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7-14-2020

Drug-Resistant Epilepsy in Children with Juvenile Huntington's Drug-Resistant Epilepsy in Children with Juvenile Huntington's

Disease: A Challenging Case and Brief Review Disease: A Challenging Case and Brief Review

Abdulhafeez Khair Thomas Jefferson University

Jessica Kabrt Rowan University

Stephen Falchek Thomas Jefferson University

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Recommended Citation Recommended Citation

Khair, Abdulhafeez; Kabrt, Jessica; and Falchek, Stephen, "Drug-Resistant Epilepsy in Children

with Juvenile Huntington's Disease: A Challenging Case and Brief Review" (2020). Department of

Neurology Faculty Papers. Paper 222.

https://jdc.jefferson.edu/neurologyfp/222

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RESEARCH ARTICLE

Drug-Resistant Epilepsy in Children with JuvenileHuntington’s Disease: A Challenging Case and BriefReviewAbdulhafeez M. Khair MD1, Jessica Kabrt DO2, Stephen Falchek MD3

ABSTRACT

Huntington’s Disease (HD) is an autosomal dominantneurodegenerative disorder with a progressive declinein cognitive, motor, and psychological function.Chorea tends to be the most common associatedmovement disorder, although other variants ofseveral abnormal movements are also seen. Adult-onset HD is the most common subtype. JuvenileHuntington’s disease (JHD) accounts for 5%–10% ofall HD cases and presents as a rapidly progressivedisorder with a multitude of characteristics. We reporton a 9-year-old male with JHD who presented withrefractory epilepsy. His EEG findings, seizure type, andantiepileptic drug usage are discussed with a briefreview of the currently available relevant literature.The currently reported case sheds light on anti-epileptic drugs that proved effective in our patientand the importance of screening for JHD when a childpresents with seizures that are difficult to control.

Keywords: Huntington Disease, Epilepsy

INTRODUCTIONHuntington’s disease (HD) is a rare genetic disorderthat is inherited in an autosomal dominant patternoften from the patients' paternal side. It is caused bythe expansion of a CAG trinucleotide repeat in theHTT gene.1 This gene produces the Huntingtonprotein, which is thought to be important for basicneuronal function. Patients with Juvenile Huntington’sDisease (JHD) often have more than 60 trinucleotiderepeats rather than the normally expected 10–35repeats. JHD is typically diagnosed when its onset isbefore the age of 20 years old.2 The clinical course israpidly progressive, often with almost all patients onlysurviving 10–15 years after the appearance of

Address for Correspondence:Abdulhafeez M. Khair MD1

1Pediatric Neurology Fellow. Ai.I. Dupont Hospital forChildren – Thomas Jefferson University. 1600 RocklandRd, Wilington DE 19809, United States. Email:Abdulhafeez.Khair@nemours.org2Osteopathic medical student, Rowan University. 42 eLaurel Rd, Stratford NJ 08084, United States3Division chief of neurology- A.I Dupont Hospital forChildren Wilmington DE. Assistant professor-ThomasJefferson University-Philadelphia PA, United States

http://dx.doi.org/10.5339/qmj.2020.18

Submitted: 13 November 2019Accepted: 27 January 2020ª 2020 Khair, Kabrt, Falchek, licensee HBKU Press. This is anopen access article distributed under the terms of theCreative Commons Attribution license CC BY 4.0, whichpermits unrestricted use, distribution and reproduction in anymedium, provided the original work is properly cited.

Cite this article as: Khair MD AM, Kabrt DO J,Falchek MD S. Drug-Resistant Epilepsy inChildren with Juvenile Huntington’s Disease:A Challenging Case and Brief Review, QatarMedical Journal 2020:18 http://dx.doi.org/10.5339/qmj.2020.18

QATAR MEDICAL JOURNALVOL. 2020 / ART. 18

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symptoms.3 JHD is characterized by bradykinesia,rigidity, dystonia, tremors, myoclonus, slurred speech,swallowing problems, and epilepsy.4 Seizures arealmost entirely limited to JHD in contrast to adult-onset HD. Epilepsy seems to be more prevalent inchildren who have symptoms before the age of 10years old.5 Chorea is also generally absent to minimalin JHD compared with adult-onset HD.5

Although seizures appear to be one of the mainsymptoms of JHD, studies elaborating on details ofsemiology, clinical course, and diagnostic studies arefew. Several years ago, a multicenter review by Cloudet al. discussed 34 cases of genetically confirmed JHDwith reported seizures, but only 16 had accompanyingEEG data.6 Seizures also appear to be responsible formore than 50% of hospitalizations of children withJHD.7 There have been more recently reported casesbecause of improvements in diagnostic technologyand clinical care leading to the expansion of availableknowledge of JHD and the features of accompanyingepilepsy. We describe a patient with refractoryepilepsy and his associated neuroimaging studies, EEGfindings, and antiseizure medications.

