ROLE OF ACETYL L-CARNITINE IN THE TREATMENT OF CARPAL TUNNEL SYNDROME

ROLE OF ACETYL L-CARNITINE IN THE TREATMENT OF CARPAL TUNNEL SYNDROME

Dissertation submitted to

THE TAMILNADU DR.MGR MEDICAL UNIVERSITY CHENNAI

In partial fulfilment of the regulations For the award of the degree of

M.D. PHARMACOLOGY Branch VI

Reg.No. 201716152

GOVT. KILPAUK MEDICAL COLLEGE AND HOSPITAL

CHENNAI-10

MAY 2020

CERTIFICATE

This is to certify that this dissertation titled “ROLE OF ACETYL L CARNITINE IN THE TREATMENT OF CARPAL TUNNEL SYNDROME” is the bonafide original work done by Dr.J.MAHALAKSHMI, Postgraduate in Pharmacology, under my overall supervision in the Department of Pharmacology, Govt. Kilpauk Medical College and Hospital, Chennai, in partial fulfilment of the regulations of the Tamilnadu Dr.M.G.R. Medical University for the award of M.D. Degree in Pharmacology (Branch VI).

Dr.C. RAMACHANDRA BHAT, M.D., Professor & HOD

Department of Pharmacology Govt. Kilpauk Medical College and Hospital, Chennai-10.

Dr. P. VASANTHAMANI

M.D, DGO, MNAMS, DCPSY, MBA DEAN,

Govt. Kilpauk Medical College & Hospital, Kilpauk, Chennai – 60 0010.

CERTIFICATE

This is to certify that this dissertation titled “ROLE OF ACETYL L CARNITINE IN THE TREATMENT OF CARPAL TUNNEL SYNDROME” is the bonafide original work done by Dr.J.MAHALAKSHMI, Post graduate in Pharmacology, under my overall supervision and guidance in the Department of Pharmacology, Govt. Kilpauk Medical College and Hospital, Chennai, in partial fulfilment of the regulations of the TamilnaduDr.M.G.R. Medical University for the award of M.D. Degree in Pharmacology (Branch VI).

Dr. T. ARUNA, M.D.

Professor & Guide

Department of Pharmacology

Govt. Kilpauk Medical College and Hospital Chennai – 600010.

DECLARATION

I solemnly declare that this dissertation titled “ROLE OF ACETYL L- CARNITINE IN THE TREATMENT OF CARPAL TUNNEL SYNDROME”, is the bonafide work done by me at the Department of Pharmacology, Govt. Kilpauk Medical College and Hospital, Chennai, under the supervision of Dr.C. RAMACHANDRA BHAT, M.D., Professor and Head of Department of Pharmacology, and guidance of Dr.T.ARUNA, M.D., Professor, Department of Pharmacology and Dr.K.MUGUNDHAN, M.D., D.M., Professor and Head of Department of Neurology, Kilpauk Medical College and Hospital, Chennai. This dissertation is submitted to The Tamilnadu Dr.M.G.R. Medical University, Chennai in partial fulfilment of the University regulations for the award of Degree of M.D.Pharmacology (Branch VI) examinations to be held in May 2020.

Place: Chennai

Date:

Dr.J.MAHALAKSHMI

ACKNOWLEDGEMENT

I would like to express my humble gratitude to Dr.P.VASANTHAMANI, M.D., D.G.O, MNAMS, DCPSY, MBA, Dean, Government Kilpauk Medical College and Hospital for giving me permission to carry out my dissertation work.

I would like to express my sincere gratitude toDr.C. RAMACHANDRA BHAT, M.D., Professor and HOD, Department of Pharmacology, Govt.

Kilpauk Medical College and Hospital, for introducing me to the world of medical research and riveting in me a strong foundation in ethics in medical research.

I am deeply grateful for the efficient support and guidance of Dr.ARUNA.T, M.D., Professor, Department of Pharmacology, Govt. Kilpauk Medical College and Hospital, for her continued guidance, commitment, and dedication during the entire course of this endeavour.

I am also grateful to Dr.K. MUGUNDAN, M.D., D.M., Professor and Head of Department of Neurology Kilpauk Medical College and Hospital, Chennai, for his enthusiasm and willingness to co guide this dissertation.

I extend my heartfelt gratitude to Dr. MALAR SIVARAMAN, M.D., Professor, Department of Pharmacology, Govt. Kilpauk Medical College and Hospital, who provided insightful inputs into the study and kept me focused throughout the study period.

I also thank Dr.G.CHENTHAMARAI. M.D., Associate Professor, Department of Pharmacology, Govt. Kilpauk Medical College and Hospital, for her motivation and valuable suggestions.

I also thank Dr.G.SASIKALA, M.D, Dr.G.RAJESH KUMAR, M.D, Dr.J.JEYASUDHA, M.D, and Dr.R.KEERTHANA BRATTIYA, M.D, Assistant Professors, Department of Pharmacology, Govt. Kilpauk Medical College and Hospital and Dr.N.MURUGANPANDIAN, M.D., D.M., Assistant Professor, Department of Neurology, Kilpauk Medical College &

Hospital, Chennai.

I specially thank my Senior post graduateDr. R.Gayathri and my junior post graduate Dr.M.Nilofer Noorie whose efforts are to be specially mentioned particularly their technical assistance rendered to shape this dissertation.. I also thank Dr.K.Roshan PrabuRaj and Dr.G.Soundara Pandian and my fellow post graduates Dr.V.Kavitha, Dr.P.Vijaya Bhanu for their immense suggestions and I extend my thanks to my 1^st year post graduates for their kind support.

This acknowledgement would be incomplete if I did not thank my family especially my husband for their blessings and good wishes. I also wish to thank the patients who voluntarily participated in the study.

J.Mahalakshmi

CONTENTS

Sl. No. Title Page No.

1 INTRODUCTION 1

2 REVIEW OF LITERATURE 8

3 AIM AND OBJECTIVES 44

4 MATERIALS AND METHODS 45

5 RESULTS 57

6 DISCUSSION 77

7 CONCLUSION 83

8 BIBLIOGRAPHY

9 ANNEXURES

i) Institute Ethics Committee Clearance Certificate

ii) Plagiarism Assessment Report iii) Case Report Form

iv) Patient Information Sheet v) Consent Form

vi) Master Chart

vii) List of Abbreviations

INTRODUCTION

Musculoskeletal disorders (MSDs) are one of the leading causes of chronic pain and sick leave around the world. ⁽¹⁾ The Musculoskeletal disorders related with work affect mainly upper limbs. The 9.4% of the musculoskeletal disorder are in the wrist and the hands. 1.5% of Musculoskeletal disorders of upper limb are reported to be due to Carpal Tunnel Syndrome (CTS). ⁽²⁾ The CTS is an expensive and frequent disease that affects adults in working age.

