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EEG findings during “paroxysmal hemiplegia” in a patient with GLUT1-deficiency
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 7 ) 1 e3
Official Journal of the European Paediatric Neurology Society
Case study
EEG findings during “paroxysmal hemiplegia” in a patient with GLUT1-deficiency S. Pellegrin*,a, G. Cantalupo a, R. Opri, B. Dalla Bernardina, F. Darra Child Neuropsychiatry, University of Verona, Verona, Italy
article info
abstract
Article history:
Background: A growing number of studies have disclosed the myriad of features that can
Received 1 June 2016
suggest the diagnosis of a Glucose-transporter-1 deficiency (GLUT1D). The occurrence of
Received in revised form
paroxysmal movement disorders such as exercise-induced dystonia and non-kinesigenic
9 January 2017
dyskinesia, received considerable emphasis, while limited attention has been paid to
Accepted 9 January 2017
other paroxysmal phenomena, as transitory neurological disorders. These paroxysmal events are roughly and variably described as limb weakness, hemiparesis or ataxia. Their
Keywords:
EEG correlate has been never documented.
Paroxysmal movement disorder
Case description and conclusion: We report the EEG pattern characterizing two acute episodes
GLUT1
of paroxysmal paresis with confusion and aphasia, in a girl with GLUT1D. The EEG picture
Hemiplegia
is characterized by a clear-cut contralateral EEG slowing, similar to what is observed in
EEG
Alternating Hemiplegia of Childhood and Hemiplegic Migraine attacks. In our patient the paroxysmal events were responsive to a ketogenic diet. © 2017 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
1.
Introduction
The Glucose-transporter-1 deficiency (GLUT1D) is associated with an heterogeneous phenotype characterized by chronic neurological and cognitive disturbances, associated with epileptic and/or non-epileptic paroxysmal manifestations. According to the literature the non-epileptic paroxysmal manifestations seem to affect about one third of the subjects with GLUT1D (28% Pons et al., 39% Ito et al.).1,2 There is no consensus on the nosology of these episodes and video-EEG recordings obtained during these paroxysmal events are lacking.
2.
Case study
The patient is a 11-year-old girl, affected by GLUT1 deficiency (GLUT1D) due to a pathogenic de novo heterozygous mutation in the SLC2A1 gene (c.418G>A; V104M). The clinical picture was characterized by acquired microcephaly, intellectual disability with severe language dysfunction, dyspraxia, ataxic gait, and seizures. Seizures appeared at the age of 18 months, as “atypical absences with atonic myoclonic component”, abolished by valproate since the age of 25 months. Since the age of 3 years she began to display self-limiting episodes, lasting few hours, without precipitating factors,
* Corresponding author. Child Neuropsychiatry, University of Verona, p.le L.A. Scuro, 10, 37134, Verona, Italy. Fax: þ39 (0)45 802 7475. E-mail address: [email protected] (S. Pellegrin). a These authors contributed equally to the manuscript. http://dx.doi.org/10.1016/j.ejpn.2017.01.002 1090-3798/© 2017 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. Please cite this article in press as: Pellegrin S, et al., EEG findings during “paroxysmal hemiplegia” in a patient with GLUT1-deficiency, European Journal of Paediatric Neurology (2017), http://dx.doi.org/10.1016/j.ejpn.2017.01.002
2
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 7 ) 1 e3
Fig. 1 e EEG findings during paroxysmal events. A: EEG at 5 years 4 months, performed during the resolution phase (about 10 min after left upper limb paroxysmal monoparesis recovery). Note the predominance of slow waves in the right hemisphere posterior region. B: EEG recorded at 9 years 10 months, during right hemiplegic paroxysmal episode, about 1 h after the onset. Note the marked inter-hemispheric asymmetry, with slow polymorphic delta-theta wave on the left hemisphere.
characterized by acute asthenia, postural instability (ataxia), somnolence, sometimes accompanied with autonomic symptoms as vomiting and pallor. These paroxysmal episodes occurred with frequency of 6e8 episodes/year, mostly isolated, sometimes in clusters lasting 2e3 days. At least in three occasions, between age 3 and 5 years, these episodes were also characterized by upper limb monoparesis (two times left and one time right). The diagnosis of GLUT1D was suspected and genetically confirmed at 5 years of age; CSF glucose analysis was never
performed. In addition to the ongoing antiepileptic treatment with valproate, a classic ketogenic diet (KD) with 3:1 ratio was introduced, with multivitamin and carnitine supplementation. During the induction phase ketone blood levels of 34,5 mmol/l were reached. The following home-monitoring was conducted measuring only urine ketones, because of poor compliance for blood testing. The ketogenic diet led to slow progressive improvement in movement and language disorder, and to the disappearance of the paroxysmal nonepileptic events.
