he ces...• Physical therapy can encourage stretching and prevent contractures • Occupational...

Andrea Gropman, M.D., FAAP, FACMG Professor, George Washington University of the Health Sciences Attending, Children’s National Medical Center

Goals 0 Discuss the major neurological features of FAOs and OAs 0  Seizures 0 Muscle disease 0 Developmental delay/MR

Fatty Oxidation Disorders (FODs)

0 Genetic disorders in which the body is unable to oxidize (breakdown) fatty acids to make energy 0 Enzyme dePiciency 0  Inherited disorder

Fatty acid oxidation disorders 0 Medium-‐chain acyl-‐CoA dehydrogenase (MCAD) dePiciency 0  Very-‐long-‐chain acyl-‐CoA dehydrogenase (VLCAD) dePiciency 0  Short-‐chain acyl-‐CoA dehydrogenase (SCAD) dePiciency 0 Multiple acyl-‐CoA dehydrogenase (MAD) dePiciency (= Glutaric aciduria type II, GA II)

0  Long-‐chain hydroxyacyl-‐CoA dehydrogenase (LCHAD) dePiciency 0  Trifunctional protein dePiciency 0  Carnitine palmitoyl-‐transferase I (CPT I) dePiciency 0  Carnitine palmitoyl-‐transferase II (CPT II) dePiciency 0  Carnitine acylcarnitine translocase dePiciency 0  Primary (systemic) carnitine dePiciency

How does it cause symptoms 0 Energy from fat keeps us going when our bodies run low of their main source of energy, sugar (glucose)

0 Our bodies rely on fat when we don’t eat for a period of time such as an overnight fast

0 When an enzyme is missing or not working well, the body cannot use fat for energy and must rely solely on glucose

How does it cause symptoms 0 Glucose is a good source of energy but there is a limited amount available

0 Once the glucose is gone, the body tries to use fat without success

0 This leads to low blood sugar, called hypoglycemia, and to the build up of harmful substances in the blood

Fatty acid oxidation defects 0 Risk: cause recurrent disturbances of brain function

0 The neurological symptoms attributed to 0 Hypoglycemia 0 Hypoketonemia 0 Effects of potentially toxic organic acids

0  Symptoms occur during fasting

Fatty acid oxidation defects 0 Symptoms

0 Drowsiness 0  Stupor and coma occur during acute metabolic crises 0  Seizures 0 Long term neurological effects

0 Muscle tone 0 Cognition/thinking

Organic acidurias:

0 Result From: 0 DePiciencies of mitochondrial enzymes that metabolize CoA activated carboxylic acids 0 derived from amino acid breakdown.

0 Neurological Symptoms 0 Encephalopathy

0 Changes in level of consciousness 0 Seizures

0 Episodic metabolic acidosis 0 caused by build up of toxic metabolites 0 Disturbance of mitochondrial energy production

Organic acidurias

0 Treatment 0 Dietary restriction of the amino acids that cannot be broken down

0 Prevention protein catabolism 0  Supplementation with carnitine and or glycine to form less toxic intermediate conjugates

0  Supplementation with biotin/vitamin to act as a co-‐factor for mitochondrial carboxylase enzymes

Neurological complications 0 Fatty acid oxidation disorders 0 Hypotonia 0  Seizures

0 due to hypoglycemia 0 Developmental delay or mental retardation

0 Muscle disease 0 VLCAD 0 VLCHAD 0 LCHAD

0 Organic acidemias 0 Tone abnormalites

0 Hypotonia 0 Hypertonia

0  Seizures 0 Developmental delay or mental retardation

0 Movement disorders

Short and Long term Neurological consequences of FAOs and OAs

0 Hypotonia 0 Low muscle tone 0 Results in delayed gross, Pine and speech milestones 0 Usually trunk muscles 0  Improves with therapy


0 Hypertonia 0 High resting muscle tone 0 Muscles are contracted and stiff 0 Prevents movements 0 Using limb muscles 0  Stretching therapies 0 Medications 0  Surgeries

0 Tendon releases and transfers


0 Movement disorders 0 Fixed postures 0  Interfere with purposeful movement 0 Writhing or rapid movements 0 May be induced by purposeful movement


0 Seizures 0  Single event that may be provoked

0 Hypoglycemia 0 Hyperammonemia

0 Repetitive events 0 Focal 0 generalized


0 Developmental delay/mental retardation 0 Variable degrees 0 Disorder affects brain

0 Hypoglycemia 0 Seizures 0 Repeated injury

Short and Long term Neurological consequences of FAOs

0 Muscle weakness 0 At rest 0 After exercise

Hypotonia 0 Medical term used to describe decreased muscle tone 0 the amount of resistance to movement in a muscle

