Expert to Expert: Paediatric Movement Disorders Pre-course ...dystonic or dyskinetic cerebral palsy,...

Expert to Expert:

Paediatric Movement Disorders

Pre-course Reading

Bristol

18-19 October 2018

CARE PATHWAYS

© September 2016, AACPDM Care Pathways, for review 2019

ACPD

M-0

218-

424

DYSTONIABottom Line ‘Evidence-Informed’ Recommendations for the Management

of Dystonia in Individuals with Cerebral Palsy Authors (AACPDM Dystonia Care Pathway Team): D Fehlings (team lead),

L Brown, A Harvey, K Himmelmann, JP Lin, A MacIntosh, J Mink, E Monbaliu, J Rice, J Silver, L Switzer, I Walter.

DEFINITIONSDystonia is a movement disorder in which involuntary sus-tained or intermittent muscle contractions cause twisting and repetitive movements, abnormal postures, or both. Dystonia in cerebral palsy (CP) presents as hypertonia, in-voluntary postures and movements, or a combination. Dys-tonia occurs in dyskinetic CP but also is commonly present in spastic CP.

WHY IS DYSTONIA IN CEREBRAL PALSY IMPORTANT?• Dystoniacanimpedemotorfunctionthroughinvoluntary

muscle contractions, limitations in muscle relaxation, andoverflow,whichistheassociationofinvoluntarymovement with intended movement which spreads to surrounding or distant muscles

• Dystoniacaninterferewithpositioningforsitting and lying

• Dystonicposturesandmovementcanbepainful

• Dystoniacaninterferewithsleep

• Dystoniacanresultinhighenergyexpenditureandmal-nutrition

• Dystonicpostures/hypertoniacancreatechallengeswith care-giving

Target Population: Individuals with dystonia in CP where the dystonia interferes with function, positioning or causes pain and disrupted sleep.

Target Clinical Providers:Physicians/Nurses/Therapistscaring for individuals with dystonia in CP.

ASSESSMENT Dystonia is a frequently overlooked element of the neuro-logicalpresentationofCP.Therefore,itisrecommendedthat a ‘dystonia’ assessment be routinely included in yourneurologicalexamination(assessingforfluctuating

hypertonia, and using tactile stimulation or voluntary movement to trigger dystonia). More informa-

tion can be found in Section 3 of this pathwayintheHATtoollink.

On your examina-

tion, determine if the dystonia is generalized or focal and assess the severity (can use a standardized scale such as the Barry Albright Dystonia Scale outlined in Section 3).Assesstheimpactofthedystoniaonfunction,pain/comfort (including sleep), and care-giving and whether management is required.

If dystonia is present, assess whether the neurologic presentation is consistent with CP (risk factors, brain imaging, and family history) or if additional work-up is required. An important masquerader of CP-related dystonia is Dopamine Responsive Dystonia. Consider the needforatrialoflevodopaand/orareferraltoaneu-rologist/geneticistforadditionaldiagnosticwork-up.

MANAGEMENTIt is important to note that much of this Dystonia Care Pathway is based on expert opinion, as the evidence for dystonia management in CP is currently limited.

• Rehabilitation Strategies: Rehabilitation strategies used by physiotherapists, occupational therapists and speech pathologists are generally considered cornerstones in the management of dystonia in CP. General principles include: 1) ensuring therapy is goal-directed, 2) avoiding asymmetry and aiming for symmetrical positioning to en-hance motor control, 3) optimizing seating and position-ingwithgoodstability/support,4)consideringorthosesand splints to increase stability and coordination, and 5) considering the need for communication supports.

• Generalized Dystonia Management: With increasing severity of dystonia, additional interventions may be required beginning with oral medications. Oral baclofen isconsideredafirstlinemedicationforthemanagementof dystonia in CP. Common indications include pain or difficultysleepingassociatedwithdystoniainCP.Iftheindividual does not respond well to oral baclofen, trihexy-phenidyl can be used as a second line medication. Other oralmedicationsshouldbeconsideredforspecificindi-cations. For example, the intermittent use of benzo-diazepines is helpful for dystonic storms or disturbed sleep, and gabapentin for dystonia associated with pain.

CARE PATHWAYS


ACPD

M-0

218-

424

Clonidine can also be considered for disturbed sleep as-sociated with dystonia.

In the presence of severe generalized dystonia associated withsignificantimpactoncare/comfort,moreaggres-sivemanagementcanbeundertaken.Thismayincludeintrathecal baclofen (ITB) or deep brain stimulation (DBS).Thesestrategiesrequireareferraltoaspecial-ist team. Individuals with severe generalized hypertonia with a combination of dystonia and spasticity may trial intrathecal baclofen. Other considerations of whether to chooseITBorDBScanbebasedonthecerebralanatomyand whether placement of the stimulator in the globus pallidusispossible.ITBshouldbeusedwithcautioninthe presence of nocturnal respiratory compromise.

AclassicfeatureofdystoniainCPisafluctuationintheseverity of the dystonia. For this reason it is important to periodically re-evaluate the individual and adjust the in-terventions as required. For some individuals with severe dystonia, a personalized plan for managing increasing dystonia can be developed and includes increasing the dose of current oral medications or introducing a second medication(e.g.clonidineorgabapentin).TheuseoftheDystonia Severity Action Plan (DSAP) may be helpful for monitoring unstable dystonia and is outlined in Section 3. A rapid and severe increase in dystonia is termed ‘Peri-odic Status Dystonicus’. It can be life-threatening and requires urgent treatment often with a combination of benzodiazepines and clonidine (enteral, intravenous, or transdermal) (see Section 3 for a management protocol for ‘Status Dystonicus’). Another important issue is the triggering of dystonia from secondary health conditions includinggastrointestinaldisorderssuchasrefluxorconstipation.Theoverallgeneralhealthoftheindividualshould be carefully monitored and secondary health is-sues actively addressed.

• Focal Dystonia Management: For individuals with focal or segmental dystonia associated with persisting pos-turescausingpainorimpactingonfunction/care-giving,periodic injections of Botulinum toxin can be undertaken. Considertargetingboththeagonist/antagonistmusclesaround the joint(s) involved with the dystonic posture.

DYSTONIABottom Line ‘Evidence-Informed’ Recommendations for the Management

of Dystonia in Individuals with Cerebral Palsy Authors (AACPDM Dystonia Care Pathway Team): D Fehlings (team lead),

L Brown, A Harvey, K Himmelmann, JP Lin, A MacIntosh, J Mink, E Monbaliu, J Rice, J Silver, L Switzer, I Walter.

CARE PATHWAYS


ACPD

M-0

218-

424

Thepurposeofthisdocumentistoprovidehealthcareprofessionalswithkeyfactsandrecommendationsfortheassessmentandtreatmentofdystoniainchildrenandyouthwithcerebralpalsy.ThissummarywasproducedbytheAACPDMDystoniaCarePathwayTeam(DFehlings(teamlead),LBrown,AHarvey,KHimmelmann,

JPLin,AMacIntosh,JMink,EMonbaliu,JRice,JSilver,LSwitzer,IWalters).Thesummaryisbasedonasystematicreviewbeingsubmittedforpeer-reviewed publication. However, health care professionals should continue to use their own judgement and take into account additional

relevantfactorsandcontext.TheAACPDMisnotliableforanydamages,claims,liabilities,orcostsarisingfromtheuseofthese recommendations including loss or damages arising from any claims made by a third party.

NATURE REVIEWS | NEUROLOGY VOLUME 11 | OCTOBER 2015 | 567

Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK (J.N., A.P., M.A.K.). Neurometabolic Unit, National Hospital, Queen Square, London WC1N 3BG, UK (S.J.H.).

Correspondence to: M.A.K. manju.kurian@ ucl.ac.uk

Monoamine neurotransmitter disorders —clinical advances and future perspectivesJoanne Ng, Apostolos Papandreou, Simon J. Heales and Manju A. Kurian

Abstract | The monoamine neurotransmitter disorders are important genetic syndromes that cause disturbances in catecholamine (dopamine, noradrenaline and adrenaline) and serotonin homeostasis. These disorders result in aberrant monoamine synthesis, metabolism and transport. The clinical phenotypes are predominantly neurological, and symptoms resemble other childhood neurological disorders, such as dystonic or dyskinetic cerebral palsy, hypoxic ischaemic encephalopathy and movement disorders. As a consequence, monoamine neurotransmitter disorders are under-recognized and often misdiagnosed. The diagnosis of monoamine neurotransmitter disorders requires detailed clinical assessment, cerebrospinal fluid neurotransmitter analysis and further supportive diagnostic investigations. Prompt and accurate diagnosis of neurotransmitter disorders is paramount, as many are responsive to treatment. The treatment is usually mechanism-based, with the aim to reverse disturbances of monoamine synthesis and/or metabolism. Therapeutic intervention can lead to complete resolution of motor symptoms in some conditions, and considerably improve quality of life in others. In this Review, we discuss the clinical features, diagnosis and management of monoamine neurotransmitter disorders, and consider novel concepts, the latest advances in research and future prospects for therapy.

Ng, J. et al. Nat. Rev. Neurol. 11, 567–584 (2015); published online 22 September 2015; doi:10.1038/nrneurol.2015.172

IntroductionMonoamine neurotransmitters are essential for signalling in the CNS and PNS, and are involved in the regulation of movement, basal muscle tone, activity levels, mood, attention, sleep, vascular tone, circulation, thermo regulation and pain modulation.1,2 Inherited disorders of monoamine synthesis, metabolism and transport are a growing group of genetic conditions that result in impaired biogenic amine homeostasis.

Several primary and secondary monoamine neurotransmitter disorders are known (Figure 1), and knowledge of monoamine metabolism and homeostasis is invaluable for accurate diagnosis and effective treatment of these disorders. Monoamines are synthesized in pre synaptic neurons and packaged into vesicles by synaptic vesicular amine transporter (also known as vesicular monoamine transporter 2; VMAT2) for subsequent release into the synaptic cleft, where they bind to postsynaptic receptors. Neurotransmission is terminated by degradation or r euptake of the monoamine (Figure 2).

In this Review, we describe the key clinical features that indicate a monoamine neurotransmitter disorder, and discuss diagnostic investigations, current treatment strategies, advances in therapeutics, and future perspectives.

Diagnosis of neurotransmitter disordersNeurotransmitter disorders can be diagnosed by combining information from a patient’s clinical history with

the findings of physical examination, specific biochemical investigations and genetic testing (Figure 3). The key steps in diagnosing these conditions are described below. Further support in the clinical assessment and investigation of these diseases is available from other resources.3,4

History and examinationDisruption of monoamine metabolism leads to diverse neurological manifestations in childhood that are evident from a clinical history and examination. For some patients, the family history reveals consanguinity, which might indicate a recessive inherited disorder. The presentation of the disorders can include cognitive and motor delay, epilepsy, autonomic dysfunction (which manifests as sweating, temperature dysregulation, hypersali vation and nasal congestion) and neuropsychiatric features such as anxiety or autistic spectrum disorder. Motor symptoms are often prominent and include gait disturbances, dystonia, dyskin esia, parkinsonism, tremor, oculogyric crises, palpebral ptosis and axial hypotonia.5,6 Patients often exhibit diurnal variation: motor symptoms become more prominent in the evening and improve after sleep.7 Other associated features include feeding difficulties and microcephaly.8

Many clinical features of monoamine neurotransmitter disorders are observed in other neurological conditions, such as cerebral palsy, primary movement disorders, paroxysmal disorders, hypoxic–ischaemic encephalopathy and epileptic encephalopathies. These shared features result in frequent misdiagnosis and underrecognition of monoamine neurotransmitter disorders.

Competing interestsThe authors declare no competing interests.

REVIEWS

© 2015 Macmillan Publishers Limited. All rights reserved

mailto:[email protected]


http://dx.doi.org/10.1038/nrneurol.2015.172

568 | OCTOBER 2015 | VOLUME 11 www.nature.com/nrneurol

Cerebrospinal fluid analysisAn abnormal cerebrospinal fluid (CSF) neurotransmitter profile is one of the most important indi cators of a neuro transmitter disorder (Figure 3).7,9,10 CSF is analysed at specialist centres with highperformance liquid chroma tography 5,6,11,12 to measure levels of homovanillic acid (HVA), 3Omethyldopa (3OMD), 3methoxy4hydroxypheny lg lycol (MHPG), 5hydroxy indoleacetic acid (5HIAA), neopterin, tetra hydrobiopterin (BH4), dihydrobiopterin (BH2) 5methyltetrahydrofolate and pyridoxal 5'phosphate (vitamin B6). CSF levels of glucose, lactate and amino acids are often analysed at the same time, especially in children with undiagnosed neurological symptoms.

Analysis of CSF requires the use of strict protocols to ensure accurate results (Box 1).5,12 Care must also be taken to ensure the correct interpretation of results. The time of day at which the CSF sample is taken should be recorded because HVA concentrations might decline in the evening in some doparesponsive pterin synthesis defects. Medication that the patient is receiving at the time of CSF sampling should also be documented, as some drugs (for example levodopa) can affect CSF neuro transmitter levels. Furthermore, results should be compared with those from agematched references because CSF concentrations of HVA, 5HIAA and BH4 are high at birth, rapidly decrease in the first few months of life, then decrease slowly into adulthood.13

Neurotransmitter disorders can be missed with CSF analysis. A common misperception is that neurotransmitter levels must markedly differ from agematched normal levels to indicate a neurotrans mitter disorder; in fact differences might be subtle. In GTP cyclohydrolase 1 (GTPCH 1) deficiency, the CSF neurotransmitter profile can be normal,14 so the clinical presentation and response to levodopa are key to the diagnosis of this condition. Furthermore, several therapies can alter CSF neurotransmitter profiles. Children with movement disorders often receive a trial of medication that masks neurotransmitter abnormalities. In deficiencies of GTPCH 1,14 6 pyruvoyl tetrahydropterin synthase (PTPS)15 and tyrosine

Key points

■ Monoamine neurotransmitter disorders are under-recognized and often misdiagnosed, as many mimic cerebral palsy and other neurological disorders

■ ‘Red flag’ symptoms of monoamine neurotransmitter disorders include diurnal variation of symptoms, a mixed movement disorder, autonomic disturbance, involvement of the eyes (ptosis, oculogyric crisis) and levodopa responsiveness

■ Many monoamine neurotransmitter disorders are amenable to treatment; appropriate therapy is curative in some disorders

■ Analysis of cerebrospinal fluid neurotransmitter levels aids identification of the specific monoamine pathway defect and is vital for accurate diagnosis of most primary neurotransmitter disorders and selection of appropriate disease-specific pharmacotherapy

■ Research in the past few years has identified novel monoamine neurotransmitter disorders that involve defects in dopamine transport and monoamine vesicle packaging

■ Discoveries of novel genetic defects and biomarkers in monoamine neurotransmitter disorders, together with novel disease models, will improve our understanding of pathophysiological mechanisms and facilitate the development of new treatments

hydroxylase, treatment with levodopa can normalize HVA levels, but concomitant abnormal levels of 3OMD indicate the use of levodopa therapy in this situation.16 Treatment with 5hydroxytryptophan can normalize levels of 5HIAA, and tetrahydrobiopterin therapy can normalize BH4.

Blood and urine analysisAnalysis of blood and urine to detect metabolites of pterins and biogenic amines can facilitate diagnosis of a monoamine neurotransmitter disorder (Figure 4).

Hyperphenylalaninaemia associated with pterin defects can be detected with the neonatal dried blood spot (DBS) screening test and plasma amino acid ana lysis (Figure 4). High plasma levels of prolactin, especially in the context of galactorrhoea,17 can be a manifestation of central dopaminergic deficiency, as dopamine has a physiological role in suppressing prolactin release,18 although normal levels do not exclude a neurotransmitter disorder.18 Prolactin levels should be interpreted using agerelated reference ranges.18

Urine levels of neopterin and biopterin can indicate pterin defects, and high urine levels of vanillylactic acid can indicate aromatic lamino acid decarboxylase (AADC) deficiency or, in some patients, pyridoxine 5'phosphate oxidase (PNPO) deficiency.19 In dopamine transporter deficiency syndrome (DTDS), the HVA:creatine ratio in urine is sometimes high,20,21 and urinary HVA and 5HIAA levels are high in brain dopamine–serotonin vesicular transport disease

(Figure 4).22

Enzyme assaysMeasuring enzyme activity can be helpful for diagnosis of a monoamine neurotransmitter disorder, particularly when such a disorder is suspected but CSF neurotransmitter analysis is atypical for the suspected condition and genetic testing identifies no diseasecausing mutation. For example, activity of fibroblast GTPCH 1 can be measured when GTPCH 1 deficiency is suspected but the patient does not exhibit the classic response to levodopa, their CSF neurotransmitter profile is normal or atypical for the condition, and/or no mutation is detected in the GCH1 gene.7 Enzyme assays can also help in the diag nosis of sepiapterin reductase deficiency, dihydro pteridine reductase deficiency and AADC deficiency (Figure 4).7

Phenylalanine loading testThe phenylalanine loading test is an adjunctive diagnostic test for pterin disorders with no hyperphenylalaninaemia.23,24 An increased phenylalanine–tyrosine ratio in the serum after oral administration of a phenylalanine load (100 mg/kg) indicates a BH4 metabolism defect. Serial ratio measurements after loading demonstrates an initially increased ratio that subsequently declines,20 although in practice, a single measurement at 2 h after loading might suffice if levels of biopterin are reduced.7 Normal tyrosine levels in followup phenylalanine loading after BH4 supplementation provides

REVIEWS



further evidence for a pterin defect. The phenyl alanine loading test should not be conducted in patients who are receiving treatment with BH4, as the phenyl alanine concentration profile remains normal in this situation.25

The phenylalanine loading test is neither 100% sensitive nor 100% specific for pterin defects. False negative results can be seen in patients with GTPCH 1 deficiency, and false positive results in heterozygote carriers of phenylalanine hydroxylase mutations.23

Trial of levodopaTreatment with levodopa aims to restore dopamine levels in disorders of dopamine synthesis, and responsiveness to this treatment can be vital for the diagnosis of monoamine neurotransmitter disorders. Patients with GTPCH 1 deficiency exhibit an excellent response to levodopa, so a levodopa trial is a major diagnostic tool in this dis order.26 Deficiencies of tyrosine hydroxylase,16 sepiapterin reductase27 and PTPS also respond to levodopa to some degree.15 Doparesponsive dystonia with onset in the first decade of life could also indicate juvenile parkinsonism associated, for example, with PARK2 mutations.28

Levodopa should be administered with a peripheral inhibitor of AADC, such as carbidopa or benserazide, to prevent conversion of the drug to dopamine in the periphery. Treatment should be commenced at a low

dose that is gradually titrated according to the patient’s tolerance and response, so as to minimize the risk of levodopainduced dyskinesia. The development of variableintensity dyskinesia with responsiveness to levodopa can indicate specific neurotransmitter disorders, such as tyrosine hydroxylase deficiency.29 If dyskinesia develops, it can often be eliminated by reducing the dose of levodopa.29,30 Gastrointestinal symptoms are commonly experienced by children on levodopa and are often managed with prophylactic antiemetics.7

Molecular geneticsMutational analysis of specific genes can confirm the diag nosis of monoamine neurotransmitter disorders. Genetic confirmation enables appropriate genetic counselling for affected families, appropriate testing of extended family, prenatal testing, and preimplantation diagnosis. Genetic confirmation of a diagnosis can also help to assess the prognosis, as correlations have been reported between genotype and phenotype in several disorders, inclu ding tyrosine hydroxylase deficiency, PTPS deficiency and DTDS.16,31,32 Some monoamine neurotransmitter disorders can be detected with micro array studies (for example, by determining copy number variants in dopa mine βhydroxylase deficiency)33 and, increasingly, with whole exome and whole genome sequencing.

Monoamine neurotransmitter disorders

Primary disorders Secondary defectsin other disorders

Disorders ofunknown origin

Enzymede�ciency

Defectivevesicle

formationand/or

packaging

■ Tyrosine hydroxylase■ AADC■ Dopamine β-hydroxylase■ Monoamine oxidase

DATde�ciencysyndrome

Vitamin B6 BH4

Brain dopamine–serotonin vesiculartransport disease

Phenylalaninenormal

Phenylalanineabnormal

■ PNPO de�ciency■ Pyridoxine- dependent epilepsy

■ Autosomal dominant GTP-CH I de�ciency■ Sepiapterin reductase de�ciency

■ Autosomal recessive GTP-CH I de�ciency■ PTPS de�ciency■ Dihydropteridine reductase de�ciency

■ Aicardi-Goutière syndrome■ Autistic spectrum disorder■ Cerebral palsy■ Dystonic disorders■ Epileptic encephalopathies■ Folate metabolism disorders■ Leukodystrophies■ Lesch–Nyhan syndrome■ Mitochondrial disorders■ Neuropsychiatric disorders■ Opsoclonus–myoclonus syndrome■ Peilizaus–Merzbacher■ Phenylketonuria■ Pantothenate kinase associated neurodegeneration■ Perinatal asphyxia/hypoxic ischaemic encephalopathy■ Pontocerebellar hypoplasia■ Rett syndrome■ Spontaneous periodic hypothermia and hyperhydrosis

■ Idiopathic focal dystonia■ Disorders of selective serotonin deficiency■ Dopa nonresponsive dystonia■ Paroxysmal kinesiogenic dyskinesia

Cofactorde�ciency

PITX3(TH

promoter)

Defectivetransportand/or

reuptake

VMAT2

Nature Reviews | Neurology

DAT

Figure 1 | Overview of primary and secondary monoamine neurotransmitter disorders. Primary disorders of dopamine and serotonin metabolism are attributable to enzyme or cofactor deficiencies, defective neurotransmitter transport and/or reuptake or defective vesicle formation and/or packaging. Neurotransmitter abnormalities are becoming increasingly recognized as secondary phenomena that result from other neurological disorders. Abbreviations: BH4, tetrahydrobiopterin; DAT, dopamine transporter; GTP-CH 1, GTP cyclohydrolase 1; PITX3, pituitary homeobox 3; PTPS, 6-pyruvoyl tetrahydropterin; VMAT2, vesicular monoamine transporter 2.

REVIEWS



Primary disordersImpaired tetrahydrobiopterin synthesis BH4 is an essential cofactor in the hydroxylation of phenyl alanine and is essential for monoamine synthesis.12 BH4 deficiencies encompass a heterogeneous group of defects in pterin synthesis or regeneration that occur with or without hyperphenyl alaninaemia (Figure 2). These conditions are treatable, and thorough diagnostic investi gations for BH4 deficiencies should be conducted in all patients with clinical symptoms

of dopamine or sero tonin deficiency, elevated phenylalanine levels detected by newborn DBS screening, or unexplained neurological symptoms.34

Autosomal dominant GTP‑CH 1 deficiencyGTPCH 1 catalyses the conversion of GTP to dihydroneopterin triphosphate, the ratelimiting step in BH4 synthesis. The incidence of autosomal dominant GTPCH 1 deficiency (also known as Segawa disease, dopa responsive dystonia or DYT5a)26,35 is 0.5 per 100,000

Figure 2 | Monoamine synthesis and metabolism in neurons. Tyrosine and tryptophan are the initial substrates in the synthesis pathway. Both substrates enter the brain via the large neutral amino acid transporter, and tyrosine is also produced in neurons by catabolism of phenylalanine. Levels of dopamine and serotonin metabolites can be measured in the cerebrospinal fluid and are crucial to the diagnosis of neurotransmitter disorders. Abbreviations: AADC, aromatic l-amino acid decarboxylase; BH2, dihydrobiopterin; BH4, tetrahydrobiopterin; DHPR, dihydropteridine reductase; PLP, pyridoxal 5'-phosphate; PTP, 6-pyruvoyl tetrahydrobiopterin; PTPS, PTP synthase; qBH2, quinoid BH2; VMAT2, vesicular monoamine transporter 2.