Please cite this article in press as: Pellegrin S, et al., EEG findings during “paroxysmal hemiplegia” in a patient with GLUT1-deficiency, European Journal of Paediatric Neurology (2017), http://dx.doi.org/10.1016/j.ejpn.2017.01.002
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 7 ) 1 e3
The adherence to KD was fluctuating and at least in two occasions e corresponding to the reappearance of paroxysmal non-epileptic episodes e the diet was discontinued. We were able to perform an EEG recording during or soon after these two episodes. The first one occurred at the age of 5 years and 4 months and was characterized by left upper limb monoparesis, pallor, vomiting, and disorientation, with spontaneous recovery after 30e40 min; the EEG performed during the resolution phase (10 min after improvement of motor function) showed a slight predominance of slow waves in the right posterior region (Fig. 1A). The second episode e 9 years and 10 months e was characterized by right lower limb weakness, followed by ipsilateral upper limb paresthesia and motor deficit, vomiting, and aphasia. The EEG recording performed during the episode, 1 h after the onset of the symptoms, showed a marked interhemispheric asymmetry, with slow polymorphic delta-theta waves on the left hemisphere, predominant on the frontocentro-temporal regions, in the absence of epileptiform abnormalities (Fig. 1B). After sleeping 2 h, on awakening the clinical and EEG picture returned to baseline. We were not able to perform neuroimaging during or soon after the episode, however the brain MRI study obtained 4 days later, didn't show any abnormality. The patient discontinued the ketogenic diet in the days preceding both episodes, as documented by undetectable urine and blood ketones on admission. After the episodes KD was reintroduced, and after the second episode a good adherence the diet has been documented by a stable ketosis. In the following years the girl did not experience any other paroxysmal events up to the actual age of 11 years and 4 months.
3.
Discussion
Some non-epileptic paroxysmal events in GLUT1D are clearly classifiable as movement disorders (i.e. paroxysmal exerciseinduced dystonia, and paroxysmal non-kinesigenic dyskinesia), others are described as prolonged episodes (hours) characterized by the variable combination of migraine, autonomic symptoms, confusion, dysphoria, intermittent ataxia, and mono-/hemi-/tetraplegia.1,2 The episodes we here reported belong to the latter phenomena. We had the chance to document that an EEG pattern of unilateral slowing, contralateral to the affected body side, characterize these acute episodes. An EEG background activity
3
slowing has been well documented in literature during fasting in GLUT1D,2 but the finding of unilateral poor reactive theta delta slowing is a completely different picture and is similar to that observed during Alternating Hemiplegia of Childhood (AHC) or Hemiplegic Migraine (HM) attacks. In literature, there are anecdotal reports of GLUT1D patients with clinical features of AHC or HM.3,4 Moreover, one recently described patient e bearing a pathogenic SLC2A1 mutation e presented with overlapping symptoms of both AHC and HM.5 On the contrary, the clinical features of our cases do not overlap with those of AHC and neither to those of HM, in particularly the girl never experienced abnormal ocular movements nor headache. Therefore, the similarity of the EEG pattern does not suggest an overlapping of the two conditions in our patient, instead it suggests a common basis for the expression of these paroxysmal non-epileptic events in different conditions. In conclusion, the pathophysiology of paroxysmal manifestations with motor deficit associated with autonomic symptoms in the context of GLUT1D remains unknown. However, the similarities in the EEG pattern we documented suggest that these episodes can share an analogous physiopathogenic mechanism with AHC and HM.
Conflict of interest All author declare to have nothing to disclose.
references
1. Pons R, Collins A, Rotstein M, Engelstad K, De Vivo DC. The spectrum of movement disorders in Glut-1 deficiency. Mov Disord 2010;25:275e81. 2. Ito Y, Takahashi S, Kagitani-Shimono K, et al. Nationwide survey of glucose transporter-1 deficiency syndrome (GLUT1DS) in Japan. Brain Dev 2015;37:780e94. 3. Rotstein M, Doran J, Yang H, et al. Glut1 deficiency and alternating hemiplegia of childhood. Neurology 2009;73:2042e4. 4. Mohammad SS, Coman D, Calvert S. Glucose transporter 1 deficiency syndrome and hemiplegic migraines as a dominant presenting clinical feature. J Paediatr Child Health 2014;50:1025e6. 5. Weller CM, Leen WG, Neville BG, et al. A novel SLC2A1 mutation linking hemiplegic migraine with alternating hemiplegia of childhood. Cephalalgia 2015;35:10e5.