CASE PRESENTATIONA 9-year-old male first presented to the neurologyconcussion clinic at the age of 4 years, a year after amotor vehicle accident. During this accident, he wasnot restrained in the car seat and sustained aconcussion. His family was not certain if he lostconsciousness during the accident. A brain magneticresonance imaging (MRI) scan at that time showed asmall cystic area with a fluid level and hemorrhages inbetween the superior wall of the right maxillary sinusand inferior wall of the right orbit, that were likelyrelated to the trauma. However, the brain parenchymastructure was described as essentially normal. Severalmonths after the accident, his family reported somenonspecific yet concerning symptoms, including beingoffbalance, frequent falling, remarkable changes in hismood, and overall easy fatigue and tiredness. He alsohad trouble with small hand muscles` functions, suchas using a fork, knife, or spoon, and holding pens,pencils, and crayons. He was referred to physical andoccupational therapy services accordingly. He showedsome clinical response after a few months of therapysessions, as he was able to run steadily, walk up, anddown stairs, use utensils appropriately, speak insentences, draw, and use pencils and crayons asbefore. A follow-up brain MRI demonstrated a

resolving lesion along the roof of the right maxillasinus that likely represents a resolving hematoma.Further updated brain MRI images revealed anabnormal T2/FLAIR hyper intensity of the bilateralcaudate nuclei and putamina with volume loss, one ofthe radiological signatures of JHD (Figs. 1–A&1–B).

Regarding his medical history, he was born at 35weeks via spontaneous vaginal delivery without anycomplications or time spent in the neonatal intensivecare unit. His list of medical problems includes balanceproblems, developmental delay, eczema, epistaxis,headache, mild intermittent asthma, and later post-concussion syndrome. The patient father wasreported to have dementia and progressive cognitiveand motor decline; however, he did not have anyformal diagnosis of a precise neurological condition.Further family history details were not available. Giventhe various concerns and family history, the patientunderwent genetic testing. Molecular testing of exon1 of the HIT gene showed 103 CAG repeats of fullpenetrance consistent with JHD.

He presented to our emergency department at theage of 9 years old because of numerous episodes ofgeneralized onset tonic-clonic seizures and severeabdominal pain. Over a short period, he had increasedseizure frequency from weekly to every other day todaily. The seizures were typically described as wholebody stiffening, then all extremities rhythmic shaking,along with eye flickering that usually lasted for 1–2 minutes. He also had focal onset seizures describedas raised bilateral upper extremity, eye deviation tothe left, left head torsion without full version, bilateraltonic lower extremities, and rhythmic movements ofthe mouth. There was no apnea, color changes, ortongue biting.

Nevertheless, at times, he had urinary incontinence.He was started on antiseizure medications, includinglevetiracetam, oxcarbazepine, clobazam, and clona-zepam as needed for spasms and prolonged seizures.His physical exam was evolving with expressive andreceptive language delay (nonverbal), truncal hypotonicity, spastic extremities with cogwheel rigidity,and worsening tremors in the upper extremities. HisEEG showed diffuse slowing and epileptiformdischarges consistent with mild diffuse encephalo-pathy and occasional focal slowing in the left posteriorquadrant, indicating underlying focal neuronal dys-function. His follow-up EEG showed rare andindependent spike and wave discharges over thecentral and temporal regions suggesting cortical hyper

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excitability and an increased risk for focal onsetseizures (Fig. 2-A). It also showed rare bursts ofgeneralized sharp and slow-wave delta dischargeswith bifrontal predominance, which suggested anincreased risk for generalized or focal onset seizurewith rapid generalization (Fig. 2–B). There was ageneralized background slowing with a posteriordominant rhythm lower than expected for his age anda poorly formed and sustained sleep architecture,which suggested mild encephalopathy. A repeatedbrain MRI demonstrated the slight interval pro-gression of ex vacuo dilatation of the frontal horns.Also, there was bifrontal periventricular hypo densitythat was related to the known atrophy of the caudatenuclei and putamina in line with JHD. With time, healso began having frequent myoclonic seizures on adaily basis. Therefore, oxcarbazepine was weanedsubsequently.