Presynapticdopaminergic

neuron

VMAT2

Dopamine reuptakeand recycling

Dopamine Serotonin 5-hydroxyindoleaceticacid

Adrenaline

Dopamine β-hydroxylase

PhenylethanolamineN-methyltransferase

Vanillylmandelicacid

3,4-dihydroxy-phenylacetic

acid

3-Methoxy-tyramine

Homovanillicacid

Monoamine oxidaseCatechol-O-methyl transferase

Aldehyde dehydrogenaseMonoamine

oxidaseCatechol-O-methyl

transferase

Vanillacticacid 3-ortho-Methyldopa

Catechol-O-methyl

transferase

AADC

PLP

Tyrosinehydroxylase

Tyrosine

Phenylalanine

Pituitaryhomeobox 3

Phenylalaninehydroxylase

Dopamine transporter

Postsynapticneuron

Dopamine receptor

Dopamine

Tryptophanhydroxylase

1 and 2

Tryptophan

GTP

GTPcyclohydrolase 1

Dihydroneopterintriphosphate

Neopterin

PTPS

PTP

Aldosereductase

Sepiapterinreductase

DHPR

qBH2 Biopterin

Pterin-4-α-carbinolaminedehydratase

BH4α-carbinolamine

Primapterin

SepiapterinBH4

3-Methyl 4-hydroxyphenylglycol

Monoamineoxidase

Noradrenaline

Pre-monoamine metabolites

Enzymes

Enzyme cofactors

Proteins that control monoaminetransport or regulation

Monoamine metabolites

Monoamines

BH4

Levodopa 5-hydroxytryptophan


REVIEWS



people, with a female:male ratio of 2.5:1.35 Patients typically present with postural dystonia that affects the lower limbs, with inturning of the foot (pes equinovarus).26,35 Marked diurnal variation (classically referred to as evening equinus) and a remarkable response to levodopa treatment (which resolves motor symptoms in most patients) are key, often diagnostic, features of the condition.26,35

Segawa proposed an agerelated clinical course of GTPCH 1 deficiency, in which disease presentation

and evolution relates to the development and maturation of the nigrostriatal pathways.14 Patients who develop the condition in middle childhood experience action dys tonia, retrocollis and, in some patients, oculogyric crisis.35 Adolescents present with asymmetrical upper limb postural tremor, and adults present with upper limb tremor, parkinsonism and gait rigidity.36 Atypical movement pheno types include writer’s cramp and spasmodic dysphonia.37 Other conditions, such as diplegic cerebral

Figure 3 | A guide to the clinical diagnosis of neurotransmitter disorders. If red-flag clinical features of monoamine neurotransmitter disorders are present, the initial diagnostic approach should include careful history-taking and thorough clinical examination (including reviews of videos if available). Appropriate metabolite analysis could include blood glucose, lactate, ammonia, amino acids, biotinidase, thyroid function tests, acylcarnitine, carnitine profile, white-cell enzymes and very-long-chain fatty acids; urine amino acids, organic acids, oligosaccharides, purines and pyrimidines; CSF glucose, lactate, amino acids, and neurotransmitter profile. Skin and muscle biopsy can also be undertaken for specialist metabolic investigations. Specific patterns of neurotransmitter levels in the CSF patterns can indicate specific neurotransmitter disorders. Abbreviations: 5-HIAA, 5-hydroxyindoleacetic acid; AADC, aromatic l-amino acid decarboxylase; AD, autosomal dominant; AR, autosomal recessive; CSF, cerebrospinal fluid; DHPR, dihydropteridine reductase; DND, dopa-nonresponsive dystonia; DTDS, dopamine transporter deficiency syndrome; GTP-CH 1, GTP cyclohydrolase 1; HVA, homovanillic acid; MAO, monoamine oxidase; NBIA, neurodegeneration with brain iron accumulation; P-DE, pyroxidine-dependent epilepsy; PITX3, pituitary homeobox 3; PNPO, pyridoxamine 5'-phosphate oxidase; PTPS, 6-pyruvoyl tetrahydropterin synthase; RBC, red blood cell; SR, sepiapterin reductase; TH, tyrosine hydroxylase; VMAT2, vesicular monoamine transporter 2.


Initial clinical assessment CSF neurotransmitter analysisDiagnosis/

genetic cause

Differential diagnosis

■ Neurometabolic disorders■ NBIA■ Dystonia–parkinsonism syndromes■ Cerebral palsy (secondary neurotransmitter abnormalities can be seen)

Response tolevodopa trial

and/or abnormalphe loading

■ Detailed clinical history■ Examination■ Video review■ MRI scan■ Blood and urine metabolite analysis■ CSF neurotransmitters

CSFpterinsnormal

Phenormal

Pheabnormal

HVAabnormal

HVAnormal

NeopterinBiopterin

NeopterinBiopterinSepiapterin

NeopterinBiopterin

NeopterinBiopterin

NeopterinBiopterin

Biopterin

‘Red �ag’ signs

■ Dystonia■ Mixed movement disorder■ Diurnal variation■ Ptosis■ Autonomic dysfunction■ Levodopa response■ Levodopa-induced dyskinesiaAssociated features

■ Neonatal encephalopathy■ Developmental delay■ Extrapyramidal tract features■ Pyramidal tract features■ Autonomic features■ Neuropsychiatric symptoms

HVA5-HIAA

HVA5-HIAA

HVA5-HIAA

HVA5-HIAAFolate

HVA5-HIAA

HVA5-HIAALevodopaabsent

HVA5-HIAAMHPG

HVA5-HIAAOMDLevodopaMHPG

HVA5-HIAAOMDLevodopa

HVA5-HIAA

HVA5-HIAA5-HT

HVA5-HIAA

HVA5-HIAA

CSFpterins

abnormal

1

3

4

2

GCH1

SPR

GCH1

QDPR

PTS

TH

DDC

PNPO

ALDH7A1

SLC6A3

MAO

SLC18A2

AD GTP-CH 1de�ciency

SRde�ciency

AR GTP-CH 1de�ciency

DHPRde�ciency

PTPSde�ciency

PITX3

THde�ciency

TH de�ciencymimic

AADCde�ciency

PNPOde�ciency

P-DE

DTDS

MAOde�ciency

DND

VMAT2de�ciency

1 3 42AADC RBC activity AADC RBC activity Urine AASA Urine HVA/HIAA

REVIEWS



palsy, hereditary spastic paraparesis and paroxysmal exerciseinduced dyskinesia, mimic GTPCH 1 deficiency.38–40 Earlyonset Parkinson disease has also been recognized in patients with GTPCH 1 deficiency.41,42

Diagnosis of GTPCH 1 deficiency is made using the results of biochemical tests, genetic analysis and a levodopa trial (Figures 3 and 4). Plasma phenylalanine levels are normal, and the phenylalanine loading test is often abnormal. Typically, the CSF neurotransmitter profile in GTPCH 1 deficiency reveals low levels of HVA, 5HIAA, BH4 and neopterin.7,6 However, levels of HVA and 5HIAA might only be slightly reduced or normal, so the diagnosis can be missed on CSF analysis.7 Normal or subtly abnormal CSF neurotransmitter levels do not, therefore, exclude GTPCH 1 deficiency, so genetic studies should still be conducted if the clinical features and levodopa response are consistent with the condition.38

To date, >100 different GCH1 mutations have been identified, which account for GTPCH 1 deficiency in ~60% of patients.43 Direct sequencing identifies no mutations in the remaining ~40% of patients; in some of these individuals, large deletions and intragenic duplications, which can be identified by using multiplex ligationdependent probe amplification, might be causative.44

In nearly all patients with classic GTPCH 1 deficiency, levodopa treatment elicits a striking response (Table 1). If no response to levodopa treatment is seen, autosomal dominant GTPCH 1 deficiency is unlikely.14 Typically, patients remain stable on levodopa treatment into adulthood, and the dose of levodopa often does not need to be increased with age or longer treatment.43 Indeed, for many patients, levodopa dosage can be decreased over time.43 In the long term, ~20% of adults on this treatment

develop levodoparelated dys kinesia.45 In rare cases, a combination treatment of BH4 and levodopa has been used in an attempt to achieve complete resolution of symptoms. BH4 monotherapy was ineffective in animal models of GTPCH 1 deficiency,46 and is reported to be clinically ineffective.24

Autosomal recessive GTP‑CH 1 deficiencyThe recessive form of GTPCH 1 deficiency presents with truncal hypotonia, a wide variety of movement disorders (including dystonia), autonomic dysfunction, seizures and developmental delay.47 Hyperphenylalaninaemia, detected with newborn DBS screening, or high plasma levels of amino acids can help to distinguish the auto somal recessive form of the condition from the autosomal dominant form.7 However, several reports of auto somal recessive GTPCH 1 deficiency that presents without hyperphenylalaninaemia suggest a phenotypic spectrum between the two forms.37,47–49

In autosomal recessive GTPCH 1 deficiency, levels of monoamine neurotransmitter metabolites in the CSF and of pterins in the urine are reduced (Figures 3 and 4). Compound heterozygous or homozygous mutations in GCH1 provide genetic confirmation of the diagnosis. If genetic tests are inconclusive, measurement of residual GTPCH 1 activity in fibroblasts might be helpful (Figure 4).48

Treatment for autosomal recessive GTPCH 1 deficiency includes BH4 supplementation,47 but BH4 monotherapy cannot fully restore monoamine neurotransmitter synthesis, so levodopa and 5hydroxytryptophan therapy is also required (Table 1).47

6‑pyruvoyl tetrahydropterin synthase deficiencyPTPS deficiency is caused by mutations in PTS and occurs at its highest frequency in Asian populations.15 The pheno type ranges from mild disease (asymptomatic at treatment initiation) to severe neurological syndromes. Mutations that preserve greater enzyme function result in milder phenotypes.31 Neonatal patients are frequently small for gestational age and have hypotonia, microcephaly and poor suck.15 Associated movement disorders include hypokinesia, ridigity, chorea, dystonia and oculogyric crisis. Severe disease is associ ated with learning disabilities, epilepsy and psychiatric symptoms.7

Detection of hyperphenylalaninaemia with neonatal DBS screening enables early diagnosis of PTPS deficiency.15,49 CSF levels of HVA and 5HIAA are usually both low, but can be normal. CSF levels of biopterin are low (Figure 3), and urine levels of neopterin are high (Figure 4).50 Treatment usually involves BH4, levodopa and 5hydroxytryptophan supplementation (Table 1),51 but dopamine agonists, anticholinergics and benzodiazepines are also commonly used.52,53

Sepiapterin reductase deficiencySepiapterin reductase deficiency is an underrecognized autosomal recessive, levodoparesponsive disorder of pterin synthesis that results from mutations in SPR.27 The largest published series (which included 43 patients)

Box 1 | Collection and analysis of CSF samples

CSF samples must be snap frozen with liquid nitrogen or dry ice immediately after collection, as BH4 is labile, and subsequently stored at –80oC until it is analysed.6,11 Addition of the metal chelator diethylene triamine penta-acetic acid and the reducing agent dithioerythritol is required to prevent oxidation of BH4.13 Delayed or slow freezing can result in metabolite degradation that leads to erroneous results. Contamination with red blood cells also leads to rapid metabolite oxidation, so CSF samples should be immediately centrifuged and the clear supernatant transferred to new tubes for snap freezing.Three sequential samples of CSF are usually collected via a lumbar tap. The first is used to measure levels of HVA and 5-HIAA, the second to measure levels of 5-MTHF and pyridoxal 5'-phosphate, and the third to measure levels of pterins. All members of each metabolite group must be measured in the same sample because a rostrocaudal concentration gradient of CSF monoamine metabolites exists.105 For the same reason, the sampling method must be clearly identified, as metabolite concentrations might seem high if a ventricular CSF sample is compared with a reference sample obtained by lumbar puncture.Abbreviations: 5-HIAA, 5-hydroxyindoleacetic acid; 5-MTHF, 5-methyltetrahydrofolate; BH4, tetrahydrobiopterin; CSF, cerebrospinal fluid; HVA, homovanillic acid.

REVIEWS




Auto

som

al d

omin

ant

GTP

-CH

1 d

e�ci

ency

Auto

som

al r

eces

sive

GTP

-CH

1 d

e�ci

ency

PTPS

de�

cien

cy

Sep

iapt

erin

red

ucta

sede

�cie

ncy

DH

PR d

e�ci

ency

Tyro

sine

hyd

roxy

lase

de�c

ienc

y

AAD

C d

e�ci

ency

PNPO

de�

cien

cy

PITX

3

Mon

oam

ine

oxid

ase

inhi

bito

r de

�cie

ncy

Dop

amin

e β-

hydr

oxyl

ase

de�c

ienc

y

Bra

in d

opam

ine–

sero

toni

nve

sicu

lar

tran

spor

t di

seas

e

DAT

de�

cien

cysy

ndro

me

A A

|| || || || || || || || || ||

Phe Phe Phe OMD

A Abnormal High Low Key diagnostic test Abnormality unexpected, or not a routine test

Cerebrospinal �uid*

HVA

5-HIAA

HVA:5-HIAA

BH2

BH4

Neopterin

Sepiapterin

5-MTHF

Vitamin B6

MHPG

3-OMD

5-HTP

Blood

Phenylalanine‡

Phenyalanine loading§

Biopterin

Prolactin

Dopamine*

Noradrenaline*

Adrenaline*

Serotonin*

Dried blood spot

Urine

Total biopterin

Neopterin

HVA

5-HIAA

HVA:creatinine

3-OMD

Vanillylactic acid

Enzyme assays

Fibroblast

Blood

Dried blood spot

Genetics

Single gene testing

Microarray

Clinical response

Trial of levodopa

Figure 4 | Neurotransmitter profiles, metabolite profiles and other diagnostic investigations in neurotransmitter disorders. *Sample handling requires snap freezing. ‡Measured in either a dried blood spot or the plasma. §Phenylalanine:tyrosine ratio measured at 1, 2, 4 and 6 h after loading. ||Prolactin might not always be increased. Abbreviations: 3-OMD, 3-orthomethyldopa; 5-HIAA, 5-hydroxyindoleacetic acid; 5-HTP, 5-hydroxytryptophan; 5-MTHF, 5-methyltetrahydrofolate; AADC, aromatic l-amino acid decarboxylase; BH2, dihydrobiopterin; DAT, dopamine transporter; DHPR, dihydropteridine reductase; GTP-CH 1, GTP cyclohydrolase 1; HVA, homovanillic acid; MHPG, 3-methoxy-4-hydroxyphenylglycol; Phe, phenylalanine; PITX3, pituitary homeobox 3; PNPO, pyridoxamine 5'-phosphate oxygenase; PTPS, 6-pyruvoyl tetrahydropterin synthase.

REVIEWS



identified considerable delays in diagnosis owing to frequent misdiagnosis as cerebral palsy.27 Early disease in children manifests as an abnormal upward gaze, paroxysmal stiffening, and axial and/or limb hypotonia.54

Core features of the disease as it evolves include axial hypotonia, oculogyric crises, weakness, dystonia with diurnal fluctuation, and motor and language developmental delay.27 Head and limb resting tremor that

Table 1 | Clinical characteristics and management of primary monoamine neurotransmitter disorders

Disorder Clinical characteristics Management*

Autosomal dominant GTP-CH 1 deficiency (Segawa syndrome)

Dopa-responsive dystonia, diurnal variation, levodopa responsiveness; mimic of spastic diplegic cerebral palsy and hereditary spastic paraparesis

Levodopa, initial dose 0.5–1.0 mg/kg daily, gradually increased to up to 5.0 mg/kg daily (<3.0 mg/kg daily is often sufficient)35,36

Autosomal recessive GTP-CH 1 deficiency

Truncal hypotonia, dystonia, seizures, developmental delay, levodopa responsiveness

BH4 1–10 mg/kg daily,37 levodopa 1–10 mg/kg daily,37 5-HTP 1–8 mg/kg daily37

PTPS deficiency Hypotonia, hypokinesia, rigidity, chorea, dystonia, oculogyric crisis, levodopa responsive

BH4 1–12 mg/kg daily,31,52 levodopa 4–18 mg/kg daily,52 5-HTP 1–10 mg/kg daily,52 dopamine agonists and MAO inhibitors to avoid dopamine-related on–off phenomena31,41,52,53

Sepiapterin reductase deficiency

Axial hypotonia, dystonia, oculogyric crisis, diurnal fluctuation, cerebral palsy-like presentation, levodopa responsiveness

Levodopa 0.5–2.0 mg/kg daily,27,56,57 5-HTP 1–6 mg/kg daily,27,56,57 selegiline 0.03–2.00 mg/kg daily27

DHPR deficiency Bulbar dysfunction, dyskinesia, tremor, dystonia, choreoathetosis, levodopa responsiveness

Levodopa 5–13 mg/kg daily,41 5-HTP 3–11 mg/kg daily,41 calcium folinate (folinic acid) 15 mg daily, dopamine agonists and MAO inhibitors to avoid dopamine-related on–off phenomena52

Pterin-4 α-carbinolamine dehydratase deficiency

Hypotonia or no symptoms, transient hyperphenylalaninaemia

Screen for hypomagnesaemia and onset of diabetes in adolescence

Tyrosine hydroxylase deficiency

Type A: Parkinsonism–dystonia, hypokinesia or bradykinesia, rigidity, diurnal variation; mimic of neuromuscular disorders and hypokinetic–rigid syndrome

Type A: levodopa 3–10 mg/kg daily,16 trial of amantidine 4–6 mg/kg daily if levodopa-induced dyskinesia does not respond to a reduction in levodopa dose29

Type B: Complex encephalopathy, focal or generalized dystonia with crises, severe parkinsonism, hypotonia, oculogyric crisis, tremor, ptosis, hypersalivation, autonomic dysfunction, levodopa responsiveness

Type B: levodopa <0.5–2.0 mg/kg daily,16 trial of amantidine 4–6 mg/kg daily if levodopa-induced dyskinesia does not respond to a reduction in levodopa dose29

AADC deficiency Hypotonia, oculogyric crisis, hypokinesia, chorea, dystonia, bulbar dysfunction, fasting hypoglycaemia

Pyridoxine 20–160 mg/kg daily,19,71,79 calcium folinate (folinic acid) 15 mg daily, dopamine agonists (rotigotine patch 0.17–0.25 mg/kg daily,79 bromocriptine 0.013–4.000 mg/kg daily, pergolide 0.006–0.750 mg/kg daily, pramipexole 5 μg/kg daily in three doses, increased to 35 μg/kg daily in three doses, ropinirole 0.25 mg daily, increased by 0.25 mg every 3 days to 0.5–4 mg daily), selegeline 0.03–2.00 mg/kg daily,19,79 trihexyphenidyl 1–12 mg daily (titrated slowly; much higher doses often tolerated, but monitoring for adverse effects is essential), benztropine 1–4 mg/daily, clonidine 0.1–3.0 mg daily (initial test dose recommended, higher doses used with caution owing to antihypertensive action), benzodiazepines

PNPO deficiency Severe drug-resistant neonatal-onset epileptic encephalopathy, in utero seizure onset, premature birth

Pyridoxal 5'-phosphate 30–50 mg/kg daily90

PITX3 deletion Mild learning difficulties, hyperactivity, sleep disturbance, distinctive facial features, hypoplastic middle fifth phalanges

Levodopa 1.0–2.5 mg/kg daily89

MAO A or B deficiency X-linked developmental delay, episodic hypotonia, learning difficulties, stereotypies and self-injurious behaviour, epicanthic folds

Consider dietary restriction of foods rich in tyramine phenylethylamine, m-tyramine and p-tyramine (cheese, chocolate, cocoa)97

Dopamine β-hydroxylase deficiency

Ptosis, orthostatic hypotension, exercise intolerance Droxidopa (100–600 mg daily in adults, with gradual titration)103

Brain dopamine–serotonin vesicular transport disease

Axial hypotonia, oculogyric crisis, parkinsonism, tremor, facial dyskinesia, ptosis, bulbar dysfunction, sleep disturbance

Initial treatment with pramipexole 0.01–0.02 mg/kg daily in two doses (dose can be doubled according to gait dystonia and tolerability), trihexyphenidyl 0.2 mg/kg daily in two doses (increase slowly according to response)85

Dopamine transporter deficiency syndrome

Feeding difficulties, irritability, axial hypotonia, dyskinesia with progressive dystonia–parkinsonism, mimic of dyskinetic cerebral palsy; later onset with juvenile parkinsonism–dystonia, complete absence of dopamine uptake on DAT scan

Pramipexole 5 μg/kg daily in three doses, increased to 35 μg/kg daily in three doses), ropinirole 0.25 mg daily, increased by 0.25 mg every 3 days up to 0.5–4 mg daily85

*Drug treatments are mainly based on reported clinical experience. Where citations are not provided for doses, the quoted doses are recommendations from the British National Formulary for children, 2014 edition. Levodopa is normally administered in combination with carbidopa. Abbreviations, 5-HTP, 5-hydroxytryptophan; AADC, aromatic l-amino acid decarboxylase; BH4, tetrahydropterin; DHPR, dihydropterin reductase; GTP-CH 1, GTP cyclohydrolase 1; MAO, monoamine oxidase; PITX3, pituitary homeobox 3; PNPO, pyridoxine 5'-phosphate oxidase; PTPS, 6-pyruvoyl tetrahydrobiopterin synthase.

REVIEWS



is inhibited by touch or spontaneous movement has also been reported.55 Parkinsonian features, sleep disorders, behavioural difficulties and psychiatric symptoms are common.56 The majority of patients have some degree of learning disability: only 8% have normal cognitive abilities.27,57

CSF levels of HVA and 5HIAA are low in sepiapterin reductase deficiency, whereas total biopterin, BH2 and sepiapterin levels are high (Figure 3). Plasma phenylalanine levels and urine pterin levels are normal, but the phenylalanine loading test is abnormal (Figure 4).23 Sepiapterin reductase activity in fibroblasts is low.

In most patients with sepiapterin reductase deficiency, the condition is doparesponsive.58 Some patients develop levodoparelated dyskinesia, so a low starting dose, followed by slow incrementation is recommended. Most patients require combination treatment with levodopa, 5hydroxytryptophan and BH4; monoamine oxidase inhibitors are often also needed for management of movement disorders (Table 1).56 The benefits added by 5hydroxytryptophan are unclear, but are thought to include modest improvements in cognition, movement disorders and sleeping patterns.56 Nevertheless, most patients retain a degree of cognitive and motor morbidity in the long term.27

BH4 regenerationDihydropteridine reductase deficiencyDHPR deficiency is the most severe pterin defect.15 The condition is usually identified by the detection of hyperphenylalaninaemia with newborn DBS screening; early diagnosis using this strategy is important because 40% of infants with DHPR deficiency are asymptomatic, but good clinical outcomes are associated with early treatment.15 DHPR deficiency manifests with bulbar dysfunction, feeding difficulty, hypersalivation, microcephaly and developmental delay.15 Associated movement dis orders include limb hypertonia with truncal hypo tonia, dyskinesia, tremor, dystonia and choreathetosis.15 Learning disabilities and seizures are also common.

DHPR deficiency leads to low CSF levels of HVA, 5HIAA and methyltetrahydrofolate, high levels of BH2, and high or normal levels of biopterin (Figure 3). Low DHPR activity measured with DBS screening supports the diagnosis, which is confirmed by the identification of mutations in QDPR.

Treatment of DHPR deficiency involves levodopa and 5hydroxytryptophan (Table 1).15 Use of BH4 therapy is controversial despite the fact that the condition is a BH4 disorder, as it might increase levels of 7,8DHPR, leading to uncoupling of neuronal nitric oxide synthase, consequent production of superoxides, and associ ated neurotoxicity.59 BH4 therapy could also have the undesired effect of inhibiting aromatic lamino acid hydroxylase.59 Oral calcium folinate is routinely administered in DHPR deficiency (Table 1), as the enzyme has an important role in the maintenance of cerebral folate.59 Some severely affected children require phenylalanine dietary restriction to normalize phenylalanine levels and prevent phenylalanineassociated neurotoxicity.15

Pterin‑4 α‑carbinolamine dehydratase deficiencyPterin4 αcarbinolamine dehydratase (PCD) is necessary for BH4 regeneration after phenylalanine hydroxy lation. PCD deficiency, which results from mutations in PCBD1, leads to mild hyperphenylalaninaemia, detectable with DBS screening, and high urine levels of 7biopterin. The CSF neurotransmitter profile is normal. PCD deficiency can present as transient hyper tonia, but some patients are asymptomatic.60 The mild hyperphenylalaninaemia usually resolves on normal diet.

