e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 2 0 ( 2 0 1 6 ) 1 0 0 e1 0 7

Official Journal of the European Paediatric Neurology Society

Original Article

Gabapentin can significantly improve dystonia

severity and quality of life in children

Natasha Yuan-Kim Liow a, Hortensia Gimeno a,b,

Daniel Edward Lumsden a, Jennifer Marianczak c, Margaret Kaminska a,
Stephen Tomlin c, Jean-Pierre Sao-Ming Lin a,*
a
Complex Motor Disorders Service, Children's Neurosciences Centre, Evelina London Children's Hospital, Guy's and
St Thomas' NHS Foundation Trust, London, UK
b
Department of Psychology, Institute of Psychiatry, Psychology and Neurology, King's College London, UK
c
Paediatric Pharmacy Evelina London Children's Hospital, Guy's and St Thomas NHS Foundation Trust, London, UK

article info abstract

Article history: Introduction: Gabapentin has been used in the management of neuropathic pain, epilepsy
Received 15 March 2015 and occasionally movement disorders.
Received in revised form Methods: A four-year retrospective, observational study analysed the use of gabapentin for
16 September 2015 severe dystonia in children at the Evelina London Children's Hospital. Motor severity was
Accepted 17 September 2015 classified according to the Gross Motor Function Classification System (GMFCS), Dystonia
Severity Assessment Plan (DSAP) and levels of impairment in activities of daily living were
Keywords: graded according to the WHO International Classification of Functioning, Disability and
Dystonia Health, Children & Youth version (ICF-CY) before and after gabapentin.
Gabapentin Results: The majority of the 69 children reported were level 5 GMFCS (non-ambulant). The
Cerebral palsy DSAP grade fell significantly from grade 3 before to grade 1 after gabapentin. Significant
NBIA improvements in median ICF-CY grades were seen following gabapentin in sleep quality,
WHO International Classification of sleep amount, mood & agreeableness, pain, general muscle tone, involuntary muscle
function contractions and seating tolerance (p < 0.01 in all areas). A significantly higher mean dose
Dystonia severity Assement Plan of 18.1 mg/kg/dose (SD: 13.3) for dystonia, compared to 7.61 mg/kg/dose (SD: 4.14) for pain
Children relief without dystonia (z ¼ 2.54, p ¼ 0.011) was noted.
Discussion & conclusion: Gabapentin may significantly ameliorate dystonia severity and
improve activities of daily living and quality of life in children with severe dystonia.
© 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights
reserved.

Abbreviations: GMFCS, Gross Motor Function Classification System; DSAP, Dystonia Severity Assessment Plan; ICF-CY, WHO Inter-
national Classification of Functioning; Disability and Health, Children & Youth; ELCH, Evelina London Children's Hospital; GABA,
gamma-aminobutyric acid; ADL, activities of daily living; DBS, deep brain stimulation; ITB, intrathecal baclofen.
* Corresponding author. Evelina London Children's Hospital, St Thomas's Hospital, Westminster Bridge Rd, London SE1 7EH, UK. Tel.: þ44
20 7188 7188; fax: þ44 20 7188 8533.
E-mail addresses: [email protected], [email protected] (J.-P.S.-M. Lin).
http://dx.doi.org/10.1016/j.ejpn.2015.09.007
1090-3798/© 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 2 0 ( 2 0 1 6 ) 1 0 0 e1 0 7 101

