Linda Cardozo MD FRCOG
- Professor of Urogynaecology, King? College Hospital, London
Lysosomal (‘white cell’) enzymes Measurement of enzyme activities in lysosomes can be used to identify children affected by lysosomal storage disease or heterozygote carriers medications and mothers milk 2014 generic chloroquine 250mg visa, as well as to monitor the response to bone marrow transplant or enzyme replacement therapy medications used to treat depression order 250mg chloroquine mastercard. Many laboratories screen for a panel of enzymes; however medication 3 checks order chloroquine mastercard, this may not include the enzyme you are specifically interested in! It is important that the laboratory has appropriate quality assurance procedures in place treatment ringworm buy cheap chloroquine 250 mg on line. Buffy coat histology When blood is centrifuged, the ‘buffy coat’ is the enriched white cell frac tion, visible as a white layer between the red cells (bottom) and the plasma (top). This sample can be fixed and prepared for electron microscopy for inclusion bodies, which can be useful in the diagnosis of lysosomal disease and neuronal ceroid lipofuscinosis. Alder–Reilly granules Dense metachromatic granules resembling toxic granulations seen in leuco cytes in mucopolysaccharidoses. A small number of acanthocytes may be seen in other forms of severe haemolytic anaemia, particularly after splenectomy. Lactate Free flowing blood is typically collected immediately into perchloric acid to deproteinize it. For the laboratory to interpret the levels of the volume of added blood must be accurately known: this is usually done by pre-weighing the tube. Metaphase spreads are selected, and the chromosomes are arranged in descending order by size and compared with a standard. Techniques constantly improve in terms of the types of staining available, and the analysis is now often computerized. This often makes it worth repeating the test if it has not been done for some years. Most commonly used to identify Prader–Willi/ Angelman (chromosome 15), 22q-, Miller–Dieker and Smith–Magenis syndromes. Comparative genome hybridization this technique is becoming increasingly available and may replace routine karyotyping in the near future. Effectively a ‘high resolution karyotype’ it detects copy number imbalances (due to deletion or duplication) relative to a control sample. Balanced rearrangements, inversions or other rearrangements that do not alter total copy number will not be detected. The accuracy of these techniques is not yet as high as conventional (‘Sanger’) sequencing and putative mutations will need to be confirmed conventionally. Ring chromosome 20 mosaicism this is a recognized syndrome of severe epilepsy and learning difficulties with severe behavioural features. Ring chromosome 20 mosaicism should be specified if this is a consideration so that more cells are examined: examination of 50 cells will identify 6% mosaicism with 95% confidence. Stop and maintain the cuff for 1 min, then release the cuff, and take blood for lactate and ammonia at 2 and 12 min. Transferrin is a sensitive and convenient marker, secreted by the liver and normally present in different isoforms due to dif ferences in glycosylation. Biotinidase the phenotypic range of this treatable deficiency state is broad (see b p. Consider testing especially where there is hypotonia, severe infan tile epilepsy, alopecia, rashes, and hearing loss. Note: most specific enzyme assays can be carried out on cultured skin fibroblasts, cultured amniotic fluid cells or chorionic villus samples. Muscle biopsy Histology Dystrophic change. Necrosis of fibres with phagocytosis, etc. Immunohistochemistry. Dystrophin (absent or deficient in Duchenne and Becker dystrophies). Nerve biopsy. Segmental demyelination and remyelination cause layers of myelin giving an onion bulb appearance to the myelin sheath, indicative of demyelinating disease. Fibroblast culture Undertake biochemical studies when: Genetic testing is not available/cannot exclude a diagnosis. Whilst not specific, the diagnosis of a number of neurological conditions may be assisted by the demonstration at electron microscopy of inclusion bodies in apocrine sweat gland-containing skin. Establishment of fibroblast culture may be indicated for enzyme analysis to investigate inborn errors of metabolism or chromosome analysis to look for tissue specific mosaicism. Skin for fibroblast culture must be scrupulously sterile or contaminants will prevent the culture establishing. Take a small sample (a few millimetres in diameter) to prevent necrosis of the centre of a larger sample. For fibroblast culture collection into tissue culture medium is strongly preferred (use saline only exceptionally). Avoid iodine containing compounds such as betadine as these interfere with cell growth in culture. Although the technique is relatively simple, success depends on obtaining several samples of adequate size from a single insertion site. Subsequent specimen processing should only be done by laboratory technicians familiar with the techniques. Procedure. Prepare the site: usually the upper third of the rectus femoris/vastus lateralis. Intrathecal medicine Inadvertent intrathecal injection of cytotoxics intended for intravenous use in the treatment of acute lymphoblastic leukaemia has been a repeated cause of medical tragedy. Intrathecal cytotoxics should only be given by paediatric oncologists in a dedicated setting. Shunt tap this should ideally only be performed