Neurological disease

Clinical examination of the nervous system

1 Examination of gait and posture

	Procedure	Abnormality	Disease
1	Responds to call	No response	Deafness Delirium
2	Rising from chair	Difficulty rising	Proximal muscle weakness Joint stiffness
3	Examine posture Retropulsion/anteropulsion	Stooped Postural instability	Parkinsonism Parkinsonism
4	Examine arms during walking	Reduced arm swing	Parkinsonism, upper motor neuron lesion
5	Examine routine walking	Circumduction (stiff leg moves outwards in ‘circular’ manner)	Upper motor neuron lesion
		‘Slapping’ due to foot drop	Lower motor neuron lesion L5 root or common peroneal nerve
		Narrow-based, short strides	Parkinsonism
		Wide-based, short strides (marche à petits pas, magnetic gait)	Frontal lobe lesion
		Wide-based, irregular strides	Cerebellar lesion
		High-stepping gait	Dorsal column lesion/sensory neuropathy

4 Examination of cranial nerves

Nerve	Name	Tests
I	Olfactory	Ask patient about sense of smell (only examine if reported change)
II	Optic	Visual acuity Visual fields ‘Swinging’ torch test for relative afferent pupillary defect Ophthalmoscopy
III	Oculomotor	Eye movements (nystagmus) Eyelid movement Pupil size, symmetry, reactions
IV	Trochlear	Eye movements
V	Trigeminal	Facial sensation Corneal reflex Ask patient about taste
VI	Abducens	Eye movements
VII	Facial	Facial symmetry and movements Ask patient about taste
VIII	Vestibulocochlear	Hearing (rub fingertips next to each ear) Tuning fork tests (Rinne and Weber) Hallpike test for benign positional vertigo
IX	Glossopharyngeal	Gag reflex (sensory)
X	Vagus	Palatal elevation (uvula deviates to side opposite lesion) Gag reflex (motor) Cough (bovine)
XI	Accessory	Look for wasting of trapezius/sternocleidomastoid Elevation of shoulders Turning head to right and left
XII	Hypoglossal	Look for wasting/fasciculation Tongue protrusion (deviates to side of lesion)

6 Root values of tendon reflexes

Reflex	Root value
Upper limb
Biceps jerk	C5/C6
Supinator jerk	C5/C6
Triceps jerk	C7
Finger jerk	C8
Lower limb
Knee jerk	L3/L4
Ankle jerk	S1

Neurological examination in old age

• Pupils: tend to be smaller, which makes fundoscopy more difficult.

• Limb tone: difficult to assess because of poor relaxation and concomitant joint disease.

• Ankle reflexes: may be bilaterally absent.

• Gait assessment: more difficult because of concurrent musculoskeletal disease and pre-existing neurological deficits.

• Sensory testing: especially difficult when there is cognitive impairment.

• Vibration sense: may be reduced in the lower legs.

Neurology has long been misperceived as a specialty in which intricate clinical examination and numerous investigations are required to diagnose obscure and untreatable conditions. In fact, it requires careful history-taking with a lesser contribution from targeted examination and considered investigation. The development of specific, effective treatments has made accurate diagnosis essential.

The brain, spinal cord and peripheral nerves combine to allow us to perceive and react to the external world, while maintaining a stable internal environment. The brain provides a platform for processing information and forming a response and, in doing so, both forms and is affected by our personality and mental state. Nervous system disorders are common, accounting for around 10% of the UK’s general practice consultations, 20% of acute medical admissions, and most chronic physical disability. While pathological and anatomical localisation is important, skill is required to identify those neurological symptoms not associated with neurological disease, to differentiate patients requiring investigation and treatment from those who need reassurance.

Initially, it is important to exclude conditions that constitute neurological emergencies (Box 26.1). If the presentation is not an emergency, more time can be taken to reach a diagnosis. The history should provide a hypothesis for the site and nature of the potential pathology, which a focused examination may refine and inform what further investigation would be useful. A discussion with the patient about possible interventions and rehabilitation may then take place.

26.1 Neurological emergencies

• Status epilepticus (p. 1159)

• Stroke (if thrombolysis available) (p. 1237)

• Guillain–Barré syndrome (p. 1224)

• Myasthenia gravis (if bulbar and/or respiratory) (p. 1226)

• Spinal cord compression (p. 1220)

• Subarachnoid haemorrhage (p. 1246)

• Neuroleptic malignant syndrome (p. 249)

As Stroke has become a specific subspecialty in many centres, it is described in a separate chapter, although it is clearly a neurological condition. This chapter should be read with it, to help clarify how the presentation, diagnosis and management of stroke differ from other conditions.

