Orthostatic myoclonus (OM) presents as a sensation of unsteadiness upon standing and walking that most commonly is suspected to represent orthostatic hypotension or orthostatic tremor. Some of these patients may also be considered as having gait ‘apraxia’ or ‘gait initiation difficulty’ before the diagnostic electrophysiological testing demonstrate the myoclonic nature of their subtle postural jerks [9]. Indeed, OM can only be confirmed by surface electromyography since the clinical features may be too subtle to allow their distinction from other orthostatic disorders (Fig. 7.2). OM may develop in the background of neurodegenerative diseases, such as Parkinson’s disease (PD), multi-system atrophy (MSA), dementia with Lewy bodies (DLB), Alzheimer’s disease (AD) and cerebral amyloid angiopathy [9, 11]. The most common misdiagnoses in patients with OM are normal pressure hydrocephalus and orthostatic tremor.

Myoclonus dystonia (M-D) (sometimes mistakenly called ‘myoclonic dystonia’) is a familial disorder of onset typically under the age of 20 years, presenting as ‘jerking’ of the upper trunk and proximal arms, either in isolation or associated with focal dystonia of the cervical region or, less commonly, hand [12]. A lower limb dystonia-only phenotype with later appearance of myoclonus has also been identified [13]. Myoclonus of the proximal arms and axial musculature may initially be misidentified as tremor or chorea. M-D can be strikingly alcohol responsive, with alcoholism manifesting in a substantial minority of patients. Intriguingly, alcoholism may directly co-segregate with the gene [14]. Observation of handwriting is a key component in the evaluation of ‘jerky’ or dystonic patients, since it reliably exacerbates or brings out proximal arm and cervical myoclonus in patients with M-D, in whom this clinical clue may otherwise be hidden [15].

M-D is inherited in an autosomal dominant fashion, with complete paternal inheritance but reduced (15 %) maternal inheritance when due to maternal imprinting in mutations in the epsilon-sarcoglycan gene on chromosome 7 (SGCE, DYT11) [16], the most common cause, estimated to account for about 30–50 % of cases. In addition to alcoholism, obsessive–compulsive behaviours and anxiety appear to co-segregate with the same gene (Fig. 7.3) [17]. Indeed, patients with M-D may be misdiagnosed with a primary psychiatric disorder, particularly when their family history is negative [18]. RELN missense mutations have been reported in familial and sporadic M-D cases phenotypically identical to DYT11-SGCE [19]. A locus on chromosome 18 has also been identified as a secondary genetic cause of myoclonus dystonia (DYT15) [20] (for a comprehensive discussion on the genetic of dystonia, see Chap. 6).Of interest, a number of other genetic disorders may present with an M-D phenotype (Table 7.3).DYT1 dystonia may present with an M-D-like phenotype [22, 23]. Missense mutations in KCTD17 (codes for potassium channel tetramerization domain-containing proteins) can lead to a presentation consistent of isolated arm myoclonus complicating with cervical, craniofacial and/or laryngeal dystonia [24]. Tyrosine hydroxylase deficiency has also been reported to present with a phenotype suggesting M-D, although with lower-body involvement and history of infantile hypotonia [25]. The marked response to levodopa in this disorder (as also shown for a kindred with GTP cyclohydrolase I (GTP-CH) deficiency and an M-D-like presentation [26]) distinguishes it from classic M-D. Anecdotally, some patients with otherwise classic M-D have demonstrated response to levodopa, suggesting that this therapeutic approach may be considered in patients with this disorder [27]. Of note, a ‘PD lookalike’ with a 5-to 6-Hz pseudo-rhythmic myoclonus, primarily involving extensor muscles, has been reported [28]. Also, an autosomal dominant M-D-like syndrome with leg-predominant myoclonus on standing and cardiac arrhythmias has been reported to be due to a mutation in the CACNA1B gene, coding for neuronal voltage-gated calcium channels CaV2.2 [29], although the pathogenicity of this mutation was recently called into question given a similar frequency in healthy populations (0.2 %) [21]. A later-onset M-D has been reported in the Silver–Russell syndrome (growth retardation and craniofacial dysmorphism with characteristic overfolded ears), due to maternal uniparental disomy of chromosome 7, with maternal imprinting leading to the absence of SGCE gene expression [30]. Finally, a M-D phenotype with short stature, joint laxity and microcephaly may be observed if the disease is due to large SGCEgene deletions rather than point mutations [13].

This form of subcortical myoclonus may emerge within days to weeks after recovery of consciousness in survivors of cardiorespiratory arrest, most often when severe respiratory dysfunction (and therefore, marked hypercapnia) antedates the cardiac arrest (anoxia) [31]. As such, in a strict etiologic sense, this disorder represents the complication of sequential hypercapnia and anoxia. Also known as Lance–Adams syndrome, it is characterized by exquisite action- and even intention-induced myoclonus: the thought of movement is capable of inducing generalized myoclonus, which is associated with gait-precluding bobbing when upright [32]. The commonest pre-arrest aetiology is severe asthma attack, which is the case in over 75 % of cases [33]. Injury to the cerebellar Purkinje cells is likely a major contributor to post-hypoxic myoclonus [34].