by a neurosurgeon as different shunt designs have different access points and some are not suitable for tapping (Figure 2. Neuropsychological testing complements and supplements assessment by an educational psychologist. Domains and modules Development is considered to be ‘domain specific’ A domain is a set of representations sustaining a particular area of knowledge. Indications for neuropsychological testing. Evaluation of developmental disorders. Visuospatial Visuospatial tests assess right hemisphere function predominantly, although a left hemisphere influence may be present if verbal mediation occurs. Visuomotor functioning Closely related to visual item perception and visuospatial processing, visuomotor functioning adds a manipulation or graphomotor component to the perceptual tasks. Social-emotional functions these are particularly important in children with non-verbal learning disabilities. Executive functions Capacities that include: Attending in a selective and focused manner. Observation of spontaneous behaviour is also necessary to assess execu tive function, as the ‘structured’ nature of formal assessment compensates for the deficits being sought. Qualitative data (the types of errors pro duced) may be useful in determining context-related processing difficulties from executive function problems. This involves three stages: Assessing the age appropriateness of behavioural function. This page intentionally left blank Chapter 3 103 Signs and symptoms Agitation and confusion 104 Back pain 106 Behaviour disorders 107 Developmental impairment 109 Exercise limitation and muscle pain 117 Eye movement abnormalities 119 Facial movement abnormalities 126 Facial sensation abnormalities 130 the floppy infant 132 Foot deformities 135 Funny turns: episodic events 136 Funny turns: likely epilepsy? Children’s Orientation and Amnesia Test) exist, but are time-consuming; norms are age-dependent. Other features of acute confusional state. Overactive and agitated, underactive and drowsy, or mixed. Visual hallucinations are a marker of confusion until proven otherwise: typically of small, moving, fear inducing things such as insects or snakes;. may co-exist with visual misinterpretations as part of the clouded sensorium. Acute management One of many important reasons for correctly distinguishing an acute con fusional state from emotional reaction is the very different approach to management. However attempts to argue, persuade, or cajole a child with an acute con fusional state will be counter-productive. Consider: Infection Discitis in toddlers. The child will often refuse to stand or will walk with a very straight back, ‘guarding’ the spine. Others. Back pain can be the initial presentation of Guillain–Barré syndrome in toddlers, causing initial confusion, although the fuller picture quickly develops.
Finally medications epilepsy buy chloroquine 250 mg, stimulation of the adrenal gland releases not only adrenaline but also endogenous painkiller opiates called enkephalins treatment associates purchase 250 mg chloroquine with visa. Before dental surgery medicine woman 250 mg chloroquine with visa, dentists often include adrenaline in the local anesthetic 10 medications discount chloroquine 250mg with visa, not only because this decreases bleeding but also because it prolongs the anesthesia time. Injection of adrenaline with the local anesthetic always produces large, physiologically active increases in circulating adrenaline levels. Adrenaline injection actually inhibits, rather than augments, responses of circulating levels of the opioid, beta-endorphin, in the setting of wisdom tooth extraction. The Believe it or not, the eyes in these drawings are identical, except for the constricted pupils and raised eyelids in the eyes on the left. Opiates such as morphine and heroin produce miosis, probably via stimulation of neurons in the - 244 - Principles of Autonomic Medicine v. At the time of the photo, during the war in Afghanistan against the Soviet occupation, the girl was living in a refugee camp in Pakistan. In an interview many years later the photographer recalled that the girl had been in school at the time. At first she had covered her face with her hands, but her teacher told her to take her hands down and let him take her picture because of the importance of their story. I would imagine that if the miosis reflected only a pupillary light reflex, she would have squinted. Students of Pupils Cartoonists frequently exploit effects of alterations in autonomic nervous system outflows to the pupils to convey the psychological state of the characters. One of them is neutral, one is cute and sweet, one is disoriented, and one is startled. The answers seem intuitively obvious: (A) is neutral, (B) is startle, (C) is disorientation, and (D) is cute. When I’ve asked doctors the same question, they often get it wrong, because of what they have been taught about the “stress response. By this rationale doctors can go against their own intuition and guess that (D) corresponds to startle. Recall that the sympathetic post-ganglionic nerves are non-myelinated and conduct signals relatively slowly. The reflex pathway is relatively long, because the sympathetic nerves to the head emanate from the thoracic spinal cord, not the brainstem like parasympathetic nerves. The immediate startle response involves miosis, probably because of more rapid effects of parasympathetic nervous system stimulation. The vagus nerves, which convey parasympathetic nervous system