Discoveries of novel mutations in PCBD1 indicate that patients with mild neonatal hyperphenylalaninaemia should be screened for diabetes mellitus and hypomagnes aemia in clinical followup. A novel deletion in PCBD1 has been proposed as a cause of dia betes, as PCD is a dimerization cofactor for the hepatocyte nuclear factor transcription factors, which are important in liver and pancreas development and function.61 Similarly, a novel homozygous deletion in PCBD1 results in a premature stop codon that abolishes the transcription factor binding and enzymatic functions of PCD, a process that is thought to cause hypomagnesaemia and diabetes.62 Reevaluation of patients with mild neonatal hyper phenyl alaninaemia owing to mutations in PCBD1 identified three patients who developed diabetes during puberty, indicating early β cell failure.63

Impaired dopamine synthesis and regulationTyrosine hydroxylase deficiencyTyrosine hydroxylase catalyses the ratelimiting step in dopamine synthesis. Analysis of the largest cohort of patients with tyrosine hydroxylase deficiency studied to date (36 patients) identified two clinical phenotypes: Type A and Type B. Type A (69%) presents during infancy or childhood with hypokinetic rigid syndrome and dystonia. Type B (31%) presents in neonates or during early infancy as complex encephalopathy.16 Diurnal variation of symptoms is frequently observed in both phenotypes.64 Oculogyric crises, ptosis, hypersalivation, tremor, focal or generalized dystonia with crises, and autonomic disturbance are associated with the condition.16 The majority of patients also have nonprogressive learning disabilities.16 Approximately 50% of patients with tyrosine hydroxylase deficiency have hyperprolactinaemia, and this abnormality is rarely associated with galactorrhoea.16,64 By 3 months of age, patients with Type B deficiency exhibit severe parkinsonism, hypo tonia and cognitive impairment.16 Reports of inter mediate phenotypes indicate a disease continuum between Type A and Type B.29 Atypical clinical presentations include disease onset in later childhood, presentation with abnormal gait, early onset spastic paraplegia, and doparesponsive myoclonusdystonia.65–67

CSF levels of HVA are low in tyrosine hydroxylase deficiency, whereas levels of 5HIAA are normal: the HVA:5–HIAA ratio is usually <1 (normal range 1–4). CSF levels of synaptic proteins also seem to be abnormal in tyrosine hydroxylase deficiency.68 In 10 patients with tyrosine hydroxylase deficiency, concentrations of the dopamine transporter (DAT), dopamine D2 receptor and

REVIEWS



VMAT2 were higher than in agematched healthy controls.68 Treatment with levodopa increased levels of the dopamine D2 receptor and HVA in a patient with Type B disease; by contrast, levels of the dopamine D2 receptor were reduced in two patients with Type A disease.68 Quantification of synaptic proteins in the CSF might provide further insight into neurotransmitter disorders and increase the possibility of personalized treatment.68

Type A tyrosine hydroxylase deficiency responds well to treatment with levodopa (Table 1).16 In Type B disease, initial doses of levodopa should be low and titrated with caution (Table 1).16 The response to levodopa alone varies, and adjunct therapy with anticholinergics and/or dopamine agonists is often required to manage difficult dystonia (Table 1). Doses of 5–10 mg/kg daily can be well tolerated in all phenotypes but some patients with tyrosine hydroxylase deficiency experience intolerable dyskinesia, even at low doses.29 This sensitivity might be caused by supersensitivity of striatal dopamine D1 and D2 receptors that results from chronic dopamine deficiency throughout development, or by excessive excitation of glutamatergic corticostriatal neurons.29 Levodoparelated dyskinesia can, therefore, be improved by decreasing the dose of levodopa, titrating the dose more slowly, or administering the NmethylDaspartic acid receptor blocker amantadine to attenuate glutamatergic drive (Table 1).69

Aromatic l‑amino acid decarboxylase deficiencyAADC mediates decarboxylation of levodopa and 5hydroxytryptophan to produce dopamine and serotonin, and requires pyridoxal 5'phosphate as a cofactor (Figure 2). AADC deficiency owing to mutations in DDC has been reported in >100 patients. One third of these patients have a common founder mutation that was identified in patients from Taiwan and South China.70

AADC deficiency can present at any age but is usually diagnosed in early childhood.19 Prominent clinical features include hypotonia (95%), oculogyric crisis (86%) and developmental delay (63%), and patients commonly present with ptosis.19 Congenital myasthenia gravis and other neuromuscular disorders are suspected in many patients before diagnosis. Approximately 50% of patients present with movement disorders (hypo kinesia, chorea, dystonia, ballismus, dyskinesia, tremor, myoclonus), bulbar dysfunction (feeding and communication difficulties) and sleep disturbance.19 Patients also experience autonomic dysfunction that manifests as excessive sweating, temperature instability, nasal congestion, hypersalivation, hypotension, impaired stress responses and irritability.19,71 Fasting hypoglycaemia with autonomic dysfunction has also been reported,72 so moni toring of blood sugar levels is advisable when patients with AADC deficiency are required to fast. Milder pheno types have been reported, in which initial symptoms are similar to myasthenia but evolve to become dystonia–parkinsonism in adulthood.73 These reports suggest that childhood symptoms can change with age, and AADC deficiency should also be considered for presentations of juvenile or earlyonset parkinsonism.

In AADC deficiency, CSF levels of HVA, 5HIAA and MHPG are low, and levels of 5hydroxytryptophan, levodopa and 3OMD are high (Figure 3). Urine levels of catecholamine metabolites (vanillylactate, 3OMD) are high, and plasma AADC activity is low or entirely absent (Figure 4).19 Neuroimaging of patients with the condition reveals nonspecific features, including cerebral atrophy, white matter abnormalities and thinning of the corpus callosum.19

Studies published in 2014 and 2015 have used novel techniques to detect AADC deficiency. The first study detected high levels of 3OMD in patients with AADC deficiency by using DBS screening, indicating that this approach could be used as a presymptomatic screening tool.74 The second detected AADC deficiency with a mass spectrometry platform that enables parallel testing for hundreds of metabolites in a single plasma specimen.75 This approach revealed markedly elevated levels of 3OMD in a boy who presented with developmental delay and hypotonia.75 Such techniques could be developed for future diagnostic use.

Levodopa is not routinely used in the treatment of AADC deficiency because the deficiency prevents conversion of levodopa to dopamine and further increases accumulation of 3OMD, which depletes Sadenosylmethionine.76 However, when three siblings who had a homozygous DDC point mutation were treated with levodopa and pyridoxal 5'phosphate, dystonia improved, though behavioural problems persisted.77 Molecular modelling and functional characterization of this point mutation suggested that it impairs binding of the AADC enzyme to its cofactor pyridoxal 5'phosphate, resulting in loss of enzyme activity.77

Treatment of AADC deficiency usually involves a combination of pyridoxine or pyridoxal 5'phosphate, folinic acid, monoamine oxidase (MAO) inhibitors and dopamine agonists (Table 1),78 although responses are variable and often disappointing: only 19% of patients report satisfactory treatment.19 For most patients, pyridoxine or pyridoxal 5'phosphate with calcium folinate is usually initiated first, followed by the addition, as needed, of a monoamine inhibitor and dopamine agonist, and then other adjunct therapies such as trihexyphenidyl. Pyridoxine is intended to boost residual AADC activity79,80 after its conversion to pyridoxal 5' phosphate.80 Pyridoxine elicits no clinical response, but can increase CSF levels of HVA and plasma levels of serotonin.81–84 No clinical consensus has been reached as to whether the administration of pyridoxine or pyridoxal 5' phosphate is more effective, but pyridoxine seems to be better tolerated.85 Patients with AADC deficiency are given calcium folinate because they are at risk of cerebral folate deficiency. This risk results from the conversion of high levels of levodopa to 3OMD, leading to depletion of Sadenosylmethionine, which is required for 5 methyltetrahydrofolate production.19,80 Dopamine agonists, such as bromocriptine, prami pexole and ropinirole, have variable effects on motor function,86 although rotigotine, which acts on dopamine D1–D5 receptors and has additional serotonergic and noradrenergic effects, has

REVIEWS



been used with some success.86 Transdermal rotigotine patches are increasingly used to prevent the pharmacological peaks and troughs that occur with enteral administration of dopamine agonists (Table 1).71 The variable success of pharmacotherapy for AADC deficiency has driven translational research into gene therapy (see Novel therapeutics below).

Pyridoxine 5'‑phosphate oxidase deficiencyPNPO catalyses production of pyridoxal 5'phosphate. PNPO deficiency therefore leads to reduced synthesis and recycling of pyridoxal 5'phosphate, resulting in reduced AADC activity and, consequently, impaired dopamine and serotonin synthesis.87

PNPO deficiency presents as a severe pharmacoresistant neonatal epileptic encephalopathy, often accompanied by a history of in utero seizures and premature birth.88 PNPO deficiency should be suspected if CSF levels of pyridoxal 5'phosphate are low. CSF glycine, taurine, histidine and threonine might also be raised.88 The CSF neurotransmitter profile might be similar to that in AADC deficiency (Figure 3).88 If so, measuring plasma AADC activity is recommended to exclude AADC deficiency. If enzyme activity is normal, sequencing of the PNPO gene should be considered.89

If PNPO deficiency is suspected, treatment with pyridoxal 5'phosphate should be trialled, and if the condition is genetically confirmed, then longterm treatment is used to reduce the seizure burden (Table 1).90 Pyridoxal 5'phosphate treatment is associated with a risk of prolonged apnoea,90 so appropriate cardiorespiratory monitoring and precautionary support should be available to patients during treatment.

Pituitary homeobox 3 mutationRecent studies have revealed a novel neurotrans mitter disorder that results from mutation of PITX3, which encodes pituitary homeobox 3. This protein is a transcription factor involved in the translation of TH, which encodes tyrosine hydroxylase. Pituitary homeobox 3 is, therefore, involved in dopamine regulation.91 A deletion at chromosome 10q24.32, which encompasses PITX3, was identified in a 17yearold male with mild learning difficulties, hyperactivity, behavioural problems and sleep disturbance.89 He had distinctive physical features of a high forehead, open mouth, synophrys, a short, broad nose and hypoplastic middle phalanges of his fifth digits.89 His CSF levels of HVA and 5HIAA and biopterin were low, and levodopa was absent. Treatment with levodopa led to improved behaviour, attention and sleep.89

Prior to publication of the case study above, the effects of Pitx3 mutations had been studied in mice. Pitx3–/– mice have selective loss of dopaminergic neurons in the substantia nigra and ventral tegmental area, leading to markedly reduced dopamine levels in the nigrostriatal pathway and dorsal striatum.92 The mice exhibit aberrant striatumdependent cognition and nigrostriatal pathway sensorimotor deficits.92,93 Treatment of these mice with levodopa, dopamine, or dopamine agonists normalizes sensori motor function.92,93 In future, wholeexome

sequencing will undoubtedly identify more patients with PITX3 mutations and improve our understanding of this novel neurotransmitter disorder.

Dopamine metabolism deficitsMonoamine oxidase deletion syndromeMAO A and B catalyse the oxidative deamination of dopamine to produce HVA and of serotonin to produce 5HIAA (Figure 2). The MAOA and MAOB genes lie in opposite orientations at Xp11.23, and share 70% sequence homology.94 Individuals with MAO B deficiency are asymptomatic, whereas individuals with MAO A deficiency have borderline intellectual deficiency and impaired impulse control.94 Individuals with deficiency of both MAOs have mental retardation, episodic hypotonia, stereotypy and selfinjurious behaviour. Levels of serotonin in the CSF and blood are high, whereas levels of dopaminerelated deaminated metabolites are low (Figures 3 and 4).95 CSF levels of 5HIAA are very low or undetectable.95

The NBD gene, deletion of which causes Norrie disease, is adjacent to MAOA and MAOB, and reports of dual MAO deletion often include NBD deletion. Patients with NBD deletions in addition to MAO deletion often exhibit features of Norrie disease, such as retinal dysplasia and congenital visual impairment.96 A report published in 2010, however, described two brothers with a 240 kb deletion that encompassed exons 2–15 of MAOA and complete deletion of MAOB, without deletion of NBD.97 These individuals presented with severe developmental delay, mental retardation, seizures, and stereotypies.97 Both had hypo tonia in infancy, worsening episodic hypotonia that resembled seizures, and mild facial dysmorphism that included epicanthal folds and long eyelashes.97 The older brother experienced recurrent screaming episodes with selfinjurious behaviour, and died unexpectedly at 5 years of age. The younger brother experienced episodes of rest lessness that were followed by hypotonia and loss of con sciousness. At 15 years of age, he was ambulant, but ran clumsily and communicated with only single words and sign language. Subsequently, three more boys with MAOA and MOAB deletions and similar clinical phenotypes have been identified.95,98 Neuroimaging and electroencephalograms in all these patients were normal.95,97,98

Patients with MAO A and/or MAO B deficiency might also be at high risk of cardiovascular complications in response to excessive dietary intake of tyramine and phenylethylamine (foods based on cheese and cocoa beans). These compounds can act as sympathomimetics, and high levels can lead to severe hypertension, intracerebral haemorrhage, cardiac arrhythmias and cardiac failure.96 One boy in adolescence experienced a sudden collapse and required intensive care support after ingesting high amounts of phenylethylamine.95 This boy’s obligate carrier grandmother had a stroke after ingesting large quantities of tyramine.96 MAO A and MAO B deactivate phenylethylamine, mtyramine, and ptyramine,95 and people with deficiency of both MAOs are up to 4fold more sensitive to intravenous tyramine than are those who have only MAO A deficiency.99 Dietary regulation of

REVIEWS



phenylethylamine and tyramine intake might, therefore, reduce cardiovascular risk in these individuals.97

Evidence from mouse studies indicates that MAOA–MAOB deletion also affects proliferation of neural stem cells. In doubleknockout mice, such proliferation is decreased from late gestation into adulthood.100 Levels of monoamines, particularly serotonin, are high in these mice, and the animals exhibit anxietylike behaviour in adulthood.

Dopamine β‑hydroxylase deficiencySynthesis of noradrenaline from dopamine is catalysed by dopamine βhydroxylase (DBH; Figure 2). DBH deficiency is a rare autosomal recessive condition that is caused by homozygous or compound heterozygous mutations in DBH and affects autonomic function. The condition presents in childhood, typically with ptosis, hypotension and fatigability.101 By early adulthood, symptoms include profound orthostatic hypotension, reduced exercise tolerance, ptosis, nasal congestion and presyncopal symptoms (dizziness, blurred vision, dyspnoea, nuchal discomfort and chest pain).101 A study of a Dutch cohort of eight patients identified that the severe orthostatic hypotension in children with DBH deficiency frequently led to a misdiagnosis of epilepsy.102

Biochemical hallmarks of DBH deficiency include minimal levels or absence of noradrenaline and adrenaline in the plasma, and 5–10fold elevated plasma levels of dopamine.33 The normal response to infusion of tyramine—an increase in plasma levels of noradrenaline—is absent in DBH deficiency, and an increase in plasma levels of dopamine is seen instead, owing to limited conversion of tyramine to noradren aline and upregulation of tyrosine hydroxylase (Figure 4).33 Hypomagne saemia and mild anaemia have also been associated with DBH deficiency.33

DBH deficiency is treated with droxidopa, which is converted directly into noradrenaline by AADC, thereby bypassing the requirement for DBH.103

Disrupted dopamine and serotonin transportBrain dopamine–serotonin vesicular transportBrain dopamine–serotonin vesicular transport disease is a transportopathy caused by mutations in SLC18A2, which encodes VMAT2 (Figure 2).22 VMAT2 facilitates dopamine and serotonin loading into synaptic vesicles for their transportation to the cell membrane and subsequent release.104 A homozygous lossoffunction SLC18A2 mutation has been identified in a single consanguineous family in which eight indivi duals were affected.22 The affected individuals presented in childhood with developmental delay, axial hypotonia and oculogyric crises. Bulbar dysfunction, ptosis, hypo mimia, facial dyskinesia, tremor, ataxia and parkinsonian shuffling gait developed in adolescence. Psychiatric and autonomic features, including temperature instability, sweating, postural hypotension, depression and sleep dis turbance, were observed in the index patient.22 Neither neuro imaging nor CSF neurotransmitter analysis (available for only one individual) revealed abnormalities. Urine levels of

HVA and 5HIAA were high, and levels of adrenaline and dopamine were low (Figure 4).22

Initial treatment with levodopa caused worsening of dystonia and chorea.22 A subsequent trial of pramipexole, however, resulted in complete and sustained amelioration of motor symptoms and restoration of ambulation in some individuals. Adverse effects of hyperactivity and weight loss were observed, but tolerable (Table 1).85

Dopamine transporter deficiency syndromeDTDS, which was first reported in 2009, was the first monoamine transportopathy to be described. This auto somal recessive condition is caused by mutations in SLC6A3, which encodes the dopamine transporter (Figure 2).20,21,32 Lossoffunction mutations lead to defective presynaptic uptake of dopamine that results in accumulation of dopamine in the synaptic cleft. This process underlies the CSF neurotransmitter profile that is charac teristic of DTDS: high levels of HVA, normal levels of 5HIAA and an HVA:5HIAA ratio >5 (Figure 4).20,21

DTDS presents in early infancy with feeding difficulties, irritability, axial hypotonia, a progressive hyper kinetic movement disorder and abnormal eye movements.20,21 During childhood, bradykinesia, hypomimia, rigidity and resting tremor predominate.20,21 As a result, DTDS is frequently misdiagnosed as dyskinetic cerebral palsy.21,32,105 MRI detects only subtle, non specific abnormalities if any,21 but 123I imaging (DaTscan® [GE Healthcare, UK]) reveals complete loss of dopamine transporter activity in basal nuclei.21

Early phenotype–genotype observations suggest that lateronset disease is associated with increased residual DAT activity.32,106 The phenotypic spectrum of DTDS is expanding: in 2014, juvenile parkinsonism32 and earlyonset parkinsonism with ADHD were identified as novel DTDS phenotypes.107 As a result, DTDS is increasingly being considered as a differential diagnosis not only for cerebral palsy, but also juvenile parkinsonism.32,107,108 Currently available therapeutic agents are of little benefit in DTDS:32,107 levodopa and dopamine agonists have been used, but only a limited response was seen in a minority of patients (Table 1).21,32,107

Secondary neurotransmitter abnormalitiesAbnormal neurotransmitter profiles—defined as changes in the levels of monoamine, pterin, folate or pyridoxal 5'phosphate metabolites in relation to agerelated reference values—can occur in neurological conditions other than primary neurotransmitter disorders (Box 2).106,109–114 Most studies of these secondary neurotransmitter disorders have separated them into those associated with abnormal levels of HVA106,109–112 or with abnormal levels of 5HIAA (selective serotonin deficiency).113–115 In these conditions, disruption of monoamine metabolism might be secondary to dopaminergic and serotonergic tract degeneration or defective monoamine metabolism.106,116

HVA disturbancesA cohort study of 1,388 patients with neurological disorders identified abnormal CSF levels of HVA in epileptic

REVIEWS



encephalopathies (26.4%), pontocerebellar hypoplasia (4.3%), Rett syndrome (4.3%), leukodys trophies (6.8%), neuropsychiatric conditions (4.2%) and mitochondriocytopathies (10.2%).106 Patients with low levels of HVA and symptoms of dopamine deficiency (that is, a movement disorder) can be given a trial of levodopa or dopamine agonists to determine whether they have any clinical benefit.

A mimic of tyrosine hydroxylase deficiencyA severe form of hypokinetic–rigid syndrome in infancy has been reported as a clinical and biochemical mimic of tyrosine hydroxylase deficiency.117 Children with the condition have a progressive neurological syndrome with low CSF levels of HVA.117 Some patients who presented with this tyrosine hydroxylase deficiency mimic were diagnosed with neurological conditions (such as mitochondrial diseases or hypoxic–ischaemic encephalopathy),118 but for many patients, no underlying cause has been identified.

In a cohort study of 15 children who presented with neonatal apnoea, axial hypotonia and limb ridigity with no identifiable aetiology, the patients developed features of infantile parkinsonism–dystonia with dyskinesia, and some exhibited oculogyric crisis.117 In all patients, CSF levels of HVA were low, whereas levels of all other markers were normal; the median HVA:5HIAA ratio was 0.5 (range 0.17–2.6, normal range 1–4).117 Neuroimaging and other neurometabolic investigations were negative. Despite the phenotypic similarities to tyrosine hydroxylase deficiency, all patients were negative for mutations in TH and its promoter region. Ongoing levodopa treatment in nine of the 15 patients has produced a variable response, and the overall longterm survival in the cohort to date is 33%.117 In future, wholeexome sequencing is likely to identify genetic causes in a proportion of children with conditions that mimic tyrosine hydroxylase deficiency.

Selective serotonin deficiencySelective serotonin deficiency comprises a heterogenous group of neurological disorders that are associated with low levels of 5HIAA but no abnormal levels of other neurotransmitter metabolites. In one study, low levels of 5HIAA were reported in 19.3% of 606 paediatric patients with a wide variety of neurological disorders, including epileptic encephalopathy, movement dis orders and autistic spectrum disorder.113 Another study reported a series of patients with idiopathic adultonset dystonia accompanied by low levels of 5HIAA.114 A further report identified paediatric patients with dystonia who had low levels of 5HIAA (≥50% below agematched reference ranges).115 This series included a subgroup of children with undetermined primary dystonic movement disorders, classified in this study as dopanonresponsive dystonia. Finally, one study identified secondary dystonia and low levels of 5HIAA in children with hypoxic–ischaemic encephalopathy, white matter disease and neurodegenerative disorders.117

No genes within the serotonergic pathway have been associated with these unresolved cases of selective

Box 2 | Secondary neurotransmitter disorders

Low HVA and normal 5‑HIAA106,109,112

■ Aicardi-Goutières syndrome ■ Allen–Herndon–Dudley syndrome ■ CACNA1A mutations with ataxia ■ Lesch–Nyhan syndrome ■ Meningitis or encephalitis ■ Mitochondrial disorders ■ Nonketotic hyperglycinaemia ■ Perinatal hypoxic ischaemic encephalopathy ■ Preterm-associated intraventricular haemorrhage ■ Pontocerebellar hypoplasia type 2 ■ Rett syndrome ■ Serine deficiency ■ Thiamine transporter 2 deficiency ■ Vanishing white matter disease

Low HVA and low 5‑HIAA106,109,112

■ Acute disseminated encephalomyelitis ■ Alexander disease ■ Congenital infections ■ Encephalitis ■ Guillain–Barré or Miller–Fisher syndrome ■ Hypoxic ischaemic encephalopathy ■ Methylentetrahydrofolate deficiency ■ Mitochondrial disorders ■ Niemann–Pick type C ■ Nonketotic hyperglycinaemia ■ Oligosaccharidosis ■ Pontocerebellar hypoplasia type 2 ■ Rett syndrome ■ Smith–Lemli–Optiz syndrome ■ Spontaneous periodic hypothermia and hyperhidrosis ■ Stroke ■ Urea cycle disorder ■ Tumour

Low HVA and low methyltetrahydrofolate106,109,110

■ White matter changes ■ Delayed myelination ■ Demyelination ■ Hypomyelination ■ Leukodystrophy

High HVA and normal 5‑HIAA106,109,110

■ Angelman syndrome ■ Hypoxic ischaemic encephalopathy ■ Mitochondrial disease ■ Meningitis or encephalitis ■ Preterm-associated intraventricular haemorrhage ■ Rett syndrome ■ Stroke ■ Thalamic necrosis ■ Urea cycle disorder

Low 5‑HIAA only113–115

■ Autism ■ Idiopathic adult-onset dystonia ■ Dopa non-responsive dystonia

High neopterin111,120–122,125,126

■ Early infantile epileptic encephalopathy ■ Aicardi–Goutières syndrome (also reported with high

neopterin and low methyltetrahydrofolate) ■ Immune disorders and infection ■ CNS infection ■ HIV infection ■ Low biopterin111

■ Early infantile epileptic encephalopathy

Abbreviations: 5-HIAA, 5-hydroxyindoleacetic acid; HVA, homovanillic acid.

