Secondary/heredodegenerative dystonia Secondary dystonia Secondary dystonias require the pr esence of a causative lesion, exposure, or event, such as an abscess, dopamine blocking age nts, CHAPTER 17 Dystonia: an overview 183 Table 17.3 Syndromic associations in diagnosing some of the most important heredodegenerati ve dystonias Syndrome Dystonia \200\223parkinsonism Disorder Parkinson \200\231s disease (PD) Gene esp. PRKN (PARK2), DJ- 1 (PARK7) \200\223 Trans mission AR Sporadic PD, CBD, PSP, MSA \200\223 Wilson disease AR ATP7B Neurodegeneration with brain iron accumulation (NBIA) AR PANK2 PLA2G6 (PARK14) Kufor \200\223Rakeb (PARK9) ATP13A2 AR AR AR FA2H Aceruloplasminaemia ( ceruloplasmin gene) Neuroferritinopathy ( FTL ) AR AR Huntington \200\231s disease AD IT-1 5 SCA2 ( ATXN2 ), SCA3 ( ATXN3 ) Spinocerebellar ataxia AD GM1 gangliosidosis AR LacZ Mitochondrial AD, AR POLG \200\223 Dystonia \200\223 ataxia MSA Spinocerebellar ataxia SCA2 ( ATXN2 ), SCA3 ( ATXN3 ) AD Wilson disease AR ATP7B Neuroacanthocytosis AD VPS13A Huntington \200\231s disease AD IT-1 5 Dentatorubral-pallidoluysian atrophy (DRPLA) AR ATN1 GM2 gangliosidosis AR HEXB3 Dystonia \200\223eye movement disorder Ataxia telangiectasia AR ATM Ataxia oculomotor apraxia 1,2 AR APTX, SETX Niemann \200\223Pick C AD NPC1, NPC2 Kufor \200\223Rakeb disease AD ATP13A2 SCA2 ( ATXN2 ) Spinocerebellar ataxia AR Huntington \200\231s disease AR IT-1 5 \200\223 See above PSP Dystonia \200\223bulbar involvement NBIA Neuroacanthocytosis Wilson disease Dystonia \200\223peripheral neuropathy Spinocerebellar ataxia Neuroacanthocytosis GM2 gangliosidosis See above AR Metachromatic leucodystrophy ARSA disease (see Chapter 23 for more details). Dystonia can be general- ized, segmental, or mul tifocal, but cranial involvement is character- istic; other common signs include a \200 \230sardonic \200\231 smile, wing-beating tremor, dysarthria, dysphagia, drooling, ataxia, and dementia. In addition to brain and liver involvement (cirrhosis, acute hepatitis), syst emic fi ndings can involve the eye (Keyser \200\223Fleischer rings), heart, kidney, bones, joints, glands, and muscles. protein. Examples include impaired temporal discrimination threshold in DYT1 manifesting an d non-manifesting mutation carriers (140) and higher temporal and spatial discrimination th reshold in adult-onset primary focal dystonia (141 \200\223143), also in unaff ected body r egions (141, 142, 144) and in patients \200\231 unaf- fected fi rst- and second-degree rela tives (145 \200\223147), suggesting a primary endophenotypic defi cit rather than a defi ci t second- ary to the presence of dystonic contractions. Kinaesthesia and vibration-induced illusion of movement have been found to be impaired in patients with APD in the aff ected a nd unaff ected body regions (148 \200\223151) and in asymptomatic fi rst-degree rela- tives , again indicating the probable primary origin of this feature. Mental rotation of corporea l objects, refl ecting mental simula- tion of movements, is abnormal in both focal hand dys tonia and cervical dystonia (152). Th is suggests that, apart from the motor defi cit, ther e is also a primary defi cit in sensory processing in primary dystonia (7). Pathophysiology of dystonia Th e pathophysiology of dystonia is unknown. Most research has focused on the primary dystonias and the role of genetic suscep- tibility in disease mechan isms. Imaging and neurophysiological abnormalities have been identifi ed in unaff ected DYT 1 mutation carriers. Th ese endophenotypic traits may require additional genetic or environ mental factors to become fully penetrant, or they may simply refl ect stochastic expression of the mutant Oxford Textbook of Movement Disorders 184 Motor, sensory, and sensorimotor integration abnormalities are thought to derive from two c lear abnormalities that have been repeatedly demonstrated across diff erent forms of the di sorder using electrophysiological and neuroimaging studies. Th e fi rst is that mechanisms that usually produce inhibition within the motor system are underfunctioning; this has been demonstrated at a cor- tical, brainstem, and spinal cord level (153). Increased motor cort i- cal excitability then causes the excessive and inappropriate muscle contraction that occ urs during motor tasks. However, such abnor- malities can be present in clinically unaff ec ted body parts and in non-manifesting DYT1 gene carriers, indicating that additional factor s are necessary to produce the clinical symptoms of dystonia (154). Th e second abnormality is that there is an excessive response to experimental protocols that produce plastic chan ges within the motor system (155 \200\223157). Again, such abnormalities are present in cli nically unaff ected body parts, but importantly are not present in non-manifesting DYT1 gen e carriers (158), where a subnormal response to plasticity protocols is seen. Th is suggest s that abnormal brain plasticity may be an essential component of the clinical mani- festat ion of dystonia. bones, ligaments, or joints can result