Received: 16 January 2023 Revised: 24 May 2023
DOI: 10.1002/jimd.12638
REVIEW
Deep brain stimulation and intrathecal/intraventricular
baclofen for glutaric aciduria type 1: A scoping review,
individual patient data analysis, and clinical trials review
Nathan A. Shlobin 1
Chima O. Oluigbo 2
1
Department of Neurological Surgery,
Northwestern University Feinberg School
of Medicine, Chicago, Illinois, USA
2
Deparment of Neurosurgery, Children's
National Hospital, Washington, DC, USA
Correspondence
Nathan A. Shlobin, Department of
Neurological Surgery, Northwestern
University Feinberg School of Medicine,
Chicago, IL 60611, USA.
Email: nathan.shlobin@northwestern.edu
Chima O. Oluigbo, Division of
Neurosurgery, Children's National
Hospital, Washington, DC 20010, USA.
Email: coluigbo@childrensnational.org
J Inherit Metab Dis. 2023;46:543–553.
Accepted: 25 May 2023
| Katherine Hofmann 2 | Robert F. Keating 2 |
Abstract
Glutaric aciduria type 1 (GA1) is an autosomal recessive disease frequently
leading to dystonia. Deep brain stimulation (DBS), intrathecal baclofen (ITB),
and intraventricular baclofen (IVB) are the current interventional treatment
options for refractory dystonia. We performed a scoping review, individual
patient data (IPD) analysis, and clinical trials review to summarize the existing
literature on these interventions in this population, characterize outcomes,
and suggest directions for future investigation. PubMed, Embase, and Scopus
were searched following PRISMA guidelines. IPD were extracted from studies
providing IPD for GA1 patients. ClinicalTrials.gov was reviewed. Of 139 arti-
cles, 7 studies with 10 patients were included. In study-level data, 2/4 (50.0%)
DBS studies found no improvement in dystonia and 3/3 (100%) on baclofen
found decreased dystonia and enteral medication regimen. In the IPD analy-
sis, four studies with 5 patients (2 IVB, 2 DBS, 1 ITB) were included. The
average percent reduction in dystonia was 29.9% ± 32.5% (median:18%,
IQR:18%–29.2%). Function improved in 4 (80.0%) patients. All patients with
reported changes in enteral dystonia-related medication regimen (3/3, 100%)
reported reduction in medication usage. No patients (0%) had perioperative
complications. Mean follow-up length was 14.8 ± 12.2 months. No interven-
tional clinical trials were found. ITB, IVB, and DBS represent present neuro-
modulatory approaches for the treatment of GA1. ITB and IVB reduce
dystonia, while DBS has a heterogeneous effect. ITB and IVB improved
function and reduced enteral medication regimens. These findings must be
viewed with caution considering limited data and a serious risk of bias.
Further large-scale studies are necessary to determine indications for ITB,
IVB, and DBS and elucidate treatment algorithms.
KEYWORDS
epilepsy, glutaric acidemia, glutaryl-CoA dehydrogenase deficiency, neuromodulation,
neurostimulation
wileyonlinelibrary.com/journal/jimd © 2023 SSIEM. 543
544
1 | INTRODUCTION
Glutaric aciduria type 1 (GA1), also known as glutaric
acidemia type 1, is an autosomal recessive disease with a
prevalence of 1 in 100 000 newborns that results from an
inherited deficiency of the mitochondrial enzyme glutaryl-
CoA dehydrogenase gene (GCDH)1,2 The GCDH gene is
located on chromosome 19p13.13 and encodes a flavin
adenine dinucleotide dinucleotide-dependent mito-
chondrial matrix protein implicated in degradation of
L-lysine, L-hydroxylysine, and L-tryptophan.3–5 More
than 200 disease-causing mutations in GCDH are
known, and over 500 patients have been reported
globally since the first characterization of this condi-
tion in 1975.6–8
Around 90% of untreated patients develop neuro-
logical disease between the age of 3–36 months after
