Neurophysiology Flashcards
Insertional activity
Needle movement through muscle causes some fibers to fire action potentials
Features: • With needle movement and lasts < 20 ms • Abnormally increased insertional activity – Early denervation (first few weeks) – Normal variants • Abnormally reduced insertional activity – In inexcitable tissue (fibrosis, fat, etc) – Physiologic contracture (McArdle’s; PFK def) – During an attack of periodic paralysis
Insertional activity is recorded as the needle is inserted into a relaxed muscle. It is increased in denervated muscles and myotonic disorders, and is decreased when the muscle is replaced by fat or connective tissue and during episodes of periodic paralysis.
Normal spontaneous activity
Seen when the electrode is in, or near, the end plate zone of the muscle
– End plate noise • From the miniature endplate potentials (MEPPs) • Small, irregular negative monophasic
– End plate spikes • Irregular • Diphasic muscle fiber action potentials (like fibrillations, but are initially electronegative (upward))
Fibrillation potentials and positive sharp waves
Abnormal spontaneous activity
Definitions
Fibrillation potentials – Spontaneous firing of a single muscle fiber action potential – Diphasic with initial positivity (downward) – Appear generally 2-4 weeks after denervation
Positive sharp waves – Origin same as fibrillation, but from an area of muscle fiber injury (often due to the needle)
Seen in
Acute denervation (loss of motor neuron innervation of the muscle fiber), i.e., axonal loss lesions – Polyneuropathies, nerve injury, radiculopathy, motor neuron disease, etc
Myopathies with active muscle fiber necrosis and regeneration – Inflammatory (polymyositis, inclusion body, sarcoid), toxic myopathies, rhabdomyolysis, certain muscular dystrophies (Duchennes, FSH)
Complex repetitive discharges
Abnormal spontaneous activity
Train of grouped muscle fiber action potentials
Fire in regular, lock-step without change in frequency or waveform morphology
Tend to begin and end abruptly
Seen in many chronic neurogenic processes and myopathies
Myotonic discharges
Abnormal spontaneous activity
Features
Not truly spontaneous – provoked by needle movement or muscle percussion
Train of muscle fiber action potential with waxing and waning frequency and amplitude (“like a dive bomber”)
Often with a positive wave appearance
Seen in
– Hereditary myotonias – myotonic dystrophy, paramyotonia congenita, myotonia congenita
– Hyperkalemic periodic paralysis (some forms)
– Occasionally in acid maltase defiency and certain toxic myopathies (chloroquine, clofibrate, statin, gemfibrozil)
Fasciculation potentials
Abnormal spontaneous activity
Spontaneous discharge of a motor axon (neuron)
Appearance of a motor unit action potential (MUAP)
Unlike MUAPs seen with voluntary activation of muscle, these are slow (< 5 Hz)
Fasciculation potentials seen in:
– Neurogenic causes • Motor neuron disease(ALS) • X-linked bulbospinal muscular dystrophy (Kennedy’s disease), Creutzfeldt-Jacob disease, chronic neuropathies and radiculopathies
– Other disorders • Cholinesteraseminhibitors: pyridostigmine and organophosphate toxicity
– Benign causes • Benignfasciculations, cramps - fasciculationsyndrome
Myokymia
Repeating discharges of groups of MUAPs (“grouped fasciculations”)
Bursts repeat at regular or semiregular intervals from 100 msec to 10 seconds
Myokymia seen in:
– Facial – multiple sclerosis, brainstem mass lesions
– Limb – radiation induced plexopathies
– Generalized – Isaac’s syndrome aka generalized myokymia
Neuromyotonia
mia in Isaac’s syndrome
Abnormal spontaneous activity
– Very high frequency bursts (>100 Hz) of MUAPs
– Rare; seen in association with generalized myokymia in Isaac’s syndrome
Cramp discharges
Appears like normal voluntarily-recruited MUAPs
Tremors
Rhythmically firing groups of MUAPs
Unlike myokymia, they vary in configuration and the individual potentials that make up each burst
Abnormal spontaneous activity in muscle fiber
Fibrillation potentials and positive sharp waves – Complex repetitive discharges – Myotonic discharges
Abnormal spontaneous activity in motor unit
Fasciculation potentials – Myokymia – Neuromyotonia – Cramp discharges – Tremor
Motor unit vs MUAP
Motor unit = motor neuron and all the muscle fibers it supplies
MUAP is the summation of a fraction of the muscle fiber action potentials of that motor unit at the recording electrode tip (usually from 8-20 muscle fibers)
MUAP amplitude
Height of the main negative spike
Generated primarily by the few muscle fibers closest to the electrode tip
Increased in:
– Neurogenic disorders with axonal collateral sprouting • Any chronic axonal loss lesion
– In severe, chronic myopathies
Decreased in:
– Myopathic disorders
– Severe disorders of neuromuscular transmission (e.g., botulism)
MUAP duration
Duration of first deviation from baseline to the return (i.e., the entire MUAP waveform)
Generated by all of the muscle fibers within the pickup territory of the electrode
Increased in:
– Neurogenic disorders with axonal collateral sprouting: any chronic axonal loss lesion
– In severe, chronic myopathies
Decreased in:
– Myopathic disorders
– Severe disorders of neuromuscular transmission (botulism, LEMS, rarely MG)
MUAP Phases and Variability
Phases
– 1 > the number of baseline crossings
– Abnormal: excess percentage of sampled MUAPs with 5 or more phases (> 4 phases)
– Nonspecific – seen in many neurogenic and myopathic disorders
