NERVE CONDUCTION STUDIES: ESSENTIALS AND PITFALLS IN PRACTICE

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1 NERVE CONDUCTION STUDIES: ESSENTIALS AND PITFALLS IN PRACTICE See end of artile for authors affiliations Correspondene to: Dr Arup Mallik, Department of Clinial Neurophysiology, Institute of Neurologial Sienes, Southern General Hospital, Glasgow G51 4TF, UK; uk A A Mallik, A I Weir J Neurol Neurosurg Psyhiatry 2005; 76(Suppl II):ii23 ii31. doi: /jnnp neurologist has sent a patient for nerve ondution studies (NCS) and has reeived the report, but what does it mean? We hope to remove some of the mysteries that may surround NCS. The tehniques and how they are affeted by disease are desribed in general terms. These priniples an be applied to speifi onditions disussed elsewhere. We also disuss the numerous pitfalls that may be enountered with NCS. Understanding these basi onepts will allow you to get the most from your linial neurophysiology department. NCS are only part of a omplete peripheral neurophysiologial examination (PNE) and are frequently aompanied by a needle eletromyogram (EMG). The ombination of both tehniques and those detailed in other artiles in this issue are often required for a omplete diagnosti study. The proess of hoosing the appropriate tests is the responsibility of the linial neurophysiologist (CN) and not the referring dotor and is planned as a dynami series of steps designed to answer speifi questions about nervous system funtion raised by the linial piture. ABBREVIATIONS Clinial neurophysiologists an employ a onfusing number of terms and abbreviations. Box 1 lists the ones we use frequently. WHAT DO YOU TELL THE PATIENT ABOUT THE TESTS? NCS involve ativating nerves eletrially with small safe pulses over several points on the skin of the limbs and measuring the responses obtained. Some people are frightened by the term eletri shoks. The tests are at worst unomfortable but most patients find them tolerable when they are explained sympathetially. There are no long term side effets. Both authors have had their own nerves tested on many oasions without diffiulty and neither of us would laim partiularly high pain thresholds. A self inflited demonstration by the CN may be helpful with the more anxious patient as well as a simple information sheet. There are very few ontraindiations to these investigations, but the most important is the presene of some ardia paemakers. With most there is no risk but disussion with the patient s ardiologist is advised if (1) the NCS are likely to involve stimulation lose to the hest wall, and (2) if a life threatening event would be risked should the paemaker either be triggered or hanged to a harmful default state if subjet to an external voltage. REFERRING PATIENTS FOR NERVE CONDUCTION STUDIES NCS give data on peripheral nervous system (PNS) funtion whih may be used to provide: diagnosis(es) desription of disease state (old/new; dynami/stati pathophysiology) longitudinal monitoring of disease with multiple studies advie on prognosis and management based on tests results and disease deteted. Nerve ondution studies may be diagnostially helpful in patients suspeted of having almost any PNS disorder inluding disorders of nerve roots, peripheral nerves, musle and neuromusular juntion. Cranial nerves and spinal ord funtion may also be assessed. Speifi linial indiations are disussed elsewhere. When referring patients, it is useful to think of the speifi questions you wish answered with the PNE. In diffiult ases it is helpful to disuss the referral (whih should ontain all relevant linial information) with the CN. The PNE is an extension of the linial history and examination and CNs will take a history and perform the relevant neurologial examination but will rely on the referral information to guide them. In straightforward onditions they may follow an initial standard protool of tests but the investigator will be ready to modify or add to these tests on the basis of the initial findings. This emphasises that when NCS are performed by tehnial staff, the CN should supervise in lose proximity and be available to arry out other appropriate tests. It is unneessary (and sometimes insulting) to speify tests in the referral as long as the linial question being asked is lear. For example, in a patient suspeted of having right arpal tunnel ii23 J Neurol Neurosurg Psyhiatry: first published as /jnnp on 16 June Downloaded from on 25 August 2018 by guest. Proteted by opyright.