an encephalopathic crisis that is characterized by acute
striatal injury and a subsequent complex movement
disorder, termed acute-onset GA1.1,9,10 Dystonia,
usually concomitant with axial hypotonia, is common
and often transitions to fixed dystonia with akinetic-
rigid parkinsonism with age.11–14 Severe movement
disorder may progress to status dystonicus and often
portends a short life expectancy.10,15,16 Additionally,
10%–20% of patients develop neurologic disease without
a noted encephalopathic crisis, termed insidious-onset
GA1.9,17–19 Insidious-onset GA1 is characterized by
dorsolateral putaminal lesions with less severe dystonia
and an asymptomatic latency phase during which lesions
are present on magnetic resonance (MRI) lesions. 20
General management consists of a low lysine diet,
carnitine supplementation, and intensified emergency
treatment during catabolic episodes and has improved
neurologic outcomes.3
Treatment of dystonia is unstandardized and
varied.3 Various oral medication options exist and are
summarized by the current guideline.3 Pallidotomy has
also been utilized for refractory dystonia, with overall
poor outcomes and no long-term data.21–23 Additional
treatment options for refractory dystonia include deep
brain stimulation (DBS), intrathecal baclofen (ITB),
and intraventricular baclofen (IVB). However, no study
has synthesized the outcomes of these interventions in
this challenging patient population. We performed a
scoping, individual patient data (IPD) analysis (IPDA),
and clinical trials review to: (1) summarize the existing
literature on these interventions in this population,
(2) characterize outcomes, and (3) suggest directions
for future investigation. This study may inform the
treatment of patients with GA1 who have refractory
dystonia.
SHLOBIN ET AL.
TABLE 1 Search terms.
Database Search terms
PubMed (“deep brain stimulation”[MeSH] OR
“baclofen”[MeSH] OR “deep brain
stimulat*”[tiab] OR “dbs“[tiab] OR
“baclofen*”[tiab] OR “intrathecal
baclofen*”[tiab] OR “intraventricular
baclofen*”[tiab] OR “ITB”[tiab] OR
“IVB”[tiab] OR “neuromodulat*”[tiab])
AND
(“glutaric acidemia I”[MeSH] OR “glutaryl-CoA
dehydrogenase”[MeSH] OR “glutaric
acidemi*”[tiab] OR “glutaric aciduri*”[tiab]
OR “Glutaryl-CoA dehydrogenase
deficien*”[tiab] OR “Glutaryl CoA
dehydrogenase deficien*”[tiab])
Embase (‘deep brain stimulat*’ OR ‘dbs’ OR ‘baclofen*’
OR ‘intrathecal baclofen*’ OR
‘intraventricular baclofen*’ OR ‘ITB’ OR
‘IVB’ OR ‘neuromodulat*’):ti,ab,kw
AND
(‘glutaric acidemi*’ OR ‘glutaric aciduri*’ OR
‘Glutaryl-CoA dehydrogenase deficien*’ OR
‘Glutaryl CoA dehydrogenase deficien*’):
ti,ab,kw
Scopus TITLE-ABS-KEY(
(“deep brain stimulat*” OR “dbs“ OR
“baclofen*” OR “intrathecal baclofen*” OR
“intraventricular baclofen*” OR “ITB” OR
“IVB” OR “neuromodulat*”)
AND
(“glutaric acidemi*" OR “glutaric aciduri*” OR
“Glutaryl-CoA dehydrogenase deficien*” OR
“Glutaryl CoA dehydrogenase deficien*”)
)
2 | MATERIALS AND METHODS
2.1 | Design and search
This study was performed per the Preferred Reporting
Items for Systematic Reviews and Meta-Analyses
(PRISMA) scoping review extension (PRISMA-ScR).24
Scoping reviews are performed to characterize the scope
of nature and extent of research activity, summarize and
disseminate research findings, and identify research gaps
in the literature.25,26 We conducted a scoping review
rather than a systematic review due to the potential for
limited data in the literature,25,26 as is common with
many orphan diseases. In November 2022, we searched
PubMed MEDLINE (National Library of Medicine),
Embase (Elsevier), and Scopus (Elsevier with search
terms related to “deep brain stimulation,” “baclofen,”
SHLOBIN ET AL. 545