0 It is not the same as muscle weakness, although the two conditions can co-‐exist

0 Not a speciPic medical disorder 0 It can be a condition on its own or it can be associated with another problem where there is progressive loss of muscle tone

Hypotonia 0 Hypotonia can be caused by a variety of conditions

0 Central nervous system (brain and muscle) 0 Muscle disorders 0 Genetic disorders

0 It is usually Pirst noticed during infancy 0 Floppy infant 0 Poor head control 0 Weak suck and swallow

Hypotonia

Clinical aspects of hypotonia 0 Can involve only the trunk or trunk and extremities 0 Delayed Motor skills (requires strength and movement against gravity)

0 Hypermobile or hyperPlexible joints 0 Drooling and speech difPiculties

Clinical manifestations of hypotonia

0 Poor tendon rePlexes 0 Decreased strength 0 Decreased activity tolerance 0 Rounded shoulder posture and curved back when sitting

Infantile hypotonia 0 Floppy, rag doll 0 DifPiculty with feeding

0 Mouth muscles cannot maintain a proper suck-‐swallow pattern or a good breastfeeding latch

0 Hypotonic infants are late in 0 Lifting their heads while lying on their stomachs 0 Rolling over 0 Lifting themselves into a sitting position 0  Sitting without falling over 0 Balancing 0 Crawling 0 Walking independently

Hypotonia and motor delays 0 Delayed developmental milestones

0 degree of delay can vary widely 0 Motor skills are particularly susceptible to the low-‐tone disability

Hypotonia and motor delays 0 They can be divided into two areas

0  gross motor skills 0  Pine motor skills 0 Fine motor skills delays

0 grasping a toy 0 transferring a small object from hand to hand 0 pointing out objects 0 following movement with the eyes 0 self feeding

Speech delays and hypotonia 0 Speak later than their peers

0 appear to understand a large vocabulary 0 can obey simple commands

0 DifPiculties with muscles in the mouth and jaw 0  inhibit proper pronunciation 0 discourage experimentation with word combination and sentence-‐forming

0 Feeding difPiculties 0 Chewing 0 Textures 0 Mouth play

Hypotonia versus weakness 0 The low muscle tone associated with hypotonia is often confused with low muscle strength 0  Muscle tone is the ability of the muscle to respond to a stretch

0 The child with low tone has muscles that are 0 slow to initiate a muscle contraction 0 contract very slowly in response to a stimulus 0 cannot maintain a contraction

0 Muscles remain loose and very stretchy

Workup for hypotonia 0 Computerized tomography (CT) scans 0 Magnetic resonance imaging (MRI) scans 0 Blood tests

0 CPK 0 Electromyography (EMG) 0 Muscle and nerve biopsy

Hypotonia 0 Often evaluated by physical and occupational therapists through a series of exercises designed to assess developmental progress, or observation of physical interactions

0 Hypotonic child has difPiculty deciphering his spatial location 0 develop recognizable coping mechanisms

0 locking the knees while attempting to walk 0 tendency to observe the physical activity of those around them for a long time before attempting to imitate

Different names for hypotonia 0 Low Muscle Tone 0 Benign Congenital Hypotonia 0 Congenital Hypotonia 0 Congenital Muscle Hypotonia 0 Congenital Muscle Weakness 0 Amyotonia Congenita 0 Floppy Baby Syndrome 0 Infantile Hypotonia

Management and treatment 0 No known treatment or cure for most (or perhaps all) causes of hypotonia

0 The outcome depends on the underlying disease 0 In some cases, muscle tone improves over time 0 Patient may learn or devise coping mechanisms that enable him to overcome the most disabling aspects of the disorder

Management of hypotonia 0 If the underlying cause is known, treatment is tailored to the speciPic disease, followed by symptomatic and supportive therapy for the hypotonia

0 In very severe cases, treatment may be primarily supportive

Management of hypotonia 0 Physical therapy can improve Pine motor control and overall body strength

0 Occupational therapy to assist with Pine motor skill development and hand control, and speech-‐language therapy can help breathing, speech, and swallowing difPiculties

0 Therapy for infants and young children may also include sensory stimulation programs

0 Ankle/foot orthoses are sometimes used for weak ankle muscles

0 Toddlers and children with speech difPiculties may benePit greatly by using sign language or picture exchange

Hypotonia 0 Diagnostic tests

0 CT or MRI scan of the brain 0 EMG to evaluate nerve and muscle function 0 EEG to measure electrical activity in the brain may also be necessary

Treatment 0 Once a diagnosis has been made

0 underlying condition is treated Pirst 0  followed by symptomatic and supportive therapy for the hypotonia

Hypertonia 0 Abnormal increase in the tightness of muscle tone 0 Reduced ability of a muscle to stretch

