# Oxygen Therapy: An Acute Treatment for Paroxysmal Dystonia in Alternating Hemiplegia of Childhood?

Quentin Welniarz, Domitille Gras, Agathe Roubertie, Maria Papadopoulou, Eleni Panagiotakaki, Emmanuel Roze

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Quentin Welniarz, Domitille Gras, Agathe Roubertie, Maria Papadopoulou, Eleni Panagiotakaki, et al. Oxygen Therapy: An Acute Treatment for Paroxysmal Dystonia in Alternating Hemiplegia of Childhood?. Movement Disorders, 2023, 38 (5), pp.906-907. 10.1002/mds.29357. inserm-04957282

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# Oxygen Therapy: An Acute Treatment for Paroxysmal Dystonia in Alternating Hemiplegia of Childhood?

Alternating hemiplegia of childhood (AHC) is an early-onset neurodevelopmental disorder caused by pathogenic variants of *ATP1A3*, which encodes for a subunit of a neuronal $Na^+/K^+$ ATPase.¹ Patients present various forms of paroxysmal manifestations associated with nonparoxysmal motor disorder and intellectual disability.² Dystonic attacks are often the most disabling manifestation, and their pharmacological treatment is very disappointing.

We report the case of a 25-year-old man with typical AHC attributed to a p.Glu815Lys variant in *ATP1A3*. He had an early psychomotor retardation. The hemiplegic episodes began at 3 months, and by 18 months he began having dystonic attacks. With aging, the dystonic attacks have become the predominant type of paroxysmal event. The dystonic attacks usually involve one or two limbs on the same side and occasionally progress toward generalized dystonia. They result in considerable pain and fatigue, with major consequences on daily activities. The patient has an intellectual disability, epilepsy, psychotic symptoms, and insomnia. His treatment comprises flunarizine, valproate, prazosin, bisoprolol, and fluoxetine. During the past 18 months, he has been experiencing up to eight dystonic attacks in a single day, which could last from 30 minutes to several hours, with an average duration of 1 hour. Acute treatment consists of a 10-mg dose of midazolam, with a maximum of two doses per day, and he used an average of 40 doses per month. Midazolam usually stops the episodes because it makes him fall asleep, but they often resume within 30 minutes after waking up. One year ago, he incidentally received a single administration of an equimolar mix of nitrous oxide/oxygen ($O_2$) for 5 minutes during a dystonic attack, which resolved rapidly. Based on this observation, we decided to introduce high-flow oxygen inhalation (100% $O_2$ at a flow rate of 12 L/min) as an acute treatment for the patient's dystonic events. $O_2$ is administered as soon as the dystonic attack

© 2023 The Authors. *Movement Disorders* published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

*Correspondence to: Dr. Emmanuel Roze, Département de Neurologie, Groupe Hospitalier Pitié-Salpêtrière, 47-83 Boulevard de l'Hôpital, 75651 Paris cedex 13, France; E-mail: emmanuel.flamand-roze@aphp.fr

**Relevant conflicts of interest/financial disclosures:** Nothing to report.

Received: 27 January 2023; Accepted: 3 February 2023

Published online 16 February 2023 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.29357

begins and for a duration of 15 minutes. Most attacks stop within 15 minutes after the beginning of the $O_2$ administration. We have not changed the recommendation regarding the use of midazolam, but midazolam consumption has decreased from 40 doses per month on average to four after the introduction of $O_2$. Oxygen therapy has not changed the frequency of the dystonic attacks, but it has led to a significant improvement in the quality of life by shortening the duration of the attacks and reducing midazolam consumption.

## Discussion

Cortical spreading depression (CSD) may be an important mechanism for paroxysmal movement disorders in *ATP1A3*-related AHC³ and in *ATP1A2*-related hemiplegic migraine.⁴ CSD is associated with tissue hypoxia, and increasing $O_2$ availability can shorten its duration.⁵ Therefore, high-flow oxygen inhalation could be expected to reduce the duration of paroxysmal events in AHC. We suggest that high-flow oxygen inhalation may be considered to treat dystonic attacks in AHC given the (1) safety of oxygen therapy, (2) rationale behind this therapeutic approach, (3) negative impact of dystonic attacks on quality of life, and (4) absence of an alternative pharmacological solution.

