- Email: [email protected]
Epilepsy in mucopolysaccharidosis disorders
Accepted Manuscript Epilepsy in mucopolysaccharidosis disorders
Maurizio Scarpa, Charles Marques Lourenço, Hernán Amartino PII: DOI: Reference:
S1096-7192(17)30502-4 doi:10.1016/j.ymgme.2017.10.006 YMGME 6257
To appear in:
Molecular Genetics and Metabolism
Received date: Revised date: Accepted date:
7 August 2017 13 October 2017 13 October 2017
Please cite this article as: Maurizio Scarpa, Charles Marques Lourenço, Hernán Amartino , Epilepsy in mucopolysaccharidosis disorders. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Ymgme(2017), doi:10.1016/j.ymgme.2017.10.006
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ACCEPTED MANUSCRIPT Supplement MPS and the brain
Epilepsy in MPS
Epilepsy in mucopolysaccharidosis disorders
Maurizio Scarpaa,* , Charles Marques Lourençob, Hernán Amartinoc
a
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Department of Paediatric and Adolescent Medicine, Helios Dr. Horst Schmidt Kliniken, Center for Rare Diseases, Wiesbaden, Germany and Department for the Woman and Child Health, University of Padova, Italy; b Neurogenetics Unit, Clinics Hospital of Ribeirao Preto, University of São Paulo, São Paulo, SP, Brazil; c Department of Child Neurology, Hospital Universitario Austral, Buenos Aires, Argentina
* Corresponding author:
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Maurizio Scarpa Department of Paediatric and Adolescent Medicine
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Helios Dr. Horst Schmidt Kliniken, Center for Rare Diseases
65199 Wiesbaden, Germany
Fax: +49 611433197
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Tel: +49 611432314
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Ludwig-Erhard-Strasse 100
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Email: [email protected]
AED: anti-epileptic drugs, EEG: electroencephalography, ERT: enzyme replacement therapy, GAG: glycosaminoglycans, HSCT: hematopoietic stem cell transplantation, LD: left deltoid , MPS: mucopolysaccharidosis, MRI: magnetic resonance imaging, PSG: polysomnography, RD: right deltoid
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Epilepsy in MPS
Abstract The mucopolysaccharidosis (MPS) disorders are caused by deficiencies of specific lysosomal enzymes involved in the catabolism of glycosaminoglycans (GAGs). The resulting GAG accumulation in cells and tissues throughout the body leads to progressive multi-organ dysfunction. MPS patients present with several somatic manifestations, like short stature,
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musculoskeletal abnormalities and cardiorespiratory dysfunction, and several primary and
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secondary neurological signs and symptoms. Epileptic seizures are neurological signs of MPS
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thought to develop due to accumulation of GAGs in the brain, triggering alterations in neuronal connectivity, signaling, and release of inflammatory mediators. The amount of
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literature on the prevalence, pathophysiology, clinical features, and management of epileptic seizures in patients with MPS is limited. This review discusses current knowledge on this
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topic, as well as two case examples, presented and discussed during a closed meeting on MPS and the brain among an international group of experts with extensive experience in managing
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Keywords:
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and treating MPS.
mucopolysaccharidoses;
lysosomal
storage
diseases;
epilepsy;
seizures;
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electroencephalography
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Epilepsy in MPS
1. Introduction The mucopolysaccharidosis (MPS) disorders are rare lysosomal storage diseases characterized by deficiencies of specific glycosaminoglycan (GAG)-degrading lysosomal enzymes, leading to intracellular GAG accumulation and progressive multi-organ dysfunction [1, 2]. Most MPS disorders are associated with somatic manifestations, including short stature, skeletal and joint
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abnormalities, and cardiorespiratory disease. Neurological abnormalities can arise secondary
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to spinal cord compression, hydrocephalus, and carpal tunnel syndrome [3-6]. In addition,
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neurocognitive decline is observed in the neuronopathic forms of MPS I (Hurler [MPS IH]), MPS II, and MPS VII, and all MPS III phenotypes, although with varying severity [7, 8]. In
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these patients, accumulation of GAGs in the brain, in particular heparan sulfate, is thought to trigger neuroinflammation, altered neuronal signaling, and neuronal cell death [9-12], which
epileptic seizures [1, 2, 8, 13-20].
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can lead to neurological manifestations such as impaired cognition, behavioral problems, and
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Epilepsy is a neurological condition resulting from changes in the electrical functioning of the
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brain. It is defined by a history of at least one seizure, a structural/functional alteration in the brain (increasing the chance of future seizures), and an association with disturbances in cognition, behavior, and mental status [21-23]. Seizures frequently occur in several MPS
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disorders where GAG accumulation in the brain might cause altered neuronal communication [24, 25]. Studies in animal models for MPS have shown abnormal development of the neuronal network [12, 26, 27]. This review discusses current knowledge on epilepsy in MPS patients, as well as two case examples, based on information from a closed meeting “The Brain in MPS: Today and Tomorrow” (April 28-30, 2016) held in Stockholm, Sweden. During this meeting, existing relevant literature and clinical data on epilepsy in MPS disorders were reviewed and discussed by 39 international MPS experts. Additional relevant literature was obtained from PubMed searches for ("Mucopolysaccharidoses"[Mesh]) AND
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(("Epilepsy"[Mesh]) OR "Seizures"[Mesh]) (33 items) and ("Mucopolysaccharidoses"[Mesh]) AND
("Epilepsy"
OR
"Seizures")
(42
items)
and
Embase
search
('mucopolysaccharidoses'/exp and 'epilepsy'/exp) and 'mucopolysaccharidosis'/de (141 items). Animal studies and publications not available in English were excluded. Searches were performed without date restriction. Additional publications were identified from reference
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lists of the most relevant MPS-related papers focusing on epilepsy and its practical
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management. The literature search was completed in October 2016.
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2. Epilepsy in MPS disorders
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2.1 Prevalence and age of onset
The overall prevalence of epilepsy in MPS is approximately 30% [28, 29], although reported
development
of
seizures
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prevalence rates vary widely between studies (Table 1). In addition, in some cases occurred
in
the
presence
of
increased
intracranial
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pressure/ventriculomegaly [30-33]. The potential presence of epilepsy in these studies was most often explored using questionnaires, medical records, and clinical evaluation (Table 1).
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Remarkably, no seizures were reported in MPS IH patients after treatment with hematopoietic cell transplant [28, 34], while enzyme replacement therapy (ERT) did not seem to have any
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effect on seizures [28, 33]. The highest prevalence has been reported in neuronopathic MPS II and in MPS III patients [28, 29, 31], who also often present with cognitive decline and behavioral problems [31]. In MPS II patients, prevalence estimates of epileptic seizures range from 13% to 34% [15, 28, 30, 35], with higher rates (28% to 63%) in those with a neuronopathic phenotype [24, 35-37]; mean age at onset is around 10 years [24, 28, 30, 33, 36, 38] (Table 1). Remarkably, Young et al reported epilepsy in 3% of non-neuronopathic MPS II patients [36]. However, it cannot be excluded that these patients had been misclassified as non-neuropathic. Patients with MPS III have the highest prevalence of
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seizures, ranging between 26 and 52% [28, 39-41]. Although prevalence does not differ greatly between the four subtypes of MPS III, the age of onset appears to be somewhat earlier in MPS IIIA patients (Table 1) [25, 41-46]. The incidence of seizures has been found to increase with advancing neurocognitive deterioration [25, 36, 47].
