Chapter 13 Neurology
Long Cases
Cerebral palsy
Children with cerebral palsy (CP) often are used for both long- and short-case examinations. The following is a very brief listing of some of the major issues raised in the CP long case, plus a short-case approach.
Background information
Classification
CP is classified according to the clinical type of neuromotor dysfunction:
Causes
1. Prenatal problems; for example, cerebral malformations, intrauterine TORCH infection (toxoplasma, other [e.g. syphilis], rubella, CMV, herpes [simplex or varicella] or HIV infection), toxins (e.g. drugs), placental insufficiency, fetal coagulation and autoimmune disorders, cerebrovascular accidents, trauma or chromosomal anomalies.
2. Perinatal problems; for example, neonatal encephalopathy, hypoglycaemia, toxins (e.g. kernicterus from hyperbilirubinaemia), viral (e.g. HSV) encephalitis, bacterial (e.g. early onset Group B streptococcus) meningitis, prematurity (babies born before 28 weeks gestation have 50 times the risk of CP compared with babies born at term; mechanisms can include intraventricular haemorrhage and periventricular leucomalacia).
3. Postnatal problems; for example, head trauma (accidental or non-accidental), hypoxic insult (from near-drowning, choking or poisoning), cerebrovascular accident, toxic encephalopathy (e.g. lead), meningitis or hypoglycaemia.
Diagnostic assessment
EEGs are only worthwhile if the patient has had fits, to determine classification of any epilepsy syndrome; they are not useful in determining the aetiology of the child’s CP.
Metabolic conditions. Treatable conditions should not be missed. Example: glutaric acidaemia type 1; mutation in the gene encoding glutaryl-CoA dehydrogenase [GCDH]; alters catabolism of amino acids lysine, hydroxylysine and tryptophan; can impersonate dyskinetic CP; treatable—low-protein (low lysine and tryptophan) diet (avoiding milk, cheese, dairy, meat, poultry, fish, dried beans and legumes, nuts, peanut butter), special low-protein formula, supplements: riboflavin and L-carnitine.
Other metabolic conditions are not treatable but have a different prognosis to CP. First example: Lesch–Nyhan syndrome (X-linked deficiency of hypoxanthine guanine phosphoribosyl-transferase, HGPRT); patients eventually self-mutilate, and diagnosis is made. Second example: Sjogren–Larsson syndrome (mutation in gene coding for fatty aldehyde dehydrogenase); patients eventually develop ichthyosis, and diagnosis is made.
Muscular dystrophies (e.g. Becker muscular dystrophy; eventually proximal myopathy and Gowers sign, and calf hypertrophy).
Mitochondrial disorders (e.g. Leigh syndrome; eventually developmental regression becomes apparent).
Malformation syndromes. Example 1: Miller–Dieker lissencephaly syndrome (MDLS), chromosome 17p13.3; subtle dysmorphic findings (e.g. wrinkled skin over glabella, downward-slanting palpebral fissures) are eventually noticed. Example 2: Rett syndrome; eventually acquired microcephaly, hand-wringing and hyperventilation become apparent.
Level I: Ambulatory in all settings
Level II: Walks without aides, but has limitations in community settings
Most children with CP are born with the condition, but abnormal features may not be noted for months; most are diagnosed by 3 years. Diagnosis of CP before 12 months is fraught with uncertainty, due to the plasticity of the newborn brain; infants can be seen who have apparently clear-cut signs of CP that then resolve by the age of 1 or 2 years. The ‘ideal’ diagnostic age for CP may be 2 years.
History
Current symptoms/functioning
1. Intellectual abilities (or present developmental status), current placement regarding education, domestic situation, employment.
2. Behaviour (e.g. hyperactivity), affect (e.g. depression).
3. Vision (e.g. cortical visual impairment, strabismus, myopia, hemianopia).
4. Speech, hearing and communication problems (e.g. expressive or receptive dysphasia, dysarthria, athetoid movements, use of aids such as communication boards and computers).
5. Activities of daily living (e.g. bathing, cleaning teeth, combing hair, dressing, writing and other hand usage, toileting, menses).