Apart from struggling with epilepsy control, he hasmultiple other neurological issues, including severespasticity with developing contractures, a minimallevel of motor function, being wheelchair-bound,

slowly progressive swallowing dysfunction, completeloss of vocalization, and continued loss of bowel andbladder control. He also continued to have a variety ofalmost constant abnormal movements, includinggeneralized bradykinesia, upper extremities tremors,facial tic-like movement, and occasional dystonicmovements. This constellation of various movementswas only stopped during sleep. His family describedsome choreiform movements, but it was felt thatthese were minimal and rather infrequent.He underwent a trial of tetrabenazine to relieve hiscontinuous movements, but the response wasminimal and complicated by a neuroleptic malignantsyndrome that led to discontinuing the medication.

DISCUSSIONHD is a degenerative neurological disorder due tothe expansion of a progressively abnormal CAGtrinucleotide repeat that results in the functionaldecline across all domains and various movementdisorders.8 JHD is a severe subtype of HD withchildhood-onset. It has more severe CAG expansion

Figure 1-A: Coronal view T2/FLAIR MRI sequence demonstrating abnormal T2/FLAIR hyperintensities of the bilateralcaudate nuclei and putamina.

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and more burdens of neuropsychiatricmanifestations.9 Typically, patients have more than60 CAG repeats, and the vast majority of cases arepaternally inherited. There is also growing andaccumulating evidence that children with more than

80 CAG repeats may constitute a distinct subgroupof highly expanded genetic locus and have moresevere outcomes.10 Seizures seem to be a veryprominent clinical feature in JHD in contrast toadult-onset HD.11

Figure 2-A: Interictal EEG showing bilateral independent epileptiform spike discharges from the right frontal, central, andtemporal areas.

Figure 1-B: Axial view T2/FLAIRMRI sequence demonstrating volume loss of the caudate nuclei bilaterally that resulted inmild expansion of the frontal horns of the lateral ventricles bilaterally.

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Here, we presented a 9-year-old male with JHD andearly-onset refractory epilepsy. Although it is notedthat many patients with JHD have epilepsy, the exactunderlying neurophysiological mechanisms and etio-logical pathways remain unclear. Older theories fromavailable neurophysiological studies suggested thatearly neuronal cortical death is probably a contributingfactor.12 Primary neuronal degeneration and changesin striatal synapses seem to be more noticeable inchildren with early and severe clinical seizures.13 Itwas noted in the available literature that younger ageat onset was related to more rapid disease progressionand shorter patient survival, which could also explainthe burden of our patient’s epilepsy.14 The age ofseizure onset appears to be a major factor regardingthe intractability and response to antiseizuremedications.15

The pathophysiology of seizures in JHD remainsunknown, especially concerning the age of presen-tation and severity. We are uncertain if the motorvehicle accident that he sustained at the age of threemight have exacerbated the rapid progression of ourpatient’s JHD symptoms. Some epidemiologicalstudies have suggested that concussions or mildtraumatic brain injury (TBI) might be associated with atwofold or greater increase in post-traumaticepilepsy. However, a study involving 330 patientsdetermined that there was not an increase in theincidence of epilepsy, and concussions and TBI shouldnot be considered significant risk factors for the first5–10 years following the events.16

It is extremely challenging to locate precise epide-miological data about genetically proven JHD since

only a handful of reported cases exist across theglobe. In the largest published report by Cloud and hisgroup, the prevalence of epilepsy was observed in34% of patients in the JHD cohort. They concludedthat the most common seizure semiology wasgeneralized tonic seizures, followed by myoclonic, andabsence seizures.6 Our reported patient has a mix ofgeneralized tonic-clonic seizures, and unaware focalseizure with secondary generalization, which is not aseizure semiology that has been reported before inJHD, to our knowledge.

Electroencephalogram (EEG) data in epileptic childrenwith JHD are sparse as well. EEG characteristics inpatients with adult-onset HD are mostly interictalepileptiform discharges. Landau reported that inter-ictal polyspike wave discharges were the mostcommon epileptiform finding in children with adoles-cent-onset JHD.17 A couple of years later, Ullrich et al.reported that generalized polyspike and slow-wavecomplexes, spike, and slow-wave complexes, multi-focal spikes, and focal spikes are the most commonlyobserved EEG changes.18 In general, it seems thatchildren with JHD tend to have more generalizedspike-wave complexes with polyspikes being themost common observation.17 Focal or multifocal EEGdischarges are less noted. Our patient’s EEG demon-strated focal surface negative sharp waves that wereidentified out of the left occipital (O1 electrode)region throughout the study, with some field-effectextending into the right occipital head region.However, they were otherwise relatively restricted tothis focus. A subsequent EEG showed mild diffuseslowing and disorganization of the background and

Figure 2-B: Interictal EEG showing runs of sharply contoured theta sharp waves and spikes in the bifrontal areas.