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Table 1. Overview of the reported prevalence and onset age of epileptic seizures in MPS disorders.
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(shown at the end of the manuscript)
2.2 Clinical presentation
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Epilepsy is a chronic condition resulting from sudden changes in the electrical functioning of the brain [21-23]. Epileptic seizures can be classified as focal (partial), generalized, or
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unknown, based on onset. Focal seizures arise in a network confined to one hemisphere of the brain and are often classified as aware or impaired awareness (also called simple or complex).
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Focal aware seizures imply that the patient stays aware, responsive, and awake during seizure activity, while this is not the case for focal seizures with impaired awareness. Generalized
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seizures begin and spread within bilateral networks in both hemispheres. Generalized seizures can be classified as absence or motor seizures. Further subdivision is quite similar to the older
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classification [48, 49] and includes tonic-clonic, myoclonic, clonic, tonic, or atonic. Finally, onset of the seizures can be unknown and, when there are no details on patient awareness and (non-)motor features, the seizure is referred to as unclassified [23, 50]. Most of the evidence in the literature on the clinical presentation of epilepsy in MPS is derived from patients with MPS II and III, and indicates that these patients typically present with generalized tonic-clonic seizures [24, 32, 37, 41, 44, 51-53]. Nocturnal myoclonic jerks, which precede the onset of generalized tonic-clonic seizures [24], as well as tonic [37], focal [54], absent, and myoclonic seizures [28, 51] have also been reported in MPS II patients. Patients can show different types of seizures at various time points [28, 51]. 5
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Only a few reports provide a more detailed characterization of the epileptic activity observed in MPS patients. Barone et al. [55] investigated electroencephalography (EEG) records at different disease stages of MPS III. Progressive EEG changes correlated with age and disease progression. While patients younger than 3 years had normal background activity while awake, slowing of occipital-dominant rhythm and background activity at wakefulness could
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be observed after 6 years of age and became more severe after 11 years of age. Bonanni et al.
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[33] described a 7-year-old MPS II patient presenting with neurological regression and
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behavioral changes. EEG recordings showed epileptiform activity in the frontal lobe, which presented as continuous and rhythmic spike-wave activity at 2.5 Hz during wakefulness,
nocturnal frontal lobe
epilepsy,
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indicative of non-convulsive status epilepticus. By the age of 10 years, the patient developed characterized
by hyperkinetic automatism,
autonomic
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changes, and vocalization [43]. On EEG, the nocturnal seizures were obvious by spikes and sharp waves. These seizures were often preceded by diffuse attenuated activity and followed
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by a rhythmic slow wave activity at 4-6 Hz in the frontal regions. The seizures mostly lasted for 12-15 s, although minor episodes of 3-8 s could also be observed [43]. The same authors
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also described an MPS IIIA patient with impaired cognition and behavioral problems, who had nocturnal frontal lobe epilepsy according to spike and spike-wave activity on the EEG,
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which was associated with sleep disturbances, including motor automatism, rotation of the trunk, and vocalization. Again, major and minor episodes were observed lasting 5-15 s and 1-3 s, respectively [43]. EEG abnormalities during sleep in MPS IIIA have also been reported by Kriel et al., who recorded 12-15 Hz activity with intervals of diffuse high-voltage slow activity [32]. Nocturnal seizures can cause sleep disorders, which in turn can result in diurnal somnolence, hyperactive behavior, and shortened attention span [33].
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2.3 Management and treatment options Optimal management of epileptic seizures requires a correct diagnosis. However, seizures can be difficult to detect in MPS patients as they often become evident by alterations and/or abnormalities in mental status, behavior and/or cognition, which are inherent features of MPS III and the severe phenotypes of MPS I and II [21, 28, 31, 51]. The occurrence of absence
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seizures and non-convulsive status epilepticus can be subtle, and hence difficult to observe. In
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addition, focal onset of generalized seizures may be missed when the manifestations are
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subtle [28].
According to the experts attending the meeting in Stockholm, a diagnostic work-up for
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epilepsy in MPS patients should include electrophysiological examination by EEG [23, 31] and polysomnography (PSG), the latter to exclude disordered breathing as a cause of sleep
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disturbances [56] since nocturnal epilepsy can also cause sleep disorders. They recommend EEG and PSG in MPS III and neuronopathic MPS II at diagnosis and on a yearly basis
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thereafter, ideally combined, to obtain a complete picture about any abnormalities or changes [23, 57]. Video-recording during EEG should be considered to capture possible autonomic
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activation and motor behavior [33, 43]. It should be noted that EEG and PSG can be very challenging in MPS III and neuronopathic MPS II patients, due to behavioral issues.
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Literature discussing treatment of epileptic seizures in MPS patients is limited. Clinical experience of several of the experts attending the meeting in Stockholm suggests that there are no differences in treatment between patients with MPS and other epilepsy patients. Hence, standard recommendations should be followed [48]. Treatment with anti-epileptic drugs (AEDs) is indicated when two or more seizures occur in a short interval (6 months to 1 year). However, the risk of complications due to seizures should be weighed against the risks of adverse events of AED treatment. The balance depends of the patient’s age and cognitive function. The initial therapeutic aim is to use one AED (monotherapy) as this reduces the
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chance of possible side effects (such as sedation, drowsiness, and hypersensitivity reactions), allows better compliance, and is cheaper. Adding an additional AED (polytherapy) [41] will likely result in significant improvement in only 10% of patients. Withdrawal of medication should only be considered when a patient has been seizure-free for a period of 2-3 years, or even longer. Medication should not be stopped suddenly as this is associated with a relapse
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rate of 20-40%.
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Several AEDs can be used in MPS patients (Table 2) [28, 31, 33, 43]. Published findings indicate that treatment with one or, less frequently, with two AEDs is generally effective for
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controlling seizures [24, 33, 38, 41, 43, 45, 46, 53]. Most MPS patients can expect partial or complete control of seizures with appropriate treatment. Studies have shown effective control
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of epilepsy with AEDs in 79-86% of patients with MPS III or IIIA [40, 42]. A study in MPS IIIB patients reported a seizure-free rate of 50% with AED treatment [44]. Grioni et al. [28]
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reported that 69% of their MPS patients (MPS I, II, and III) were seizure-free and 31% had decreased seizure frequency with AED treatment. While generalized tonic-clonic seizures
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tended to resolve with medication, partial seizures did not completely disappear. Bonnani et al. described effective treatment of non-convulsive status epilepticus in an MPS II patient
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with ethosuximide [33]. The same group also reported successful management of nocturnal frontal lobe epilepsy in two patients with MPS II and III with clobazam (and carbamazepine) [43].