Functional anatomy and physiology

Cells of the nervous system

The nervous system comprises billions of connections between billions of specialised cells, supplied by a complex network of specialised blood vessels. In addition to neurons, there are three types of glial cells. Astrocytes form the structural framework for neurons and control their biochemical environment. Astrocyte foot processes are intimately associated with blood vessels, forming the blood–brain barrier (Fig. 26.1). Oligodendrocytes are responsible for the formation and maintenance of the myelin sheath, which surrounds axons and is essential for the rapid transmission of action potentials by saltatory conduction. Microglial cells derive from monocytes/macrophages and play a role in fighting infection and removing damaged cells. Peripheral neurons have axons invested in myelin made by Schwann cells. Ependymal cells line the cerebral ventricles.

Generation and transmission of the nervous impulse

The role of the central nervous system (CNS) is to generate outputs in response to external stimuli and changes in internal conditions. Each neuron receives input by synaptic transmission from dendrites (branched projections of other neurons), which may sum to produce output in the form of an action potential. This is conducted down axons, with synaptic transmission to other neurons or, in the motor system, to muscle cells. These processes require the maintenance of an electrochemical gradient across neuron cell membranes by specialised membrane ion channels. Synaptic transmission involves the release of neurotransmitters that modulate the function of the target cell by interacting with structures on the cell surface, including ion channels and other cell surface receptors (Fig. 26.2). At least 20 different neurotransmitters are known to act at different sites in the nervous system, and all are potentially amenable to pharmacological manipulation.

Fig. 26.2 Neurotransmission and neurotransmitters.
(1) An action potential arriving at the nerve terminal depolarises the membrane and this opens voltage-gated calcium channels. (2) Entry of calcium causes the fusion of synaptic vesicles containing neurotransmitters with the pre-synaptic membrane and release of the neurotransmitter across the synaptic cleft. (3) The neurotransmitter binds to receptors on the post-synaptic membrane either (A) to open ligand-gated ion channels which, by allowing ion entry, depolarise the membrane and initiate an action potential (4), or (B) to bind to metabotrophic receptors that activate an effector enzyme (e.g. adenylyl cyclase) and thus modulate gene transcription via the intracellular second messenger system, leading to changes in synthesis of ion channels or modulating enzymes. (5) Neurotransmitters are taken up at the pre-synaptic membrane and/or metabolised.
(cAMP = cyclic adenosine monophosphate; DNA = deoxyribonucleic acid; mRNA = messenger ribonucleic acid)

The neuronal cell bodies may receive synaptic input from thousands of other neurons. The synapsing neuron terminals are also subject to feedback regulation via receptor sites on the pre-synaptic membrane, modifying the release of transmitter across the synaptic cleft. In addition to such acute effects, some neurotransmitters produce long-term modulation of metabolic function or gene expression. This effect probably underlies more complex processes in, for example, long-term memory.

Functional anatomy of the nervous system

Major components of the nervous system and their interrelationships are depicted in Figure 26.3.

Fig. 26.3 The major anatomical components of the nervous system.

Cerebral hemispheres

The cerebral hemispheres coordinate the highest level of nervous function, the anterior half dealing with executive (‘doing’) functions and the posterior half constructing a perception of the environment. Each cerebral hemisphere has four functionally specialised lobes (Fig. 26.4 and Box 26.2), but some functions are lateralised, and this depends on cerebral dominance (i.e. the hemisphere in which language is represented). Cerebral dominance aligns limb dominance with language function: in right-handed individuals the left hemisphere is almost always dominant, while around half of left-handers have a dominant right hemisphere.

26.2 Cortical lobar functions

Lobe	Function	Effects of damage
Lobe	Function	Cognitive/behavioural	Associated physical signs	Positive phenomena
Frontal	Personality Emotional control Social behaviour Contralateral motor control Language Micturition	Disinhibition Lack of initiation Antisocial behaviour Impaired memory Expressive dysphasia Incontinence	Impaired smell Contralateral hemiparesis Frontal release signs¹	Seizures – often nocturnal with motor activity Versive head movements
Parietal: dominant	Language Calculation	Dysphasia Acalculia Dyslexia Apraxia³ Agnosia⁵	Contralateral hemisensory loss Astereognosis² Agraphaesthesia⁴ Contralateral homonymous lower quadrantanopia Asymmetry of optokinetic nystagmus (OKN)	Focal sensory seizures
Parietal: non-dominant	Spatial orientation Constructional skills	Neglect of contralateral side Spatial disorientation Constructional apraxia Dressing apraxia	Contralateral hemisensory loss Astereognosis² Agraphaesthesia⁴ Contralateral homonymous lower quadrantanopia Asymmetry of OKN	Focal sensory seizures
Temporal: dominant	Auditory perception Language Verbal memory Smell Balance	Receptive aphasia Dyslexia Impaired verbal memory	Contralateral homonymous lower quadrantanopia	Complex hallucinations (smell, sound, vision, memory)
Temporal: non-dominant	Auditory perception Melody/pitch perception Non-verbal memory Smell Balance	Impaired non-verbal memory Impaired musical skills (tonal perception)	Contralateral homonymous upper quadrantanopia	Complex hallucinations (smell, sound, vision, memory)
Occipital	Visual processing	Visual inattention Visual loss Visual agnosia	Homonymous hemianopia (macular sparing)	Simple visual hallucinations (e.g. phosphenes, zigzag lines)

¹ Grasp reflex, palmomental response, pout response.