2 ii24 Box 1: List of abbreviations and terminology used ACh: aetylholine AIDP: aute inflammatory demyelinating polyneuropathy AMAN: aute motor axonal neuropathy CMAP: ompound musle ation potential CN: linial neurophysiologist DRG: dorsal root ganglion EMG: eletromyogram LEMS: Lambert-Eaton myastheni syndrome MG: myasthenia gravis NAP: nerve ation potential NCS: nerve ondution studies NMTD: neuromusular transmission disorders PNE: peripheral neurophysiologial examination PNS: peripheral nervous system RNS: repetitive nerve stimulation SNAP: sensory nerve ation potential TMS: transranial magneti stimulation Condution blok: A redution of proximal CMAP area/ amplitude of at least 20% (usually. 50%) ompared with distal CMAP area/amplitude. The duration of the proximal CMAP should not inrease by. 20% (see temporal dispersion) Temporal dispersion: A redution in proximal CMAP amplitude ompared with distal CMAP amplitude when the proximal CMAP duration inreases by. 20% Orthodromi: Nerve ation potentials arried in the physiologial diretion Antidromi: Nerve ation potentials arried in the diretion opposite to the physiologial syndrome it is unneessary to ask for NCS of the right median nerve. (The wise CN will study both median nerves anyway as this ondition is frequently bilateral.) Basi nerve and musle physiology The referring dotor needs only a minimal knowledge of basi and applied physiology to understand the test results, but all PNE reports should be written in terms that do not assume speialist knowledge. A minimum knowledge set to understand the priniples of the tehniques is shown in box 2 with links to more detail. The prinipals of nerve ondution studies NCS involve the appliation of a depolarising square wave eletrial pulses to the skin over a peripheral nerve produing: (1) a propagated nerve ation potential (NAP) reorded at a distant point over the same nerve: and (2) a ompound musle ation potential (CMAP) arising from the ativation of musle fibres in a target musle supplied by the nerve. In both ases these may be reorded with surfae or needle eletrodes. Surfae eletrodes are designed to give information about the whole of a musle stimulated, giving data for the time taken for the fastest axons to ondut an impulse to the musle and the size of the response. Needle eletrodes for NCS give very aurate ondution time information, but beause they reord from only a small area of musle or nerve, they give poor or, in the ase of the latter, more omplex information making numerial analysis diffiult. However, needle reordings are most appropriate when severe musle wasting has ourred, or when the depth Box 2: Minimum basi physiologial knowledge to understand nerve ondution studies Membrane potential: genesis; threshold effets; effet of membrane damage; denervation Single axon: saltatory and non-saltatory ondution; fators whih determine ondution veloity: diameter, myelination, inter-nodal distane Whole nerve omposition: fasiular struture; size and ondution veloity distribution; afferent and efferent modalities and their relative ontribution Neuromusular transmission: nerve terminal funtion; transmitter prodution, storage and release; post-synapti membrane struture and funtion; reeptor dynamis; endplate potentials; propagated musle ation potentials External eletrial/magneti stimulation: loal depolarisation; bidiretional propagation one depolarised; effets of skin and subutaneous tissue impedane; eletrial indutive effet of applied magneti field; stimulation threshold depends on: membrane properties(aommodation), nerve fibre loation and size with respet to stimulator Musle funtion: exitation ontration oupling; musle fibre types and funtion; fatigue For an exellent interative physiologial eduation tool see Rihard Carpenter s Neurolab at a.uk/web/opyright.htm. of a musle under study makes a surfae reording impossible. Nerves may be stimulated through the skin with surfae stimulators, or via a needle plaed lose to a nerve or a nerve root. Spinal root and erebral ortial stimulation may also be arried out using transutaneous magneti stimulation (TMS) dealt with elsewhere in this issue. Thus the full length of the motor pathway may be assessed from ortex to ord, root, neuromusular juntion, and the ontratile apparatus. Choie of the stimulation points depends both on the desire to braket above and below the point of a proposed foal lesion and the anatomial availability of the appropriate struture. The aim of the NCS Our minimum knowledge set above has shown us that peripheral nerves ontain many nerve fibres of different diameters, degrees of myelination, and afferent or efferent onnetions. The NCS studies the fastest 20% of these fibres and the aim of the investigation is to doument foal or ontinuous abnormalities in the length of the mixed, motor or sensory nerve. Partiular attention is paid to the following questions as the test progresses: Is the fastest ondution veloity normal? Is the veloity gradient normal. Normally nerves loser to the neuraxis and more ephalad ondut faster than more distal and audal nerves. Is the CMAP normal in size and shape? Does the CMAP alter in size, shape or duration between stimulation points? giving evidene for temporal dispersion (see terms, box 2). giving evidene for ondution blok (see terms, box 2). Normal values for NCS Age mathed Normal values for NCS parameters are either derived from studies of groups of neurologially normal subjets or ulled from the literature. Regrettably in the view J Neurol Neurosurg Psyhiatry: first published as /jnnp on 16 June Downloaded from on 25 August 2018 by guest. Proteted by opyright.