and “glutaric aciduria.” Full search terms are viewed

in Table 1. Additional results were identified via hand-
searching the reference lists of retrieved articles and
other background articles. No restrictions on date, article
type, or language were applied. No protocol was prepared
or registered.

2.2 | Screening

After searches were performed, results were combined

in an Endnote X9 (Clarivate Analytics, London,
United Kingdom) project. The automated deduplica-
tion feature was used to remove duplicates. Two
reviewers (Nathan A. Shlobin, Katherine Hofmann)
independently screened articles for relevance via title
and abstract. These same reviewers screened articles
progressing to the next stage by full text based on pre-
specified inclusion and exclusion criteria. At both
stages, disagreements were resolved by discussion and
consensus between the two reviewers. Inclusion
criteria were designed using a modified population,
intervention, comparator, outcome (PICO) framework, FIGURE 1 PRISMA flowchart.
with no comparator term. Inclusion criteria were peer-
reviewed full-text articles, providing primary data,
written in English, population of people with GA1, For the IPDA, IPD were collected from all studies
intervention of DBS or intrathecal or intraventricular providing demographic, clinical, and outcome data
baclofen, and providing outcomes on safety and effi- including length of follow-up for people with GA1 who
cacy. Studies that provided data on other patients in underwent DBS or intrathecal or intraventricular
addition to GA1 patients were included provided these baclofen therapy. Demographic data included age at
studies met inclusion criteria. Exclusion criteria were surgery and sex. Clinical data were the intervention
nonhuman studies, conference abstracts, commentar- and target. Outcome data were baseline and follow-up
ies/letters to the editor, reviews, meta-analyses, and dystonia as measured by the Barry-Albright Dystonia
not meeting the modified PICO framework. Scale (BADS)29 and percent reduction in dystonia,
function, enteral medication regimen, complications,
and length of follow-up. Data from the IPDA were
2.3 | Data extraction and analysis synthesized quantitatively.

All data were stored in Excel 2010 (Microsoft Inc.). Quan-

titative analyses were conducted in Prism 8 (GraphPad
Software).
Data regarding demographics, treatments, and out-
comes were extracted from the included studies. For the
scoping review portion, these data were synthesized
quantitatively given the anticipated low sample sizes
and limited number of studies. The Grading of Recom-
mendations Assessment, Development, and Evaluation
(GRADE) framework was used to determine the quality of
included studies.27 The Risk of Bias of Non-randomized
Studies—of Interventions (ROBINS-I) tool was used to
determine the risk of bias.28 The risk of bias for this study
overall was determined by considering the risk of bias of
all included studies in aggregate.
2.4 | Clinical trials review
The ClinicalTrials.gov (clinicaltrials.gov) research
database registers over 433 000 studies in over
200 nations. This database was searched in November
2022 to locate existing clinical trials on GA1. When
keywords are input, the database automatically adds
similar keywords. In this study, “glutaric aciduria I”
and “glutaric acidemia I" were utilized, with mapped
terms of “glutaric acidemia,” “GA1,” “acidemia,” and
“glutaric.” Inclusion criteria were: (1) any stage,
(2) interventional trials, and (3) focusing on outcomes
of treatment for GA1. Trials that mentioned GA1 as a
keyword without further description were excluded.
546 SHLOBIN ET AL.

Publications presenting the results of trials were iden-
tified via three steps: (1) browsing the study page on
ClinicalTrials.gov for linked publications, (2) inputting
the ClinicalTrials.gov Identifier into Google Scholar
and PubMed, and (3) inputting the lead investigator's
name into Google Scholar and PubMed. Published pro-
tocols were excluded.
3 | R E SUL T S
3.1 | Included studies
Of 139 resultant articles retrieved via database and hand
searches, a total of seven studies were included in the
scoping review (Figure 1).30–36 These studies included a
total of 10 GA1 patients, of which 5 were treated with
DBS,30,33,35,36 3 with intrathecal baclofen,31,34 and 2 with
intraventricular baclofen.32 Five (71.4%) of studies were
case series, and 2 (28.6%) were case reports. The earliest
study was published in 2010, and the most recent was
published in 2022. All studies had quality ratings of very
low or low. The risk of bias of all studies was serious to
critical, rendering the risk of bias for this study critical
overall. Table 2 presents all included studies.
3.2 | Study-level data
Two (50.0%) of the four DBS studies found no improve-
ment in dystonia,35,36 while two (50.0%) found reduced
dystonia, one of which also found improved function.30,33
All three on ITB/IVB found reduced dystonia and
decreased enteral medication regimen.31,32,34 The enteral
medication regimen varied by patient but included anti-
spasmodics, sedatives, analgesics, and anxiolytics. A
study on ITB noted that patients experience a honey-
moon period, during which dystonia symptoms decrease,
but the symptoms increase following this honeymoon
period.34
3.3 | Individual patient data
Four studies with five patients were included in the
IPDA.30–32,35 The average age at DBS, ITB, or IVB was
16.3 ± 4.7 years old. Three (60.0%) were male. Two
(40.0%) patients had IVB and 1 (20.0%) had ITB. The
other two patients (40.0%) underwent DBS, one of which
underwent right globus pallidus internus (GPi) DBS and
the other of which underwent bilateral GPi DBS. Four
(80.0%) patients had reductions in dystonia, while the

TABLE 2 Included studies.