1. Dystonia What this paper adds

 Gabapentin can provide significant relief of childhood
Dystonia is a movement disorder characterised by involuntary
dystonia
muscle contractions that are sustained or rapidly fluctuating,
 Gabapentin relieves dystonia-related pain, poor sleep,
resulting in abnormal postures of limbs or the whole body
distress and lack of contentedness
with repetitive twisting movements1 affecting 33/100,000
 Gabapentin can improve activity and participation in
population2,3 and classified into ‘primary’ or ‘secondary’
children with severe dystonia not responding to con-
causes.4 Primary dystonias have only dystonic movements,
ventional management.
and neuroimaging is normal.3,4 Secondary dystonias are arise
from many causes, e.g. the ‘cerebral palsies’ following pre-
maturity, perinatal hypoxia, kernicterus and other vascular,
movement disorders.14 Gabapentin enacarbil, a gabapentin pre-
structural or neurometabolic injuries to the developing brain.5
cursor has some efficacy in restless leg syndrome (RLS),.15 Pre-
The natural history of dystonia varies according to cause.
gabalin, a recently developed derivative of gabapentin with a
Primary dystonias may plateau in severity.6 Dopa-responsive
similar profile16 was superior in doubleeblind trials to dopa-
dystonias can recover completely with levodopa treatment.7
mine agonists such as pramipexole in RLS and thought to act on
But for most children, dystonia exerts a significant, life-long
separate pathways from striatal dopaminergic neurones.17
reduction of activity and participation.8,9 A recent large, UK,
Use of gabapentin for familial paroxysmal dystonic chor-
supra-regional, demographic study of the management of
eoathetosis led to a reduction in dystonia symptoms and
hypertonus in children reported that less than 8% of all
reduced frequency of dystonic episodes which returned on the
referred dystonia cases improved: in fact dystonia severity in
sudden discontinuation of gabapentin as described previously.24
primary, secondary and heredodegenerative dystonias aeti-
The management of childhood dystonia is challenging,
ologies respectively worsened in 60.2% or remained at best
particularly status dystonicus or ‘brittle dystonia’.18 Anec-
static in 31.5%. giving a bleak prognosis for spontaneous
dotal evidence exists for gabapentin use in adult movement
improvement.9
disorders (RLS & Wilson's Disease) but use in childhood,
including severe dystonic cerebral palsy (CP) has not been
reported. This study aims to:
2. Current management
1. Evaluate the use of gabapentin in a cohort of children with
The management of dystonias, are summarised in Table 1,
dystonia at the Evelina London Children's Hospital (ELCH)
mostly failing to eliminate dystonia completely or efficacious
2. Explore the dosage range of gabapentin in childhood
only in certain subtypes or individuals.10 Adverse effects of
dystonia
anti-dystonic medication, particularly sedation, are dose-
3. Examine the use of gabapentin as mono or adjunctive
limiting in 2/3 of cases in our cohort9 (unpublished data).
therapy for childhood dystonia

2.1. Gabapentin

Gabapentin, used in partial seizures,11 is an analogue of

3. Methods
gamma-aminobutyric acid, but neither acts as a GABA agonist
A retrospective, observational cohort study was performed on
or antagonist. Mechanisms of action of gabapentin are largely
a series of children with dystonia attending ELCH.
unknown. Gabapentinoid drugs interact with alpha subunits
(a2d-1 and a2d-2) of voltage-gated calcium channels.12
Thrombospondin, an astrocyte-secreted protein, promotes 3.1. Participants
synaptogenesis in the central nervous system, acting on the
a2d-1 receptor. Gabapentin antagonizes thrombospondin Children treated with gabapentin from January 2009 to January
binding to a2d-1 receptors, thus inhibiting the synthesis of 2014 were identified from the ELCH pharmacy database and
glutaminergic excitatory synapses in vitro and in vivo.13 included in the analysis if they had a diagnosis of dystonia.
Gabapentin is used in neuropathic pain syndromes such as Motor severity was classified using the Gross Motor Function
post-herpetic and trigeminal neuralgia14 with limited use in Classification System (GMFCS)20 for locomotor ability as fol-
lows: Level I: athletic mobility to level V: non-ambulant.19
Children with gabapentin use without movement disorder
What is known about this subject were analysed as a pain-relief comparator group.
 Refractory dystonia in children is difficult to manage.
 Gabapentin antagonizes binding of thrombospondin to 3.2. Measures
voltage-gated calcium channel a2d-1 receptors and
inhibits synthesis of glutaminergic excitatory synap- The WHO International Classification of Functioning,
ses with compelling class one evidence of benefit in Disability and Health, Children & Youth version (ICF-CY) was
restless legs syndrome. used to grade function of activities of daily living (ADLs).19 The
 Little is known about gabapentin in dystonia. newly defined Dystonia Severity Assessment Plan (DSAP)
grading was also used (Table 2).21 This is a parent/carer/allied
102 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 2 0 ( 2 0 1 6 ) 1 0 0 e1 0 7

