Investigations

Clinical neurophysiology
Robin P Kennett

Whats new?
 Most EEG recordings now have a linked video, allowing more precise electroclinical evaluation of epilepsy syndromes and sporadic symptoms The electrophysiological features of acquired demyelinating peripheral neuropathies are being better defined, and treatment modified depending on the presence of conduction block.

Abstract
The electroencephalogram (EEG) is a simple, non-invasive test of brain function that is mostly used for the diagnosis and classification of epilepsy. Bilateral 3/second spike and slow wave complexes are seen in primary generalized epilepsy and localized spike discharges occur in partial seizures. Prolonged recordings of seizures, allowing a clinical and electrographic correlation, are helpful for precise diagnosis. The EEG may show characteristic waveforms (slow waves, triphasic or repetitive complexes) that help in the management of other brain diseases such as encephalitis and encephalopathy. Evoked potentials are used to confirm the presence of central nervous system demyelination in suspected multiple sclerosis where imaging changes are equivocal. Operative or intensive care unit monitoring of central nervous system function with evoked potentials or EEG are used in spinal surgery and for patients with status epilepticus or head injury. Nerve conduction and needle electromyography (EMG) are used to investigate peripheral neuromuscular disorders, especially to confirm the presence and assess the severity of peripheral nerve disease. Clinical neurophysiologists are often asked to investigate patients with undiagnosed neurological symptoms, and in these patients the tests provide objective information as an extension to the clinical examination. Measurement of sensory nerve action potentials helps locate lesions in sensory pathways. A combination of motor nerve conduction and needle EMG is particularly useful when investigating patients with weakness. Specialized computer-based EMG studies help quantify abnormalities in myasthenia, motor neurone diseases and primary myopathy.

Evoked potentials remain useful to diagnose some patients with multiple sclerosis.  Long-term EEG monitoring for epilepsy and on intensive treatment unit (ITU) are becoming more widely available

Electroencephalogram
Electrodes attached to the scalp with conductive paste are most often used to record electrical potentials originating in the cerebral cortex. The signals vary in frequency and amplitude between different regions of the head; the most consistently observed activity is at 812 cycles/second over the occipital region when the subjects eyes are closed (the alpha rhythm). The mechanism that generates EEG rhythms is not fully understood but is thought to involve diffusely projecting neuronal circuits connecting the thalamus and cerebral cortex. The normal EEG changes in appearance with the subjects state of alertness and with development from birth to adulthood. A wide range of patterns are seen in normal individuals. These factors can make diagnosis of cerebral disease difficult, but three types of electrical discharges are strongly associated with disorders of cortex function (Figure 1). Excessive slow-wave discharges (< 8Hz), when generalized, indicate a diffuse disorder such as metabolic, endocrine or ischaemic encephalopathy, or neurodegenerative dementia. When localized, they indicate focal or multifocal structural cortical disease imaging procedures are required to show the anatomical basis for these EEG changes. Spike and slow-wave complexes are the hallmark of epilepsy and may be seen during seizures (ictal discharges) or, more often, subclinically between attacks (interictal epileptic discharges, IEDs). Generalized spike and slow-wave complexes occur in primary generalized epilepsy, in which they are bilaterally synchronous, maximal over the front of the head and repeat at a rate of about 3 per second. In some photosensitive patients, these discharges can be provoked by a light flickering at a rate of about 18 flashes per second. Focal spike and slow-wave discharges are characteristic of partial epilepsy and are localized to the region of the cortex where the seizures are likely to originate (most commonly the temporal or frontal lobes). Complex discharges have diverse waveforms, but typically exhibit a periodic discharge pattern, appearing rhythmically at
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Keywords electroencephalogram; electromyography; epilepsy; evoked

potentials; motor neurone disease; myopathy; nerve conduction; peripheral neuropathy

In clinical neurophysiology, electrical potentials recorded in the resting state or following an external stimulus are used to determine the function of the central or peripheral nervous system. The three main groups of tests are:  electroencephalogram (EEG) (recordings of spontaneous activity from the brain)  evoked potentials recorded from the central nervous system (CNS) following an external sensory stimulus  nerve conduction studies/electromyography (EMG) (used to investigate peripheral neuromuscular structures).