Table 2. Overview of anti-epileptic drugs that can be used in MPS patients ([48] and personal communication Dr. M. Scarpa) (shown at the end of the manuscript)
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3. Case reports on epileptic seizures in MPS disorders 3.1 Case 1: MPS II Case 1 is a male patient with neuronopathic MPS II. He was diagnosed at the age of 2 years based on dysmorphic features and skeletal disease (gibbus deformity, joint stiffness). In addition, he presented with an umbilical hernia, hepatomegaly, bilateral otitis media, and
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enlarged adenoids. Absence of detectable enzyme activity in leukocytes confirmed diagnosis
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of MPS II; molecular testing revealed the missense mutation R468Q. A developmental delay
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became apparent at the age of 3 years, when the boy started to lose acquired skills like the ability to use a pencil and to play with toys in a symbolic way. By the age of 5 years, he
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presented with day- and nighttime urinary incontinence, insomnia, and severe behavioral problems (hyperactivity and lack of impulse control), for which he received risperidone
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1 mg/day. Progressive impairment in expressive and receptive language significantly limited his communication ability, resulting in unintelligible language by the age of 6 years. Weekly
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treatment with enzyme replacement therapy (ERT) was started at 8 years of age, with home
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infusions from 13 years of age onward. Although somatic signs and symptoms and quality of life improved, ERT did not stop the neurological regression. At the age of 11 years, uncontrollable repetition of chewing and stereotyped head movement
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became apparent. Brain magnetic resonance imaging (MRI) revealed cortical atrophy, with severe ventricular enlargement, and bilateral hyperintensity in the periventricular white matter (Figure 1A and B). One year later, the patient started to suffer from simple (aware) partial seizures with secondary generalization. Brain MRI did not show any significant changes. Interictal sleep EEG showed abnormal background activity with occasional bursts of spikewave complexes in the left frontotemporal area. Seizure activity could be effectively controlled with oxcarbazepine (20 mg/kg/day).
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Figure 1. Brain magnetic resonance imaging in an 11-year old MPS II patient, showing cortical atrophy, ventricular enlargement, and bilateral hyperintensity in the periventricular white matter.
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1.5-column fitting image
By the age of 16 years, the patient presented with abnormal intermittent myoclonic
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movements of the right arm (video 1), and a change in behavior: the patient was perceived as being more disconnected from his environment. EEG recordings (Figure 2A) showed
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abnormal background slow rhythm and ictal sustained, bilateral frontal fast activity (Figure 2B), suggestive of a non-convulsive status epilepticus of frontal origin. The patient was hospitalized for 48 hours. Seizure control was achieved with intravenous lorazepam (0.1 mg/kg/dose;
twice)
and
diphenylhydantoin
(20
mg/kg/dose).
Subsequently,
the
oxcarbazepine dose was increased to 30 mg/kg/day and risperidone treatment for insomnia and severe behavioral problems was withdrawn. Over the next weeks, levetiracetam was added at 250 mg/12 hours and then 500 mg/12 hours. When the patient became more sleepy and hypoactive, a new brain MRI scan showed worsening of ventricular enlargement and ventriculoperitoneal shunting was performed. After surgery, the patient’s alertness and mood 10
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improved and the seizures did not recur. The EEG after shunting showed marked improvement in background activity with disappearance of frontal epileptic activity. Because of persistence of isolated interictal focal spikes, the patient remained on a prophylactic low dosis of levetiracetam (20 mg/kg/day). Infusions with ERT were continued without change. Epilepsy in this patient was probably related to hydrocephalus, which is a common
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complication in MPS.
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Video 1. Example of myoclonic movements in the right arm of the MPS II patient described in case 1 at the age of 16 years.
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Please use colors for reproduction of this figure in the online version and black & white for
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1-column fitting image of the video
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the printed version.
Figure 2. Electroencephalography in the MPS II patient described in case 1 at the age of 16 years (A), showing left frontal lobe discharges indicative of status epilepticus (B). Please use colors for reproduction of this figure in the online version but black & white for the 11
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printed version.
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2-column fitting image
This case report shows how severe neurocognitive deficits in MPS II can hinder recognition
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of non-convulsive status epilepticus. In addition, it demonstrates that hydrocephalus, often
epilepticus.
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3.2 Case 2: MPS VI
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under-recognized or mistaken for only brain atrophy, can be related to non-convulsive status
Case 2 is an adult female patient with slowly progressing MPS VI. She started ERT in 2007 at the age of 15 years, but is on intermittent treatment since 2016 due to governmental issues. Previous brain MRI exams showed mild ventriculomegaly. The patient had complaints of migraine and anxiety, for which she was treated with sertraline (25 mg/day) in 2012. Despite good response, the patient decided to suspend sertraline after one year of treatment. One year later, in 2013, a focal seizure was noted during administration of ERT (video 2). From the age of 23 years, the family also reported focal seizures, characterized by a sudden arrest of
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talking, which resumed after a few seconds to minutes, not consciously experienced by the patient.
Video 2. Example of focal seizure with impaired awareness in the MPS VI patient described in case 2.
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Please use colors for reproduction of this figure in the online version and black & white for
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the printed version.
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1-column fitting image of the video
Brain MRI did not reveal any changes (Figure 3), but EEG findings were compatible with focal epilepsy. The EEG, performed in 2014 while the patient was awake with two hyperventilation proofs and photonic stimulation, showed normal basal activity but slow theta wave and delta waves in the bilateral fronto-temporal hemispheres occurring independently and bi-synchronous, and more frequently in the left hemisphere. A year later, another EEG recording showed acute wave type epileptiform seizures and slow waves in the left frontotemporal with the maximum negative activity in the anterior temporal area; there were also acute wave type epileptiform paroxysms in the left temporal-parietal with the maximum 13
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negative activity in the medium temporal area. Seizure control was not achieved with carbamazepine (200 mg/day) treatment. Therefore, treatment with valproic acid was started. She initially received high doses of valproic acid (1500 mg/day), which caused side effects of hand tremor, gait instability, and hair loss. Therefore, the dose was gradually decreased to 250 mg/day. This led to improvements in tremor, but the complaints of hair loss persisted. The
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patient also started using lamotrigine (125 mg/day) at that time. Lamotrigine caused
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cutaneous rash that disappeared with a lower dose. Since the patient had persistent side effects
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of lamotrigine, the dose was further decreased progressively to 25 mg/day until cessation. Valproic acid treatment was also stopped at her last visit since the patient could not tolerate
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higher doses. The patient had 10-12 seizures/month while receiving valproic acid and lamotrigine therapy. When she switched to monotherapy with topiramate (eventually 175
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mg/day), crisis, she was free of seizures for almost 8 months. The patient’s family did not report any epileptic events during sleep, although sleep deprivation (when she had to get up
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very early) may have been a trigger for some of her seizures. Considering the limited evidence for occurrence of epileptic seizures in MPS VI patients, it is questionable whether
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epilepsy.