Table 2 e A table to demonstrate the 'Severity' grading

Useful in adult focal dystonia (e.g. blephrospasm and writer's cramp) but less effective in

Only for refractory dystonias. Highly invasive, small surgical risks, expensive to deliver
and monitor clinically. Risk of infection. Efficacy in secondary dystonias being explored
system for the newly defined DSAP dystonia

Ineffective in many cases, with some showing worsening hypotonia and respiratory
GI upset, dry mouth, hypotension, respiratory/cardiovascular depression, sedation,
management system.21 *DIC ¼ disseminated
Tachycardia, agitation, confusion, delusions, dizziness, drowsiness, constipation,
Table 1 e A table demonstrating some of the current management options available for dystonia, their mechanisms of action and their shortcomings.10,12,25,31e34

Increased jitter in other muscles, excessive paralysis, influenza-like symptoms,

intravascular coagulation.

Nausea/vomiting, taste disturbance, dry mouth, anorexia, arrhythmias, LIDs*

Ineffective in non-dopa-responsive dystonias. May exacerbate dystonia and
Dystonia severity assessment plan (DSAP)
Grade Description
Only effective in 50% of children/adolescents, <50% efficacy in adults.

1 The child sits comfortably and has regular

periods of uninterrupted sleep. Child stable on
medication.
Side-effects/shortcomings

2 The child is irritable and cannot settle. Dystonic

posturing interferes with sitting activities. The
Poorly tolerated in chorea or dystonic-choreoathetosis

child can only tolerate lying despite usual

baseline medication.
3 Not able to tolerate lying and/or unable to get to
sleep or sleep disturbed. No evidence of

children with more generalised dystonias

metabolic decompensation, CK < 1000 IU/L
4 Early multi-organ failure.
Clinically as above with:
urinary retention, blurred vision.

Pyrexia (in absence of infection),

Evidence of metabolic compromise (e.g.
elevated potassium, low calcium, evidence of
autonomic dysfunction

rising creatinine and/or urea)

drowsiness, confusion

Evidence of myoglobinuria. CK > 1000 IU/L

5 Immediately life-threatening:
hyperkinesias

As above with:
compromise

Full metabolic decompensation

Respiratory, cardiovascular, haematological
(e.g. DIC*) or renal compromise requiring organ
support.
Requires intensive care.
ion mediated release of Actyl Choline at motor nerve
Competitive inhibitor of Acetylcholine action (ACH)

Neuromuscular blockade via inhibition of calcium-

Direct antispasmodic effects on smooth muscle

health professional/medical and nursing management scale

Thought to modulate abnormal neuronal firing
GABA B agonist: acts to centrally relax skeletal

focussing directly on the ability of the child to sit comfortably;

Mechanism of action/rationale

Precursor to dopamine, acts on CNS as per

to lie comfortably and sleep at night.

3.3. Procedure
patterns in the basal ganglia

GMFCS20 and DSAP21 gradings were applied using children's

clinical records. The DSAP was assessed before and after the
endogenous dopamine

introduction of gabapentin. A level of ICF-CY impairment or

difficulty was assigned to a number of categories for each
child (Table 3). Scoring was based on the frequency, intru-
terminals

siveness or severity of the specific impairment or difficulty

muscle

reported in the clinical record. The baseline ICF-CY was taken

prior to initiation of gabapentin and the second after the
maximal optimal dose of gabapentin in mg/kg/dose three
times a day was reached.
Any ADL category discussed in more than 50% of the clin-
Anticholinergics (e.g. Trihexyphenidyl)

Antispasmodics (e.g. baclofen), oral or

*Levodopa-induced-dyskinesias.

ical records was included for analysis.