0  increased stiffness 0 Accompanied by spasticity

Causes of hypertonia 0 Damage to upper motor neurons

0 Causes hypertonia 0  Spasticity (overactive rePlexes) 0 Rigidity (constant muscle contractions)

Hypertonia 0 Other names for hypertonia

0 Cerebral palsy 0 Hemiparesis 0 Quadriparesis 0 Hemiplegia 0 Diplegia

Damage of motor tracts in hypertonia

Hypertonia

•  Diagnostic tests – CT or MRI scan of the brain – EEG to measure electrical activity in the brain

may also be necessary

Diagnosis of hypertonia

Management of hypertonia •  Physical therapy can encourage stretching and prevent

contractures •  Occupational therapy to assist with fine motor skill

development and hand control, and speech-language therapy can help breathing, speech, and swallowing difficulties

•  Ankle/foot orthoses are used to prevent contractures at the heel cords

•  Toddlers and children with speech difficulties may benefit greatly by using sign language or picture exchange

Spells, seizures, and epilepsy 0 The medical syndrome of recurrent, unprovoked seizures is termed epilepsy

0 A single seizure is not yet epilepsy 0 A “spell” may be a seizure or may be something else

0 Movement disorder 0 GERD 0  Sleep disorder

Things that go bump in the night: Spells, seizures, and epilepsies

0 A seizure 0 Temporary abnormal electrophysiologic phenomenon of the brain 0 Results in abnormal synchronization of electrical neuronal activity

0 Can manifest as 0 Alteration in mental state/awareness 0 Tonic or clonic movements 0 Convulsions 0 Various other psychic symptoms (such as déjà vu or jamais vu

Seizures 0 Cause involuntary changes in

0 body movement 0 Function 0  Sensation 0 Awareness 0 behavior

0 Can last from 0  few seconds 0  status epilepticus, a continuous seizure that will not stop without intervention

0 Seizure is often associated with a sudden and involuntary contraction of a group of muscles

Seizures 0 A seizure can also be as subtle as

0 Marching numbness of a part of the body 0 A brief loss of memory 0  Sparkling or Plashes 0  Sensing an unpleasant odor 0 A strange sensation in the stomach 0  Sensation of fear

Seizures 0 Seizures are typically classiPied as

0 Motor 0  Sensory 0 Autonomic 0 Emotional/cognitive

Seizures 0 Symptoms depend on where in the brain the disturbance in electrical activity occurs

0 In children, seizures often happen in sleep or the transition from sleep to wake

0 A person having a tonic-‐clonic seizure may cry out, lose consciousness and fall to the ground, and convulse, often violently

Seizures 0 Complex partial seizure

0 Person may appear confused or dazed 0 not be able to respond to questions or direction

0 Sometimes, the only clue that a person is having an absence seizure 0 Rapid blinking 0 Mouthing movements 0 Few seconds of staring into space

Hypoglycemia and seizures 0 Hypoglycemia

0 Lower than normal level of glucose (sugar) in the blood 0 Why is this important?

0 Brain metabolism depends primarily on glucose for fuel in most circumstances

0 A limited amount of glucose can be made from glycogen stored in astrocytes, but it is used up within minutes

0 Brain is dependent on a continual supply of glucose diffusing from the blood into central nervous system and into the neurons themselves

Hypoglycemia 0 Caused by a continuing demand for glucose by brain and other organs 0 Results from the primary biochemical defect of fatty-‐acid oxidation since fats cannot be broken down efPiciently

0 Treatment 0 Avoidance of catabolism (more break down)

0 Requires the use of fatty acids except in FAOs 0 L-‐Carnitine supplementation 0 Some patients may benePit from medium-‐chain triglyceride supplementation as a source of fat

Hypoglycemia and seizures 0 If the amount of glucose supplied by the blood falls, the brain is one of the Pirst organs affected

0 In most people, reduction of mental abilities occur when the glucose falls below 65 mg/dl (3.6 mM)

Hypoglycemia and seizures 0 Impairment of action and judgement usually becomes obvious below 40 mg/dl (2.2 mM)

0 Seizures may occur as the glucose falls further 0 As blood glucose levels fall below 10 mg/dl (0.55 mM), most neurons become electrically silent and nonfunctional, resulting in coma

Hypoglycemia and seizures 0 Brief or mild hypoglycemia produces no lasting effects on the brain 0 Can temporarily alter brain responses to additional hypoglycemia

0 Prolonged, severe hypoglycemia can produce lasting damage of a wide range 0  Impairment of cognitive function, motor control, or even consciousness

Hypoglycemia and seizures 0 The likelihood of permanent brain damage from any given instance of severe hypoglycemia is difPicult to estimate

0 Depends on a many factors 0 Age 0 Underlying disorder 0 Recent blood and brain glucose concurrent 0 Problems such as hypoxia 0 Availability of alternative fuels