6. Feeding and nutrition (e.g. sucking and swallowing ability, tube feeds, gastrostomy, gastro-oesophageal reflux, aspiration, failure to thrive).
7. Seizures (e.g. type, duration, frequency, usual treatment including side effects, compliance and drug levels, last seizure).
8. Mobility (e.g. walking ability [‘community’, ‘household’ or ‘non-functional’ ambulator], gait pattern, wheelchair mobility), skeletal problems (e.g. kyphoscoliosis, lumbar lordosis, spondylolisthesis, hip subluxation and dislocation, pseudoacetabulum formation, contractures, unequal leg length), abnormal posturing.
9. Other problems: urinary incontinence, constipation, management of menses, chest infections, pressure sores.
Birth history
1. Maternal past history of miscarriages or infertility.
2. Pregnancy: hyperemesis, hypertensive disease of pregnancy, teratogenic medications, placental problems, clinical evidence of, or exposure to, infection (e.g. TORCH), quality of fetal movements, gestational age.
3. Delivery: presentation (e.g. breech, face), instrumental delivery, Apgar score, resuscitation required, birth weight, need for oxygen, nursery care.
4. Neonatal period: respiratory distress, feeding difficulties, seizures, hyperbilirubinaemia (phototherapy or exchange transfusion), intraventricular haemorrhage (IVH), periventricular leukomalacia (PVL), hydrocephalus, retinopathy of prematurity (ROP).
Important signs in examination of the child with CP
See the short case on hemiplegia in this chapter for a suggested examination procedure.
General observations
1. Dysmorphic features (e.g. chromosomal anomalies).
2. Parameters: head circumference (often obvious microcephaly), weight (often failing to thrive), height (usually decreased), progressive percentile charts.
3. Posture (e.g. fisting, increased extensor tone, asymmetric tonic neck reflex [ATNR], hemiplegic, quadriplegic).
4. Movement: (a) involuntary (e.g. choreoathetoid movements, dystonic spasms, seizures); (b) voluntary (e.g. immature gait pattern with wide base, up on toes, arms out for balance; hemiplegic, diplegic gaits; note posturing of arms when walking).
5. Asymmetry (e.g. hemiatrophy: look at the size of the thumbnails and the great toenails for subtle clues to asymmetry).
6. Behaviour (e.g. lack of interaction with environment, crying).
7. Eye signs (e.g. squint, nystagmus).
8. Bulbar signs (e.g. dysarthria, drooling).
9. Interventions (e.g. nasogastric tube, gastrostomy tube, scars of orthopaedic procedures).
Demonstration of signs of CP
1. If possible, perform a standard gait examination.
2. If the child cannot walk, but can crawl, look for abnormal crawling: (a) those with spastic diplegia or quadriplegia—buttock crawling and ‘bunny-hopping’ (jumping while on knees); (b) those with hemiplegia—asymmetrical crawl.
3. Gross motor ‘180° manoeuvre’, incorporating primitive reflexes:
4. Inspect carefully for tendon release scars.
5. Palpate muscle bulk in each muscle group.
6. Tone: as above, plus assessment of upper and lower limbs, and evaluation of contractures (e.g. tight hip adductors, and tendo achilles).
7. Power: voluntary movement, functional power (grasp of toys, cloth cover test).
8. Reflexes: the head should be held in the midline (e.g. by an examiner) so that an ATNR does not give a false impression of unilateral hypertonia; note whether there is any crossed adductor reflex, spread of reflexes, clonus or upgoing plantar responses.
Complications of CP
1. Measure the head (for microcephaly, or macrocephaly due to hydrocephalus).
2. Check the vision, visual fields and extraocular movements (for myopia, squint).
3. Check the hearing (for sensorineural deafness).
4. Check the ears (for chronic serous otitis media).
5. Ask to check the gag reflex (bulbar dysfunction).
6. Look at the teeth (for dental caries).
7. Look at the back (for kyphoscoliosis).
8. Inspect and auscultate the chest (for chest infection).
9. Palpate the abdomen (for constipation).
10. Examine the hips (for dislocation).
11. Screen nutritional status (demonstrate fat and protein stores).
12. Perform a functional assessment for activities of daily living (e.g. offer cup, spoon, fork, knife, comb, toothbrush; ask the child to put on a piece of clothing).
