Escolar Documentos
Profissional Documentos
Cultura Documentos
Tics
Psychoeducaon
Stage 1
No indicaon
for treatment Monitoring
no Stage 2
Indicaon for
treatment with preference Symptom-focused Stage 3
for behavioural treatment behavioural therapy
Pharmacotherapy and
no Sll indicaon to behavioural therapy Fig 1. Therapeutic algorithms for
treatment treatment of tic disorders.
Polypharmacotherapy Decision tree for the treatment of
Indicaon for tics (specically focused on
treatment with preference Pharmacotherapy Tourette syndrome and other
for pharmacological treatment Other treatments primary tic disorders).11 DBS = deep
(eg DBS) brain stimulation.
Clinical characteriscs
Isolated (formerly known as primary) dystonia encompasses or tremor, respectively, are associated with dystonia; lethargy,
all those conditions in which dystonia is the sole relevant dizziness and confusion may be associated with these drugs.
clinical feature, with the exception of associated tremor. Dopamine-depleting drugs such as tetrabenazine may be
This is a genetically heterogeneous group of disorders. Early helpful in a smaller proportion of cases. L-dopa in small
onset forms (ie age at onset <26 years) become frequently doses (50200 mg) represents the first line treatment for
generalised and are associated with TOR1A (DYT1, without dopa-responsive dystonias and, given the costs of genetic
cranio-cervical involvement) and THAP1 (DYT6, with screening for these forms of dystonia, an empiric trial of
cranio-cervical involvement) gene mutations. More than L-dopa is usually offered to all patients with early onset
five other potentially causative genes have been described in dystonia in whom there is no evidence of neurodegeneration
the last 3 years, which are also associated with adult-onset or brain structural lesions. 26 Chemodenervation with
(focal) forms. However, their role in aetiology and diagnosis botulinum neurotoxins (three forms of botulinum toxin A
is still under investigation.24 Combined dystonia syndromes and one of botulinum toxin B are available in the UK) is a
include myoclonus-dystonia syndromes (also genetically very effective and widely available treatment for segmental/
heterogeneous) and dystonia-parkinsonism syndromes; focal dystonias in which the topography of the muscles
the latter group includes dopa-responsive forms and involved can be determined.27 Electromyographic and
heredodegenerative diseases that include the complex family ultrasound guidance techniques have greatly advanced
of neurodegeneration with brain iron accumulation disorders recently for those body regions, like upper and lower limbs,
(Box 2). in which the superficial injection approach is hindered by
the complexity of anatomical localisation of the muscles
contributing to dystonia.25,28
Treatment
DBS is considered for highly disabling, medically refractory
The mainstay treatment for isolated dystonia and the dystonias. DBS of the globus pallidus internus (GPi) has been
majority of secondary dystonias remains pharmacological, shown to be very effective for the treatment of DYT1 dystonia
even though early DBS for monogenic forms of isolated and, to a slightly lesser extent, for non-DYT1, early-onset
generalised dystonia is now extensively applied. generalised dystonias. A 3545% improvement in severity was
Anticholinergic drugs (eg trihexyphenidyl) remain first also reported for refractory cervical dystonia treated with GPi
line agents for multifocal or generalised dystonias, and DBS. There is a less quality evidence to support DBS of the
their dose should be titrated gradually to minimise side subthalamic nucleus in cervical dystonia and for GPi DBS of
effects, particularly dry mouth, gastrointestinal upset, secondary dystonias or other focal dystonias (cranial, upper
urinary retention and confusion.25 Muscle relaxants such limb).29 The full benefit of GPi DBS in dystonia is usually
as baclofen (available also in intrathecal pump infusion achieved after several months, with stable efficacy for more
formulation) and clonazepam can be helpful when spasticity than 5 years.30,31
> Myoclonus-dystonia: most common cause is SGCE gene mutations > CNS lesion
Dystonia associated with neurodegenerative disorders Brain tumour, Stroke, Hypoxia, Intracranial haemorrhage,
CNS trauma, congenital malformations, cervical cord lesions.
> Autosomal dominant
> Perinatal cerebral injury
Huntington disease
Cerebral palsy, delayed-onset dystonia, perinatal hypoxia,
Machado-Joseph disease (SCA3) kernicterus.