• Variability
– A normal MUAP will have the identical appearance from one firing to the next
– A MUAP that changes shape from one to the next has abnormal variability – seen primarily in NMJ disorders (MG, LEMS, botulism)
MUAP Recruitment
If the firing rates(frequencies) are too fast for the number of MUAPs seen – increased recruitment frequency
Neurogenic recruitment = reduced recruitment
– A pattern of too few MUAPs for the amount of muscle contraction and those MUAPs are firing at an increased frequency
Myopathic recruitment = increased recruitment
– A pattern of too many MUAPs for the amount of muscle contraction
– Also called early (full) recruitment
Radiculopathy on EMG
EMG diagnosis depends on demonstrating acute and/or chronic denervation in at least two or more limb muscles of the same root, but of different nerve, innervation
Paraspinal muscle abnormalities (fibrillation potentials) with acute or ongoing denervation supports the proximal (i.e., root localization - but the absence of these findings does not exclude a root localization
F wave latencies are generally normal despite traversing the root level – the short segment of compressed nerve at the root is diluted out by the much longer distal nerve (orders of magnitude longer) that are conducting normally
**An intact sensory response (SNAP) at the same level where there is significant denervation is strong evidence that the lesion is pre-ganglionic (proximal to the dorsal root ganglia) at the root level
– example, superficial peroneal sensory response is normal with L5 radiculopathies
F wave physiology
F-waves are evoked by strong electrical stimuli (supramaximal) applied to the skin surface above the distal portion of a nerve.[3] This impulse travels both in orthodromic fashion (towards the muscle fibers) and antidromic fashion (towards the cell body in the spinal cord) along the alpha motor neuron.[4][7][13][14] As the orthodromic impulse reaches innervated muscle fibers, a strong direct motor response (M) is evoked in these muscle fibers, resulting in a primary compound muscle action potential (CMAP).[3][7] As the antidromic impulse reaches the cell bodies within the anterior horn of the motor neuron pool by retrograde transmission, a select portion of these alpha motor neurons, (roughly 5-10% of available motor neurons), ‘backfire’ or rebound.[2][3][4][5] This antidromic ‘backfiring’ elicits an orthodromic impulse that follows back down the alpha motor neuron, towards innervated muscle fibers. Conventionally, axonal segments of motor neurons previously depolarized by preceding antidromic impulses enter a hyperpolarized state, disallowing the travel of impulses along them.[15] However, these same axonal segments remains excitable or relatively depolarized for a sufficient period of time, allowing for rapid antidromic backfiring, and thus the continuation of the orthodromic impulse towards innervated muscle fibers.[15][13] This successive orthodromic stimulus then evokes a smaller population of muscle fibers, resulting in a smaller CMAP known as an F-wave.
Plexopathy on EMG
Evidence of denervation on EMG examination in the distribution of a part of the plexus, and that is outside the distribution of a single nerve or root
Paraspinal muscles are normal
Absent or reduced sensory responses (SNAPs) in the corresponding levels
– example, the ulnar sensory response would be reduced in a lower trunk brachial plexus lesion
Mononeuropathies on EMG
Focal slowing is seen across sites of chronic entrapment – e.g., carpal tunnel syndrome
Conduction block is more common and more prominent in acute compressive neuropathies
– e.g., radial neuropathy at the spiral groove
Both can have varying degrees of slowing and block across the site of the lesion; both also have varying degrees of associated axonal loss (from minimal to severe)
In decreasing frequency, the most common are: carpal tunnel syndrome, ulnar neuropathy at the elbow, and peroneal neuropathy at the fibular head
Median neuropathy at the wrist
The various electrophysiological attributes of the median nerve in the assessment for CTS are, in ascending order of sensitivity (top to bottom):
– least sensitive is the finding of denervation of the APB muscle on needle EMG
– loss of the sensory amplitude
– prolongation of the distal motor latency
– slowing of conduction in the routine sensory studies (antidromic or orthodromic)
– most sensitive studies are: sensory comparison studies:
– comparison of the median and ulnar sensory response peak latencies at a fixed short distance across the carpal tunnel (usually 8 cm from palm to wrist) – stimulate palm and record wrist, or
– comparison of the antidromic median sensory conduction across the wrist to digit 4 with ulnar sensory conduction across the wrist to digit 4 over the same distance, or
– comparison of the antidromic median sensory conduction across the wrist to digit 1 (thumb) with radial sensory conduction across the wrist to digit 1 over the same distance
Features of axonal loss NCS
Reduced motor (CMAP) and sensory (SNAP) amplitudes
Conduction velocity (CV) may be reduced due to the loss of the fastest conducting fibers
CV will not fall below 70-75% the lower limit of normal – does not reach the “demyelinating range
Other measures of motor CV are minimally affected, even with severe axonal loss
Distal motor latency (remains < 150% ULN)
F wave latency (remains < 130% ULN)
No conduction block or abnormal temporal dispersion
Seen in