The DSAP was captured from clinical records at baseline
and after optimising gabapentin. Side-effects and reason (if
any) for discontinuing treatment were recorded.
Background concurrent management regimens were
Deep Brain Stimulation
Botulinum Toxin A/B

recorded e.g. deep brain stimulation (DBS) or intrathecal

baclofen infusion pump (ITB) implantation prior to starting
gabapentin or medication started concurrently or after start-
intrathecal
Treatment

ing gabapentin (see Supplementary Table 1).

Levodopa

Three groups were identified: Group1: ‘Surgical’ (receiving

DBS/ITB); Group 2: ‘started other medications’ and Group 3:
‘pure gabapentin’ alone group.
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walk. Dystonia aetiology included 25/69 cases of cerebral palsy

Table 3 e A table demonstrating the ICF-CY categories
(CP) and 44/69 with dystonia of varying aetiologies, including
assessed and graded for each dystonic patient before and
after. pantothenate kinase-associated neurodegeneration (PKAN),
(Supplementary Tables 2 and 3).
ICF-CY graded criteria Illustration of grade
D420 Transferring oneself 0 ¼ no impairment/difficulty
4.1. ICF-CY impairment grading for ADLs
D4153 Maintaining a sitting 1 ¼ mild impairment/difficulty
position (present<25% of the time, intensity
is tolerable, rare) The ICF-CY grades for commonly reported ADLs improved
B1340 Amount of sleep 2 ¼ moderate impairment/difficulty following gabapentin and are summarised in Table 4 and
(present <50% of the time, intensity Fig. 1. Specific improvements were seen in sitting, frequency
is interfering in day-to-day life, of involuntary muscle contractions, general muscle tone,
occasional) sleep amount, sleep quality, pain and mood levels (Wilcox-
B1342 Maintenance of sleep 3 ¼ severe impairment/difficulty
oneManneWhitney Tests: p < 0.01).
(present >50% of the time, intensity
partially disruptive, often)
B1261 Agreeableness 4 ¼ complete impairment/difficulty 4.2. Severity grading
(present >95% of the time, intensity
totally disruptive, constant) Following gabapentin, there was a significant decrease in the
B7356 Tone of all muscles 8 ¼ not specified (insufficient
severity of dystonia as described by DSAP criteria (z ¼ 5.607,
of the body information)
p < 0.01), the median DSAP dropping from 3 to 1 (Fig. 2).
B7650 Involuntary 9 ¼ not applicable
contractions of muscle
B2800 Generalised Pain 4.3. Dosage

Gabapentin doses for children with a movement disorder were

3.4. Data analysis higher than in children without a movement disorder (Man-
neWhitney U test: z ¼ 2.54, p ¼ 0.011) illustrated by the dose
Statistical analyses were performed using the Statistical Pack- frequency histograms in each group (Fig. 3). The mean dose used
age of Social Science (SPSS, version 21). Baseline and post- in children with a movement disorder was 18.1 mg/kg/dose
gabapentin ICF-CY categories were compared using Wilcox- three times a day (SD: 13.3), compared with 7.61 mg/kg/dose (SD:
oneManneWhitney test. The ManneWhitney U test was used 4.14) three times a day in children with pain or discomfort alone.
to analyse the differences in dose data between the groups with Gabapentin is licensed at a dose of 50 mg/kg/day for children
and without movement disorders. In both cases a p-value of aged 6e12 years and doses used in this cohort of children with
<0.05 was considered statistically significant. There are many dystonia fall largely within the terms of the current British Na-
ties in the ICF-CY categories due to its small range of values tional Formulary for Children 2014 recommendation of a
which could compromise the rank-based tests which assume maximum 70 mg/kg/day for children aged 2 years and upwards.
underlying continuous distributions, however the comparisons Six children with very varied aetiologies of dystonia
involving these tests are very significant so the loss of power received very high daily doses of gabapentin to achieve
due to violating the assumption of continuity is not an issue. symptom relief and the details are shown in Table 5, including
2 cases of PANK2-positive NBIA and 4 cases of cerebral palsy in
whom doses ranged from 132 to 214 mg/kg/day for excep-
4. Results tional pain, discomfort and break-through dystonia.
When children were subdivided into those who had
Of 82 patients (mean age 10.2 years, SD 4.37, min 1.4, max 18.6 received ‘DBS &/or ITB’ (n ¼ 30), ‘started new medications’
years) receiving gabapentin, 13/82 were on gabapentin for an (n ¼ 6) and ‘pure gabapentin’ (n ¼ 33) groups respectively, it
indication other than movement disorders and 69/82 for their was still possible to see the significant ameliorating effects of
movement disorder. GMFCS was recorded for 39/69 dystonic gabapentin in the ‘DBS &/or ITB’ and ‘pure’ groups respec-
children, and 33/39 classified as GMFCS level V, i.e. unable to tively across all domains except transfers which improved in