Robin P Kennett FRCP is Consultant in Clinical Neurophysiology at the John Radcliffe Hospital, Oxford, UK. His interests include diagnosis of neuromuscular disorders and indications for surgical treatment of epilepsy. Competing interests: none declared.

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Investigations

2-second epochs of EEG recordings

1 2 6 2 3 4 7 8 4 Right 3 5 6 7 8 a Normal b Generalized slow-wave activity in a patient with HIV encephalopathy c Left hemisphere slow waves in a patient with cerebral vasculitis

d Bilateral spike and slow-wave complexes in primary generalized epilepsy Figure 1

e Focal spike and slow waves in left mesial temporal epilepsy

f Bilateral complexes show a burst-suppression pattern in thiopentone narcosis

g Left occipital recurrent complexes in a patient with cerebritis

a rate of about 12 per second. Symmetrical complexes with a triphasic waveform are seen in sporadic CreutzfeldtJakob disease and in hepatic encephalopathy. Repetitive waves with a more complicated appearance are characteristic of the now rare subacute sclerosing panencephalitis. Lateralized discharges simi lar to IEDs occur in disorders causing acute necrosis of the cortex (e.g. infarction, herpes simplex encephalitis). EEG in epilepsy A single 2060-minute EEG reveals IEDs in about 50% of patients with epilepsy. The sensitivity increases to more than 90% with repeated recordings using activating procedures (photic stimulation and over-breathing enhance electrical abnormalities in primary generalized epilepsy, and sleep or sleep deprivation can trigger IEDs in most types of epilepsy). In most patients with epilepsy, therefore, standard EEG can be used for diagnosis and syndromic classification. Conversely, because of the low sensitivity, a normal standard EEG cannot exclude the diagnosis of epilepsy. False-positive EEGs showing spike and slow-wave complexes in individuals who do not have epilepsy are obtained in less than 0.5% of the population. Standard EEGs are usually recorded with a simultaneous video of the patient, which helps identify artefact and allows a correlation between electrical abnormalities and symptoms that may occur during the investigation. When doubt remains about
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the nature of the patients symptoms it can be helpful to prolong the recording for up to 3 days using an ambulatory recorder. This has the advantage of recording in the patients usual environment, and prolonging recordings during sleep helps detect IEDs, but attacks cannot be observed. Another method of prolonged EEG recording is videotelemetry, in which time-locked scalp EEG and video recordings (most often made in a confined ward environment) allow precise correlation of clinical and electrical changes during attacks. This technique is most useful in the preoperative assessment of candidates for surgical treatment of epilepsy and for those with intractable attacks that otherwise defy diagnosis. Surgery is most often performed for the syndrome of mesial temporal epilepsy. This can often be sufficiently defined before surgery by a combination of interictal and scalp ictal EEG recordings, assuming they accord with imaging and neuropsychological data. In contrast, neocortical epilepsy without identifiable structural cortical disease usually requires evaluation by seizure recordings using intracranial electrodes to determine the safe extent of cortical excision. EEG in intensive treatment unit (ITU) monitoring Computer technology now allows long-term monitoring using a full set of scalp electrodes to facilitate management of patients with impaired consciousness from status epilepticus or

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Investigations

ncephalopathy, following head injury, or during administration e of anaesthetic drugs.

Evoked potentials
In the most widely used method of recording visual evoked potentials, the patient looks, one eye at a time, at a checkerboard pattern projected onto a monitor. The checks change from black to white at a rate of about three times per second, and recordings are made from the occipital scalp region. The potential evoked by a single checkerboard reversal is of lower amplitude than the background EEG, so about 100 pattern reversals must be averaged to distinguish the evoked signal from background noise. This is a sensitive test for acute optic neuritis, in which the potential from the affected eye is delayed (Figure 2). The potential often remains delayed following recovery of vision, or after a subclinical episode of optic nerve demyelination, and the test aids diagnosis of multiple sclerosis. Recordings may also be made from the retina (electroretinography), helping in the diagnosis of retinal dystrophy. Scalp recordings of the cortical potentials evoked by electrical nerve stimulation (somatosensory evoked potentials) or auditory stimulation (brainstem auditory evoked potentials) may also help in the diagnosis of multiple sclerosis, but these tests are less sensitive than pattern-reversal visual evoked potentials. Sensory potentials evoked during spinal surgery can be used to monitor spinal cord function.

