl exes, and generalized stiff ness in the neonatal period (56, 57). Clin ically, an excessive head retraction refl ex can be elicited (see Video 25.5). Hyperekplexi a is a hereditary disorder with mutations in diff erent parts of the inhibitory glycine rec eptor (GlyR) (21). Th e alpha-1 subunit of the glycine receptor (GLRA1) is the main gene fo r hyperekplexia. Dominant, recessive, and compound heterozy- gote mutations are identifi ed . Th is gene is aff ected in about 80% of all hyperekplexia pedigrees, and can be regarded as the most Static myoclonic encephalopathy Post-hypoxic myoclonus (PHM) is an important example of sta tic myoclonic encephalopathy. Lance \200\223Adams syndrome develops with a delay of a few d ays aft er the hypoxic episode. Disabling action myoclonus appears when moving a limb and i s usually stimulus-sensitive, combined with negative myoclonus, resulting in postural lapse s (53) (see Video 25.4). Patients may also suff er from z Video 25.4 Th e video shows a patient with post-anoxic encephalopathy (Lance \200\223Adam s syndrome) several years after the anoxic incident. Stretching of the arms shows an irregu lar jerky tremor. Th e patient \200\231s main problem is standing and walking. During stand ing between two subjects the postural lapses due to the negative myoclonus can be seen. z Video 25.5 Th e video shows a patient with hyperekplexia (mutation in the GLRA1 gene). An excessive head retraction re \202 ex is illustrated. Mov Disord . 2012 May;27(6):795-6. d oi: 10.1002/mds.24917. Epub 2012 Jan 30. A new hyperekplexia family with a recessive frames hift mutation in the GLRA1 gene. Zoons E, Ginjaar IB, Bouma PA, Carpay JA, Tijssen MA. Oxford Textbook of Movement Disorders 262 important contributor to autosomal dominant hereditary hyper- ekplexia. Th e second most im portant gene, which accounts for hyperekplexia in about 20% of cases, is the GlyT2 (SCL6A5) encod- ing the presynaptic sodium- and chloride-dependent glycine trans- porter 2 (58). Th e mode of inheritance is recessive with compound heterozygosity in the majority of cases. Genetic heterogeneity has been confi rmed in very rare sporadic cases of hyperekplexia with mutations aff ecting other postsynaptic glycinergic proteins, includ- ing the GlyR subunit ( GLRB ), gephyrin ( GPHN ), and RhoGEF collybistin ( ARHGEF9 ). Other than hereditary hyp erekplexia, excessive startle refl exes can also be symptomatic, usually due to lesions in the brainstem (21). Psychiatric co-morbidity, such as depression, anxiety, and panic disorders, occurs in 50 \200\22360% (68). Electrophysiological testing can be helpful in such cases. EMG registrati on shows variable and inconsistent muscle activity patterns. A premovement potential (Berei tschaft spotential) on the averaged EEG activity over several jerks (back-averaging) makes diagnosis of functional jerks likely, although absence of this potential does not exclude a psychogenic origin (67, 69, 70). Pathophysiology Cortical myoclonus Cortical myoclonus is pathophysiologically related to ep ilepsy. It was fi rst described by Ginker and colleagues (71) with EEG trains of spike and wave discharges correlating with myoclonus in familial myoclonus epilepsy. Shibasaki and Ku roiwa (72) were the fi rst to report back-averaging of EEG time-locked to the myoclonic jer ks on the EMG (jerk-locked back-averaging), showing contralateral cor- tical discharges pre ceding myoclonus by intervals consistent with conduction in corticospinal pathways (i.e. 15 \200\22325 ms when recorded from the upper limb, and 40 ms from the lower limb). Frequent myoclonic jerks do not allow back-averaging. Alternatively, coher- ence analysis can reveal the correlation between cortical and muscle activity and between muscles (73). In cortical myoclonus an exag- gerated corticomuscular and intermuscular coherence in the alpha and be ta bands can be found with a phase diff erence compatible with a cortical drive (9, 74, 75) . Magnetoencephalography (MEG) studies suggest a generator in the primary motor cortex (76) . Orthostatic myoclonus is an irregular jerking of the legs induced or increased by an uprigh t posture. Clinically, a slowly progressive unsteadiness of stance and gait is seen. EMG sh ows non-rhythmic short burst durations (20 \200\223100 ms) (59, 60). Th is type of myoclonu s is not classifi ed as yet, but is most likely of subcortical origin. It may occur in isol ation, but is oft en associated with an underlying neurodegenerative disorder, particularly