3 Figure 1 (A, B). Median motor nerve ondution study. Ative reording eletrode is over the APB musle, with stimulation at the wrist, elbow, axilla, and brahial plexus. Panel B shows the motor response from stimulation at all four sites. Responses are of the same shape but the lateny is longer with more proximal stimulation. (C) The ompound musle ation potential (CMAP) and its parameters. of the authors the most frequent statistis used are limits of 95% or less frequently 99% onfidene limits of a normal group to indiate abnormality of a single parameter. This approah may mislead as a rude separation between normal and abnormal dilutes the information whereas a Z sore, for example, indiating the separation between a single value and the group mean expressed in SD, may be more informative. Alternatively, (a) a number of eletrophysiologial parameters may be taken together either as an index or sore, or (b) the neurophysiologist assesses a number of parameters together to make a judgement as to whether a linially relevant numerial abnormality should be emphasised in the report interpretation or not. There are a number of physial parameters that require orretion or allowane for. The most important is temperature. The fastest motor nerve ondution veloity (FMNCV) is redued by approximately 1 m/s per C temperature fall. Conventionally, studies are performed as lose to a surfae reorded temperature of 34 C. If that is not ahieved by adequate heating or the limb, rarely a temperature orretion must be applied. Some measures of ondution require orretion for limb length or height. Finally nerve ondution data alter with age. The motor ondution slows by m/s per deade after 20 years and the sensory by 2 4 m/s. SPECIFIC NERVE CONDUCTION STUDY TECHNIQUES Motor nerve ondution studies Motor studies are performed by eletrial stimulation of a nerve and reording the ompound musle ation potential (CMAP) from surfae eletrodes overlying a musle supplied by that nerve. The reording eletrodes are performed using adhesive ondutive pads plaed onto the skin overlying the target musle. The ative eletrode is plaed over the musle belly and the referene over an eletrially inative site (usually the musle tendon). A ground eletrode is also plaed somewhere between the stimulating and reording eletrodes providing a zero voltage referene point. The median motor study might involve stimulation at the wrist, the elbow, and less frequently the axilla and the brahial plexus (fig 1A,B). The CMAP is a summated voltage response from the individual musle fibre ation potentials. The shortest lateny of the CMAP is the time from stimulus artefat to onset of the response and is a biphasi response with an initial upward defletion followed by a smaller downward defletion. The CMAP amplitude is measured from baseline to negative peak (the neurophysiologial onvention is that negative voltage is demonstrated by an upward defletion) and measured in millivolts (mv) (fig 1C). To reord the CMAP, the stimulating urrent or voltage is gradually inreased until a point is reahed where an inrease in stimulus produes no inrement in CMAP amplitude. It is only at this (supramaximal) point that reproduible values for CMAP amplitude and the lateny between the stimulus and the onset of the CMAP an be reorded aurately. The nerve is then stimulated at a more proximal site in the median nerve this will be the anteubital fossa, lose to the bieps tendon. In the normal state stimulating the median nerve at the wrist and the elbow results in two ii25 J Neurol Neurosurg Psyhiatry: first published as /jnnp on 16 June Downloaded from on 25 August 2018 by guest. Proteted by opyright.

4 R M E D I A N - A P B m s µ V NEUROLOGY IN PRACTICE ii26 Figure 2 Median orthodromi sensory study. The index finger digital nerves are stimulated via ring eletrodes and the response reorded over the median nerve at the wrist. CMAPs of similar shape and amplitude beause the same motor axons innervate the musle fibres making up the response. However, the lateny will be greater for elbow stimulation ompared with wrist stimulation beause of the longer distane between the stimulating and reording eletrodes (fig 1B). The differene in lateny represents the time taken for the fastest nerve fibres to ondut between the two stimulation points as all other fators involving neuromusular transmission and musle ativation are ommon to both stimulation sites. If one measures the distane between the two sites then the fastest motor nerve ondution veloity an be alulated as follows: FMNCV (m/s) = distane between stimulation site 1 and site 2 (mm)/[lateny site 2 lateny site 1 (ms)]. Sensory ondution studies The sensory nerve ation potential (SNAP) is obtained by eletrially stimulating sensory fibres and reording the nerve ation potential at a point further along that nerve. One again the stimulus must be supramaximal. Reording the SNAP orthodromially refers to distal nerve stimulation and reording more proximally (the diretion in whih physiologial sensory ondution ours). Antidromi testing is the reverse. Different laboratories prefer antidromi or orthodromi methods for testing different nerves. An orthodromi median sensory study is shown in fig 2. The sensory lateny and the peak to peak amplitude of the SNAP are measured. The veloity orrelates diretly with the sensory lateny and therefore either the result may be expressed as a lateny over a standard distane or a veloity. Only the 20% largest diameter and fastest onduting sensory fibres are tested using onventional sensory studies funtionally supplying fine touh, vibration, and position sense. Predominantly small fibre neuropathies affeting the other 80% of fibres exist usually with prominent symptoms of pain and onventional sensory studies may be normal. In suh ases quantitative sensory testing and autonomi testing will be required, whih are beyond the sope of this artile (see Interpretation pitfalls). Fwaves F waves (F for foot where they were first desribed) are a type of late motor response. When a motor nerve axon is eletrially stimulated at any point an ation potential is propagated in both diretions away from the initial stimulation site. The distally propagated impulse gives rise to the Cell body M Axon F wave F Stimulus Musle Figure 3 Shemati representation of the early M response from the distally propagated ation potential and the later F wave from the proximally propagated ation potential. The latter depolarises the axon hillok ausing it to bakfire. Atual F wave responses are shown in the lower trae. F waves vary in lateny and shape due to different populations of axons bakfiring eah time. CMAP. However, an impulse also onduts proximally to the anterior horn ell, depolarising the axon hillok and ausing the axon to bakfire. This leads to a small additional musle depolarisation (F wave) at a longer lateny. Only about 2% of axons bakfire with eah stimulus. Unlike the M response (fig 3), F waves vary in lateny and shape beause different populations of neurones normally bakfire with eah stimulus. The most reliable measure of the F wave is the minimum lateny of firings. Why are F waves useful? F waves allow testing of proximal segments of nerves that would otherwise be inaessible to routine nerve ondution studies. F waves test long lengths of nerves whereas motor studies test shorter segments. Therefore F wave abnormalities an be a sensitive indiator of peripheral nerve pathology, partiularly if sited proximally. The F wave ratio whih ompares the ondution in the proximal half of the total pathway with the distal may be used to determine the site of ondution slowing for example, to distinguish a root lesion from a patient with a distal generalised neuropathy. Errors The main soures of non-biologial error in NCS measurements are the identifiation and measurement of waveform onset and the measurement of the length of the nerve segment on the limb. Calulations have shown that in a nerve with a ondution veloity of 50 m/s, the 26SD experimental error for veloity is 14 m/s over 10 m and 4.7 m/s over 25 m. Of the error, time measurement is 92.3% and distane 7.7%, so the use of the measuring tape is quite adequate in onventional NCS. M M F J Neurol Neurosurg Psyhiatry: first published as /jnnp on 16 June Downloaded from on 25 August 2018 by guest. Proteted by opyright.