² Inability to determine three-dimensional shape by touch.

³ Inability to perform complex movements in the presence of normal motor, sensory and cerebellar function.

⁴ Inability to ‘read’ numbers or letters drawn on hand, with the eyes shut.

⁵ Inability to recognise familiar objects, e.g. faces.

The frontal lobes are concerned with executive function, movement, behaviour and planning. In addition to the primary and supplementary motor cortex, there are specialised areas for the control of eye movements, speech (Broca’s area) and micturition.

The parietal lobes integrate sensory perception. The primary sensory cortex lies in the post-central gyrus of the parietal lobe. Much of the remainder is devoted to ‘association’ cortex, which processes and interprets input from the various sensory modalities. The supramarginal and angular gyri of the dominant parietal lobe form part of the language area (p. 1169). Close to these are regions dealing with numerical function. The non-dominant parietal lobe is concerned with spatial awareness and orientation.

The temporal lobes contain the primary auditory cortex and primary vestibular cortex. On the inner medial sides lie the olfactory cortex and the parahippocampal cortex, which is involved in memory function. The temporal lobes also contain much of the limbic system, including the hippocampus and the amygdala, which are involved in memory and emotional processing. The dominant temporal lobe also participates in language functions, particularly verbal comprehension (Wernicke’s area). Musical processing occurs across both temporal lobes, rhythm on the dominant side and melody/pitch on the non-dominant.

The occipital lobes are responsible for visual interpretation. The contralateral visual hemifield is represented in each primary visual cortex, with surrounding areas processing specific visual submodalities such as colour, movement or depth, and the analysis of more complex visual patterns such as faces.

Deep to the grey matter in the cortices, and the white matter (composed of neuronal axons), are collections of cells known as the basal ganglia that are concerned with motor control; the thalamus, which is responsible for the level of attention to sensory perception; the limbic system, concerned with emotion and memory; and the hypothalamus, responsible for homeostasis, such as temperature and appetite control. The cerebral ventricles contain cerebrospinal fluid (CSF), which cushions the brain during cranial movement.

CSF is formed in the lateral ventricles and protects and nourishes the CNS. The CSF flows from third to fourth ventricles and through foramina in the brainstem to dissipate over the surface of the CNS, eventually being reabsorbed into the cerebral venous system (see Fig. 26.41, p. 1217).

Fig. 26.41 The circulation of cerebrospinal fluid.
(1) CSF is synthesised in the choroid plexus of the ventricles, and flows from the lateral and third ventricles through the aqueduct to the fourth ventricle. (2) At the foramina of Luschka and Magendie it exits the brain, flowing over the hemispheres (3) and down around the spinal cord and roots in the subarachnoid space. (4) It is then absorbed into the dural venous sinuses via the arachnoid villi.

The brainstem

In addition to containing all the sensory and motor pathways entering and leaving the hemispheres, the brainstem houses the nuclei and projections of the cranial nerves, as well as other important collections of neurons in the reticular formation (Fig. 26.5). Cranial nerve nuclei provide motor control to muscles of the head (including the face and eyes) and coordinate sensory input from the special sense organs and the face, nose, mouth, larynx and pharynx. They also relay autonomic messages, including pupillary, salivary and lacrimal functions. The reticular formation is predominantly involved in the control of conjugate eye movements, the maintenance of balance, cardiorespiratory control and the maintenance of arousal.

The motor system

A programme of movement formulated by the pre-motor cortex is converted into a series of signals in the motor cortex that are transmitted to the spinal cord in the pyramidal tract (Fig. 26.6). This passes through the internal capsule and the ventral brainstem before decussating in the medulla to enter the lateral columns of the spinal cord. The pyramidal tract ‘upper motor neurons’ synapse with the anterior horn cells of the spinal cord grey matter, which form the lower motor neurons.

Any movement necessitates changes in posture and muscle tone, sometimes in quite separate muscle groups to those involved in the actual movement. The motor system consists of a hierarchy of controls that maintain body posture and muscle tone, on which any movement is superimposed. In the grey matter of the spinal cord, the lowest order of the motor hierarchy controls reflex responses to stretch. Muscle spindles sense lengthening of the muscle; they provide the afferent side of the stretch reflex and initiate a monosynaptic reflex leading to protective or reactive muscle contraction. Inputs from the brainstem are largely inhibitory. Polysynaptic connections in the spinal cord grey matter control more complex reflex actions of flexion and extension of the limbs that form the basic building blocks of coordinated actions, but complete control requires input from the extrapyramidal system and the cerebellum.