Table 4 e A table summarising the median ICF-CY grade before and after the use of gabapentin and a
WilcoxoneManneWhitney measure of the significance of change for all ICF-CY categories except transferring oneself. Each
function has a unique WHO reference number that allows research using this system to be found in the literature.
ICF Criteria Median Pre-gabapentin Median Post-gabapentin WilcoxoneManneWhitney test
D4153 Maintaining a sitting position 3 1 Y (Z ¼ 4.740, p < 0.01)
B7650 Involuntary contractions of muscle 4 2 Y (Z ¼ 5.165, p < 0.01)
B7356 Tone of all muscles of the body 4 2 Y (Z ¼ 5.110, p < 0.01)
B1340 Amount of sleep 3 1 Y (Z ¼ 5.573, p < 0.01)
B1342 Maintenance of sleep 3 1 Y (Z ¼ 5.437, p < 0.01)
B2800 Generalised pain 3 2 Y (Z ¼ 4.339, p < 0.01)
B1261 Agreeableness 2 1 Y (Z ¼ 4.774, p < 0.01)
D420 Transferring oneself 4 4 n/a
104 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 2 0 ( 2 0 1 6 ) 1 0 0 e1 0 7

Fig. 1 e Box and whisker plots summarising the change in WHO International Classification of Function (ICF-CY) grades for
key activities of daily living before and after the use of gabapentin in patients with dystonia. The beige boxplots denote ICF
grading of the impairment prior to gabapentin initiation and the red boxplots denote the grades following gabapentin use.
Circles represent outliers and are numbered by the case number in the dataset. There was a significant decrease
(WilcoxoneManneWhitney Test p < 0.01) in medians noted in all areas except for ease of ‘transferring oneself.’ (For
interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

the ‘DBS &/or ITB’ group after gabapentin only (Fig. 4. the first general description of a dosage schedule and efficacy
Supplementary Table 3). of gabapentin in childhood dystonia on a child's ability to
participate in ADLs and agrees with the sole previous case
report.23
5. Discussion The sedative effects of ‘conventional’ muscle relaxants
and general sedative medication give dystonic children a very
Although gabapentin can improve quality of life (QoL) mea- monotonous existence, either asleep with no symptoms or
sures in some cases of orthostatic tremor22 and RLS18 this is awake with terrible difficulties. In comparison, gabapentin
may provide relief from a variety of symptoms without unduly
compromising child alertness or ability to actively participate
in daily life with sparse levels of side-effects: no patients
discontinuing gabapentin for reported adverse effects.
By using the ICF framework, we monitored a range of
every-day activities that were important to the lives of these
children and carers, unlike the many interventional studies
for dystonia in childhood that failed to measure what matters
most.35 Gabapentin may help reduce the frequency of cases of
childhood dystonia presenting as movement disorder
emergencies.36

5.1. Paediatric dose of gabapentin

Our findings in childhood dystonia raise intriguing questions

about the exact mechanism of action of gabapentinoid
drugs.17
Despite only limited reports of gabapentin use in children,
and even fewer describing a therapeutic range, we found
Fig. 2 e A box and whisker plot demonstrates the significant differences in the gabapentin dose required to
significant decrease in severity according to the DSAP alleviate dystonic motor symptoms and pain alone, suggest-
criteria following the introduction of gabapentin (Wilcoxon ing different mechanisms of gabapentin action in anti-
ManneWhitney: z ¼ ¡5.607, p < 0.01). dystonia and analgesic roles respectively.
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Fig. 3 e A frequency histogram to show the distribution of doses (mg/kg/day) used for both movement disorders and for
other indications. The mean dose used in patients with a movement disorder was 18.1 mg/kg/dose (SD: 13.3), compared
with 7.61 mg/kg/dose (SD: 4.14) in patients without a movement disorder (ManneWhitney U Test: z ¼ ¡2.54, p ¼ 0.011).