REVIEWS



serotonin deficiency.113 Treatment with selective serotonin reuptake inhibitors or 5hydroxytryptophan to increase serotonin levels could be considered for patients with selective serotonin deficiency and dopa nonresponsive dystonia.7

Immune‑related disordersThe immunoinflammatory response to Th1type IFNγ and tumour necrosis factorα can lead to an increase in neopterin levels.119 Neopterin is, therefore, a biomarker of activated cellmediated immunity. Such immunerelated elevation of neopterin levels is observed in encephalitis, HIV infection and neuroborreliosis.120,121

The disorder Aicardi–Goutières syndrome (AGS) is associated with high CSF levels of neop terin. The disorder is genetic, with clinical features that can mimic in utero infection.122 Six genes are currently associated with AGS: TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1 ADAR1.123,124,125 Features that indicate a diagnosis of genetic AGS include neuro developmental delay, chilblain like skin lesions, early microcephaly, dystonia and sterile pyrexia. The condition also results in a classic triad of CSF biomarkers: high levels of IFNα and neopterin, and chronic sterile CSF lymphocytosis.122,125 Levels of neopterin are highest at the earliest stages of disease and can normalize over time.122,125 Levels of HVA, 5HIAA and 5MTHF are usually normal,62 although low levels of 5MTHF have been reported.126 Patients with AGS also have a markedly increased expression of interferonstimulated genes, known as an interferon signature, that is often sustained. This signature reliably differentiates individuals with AGS from controls.122 Another distinctive feature of AGS is intracranial calcification— detectable with CT—in the basal ganglia (putamen, globus pallidus), thalamus and white matter, often accompanied by leukodystrophy that affects the frontotemporal regions and can be detected with MRI.125

ManagementClinical interpretation of secondary neurotransmitter abnormalities and selection of therapeutic strategies require discussion with a neurometabolic laboratory and a neurotransmitter disease expert.127 The benefits of levodopa in patients with low levels of HVA with a secondary cause (for example, mitochondrial disease) are unclear. In patients with symptomatic dopamine deficiency, a trial of levodopa is certainly warranted, and might improve motor function in some of these patients.117 Treatment of central dopamine and/or serotonin deficiency should, therefore, be considered for symptomatic patients with secondary neurotransmitter abnormalities, even though longterm data about the effects of such intervention are currently lacking.

Future advancesDiagnosticsWhole exome and genome sequencing is likely to revolutionize diagnostic and therapeutic practice in monoamine neurotransmitter disorders. These techniques are becoming more economical and accessible, and will

undoubtedly expand the clinical phenotypes that are associated with mutation of specific genes and improve the diagnosis of monoamine neurotransmitter dis orders. For example, whole exome sequencing has identified syndromic intellectual disability as a new phenotype of AADC deficiency that is associated with Marfanoid features and facial dysmorphism.128 New genetic neurotransmitter disorders are also likely to be identified with these techniques.

ResearchThe relationship between genotype and clinical pheno type is an important area of future study. Many monoamine neurotransmitter disorders encompass an expanding spectrum of phenotypes and atypical clinical presentations, and some genotype–phenotype corre lation is seen in many of these disorders. Detailed delineation of the clinical and genetic features of newly identified patients with monoamine neurotransmitter abnormalities will further improve our understanding of these correlations.

Novel approaches to determine how mutations alter protein function might provide insight into disease mechanisms and provide the first steps towards personalized medicine. In AADC deficiency, studies are already underway to use bioinformatic, kinetic and spectroscopic analyses to characterize the molecular consequences of missense mutations so as to understand the disease mechanisms and responses to treatment in patients with different mutations.129

To date, research into neurotransmitter disorders has been limited by the availability of robust neuronal models of disease. The development of in vitro models by the generation of dopaminergic neurons from patientderived induced pluripotent stem cells has the potential to resolve this limitation.130,131 Future research that makes use of cerebral organoids (threedimensional organoid culture systems that derive from human pluripotent stem cells and develop discrete interdependent brain regions) could also increase our understanding of neurotransmitter systems in the context of wider brain neural networks.132

Current animal models of neurotransmitter disorders were developed by using antisense morpholino oligonucleotides or homologous recombination. CRISPR–Cas9 gene editing is a more efficient method that enables rapid development of zebrafish and murine models.133,134 Use of this technique to develop models of known and novel monoamine neurotransmitter dis orders will enable studies that increase our understanding of midbrain and dopaminergic neurogenesis and disease mech anisms, and will provide platforms for the development of novel therapeutics.

TherapiesNovel therapeutics are currently being developed for primary neurotransmitter disorders, particularly disorders that are refractory to current pharmacological strategies. Pseudoexon exclusion therapy with antisense morpholino oligonucleotides modifies gene expression

REVIEWS



by blocking translation of RNA. This technique was used to modulate splice mutations in the treatment of PTPS deficiency, and restored PTPS activity in fibroblast cell lines that were derived from three patients with intronic mutations that caused splicing defects.135

Clinical trials of gene therapy have been conducted in adult Parkinson disease with some success.135 In one trial, gene therapy with human AADC, delivered with the adenoassociated virus, was shown to be safe and resulted in stable expression of the gene and an improvement in parkinsonian rating scores that enabled a reduction in medication.136 In another trial, lentiviralbased gene therapy in Parkinson disease showed that TH, AADC and GCH delivery was safe and well tolerated, and improved motor scores.137 In another study, AADC delivery by stereotactic injection of adenoassociated virus to the putamina improved symptoms in four children with AADC deficiency, although initially caused dyskin esia.138 This gene therapy approach also increased puta minal uptake of 618Ffluorolevodopa and increased CSF levels of dopamine and serotonin metabolites.138 Subsequent development of the DdcKI mouse model of AADC deficiency has enabled evaluation of different gene therapy constructs, leading to the conclusion that neuronal specific viral vectors are more effective than ubiquitous promoters in reducing dyskinesia.139 Nevertheless, the role that gene therapy can have in treatment of monoamine neurotrans mitter disorders is undetermined, and further clinical trials are needed to learn more about the safety, efficacy and longterm benefits of this approach.

ConclusionsChildhood neurological disorders of monoamine dysregulation are an expanding group of genetic neurometabolic syndromes. Some of these conditions show a striking response to treatment, but the diagnosis and treatment of many remain challenging. In future research, rapid whole genome sequencing and biomarker discovery will identify novel neurotransmitter disorders and phenotypes, and will improve our understanding of genotype–phenotype correlation. Disease modelling with novel methods will reveal pathophysiological mechanisms and enable trials of novel smallmolecules treatments. The generation of sophisticated neuronal models of disease from patientderived induced pluripotent stem cells will improve our understanding of disease within the brain and provide a platform for highthroughput drug screening. The ability to rapidly develop transgenic animal models will also facilitate screening of new drug treatments and gene therapy. In combination, such novel therapies will form the basis of personalized medicine for these disorders.

1. Goldstein, D. S. Catecholamines in the periphery. Overview. Adv. Pharmacol. 42, 529–539 (1998).

2. Yildiz, O., Smith, J. R. & Purdy, R. E. Serotonin and vasoconstrictor synergism. Life Sci. 62, 1723–1732 (1998).

3. Hoffmann, G. F. & Blau, N. (Eds) Congenital Neurotransmitter Disorders: A Clinical Approach (Nova Science Publishers, 2014).

4. Blau, N. & Thöny, B. PND database [online] http://www.biopku.org/pnddb (2015).

5. Pearl, P. L., Capp, P. K., Novotny, E. J. & Gibson, K. M. Inherited disorders of neurotransmitters in children and adults. Clin. Biochem. 38, 1051–1058 (2005).

6. Assmann, B., Surtees, R. & Hoffmann, G. F. Approach to diagnosis of neurotransmitter diseases exemplified by the differential diagnosis of childhood-onset dystonia. Ann. Neurol. 54 (Suppl. 6), S18–S24 (2003).

7. Kurian, M. A., Gissen, P, Smith, M., Heales, S. Jr & Clayton, P. T. The monoamine neurotransmitter disorders: an expanding range of neurological syndromes. Lancet Neurol. 10, 721–733 (2011).

8. Fernández-Alvarez, E. Movement disorders in children: recent advances in management. Indian J. Pediatr. 76, 531–536 (2009).

9. Marín-Valencia, I. et al. Biochemical diagnosis of dopaminergic disturbance in paediatric patients: analysis of cerebrospinal fluid homovanillic acid and other biogenic amines. Clin. Biochem. 41, 1306–1315 (2008).

10. Garelis, E., Young, S. N., Lal, S. & Sourkes, T. L. Monoamine metabolites in lumbar CSF: the question of their origin in relation to clinical studies. Brain Res. 79, 1–8 (1974).

11. McConnell, H. & Bianchine, J. Cerebrospinal fluid. in Neurology and Psychiatry. Ch. 3 35–42 (Chapman & Hall Medical, 1994).

12. Bräutigam, C., Weykamp, C., Hoffmann, G. F. & Wevers, R. A. Neurotransmitter metabolites in CSF: an external quality control scheme. J. Inherit. Metab. Dis. 25, 287–298 (2002).

13. Hyland, K. et al. Cerebrospinal fluid concentrations of pterins and metabolites of serotonin and dopamine in a pediatric reference population. Pediatr. Res. 34, 10–14 (1993).

14. Segawa, M. Hereditary progressive dystonia with marked diurnal fluctuation. Brain Dev. 33, 195–201 (2011).

15. Opladen, T., Hoffmann, G. F. & Blau, N. An international survey of patients with tetrahydrobiopterin deficiencies presenting with hyperphenylalaninaemia. J. Inherit. Metab. Dis. 35, 963–973 (2012).

16. Willemsen, M. A. et al. Tyrosine hydroxylase deficiency: a treatable disorder of brain catecholamine biosynthesis. Brain 133, 1810–1822 (2010).

17. Yeung, W. L., Lam, C. W., Hui, J., Tong, S. F. & Wu, S. P. Galactorrhea—a strong clinical clue towards the diagnosis of neurotransmitter disease. Brain Dev. 28, 389–391 (2006).

18. Aitkenhead, H. & Heales, S. J. Establishment of paediatric age-related reference intervals for serum prolactin to aid in the diagnosis of neurometabolic conditions affecting dopamine metabolism. Ann. Clin. Biochem. 50, 156–158 (2013).

19. Brun, L. et al. Clinical and biochemical features of aromatic L-amino acid decarboxylase deficiency. Neurology 75, 64–71 (2010).

20. Kurian, M. A. et al. Homozygous loss-of-function mutations in the gene encoding the dopamine transporter are associated with infantile parkinsonism–dystonia. J. Clin. Invest. 119, 1595–1603 (2009).

21. Kurian, M. A. et al. Clinical and molecular characterisation of hereditary dopamine transporter deficiency syndrome: an observational cohort and experimental study. Lancet Neurol. 10, 54–62 (2011).

22. Rilstone, J. J., Alkhater, R. A. & Minassian, B. A. Brain dopamine–serotonin vesicular transport disease and its treatment. N. Engl. J. Med. 368, 543–550 (2013).

23. Saunders-Pullman, R. et al. Phenylalanine loading as a diagnostic test for DRD: interpreting the utility of the test. Mol. Genet. Metab. 83, 207–212 (2004).

24. Guldberg, P., Henriksen, K. F., Lou, H. C. & Güttler, F. Aberrant phenylalanine metabolism in phenylketonuria heterozygotes. J. Inherit. Metab. Dis. 21, 365–372 (1998).

25. Opladen, T., Hoffmann, G. F, Kühn, A. A. & Blau, N. Pitfalls in phenylalanine loading test in the diagnosis of dopa-responsive dystonia. Mol. Genet. Metab. 108, 195–197 (2013).

26. Segawa, M. Autosomal dominant GTP cyclohydrolase 1 (AD GCH 1) deficiency (Segawa disease, dystonia 5; DYT 5). Chang Gung Med. J. 32, 1–11 (2009).

27. Friedman, J. et al. Sepiapterin reductase deficiency: a treatable mimic of cerebral palsy. Ann. Neurol. 71, 520–530 (2012).

28. Clot, F. et al. Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with Dopa-responsive dystonia. Brain 132, 1753–1763 (2009).

Review criteria

We searched PubMed for English-language, full-text articles published between January 1990 and June 2015, using the search terms “monoamine” and “neurotransmitter”. Relevant articles were read and their references were screened for further relevant articles. Articles were included in the Review on the basis of research quality and current or potential impact on clinical practice.

REVIEWS


http://www.biopku.org/pnddb


29. Pons, R. et al. Levodopa-induced dyskinesias in tyrosine hydroxylase deficiency. Mov. Disord. 28, 1058–1063 (2013).

30. López- Laso, E., Beyer, K., Opladen, T., Artuch, R. & Saunders-Pullman, R. Dyskinesias as a limiting factor in the treatment of Segawa disease. Pediatr. Neurol. 46, 404–406 (2012).

31. Leuzzi, V. et al. Phenotypic variability, neurological outcome and genetics background of 6-pyruvoyl-tetrahydrobiopterin synthase deficiency. Clin. Genet. 77, 249–257 (2010).

32. Ng, J. et al. Dopamine transporter deficiency syndrome: phenotypic spectrum from infancy to adulthood. Brain 137, 1107–1119 (2014).

33. Timmers, H. J., Deinum, J., Wevers, R. A. & Lenders, J. W. Congenital dopamine-β-hydroxylase deficiency in humans. Ann. N. Y. Acad. Sci. 1018, 520–523 (2004).

34. Blau, N., van Spronsen, F. J. & Levy, H. L. Phenylketonuria. Lancet 376, 1417–1427 (2010).

35. Furukawa, Y. GTP cyclohydrolase 1-deficient dopa-responsive dystonia. GeneReviews [online] http://www.ncbi.nlm.nih.gov/books/NBK1508 (updated 2015).

36. Segawa, M., Hosaka, A., Miyagawa, F., Nomura, Y. & Imai, H. Hereditary progressive dystonia with marked diurnal fluctuation. Adv. Neurol. 14, 215–233 (1976).

37. Trender-Gerhard, I. et al. Autosomal-dominant GTPCH1-deficient DRD: clinical characteristics and long-term outcome of 34 patients. J. Neurol. Neurosurg. Psychiatry 80, 839–845 (2009).

38. Lee, J. H., Ki, C. S., Kim, D. S., Cho, J. W., Park, K. P. & Kim, S. Dopa-responsive dystonia with a novel initiation codon mutation in the GCH1 gene misdiagnosed as cerebral palsy. J. Korean Med. Sci. 26, 1244–1246 (2011).

39. Jan, M. M. Misdiagnoses in children with dopa-responsive dystonia. Pediatr. Neurol. 31, 298–303 (2004).

40. Dale, R. C. et al. Familial paroxysmal exercise-induced dystonia: atypical presentation of autosomal dominant GTP-cyclohydrolase 1 deficiency. Dev. Med. Child Neurol. 52, 583–586 (2010).

41. Mencacci, N. E. et al. Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers. Brain 137, 2480–2492 (2014).

42. Lewthwaite, A. J. et al. Novel GCH1 variant in Dopa-responsive dystonia and Parkinson’s disease. Parkinsonism Relat. Disord. 21, 394–397 (2015).

43. Thöny, B & Blau, N. Mutations in the BH4-metabolizing genes GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase, sepiapterin reductase, carbinolamine-4a- dehydratase, and dihydropteridine reductase. Hum. Mutat. 27, 870–878 (2006).

44. Steinberger, D. et al., Utility of MLPA in deletion analysis of GCH1 in dopa-responsive dystonia. Neurogenetics 8, 51–55 (2007).

45. Hwang, W. J., Calne, D. B., Tsui, J. K. & de la Fuente-Fernández, R. The long-term response to levodopa in dopa-responsive dystonia. Parkinsonism Relat. Disord. 8, 1–5 (2001).

46. Sumi-Ichinose, C. et al. Catecholamines and serotonin are differently regulated by tetrahydrobiopterin. A study from 6-pyruvolytetrahydrobiopterin synthase knockout mice. J. Biol. Chem. 276, 41150–41160 (2001).

47. Opladen, T. et al. Clinical and biochemical characterization of patients with early infantile onset of autosomal recessive GTP

cyclohydrolase I deficiency without hyperphenylalaninemia. Mov. Disord. 26, 157–161 (2011).

48. Bonafé, L., Thöny, B., Leimbacher, W., Kierat, L. & Blau, N. Diagnosis of dopa-responsive dystonia and other tetrahydrobiopterin disorders by the study of biopterin metabolism in fibroblasts. Clin. Chem. 47, 477–485 (2001).

49. Horvath, G. A. et al. Autosomal recessive GTP cyclohydrolase I deficiency without hyperphenylalaninemia: evidence of a phenotypic continuum between dominant and recessive forms. Mol. Genet. Metab. 94, 127–131 (2008).

50. Longo, N. Disorders of biopterin metabolism. J. Inherit. Metab. Dis. 32, 333–342 (2009).

51. Smith, I. & Dhondt, J. L. Birthweight in patients with defective biopterin metabolism. Lancet 325, 818 (1985).

52. Jäggi, L. et al. Outcome and long-term follow up of 36 patients with tetrahydrobiopterin deficiency. Mol. Genet. Metab. 93, 295–305 (2008).

53. Porta, F., Mussa, A., Concolino, D., Spada, M. & Ponzone, A. Dopamine agonists in 6-pyruvoyl tetrahydrobiopterin synthase deficiency. Neurology 73, 633–637 (2009).

54. Dill, P. et al. Child neurology: paroxysmal stiffening, upward gaze, and hypotonia: hallmarks of sepiapterin reductase deficiency. Neurology 78, e29–e32 (2012).

55. Leuzzi, V. et al. Very early pattern of movement disorders in sepiapterin reductase deficiency. Neurology 81, 2141–2142 (2013).

56. Friedman, J., Hyland, K., Blau, N. & MacCollin, M. Dopa-responsive hypersomnia and mixed movement disorder due to sepiapterin reductase deficiency. Neurology 67, 2032–2035 (2006).

57. Neville, B. G., Parascandalo, R., Farrugia, R. & Felice, A. Sepiapterin reductase deficiency: a congenital dopa-responsive motor and cognitive disorder. Brain 128, 2291–2296 (2005).

58. Bonafé, L., Thöny, B., Penzien, J. M., Czarnecki, B. & Blau, N. Mutations in the sepiapterin reductase gene cause a novel tetrahydrobiopterin-dependent monamine-neurotransmitter deficiency without hyperphenylalaninemia. Am. J. Hum. Genet. 69, 269–277 (2001).

59. Crabtree, M. J. et al. Quantitative regulation of intracellular endothelial nitric-oxide synthase (eNOS) coupling by both tetrahydrobiopterin–eNOS stoichiometry and biopterin redox status: insights from cells with tet-regulated GTP cyclohydroxylase I expression. J. Biol. Chem. 284, 1136–1144 (2009).

60. Thöny, B. et al., Mutations in the pterin-4α- carbinolamine dehydratase (PCBD) gene cause a benign form of hyperphenylalaninemia. Hum. Genet. 103, 162–167 (1998).

61. Mendel, D. B. et al. Characterization of a cofactor that regulates dimerization of a mammalian homeodomain protein. Science 254, 1762–1767 (1991).

62. Ferrè, S. et al. Mutations in PCBD1 cause hypomagnesemia and renal magnesium wasting. J. Am. Soc. Nephrol. 25, 574–586 (2014).

63. Simaite, D. et al. Recessive mutations in PCBD1 cause a new type of early-onset diabetes. Diabetes 63, 3557–3564 (2014).

64. Mak, C. M. et al. Biochemical and molecular characterization of tyrosine hydroxylase deficiency in Hong Kong Chinese. Mol. Genet. Metab. 99, 431–433 (2010).

65. Giovanniello, T. et al. Tyrosine hydroxylase deficiency presenting with a biphasic clinical course. Neuropediatrics 38, 213–215 (2007).

66. Stamelou, M. et al. Myoclonus-dystonia syndrome due to tyrosine hydroxylase deficiency. Neurology 79, 435–441 (2012).

67. Espay, A. J. & Chen, R. Myoclonus. Continuum (Minneap. Minn.) 19, 1264–1286 (2013).

68. Ortez, C. et al. Cerebrospinal fluid synaptic proteins as useful biomarkers in tyrosine hydroxylase deficiency. Mol. Genet. Metab. 114, 34–40 (2015).

69. Blanchet, P. J., Konitsiotis, S. & Chase, T. N. Amantadine reduces levodopa-induced dyskinesias in parkinsonian monkeys. Mov. Disord. 13, 798–802 (1998).

70. Lee, H. F., Tsai, C. R., Chi, C. S., Chang, T. M. & Lee, H. J. Aromatic L-amino acid decarboxylase deficiency in Taiwan. Eur. J. Paediatr. Neurol. 13, 135–140 (2009).

71. Mastrangelo, M., Caputi, C., Galosi, S., Giannini, M T. & Leuzzi, V. Transdermal rotigotine in the treatment of aromatic L-amino acid decarboxylase deficiency. Mov. Disord. 28, 556–557 (2013).

72. Arnoux, J. B. et al. Aromatic l-amino acid decarboxylase deficiency is a cause of long-fasting hypoglycaemia. J. Clin. Endocrinol. Metab. 98, 4279–4284 (2013).

73. Leuzzi, V. et al. Report of two never treated adult sisters with aromatic l-amino acid decarboxylase deficiency: a portrait of the natural history of the disease or an expanding phenotype? JIMD Rep. 15, 39–45 (2015).

74. Chen, P. W. et al. Diagnosis of aromatic l-amino acid decarboxylase deficiency by measuring 3-O-methyldopa concentrations in dried blood spots. Clin. Chim. Acta 431, 19–22 (2014).

75. Atwal, P. S. et al. Aromatic l-amino acid decarboxylase deficiency diagnosed by clinical metabolomic profiling of plasma. Mol. Genet. Metab. 115, 91–94 (2015).

76. Surtees, R. & Hyland, K. l-3,4-dihydroxyphenylalanine (levodopa) lowers central nervous system S-adenosylmethionine concentrations in humans. J. Neurol. Neurosurg. Psychiatry 53, 569–572 (1990).

77. Chang, Y. T. et al. Levodopa-responsive aromatic l-amino acid decarboxylase deficiency. Ann. Neurol. 55, 435–438 (2004).

78. Allen, G. F., Land, J. M. & Heales, S. J. A new perspective on the treatment of aromatic l-amino acid decarboxylase deficiency. Mol. Genet. Metab. 97, 6–14 (2009).

79. Manegold, C. et al. Aromatic l-amino acid decarboxylase deficiency: clinical features, drug therapy and follow-up. J. Inherit. Metab. Dis. 32, 371–380 (2009).

80. Allen, G. F. et al. Pyridoxal 5'-phosphate deficiency causes a loss of aromatic l-amino acid decarboxylase in patients and human neuroblastoma cells, implications for aromatic l-amino acid decarboxylase and vitamin B6 deficiency states. J. Neurochem. 114, 87–96 (2010).

81. Pons, R. et al. Aromatic l-amino acid decarboxylase deficiency: clinical features, treatment and prognosis. Neurology 62, 1058–1065 (2004).

82. Hyland, K., Surtees, R A., Rodeck, C. & Clayton, P. T. Aromatic l-amino acid decarboxylase deficiency: clinical features, diagnosis, and treatment of a new inborn error of neurotransmitter amine synthesis. Neurology 42, 1980–1988 (1992).

83. Maller, A., Hyland, K., Milstein, S., Biaggioni, I. & Butler, I. J. Aromatic l-amino acid decarboxylase deficiency: clinical features,

REVIEWS


http://www.ncbi.nlm.nih.gov/books/NBK1508/



diagnosis, and treatment of a second family. J. Child Neurol. 12, 349–354 (1997).

84. Swoboda, K. J., Saul, J. P., McKenna, C. E., Speller, N. B. & Hyland, K. Aromatic l-amino acid decarboxylase deficiency: overview of clinical features and outcomes. Ann. Neurol. 54 (Suppl. 6), S49–S55 (2003).

85. Ng, J., Heales, S. J. & Kurian, M. A. Clinical features and pharmacotherapy of childhood monoamine neurotransmitter disorders. Paediatr. Drugs 16, 275–291 (2014).