Lower motor neurons

Lower motor neurons in the anterior horn of the spinal cord innervate a group of muscle fibres termed a ‘motor unit’. Loss of lower motor neurons causes loss of contraction within this unit, resulting in weakness and reduced muscle tone. Subsequently, denervated muscle fibres atrophy, causing muscle wasting, and depolarise spontaneously, causing ‘fibrillations’. Except in the tongue, these are usually only perceptible on electromyelography (EMG; p. 1152). With the passage of time, neighbouring intact neurons sprout to provide re-innervation, but the neuromuscular junctions of the enlarged motor units are unstable and depolarise spontaneously, causing fasciculations (which are large enough to be visible to the naked eye). Fasciculations therefore imply chronic partial denervation with re-innervation.

Upper motor neurons

Upper motor neurons have both inhibitory and excitatory influence on the function of anterior horn motor neurons. Lesions affecting the upper motor neuron result in increased tone, most evident in the strongest muscle groups (i.e. the extensors of the lower limbs and the flexors of the upper limbs). The weakness of upper motor neuron lesions is conversely more pronounced in the opposing muscle groups. Loss of inhibition will also lead to brisk reflexes and enhanced reflex patterns of movement, such as flexion withdrawal to noxious stimuli and spasms of extension. The increased tone is more apparent during rapid stretching (‘spastic catch’), but may suddenly give way with sustained tension (the ‘clasp-knife’ phenomenon). More primitive reflexes are also released, manifest as extensor plantar responses. Spasticity may not be present until some weeks after the onset of an upper motor neuron lesion. Chronic spasticity in a patient with a spinal cord lesion may also be exacerbated by increased sensory input – for example, from a pressure sore or urinary tract infection.

The extrapyramidal system

Circuits between the basal ganglia and the motor cortex constitute the extrapyramidal system, which controls muscle tone, body posture and the initiation of movement (see Fig. 26.6). Lesions of the extrapyramidal system produce an increase in tone that, unlike spasticity, is continuous throughout the range of movement at any speed of stretch (‘lead pipe’ rigidity). Involuntary movements are also a feature of extrapyramidal lesions (p. 1165), and tremor in combination with rigidity produces typical ‘cogwheel’ rigidity. Extrapyramidal lesions also cause slowed and clumsy movements (bradykinesia), which characteristically reduce in size with repetition, as well as postural instability, which can precipitate falls.

The cerebellum

The cerebellum fine-tunes and coordinates movements initiated by the motor cortex. It also participates in the planning and learning of skilled movements through reciprocal connections with the thalamus and cortex, and in articulation of speech. A lesion in a cerebellar hemisphere causes lack of coordination on the same side of the body. Cerebellar dysfunction impairs the smoothness of eye movements, causing nystagmus and renders speech dysarthric. In the limbs, the initial movement is normal, but as the target is approached, the accuracy of the movement deteriorates, producing an ‘intention tremor’. The distances of targets are misjudged (dysmetria), resulting in ‘past-pointing’. The ability to produce rapid, accurate, regularly alternating movements is also impaired (dysdiadochokinesis). The central vermis of the cerebellum is concerned with the coordination of gait and posture. Disorders of this therefore produce a characteristic ataxic gait (see below).

Vision

The neurological organisation of visual pathways is shown in Figure 26.7. Fibres from ganglion cells in the retina pass to the optic disc and then backwards through the lamina cribrosa to the optic nerve. Nasal optic nerve fibres (subserving the temporal visual field) cross at the chiasm, but temporal fibres do not. Hence, fibres in each optic tract and further posteriorly carry representation of contralateral visual space. From the lateral geniculate nucleus, lower fibres pass through the temporal lobes on their way to the primary visual area in the occipital cortex, while the upper fibres pass through the parietal lobe.

Fig. 26.7 Visual pathways and visual field defects.
Schematic representation of eyes and brain in transverse section.

Normally, the eyes move conjugately (in unison), though horizontal convergence allows visual fusion of objects at different distances. The control of eye movements begins in the cerebral hemispheres, particularly within the frontal eye fields, and the pathway then descends to the brainstem with input from the visual cortex, superior colliculus and cerebellum. Horizontal and vertical gaze centres in the pons and mid-brain, respectively, coordinate output to the ocular motor nerve nuclei (3, 4 and 6), which are connected to each other by the medial longitudinal fasciculus (MLF) (Fig. 26.8). The MLF is particularly important in coordinating horizontal movements of the eyes. The extraocular muscles are then supplied by the oculomotor (3rd), trochlear (4th) and abducens (6th) cranial nerves.

Fig. 26.8 Control of conjugate eye movements.
Downward projections pass from the cortex to the pontine lateral gaze centre (A). The pontine gaze centre projects to the 6th cranial nerve nucleus (B), which innervates the ipsilateral lateral rectus and projects to the contralateral 3rd nerve nucleus (and hence medial rectus) via the medial longitudinal fasciculus (MLF). Tonic inputs from the vestibular apparatus (C) project to the contralateral 6th nerve nucleus via the vestibular nuclei.