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the seizures were related to the MPS disorder. None of the patient’s parents had a history of
Figure 3. Brain MRI of the MPS VI patient described in case 2 showing no brain abnormalities; A-C T1-weighted, D T2-weighted. 1.5-column fitting image
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4. Conclusions
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Currently available literature shows that epilepsy is a frequent manifestation of MPS
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disorders, occurring in approximately 30% of patients. Patients with MPS I and, particularly, MPS II and III are most prone to develop epilepsy. Seizures in MPS patients are mostly tonicclonic, but myoclonic, absence, focal seizures, non-convulsive status epilepticus, nocturnal myoclonic jerks, and frontal lobe epilepsy have been reported as well, although less frequently. The incidence and severity of seizure activity on EEG recordings tends to increase with disease progression. Detection of epileptic activity in MPS patients can be difficult as seizures can be subtle and may be difficult to recognize in patients who already have cognitive deficits and behavioral problems. This highlights the importance of regular monitoring of epileptic activity in these 15
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patients, ideally with (video-)EEG (potentially combined with PSG), to detect changes in electrical activity. Despite the high prevalence and debilitating nature of epilepsy in MPS patients, current literature on the pathophysiology, clinical presentation, and treatment of seizures in these patients remains extremely limited. As seizure activity and changes in cognition and behavior
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seem to be intertwined, the mutual interaction between both manifestations (including the
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potential role of hydrocephalus) requires further investigation. In addition, the association
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between nocturnal seizures and non-respiratory sleep disorders, which very commonly occur in MPS II and MPS III patients [58], deserves more attention. Finally, there is need for more
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clinical data about the effects and side effects of different AEDs in MPS patients. In order to broaden current knowledge, researchers should be encouraged to publish their experiences
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with epilepsy in MPS patients.
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Financial disclosures Dr. Scarpa received unrestricted research and educational grants from Actelion, BioMarin, Genzyme, and Shire. He has no personal financial interests in any of the drugs produced for lysosomal storage disorders. Dr. Lourenço received travel grants, speaker honoraria, investigator fees, and unrestricted
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research and/or educational grants from Actelion, Amicus, BioMarin, Genzyme, Pfizer,
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Protalix, and Shire.
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Dr. Amartino is a contracted investigator for Shire, Amicus, BlueBirdBio and received
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honoraria and travel support from BioMarin and consulting fees from Shire.
Consent for publication
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Written informed consent was obtained for publication of these case reports and any
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Acknowledgements
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accompanying images. A copy of the written consent is available.
The authors are grateful to Ismar Healthcare NV for their assistance in the writing of this
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manuscript, which was funded by BioMarin Pharmaceutical Inc. The expert meeting in Stockholm was also sponsored by BioMarin Pharmaceutical Inc.
Funding
This work was supported by BioMarin Pharmaceutical Inc.
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R. Barone, M.D. Cocuzza, C. Guida, G. Miano, V. Sofia, A. Fiumara. EEG features in
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disorders in the mucopolysaccharidoses. Mol Genet Metab VOLUME Suppl (2016) PAGES.
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Tables Table 1. Overview of the reported prevalence and onset age of epileptic seizures in MPS disorders. Reference
MPS type; N
Grioni 2010 [28]
MPS I (HSCT); N=10 MPS I (no HSCT); N=7 § MPS II; N=16 § MPS III; N=13 MPS IV; N=11 MPS VI; N=4 § MPS I, II, III, IV, and VI; N=16 MPS I, II, III, IV, and VI; N=58 MPS I; N=20 MPS II; N=22 MPS VI; N=12 Neuronopathic MPS II; N=52 Attenuated MPS II; N=31 MPS II; N=52
Albuquerque 2010 [31] Kuzenkova 2013 [29] Mendes 2016 [30]
Young 1982 [36] Young 1983 [24]
Age (years)* Prevalence of seizures 8 0 28 29% 16 31% 17 46% 18 0 6 0 10.3 25% 9.5
C A
Diagnostic tool
-
-
Neurological evaluation Clinical examination
Focal (partial) seizures Focal (partial) seizures Focal (partial) seizures -
I R
T P
C S
U N
Range 7-30 Range 0.9-28 Range 3-26 -
0 19% 17% 59% 3% 63%
Generalized tonic & atonic Partial with generalization Generalized tonic-clonic
Range 2-17 7 and 21 12 10
Median 8.2
13%
-
-
T P
E C
Seizure onset age (years)* 14 and 31 10 13 -
A M
41%
D E
Main type of seizure
Schwartz 2007 [35]
MPS II; N=77
Holt 2011 [15]
MPS II; N=50
6.0
34%‡
-
-
JiménezArredondo [37]
MPS II; N=9
7.3
56%
Generalized tonic-clonic
-
Video EEG Neurological evaluation
EEG
Clinical examination Interview Medical records Clinical evaluation Questionnaire Clinical evaluation Medical records
26
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MPS type; N
Nidiffer 1983 [40] Cleary 1993 [39] Moog 2007 [44]
Epilepsy in MPS Main type of seizure
MPS III; N=30 MPS IIIA, B, and C; N=62 MPS IIIB; N=20
Age (years)* Prevalence of seizures 10.4 52% 26% 55%
Ruijter 2008 [46]
MPS IIIC; N=29
-
45%
-
Valstar 2010 [42]
MPS IIIA; N=110
-
66%
-
Valstar 2010 [45]
MPS IIIB; N=52
-
51%
Héron 2011 [25]
MPS IIIA; N=76 MPS IIIB; N=16 MPS IIIC; N=13 MPS IIID; N=6 MPS IIIA, B, and C; N=55
13
Delgadillo 2013 [41]
D E
E C
T P
Generalized tonic-clonic Generalized tonic-clonic
U N
A M
40% 50% 31% 17% 45%
T P
I R
C S
Seizure onset age (years)* 6.9 >8 34.3
23
Median 11
-
>9
Generalized tonic-clonic
8.7 8.8 Range 8-31 9.4 Median 8.7 MPS IIIA: 7 MPS IIIB: 12.5 MPS IIIC: 10.4
C A
Diagnostic tool Questionnaire Clinical evaluation Interview Medical records Clinical evaluation Questionnaire Medical records Clinical evaluation Questionnaire Medical records Clinical evaluation Questionnaire Medical records Clinical evaluation Medical records Clinical evaluation
Questionnaire
* Age and onset age are presented as mean unless indicated otherwise ‡ Seizure-like behavior § Treated with enzyme replacement therapy since time it was commercially available HSCT: hematopoietic stem cell transplantation; -: not reported
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Table 2. Overview of anti-epileptic drugs that can be used in MPS patients ([48] and personal communication Dr. M. Scarpa) Type of seizure
Medication
Used in MPS disorder
Generalized tonic-clonic seizures Drug of choice: carbamazepine, valproic acid, phenobarbital,
T P
I, II, and III [28]
Alternatives: topiramate, phenytoin†, lamotrigine (as adjunct or alone), gabapentin (as adjunct) Focal seizures
I R
C S
Drug of choice: carbamazepine, topiramate, valproic acid
I, II, and III [28]
U N
Alternatives: phenobarbital, phenytoin†, lamotrigine (as adjunct or alone), gabapentin (as adjunct) Absence
A M
Drug of choice: valproic acid, ethosuximide
D E
II [33]
Alternatives: clonazepam, lamotrigine Myoclonic, Atonic
T P
Drug of choice: valproic acid
E C
Alternative: clonazepam Status epilepticus
C A
Drug of choice: diazepam (intravenous), phenytoin (intravenous), valproic acid
II and III [28]
Alternative: phenobarbital (intravenous)
Febrile seizures
Diazepam (rectal* or intravenous)
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* Preferred; † Phenytoin should not be used as first choice in generalized or focal seizures as it produces gingival hypertrophy, which is also a manifestation of MPS.