Carpal tunnel syndrome is the most common entrapment neuropathy affecting the median nerve. It was first described by Paget in 1854. ⁽³⁾ Entrapment or compression usually occurs between the following structures in the carpal tunnel - superiorly by flexor retinaculum (transverse carpal ligament), inferiorly by Flexor tendons (flexor digitorum superficialis, flexor digitorum profundus, flexor pollicis longus) and carpal bones (scaphoid and trapezium). ⁽⁴⁾

According to The American Academy of Orthopaedic Surgeons (AAOS) Guidelines on diagnosis of CTS defines it as a symptomatic compression of the Median nerve at the level of wrist joint. ⁽⁵⁾

Carpal tunnel syndrome is estimated to occur in 3.8% of general population of the world with estimated annual incidence rate is 0.5%-5.1% per thousand populations. Among these females are more affected than males with ratio of 7:3. Though all the age groups are affected more prevalence is seen between 4^th and 6^th decade. ⁽⁶⁾ In western population carpal tunnel syndrome consists of 60% of Upper limb musculoskeletal disorder (MSD). ⁽¹⁾ The

prevalence of CTS is 73% in fish processing industries. These data suggests that the burden of disease is mere increase in the sensitivity rather than increase in the prevalence. In Recent years the increase in life span and chronic diseases like diabetes have increased the prevalence of this disorder. ⁽⁷⁾ Prevalence among the diabetic patients without diabetic neuropathy is estimated to be around 14%. In pregnancy the prevalence is around 2%. ^(6,8) The prevalence of CTS among Indian populated has not been studied properly. Although a study conducted in south India by authors Murthy & Meena in occurrence of various peripheral nerve disorders, it has been stated that CTS constituted only 7% of peripheral neuropathy and 83% of entrapment neuropathy. ⁽⁹⁾

Although CTS is an idiopathic syndrome, many risk factors are associated with the disease. Major risk factors are environmental factors such as prolonged posturing of hand, like extreme flexion or extension of wrist, repetitive use of flexor muscles of the forearm / hand and prolong exposure to vibration. Other factors contributing to CTS are extrinsic factors like increase in the volume of carpal tunnel such as in pregnancy, obesity, menopause, renal failure, hypothyroidism, heart failure, contraceptive pills. Intrinsic factors like increase in the volume of the tunnel within the nerve like tumours and factors that alter the contour of the tunnel as in distal radius fracture. Neuropathic factors like alcoholism, both toxicity and deficiency of vitamins, exposure to toxins also leads to carpal tunnel syndrome. This factor directly affects the nerve without alteration in the carpal tunnel pressure. ⁽¹⁰⁾ Patients with diabetes mellitus have lower threshold for nerve damage which leads to increase in the incidence of carpal tunnel syndrome. Combination of Mechanical trauma,

increased pressure and ischemic injury are the proposed pathophysiology of CTS.

`Carpal Tunnel Syndrome (CTS) produces sensory motor disturbances of the median nerve, which impair the functional ability. There are various clinical presentations for this disease. Bilateral disease is common, in which the dominant hand is affected first. Hand pain is the most common symptom. It is anticipated that 1 in 5 patients with following symptoms such as pain, numbness and tingling sensation in the first three digits and lateral half of the fourth digit of the hand are suspected to have CTS based on clinical examination and electrophysiological testing. The symptoms are usually aggravated by movement of the wrist and more prominent at night. The pain persists throughout the day if the entrapment is worsened. When the disease is progressed, the patients usually presents with thenar muscle wasting and hand grip weakness. ⁽¹¹⁾ A clear history that elicits relevant personal and work exposures and the nature of symptoms can lead to a high probability of a correct diagnosis. Hand diagrams and diagnostic questionnaires are available to provide structure to this process. ⁽¹²⁾ A variety of provocative tests has been described and has variable accuracy. The Phalen’s wrist flexion and the carpal compression tests have the highest overall accuracy, while Tinel’s nerve percussion test is more specific to axonal damage that may occur as a result of moderate to severe CTS. ^(8,11) Sensory evaluation of light touch, vibration, or current perception thresholds can detect early sensory changes, whereas 2-point discrimination changes and thenar atrophy indicate loss of nerve fibres occurring with more severe disease.^.(8,11,13)

Many conditions that mimic carpal tunnel syndrome have to be ruled out before reaching the diagnosis of CTS. These are cervical radiculopathy (involvement of C6 & C7), brachial plexopathy (especially upper trunk), proximal median neuropathy when occurs at the level of pronator teres, thoracic outlet syndrome, central nervous system disorders like multiple sclerosis, small cerebral infarction. ⁽¹⁴⁾

The available diagnostic tests for CTS are Electro diagnostic tests, Ultrasonography and Magnetic resonance imaging. Electro diagnosis can encompass a variety of tests including Nerve conduction study and Electromyography, and is commonly used to assess the presence / severity of neuropathic changes and to preclude alternative diagnoses that overlap with CTS in presentation. ⁽¹⁵⁾ The pathophysiologic changes occurring with different stages of nerve compression must be considered when interpreting diagnostic test results and predicting response to physical therapy management. Though these tests aid in diagnosing the condition clinical diagnosis is considered to be gold standard. (8,11,15-16)

The American Academy of Orthopaedic Surgeons (AAOS) formulated guidelines to predict the probability of CTS. Appropriate Use Criteria (AUC) has been proposed by them which categorise the disease into low probability, moderate probability and high probability based on clinical and electrophysiological studies. ^(5,17)

Treatment of CTS includes Non-pharmacotherapy, Pharmacotherapy and Surgery. These treatment options depend upon the clinical severity and electrophysiological findings (degree of nerve involvement) and individual

patient’s preference. The non pharmaco-therapeutic measures include physiotherapy (tendon gliding exercise)⁽¹⁸⁾, hand splint⁽¹⁹⁾, laser therapy,^(20,21) ultrasound and yoga. Pharmacotherapy consists of steroid injection into carpal tunnel, oral steroids^(21,22) and Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). ⁽²³⁾ Steroids act by virtue of reducing the inflammation, edema thereby providing symptomatic relief. In spite of providing symptomatic improvement, it aggravates the CTS by reducing the synthesis of collagen and proteoglycan which leads to decreased mechanical strength of tendon. ^(22,23)

Previous studies have proved that diuretics and oral steroids have a beneficial effect in carpal tunnel syndrome by reducing interstitial fluid pressure. These pharmaco-therapeutic measures are generally recommended for mild and moderate CTS. The study done by O’Conner et al., has shown that the significant improvement obtained from pharmacotherapy is short lasting with reduced efficacy in the long term. ⁽²⁴⁾

Surgical correction is usually preferred for severe CTS, which consist of carpal tunnel release which is also done endoscopically. In this procedure, transverse carpal ligament is incised, leading to increase in carpal tunnel space and decrease in interstitial pressure. Studies have found that this procedure gives a long term benefit in 70 to 90% of patients. ⁽²⁵⁾

Though surgical repair is highly effective in the long term, most of the patients generally prefer pharmacological measures due to various reasons like surgical cost, fear and loss of pay and time spent for hospital stay. But the available drugs like Non-steroidal anti-inflammatory drugs ( NSAIDs), steroids produce unwanted adverse effects on long term use.