axonal neuropathies, nerve trauma, etc
motor neuron disorders and radiculopathies (motor amplitudes only)
aswellasasecondary,or“bystander,”effectin primary demyelinating neuropathies
– although demyelinating neuropathies often have features of axonal loss, axonal neuropathies do nothave features of primary demyelination
ULN = upper limit of normal
Demyelination on NCS
Demyelination – two independent markers
(1) Substantial changes in measures of conduction velocity (CV)
- Conduction velocity slowing (motor) • Prolonged distal motor latencies
- Prolonged F wave latencies
– Motor CV < 70% LLN: normal forearm (median/ulnar) motor CV > 50 m/s, so unequivocal demyelination if < 35 m/s, normal foreleg (peroneal/tibial) motor CV > 40 m/s, so unequivocal demyelination if < 29 m/s
– DML > 150% ULN: normal ulnar DML < 3.3 msec, so > 4.9 msec
– F wave latencies > 130% ULN: normal ulnar F latency < 32 msec, so > 48 msec (or > 150% if CMAP amplitude < 80% LLN)
(2) Conduction block and/or abnormal temporal dispersion
Suggested criteria for demyelination in chronic neuropathy (2010 PNS/EFNS consensus criteria)
– Conduction block (>50% drop), abnormal temporal dispersion (>30% increase in duration)
Conduction block
Refers to motor neurons
Partial conduction block (CB) - amplitude or area of the proximal response (for example elbow) is significantly smaller than the distal response (wrist), without an increase in the response duration
CB reflects the block of conduction through a subset of motor axons in the nerve due to segmental demyelination
Definite in any nerve
– >50% drop in CMAP amplitude
– >50% drop in CMAP area
– >30% drop in area or amplitude over a short nerve segment (such as radial across the spiral groove, ulnar across the elbow, or peroneal across the fibular head)
Temporal dispersion normval vs pathological
Can be seen normally
TD is more substantial when there is an increased range of conduction velocities due to demyelination
Abnormal temporal dispersion is due to demyelination – results in a greater than 30% increase in duration (comparing the proximal CMAP to the distal CMAP)
CB and TD
Conduction block and temporal dispersion
Abnormal temporal dispersion = greater than a 30% increase in proximal CMAP duration compared to the distal CMAP
Both abnormal TD and the presence of CB reflect the presence of primary demyelination!
Demyelinating vs axonal neuropathies
Axonal neuropathies
– Loss of sensory (SNAP) and motor (CMAP) amplitudes
– No, or mild, slowing of conduction (CV, DML and F latencies) velocity parameters
Demyelinating neuropathies
– Patchy, multifocal conduction slowing with dispersion and conduction block: suggests an acquired demyelinating process, likely GBS or CIDP
– Uniform slowing without conduction block or dispersion: suggests a genetic (life-long) inherited demyelinating neuropathy
Acute nerve injury
Important – the timing of the changes seen after an acute nerve lesion
After an acute axonal lesion, Wallerian degeneration of the nerve distal to the lesion occurs
However, as this occurs the distal nerve canstill conduct action potentials for a period of time
– CMAPs (motor responses) stable for 2-3 days and then nadir, or disappear, in 5-7 days (CMAPs go first)
– SNAPs (sensory responses) stable for 5-6 days and then nadir, or disappear, by 10 days
Timing of prognosis for acute nerve injury
Given the timing of the NCS changes seen after an acute nerve lesion – the maximal extent of the axonal loss is evident by 10 days
Therefore, prognostic statements can be made with NCS by 10 days after the injury
Differentiating conduction block producing weakness (good prognosis) from axonal loss (worse prognosis) can be made at that time
– Lesions that are primarily conduction block recover quickly (over weeks) – since it requires only remyelination of the area of focal compression
– Axon loss lesions require recovery either by collateral sprouting or nerve regeneration – processes that are much slower (over months, if at all in the case of complete lesions)
Nerve injury timeline
F waves
A late recorded surface potential from a backfiring motor neuron after antidromic stimulation of the motor nerve distally
Since the impulse traverses the entire motor axon antidromically and then back down orthodromically to be recorded from the muscle, it provides some information about proximal motor conduction
Primarily helpful in demyelinating neuropathies (GBS and CIDP), where it may be quite prolonged
Seen with supramaximal stimulation
H waves (H reflex)
An electrically evoked monosynaptic spinal reflex
Primarily obtained only from the tibial nerve (unlike F waves that can be obtained from almost any motor nerve)
Stimulation of the tibial nerve excites IA sensory afferents, then after reflex in cord travels back down the motor axons to the soleus where it is recorded with surface electrodes
The recorded motor response is from most of the motor units in the muscle (not one as in the F wave)
From a submaximal stimuli
F wave vs H reflexes
The F-wave and the H-reflex are late responses on NCS.
The F-wave is obtained after supramaximal stimulation of a motor nerve while recording from a muscle. The electrical impulse travels antidromically (conduction along the axon opposite to the normal direction of impulses) along the motor axons toward the motor neuron, backfiring and then traveling orthodromically (conduction along the motor axon in the normal direction) down the nerve to be recorded at the muscle.