Parkinson \200\231s disease (59, 60). Orthostatic myoclonus has also been described in one family suff ering from action-induced multifocal dystonia and generalized myoclonus. Th e most troublesome feature of their disorder was an orthostatic myoclonus in the lower limbs (61). Spinal Segmental myoclonus Spinal segmental myoclonus is the result of spinal systems becom - ing hyperexcitable due to a spinal cord lesion such as a tumor, syringomyelia, myelitis, or ischaemia. An EMG \200\223fMRI study in FCMTE patients linked cortical myo- clonus to parietal (sensor y area) brain activation (77). Th is is in concordance with changes in sensory input that a re likely to play an important role in the generation of the jerks. Th is is supported by c linical stimulus sensitivity and the electrophysiological signs of cor- tical hyperexcitabi lity, as illustrated by a gSSEP and the presence of a C-refl ex (see Fig. 25.1). With SSEP recordings the P25/P30 and N35 peak amplitudes are enlarged (77). Th e C-refl ex response c an be seen in the ipsilateral thenar muscle with a latency of around 45 ms (17). Neuropatho logical studies show involvement of cerebellum, fron- totemporal cortex, hippocampus, thala mus, and other areas (78, 79). Th e recent hypotheses about the increased cortical excitabi lity point towards cerebellar changes. In cerebellar disease decreased cortical inhibition via the cerebellothalamocortical loop is hypoth- esized to result in cortical myoclonus. Pr imary cerebellar changes were observed by Hunt (80), in patients with coeliac disease (47), and in patients with FCMTE (79). Propriospinal myoclonus Occasionally, lesions in the spinal cord have been reported, but pr opriospinal myoclonus (PSM) is usually idiopathic (62). In idio- pathic PSM a psychogenic o rigin might be considered. Recently, a Bereitschaft spotential was shown in 15 of 20 patien ts diagnosed with idiopathic spinal myoclonus (22). In another study, axial jerk- ing close ly resembling PSM had a psychogenic origin in 34 out of 35 patients (63). Further prospecti ve studies of PSM are required (for more details see \200\230Pathophysiology \200\231). Peripheral Hemifacial spasm is the most frequent example of peripheral myo- clonus (64). Je rks and tonic contractions occur in muscles inner- vated by the ipsilateral facial nerve. I n two-thirds of 135 patients in one series, it was caused by vascular compression of the fa cial nerve at the exit zone (65). Other very rare examples include myoclonus aft er lesions of the brachial plexus and spinal root, and aft er ampu- tation ( \200\230jumping stump \200\231). Cortical increased excitability due to intrinsic changes in the cortex cannot be ruled out. In the absence of structural changes, functional cortical changes may exist, for instance due to a chan- nelopathy recognized in the inherited epilepsy syndromes. Psychogenic myoclonus An important cause of myoclonus not included in the current classifi cations is psychogenic myoclonus . Psychogenic myoclonus comprises around 15% of psychogeni c movement disorders (66, 67). In a study of 212 patients with myoclonus, psychogenic myo- clonus was diagnosed in 8.5% (68). Th e distribution of segmental myoclonus is most frequen t, but generalized and focal presenta- tions also occur. Th e myoclonus is seen at rest in all patients and increases with movement in most (68). Th ere are some general features com mon to all functional movement disorders, such as an abrupt onset, fast progression, distra ctibility, and variability (66). Asterixis Patients with cortical myoclonus usually manifest both positive and negative myoc lonus (81). In postanoxic myoclonus, positive myo- clonus correlated with an EEG spike, and negative myoclonus with an EEG slow wave (4). A hypothesized mechanism of cortical negativ e myoclonus is that stimulation of areas in the primary sensorimotor cortex produces a sile nt period in the corresponding muscle when electrically stimulated (82). Th e most frequent form is asterixis, or fl apping tremor, with EMG registration highlighting brief periods CHAPTER 25 Myoclonus 263 R Medianus - Reuzenpotential N9 Erb 1.1 5ms 2 V 3.30mA 300 1 N11 N13 Neck 1.2 5ms 2 V 3.30mA 300 2 N11 \200\231 N35 C4 \200\231 1.3 5ms 2 V 3.30mA 300 3 N20 N18 P14 4 C3 \200\231 1.4 5ms 2 V 3.30mA 300 P25 Fig. 25.1 A giant somatosensory evoked potential (gSSEP) is seen over C3 (trace 4) after st imulation of the right median nerve. Traces 1 \200\2233 show the right-sided response at Er b \200\231s point, the neck muscles, and C4. N11 ms N13 ms P14 ms N18 ms N20 ms P25 ms N35 ms onset R ms top-top R ms P14-N20 V N20-P25 V P25-N35 V N9 ms Run 1.1 Erb 1.2 Nek 8.6 10.9 13.1 1.3 C4 \200\231 1.4 C3 \200\231 21.0 26.2 6.5 4.0 0.34 5.5 11.3 14.0 15.6 17.1 (50 \200\223200 ms) of loss of EMG activity against gravity. Another form of negative myocl onus gives longer-lasting EMG silences (200 \200\223500 ms) in the axial and proximal lower limb muscles. Patients may lose postural stability during this type of negative myoclonus. study, showing polyphasic MEPs possibly refl ecting central neu- ronal membrane instability . A functional MRI study revealed dis- organized sensorimotor integration consistent with o ther types of dystonia (63, 85, 87). Th ese cortical functional changes may be sec- ondary to basal ganglia pathology. It is of interest that recent stud- ies point towards the cereb ellum in the pathophysiology of MD. Impaired saccadic adaptation in MD is compatible with c erebellar dysfunction (88). Even more convincingly, a major brain-specifi c SGCE isoform is diff erentially expressed in the human brain with a notably high expression in the cerebel lum, namely in the Purkinje cells and neurons of the dentate nucleus (89). Th ese fi ndings illus- trate that dysfunction of the cerebellum is involved in the patho- genesis of both cortical and subcortical myoclonus. Subcortical myoclonus Myoclonus \200\223dystoni a patients have variable but mainly short E MG bursts (25 \200\223750 ms) (18, 33), that are believed to originate from the basal gangl ia. Local fi eld potential recordings from the globus pal- lidus interna (GPi) in MD patien ts showed signifi cant coherence between dystonic muscle activity and GPi (83). Reduced str iatal D2 receptor binding was also detected in MD (84). Electrophysiological studies includ ing (EMG \200\223)EEG, SSEP, and transcranial magnetic stimulation (TMS) reveal no changes in cortical excitability (85, 86). Cortical functional changes have been described in a TMS Brainstem reticular refl ex myoclonus is characterized by abnor- mal activity starting in t he brainstem and subsequently spreading Oxford Textbook of Movement Disorders 264 in both rostral and caudal directions, producing generalized jerks due to the bilateral pat hways involved. In reticular refl ex myo- clonus the pattern of spread resembles the startl e refl ex, but in con- trast with reticular myoclonus in hyperekplexia the EMG responses in the intrinsic hand and foot muscles are relatively delayed (90). Furthermore, the latencie s of muscle activity aft er an auditory stimulus in reticular refl ex myoclonus are very sh ort, compatible with the pyramidal tract, while startle refl ex latencies are longer, trave ling through slower corticospinal tracts (54, 90). Th e jerks in reticular refl ex myoclonu s are thought to originate from the reticu- lar formation. Th e brainstem motor systems are closely related to subcortical refl ex centers, possibly explaining the stimulus sensitiv- ity (12, 13, 20). associated microstructural abnormalities of the spinal cord in one study (92). Clinical features Classifying myoclonus according to clinical signs enables a clear descrip tion to be given of the characteristics of myoclonus in indi- vidual patients and to furthe r categorize patients in an anatomical classifi cation (Table 25.3). Diff erent aspects are useful to determine the type of myoclonus. Th e distribution of myoclonus can be focal, segmental, axial, or generalized (11). Th e te mporal pattern of myoclonus is usually arrhythmic, but can also be rhythmic (as in segmenta l myoclonus) or oscillatory (11). Synchronized jerks (e.g. brainstem myoclonus) can be diff erentiated from asynchronous jerks (11). Th e relation to motor activity can be classifi e d as myoclonus at rest or during voluntary activity, such as action or intention. Action my oclonus is frequently seen in patients with cortical myoclonus. Stimulus sensitivity means that the myoclonus can be triggered by sudden and unexpected tactile, visual, or auditory s timuli (as in cortical or brainstem myoclonus). Finally, myoclonus can present as muscular contractions (positive myoclonus) or as an interruption of a muscle contraction (negative m yoclonus). Two forms have been described (6): asterixis or fl apping tremor, and negative m yoclonus in the axial and proximal lower limb muscles, resulting in patients losing their b alance. 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.