Acetyl L carnitine (ALCAR) has been found effective in various types of peripheral neuropathy, including CTS. ⁽²⁶⁾ Acetyl L carnitine consists of L- carnitine and acetyl group. The function of L-carnitine is to transport long chain fatty acids into the mitochondria and medium and small chain fatty acids out of the mitochondria. Acetyl group of ALCAR delivers acetyl group for the formation of acetyl choline. ⁽²⁷⁾

The analgesic effect of ALCAR is proposed by various mechanisms. It selectively stimulates the expression of Metabotropic glutamate (mGlu) receptors 2 & 3 in the spinal cord, without changing the expression of other receptors like mGlu1a, mGlu 5 receptors. This up regulation of mGlu 2 receptor negatively regulates glutamate release, contributing to reduced neuronal damage. It also induces expression of heat shock protein and redox- sensitive transcription factor. Analgesic effect of ALCAR occurs only by repeated administration of drugs, suggesting that ALCAR is involved in the regulation of neuroplasticity. ⁽²⁸⁾

Muscarinic and nicotinic antagonistic activity of ALCAR has been demonstrated in animal studies. Analgesic effect of this drug is also produced by the cholinergic pathway. ⁽²⁹⁾ ALCAR regulates sphingomyelin level in the cell membrane, thereby maintaining fluidity of cell membrane which has been demonstrated by human studies. It also prevents excessive neuronal damage by acting as a reservoir for cellular energy production in mitochondria. ⁽²⁷⁾ Studies have shown that it reduces oxidative damage and excitotoxicity in brain tissue and CSF, thereby producing beneficial effect in preventing cell death and ischemia induced neuronal damage. (28,29,30)

There are only few clinical trials of ALCAR that has proved to be efficacious in improving the hand function in carpal tunnel syndrome. Hence, this open label prospective interventional study was undertaken to investigate whether oral administration of ALCAR was effective in improving nerve conduction and hand function in CTS compared to the standard therapy.

REVIEW OF LITERATURE

Anatomy

The carpal tunnel is an osteofibrous canal situated in the volar wrist. The boundaries are the carpal bones and the flexor retinaculum. In addition to the medial nerve, the carpal tunnel contains nine tendons: the flexor pollicis longus, the four flexor digitorum superficialis and the four flexor digitorum profundus. The boundaries are the carpal bones forming the floor, and the flexor retinaculum (or transverse carpal ligament) forming the roof. The retinaculum is about 3–4 cm wide and flexor retinaculum attached to the scaphoid tubercle and the ridge of the trapezium on radial aspect and to the pisiform and the hook of the hamate on the ulnar side. On the radial side it divides into two layers, a superficial layer and a deep layer to accommodate the tendon of the flexor carpi radialis. ⁽⁴⁾

Fig : 1 - Anatomy of carpal tunnel.

Median nerve passes through the carpal tunnel beneath the flexor retinaculum, and divides to form two common palmar digital nerves, the first of which supplies the radial two lumbricals and a common branch between the index and middle fingers. The second runs between the ring and middle finger, and divides to give the proper digital nerves. The branch also provides sensation to the radial three and a half fingers on their palmar aspect as well as the nail beds of the index, middle and half the ring finger, via the proper digital nerves. The median nerve also gives off a recurrent branch to the muscles of the thenar eminence (flexor pollicis brevis, abductor pollicis brevis, and opponens pollicis). ^(4,8)

Fig : 2 - Branching patterns of the recurrent motor branch of the median Nerve

Risk factors and causes

The presumed risk factors for CTS include diabetes mellitus, menopause, hypothyroidism, obesity, arthritis and pregnancy. ^(10,31)There is strong suspicion that hormonal changes play a role in the cause of this disorder although no evidence support this hypothesis, recent studies provides in support of this risk factors for the disorder.

The relationship between hypothyroidism and CTS have been analysed in comprehensive meta-analysis showed a moderate association, but confounding factors like rheumatoid arthritis, obesity along with publication bias, account for increased risk. ⁽³¹⁾

Epidemiological data shows proof of incidence in pregnancy which is a risk of carpal tunnel syndrome probably due to oedema and hormonal alterations. The incidence is as high as 7%-43% when diagnosed electro physiologically and 31%-62% when diagnosed with history and clinical findings alone. ⁽⁸⁾ Striking symptoms with motor weakness seen in acute onset is seen widely, while symptoms often continue after delivery. ⁽³²⁾ First trimester onset of symptoms is related to impaired quality of life during pregnancy and postpartum, proper antenatal treatment can avoid postpartum difficulties in treatment, so strict monitoring is recommended.

There is strong evidence that supports association of both types of diabetes with this disorder. Overweight is also risk factor for CTS. ⁽³³⁾ Although no evidence for specific mechanism has been found. Association between computer use and CTS is still a controversy. Though it’s been considered as

minor risk factor due to mechanical stress caused by tendon overuse, recent findings from the meta analysis for associated of modest computer use and this disorder showed no association. ^(33,34)

Pathophysiology

Many pathophysiological mechanisms in CTS have been quoted in various literatures, like increased pressure in the tunnel, median nerve micro circulation injury, median nerve connective tissue compression and synovial tissue hypertrophy all in combination for the occurrence of the disorder.

Increased pressure

There are two sites anatomically for median nerve compression 1. At the proximal edge of the carpal tunnel 2. At the narrowest portion at the hook of hamate. In the first area it’s caused by the wrist flexion due to changes in thickness and rigidity between ante brachial fascia and proximal portion on flexor retinaculum. Normal pressure in the carpal tunnel may range from 2-10 mmHg tunnel pressure was higher in idiopathic CTS. ⁽³⁵⁾

Increased pressure is the basis for the pathological alterations in the surrounding nerve as well as ligaments due to changes in the flexibility and amount of connective tissue. It’s also attributed to the cause of ischemic compression of median nerve along with external compression which is supported by number of studies. ⁽³⁶⁾ When the transverse carpal ligament was released, normal pulsatile blood flow within the median nerve was restored which was observed through Doppler flowmetry. (13,37,38)

Median nerve microcirculation injury

The barriers around the median nerve in the carpal tunnel are formed by inner cells of perineurium and endoneurial capillary endothelial cells. The nutrient branches from radial and ulnar arteries proximal to the flexor retinaculum forms the endoneurial micro vessels. Breakdown of this vasculature caused by increased pressure leads to protein and inflammatory cells accumulation thereby, inducing closed compartment syndrome which causes increased permeability, which promotes increase in endoneurial fluid pressure and intra fascicular edema. ^(38,39)

Edema leads to increase in diffusion for capillary oxygen which might cause hypoxia which in turn leads to up-regulation of various angiogenic factors comprises Hypoxia Inducible Factor 1 (HIF-1 ) and Vascular Endothelial Growth Factors (VEGF) and it leads to axonal degeneration. ⁽³⁹⁾

Fig : 3 - A schematic presentation for vascular mechanism of CTS and median nerve injury is presented in CTS.

Increased carpal tunnel pressure Median nerve compression and entrapment Changes of micro vascular structure of the nerve Biochemical disturbances

Reduction in the endoneural blood flow Increased permeability of

endoneural vessels

Edema Increased diffusion distance

for oxygen

Hypoxia Up regulation of angiogenic factors

(HIF-1 and VEGF)

Axonal degeneration of median nerve and neuritis

Median nerve connective tissue alterations

Layers of the connective tissue surrounding the nerve fibres are mesoneurium, epineurium, perineurium and endoneurium. The epineurium integrity is critical for gliding properties which is critical for extensibility of these layers in nerve gliding, which accommodate joint motion to protect the nerve from stretching and injury.

The normal gliding of median nerve at wrist can move up to 9.6 mm between full flexion and extension of the joint in normal population whereas

when connective tissue is stiff which limits and exposes the nerve to shearing forces which could cause injury. ^{(39, 40)}

Human studies of entrapment neuropathies revealed the compression of median nerve during surgeries and autopsies, while the proximal and distal segment enlargement. The compression site develops nerve demyelination and spreads to throughout the internodal segment while axons are intact subsequently develops neuropraxia. Persistent compression interrupts the endoneural capillary blood flow, altered blood-nerve barrier and endoneural edema, which starts vicious cycle of venous congestion, ischemia and metabolic alterations. ⁽³⁹⁾ When this cycle continues for considerable amount of time axonal degeneration, macrophage attraction as well as activation, release of inflammatory cytokines, nitric oxide and chemical neuritis followed by axonal interruption and distal Wallerian degeneration.^(40,41) After surgical decompression, there is delay in sensory recover which depends on axonal regeneration.