signals to the heart from each side of the lower brainstem, are also myelinated and conduct signals rapidly. Doctors are also taught, in this case correctly, that a “blown,” dilated pupil on one side and deviation of the eye on that side can disclose a catastrophe inside the head, such as from a clot on the brain. I think cartoonists exploit the instinctive communication value of this appearance to convey disorientation or delirium, as in panel (C). In coronary artery disease, what normally would be appropriate changes in autonomic functions can be lethal. This is an example of a dysautonomia from worsening of an independent pathological state. Probably the most common type of dysautonomia involves compensatory, normal autonomic nervous system responses that worsen an independent disease process, rather than involving an abnormality of the autonomic nervous system itself. A classic example is sudden death in an old man - 249 - Principles of Autonomic Medicine v. In a person with coronary artery disease, normal sympathetic noradrenergic and adrenergic system activation can incite a lethal positive feedback loop when myocardial oxygen consumption exceeds the supply. Changes in activities of components of the autonomic nervous system can even be harmful when the changes compensate for abnormal functioning of a different body system. For instance, in heart failure, the heart fails to deliver an appropriate amount of blood to body organs. Among several compensatory adjustments, one is increased sympathetic noradrenergic system outflow to heart. This improves the pumping function of the heart; however, compensatory activation of the sympathetic noradrenergic system also promotes overgrowth of heart muscle, which can stiffen the heart walls and worsen the heart failure. In other forms of dysautonomia, the problem is from abnormal functioning within the autonomic nervous system itself. In several diseases, such as diabetes, the patients do worse in the long run if they have autonomic failure. Often it is difficult and sometimes impossible to determine whether the lesion is at the level of the autonomic nerves, the spinal cord, the brainstem, or higher structures. An example of acute sympathetic noradrenergic failure is fainting associated with decreased sympathetic noradrenergic system outflow to skeletal muscle. An example of chronic sympathetic noradrenergic failure is neurogenic orthostatic hypotension associated with loss of sympathetic noradrenergic nerves. An example of acute sympathetic noradrenergic activation is paroxysmal hypertension due to increased sympathetic noradrenergic outflows in a patient with a hemorrhagic stroke. An example of chronic sympathetic noradrenergic activation is hypernoradrenergic hypertension. Some dysautonomias involve abnormalities of specific components of the autonomic nervous system and not others. For instance, in dopamine-beta-hydroxylase deficiency, there is failure of the sympathetic noradrenergic system, due to the inability to synthesize norepinephrine, but other components of the autonomic nervous system are intact. In Sjogren’s syndrome there seems to be a rather selective parasympathetic cholinergic lesion. In autonomically mediated syncope, the sympathetic adrenergic and parasympathetic systems are activated, whereas sympathetic noradrenergic system outflow (at least to skeletal muscle) can abruptly cease. Finally, Parkinson’s disease involves prominent loss of sympathetic noradrenergic nerves in the heart, whereas sympathetic cholinergic function, as indicated by sweating, can be increased, normal, or decreased. The Ironic Case of John Hunter Normal changes in activities of the autonomic nervous system can be harmful or even lethal in the setting of an independent disease state. For instance, in patients with coronary heart disease, what would otherwise be considered physiologic responses to emotional distress can provoke attacks of chest pressure (angina pectoris) and even sudden death. One of the earliest and best documented—and surely the most ironic—illustrations of this phenomenon was the case of Dr. John Hunter, the renowned academic surgeon who is considered to be the father of experimental pathology in England. His colleague, William Heberden, gave the first clear description of angina pectoris as a symptom of coronary artery disease. In March, 1775, Hunter performed an autopsy on one of Heberden’s patients who had died suddenly during a violent spell of anger. Hunter described coronary arteriosclerosis when he observed, “The two coronary arteries, from their origin to many of their ramifications upon the heart, were become one piece of bone. His coachman being beyond his times, or a servant not attending to his directions, brought on the spasms, while a real misfortune produced no effect. John Hunter, from a portrait by Sir Joshua Reynolds Home described eloquently the prolonged episodes of severe chest pain from which Hunter suffered. These episodes were accompanied by pallor followed by swooning: - 254 - Principles of Autonomic Medicine v. In Home’s words, “On October 16, 1793, when in his usual state of health, he went to St. Robertson, one of the physicians of the hospital, he gave a deep groan and dropt down dead. His myocardium was scarred, and his coronary arteries were so calcified that Home described them as “bony tubes. He also did not die of congestive heart failure, which produces cardiac enlargement, since according to Home, “The heart itself was very small, appearing