5.2. Limitations

Six cases had other drugs added; 21/69 had pre-existing DBS
alone, 2/69 had DBS after ITB and 7/69 had ITB alone. However
a gabapentin benefit was seen in 33/69 ‘pure’ cases not
receiving neurosurgery or new medication.
Invasive procedures such as DBS and ITB produce excellent
symptom relief.26e30 Gabapentin was started some time after
the original operation and any improvement in ICF grades
were on top of any baseline improvement derived from the
original surgical intervention. Children with implanted DBS
and ITB systems needed additional support with gabapentin
for pre-existing deformities e.g. discomfort from scoliosis and
hip subluxation/dislocation; short hamstring muscles
restricting hip flexion and reducing sitting tolerance. Most

Table 5 e Cases receiving greater than 70 mg/kg/day of

gabapentin. Doses ranged from 132 to 214 mg/kg/day for
exceptional pain, discomfort and break-through
dystonia. These doses were well tolerated.
Diagnosis Dose (mg/kg/day)
PKAN: PANK2-positive NBIA 132.4
Fig. 4 e A flowchart to demonstrate the breakdown of the
PKAN: PANK 2-positive NBIA 144.0
Cerebral palsy secondary to G6PD 133.3 intervention profile of the patients and the significance of
deficiency and the change in ICF-CY grades before and after the use of
hyperbilirubinaemia gabapentin. Key: ST ¼ seating tolerance, IM ¼ involuntary
Cerebral palsy 214.3 muscle contractions, GM ¼ general muscle tone,
Cerebral palsy 108.3 SA ¼ sleep amount, SQ ¼ sleep quality, GP ¼ generalised
Cerebral palsy 150
pain, MA ¼ mood/agreeableness, T ¼ transferring.
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drugs started over the same time such as antibiotics and iron
supplements were unrelated to movement disorder. Potential conflicts of interest
Only the most common ICF categories were analysed and
missing data was dealt with via pairwise deletion. Prospective Daniel Edward Lumsden, Hortensia Gimeno, Margaret
parent-carer recording of DSAP and ICF-CY criteria at initial Kaminska and Jean-Pierre Sao Ming Lin have received unre-
contact would more accurately measure the changing impact stricted educational support from Medtronic Ltd.
of dystonia on the lives of children and their families after Jean-Pierre Sao-Ming Lin has acted as a consultant for
intervention. Medtronic Ltd.
Stephen Tomlin, Jennifer Marianczak: None.

6. Conclusion
Financial disclosure
Gabapentin in childhood dystonia improves participation in
The authors have no financial relationships relevant to this
ADLs including improved sleep, mood, pain, relief of dystonic
article to disclose.
spasms according to WHO ICF-CY and DSAP grades. Higher,
but safe gabapentin doses are required for dystonia compared
to pain alone.

Acknowledgements

Author contributions We would like to thank the children, careers and referring
physicians.
Natasha Yuan Kim Liow contributed to the design, collected
the data, designed and performed the statistical analyses,
wrote the first draft and reviewed the manuscript. Appendix A. Supplementary data
Hortensia Gimeno contributed to the design, suggested the
use of ICF-CY categories, reviewed and edited the manuscript. Supplementary data related to this article can be found at
Daniel Edward Lumsden helped with the literature http://dx.doi.org/10.1016/j.ejpn.2015.09.007.
research strategy, reviewed and edited the manuscript.
Jennifer Marianczak identified the cases using gabapentin
within ELCH, reviewed and edited the manuscript.
references
Margaret Kaminska managed the children, reviewed and
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Stephen Tomlin oversaw the use of gabapentin within
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