5 Table 1 Typial nerve ondution study abnormalities seen with axon loss or demyelination Axon loss NERVE CONDUCTION STUDIES IN DISEASE General NCS provides information to loate lesions in the length of a nerve, and pathophysiologial information. Peripheral nerve pathology primarily affets axons or myelin. In reality, the two pathologies often o-exist but usually one predominates (table 1). In foal lesions haraterisation of the pathophysiologial proess an be important for determining prognosis. A patient with a radial nerve palsy at the spiral groove ausing wrist drop is more likely to make a omplete and speedier reovery (6 12 weeks) if this is mainly due to foal demyelination and/or ondution blok (neuropraxia) ompared with when signifiant axonal injury has also ourred (6 12 months). In generalised proesses it is also important to determine whether a peripheral neuropathy is demyelinating or axonal as this will affet further investigation and management. For example, aute inflammatory demyelinating polyneuropathy (AIDP or Guillain-Barré syndrome) results in a harateristi pattern of segmental nerve demyelination and may be treated with human immunoglobulin or plasma exhange. Conversely a length dependent axonal neuropathy developing in a patient on hemotherapy requires reassessment of the hemotherapy or addition of a protetive agent. Neuropathies may be lassified pathologially in this fashion, anatomially or eletrophysiologially. Motor NCS In axonal loss The most striking abnormality is a redution in CMAP amplitude as fewer funtioning motor axons are onneted to musle fibres. Sine myelin is unaffeted, the remaining Demyelination Sensory responses Small or absent Small or absent Distal motor lateny Normal or slightly prolonged Prolonged CMAP amplitude Small Normal (redued if ondution blok or temporal dispersion) Condution blok/temporal dispersion Not present (responses may disperse slightly) Present Motor ondution veloity Normal or slightly redued Notably redued F waves minimum lateny Normal or slightly prolonged Signifiantly prolonged It is not neessary to have all the features of axon loss or demyelination to ome to a onlusion. Some onditions only affet motor or sensory nerves, and some proesses are length dependent and others universal. It an sometimes be quite diffiult to deide whether a proess is primarily demyelinating or demyelinating with seondary axonal hanges as features of both may oexist. Condution blok Distal stimulation Proximal stimulation Temporal dispersion Figure 4 Both these traes show demyelination in median motor studies. The trae on the left shows almost omplete ondution blok with an absent response with proximal stimulation. The trae on the right shows temporal dispersion where the CMAP duration inreases by almost 40% with proximal stimulation. In both situations the CMAP amplitude with proximal stimulation is smaller. axons ondut normally and one would expet latenies and ondution veloities to remain normal. However, with inreasing motor axon loss some of the largest fastest onduting fibres will be lost. Therefore distal motor lateny may be slightly prolonged (, 120% of normal limit) and ondution veloity slightly slowed (. 80% of normal limit). The dynamis and timing of an axonal insult an affet the abnormalities seen. Immediately after a traumati omplete transetion of the nerve, the portion of the nerve distal to the lesion will be normal as there has not been time for axonal degeneration to our. The CMAP amplitude will only start to fall a few days later. Conversely, if there is a very slow loss of axons in a generalised neuropathy, the remaining unaffeted axons may have time to sprout new onnetions to musle fibres that have lost their innervation (ollateral reinnervation) and the CMAP may remain within the normal amplitude range even though the total number of nerve axons is smaller. However, the immature regenerating fibres have slower veloities due to the effet of the short internodal distanes and this produes a more dispersed CMAP. In demyelination With loss of myelin thikness nerve ondution is slowed and, if severe enough, saltatory ondution fails (ondution blok). NCS shows severely prolonged motor latenies and notably slowed ondution veloities. The preise hanges seen depend on the site and extent of demyelination. If demyelination is very proximal then distal motor lateny and ondution veloity may be normal in whih ase only F waves may show abnormalities. Normal nerve Demyelination Responses arrive at reording eletrode almost together Responses arrive at different times phase anellation = = Temporal dispersion Figure 5 Shemati representation of phase anellation and temporal dispersion in demyelination. In the normal nerve, the responses are synhronised in time and therefore summate (amplitude is higher that that of the individual omponents). Temporal dispersion results in an inreased duration and redued amplitude of CMAP. ii27 J Neurol Neurosurg Psyhiatry: first published as /jnnp on 16 June Downloaded from on 25 August 2018 by guest. Proteted by opyright.

