DR. HELLY GOEZ

PEDIATRIC NEUROLOGY

DEVELOPMENTAL PEDIATRICS

UNIVERSITY OF ALBERTA

Just a Movement, bad mood? Hmm.. Not really

Objectives

Classification Pediatric movement disorders.

To present examples of “common” movement disorders- metabolic conditions.

To present examples of inborn errors of metabolism labeled as “common” neurological conditions.

To recognize the versatility of neurological presentation.

To recognize the difference in the approach to Pediatric Movement Disorders as compared to Adult Movement Disorders.

To understand the importance of diagnosis in childhood.

Classification

Hyperkinetic: Most of Pediatric Movement Disorders

Tics

Streotypies

Chorea

Ballismus

Dystonia

Myoclonus

Tremor

Hypokinetic: Parkinsonism

Cerebral Palsy?

5 Year-old admitted due to status Epilepticus.

Previously diagnosed with Cerebral Plasy.

Born at term, AGA, Apgar scores-normal.

Family History: remarkable for early speech delay- father.

Child had Global Developmental Delay.

Moderate to severe Gross Motor delay.

Moderate to severe fine motor delay.

Severe- mixed, Language delay.

History Continued

At the age of 3 years- diagnosed with CP “mild spasticity in lower limbs”.

At the age of 4 years- diagnosed with mild bilateral hand tremor “when trying to hold a crayon”.

Was “less stable” over time (suggested that “the gap increased”).

Neurological Examination

Microcephaly (3%)

Occasional eye contact.

Mild axial ataxia.

Spasticity- lower limbs, and increased Deep Tendon Reflexes.

Pronounced upper and lower limb chorea.

Investigations

Newborn neonatal metabolic screen- normal.

Mitochondrial sequencing, muscle biopsy normal.

Brain MRI: Generally normal, suspected mild non-specific Fronto-Temporal atrophy.

CSF: Glucose ratio (CSF-Plasma), Protein, lactate, amino acids-normal.

Neurotransmitters: decreased 5 methyl tetrahydrofolate (normal folate in plasma and RBC).

Mutation- FOLR1 gene.

Treated: Folinic Acid with significant improvement in movement disorder.

Cerebral Folate Deficiency Syndrome

Dyskinesia-Pyramidal syndrome

Temper tantrums/social communication issues/Seizures?

A 9-year-old boy - 6-year history of episodic loss of axial and appendicular muscle tone leading to falls followed by streching of the legs and stiffening of trunk.

While in KG, continuous crying and kicking, “temper tantrums after playing with other children outdoors”.

An average of 7 attacks per month with each event lasting from a few minutes to an hour.

Frequency and severity increased during bouts of illness.

No cognitive regression.

Birth history and developmental milestones were normal.

Neurological examination was normal

investigations

Brain MRI- normal

EEG (sleep, awake)- normal

CSF -low glucose at 2.2mmol/L (ref: 2.8-4.4 mmol/L) with a CSF/Blood glucose ratio of 0.46 (ref: 0.45-0.9). CSF lactate and protein levels were normal. CSF testing for neurotransmitters was normal.

Genetic testing for disorders associated with dystonia (TOR1A, SCGE, GCH1 and TH genes) –normal

channelopathies (CACN1, KCNA, CACNB4, and SLC1A3) - normal

Back to Hx:

Events triggered by physical activity: running, jumping.

Completely normal between episodes

Dystonic posturing of legs and torso.

So what is it?

Sequencing for SLC2A1 -heterozygous variant of c.694C>T (p.232 arginine to cysteine). The mutation was not found in his parents.

Modified ketogenic diet - resulted in a complete resolution of his symptoms.

GLUT1DS

• The classical phenotype (85%)-symptoms involving 4 domains: behavior, cognition, epilepsy, movement disorders.

• Onset of symptoms generally occurs early in childhood (< 2 years of age)

• Severe forms: cognitive impairment, developmental delay, infantile refractory epilepsy, multiple seizure types, microcephaly, movement disorders (ataxia, dystonia) and spasticity

Non classical

less severe clinical course: symptoms may present intermittently.

Notable cases of the non-classical phenotype: alternating hemiplegia, choreoathetosis, dystonia, early-onset absence epilepsy, paroxysmal exercise-induce dyskinesia (PED).

Developmental Coordination Disorder? ADHD?

A 16 year old diagnosed with ADHD, LD, DCD.

Admitted- ankle fracture

“always clumsy, and never pays attention.”

Psycho educational assessment: “slow to respond..processing speed difficulties..slow speech..”

Normal PMHX

FHX- unremarkable

Again- Hx..Hx..Hx..