Investigations
1. Brain imaging (MRI) may show abnormalities in some 90% of patients with CP. It may show the basis of CP (e.g. gross malformations, hydrocephalus, intracranial calcification from congenital infection). It may suggest the timing of the aetiology (e.g. cortical dysplasias develop around 12–20 weeks’ gestation; periventricular leukomalacia around 28–34 weeks’ gestation; cortical and subcortical gliosis and atrophy in parasagittal watershed areas in term babies with intrapartum hypoxia) or show unexpected degenerative disorders (e.g. one of the leukodystrophies).
2. TORCH screen (including HIV), in infants, for intrauterine infection.
3. Urinary metabolic screen (various inborn errors of metabolism).
4. Chromosomes (various anomalies).
5. Lumbar puncture in dyskinetic CP, to diagnose the treatable genetic condition, glucose transporter 1 deficiency syndrome, especially if there are associated refractory seizures (see below).
Management
Physiotherapy, occupational therapy, splints/orthoses
Serial casting is useful for reversing ankle/foot equinus in younger children. Over 2–6 weeks, the calf muscle is stretched gradually, with the foot and ankle held in position by a below-the-knee plaster.
Management of spasticity
In 2010, the American Academy of Neurology released an evidence-based review of pharmacological treatments for childhood spasticity due to CP, where a multidisciplinary panel reviewed relevant literature from 1966 to 2008. In the case of localised/segmental spasticity that warrants treatment, the AAN recommendation was that botulinum toxin A (BTX-A) is effective and generally safe in reducing spasticity in the upper and lower extremities, but there is conflicting evidence regarding functional improvement, and severe generalised weakness can occur; there is insufficient data to support or refute BTX-A use to improve motor function. There is insufficient data to support or refute other medications used for the same indication (and these are not discussed further): phenol, alcohol and BTX type B. In the case of generalised spasticity that warrants treatment, the AAN recommendation was that diazepam could be considered for short-term treatment, and also tizanidine may be considered; but, again, there is insufficient data to support or refute other medications used for the same indication: dantrolene, oral baclofen or continuous intrathecal baclofen. The latter is discussed because patients who have received this treatment may present in the examination, so a candidate should have some knowledge of the side effects.
Intrathecal baclofen (IT-BLF)
In view of the lack of data to support this treatment, it may well become of historical interest only. There are many and varied side effects, several related to the mode of delivery: an implantable drug-delivery pump system for continuous infusion. Significant complications include central side effects such as apnoea, respiratory depression, bradycardia, hypotension and sedation, mechanical complications including pump or side-port failure, catheter kinks, extrusions or dislodgement, cerebrospinal fluid fistula, local infection and meningitis; also, rapidly progressive scoliosis has been reported.
Orthopaedic procedures
Surgical procedures for spastic hip displacement
• Preventative (soft-tissue surgery): adductor longus release, gracilis release, adductor brevis release, iliopsoas lengthening, obturator neurectomy (anterior branch only).
• Reconstructive (redirectional osteotomies): femoral varus derotation osteotomy, pelvic osteotomy, combined femoral and pelvic osteotomy with or without open reduction.
• Salvage: excision of proximal femur, valgus osteotomy, interpositional arthroplasty, replacement arthroplasty, arthrodesis.
These procedures lead to significant improvements in function, including improved walking speed.
Other orthopaedic procedures
Upper limb surgery may be offered to correct a flexion–pronation deformity of the wrist, to achieve a better functional position; however, usually only cosmetic improvement is achieved, with little gain functionally, largely because of associated cortical sensory loss. Some children will require surgery for scoliosis (e.g. placing of Luque rods).
Excessive salivation (sialorrhoea)
Anticholinergic drugs (e.g. glycopyrrolate) have been used for excessive drooling with some success, but can have unpleasant side effects, such as urinary retention, constipation, blurred vision, headache, drowsiness, dizziness and behaviour changes.
