Typical and Atypical Epilepsy Phenotypes of Amenably Treatable

Infantile Epilepsies December 9, 2013

MOHAMAD MIKATI MD

Davison Professor of Pediatrics, Professor of Neurobiology, Chief, Division of Pediatric

Neurology, Duke University

American Epilepsy Society | Annual Meeting

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Disclosure

None

American Epilepsy Society | 2013 Annual Meeting

Most of the therapies mentioned for the rare disorders I present are

not FDA approved

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Learning Objectives

• Recognize the spectrum of presentations of amenably treatable infantile epileptic encephalopathies:

•Things are not always what they seem

•Develop strategies to diagnose such disorders in the clinic

•Make it simple

American Epilepsy Society | 2013 Annual Meeting 3

Vitamin Responsive Syndromes Other Disorders

Clinical Approach and Utility

Outline

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Presentations of Biotinidase Deficiency

• Symptoms usually begin at 2 to 3 months of age and consist of: seizures (which can be generalized tonic-clonic, myoclonic, or infantile spasms), hypotonia, episodic ataxia, respiratory disturbances, high-frequency hearing loss, optic atrophy, and developmental delay dermatitis, alopecia, conjunctivitis, and chronic candidiasis.

• We reported the occurrence of Biotinidase deficiency with infantile spasms and mental delay without rash or other Sxs.

Mikati et al. J Child Neurol. 2006 Nov;21(11):978-81

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Presentations of Biotinidase Deficiency New Insights

• Bunch et al. reported occurrence of frontal subcortical cysts, mega cisterna magna with generalized epilepsy

• Singhi and Ray reported presentation as Ohtahara syndrome.

• Krishanakumar et al. reported presentation with low CSF glucose and high lactate ~ to GLUT1 deficiency

Bunch and Singh Seizure. 2011 Jan;20(1):83-6. NYU Singhi and Ray. J Child Neurol. 2011 Apr;26(4):507-9. Chandighar

Jkrishnakumar D et al. Child Neurol. 2012 Dec 6. [Epub ahead of print] Addenbrooke’s Hosp Cambridge 6

The syndrome of Biotin/Thiamine Responsive Epilepsy

• We described a infantile onset milder form with mild neonatal seizures mild delay and reversal of MRI changes on Biotin.

• Yamada: severe infantile (2-11 m) form epileptic spasms cerebral-cerebellar atrophy, increased signal in basal ganglia, thalami multifocal spikes, no hypsarrhythmia.

Ozand PT, et al. Brain. 1998 Jul;121 ( Pt 7):1267-79. Tabarki et al. Neurology 2013;80:261–267. El-Hajj TI, Karam PE, Mikati MA. Neuropediatrics. 2008

Oct;39(5):268-71.Yamada et al. BMC Medical Genetics 2010, 11:171.

• Ozand: autosomal recessive, dystonia seizures and neurological deterioration due to SLC19A3 mutation with onset in childhood and response to out to both Biotin (dose: 2-3mg/kg) and Thiamine (100-300mg/d).

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Cerebral Folate Deficiency

Gordon et al Developmental Medicine & Child Neurology 2009, 51: 180–182.Bonkowsky et a.. Journal of Child Neurology Volume 23 Number 12 December 2008 1460-1463

• Etiology: mutations in the FOLR1 (folate receptor alpha gene), blocking antibodies for folate receptors or secondary to mitochondrial disorders, Rheumatoid arthritis, Rett, autism.

• Onset: 4-6months of age with delay in development,, hypotonia, and ataxia, dyskinesias (choreo-athetosis, hemiballismus), spasticity, epilepsy and a times progressive encephalopathy.

• Treatment of the condition with folinic acid 0.5-3 mg/kg/day.

(A) Left hemisphere 3-4 Hz spike and wave discharges. (B) Mild cerebellar

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Cerebral Folate Deficiency Recent Insights

Steele SU, Cheah SM, Veerapandiyan A, Gallentine W, Smith EC, Mikati MA. Electroencephalographic and seizure manifestations in two patients with folate receptor autoimmune antibody-mediated primary cerebral folate deficiency. Epilepsy Behav. 2012 Aug;24(4):507-12.