The pupillary response to light is due to a combination of parasympathetic and sympathetic activity. Parasympathetic fibres originate in the Edinger–Westphal subnucleus of the 3rd nerve, and pass with the 3rd nerve to synapse in the ciliary ganglion before supplying the constrictor pupillae of the iris. Sympathetic fibres originate in the hypothalamus, pass down the brainstem and cervical spinal cord to emerge at T1, return up to the eye in association with the internal carotid artery, and supply the dilator pupillae.

Speech

Much of the cerebral cortex is involved in the process of forming and interpreting communicating sounds, especially in the dominant hemisphere (see Box 26.2, p. 1142). Decoding of speech sounds (phonemes) is carried out in the upper part of the posterior temporal lobe. The attribution of meaning, as well as the formulation of the language required for the expression of ideas and concepts, occurs predominantly in the lower parts of the anterior parietal lobe (the angular and supramarginal gyri). The temporal speech comprehension region is referred to as Wernicke’s area (Fig. 26.9). Other parts of the temporal lobe contribute to verbal memory, where lexicons of meaningful words are ‘stored’. Parts of the non-dominant parietal lobe appear to contribute to non-verbal aspects of language in recognising meaningful intonation patterns (prosody).

Fig. 26.9 Areas of the cerebral cortex involved in the generation of spoken language.

The frontal language area is in the posterior end of the dominant inferior frontal gyrus known as Broca’s area. This receives input from the temporal and parietal lobes via the arcuate fasciculus. The motor commands generated in Broca’s area pass to the cranial nerve nuclei in the pons and medulla, as well as to the anterior horn cells in the spinal cord. Nerve impulses to the lips, tongue, palate, pharynx, larynx and respiratory muscles result in the series of ordered sounds recognised as speech. The cerebellum also plays an important role in coordinating speech, and lesions of the cerebellum lead to dysarthria, where the problem lies in motor articulation of speech.

The somatosensory system

Sensory information from the limbs ascends the nervous system in two anatomically discrete systems (Fig. 26.10). Fibres from proprioceptive organs and those mediating well-localised touch (including vibration) enter the spinal cord at the posterior horn and pass without synapsing into the ipsilateral posterior columns. Neural fibres conveying pain and temperature sensory information (nociceptive neurons) synapse with second-order neurons that cross the midline in the spinal cord before ascending in the contralateral anterolateral spinothalamic tract to the brainstem.

Fig. 26.10 The main somatic sensory pathways.

The second-order neurons of the dorsal column sensory system cross the midline in the upper medulla to ascend through the brainstem. Here they lie just medial to the (already crossed) spinothalamic pathway. Brainstem lesions can therefore cause sensory loss affecting all modalities of the contralateral side of the body. Sensory loss on the face due to brainstem lesions is dependent on the anatomy of the trigeminal fibres within the brainstem. Fibres from the back of the face (near the ears) descend within the brainstem to the upper part of the spinal cord before synapsing, the second-order neurons crossing the midline and then ascending with the spinothalamic fibres. Fibres conveying sensation from progressively more forward areas of the face descend a shorter distance in the brainstem. Thus, sensory loss in the face from low brainstem lesions is in a ‘balaclava helmet’ distribution, as the longer descending trigeminal fibres are affected. Both the dorsal column and spinothalamic tracts end in the thalamus, relaying from there to the parietal cortex.

Pain

Pain is a complex percept that is only partly related to activity in nociceptor neurons (Fig. 26.11). In the posterior horn of the spinal cord, the second-order neuron of the spinothalamic tract is affected by a number of influences in addition to its synapse with the fibres from nociceptors. Branches from the larger mechanoceptor fibres destined for the posterior column also synapse with the second-order spinothalamic neurons and with interneurons of the grey matter of the posterior horn. The nociceptor neurons release neurotransmitters (such as substance P), in addition to excitatory transmitters, which influence the excitability of the spinothalamic neurons. Activity in the posterior horn neurons is modulated by fibres descending from the peri-aqueductal grey matter of the mid-brain and raphe nuclei of the medulla. Neurons of this ‘descending analgesia system’ are activated by endogenous opiate (endorphin) peptides. The spinal cord’s posterior horn is therefore much more than a relay station in pain transmission; its complexity allows it to ‘gate’ and modulate painful sensation before it ascends in the spinothalamic tract. In the diencephalon, the perception of pain is further influenced by the rich interconnections of the thalamus with the limbic system.

Sphincter control

The sympathetic supply to the bladder leaves from T11–L2 to synapse in the inferior hypogastric plexus, while the parasympathetic supply leaves from S2–4. In addition, a somatic supply to the external (voluntary) sphincter arises from S2–4, travelling via the pudendal nerves.

Storage of urine is maintained by inhibiting parasympathetic activity and thus relaxing the detrusor muscle of the bladder wall. Continence is maintained by simultaneous sympathetic and somatic (via the pudendal nerve) mediated tonic contraction of the urethral sphincters. Voiding is usually under conscious control, and triggered by relaxation of tonic inhibition on the pontine micturition centre from higher centres, leading to relaxation of the pelvic floor muscles and external and internal urethral sphincters, along with parasympathetic-mediated detrusor contraction.

