An Institutional study on the comparison of Trigeminal and ...

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An Institutional study on the comparison of

Trigeminal and Radial nerve RNS with Facial,

Spinal accessory and Ulnar nerve RNS in

patients with Myasthenia Gravis

Thesis submitted in fulfillment of the rules and regulations for DM

Degree Examination of Sree Chitra Tirunal Institute for Medical Sciences

and Technology, Thiruvananthapuram

By Dr. Jayakrishnan Chellenton

Resident in Neurology

Month and Year of Submission: October 2012

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CERTIFICATE

I, Dr. Jayakrishnan Chellenton hereby declare that I have actually carried out the

project under report.

Date: 05-10-2012 Dr. Jayakrishnan Chellenton

Place: Thiruvananthapuram Resident in Neurology.

Forwarded; He has carried out the project under report.

Dr. Sarada C (Guide), Dr. Muraleedharan Nair,

Professor, Professor & Head,

Department of Neurology, Department of Neurology,

SCTIMST. SCTIMST.

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Acknowledgements

I express my heartfelt gratitude and indebtness to my esteemed teacher and guide Dr Sarada C , Professor of Neurology, SCTIMST, Thiruvananthapuram. In spite of multifarious demand on her precious time, she constantly helped, guided and encouraged me in completing this work. her in-depth knowledge, vast experience and dedication to research inspired me at every step of the study. I am indebted to Dr. M. D. Nair, Senior Professor and Head, Department of Neurology for the constant support and encouragement. I take this opportunity to sincerely thank Dr. K Radhakrishnan, Director & Senior Professor of Neurology, SCTIMST for providing me the opportunity to do this study. Lastly, I would like to thanks all the patients who consented to their participation in the study.

Dr.Jayakrishnan C

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INDEX

i. Introduction 5

ii. Review of literature 6

iii. Aims of the study 20

iv. Materials and Methods of the study 21

v. Observations and Results 24

vi. Discussion 47

vii. Conclusion 50

viii. Bibliography 51

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Introduction:-

Neuromuscular Junction (NMJ) is designed for rapid translation of the electrical

impulse of the nerve to the muscle using the chemical acetylcholine (Ach).

Neuromuscular junction (NMJ) is the anatomical site affected by myasthenia gravis

(MG), Lambert-Eaton myasthenic syndrome (LEMS) , Botulism, and congenital

myasthenic syndromes (Bashar Katirji et al 2007).Acquired myasthenia gravis (MG)

is a prototypical, antibody-mediated autoimmune disorder of the neuromuscular

junction (NMJ) (Donald B Sanders et.al 2009). Fluctuating muscular weakness that

increases with effort is the characteristic manifestation of MG. A wide range of

clinical presentations and associate features allow classification of MG into

subtype’s based on disease distribution (ocular vs generalised), age at onset, thymic

abnormalities, and autoantibody profiles appropriate recognition of these clinical

subtypes helps to determine management strategies and prognosis. The methods

used for identification of MG cases includes clinical history, physical examination

(demonstration of fatigability and fluctuating weakness), electrophysiological (RNS

and SFEMG) and serological (Anti AChR antibody). Repetitive Nerve

Stimulation(RNS) has been recommended as a method for confirmation of MG.

The sensitivity of the RNS depends on multitude of other factors as the muscle in

which the test is done & medication status. The common and well established

nerve muscle pair in the literature is Facial nerve- Nasalis muscle, Spinal accessory

nerve- Trapezius muscle, Ulnar nerve- Adbuctor Digiti Minimi (AAEM

PRACTICE guidelines 2001 Muscle Nerve 24: 1236–1238, 2001). The muscles of

mastication and the wrist extensors are group of muscles which exhibit weakness

in MG patients. There are studies which tried to study the RNS in these groups of

muscles. Since the RNS is relatively well established and cost effective method for

proving the diagnosis of MG, its utility is very high. The plan of the study was to

assess the RNS in these relatively common weak muscles (mastication and finger

extensors ) in MG patients, and to assess if these muscles gives a higher pick up

rate for identifying new cases.

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Review of literature

History:-

The 1672 description by Thomas Willis in De Anima Brutorum of a “prudent and

honest woman” with fluctuating muscle weakness “not only in the members but

also in her tongue” (Willis, 1672) is often cited by English-speaking authors as the

first description of case of MG. In 1879 Wilhelm Erb, Professor Extraordinarius in

Nikolaus Friedreich’ clinic in Heidelberg, described “a new bulbar symptom

complex” in three patients with bilateral drooping eyelids severe neck weakness

and trouble chewing, in which the muscle atrophy characteristic of progressive

bulbar palsy was absent (Erb, 1879). Carl Eisenlohr, one of Erb’s pupils working in

Hamburg, was the first to emphasize the extraocular muscle weakness in this

syndrome and the remarkable fluctuation of muscle strength during the day

(Eisenlohr, 1887). In 1893 Goldflam described in detail “an apparently curable

bulbar paralytic symptom-complex with involvement of the extremities” in three

patients with fluctuating weakness of extraocular muscles, jaw muscles and limbs

as well as attacks of dyspnea (Goldflam, 1893). Friedrich Jolly, Professor of

Nervous Disease at the University of Berlin, in 1895 he coined the term

“myasthenia gravis pseudoparalytica (generalisata)” to describe the condition in

two teenage boys characterized by progressive weakness of muscle contraction on

repetitive stimulation that improved with rest (Jolly, 1895). Harriet Edgeworth,

who herself had myasthenia, after numerous failed regimens, she noted sustained

improvement of her MG symptoms with ephedrine, a derivative of the ancient

Chinese herb “ma huang”. Walker discovered that the antidote to curare,

physostigmine, injected subcutaneously, temporarily relieved her MG patients’

symptoms of eyelid, jaw and arm muscle weakness and difficulty swallowing In

1954, pyridostigmine emerged as the new drug of choice for the short-term

treatment of the symptoms of MG. In 1899 Oppenheim reported as an incidental

finding the presence of a tumor “the size of a mandarin orange” growing from the

thymic remnant of a patient who died from MG. E. Farquhar Buzzard of

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London showed lymphoid deposits, which he termed “lymphorrhages,” were

present in muscles, adrenals, thyroid, and liver at autopsies of MG patients who

did not have thymic abnormalities. Blalock performed the first transternal

thymectomy on an MG patient without a thymic tumor, and in the next six weeks

performed six such operations, claiming improvement in MG had resulted in most

of the cases (Blalock et al., 1941). Fambrough, Daniel Drachman and S. Satyamurti

to the elucidation of the pathogenesis of MG, in which the number of junctional

acetylcholine receptors in myasthenic muscles was found to be reduced to 11–30%

of that in normal control muscles (Fambrough et al., 1973). Jim Patrick and Jon

Lindstrom postulated that human MG might be an immune response to human

acetylcholine receptor, and this was demonstrated soon after, 85% of patients with

MG demonstrating serum antibodies to human acetylcholine receptor (Lindstrom

et al., 1976).

