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PubMed This is a summary of 18 peer-reviewed journal articles Updated
Neurology · CDKL5 Deficiency Disorder

Seizure Types and Medical Treatments

At a Glance

Seizures in CDKL5 deficiency disorder often begin in early infancy and remain difficult to control. Treatment may combine ganaxolone or other anti-seizure medicines with a ketogenic diet or vagus nerve stimulation, while balancing seizure reduction against alertness and quality of life.

Managing epilepsy in CDKL5 Deficiency Disorder (CDD) is often the most demanding part of a caregiver’s journey. Because the brain’s “master switch” protein is missing or altered, the brain is prone to frequent and intense electrical storms [1]. For the vast majority of children, these seizures are refractory, meaning they are highly resistant to standard medical treatments [2][3].

Common Seizure Patterns

Seizures in CDD typically begin very early, with a median onset of just 6 weeks of age [2][4]. While every child is different, research identifies several common patterns:

  • Early Infancy: Seizures often begin as epileptic spasms (brief, jerky movements of the arms or trunk) or focal motor seizures [2][5].
  • Evolution Over Time: As children grow, their seizure types often change. Tonic seizures (stiffening of the body) may become more frequent, while spasms sometimes diminish [5][6].

Targeted Medical Treatment: Ganaxolone (Ztalmy)

In 2022, ganaxolone (Ztalmy) became the first FDA-approved medication specifically for adjunctive treatment of seizures associated with CDD in patients 2 years of age and older in the United States [7].

In a major clinical trial (the Marigold study), researchers found:

  • Efficacy: Children taking ganaxolone saw a 30.7% median reduction in “major motor seizures” (the most severe, visible seizures), compared to only a 6.9% reduction for those on a placebo [8]. This is a group median change in a controlled trial, not an expected individual response or a guarantee of seizure freedom.
  • Long-term Use: For children who continued the medication for up to two years in an uncontrolled open-label extension, sustained seizure reduction of about 43% to 48% was observed, though some patients discontinued treatment during that time [7][9].
  • Common Side Effects: The most frequent side effects were somnolence (extreme sleepiness), pyrexia (fever), and upper respiratory tract infections [8][7]. Somnolence is usually dose-related and must be carefully monitored, especially if your child is taking other sedating medications.

Conventional Medications and Polytherapy

Before or alongside targeted treatments, doctors often prescribe “conventional” Anti-Seizure Medications (ASMs) such as levetiracetam, valproate, and clobazam [10].

Because CDD is so resistant to treatment, most children require polytherapy (taking multiple medications at once) [11]. However, adding more drugs comes with trade-offs:

  • Side Effect Burden: Research shows that as the number of medications increases, the side-effect burden (such as heavy sedation, or liver/pancreas toxicity with valproate) often increases as well, making the benefit-risk decision highly individualized [10].
  • Diminishing Returns: No single conventional medication has been proven “superior” for CDD, and many children remain without sustained seizure freedom even on extensive combinations [12][13].

Safety Warning: Never change or taper an anti-seizure medication without the prescribing clinician. Abrupt withdrawal can cause life-threatening status epilepticus.

Non-Drug Treatment Options

When medications are not enough, two non-pharmacologic options are often considered:

Treatment How it Works Reported Efficacy in CDD Common Concerns
Ketogenic Diet A specialized high-fat, low-carbohydrate medical diet [14]. About 18% to 50% of children show a significant clinical response [15]. Gastrointestinal issues like severe constipation and vomiting are common [15]. It requires a specialized medical team, laboratory monitoring, and planning for dehydration or kidney stones.
Vagus Nerve Stimulation (VNS) A small device implanted under the skin that stimulates the vagus nerve in the neck, which then modulates brain networks [16]. Roughly 69% of caregivers reported some improvement in seizure frequency, duration, or intensity in observational data [16]. It involves surgery, battery replacements, and possible side effects like hoarseness, cough, or sleep-related breathing issues [16].

Balancing Control and Quality of Life

The ultimate goal of treatment is to find the right balance. While reducing seizure frequency is important, it should not come at the cost of your child’s ability to be awake, interact, and enjoy their day [17][18]. Success in CDD is often measured not just by a seizure count, but by improvements in alertness, mood, and the ability to participate in family life [16][18].