T P
I R
C S
U N
D E
A M
T P
E C
C A
29
Maurizio Scarpa, Charles Marques Lourenço, Hernán Amartino PII: DOI: Reference:
S1096-7192(17)30502-4 doi:10.1016/j.ymgme.2017.10.006 YMGME 6257
To appear in:
Molecular Genetics and Metabolism
Received date: Revised date: Accepted date:
7 August 2017 13 October 2017 13 October 2017
Please cite this article as: Maurizio Scarpa, Charles Marques Lourenço, Hernán Amartino , Epilepsy in mucopolysaccharidosis disorders. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Ymgme(2017), doi:10.1016/j.ymgme.2017.10.006
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ACCEPTED MANUSCRIPT Supplement MPS and the brain
Epilepsy in MPS
Epilepsy in mucopolysaccharidosis disorders
Maurizio Scarpaa,* , Charles Marques Lourençob, Hernán Amartinoc
a
SC
RI
PT
Department of Paediatric and Adolescent Medicine, Helios Dr. Horst Schmidt Kliniken, Center for Rare Diseases, Wiesbaden, Germany and Department for the Woman and Child Health, University of Padova, Italy; b Neurogenetics Unit, Clinics Hospital of Ribeirao Preto, University of São Paulo, São Paulo, SP, Brazil; c Department of Child Neurology, Hospital Universitario Austral, Buenos Aires, Argentina
* Corresponding author:
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Maurizio Scarpa Department of Paediatric and Adolescent Medicine
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Helios Dr. Horst Schmidt Kliniken, Center for Rare Diseases
65199 Wiesbaden, Germany
Fax: +49 611433197
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Tel: +49 611432314
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Ludwig-Erhard-Strasse 100
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Email: [email protected]
AED: anti-epileptic drugs, EEG: electroencephalography, ERT: enzyme replacement therapy, GAG: glycosaminoglycans, HSCT: hematopoietic stem cell transplantation, LD: left deltoid , MPS: mucopolysaccharidosis, MRI: magnetic resonance imaging, PSG: polysomnography, RD: right deltoid
ACCEPTED MANUSCRIPT Supplement MPS and the brain
Epilepsy in MPS
Abstract The mucopolysaccharidosis (MPS) disorders are caused by deficiencies of specific lysosomal enzymes involved in the catabolism of glycosaminoglycans (GAGs). The resulting GAG accumulation in cells and tissues throughout the body leads to progressive multi-organ dysfunction. MPS patients present with several somatic manifestations, like short stature,
PT
musculoskeletal abnormalities and cardiorespiratory dysfunction, and several primary and
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secondary neurological signs and symptoms. Epileptic seizures are neurological signs of MPS
SC
thought to develop due to accumulation of GAGs in the brain, triggering alterations in neuronal connectivity, signaling, and release of inflammatory mediators. The amount of
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literature on the prevalence, pathophysiology, clinical features, and management of epileptic seizures in patients with MPS is limited. This review discusses current knowledge on this
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topic, as well as two case examples, presented and discussed during a closed meeting on MPS and the brain among an international group of experts with extensive experience in managing
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Keywords:
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and treating MPS.
mucopolysaccharidoses;
lysosomal
storage
diseases;
epilepsy;
seizures;
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electroencephalography
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Epilepsy in MPS
1. Introduction The mucopolysaccharidosis (MPS) disorders are rare lysosomal storage diseases characterized by deficiencies of specific glycosaminoglycan (GAG)-degrading lysosomal enzymes, leading to intracellular GAG accumulation and progressive multi-organ dysfunction [1, 2]. Most MPS disorders are associated with somatic manifestations, including short stature, skeletal and joint
PT
abnormalities, and cardiorespiratory disease. Neurological abnormalities can arise secondary
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to spinal cord compression, hydrocephalus, and carpal tunnel syndrome [3-6]. In addition,
SC
neurocognitive decline is observed in the neuronopathic forms of MPS I (Hurler [MPS IH]), MPS II, and MPS VII, and all MPS III phenotypes, although with varying severity [7, 8]. In
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these patients, accumulation of GAGs in the brain, in particular heparan sulfate, is thought to trigger neuroinflammation, altered neuronal signaling, and neuronal cell death [9-12], which
epileptic seizures [1, 2, 8, 13-20].
MA
can lead to neurological manifestations such as impaired cognition, behavioral problems, and
ED
Epilepsy is a neurological condition resulting from changes in the electrical functioning of the
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brain. It is defined by a history of at least one seizure, a structural/functional alteration in the brain (increasing the chance of future seizures), and an association with disturbances in cognition, behavior, and mental status [21-23]. Seizures frequently occur in several MPS
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disorders where GAG accumulation in the brain might cause altered neuronal communication [24, 25]. Studies in animal models for MPS have shown abnormal development of the neuronal network [12, 26, 27]. This review discusses current knowledge on epilepsy in MPS patients, as well as two case examples, based on information from a closed meeting “The Brain in MPS: Today and Tomorrow” (April 28-30, 2016) held in Stockholm, Sweden. During this meeting, existing relevant literature and clinical data on epilepsy in MPS disorders were reviewed and discussed by 39 international MPS experts. Additional relevant literature was obtained from PubMed searches for ("Mucopolysaccharidoses"[Mesh]) AND
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Epilepsy in MPS
(("Epilepsy"[Mesh]) OR "Seizures"[Mesh]) (33 items) and ("Mucopolysaccharidoses"[Mesh]) AND
("Epilepsy"
OR
"Seizures")
(42
items)
and
Embase
search
('mucopolysaccharidoses'/exp and 'epilepsy'/exp) and 'mucopolysaccharidosis'/de (141 items). Animal studies and publications not available in English were excluded. Searches were performed without date restriction. Additional publications were identified from reference
PT
lists of the most relevant MPS-related papers focusing on epilepsy and its practical
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management. The literature search was completed in October 2016.
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2. Epilepsy in MPS disorders
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2.1 Prevalence and age of onset
The overall prevalence of epilepsy in MPS is approximately 30% [28, 29], although reported
development
of
seizures
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prevalence rates vary widely between studies (Table 1). In addition, in some cases occurred
in
the
presence
of
increased
intracranial
ED
pressure/ventriculomegaly [30-33]. The potential presence of epilepsy in these studies was most often explored using questionnaires, medical records, and clinical evaluation (Table 1).
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Remarkably, no seizures were reported in MPS IH patients after treatment with hematopoietic cell transplant [28, 34], while enzyme replacement therapy (ERT) did not seem to have any
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effect on seizures [28, 33]. The highest prevalence has been reported in neuronopathic MPS II and in MPS III patients [28, 29, 31], who also often present with cognitive decline and behavioral problems [31]. In MPS II patients, prevalence estimates of epileptic seizures range from 13% to 34% [15, 28, 30, 35], with higher rates (28% to 63%) in those with a neuronopathic phenotype [24, 35-37]; mean age at onset is around 10 years [24, 28, 30, 33, 36, 38] (Table 1). Remarkably, Young et al reported epilepsy in 3% of non-neuronopathic MPS II patients [36]. However, it cannot be excluded that these patients had been misclassified as non-neuropathic. Patients with MPS III have the highest prevalence of
4
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Epilepsy in MPS
seizures, ranging between 26 and 52% [28, 39-41]. Although prevalence does not differ greatly between the four subtypes of MPS III, the age of onset appears to be somewhat earlier in MPS IIIA patients (Table 1) [25, 41-46]. The incidence of seizures has been found to increase with advancing neurocognitive deterioration [25, 36, 47].