Nerve conduction studies and needle electromyography

Peripheral nerve conduction studies are performed most easily using electrical stimulation on the skin surface (Figure 3). An electric current sufficiently large to excite all axons is applied to a nerve trunk and the propagated activity is recorded at a distance, either along the nerve or from a target muscle. The response recorded from the skin is the sum of individual nerve or muscle fibre action potentials. Only small recordings (550V) are obtained from sensory nerves; this necessitates electronic

Nerve conduction in the leg. The white recording electrode is placed over the extensor digitorum brevis muscle a for peroneal motor studies and b over the sural nerve for sensory conduction. The blue device delivers electrical nerve stimulation. Figure 3

Visual evoked potentials recorded from a patient with acute left optic neuritis

Right eye

P2 Left eye P2
0 100 200

The P2 wave is normal from the right eye but delayed from the left

Figure 2

averaging to separate the nerve potential from background noise. Compound muscle action potentials are larger (1025 mV in the hand). Measurement of conduction distance allows calculation of maximal motor or sensory conduction velocities (Figure 4); these are normally 5060 m/s in the arm and 4050 m/s in the leg. The most reliably tested nerves are the median, ulnar and radial in the arm, and the peroneal, tibial and sural in the leg. Examination of proximal nerves is technically more difficult; it is usually impossible to calculate the conduction velocity. EMG is usually performed using an electrode with a recording wire passed through the barrel of a hypodermic needle (concentric needle electrode). This electrode records the electrical potential generated by about ten muscle fibres in the vicinity of the needle tip. In normal muscle, no electrical activity occurs at rest, but with voluntary contraction progressively more motor neurones discharge and summated electrical responses from muscle fibres (motor unit action potentials, MUAPs) can be recorded. In strong contractions, this recruitment pattern of overlapping MUAPs forms an interference pattern that fills the recording oscilloscope screen. In conditions causing degeneration of motor neurones (e.g. axonal peripheral neuropathy and motor neurone disease), muscle fibres losing their nerve supply depolarize spontaneously. These small potentials recorded from muscles at rest are
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Investigations

Normal sensory and motor nerve conduction

EMG recordings
a 10 V F F 200 V

Conduction time

5 milliseconds PSW Record Stimulate Conduction distance b

200 V

Record Stimulate 1

Conduction distance

Stimulate 2

2 mV

5 mv 5 milliseconds a Concentric needle electrode recordings from a denervated muscle at rest showing fibrillation potentials (F) and positive sharp waves (PSW). b examples of single motor unit action potentials (MUAPs), recorded from a normal muscle (upper trace), a patient with chronic inflammatory myopathy (middle trace) and a chronic neurogenic disorder (bottom trace). Note the change of sensitivity for the neurogenic potential, which is much larger. Both the neurogenic and myopathic MUAPs have a more complex shape than the normal unit Figure 5

Conduction time 2

Maximal conduction velocity Conduction distance (mm) = (m/second) Conduction time (milliseconds)
Sensory nerve action potential (upper tracing), and compound muscle action potentials recorded from a distal muscle following nerve stimulation at two points (lower tracings). Note the difference in amplitude between the different types of recording, and method for calculating the maximal conduction velocity.

be much greater than normal, producing complex MUAPs with large amplitudes (Figure 5b). Fibrillation potentials become less prominent during re-innervation. Fasciculations are spontaneous discharges of motor units that produce a visible twitch and an EMG signal looking like a MUAP. Groups of spontaneous motor unit discharges are seen in neuromyotonia and after radiation damage to nerves. Quantitative electromyography Computer analysis of EMG signals is most often used in singlefibre EMG. A special electrode with a small recording surface can selectively detect electrical potentials from one or two muscle fibres. The time interval between muscle action potentials varies on successive discharges of the motor unit; this jitter is a measure of neuromuscular transmission and is increased in myasthenic disorders, in early re-innervation and in some primary myopathies (Figure 6). A calculated value of jitter may be used to assess the severity of myasthenia and to quantify response to treatment. Computer analysis can also be performed on the interference pattern. The complexity of the EMG signal can be assessed by plotting the number of changes in polarity (turns) against the amplitude of each turn per unit time. A cloud of points with differing contraction strengths can be compared with normal controls; this is most helpful in the diagnosis of muscle diseases. In another technique,
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Figure 4

termed fibrillations and positive sharp waves (Figure 5a). The number of motor units and the density of the interference pattern on maximal contraction decreases, according to the extent of denervation. During recovery by re-innervation, the shape of the MUAPs varies between motor unit discharges because of insecure neuromuscular transmission at new nervemuscle junctions, and the number of muscle fibres in the motor unit may