• Seizures: myoclonic astatic, tonic, myoclonic, rarely focal • EEG: Generalized 3-4 Hz SSW, multifocal spikes • We reported occurrence of infantile spasms and of

electrical status epilepticus, ESES, in sleep as epileptic manifestation of cerebral folate deficiency

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Pyridoxine Dependent Epilepsy

• Seizures: partial + generalization, myoclonic, atonic.

• Transient response to AEDs was observed

• An early encephalopathy with an apparent ocular apraxia

• EEG: Suppression burst, Generalized irregular SSW, uni or bilateral EEG szs, multifocal spikes, hysarrhythmia

Pearl PLJ Inherit Metab Dis. 2009 Apr;32(2):204-13 . Gospe SM Chang Gung Med J. 2010 Jan-Feb;33(1):1-12. Mikati et al, Electroencephalogr Clin Neurophys 1991;78:215

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Pyridoxine Dependent Epilepsy Recent Insights

• We reported that EEG burst suppression may fluctuate for up to 5 days after start of therapy

• Others reported presence of cerebral atrophy, mega cisterna magna hydrocephalus, FCD and thin posterior CC common (abnormal MRI in half)

• Low lysine diet,folinic acid (folinic responsive szs allelic)

Naasan et al. Epileptic Disord 2009; 11 (4): 1-8. Bok LA et al Developmental Medicine & Child Neurology 2012, 54: 849–854. Baxter 1996, Gospe 1998. van Karnebek et al. Mol Genet Metab. 2012 Nov;107(3):335-

44. 11

Pyridoxine Responsive Seizures

• The UK survey identified infants and children who responded to pyridoxine and in whom it was later discontinued without recurrence

• Some children with infantile spasms respond to pyridoxine (12% in largest series)

• Struys et al reported 2 sibs with B6-responsive szs and increased urinary α-AASA. Subsequent studies: molybdenum cofactor deficiency due to homozygous MOCS2 mutation.

Baxter P Developmental Medicine & Child Neurology 2001, 43: 416–420 Struys EA et al. ,Pediatrics 2012;130;e1716; Netherlands

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Pyridoxal-5-Phospahte Dependent Epilepsy

• Presents neonatally with mostly myoclonic, but also tonic, and clonic, seizures and status epilepticus with burst suppression pattern on EEG.

B. Schmitt, M. Baumgartner, P.B. Mills et al.Seizures and paroxysmal events: symptoms pointing to the diagnosis of pyridoxine-dependent epilepsy and pyridoxine phosphate oxidase deficiency Dev Med Child Neurol, 52 (2010), pp. e133–e142. A. Veerapandiyan et al. / Epilepsy &

Behavior 20 (2011) 494–501

• We reported the occurrence of neonatal tonic SE, of focal SE and of ESES in P5P dependent epilepsy

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Vitamin Responsive Syndromes Other Disorders

Clinical Approach and Utility

Outline

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Brain Malformations in Inborn Errors of Metabolism

Mikati MA, et al. Pediatr Neurol 2007;36:48-50.Kerrigan JF et al. Ann Neurol 2000;47: 583-8. Caruso PA et al.Neuroradiology 2004;46:3-14. Levy HL et al. J Pediatr 1996;128:770-5. Nissenkorn A et al. Neurology 2001;56:1265-72. Brown GK. J. Inherit. Metab.Dis. 28 (2005) 393^401

• Agenesis of the corpus callosum has been reported with peroxisomal disorders, mitochondrial disease, maternal phenylketonuria, nonketotic hyperglycinemia, and Smith-Lemli-Opitz

• Mitochondrial disease: Cortical dysplasia, heterotopias, aplasia of the corticospinal tracts dysplasia of inferior olive

• SCAD: We reported a case of short-chain acyl-coenzyme A dehydrogenase deficiency with West syndrome, frontal meningocele, abnormal cortical gyration, and partial corpus callosum agenesis

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Presentations of EAST Syndrome

• KCNJ10 (Kir4.1) encodes an inwardly rectifying K channel

• Presents first with GTCs in the infancy and later patients develop hyokalemic alkalosis ataxia and sensorineural hearing loss as they fail to speak or walk

• MRI: increased signal in CBL nuclei, thin cord

Cross JH et al. Developmental Medicine and Child Neurology Volume 55, Issue 9, September 2013, Pages 846-856 Neurological features of epilepsy, ataxia, sensorineural deafness, tubulopathy syndrome

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Favorable Outcome in Molybdenum Cofactor Type A Deficiency Treated With cPMP

• Newborn started on a daily cPMP dose of 80 mg/kg at 4 hours of age normalized S-sulfocysteine, uric acid, and xanthine levels

• Therapy stopped seizures prevented regression normalized exam and almost normalized long term outcome at 21 m.