Personality and mood

The physiology and pathology of mood disorders are discussed elsewhere (Ch. 10) but it is important to remember that any process affecting brain function will have some effect on mood and affect. Conversely, mood disorder will have a significant effect on perception and function. It can be difficult to disentangle whether psychological and psychiatric changes are the cause or the effect of any neurological symptoms.

Sleep

The function of sleep is unknown but it is required for good health. Sleep is controlled by the reticular activating system in the upper brainstem and diencephalon. It is composed of different stages that can be visualised on electroencephalography (EEG). As drowsiness occurs, normal EEG background alpha rhythm disappears and activity becomes dominated by deepening slow-wave activity. As sleep deepens and dreaming begins, the limbs become flaccid, movements are ‘blocked’ and EEG signs of rapid eye movements (REM) are superimposed on the slow wave. REM sleep persists for a short spell before another slow-wave spell starts, the cycle repeating several times throughout the night. REM periods become longer as the sleep period progresses. REM sleep seems to be the most important part of the sleep cycle for refreshing cognitive processes, and REM sleep deprivation causes tiredness, irritability and impaired judgement.

Localising lesions in the brainstem

After taking a history and examining the patient, the clinician should have an idea of the nature and site of any pathology. Given the density of tracts and nuclei in the brainstem (see Fig. 26.5), detailed localisation may be possible on the basis of history and examination alone, to be confirmed or refuted by investigation.

Brainstem lesions typically present with symptoms due to cranial nerve, cerebellar and upper motor neuron dysfunction and are most commonly caused by vascular disease. Since the anatomy of the brainstem is very precisely organised, it is usually possible to localise the site of a lesion on the basis of careful history and examination in order to determine exactly which tracts/nuclei are affected, usually invoking the fewest number of lesions.

For example, in a patient presenting with sudden onset of upper motor neuron features affecting the right face, arm and leg in association with a left 3rd nerve palsy, the lesion will be in the left cerebral peduncle in the brainstem and the pathology is likely to have been a small stroke, as the onset was sudden. This combination of signs is known as Weber’s syndrome, and is one of several well-described brainstem syndromes, which are listed in Box 26.3. The effects of individual cranial nerve deficits are discussed in the sections on eye movements (p. 1169) and on facial weakness, sensory loss in brainstem lesions, dysphonia and dysarthria, and bulbar symptoms (pp. 1163, 1165, 1168 and 1173).

26.3 Major focal brainstem syndromes

Name of syndrome	Site of lesions	Clinical features
Weber	Anterior cerebral peduncle (mid-brain)	Ipsilateral 3rd palsy Contralateral upper motor neuron 7th palsy Contralateral hemiplegia
Claude	Cerebral peduncle Involving red nucleus	Ipsilateral 3rd palsy Contralateral cerebellar signs
Parinaud	Dorsal mid-brain (tectum)	Vertical gaze palsy Convergence disorders Convergence retraction nystagmus Pupillary and lid disorders
Millard–Gubler	Ponto-medullary junction	Ipsilateral 6th palsy Ipsilateral lower motor neuron 7th palsy Contralateral hemiplegia
Wallenberg	Lateral medulla	Ipsilateral 5th, 9th, 10th, 11th palsy Ipsilateral Horner’s syndrome Ipsilateral cerebellar signs Contralateral spinothalamic sensory loss Vestibular disturbance

Investigation of neurological disease

Experienced clinicians will make around 90% of neurological diagnoses on history alone, with a lesser contribution from examination and investigation. As investigations become more complex and more easily available, it is tempting to adopt a ‘scan first, think later’ approach to neurology. The frequency of ‘false-positive’ results, the wide range of normality and the unnecessary expense, inconvenience and worry caused to patients should encourage a more thoughtful approach. Investigation may include assessment of structure (imaging) and function (neurophysiology). Neurophysiological testing has become so complex that in many countries it constitutes a separate specialty focusing on electroencephalography, evoked potentials, nerve conduction studies and electromyography.

Neuroimaging

Neurological imaging has traditionally allowed assessment of structure only. Various techniques are available, including X-rays (plain X-rays, computed tomography (CT), CT angiography, myelography and angiography), magnetic resonance (MR imaging (MRI), MR angiography (MRA)) and ultrasound (Doppler imaging of blood vessels). The uses and limitations of each of these are shown in Box 26.4.