Epidemiology:-

MG is a relatively uncommon disease, although prevalence has increased over time

with recent estimates approaching 20 per 100 000 in the US population (Phillips

LH et.al). Incidence varies widely from 1.7 to 10. 4 per million, depending on the

location of study(Phillips LH 2nd & Torner JC et .al) and has been reported to be as

high as 21 per million in Barcelona, Spain(Aragones JM et.al) The occurrence of

MG is influenced by sex and age: women are affected nearly three times more

often than men during early adulthood (aged <40 years), whereas incidence is

roughly equal during puberty and after the age of 40 years. After 50 years of age,

incidence is higher in men. Childhood MG is uncommon in Europe and North

America, comprising 10–15% of MG cases, but is much more common in Asian

countries such as China, where up to 50% of patients have disease onset under the

age of 15 years, many with purely ocular manifestations.

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Clinical presentation:-

The clinical hallmark of MG is fatigable weakness, usually involving specific

susceptible muscle groups. Patients often note that their weakness fluctuates from

day to day or even from hour to hour, worsens with activity, and improves with

rest. Patients can have varying degrees of ptosis, diplopia, dysarthria, dysphagia,

dyspnea, facial weakness, or fatigable limb or axial weakness. Ocular weakness,

presenting as fluctuating ptosis and/or diplopia, is the most common initial

presentation of MG, occurring in approximately 85% of patients (Grob D et.al).

Disease progression to generalised weakness usually occurs within 2 years of

disease onset. Weakness of facial muscles is quite common and many patients with

MG have detectable weakness of eyelid closure with or without lower facial

weakness when examined carefully, even when these muscle groups are not

symptomatically weak. Bulbar weakness, presenting with painless dysphagia,

dysarthria, or chewing difficulties, is the initial symptom in up to 15% of patients.

Weakness involving respiratory muscles is rarely the presenting complaint.

Although rare, a prominent limb-girdle distribution of weakness or even focal

weakness in single muscle groups can occur.( Rodolico C et.al, Nations SP et.al).

The course of MG is variable. Many patients experience intermittent worsening of

symptoms triggered by infections, emotional stress, surgeries, or medications,

particularly during the first year of the disease. Progression to maximum severity

typically occurs within the first 2 years of onset. (Grob D et.al). Spontaneous long-

lasting remissions are uncommon, but have been reported in 10–20% of

patients(Grob D et.al).

MG subtypes:-

Patients with generalised MG can be divided into early-onset and late-onset

disease, with early-onset MG usually defined as beginning before the age of 40

years. These patients are more often female, have anti-AChR antibodies, and

enlarged hyperplastic thymus glands. In addition to anti-AChR antibodies, other

organ-specific autoantibodies might be present, and patients might be affected by

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other autoimmune diseases, most commonly autoimmune thyroid disease

(Christensen PB et.al, Tola MR et.al ). Antibodies to non-AChR muscle

components are not typically seen in early-onset MG (Oosterhuis HJ et.al).

Patients with onset after the age of 40 years are more often male and usually have

normal thymic histology or thymic atrophy. Patients with late onset MG can

present with ocular or generalised weakness, but typically have a more severe

disease course compared with early-onset MG, and spontaneous remissions are

rare.( Aarli JA et.al). In addition to anti-AChR antibodies, these patients usually

have antibodies to striated muscle proteins such as titin and the ryanodine

receptor.( Romi F et.al) The presence of these anti-muscle antibodies particularly

anti-ryanodine receptor antibodies, has been associated with more severe,

generalised, or predominantly oropharyngeal weakness, and frequent myasthenic

crises.( Romi F et .al, 2000 & 2007). About 10–15% of patients with MG have a

thymic epithelial tumour—a thymoma. Thymoma-associated MG is equally

common in men and women, and can occur at any age, with peak onset at the age

of 50 years. Clinical presentations tend to be more severe than in nonthymomatous

patients with early-onset MG, commonly with progressive generalised and

oropharyngeal weakness. However, long-term prognosis is similar to that of late

onset, non-thymomatous MG.( Romi F et.al 2003, Bril V et.al de Perrot M et.al ),

with rare exceptions(Maggi L et.al ). MG patients with thymoma have high titres

of anti-AchR antibodies, and they usually also have antibodies against titin.

Additional paraneoplasia-associated antibodies (and their related syndromes) might

occur in thymomatous MG, including anti-voltage-gated K+ and Ca2+ channel,

anti-Hu (antineuronal nuclear autoantibody 1), antidihydropyrimidinase- related

protein 5 (formerly anticollapsin response mediator protein 5), and anti-glutamic

acid decarboxylase antibodies.( Vernino S et.al ). The presence of auto antibodies

to a voltage-gated K+ channel, KCNA4 (formerly Kv1.4), has been recently

reported in Japanese patients with severe MG, thymoma, and concomitant

myocarditis and/or myositis(Suzuki S et.al ). In patients with thymoma, surgery

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(thymothymectomy) often completely and permanently removes the tumour, but

symptoms of MG usually persist and require chronic immunotherapy.

Approximately 15% of patients with generalised MG do not have anti-AChR

antibodies on current assay methods. In about 40% of these patients, antibodies to

MUSK, another postsynaptic NMJ protein, are found.( McConville J et.al )

Whereas patients with anti-MUSK antibodies can have presentations similar to

anti-AChR-positive MG, they commonly have atypical clinical features, such as

selective facial, bulbar, neck, and respiratory muscle weakness and marked muscle

atrophy, occasionally with relative sparing of ocular muscles.( Evoli A et.al ,

Sanders DB et.al 2003 ) Respiratory crises are more common than in generalised

anti-AChR-positive disease. Weakness can involve muscles that are not usually

symptomatic in MG, such as paraspinal and upper oesophageal muscles(Sanders

DB et.al 2008). Enhanced sensitivity, nonresponsiveness, or even clinical

worsening in response to anticholinesterase agents have also been reported.(

Hatanaka Y et.al ) Disease onset in patients with anti-MUSK MG tends to be

earlier, and patients are predominantly female. Thymus histology is usually

normal(Leite et.al). Patients with MG who lack both anti-AChR and anti- MUSK

antibodies (so-called seronegative MG) are clinically heterogeneous and can have

purely ocular, mild generalised, or severe generalised disease. The true prevalence

of seronegative MG might be quite low, because some patients might have low-

affinity anti-AChR antibodies that are not detected with currently available assays.

Not surprisingly, these patients are essentially indistinguishable from patients with

anti-AChR-positive MG in terms of clinical features, pharmacological treatment

response, and even thymic abnormalities in some cases(Vincent A et.al).

Myasthenic weakness that remains limited to the ocular muscles is termed ocular

MG, and comprises 17% of all MG in white populations. Ocular MG seems to be

more common in Asian populations (up to 58% of all patients (Chiu H.C et.al ). If

weakness remains limited to the ocular muscles after 2 years, there is a 90%

likelihood that the disease will not generalise.Up to 50% of patients with ocular

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MG have anti-AChR antibodies, but higher antibody titres do not necessarily

predict generalisation(Kupersmith MJ et.al ). Anti-MUSK anti bodies are rarely

found in ocular MG.( Bennett DL et.al, Caress JB et.al , Chan JW et.al)

Immunopathogenesis and immunogenetics:-

The NMJ in MG:- The NMJ has three basic components : (1) the presynaptic

motor nerve terminal, where acetylcholine is synthesised, stored, and released; (2)

the synaptic space; and (3) the postsynaptic muscle membrane, which contains the

AChRs and the enzyme acetylcholinesterase. Neuromuscular transmission begins

when a nerve action potential enters the nerve terminal and triggers the release of

acetylcholine. Exocytosis of synaptic vesicles containing acetylcholine requires

calcium, which enters the depolarised nerve terminal via voltage-gated Ca2+

channels. Acetylcholine diffuses across the synaptic cleft and interacts with the

AChRs on the postsynaptic muscle membrane, causing a local depolarisation, the

endplate potential (EPP). The EPP in normal NMJs is much larger than the

threshold for generation of a muscle fibre action potential; this difference has been

defined as the safety factor of neuromuscular transmission. The action of

acetylcholine on the postsynaptic membrane is terminated by acetylcholinesterase.