Admitted that recently choking on liquids “just a little bit- when drinks quickly in the morning, as he is always waking up last minute..”

Recently, “hard to put thoughts into words. Words do not come out”.

Can no longer play hockey (tired, clumsy).

Neuro Exam

explosive dysarthria

slow progression of speech

moderate supranuclear gaze palsy

mild, bilateral, symmetrical dysdiadochokinesis

Gait: narrow-based-waddling, difficulties initiating his stride

Posturing arms

Mini mental examination -normal

Lab

• complete blood count peripheral smear

• electrolytes

• liver enzymes

• renal function tests

• creatine kinase

• thyroid stimulating hormone and free-T4 normal

• vitamin B12

• vitamin E

• calcium, magnesium, zinc

• ammonia

• Lipid profile:normal levels of triglycerides, LDL-cholesterol, low HDL-cholesterol: 22 mg/dL (35-100 mg/dL).

• Antinuclear antibody screen -negative.

• Lactate, amino acids-serum and urine, organic acids, oligosaccharides in urine, carnitine profile- normal.

• Ceruloplasmin borderline low: 0.16 g/L (0.17-0.66 g/L), consistently low serum copper level of 6.4 umol/L (11-28 umol/L).

• 24-hours urine copper level borderline low: 0.1 umol/L (0.1-0.8 umol/L).

• antitransglutaminase IgA -negative.

• Acid sphingomyelinase in white blood cells -normal.

• Brain and Spine MRI- normal

Labs- con’t

• Muscle biopsy:significant depletion of copper: 0.06 umol/g dry weight (0.25-1 umol/g). Non-specific myopathic changes, with no features of mitochondrial or storage disorders.

• Gatsrointestinal biopsies: gastric, duodenal, small bowel and colonic mucosae- histologically normal, with a significant decrease in tissue copper levels: 0.19 umol/g dry weight (0.25-1 umol/g).

• Neurotransmitter profiles in CSF: normal 5-methylhydrofolate, 3-0-methyldopa and neopterin. Decreased levels of 5-hydroxyindoleacetic acid: 44 nmol/L (67-140 nmol/L), and homovanillic acid: 92 nmol/L (145-324 nmol/L) were noted (last two are products of monoamine oxidase, a cuproenzyme).

• Genetics: negative-spinocerebellar ataxia, Wilson (ATP7B gene), and Menkes/occipital horn syndrome (ATP7A gene). An array-based comparative genomic hybridization-normal.

More labs and thoughts

Skin biopsy -inconclusive: esterification of cholesterol in response to stimulation of LDL uptake was depressed relative to normal but was higher than the positive control, and filipin staining was not abnormal

Oral supplementation of copper gluconate, 2 mg/day. After 3 months-serum copper and ceruloplasmin levels have normalized.

Stabilized clinically: dysarthria and ataxia- no further regression; no signs of reversal or regaining lost skills.

6-8 months later mild suspected regression:

carrying two heterozygous mutations in the NPC1 gene: in exon 20: C.3019C>G (CCT>GCT), causing the amino acid change p.P1007A (Pro1007Ala), and in exon 21: C/3182T>C (ATA>ACA), causing the amino acid change p.I1061T (Ile1061Thr).

Started Miglustat- resulting in plateau.

So how is this explained?

• A possible connection between the copper deficiency and induction of Niemann-Pick type C.

• The most consistent lipoprotein abnormality associated with Niemann-Pick type C: decreased serum levels of HDL (inhibition of the ATP binding Cassette (ABCA1) transporter)

• Regulates HDL formation and inhibited by high concentrations of intracellular cholesterol.

• An increase in cholesterol formation might lead to an increased intracellular storage of cholesterol-further hindering the ABCA1 activity.

• Copper deficiency increases the synthesis of cholesterol in the liver (induction of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase).

• Hypothesis ?:copper deficiency may increase production and intracellular accumulation of cholesterol, further reduction in ABCA1 activity, reduction in serum HDL levels.

• Another possible link -defect in acid sphingomyelinase (reported cause of Niemann Pick types A and B). Patients with Nieman-Pick type C also exhibit reduced activity of this enzyme.

• Activation of acid sphingomyelinase required copper thus inducing symptoms of Niemann-Pick.

Neonatal “sleep myoclonus”/Hypoxic Ischemic Encephalopathy?

Presenting at 6 days of life with myoclonic jerks.

Admitted for further investigations.

Born at 38 weeks, 3.5 kg, Apgars: 7-9-9.

Emergency C-Section for prolonged 2nd stage.