Always work closely with your neurology team to track both the benefits and the side effects of every treatment change.

Common questions in this guide

When do seizures usually start in CDKL5 deficiency disorder?
Seizures often begin in early infancy, with a median onset of about 6 weeks of age. Early patterns may include epileptic spasms or focal motor seizures, and seizure types can change as a child grows.
What is ganaxolone used for in CDD?
Ganaxolone, also called Ztalmy, is an FDA-approved add-on medicine for seizures associated with CDKL5 deficiency disorder in patients age 2 years and older in the United States. In clinical trials, it reduced major motor seizures more than placebo, but it does not guarantee seizure freedom.
What side effects can ganaxolone cause?
Common side effects include sleepiness, fever, and upper respiratory infections. Sleepiness can increase with the dose and may be more concerning when a child also takes other medicines that cause sedation, so the prescribing team should monitor it.
Why might a child with CDD need more than one seizure medicine?
Seizures in CDKL5 deficiency disorder are often difficult to control, so clinicians may combine medicines when one treatment is not enough. Several medicines can increase sedation and other risks, including liver or pancreas injury with valproate, so the regimen should be reviewed individually.
When might the ketogenic diet or VNS be considered for CDD?
A ketogenic diet or vagus nerve stimulation may be considered when seizures remain difficult to control despite medicines. The diet requires a specialized team and monitoring, while VNS requires surgery and later battery replacements, so each option should be discussed with the neurology team.
Can anti-seizure medicines be stopped suddenly?
No. A child's anti-seizure medicine should never be changed or tapered without guidance from the prescribing clinician because abrupt withdrawal can trigger life-threatening status epilepticus.
How should treatment success be measured in CDKL5 deficiency disorder?
Treatment success may include fewer or less severe seizures as well as better alertness, mood, and ability to participate in family life. A detailed seizure diary can help the care team track patterns, benefits, and side effects after treatment changes.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.What is the primary seizure type my child is experiencing right now, and how might that change as they get older?
  2. 2.Is my child a candidate for ganaxolone, and how should we monitor for the side effect of somnolence (extreme sleepiness)?
  3. 3.How many anti-seizure medications are currently in my child's regimen, and can we simplify the plan to reduce side effects like sedation?
  4. 4.At what point should we consider non-medication options like the ketogenic diet or Vagus Nerve Stimulation (VNS)?
  5. 5.How will we measure success in my child's treatment—is it only about seizure frequency, or are we also tracking alertness and developmental progress?
  6. 6.What specific side effects should I watch for with each medication my child is taking, and which ones require an immediate call to your office?

Questions For You

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References

References (18)
  1. 1

    International Consensus Recommendations for the Assessment and Management of Individuals With CDKL5 Deficiency Disorder.

    Amin S, Monaghan M, Aledo-Serrano A, et al.

    Frontiers in neurology 2022; (13()):874695 doi:10.3389/fneur.2022.874695.

    PMID: 35795799
  2. 2

    Seizure variables and their relationship to genotype and functional abilities in the CDKL5 disorder.

    Fehr S, Wong K, Chin R, et al.

    Neurology 2016; (87(21)):2206-2213 doi:10.1212/WNL.0000000000003352.

    PMID: 27770071
  3. 3

    CDKL5 Deficiency Disorder-Related Epilepsy: A Review of Current and Emerging Treatment.

    Hong W, Haviland I, Pestana-Knight E, et al.

    CNS drugs 2022; (36(6)):591-604 doi:10.1007/s40263-022-00921-5.

    PMID: 35633486
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    CDKL5 deficiency disorder: Relationship between genotype, epilepsy, cortical visual impairment, and development.

    Demarest ST, Olson HE, Moss A, et al.

    Epilepsia 2019; (60(8)):1733-1742 doi:10.1111/epi.16285.

    PMID: 31313283
  5. 5

    CDKL5-associated developmental and epileptic encephalopathy: A long-term, longitudinal electroclinical study of 22 cases.

    Darra F, Monchelato M, Loos M, et al.

    Epilepsy research 2023; (190()):107098 doi:10.1016/j.eplepsyres.2023.107098.