too little for the cavity in which it lay, and did not give the idea of its being the effect of an unusual degree of contraction, but more of its having shrunk in its size. The adrenaline-induced increase in myocardial oxygen consumption was not balanced by an increase in oxygen supply because of the rigidified coronary arteries. The angina pectoris exacerbated the distress and thereby the adrenaline secretion, precipitating a lethal arrhythmia. The Dysautonomias Universe Different types of dysautonomia occur in the different stages of life. In infants and children, dysautonomias often reflect problems in the development of the autonomic nervous system. There are also genetic diseases of proteins required for synthesizing or storing catecholamines. In Hirschsprung’s disease, there is a lack of development of nerve cells of the enteric nervous system in the colon, usually without an identified mutation.
The func tions of sequences within the promoter were studied through random mutagenesis and high throughput clone analysis; 75% of all mutations that afect promoter function fall within these -35 or -10 regions medications used for fibromyalgia discount 250mg chloroquine with visa. The mutagenesis has been applied in three diferent ways with broadly similar results treatment ibs order 250mg chloroquine with mastercard. We replace the six nucleotide -10 region with random sequence to achieve the widest range of promoter strengths within the smallest populations medications quizlet cheap chloroquine 250 mg without a prescription. Conversely medications made from animals order generic chloroquine line, Jensen and his colleagues randomize the sequences outside the conserved -35 and -10 regions, presumably to achieve a more gradual variation of promoter strengths. The best screens are sensitive, high in throughput, broad in dynamic range and precise (such that isogenic clones exhibit lit tle phenotypic variance). Candidate expression plasmids should always be re-evaluated (using the high throughput screen) several times to demonstrate that they consistently produce the desired phenotype. Multi-copy plasmids are most ofen employed because they enable the highest cloning efciencies, and therefore the most diverse libraries. When plasmids do not segregate evenly between daughter cells, and when the constitutive or leaky expression of a gene imparts a growth disadvantage, individual cells within a genetically homogeneous population will express diferent amounts of protein. Expression vectors with tightly regulated promoters are usually more stable than those that are leaky or constitutive. Another way to stabilize an expression construct (promoter-gene) is to integrate it into the bacterial chromosome. It might also be possible to integrate libraries of expression constructs (mutant promoter-reporter gene-selectable marker) into the chromosome using “gene gorging,” which utilizes self-linearizing plas mids as templates for recombination. The Tth/Vent polymerase mixture used in this protocol is modestly mutagenic28 and recombinagenic. The resulting colonies should be evaluated in high throughput screens (see Section 3. Alternatively, inducible vectors for the over-production of the λ Red operon can be used to increase recombination rates in any strain. It seems likely that we were expressing the Gam, Redα and Redβ proteins at suboptimal levels,38 and that recombination frequency is sequence dependent. One possible solution would be to apply the aforementioned “gene gorging” technique. The polymerase-catalyzed extension of this mega-primer dimer produces a single recombined product. Tird, we use sequence analysis sofware to visualize the top and bottom strands of the virtual construct. Fourth, the primers are copied and pasted from the sequence analysis sofware back into the word processing fle. Primer 2 is identical to the bottom strand at the intersection of the lef fank (Tm = 80°C) and the expression/selection cassette (Tm = 40°C). Primer 3 is the top strand at the intersection of the lef fank (Tm = 40°C) and the expression/selection cassette (Tm = 80°C). The extension of annealed templates is likely catalyzed by the Vent polymerase, which has strong strand displacement activity ( Saturated cultures are diluted 1/15-fold (20 μl of culture into 300 μl of media) and shaken vigorously for 2 hours at 30°C. More recently, a number of groups have developed trans-acting riboregulators that conditionally reg ulate gene expression. The efciency of any synthetic process depends on appropriately balancing the concentrations of the reactants, intermediates, products, and catalysts. This is particularly true in metabolic processes where intermediates may be toxic, act as inhibitors, or be diverted to other path ways if not acted on readily. Furthermore, protein synthesis places an additional burden on the cell and ill-timed production of an enzyme can lead to an inefcient process. Ideally, all components in a multi-step synthesis would be present at the right concentration and at the right time. Such control thus requires the ability to dynamically tune the level of enzyme activity, for example by increasing activity when a substrate is plentiful, and decreasing activity when a substrate is scarce, or when the immediate downstream product is abundant. Living systems have evolved a variety of mechanisms to regulate metabolism based on the demands of the cell. Many of these mechanisms rely on ligand-induced allostery, where binding of a metabolite regulates