In MG, loss of functional AChRs results in a decrease in EPP amplitudes that fall

below the threshold required for muscle fibre action potential generation during

repetitive nerve depolarisations, resulting in neuromuscular transmission failure.

Anti-AChR MG:-

The pathogenic role of anti-AChR antibodies in MG has been clearly shown(Toyka

KV et.al, Lambert EH et.al) and is further substantiated clinically by the often

dramatic improvement that follows removal of circulating antibodies by plasma

exchange(Newsom-Davis J et.al ). The antibodies are usually of the IgG1 or IgG3

isotype and are thus capable of activating complement. They bind to the

extracellular domain of the AChR molecule, but are heterogeneous in their

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reactivity with different regions on the AChR.( Vincent A et.al 1998) Although

antibodies to the AChR directly result in the destruction of the muscle endplate,

the high-affinity, highly mutated nature of the anti-AChR IgGs indicates that the

autoantibody response is T-cell dependent, with CD4 T cells helping the B cells to

produce the pathogenic antibodies.( Protti MPet.al, Wang ZY et.al, Aissaoui A

et.al). Three main mechanisms underlie the loss of functional AChRs.( Drachman

DB et.al 1998).The most important is complement mediated lysis of the muscle

endplate resulting in morphological damage to the postsynaptic muscle

membrane.( Engel AG et.al 1978 ). This causes a simplification and distortion of

the normal folded pattern of the postsynaptic membrane , which not only has a

functional impact on AChRs but also results in a reduction in the number of

voltage-gated Na+ channels, increasing the muscle fibre action potential

threshold.( Ruff RL et.al ). Second, accelerated internalisation and degradation of

AChRs caused by cross-linkage of AChRs by divalent antibodies results in a

temperature dependent loss of AChRs.( Heinemann S et.al ) Finally, direct

blockade of AChRs by antibodies attached to acetylcholine binding sites might be

important in some patients.( Burges J et.al )

Early-onset MG:-

Although the trigger or inciting factor leading to the autoimmune derangement in

MG remains a mystery, several lines of evidence implicate the thymus gland in this

process. Greater than 80% of early-onset, anti-AChRpositive patients have thymic

hyperplasia(Leite MI et.al )characterised by the presence of lymphocytic infiltrates

and germinal centres similar to those found in lymph nodes. Hyperplastic thymus

glands from patients with MG contain T cells, B cells, and plasma cells, as well as

myoid cells that express AChR.( Schluep M et.al ). In fact, they contain all the

components necessary for the development of an immune response to the AChR,

an thymocytes in cultur spontaneously generate anti-AChR antibodies(Scadding

GK et.al 1981) These findings support the concept of an intrathymic pathogenesis

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and suggest that the hyperplastic thymus is involved in the initiation of the anti-

AChR immune response in early-onset MG.

Late-onset MG (without thymoma):-

The mechanism for autosensitisation to AChRs in late onset MG is not clear

because these patients typically lack thymic abnormalities. The similar clinical

presentation and autoantibody profile in some patients with late-onset MG

compared with thymomatous MG raises the possibility that they have occult

thymomas suppressed by anti-tumour autoimmune reactions.

Thymomatous MG:-

Thymomas are frequently associated with autoimmunity, probably due to

dysregulation of lymphocyte selection and presentation of self-antigens expressed

by neoplastic cells. Neoplastic epithelial cells in thymomas express numerous self-

like antigens, including AChR-like, titinlike, and ryanodine-receptor-like epitopes.

(Morgenthaler TI et.al ).Frequent concurrent autoimmunity against these seemingly

unrelated auto antigens in thymomatous MG suggests that their targeted,

potentially cross-reacting, proteins play a part in the production of disease.

(Mygland A et.al). MG-associated thymomas are rich in autoreactive T cells.

( Kadota Y et.al ). The current concept of the immunopathogenesis of thymoma-

related autoimmunity is that potentially autoreactive T cells are positively selected

(for survival) and exported to the periphery where they are activated to provide

help for autoantibody-producing B cells by mechanisms that are not yet known.

Negative selection and regulation of potentially autoreactive T cells might be

impaired in thymoma due to a deficiency in the expression of the autoimmune

regulator gene (AIRE), and selective loss of T-regulatory cells.( Scarpino S et.al,

Strobel P et.al ).

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Anti-MUSK MG:-

MUSK is a trans membrane endplate polypeptide involved in a signalling pathway

that maintains the normal functional integrity of the NMJ(Valenzuela DM et.al ).

Recent evidence indicates that anti-MUSK antibodies adversely affect the

maintenance of AChR clustering at the muscle endplate, leading to reduced

numbers of functional AChRs(Shiraishi Het.al, Cole RN et.al ). Furthermore,

myasthenic weakness has been reproduced in experimental animals by

immunisation with recombinant MUSK ectodomain.( Shigemoto K et.al ) . MUSK

antibodies are mainly IgG4, unlike the IgG1 and IgG3 anti-AChR antibodies, and

are not complement activating. The precise pathophysiology of the myasthenic

weakness and prominent muscle atrophy in anti-MUSK MG has yet to be

elucidated, because muscle biopsy studies have shown little AChR loss(Shiraishi

Het.al ) but detailed studies of neuromuscular transmission have not been done in

the most affected muscles. The preferential involvement of facial, bulbar, and axial

muscles might indicate a different composition of the NMJs in these muscles. The

events leading to autosensitisation to MUSK are not known, but the thymus gland

is probably not involved.

Anti-AChR and anti-MUSK-negative MG (seronegative

generalised MG):-

Patients who do not have either anti-AChR or anti- MUSK antibodies improve

with immunosuppressive treatments, plasma exchange, and even thymectomy.

(Mossman S et.al ). Furthermore, muscle biopsies in these patients show AChR

loss, and thymic histology often shows hyperplasia and germinal centres similar to

anti-AChRpositive MG. Recently, low-affinity IgG antibodies that bind

preferentially to AChRs clustered on transfected cell surfaces have been found in

66% of patients with MG who were antibody-negative on conventional anti-AChR

and anti-MUSK antibody assays(Leite MI et.al 2008). These low-affinity antibodies

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were mainly of the IgG1 subclass and had the capacity to activate complement,

supporting their pathogenic role.

Ocular MG:-

The immunopathogenesis of ocular MG is likely to be similar to that of early-onset

or late-onset generalised MG. Enhanced susceptibility of extraocular muscles to

MG might result from differences in NMJ morphology and physiology.

Extraocular muscles have less prominent synaptic folds, fewer postsynaptic AChRs

and smaller motor units, and are subject to high firing frequencies (Luchanok U

et.al). Another possibly relevant factor is low expression of complement regulators

in extraocular muscles, which might make them more vulnerable to complement

mediated damage(Kaminski HJ et.al, Soltys J et.al ).