Synovial tissue hypertrophy

Synovial tissue hypertrophy of flexor tendons may increase the carpal tunnel pressure which in turn develops CTS. ⁽⁴²⁾ In idiopathic CTS several biochemical and histological studies have evidence of tenosynovitis as a predominant risk. ⁽⁴⁰⁾ In Symptomatic CTS patients the synovial biopsy there is increased levels of prostaglandin E2 and VEGF, response to this in synovial connective tissue, there is increased fibroblast density, collagen fibre size, vascular proliferation and type 3-collagen. ⁽⁴³⁾

Clinical features

Symptoms depend upon the disease severity. Patients in the early stages usually have symptoms due to sensory component of the nerve and in latter stages the motor involvement produces symptoms. Patients commonly complain burning pain associated with tingling and numbness in the median nerve distribution to the wrist. Classically the thumb, index and middle fingers and radial half of the ring finger is involved.

Patients complain of pain, tingling and numbness of whole hand, but careful scrutiny will identify that little finger is not commonly involved as the innervations for the same is ulnar nerve. Sometimes, when ulnar nerve is affected at the same time all five fingers may be involved. Nocturnal paraesthesia has been reported in up to 51 - 91 % sensitive and 27 - 68 % specific. (11-14,43)

Weakness and feeling of clumsiness in affected hand are less commonly seen, which becomes worse by activity or work.

In some patients the presenting complaints may be pain radiating to forearm, elbow and even sometimes shoulder, but sensory changes will never have any evidence above the wrist. ⁽¹¹⁾ In clinical practice there is no limiting symptom for the diagnosis of the CTS. The observed pattern of sensory abnormality may be due to a peripheral or central nervous system mechanism that is the simultaneous involvement of ulnar or central sensitization, respectively.(12,15,43-45)

The American Academy of Neurology's (AAON) guidelines state that the likelihood of a diagnosis increases with the number of standard symptoms and provocative factors present. ⁽⁴⁶⁾

AAONs Standard and provocative symptoms of carpal tunnel syndrome

Dull, aching discomfort in the hand, forearm, or upper arm.

Paraesthesia in the hand.

Weakness or clumsiness of the hand.

Dry skin, swelling, or colour changes in the hand.

Occurrence of any of the above in the median distribution.

Provocation of symptoms by sleep.

Provocation of symptoms by sustained hand or arm positions.

Provocation of symptoms by repetitive actions of the hand or wrist.

Mitigation of symptoms by changing hand posture or shaking the wrist.

Clinical Signs

Various tests have been explained which helps the CTS diagnosis. There are no specific diagnostic tests. Most of the available tests are more complementary to each other than diagnostic to CTS. When in diagnosis of the disorder the combination of symptoms, signs and diagnostic tests are taken into account. The characteristic physical findings are of limited value.

Several tests for the diagnosis of CTS are Tinel’s sign, Phalen’s sign, square wrist sign, closed fist sign, flick sign, Katz hand diagram, flexion and extension of wrist test, pressure provocation test, and tourniquet test. The evaluation of the diagnostic use of the following tests are of limited value square wrist sign, flick sign, closed fist sign, and tourniquet test. Although, it’s safe to say that the prior usage of these tests needs further evidence to support their role in diagnosis of this disorder.

Tinel’s Sign

Tinel in the year 1915, (5,8,12,44)

noticed that tingling sensation arises when an injured nerve was percussed over its proximal stump and hypothesized that this was a sign of an axonal degeneration and his sign to be used in blunt traumatic injury patients to follow regenerative course. In this test, when the examiner taps lightly over the median nerve site at the distal wrist crease causes development of tingling or discomfort in the area supplied by the median nerve is taken as positive sign.

Fig : 4 - Tinel’s test in CTS.

As the outcome of the test can be influenced by several factors this is not a precise test. The testing technique is an essential factor for eliciting the sign and mild difference may account for the reported prevalence. The associated with sensitivities of 23% to 67%, and specificities of 55% to 100%.(5,15, 44,46)

Phalen’s Test

In 1957 Phalen and Kendrick described the test.⁽⁴⁵⁾ The patients symptoms are reproduced when the flexion of the wrist causes paraesthesia in the median nerve distribution when the compression of nerve between transverse carpal ligament and flexor tendons in the carpal tunnel. Phalen’s test is performed by holding the forearm vertically with elbow resting on the table and the both hands to drop with complete wrist flexion for approximately one minute. When the paraesthesia develops within one minute the test is considered positive. The reported sensitivity ranges between 10% and 91% and specificity between 33% and 100 %. (5,8,44,46)

Fig : 5 - Phalen’s test in CTS

Katz Hand Diagram

This diagram shows dorsal and palmar aspect of patient’s hands and arms. This diagram is used to mark the specific location of symptoms, characterized by pain, numbness, tingling or other. The grading is by classic, probable or unlikely to be CTS based criteria in the hand diagram. ⁽¹²⁾ The sensitivity of the test is 80% and the specificity is 90% for the diagnosis of CTS. ^(5,8,12)

Fig : 6 - Katz hand diagram.

Classic pattern Probable pattern Unlikely pattern

Square Wrist Sign

The report by Kuhlman et al., the wrist of square shape where the dimensions of anterior – posterior of wrist divided by medio lateral dimensions is greater than 0.70 ^(5,8,12) and abductor pollicis brevis weakness were considered as two most sensitive signs. This test is associated with a sensitivity of 47% to 69% and specificity of 73% to 83%. ⁽⁴⁴⁾

The Tethered Median Nerve Stress Test

In 1986 Le Ban described this test. He performed by hyper extending the supinated wrist and distal interphalangeal joint of the index finger for minute. The pain is felt over the volar aspect of proximal forearm for patients with chronic carpal tunnel syndrome. ^(5,8,44)

Pressure Provocation Test

When the examiner applies pressure with his/her thumb on the palmar aspect of the patient’s wrist at the level of carpal tunnel for one minute, the presence of pain, tingling and numbness in the median nerve distribution indicates a positive result. The reported sensitivity is between 28% and 63%

and specificity is between 33% and 74%. (12,15,44)

Tourniquet Test

When the blood pressure cuff is tied around the patients arm in the area distribution of median nerve and is inflated to above the systolic pressure for a minute or two. The development of paraesthesia is taken as a positive result.

This test is based on the idea that the irritated and compressed median nerve is more susceptible to ischemia. The tourniquet’s test sensitivity lies between 21% and 52% with a specificity between 36% and 87 %. ^(8,44,45)

Motor examination

The motor component involvement is usually seen by finger weakness along with an inability to punch or frequent grasped object droppings.

Functional loss is indicated by thenar atrophy which is a late sign. Chronic CTS produces thenar atrophy along with loss of abduction of thumb and strength of opposition. The thenar atrophy is preceded by diminished sensation to pinprick along the distribution of median nerve.

The atrophy of abductor pollicis brevis, oppones pollicis and flexor pollicis brevis was observed in 41% of hands in Phalen’s series. The most commonly affected muscle is abductor pollicis brevis and its function testing is very useful in the diagnosis of CTS.

The better method than clinical examination might be hand dynamometry, ^(5,46) but it’s uncommonly used in day to day clinical practice because of time limitations and specialist equipment need.

