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Chapter VII

LABORATORY ASSESSMENT

UNDERSTANDING THRESHOLDS AND DEFICITS

NEED FOR THEIR QUANTIFICATION

DESIRABLE QUALITIES IN ASSESSMENT MODALITIES

TESTING BY MONOFILAMENT

TESTING FOR AND INTERPRETATION OF VIBRATION THRESHOLDS

TESTING FOR HEAT AND COLD PERCEPTION THRESHOLDS

CASE IV SYSTEM, EMG AND NCV

Understanding thresholds and deficits while testing for neuropathy:

Clinical testing of peripheral nervous system gives only a qualitative or at best semi quantitative assessment. It does not exactly quantify deficits. The greater the deficits on testing, the more vulnerable the foot becomes to the development of ulcers, which can get infected and is under a greater chance of getting amputated. Qualitative testing cannot correlate the findings of clinical testing precisely to identify the level of risk a foot has. And if this cannot be done, anticipatory measures to prevent the foot from getting ulcerated would be difficult to initiate.

Need for quantification:

Thus some form of quantitative assessment of the diabetic foot is essential that can identify the foot at high risk as also the quantum of the risk associated with it as compared to normal foot. This can be done by semi quantitative methods using instruments in a graded manner, progressing to more precise quantitative methods. All the sensations of lower limbs however are not quantifiable. The touch and pain are qualitative and / or subjective and quantifying them is not without inherent errors, especially pain. On the other hand a combination of touch-pressure, vibration and thermal stimuli are highly quantifiable. These can be tested in quantitative manner by using increasingly precise instruments.

Precautions and care exercised during testing:

There could be inherent errors that may get into the testing, eg to the instruments, the users, the imperfections on the part of the patients to understand while reporting and when recorded.

Any test for sensory neuropathy (and for that matter, motor and autonomic neuropathy) becomes meaningful when attention is paid to:

1. The choice of the evaluation procedure which carries with it, its limitations on quantification, reproducibility, sensitivity and specificity as compared, with other tests that bring out similar data.

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2. The tests inherently bring in, the operator or hands on variables and the varying

patient responses that need to be cross checked and controlled.

3. The analysis of the tests performed. The test procedure could still have a subjective

element that can seriously interfere with the accuracy of the data obtained (and

recorded.)

4. The standardization is an important consideration especially if a procedure is

inherently multistage or complicated and depends on subjective responses as in

sensory neuropathy testing. (In motor neuropathy by some contrast the subjective

element is less, as evidenced in electromyography and clinical testing correlations.)

The issue of the standardized outputs (as in say vibration threshold measuring

instruments) or sensitivity of instruments is also an important consideration.

5. The reference values that we may use should be standard, they should be reasonably

simple to understand and usable, even if there normative ranges are multivariate

dependant (like age, duration of diabetes) the distinction of what is normal and what

is not should be clear.

As much as these considerations are valid and valuable in controlled clinical trials or epidemiological studies, they are important for clinical practice as well. In fact, the greater the accuracy or sensitivity or reliability of them, the yield of information is as valuable even if the number of patients that we may analyze are smaller.

Qualities desirable in a modality of testing:

They are the relevance, reliability, specificity and sensitivity of these methods for the prediction of a foot at high risk.

The laboratory tests for sensory neuropathy: The monofilament, vibration

and heat and cold perceptions:

The “Semmes Weinstein Nylon Monofilament” carries out the test for the combined sensation of light touch and pressure. The filament is held as indicated on the filament perpendicular to the sole and is pressed and removed immediately evenly from the heads of the 1st 3rd and the 5th metatarsals, mid foot and the dorsum of each foot. The findings are recorded as sensed or not sensed. The test correlates satisfactorily well with more precise vibration perception thresholds to indicate a foot is at increased risk. The monofilament most commonly used is the 10 grams monofilament meaning thereby that it exerts a pressure of 10 grams when pressed perpendicular to the sole. This quick test can by and large help decide a foot at risk for further evaluation.