Diagnosis:-

The tests that are available to confirm the clinical diagnosis of MG include bedside

tests, such as the edrophonium or ice-pack test, electrophysiological tests, and tests

to measure the concentrations of serum autoantibodies .

1. Bedside tests:-

Edrophonium chloride is a short-acting acetylcholinesterase inhibitor that prolongs

the duration of action of acetylcholine in the NMJ, increasing the amplitude and

duration of the EPP. The edrophonium test, which consists of administering

edrophonium intravenously and observation of the patient for an improvement in

muscle strength, can be most objectively and reliably interpreted when resolution

of eyelid ptosis or improvement in strength of a single paretic extraocular muscle

are the endpoints(Pascuzzi RM et al 2003) Published reports indicate that its

sensitivity in the diagnosis of MG is 71.5–95% for generalised disease.( Pascuzzi R

M et al 2003) . Serious complications of bradycardia and syncope are rare( Ing EB

et.al )but cardiac monitoring during the procedure is advocated by some( Pascuzzi

RM et al 2003) .

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The ice-pack test is a non-pharmacological test with no morbidity that is done by

placing an ice pack over the eye for 2–5 mins and assessing for improvement in

ptosis(Golnick KC et.al, Meriggioli MN et.al) Its use should mainly be considered

in a patient with ptosis in whom the edrophonium test is contraindicated.

Electrophysiological tests:-

Repetitive nerve stimulation is the most commonly used electrophysiological test

of neuromuscular transmission. In disorders of the NMJ, low rates of nerve

stimulation (2–5 Hz) produce a progressive decrease or decrement in the

amplitude of the compound muscle action potential. The result of the repetitive

nerve stimulation test is abnormal in approximately 75% of patients with

generalised MG (<50% of ocular MG), and is more likely to be abnormal in a

proximal or facial muscle(Meriggioli MN et.al). Neuromuscular jitter results from

fluctuations in the time taken for the EPP to reach the threshold for muscle fibre

action potential generation, and can be measured by single-fibre electromyography

(SFEMG). SFEMG is done using a specially constructed concentric needle

electrode that allows identification of action potentials from individual muscle

fibres. SFEMG reveals abnormal jitter in 95–99% of patients with MG if

appropriate muscles are examined.( Oh SJ et.al, Benatar M et.al ). Jitter can also be

assessed, although with somewhat less sensitivity, by using conventional

electromyography electrodes(StalbergEV et.al ). Although highly sensitive,

increased jitter is not specific for primary NMJ disease, and might be found in

nerve or even muscle disease(Meriggioli MN et.al)

2. Repetitive nerve stimulation (RNS):-

The use of repetitive nerve stimulation (RNS) dates back to the late 1800s, when

Jolly made visual observations of muscle movement that occurred after nerve

stimulation.

The NMJ essentially forms an electrical-chemical-electrical link between nerve and

muscle. ACh molecules are packaged as vesicles in the presynaptic terminal in

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discrete units known as quanta; each quantum contains approximately 10,000

molecules of ACH. The quanta are located in three separate stores. The primary,

or immediately available, store consists of approximately 1,000 quanta located just

beneath the presynaptic nerve terminal membrane. This store is immediately

available for release. The secondary, or mobilization, store consists of

approximately 10,000 quanta that can resupply the primary store after a few

seconds. Finally, a tertiary, or reserve, store of more than 100,000 quanta exists far

from the NMJ in the axon and cell body. The binding of ACH to ACHRs opens

sodium channels, resulting in a local depolarization, the endplate potential (EPP).

The size of the EPP is proportional to the amount of ACH that binds to the

ACHRs. In a process similar to the generation of a nerve action potential, if the

EPP depolarizes the muscle membrane above threshold, an all-or-none muscle

fiber action potential is generated and propagated through the muscle fiber. Under

normal circumstances, the EPP always rises above threshold, resulting in a muscle

fiber action potential. The amplitude of the EPP above the threshold value needed

to generate a muscle fiber action potential is called the safety factor. During slow

RNS (2-3 Hz) in normal subjects, ACH quanta are progressively depleted from the

primary store, and fewer quanta are released with each successive stimulation. The

corresponding EPP falls in amplitude, but because of the normal safety factor, it

remains above threshold to ensure generation of a muscle fiber action potential

with each stimulation. After the first few seconds, the secondary (mobilization)

store begins to replace the depleted quanta with a subsequent rise in the EPP. In

myasthenia gravis, CMAP decreases on RNS , this occurs as a result of fewer

ACHRs and, accordingly, less binding of ACH. The reduced safety factor, in

conjunction with normal depletion of quanta, results in subsequent EPPs falling

below threshold and their corresponding muscle fiber action potentials not being

generated . As the number of individual MFAPs declines, a decrement of CMAP

amplitude and area occurs. This decrement reflects fewer EPPs reaching threshold

and fewer individual MFAPs contributing to the CMAP. Often, after the fifth or

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sixth stimulus, the secondary stores are mobilized and no further loss of MFAPs

occurs. This results in stabilization or some times slight improvement or repair of

the CMAP decrement after the fifth or sixth stimulus, giving the characteristic "U-

shaped" decrement. In normal subjects, maximal exercise results in the usual

generation of a muscle fiber action potential. In postsynaptic NMJ disorders,

exercise, results in higher EPPs. Because the EPP usually is above threshold at

baseline, the result is the same: the generation of a muscle fiber action potential.

Exercise likewise may repair or improve a low EPP that has developed during slow

RNS. If the EPP has dropped below threshold, subsequent exercise may increase

the EPP back to above threshold. In presynaptic NMJ disorders, exercise, like

rapid RNS, often can facilitate low EPPs. If the baseline EPP is below threshold,

exercise may increase the EPP above threshold so that a muscle fiber action

potential is generated where one had not been present previously. The effects of

rapid RNS or voluntary exercise just described occur with brief periods of exercise

or rapid RNS, typically 10 seconds. This process is known as postexercise (or

posttetanic) facilitation. The phenomenon of postexercise (or posttetanic)

exhaustion is less well understood. Immediately after a prolonged exercise or rapid

RNS (usually 1 minute), EPPs typically increase initially, but then subsequently

decline over the next several minutes, usually falling below baseline. In normal

subjects with a normal safety factor, the EPP never falls below threshold.

However, in patients with impaired NMJ transmission, slow RNS performed 2 to 4

minutes after a prolonged exercise may result in a greater decline of the EPP, such

that the EPP does not reach threshold and its muscle fibre action potential is not

generated.