6 1 2 3 R ULNA R- Ort ho -V 4 V 1 10ms 10µV R ULNA R- Ort ho -V 4 V 1 10ms 10µV 10 ii28 Spinal ord Normal sensation No lesion Pre-ganglioni lesion Post-ganglioni lesion DRG Abnormal sensation Condution blok or temporal dispersion both result in a redution in CMAP amplitude. The CMAP area is used to assess the ontribution of these two proesses. In ondution blok there is omplete failure of ondution in some or all of the motor axons studied. Therefore the CMAP area with stimulation proximal to site of ondution blok is smaller (. 20% redution) ompared with distal stimulation (fig 4). For true ondution blok to be deteted, the proximal CMAP duration must not inrease by. 20%. In temporal dispersion (fig 4) there is a loss of synhrony in the nerve ation potentials resulting in a loss of CMAP amplitude beause the positive part of one musle fibre ation potential anels out the negative part of another (phase anellation) (fig 5). Clinial orrelates of motor ondution veloity slowing and ondution blok It is important to realise that slowing of ondution veloity alone without ondution blok does not result in weakness as the impulses are still onduted from nerve to musle. A good example of this is the presene of profound slowing of motor nerve ondution in totally asymptomati primary relatives of patients with demyelinating hereditary motor and sensory neuropathy. Sensory NCS In generalised disorders In both axonal and demyelinating pathologies the SNAP amplitude is redued for different reasons. Sensory axonal loss will result in a smaller SNAP. Demyelination also produes small SNAPs but with prolonged durations. As they are of muh shorter duration than CMAPs they are more suseptible to phase anellation (fig 5). The distribution of sensory NCS abnormalities may be helpful in determining aetiology. For example, the loss of SNAPS in the lower limbs is ommon in an axonal dying bak neuropathy related to drugs like vinristine, whereas equal involvement of upper and lower limb SNAPS raise the possibility of a sensory ganglionopathy suh as that related to thalidomide treatment. Abnormal sensation Normal SNAP Normal SNAP Abnormal SNAP NEUROLOGY IN PRACTICE Figure 6 Sensory responses are normal in pre-ganglioni lesions even though sensation may be abnormal linially. Post-ganglioni lesions result in abnormal sensory responses. DRG, dorsal root ganglion. Foal lesions Multiple sensory NCS allow the investigator to loate sensory neuropathies that involve single or multiple digital nerves distally (for example, vasulitis or hand arm vibration syndrome) right up to the major trunks, ords, and divisions of the brahial plexus proximally. In proximal nerve trauma, maintenane of the sensory potential depends on the intat ell bodies in the dorsal root ganglia. Thus sensory NCS are extremely useful in loalising a PNS lesion as either pre- and/or post-ganglioni. In a patient with a linially suspeted C8, T1 root lesion and with appropriate anaesthesia in that dermatome, the absene of the ulnar and medial antebrahial utaneous sensory potential plaes the lesion distal to the dorsal root ganglion (DRG) in the lower trunk of the brahial plexus and not at root level (fig 6). Needle EMG an then be used to define this further. Fwaves Generalised disorders F waves are sensitive to all forms of generalised peripheral neuropathy with their absene or a prolonged minimum lateny ourring early. For example, in AIDP where demyelination may be segmental, proximal and pathy, F wave abnormalities may be the earliest and (in mild ases) the only eletrophysiologial abnormality seen. In axonal pathology F wave latenies may also be mildly delayed in keeping with the motor ondution veloity slowing seondary to the loss of the fastest onduting motor axons. In motor neuronopathies suh as the motor neurone diseases, prolongation of any F wave lateny is strong evidene either that this is the inorret diagnosis (suh as in multifoal motor neuropathy) or that a seond pathologial proess is present. Foal lesions F waves may be absent in foal peripheral nerve or anterior spinal disorders. They were initially also thought to be very J Neurol Neurosurg Psyhiatry: first published as /jnnp on 16 June Downloaded from on 25 August 2018 by guest. Proteted by opyright.