The H-reflex is the electrophysiologic equivalent of the ankle reflex (S1 reflex arc) and is obtained by stimulating the tibial nerve at the popliteal fossa while recording at the soleus. The electrical impulse travels orthodromically through a sensory afferent, enters the spinal cord, and synapses with the anterior horn cell, traveling down the motor nerve to be recorded at the muscle.
Visual evoked potentials
Tests visual pathway from the optic nerve to the occipital cortex
Major peak is the P100 – measured value is the P100 latency
Generated in the striate and pre-striate regions (area 17 and 18) – primary and association visual areas
VEP abnormalities
Criteria of abnormal P100 response – Latency delay > 2.5 or 3 SD from normal (e.g., > 110 msec) – Latency difference side-to-side > 2.5 or 3 SD from normal (e.g., > 8 msec delay one side compared to the other) – Absent: Reduced amplitude not typically used - too variable in normals
Interpretation – Absent or delayed P100 on one side = abnormal prechiasmatic lesion (includes ocular and retinal causes): likely optic nerve, if corrected visual acuity is relatively normal (20/100 or better) – Bilateral absent or delayed P100 = abnormal visual function bilaterally: likely visual pathway conduction, if corrected visual acuity is relatively normal
Prolonged vs delayed P100
Disorders producing a significantly prolonged P100 latency
– Demyelinating disease (MS and optic neuritis)
– Leukodystrophies,spinocerebellardegenerations,subacute combined degeneration (B12 deficiency), vitamin E def
Disorders producing primarily reduced amplitudes and only mild P100 delays (usually with significantly reduced visual acuity)
– Vascular lesions of the optic nerve (e.g., anterior ischemic optic neuropathy)
– Compressive lesions of optic nerve
– Ocular disease (e.g., glaucoma)
Delayed P100 latency (>110) – c/w abnormal pre-chiasmatic visual pathway conduction on the left (OS, e.g., optic neuritis)
BAEPs
Wave I – ipsilateral, distal VIIIth nerve action potential
Wave II – ipsilateral proximal VIIIth nerve and rostral medulla (trapezoid body)
Wave III – bilateral superior olivary nucleus (lower pons)
Wave IV – bilateral lateral lemniscus (mid to upper pons)
Wave V – bilateral rostral lateral lemniscus and inferior colliculi (upper pons)
Waves I to V are far-field potentials and polarity is upgoing (positive) – Note: far-field potentials are upgoing for electropositive (the opposite convention of near field e.g., for VEP)
BAEPs interpretation
All waveforms absent = abnormal peripheral auditory function on that side
Prolongation of interpeak latencies, or side to side difference, of > 2.5 or 3 SD from normal = abnormal conduction in that segment
– Example – delayed I-III latency on the left = abnormal auditory conduction in the auditory pathway between the distal VIIIth nerve and the superior olivary nucleus on that side
Absent waveforms with present wave I = abnormal conduction at or rostral to the peaks that are present
– Example – normal waves I-III, but absent waves IV and V = abnormal auditory conduction in pontomesencephalic pathways (rostral to the superior olivary nucleus) on that side
BAEP abnormalities in different conditions
Demyelinating disease – Prolonged interpeak latencies – Absent waves after II or III (e.g., III, IV and V or IV and V absent)
Acoustic neuromas – Early prolongation of the I-III latency
Toxic or metabolic coma – normal
Brain death – I and II may be preserved (from the VIIIth nerve)
SSEPs
Predominantly generated from large sensory afferents (proprioception and vibration) and their central projections
Central propagation occurs in the spinal cord predominantly in the dorsal columns to the gracile and cuneate nuclei in the medulla and in the SS pathways in the brain (medial lemniscus, thalamus, thalamocortical projections and SS cortex)
Mix of near-field and far-field potentials (although near-field waveforms are used for routine studies for the most part)
Median SSEP
Median SSEP
– Stimulation of the median nerve
– Recorded separately from each side
Origins
– N9 (or EP) – from underlying brachial plexus; recorded at Erb’s point (nerve action potential)
– N13 – postsynaptic activity in the cervical cord
– N20 – primary somatosensory cortex
– P22 – cortical positivity following N20
* all are near-field – traveling (N9) or stationary (N13 and N20)
Abnormalities
– Prolonged N13-N20 latency - consistent with abnormal somatosensory conduction anywhere from the cervical cord to cortex
– Absent N13 and N20 peaks – consistent with abnormal somatosensory conduction rostral to the brachial plexus on that side
Tibial SSEP
PP, also called PF– popliteal fossa (nerve action potential in tibial nerve at the level of the knee)
N22, also called LP (lumbar potential)– most caudal thoracic and upper lumbar cord (postsynaptic activity in the dorsal gray matter)
P37 – primary somatosensory cortex
SSEPs in cardiopulmonary arrest
After cardiopulmonary arrest
– Bilateral absence of N20 reponses with median nerve stimulation recorded on day 1 to 3 accurately predicts a poor outcome
– Converse is not true: presence of N20 does not reliably predict good outcome
Cortical responses are abolished by deep sedation or general anesthesia
Conduction vs sensorineural hearing loss
Conductive hearing loss – limits external sound from getting through the external ear (cerumen impaction) or middle ear (ossicle fixation; fluid; etc)
Sensorineural hearing loss
– Cochlear – from the sensory apparatus in the inner ear that converts sound to neural signals
– Retrocochlear – from the auditory neural system
Audiogram
Primary test used in the evaluation of hearing loss. Should be obtained in all patients with this complaint.