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occasional focal slowing in the left posterior quadrant.His longer monitoring EEG in the epilepsy unit wasrecently able to demonstrate rare and independentspike and wave discharges over the central (Fz/Cz.F7/FP2/F4/FP1/F3) and temporal (T6) regions,which suggest cortical hyperexcitability and anincreased risk for focal onset seizures. This particularvideo EEG also captured rare bursts of generalizedsharp and slow-wave delta discharges with bifrontalpredominance, which suggest an increased risk forgeneralized onset seizures, or focal onset seizureswith rapid generalization (Figs. 2–A & 2–B).In adulthood-onset HD, several neuroimagingcharacteristics have been reported. In our patient, abrain MRI obtained at the age of 8 years old showedan abnormal T2/FLAIR hyper intensity of the bilateralcaudate nuclei and putamina with volume loss of thecaudate nuclei bilaterally. This volume loss resulted inthe mild expansion of the frontal horns of the lateralventricles bilaterally, which were thought to beconsistent with the diagnosis of JHD (Figs. 1–A &1–B). His brain MR Spectroscopy demonstratednormal metabolite patterns. Some reports describedbrain MRIs that showed hyper intensity involving thecaudate nucleus and putamen on both sides19 Otherstudies reported subcortical nonspecific T2 hyperintense lesions, particularly in patients with the rigid,more than the classical hyperkinetic form.20 Cerebralvolumetric loss has also been described in the basalganglia, thalami, hippocampi, substantia nigra, andcerebellum with varying degrees of atrophy corre-lating with the disease stage.21 Spectroscopy andbrain positron emission tomography scans mightprovide a promising biomarker by enabling the earlydetection of abnormal striatal glucose metabolism.22

Studies demonstrated that these neuroimagingchanges occurred before the emergence of clinicalsymptoms.23 Nevertheless, not much is known abouttypical MRI findings in JHD. One very recent cohortsuggested that MRI findings probably extend beyondtypical striatal structures as significant cerebellarenlargement was discovered in the JHD cohort, whichmay explain the observation of more hypokineticsymptoms in children with JHD.24

Considering the rarity of available data, the unavail-ability of consensus regarding seizure management inJHD is not surprising. The most commonly usedantiseizure medications include sodium valproate,followed by phenytoin, and carbamazepine.25 Otherless used therapies include clonazepam, phenobarbi-tal, ethosuxamide, gabapentin, zonisamide, andlamotrigine, among others.5 Although seizures appearto be one of the major symptoms in JHD, mostpatients are being managed with single monotherapyagents. Intractable drug-resistant epilepsy is ratherrare in the cohort of patients with genetically provenJHD. Our reported patient went through severalantiseizure medications until the combination ofoxcarbazepine, levetiracetam, and clobazam provedto be the most successful and has been well-tolerated.

CONCLUSIONSJHD is a severe neurodegenerative brain disorder thatpresents serious diagnostic challenges and manage-ment limitations. Epilepsy is one of the majorneurological manifestations in JHD, but intractabledrug-resistant epilepsy is relatively rare. There are noscientifically rigorous systematic reviews of epilepsycharacteristics, EEG features, imaging findings, andevidence-based management strategies. Thisreported case may provide insight into a uniquepatient with JHD and refractory epilepsy. Our patientdemonstrated an early-onset clinical presentation,focal EEG findings, and medication-resistant epilepsy,which have not been extensively analyzed in thispopulation. It will be interesting to continue to learnabout how epilepsy in patients with JHD is beingaddressed with the vast array of new antiepilepticstrategies being produced. Future reviews andprospective studies will hopefully help to determinewhich seizure management approach is best in thisvulnerable group of rare patients to help themmaintain the best possible quality of life. A majorlimitation of our reported case is that he had a historyof TBI just before the emergence of his symptoms.This confounding incident made the process of cross-linking the clinical manifestations to the results ofdiagnostic studies more challenging.

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