Veldman A, Santamaria-Araujo JA, Sollazzo S, et al. Successful treatment of molybdenum cofactor deficiency type A with cPMP. Pediatrics. 2010;125(5). Hitzet M et al. Pediatrics 2012;130:e1005–e1010Groningen

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CSF Neurotransmitter Disorders

• Presentation: developmental delay, movement disorders and epilepsy

• Therapy: Often benefit from one or more of: L-Dopa tetrahydrobiopterin, tryptophan, folinic acid

Pons R. J Inherit Metab Dis (2009) 32:321–332, Springer.

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Presentations of Glucose Transporter Deficiency

• Microcephaly, MR, ataxia,

• Dystonic choreoathetosis, exercise induced dyskinesia

• Neonatal Seizures

• Infantile myoclonic seizures or infantile spasms

• Early-onset absence

• Myoclonic absence

• Lennox-Gastaut syndrome

• Early onset JME at times with TV screen "attraction“

Vykuntaraju KN, et al. Indian J Pediatr. 2013 Apr 19.Tzadok M, Nissenkorn A, Porper K, Matot I, Marcu S, Anikster Y, Menascu S, Bercovich D, Zeev BB. The Many Faces of Glut1 Deficiency Syndrome. J Child Neurol. 2013 Jan 22.

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Presentations of GLUT1 Deficiency New Insights

• Myoclonic epilepsy unresponsive to eight anticonvulsants. Oral steroid treatment achieved dramatic seizure control

• Alternating Hemiplegia of Childhood (only episodes of hemiplegia and delay with improvement in sleep and delay, no dystonia reported)

Vieker et al. Neuropediatrics. 2012 Oct;43(5):275-8. Rotstein M, et al. Neurology. 2009 Dec 8;73(23):2042-4.

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Development Delay, Epilepsy, and Neonatal Diabetes (DEND)

• Normally with increased sugar KATP normally closes when the ATP/ADP ratio rises, due to increased blood glucose. Thus, K+ remains intracellular, the cell depolarizes releasing insulin through Ca++.

• Mutations make the channel less sensitive to this inhibition.

• Therapy with sulfonylureas restores channel susceptibility to inhibition

Pearl PL. J Inherit Metab Dis. 2009 Apr;32(2):204-13. 21

Hyperinsulinism-Hyperammonemia Syndrome

• Gain of function mutations in the mitochondrial enzyme glutamate dehydrogenase, this increases ATP and inhibition of KATP

• Symptoms: Generalized seizures, especially absence-type seizures, in the absence of hypoglycemia.

• Therapy: KATP channel agonist diazoxide.

Palladino AA et alRev Endocr Metab Disord (2010) 11:171–178

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Guanidinoacetate-Methyltransferase Deficiency

• Presentation: Creatine

disorders initially present as

febrile, tonic, or tonic-clonic

seizures with drop attacks

and myoclonic or generalized

seizures are the most

frequent. Absence, focal

seizures, can also occur

• Also: We reported two sibs

one with Lennox-Gastaut

syndrome. The second had

late onset West syndrome. Mikati A, et al. Epileptic Disord. 2013 Oct 28. 23

Alternating Hemiplegia of Childhood

• Caused by ATP1A3 mutations

• Presents with abnormal eye movements, dystonia, hemiplegia, seizures and delay

• Flunarizine helps

24 Henizen et al. Nat Genet. 2012 Sep;44(9):1030-4.

AHC and Neonatal Status

Saito et al., Epilepsy Research 2010: 90; 248-258

• Neonatal seizures: 4/9 cases • Seizure types: tonic, myoclonic,

clonic, cyanosis and apnea repeated episodes of status with

delayed development • MRI:

cerebral cerebellar and hippocampal atrophy

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Other Treatable Etiologies

• Coenzyme Q deficeincy: of various causes has been associated with and IS and EIME at times with CFC syndrome, nephrotic syndrome and cardiomyopathy, but replacement therapy has not consistently helped

• Serine synthesis Defects: Can present with neonatal seizures and later delay and microcephaly, therapy with L-serine (500 mg/kg/d, and glycine 200 mg/kg/d has been effective

Huntsman et al Can. J. Neurol. Sci. 2009; 36: 105-108 Scalais et al. Eur J Paediatr Neurol. 2013 Jun 28 Aeby et al.