function. Furthermore, while most of the known natural riboswitches have been discovered in prokaryotes, a eukaryotic riboswitch from A. Like riboswitches that control translation, those that regulate transcrip tion most ofen decrease gene expression in a metabolite-dependent fashion. Typically, the mechanism for this decrease involves a ligand-mediated early termination of transcription. The adenine riboswitch is particularly interesting because the aptamer core that recognizes the ligand is nearly identical to that found in the guanine riboswitch. Tus, although full-length riboswitch transcripts produced in vitro may be able to equilibrate between two structures upon ligand binding, it is unclear whether this is relevant in vivo. However, the explosion of new gene sequences and rapid advances in protein engineering now enable the heterologous expression of entirely novel metabolic pathways. As such, there is an increasing demand for new ligand-dependent gene con trol systems. In the following sections, we will describe how powerful in vitro selection techniques coupled with high throughput screening methods enable the creation of riboswitches that respond to entirely new compounds. Such riboswitches may become useful tools for controlling engineered meta bolic pathways. However, because translation initiation in eukaryotes difers substantially from that in prokaryotes, many of the strategies used to cre ate these ligand-regulated systems, such as the use of multiple aptamer sequences,98,100 are not generally applicable to producing riboswitches that function in prokaryotic systems. Tough most of the known riboswitches have been discovered in prokaryotes, there are relatively few examples of engineered riboswitches that control gene expression in these organisms. Expression levels of the xylose repressor protein were determined by monitoring the theophylline-dependent repression of a separate reporter gene under the control of two xyl operator sequences. To our surprise, we discovered that theophylline activated gene expression in a dose-dependent fashion. Although we were able to establish that the riboswitch acted post-transcriptionally and appeared to be under thermodynamic control, we were unable to determine the precise mechanism of activation. In addition, the riboswitch could efect the ligand-dependent expression of diferent genes, including an antibiotic resistance gene that coupled cell growth to the presence of a nonmetabolite, which suggested that cell growth could eventually be tied to the product of a biotransformation. While early studies of engineered and synthetic riboswitches have been promising, for riboswitches to become a standard feature of the metabolic engineer’s toolbox, it will be critical to develop methods to rapidly produce riboswitches that respond to new compounds in a selective, tunable, and predictable fashion. In the following sections, we will describe techniques that our lab has developed to create ribo switches with improved performance characteristics, which have also resulted in a better understanding of how riboswitches function. To create a riboswitch that can efectively regulate an engineered metabolic pathway, it is impor tant to discover aptamers that selectively recognize a desired compound while discriminating against closely related compounds. This has allowed the discovery of aptamers that recognize a wide variety of compounds, including amino acids, alkaloids, and polyketides, and discriminate on the basis of subtle modifcations in structure or stereochemistry. Extensive washing can eliminate nonspecifc binding sequences, and washing with structurally related ligands can be used to eliminate nonselective binders. Repeated * We thus considered this riboswitch to be “synthetic” rather than “engineered”, as engineering typically implies the use of design principles that result in a desired outcome, even if the specifc details remain murky. Using iterative rounds of gel-based selection, where sequences that cleave in the presence of a desired ligand are amplifed, and those that cleave in its absence are discarded, it is possible to discover new ligand-dependent aptamers. An advantage of allosteric selection is that the ligands are used in solu tion in an unmodifed form, which eliminates the need for attaching them to a solid support. Tus, it is too early to evaluate the promise of any single strat egy for creating new riboswitches, and certainly new strategies (both rational and evolution-based) will emerge in the coming years as our understanding of riboswitch mechanisms improves. Tat said, it is worth briefy discussing the history of engineered riboswitches to see where we are and where metabolic engineers may want to go. Most of these switches are thought to repress protein translation by introducing an additional barrier to translation upon ligand binding which promotes the dissociation of the ribosome and the termination of protein synthesis. In prokaryotes, there are fewer examples of synthetic riboswitches, and the two best known examples88,89 respond to the same molecule (theophylline), but were created using diferent strategies and act via diferent mechanisms. What is clear, however, is that all of these riboswitches were created from pre-existing aptamers that were selected for another purpose. Tus, one the one hand, all of these examples have benefted from the availability of these aptamer structures and the extensive body of knowledge about their structures and binding mechanisms.