Antenatal fetal U/S: brain-left mild venticulomegaly, mild pulmonic stenosis.

Family History: unremarkable for the mother, unknown for the father.

Neurological examination

Growth parameters: all 50-75%

No dysmorphic features, skin stigmata, midline anomalies, organomegaly

Normal red reflex

Symmetrical face

Neonatal reflexes: Galant, sucking, stepping, placing, palmar grasp- normal

Asymmetrical tonic neck reflex- present on the left, absent on the right.

Increased tone lower limbs (right>left), increased Deep tendon reflexes lower limbs

Decreased axial tone

Jitteriness

Course and investigations

One seizure during admission. EEG unremarkable afterwards.

Myoclonic jerks with no correlation with EEG findings.

MRI: Multifocal White matter changes with left caudo-thalamoic cyst.

Newborn metabolic screen-Normal.

Sepsis work up- normal (blood-urine-CSF).

Bedside physician rounds

Suggested- hypoxic ischemic encephalopathy “she might be probably a mild CP”.

Myoclonic jerks “are probably benign sleep myoclonus, that are normal in babies”.

BUT- WHAT WAS DIFFERENT??

Observation-observation-observation

The increased tone in the first few days of life.

Jitteriness, and startle >>>typical newborn.

The distribution of the white matter changes (not typical to Periventricular Leucomalacia-PVL).

Apgars not necessarily correlate with HIE??

CSF sent for Neurotransmitters.

And…?

Alpha-aminoadipic-semialdehyde was highly abnormal.

Features in keeping with pyridoxine responsive condition.

ALDH7A1 mutation.

Treated with Pyridoxine- Jitteriness resolved, Myoclonus decreased.

Vomiting and neck turning

• At 3 months – episodic crying and tilting of right side of body once a month.

• Last 4-10 days. Sometimes upon awakening. Eventually associated with vomiting for one day and resolve on it’s own.

• Initially presented to Neurosurgery at 8 mo. with episodic

torticollis associated with irritability.

First seen in Neurology clinic at 13 months of age.

• Normal level of consciousness, no unusual eye movements and no eye deviation during.

• Cranky ,tired, crying a lot during but will eat and drink before as well as after vomiting.

• Initially seem to respond to ibuprofen (episodes less severe).

PMHx

• Pregnancy: unremarkable twin pregnancy.

• Birth: 1st twin born at 35 weeks by spontaneous vaginal delivery. BW: 2.6kg (70%ile). Normal APGARs. No interventions.

• Development: normal

Other

Review of Systems

Normal vision (assessed by optometry)

Normal bowel and bladder function, hearing, sleeping and appetite.

Appropriate weight gain despite vomiting.

Physical Examination

• Ht., Wt., HC. = ~ 100%ile

• Alert and awake

• No dysmorphic features, skin stigmata or midline anomalies. No organomegaly.

• CN: full EOM with pupils equal to light and accommodation. Fundoscopy normal and visual fields intact. Hearing grossly normal and face symmetrical. Normal palate and tongue bulk and movement.

Physical Examination

Motor: normal bulk, tone and strength.

Reflexes: normal

Other: no abnormal involuntary movements.

NORMAL

Differential Diagnosis of PediatricTorticollis

• Posterior fossa SOL

• Cervical vertebral anomalies

• CN IV palsy

• Reflux

• Focal seizure +/- altered consciousness

• Congenital torticollis

• Idiopathic torsional dystonia

• Migraine variants: paroxysmal dystonia

• The clue: paroxysmal or fixed?

FHx

• Strong history of migraines in both sides of the family

Treatment

Started on diphenhydramine PRN q4h during event at about 14 months with further improvement (milder and shorter events).

H1 agonist

Antimuscarinic

Pediatric Migraine Variants

• Periodic or paroxysmal in character

• Normal neurological examination in between attacks

• Positive family history for migraines (65-100%)

• 26% evolve into classic migraines

Tourette?? Complex Tics?

• A 16 year old male presented to the emergency room -a sudden onset of abnormal tongue movements-six weeks prior to referral

• Previously healthy.

• No history of preceding infection, travel or drug ingestion.

• Family history –unrevealing.

• Tongue movements were described as “snake-like”. Tongue deviating to the left in a twisted fashion with wave-form movements of the right side of the tongue.

• Suppressed (1-2 seconds)when patient asked to voluntarily extrude his tongue

• Did not interfere with swallowing or with speech.

• Did not persist during sleep.

• three weeks later- progressed: hands moved in a flapping-like motion.

• sudden and coarse-ballismic like.

• tic-like -proximal and distal parts of the upper limbs.