Compares pure tone thresholds for air and bone conduction at frequencies between 250 and 8000 Hz – allows distinction between conductive and sensorineural hearing loss.
Tests pure tone air and bone conduction (at frequencies of 250, 500, 1000, 2000, 4000 and 8000 Hz); threshold is dB heard 50% of the time – earphones for air conduction, – bone oscillator on the mastoid for bone conduction
Any difference between air and bone conduction thresholds is an “air/bone gap” – a gap (bone > air) is consistent with conductive hearing loss
Also includes a standardized test of speech discrimination (word discrimination score): poorer with neural than cochlear hearing loss
Tympanogram (aka impedance audiometry) also usually done: assesses the middle ear by looking at tympanic membrane (TM) compliance – no mobility consistent with fluid behind TM – stiff but mobile consistent with otosclerosis
BAEP in hearing loss
Rarely helpful in select patients with hearing loss
Delay or absence of the potentials (waves II to V) after a normal wave I highly correlates with neural (retrocochlear) lesions – called “auditory neuropathies. This is seen with acoustic neuromas (involves the proximal VIIIth nerve) – but MRI is usually the test of choice for this
Unlike the audiogram the patient’s response is not needed, so BAEPs can provide objective data if the patient can’t cooperate – cognitively impaired or young patients, unresponsive patients, and in malingerersg patients, unresponsive patients, and in malingerers
Ventricular system and CSF
Consists of two lateral ventricles which connects to the midline 3rd ventricle via the interventricular foramina of Monro. The 3rd ventricle communicates with the 4th via the aqueduct of Sylvius. The 4th ventricle communicates with the subarachnoid spaces via the midline foramen of Magendie and the bilateral foramina of Luschka.
CSF is manufactured in the choroid plexus in the
Reabsorption occurs through arachnoid villa and granulations in the superior sagittal sinus
CSF creation/resorptions and function
CSF is manufactured in the choroid plexus. Reabsorption occurs through arachnoid villa and granulations in the superior sagittal sinus.
Physical support – Protective role
Excretory function and “sink action” – Removal of metabolic by-products
Intracerebral transport – Local transport of releasing factors i.e. TRF,
Control of the chemical environment – pH, electrolytes
CSF volume
Total volume of CSF is about 140 ml
About 500 ml produced each day at a rate of about 20cc/hr or 0.35 ml/minute
Total CSF volume turned over about 3.5 times/day
CSF OP
Opening pressure– Normal: 6-20 cm H2O (60-200 mm H2O) • Measured in the lateral decubitus position • Patient needs to be relaxed • L3-L4 interspace • Normal is up to 25 cm H2O in obese patients
Varies due to: respiration, • Can vary by 2 - 10mm H2O depending on depth of breathing, posture, arterial blood pressure, venous pressure, thoracic pressure- valsalva, cough, sneeze, blood gases i.e. CO2 a potent vasodilator increases cerebral blood flow and CSF pressure, hypothermia
Causes of hydrocephalus
Oversecretion (choroid plexus papilloma) Defective absorption (impaired venous drainage)
Obstruction of CSF pathways – Noncommunicating (intraventricular), examples: aqueductal stenosis, tumors – Communicating (Extraventricular), examples: postinflammatory, post-traumatic, post-hemorrhagic, congenital
NPH
Primary NPH – No antecedent history
Symptomatic NPH – Following subarachnoid hemorrhage or meningoencephalitis
No signs or symptoms of increased ICP – No headache or papilledema with normal csf pressure
Pseudotumor Cerebri
Diagnosis of exclusion
Clinical manifestations usually present with headache and visual disturbances CSF pressure is elevated
Intracranial hypotension
Low pressure usually leads to postural headaches
Seen most commonly after lumbar puncture
Can occur spontaneously
CSF appearance
Color: clear, yellow, pink, red, etc.
Turbidity (cloudy): RBC’s, WBC’s Viscosity, mucin from adeno CA, yeasts Pigments
Xanthochromia (bilirubin): centrifuge cellular elements to determine traumatic tap, should be analyzed after 12 hours of a suspected SAH
CSF WBCs
– WBC’s lyse within 2 hours at room temp
– Normal counts: • Accept 0-6 WBC/mm3 as normal (Fishman 1992) • For a traumatic spinal tap subtract 1 WBC/mm3 for each 700 RBC/mm3, assuming a normal hemogram
WBC profile
Abnormal >6 WBC/mm3
Profile – Small lymphocytes (B, T), lymphoid cells – Mononuclear phagocytes: monocytes, macrophages – Polymorphonuclear granulocytes: neutrophils, eosinophils, basophils – Atypical cells: tumor cells
“Poly” WBC predominance
Bacterial infection (meningitis, abscess) – S. pneumoniae, N. meningtidis Viral meningitis (early, then lymphocytic)
Eosinophilic WBC
Parasitic infection
Atypical WBC
Tumors – Need cytology and flow cytometry – May require serial taps (3x)
WBC lymphocytic predominance (lymphocytic meningitis)
– “Aseptic” or viral meningitis • Enterovirus, mumps, e.g. • Protein only mildly elevated, normal glucose
– Subacute or chronic meningeal processes • Tuberculosis • Lyme • Syphilis • Fungi
CSF glucose
Reflects the blood glucose level about 4 hours prior to LP
CSF glucose normally 2/3 (0.66) of blood glucose level
Ratio may fall to 2/5 (0.40) with a blood glucose of 700 mg/dl (saturation kinetics)
Decreased CSF glucose
Can be decreased due to: Increased glucose utilization by 1.) the brain and spinal cord in disease states or 2.) by polys in meningitis, Utilization by bacteria probably insignificant; Decreased rate of glucose entry (transporter) → Usually indicates a diffuse meningeal process not a localized cerebritis or abscess
Common causes of decreased CSF glucose
Acute purulent meningitis, TB meningitis, Syphillitic meningitis, Fungal meningitis, Meningeal sarcoidosis, Leptomeningeal metastases, Hypoglycemia
CSF protein
Normal: 15-45 mg/dl in normal adults • Albumin (50%) • Prealbumin • Globulins (IgG, e.g.)