Differential diagnosis

On the general examination of the patients, the alert for the similar conditions like endocrine disease and connective tissue disorders or predispose to CTS and other hand disease such as Raynaud's phenomenon, vibration white finger, trigger finger, and Dupuytren's contracture, which can all coexist with CTS. ⁽¹⁴⁾

Conditions that may be confused with carpal tunnel syndrome

1. Cervical radiculopathy (especially C6/7) — look for local neck pain on movement and neurological signs outside the territory of the distal median nerve.

2. Ulnar neuropathy — this can also produce nocturnal paraesthesia; the distribution will usually be to the medial side of the hand.

3. Raynaud's phenomenon — this should be recognisable from a history of symptoms related to cold exposure.

4. Vibration white finger—suspect this if the patient uses vibrating hand tools at work. Osteoarthritis of the metacarpophalangeal joint of the thumb—this can produce a spurious appearance of thenar wasting but not true weakness or sensory deficit.

5. Tendonitis—specific tests may help in diagnosis, such as Finkelstein's test for De Quervain's tenosynovitis.

6. Generalised peripheral neuropathies—these should be recognised from the wider distribution of symptoms and reflex changes.

7. Motor neuron disease—this can present with wasting in one hand but does not produce sensory symptoms.

8. Syringomyelia—features such as prominent loss of temperature sensation in the hands should give a clue.

9. Multiple sclerosis—this should be recognised from the presence of neurological abnormalities disseminated in location and time.

DIAGNOSIS

Two papers by the Quality Standards Subcommittee of the American Academy of Neurology and American Association of Electro diagnostic Medicine (AAEM), American Academy of Neurology and American Academy of Physical Medicine and Rehabilitation define the guidelines for clinical and neurophysiologic diagnosis of CTS. ^(47,48)

The gold standard for diagnosis of CTS is clinical assessment but the careful history in absence of motor and sensory deficit is important. ⁽⁴⁹⁾ There is difficulty in interpretation of symptoms for physicians so the Katz diagrams which is a self-administered test help to reduce the sources of errors and bias.⁽¹²⁾The provocative tests are unreliable and not sufficient since they have low positive predictive value such tests as Phalen's and tinel’s test, so these tests are not used alone for diagnosis of CTS. ⁽⁴⁴⁾ Validated patient-centred measures (eg, the Boston Carpal Tunnel Syndrome Questionnaire [BCTQ]) are able to quantify symptoms and disability. ^(5,50) Level of disability is correlated with both clinical findings and nerve conduction findings. ^(5,50)

Therefore, nerve conduction study is considered as the gold standard in diagnosis of CTS, ⁽¹⁴⁾ even though it’s not widely accepted and recognized due to false positives and negatives are known to exist. ⁽⁴⁷⁾

This gives rise to problems in evaluating whether any individual test is accurate in diagnosing CTS, because there isn’t an accepted “gold standard”

against which other tests can be compared. The combination of clinical symptoms and signs with electro-diagnostic findings is the most valid way of diagnosing CTS. ^(15,50)

The role of BCTQ (Boston Carpal Tunnel Questionnaire)

BCTQ is the most commonly used outcome measure in the assessment of patients with CTS. The questionnaire comprises two scales, a symptom severity scale and a functional status scale. The symptom severity scale has 11 questions scored from 1 point (mildest) to 5 points (most severe). The similarly functional status scale has eight questions scored from 1 point (no difficulty with activity) to 5 points (cannot perform the activity at all). ^(5,50)

The role of DN4 (Douleur Neuropathique 4 Questionnaire)

It is a clinician-administered questionnaire consisting of 10 items. Seven items related to pain quality (i.e. sensory and pain descriptors) are based on an interview with the patient and 3 items based on the clinical examination. It evaluates neuropathic pain following central and peripheral neurological lesions. It is also used for diagnostic purposes, allowing the clinician to determine if the pain is of neuropathic origin. ⁽⁵¹⁾

The role of Nerve Conduction Studies (NCS) ⁽⁵²⁾ The aim of the test

1. To detect the focal damage to the median nerve in the carpal tunnel.

2. The severity of the neurophysiological changes quantification by the scale.

3. To define pathophysiology of the nerve such as conduction block, demyelination or degeneration of axon.

Both sensory and motor nerve conduction velocity in the median nerve at the wrist level is affected in the nerve conduction studies. There is delay in the velocity of the sensory component in the early stages of the disease than the motor conduction velocity of the nerve conduction study. This sensory nerve conduction delay is measured by placing an electrode near the base of the ring finger after that median nerve is stimulated approximately 13 cm proximal to the recording electrode. Surface electrodes are used to measure the motor nerve conduction velocity in the area elbow to wrist. ⁽⁴⁷⁾

The sensitivity varies between 49% - 84% and specificity from 95%- 99% (15,16,50,51)

for the median nerve conduction studies. There is delay in the conduction velocity at the compression point due to demyelination of the nerve in the entrapment neuropathies. The diagnostic value is increased by 10% when the sensory and motor conduction velocity is measured for the patients with clinical symptoms without changes in the sensory conduction velocity. ^(53,54) Another 10% is increased when the latency of the conduction velocities are

measured between the median and ulnar nerve for the ring finger and when compared to median and radial nerve latency for thumb for the patients with normal sensory and motor conduction velocities.

The nerve conduction velocity also helps in the diagnosis of the other conditions presenting with similar symptoms such as cervical radiculopathy, polyneuropathy, other median nerve entrapment syndromes. ^(2,14,17) Even though the NCS has certain limitations it’s still considered as the gold standard test for the confirmation of diagnosis. Some asymptomatic individuals can test positive for NCS, similarly small percentage may test negative despite the symptoms for CTS. In the survey of 2466 patients by Atroshi et al., in Sweden revealed the CTS incidence in general population. ⁽⁵³⁾ 14.4% had complaints of pain, tingling and numbness in the median nerve distribution. 4.9% had symptoms positive for neuropathic symptoms of CTS. However 18%

asymptomatic subjects had abnormal NCS. ^(53,54)

Nerve Conduction Analysis ^(53-55)

The electrophysiological classification ⁽¹⁵⁾, in agreement with the AAEM guidelines, follows the neurophysiological progression of CTS severity and includes the following classes:

Negative CTS: Normal findings on all tests (including comparative and segmental studies).

Minimal CTS: Abnormal findings only on comparative or segmental tests.

Mild CTS : Sensory nerve conduction velocity (SCV) slowed in the finger-wrist tract with normal Distal motor latency (DML).

Moderate CTS: SCV slowed in the finger-wrist tract with increased DML.

Severe CTS : Absence of sensory response in the finger-wrist tract with increased DML.

Extreme CTS: Absence of thenar motor response

Nerve Ultrasonography (USG)

The diagnostic findings for CTS are thickening of the median nerve, nerve flattening within the tunnel and flexor retinaculum bowing in the ultra sound. ⁽⁵⁴⁾ There is still debate regarding the measurement that should be taken within the tunnel and abnormal values are yet to be constituted. ⁽⁵⁵⁾ The cross sectional area for the median nerve has been classified the severity of CTS as normal, mild, moderate and severe in USG. ⁽⁵⁶⁾

The diagnostic utility of USG and Electro diagnostic study (EDS) has been compared in recent prospective study revealed that both techniques had equal sensitivity. The sensitivity increased to 76.5% when EDS and USG has been used concomitantly. But a significant flaw is 23.5% of patients with clinically diagnosed CTS remain undetected. The underlying cause of CTS can be detected by which facilitated treatment planning. ^(55-57)

Magnetic resonance imaging (MRI)

The rare pathological cause like ganglion, haemangioma or any bony deformity for CTS is best detected by MRI. The sensitivity is 96%, for the sagittal images in showing the site accurately and nerve compression severity determination, although specificity is extremely low at 33% - 38%. ⁽⁵⁸⁾ For the diagnosis of CTS, the signs in the T2 weighted images are median nerve swelling and increased signal intensity which indicated axonal transportation, myelin sheath degeneration or oedema. ^(58,59)

MRI predicts the good surgical outcomes that are the length of the abnormal nerve signal on T2 weighted MRI and median ulnar sensory latency difference. MRI benefits patients who need surgical intervention. MRI provides anatomical information more than information on nerve impairment and function the reason because the results of the MRI do not correlate with the patient’s symptoms severity.