Cognition/learning and communication
The risk of associated cognitive and learning difficulties varies with the type of CP. Those with quadriplegic CP have the highest risk of cognitive impairment and those with hemiplegic CP have the lowest risk. In children with movement impairment hindering their verbal communication, augmentative and alternative communication systems are available. Aided formal communication systems include communication boards and books, where pictures and symbols are used to communicate specific messages, and electronic devices of varying complexity, some allowing the person to communicate with recorded speech; unaided formal communication systems include key word signing (Makaton vocabulary), and informal communication systems include facial expression, eye contact, vocalisations, body language and gestures, to convey feelings, wants and needs.
Pain
This is a common complaint, which can be very challenging in the non-verbal child with severe CP. The most common sites of pain seem to be gastrointestinal (constipation, GORD), and orthopaedic/musculoskeletal (scoliosis, hip dislocation, patella alta); other possibilities include: neuromuscular—muscle spasms; head and neck—migraine, raised intracranial pressure, glaucoma, corneal abrasions, tooth abscess, temporomandibular joint pain; urological—urolithiasis, bladder spasm; skin—boils, decubitus ulcers. A thorough history (e.g. temporal association with feeding, or nappy changes) and thorough general examination (e.g. inspecting the mouth with a torch and spatula to find tooth abscesses) may find the cause, but often empirical interventions are tried before the patient is eventually free of discomfort.
Prognosis
A few ‘rules of thumb’ are worth knowing when parents ask about prognosis; most parents ask whether their child will walk. While unlikely to be an active discussion issue with a patient in a long case, examiners may ask hypothetical questions such as how to approach answering the parents’ concerns when the concept of permanent neurological damage has been mentioned. Note the following: children with hemiplegic or diplegic CP usually walk, those with quadriplegic CP rarely walk; those with the dyskinetic subtype are more difficult to predict. Most children who can sit independently by 2 years will walk, but most children who cannot sit by 4 years are unlikely to walk. In terms of life span, only the most profound degrees of CP are associated with a decreased life expectancy. If a child cannot lift the head to prone, and requires tube feeding, the median survival is around 17 years.
Dystrophinopathies: Duchenne muscular dystrophy (DMD)
Background information: genetics of DMD
DMD is an X-linked recessive disorder, due to mutations (often deletions) in the dystrophin gene on the X chromosome (Xp21.2). It has a frequency of 1 in 3600–6000 male births. The DMD gene is the largest known human gene. It is around 2000 kilobases in size and codes for dystrophin, a large, rod-like 427-kD protein containing 3685 amino acids and located at the inner face of the muscle cell membrane. Dystrophin binds with a group of ‘dystrophin-associated proteins’ (DAPs) (e.g. sarcoglycans, dystroglycans, merosin) that span the muscle membrane, linking the muscle cytoskeleton and the extracellular matrix (see Figure 13.1). Absence of dystrophin disrupts the link, making the muscle membrane susceptible to damage from shearing stresses. Hence, dystrophin-deficient muscle is very susceptible to muscle injury, and degeneration of muscle fibres is a feature of dystrophic muscle. Dystrophin is undetectable in the muscle of DMD patients. Virtually all males with DMD have identifiable mutations. Over 4700 mutations in the DMD gene have been identified. Disease-causing alleles can include deletion of the complete gene, deletion or duplication of exons, small deletions, insertions and single base changes. Around two thirds of patients with DMD have intragenic out-of-frame (gross rearrangements) deletions, and around 10% have duplications of one or more exons of the gene; the remaining 25% have point mutations or other small rearrangements, including intronic deletions, insertions of repetitive sequences and splice site mutations. Generally out-of-frame mutations cause lack of dystrophin (and DMD), whereas in-frame mutations cause abnormal but partially functional dystrophin, resulting in BMD. The tissue distribution of dystrophin correlates with clinical features. It is found in skeletal, cardiac and smooth muscle, and results in skeletal muscle weakness and cardiomyopathy. In DMD-associated DCM, dystrophin expression is abnormal in myocardium, but may be normal or mildly abnormal in skeletal muscle. Dystrophin is found within the central nervous system, resulting in a static encephalopathy and cognitive deficits. Various forms of dystrophin are expressed in neurons and glia in the brain, especially the cortex, hippocampus, cerebellum and retina. Molecular genetic testing of DMD can confirm diagnosis of a dystrophinopathy without need for muscle biopsy in most patients ith DMD or BMD. There is a high incidence of new mutations, and two thirds of new patients have no positive family history.