Please cite this article in press as: Pellegrin S, et al., EEG findings during “paroxysmal hemiplegia” in a patient with GLUT1-deficiency, European Journal of Paediatric Neurology (2017), http://dx.doi.org/10.1016/j.ejpn.2017.01.002
Official Journal of the European Paediatric Neurology Society
Case study
EEG findings during “paroxysmal hemiplegia” in a patient with GLUT1-deficiency S. Pellegrin*,a, G. Cantalupo a, R. Opri, B. Dalla Bernardina, F. Darra Child Neuropsychiatry, University of Verona, Verona, Italy
article info
abstract
Article history:
Background: A growing number of studies have disclosed the myriad of features that can
Received 1 June 2016
suggest the diagnosis of a Glucose-transporter-1 deficiency (GLUT1D). The occurrence of
Received in revised form
paroxysmal movement disorders such as exercise-induced dystonia and non-kinesigenic
9 January 2017
dyskinesia, received considerable emphasis, while limited attention has been paid to
Accepted 9 January 2017
other paroxysmal phenomena, as transitory neurological disorders. These paroxysmal events are roughly and variably described as limb weakness, hemiparesis or ataxia. Their
Keywords:
EEG correlate has been never documented.
Paroxysmal movement disorder
Case description and conclusion: We report the EEG pattern characterizing two acute episodes
GLUT1
of paroxysmal paresis with confusion and aphasia, in a girl with GLUT1D. The EEG picture
Hemiplegia
is characterized by a clear-cut contralateral EEG slowing, similar to what is observed in
EEG
Alternating Hemiplegia of Childhood and Hemiplegic Migraine attacks. In our patient the paroxysmal events were responsive to a ketogenic diet. © 2017 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
1.
Introduction
The Glucose-transporter-1 deficiency (GLUT1D) is associated with an heterogeneous phenotype characterized by chronic neurological and cognitive disturbances, associated with epileptic and/or non-epileptic paroxysmal manifestations. According to the literature the non-epileptic paroxysmal manifestations seem to affect about one third of the subjects with GLUT1D (28% Pons et al., 39% Ito et al.).1,2 There is no consensus on the nosology of these episodes and video-EEG recordings obtained during these paroxysmal events are lacking.
2.
Case study
The patient is a 11-year-old girl, affected by GLUT1 deficiency (GLUT1D) due to a pathogenic de novo heterozygous mutation in the SLC2A1 gene (c.418G>A; V104M). The clinical picture was characterized by acquired microcephaly, intellectual disability with severe language dysfunction, dyspraxia, ataxic gait, and seizures. Seizures appeared at the age of 18 months, as “atypical absences with atonic myoclonic component”, abolished by valproate since the age of 25 months. Since the age of 3 years she began to display self-limiting episodes, lasting few hours, without precipitating factors,
* Corresponding author. Child Neuropsychiatry, University of Verona, p.le L.A. Scuro, 10, 37134, Verona, Italy. Fax: þ39 (0)45 802 7475. E-mail address: [email protected] (S. Pellegrin). a These authors contributed equally to the manuscript. http://dx.doi.org/10.1016/j.ejpn.2017.01.002 1090-3798/© 2017 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. Please cite this article in press as: Pellegrin S, et al., EEG findings during “paroxysmal hemiplegia” in a patient with GLUT1-deficiency, European Journal of Paediatric Neurology (2017), http://dx.doi.org/10.1016/j.ejpn.2017.01.002
2
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 7 ) 1 e3
Fig. 1 e EEG findings during paroxysmal events. A: EEG at 5 years 4 months, performed during the resolution phase (about 10 min after left upper limb paroxysmal monoparesis recovery). Note the predominance of slow waves in the right hemisphere posterior region. B: EEG recorded at 9 years 10 months, during right hemiplegic paroxysmal episode, about 1 h after the onset. Note the marked inter-hemispheric asymmetry, with slow polymorphic delta-theta wave on the left hemisphere.
characterized by acute asthenia, postural instability (ataxia), somnolence, sometimes accompanied with autonomic symptoms as vomiting and pallor. These paroxysmal episodes occurred with frequency of 6e8 episodes/year, mostly isolated, sometimes in clusters lasting 2e3 days. At least in three occasions, between age 3 and 5 years, these episodes were also characterized by upper limb monoparesis (two times left and one time right). The diagnosis of GLUT1D was suspected and genetically confirmed at 5 years of age; CSF glucose analysis was never
performed. In addition to the ongoing antiepileptic treatment with valproate, a classic ketogenic diet (KD) with 3:1 ratio was introduced, with multivitamin and carnitine supplementation. During the induction phase ketone blood levels of 34,5 mmol/l were reached. The following home-monitoring was conducted measuring only urine ketones, because of poor compliance for blood testing. The ketogenic diet led to slow progressive improvement in movement and language disorder, and to the disappearance of the paroxysmal nonepileptic events.