Number of
glutaric aciduria
patients managed
with
Paper Study design Quality grade Risk of bias neuromodulation Treatment Key findings
30
Air et al. Case series Low Serious 1 DBS Reduced dystonia and
improved
functionality in left
arm
Frenkel et al.31 Case report Very low Critical 1 Intrathecal baclofen Reduced hypertonia and
enteral medication
regimen
Ghatan et al.32 Case report Very low Critical 2 Intraventricular Reduced dystonia and
baclofen enteral medication
regimen
Lipsman et al.33 Case series Low Serious 1 DBS Reduced dystonia
34
Puertas et al. Case series Low Serious 2 Intrathecal baclofen Reduced dystonia for a
honeymoon period
and reduced enteral
medication regimen
Tsering et al.35 Case series Low Serious 1 DBS No relief in dystonia
36
Tustin et al. Case series Low Serious 2 DBS No improvement in
gross motor function
or dystonia severity

Abbreviation: DBS, deep brain stimulation.

 SHLOBIN ET AL.

TABLE 3 Individual patient data.

Enteral
dystonia-
Baseline Follow-up related Length of
Age at Change in dystonia dystonia % Reduction medication follow-up
Paper surgery Sex Intervention Target dystonia (BADS) (BADS) in dystonia Functionality regimen Complications (months) Other
30
Air et al. 16.8 M DBS Right GPi Improved 28 23 18 Improved NA None 3 Subsequent left
DBS placement
(after these
outcomes were
tabulated)
Frenkel 15 F Baclofen Intrathecal Improved 12 9 25 Improved Reduced None 24 Last BADS
et al.31 measurement at
3 months
Ghatan 10 F Baclofen Intraventricular Improved 30.7 4.5 85 Improved Reduced None 30 Dystonic storms
et al.32 stopped No
more chronic
pain, insomnia,
emotional
distress, or
autonomic
dysfunction
Reduced
medications for
pain, anxiety,
depression
23 M Baclofen Intraventricular Improved 29.7 24.3 18 Improved Reduced None 14 Pain relief Died at
18 months due
to chronic
pulmonary
disease
Tsering 16.6 M DBS Bilateral GPi No change 21 21 0 No change NA None 2.9 NA
et al.35

Abbreviations: BADS, Barry-Albright Dystonia Scale; DBS, deep brain stimulation; F, female; M, male; NA, not applicable.
547
548 SHLOBIN ET AL.

TABLE 4 Individual patient data

Outcome All (n = 5) DBS (n = 2) IVB (n = 2) ITB (n = 1)
outcomes.
Dystonia
Improved 4 (80.0%) 1 (50.0%) 2 (100%) 1 (100%)
No change 1 (20.0%) 1 (50.0%) 0 (0%) 0 (0%)
Decreased 0 (0%) 0 (0%) 0 (0%) 0 (0%)
Not specified NA 0 (0%) 0 (0%) 0 (0%)
Enteral medication regimen
Improved 3 (60.0%) 0 (0%) 2 (100%) 1 (100%)
No change 0 (0%) 0 (0%) 0 (0%) 0 (0%)
Decreased 0 (0%) 0 (0%) 0 (0%) 0 (0%)
Not specified 2 (40.0%) 2 (100%) 0 (0%) 0 (0%)
Function
Improved 4 (80.0%) 1 (50.0%) 2 (100%) 1 (100%)
No change 1 (20.0%) 1 (50.0%) 0 (0%) 0 (0%)
Decreased 0 (0%) 0 (0%) 0 (0%) 0 (0%)
Not specified NA 0 (0%) 0 (0%) 0 (0%)