It’s usually used for detecting the failure of carpal tunnel release at the point of nerve entrapment also for other diagnosis with ambiguous symptom and for conformation of space occupying lesion. ⁽⁵⁹⁾

Electromyography (EMG)

EMG is commonly employed to exclude other conditions such as polyneuropathy, plexopathy, and radiculopathy, and to assess severity. Hence, it’s not necessary for patients whose diagnosis of CTS is clear cut with classical signs and symptoms suggestive of CTS along with confirmatory

findings on NCS when there is no suspicion for other aetiology. It is also useful to assess the severity of CTS if surgery is being considered. ⁽⁶⁰⁾ The pathological changes in the muscles innervated by median nerve especially in assessing the abductor pollicis brevis muscle while the electrophysiological examination in the portion of EMG. It also reveals either active denervation or chronic changes that indicate denervation with subsequent reinnervation.

These findings are supportive of the diagnosis of CTS in the context of normal findings in both non median-innervated muscles and proximal median nerve-innervated muscles.

One suggested protocol for EMG evaluation of CTS involves needle examination of the following muscles: ⁽⁶⁰⁾

Abductor pollicis brevis

Two or more C6-C7 innervated muscles (eg - pronator teres, triceps brachii, extensor digitorum communis) to look for evidence of cervical radiculopathy. Additional muscles are investigated if the abductor pollicis brevis is abnormal. ⁽⁶⁰⁾

Two or more proximal median-innervated muscles (egs, flexor carpi radialis, pronator teres, flexor pollicis longus) to rule out a proximal median neuropathy.

Two or more lower trunk C8-T1 non median-innervated muscles (eg - first dorsal interosseous, extensor indicis proprius) to rule out brachial plexopathy, polyneuropathy and C8 to T1 radiculopathy.

TREATMENT:

The treatments for CTS are classified under 2 methods

1. Conservative treatment, 2. Surgical treatment.

Mild to moderate symptoms of CTS are generally offered conservative treatment which include oral and intravenous steroids, corticosteroids, vitamin B6, non-steroidal anti-inflammatory drug (NSAID), ultrasound, yoga, carpal bone mineralisation and the use of hand splints. ^(16,17) In a study by O’Connor et al., in his study reported that there are only short term benefits with this conservative approach of treatment but their efficacy in long term remains questionable. ⁽²⁴⁾ Other treatment options are magnet therapy, exercise (tendon gliding exercise) or chiropractic treatment failed to show any remarkable improvement when compared to the placebo in a case control study. ^(18-22)

Laser therapy

The low power laser therapy or low level laser therapy exposes the tissues to minimal levels of red and near infrared light (the laser is called low level laser because the light energy density is lower that used in other form of surgical procedures). This is one of the non-surgical options for carpal tunnel syndrome treatment. There are numerous methods of laser at present so this form of treatment covers many approaches.

When compared to placebo in a randomised control study laser therapy was effective in short term especially in patients with mild to moderate symptoms of CTS. ^(20,21)

Higher efficacy is seen in gallium arsenide laser with wrist splint in another study when compared to placebo. Hand grip strength improvement is seen with laser therapy and wrist splint up to 3 months post treatment. ⁽⁶¹⁾ Their results of all the studies are not of same results, another study showed laser therapy did not show any improvement compared to placebo where only sensory nerve conduction was improved. ⁽⁶²⁾

Several studies compared laser therapy with other non-surgical treatments. Such as in a randomised controlled trial (RCT) comparing laser therapy with fascial manipulation which provided transient, short term pain relief, whereas latter showed pain improvement and function over a long period of time. ⁽⁶³⁾ In another study high intensity laser therapy was combined with transcutaneous electrical stimulation (TENS) which acts only on large diameter type-A sensory fibres, laser therapy was effective than TENS , in terms of pain, paraesthesia, median nerve sensory conduction velocity and distal motor latency. ⁽⁶⁴⁾

Pharmacotherapy Steroids

One of the commonly used treatments for carpal tunnel syndrome is local corticosteroid injections. The role of the steroids is to reduce oedema. The major adverse effect seen with use of steroids is that it limits collagen reduction and proteoglycan synthesis, which limits tenocytes and hereby reducing mechanical tendon strength leading to further degeneration. ^{(21- 23)}

A recent systematic review by Marshall et al., reports that steroid injections when given to symptomatic CTS patients had significant improvement clinically but post treatment they showed relapse within one month. ⁽⁶⁴⁾ When the corticosteroids was compared to other drugs there was great reductions in nerve dimensions than non-steroidal anti-inflammatory drugs and splint use alone in some patients with carpal tunnel syndrome.

Procaine hydrochloride and triamcinolone acetonide injection was effective than placebo. ⁽⁶⁵⁾ A study compared 17- -hydroxyprogesterone caproate and corticosteroid treatment showed both were efficacious. But patients on 17- - hydroxyprogesterone caproate was symptom free for 3 months. ⁽⁶⁶⁾ Steroid injection was also compared with extracorporeal shock wave therapy which uses acoustic wave causing transient pressure which increases in tissues producing no damage. But no outcome difference was noted. ⁽⁶⁷⁾

Non-Steroidal Anti-Inflammatories (NSAIDs):

Although NSAIDs are used widely there is only limited evidence for effectiveness in CTS. In few RCT studies which study the effectiveness of tenoxicam in 22 patients compared to placebo, oral prednisolone and diuretic trichlormethiazide in mild to moderate CTS revealed no difference in symptom severity between placebo and NSAIDs at 4 weeks. ⁽²²⁾ Another RCT compared the effect of splinting with combination of splint and adjuvant therapies including ketoprofen, phonophoresis had less pain at 8 weeks; there was no significant difference between the 3 study groups. On conclusion NSAIDs has limited role in the symptomatic management of CTS, but has only role in treating tendonitis. ^{(68, 61)}

Palmitoylethanolamide

A nuclear factor agonist improved the median nerve motor latency, reduced the proportion of patients with tinel’s sign positive and reduction in symptoms of discomfort compared with placebo. But further studies are needed to substantiate these results. ⁽⁶⁹⁾

Gabapentin

The no difference in effectiveness of gabapentin has been seen in pain reduction, numbness paraesthesia, weakness or clumsiness or nocturnal awakening in randomised controlled trial when the findings was compared to placebo. ⁽⁷⁰⁾

Diuretics

The usage of diuretics with rationale of reducing oedema in patients presenting with compression have been studied. Two RCT was done to study the effective and role of diuretics, change et al study revealed that there was no difference in symptom severity at 4weeks between placebo and diuretics.⁽⁷¹⁾ Another RCT compared bendo flumethiazide to placebo in 48 patients. The study of 6 month showed no effective role in reducing symptoms between bendro fluthiazide groups vs. placebo with relative risk being 0.98. So role of diuretics is limited in treatment of CTS.