in abnormal postures. In Sandifer syndrome, patients (typically young boys) with hiatus hernia develop head tilt in association with gastro-oes ophageal refl ux. Once the presence of dystonia is established, the next diag- nostic step is to diff erentia te between primary and secondary/ heredodegenerative dystonia. Distribution and age at onse t provide important clues for this diff erential. Primary dystonia has an ana- tomical dist ribution which depends on age at onset. Young-onset primary dystonia tends to be generalize d or multifocal, with onset of dystonia typically in a limb (typically lower), sparing cran ial muscles. Adult-onset dystonia is more commonly focal or seg- mental and oft en in an up per limb (such as task-specifi c writer \200\231s cramp), or it may aff ect the neck and he ad, while legs are almost never aff ected. Th erefore an unusual pattern (e.g. adult-onset lower limb dystonia) is a clue pointing to secondary/heredo- degenerative dystonia. If dystonia is primary, genetic testing for DYT1 dystonia is indi- cated for patients with onset of dystonia before 26 years of age, as well as for patients with later onset who have a relative with young-onset dystonia. Data to guide DYT6 testing are insuffi - cient at pr esent, but may be indicated in DYT1-negative individu- als with early-onset arm, cranial, o r cervical involvement. Most patients with clinically typical DRD will have identifi ed mut a- tions in GTPCH1 if comprehensive analysis is performed, includ- ing testing for deletion s. Genetic testing for myoclonus \200\223dystonia is available, although many sporadic case s do not harbor SGCE mutations. Evaluation of secondary/heredodegenerative dystonia is dict ated by clues provided by the history and examination. Routine blood tests, kidney, liver, thyroid function, iron, ferritin, copper, ceruloplasmin, white cell enzymes, acanthocytes, lactate, pyruvate, creatine kinase, and antinuclear antibody screen may be indicated. Speci fi c clinical fi ndings or laboratory abnormalities may dictate further investigations, inc luding electrophysiological studies, lum- bar puncture, muscle or skin biopsy, metabolic st udies of blood, urine, or cerebrospinal fl uid, MRI brain imaging with sequences to detect iron, and dopamine transporter imaging. Genetic testing is also available for many of the h eredodegenerative dystonias (see Table 17.3). Lastly, one should keep in mind the possibili ty of psy- chogenic dystonia which could be diagnosed based on established clinical criteri a (20). One pathophysiological hypothesis for these abnormalities is that altered basal ganglia inp ut to the motor cortex causes reduced excitability of cortical inhibitory circuits. Evidenc e from DBS expe- rience in primary dystonia patients and DYT1 animal fi ndings points to dy sfunction in the globus pallidus internus (GPi) which may be related to abnormal striatal d opaminergic signaling and increased cholinergic tone; this dysfunction leads to abnormal sy nchronization of the basal ganglia output to the thalamus and sensory feedback misprocessin g. Together they have the eff ect of increasing striatal, brainstem, and cortical plasticit y, and producing, over time, neural reorganization and overt dystonia. D2 receptors are def i cient in the putamen in focal dystonia, and this could cause a decrease in D2-dependent i nhibition of GABA transmission and subsequently a loss of inhibition in the basal ganglia. Th is abnor- mality in D2-receptor function has also been found in clinically unaff ected D YT1 gene carriers (159), suggesting that D2-receptor dysfunction represents a feature of th e non-manifesting carrier state. In summary, genetic susceptibility could lead to a neurochemical and functional imbalance i n the basal ganglia (but possibly even more widespread) that subsequently may lead to a wid espread loss of inhibition and increased plasticity, which could explain a number of motor and non-motor features seen in unaff ected rela- tives of patients with primary dystonia an d unaff ected mutation carriers. Th e presence of other genetic or environmental factors, s uch as repetitive activity, trauma, or emotional arousal and stress, could lead to a breakd own of compensatory mechanisms and ulti- mately to the motor manifestation of dystonia. Treatment of dystonia A comprehensive algorithm for the treatment of dystonia is given in F ig. 17.2. Primary dystonia and dystonia-plus syndromes Young-onset primary dystonia A trial of levodo pa is recommended for all patients with early onset of symptoms to exclude DRD. Although a daily dose of 600 mg levodopa is sometimes required, failure to respond to a dose of 300 mg /day usually excludes the diagnosis of DRD. Once DRD is excluded, anticholinergic agents su ch as trihexyphenidyl are usually tried. Use is oft en limited by peripheral anticholiner- gic adverse eff ects, including blurred vision, dry mouth, urinary retention, sedation, and confusion, and doses should be titrated slowly. Anticholinergic medications can be used si ngly or in combination with