other (20.0%) had no change. Measured via the BADS,
average baseline dystonia was 24.3 ± 7.8 (median: 28, first
quartile: 21, third quartile: 29.7), and average follow-up
dystonia was 16.4 ± 9.0 (median: 21, first quartile: 9, third
quartile: 21). The average percent reduction in dystonia
was 29.9% ± 32.5% (median: 18%, first quartile: 18%, third
quartile: 29.2%). Function improved in 4 (80.0%) patients
and was unchanged in the remaining (20.0%) patient.
The three patients with reported changes in enteral
dystonia-related medication regimen all (100%) reported
reduced regimens. One patient with IVB had a cessation of
dystonic storms, chronic pain, insomnia, emotional distress,
and autonomic dysfunction along with reduction in medi-
cations used for pain, anxiety, and depression.32 The other
IVB patient had pain relief but died at 18 months due to
chronic pulmonary disease.32 None (0%) of the patients had
reported perioperative complications. The patient who had
right GPi DBS placement underwent subsequent left GPi
DBS placement following tabulation of outcomes.30 The
mean follow-up length was 14.8 ± 12.2 months (median:
14 months, first quartile: 3 months, third quartile:
24 months). Table 3 presents IPD. Table 4 presents
outcomes in general and by treatment type.
injury from hyperammonemia. Neither study focused on
treatment of GA1.
4 | DISCUSSION
We present a scoping review and IPDA of outcomes of
DBS, ITB, and IVF for GA1 along with a clinical trial
review. Although these neuromodulatory approaches have
been utilized for refractory dystonia, including in GA1,3
their outcomes have not been synthesized. We emphasize
three primary findings: these approaches (1) improve dys-
tonia and function, (2) reduce enteral dystonia-related
medication regimens, and (3) have a low complication
rate. However, it is important to contextualize these find-
ings within significant limitations, namely the low number
of patients in existing studies, absence of clinical trials,
and low quality and serious risk of bias inherent in exist-
ing studies. However, to the best of our knowledge, this
study is the first scoping review and IPDA of outcomes of
DBS, ITB, and IVB for GA1 and first clinical trial review
for GA1. This study may inform the treatment of GA1
patients with refractory dystonia while further data are
collected in larger cohorts within this patient population.