86. Cawello, W. et al. Pharmacokinetics, safety and tolerability of rotigotine transdermal patch in health Japanese and Caucasian subjects. Clin. Drug Investig. 34, 95–105 (2014).

87. Mills, P. B. et al. Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency). Brain 133, 2148–2159 (2010).

88. Mills, P. B. et al. Neonatal epileptic encephalopathy caused by mutations in the PNPO gene encoding pyridox(am)ine 5'-phosphate oxidase. Hum. Mol. Genet. 14, 1077–1086 (2005).

89. Derwinska, K. et al. Clinical improvement of the aggressive neurobehavioral phenotype in a patient with a deletion of PITX3 and the absence of l-DOPA in the cerebrospinal fluid. Am. J. Med. Genet. B Neuropsychiatr. Genet. 159B, 236–242 (2012).

90. Stockler, S. et al. Pyridoxine dependent epilepsy and antiquitin deficiency: clinical and molecular characteristics and recommendations for diagnosis, treatment and follow-up. Mol. Genet. Metab. 104, 48–60 (2011).

91. Reddy, S. D. et al. Multiple coregulatory control of tyrosine hydroxylase gene transcription. Proc. Natl Acad. Sci. USA 108, 4200–4205 (2011).

92. Hwang, D. Y. et al. 3,4-dihydroxyphenylalanine reverses the motor deficits in Pitx3-deficient aphakia mice: behavioral characterization of a novel genetic model of Parkinson’s disease. J. Neurosci. 25, 2132–2137 (2005).

93. Hwang, D. Y., Ardayfio, P., Kang, U. J., Semina, E. V. & Kim, K. S. Selective loss of dopaminergic neurons in the substantia nigra of Pitx3-deficient aphakia mice. Brain Res. Mol. Brain Res. 114, 123–131 (2003).

94. Lenders, J. W. et al. Specific genetic deficiencies of the A and B isoenzymes of monoamine oxidase are characterized by distinct neurochemical and clinical phenotypes. J. Clin. Invest. 97, 1010–1019 (1996).

95. O’Leary, R. E. et al. De novo microdeletion of Xp11.3 exclusively encompassing the monoamine oxidase A and B genes in a male infant with episodic hypotonia: a genomics approach to personalized medicine. Eur. J. Med. Genet. 55, 349–353 (2012).

96. Gillman. P. K. Advances pertaining to the pharmacology and interactions of irreversible nonselective monoamine oxidase inhibitors. J. Clin. Psychopharmacol. 31, 66–74 (2011).

97. Whibley, A. et al. Deletion of MAOA and MAOB in a male patient causes severe developmental delay, intermittent hypotonia and stereotypical hand movements. Eur. J. Hum. Genet. 18, 1095–1099 (2010).

98. Saito, M. et al. MAOA/B deletion syndrome in male siblings with severe developmental delay and sudden loss of muscle tonus. Brain Dev. 36, 64–69 (2014).

99. Collins, F. A. et al. Clinical, biochemical, and neuropsychiatric evaluation of a patient with a contiguous gene syndrome due to a microdeletion Xp11.3 including the Norrie disease locus and monoamine oxidase (MAOA

and MAOB) genes. Am. J. Med. Genet. 42, 127–134 (1992).

100. Chen, K., Holschneider, D. P., Wu, W., Rebrin, I. & Shih, J. C. A spontaneous point mutation produces monoamine oxidase A/B knock-out mice with greatly elevated monoamines and anxiety-like behaviour. J. Biol. Chem. 279, 39645–39652 (2004).

101. Robertson, D. & Garland, E. M. Dopamine beta-hydroxylase deficiency. GeneReviews [online] http://www.ncbi.nlm.nih.gov/books/NBK1474/ (updated 2013).

102. Wassenberg, T. et al. Clinical and biochemical characteristics of dopamine beta hydroxylase deficiency: expanding the clinical spectrum caused by norepinephrine and epinephrine deficiency [poster]. 4th International Symposium on Paediatric Movement Disorders P36 (2015).

103. Man in ’t Veld, A. J. et al. dl-Threo-3,4-dihydroxyphenylserine restores sympathetic control and cures orthostatic hypotension in dopamine beta-hydroxylase deficiency. J. Hypertens. Suppl. 6, S547–S549 (1988).

104. Fon, E. A. et al. Vesicular transport regulates monoamine storage and release but is not essential for amphetamine action. Neuron 19, 1271–1283 (1997).

105. Carlsson, A. The occurrence, distribution and physiological role of catecholamines in the nervous system. Pharmacol. Rev. 11, 490–493 (1959).

106. Molero-Luis, M. et al. Homovanillic acid in cerebrospinal fluid of 1388 children with neurological disorders. Dev. Med. Child Neurol. 55, 559–566 (2013).

107. Hansen, F. H. et al. Missense dopamine transporter mutations associated with adult parkinsonism and ADHD. J. Clin. Invest. 124, 3107–3120 (2014).

108. Bhatia, K. P. ‘That DAT’gene that causes dystonia-parkinsonism: broadening the phenotype. Brain 137, 976–977 (2014).

109. García-Cazorla, A. et al. Secondary abnormalities of neurotransmitters in infants with neurological disorders. Dev. Med. Child Neurol. 49, 740–744 (2007).

110. Marín-Valencia, I. et al. Biochemical diagnosis of dopaminergic disturbances in paediatric patients: analysis of cerebrospinal fluid homovanillic acid and other biogenic amines. Clin. Biochem. 41, 1306–1315 (2008).

111. Duarte, S. et al. Cerebrospinal fluid pterins and neurotransmitters in early severe epileptic encephalopathies. Brain Dev. 30, 106–111 (2008).

112. Mericmek-Mahmutoglu, S. et al. Prevalence of inherited neurotransmitter disorders in patients with movement disorders and epilepsy: a retrospective cohort study. Orphanet J. Rare Dis. 10, 12 (2015).

113. De Grandis, E. et al. Cerebrospinal fluid alterations of the serotonin product, 5-hydroxyindolacetic acid, in neurological disorders. J. Inherit. Metab. Dis. 33, 803–809 (2010).

114. Naumann, M., Götz, M., Reiners, K., Lange, K. W. & Riederer, P. Neurotransmitters in CSF of idiopathic adult-onset dystonia: reduced 5-HIAA levels as evidence of impaired serotonergic metabolism. J. Neural Transm. 103, 1083–1091 (1996).

115. Assmann, B., Köhler, M., Hoffmann, G. F., Heales, S. & Surtees, R. Selective decrease in central nervous system serotonin turnover in children with dopa-nonresponsive dystonia. Pediatr. Res. 52, 91–94 (2002).

116. Marecos, C., Ng, J., Kurian, M, A. What is new for monoamine neurotransmitter disorders? J. Inherit. Metab. Dis. 37, 619–626 (2014).

117. Ng, J. et al. TH gene-negative infantile onset severe dopamine deficiency syndrome: a novel neurotransmitter disorder? [abstract]. Dev. Med. Child. Neurol. 55 (Suppl. S1), 16 (2013).

118. Moran, M. M, Allen, N. M, Treacy, E. P. & King, M. D. “Stiff neonate” with mitochondrial DNA depletion and secondary neurotransmitter defects. Pediatr. Neurol. 45, 403–405 (2011).

119. Werner, E. R. et al. Tetrahydrobiopterin biosynthesic activities in human macrophages, fibroblasts, THP-1 and T-24 cells. J. Biol. Chem. 265, 3189–3192 (1990).

120. Millner, M. M. et al. Neopterin concentrations in cerebrospinal fluid and serum as an aid in differentiating central nervous system and peripheral infections in children. Clin. Chem. 44, 161–167 (1998).

121. Hagberg, L. et al. Cerebrospinal fluid neopterin: an informative biomarker of central nervous system immune activation in HIV-1 infection. AIDS Res. Ther. 7, 15 (2010).

122. Rice, G. I. et al. Assessment of interferon-related biomarkers in Aicardi-Goutières syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study. Lancet Neurol. 12, 1159–1169 (2013).

123. du Moulian, M., Nürnberg, P., Crow, Y. J. & Rutsch, F. Cerebral vasculopathy is a common feature in Aicardi-Goutières syndrome associated with SAMHD1 mutations. Proc. Natl Acad. Sci. USA 108, E232 (2011).

124. Livingston, J. H. et al. A type I interferon signature identifies bilateral striatal necrosis due to mutations in ADAR1. J. Med. Genet. 51, 76–82 (2014).

125. Crow, Y. J. Aicardi-Goutières syndrome. GeneReviews [online] http://www.ncbi.nlm.nih.gov/books/NBK1475/ (updated 2014).

126. Blau, N. et al. Cerebrospinal fluid pterins and folates in Aicardi-Goutières syndrome: a new phenotype. Neurology 61, 642–647 (2003).

127. Kurian, M. A. What is the role of dopamine in childhood neurological disorders? Dev. Med. Child Neurol. 55, 493–494 (2013).

128. Graziano, C. et al. Syndromic intellectual disability: a new phenotype caused by an aromatic amino acid decarboxylase gene (DDC) variant. Gene 559, 144–148 (2015).

129. Montioli, R. et al. A comprehensive picture of the mutations associated with aromatic amino acid decarboxylase deficiency, from molecular mechanisms to therapy implications. Hum. Mol. Genet. 23, 5429–5440 (2014).

130. Nguyen, H. N. et al., LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress. Cell Stem Cell. 8, 267–280 (2011).

131. Reinhardt, P. et al. Genetic correction of a LRRK2 mutation in human iPSCs links parkinsonian neurodegeneration to ERK-dependent changes in gene expression. Cell Stem Cell. 7, 354–367 (2013).

132. Lancaster, M. A. et al. Cerebral organoids model human brain development and microcephaly. Nature 501, 373–379 (2013).

133. Hwang, W. Y. et al. Efficient genome editing in zebrafish using a CRISPR–Cas system. Nat. Biotechnol. 31, 227–229 (2013).

134. Li, D. et al. Heritable gene targeting in the mouse and rat using a CRISPR–Cas system. Nat. Biotechnol. 31, 681–683 (2013).

REVIEWS







135. Brasil, S. et al. Pseudoexon exclusion by antisense therapy in 6-pyruvoyl-tetrahydropterin synthase deficiency. Hum. Mutat. 32, 1019–1027 (2011).

136. Eberling, J. L. et al. Results from phase I safety trial of hAADC gene therapy for Parkinson disease. Neurology 70, 1980–1983 (2008).

137. Palfi, S. et al. Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson’s disease: a dose escalation, open-label, phase 1/2 trial. Lancet 383, 1138–1146 (2014).

138. Hwu, W. L. et al. Gene therapy for aromatic l-amino acid decarboxylase deficiency. Sci. Transl. Med. 4, 134ra61 (2012).

139. Lee, N. C. et al. Benefits of neuronal preferential systemic gene therapy for neurotransmitter deficiency. Mol. Ther. http://dx.doi.org/10.1038/mt.2015.122 (2015).

AcknowledgementsM.A.K. is funded by a Wellcome Intermediate Clinical Fellowship (WT098524MA) and receives funding from the Rosetrees Trust and the Gracious Heart Charity Foundation. J.N. is funded by a Medical Research Council Clinical Research Training Fellowship (MR/K02342X/1). M.A.K. and J.N. are both funded by Great Ormond Street Hospital Children’s Charities. A.P. receives funding

from Actelion to study undiagnosed neurodegenerative disorders, the NBIA Disorders Association and Child Brain Research. None of the authors received funding for the preparation of this manuscript.

Author contributionsJ.N. wrote the first draft and provided substantial input into revision of the manuscript. A.P. prepared tables and figures and contributed to revision of the manuscript. S.J.H. contributed to the critique of the manuscript and figures. M.A.K. provided substantial input into the manuscript concept, design, content and revision of each draft.

REVIEWS


http://dx.doi.org/10.1038/mt.2015.122

http://dx.doi.org/10.1038/mt.2015.122

REVIEW

CURRENTOPINION Status dystonicus in childhood

Copyright

www.co-pediatrics.com

a b,c d,e
Daniel E. Lumsden , Mary D. King , and Nicholas M. Allen
Purpose of review

Dystonia is a common paediatric neurological condition. At its most severe, dystonia may lead to life-threatening complications, a state termed status dystonicus. This review provides an update on thedefinition, causes, management and outcome of childhood status dystonicus.

Recent findings

High-quality studies in childhood status dystonicus are lacking, though an increasing number of case serieshave been published. Status dystonicus appears to occur more frequently in children compared with adults,with a clear precipitant identified in around two-thirds of cases. Although febrile illness remains thecommonest trigger for status dystonicus, unplanned interruption to deep brain stimulation (DBS) isincreasingly reported as a precipitant. In parallel with this, neurosurgical intervention for status dystonicusappears to have become more widely used, though optimum timing and patient selection remains unclear.In most cases, a multistaged approach is required; we propose an ‘ABCD’ approach – Addressingprecipitants, Beginning supportive measures, Calibrating sedation and Dystonia specific medications.Outcomes following status dystonicus appear to have slightly improved in recent years, potentially as aconsequence of increasing use of DBS, though mortality has remained around 10%.

Summary

Future work is needed to inform evidence-based guidelines for the management of status dystonicus. Oneof many pressing questions is the precise indication, and timing of interventions such as DBS.

Keywords

dystonia, dystonic storm, life-threatening dystonia, rhabdomyolysis, status dystonicus

aComplex Motor Disorder Service, Paediatric Neurosciences, EvelinaLondon Children’s Hospital, Guy’s and St Thomas’ NHS FoundationTrust,Westminister Bridge Road, London, United Kingdom, bDepartmentof Paediatric Neurology and Clinical Neurophysiology, Temple StreetChildren’s University Hospital, cAcademic Centre on Rare Diseases,University College, Dublin, dDepartment of Paediatrics, National Univer-sity of Ireland Galway and eGalway University Hospital, Galway, Ireland

Correspondence to Nicholas M. Allen, MD, National University of IrelandGalway, Galway H91 TK33, Ireland. Tel: +353 2071887188;e-mail: [email protected], [email protected]

Curr Opin Pediatr 2017, 29:674–682

DOI:10.1097/MOP.0000000000000556

INTRODUCTION

Dystonia is a common presentation in the field ofpaediatric neurodisability. The term was first used byOppenheim [1] over 100 years ago, describing a dis-order of fluctuating tone affecting four children.Since then, understanding of dystonia has evolved,with changes in how the disorder is classified, cate-gorized and conceptualized. Originally considered adisorder of basal ganglia function, it is now recog-nized that dystonia may arise because of disturbedfunction across much more widely distributed net-works [2]. The most recent consensus update definesdystonia as ‘a movement disorder characterized bysustained or intermittent muscle contractions caus-ing abnormal, often repetitive, movements, postures,or both’ [3,4

&

]. Dystonia in children differs fromthat in adults in a number of ways: being mostcommonly a symptomatic condition, co-existingwith other neurological abnormalities includingspasticity, being expressed on the background ofa developing brain, and presenting often as a sus-tained hypertonicity, rather than more intermittentinvoluntary movements [5–7]. This review will focus

© 2017 Wolters Kluwer

on providing an update on the more severe presenta-tion of dystonia in childhood, ‘status dystonicus’.

DEFINING AND DELINEATING

Dystonia is usually a fluctuating state, where clini-cally the intensity varies over minutes, hours or daysand there is paucity of readily available biomarkersfor detection. At its most extreme, periods of ‘severedystonia’ may be life-threatening but preciselydefining when this state is entered remains

Health, Inc. All rights reserved.

Volume 29 � Number 6 � December 2017



KEY POINTS

� Status dystonicus represents the severe end of adeteriorating spectrum of dystonia severity.

� Status dystonicus appears to occur more commonly inchildren than in adults, with febrile illness the mostcommonly identified trigger, in established dystoniapatients.

� Comprehensive prospective studies to guide statusdystonicus management are lacking, but there isemerging consensus as to the need for a multiprongedapproach, which we summarize as: Addressing theprecipitants, Beginning supportive measures,Calibrating sedation and Dystonia specificmanagements.

� Neurosurgical intervention appears to be more frequentin the management of status dystonicus, though debateremains as to the ideal candidates and optimal timingof DBS insertion, in the course of status dystonicus.

Status dystonicus in childhood Lumsden et al.

challenging [8]. A variety of broadly overlappingterms continue to be used to encapsulate this state,including ‘status dystonicus’, ‘desperate dystonia’,‘dystonic crisis’, ‘dystonic storm’, and ‘life-threaten-ing dystonia’. Recently, status dystonicus appears tohave become the most commonly used term, usedfor the remainder of this review, inclusive of allother terms used to describe extreme dystonia.

Copyright © 2017 Wolters Kluwe

Grade 1

Grade 2

Gr

Increasing Dysto

Home Hospita

Sits comfortably Regular sleep Stable on medication

Irritable and cannot settle Posturing interferes with seating activities Can only tolerate lying despite baseline medications

Cannot tolerSleep disturNo signs of metabolic (edehydrationairway comp

No assessment or change in management needed

Assessment within days Adjust medication or dystonia plan

Urgent asserequired Exclude medecompensEscalate manageme

FIGURE 1. Screening for dystonia severity (grade) and actiondystonia patients); Modified with permission from Lumsden et al.

1040-8703 Copyright � 2017 Wolters Kluwer Health, Inc. All rights rese

The criteria for status dystonicus proposed byManji et al. [9], ‘increasingly frequent and severeepisodes of generalized dystonia’, which necessitateurgent hospital admission, are frequently citedbut are not well defined. Manji et al. note in theirreport that all cases in their series demonstratedone or more of the following life-threateningcomplications: bulbar weakness compromisingupper airway patency with the risk of progressiveimpairment of respiratory function leading to thedevelopment of respiratory failure, exhaustion andpain and metabolic imbalances. Some authors haveconsidered the presence of one or more of theseadditional features as necessary for the diagnosisof status dystonicus.

Recognising status dystonicus as the severe endof a continuum of deterioration, facilitates theapplication of a simplified Dystonia Severity ActionPlan (DSAP) [10] ranging from grades 1 to 5 (Fig. 1)[11,12]. Although status dystonicus is the tradition-ally applied umbrella term encompassing ‘life-threatening dystonia’ and ‘dystonic storm’, alongthe DSAP scheme ‘status dystonicus/SD’ or ‘dystoniccrisis’ as generally applied corresponds to DSAPgrades 4 and 5. ‘Life-threatening dystonia’ corre-sponds to DSAP grade 5 and the term ‘dystonicstorm’ has been described as the temporal evolutionof status dystonicus, that is, a rapid deterioration indystonia over hours or days to reach DSAP grades 4and 5 [13

&

]. Grade 3 DSAP is a pre-status dystonicus

r Health, Inc. All rights reserved.

ade 3

Grade 4

Grade 5

nia Severity

l ICU

ate lying bed

.g. fever, ) or romise

Clinically as Grade 3 but with metabolic disturbance: Fever, dehydration, abnormal electrolytes, CK >1000 IU/L, myoglobinuria

Severe generalised dystonia, clinically as per Grade 4 but with full metabolic decompensation (metabolic, renal) or respiratory-cardiovascular compromise, requiring organ support

Status Dystonicus Managementssment

tabolic ation

nt

plan. Dystonia severity action plan (DSAP) (for established[10].

rved. www.co-pediatrics.com 675

Neurology

state, requiring urgent assessment, likely hospitali-zation, assessment for triggers, and management.

DIFFERENTIAL DIAGNOSIS

A number of neurological emergencies occur inchildren which may appear similar to status dysto-nicus, with significant overlap in clinical features(Table 1). More detailed comparison of these differ-ential diagnoses is previously outlined [13

&

,14].

ADDITIONAL HYPERKINETIC ELEMENTS INCHILDREN WITH STATUS DYSTONICUS

In children with dystonia, other elements of dyski-nesia may often co-exist, for example, dystoniachoreoathetosis in bilateral cerebral palsy, and assuch, these movements may also be seen with dys-tonic spasms in status dystonicus. However, ifthe underlying cause of the movement disorder orcontext is poorly understood and dyskinetic (e.g.choreiform) movements are a prominent feature ofthe acute presentation, then alternative diagnosesto status dystonicus should be considered, for exam-ple, anti-N-methyl-D-aspartate receptor (NMDAR)-antibody encephalitis, Sydenham’s chorea, and soon (Table 1). The presence of dyskinetic movementswith dystonic spasms in status dystonicus would notalter the management approach, but other disease-specific treatments may also be warranted (e.g.immunotherapy) for alternative diagnoses.

CAUSES AND TRIGGERS OF STATUSDYSTONICUS

Robust prospective studies across a population ofchildren at risk of developing status dystonicus arelacking. The most comprehensive systematic analy-sis of status dystonicus available was published byFasano et al. [15], describing a total of 89 episodes ofstatus dystonicus in 68 patients, 58.8% of whomwere under age 15 years. Cases were categorized as‘phasic’ if mainly characterized by rapid and repeti-tive dystonic movements, or ‘tonic’ (68.5%) ifmainly characterized by sustained contractionsand abnormal postures. A clear precipitant couldbe identified in 67.4% of episodes (of these 51.7%were because of infection, 30% drug adjustments,6.7% surgical procedures, 5% metabolic disordersand 5% DBS failure or interruption). The aetiologicalclassification of the underlying dystonia for thesecases was secondary dystonia in 37.6% (59.3% ofwhom had cerebral palsy), primary dystonia 25.8%(TOR1A gene mutations in 18.8%) and heredodege-nerative (27%). Updating this literature, we identi-fied a further 44 episodes of status dystonicus

Copyright © 2017 Wolters Kluwer

676 www.co-pediatrics.com

reported in 41 cases (supplemental material,http://links.lww.com/MOP/A28), occurring in 35/44 (79.5%) occasions before age 16 years, with simi-lar causes. For those episodes, wherever a precipitantcould be identified [32/44 (72%)], fever or infectionaccounted for 17/32 (53.1%), interruption or dis-continuation of DBS in 6/32 (18.8%), medicationchanges 3/32 (9.4%), surgery 2/32 (6%), followed bysingle episodes: metabolic disturbances, DBS sur-gery, abdominal discomfort and acute brain injury.

MANAGEMENT

The management of childhood status dystonicus ismultifaceted but a basic approach can be summa-rized by ABCD (Fig. 2):

(1)

Hea

Address precipitants
(2) Begin supportive care (3) Calibrate sedation (4) Dystonia specific medications
These elements are often considered and/or exe-cuted together. A robust evidence-base is lacking,and existing guidance is based upon expert opinionand personal experiences [13

&

,14].