other drugs, including baclofen, clonazepam, Di \200 erential diagnosis of dystonia A variety of central and peripheral nervous system disorders, as well as non-neurological conditions, such as neuromyotonia, myotonic disorder s, infl ammatory myopathies, and glycogen storage diseases, can be associated with abnormal postures that resemble dystonia. Stiff person syndrome causes contraction of axial and pro ximal limb muscles. Carpopedal spasms of tetany can be the manifestation of hypocalcaemia, hypomagnesaemia, or alkalosis. Orthopedic and rheumatological processes involving CHAPTER 17 Dystonia: an overview 185 Dystonia Generalized (young-onset) Focal or segmental (adult-onset) Functional impairment or other need for treatment Botulinum toxin type A 1st option Drugs 1st option \200 Trial of levodopa \200 Anticholinergics \200 Baclofen, tetraben azine \200 Benzodiazepines \200 Neuroleptics? Drugs 2nd option or for additional problems Botulinum toxin type B Resistance to type A Botulinum toxin for focal problems Refractory or increasing disability ? DBS ? Peripheral selective denervation surgery DBS Refractory to treatment or worsening Fig. 17.2 Algorithm for the treatment of dystonia. or tetrabenazine. Botulinum toxin (BoNT) injections have a lim- ited role in generalized dy stonia but can be helpful in focal or segmental dystonia. Deep brain stimulation (DBS) of t he inter- nal segment of the GPi can be of remarkable benefi t. DYT1 dys- tonia was shown t o improve by 40 \200\22390% (160 \200\223164) and effi cacy is sustained aft er more than 5 years of follow-up (165, 166). Improvement frequently follows a particular pattern, with p hasic, myoclonic, and tremulous elements improving earlier than tonic elements, the latter oft en with a delay of weeks or months (160, 161, 167). be avoided. Th ere is evidence that patients with SLC2A1 /GLUT1 mutation may improve by fol lowing a ketogenic diet (175). Secondary/heredodegenerative dystonia When dystonia is secondary, treatment of the underlyi ng condition may produce improvement in the dystonia. Structural lesions may be amenable to surgical correction. Treatment of a drug-induced acute dystonic reaction may be an emergency because of possible respiratory compromise. It comprises stopping the offending drug, monitoring basic functio ns, and use of anticholinergic drugs (benzatropine, pro- cyclidine intravenously). Antichol inergic drugs such as trihexy- phenidyl, benzodiazepines, baclofen, and tetrabenazine, and also BoNT, are used for treatment of tardive dystonia. Tardive dystonia appears also to be a good indication for GPi DBS with benefits similar to those seen in primary dystonia (176) . Patients with cerebral palsy may achieve a 10 \200\22340% benefit in motor scores (177). Adult-onset primary dystonia BoNT injections are the fi rst-line treatment option for cervi cal dystonia and are also effi cacious for blepharospasm, focal upper extremity dystonia, a dductor laryngeal dystonia, and focal lower limb dystonia (61, 168, 169). Side eff ects can arise from unintended weakness in nearby muscles due to diff usion of toxin. Antibodies to BoNT can develop with repeated injections, resulting in loss of therapeutic eff ect. Th e use of oral drugs (anticholinergics) is less eff ective than in young-onset dystonia, altho ugh large controlled studies are lacking. Long-term GPi DBS is eff ective for various types of adult-onset primary dystonia. In patients with cervical dystonia, GPi DBS has been used primarily in those who were thought not to be ideal candidates for peripheral denervation, including patients with head tremor and myoclonus, or marked phasic dystonic movements. In dications have been widened in the past few years (170 \200\223172). With to regard to heredodegenerative dystonia, treatment depends on the underlying conditio n. Management of Wilson disease con- sists of copper chelation therapy (usually with penici llamine as a fi rst-line agent) and oral zinc, which induces copper-binding met- allothione in in enterocytes. Some inborn errors of metabolism may respond to dietary restriction or s upplementation. Th ere is some preliminary evidence of benefi t from GPi DBS, but further s tudies are needed (178, 179). Supportive treatment Because patients with dystonia oft en have associated co-morbidi- ties , consultation with specialists, including orthopedic surgeons and psychiatrists, can be us eful. Many patients derive benefi t from physical, occupational, and speech therapy. Variou s devices have been developed that provide sensory input via the aff ected body part, simul ating a sensory trick. Alternative and complementary Paroxysmal dystonia For PNKDs, avoiding the precipitants helps but oral treatments are larg ely inadequate. Th ere may be a limited response to phenytoin, acetazolamide, benzodiazepin es, and levodopa (173, 174). PKDs show a typically excellent response to carbamazepine (100 \200\223200 mg/day), and other treatment options include phenytoin and acetazolamide (173, 174). 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