The tests for the sensation of vibration are carried out by vibration threshold measuring instruments like Sensitometer. The thermal threshold is tested by an electrical instrument that can apply progressively lowered or elevated measurable temperatures to the skin, to see the threshold at which, the sensation of pain is evoked. The usual clinical testing is relatively simple and could be applied easily. The quantitative testing for detection for hot and cool thresholds would require a sophisticated instrument. These instruments are not easily available in our country and DFSI and NNEF have helped successfully develop them and are now manufactured in India. Following are some details of these two modalities.

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Testing vibration perception:

This is an electrically operated small instrument contained in a box that has now been developed in India and has been validated against English Instruments as equally good. It weighs 6 kg (Fig 62). It works on the principle of application of electrical energy to a calibrated vibrator. This voltage can be increased from 0 to 50 V by turning the control switch to the right in a clockwise manner gradually. The volts appear on the top of the semicircle and the vibratory amplitude calibrated as microns of motion appear below the semicircle. (Fig. 27)

The silent switch is used to detect if the patient is 1) is either not able to understand the test and what is it that he needs to report, 2) or is trying to accommodate to the demand of the operator to report if he feels the vibration or not or 3) he is simply bluffing. It is used to stop the vibrations while testing but does not lower the indicator from the voltage at which the vibrations were delivered at that time.

The procedure of testing should be explained to the patient in detail to remove any apprehension and to obtain proper response.

The trial run:

It is preferable to place the vibrator on the fingertips of the hand of the patient to show the patient the kind of sensation that he is going to get by increasing the voltage slowly. The feet may then be tested by slowly rotating the switch to right till the patient gets the sensation and says yes. Increase it a little to see if the sensation is more pronounced. Then slowly turn back to see whether the patient indicates absence of sensation little below the point at which he / she had indicated the sensation for the first time. Increase the voltage again very gradually to see the voltage at which he again registers the sensation of vibration. Record the voltage for that point. Then record the voltages at the heads of the first, third and the fifth metatarsal, the mid foot and the heel of both the feet. All the points tested by the S W Monofilament should also be tested for the vibration perception threshold.

Record voltage at each point in the data record form. In one of the instrument available the multiple voltages recorded can be shown in a graphical for like an audiometric measurement.

It is important to tell the patients to report the earliest and the most minimal of the sensation of vibration, as soon they are sure. Otherwise, they tend to wait till it is quite strong. That will give an erroneously high reading.

The single reading to be entered is the mean of two or three readings done at that point and should be nearly the same or less than 10% away from each other.

The factors that may affect the threshold of vibration:

Age: With increasing age the threshold goes on increasing, above the age of 50.

The lower extremities: The nerves of the lower extremities appear to be more vulnerable to increasing threshold as age advances. The longer the length of the nerve fibre the more it may be susceptible to loss of vibration giving rise to higher

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threshold. In person with diabetes, the threshold for vibration is more likely to be higher than the normal individuals even in the upper extremities.

Fatigue: Fatigue usually raises the vibration perception threshold,

Muscle tone: An inverse relationship is found to exist between the muscle tone and the Vibration Perception Thresholds. Therefore, it is recommended that the testing is carried out in a single position with patient resting and relaxing for 5 to 10 minutes before testing.

Neuropathy: All such factors that cause neuropathy e.g diabetes mellitus, will cause an elevation in VPT.

Some important interrelations of thresholds and neuropathic abnormalities:

1. The vibration perception thresholds (VPTs) are significantly increased in both upper

and lower limbs in persons with diabetes patient.

2. The VPTs for great toe is higher and higher VPTs of great toes are associated

positively with longer duration of diabetes.

3. VPTs values positively correlate with observed sensory loss and areflexia, correlate

with increasingly severe stages of person with diabetes neuropathy.

4. One abnormality of quantitative sensory testing correlates well with some other form

of quantitative testing. For example vibration and cooling thresholds were strongly

associated with clinical deficits.

5. The vibration and cooling threshold help establish minimum criteria to diagnose

polyneuropathy.

A sample of report that can be given to the patient is attached above in the section on the clinical and laboratory assessment for vibration perception threshold.