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Table 1. Overview of the reported prevalence and onset age of epileptic seizures in MPS disorders.
SC
RI
(shown at the end of the manuscript)
2.2 Clinical presentation
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Epilepsy is a chronic condition resulting from sudden changes in the electrical functioning of the brain [21-23]. Epileptic seizures can be classified as focal (partial), generalized, or
MA
unknown, based on onset. Focal seizures arise in a network confined to one hemisphere of the brain and are often classified as aware or impaired awareness (also called simple or complex).
ED
Focal aware seizures imply that the patient stays aware, responsive, and awake during seizure activity, while this is not the case for focal seizures with impaired awareness. Generalized
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seizures begin and spread within bilateral networks in both hemispheres. Generalized seizures can be classified as absence or motor seizures. Further subdivision is quite similar to the older
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classification [48, 49] and includes tonic-clonic, myoclonic, clonic, tonic, or atonic. Finally, onset of the seizures can be unknown and, when there are no details on patient awareness and (non-)motor features, the seizure is referred to as unclassified [23, 50]. Most of the evidence in the literature on the clinical presentation of epilepsy in MPS is derived from patients with MPS II and III, and indicates that these patients typically present with generalized tonic-clonic seizures [24, 32, 37, 41, 44, 51-53]. Nocturnal myoclonic jerks, which precede the onset of generalized tonic-clonic seizures [24], as well as tonic [37], focal [54], absent, and myoclonic seizures [28, 51] have also been reported in MPS II patients. Patients can show different types of seizures at various time points [28, 51]. 5
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Epilepsy in MPS
Only a few reports provide a more detailed characterization of the epileptic activity observed in MPS patients. Barone et al. [55] investigated electroencephalography (EEG) records at different disease stages of MPS III. Progressive EEG changes correlated with age and disease progression. While patients younger than 3 years had normal background activity while awake, slowing of occipital-dominant rhythm and background activity at wakefulness could
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be observed after 6 years of age and became more severe after 11 years of age. Bonanni et al.
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[33] described a 7-year-old MPS II patient presenting with neurological regression and
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behavioral changes. EEG recordings showed epileptiform activity in the frontal lobe, which presented as continuous and rhythmic spike-wave activity at 2.5 Hz during wakefulness,
nocturnal frontal lobe
epilepsy,
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indicative of non-convulsive status epilepticus. By the age of 10 years, the patient developed characterized
by hyperkinetic automatism,
autonomic
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changes, and vocalization [43]. On EEG, the nocturnal seizures were obvious by spikes and sharp waves. These seizures were often preceded by diffuse attenuated activity and followed
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by a rhythmic slow wave activity at 4-6 Hz in the frontal regions. The seizures mostly lasted for 12-15 s, although minor episodes of 3-8 s could also be observed [43]. The same authors
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also described an MPS IIIA patient with impaired cognition and behavioral problems, who had nocturnal frontal lobe epilepsy according to spike and spike-wave activity on the EEG,
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which was associated with sleep disturbances, including motor automatism, rotation of the trunk, and vocalization. Again, major and minor episodes were observed lasting 5-15 s and 1-3 s, respectively [43]. EEG abnormalities during sleep in MPS IIIA have also been reported by Kriel et al., who recorded 12-15 Hz activity with intervals of diffuse high-voltage slow activity [32]. Nocturnal seizures can cause sleep disorders, which in turn can result in diurnal somnolence, hyperactive behavior, and shortened attention span [33].
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Epilepsy in MPS
2.3 Management and treatment options Optimal management of epileptic seizures requires a correct diagnosis. However, seizures can be difficult to detect in MPS patients as they often become evident by alterations and/or abnormalities in mental status, behavior and/or cognition, which are inherent features of MPS III and the severe phenotypes of MPS I and II [21, 28, 31, 51]. The occurrence of absence
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seizures and non-convulsive status epilepticus can be subtle, and hence difficult to observe. In
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addition, focal onset of generalized seizures may be missed when the manifestations are
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subtle [28].
According to the experts attending the meeting in Stockholm, a diagnostic work-up for
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epilepsy in MPS patients should include electrophysiological examination by EEG [23, 31] and polysomnography (PSG), the latter to exclude disordered breathing as a cause of sleep
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disturbances [56] since nocturnal epilepsy can also cause sleep disorders. They recommend EEG and PSG in MPS III and neuronopathic MPS II at diagnosis and on a yearly basis
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thereafter, ideally combined, to obtain a complete picture about any abnormalities or changes [23, 57]. Video-recording during EEG should be considered to capture possible autonomic
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activation and motor behavior [33, 43]. It should be noted that EEG and PSG can be very challenging in MPS III and neuronopathic MPS II patients, due to behavioral issues.
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Literature discussing treatment of epileptic seizures in MPS patients is limited. Clinical experience of several of the experts attending the meeting in Stockholm suggests that there are no differences in treatment between patients with MPS and other epilepsy patients. Hence, standard recommendations should be followed [48]. Treatment with anti-epileptic drugs (AEDs) is indicated when two or more seizures occur in a short interval (6 months to 1 year). However, the risk of complications due to seizures should be weighed against the risks of adverse events of AED treatment. The balance depends of the patient’s age and cognitive function. The initial therapeutic aim is to use one AED (monotherapy) as this reduces the
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Epilepsy in MPS
chance of possible side effects (such as sedation, drowsiness, and hypersensitivity reactions), allows better compliance, and is cheaper. Adding an additional AED (polytherapy) [41] will likely result in significant improvement in only 10% of patients. Withdrawal of medication should only be considered when a patient has been seizure-free for a period of 2-3 years, or even longer. Medication should not be stopped suddenly as this is associated with a relapse
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rate of 20-40%.
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Several AEDs can be used in MPS patients (Table 2) [28, 31, 33, 43]. Published findings indicate that treatment with one or, less frequently, with two AEDs is generally effective for
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controlling seizures [24, 33, 38, 41, 43, 45, 46, 53]. Most MPS patients can expect partial or complete control of seizures with appropriate treatment. Studies have shown effective control
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of epilepsy with AEDs in 79-86% of patients with MPS III or IIIA [40, 42]. A study in MPS IIIB patients reported a seizure-free rate of 50% with AED treatment [44]. Grioni et al. [28]
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reported that 69% of their MPS patients (MPS I, II, and III) were seizure-free and 31% had decreased seizure frequency with AED treatment. While generalized tonic-clonic seizures
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tended to resolve with medication, partial seizures did not completely disappear. Bonnani et al. described effective treatment of non-convulsive status epilepticus in an MPS II patient
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with ethosuximide [33]. The same group also reported successful management of nocturnal frontal lobe epilepsy in two patients with MPS II and III with clobazam (and carbamazepine) [43].