Addressing the precipitants

In two-thirds of cases, it is possible to identify astatus dystonicus trigger, which should be treatedwhenever possible. A common trigger is infection.Although the commonest infective trigger, gastro-enteritis, is usually viral, sepsis should be ruled outand empiric treatment should be considered in allcases, as well as searches for other sources. Pain maybe a prominent trigger after surgery or trauma, andanticipatory strategies should be in place to preventit (being mindful that opioid-based treatments maycompound the respiratory depressant effect of seda-tive measures aimed at reducing dystonia). Gastro-intestinal discomfort may also precipitate statusdystonicus, for example, gastroesophageal refluxor constipation. Given the increasing reports ofstatus dystonicus triggered by an unplanned discon-tinuation of neuromodulation with DBS or intrathe-cal baclofen (ITB), it is important that cliniciansconsider this possibility promptly. Medicationchanges are another important trigger. If with-drawal of a regular antidystonic medication hasresulted in status dystonicus, then this medicationshould, wherever possible, be reinstated. Medica-tions that have been identified as triggers inreported status dystonicus cases include pimozideand haloperidol, both dopamine-blocking agents(sometimes used to treat status dystonicus), and

lth, Inc. All rights reserved.


http://links.lww.com/MOP/A28

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

Tab

le1

.D

iffer

entia

ldia

gnos

isof

stat

usdy

ston

icus

and

core

clin

ical

feat

ures

Neu

rolo

gic

al

emer

gen

cyM

oto

ro

rm

ove

men

tfe

atu

res

Tim

eco

urs

eo

nset

Trig

ger

or

cau

seR

hab

do

my

oly

sis

Au

tono

mic

fea

ture

s

Red

uce

dco

nsci

ou

sle

vel

Psy

cho

sis/

del

iriu

m/

ag

ita

tio

n

Stat

usdy

ston

icus

Seve

regen

eral

ized

dyst

onia

,w

hich

may

beac

com

pani

edby

othe

rhy

perk

ines

ia

Hou

rs–da

ysor

long

erde

pend

ing

ontri

gger

Iden

tifie

din�

two-

thirds

ofth

eca

ses

Hig

hrisk

Not

unco

mm

onN

oN

o

Neu

role

ptic

mal

igna

ntsy

ndro

me

Rigid

ity,

ofte

naf

fect

ing

low

erlim

bsan

dtru

nk,

with

feat

ures

ofPa

rkin

soni

sm

Day

s–w

eeks

Neu

role

ptic

san

dso

me

drug

sfo

rdy

ston

ia(e

.g.

pim

ozid

e)H

igh

risk

Ver

ypr

omin

ent

Yes

No

Sero

toni

nsy

ndro

me

Prom

inen

tcho

rea/

myo

clon

us,

hype

rref

lexi

a,cl

onus

,rigid

ity

Hou

rs–da

ysSe

roto

nerg

icag

ents

–SS

RIs,

TCA

,M

AO

-Bi,

MD

MA

(ecs

tasy

),tri

ptan

s

Hig

hrisk

Ver

ypr

omin

ent

Yes

Yes

Mal

igna

nthy

perth

erm

iaRi

gid

ityA

cute

Dep

olar

isin

gm

uscl

ere

laxa

nts

orin

hala

tiona

lana

esth

etic

ingen

etic

ally

pred

ispo

sed

case

s,fo

rex

ampl

eRy

R1m

utat

ion

Hig

hrisk

Prom

inen

tN

oN

o

Paro

xysm

alau

tono

mic

inst

abili

tyw

ithdy

ston

ia

Dys

toni

cpo

stur

ing,

typi

cally

exte

nsor

invo

lvin

gtru

nk

Hou

rs–da

ysSy

mpt

omat

icbr

ain

inju

ry–

for

exam

ple

traum

a,hy

poxi

a,in

fect

ion

Unu

sual

Ver

ypr

omin

ent

(par

oxys

mal

)Yes

Yes

Intra

thec

alba

clof

en(IT

B)w

ithdr

awal

synd

rom

e

Rebo

und

inun

derly

ing

mov

emen

tdis

orde

r,w

ithpr

omin

ents

past

icity

and

clon

us

Acu

te,

hour

sIT

Bpu

mp

failu

re,

cath

eter

mig

ratio

n,di

scon

nect

ion

Hig

hrisk

Prom

inen

tYes

Yes

Acu

tedy

ston

icre

actio

nA

cute

,ty

pica

llyfo

cal

dyst

onia

Acu

teM

edic

atio

nin

ges

tion,

for

exam

ple,

cycl

izin

e,ha

lope

rido

l

Ver

yun

usua

lU

nusu

alN

oN

o

Syde

nham

’sch

orea

Prom

inen

tcho

rea

Hou

rs–da

ysM

anife

stat

ion

ofrh

eum

atic

feve

rfo

llow

ing

beta

-ha

emol

ytic

stre

ptoc

occa

lin

fect

ion

Ver

yun

usua

lV

ery

unus

ual

No

Yes

Aut

oim

mun

een

ceph

aliti

sD

yski

nesi

a,of

ten

prom

inen

tch

orea

,w

ithbu

ccol

ingua

linv

olve

men

t

Day

s–w

eeks

Post

infe

ctio

us,

auto

antib

odie

sid

entif

ied

ina

prop

ortio

nU

nusu

alPr

omin

ent

Yes

Yes

Dru

gin

toxi

catio

nV

aria

ble

dysk

ines

iaA

cute

Inges

ted

drug

Ver

yun

usua

lN

otun

com

mon

Yes

Yes

MA

O-B

i,m

onoa

min

eox

idas

ety

peB

inhi

bito

rs;

RyR1

,ry

anod

ine

rece

ptor

skel

etal

mus

cle

mut

atio

ns(m

osto

ften)

;SS

RIs,

sero

toni

nse

lect

ive

reup

take

inhi

bito

rs;

TCA

,tri

cycl

ican

tidep

ress

ants

.A

dapt

edfrom

Alle

net

al.

[14]

and

Term

sara

sab

and

Fruc

ht[1

3&

].


1040-8703 Copyright � 2017 Wolters Kluwer Health, Inc. All rights reserved. www.co-pediatrics.com 677

Management of Paediatric Status Dystonicus

• Chloral hydrate 30- 100mg/kg 3-6 hourly • Enteral clonidine, initially 3

micrograms/kg eight hourly • IV clonidine, initially 0.5 micrograms/

kg/hour • IV Midazolam 30-100 micrograms/

kg/hour • General anaesthesia, e.g propofol (some sedatives may treat dystonia e.g benzopdiazepine/clonidine)

Enteral (polytherapy if required) • Trihexyphenidyl • Gabapentin • Baclofen • Tetrabenazine • Haloperidol • L-DOPA

• Urgent admission to HDU/PICU • IV hydration • Antipyretics +/- cooling blankets • General comfort • Analgesia and sleep promotion • Monitoring – CK, electrolytes, liver

profile • Intensive supports

• Intubation/Ventilation • Inotropes if required • Dialysis if required

Progression to neurosurgical intervention: • ITB (test dose prior to insertion) • DBS • Pallidotomy

Refractory Cases

p• Intensive su

• Intub• Inotr• Dialy

Enteral (p• Trihex• Gaba

B l

0- rly initially 3

ght hourly ly 0.5 micrograms/

Address Precipitant

Begin Supportive Care

Calibrate Sedation

Dystonia Specific Medications

• Antibiotics if infection present • Discontinue pharmacological

precipitants • Identify potential

musculoskeletal drivers e.g. hip subluxation/dislocation

• Constipation disimpaction • Gastro-oesphageal reflux

treatment • Review for DBS/ITB

interruption/malfunction

FIGURE 2. Management of paediatric status dystonicus.

Neurology

metoclopramide. In Wilson disease, chelation ther-apy with penicillamine, zinc sulphate or trientinehave also been linked to the development ofstatus dystonicus.

Begin supportive measures

Supportive measures are required to manage thedirect consequences of the excessive muscle spasms,and the side-effects caused by many of the medica-tion treatment strategies. Respiratory compromisemay be because of pharyngeal or laryngeal spasm,compromised chest wall expansion from diaphrag-matic or truncal dystonia or respiratory depressionfrom exhaustion, potentiated by medication use.Early placement of a nasogastric tube may avoidpotential aspiration and subsequent pneumonia,and provide a secure route for the delivery of enteralmedications and feed or hydration. Intubation and



ventilation may be required, but should not beconsidered mandatory. Tracheal tube per se mayoccasionally drive further dystonic posturing.

Cardiovascular instability may occur because ofa combination of intravascular depletion because ofdehydration, autonomic instability or cardiacarrhythmias because of metabolic disturbances.Intravenous (i.v.) fluids are generally required inthe acute phase, particularly as gut motility maybe impaired by a combination of dystonia and seda-tive or antidystonic medications. Metabolic/bio-chemical derangement may be a potentially life-threatening complication of status dystonicus, par-ticularly whenever significant rhabdomyolysis hasoccurred (creatine kinase more than 1000 IU/l).Myoglobinaemia may result in renal impairmentand electrolyte disturbance, compounded by prere-nal hypoperfusion because of dehydration. Renalimpairment may necessitate haemodialysis or




filtration. Repeated venipuncture may also drivedystonia and a balance is required between thebenefits of close monitoring of biochemistry andthe risk of creating further pro-dystonic drive.

Calibrating sedation

A cardinal feature of dystonia is remission with sleep[16]. A mainstay of the acute treatment of statusdystonicus is the balanced administration of sedativemedications to reduce dystonia severity and encour-aging consistent periods of restful sleep. Cautionis required with such medications because of thepotential for respiratory depression. A hierarchicalapproach to temporizing agents is recommended.

Chloral hydrate may be administered enterally(30–100 mg/kg up to 3–4 hourly) to induce sleep.We tend to avoid ‘stat’ doses of benzodiazepines toavoid respiratory depression, reserving i.v. loraze-pam or buccal midazolam for the uncommon situa-tion whenever dystonic spasms result in acuteairway compromise. In this situation however,anaesthetic airway management is essential.

Clonidine has emerged for the management ofsevere dystonia [17

&

], and in status dystonicus can beused in combination with chloral hydrate. Adminis-tered enterally, a typical starting dose is 3 mg/kg perdose, initially 8-hourly but with escalation up to3-hourly doses, delivering the equivalent of 3–5 mg/kg per hour in severe status dystonicus. Cloni-dine may also be delivered i.v., initially at a rate of0.5 mg/kg per hour. Frequent review of vital signsincluding heart rate (resting tachycardia to measurediscomfort, dehydration, etc.) and side-effects ofmedications, for example, hypotension, hypoventi-lation and sleep are important components of themonitoring strategy. Whenever status dystonicus isnot controlled by a combination of chloral hydrateand clonidine, escalation to more aggressive sedationmay be required, typically with continuous i.v. mid-azolam (30–100 mg/kg per hour) which may necessi-tate intubation and ventilation. If severe dystonicspasms continue, anaesthetic agents may be required(e.g. i.v. propofol or barbiturate infusions) and ifdystonia remains refractory, nondepolarizing para-lyzing agents are considered (avoiding depolarizingagents because of rhabdomyolysis risk).

Dystonia-specific medications

Temporizing measures providing sedation shouldbe considered a ‘holding measure’ (for days oreven weeks) whilst the trigger to the episode ofstatus dystonicus is addressed, and a long-term man-agement plan should be established. In some cases,it may be possible to abolish episodes of status



dystonicus with temporizing measures alone, andthen reduce these medications to a tolerable back-ground level at which a good quality of life isachieved without excessive sedation.

More often, additional measures are required,and escalation wherever necessary should bedeployed without delay. A large number of enteralmedications have been described in the treatment ofstatus dystonicus, including trihexyphenidyl, halo-peridol, pimozide, tetrabenazine, gabapentin, bac-lofen, levodopa, as well as antiepileptics such asvalproate, phenytoin and acetazolamide. In lightof this, it is not possible to make an evidence-basedrecommendation as to which oral agent should beconsidered ‘first-line’. As status dystonicus generallyoccurs in children with a longstanding dystonicmovement disorder, medication choices are likelyto be dictated by pre-existing pharmacological man-agement. In reported status dystonicus cases, first-line pharmacological therapies are rarely (�10%)effective alone [15]. This may represent a publica-tion bias towards the most complex cases requiringinterventions such as DBS whereas cases in whichstatus dystonicus management was relativelystraightforward are less likely to be published. Inpractice, early addition of specific antidystonia med-ications is important. Polypharmacy is often neces-sary and higher than regular starting doses, withrapid escalation over the early days and weeks, maybe utilized, until benefit is achieved or unacceptableside-effects are observed.

For some disorders, certain medications shouldbe avoided in status dystonicus. In aromatic L-aminoacid decarboxylase (AADC)-deficiency dopamineantagonists and L-DOPA should be avoided [18

&

].In pantothenate kinase-associated neurodegenera-tion (PKAN), use of L-DOPA has been discouragedbecause of a lack of benefit, whereas use of medi-cations with D2 antagonist activity (e.g. haloperidolor atypical antipsychotics) is discouraged because ofthe risk of tardive dyskinesia [19

&

]. Precision thera-pies addressing the molecular basis of the expandingnumber of ‘genetic’ dystonias are currently lacking,but may emerge in future.

OUTCOMES

In the review by Fasano et al. [15] a multistageapproach to management was described in mostcases, with a surgical intervention (DBS, ‘lesioning’or ITB) in 40.2% of status dystonicus episodes. Areturn to pre-status dystonicus baseline occurred in36.8% of cases, an improvement compared withthis baseline in 36.8% of cases, worsening in 16.2%and death in 10.3%. In our updated review, manage-ment of status dystonicus episodes was variably



Neurology

documented but with similar outcomes: 43.2%improved compared with pre-status dystonicus base-line, 27.3% returned to baseline, 18.2% improved butnot back to pre-status dystonicus baseline, and in11.4%, status dystonicus resulted in death. A neuro-surgical intervention was delivered in a higher pro-portion of cases in the updated review (65.9 versus40.2% within the Fasano et al. [15] review).


FIGURE 3. Sleep–wake chart. (a) Chart during status dystonicus aannotate pharmacotherapy, as well as other bedside parameters anwere managed in ICU and ward.


THE ROLE OF NEUROSURGICALINTERVENTIONAn unresolved question is, at which point, if at all,in the course of status dystonicus should neurosur-gical intervention be provided? Traditionally, neu-rosurgical intervention has been considered a lastresort, but given the apparent benefit reportedrecently, it has been argued that early intervention


nd (b) post status dystonicus. Note this chart can be modified tod can be used at ward and intensive care level. Both patients



be considered to avoid prolonged exposure to statusdystonicus and related complications [13

&

,20&

].Recently it has been suggested that in ‘dystonicstorm’ in the absence of a clear pharmacologicalprecipitant, in conditions known to be highlyresponsive to DBS (e.g. DYT1), neurosurgical inter-vention should be considered within the first 24 h[13

&

]. In practice, this is likely to apply to few chil-dren as most presenting with status dystonicus havean underlying symptomatic or heredodegenerativedystonia, where outcome following DBS is less cer-tain [21,22]. Even in the ‘ideal’ DBS candidate, thedecision is not to be taken lightly. Complications toDBS surgery are not uncommon (infection ofimplanted devices is at least 10%) [23

&

], frequentlyresulting in the removal of the implanted equip-ment, and abrupt interruption of DBS delivery.Children reaching DSAP grade 5 are typically medi-cally unstable or could be poorly nourished increas-ing surgical risks.

We suggest a measured approach to progressionto DBS or ITB in children with status dystonicus,with early discussion regarding this option. Phar-macological management of status dystonicusshould be attempted and the speed of progressionto DBS should influenced by the likelihood of bene-fit on an individual basis. Even in children withDYT1 dystonia, if status dystonicus can be con-trolled pharmacologically it may be possible toattain a period of prior medical stability to facilitateeducation on post-operative management of DBS,and clear goals.

Compared with DBS, the role of ITB in statusdystonicus is less clear [24]. Similarly, a decisionshould be made on an individual basis. For example,ITB would generally be considered before DBS,in the child with significant spasticity with dysto-nia. Along the pathway of treatment, discussionsregarding available therapeutic options should be


Table 2. Selected future questions

Robust, multicenter prospective studies to delineate the epidemiology and

True incidence and prevalence of status dystonicus amongst children, and

Lifetime/annual risk for those with dystonia developing status dystonicus

Risk factors for status dystonicus, and to what extent can they be modifieneurodisability to reduce the risk of low-impact/occult fractures driving

Can biomarkers be identified to quantify the risk of status dystonicus devedeterioration and recovery

The true impact of status dystonicus in childhood; long-term mortality, neu

Optimal timing to initiate interventions

Are the optimal early interventions disorder specific, or generalizable ac

Role of DBS and other neurosurgical interventions for the management ofbe prioritized

Novel patient-specific, precision-based and molecular-based therapies for


balanced with prognosis, the underlying cause ofthe status dystonicus, goal setting and sometimesavailable resources.

MONITORING DYSTONIA SEVERITY INSTATUS DYSTONICUS

The objective measurement of dystonia severity ischallenging, relying on lengthy scales that utilizestandardized video-protocol formats [25–27]. Thesescales are impractical in the acute clinical setting,and are also limited by a significant ceiling effect.Application of the DSAP facilitates an objective,practice-based tracking of dystonia severity but oncegrades 4 and 5 have been reached, additional bio-markers related to medical complications or severitycan serve as useful adjuncts. Rising creatine kinaselevels are concerning as a marker of potential acutekidney injury whereas falling levels suggest a trendtoward status dystonicus control. Similarly, trans-aminase measurements may also correlate with dys-tonia severity. Heart rate (tachycardia) will helprecognize periods of control versus discomfort[28]. As the major aim of acute status dystonicusmanagement is the establishment of regular sleep,sleep–wake charts should help determine trendsand treatment responses (Fig. 3). Educating thefamily and multidisciplinary team regarding apotential lengthy in-patient admission, should facil-itate expectations and consistency.

UNANSWERED QUESTIONS

Status dystonicus remains a poorly understoodentity, with many questions requiring clarificationthrough future research. Answering these questionswill go some way towards generating a backgroundof evidence upon which future guidelines may bebased (Table 2).


clinical characteristics

comparisons to adults

d, for example, optimizing bone health in children with long-termstatus dystonicus through pain

loping over a given time frame, or to objectively track both

rological and developmental morbidity, impact on participation

ross all patients regardless of the underlying cause

status dystonicus and the cases for whom such interventions should

genetic dystonias


Neurology

CONCLUSION

Status dystonicus represents the extreme end of adeteriorating dystonia spectrum, the mortalityremaining unchanged (�10%) in recent years.Robust epidemiological studies are lacking, butthe available evidence suggests that status dystoni-cus is more commonly encountered in children,particularly in those with acquired or heredodege-nerative dystonia. In two-thirds of cases, a precipi-tant can be identified, most commonly infection.Over the last decade, interruption of DBS neuro-modulation appears to have become a commonstatus dystonicus trigger. In parallel, neurosurgicalinterventions for the treatment of status dystonicusappear to have become more available (40.2–65.9%of reported cases). Management suggestions remainlargely based upon expert opinion. The ABCDapproach discussed, helps formulate individualmanagement strategies.

Acknowledgements

None.

Financial support and sponsorship

None.

Conflicts of interest

There are no conflicts of interest.

REFERENCES AND RECOMMENDEDREADINGPapers of particular interest, published within the annual period of review, havebeen highlighted as:
& of special interest&& of outstanding interest
1. Oppenheim H. Uber eine eigenartige Krampfrankheit des kindlichen undjugendlichen Alters (Dysbasia Lordotica progressive, Dystonia Musculorumdeformans). Neurol Centrabl 1911; 30:1090–1107.

2. Hendrix CM, Vitek JL. Toward a network model of dystonia. Ann N Y Acad Sci2012; 1265:46–55.

3. Albanese A, Bhatia K, Bressman SB, et al. Phenomenology and classifi-cation of dystonia: a consensus update. Mov Disord 2013; 28:863–873.

4.&

Lumsden DE, Gimeno H, Lin JP. Classification of dystonia in childhood.Parkinsonism Relat Disord 2016; 33:138–141.

This article demonstrates an application in practise to a cohort of children andyoung people with dystonia of the most recent consensus update on dystoniaclassification.5. Roubertie A, Rivier F, Humbertclaude V, et al. The varied etiologies of

childhood-onset dystonia. Rev Neurol (Paris) 2002; 158:413–424.6. Mink JW. Special concerns in defining, studying, and treating dystonia in

children. Mov Disord 2013; 28:921–925.



7. Lin JP, Lumsden DE, Gimeno H, Kaminska M. The impact and prognosis fordystonia in childhood including dystonic cerebral palsy: a clinical and demo-graphic tertiary cohort study. J Neurol Neurosurg Psychiatry 2014;85:1239–1244.

8. Jankovic J, Penn AS. Severe dystonia and myoglobinuria. Neurology 1982;32:1195–1197.

9. Manji H, Howard RS, Miller DH, et al. Status dystonicus: the syndrome and itsmanagement. Brain 1998; 121(Pt 2):243–252.

10. Lumsden DE, Lundy C, Fairhurst C, Lin JP. Dystonia Severity Action Plan: asimple grading system for medical severity of status dystonicus and life-threatening dystonia. Dev Med Child Neurol 2013; 55:671–672.

11. Combe L, Abu-Arafeh I. Status dystonicus in children: early recognition andtreatment prevent serious complications. Eur J Paediatr Neurol 2016;20:966–970.

12. Gorman KM, Lynch SA, Schneider A, et al. Status dystonicus in two patientswith SOX2-anophthalmia syndrome and nonsense mutations. Am J MedGenet A 2016; 170:3048–3050.

13.&

Termsarasab P, Frucht SJ. Dystonic storm: a practical clinical and videoreview. J Clin Mov Disord 2017; 4:10.

A detailed review of ‘dystonic storm’, which includes both a proposed pathophy-siological explantion for how episodes of severe dystonia may develop, as well asan alternative treatment algorithm for status dystonicus.14. Allen NM, Lin JP, Lynch T, King MD. Status dystonicus: a practice guide. Dev

Med Child Neurol 2014; 56:105–112.15. Fasano A, Ricciardi L, Bentivoglio AR, et al. Status dystonicus: predictors of

outcome and progression patterns of underlying disease. Mov Disord 2012;27:783–788.

16. Fish DR, Sawyers D, Smith SJ, et al. Motor inhibition from the brainstem isnormal in torsion dystonia during REM sleep. J Neurol Neurosurg Psychiatry1991; 54:140–144.

17.&

Sayer C, Lumsden DE, Kaminska M, Lin JP. Clonidine use in the outpatientmanagement of severe secondary dystonia. Eur J Paediatr Neurol 2017;21:621–626.

A provisional report of clonidine use in the outpatient setting for severe dystonia.18.&

Wassenberg T, Molero-Luis M, Jeltsch K, et al. Consensus guideline for thediagnosis and treatment of aromatic l-amino acid decarboxylase (AADC)deficiency. Orphanet J Rare Dis 2017; 12:12.

A detailed review and proposed guideline for the manaement of various aspects ofAADC.19.&

Hogarth P, Kurian MA, Gregory A, et al. Consensus clinical managementguideline for pantothenate kinase-associated neurodegeneration (PKAN).Mol Genet Metab 2017; 120:278–287.

A detailed review and proposed guideline for the management of various aspectsof PKAN.20.&

Ben-Haim S, Flatow V, Cheung T, et al. Deep brain stimulation for statusdystonicus: a case series and review of the literature. Stereotact FunctNeurosurg 2016; 94:207–215.

A cases series highlighting the potential utility of DBS in status dystonicusmanagement.21. Andrews C, Aviles-Olmos I, Hariz M, Foltynie T. Which patients with dystonia

benefit from deep brain stimulation? A metaregression of individual patientoutcomes. J Neurol Neurosurg Psychiatry 2010; 81:1383–1389.

22. Lumsden DE, Kaminska M, Gimeno H, et al. Proportion of life lived withdystonia inversely correlates with response to pallidal deep brain stimulationin both primary and secondary childhood dystonia. Dev Med Child Neurol2013; 55:567–574.

23.&

Kaminska M, Perides S, Lumsden DE, et al. Complications of deep brainstimulation (dbs) for dystonia in children - the challenges and 10 year experiencein a large paediatric cohort. Eur J Paediatr Neurol 2017; 21:168–175.

Report of the complications encountered in a large cohort of children undergoingDBS.24. Grosso S, Verrotti A, Messina M, et al. Management of status dystonicus in

children. Cases report and review. Eur J Paediatr Neurol 2012; 16:390–395.25. Burke RE, Fahn S, Marsden CD, et al. Validity and reliability of a rating scale for

the primary torsion dystonias. Neurology 1985; 35:73–77.26. Barry MJ, VanSwearingen JM, Albright AL. Reliability and responsiveness of the

Barry-Albright Dystonia Scale. Dev Med Child Neurol 1999; 41: 404–411.27. Monbaliu E, Ortibus E, De Cat J, et al. The Dyskinesia Impairment Scale: a new

instrument to measure dystonia and choreoathetosis in dyskinetic cerebralpalsy. Dev Med Child Neurol 2012; 54:278–283.

28. Mrkobrada S, Gnanakumar V. The correlation of dystonia severity and serumtransaminases in a child with a brain injury. Pediatr Neurol 2014;51:573–575.



DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY GUIDELINE

Status dystonicus: a practice guide

NICHOLAS M ALLEN1 | JEAN-PIERRE LIN2 | TIM LYNCH3 | MARY D KING1

1 Department of Paediatric Neurology and Clinical Neurophysiology, Children’s University Hospital, Dublin, Ireland. 2 General Neurology & Complex Motor DisordersService, Evelina Children’s Hospital, Guy’s & St Thomas’ NHS Foundation Trust, London, UK. 3 Department of Neurology, Dublin Neurological Institute at the MaterMisericordiae University Hospital, Dublin, Ireland.