Hypoglycemia, symptoms 0 Abnormal thinking, impaired judgement

0 anxiety, moodiness, depression, crying

0  irritability, combativeness

0 Personality change, emotional lability

0 Fatigue, weakness, apathy, lethargy, daydreaming, sleep

0 Confusion, amnesia, dizziness, delirium

0 Staring, "glassy" look, blurred vision, double vision

Hypoglycemia, symptoms 0 Automatic behavior, also known as automatism 0 DifPiculty speaking, slurred speech 0 Ataxia, incoordination, sometimes mistaken for "drunkenness"

0 Focal or general motor dePicit, paralysis, hemiparesis

0 Paresthesia, headache 0 Stupor, coma, abnormal breathing 0 Generalized or focal seizures

Management of hypoglycemic seizures

0 Failure to administer glucose would be harmful to the patient

0 Recurrent seizures 0 Anti-‐epilepsy drugs

0 Give single drug at lowest concentration if possible 0 Careful with certain conditions

0 Drug treatment geared towards whether focal, generalized, etc. 0 Trileptal, Keppra, Zonergran, Lamictal, Depakote, Klonopin, Dilantin, Tegretol

Movement disorders-‐Organic acidemias

0 Dystonia 0 Abnormal Pixed posture of an extremity (arms or legs, neck)

0  sustained muscle contraction 0  resulting in abnormal posture

0 Chorea 0 Fast, dance like movements of the distal extremities (Pingers and toes)

0 Athetosis 0  Slow, writhing movements of the extremities

Movement disorders-‐Organic acidemias

0 Patient may have combination of movement disorders at baseline or with special circumstances 0  Stress 0  Illness 0 Attempt at purposeful movement

FAOs and Muscle disease 0 SCAD 0 VLCAD 0 LCHAD

0 Symptoms 0 Weakness 0 Pain/cramps 0 Exercise intolerance 0 Red urine 0 Muscle breakdown 0  rhabdomyolysis

Rhabdomyolysis

0 Elevations of CPK

FAOs with muscle disease 0 SCAD

0 Hypotonia 0 metabolic acidosis 0 NBS:

0 elevated C4 0 UOA have elevated ethylmalonic acid

0 Common mild variants of ? SigniPicance

FAOs with muscle disease 0 LCHAD

0 Cardiomyopathy 0 hypotonia, 0  rhabdomyolysis 0 moms have HELLP syndrome 0 NBS

0 Acylcarnitine proPile with elevated C14-‐OH,C16-‐OH ,C18-‐OH and C18:1-‐OH

FAOs with muscle disease 0 VLCAD

0 Cardiomyopathy 0 hepatomegaly, 0  SIDS 0 Rhabdomyolysis 0 Acylcarnitine proPile:

0 Elevations of C14:1and C14:1/ C12:1

General management guidelines-‐medical

0 Fatty acid oxidation 0 Provide brain fuel

0 Glucose 0 Calories 0 Sick day management

0 Organic acidurias 0 Provide brain fuel

0 Calories 0 Glucose and nonprotein/fat

0 Sick day management

General management guidelines-‐medical

0 Malignant hyperthermia 0 Risk with anesthesia for surgery

0 G tube 0 Orthopedic surgery to correct hypertonia 0 Dental work 0 Etc.

Management of metabolic disorders

0 Mechanical assistance with basic life functions 0 breathing and feeding 0 physical therapy to prevent muscle atrophy and maintain joint mobility

0 Treatments to improve neurological status 0 medication for a seizure disorder 0 medicines or supplements to stabilize a metabolic disorder

0  surgery to help relieve the pressure from hydrocephalus (increased Pluid in the brain).

General management guidelines-‐therapies

0 Physical therapy 0 Large muscles, gross motor skills

0 Occupational therapy 0 Fine motor skills

0 Speech therapy 0  Speech articulation, communication

0 Feeding therapy 0 May be done by either speech or occupational therapist

Metabolic crisis 0 extreme sleepiness 0 behavior changes 0 irritable mood 0 poor appetite 0 Other symptoms then follow: 0 fever 0 nausea 0 diarrhea 0 vomiting 0 hypoglycemia

Consequences of metabolic crises

0  If a metabolic crisis is not treated, a child with CTD can develop: 0  • breathing problems 0  • swelling of the brain 0  • seizures 0  • coma, sometimes leading to death 0  Babies who are not treated may have other effects: 0  • enlarged heart 0  • enlarged liver 0  • muscle weakness 0  • anemia 0  Repeated episodes of metabolic crisis can cause brain damage. This can result in 0  learning problems or mental retardation. 0  Symptoms of a metabolic crisis often happen after having nothing to eat for more 0  than a few hours. Symptoms are also more likely when a child with CTD gets sick 0  or has an infection.

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