3. Immunological tests:-

The most commonly used immunological test for the diagnosis of MG measures

the amount of serum antibody that precipitates muscle AChR, as detected by

binding with the radiolabelled cholinergic antagonist α-bungarotoxin. The

sensitivity of this test is approximately 85% for generalised MG and 50% for

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ocular MG(Lindstrom JM et al, Vincent A et .al 1985). Anti-AChR antibody

concentrations vary widely among patients with similar degrees of weakness and

thus cannot reliably predict the severity of disease in individual patients. Of note,

patients might be falsely seronegative due to immunosuppression or if the test is

done too early in the disease.( Chan KH et.al )Other assays that measure the

capacity of patient serum to inhibit binding of cholinergic ligands (AChR-blocking

antibodies) or to induce modulation of AChRs in cell cultures (AChR modulating

antibodies) add relatively little to the diagnostic sensitivity. Striated muscle

(striational) antibodies that recognise muscle cytoplasmic proteins (titin, myosin,

actin, and ryanodine receptors) are detected in 75–85% of patients with

thymomatous MG and also in some thymoma patients without MG.(Cikes N et.al )

.The presence of these antibodies in early-onset MG raises the suspicion of a

thymoma. Titin antibodies and other striational antibodies are also found in up to

50% of patients with late-onset, nonthymomatous MG, so are less helpful as

predictors of thymoma in patients aged over 50 years( Buckley C et.al). Reports

indicate that anti-KCNA4 antibodies might be a useful marker to identify patients

with thymoma and concomitant myocarditis/myositis. Patients with generalised

MG who are anti-AChR negative should be tested for anti-MUSK antibodies,

which are found in approximately 40% of patients in this group. Low-affinity anti-

AChR antibodies binding to clustered AChRs have been found in 66% of sera

from patients with seronegative generalised MG(Leite MI et.al 2008) but this test is

not currently commercially available. This cell-based assay might eventually provide

a more sensitive diagnostic test in this subgroup.

20

AIMS OF THE STUDY:-

1. To study the prevalence of abnormal decrement response from the five

nerves according to the severity of MG (MGFA class I, II and III).

2. To note the magnitude of abnormal mean(range) decrement response from

the individual nerves.( Ulnar, Radial, Spinal accessory, Facial and

Trigeminal).

3. To detect whether significant difference occurs in the decrimental response

from various muscles between rest and exercise of 1 minute.

21

Materials and Methods

Inclusion criteria.

1. A clinical history and examination consistent with the diagnosis of MG.

2. One of the following:

a. Abnormal decrement on RNS in two or more nerves (apart from the

trigeminal).

b. Positive acetylcholine receptor (AChR) antibodies.

c. All classes of MG will be included

Exclusion criteria

1. The presence of any other neuromuscular disorder.

2. The use of anticoagulants with an INR 3.0.

3. Congenital MG

Materials and Method

• Patient number : 40 patients in various MGFA grades of severity of disease.

• Patient characteristics details:-

– Age, gender.

– Date of onset and duration of symptoms.

– Distribution and severity of weakness

• Generalized.

• Proximal, distal.

• Ocular, bulbar.

• Sevirity grading according to MGFA classification.

• Current medication

• The Anti-AchE medication will be withheld for 6 hours prior to the test.

• RNS will be done at 3 Hz stimulation for 2 sec.

• Comparison between potential 1 and 4( amplitude)

• RNS will be initially performed in:-

22

– Ulnar Nerve & Abductor digiti minimi.

– Spinal accessory Nerve & Trapezius.

– Facial nerve & Nasalis muscle.

• The trains of four stimuli will be performed three times at rest to ensure

technical reliability.

• Each muscle will then be exercised isometrically for 1 min.

• RNS will be performed --immediately after exercise, and at 1 min, 2 min, 3

min and 5 min after exercise.

• Method of Radial N RNS:-

– For doing Radial nerve & EIP RNS, 5-mm disc electrodes will be

taped over the EIP (G1) . The reference electrode (G2) will be placed

four fingerbreadths proximal to the ulnar styloid process. The

ground electrode will be taped on the dorsal forearm. The

stimulation will be given in the spiral groove at 3 Hz at rest and up to

5 minutes following 1 minute of isometric exercise (Adriana Petreska

et al)

• Method of Trigeminal N RNS:-

– Trigeminal RNS will be performed by stimulating the masseteric

branch of the trigeminal nerve with a needle stimulator. Needle will

be inserted approximately 0.5–1.0 cm into the mandibular notch

between the coronoid process and condoyle of the mandible, below

the zygomatic process. The mandibular notch is readily palpated

approximately 1 cm anterior to the tragus of the ear and just under

the zygoma. A surface anode will be placed on the ipsilateral

zygomatic process. The CMAP will be recorded using 5-mm disc

electrodes, with the active electrode (G1) taped to the masseter

muscle approximately one third of the way between the angle of the

mandible and the zygoma. The reference electrode (G2) over the

angle of the mandible(G. Pavesia et.al. & Devon Rubin et.al ) The

23

percentage decrement in CMAP amplitude between the first and

fourth potentials will be recorded for each train of stimuli. Criteria of

abnormality will be a decrement of 10% or greater in all nerves tested

after repetitive stimulation

•

24

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25

Duration of illness:-

The minimum duration of illness was 1 year and maximum duration was 15 years.

The mean duration of illness was 4.55 +/- 4.2 years.

Duration of illness.

N Minimum Maximum Mean Std. Deviation

Duration of

illness 40 1 15 4.55 4.284

Clinical symptomatalogy:-

The clinical symptoms with which the patient presented in the hospital was

analysed.

Most of this data is based on the history of the presenting complaints.

1. Ocular symptoms:-

Drooping of the eye lid was a very common symptom at presentation. Only

01(one) patient denied that he had any drooping of the eyelids.

Frequency of Ptosis at presentation.

Frequency Percent

Bilateral 37 91.4

No droop 1 2.4

Unilateral 2 6.2

Total 40 100.0

26

The pto

( 1/40).

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ymmetrical

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39

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27

Diurnal variation in ptosis was present in 97.5%( 39/40) patients.

Diurnal variation in ptosis.

Frequency Percent

Y 39 97.5

N 1 2.5

Total 40 100.0

On examination 95%( 38/40) patients had ptosis.

Ptosis on examination

Frequency Percent

N 2 5

Y 38 95

Total 40 100.0

Ptosis was asymmetrical in 97.5%( 39/40) patients on examination.

Asymmetry of ptosis on examination

Frequency Percent

Asy 39 97.5

Not Asy 1 2.5

Total 40 100.0

On examination fatigability of the LPS was demonstrable in 100% of the patients.

2. Diplopia:-

Diplopia was present 97.5% of the cases (39/40), diplopia was for distant vision in

70% ( 28/40), near vision 27.5% ( 11/40). No diplopia was informed by only one

patient.

28

Diplopia

Frequency Percent

Far 28 70

Near 11 27.5

No 1 2.5

Total 41 100.0

Historically the diplopia was of crossed type in 67.5% ( 27/40).

Crossed/uncrossed diplopia

Frequency Percent

Not crossed 13 32.5

Crossed 27 67.5

Total 41 100.0

Diurnal variation in diplopia was noted in 75% of the cases.

Diurnal variation in diplopia

Frequency Percent

N 10 25

Y 30 75

Total 41 100.0

29

Squint was noted in the examination in 50% of the cases.

Squint on examination

Frequency Percent

N 20 50

Y 20 50

Total 40 100.0

3. Facial weakness :-

Eye closure( Orbicularis Oculi) weakness historically was present in 67.5%( 27/40)

patients at presentation.

Eye closure weakness

Frequency Percent

N 13 32.5

Y 27 67.5

Total 40 100.0

Fatigability of the eye closure weakness was present in 72.5 % (29/40) patients.