Pyridoxine

Vitamin B6 acts as a co factor in various protein synthesis in heme synthesis, biosynthesis of lipids and glycogenolysis. The trials which compared the effect of pyridoxine in treatment of CTS failed to show any improvement symptomatically. (20,21,73)

Musculoskeletal manipulation and splinting

Another widely used treatment modality for CTS is musculoskeletal manipulation. This includes massage, exercise and mobilisation of wrist joint.

Use of splints is also another non-surgical approach. This method reduces the mechanical stress between median nerve and carpal tunnel along with surrounding tissues. This reduces oedema which explains the possible mechanism of splinting and gliding exercises. There is improvement of hand function and disease severity with formal education of the patient with use of splint for 8 weeks with no intervention. ⁽¹⁷⁾ Meta-analysis of the studies shows there is no sufficient evidence to prove the efficacy of the splint in comparison with other treatment or nocturnal splints. ⁽⁷³⁾ Lumbrical stretches and splints when used in combination are shown to be more effective than splints. ^(73,74)

Tendon gliding exercises

Tendon gliding exercises (moving hand flexor tendons through five different finger positions: straight, hook, fist, table top, and straight fist), splint and paraffin therapy when used in combination might be considered better when compared to conventional treatment in combination or alone when

Madenci massage technique is used along with splints has shown a positive result than splint use alone. ⁽¹⁸⁾ There is negligible evidence about the effectiveness of exercise and mobilisation.

Fig : 7 - Tendon gliding exercises.

Complementary therapies

Several non-surgical therapies have been assessed in carpal tunnel syndrome patients. In a randomised clinical trial, Linseed oil might provide improvement in symptom severity, functional score and median nerve conduction velocity. ⁽⁷⁵⁾

When the placebo was compared with acupuncture in a study there was no difference however when used in combination with prednisolone shown to improve electrophysiological measures and symptom severity.

The extract from the plant laminaceae family, an ointment of eremostachys laciniata is a Persian treatment medicine as an anti-inflammatory and analgesic was compared with placebo ointment and splints were given for both groups. ⁽⁷⁶⁾ The pain perception and palmar apprehension was improved but the use should be confirmed with further studies and to understand long term effects of this treatment.

A low frequency electrical stimulation of nerves that is the interferential current therapy showed results of improvement in function, symptom severity and electrophysiological measures compared with TENS and splint use. ⁽⁷⁷⁾ A type of thermotherapy which is local microwave thermotherapy used in various musculoskeletal diseases was more successful than sham therapy in producing short term improvements in pain and function in carpal tunnel patients.

Surgical treatment

There are many surgical options for the treatment of carpal tunnel syndrome patients which consists of release of carpal tunnel content by transecting the transverse carpal ligament (TCL) is considered as the most effective treatment which alters the relationship between median nerve tendons and the carpal tunnel.

The approaches to this surgical decompression can be done by traditional open method, minimally invasive approach or by endoscopic technique. (25,78,79)

The long term outcome is a major success with surgery. But the functional outcome difference between the open and endoscopic approach remains the same. However there are few advantages for the endoscopic

approach such as shorter post-operative recovery, minimal scar tenderness and earlier return to patient are day to day routines. ^(78,79)

Open carpal tunnel release procedure

From the distal wrist crease to the Kaplan’s cardinal line a longitudinal incision is made in the skin. Till the TCL is identified sharp dissected and it’s divided to expose median nerve. Proximally division is continued for release of ante brachial fascia. At the palmar fat pad the TCL division is completed distally. ⁽⁸⁰⁾

Fig : 8 - Schematic presentation of open carpal tunnel release

Different open carpal tunnel release techniques are available (like limited open release with direct vision and tunnelling technique or standard open carpal tunnel release) ⁽⁸⁰⁾ all with similar effectiveness. When compared to the standard technique, Z type lengthening of the transverse carpal ligament

provided significant function and satisfaction score.⁽⁸¹⁾ Better outcomes are seen with minimally invasive techniques proved by meta-analysis which compared open technique with minimally invasive approach provided an early return to work, fever complications, higher satisfactory rate by patients shorter recovery time along with improvement in various functional score and electro diagnostic assessment. ^(25,82)

Endoscopic Carpal Tunnel Release

This procedure was first described by Chow et al., with two port technique. This was augmented by Agee et al., with one port for the access, which was built in hope that this will drastically decrease incision related complication. ⁽⁷⁹⁾

Complications due to carpal tunnel release surgery are reported to occur in 1-25% of the patients. Complex regional pain syndrome is one potential and severe complication of this procedure. Other notable complications are scar tenderness, transient neuropraxia; pillar pain and resurgery may be required in few patients. In patients requiring resurgery use of vascularised flap coverage have higher success rate than simple decompression. ⁽⁸⁰⁾

Conventional Treatment of Choice

The ideal treatment for this syndrome has yet to be proven by research.

Surgery definitely have superior outcome than non-surgical method but the significant adverse events has been noted in the same. Few points are to be considered before treating the patients. (25,83,84)

1. Lesser adverse effects are seen with non-operative treatments so, it should be tried as first line treatment in initial stages of the disease. ⁽⁸⁴⁾ 2. Conservative treatments are helpful in patients who eventually require

surgery, although it has lesser side effects the median nerve compression is not relieved by the non-surgical techniques, there is always a risk of on-going median nerve damage.

3. Surgery is the primary treatment for severe disease and also for patients who failed a trial of non-conservative treatments. Both open and endoscopic carpal tunnel release are adequate to release CTL.

Novel adjunct therapies for nerve regeneration

Multiple therapeutic options to improve nerve generation.one of the pathway is ERK1/2 pathway which shows promising increase in the neural regeneration. Few agents are geldanamysin and tacrolimus, both increase outgrowth of neurite with significant side effects. Being an immunosuppressive agent geldanamycin causes hepatotoxicity, while tacrolimus being used in transplant patients is a potent immunosuppressant. Acetyl L-Carnitine (ALCAR) also works by up regulating the ERK1/2 pathway to increase nerve regeneration. When compared to the previous available agents ALCAR has much lesser side effects with major side effects being nausea in 1% of patients.⁽⁸⁵⁾

Fig : 9 - Molecular mechanisms of peripheral nerve regeneration and pharmacologic targets.

Acetyl-L-carnitine

Acetyl-L-carnitine is a delivery form for L-carnitine and acetyl groups.

The functions of L-carnitine includes transport of long-chain fatty acids across the mitochondrial membranes into the mitochondria and transport of small- chain and medium-chain fatty acids out of the mitochondria in order to, among other things, maintain normal coenzyme A levels in these organelles. The acetyl component provides for the formation of the neurotransmitter acetylcholine. ^{(27, 86)}

Pharmacokinetics

L-carnitine and acetyl-L-carnitine are administered orally, intravenous, intramuscular. They are absorbed in the jejunum by simple diffusion; transport into cellular tissue is via an active transport mechanism, with studies showing plasma concentration of ALCAR and L-carnitine reaching equilibrium via

carnitine acetyl-transferase activity. Acetyl-L-carnitine is better absorbed from the small intestine than L-carnitine and more efficiently crosses the blood-brain barrier (i.e., gets into brain tissue). Half-life of ALCAR is 4.2hours. ALCAR undergo minimal metabolism and are subsequently excreted in the urine via renal tubular reabsorption.The rate of clearance increases with the plasma concentration of these substances. ⁽⁸⁷⁾

Therapeutic Doses:

Adult: IV: 50 to 300 mg/kg depending on indication. Oral: 1 to 3 g or 100 mg/kg depending on indication.