**Acknowledgments:** The parents of the patient and the patient have given written consent for the publication.

## Conflict Of Interest

The authors declare no conflict of interest related to this research.

## Data Availability Statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Quentin Welniarz, PhD,¹,²,✉ Domitille Gras, MD,²
Agathe Roubertie, MD, PhD,³ Maria T. Papadopoulou, MD,⁴
Eleni Panagiotakaki, MD, PhD,⁴ and
Emmanuel Roze, MD, PhD¹,²*

¹Assistance Publique - Hôpitaux de Paris (APHP), Salpêtrière Hospital, Medical and University Department (DMU) neurosciences, Paris, France, ²Sorbonne University Inserm, Centre National de la Recherche Scientifique (CNRS), Paris Brain Institute, Paris, France, ³CHU Montpellier, Département de Neuropédiatrie, Institut des. Neurosciences de Montpellier (INM) Université de Montpellier, Institut National de la Santé et de la Recherche Médicale (INSERM) U 1298, Montpellier, France, ⁴Department of Clinical Epileptology, Sleep Disorders and Functional Neurology, University Hospitals of Lyon (HCL), Member of the European Reference Network for rare and complex epilepsies (ERN EpiCARE), Lyon, France

## References

1. Mikati MA, Panagiotakaki E, Arzimanoglou A. Revision of the diagnostic criteria of alternating hemiplegia of childhood. Eur J Paediatr Neurol 2021;32:A4–A5.
2. Panagiotakaki E, Gobbi G, Neville B, Ebinger F, Campistol J, Nevšimalová S, et al. Evidence of a non-progressive course of alternating hemiplegia of childhood: study of a large cohort of children and adults. Brain 2010;133(12):3598-3610.

3. Hunanyan AS, Fainberg NA, Linabarger M, Arehart E, Leonard AS, Adil SM, et al. Knock-in mouse model of alternating hemiplegia of childhood: behavioral and electrophysiologic characterization. Epilepsia 2015;56(1):82-93.

4. Smith SE, Chen X, Brier LM, Bumstead JR, Rensing NR, Ringel AE, et al. Astrocyte deletion of α2-Na/K ATPase triggers episodic motor paralysis in mice via a metabolic pathway. Nat Commun 2020;11(1): 6164.

5. Takano T, Tian GF, Peng W, Lou N, Lovatt D, Hansen AJ, et al. Cortical spreading depression causes and coincides with tissue hypoxia. Nat Neurosci 2007;10(6):754-762.

Impact of APOE Genotype on
Cognition in Idiopathic and
Genetic Forms of Parkinson's
Disease

The ε4 allele of the apolipoprotein (APOE) gene is increas-
ingly recognized to be associated with the development of cog-
nitive decline in idiopathic Parkinson's disease (iPD).¹ The
putative role of APOE as a genetic modifier of cognitive trajec-
tories in genetic forms of Parkinson's disease (PD) is largely
unexplored.² We have analyzed two independent PD cohorts.
The first cohort (Athens) included 50 iPD patients, 35 patients
with the p.A53T α-synuclein (SNCA) mutation and 59 patients
with glucocerebrosidase (GBA1) mutations (13 mild/46 severe).
The second cohort (Tübingen) included 292 patients with
GBA1 mutations (170 risk/52 mild/70 severe). All patients were
genotyped for APOE (Figure S1, Data S1) and underwent cog-
nitive testing using the Montreal Cognitive Assessment test
(MoCA) (Table 1). Additionally, patients from the Tübingen
cohort have also undergone analysis of cerebrospinal fluid
(CSF) biomarkers (Table 1, and expanded cohort in Table S2).