Correspondence to Dr Nicholas M Allen, Department of Paediatric Neurology, Children’s University Hospital, Temple Street, Dublin 1, Ireland. E-mail: [email protected]

PUBLICATION DATA

Accepted for publication 7th October 2013.

Published online 4th December 2013

ABBREVIATIONS

DBS Deep brain stimulation

ITB Intrathecal baclofen

Status dystonicus is a rare, but life-threatening movement disorder emergency. Urgent

assessment is required and management is tailored to patient characteristics and complica-

tions. The use of dystonia action plans and early recognition of worsening dystonia may

potentially facilitate intervention or prevent progression to status dystonicus. However, for

established status dystonicus, rapidly deployed temporizing measures and different depths of

sedation in an intensive care unit or high dependency unit are the most immediate and effec-

tive modalities for abating life-threatening spasms, while dystonia-specific treatment takes

effect. If refractory status dystonicus persists despite orally active anti-dystonia drugs and

unsuccessful weaning from sedative or anaesthetic agents, early consideration of intrathecal

baclofen or deep brain stimulation is required. During status dystonicus, precise documenta-

tion of dystonia sites and severity as well as the baseline clinical state, using rating scales

and videos is recommended. Further published descriptions of the clinical nature, timing of

evolution, resolution, and epidemiology of status dystonicus are essential for a better

collective understanding of this poorly understood heterogeneous emergency. In this review,

we provide an overview of the clinical presentation and suggest a management approach for

status dystonicus.

UNDERSTANDING AND DIAGNOSING STATUSDYSTONICUSDystonia: phenomenology and classificationDystonia, traditionally classified as a hyperkinetic movementdisorder, manifests in a variety of ways. It is characterized byinvoluntary sustained or intermittent muscle contractionscausing repetitive twisting movements, abnormal postures,or both.1 A characteristic feature of dystonia is the presenceof muscle co-contraction, exacerbation with the intention tomove and/or non-specific afferent stimuli, and complete res-olution of dystonia by sleep, irrespective of the mechanismof dystonia. This last observation distinguishes dystoniafrom lower brainstem, spinal, and intramuscular hyper-acti-vation states. Dystonia distorts voluntary movements andoften coexists with other movement and motor disorderssuch as choreoathetosis in dyskinetic cerebral palsy (CP),myoclonus, or parkinsonism. Dystonic postures may give theimpression of hypokinesia.1,2 Topographically, dystonia mayaffect a single body site (focal dystonia), several body sites, orbe classified as generalized (involving both legs and one ormore body region such as axial muscles). Until recently,3

dystonia was usually classified in terms of whether itoccurred as part of a primary dystonia disorder, a dystonia-plus syndrome, a paroxysmal dyskinesia (dystonia), a hered-odegenerative disorder, or secondary dystonia (acquiredsecondary to a symptomatic cerebral, brainstem, or spinalcord insult). Secondary dystonia is more common in

children,4 and CP is the most common cause. This reviewfocuses on the most acute life-threatening complication ofdystonia, status dystonicus.

Status dystonicusStatus dystonicus, also known as dystonic storm or dystoniccrisis, is a life-threatening movement disorder emergency.Although considered rare (only about 100 published cases),status dystonicus is most likely an underreported condition,heterogeneous in its aetiology, pathogenesis, presentation,course, and outcome. Status dystonicus affects all age groupsbut up to 60% of patients are between ages 5 years and16 years, although patients may be younger or older, with amale preponderance.5 Neurometabolic disorders such asglutaric aciduria type 1 may precipitate status dystonicus asearly as 7 months of age and the extensor dystonia is oftenmistaken for status epilepticus.

Phenomenology and diagnosisStatus dystonicus is characterized by the development ofincreasingly frequent or continuous severe episodes ofgeneralized dystonic spasms (contractions) and requiresurgent (hospital) management.6,7 Recent phenomenologicalcategorization divides episodes of status dystonicus into eithertonic (mainly sustained contractions and abnormal postures) orphasic (rapid and repetitive dystonic contractions) phenotypes.The tonic phenotype is more common in males and in

© 2013 Mac Keith Press DOI: 10.1111/dmcn.12339 105

secondary (acquired) dystonias, and has a potentially worseoutcome.5 The movements of status dystonicus may alsooverlap with additional, sometimes prominent, hyperkinesiassuch as choreoathetosis, which can make objective recogni-tion complicated.6,8,9 Currently, there is no internationallyagreed definition for status dystonicus. Criteria, includinglife-threatening complications proposed by Manji et al. areoften cited.6 All patients in that case series developed one ormore of the following: (1) bulbar weakness compromisingairway patency, (2) progressive impairment of respiratoryfunction leading to respiratory failure, (3) metabolicderangements, and (4) exhaustion and pain.

In practice, status dystonicus often occurs at the end ofa continuum of worsening dystonia. Along such a contin-uum, a recently described simplified dystonia severityaction plan may be useful to assess children at risk of sta-tus dystonicus and decide on the level of care requiredfor management (see Fig. 1 and the supplementary mate-rial of Lumsden et al. for related clinical vignettesemployed to validate the scale).10 In addition, the sitesand severity of the dystonia may be documented usingdystonia rating scales such as the Dyskinesia ImpairmentScale for patients with cerebral palsy2 or the Burke-Fahn-Marsden rating scale.11 Video recordings areimportant for diagnosis and follow-up of treatmentresponse. The baseline neurological state (coexistingspasticity, etc.) should also be recorded.

AetiologyStatus dystonicus usually emerges gradually after weeks ormonths in the patient with an underlying dystonia diagnosis.However, status dystonicus may also present during newonset dystonic disorders without previous or only milddystonic movements.5,10,12,13 Some patients are prone torecurrent episodes. The acquired dystonias are the mostcommon underlying dystonias leading to status dystonicus(38% of cases), CP being the most common individual sec-ondary cause followed by the previously termed ‘heredode-generative dystonias’ (particularly neurodegeneration withbrain iron accumulation, Wilson disease, and mitochondrialdisorders) and the ‘pure primary dystonias’.5 However, anyform of dystonia has the potential to escalate into statusdystonicus. If the cause of the underlying dystonia is notestablished, the history and clinical features will guideappropriate metabolic, genetic, neurophysiological, and neu-roimaging investigations.

Trigger factorsStatus dystonicus is often a triggered event. The main trig-gers include infection (particularly gastroenteritis with dehy-dration) and medication adjustment.7,13,14 Trauma, surgicalprocedures, anaesthesia, ‘metabolic disorder’ decompensa-tion,15 stress,7 pain, gastro-oesophageal reflux disease, con-stipation, and puberty-related deterioration in CP are lesscommonly reported, but these conditions, as well as discom-fort of any cause, should be considered.6 In about one-thirdof cases no obvious trigger is identified.5,13,14

Medications reported to trigger status dystonicus areimportant, particularly the dopamine-receptor blockerspimozide (exacerbated status dystonicus)16 and haloperidolas both can be used to treat dystonia and chorea.17 Metoclo-pramide8 can have the same effect. Clonazepam has beenreported as a trigger (possibly coincidental) of status dysto-nicus.6,18,19 In Wilson disease the introduction of chelationtherapy with penicillamine,20,21 zinc sulphate,7 or trientine22

have also been implicated in status dystonicus. Clozapinetreatment has been implicated,19 as well as withdrawal oflithium and tetrabenazine.6 Deep brain stimulation failurecaused by hardware problems,5,8 intrathecal baclofen pumpfailure,12 as well as routine baclofen, and benzodiazepinewithdrawal in general should be considered where relevant.

Complications and related investigationsThe muscle spasms or dystonic movements during statusdystonicus give rise to complications that are at best painfuland uncomfortable, and at worst life-threatening.5 Severegeneralized muscle spasms may cause respiratory compro-mise and severe metabolic disturbances, particularly rhabd-omyolysis and acute renal failure. The initial investigationsare based on consideration of the complications, need formonitoring, supportive measures, and likely trigger factors.

Respiratory failure can be a function of dystonic bulbarspasms (pharyngeal, laryngeal), truncal-respiratory musclespasm, diaphragm dystonia, generalized exhaustion, aspira-tion pneumonia, and indeed the need for highly sedativeand relaxant cocktails of drugs used to control status dysto-nicus. Relevant respiratory investigations for these compli-cations and triggers include chest X-ray, pulse oximetry,and blood gas monitoring, all of which should be part ofthe initial and ongoing supportive measures.

The biochemical derangements resulting from significantrhabdomyolysis23 include elevated creatine kinase (usually>5 times normal range, e.g. >1000 IU/L), myoglobinaemia,myoglobinuria, electrolyte abnormalities, and acid-base dis-turbances. Muscle spasm-induced exothermia commonlyleads to hyperpyrexia and dehydration. As well as clinicallymonitoring perfusion status (e.g. vital signs, capillary refilltime, urine output), empirical tests for rhabdomyolysis anddehydration include renal chemistry, creatine kinase, bloodgas analysis, urine and/or blood for myoglobin levels. Apositive urine dipstick test for blood without red cells onmicroscopy is suggestive of recent muscle injury (over sev-eral hours).24 The creatine kinase may need to be repeated ifnegative at presentation because of a potential lag in eleva-tion. Further monitoring and investigations related to themanagement of rhabdomyolysis and renal failure (hypocalca-emia, hyperkalaemia, acidosis, haematological derange-ments, coagulopathy, pancreatic dysfunction, arrhythmias,compartment syndrome, and more) should involve appropri-ate medical, nephrology, and intensive care input.

What this paper adds• An overview of status dystonicus and a practical approach to the manage-

ment of status dystonicus and ‘pre-status dystonicus’.

106 Developmental Medicine & Child Neurology 2014, 56: 105–112

Status dystonicus patients are vulnerable to secondarycomplications such as dysphagia, anarthria, thrombosis,gastric bleeding, injuries, fractures, and sepsis.16,22,25 Somepatients require tracheostomy or gastrostomy and someexperience side effects or serious complications of treat-ment.6,16 A careful search for systemic or intracranial infec-tion is usually warranted (appropriate septic screen).

Differential diagnosisA variety of other emergency life-threatening movement dis-orders can have complications similar to status dystonicus(Table I). These include the neuroleptic malignant syndrome,serotonin syndrome, malignant hyperthermia, and intrathecalbaclofen (ITB) withdrawal.6,12,16,17,26–29 Paroxysmal auto-nomic instability with dystonia is increasingly recognized inchildren.12,30,31 Acute dystonic reactions (usually to drugs)arise dramatically and may cause severe dystonic symptoms(e.g. oculogyric crisis, jaw opening, or closing dystonia).Rhabdomyolysis, muscle rigidity, and stiffness from othercauses warrant consideration (Table I).6,19,29

In severe status dystonicus the typical patient has anestablished or evolving dystonia disorder and develops wors-ening severe generalized dystonia, fever, dehydration, orrhabdomyolysis and respiratory complications. Documenta-tion of the precise evolution of the motor and other featuresof these disorders is crucial as some children have been diag-nosed with neuroleptic malignant syndrome when drugsmay not have been involved.30,32 ITB withdrawal can pro-duce clinical features resembling status dystonicus.12,27–29

MANAGEMENT‘Pre-status dystonicus’In some situations patient-specific management plans areused for known patients with brittle dystonia (characterizedas difficult to manage or frequently requiring urgent medi-cal attention) depending on the goals of treatment.33 In thecase of patients who are hospitalized with severe subacuteworsening dystonia or pre-dystonic crisis, lighter levels ofsedation may be used alone or in combination to helpachieve sleep, for example enteral chloral hydrate(30–100mg/kg, administered 3–6 hourly). In addition, oral,enteral or intravenous (IV) clonidine30 has a less sedating,non-respiratory depressant effect and may prove effective inachieving control or preventing breakthrough dystonia.Doses of 1-5lg/kg/dose may be administered three timesdaily, but may need to be offered every 3 hours (amountingup to 3,000lg per day in some cases with weights exceeding70kg). Clonidine can be administered by continuous enteralinfusion via NG tube or gastrostomy if necessary by calcu-lating the total daily dose and dividing by 24 hours to deli-ver. Where the enteral route is unsuitable owing tovomiting, diarrhoea, gastrointestinal bleeding or ileus, theequivalent doses may have to be administered as IV hourlyinfusion (doses of 0.25–2.0lg/kg/hr), with consideration ofhigher or bolus doses as tolerated (JP Lin, unpublisheddata). Chlormethiazole6 (if available) or trimeprazine mayalso achieve lighter levels of sedation. Roubertie et al. also

suggest effective use of intravenous amitriptyline for painfuldystonic spasms.34 The addition or modification of otherantidystonia agents according to the patient plan (e.g. tri-hexyphenidyl, gabapentin, or baclofen) should be consid-ered. Benzodiazepines also may need to be considered.Although these practical suggestions may help prevent pro-gression to status dystonicus and mostly represent lighterlevels of sedation, very little has been published regardingthese approaches. For status dystonicus, more prompt andaggressive treatment is often indicated.9,10,22,34

Established status dystonicusAs status dystonicus is rarely reported, the evidence fortreatment is derived from summation of case reports orseries and is therefore empiric. Medical stabilization withsupportive care is the initial priority. Figure 1 outlines apractical screening and management approach to statusdystonicus.

Stabilization and supportive measuresIn order to control an episode of status dystonicus as safelyas possible, treatment should take place in the intensive careor high dependency unit. Immediate management of thecomplications is paramount. Depending on clinical indica-tion (respiratory or systemic compromise, need for comfortor sedation), the initial stabilization measures often, but notalways, involve intubation and mechanical ventilation.6

Intravenous fluid resuscitation, antibiotics, nutritionalrequirements (nasogastric or parenteral) and antipyreticsshould be provided early. Rhabdomyolysis requires specifictherapy (e.g. intravenous fluids, urine alkalinization, dantro-lene, neuromuscular paralysis, and/or dialysis in acute renalfailure).22,35 Trigger factors and other complications shouldbe prevented or identified and treated specifically. Otherpatient comfort and sleep promoting measures includeappropriate positioning and minimal handling, and opioidanalgesia may be required. A relatively long intensive careunit course should be anticipated for each presentation.

Temporizing treatmentsStatus dystonicus exerts its life-threatening effects preciselybecause sustained active muscle contraction leads toexhaustion and rhabdomyolysis. Depending on the clinicalstate and complications, an important initial measure is tohelp the child achieve some sleep without compromisingrespiration. Judicious use of a few doses of chloral hydrate(see Fig. 1) via nasogastric tube when oral medication isimpossible to administer may enable sleep. Oral, enteral orintravenous clonidine (as in the case of pre-status dystoni-cus) should also be used because of its non-respiratorydepressant advantages. In addition, rapid escalation ofenteral doses of clonidine as high as 3-5μg/kg/hr (adminis-tered in 3-hourly bolus doses) have been tolerated success-fully in several children with established status dystonicus,the dose being revised every 3 to 6 hours (JP Lin, unpub-lished data). If the enteral route is unsuitable, an IVclonidine infusion may be necessary to establish dystonia

Guideline 107

TableI:

Differen

tiald

iagn

osisof

status

dyston

icus

andco

reclinical

features

Disorder

Motorfeatures

Onse

tTrigger/ca

use

Rhabdomyolysis

Autonomic

features

Mental

status

Hypertherm

iaOther

Status

dystonicus

Severe

generalized

dystonia/other

hyperkinesias

Worseningdystonia

usu

ally,kn

ownpatient

Manytriggers

(must

out-rule

infection),Underlyingdystonia

disorderusu

ally(seetext)

Significa

ntrisk

Unusu

al

(background

autonomic

symptomsoccur

indopamine

transp

orter

deficiency

)

Usu

allyok

Common

Resp

iratory

compromise,

Treat:se

etextand

Figure

1

Neuroleptic

malignant

syndrome

Rigidity(trunk/

lowerlimbs)

Idiosy

ncraticand

variable,usu

allywithin

weeks

ofmedication

introductionorch

ange

Atypical>typicalneuroleptics/

dopaminewithdrawal,

metoclopramide,

proch

lorperazine.Somedrugs

use

dfordystonia

(e.g.

tetrabenazine,lithium,

pim

ozide)

Significa

ntrisk

Prominent(e.g.

tach

yca

rdia,

tach

ypnoea,

labileBP,

sweating)

Usu

ally

reduce

dCommon

Resp

iratory

compromise,

Treat:stopprecipitant,

bromocriptine,BZDs,

dantrolene,su

pportive

Serotonin

syndrome

Neuromuscular

excitability

(rigidity,clonus,

hyperreflexia,leg

myoclonus/

tremor>arm

s/trunk)

Within

hours,dose

related,mayreso

lve

quicklywhentrigger

removed.Sometimes

longerprodrome

(confusion,agitation)

Serotonergic

agents

(SSRIs,

TCAs,

MAO-Bi,‘ecstasy

’or

MDMA,otherenhance

rs),

antimigrainemedications(e.g.

triptans),ce

rtain

‘cough

mixtures’,Dose

-related

Significa

ntrisk

Prominent(e.g.

tach

yca

rdia,

tach

ypnoea,

labileBP,

sweating)

Usu

ally

reduce

d,

agitation,

seizures

Common,

afactorin

mortality

after

‘ecstacy

’intake

Flush

edappearance

,resp

iratory

compromise,

leuco

cytosis,

transa

minitis,Treat:stop

precipitant,

cyproheptadine,BZDs,

supportive

Malignant

hypertherm

iaMuscle

rigiditye.g.

masseter,

limbs,

trunk

Usu

allyintra/peri-

operatively

Geneticpredisposition(family

history

-RyR1mutation),

depolarizingmuscle

relaxant,

halogenatedinhalational

anaesthetic

Significa

ntrisk

Prominent

(tach

yca

rdia,

tach

ypnoea,

labileBP,

sweating)

Maybe

reduce

dVery

prominent

Resp

iratory

compromise,

mixedmetabolic

-resp

iratory

acidosis,

Treat:removetrigger,

supportive,dantrolene

Paroxysm

al

autonomic

instability

withdystonia

(PAID)

Dystonic

posturing,

extenso

rposturing,

hypertonia

Usu

allyin

ICU

post

brain

injury.Manifestsin

dailycy

clesoverdays

fordiagnosis

Symptomaticbrain

injury

(hypoxia,trauma,infection)

Alsodescribedrarely

insy

ndromes(e.g.Triso

my21/

Rett

syndrome)

Notusu

ally

described

Markedinstability

(e.g.tach

yca

rdia,

hypertension,

sweating,pupil

dilatation)

Usu

ally

reduce

d,

agitation

Common

Treat:su

pportive.May

resp

ondto

propranolol,

clonidine,gabapentin,

otheradrenergic

inhibitors

Intratheca

lbaclofen(ITB)

withdrawal

syndrome

Usu

allyse

vere

rebound

spasticity,

dyskinesia

sometimes

Acu

te(12–2

4h)orwithin

firstfew

daysofITB

interruption

ITBpumpfailure

foranyreaso

nSignifica

ntrisk

Canbeprominent

(e.g.tach

yca

rdia,

tach

ypnoea,

labileBP)

Reduce

d,

delirium,

seizures

Common

Pruritis,

paraesthesias,

multi-organdysfunction,

Treat:su

pportive,BZDs,

other,

e.g.dantrolene

Acu

tedystonic

reactions

Acu

tefoca

ldystonia,e.g.

OGC,

opisthotonus,

oromandibular

dystonia,

laryngeal

Immediately

tohours

or

daysofdrugtrigger

Neuroleptics

anddopamine

blockers

(metoclopramide),

someantidepressants

and

antico

nvulsants

Extremely

rare

––

–Canthreatenairway,Treat:

removedrug,addI.V

or

I.M

antich

olinergic

or

clonazepam

inOGC

Otherdisorders

whichmayca

use

oneormore

ofmuscle

rigidity,stiffness,dystonia

orrhabdomyolysis:

Medical

Sepsis,

meningitis,electrolyte

disturbance

(hypoca

lcaemia),thyroid

storm

.Ence

phalitis(infective,paraneoplastic

orautoim

muneparticularlyNMDAR-A

bmediated).Poisons(e.g.

strych

nine),drugwithdrawal(e.g.opioid),metabolicdisorders

(myopathies,

etc.),tetanus,

rabies

Neurological

Tardivedystonia,se

izures,

stiffpersonsy

ndrome,hyperekp

lexia.Parkinso

ndisease

(a)Wearing‘off’and‘on’dystonia

inlate

disease

(whileoff

L-dopa;se

vere

dystonic

spasm

softoes

(curlingorextension)orabdomen/chest

orjaw

openingdystonia)oftenease

dbyL-dopaorS.C

apomorphine;(b)hyperpyrexia-dyskinesia

syndrome

Psy

chiatric

Malignantca

tatonia

(from

manic

state

toca

tatonia

withstrangeposturing,mayalsorese

mble

NMDAR-A

bmediatedence

phalitis).Functionaldisorders

BP,bloodpressure;ICU,intensiveca

reunit;OGC,ocu

logyriccrisis;SSRIs,se

rotonin

selectivereuptake

inhibitors;TCAs,

tricyclic

antidepressants;MAO-Bi,monoamineoxidase

typeB

inhibitors;BZDs,

benzo

diazepines;

NMDAR-A

b,N-m

ethyl-D-asp

artate

rece

ptorantibodies;

RyR1,ryanodinerece

ptorskeletalmuscle

mutations(m

ost

often);I.V,intravenous;

I.M,intramus-

cular;

S.C,su

bcu

taneous.


Gra

de 1

•S

its c

omfo

rtab

ly•

Reg

ular

sle

ep•

Sta

ble

on m

edic

atio

n

Gra

de 4

Gra

de 3

Gra

de 2

•C

linic

ally

as

in G

rade

3

with

met

abol

ic

dist

urba

nce:

feve

r,

dehy

drat

ion,

abn

orm

al

elec

trol

ytes

, C

K >

1000

IU/L

, myo

glob

inur

ia

•C

an’t

tole

rate

lyin

g•

Sle

ep d

istu

rbed

•N

o si

gns

of m

etab

olic

(e

.g. f

ever

, deh

ydra

tion)

or

airw

ay c

ompr

omis

e

•S

ever

e ge

nera

lized

dys

toni

a•

As

per

Gra

de 4

with

full

met

abol

ic d

ecom

pens

atio

n(m

etab

olic

, ren

al)

or

resp

irato

ry-c

ardi

ovas

cula

r co

mpr

omis

e: o

rgan

sup

port

Gra

de 5

•S

edat

ive

hypn

otic

(sl

eep)

e.g.

ent

eral

chl

oral

hyd

rate

30

to

100m

g/kg

q 3

–6 h

ourly

to

ach

ieve

sle

ep

•N

on-r

espi

rato

ry d

epre

ssan

t e.

g. e

nter

al o

r IV

clon

idin

e

±+

•S

edat

ive

hypn

otic

(sp

asm

s)IV

mid

azol

am30

to

100

µg/k

g/hr

(to

lera

nce

may

de

velo

p qu

ickl

y)±

•G

ener

al a

naes

thes

iae.

g. p

ropo

fol 0

.3 to

3m

g/kg

/hr

(mon

itorin

g fo

r pr

opof

ol

in

fusi

on s

yndr

ome)

±•

Par

alyt

ic a

gent

s(n

on-d

epol

ariz

ing

e.g.

pa

ncur

oniu

m)

2. T

empo

rizin

g m

easu

res

3. D

ysto

nia-

spec

ific

•Ir

ritab

le a

nd c

anno

t set

tle•

Pos

turin

g in

terf

eres

with

se

atin

g ac

tiviti

es•

Can

onl

y to

lera

te ly

ing

desp

ite b

asel

ine

med

icat

ion

•U

rgen

t ad

mis

sion

•H

DU

or

ICU

•IV

hyd

ratio

n•

Ant

ipyr

etic

s•

Coo

ling

blan

kets

•A

nalg

esia

•M

onito

r (C

K, r

enal

,

othe

r pa

ram

eter

s)•

Iden

tify

and

trea

t trig

gers

(e

.g. I

V a

ntib

iotic

s)•

Gen

eral

com

fort

and

sle

ep•

Kno

wn

patie

nt: c

onsi

der

sp

ecifi

c pl

an•

Intu

bate

PR

N

Initi

al o

ral p

olyt

hera

py:

•T

rihex

yphe

nidy

l(a

ntic

holin

ergi

c)•

Tet

rabe

nazi

ne

(cat

echo

lam

ine

depl

eter

)•

Hal

oper

idol

(do

pam

ine

re

cept

or b

lock

er)

Con

side

r tr

ial:

Bac

lofe

nB

enzo

diaz

epin

e G

abap

entin

(W

ilson

)L-

dopa

Oth

er (

see

text

)

Sta

tus

dyst

onic

us

Non

-inva

sive

*

1. S

uppo

rtiv

e ca

re

•A

sses

smen

t (w

ithin

day

s)•

Adj

ust m

edic

atio

n or

dy

ston

ia p

lan

•N

o as

sess

men

t or

chan

ge in

pla

n ne

eded

Dys

toni

a-sp

ecifi

c or

al a

gent

s (S

tatu

s D

ysto

nicu

s)•

Ifsp

asm

spe

rsis

tor

depe

nden

ceon

IVse

dativ

e/an

aest

hetic

agen

tde

velo

ps,

early

addi

tion

ofot

her

agen

tsi.e

.tr

ihex

yphe

nidy

l ±te

trab

enaz

ine

inco

mbi

natio

n (if

patie

ntno

tal

read

yon

thes

e).