Myoclonus in the setting of PD often reflects emergent dementia or suggests an iatrogenic complication from the use of levodopa or amantadine [35]. Levodopa has been reported to induce a multifocal, spontaneous or action-induced myoclonus in correlation with an onset-of-dose or transitional dyskinesia [36]. Since it disappears partially or completely once optimal clinical efficacy is achieved, this complication is assumed to correspond to a state of intermediate dopaminergic stimulation. Amantadine is typically associated with myoclonus of the limbs and orofacial region and disappears when the dose is reduced or the drug discontinued [37]. Iatrogenic involvement of speech may be more common [38]. This complication may be expected with greater frequency among those with associated renal dysfunction because approximately 90 % of the oral dose of amantadine is excreted in the urine and little amantadine can be removed by haemodialysis.

Aside from the considerations above in PD, myoclonus in the setting of neurodegenerative parkinsonisms is characteristic of MSA, corticobasal syndrome (CBS) and, less commonly, dementia with Lewy bodies. The term ‘mini-polymyoclonus’ has been used to describe the low-amplitude, irregular and arrhythmic myoclonus of the hands or of one or several fingers in MSA patients when the arms are held outstretched or during movement initiation [1], which are often confused with a form of tremor [39]. Spontaneous or action-induced myoclonus in the face commonly accompanies MSA. In these patients, the earliest imaging abnormality is asymmetric hypointensity of the posterolateral putamen on gradient echo, suggestive of excessive iron deposition (see Fig. 1.​6 in Chap. 1). In CBS, action-induced and stimulus-sensitive myoclonus of the most affected – dystonic – limb may be a clinical predictor of Alzheimer’s pathology [40], although it has been documented in one fourth of patients with pathology-proven corticobasal degeneration (CBD) [41]. The clinical diagnosis of CBS is supported by the finding of asymmetric atrophy of the parietal and temporal lobes (see Fig. 1.​8 in Chap. 1).

Opsoclonus-myoclonus ataxia syndrome (OMAS) applies to the combination of ataxia and myoclonus in the setting of chaotic myoclonic eye movements, which create an illusion of environmental movement known as oscillopsia. Whereas paediatric OMAS is overwhelmingly of paraneoplastic nature (neuroblastoma or ganglioneuroblastoma), adult-onset OMAS is less so, although it can occur in the setting of anti-Hu antibodies in small-cell lung cancer and anti-Ri antibodies in breast cancer. More commonly, adult-onset OMAS may complicate postinfectious (shortly after infections with Epstein–Barr virus, mycoplasma pneumonia, St Louis encephalitis, Coxsackie B3, HIV, mumps) or autoimmune disorders (antibodies against glutamic acid decarboxylase, anti-N-methyl-D-aspartate receptor, antigliadin, anti-endomysial and anti-GQ1b IgG) [42]. Some of these autoantibodies bind to the surface of Purkinje cells and granular neurons in the cerebellum, further supporting the role of this structure in the generation of myoclonus [43].

The progressive myoclonic encephalopathies (PMEs) belong to the spectrum of myoclonic epilepsies [44] (Table 7.4). PMEs are suspected in patients with childhood-onset myoclonus, seizures, ataxia and, with variable prevalence, hallucinations, cognitive impairment and history of consanguinity. Most of the disorders in this category are autosomal recessive, except for dentato-rubro-pallido-luysian atrophy (DRPLA) , which is autosomal dominant, and mitochondrial encephalomyopathy with ragged-red fibres (MERRF) , which is of maternal inheritance [45] (Table 7.5). Whereas cognitive function is commonly impaired across PMEs, Unverricht–Lundborg disease, one of the most common aetiologies, is among the few where cognitive function is relatively preserved when compared to other PME aetiologies, and in which seizures tend to decrease in frequency in late teenage years [49].

Most autosomal recessive PME are lysosomal diseases, except for Lafora disease in which neither the accumulating material nor the gene products are in lysosomes [49].

When myoclonus arises in the setting of renal failure, most patients are encephalopathic (Table 7.6). One exception is action myoclonus-renal failure syndrome (AMRF), an autosomal recessive disorder caused by mutations of the SCARB2 gene and associated with progressive action myoclonus, ataxia and, in most cases, epilepsy in adolescents or young adults with renal failure but not affecting cognition [52]. The neurological manifestations precede renal involvement in about one third of the cases [53]. Initial proteinuria progresses to renal failure and ultimately requires renal transplantation. Unlike patients with uraemic encephalopathy, patients with AMRF do not exhibit a reversal of myoclonus or ataxia after dialysis or transplantation, suggesting a non-uraemic pathogenesis for these manifestations. Renal biopsy shows focal segmental glomerulosclerosis, which is more common in the setting of human immunodeficiency virus infection. EEG may demonstrate spike and spike-wave complexes. Brain autopsy demonstrates extraneuronal lipofuscin accumulation in the cerebellar and cerebral cortices [54].

At the subtlest end of the severity spectrum, myoclonus can be difficult to distinguishing from the ‘minor jerks’ and ‘twitches’ typical of the peripheral nerve hyperexcitability syndrome (see neuromyotonia in Chap. 6). These movements are of lower amplitude and tend not to alter the position of the body parts in which they occur. The most important such jerks are fasciculations (intermittent contractions of muscle fibres supplied by a single motor unit) and myokymia (involuntary, subtle, continuous, rippling quivering of muscles) (Table 7.7). Tremor, tics and chorea are other ‘jerks’ that need to be distinguished from myoclonus. Myoclonus is generally non-rhythmic but, especially when rapid, may become pseudo- rhythmic, and it is sometimes mistaken for tremor; this occurs in cases of spinal segmental myoclonus and hereditary cortical myoclonus, incorrectly termed ‘cortical tremor’. At the most severe end, myoclonus may be confused with ballism, a rapid form of chorea, and with hyperekplexia.