In the iPD and in the p.A53T SNCA subgroups of the Athens
cohort, carriers of at least one APOE ε4 exhibited lower MoCA
scores as compared to non-carriers when using age, sex, disease

© 2023 International Parkinson and Movement Disorder Society.

**Key Words:** Parkinson's disease; apolipoprotein E; cognitive decline; α-synuclein gene; glucocerebrosidase gene

*Correspondence to:* Dr. Leonidas Stefanis, Department of Neurology, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece and Center of Clinical Research, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Vasilisis Sofias 72 str, 11528, Athens, Greece; E-mail: istefanis@bioacademy.gr

**Relevant conflicts of interest/financial disclosures:**

**Funding agency:** This study was partially funded by the “National Network for Neurodegenerative Diseases (EΔΙΑΝ)” (GSRT).

Christos Koros, Kathrin Brockmann, Thomas Gasser, Leonides Stefanis equally contributed to this paper.

Received: 24 October 2022; Accepted: 16 December 2022

Published online 6 May 2023 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/mds.29399

duration, and education as covariates (P = 0.044 and
P = 0.039, respectively) (Figure S2, Table 1). In contrast, in the
GBA1 subgroups from the Athens and Tübingen cohorts, no
difference in MoCA score related to APOE ε4 status was
detected (P = 0.729 and P = 0.585, respectively) (Figure S3,
Table 1). Moreover, there were no associations between APOE
genotype and Alzheimer's disease (AD)-related biomarker mea-
surement outcomes in CSF in the Tübingen GBA1 cohort
(Table 1, Data S1, Table S2).

Our results are in accordance with literature data regarding
the already described impact of APOE ε4 on cognitive decline
of iPD.¹,³ Notably, the APOE ε4 effect on cognitive dysfunction was also present in the p.A53T SNCA subgroup, which
represents the prototypical genetic synucleinopathy. APOE ε4
carriers in this genetic cohort exhibited significantly lower
MoCA scores and were more often characterized as
demented, based on MOCA cut-offs, compared to non-
carriers (Table 1). Therefore, APOE appears to act as a
genetic modifier of cognitive impairment in this genetic SNCA
cohort, although this remains to be further demonstrated with
larger numbers of subjects. Recent data suggest that APOE
ε4 may directly exacerbate α-synuclein pathological deposition, beyond its established role in promoting AD co-pathology.⁴,⁵ Previous data from our group, showing marginally
low β-amyloid in some p.A53T SNCA PD carriers, suggest
that at least β-amyloid co-pathology, influenced by APOE status, could be a factor in the mediation of cognitive decline.⁶

Regarding the GBA1 subgroups, we did not find an effect of APOE genotype on cognitive function in two independent cohorts of GBA1 mutation carriers, who are considered a model of α-synuclein-related cognitive decline.⁷ The absence of differences in CSF biomarker profiles between APOE ε4 carriers and non-carriers in the GBA1 cohort further supports that the APOE genotype, and hence, probably also AD co-pathology, is irrelevant in this genetic PD form. Specifically, in the GBA1_severe subgroup that develops early cognitive impairment, APOE ε4 did not play a role, neither clinically nor on biomarker levels (Table 1, Figure S3 and Table S2). This substantiates the hypothesis of a predominant α-synuclein pathology, which is also linked to a pronounced α-synuclein seeding profile. The joint results from our current study and former research suggest differences in factors associated with cognitive decline (genetic, epigenetic, or environmental) between different genetic forms of synucleinopathies, even those that would be expected to be closely related, such as is the case of GBA1 and SNCA mutations. In this respect, carriers of the p.A53T SNCA mutation resemble more closely iPD compared to GBA1 mutation carriers, given the presence of low CSF β-amyloid levels in some cases⁶ and the association of cognitive decline with the APOE ε4 genotype reported here.

Ethical and Regulatory Aspects

This study was conducted in accordance with the Declaration
of Helsinki and the current European Data Protection Regula-
tion. Written informed consent was obtained from all partici-
pants. We confirm that we have read the Journal's position on
issues involved in ethical publication and affirm that this work is
consistent with those guidelines. The authors take full