Table 2. Overview of anti-epileptic drugs that can be used in MPS patients ([48] and personal communication Dr. M. Scarpa) (shown at the end of the manuscript)
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3. Case reports on epileptic seizures in MPS disorders 3.1 Case 1: MPS II Case 1 is a male patient with neuronopathic MPS II. He was diagnosed at the age of 2 years based on dysmorphic features and skeletal disease (gibbus deformity, joint stiffness). In addition, he presented with an umbilical hernia, hepatomegaly, bilateral otitis media, and
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enlarged adenoids. Absence of detectable enzyme activity in leukocytes confirmed diagnosis
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of MPS II; molecular testing revealed the missense mutation R468Q. A developmental delay
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became apparent at the age of 3 years, when the boy started to lose acquired skills like the ability to use a pencil and to play with toys in a symbolic way. By the age of 5 years, he
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presented with day- and nighttime urinary incontinence, insomnia, and severe behavioral problems (hyperactivity and lack of impulse control), for which he received risperidone
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1 mg/day. Progressive impairment in expressive and receptive language significantly limited his communication ability, resulting in unintelligible language by the age of 6 years. Weekly
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treatment with enzyme replacement therapy (ERT) was started at 8 years of age, with home
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infusions from 13 years of age onward. Although somatic signs and symptoms and quality of life improved, ERT did not stop the neurological regression. At the age of 11 years, uncontrollable repetition of chewing and stereotyped head movement
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became apparent. Brain magnetic resonance imaging (MRI) revealed cortical atrophy, with severe ventricular enlargement, and bilateral hyperintensity in the periventricular white matter (Figure 1A and B). One year later, the patient started to suffer from simple (aware) partial seizures with secondary generalization. Brain MRI did not show any significant changes. Interictal sleep EEG showed abnormal background activity with occasional bursts of spikewave complexes in the left frontotemporal area. Seizure activity could be effectively controlled with oxcarbazepine (20 mg/kg/day).
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Figure 1. Brain magnetic resonance imaging in an 11-year old MPS II patient, showing cortical atrophy, ventricular enlargement, and bilateral hyperintensity in the periventricular white matter.
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1.5-column fitting image
By the age of 16 years, the patient presented with abnormal intermittent myoclonic
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movements of the right arm (video 1), and a change in behavior: the patient was perceived as being more disconnected from his environment. EEG recordings (Figure 2A) showed
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abnormal background slow rhythm and ictal sustained, bilateral frontal fast activity (Figure 2B), suggestive of a non-convulsive status epilepticus of frontal origin. The patient was hospitalized for 48 hours. Seizure control was achieved with intravenous lorazepam (0.1 mg/kg/dose;
twice)
and
diphenylhydantoin
(20
mg/kg/dose).
Subsequently,
the
oxcarbazepine dose was increased to 30 mg/kg/day and risperidone treatment for insomnia and severe behavioral problems was withdrawn. Over the next weeks, levetiracetam was added at 250 mg/12 hours and then 500 mg/12 hours. When the patient became more sleepy and hypoactive, a new brain MRI scan showed worsening of ventricular enlargement and ventriculoperitoneal shunting was performed. After surgery, the patient’s alertness and mood 10
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improved and the seizures did not recur. The EEG after shunting showed marked improvement in background activity with disappearance of frontal epileptic activity. Because of persistence of isolated interictal focal spikes, the patient remained on a prophylactic low dosis of levetiracetam (20 mg/kg/day). Infusions with ERT were continued without change. Epilepsy in this patient was probably related to hydrocephalus, which is a common
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complication in MPS.
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Video 1. Example of myoclonic movements in the right arm of the MPS II patient described in case 1 at the age of 16 years.
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Please use colors for reproduction of this figure in the online version and black & white for
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1-column fitting image of the video
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the printed version.
Figure 2. Electroencephalography in the MPS II patient described in case 1 at the age of 16 years (A), showing left frontal lobe discharges indicative of status epilepticus (B). Please use colors for reproduction of this figure in the online version but black & white for the 11
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printed version.
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2-column fitting image
This case report shows how severe neurocognitive deficits in MPS II can hinder recognition
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of non-convulsive status epilepticus. In addition, it demonstrates that hydrocephalus, often
epilepticus.
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3.2 Case 2: MPS VI
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under-recognized or mistaken for only brain atrophy, can be related to non-convulsive status
Case 2 is an adult female patient with slowly progressing MPS VI. She started ERT in 2007 at the age of 15 years, but is on intermittent treatment since 2016 due to governmental issues. Previous brain MRI exams showed mild ventriculomegaly. The patient had complaints of migraine and anxiety, for which she was treated with sertraline (25 mg/day) in 2012. Despite good response, the patient decided to suspend sertraline after one year of treatment. One year later, in 2013, a focal seizure was noted during administration of ERT (video 2). From the age of 23 years, the family also reported focal seizures, characterized by a sudden arrest of
12
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talking, which resumed after a few seconds to minutes, not consciously experienced by the patient.
Video 2. Example of focal seizure with impaired awareness in the MPS VI patient described in case 2.
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Please use colors for reproduction of this figure in the online version and black & white for
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the printed version.
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1-column fitting image of the video
Brain MRI did not reveal any changes (Figure 3), but EEG findings were compatible with focal epilepsy. The EEG, performed in 2014 while the patient was awake with two hyperventilation proofs and photonic stimulation, showed normal basal activity but slow theta wave and delta waves in the bilateral fronto-temporal hemispheres occurring independently and bi-synchronous, and more frequently in the left hemisphere. A year later, another EEG recording showed acute wave type epileptiform seizures and slow waves in the left frontotemporal with the maximum negative activity in the anterior temporal area; there were also acute wave type epileptiform paroxysms in the left temporal-parietal with the maximum 13
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Epilepsy in MPS
negative activity in the medium temporal area. Seizure control was not achieved with carbamazepine (200 mg/day) treatment. Therefore, treatment with valproic acid was started. She initially received high doses of valproic acid (1500 mg/day), which caused side effects of hand tremor, gait instability, and hair loss. Therefore, the dose was gradually decreased to 250 mg/day. This led to improvements in tremor, but the complaints of hair loss persisted. The
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patient also started using lamotrigine (125 mg/day) at that time. Lamotrigine caused
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cutaneous rash that disappeared with a lower dose. Since the patient had persistent side effects
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of lamotrigine, the dose was further decreased progressively to 25 mg/day until cessation. Valproic acid treatment was also stopped at her last visit since the patient could not tolerate
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higher doses. The patient had 10-12 seizures/month while receiving valproic acid and lamotrigine therapy. When she switched to monotherapy with topiramate (eventually 175
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mg/day), crisis, she was free of seizures for almost 8 months. The patient’s family did not report any epileptic events during sleep, although sleep deprivation (when she had to get up
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very early) may have been a trigger for some of her seizures. Considering the limited evidence for occurrence of epileptic seizures in MPS VI patients, it is questionable whether
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epilepsy.