3.4 | Clinical trials review

A total of 2 trials were retrieved (NCT03163121,
NCT04602325), of which 0 were included in view of the fact
that they did not focus on treatment of dystonia in GA1.
The former focused on malaria rather than GA1, while the
latter focused on identifying systemic biomarkers of brain
4.1 | Diagnosis and medical treatment
of GA1
The diagnostic process of GA1 is heterogeneous based on
timing of presentation, clinical features, and available
laboratory studies. However, recent guidelines indicate
SHLOBIN ET AL.
that GA1 should be tested for as part of newborn screen-
ing and confirmed with quantitative analysis of GA and
3-hydroxyglutaric acid in the urine and blood followed by
molecular genetic analysis of the GCDH gene or GCDH
enzyme analysis in leukocytes or fibroblasts.3 Brain
MRIs generally demonstrate widening of the sylvian
fissure and mesencephalic cistern with expansion of the
cerebrospinal fluid spaces anterior to the temporal lobes,
often with abnormalities of the basal ganglia and white
matter.37 Recently, individuals with GA1 have been strat-
ified into high and low excretors somewhat arbitrarily
based on residual GCDH activity measured via urinary
glutaric acid (GA) excretion.3,38 In general, low excretors
have a residual GCDH activity of 3%–30%, and high
excretors have a residual activity of 0–2%.18,39,40 Cognitive
morbidity is high in individuals with a biochemical high
excretor phenotype.41,42
Early diagnosis is essential for favorable outcomes in
GA1.43 Newborn screening programs for GA1 have
improved the neurological outcome of individuals with
the disease by allowing for earlier intervention to limit
the progression of the complex neurological disorder.16,44
Diet is a cornerstone of treatment, involving low lysine
diet and carnitine supplementation, as is emergency
treatment during crises.3 However, dystonia may occur in
cases of insufficient dietary treatment or non-adherence
to emergency treatment.41,42 Medical treatment of dysto-
nia is highly variable, including oral baclofen, zolpidem,
or zopiclone, anticholinergics, botulinum toxin, or gaba-
pentin.3 Benzodiazepines show positive effects in over
90% of individuals.3 Diazepam and clonazepam are most
commonly used and generally combined with baclofen.3
4.2 | Neurosurgery for GA1
Given the efficacy of for certain forms of dystonia,45 bilat-
eral pallidotomy has been utilized for refractory dystonia
in GA1. Two case reports demonstrated that bilateral palli-
dotomy improved dystonia.22,23 A cohort study including a
case of a child with GA1 managed with pallidotomy deter-
mined that the patient had only marginal improvement,
namely in axial dystonia and relief of arching posture.21
This study concluded that primary dystonia responds bet-
ter than secondary dystonia to pallidal procedures.21 How-
ever, long-term outcomes of pallidotomy in GA1 patients
are unknown.3 DBS, ITB, and IVB have emerged as alter-
native treatment options. Our study indicates that, based
on limited data, ITB and IVB reduce dystonia, while DBS
has a more heterogeneous effect.30–32,34–36 ITB and IVB
represent a promising opportunity for treating secondary
dystonia.31 Therapeutic doses delivered intrathecally and
intraventricularly are lower than doses delivered enterally,
549
potentially decreasing dose-dependent side effects and the
risk of tolerance.31,32,46 Our study echoed this finding, as
all three patients with ITB and IVB in the IPDA experi-
enced reductions in enteral medication regimens. Ghatan
et al. selected IVB rather than ITB for dystonia in GA1
patients due to equivalent safety profiles and the presumed
supraspinal mechanism of the anti-dystonic effects of bac-
lofen.31,32 However, Stadler et al. found that ITB is bene-
ficial in a GA1 patient with dystonia and concomitant
spasticity.31 A limited reduction in dystonia with DBS is
consistent with an earlier meta-analysis of pediatric dys-
tonia that demonstrated that individuals with GA1
responded most poorly to DBS of all subpopulations.47
However, an older cohort study determined that children
with GA1 had the capacity to respond to DBS.48 Lastly, no
complications occurred in the patients included in the
IPDA. The complication rate for DBS, ITB, and IVB is
consistently low.49–53 However, some studies indicate that
IVB may have a lower complication rate than ITB.51,52
Nonetheless, the most effective recommendation is to pre-
vent secondary dystonia by following current guideline
recommendations for GA1.3
4.3 | Implications for clinical decision-
making and patient education
Making treatment recommendations with limited evi-
dence and educating patients within these constraints
represent perpetual challenges for functional neurosur-
geons and movement disorder neurologists who treat rare
diseases, such as refractory dystonia secondary to GA1.
Investigators have proposed an ethical framework for the
implantation of neuromodulatory devices based on
important ethical principles.54 The first step is determin-
ing the optimal treatment for the individual patient by
identifying all treatment options, listing risks and benefits
of all treatment options, and ranking treatment options by
comparing risks and benefits.54 In the case of GA1 patients
with refractory dystonia, this is challenging given limited
data on ITB, IVB, and DBS for these patients. The neuro-
surgeon should combine the best available data with their
clinical judgment, in the setting of a multidisciplinary
team including the movement disorder neurologist, phys-
iatrist and physical and occupational therapists, to deter-
mine which treatment has the greatest likelihood of
efficacy with the lowest risk in the individual patient.54–56
Importantly, the neurosurgeon and this multidisciplinary
team must seek to understand the values and beliefs of
patients and caregivers, as treatment decisions must be
based on patient and caregiver preferences. The second
step is incorporating socioeconomic considerations in opti-
mal treatment for the individual patient, when necessary,
550
and prioritizing patients to receive neuromodulatory
devices based on utility and resource allocation consider-