Interpreting the values of the VPT:

It is not the first value on a patient that is the most important observation. It is the direction in which the second value appears is important and the quantum change. We may obtain a second value in the next one year. If the second or the third values are progressively higher then it is clear that there is a progressive deterioration in the neuropathic status of the individual. If the values do not vary much and cluster around the first value, the position regarding the status of neuropathy is more or less stable. If the change is unidirectional (or monotone) then higher the value or the quantum of the change, the greater will it indicates the deterioration to be.

On foot, if a patient fails to detect the vibrations when the voltage applied exceeds 25V, it is indicative of threefold to fourfold increased risk of developing foot ulceration. When the threshold for detecting vibration exceeds 42V the risk rises to nearly 17 fold.

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Testing for sensations of Heat, Cold, Heat and Cold by HCP Sensitometer.

India is a hot country with barefoot walking a common practice. A person with Diabetic Foot may not sense temperatures as high as engine casing which may result in to burn injuries. Thus it is logical to verify the integrity of the thermal sensations like cool warm and pain associated with it, for safety reasons.

Normal ranges of these thresholds:

32 to 340C is neutral zone, just below 320C & up to 300C is the Cool threshold range -age dependant. The sensation of cool pain appears between 27 to 250C. 36 to 380C is the interval for the sensation of warmth, 42 to 450C is the heat pain zone. Above ranges are true for clinical practice in an ambient temperature of 27 to 370C and skin temperature doesn't affect significantly in clinical practice.

Sensitometer-HCP (Figure 61) is used by many in India since 2003. It offers reliable and reproducible thresholds. It needs about 15 to 20 minutes of a technician. It indicates simultaneous possibility of Autonomic Dysfunction. The normal heat pain threshold range is 42 to 450C, erythema takes place after an hour at 450C, needs 10 seconds to a minute at 500C for tissue damage, and just one second at 550C. When the heat and cold perceptions are lost in feet, as compared to the hands the patient can perceive the problem especially when the quantification of the deficit is shown.

A rate of one degree per second is generally recommended by some investigators. But for heat and cold thresholds the rate of rise or fall of temperature seems best at 1 degree Centigrade over 4 seconds since C fibers carry sensations at a much slower speed, have a period of latency of about 500 milliseconds before the impulse gets initiated. Consequently there is a delay in reaching the sensation to the cortical areas. There is a further delay for the registration of the sensation and response to it. These factors determine the rate of rise or fall of temperature that the patient needs to sense and respond to. This makes testing a little longer but gives precise thresholds, reduces the need for many readings, averaging etc.

Concept of heat pain and cold pain should be understood; these thresholds are higher and lower than heat and cold respectively.

Cool pain is sensation of coolness with an additional component of un-comfort. Some thing similar to standing near the AC.

Heat pain is warmth plus pricking sensation.

It is the slight un-comfort to be detected for the thresholds and not the ability to bear chill or heat.

Case IV System for Neuropathy:

Following is a small simplified review of the research that has gone in, in the quantitative and clinical methods of investigation in peripheral neuropathy to answer the issues. Elaborate systems to identify the neuropathic symptom score, the neuropathy deficit identification or to estimate on analog scales positive symptoms like pain or hyperesthesia were first worked out. Using computer analyzable codes

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the data was entered and the information was obtained using trained observers in an unbiased manner. The data consisted of examination findings, as also the instrumental testing that would give more quantified results. All this was fed to a “Computer Assisted Sensory Evaluation System IV” and then analyzed for results. PK Thomas and Peter Dyke were the investigators who developed this system and used it over long years with continuing improvements. This system tests all the sensations and the positive symptoms as also the deficits. Dyke and Thomas found that if any one sensation tested by this system was found to be abnormal then there would be at least one more sensation that is likely to be abnormal indicating that the foot is at a higher risk. On further testing the possibility of whether an abnormality detected by one test could be correlated to the abnormality detected by another test within the system, it was found that the correlation was good. The question of quantifying the associated risk in the presence of such findings was answered by conducting trial in the Rochester population.

Electromyography and nerve conduction velocity:

It is a modality that has become available more routinely in only last few years with the subspecialty of neurology. For primary physicians and Diabetologists, its routine use is still expensive, not easily available. That makes the repeat testing for assessing the efficacy of interventional strategies not only costly but also difficult.