Basal ganglia calcifications syndromes Functional dystonia
SCAs BPAN = beta-propeller protein-associated neurodegeneration; CNS = central nervous
Neuroferritinopathy system; GTP = guanosine triphosphate; MAO = monoamine oxydase; MELAS =
mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes;
> Autosomal recessive MERRF = myoclonic epilepsy with ragged red fibers; MPAN = mitochondrial
membrane protein-associated neurodegeneration; SCAs = spinocerebellar ataxias.
Juvenile Parkinsons disease
Wilsons disease
Neuroacanthocytosis syndromes Chorea
Hallervorden-Spatz disease Clinical presentation
Neurodegeneration with brain iron accumulation syndromes Chorea is a movement disorder characterised by rapid,
(pantothenate kinase associated neurodegeneration, purposeless, non-stereotyped movements flowing randomly
PLA2G6 associated neurodegeneration, Kufor Rakeb from one part of the body to another.32 Chorea is caused by
syndrome, MPAN, BPAN, aceruloplasminemia) a multitude of conditions with different pathophysiological
Lysosomal storage disorders mechanisms. In the majority of cases, the clinical context in
which chorea develops is the key to defining its aetiology. The
Ataxia-Telangiectasia
different causes of chorea may be recognised based on course
Homocystinuria (acute/subacute, ie reaching a peak of severity within days/
> Recessive X-linked weeks, or chronic, ie gradually progressing over months or
Lubag disease years) and body distribution (focal, segmental, unilateral,
generalised). An updated list of the different aetiologies of
Lesh-Nyhan syndrome
chorea and relative diagnostic work-up is provided in Table S1.
Rett syndrome Within the rubric of acute/subacute chorea, the spectrum
> Mitochondrial disorders of immune-mediated causes of chorea has broadened
extensively to include a vast group of autoantibody-induced
Leber disease
encephalopathies (such as those associated with anti-LGI1,
MELAS anti-GAD65, anti-CASPR2, anti-GABA-B receptor antibodies,
MERRF in addition to the choreiform movements documented
Leighs disease in anti-NMDA-receptor antibody-related encephalitis).33
Furthermore, there is increasing interest in the behavioural
> Parkinsonian syndromes and cognitive aspects of the prototype of immune-mediated
Parkinsons disease choreas, ie Sydenhams (or rheumatic) chorea (SC).34 Executive
Progressive Supranuclear Palsy dysfunction, obsessive-compulsive disorder, mood disorders,
anxiety, ADHD, tic disorders and (rarely) psychosis are
Cortico-basal syndrome
important comorbidities in patients with SC.33
Multiple system atrophy Among chronic or progressive chorea, Huntingtons disease
Dystonia associated with acquired causes (HD) remains the most frequent cause. This is an autosomal
dominant trinucleotide repeat disorder related to the IT15
> Medications
gene coding for the protein huntingtin.35 Usually, chorea is
Dopaminergic (L-dopa, dopamine agonists), dopamine the prominent movement disorder of adult-onset HD, whereas
receptor blocking drugs (neuroleptics, prochlorperazine, juvenile HD (Westphal variant) typically presents with an
metoclopramide), selective serotonin reuptake inhibitors, akinetic-rigid syndrome and progresses more rapidly.36
MAO inhibitors, antiepileptic drugs, ergots, flecainide, Personality changes, depression, hostility and/or increased
cocaine, ranitidine, calcium antagonists, anaesthetic interpersonal sensitivity, obsessive-compulsive symptoms,
agents. phobias and anxiety appear early in the course of the illness. As
16 Schrock LE, Mink JW, Woods DW et al. Tourette syndrome deep 31 Tierney TS, Lozano AM. Surgical treatment for secondary dystonia.
brain stimulation: review and updated recommendations. Mov Mov Disord 2012;27:1598605.
Disord 2015;30:44871. 32 L1 Burnett, Jankovic J. Chorea and ballism. Curr Opin Neurol
17 Kefalopoulou Z, Zrinzo L, Jahanshahi M et al. Bilateral globus Neurosurg 1992;5:30813.
pallidus stimulation for severe Tourettes syndrome: a double-blind, 33 OToole O, Lennon VA, Ahlskog JE et al. Autoimmune chorea in
randomised crossover trial. Lancet Neurol 2015;14:595605. adults. Neurology 2013;80:113344.
18 Ackermans L, Duits A, van der Linden C et al. Double-blind clinical 34 Williams KA, Swedo SE. Post-infectious autoimmune disorders:
trial of thalamic stimulation in patients with Tourette syndrome. Sydenhams chorea, PANDAS and beyond. Brain Res 2015;1617:14454.