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Investigations

Neurophysiological findings in myasthenia gravis

Jitter

a Compound action potentials from a muscle following nerve stimulation at 3/second. There is a progressive reduction in response amplitude to the mid-section of the trace. b Two muscle fibre action potentials from the same motor unit obtained using a single-fibre electrode. Seven discharges have been superimposed to show the increased variability in time interval between the two potentials (jitter), which is caused by insecure neuromuscular transmission

Figure 6

the interference pattern is automatically decomposed into constituent MUAPs, allowing quantification of variables such as duration, amplitude and polyphasicity. Computer-derived techniques in development include graded electrical stimulation to count the number of motor units (this may be helpful in quantifying disease progression in motor neurone disease) and threshold tracking, which measures nerve membrane excitability properties. Uses of nerve conduction and electromyography (Table 1) Peripheral neuropathy: nerve conduction studies are important to distinguish between treatable demyelinating peripheral

neuropathy (e.g. acute inflammatory demyelinating polyneuropathy (AIDP), chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy with conduction block) and untreatable axonal neuropathy (most metabolic, nutritional and toxic neuropathies). Peripheral nerve demyelination impairs saltatory conduction and reduces maximal conduction velocity. It causes dispersion of compound action potentials because the range of nerve conduction velocity is increased, and there may be a failure of electrical impulse transmission, producing conduction block. In hereditary demyelinating neuropathy, conduction block and dispersion are less pronounced than in acquired disease, despite the very low conduction velocity. When demyelination is confined to proximal nerve segments, as in AIDP, the only abnormal finding may be delay of the F-response a late response recorded from muscles because a proportion of nerve impulses travel to the motor neurone cell body and back again. Criteria based on conduction velocity, conduction block and prolongation of distal motor and F-response latencies have been established for the diagnosis of demyelinating neuropathies. In contrast, axonal peripheral neuropathy causes a reduction in the number of excitable nerve fibres, resulting in small compound muscle and sensory action potentials but with normal conduction velocities in the surviving axons. Often, the changes in axonal degeneration are combined with mild slowing of conduction velocity, as in diabetic distal symmetrical peripheral neuropathy. Marked slowing of conduction velocity in diabetes suggests CIDP.

Indications for nerve conduction studies and electromyography (EMG)

Clinical presentation Localized weakness and sensory symptoms Differential diagnosis Peripheral nerve lesion Radiculopathy Generalized weakness and sensory symptoms Peripheral neuropathy Neurophysiological findings Nerve conduction and EMG changes limited to the distribution of one nerve Sensory nerve action potential retained in the area of numbness; EMG changes, if any, confined to one myotome Slow motor and sensory conduction velocities in demyelinating neuropathy Reduced response amplitudes and EMG signs of denervation in axonal neuropathy Combination of the above often found Normal motor and sensory nerve conduction Retained sensory nerve conduction, widespread fasciculation potentials and EMG signs of denervation/re-innervation Slowing of motor conduction velocity; may exhibit conduction block, retained sensory responses Myasthenia gravis may exhibit muscle action potential decrement on repetitive nerve stimulation, abnormal jitter on single-fibre EMG LambertEaton myasthenic syndrome low resting compound muscle action potential amplitude, increasing after maximal voluntary activation or tetanic nerve stimulation Usually normal nerve conduction; EMG may show fibrillation potentials caused by muscle fibre necrosis, myotonia, low-amplitude polyphasic motor unit action potentials, full interference pattern of electrical activity despite weak contraction

Weakness without sensory symptoms

Polyradiculopathy and spinal cord lesions Motor neurone disease Motor neuropathies Neuromuscular transmission disorders