• dystonia-like posturing of the neck and the torso -resolved spontaneously and did not occur during sleep.

• No cognitive or mental changes reported.

Neuro Exam

Alert ,attentive, no distress.

Tongue and limb movements noted.

Limb movements could be suppressed voluntarily, although “needed to focus and make an effort”.

Muscle pain after trying to suppress for more than a few minutes.

Normal neurological examination.

Mini-mental status examination was normal.

Opthalmological evaluation (visual acuity ,slit lamp), retina, lens- normal.

labs

• complete blood count, peripheral blood smear

• electrolytes, calcium, magnesium,

• vitamins E and B12,

• liver enzymes, renal function,

• glucose, thyroid stimulating hormone, free-T4,

• creatine kinase , lactate

• Lipid profile: HDL , LDL cholesterol, triglycerides, lipoprotein A, apolipoproteins

• Serum and urine amino acids, organic acids,

• Immunological, serological tests: anti-streptolysine , anti-nuclear antibody screen. Immunoglobulins G, M, A and E,

• Alpha fetoprotein, acute phase reactants, sedimentation rate, and C-reactive protein,

• Throat swab, blood and urine cultures -all negative.

• Toxicologic screen - negative.

• Ceruloplasmin and copper levels low: 0.13 g/L (0.17-0.66 g/L) and 8 umol/L (11-28 umol/L), respectivelyx3

• 24-hour urine collection - copper excretion; penicillamine challenge - increased urinary copper levels of 6.2 umol/L (0.1-0.8 umol/L).

• Post challenge test -a significant worsening in limb and tongue dyskinetic movements.

• Abdominal ultrasound and brain MRI-normal.

• ATP7B gene sequencing (Wilson’s disease),molecular diagnostic test for Huntington’s disease- negative.

So what happened?

Prescribed with oral zinc gluconate supplement, at a dose of 50 mg three times a day (tetrathiomolybdate was not commercially available in Canada).

Eight weeks after initiation of treatment, the movements disappeared, although copper and ceruloplasmin levels improved - did not normalized.

Does it make sense? Yes!

• Some abnormalities of copper metabolism do not fall under the category of any known disease;

• “Non-Wilson, non-Menkes” copper metabolism disorders.

• Cases characterized :movement disorders (dystonia, myoclonus, tremor, Parkinsonism), gait disturbances.

• Dysarthria, cognitive degeneration, sensory deficits- described.

• Robertson et al – 10/80 patients with Tourette syndrome, had low serum copper.

• Rapid disappearance of copper from the serum and an abnormally slow liver uptake of copper.

• Our patient: despite the low serum levels of copper, the urinary levels were high, suggesting a storage!! disorder- we chose to treat with zinc supplementation.

• Rationale -zinc induces cell metalothionin.

• validating the statement by Kumar et al: “low serum copper is not always indicative of copper deficiency” and “urinary copper levels should be taken into account when planning therapy”.

Mild CP?

12 Year old admitted for behavioral changes and irritative catatonia.

History- suggestive of fetal distress around the time of delivery, no intervention needed.

Was diagnosed with early global developmental delay. Later- language, speech, cognitive delay.

Received a diagnosis of mild CP.

EXAM

Agitated, catatonic, drooling

Increased deep tendon reflexes

Mild rigidity left upper limb

Otherwise-gross neurological examination-unremarkable

Investigations and course:

Negative anti neuronal surface and nuclear antibodies in serum.

Normal EEG, MRI, MRS

Discharged then re-admitted with same.

CSF: negative antibodies, low serotonin metabolites

Trials of medications- SSRI.

Whole Exome Sequencing: NBIA (wdr45).

The “cranky” infant

18 months old

Normal past medical history

A week of Upper Respiratory Tract Infection and Otitis Media

Prolonged irritability- 2 months post

Stopped saying the few words that used to say

“Was sad”

Reluctant to play

“Balance became an issue”

Parents insisted: “something happened to our child”

Admitted: normal MRI, EEG, CSF, blood work

Post discharge: worsening balance

Exam

Irritable

No eye contact

No visual tracking

Smiles when mother sings to him

Microcephaly

Mild spasticity lower limbs, increased DTRs

No organomegaly

….and- when mom sings to him- able to do fundoscopy- Retinitis pigmentosa

Neuronal Ceroid Lipofuscinosis

Summary

Complex and unusual presentation

From non-specific developmental delay through movement disorders, seizures, and mood “disorders”.

Different age groups: neonatal, infancy, childhood, teenage, young adult.

The key: Observation-history taking-critical thinking- and challenging “common diagnosis”.

Thank you