ations, when applicable.54 ITB, IVB, and DBS will likely
place further financial burden on GA1 patients and their
caregivers and the healthcare system. The financial impli-
cations impacts the access to these treatments. Studies
have documented disparities in access to neurosurgical
treatments in other patient populations.57,58
Extrapolating existing cost-effectiveness studies
focused on these treatment modalities may be required,
as cost-effectiveness analyses specific to GA1 are lack-
ing. Newborn screening for GA1 is cost-effective.59 In
general, DBS for dystonia may be cost-effective, while
ITB is considered cost-effective.60,61 No data exist on
the cost-effectiveness of IVB. The third step focuses on
decision maintenance over time, including review of
the decision-making process, correction of gaps in
understanding or misconceptions, and longitudinal
information provision.54 Neurosurgeons must commu-
nicate with other members of the treatment team to
evaluate treatment success and modify treatment plans.
They must also communicate with patients and care-
givers to promote understanding, empowerment, and
satisfaction. Neurosurgeons should use patient and care-
giver health literacy as a foundation for their discussions,
provide clear communication, and utilize multimodal
educational interventions.54–56,62–64
4.4 | Limitations and future directions
This study has limitations. This study was at serious risk
of bias given most studies were uncontrolled case
reports or case series. This composition of study designs
may also introduce variability given different patient
selection and treatment practices across institutions. A
study-level meta-analysis could not be conducted given
the paucity of study-level data with sufficient sample
sizes, leading to inadequate power. The low sample size
also precluded comparison of the outcomes of ITB, IVB,
and DBS. Only published peer-reviewed studies were
included, potentially resulting in publication bias if neg-
ative results were not published. However, we could not
test for publication bias in this study due to low sample
size. DBS targets were either unilateral or bilateral and
stimulation parameters were not listed, preventing
determination of optimal approaches for DBS in GA1
patients. Functional impact was described generally
given heterogeneous descriptions of treatment effects on
daily life and quality of life across studies. Specific muta-
tions leading to GA1 were not reported, preventing us
from determining the effect of genotype on treatment
SHLOBIN ET AL.
outcomes. Follow-up lengths were variable, perhaps
obscuring an effect of time on treatment efficacy.
Despite these limitations, this is a methodologically rig-
orous analysis of neuromodulatory surgical approaches
for people with GA1.
Unfortunately, there are no ongoing clinical trials that
focus on surgical interventions for GA1. Future studies are
necessary. Large prospective studies of GA1 patients with
refractory dystonia will better characterize treatment
approaches. Compiling GA1 cases undergoing ITB, IVB,
and DBS would be helpful. Two existing registries, the
Unified European Registry for Inherited Metabolic Disorders
(u-imd-registry.org) and European registry and network for
Intoxication type Metabolic Disease (e-imd.org), may be use-
ful in collecting and evaluating data on the effect of ITB,
IVB, and DBS on GA1 patients. Studies should examine
demographic, clinical, and treatment factors associated
with improved dystonia, improved function, and reduced
enteral medication regimen. Additional studies should
examine the influence of specific mutations on treatment
outcomes. Future studies should seek to compare ITB,
IVB, and DBS to each other in GA1 patients to determine
appropriate indications for these approaches.
5 | CONCLUSIONS
ITB, IVB, and DBS represent new neuromodulatory
approaches for the treatment of GA1. ITB and IVB reduce
dystonia, while DBS has a limited effect on dystonia. ITB
and IVB also improved function and reduce enteral medi-
cation regimens. However, these findings must be viewed
with caution considering heterogeneous data and a seri-
ous risk of bias in the existing literature. Future studies
employing larger cohorts of GA1 patients are necessary
to characterize the safety and efficacy of these interven-
tions in this population, as well as to determine indica-
tions for ITB, IVB, and DBS and elucidate treatment
algorithms.
AUTHOR CONTRIBUTIONS
Nathan A. Shlobin: Conceptualization, investigation,
methodology, formal analysis, writing-original draft,
project administration. Katherine Hofmann: Investi-
gation, methodology, formal analysis, writing-review
and editing. Robert F. Keating: Methodology, writing-
review and editing, supervision. Chima O. Oluigo:
Conceptualization, methodology, writing-review and
editing, supervision.
F U N D I N G IN F O R M A T I O N
No funding was received.
SHLOBIN ET AL.
CONFLICT OF INTEREST STATEMENT
Nathan A. Shlobin, Katherine Hofmann, Robert
F. Keating, and Chima O. Oluigbo declare that they have
no conflict of interest.
DATA AVAILABILITY STATEMENT
Shared data are available for this manuscript. Authors
agree to the journal policy regarding data availability. All
data for this manuscript can be accessed in the text and
tables.
I NFOR ME D C O NS EN T S TAT EM EN T
All procedures followed were in accordance with the
ethical standards of the responsible committee on human
experimentation (institutional and national) and with
the Helsinki Declaration of 1975, as revised in 2000.
Informed consent was obtained from all patients for
being included in the study.
ANIMAL RIGHTS
This article does not contain any studies with human or
animal subjects performed by the any of the authors.
ORCID
Nathan A. Shlobin https://orcid.org/0000-0003-2079-
6125
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How to cite this article: Shlobin NA,
Hofmann K, Keating RF, Oluigbo CO. Deep brain
stimulation and intrathecal/intraventricular
baclofen for glutaric aciduria type 1: A scoping
review, individual patient data analysis, and
clinical trials review. J Inherit Metab Dis. 2023;
46(4):543‐553. doi:10.1002/jimd.12638