Fatigue of eye closure

Frequency Percent

N 11 27.5

Y 29 72.5

Total 40 100.0

Weakness of the facial muscles in form of snarling smile (57.5% 23/40), whistling

difficulty (62.5%, 25/40), and difficulty in feeding using a spoon (57.5%, 23/40),

was also noted.

30

On examination weakness of upper face muscles was noted in 72.5% of the cases

Upper facial weakness on examination

Frequency Percent

N 11 27.5

Y 29 72.5

Total 40 100.0

Lower facial weakness on examination

Frequency Percent

N 13 32.5

Y 27 67.5

Total 40 100.0

4. Chewing difficulty & Bulbar weakness:-

Historically difficulty in chewing food was noted in 60 %( 24/40) patients. Nasal

twang of voice was present in 45% (18/40) and dysphagia was noted in 40%

(16/40) patients. On examination palatal weakness was present in 10% (4/40)

patients.

5. Neck weakness &Limb weakness:-

Historically 32.5 %( 13/40) patients had head drop at some time in their course of

illness. On examination neck (extensor) weakness was noted in 67.5 %( 27/40)

Historically proximal upper limb weakness was present in 65%(26/40) patients.

Proximal lower limb weakness was present in 62.5%(25/40). Weakness of the

trunk was present in 5%(2/40) patients historically. On examination the minimum

power in the proximal group of muscles in the upper and lower limb was MRC

grade 4/5.

31

6. Dysponea &Myasthenic crisis:-

Historically 4/40(10%)of the cases reported to have dysponea in the course of

their illness, which was non cardiogenic.

Four of the 40 (10%) cases had developed myasthenic crisis in the course of their

illness.

The maximum number of crisis up to now in an individual patient was 5.

7. Fatigability test:-

On clinical test of fatigability, the results were as follows.

Bedside test for fatigability

Minimum Maximum Mean Std. Deviation

Ptosis time(sec) 25 200 66.70 37.883

Squats(no.) 0 15 9.13 4.910

SBC(no.) 12 42 28.10 7.578

39

39

39

27

23

24

24

27

26

25

4

1

1

1

13

17

16

16

13

14

15

36

0 5 10 15 20 25 30 35 40 45

oclular symfat ocluar

Diurnal …eye closure …

snarlchewing dif

dysphagiahead drop

UL weaknessLL weakness

Dysponea

yes no

32

MGFA staging:-

MGFA staging of the patients showed that maximum cases were in stage

2A(16/40) and minimum were of stage 4.

MGFA stage

Frequency Percent

1 11 27.5

2A 16 40

2B 7 17.5

3A 2 5

3B 3 7.5

4 1 2.5

11

16

7

2 31

27.5

40

17.5

57.5

2.5

0

5

10

15

20

25

30

35

40

45

1 2A 2B 3A 3B 4

number of cases percent

33

Thymus status and HPE of thymectomy cases:-

Thymoma was present in 44(8/15 ) of the study patients. 37.5%(15/40) patients

had undergone a thymectomy. Four patients had a thymic malignancy.

Histopathology of thymus

Frequency Percent

Hyperplasia 3 16

Malignant 4 22

Thymoma 8 44

HPE Not avilable 3 16

Immunomodulation of the patients:-

Glucocorticoids was being used by 52.5%(21/40) cases. Azathioprine was being

used by 15%( 6/40). Mycophenolate mofetil was being used by 5%(2/40) of the

study population.

Twenty percent (8/40) patient had developed hypertension. Ten percent (6/40) of

the patient had developed Diabetes mellitus secondary to chronic use of

glucocorticoids.

Anticholine esterase inhibitor therapy:-

The mean dose of Pyridostigamine in the study population was 180mg/day. The

mean dose of Neostigamine in the study population was 30mg/day.

Trigeminal Nerve conduction study:-

The Mandibular division of the left Trigeminal nerve was stimulated in all the

patients. The mean CMAP amplitude was 6.83mV and the mean latency was

1.10mseconds.

34

Mandibular nerve distal latency & CMAP


Man Lat(ms) 1 2 1.10 0.195

Man

CMAP(mV) 3 13 6.83 2.100

Repetitive nerve stimulation data:-

The percentage of RNS positivity from individual nerve muscle pair is as follows:

1. Facial nerve:- showed decremental response in 31/40(77.5%) cases

2. Mandibular nerve: - showed decremental response in 29/40(72.5%) cases.

3. Spinal accessory nerve: - showed decremental response in 27/40(67.5%)

cases.

4. Ulnar nerve: - showed decremental response 18/40(45%) cases.

5. Radial nerve: - showed decremental response in 25/40(62.5%) of the cases.

31 29 27

18

25

77.572.5

67.5

45

62.5

0

10

20

30

40

50

60

70

80

90

Facial Mandibular Spinal Acc Ulnar radial

decrement pat.numberspercentage

35

Decremental response from Facial nerve is as follows.

Facial Nerve RNS % decrement in CMAP


Pre ex 0 45 15.32 12.080

Post ex imm 0 56 19.63 14.958

Post ex

1 min 0 60 20.78 15.656

Post ex

2 min 0 55 18.88 14.152

Post ex

3 min 0 45 16.13 12.538

Post ex

5 min 0 45 15.33 12.425

3129

2725

911

13

22

15

0

5

10

15

20

25

30

35

Facial Mandibular Spinal Acc Ulnar Radial

Decremental response presentNo decremental response

36

Decremental response in Mandibular nerve is as follows:-

Mandibular nerve RNS % decrement in CMAP


Man Pre ex 0 78 21.22 20.173

Post ex

imm 0 87 27.00 23.849

Post ex

1 min 0 76 27.08 22.164

Post ex

2 min 0 70 23.85 19.744

Post ex

3 min 0 68 20.80 18.246

Post ex

5 min 0 65 18.92 17.095

Spinal Accessory nerve decremental response was as follows:-

Spinal Accessory nerve RNS % decrement in CMAP


Spi Acc pre ex 0 56 15.87 14.242

Post ex

imm 0 67 20.30 17.250

Post ex

1 min 0 65 19.40 17.319

Post ex

2 min 0 56 17.48 14.927

Post ex

3 min 0 54 16.17 14.345

Post ex

5 min 0 49 15.17 13.072

37

The decremental response from Ulnar nerve is as follows:-

Ulnar Nerve RNS % decrement in CMAP


Uln pre ex 0 34 8.60 9.336

Post ex imm 0 43 11.40 12.620

Post ex

1 min 0 48 12.52 13.829

Post ex

2 min 0 46 12.20 13.398

Post ex

3 min 0 50 10.60 12.057

Post ex

5 min 0 42 8.92 9.609

The decremental response from Radial nerve was:-

Radial nerve % decrement of CMAP


Rad pre ex 0 72 15.70 16.578

Post ex imm 0 70 19.97 19.153

Post ex

1 min 0 65 19.73 18.637

Post ex

2 min 0 67 18.23 18.055

Post ex

3 min 0 73 17.00 17.556

Post ex

5 min 0 58 15.48 15.941

38

The RNS results as per the MGFA groups:-

1. MGFA grade 1:-

There were 11 patients in this group.

The Facial nerve RNS , showed decremental response in 4/11( 36.4%)

patients. Mandibular nerve RNS showed similar (4/11 ) number of

decremental response.

There were 7/11 patients (63.6%) who had not shown a decremental response

in either Facial or Mandibular RNS .

One patient had shown a decremental response in the Spinal accessory nerve

RNS.