26.4 Imaging techniques for the nervous system

Technique	Applications	Advantages	Disadvantages	Comments
X-ray/CT	Plain X-rays, CT, CTA Radiculography Myelography Intra-arterial angiography	Widely available Relatively cheap Relatively quick	Ionising radiation Contrast reactions Invasive (myelography and angiography)	X-rays: used for fractures or foreign bodies CT: first line for stroke Intra-arterial angiography: gold standard for vascular lesions
MRI	Structural imaging MRA Functional MRI MR spectroscopy	High-quality soft tissue images, useful for posterior fossa and temporal lobes No ionising radiation Non-invasive	Expensive Less widely available MRA images blood flow, not vessel anatomy Claustrophobic Pacemakers contraindicate MRI Contrast (gadolinium) reactions	Functional MR and spectroscopy: mainly research tools
Ultrasound	Doppler Duplex scans	Cheap Quick Non-invasive	Operator-dependent Poor anatomical definition	Screening tool to assess need for carotid endarterectomy
Radio-isotope	Isotope brain scan SPECT PET	In vivo imaging of functional anatomy (ligand binding, blood flow)	Poor spatial resolution Ionising radiation Expensive Not widely available	Isotope scans obsolete. SPECT: useful in movement disorders, epilepsy and dementias PET: mainly research tool

(CT = computed tomography; CTA = computed tomographic angiography; MRA = magnetic resonance angiography; MRI = magnetic resonance imaging; PET = positron emission tomography; SPECT = single photon emission clinical tomography)

It is now possible to use imaging techniques to assess CNS function. Single photon emission clinical tomography (SPECT) scanning can use the lipid-soluble properties of radioactive tracers to mark cerebral blood flow at the time of injection. This can be useful in investigating dementia or epilepsy. SPECT can also be used in the diagnosis of movement disorders: for example, by examining dopamine activity to assess the function of the basal ganglia in patients with possible parkinsonism.

Functional MRI (fMRI) can be used to assess blood flow during specific tasks (e.g. speaking, remembering, calculation), which can provide ‘maps’ of cortical function that are accurate enough to help plan lesionectomy and epilepsy surgery. Similarly, MR spectroscopy is being developed to identify the chemical composition of specific regions, providing clues as to whether lesions are ischaemic, neoplastic or inflammatory.

Head and orbit

Plain skull X-rays are now largely restricted to the diagnosis of fractures and sinus disease. CT or MRI is needed for intracranial imaging. CT will show bone and calcification well, and will easily image collections of blood. It will also detect abnormalities of the brain and ventricles, such as atrophy, tumours, cysts, abscesses, vascular lesions and hydrocephalus. Diagnostic yield is often improved by the use of intravenous contrast and thinner slicing using spiral CT. Surrounding bone structures render posterior fossa CT images less useful, and CT is less sensitive to white matter changes than MRI.

MRI resolution is unaffected by bone and so is more useful in the investigation of posterior fossa disease. Its sensitivity to cortical and white matter changes makes it effective in picking up inflammatory conditions such as multiple sclerosis, and in investigating epilepsy. Different MRI techniques will increase sensitivity to acute ischaemic stroke and may allow detection of abnormalities by filtering signals from other tissues (e.g. adipose tissues in the orbits).

Examples of brain imaged by the various techniques are shown in Figure 26.12.

Fig. 26.12 Different techniques of imaging the head and brain.
A Skull X-ray showing lytic skull lesion (eosinophilic granuloma – arrow). B CT showing complete middle cerebral artery infarct (arrows). C MRI showing widespread areas of high signal in multiple sclerosis (arrows). D SPECT after caudate infarct showing relative hypoperfusion of overlying right cerebral cortex (arrows).

Cervical, thoracic and lumbar spine

Plain X-rays are useful in the investigation of trauma to vertebrae, but their value in providing information about non-bony tissues is limited, which makes them far less helpful in the assessment of inflammatory and degenerative conditions of the spine. MRI has transformed the investigation of these areas, since it can give information not only about the vertebrae and intervertebral discs, but also about their effects on the spinal cord and nerve roots. Myelography is an invasive technique involving injection of contrast into the lumbar theca. While the outline of the nerve roots and spinal cord provides information about abnormal structure, the accuracy and wide availability of MRI have reduced the need for this. Myelography may still be used for technical reasons or where MRI is unavailable, contraindicated, or precluded by the patient’s claustrophobia. Examples of the cervical spine imaged by plain X-rays, myelography and MRI are shown in Figure 26.13.

Fig. 26.13 Different techniques of imaging the cervical spine.
A Lateral X-ray showing bilateral C6/7 facet dislocation. B Myelogram showing widening of cervical cord due to astrocytoma (arrows). C MRI showing posterior epidural compression from adenocarcinomatous metastasis to the posterior arch of T1 (arrows).

The electroencephalogram (EEG) is used to detect electrical activity arising in the cerebral cortex. The EEG involves placing electrodes on the scalp to record the amplitude and frequency of the resulting waveforms. With closed eyes, the normal background activity is 8–13 Hz (known as alpha rhythm), most prominent occipitally and suppressed on eye opening. Other frequency bands seen over different parts of the brain in different circumstances are beta (faster than 13/s), theta (4–8/s) and delta (slower than 4/s). Normal EEG changes evolve with age and with alertness; lower frequencies predominate in the very young and during sleep.