    PMID: 36739728
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    The natural history of CDKL5 deficiency disorder into adulthood.

    Aledo-Serrano A, Lewis-Smith D, Leonard H, et al.

    medRxiv : the preprint server for health sciences 2025; doi:10.1101/2025.01.12.24318239.

    PMID: 39867409
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    Ganaxolone: A Review in Epileptic Seizures Associated with Cyclin-Dependent Kinase-Like 5 Deficiency Disorder.

    Hoy SM

    Paediatric drugs 2025; (27(1)):111-118 doi:10.1007/s40272-024-00670-6.

    PMID: 39792341
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    Safety and efficacy of ganaxolone in patients with CDKL5 deficiency disorder: results from the double-blind phase of a randomised, placebo-controlled, phase 3 trial.

    Knight EMP, Amin S, Bahi-Buisson N, et al.

    The Lancet. Neurology 2022; (21(5)):417-427 doi:10.1016/S1474-4422(22)00077-1.

    PMID: 35429480
  9. 9

    Long-term treatment with ganaxolone for seizures associated with cyclin-dependent kinase-like 5 deficiency disorder: Two-year open-label extension follow-up.

    Olson HE, Amin S, Bahi-Buisson N, et al.

    Epilepsia 2024; (65(1)):37-45 doi:10.1111/epi.17826.

    PMID: 37950390
  10. 10

    Caregiver Perspective of Benefits and Side Effects of Anti-Seizure Medications in CDKL5 Deficiency Disorder from an International Database.

    Wong K, Junaid M, Alexander S, et al.

    CNS drugs 2024; (38(9)):719-732 doi:10.1007/s40263-024-01105-z.

    PMID: 39060900
  11. 11

    Measuring the Burden of Epilepsy Hospitalizations in CDKL5 Deficiency Disorder.

    Junaid M, Wong K, Korolainen MA, et al.

    Pediatric neurology 2025; (163()):68-75 doi:10.1016/j.pediatrneurol.2024.11.010.

    PMID: 39705835
  12. 12

    Clinical manifestations and epilepsy treatment in Japanese patients with pathogenic CDKL5 variants.

    Kobayashi Y, Tohyama J, Takahashi Y, et al.

    Brain & development 2021; (43(4)):505-514 doi:10.1016/j.braindev.2020.12.006.

    PMID: 33436160
  13. 13

    CDKL5 deficiency-related neurodevelopmental disorders: a multi-center cohort study in Italy.

    Dell'Isola GB, Fattorusso A, Pisani F, et al.

    Journal of neurology 2024; (271(8)):5368-5377 doi:10.1007/s00415-024-12421-1.

    PMID: 38874638
  14. 14

    Use of the ketogenic diet to manage refractory epilepsy in CDKL5 disorder: Experience of >100 patients.

    Lim Z, Wong K, Olson HE, et al.

    Epilepsia 2017; (58(8)):1415-1422 doi:10.1111/epi.13813.

    PMID: 28605011
  15. 15

    Efficacy of ketogenic diet in CDKL5-related epilepsy: a single arm meta-analysis.

    Zhang J, Ma J, Chang X, et al.

    Orphanet journal of rare diseases 2022; (17(1)):385 doi:10.1186/s13023-022-02492-6.

    PMID: 36274176
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    Vagus nerve stimulation for the treatment of refractory epilepsy in the CDKL5 Deficiency Disorder.

    Lim Z, Wong K, Downs J, et al.

    Epilepsy research 2018; (146()):36-40 doi:10.1016/j.eplepsyres.2018.07.013.

    PMID: 30071384
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    Effects of ganaxolone on non-seizure outcomes in CDKL5 Deficiency Disorder: Double-blind placebo-controlled randomized trial.

    Downs J, Jacoby P, Specchio N, et al.

    European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society 2024; (51()):140-146 doi:10.1016/j.ejpn.2024.06.005.

    PMID: 38959712
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    Clinical evolution and epilepsy outcome in three patients with CDKL5-related developmental encephalopathy.

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    PMID: 31225800

This page is for educational purposes and does not constitute medical advice about your child's CDKL5 deficiency disorder. Your child's neurology team should guide medication changes, monitoring, and decisions about dietary or device-based treatment.

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