The values of the decremental response in the MGFA group1 patients were as

follows.

0

5

10

15

20

25

30

Pre ex post ex imm post ex 1min post ex 2min post ex 3 min post ex 5 min

facial nervemandibularSpinal accessoryUlnar radial

39

Decremental response in MGFA grade 1 patients


Facial Pre ex 0 12 5.82 3.573

Post ex imm 0 12 6.73 3.927

Post ex 1 min 0 11 6.45 3.984

Post ex 2 min 0 11 6.45 4.059

Post ex 3 min 0 11 4.91 3.727

Post ex 5 min 0 10 4.64 3.557

Mand. Pre ex 0 16 5.73 5.159

Post ex imm 0 20 7.64 6.667

Post ex 1 min 0 25 8.36 7.632

Post ex 2 min 0 20 6.91 5.991

Post ex 3 min 0 14 6.18 4.729

Post ex 5 min 0 15 5.91 4.742

The Facial N RNS showed mean decrement of 5.82%( range 0-12%) in pre

exercise stage. In the post exercise RNS, the mean decrement was

6.45%(range 0-11%).

In the Mandibular N RNS, the mean decrement in pre exercise stage was

5.73%( range 0-16%), in the post exercise stage the mean decrement was

8.36%( range 0-25%).

2. MGFA grade 2:-

There were 23 patients in this group. The Facial N RNS showed decremental

response in 91.3 %( 21/23) of the patients in this group. Mandibular N RNS

showed decremental response in 82.6 %( 19/23) of these patients. Spinal

Accessory N RNS showed decremental response in 87% (20/23) of these

40

patients . Ulnar N RNS showed decremental response in 52.2 %( 12/23) of

these patients. Radial N RNS showed decremental response in 82.6 %( 19/23)

of these patients.

The decremental response from the various nerves was as follows.

Percentage Decremental response of RNS in MGFA grade 2 patients


Fac Pre ex 0 45 16.57 11.228

Post ex imm 0 56 20.39 11.991

Post ex1 min 0 60 22.83 14.259

Post ex 2 min 0 55 20.26 12.693

Post ex 3 min 0 45 18.00 11.886

Post ex 5 min 0 45 17.00 11.778

Man Pre ex 0 68 21.48 16.981

Post ex imm 0 87 28.74 21.331

Post ex 1 min 0 76 30.13 20.846

Post ex 2 min 0 56 25.52 16.727

Post ex 3 min 0 59 22.17 16.331

Post ex 5 min 0 65 20.22 16.630

Spinal Acc pre ex 0 54 18.48 13.385

Post ex imm 0 67 23.09 14.519

Post ex 1 min 0 65 21.87 15.268

Post ex 2 min 0 56 20.39 14.093

Post ex 3 min 0 54 18.78 14.400

Post ex 5 min 0 49 18.09 13.287

Ulnar pre ex 0 34 9.74 8.729

Post ex imm 0 43 12.61 11.969

Post ex 1 min 0 45 13.87 12.639

Post ex 2 min 0 45 13.30 12.197

Post ex 3 min 0 43 11.52 10.453

41

Post ex 5 min 0 42 10.13 9.758

Radial pre ex 0 72 19.13 17.041

Post ex imm 0 70 24.22 18.427

Post ex 1 min 0 65 23.43 17.231

Post ex 2 min 0 67 21.39 17.503

Post ex 3 min 0 73 20.52 18.105

Post ex 5 min 0 58 18.96 16.255

The Facial N RNS showed a mean decrement of 16.57%(range 0-45%) in pre

exercise stage, in the post exercise stage the mean decrement was 22.83% (

range 0-60%). In the Mandibular N RNS, the mean decrement in the pre

exercise stage was 21.48%( range 0-68%), the mean decrement in the post

exercise stage was 30.13% ( range 0-87%). In the Spinal Accessory N RNS the

mean decrement in the pre exercise stage was 18.84% ( range 0-54%), in the

post exercise stage the mean decrement was 21.87%( range 0-67%). In the

Ulnar N RNS the mean decrement in the pre-exercise stage was 9.74%( range

0-34%), in the post exercise stage the mean decrement was 13.87%(range 0-

45%). In the Radial N the mean decrement before exercise was 19.13%(range

0-72%), post exercise the decrement was 24.22%(range 0-72%).

3. MGFA grade 3&4:-

In this grade of Myasthenic weakness all the tested nerves showed a

decremental response. The decrement response from the individual nerves was

as follows.

42

Percentage Decremental response in RNS in MGFA 3 &4 grade disease Minimum Maximum Mean Std. Deviation

Fac Pre ex 15 45 28.00 12.617

Post ex imm 21 56 40.33 14.081

Post ex1 min 25 53 39.17 10.439

Post ex 2 min 23 48 36.33 10.309

Post ex 3 min 20 42 29.50 8.313

Post ex 5 min 18 40 28.50 9.793

Mandibular Pre ex 21 78 48.67 20.491

Post ex imm 18 83 55.83 22.560

Post ex 1 min 17 70 49.67 19.429

Post ex 2 min 17 70 48.50 19.087

Post ex 3 min 20 68 42.33 18.533

Post ex 5 min 18 56 37.83 14.428

Spinal Accessory pre ex 15 56 27.67 15.095

Post ex imm 15 59 38.67 17.512

Post ex 1 min 20 60 38.17 15.664

Post ex 2 min 21 45 31.17 10.323

Post ex 3 min 18 40 28.33 8.165

Post ex 5 min 19 35 24.67 6.408

Ulnar pre ex 0 32 17.50 10.784

Post ex imm 7 43 24.67 13.186

Post ex 1 min 8 48 28.50 13.202

Post ex 2 min 12 46 28.50 11.726

Post ex 3 min 10 50 24.83 13.949

Post ex 5 min 10 25 18.83 5.707

Radial pre ex 16 36 30.17 7.627

Post ex imm 26 47 38.33 9.331

Post ex 1 min 28 48 39.83 8.635

Post ex 2 min 27 49 37.33 7.891

Post ex 3 min 24 40 32.83 5.879

Post ex 5 min 15 41 28.83 8.796

43

Comparison of the decremental response in the Mandibular N and

Radial N with Facial N, Spinal Accessory N and Ulnar N data:-

The results of the RNS from the Mandibular nerve were compared with the

Facial and the Spinal accessory nerve.

Mandibular Dec / Facial Decrement Cross- tabulation

Facial Decrement

1 Yes 2 No Total

Mandibular Dec

1 Yes

Count 28 1 29

% within Mandibular Dec 96.6% 3.4% 100.0%

% within Facial Decrement 90.3% 11.1% 72.5%

2 No

Count 3 8 11



Total

Count 31 9 40



Concordance 36/40 between Mandibular N and Facial N RNS.

Symmetric Measures

Value

Asymp. Std.

Errora Approx. Tb P Value.

Measure of

Agreement

Kappa .734 .124 4.685 .000

N of Valid Cases 40

44

Comparison of the Mandibular N decrement with Spinal Accessory N

decrement.

Mandibular Dec / Spinal Accessory Dec Cross-tabulation

SpinalAccessory Dec

1 Yes 2 No Total

Mandibular Dec

1 Yes

Count 25 4 29


% within SpinalAccessory

Dec 92.6% 30.8% 72.5%

2 No

Count 2 9 11



Dec 7.4% 69.2% 27.5%

Total

Count 27 13 40



Dec 100.0% 100.0% 100.0%

Concordance was 34/40 between Mandibular N and Spinal Accessory N.