Most protein derived from serum (7 gm/dl) • Exceptions: Myelin basic protein, glial fibrillary acidic protein (GFAP), tau protein, and intrathecal IgG synthesis etc.
Elevated CSF protein
• Vasogenic brain edema • Increased permeability of the blood-brain barrier • Defect in protein absorption (high protein causes this) • (Subtract 1 mg/dl protein for 1000 RBC/mm3 )
Causes of elevated CSF protein
• Meningitis (Bacterial 100-500 mg/dl, Viral <100 mg/dl) • Encephalitis • Cerebral abcess • Cerebral infarction • Multiple sclerosis • Guillain-Barré syndrome • Spinal block (neoplasm in the spinal canal) • Neurosyphilis • Venous thrombosis
Quantitative CSF IgG
Normal CSF IgG is 5-12% of total CSF protein
Compared to 15-18% of total serum protein
IgG Index = (IgGcsf/IgGserum)/(Albcsf/Albserum_
IgG synthesis rate calculates the daily intrathecal production of IgG and corrects for the amount of IgG that enters the CSF from the serum
Oligoclonal bands
Oligoclonal bands– Agarose gel electrophoresis – Isoelectric focusing
Monoclonal bands (1 band)
Oligoclonal bands (2-5 bands)
Best detection method is immunofixation instead of silver stains or coomasie blue.
Need to match with serum sample
Seen in 85-95% of clinical definite MS patients which persists and 100% of patients with SSPE which spontaneously resolve
Can be seen in other conditions much less commonly (25%) including other infectious and inflammatory diseases,GBM, GBS and ALD
Tuberculous Meningitis CSF
Elevated WBC (100-500 WBC/mm3) – Lymphocytic predominance (occ. poly. predom.) – Elevated protein (100-500 mg/dl), Low glucose
Acid-fast bacilli (AFB) stain only 4-24% sensitive – Cultures may take 2-6 weeks
– PCR for M. tuberculosis 32-90% sensitive
Lyme Meningitis
Headache, papilledema, cranial nerve palsies, radiculopathies, Possible exposure in an endemic area
– Positive serum serologies or PCR
– CSF • Elevated protein, pleocytosis (lymphocytic) • Lyme antibodies: ELISA, Western blot • PCR
Fungal meningitis
Cryptococcus: • immunocompromised, headache, papilledema, cranial nerve palsies • CSF: India ink stain, cryptococcal antigen
Coccidioidomyocosis • California and southwest U.S. • Hydrocephalus, multiple cerebral granulomata • Elevated CSF protein, mildly low glucose • CSF IgG • Lymphocytic pleocytosis
Other causes of CSF lymphocytic pleocytosis
– Neurosarcoidosis – Leptomeningeal metastases – Vasculitis – Multiple sclerosis and other demyelinating diseases – Parasites (cysticercosis, e.g.)
“Classic”neurons
Purkinje and pyramidal cells – large nucleus with single prominent nucleolus (circle) – large cell body – On H&E, prominent basophilic material in the cytoplasm (Nissl substance) (arrow) – The Bielschowsky silver stain demonstrates axons and dendrites (Bottom)
Stains positive for synaptophysin and NeuN
Normal glia
Astrocytes (star cells) – 5 to 10 times more than neurons– On H&E stain, appear as oval nuclei without cytoplasm (arrow) – Stain positive for glial fibrillary acidic protein (GFAP) (circle).
Normal glia
Oligodendroglia
– Myelin producing cells of the central nervous system
– Located in white matter (circles) tracts and in gray matter around neurons (arrow).
– Small, dark, round nuclei surrounded by a perinuclear halo
• The halo is an artifact from fixation.
Inflammatory cells of CNS
Microglia
– Small, dark, oval nuclei without cytoplasm (circle).
– Derived from monocytes
Inflammatory cells of CNS
Macrophages
– Large cells with granular cytoplasm (circle).
– Stain positive for CD68
Normal Ependymal cells
Single layer of columnar or cuboidal epithelial cells (circle).