Cognitive ‘syndromes’ Frontal lobe function Deficits in attention treatment kidney stones best purchase chloroquine, impulsivity symptoms panic attack order chloroquine cheap, perseveration (‘stuck in a groove’) medicine 100 years ago order discount chloroquine line, mis construes sarcasm medicine 2020 chloroquine 250mg free shipping, irony. Good at superficial social ‘chit-chat’ (over-learned), but poor ‘emotional intelligence’. Temporal lobe dysfunction. Language dysfunction (receptive or expressive dysphasia) in dominant temporal lobe disease: visual field defect (superior, contralateral quadrantanopia). Parietal lobe dysfunction Poor 2-point discrimination, graphaesthesia (interpretation of letters drawn on the hand) or shape discrimination (identification of a coin or paper clip in the contralateral hand particularly in non-dominant lobe disease). It is, however, very language-orientated, with relatively limited testing of memory, visuospatial function, or executive skills (see Box 1. To assess this formally, first check nostril patency (sniff with the other nostril occluded) then use pleasant odours (chocolate, etc. Very irri tant odours can be detected somatically by the nasal mucosa (trigeminal nerve). Fields In older children, visual fields can be tested by confrontation with both eyes open. Isolated nasal visual field defects (without temporal field defects) are rare other than in relation to chronic vigabatrin use (see b p. In infants, gross field preservation can be inferred by the refixation reflex: the child refixing on a target as it moves from central into peripheral vision in each direction. In younger children (age 5–7 yrs), make a game of having them sit in your (swivelling! Fundoscopy in toddlers requires an assistant to attempt to secure attention, and patience! In neonates get the mother to hold the child against her with head on her shoulder looking to the side, whilst quietly awake. Perform fundoscopy in the child’s right eye with your right eye and vice versa so as not to block the view of the non-examined eye with your head and so prevent their fixing on a distant target. Visual loss is promi nent in papillitis and is the usual presenting complaint (only in the mildest cases is it confined to loss of colour vision). Normal red reflex appearances vary in dif ferent ethnic groups: if in doubt, check appearances in parents. An abnormal red reflex can be absent (dark pupil), partially obscured (by an opacity in lens or media) or of an abnormal colour or brightness. Pulsation, if seen, confirms normal intracranial pressure, which can be very useful reassurance but is absent in 10% of the normal population. Rest your thumb on the eyebrow and stabilize the ophthalmoscope on your thumb: this minimizes confusing parallax effects due to movement of the ophthalmoscope relative to the eye. Pulsation is best seen at the ‘knuckle’ where the vessel turns perpen dicular to view to enter optic cup (A), as a pulsation of the vein profile particularly at tortuosities (B), or as in Figure 1. Test for the ipsilateral anhidrosis by sliding a clean metal teaspoon lightly over the forehead and noting the slight drag on crossing to the stickier, normal side. The affected pupil is larger and reacts poorly to light (thus, asymmetry may be more marked in, or on initially moving to , brighter conditions), but contracts briskly on accommodating to a near target. Afferent pupillary defect A non-reactive pupil can arise from a lesion either in the afferent (optic nerve) or the efferent (third nerve) limb of the pupillary light reflex. Due to the bilateral consensual nature of the pupillary light reflex, an eye with an interrupted optic nerve, but intact third nerve will still constrict when the opposite eye is illuminated, but both pupils will dilate when the injured eye is illuminated. Swing onto one pupil for 5s then promptly swing over to the other pupil for another 5s then back, and continue repeatedly until a con sistent impression is gained of whether one pupil is dilating as the torch swings onto it. The difference will be that the consensual response will be present: the pupil will constrict when the other eye is illuminated. Duane retraction syndrome: on attempted adduction, limitation or absence of abduction, variable limitation of adduction and palpebral fissure narrowing because of globe retraction. This is very useful in detecting subtle non-alignment of eyes in the neutral position. Eye movements. In an older child, test smooth pursuit of a slowly moving target and saccadic eye movements (‘Look at mummy. If the child’s