J Inherit Metab Dis. 2007 Oct;30(5):827. van der Crabben et al J Inherit Metab Dis. 2013 Jul;36(4):613-9.

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Outline

• Vitamin Responsive Disorders

• Other Disorders

• Clinical Approach and Utility

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Clinical Approach

• Things are not what they seem: be familiar with the spectrum of presentations typical & atypical.

• Keep it simple: – Screen for inborn errors of metabolism and

vitamin responsive entities that you do not want to miss

– Target specific genes sequencing to the disorder you are suspecting the most

– If there are none then resort to gene panel or whole exome sequencing

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Workup Targeted to Ruling Out Amenably Treatable Conditions

• Blood and Urine: Amino acids, Organic acids, Acyl carnitine profile, carnitine free and total, lactate, pyruvate, ammonia, biotinidase, pipecolic acid, creatine, guanidino acetic acid, alpha amino adipic acid semialdehyde, MRS for creatine peak,

• CSF: amino acids lactate ammonia, routines, neurotransmitter studies, Pyridoxal 5’-phosphate, 5-methyltetrahydrofolate

• Gene Testing: Targeted gene testing, or panels, or exome sequencing

Inherited Metabolic Epilepsies, Phillip L. Pearl MD, ed. Demos Publications, 2013. 29

Predictors for Positive Genetic Testing Results in Pediatric Drug Resistant Epilepsy

Negative Positive P value

Epileptic Encephalopathy No Present

89%(8) 14% (2)

11%(1) 86% (14)

0.005

Seizure Type Focal Generalized

75% (6) 24% (4)

25% (2) 76% (13)

0.028

Retrospective study in select population in a tertiary care center, Ream and Mikati AES meeting Poster 3.278 Washington DC Dec 9, 2013. 30

Diagnostic Yield of Genetic Testing (Retrospective Study in Select Population)

Test % of patients with at least

one positive genetic test

result (# positive/ # tested)

Exome sequencing 83.3% (5/6)

Epilepsy gene panels 46% (6/13)

Single gene sequencing 26.7% (4/15)

Microarray 16.7% (2/12)

Karyotype 14.3% (1/7)

Retrospective study in select population in a tertiary care center, Ream and Mikati AES meeting Poster 3.278 Washington DC Dec 9, 2013. 31

• Mutations influencing therapy: 27.6% (8/29).

• VUS variants of unknown significance: 34.5% (10/29)

• Unexpected mutations: 20.7% (6/29)

Utility of Genetic Testing and Novel Presentations and Therapy

• IS, CC agenesis: GLUT1 (NL CSF gluc) • PME: SCN1A from dad, de novo EFHC1 • IS: WDR45 (NBIA) • IS hemimegalencephaly: PTEN gene mutation

32 Mester J, Eng C. When overgrowth bumps into cancer: the PTEN-opathies. Am J Med Genet C Semin Med Genet. 2013 May;163C(2):114-21.

CONCLUSIONS Manifestations of Infantile EIEE

• Vitamin responsive disorders (Biotin, Thiamine, Folinic acid, B6 and P5P) have “classical” presentations and a range of manifestations including abnormal MRIs

• Other treatable genetic causes also have a range of presentations including brain malformations

• A systematic approach based on the above knowledge allows for successful diagnosis and early therapy of the above disorders.

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Acknowledgements

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Duke Pediatric Epilepsy Team – Margie Ream

– Aravind Veerapandiyan

– Sonya Steel

– Sue Mea Cheah

– Bill Gallentine

– Eddie Smith

– Abeer Hani

American University of Beirut Epilepsy Team: ‒ A. Rahi ‒ S. Natour ‒ A. Shamsedin ‒ P. Karam ‒ T. El-Hajj ‒ G. Naasan ‒ S. Garzedin ‒ S. Abu Mosleh

Collaborators --K. Krishnamoorthy

-C.T. Lombroso -Gregory Holmes -Marie McDonald -V. Shashi -P. Zalloua -David Goldstein -Erin Heinzen -International consortium on AHC collaborators (43 in number) K. Swoboda, A. Arzinamologlou, T. Synch, S. Sisodya, I. Scheffer, B. Lynch, K. Silver etc.