Brain 2011;134:83244. 35 MacDonald ME, Abrose CM, Duyao MP et al. A novel gene con-
19 Geyer HL, Bressman SB. The diagnosis of dystonia. Lancet Neurol taining a trinucleotide repeat that is expanded and unstable on
2006;5:78090. Huntingtons disease chromosomes. Cell 1993;72:97183.
20 Albanese A, Lalli S. Is this dystonia? Mov Disord 2009;24:172531. 36 Quarrell OW, Nance MA, Nopoulos P et al. Managing juvenile
21 Fung VS, Jinnah HA, Bhatia K, Vidailhet M. Assessment of patients Huntingtons disease. Neurodegener Dis Manag 2013;3:26776.
with isolated or combined dystonia: an update on dystonia syndromes. 37 Paulsen JS and Conybeare RA. Cognitive changes in Huntingtons
Mov Disord 2013;28:88998. disease. Adv Neurol 2005:96:20925.
22 Martino D, Liuzzi D, Macerollo A et al. The phenomenology of the 38 Morreale MK. Huntingtons disease: looking beyond the movement
geste antagoniste in primary blepharospasm and cervical dystonia. disorder. Adv Psychosom Med 2015;34:13542.
Mov Disord 2010;25:40712. 39 Martino D, Stamelou M, Bhatia KP. The differential diagnosis of
23 Albanese A, Bhatia K, Bressman SB et al. Phenomenology and classi- Huntingtons disease-like syndromes: red flags for the clinician.
fication of dystonia: a consensus update. Mov Disord 2013;28:86373. J Neurol Neurosurg Psychiatry 2013;84:65066.
24 B1 Balint, Bhatia KP. Dystonia: an update on phenomenology, classifi- 40 KJ1 Peall, Lumsden D, Kneen R et al. Benign hereditary chorea
cation, pathogenesis and treatment. Curr Opin Neurol 2014;27:46876. related to NKX2.1: expansion of the genotypic and phenotypic
25 Albanese A, Barnes MP, Bhatia KP et al. A systematic review on the spectrum. Dev Med Child Neurol 2014;56:6428.
diagnosis and treatment of primary (idiopathic) dystonia and dystonia 41 Mencacci NE, Erro R, Wiethoff S et al. ADCY5 mutations are
plus syndromes: report of an EFNS/MDS-ES Task Force. Eur J Neurol another cause of benign hereditary chorea. Neurology 2015;85:808.
2006;13:43344. 42 Bhatia KP. Paroxysmal dyskinesias. Mov Disord 2011;26:115765.
26 Jankovic J. Treatment of dystonia. Lancet Neurol 2006;5:86472. 43 Jankovic J. Treatment of hyperkinetic movement disorders. Lancet
27 Simpson DM, Blitzer A, Brashear A et al. Assessment: Botulinum Neurol 2009;8:84456.
neurotoxin for the treatment of movement disorders (an evidence- 44 Edwards TC, Zrinzo L, Limousin P, Foltynie T. Deep brain stimula-
based review): report of the Therapeutics and Technology Assessment tion in the treatment of chorea. Mov Disord 2012;27:35763.
Subcommittee of the American Academy of Neurology. Neurology 45 Pouclet-Courtemanche H, Rouaud T, Thobois S et al. Long-term
2008;70:1699706. efficacy and tolerability of bilateral pallidal stimulation to treat
28 Albanese A, Asmus F, Bhatia KP et al. EFNS guidelines on diagnosis tardive dyskinesia. Neurology 2016;86:6519.
and treatment of primary dystonias. Eur J Neurol 2011;18:518.
29 Volkmann J, Wolters A, Kupsch A et al. Pallidal deep brain stimulation
in patients with primary generalised or segmental dystonia: 5-year
follow-up of a randomised trial. Lancet Neurol 2012;11:102938. Address for correspondence: Dr D Martino, International
30 Vidailhet M, Vercueil L, Houeto JL et al. Bilateral deep-brain Parkinsons Centre of Excellence, Kings College and Kings
stimulation of the globus pallidus in primary generalised dystonia. College Hospital, Denmark Hill Campus, London SE5 9RS, UK.
N Engl J Med 2005;352:459500. Email: davidemartino@nhs.net