In recent years, digital technology has allowed longer, cleaner EEG recordings that can be analysed in a number of ways and recorded alongside contemporaneous video of any clinical ‘event’. Meanwhile, the development of intracranial recording allows more sensitive monitoring via surgically placed electrodes in and around lesions to help increase the efficacy and improve the safety of epilepsy surgery.

Abnormalities in the EEG result from a number of conditions. Examples include an increase in fast frequencies (beta) seen with sedating drugs such as benzodiazepines, or marked focal slowing noted over a structural lesion such as a tumour or an infarct. Improved quality and accessibility of imaging have made EEG redundant in lesion localisation, except in the specialist investigation of epilepsy (p. 1182). EEG remains useful in progressive and continuous disorders such as reduced consciousness (p. 1159), in encephalitis (p. 1205), and in certain dementias such as Creutzfeldt–Jakob disease (p. 1211).

Since sleep induces marked changes in cerebral activity, EEG can be useful in characterising those conditions where sleep patterns are disturbed. In paroxysmal disorders such as epilepsy, EEG is at its most useful when it captures activity during one of the events in question. Up to 5% of some normal populations may demonstrate epileptiform discharges on EEG which prevent its use as a screening test for epilepsy. Over 50% of patients with proven epilepsy will have a normal ‘routine’ EEG, and, conversely, the presence of epileptiform features does not of itself make a diagnosis (most notably in younger patients with a family history of epilepsy). In view of this, the EEG should not be used where epilepsy is merely ‘suspected’.

The EEG in epilepsy is predominantly used in its classification and prognosis, and in some patients to localise the seat of epileptiform discharges when surgery is being considered. During an epileptic seizure, high-voltage disturbances of background activity (‘discharges’) will often be noted. These may be generalised, as in the 3-Hz ‘spike and wave’ of childhood absence epilepsy, or more focal, as in localisation-related epilepsies (Fig. 26.14). Techniques such as hyperventilation or photic stimulation can be used to increase the yield of epileptiform changes, particularly in the generalised epilepsy syndromes. While some argue that it is possible to detect ‘spikes’ and ‘sharp waves’ to lend support to a clinical diagnosis, these are non-specific and therefore not diagnostic.

Fig. 26.14 EEGs in epilepsy.
A Generalised epileptic discharge, as seen in epilepsy syndromes such as childhood absence or juvenile myoclonic epilepsy. B Focal sharp waves over the right parietal region (circled), with spread of discharge to cause a generalised tonic–clonic seizure.

Nerve conduction studies

Electrical stimulation of a nerve causes an impulse to travel both efferently and afferently along the underlying axons. Nerve conduction studies (NCS) make use of this, recording action potentials as they pass along peripheral nerves and (with motor nerves) as they pass into the muscle belly. Digital recording has enhanced sensitivity and reproducibility of these tiny potentials. By measuring the time taken to traverse a known distance, it is possible to calculate nerve conduction velocities (NCVs). Healthy nerves at room temperature will conduct at a speed of 40–50 m/s. If the recorded potential is smaller than expected, this provides evidence of a reduction in the overall number of functioning axons. Significant slowing of conduction velocity, in contrast, suggests impaired saltatory conduction due to peripheral nerve demyelination. Such changes in NCS may be diffuse (as in a hereditary demyelinating peripheral neuropathy, p. 1223), focal (as in pressure palsies, p. 1224) or multifocal (e.g. Guillain–Barré syndrome, p. 1224; mononeuritis multiplex, p. 1224). The information gained can allow the disease responsible for peripheral nerve dysfunction to be better deduced (see Box 26.99, p. 1223).

Stimulation of motor nerves allows for the recording of compound muscle action potentials (CMAPs) over muscles (Fig. 26.15). These are around 500 times larger than sensory nerve potentials, typically around 1–20 millivolts. Since a proportion of stimulated impulses in motor nerves will ‘reflect’ back to the anterior horn cell body (forming the ‘F’ wave), it is also possible to obtain some information about the condition of nerve roots.

Fig. 26.15 Motor nerve conduction tests.
Electrodes (R) on the muscle (abductor pollicis here) record the compound muscle action potential (CMAP) after stimulation at the median nerve at the wrist (S₁) and from the elbow (S₂). The velocity from elbow to wrist can be determined if the distance between the two stimulating electrodes (d) is known. A prolonged L₁ (L = latency) would be caused by dysfunction distally in the median nerve (e.g. in carpal tunnel syndrome). A prolonged L₂ is caused by slow nerve conduction (as in demyelinating neuropathy). The F wave is a small delayed response that appears when the electrical signal travels backwards to the anterior horn cell, sparking a second action potential in a minority of fibres (see text).
(NCV = nerve conduction velocity)

Repetitive nerve stimulation (RNS) at 3–15/s provides consistent CMAPs in healthy muscle. In myasthenia gravis (p. 1226), where there is partial blockage of acetylcholine receptors, however, there is a diagnostic fall (decrement) in CMAP amplitude. In contrast, an increasing CMAP with high-frequency RNS is seen in Lambert–Eaton myasthenic syndrome (p. 1227).