No doubt electromyography and nerve conduction velocity is the gold standard for assessing neuropathic abnormalities and differentiating them primarily for the pathologic abnormality of nerve fibers viz. axonal or myelin abnormalities. No other method of testing neuropathy gives this particular differentiation in such clear terms. Its use for monitoring is the gold standard as the subjective elements are minimal and it is only operator controlled. Additionally, it has great value in differentiating between the purely nerve fiber pathology, vis-à-vis, the possible disconnections of reflex arc at the spinal level. And lastly its usefulness for assessment of the posterior columns of spinal cord is valuable to those who deal with spinal cord and vertebral column problems, though not always for the assessments for Diabetologists.

If there is detectable abnormality in say vibration perception, there will be some abnormality in the EMG / NCV testing also. Thus suffice it to say that the simpler tools like vibration threshold measuring instruments we have sought to elaborate upon in this volume, to be placed in the hands of physician and Diabetologists to prevent foot problem are like surrogate markers for the EMG / NCV abnormality. Often therapeutic intervention will cause some of the parameters of EMG and NCV to improve but that does not always mean a reversal of neural pathologies as a whole, or often the Neuropathic Symptoms Scores, may not improve, as shown by several reviews on whether the neuropathy is reversible or not in diabetes later in this monograph.

A note of nerve conduction velocity and normal values:

In order to complete the perspective on assessment of sensory neuropathy, we would like the reader to keep a few salient features of the nerve conduction velocity studies.

Nerve conduction (sensory) velocity studies primarily assess the amplitude of the sensory action potentials and velocities. The amplitudes are basically the summation

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of all the electrical amplitudes of individual axons, which generate them and are being tested. Thus, any abnormality i.e., decrease in the amplitude is primarily a function of the number of axons that are available to generate the amplitudes. Obviously if the neuropathy is of the axonal degenerative type, as a result of diabetes then it will be primarily reflected as decrease of amplitude from the normal values.

The velocity of electrical impulse that is carried by the axons is dependant upon the state of myelination - that is either its loss or other structural irregularities. The nerve fibers that are well myelinated have Ranvier's nodes. These nodes are facilitatory to the fast transmission of the electrical conduction. As such when there is demyelination, the velocities drop and the nerve conduction manifests as a demyelinating type of axonal abnormalities.

Both, the amplitude as well as the velocity can decrease in diabetic neuropathy in which case a mixed picture of axonal degeneration as well as demyelination emerges from these studies.

Limitations of NCV:

For the decrements of either velocities and / or amplitudes, a large number of axonal fibers need to be either dead or demyelinated to get a consistent picture of neural pathology. The other sensory modalities like vibration or heat and cold could be detectable earlier than that. Specifically EMG and NCV do not detect the small C fiber functions which becomes easily detectable by Heat and Cold Perception Threshold measuring instruments now available in India.

References:

1. Boulton AJM, Kubrusly DB, Bowker JH, et al. TI: Impaired Vibratory Perception

and Diabetic Foot Ulceration Diabet Med 1986; 3:335.

2. Boulton AJM, Mueller MJ. Identifying patients with diabetes mellitus who are at risk

for lower extremity complications. Use of Semmes Weinstein monofilaments. Phys

Ther 1996; 76: 68.

3. Kumar S, Fernando DJ, Veves A, et al. Semmes Weinstein monofilaments: A simple,

effective and inexpensive screening device for identifying diabetic patients at risk of

foot ulceration . Diab Res Clin Pract 1991; 13:63.

4. Young MJ, Bready JL, Veves A, et al. The prediction of diabetic neuropathic foot

ulceration using vibration perception thresholds: A prospective study. Diabetes Care

1994; 17:57.

Note: A table of normal values for the EMG / NCV is given as Appendix obtained from a reputed neurology institute that is engaged in these studies for last over 15 years. We record our thanks for the gesture of Central India Institute Of Medical Sciences, 88/2, Bajaj Nagar, Nagpur 440010, and of Dr. G M Taori MD MRCP, Chief Neurologist and Director and Dr. Leena Vyas M.B.B.S, the electrophysiologist of the Dept of Neurology.