7 Pre-exerise Immediately post-exerise 1 min post-exerise 2 min post-exerise Figure 7 (A) Normal repetitive nerve stimulation from abdutor digiti minimi musle in the hand. The amplitude of the CMAPs within eah train does not derement nor is there any signifiant inrement in CMAP amplitude after exerise. (B) Repetitive nerve stimulation in myasthenia gravis from the nasalis musle. Four stimulus trains are given all at baseline with no exerise. A reproduible derement of 55% is seen (train 3 is tehnially unsatisfatory beause of movement artefat). useful in identifying individual root distribution abnormalities. However, partiularly in the upper limbs, the substantial overlap of segmental innervation in the distally available peripheral nerves makes this test on its own of low sensitivity and anatomial speifiity. In addition, the effet of demyelination is diluted by the length of the path over whih the F wave passes. In distinguishing the presene of a distal or proximal lesion, the use of the F wave ratio whih ompares the F wave lateny in the upper and lower halves of the limb (onventionally using knee and elbow as the dividing line) may be useful. REPETITIVE NERVE STIMULATION Repetitive nerve stimulation (RNS) is used in the evaluation of patients with suspeted neuromusular transmission disorders (NMTD) suh as myasthenia gravis (MG) or Lambert-Eaton myastheni syndrome (LEMS). RNS is a modified motor NCS where instead of reording CMAPs with single supramaximal eletrial stimuli, a train of 8 10 stimuli is applied and the sequential response amplitudes and/or areas measured. This may be arried out at low (3 4 Hz) or high frequeny stimulation (20 50 Hz). In the latter ase the train is prolonged to allow 2 10 seonds of ontinuous data to be measured. Both distal and proximal musles/nerves should be studied in every patient suspeted of an NMTD as the sensitivity of the test is greatly inreased by this means. With low frequeny stimulation in normal subjets, the CMAP amplitude and/or area falls over the first 4 5 stimuli by a maximum of 10 12%. The maximum fall should be between potentials 1 and 2 (see RNS pitfalls). A number of department speifi protools have been published to study the RNS over time both before and after a period of maximum voluntary ontration of the musle to pik up early or late NMT failure (fig 7). High frequeny stimulation may be used to disover evidene of a post-synapti transmitter release disorder like LEMS. It is painful and requires onsiderable patient tolerane. There is evidene that reording low frequeny RNS immediately before and after a seond period of maximum voluntary ontration by the patient is equally sensitive and is more humane (fig 8). There are many pitfalls in the RNS test and artefat almost always gives rise to an abnormal test. Thus adherene to a strit protool and heightened suspiion on the part of the CN to an abnormal result is essential as are repeated studies for reproduibility of abnormalities (see RNS pitfalls). Physiologial basis for the RNS The neuromusular juntion onsists of the motor axon terminal, the synapti left, and the post-synapti musle membrane. As the motor axon potential depolarises the nerve terminal, voltage gated alium hannels open inreasing the onentration of alium in the pre-synapti nerve terminal. This in turn failitates the release of quanta of aetylholine (ACh) from the nerve terminal into the synapti left. ACh binds to reeptors on the post-synapti membrane ausing depolarisation (end plate potential). The size of the end plate potential is dependent on the amount of ACh released and its ii29 J Neurol Neurosurg Psyhiatry: first published as /jnnp on 16 June Downloaded from Ulnar CMAP Pre-exerise Post-exerise Pre-exerise 0 ses post-exerise 30 ses post-exerise 1 min post-exerise Figure 8 These traes show typial eletrophysiologial features of a presynapti neuromusular transmission disorder in a patient with LEMS. The traes on the left show a small amplitude ulnar CMAP that after exerise inreases fourfold in amplitude. The traes on the right show repetitive nerve stimulation studies. The amplitude inreases postexerise. Trains 1, 3, and 4 show a derement of 30% whih repairs with exerise (train 2). on 25 August 2018 by guest. Proteted by opyright.