Stains positive for Vimentin
Subependymal plate: relatively acellular neuropil below the ependymal cells (arrow)
Meningothelial cells
– Investing epithelial cells that form the arachnoid membrane (circle)
– Stains positive for epithelial membrane antigen (EMA)
Choroid Plexus (bottom) – Large cuboidal epithelium overlying blood vessels, connective tissue and meningothelial cells (circle). – Stains positive for transthyretin
Normal spinal cord
On Toluidine blue stains, peripheral and central myelin stains dark blue.
In this crosssection, there is homogenous staining of the tracks as well as the dorsal and ventral roots (circles).
Spontaneous activity
Spontaneous activity is assessed with the muscle at rest, and examples include fibrillation potentials, fasciculation potentials, and myokymia and myotonic potentials. All spontaneous activity is abnormal.
MUP features of neurogenic vs myopathic injury
MUPs are obtained while the needle is inserted into the muscle during voluntary contraction. Various characteristics are of consideration, including recruitment pattern and MUP morphologic features, such as duration, amplitude, and configuration.
- Recruitment is a measure of the number of MUPs firing during increased force of voluntary muscle contraction. In axon loss lesions, reduced recruitment is characterized by a less-than- expected number of MUPs firing more rapidly than expected. Early or rapid recruitment occurs in myopathic processes with loss of muscle fibers, in which an excessive number of short-duration and small-amplitude MUPs fire during the muscle contraction
- With poor voluntary effort/CNS disorders → weakness, recruitment is reduced with normal MUPs firing at slow or moderate rates, sometimes variable
- In neuropathic disease, MUPs disclose increased duration and amplitude, and may be polyphasic
- In myopathic disorders, MUPs are of reduced duration and amplitude, and may also be polyphasic.
EMG Neuropathy vs Myopathy
EMG in different lesions
NCS
NCS are classified into sensory and motor conduction studies.
Sensory NCS - stimulate a sensory nerve then record the transmitted potential at a different site along the same nerve. Three main measures: SNAP amplitude - measure of the number of axons conducting between stimulating and recording site, sensory latency (onset and peak): time to travel between stimulation and recording sites, and conduction velocity: measured in meters per second and is obtained dividing the distance between stimulation site and the recording site by the latency: Conduction velocity = Distance/Latency.
Motor NCS are obtained by stimulating a motor nerve and recording at the belly of a muscle innervated by that nerve. The CMAP is the resulting response, and depends on the motor axons transmitting the action potential, status of the neuromuscular junction, and muscle fibers. The CMAP amplitudes, motor onset latencies, and conduction velocities are routinely assessed and analyzed. As with sensory NCS, conduction velocity is calculated by dividing distance by time. In this case, however, the distance between two stimulation sites is divided by the difference in onset latencies of those two sites, providing the conduction velocity in the segment of nerve between the two stimulation sites. This method of calculating conduction velocity thereby avoids being confounded by time spent traversing the neuromuscular junction and triggering a muscle action potential (since these are subtracted out).
NCS axonal vs demyelinating
In general, for sensory and motor responses, a decrease in the amplitudes correlates with axon loss lesions. On the other hand, prolonged latencies and slow conduction velocities correlate with demyelination. Low amplitudes can result from demyelinating conduction block when the nerve stimulation is proximal to the block.
SNAPs in radiculopathy
In a radiculopathy, there are normal SNAPs despite sensory symptoms, because SNAPs are recorded distal to the lesion, in the postganglionic projections from the dorsal root ganglion.
The dorsal root ganglion is located just outside the spinal canal within the intervertebral foramen. It has sensory unipolar neurons with preganglionic fibers that extend proximally and enter the spinal cord through the dorsal horns, projecting rostrally in the spinal cord. The postganglionic fibers project distally through the spinal nerves and peripheral nerves, carrying information from a dermatome. On the other hand, the motor fibers originate from the anterior horn cells within the spinal cord, projecting distally through spinal nerves and peripheral nerves, carrying motor innervation to a myotome.
A radiculopathy occurs from an intraspinal canal lesion resulting in damage of the preganglionic fibers. The cell body in the dorsal root ganglia and the postganglionic fibers remain unaffected, and therefore, even though sensory symptoms are prominent, the SNAPs are normal.
When are fibrillation potentials seen after onset of motor axon loss? Decreased recruitment? Large and polyphasic MUPs
Fibrillation potentials and decreased recruitment are seen 3 weeks after the onset of motor axon loss
3 to 6 months later, large and polyphasic motor unit potentials (MUPs) emerge: The presence of these large and polyphasic MUPs is dependent on reinnervation and collateral innervation, typically occurring in a proximal to distal fashion, with proximal muscles more successfully reinnervated as compared to distal muscles.
Repetitive nerve stimulation in NMJ disorders
Presynaptic: Whenever CMAPs are found to be low in amplitude, a presynaptic disorder such as Lambert–Eaton syndrome or botulism should be suspected. An increment in the CMAP amplitudes after exercise or rapid repetitive stimulation (20-50 Hz by overcoming efflux of Ca2+) is a feature of a presynaptic disorder, and not of MG.
Postsynaptic: There is a decrement of CMAP amplitudes with slow repetitive nerve stimulation (2 to 3 Hz), with a decrement of greater than 10% being consistent with MG.