Please cite this article in press as: Pellegrin S, et al., EEG findings during “paroxysmal hemiplegia” in a patient with GLUT1-deficiency, European Journal of Paediatric Neurology (2017), http://dx.doi.org/10.1016/j.ejpn.2017.01.002
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 7 ) 1 e3
The adherence to KD was fluctuating and at least in two occasions e corresponding to the reappearance of paroxysmal non-epileptic episodes e the diet was discontinued. We were able to perform an EEG recording during or soon after these two episodes. The first one occurred at the age of 5 years and 4 months and was characterized by left upper limb monoparesis, pallor, vomiting, and disorientation, with spontaneous recovery after 30e40 min; the EEG performed during the resolution phase (10 min after improvement of motor function) showed a slight predominance of slow waves in the right posterior region (Fig. 1A). The second episode e 9 years and 10 months e was characterized by right lower limb weakness, followed by ipsilateral upper limb paresthesia and motor deficit, vomiting, and aphasia. The EEG recording performed during the episode, 1 h after the onset of the symptoms, showed a marked interhemispheric asymmetry, with slow polymorphic delta-theta waves on the left hemisphere, predominant on the frontocentro-temporal regions, in the absence of epileptiform abnormalities (Fig. 1B). After sleeping 2 h, on awakening the clinical and EEG picture returned to baseline. We were not able to perform neuroimaging during or soon after the episode, however the brain MRI study obtained 4 days later, didn't show any abnormality. The patient discontinued the ketogenic diet in the days preceding both episodes, as documented by undetectable urine and blood ketones on admission. After the episodes KD was reintroduced, and after the second episode a good adherence the diet has been documented by a stable ketosis. In the following years the girl did not experience any other paroxysmal events up to the actual age of 11 years and 4 months.
3.
Discussion
Some non-epileptic paroxysmal events in GLUT1D are clearly classifiable as movement disorders (i.e. paroxysmal exerciseinduced dystonia, and paroxysmal non-kinesigenic dyskinesia), others are described as prolonged episodes (hours) characterized by the variable combination of migraine, autonomic symptoms, confusion, dysphoria, intermittent ataxia, and mono-/hemi-/tetraplegia.1,2 The episodes we here reported belong to the latter phenomena. We had the chance to document that an EEG pattern of unilateral slowing, contralateral to the affected body side, characterize these acute episodes. An EEG background activity
3
slowing has been well documented in literature during fasting in GLUT1D,2 but the finding of unilateral poor reactive theta delta slowing is a completely different picture and is similar to that observed during Alternating Hemiplegia of Childhood (AHC) or Hemiplegic Migraine (HM) attacks. In literature, there are anecdotal reports of GLUT1D patients with clinical features of AHC or HM.3,4 Moreover, one recently described patient e bearing a pathogenic SLC2A1 mutation e presented with overlapping symptoms of both AHC and HM.5 On the contrary, the clinical features of our cases do not overlap with those of AHC and neither to those of HM, in particularly the girl never experienced abnormal ocular movements nor headache. Therefore, the similarity of the EEG pattern does not suggest an overlapping of the two conditions in our patient, instead it suggests a common basis for the expression of these paroxysmal non-epileptic events in different conditions. In conclusion, the pathophysiology of paroxysmal manifestations with motor deficit associated with autonomic symptoms in the context of GLUT1D remains unknown. However, the similarities in the EEG pattern we documented suggest that these episodes can share an analogous physiopathogenic mechanism with AHC and HM.
Conflict of interest All author declare to have nothing to disclose.
references
1. Pons R, Collins A, Rotstein M, Engelstad K, De Vivo DC. The spectrum of movement disorders in Glut-1 deficiency. Mov Disord 2010;25:275e81. 2. Ito Y, Takahashi S, Kagitani-Shimono K, et al. Nationwide survey of glucose transporter-1 deficiency syndrome (GLUT1DS) in Japan. Brain Dev 2015;37:780e94. 3. Rotstein M, Doran J, Yang H, et al. Glut1 deficiency and alternating hemiplegia of childhood. Neurology 2009;73:2042e4. 4. Mohammad SS, Coman D, Calvert S. Glucose transporter 1 deficiency syndrome and hemiplegic migraines as a dominant presenting clinical feature. J Paediatr Child Health 2014;50:1025e6. 5. Weller CM, Leen WG, Neville BG, et al. A novel SLC2A1 mutation linking hemiplegic migraine with alternating hemiplegia of childhood. Cephalalgia 2015;35:10e5.
Please cite this article in press as: Pellegrin S, et al., EEG findings during “paroxysmal hemiplegia” in a patient with GLUT1-deficiency, European Journal of Paediatric Neurology (2017), http://dx.doi.org/10.1016/j.ejpn.2017.01.002