Figure 13.1 Subsarcolemmal cytoskeleton.
Redrawn from; South, Isaacs, Roberton 2007. Practical Paediatrics 6th edition, p. 609, Figure 17.3.4.
Molecular tests for DMD
1. Multiplex PCR, Southern blotting and FISH are utilised to detect deletions, which account for two thirds of mutations in DMD.
2. Southern blotting and quantitative PCR analysis are utilised to detect duplications, which account for 6–10% mutations in males with DMD.
3. Multiple ligation probe amplification (MLPA) is utilised to analyse deletion/duplication of the gene in probands and carrier females.
4. Mutation scanning or sequence analysis is utilised to detect small deletions or insertions, single base changes, and splicing mutations that make up around a third of mutations in DMD.
5. More recent methods, including single-condition amplification internal primer sequencing (SCAIP) and denaturing gradient gel electrophoresis (DGGE)-based whole-gene mutation scanning, are utilised to detect the remaining third of mutations not yet elucidated by the above tests.
6. Muscle biopsy-based approaches utilising protein- and RNA-based analyses in combination with direct cDNA sequencing increase the mutation detection frequency to almost 100%.
7. Prenatal diagnosis is available by chorionic villus biopsy or amniocentesis by direct testing for abnormalities in the dystrophin gene.
Recent advances
In the last few years, the natural history of this disease has been changed by interventions (e.g. steroids, cardiac, respiratory, orthopaedic, rehabilitative), quality of life has improved and affected patients may now reach their fourth decade (a significant advance on the previous life expectancy of 19 years). Research into DMD has continued to accelerate, with a number of different treatment strategies being proposed. The role of steroids has become clearer. Glucocorticoids remain the only medication currently available that can slow down the decrease in muscle strength and function in DMD; this then reduces scoliosis and stabilises respiratory function. Low-dose steroids are very useful when boys are still walking, to improve motor function. The time of commencement of steroids remains controversial; currently, recommendations are to wait until identifying a plateau in the child’s motor development, where there is no longer progress in motor skills. Once that plateau is identified, steroids are commenced; they are not recommended for children still gaining motor skills, especially under 2 years. Typically, an affected male will progress with motor skills until 4–6 years old. Presently (2010), corticosteroid therapy is the treatment of choice for affected patients between 5 and 15 years of age. Some studies, however, suggest that the ideal window for treatment could be under 5 years. These patients need close monitoring, adjusting dose and timing to avoid unwanted side effects, especially weight gain.
Primitive stem cells in bone marrow have been shown to migrate into muscle and become new muscle cells. Stem cell therapy is under investigation but still experimental. Gentamicin has been found to permit cells to ignore an abnormal stop codon in the dystrophin gene and to proceed and synthesise the protein in the 15% of DMD patients who have premature stop codons as their underlying mutation. PTC124 is a new agent that may permit ribosomal read through of nonsense mutations. Morpholino antisense oligonucleotides permit exon skipping.
History
Current problems
1. Functional abilities with activities of daily living (e.g. dressing, writing, toileting); aids required (e.g. splints, supportive prostheses, computer-assisted communication/learning).
2. Mobility (e.g. long leg braces, wheelchair use, school and home access).
3. Home modifications required (e.g. ramps, bathroom fittings, specialised beds and mattresses).
4. Transport needs (e.g. van with hoist).
5. Scoliosis (e.g. progression, any planned surgery).
6. Joint contractures (AFOs, night splints).
7. Respiratory problems (e.g. symptoms of respiratory failure at later stage, sleep disordered breathing, non-invasive ventilation).