Repetitive nerve stimulation in NMJ disorders
Presynaptic: Whenever CMAPs are found to be low in amplitude, a presynaptic disorder such as Lambert–Eaton syndrome or botulism should be suspected. An increment in the CMAP amplitudes after exercise or rapid repetitive stimulation (20-50 Hz by overcoming efflux of Ca2+) is a feature of a presynaptic disorder, and not of MG.
Postsynaptic: There is a decrement of CMAP amplitudes with slow repetitive nerve stimulation (2 to 3 Hz), with a decrement of greater than 10% being consistent with MG.
Single fiber EMG
Jitter analysis by single-fiber EMG (SFEMG) is performed by recording with a single-fiber needle electrode positioned to detect potentials from two muscle fibers of the same motor unit. The variability of the interpotential interval between these two potentials is the jitter, and it is abnormal in MG due to delayed neuromuscular transmission. Neuromuscular blocking can also be detected, and is measured by the percentag specific for MG, being frequently abnormal in other neuromuscular junction disordere of discharges in which one of the potentials is missing. SFEMG is highly sensitive but not
Single fiber EMG
Jitter analysis by single-fiber EMG (SFEMG) is performed by recording with a single-fiber needle electrode positioned to detect potentials from two muscle fibers of the same motor unit. The variability of the interpotential interval between these two potentials is the jitter, and it is abnormal in MG due to delayed neuromuscular transmission. Neuromuscular blocking can also be detected, and is measured by the percentag specific for MG, being frequently abnormal in other neuromuscular junction disordere of discharges in which one of the potentials is missing. SFEMG is highly sensitive but not specific for MG, being frequently abnormal in other neuromuscular junction disorders (including LEMS)
NCS/EMG in LEMS
Sensory NCS are normal, but CMAP amplitudes are usually low to borderline low at rest because many fibers fail to reach threshold after a stimulus, given inadequate release of acetylcholine vesicles. Brief exercise facilitates the release of acetylcholine and results in an increment in the CMAP amplitudes.
Peripheral nerve injury on NCS/EMG
Nerve injury can range from focal demyelination: slowing at a specific site, conduction block to axonal injury: Wallerian degeneration in 7-10 days, during this time →pseudo conduction block but after 10 says distal axon degnerates and can no longer conduct with resolution of pseudo conduction block and nerve transection
Focal demyelination: A focal nerve injury can cause segmental demyelination, which is characterized by the presence of slowing at a specific site, or the presence of a conduction block, which is a decrease in the CMAP amplitude with proximal stimulation as compared to distal stimulation, without significant temporal dispersion. The presence of conduction block therefore suggests segmental demyelination and helps localize the site of injury. A conduction block is reversible, given that the lesion is demyelinating.
Axonal injury: If the injury is severe, an axon loss lesion may occur, eventually leading to Wallerian degeneration, which is typically completed in 7 to 10 days from the injury. During this time, a pseudoconduction block may be observed due to axon loss. After 10 days, the distal axon degenerates and can no longer conduct. Therefore the pseudoconduction block due to axonal interruption resolves. NCS alone cannot localize a focal axon loss lesion 3 weeks following peripheral nerve injury.
Once denervation occurs, spontaneous muscle activity appears on EMG, manifested by fibrillation potentials, which usually appear after the third week from the injury.
Small fiber neuropathies - helpful tests and treat
Small fibers include myelinated A-δ and unmyelinated C-fibers, which are involved in autonomic, temperature, and pain transmission. Patients with small-fiber neuropathy present with painful burning sensations and dysesthesias distally (most frequently in the feet). Some patients may have autonomic manifestations that compromise sweating, vasomotor control, gastrointestinal, and genitourinary functions. In pure small-fiber neuropathy, besides sensory findings, the neurologic examination is normal, including motor and reflex examination, distinguishing it from large-fiber neuropathy. Symptoms may also include hyperesthesia (increased sensitivity to painful stimuli) and allodynia (pain resulting from stimuli that would not be expected to be painful).
A cause is not found in the majority of cases. There are multiple causes of small-fiber neuropathy that account for a small percentage of the cases and should be investigated. Of the cases in which an etiology is found, diabetes and impaired glucose tolerance are the most common. Other less common causes include hypothyroidism, chronic alcohol toxicity, amyloidosis, vasculitis, sarcoidosis, HIV, hyperlipidemia, Sjogren’s syndrome, and connective tissue disorders.
EMG/NCS are normal because these tests evaluate the integrity of large nerve fibers. Tests that help in making the diagnosis include quantitative sudomotor axon-reflex test (QSART), thermoregulatory sweat test (TST), and skin biopsy. QSART evaluates postganglionic sympathetic cholinergic sudomotor function, and is performed by stimulation of sweat glands by iontophoresis of acetylcholine. TST assesses the pattern of sweatingand dysfunction of sweating by placing the patient in a warming chamber while covered by a reactive powder that changes color with sweat. In small-fiber neuropathy with distal involvement, abnormal sweating is typically detected in hands and feet but not in the trunk. Skin biopsy determines intraepidermal nerve fiber density, which is significantly reduced in segments involved in small-fiber neuropathy.
The treatment should target the underlying cause when determined. Symptomatic treatment includes medications for neuropathic pain, including gabapentin, pregabalin, carbamazepine, and amitriptyline, among others.