Toxicity: Intravenous doses as high as 300 mg/kg have been administered with no apparent toxicity. ^{(86, 87)}

Mechanism of action:

1. Anti-nociceptive activity of ALCAR: It might result from different mechanisms.

a. ALC selectively induces the expression of mGlu2 receptor by enhancing the activity of the nuclear factor (NF)-kB family of transcription factors.

b. mGlu2 receptors localized in the spinal cord and other regions of the nociceptive system negatively regulate glutamate release thereby reducing the neuronal exitotoxicity. ^(28,88)

c. However, other animal studies showing that the ALCAR effect on pain is modulated by nicotinic and muscarinic antagonists

indicate that the ant nociceptive activity of this drug might be mediated through the cholinergic pathway. ^(27,89)

d. Human studies show ALCAR has the ability to stabilize cell membrane fluidity via regulation of sphingomyelin levels. It also provides a surface reservoir for cellular energy production in mitochondria, thereby preventing excessive neuronal cell death.⁽²⁶⁾ It has been suggested that acetyl-L-carnitine helps to maintain neuronal metabolic activity by promoting glucose and lactate uptake and utilization through its role as a precursor of glutamate in neurons.

ALC also reduces oxidative stress and inhibits excitotoxicity in brain tissue and CSF, thereby preventing cell death and ischemia induced neuronal damage. Acetyl-L-carnitine has also been shown to increase hippocampal binding of glucocorticoids and of nerve growth factor. (28-30,89)

2. ALCAR prevents degeneration and causes regeneration in transected peripheral nerves. Taglialaltela et.al., showed that neuronal preservation can be attributed to increases in NGF receptors. ⁽⁹⁰⁾ Barhwal et.al. later demonstrated that this increase in NGF receptors led to increased ERK1/2 phosphorylation that in turn resulted in up regulation of CREB and neuroprotective factors. ⁽⁹¹⁾ These mechanism of ALCAR found to be beneficial in diabetic neuropathy, HIV antiretroviral toxic neuropathy (ARN) and chemotherapy induced peripheral neuropathy (CIPN).⁽²⁶⁾

Other uses ⁽⁸⁷⁾

Hepatic encephalopathy

Male infertility (Asthenospermia) Multiple sclerosis-related fatigue Peyronie's disease

Sciatica

Chronic cerebral ischemia alcoholism Alzheimer's disease.

Amyotrophic lateral sclerosis (ALS, Lou gehrig's disease) Fibromyalgia.

Contraindication ⁽⁸⁷⁾

Psychiatric disturbances, Cirrhosis, High blood pressure, Hepatitis C, peripheral vascular disease, respiratory diseases, Sleep disorders, Renal failure.

Giorgio Cruccu et al in his study, used Acetyl L-Carnitine 500mg twice daily orally for four months in 82 patients with mild to moderate Carpal tunnel syndrome and he showed significant improvement in sensory neurophysiological scores and Boston carpal tunnel questionnaire scores. ⁽⁹²⁾ Only very studies are available in evaluating role of ALCAR in carpal tunnel syndrome. So in this study we used 500 mg thrice daily dose of Acetyl L carnitine in patients with mild to moderate carpal tunnel syndrome to see the efficacy and tolerability.

AIM AND OBJECTIVES

Aim

To study the efficacy of Acetyl L-Carnitine in the management of patients with carpal tunnel syndrome.

Objectives

1) To assess the efficacy of Acetyl L-Carnitine on neuroprotection, neuropathic symptoms, and hand function in patients with carpal tunnel syndrome (CTS) in comparison with standard treatment.

2) To assess the recurrence of symptoms with Acetyl L-Carnitine in comparison with standard treatment.

MATERIALS AND METHODS

This was a prospective, open label; randomized, interventional study was conducted at the out-patient Department (OPD) of Neurology, Kilpauk Medical College, Chennai, from May 2018 to April 2019.

Approval from the Institutional Ethics Committee was obtained prior to the commencement of the study. The study was conducted according to the guidelines laid down by ICMR on the conduct of biomedical research.

Sample size

The sample size for this study was calculated with the help of Open Epi, version 3 software. The power of the study set at 80%, two side confidence interval 95%. The expected improvement in sensory nerve conduction velocity in the ALCAR treatment group was assumed to be 30% higher than the standard treatment group. The resultant sample size was calculated to be 74 with 37 patients in each group. Considering dropouts from study, we have fixed 40 patients in each group as sample size.

Screening

The study procedure required screening for patients with carpal tunnel syndrome, from those who attended outpatient department of the hospital.

Carpal tunnel syndrome was diagnosed based on mainly clinical examination and was supported by nerve conduction study. Patients with symptoms of CTS

were subjected to clinical examination and nerve conduction study. Then they were subjected to routine blood examination including serum TSH levels.

Inclusion criteria:

1. Patients newly diagnosed as CTS.

2. Patients of both sex, aged 18-65 years

Exclusion criteria

1. Patients with severe CTS requiring surgery.

2. Patients with other peripheral nerve diseases.

3. Orthopedic condition affecting wrist joint other than CTS.

4. Uncontrolled diabetes mellitus.

5. Hypothyroidism.

6. Patients with renal failure.

7. Patients with seizure disorder.

Recruitment

Patients fulfilling the inclusion criteria and exclusion criteria were selected for the study and they were given a brief description about the study.

Written informed consent was obtained from those patients who were willing to participate in the study.

Randomization

Computer based randomization table was used to randomize the patients. Patients diagnosed with CTS and those willing to participate in the study were randomized equally with the help of random numbers table into 2 groups.

Control Group ALCAR Group

n = 40 n = 40

Patients received standard treatment for 12 weeks

In addition to standard treatment, received Acetyl L carnitine for 12

weeks.

Group 1 - Standard treatment for CTS consists of physiotherapy [tendon gliding exercise], splinting. Group 2 – Received treatment consists of T.Acetyl L carnitine 500 mg three times a day along with standard treatment which includes physiotherapy [tendon gliding exercise], splinting for 3 months.

In both groups patients treated with NSAIDs / Steroids whenever needed as per neurologist advice.

Assessment of participants

A detailed history was obtained from every patient included for the study. General examination, vital signs and systemic examination were performed on these patients. The findings were noted in the case report form (CRF).

Procedure

80 patients diagnosed with CTS were included in the study. Following screening and brief explanation about the study and getting informed consent they were randomised into two groups.

These patients had 2 check-ups.

1^st check-up: Patients were asked to review with investigation results (blood and nerve conduction study)

2^nd check-up: After conformation of the diagnosis, randomisation was done. The symptom severity and functional severity was documented by using Boston carpal tunnel questionnaire, ⁽⁹³⁾ Doubler neuropathic pain questionnaire.⁽⁹⁴⁾ Then respective treatment was initiated in both groups.

Participants in both the groups were followed up thrice.

At the end of 4^th, 12^th and 20^th week of initiation of treatment - Patients in both groups were assessed for improvement of symptoms by using Boston carpal tunnel questionnaire, Doulear neuropathic pain questionnaire. They were also enquired for side effects and general examination was done at each visit.

End of 12^th week - blood investigations and nerve conduction study were also repeated and the following parameters were compared.

1. The distal latency, amplitude and conduction velocity of sensory nerve action potential (SNAP).

2. The distal latency, amplitude and conduction velocity of compound muscle action potential (CMAP).