8. Cardiac symptoms (e.g. arrhythmias, symptoms of cardiac failure).
9. Gastrointestinal problems (e.g. incontinence, vomiting).
10. Difficulties with micturition.
11. School (e.g. any access problems, educational problems, any help needed or provided with toileting; attitudes of class teacher, headmaster, fellow students).
Past history
1. Initial diagnosis: when, where, presenting symptoms (e.g. late walking, tendency to fall, method of rising after fall, clumsiness, muscle cramps, learning delay, cognitive impairment, global or gross motor developmental delay).
2. The time period between onset of symptoms and diagnosis.
3. What investigations were undertaken to make the diagnosis.
4. Stages of deterioration (e.g. age at which the child lost the ability to climb stairs, stand from the floor or walk independently).
5. Number of hospitalisations.
6. Development of complications (e.g. scoliosis, cardiac failure) and their management.
Social history
1. Impact on child (e.g. difficulties at school, poor job prospects, limitations on lifestyle, body image, self-esteem, peer reactions).
2. Impact on family (e.g. parental coping, difficulties between mother and father, genetic implications for further children; financial considerations, such as cost of wheelchairs, home modifications, transport, hospitalisations, private health insurance; physical burden of helping children in and out of wheelchairs, cars, bed, bath).
4. Social supports (e.g. social worker, DMD Family Support Group provided by the Muscular Dystrophy Association, visits to school by occupational therapist and community liaison nurse from hospital muscle clinic to meet class and teachers).
Family history
Other known family members with DMD, other males with developmental delay or late walking.
Examination
Gait
Boys with DMD can walk well on their toes, but are unable to walk on their heels, and if they try they end up inverting the feet. On squatting, these children are slow to return to standing, need to extend the knee before the hip, and lean on their thighs to assist extension at the hip.
Of particular importance is the elicitation of Gower’s sign. The boy is asked to lie supine on the floor and then to get up. This first leads to rolling over to be prone (he cannot sit up because of weak neck and spine flexion), then on to the knees, then on ‘all fours’—that is, hands and feet—then ‘climbing up’ the legs to stand. Gower’s sign is often used as a functional timed test: timing how long it takes to arise from the floor is useful to monitor deterioration over time. See Figure 13.2.
Muscle power
After comprehensive assessment of muscle power, check for tone and reflexes (knee jerks often lost) and contractures, especially at the ankles, knees and hips.
Management
The main management areas are described below.
Psychosocial
1. Education of parents and patient. Clarification of misinformation from other sources requires multiple informative sessions with the various disciplines involved in the comprehensive management of these patients. Regular feedback is needed to ensure that no misunderstandings occur. Other family members (e.g. siblings, grandparents, aunts, uncles and cousins) are often very much involved emotionally and tend to be neglected.
2. Expectation of a grief reaction to the diagnosis and its implications. Preparatory explanation to parents of probable feelings such as guilt, anger and depression. Explanation regarding any misapprehensions or strange beliefs about the nature of the illness.
3. Ensuring sufficient social supports, both from professionals (such as social workers) and non-professionals (such as other affected patients, families of other patients and groups such as the Muscular Dystrophy Association [MDA], Montrose Access [Qld] or Northcott [NSW]). The MDA provides parents’ groups and a useful handbook that deals with the home situation, recreational activities, education and vocational possibilities. There are excellent sites on the internet, including http://mdausa.org>and <http://www.treat-nmd.eu/patients/DMD/family guide/
4. Informing about financial assistance measures, such as any government benefits (which may assist directly with the child’s care, transport costs, accommodation costs and provision of aids). The illness places a very large financial burden for home modification (such as ramps, bathroom modification, lifting machines) on the family.
5. Discussion of treatment difficulties (such as non-compliance), seeking other opinions, and understanding and acceptance of alternative therapies sought by parents.
6. A major point is helping the family to determine how various people (especially the affected son) are to be informed. The paediatrician may not be the person who will help most, but he or she does have responsibility to ensure that it is done adequately. The consequences of failure in this aspect of management may include: parents who will not discuss the disease with their son, siblings, teachers or each other; one parent (usually the father) who withdraws from reality; and help being refused (because the parents believe that the child will be cured by divine intervention).