•N

ext

cons

ider

addi

tion

ofha

lope

ridol

,ba

clof

en,

gaba

pent

in.

•U

sehi

gher

than

regu

lar

star

ting

dose

s4,53

(incr

easi

ngov

erda

ysto

first

wee

ks)

until

side

-effe

cts

orbe

nefit

obse

rved

(ant

icip

ate

the

effe

cts

ofpo

lyph

arm

acy

and

ratio

naliz

e).

•C

onsi

der

inva

sive

ther

apy

depe

ndin

gon

indi

vidu

alpa

tient

prob

lem

san

dlo

ng-t

erm

goal

s.

•U

rgen

t ass

essm

ent

•E

xclu

de m

etab

olic

deco

mpe

nsat

ion

(e.g

. CK

) •

Esc

alat

e m

anag

emen

t•

± h

ospi

tal a

dmis

sion

Whe

re p

ossi

ble

patie

nts

with

sev

ere

or b

rittle

dys

toni

ash

ould

hav

e a

pers

onal

ized

plan

that

can

be

impl

emen

ted

at t

he f

irst

sign

of

wor

seni

ng d

ysto

nia

i.e. d

urin

g D

SA

P g

rade

s 2-

3.

Tim

ely

inte

rven

tions

, an

d ad

just

men

t to

the

regu

lar

plan

may

hel

p pr

even

t det

erio

ratio

n th

roug

h dy

ston

ia s

ever

ity g

rade

s le

adin

g to

st

atus

dys

toni

cus.

Sug

gest

ions

:•

Trih

exyp

heni

dyl:

slow

incr

emen

t as

tol

erat

ed t

o m

axim

um b

enef

it.•

Gab

apen

tin: p

artic

ular

ly to

tal b

ody

dyst

onia

whe

re s

eatin

g/sl

eepi

ng

diffi

cult

and

child

freq

uent

ly d

istr

esse

d.•

Ent

eral

(or

IV)

clon

idin

e: th

e le

ast

seda

tive

dose

pos

sibl

e.•

Oth

er:

benz

odia

zepi

nes,

bac

lofe

n, t

etra

bena

zine

.

Inva

sive

(c

onsi

der

early

ref

ract

ory

case

s)

•IT

B(t

est b

efor

e pu

mp)

•D

BS

(GP

i)

•P

allid

otom

y

*

with

use

of

high

(bo

lus

or

cont

inuo

us in

fusi

on)

dose

sas

tol

erat

ed (

see

Tex

t fo

r do

ses)

Figu

re1:

Screen

ingfordystonia

severity(grade

)an

dac

tionplan

with

overview

oftheman

agem

entof

status

dystonicus.D

SAP,dystonia

severityac

tionplan

(forestablisheddyston

iapa

tients);G

Pi,G

lobu

spa

llidu

sinternus;ITB

,intrathecal

baclofen;D

BS,

deep

brainstimulation;

CK,c

reatinekina

se;ICU

,inten

sive

care

unit;

HDU,h

ighde

pend

ency

unit;

IV,intraveno

us.M

odified

with

perm

ission

from

Lumsden

etal.10

andS.

Fruc

ht,M

ovem

entDisorde

rEm

ergenc

ies:Diagnosisan

dTrea

tmen

t(2nd

edition,N

Y:Hum

anaPress,2011).

Guideline 109

control (see ‘Pre-status dystonicus’ for dose considera-tions). In practice, if additional ‘as required’ medication isneeded to settle a child, the background clonidine dosemust be increased to achieve comfort, sleep and metabolicstability.

When more aggressive treatment is indicated, the pre-cise approach depends on individual case severity anddegree of complications.9,10,22,34 Stronger sedation andmuscle relaxation or muscle paralysis are the measuresmost likely to achieve prompt resolution of the dystonicspasms.5,22 A benzodiazepine, i.e. continuous intravenousmidazolam is usually chosen because of its muscle relax-ant effect, rapid onset of action, and short half-life, andshould be titrated efficiently to control dystonic spasms(see Fig. 1). For refractory spasms, anaesthetic agents(propofol most often) followed by non-depolarizing mus-cle paralyzing agents (as depolarizing agents, e.g. sux-amethonium, are associated with rhabdomyolysis) andbarbiturates are then indicated.22

The duration of initial intubation and temporizing mea-sures utilized are determined by periodic evaluation of thepatient’s clinical response while specific antidystonia treat-ments are being concurrently considered. As ileus may be aserious complication of both status dystonicus and thepolypharmacy used in its management, it is essential tokeep the combination of drugs to a minimum, using a fewdrugs at optimal doses, often exceeding usual ranges buttitrated against oxygen saturations, heart rate, and bloodpressure. Also, it is essential to remember that facilitatingregular periods of sleep is a safe and secure mechanism ofmanaging status dystonicus that may need to be main-tained for several weeks or possibly months allowing timeto explore the underlying problems and management.Some degree of success may be claimed when the child’sheart rate dips slightly from baseline wakeful state duringtrue sleep; a feature not obtained if the child is dystonic.Intermittent reductions of the sedative and anaestheticagents administered should be attempted, as some patientsdevelop dependence on, or tolerance of sedative medica-tions. In others, the status dystonicus abates. Wheresuccess is achieved, initial attempts should be made tomaintain the beneficial agents by appropriate routes ofadministration (e.g. oral, nasogastric, or gastrostomy cloni-dine, midazolam, and/or specific antidystonia drugs).13

Dystonia-specific drugsAlthough clonidine and midazolam also have specificsometimes effective antidystonia properties, and may con-trol an episode of status dystonicus, other specific oralantidystonia agents are also recommended. The variety ofdrugs used is broad with success in approximately 10% ofcases only,5 but as they are non-invasive a trial of theseagents should be considered in the first instance and beforesurgery. In our practice, we consider these medicationsonce stabilization measures have been achieved andtemporizing treatments described have been initiated andthe response observed. The drugs reported to have most

success are often used in combination and include ananticholinergic (trihexyphenidyl), a dopamine blocker(haloperidol or pimozide), and a catecholamine depleter(tetrabenazine) (Fig. 1).5,6,13,14,16,22

Many other oral drugs have been tried. In Wilsondisease several patients with refractory status dystonicuswere treated with gabapentin and significantly improvedwhere other antidystonia drugs failed, so it should be usedin this condition, and considered in other aetiologies.21

Other benzodiazepines (clonazepam, flurazepam, diaze-pam) have been used with13 and without success.7,36 Trialsof oral baclofen,25 levodopa, or levodopa-carbidopa havealso been suggested, leading to improvement in a fewcases.6,7,37 Primary anticonvulsants including valproate,carbamazepine, primidone, phenytoin,38 and acetazola-mide6 have been used in various combinations, often withlimited benefit. Benztropine, biperidin, lithium, bromo-criptine,6,7 chlorpromazine, olanzapine,39 clozapine, and ri-spiridone7 have also been used with mostly limited success.Many of the drugs used to treat dystonia can have signifi-cant side effects and some such as pimozide (e.g. cardiacside effects) may exacerbate status dystonicus (see ‘Triggerfactors’).6,16,22 In such situations the drug should bediscontinued.

As the response overall to orally active antidystoniadrugs is reported to be poor, with significant risk topatients who develop dependence on sedative or anaes-thetic agents and remain in refractory status dystonicus,more invasive step-up surgical therapies including ITB,deep brain stimulation (DBS), or pallidotomy, need to beconsidered early, once acute or active systemic infectionshave been clearly excluded or treated.

Invasive therapiesIntrathecal baclofen. Intrathecal baclofen has been tried in asmall number (~10%) of patients with refractory statusdystonicus with various reports of benefit12–14,40,41 and fail-ure.5,6,22,36,38,39,42 Some of these failures have been theresult of complications36 or tolerance,38 which may poten-tially limit the use of ITB over long periods. ITB is notwithout other risks such as over-dosage, withdrawal syn-drome, and commonly catheter migration or breakage,although it is considered less invasive than brain surgery.Deep brain stimulation. Deep brain stimulation has beenan effective treatment for status dystonicus in the major-ity of treated patients (approximately 25).5,7–9,14,17,19,22,42–50

The globus pallidus interna (bilaterally) is the currentanatomical site of choice for this surgical procedure. Theeffects of DBS were obvious and occurred usually withindays or weeks; only occasionally did the effect take months.Although the evidence for DBS in status dystonicus isgenerated from case reports or series, DBS allowed manypatients to become weaned from sedative and anaestheticagents8 and in some improvement to baseline or beyondthe level of their pre-morbid states.49 Further plausibleevidence for DBS is suggested by device interruption(stimulation or battery), which provoked the appearance of


dystonic spasms, with resolution after switching stimulatorsback on or by device adjustments.9,42,45

Given the observed benefit of DBS, some authors feelthat a rapid and aggressive approach is justified to avoidthe longer-term complications of status dystonicus andserious morbidity or mortality.8 However, DBS is notwithout side effects. Operating on patients with statusdystonicus is particularly challenging because of a higherrate of hardware (15%) and other serious complications inalready compromised patients.9 Further challenges existwith urgent DBS surgery in children compared with adults,as a result of anatomical and developmental factors(although it has been used in a child as young as 5 yearswith status dystonicus).49 Where the globus pallidusinterna was not an option (because of damage), the subtha-lamic nucleus may be targeted, as recently seen in a4-year-old with severe methylmalonic acidaemia andrefractory dystonia.51 Thus, evaluation for DBS must beconsidered on an individual basis.Pallidotomy and thalamotomy. DBS has largely replaced pal-lidotomy, thalamotomy, and pallidothalamotomy for thetreatment of dystonia. These ‘lesional’ procedures havebeen used in approximately 10 cases of status dystonicuswith a variety of underlying dystonia disorders with vari-able outcomes. If DBS is not available, unilateral pallidoto-my could be considered.5–7,14,36,37,42,52

CONCLUSIONStatus dystonicus is a rare but life-threatening movementdisorder emergency usually occurring in the context of vari-ous established dystonia disorders. Management should betailored to individual patient characteristics and complica-tions.5,49 The use of dystonia severity action plans aids theearly recognition of worsening dystonia, and communica-tion between health professionals, and may potentially facil-

itate intervention. For established status dystonicus,sedation in a high dependency or intensive care unit is themost immediate and effective intervention while exploringthe specific or individual problems and management issues.The outcome of status dystonicus is variable and for themost part unpredictable. Mortality is reported at approxi-mately 10%, recently suggested to be more common inmales with a tonic phenotype and the heredodegenerativeand secondary dystonias in which relapses are also morecommon.5 Some patients experience progressively worsen-ing dystonia after status dystonicus, but this is not alwaysso. Thankfully the majority of surviving cases gain eitherpartial or complete recovery when compared with baselineneurological status and some improve beyond that.5 Furtherreports of the clinical nature and epidemiology of status dy-stonicus are essential for a better collective understandingof this poorly understood heterogeneous emergency.

ACKNOWLEDGEMENTS

We would like to thank the relevant authors for permission to

modify aspects of their material to produce Figure 1.

DISCLOSURES

Dr Jean-Pierre Lin (JPL) has received honoraria for educational

and consulting projects not related to this work from Medtronics

Ltd and grants from Action Medical Research and the Dystonia

Society UK. JPL is on the medical Advisory Boards of The Dysto-

nia Society UK and Dystonia Europe and Chairs the British Paedia-

tric Neurology Association Movement Disorders Special Interest

Group (BPNAMDSIG). Prof. Tim Lynch has received honoraria

from a number of companies not related to this work including

Biogen, Lundbeck, Novartis, Solvay and unrestricted grant spon-

sorship for research from Bayer-Schering, Merck Serono, for the

Dublin Neurological Institute from Elan and Sanofi-Aventis.

REFERENCES

1. Sanger TD, Chen D, Fehlings DL, et al. Definition and

classification of hyperkinetic movements in childhood.

Mov Disord 2010; 25: 1538–49.

2. Monbaliu E, Ortibus E, De Cat J, et al. The Dyskinesia

Impairment Scale: a new instrument to measure dystonia

and choreoathetosis in dyskinetic cerebral palsy. Dev

Med Child Neurol 2012; 54: 278–83.

3. Albanese A, Bhatia K, Bressman SB, et al. Phenomenol-

ogy and classification of dystonia: a consensus update.

Mov Disord 2013; 28: 863–73.

4. Roubertie A, Rivier F, Humbertclaude V, et al. The var-

ied etiologies of childhood-onset dystonia. Rev Neurol

2002; 158: 413–24. (In French).

5. Fasano A, Ricciardi L, Bentivoglio AR, et al. Status

dystonicus: predictors of outcome and progression pat-

terns of underlying disease. Mov Disord 2012; 27: 783–8.

6. Manji H, Howard RS, Miller DH, et al. Status dystonicus:

the syndrome and its management.Brain 1998;121: 243–52.

7. Teive HA, Munhoz RP, Souza MM, et al. Status Dystoni-

cus: study of five cases. Arq Neuropsiquiatr 2005; 63: 26–9.

8. Apetauerova D, Schirmer CM, Shils JL, Zani J, Arle JE.

Successful bilateral deep brain stimulation of the globus

pallidus internus for persistent status dystonicus and

generalized chorea. J Neurosurg 2010; 113: 634–8.

9. Walcott BP, Nahed BV, Kahle KT, Duhaime AC, Shar-

ma N, Eskandar EN. Deep brain stimulation for medi-

cally refractory life-threatening status dystonicus in

children. J Neurosurg Pediatr 2012; 9: 99–102.

10. Lumsden DE, Lundy C, Fairhurst C, Lin JP. Dystonia

Severity Action Plan: a simple grading system for medi-

cal severity of status dystonicus and life-threatening dys-

tonia. Dev Med Child Neurol 2013; 55: 671–2.

11. Burke RE, Fahn S, Marsden CD, Bressman SB, Mosko-

witz C, Friedman J. Validity and reliability of a rating

scale for the primary torsion dystonias. Neurology 1985;

35: 73–7.

12. Muirhead W, Jalloh I, Vloeberghs M. Status dystonicus

resembling the intrathecal baclofen withdrawal syn-

drome: a case report and review of the literature. J Med

Case Rep 2010; 4: 294.

13. Grosso S, Verrotti A, Messina M, Sacchini M, Balestri P.

Management of status dystonicus in children. Cases

report and review. Eur J Paediatr Neurol 2012; 16: 390–5.

14. Mariotti P, Fasano A, Contarino MF, et al. Management

of status dystonicus: our experience and review of the

literature. Mov Disord 2007; 22: 963–8.

15. Jamuar SS, Newton SA, Prabhu SP, et al. Rhabdomyol-

ysis, acute renal failure, and cardiac arrest secondary to

status dystonicus in a child with glutaric aciduria type I.

Mol Genet Metab 2012; 106: 488–90.

16. Marsden CD, Marion MH, Quinn N. The treatment of

severe dystonia in children and adults. J Neurol Neuro-

surg Psychiatry 1984; 47: 1166–73.

17. Guerrini R, Moro F, Kato M, et al. Expansion of the

first PolyA tract of ARX causes infantile spasms and sta-

tus dystonicus. Neurology 2007; 69: 427–33.

18. Mishra D, Singhal S, Juneja M. Status dystonicus a rare

complication of dystonia. Indian Pediatr 2010; 47: 883–5.

19. Kovacs N, Balas I, Janszky J, Simon M, Fekete S, Kom-

oly S. Status dystonicus in tardive dystonia successfully

Guideline 111

treated by bilateral deep brain stimulation. Clin Neurol

Neurosurg 2011; 113: 808–9.

20. Svetel M, Sternic N, Pejovic S, Kostic VS. Penicilla-

mine-induced lethal status dystonicus in a patient with

Wilson’s disease. Mov Disord 2001; 16: 568–9.

21. Paliwal VK, Gupta PK, Pradhan S. Gabapentin as a rescue

drug in D-penicillamine-induced status dystonicus in

patients withWilson disease.Neurol India 2010; 58: 761–3.

22. Nirenberg MJ, Ford B. Dystonic Storm. In: Frucht SJ,

editor. Movement Disorder Emergencies: Diagnosis and

Treatment (2nd edn). New York, NY: Springer, Human

Press, 2013: 125–35.

23. Jankovic J, Penn AS. Severe dystonia and myoglobinuria.

Neurology 1982; 32: 1195–7.

24. Watemberg N, Leshner RL, Armstrong BA, Lerman-

Sagie T. Acute pediatric rhabdomyolysis. J Child Neurol

2000; 15: 222–7.

25. Vaamonde J, Narbona J, Weiser R, Garcia MA, Brannan

T, Obeso JA. Dystonic storms: a practical management

problem. Clin Neuropharmacol 1994; 17: 344–7.

26. Rosenberg H, Davis M, James D, Pollock N, Stowell K.

Malignant hyperthermia. Orphanet J Rare Dis 2007; 2:

21.

27. Coffey RJ, Edgar TS, Francisco GE, et al. Abrupt with-

drawal from intrathecal baclofen: recognition and man-

agement of a potentially life-threatening syndrome. Arch

Phys Med Rehabil 2002; 83: 735–41.

28. Kipps CM, Fung VS, Grattan-Smith P, de Moore GM,

Morris JG. Movement disorder emergencies. Mov Disord

2005; 20: 322–34.

29. Munhoz RP, Moscovich M, Araujo PD, Teive HA.

Movement disorders emergencies: a review. Arq Neuro-

psiquiatr 2012; 70: 453–61.

30. Kirkham FJ, Haywood P, Kashyape P, et al. Movement

disorder emergencies in childhood. Eur J Paediatr Neurol

2011; 15: 390–404.

31. Blackman JA, Patrick PD, Buck ML, Rust RS Jr. Parox-

ysmal autonomic instability with dystonia after brain

injury. Arch Neurol 2004; 61: 321–8.

32. Wait SD, Ponce FA, Killory BD, Wallace D, Rekate HL.

Neuroleptic malignant syndrome from central nervous

system insult: 4 cases and a novel treatment strategy. Clin-

ical article. J Neurosurg Pediatr 2009; 4: 217–21.

33. Kurian MA, Li Y, Zhen J, et al. Clinical and molecular

characterisation of hereditary dopamine transporter defi-

ciency syndrome: an observational cohort and experi-

mental study. Lancet Neurol 2011; 10: 54–62.

34. Roubertie A, Mariani LL, Fernandez-Alvarez E, Doum-

mar D, Roze E. Treatment for dystonia in childhood.

Eur J Neurol 2012; 19: 1292–9.

35. Chatzizisis YS, Misirli G, Hatzitolios AI, Giannoglou

GD. The syndrome of rhabdomyolysis: complications

and treatment. Eur J Intern Med 2008; 19: 568–74.

36. Kyriagis M, Grattan-Smith P, Scheinberg A, Teo C, Nak-

aji N, Waugh M. Status dystonicus and Hallervorden-

Spatz disease: treatment with intrathecal baclofen and pal-

lidotomy. J Paediatr Child Health 2004; 40: 322–5.

37. Opal P, Tintner R, Jankovic J, et al. Intrafamilial pheno-

typic variability of the DYT1 dystonia: from asymptom-

atic TOR1A gene carrier status to dystonic storm. Mov

Disord 2002; 17: 339–45.

38. Dalvi A, Fahn S, Ford B. Intrathecal baclofen in the treat-

ment of dystonic storm.MovDisord 1998; 13: 611–2.

39. Nardocci N, Temudo T, Echenne B. Status dystonicus

in children. In: Fernandez-Alvarez E, editor. Paediatric

Movement Disorders. Progress in Understandings.

France: John Libbey Eurotext, 2005: 71–6.

40. Narayan RK, Loubser PG, Jankovic J, Donovan WH,

Bontke CF. Intrathecal baclofen for intractable axial dys-

tonia. Neurology 1991; 41: 1141–2.

41. Paret G, Tirosh R, Ben ZB, Vardi A, Brandt N, Barzilay

Z. Intrathecal baclofen for severe torsion dystonia in a

child. Acta Paediatr 1996; 85: 635–7.

42. Elkay M, Silver K, Penn RD, Dalvi A. Dystonic storm

due to Batten’s disease treated with pallidotomy and

deep brain stimulation. Mov Disord 2009; 24: 1048–53.

43. Coubes P, Echenne B, Roubertie A., et al. [Treatment

of early-onset generalized dystonia by chronic bilateral

stimulation of the internal globus pallidus. Apropos of a

case]. Neurochirurgie 1999; 45: 139–44.

44. Angelini L, Nardocci N, Estienne M, Conti C, Dones I,

Broggi G. Life-threatening dystonia-dyskinesias in a

child: successful treatment with bilateral pallidal stimula-

tion. Mov Disord 2000; 15: 1010–2.

45. Zorzi G, Marras C, Nardocci N, et al. Stimulation of

the globus pallidus internus for childhood-onset dysto-

nia. Mov Disord 2005; 20: 1194–200.

46. Jech R, Bares M, Urgosik D, et al. Deep brain stimula-

tion in acute management of status dystonicus. Mov Dis-

ord 2009; 24: 2291–2.

47. Martinez-Torres I, Limousin P, Tisch S, et al. Early

and marked benefit with GPi DBS for Lubag syndrome

presenting with rapidly progressive life-threatening dys-

tonia. Mov Disord 2009; 24: 1710–2.

48. Grandas F, Fernandez-Carballal C, Guzman-de-Villoria J,

Ampuero I.Treatmentof a dystonic stormwithpallidal stimula-

tion in a patient with PANK2 mutation. Mov Disord 2011; 26:

921–2.

49. Aydin S, Abuzayed B, Uysal S, et al. Pallidal deep brain

stimulation in a 5-year-old child with dystonic storm:

case report. Turk Neurosurg 2013; 23: 125–8.

50. Schumacher J, Wille C, Vesper J. Management of postop-

erative respiratory failure in a patient with acute diaphrag-

matic status dystonicus. Br J Anaesth 2012; 108: 329–30.

51. Chakraborti S, Hasegawa H, Lumsden DE, et al. Bilat-

eral subthalamic nucleus deep brain stimulation for

refractory total body dystonia secondary to metabolic

autopallidotomy in a 4-year-old boy with infantile meth-

ylmalonic acidemia. J Neurosurg Pediatr 2013; 12: 374–9.

52. Balas I, Kovacs N, Hollody K. Staged bilateral stereo-

tactic pallidothalamotomy for life-threatening dystonia

in a child with Hallervorden-Spatz disease. Mov Disord

2006; 21: 82–5.

53. Forsyth R, Newton R, editors. Oxford Specialist Hand-

books in Paediatrics. Paediatric Neurology. Status

Dystonicus. 2nd edn. Oxford, UK: Oxford University

Press, 2012. 474–9.


Date post:	13-Oct-2020
Category:	Documents
Upload:	others
View:	4 times
Download:	0 times

Expert to Expert: Paediatric Movement Disorders Pre-course ...dystonic or dyskinetic cerebral palsy,...

Documents