8 ii30 Table 2 Performane of tests Tehnique Pitfall Explanation Motor NCS Temperature A low FMNCV or long DL may relate to low skin temperature. It should always be reorded and ool limbs heated F waves No pathway length allowane Beause of the long pathway, normal values have to be related to limb length, pathway measurement or body height Motor NCS Waveform measurements If the onset of the CMAP is positive that is, a downward defletion the ative reording eletrode is misplaed away from the motor point and spurious lateny and amplitude values will our If an initially positive going waveform is only seen in proximal median nerve stimulation there is a likelihood of an anatomi anomaly in the forearm Motor and sensory NCS Motor and sensory NCS Inadequate numbers of nerves studied In order to determine whether abnormalities are foal, generalised, length dependent, a sample of nerves in upper and lower limbs usually need to be studied Even in simple entrapment neuropathies, studies should be bilateral and inlude at least one other nerve not under suspiion to exlude an underlying generalised proess Inadequate range of stimulus sites Dependent on the linial piture stimulation may be required proximally to detet foal proximal abnormality. However, partiularly with root and plexus stimulation, are in ensuring supramaximal stimulation is vital Motor NCS Eletrode positioning If optimal positioning not used, the indifferent eletrode may ontribute signifiantly to amplitude measurements Motor NCS Nerve length measurement A flexible ruler/tape is neessary to follow the nerve path aurately Some measurements around joints are affeted by flexion/extension of the joint. For example, the least errors are found in ulnar NCS if the elbow is flexed to.100 Motor NCS Not supramaximal If the CMAP is not reorded supramaximally at all sites, the measured FMNCV will be in error. Spurious ondution blok may be seen if proximal nerve stimulation is not supramaximal Motor NCS Over stimulation If a nerve is stimulated with too high a urrent/voltage, adjaent nerves may be reruited and produe spurious results Sensory NCS Stimulus artefats Partiularly in the lower limb nerves the stimulus may ause an artefat whih alters the NAP shape. This must be allowed for in alulation if it annot be abolished Sensory NCS Absent potentials In some nerves, using the orthodromi tehnique, the 95% onfidene limits may inlude zero mirovolts. Thus an absent potential may not be abnormal Motor and sensory NCS Normal values Failure to use age speifi normal values in the very young and very old may lead to error RNS Inadequate positioning and movement restrition Inadequate failitation Too short an analysis period Limited sites Wrong test If the reording eletrodes do not lie right over the motor point, a spurious derement may be reated as the musle ontrats repeatedly. Care over positioning and ideally splintage of the musle so that it remains isometri helps Patients may need ontinuous enouragement to obtain seond maximal voluntary ontration RNS trains should be followed for at least 3 minutes (preferably 5) to pik up the oasional postfailitation exhaustion The sensitivity of RNS in NMT disorders is greatly inreased by studying both proximal (nasalis, trapezius) musles as well as distal (abdutor digiti minimi). As a rule of thumb, a patient who has an unequivoally normal edrophonium test will frequently also have a normal distal and proximal RNS test. In these irumstanes the authors go straight to single fibre eletromyography of an intermediate and proximal musle as a more sensitive test. CMAP, ompound musle ation potential; DL, distal lateny; FMNCV, fastest motor nerve ondution veloity; NAP, nerve ation potential; NCS, nerve ondution studies; NMT, neuromusular transmission; RNS, repetitive nerve stimulation. Table 3 Pitfall Interpretation Explanation NEUROLOGY IN PRACTICE Overinterpretation of results A limited numerial abnormality must be reported but plaed in the ontext of the linial problem for example, the finding of a sublinial arpal tunnel abnormality on NCS does not make the diagnosis of arpal tunnel syndrome An NCS abnormality may relate to a previous and urrently irrelevant injury or operation Over simplifiation of results All studies should be interpreted together in ase multiple diagnoses are present. Oum s razor may be too sharp. For example, in a patient with obvious polymyositis, NCS should ideally be performed to delineate any additional oexisting neuropathy Misinterpretation of NCS results If the FMNCV is normal, the patient may still have slowing of ondution of other nerve fibres related to a neuropathy If the SNAPS are normal in all respets the patient may still have a small fibre sensory neuropathy produing symptoms and signs If a nerve is reported unstimulatable, think of anomalous innervation or anatomial variation of nerve position before onluding pathology Misinterpretation of RNS results If a derement ontinues throughout the RNS train, this is probably artefat If a derement is found in RNS, it is not pathognomi of myasthenia gravis. It has been found to be abnormal in a number of onditions with abnormal nerve terminal funtion (motor neurone disease, ative axonal neuropathy) or musle membrane instability (polymyositis) While MG and LEMS are the most ommon NMT disorders, the unwary will miss orretly diagnosing ongenital myastheni syndromes, botulism, drug and toxins (for example, organophosphates), all of whih have harateristi PNE patterns when all tests are interpreted together with the linial piture For the referrer If the referring dotor has not asked a speifi question of the CN investigator, they should not be surprised if oasionally their request for a PNE is misunderstood A PNE request should never be ouhed in please exlude terms. While probabilities may be disussed, total exlusion of a diagnosis depends on non-biologial errors suh as sampling In the UK, CN are a sare resoure, often struggling with large waiting lists. Thus all referrals should be onsidered in terms of: (a) what knowledge will I gain about my patient from this investigation? (b) Will the result hange my management? () How urgent should the request be? CN, linial neurophysiologist; LEMS, Lambert Eaton myastheni syndrome; MG, myasthenia gravis; PNE, peripheral neurophysiologial examination; SNAPS, sensory nerve ation potentials. J Neurol Neurosurg Psyhiatry: first published as /jnnp on 16 June Downloaded from on 25 August 2018 by guest. Proteted by opyright.