Symmetric Measures

Value

Asymp. Std.


Measure of

Agreement

Kappa .644 .132 4.101 .000

N of Valid Cases 40

45

The comparison of the RNS results from Ulnar nerve with Radial nerve

showed:-

Radial Dec / Ulnar Dec Cross-tabulation

Ulnar Dec

1 Yes 2 No Total

Radial Dec

1

Yes

Count 18 7 25

% within Radial Dec 72.0% 28.0% 100.0%

% within Ulnar Dec 100.0% 31.8% 62.5%

2

No

Count 0 15 15

% within Radial Dec .0% 100.0% 100.0%

% within Ulnar Dec .0% 68.2% 37.5%

Tot

al

Count 18 22 40

% within Radial Dec 45.0% 55.0% 100.0%

% within Ulnar Dec 100.0% 100.0% 100.0%

Concordance was 33/40 between Radial N and Ulnar N .

Symmetric Measures

Value

Asymp. Std.


Measure of

Agreement

Kappa .659 .110 4.431 .000

N of Valid Cases 40

46

The Mandibular nerve RNS when compared to Facial nerve RNS showed a

sensitivity of 90.3% and a specificity of 88.9%. The concordance rate between the

two was 36/40, and showed a Kappa of 0.734.

RNS of Mandibular nerve when compared to Spinal Accessory nerve RNS showed

a sensitivity of 92.6% and a specificity of 69.2%. The concordance was 34/40, and

the kappa was 0.644.

The RNS from the Radial nerve when compared to Ulnar nerve showed a

sensitivity of 100% and a specificity of 68.2%, with a concordance rate of 33/40,

kappa was 0.659.

47

Discussion:-

The mean age of the patients in our study was 40+/- 14 years, not comparable

to the results from the study by Devon et.al (63.8yrs) or G.Pavesi et.al (59+/-

17years). In our study the population was younger. The duration of the illness

varied from 1-15 years, mean was 4 years. In Devon et.al study the mean

duration of illness was 12 months. In our study the disease was a more

established variant.

Mandibular nerve stimulation in the study by (G. Pavesia L et.al) had shown a

CMAP amplitude of 2 to 8.8mV, the mean amplitude was 4.5mV. The onset

latency in the G. Pavesia et.al study ranged from 1.5 to 2.2 ms. The study done

by Devon et.al showed a CMAP range from(1.7 – 8.2mV). In our study the

onset latency ranged from 1- 2 milliseconds, with mean value of 1.1ms. The

CMAP amplitude varied from 3-13mV, with a mean CMAP of 6.83mV.The

CMAP were low in patients with Cushingoid habitus due to chronic steroid

therapy.

The stimulation of the Mandibular nerve in both the studies was done by a

monopolar needle electrode. The needle stimulation is a relatively painless

procedure, only precaution needed is to check for any oral anti-coagulant use

by checking the PT&INR in relevant cases, and if INR>3 to avoid this

procedure.

In our study the recording and the reference electrode was placed in similar

position as in the Devon et.al study( G1 on the Masseter , 1/3rd the way from

angle of the mandible to the Zygoma, G2 was placed on the ipsilateral

Zygoma). This technique we found that the artifact due the stimulating

electrode being close to the recording electrode was less, and the CMAP was

of better amplitude than the technique prescribed by G. Pavesia et.al( where

the reference electrode was placed on the contralateral Zygoma).

48

In our study the Facial nerve RNS at rest had shown a mean decrement of

15% , which increased to 20.78% after 1 minute post exercise state. The

maximum decrement noted in our study was 60% after 1 minute post exercise

stage. In the Mandibular Nerve RNS the mean decrement at rest was 21.22%,

which increased to 27% after 1 min post exercise stage, the maximum

decrement noted was 87% in immediate post exercise stage. Our study when

compared to the data published by Devon et.al, showed a similar mean

decrement at rest (Facial at rest mean 14%, Trigeminal 17.3% in Devon et.al).

After exercise the data from Devon et.al study showed a mean decrement of

14.1%(3min)in Facial N and 16.5%(3min) in Mandibular N.

The Spinal Accessory nerve RNS in our study showed a mean decrement of

15.87% at rest and 20.30% after exercise. The Ulnar nerve RNS showed a

mean decrement of 8.6% at rest and 12.52% after exercise, similarly the Radial

nerve RNS in our study showed a resting decrement of 15.70% and 19.73%

after exercise. This was in consistent with the data from Devon et.al and

Adriana Petretska et.al. In the Radial N RNS from Adriana Petretska et.al

study showed a decrement of 35% at rest and 45% post exercise.

The Facial N and Mandibular N RNS showed not much difference in the

decremental response in the MGFA grade 1 patients, unlike the data by Devon

et.al. The degree of decrement was also not much different between the Facial

N RNS and Mandibular N RNS.

In MGFA grade 2 patients Facial N RNS had a greater pick up than

Mandibular N RNS. The amount of the decremental response was though

higher in the Mandibular N RNS. Radial N RNS showed more pick up than

the Ulnar N RNS in this group. The amount of decrement in the Radial N

RNS was higher than Ulnar N RNS.

In the MGFA grade 3&4 patients there was not much difference between the

traditional and the new nerves.

49

The study tried to compare the results from the well established nerve muscle

pairs in the EMG lab of SCTIMST with the 2 new nerve muscles

combinations. The sensitivity of the Mandibular N -Masseter nerve muscle

combination in comparison to Facial N-Nasalis nerve muscle combination was

that of 90.3%, and specificity was 88.9%. The same compared to Spinal

Accessory-Trapezius muscle combination showed a sensitivity of 92.6% and

specificity of 69.2%. The concordance rate/kappa between Mandibular N

RNS with Facial N RNS was 0.734. The Kappa between Mandibular N and

Spinal Accessory nerve was 0.644.

Radial Nerve- EIP muscle combination when compared to Ulnar Nerve-

ADM muscle combination showed a sensitivity of 100% and specificity of

68.2%. The kappa was 0.659.

When these nerve muscle pairs were compared in the subgroups of varying

MGFA stages the sensitivity and specificity remained the same.

50

CONCLUSIONS:-

1. Trigeminal RNS (Mandibular-Masseter) is as good as Facial nerve RNS in

sensitivity and specificity, with good concordance between the two.

2. Trigeminal RNS (Mandibular-Masseter) is as good as Spinal Accessory

Nerve RNS in sensitivity and specificity, with good concordance between

the two.

3. Radial N RNS (Radial N-EIP) is better than Ulnar nerve RNS .

4. In the milder stages of the disease Facial N RNS was having a higher pick

up rate than Trigeminal N RNS, but the amount of decrement response

was higher in Trigeminal N RNS.

5. In the higher grade disease there was no difference in the “traditional”

nerve-muscle pairs and the “new” nerve –muscle pairs.

LIMITATIONS OF THE STUDY:-

1. There was no normal population (control) study population for the

RNS in Trigeminal N.

2. The RNS in Mandibular N requires a needle stimulator, though the

procedure was not painful, and none of the patient had any adverse

effects.

51

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