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the seizures were related to the MPS disorder. None of the patient’s parents had a history of
Figure 3. Brain MRI of the MPS VI patient described in case 2 showing no brain abnormalities; A-C T1-weighted, D T2-weighted. 1.5-column fitting image
14
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4. Conclusions
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Supplement MPS and the brain
Currently available literature shows that epilepsy is a frequent manifestation of MPS
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disorders, occurring in approximately 30% of patients. Patients with MPS I and, particularly, MPS II and III are most prone to develop epilepsy. Seizures in MPS patients are mostly tonicclonic, but myoclonic, absence, focal seizures, non-convulsive status epilepticus, nocturnal myoclonic jerks, and frontal lobe epilepsy have been reported as well, although less frequently. The incidence and severity of seizure activity on EEG recordings tends to increase with disease progression. Detection of epileptic activity in MPS patients can be difficult as seizures can be subtle and may be difficult to recognize in patients who already have cognitive deficits and behavioral problems. This highlights the importance of regular monitoring of epileptic activity in these 15
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patients, ideally with (video-)EEG (potentially combined with PSG), to detect changes in electrical activity. Despite the high prevalence and debilitating nature of epilepsy in MPS patients, current literature on the pathophysiology, clinical presentation, and treatment of seizures in these patients remains extremely limited. As seizure activity and changes in cognition and behavior
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seem to be intertwined, the mutual interaction between both manifestations (including the
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potential role of hydrocephalus) requires further investigation. In addition, the association
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between nocturnal seizures and non-respiratory sleep disorders, which very commonly occur in MPS II and MPS III patients [58], deserves more attention. Finally, there is need for more
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clinical data about the effects and side effects of different AEDs in MPS patients. In order to broaden current knowledge, researchers should be encouraged to publish their experiences
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with epilepsy in MPS patients.
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Financial disclosures Dr. Scarpa received unrestricted research and educational grants from Actelion, BioMarin, Genzyme, and Shire. He has no personal financial interests in any of the drugs produced for lysosomal storage disorders. Dr. Lourenço received travel grants, speaker honoraria, investigator fees, and unrestricted
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research and/or educational grants from Actelion, Amicus, BioMarin, Genzyme, Pfizer,
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Protalix, and Shire.
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Dr. Amartino is a contracted investigator for Shire, Amicus, BlueBirdBio and received
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honoraria and travel support from BioMarin and consulting fees from Shire.
Consent for publication
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Written informed consent was obtained for publication of these case reports and any
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Acknowledgements
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accompanying images. A copy of the written consent is available.
The authors are grateful to Ismar Healthcare NV for their assistance in the writing of this
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manuscript, which was funded by BioMarin Pharmaceutical Inc. The expert meeting in Stockholm was also sponsored by BioMarin Pharmaceutical Inc.
Funding
This work was supported by BioMarin Pharmaceutical Inc.
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Tables Table 1. Overview of the reported prevalence and onset age of epileptic seizures in MPS disorders. Reference
MPS type; N
Grioni 2010 [28]
MPS I (HSCT); N=10 MPS I (no HSCT); N=7 § MPS II; N=16 § MPS III; N=13 MPS IV; N=11 MPS VI; N=4 § MPS I, II, III, IV, and VI; N=16 MPS I, II, III, IV, and VI; N=58 MPS I; N=20 MPS II; N=22 MPS VI; N=12 Neuronopathic MPS II; N=52 Attenuated MPS II; N=31 MPS II; N=52
Albuquerque 2010 [31] Kuzenkova 2013 [29] Mendes 2016 [30]
Young 1982 [36] Young 1983 [24]
Age (years)* Prevalence of seizures 8 0 28 29% 16 31% 17 46% 18 0 6 0 10.3 25% 9.5
C A
Diagnostic tool
-
-
Neurological evaluation Clinical examination
Focal (partial) seizures Focal (partial) seizures Focal (partial) seizures -
I R
T P
C S
U N
Range 7-30 Range 0.9-28 Range 3-26 -
0 19% 17% 59% 3% 63%
Generalized tonic & atonic Partial with generalization Generalized tonic-clonic
Range 2-17 7 and 21 12 10
Median 8.2
13%
-
-
T P
E C
Seizure onset age (years)* 14 and 31 10 13 -
A M
41%
D E
Main type of seizure
Schwartz 2007 [35]
MPS II; N=77
Holt 2011 [15]
MPS II; N=50
6.0
34%‡
-
-
JiménezArredondo [37]
MPS II; N=9
7.3
56%
Generalized tonic-clonic
-
Video EEG Neurological evaluation
EEG
Clinical examination Interview Medical records Clinical evaluation Questionnaire Clinical evaluation Medical records
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MPS type; N
Nidiffer 1983 [40] Cleary 1993 [39] Moog 2007 [44]
Epilepsy in MPS Main type of seizure
MPS III; N=30 MPS IIIA, B, and C; N=62 MPS IIIB; N=20
Age (years)* Prevalence of seizures 10.4 52% 26% 55%
Ruijter 2008 [46]
MPS IIIC; N=29
-
45%
-
Valstar 2010 [42]
MPS IIIA; N=110
-
66%
-
Valstar 2010 [45]
MPS IIIB; N=52
-
51%
Héron 2011 [25]
MPS IIIA; N=76 MPS IIIB; N=16 MPS IIIC; N=13 MPS IIID; N=6 MPS IIIA, B, and C; N=55
13
Delgadillo 2013 [41]
D E
E C
T P
Generalized tonic-clonic Generalized tonic-clonic
U N
A M
40% 50% 31% 17% 45%
T P
I R
C S
Seizure onset age (years)* 6.9 >8 34.3
23
Median 11
-
>9
Generalized tonic-clonic
8.7 8.8 Range 8-31 9.4 Median 8.7 MPS IIIA: 7 MPS IIIB: 12.5 MPS IIIC: 10.4
C A
Diagnostic tool Questionnaire Clinical evaluation Interview Medical records Clinical evaluation Questionnaire Medical records Clinical evaluation Questionnaire Medical records Clinical evaluation Questionnaire Medical records Clinical evaluation Medical records Clinical evaluation
Questionnaire
* Age and onset age are presented as mean unless indicated otherwise ‡ Seizure-like behavior § Treated with enzyme replacement therapy since time it was commercially available HSCT: hematopoietic stem cell transplantation; -: not reported
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Table 2. Overview of anti-epileptic drugs that can be used in MPS patients ([48] and personal communication Dr. M. Scarpa) Type of seizure
Medication
Used in MPS disorder
Generalized tonic-clonic seizures Drug of choice: carbamazepine, valproic acid, phenobarbital,
T P
I, II, and III [28]
Alternatives: topiramate, phenytoin†, lamotrigine (as adjunct or alone), gabapentin (as adjunct) Focal seizures
I R
C S
Drug of choice: carbamazepine, topiramate, valproic acid
I, II, and III [28]
U N
Alternatives: phenobarbital, phenytoin†, lamotrigine (as adjunct or alone), gabapentin (as adjunct) Absence
A M
Drug of choice: valproic acid, ethosuximide
D E
II [33]
Alternatives: clonazepam, lamotrigine Myoclonic, Atonic
T P
Drug of choice: valproic acid
E C
Alternative: clonazepam Status epilepticus
C A
Drug of choice: diazepam (intravenous), phenytoin (intravenous), valproic acid
II and III [28]
Alternative: phenobarbital (intravenous)
Febrile seizures
Diazepam (rectal* or intravenous)
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* Preferred; † Phenytoin should not be used as first choice in generalized or focal seizures as it produces gingival hypertrophy, which is also a manifestation of MPS.
T P
I R
C S
U N
D E
A M
T P
E C
C A
29