9 binding to reeptors. In the healthy state, the end plate potential reahes a threshold level and auses an ation potential to be propagated along a musle fibre resulting in musle ontration. Normally there is a large safety fator for neuromusular transmission with the amount of ACh released per impulse several times that required to generate a threshold level end plate potential. In low frequeny RNS, the rate of stimulation is suh that the end plate physiology is stressed, but not to the level that produes the natural failitation of NMT at greater stimulation frequenies. Thus an abnormal fall (derement) in CMAP amplitude and/or area at low stimulation rates indiates a drop in the safety fator for transmission whether from a pre- or post-synapti ause. In high frequeny stimulation natural failitation is enhaned by pre-synapti Ca ++ influx and this may ounterat a proess suh as LEMS where quantal release is depressed. RNS in disease NMT disorders may be ongenital or aquired and in broad terms an be thought of as pre-synapti or post-synapti depending on where the defet lies. Post-synapti disorders of neuromusular juntion transmission The arhetypal post-synapti disorder is myasthenia gravis (MG) where antibodies to aetylholine reeptors (AChR) ause degradation and inreased turnover of reeptor as well as marophage initiated post-synapti membrane simplifiation. In MG the safety fator is lost beause as AChRs are depleted, less post-synapti depolarisation ours and some end plate potentials do not reah threshold for genesis of a propagated musle membrane potential produing neuromusular blok. If this proess affets a signifiant proportion of the tested musle end plates, the RNS baseline train will show a signifiant derement (greater than 10%). The derement is usually measured by omparing the amplitude of the third or fourth CMAP in the train to the first (fig 7B). Very often some slight failitation redues the derement over potentials 7 10 of the train. An abnormal derementing RNS test is non-speifi and an be seen in a number of irumstanes where musle ontration proesses may fail with repetitive stimulation (see RNS pitfalls). Pre-synapti disorders In LEMS there are antibodies to voltage gated alium hannels (pre-synapti disorder) ausing impaired release of ACh quanta. Low frequeny RNS stimulation may produe exatly the same derement as seen in MG with additionally a small initial CMAP amplitude. Here alium influx into the nerve terminal is redued due to the ation of voltage gated alium hannel antibodies and in turn ACh release into the synapti left is redued and some end plate potentials will be sub-threshold. However, the diagnosti abnormality is of a signifiant. 100% inrement in the CMAP amplitude after exerise or fast repetitive stimulation. Exerise inreases alium influx and the CMAP amplitude may inrease by up to 10 times. In this ase we are just omparing the amplitude of the first CMAP in the train before and after exerise (fig 8). Despite this inrement, within eah low frequeny train a further derement may our due to ACh depletion. PITFALLS There are many pitfalls that an trap the unwary both in the performane and the interpretation of the NCS and RNS. For onveniene these are separated in tables 2 and 3. The tehnial pitfalls more appropriately addressed to the reader who is an expert or training in CN are not inluded. CONCLUSIONS Nerve ondution studies as part of the PNE are an extension of the linial history and examination and are important in the management of ranial and peripheral neuromusular disease as well as ontributing to diagnosis of spinal ord lesions. NCS an be extremely useful both in loalising lesions and determining the pathologial proesses responsible. We have listed many of the pitfalls both for the CN arrying out and interpreting the tests as well as for the referring dotor. For the former it is vital both to arry out tests aurately and reproduibly and to develop an investigation strategy based on the patient s symptoms and signs rather than a fixed protool. The investigator should then report the results learly and then plae them in the ontext of the linial situation. For the neurologist or other referring dotor, it is equally vital that the linial questions asked are expliit and answerable for the most to be gained from what an be a onsiderable investment in time and skills for the investigator and tolerane of disomfort in the patient. For the best use of sare resoures therefore training and awareness of all the tehniques detailed in this monograph are essential as part of general neurologial training.... Authors affiliations A Mallik, A I Weir, Department of Clinial Neurophysiology, Institute of Neurologial Sienes, Southern General Hospital, Glasgow, UK REFERENCES 1 Oh SJ. Priniples of linial eletromyography ase studies. Baltimore: Lippinott Williams & Wilkins, An extremely readable book with exellent explanatory setions on nerve ondution tehniques and lots of ase studies. 2 Binnie C, Cooper R, Mauguière F, et al. Clinial neurophysiology Vol 1 & 2, Elsevier, A referene text overing all aspets of linial neurophysiology inluding nerve ondution studies. Primarily aimed towards those training in linial neurophysiology. 3 Kimura J, Fats, Fallaies, et al. Twenty-First annual Edward H Lambert Leture. Musle & Nerve 1997;20: Reviews basi tehniques, priniples and pitfalls of nerve ondution studies. An exellent introdution to nerve ondution studies. 4 DeLisa JA, Lee HJ, Baran EM, et al. Manual of nerve ondution veloity and linial neurophysiology, 3rd ed. Baltimore: Lippinott Williams & Wilkins, Line drawings illustrate how to atually perform most nerve ondution studies. 5 BSCN website. Contains part of the Glasgow interative EMG ourse with examples of all the abnormalities disussed as well as self assessment ases. 6 Donofrio PD, Albers JW. Polyneuropathy: lassifiation by nerve ondution studies and eletromyography. Musle & Nerve 1990;13: ii31 J Neurol Neurosurg Psyhiatry: first published as /jnnp on 16 June Downloaded from on 25 August 2018 by guest. Proteted by opyright.