visual acuity is adequate to fix on your face, the motion-induced nystagmus will be rapidly suppressed despite continuing rotation. Abnormal conjugate eye movements. Down (sunsetting in raised intracranial pressure). Diplopia Paralytic eye movement abnormalities, particularly if acute give rise to subjective diplopia. The false image (the most lateral one) will be from the affected eye and will disappear when the affected eye is occluded, although younger chil dren will struggle to report this reliably. Covering one eye with red glass and asking children to consider the red image can help. Diplopia is often distressing; children may cover or occlude one eye, and dislike having it open. Only a readily identifiable and rare ocular cause, such as lens dislocation could otherwise give rise to this. Cranial nerve V For an approach to the evaluation of disturbances of facial sensation, see Table 3. Note whether boundaries of any reported area of altered perception correspond to the anatomical boundaries of the divisions of the trigeminal nerve (see Figure 3. Corneal reflex Approach with a wisp of cotton wool from the side to avoid a blink due to visual threat. Note whether a blink is elicited and also ask whether the sensation felt similar on each side. Informally, observing the blink produced by brushing eyelashes elicits similar information. Motor functions of trigeminal nerve Test the ability to resist attempted jaw closure (lateral pterygoid). Jaw jerk Elicit by asking the child to let their mouth fall open, gently holding their chin and tapping your own thumb: explain what you are going to do before approaching the child’s face with a tendon hammer! A readily elicited, exaggerated jaw jerk confirms that an upper motor neuron picture is of cerebral, rather than high cervical spine origin. Ask the child to imitate facial expressions (grimace, frown, smile, forced eye closure). The child should normally be able to bury their eyelashes in forced eye closure: distinguish upper motor neuron involvement of the seventh cranial nerve (minimal effect on eye closure or eyebrow elevation) from lower motor neuron cranial nerve lesions (typically marked effect on eye closure). Middle ear disease (chronic serous otitis media; ‘glue ear’) is a common cause of conductive hearing loss in younger children, also in children with Down syndrome and any disorder of palatal function (including acquired palatal palsies, as well as cleft palate). Rinne tuning fork testing is reliable in children as young as 5 if performed carefully. In the conscious child, it is rarely necessary to elicit a gag reflex formally to assess palatal and bulbar function: this can be inferred from observation of feeding and swallowing behaviour. Symmetry of palatal movement can be assessed by observing whether the uvula is midline and moves vertically upward on saying ‘aah’. In the disabled child, demonstration of the presence of a detectable gag reflex is not an adequate demonstration of the safety of oral feeding and a formal feeding and swallowing assessment is required (see b p. Assess power by asking the child to turn their head to the contral ateral side and then prevent you pushing back. The integrity of 12th nerve function is assessed by observation of the tongue at rest in the open mouth (fasciculation? The latter forms a very sensitive screening test that will detect all but perhaps the mildest of pyramidal weaknesses, although formal neurolog ical evaluation may be very helpful in identifying the cause of a puzzling gait or postural abnormality. Formal peripheral neurological examination Appearance. Note the symmetry of muscle bulk and limb length. Mild pyramidal weakness (causing perhaps only a subtle tendency to walk on the toes) may be reflected in greater wear at the toe. Tone. Younger children can find it hard to ‘just relax’, which can cause misleading impressions of increased tone. The two may co-exist, particularly in cerebral palsy and acquired brain injury where the failure to consider extrapyramidal stiffness can result in effective therapies being missed. Dystonia in a limb can sometimes be brought out by passively moving the arm whilst asking the child to perform repeated movements. Formal examination of power in the legs is best performed in supine lying, although seated assessment is possible. Mild pyramidal weakness results in pronator drift: a downward drift and pronation of the affected arm. Dynamic assessment of power by examination of posture, gait, and move ment may be more informative.
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