Primary myopathy

Table 1

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Investigations

Entrapment neuropathy: Typically, disorders such as carpal tunnel syndrome, ulnar neuropathy at the elbow and peroneal palsy at the knee cause selective demyelination with focal slowing of conduction velocity or block, which is used to localize the lesion. The degree of the conduction abnormality may indicate the severity and longevity of the nerve lesion. Radiculopathy: mild radiculopathies may not show any electrophysiological change, but in more severe cases the finding of retained sensory nerve action potentials in a numb area indicates a lesion proximal to the dorsal root ganglia; there may also be electromyographic signs of denervation confined to the appropriate myotome. Denervation of the paraspinal muscles confirms the proximal location. Motor neurone disease: sensory nerve conduction studies stay within the normal range. Muscle responses evoked by electrical stimulation are small but motor conduction velocity is normal. Needle EMG shows signs of denervation in a wide anatomical distribution, including paraspinal muscles, often with fasciculations. Multifocal motor neuropathy with conduction block may produce a similar clinical picture but nerve conduction studies show the conduction block, and fibrillations are more restricted than in motor neurone disease. Myasthenic disorders: in myasthenia gravis, the amplitude of the compound muscle action potential is usually normal. In LambertEaton myasthenic syndrome, muscle action potentials are small at rest, but increase in size immediately after maximal voluntary contraction for 1520 seconds, or with tetanic nerve stimulation at a rate of 20 per second. In both conditions, there is a progressive reduction in amplitude across the first four or five compound muscle action potentials evoked by repetitive nerve stimulation at a rate of 3 per second (Figure 6). Primary myopathy: muscle diseases often lead to shrinkage of muscle fibres. When the process is uniform, MUAPs have normal outlines but are smaller than normal; when non-uniform, MUAPs become small but more complex (Figure 5b). The number of motor neurons is usually normal, so maximal contraction, albeit weak, produces a full interference pattern. This picture is seen in most metabolic myopathies and in some muscular dystrophies. In Duchenne and Becker muscular dystrophy and acquired inflammatory myopathy, muscle fibre necrosis probably causes disconnection of parts of muscle fibres from their nerve supply. This functional denervation produces fibrillation potentials, and collateral re-innervation with compensatory muscle fibre

ypertrophy gives rise to long-duration, unstable polyphasic h MUAPs that may have high-amplitude components. In myotonic dystrophies, needle insertion provokes bursts of muscle action potentials of diminishing frequency and amplitude, giving rise to a characteristic dive-bomber sound when amplified through a loudspeaker.

Further reading Aminoff MJ, ed. Electrodiagnosis in clinical neurology, 5th edn. Oxford: Elsevier, 2005. British Society for clinical neurophysiology website. Available at: http:// www.bscn.org.uk (accessed 19.06.08). Brown WF, Bolton CF, eds. Clinical electromyography, 2nd edn. Boston: Butterworth-Heinemann, 1993. Daube JR, ed. Clinical neurophysiology, 2nd edn. Oxford: Oxford University Press, 2002. Ebersole JS, Pedley TA, eds. Current practice of clinical electroencephalography, 3rd edn. Philadelphia: Lippincott, Williams & Wilkins, 2003. Fisch BJ. Fisch & Spehlmanns EEG primer, 3rd edn. Oxford: Elsevier, 1999.

Practice points
Scalp EEG recordings are non-invasive and readily available. Although they have limited sensitivity they may show specific wave forms in epilepsy EEGs allow an electro-clinical classification of epilepsy that is important in selecting the most appropriate anticonvulsant  Long-term EEG recordings are available to help with a correct diagnosis in patients with unexplained recurrent symptoms, and are an essential part of pre-surgical evaluation of epilepsy  Despite advances in imaging in multiple sclerosis, evoked potentials still have an important diagnostic role in some patients. Retinal evoked potentials are used in neuroophthalmology and for retinal dystrophy Nerve conduction studies and EMG are used to provide objective evidence of peripheral nerve disease. This helps determine management of the common entrapment neuropathies. Nerve conduction plays an important role in separating demyelinating from axonal generalized peripheral neuropathy  Peripheral neurophysiological studies are helpful in the diagnosis of patients presenting with weakness alone

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