Clinical manifestations

Presentation and course

The clinical manifestations of carpal tunnel syndrome consist of intermittent pain, numbness, and tingling in the fingers dependent on the hand and wrist position and commonly associated with subjective grip weakness. The symptoms occur initially at night only and may wake the patient from sleep. In a more severe carpal tunnel syndrome, the symptoms also occur during the day. They are often provoked by hyperextension or hyperflexion of the wrist during activities, such as driving, or during work-related repeated hand movements. The pain can radiate up into the forearm or even up to the shoulder. There frequently is subjective hand swelling and stiffness. The patient will often shake their hand and fingers to obtain relief from the discomfort (flick sign). Usually, the dominant hand is more involved than the nondominant hand. Although positive sensory symptoms such as pain and tingling predominate, occasionally, the only symptom is loss of dexterity. Atrophy of the thenar eminence muscles is the hallmark of the severe stage of carpal tunnel syndrome. The incidence of carpal tunnel syndrome is highest in middle-aged women. There is also an association with pregnancy, predominately during the third trimester.

On clinical examination, there can be a discrete sensory disturbance in the first three fingers, typically sparing the palm, and weakness or atrophy of the thenar muscles with a positive Tinel's sign over the carpal tunnel. Phalen's test, in which the patient hyperflexes the wrist for 1 minute, may provoke the symptoms (55). Alternatively, hyperextension of the wrist for 1 minute may have the same effect. Phalen's test is somewhat more specific for carpal tunnel syndrome than the Tinel's sign, but both can be present in normal individuals (23). It is often more the clinical history than the physical examination that is highly suggestive of carpal tunnel syndrome.

Prognosis and complications

Comprehensive data on the natural history of carpal tunnel syndrome is surprisingly lacking. In a review of literature from 1988 to 2007, the outcomes of surgical treatment did not improve (08). With only lifestyle and occupational modifications, about 20% of patients significantly or completely improve, 40% remain unchanged or have mild improvement, and 40% worsen over time. Complete or dramatic improvement occurs in 75% of patients who undergo surgical decompression and 70% of those who receive corticosteroid injection, but only about half of patients who had a corticosteroid injection had persisting benefits after 7 years of follow-up (41; 08). In a study of 100 patients with carpal tunnel syndrome who were treated with surgery versus corticosteroid injection and followed with electrodiagnostic testing, surgery was more effective in patients with moderate carpal tunnel syndrome, and clinical recovery was more pronounced than the electrophysiologic recovery (13). The complications of untreated carpal tunnel syndrome include persistent weakness and sensory loss in the distal median nerve distribution.

Clinical vignette

A 41-year-old female artist presented with a 2-year history of numbness in both hands, the right greater than the left. The numbness was most severe in the right thumb and was specifically brought on by painting and sculpting. Numbness, pain, and tingling in both hands woke her up at night. Shaking her hands provided some relief. There were no complaints of shoulder, neck, or upper arm pain and no history of diabetes mellitus, hypothyroidism, or rheumatoid arthritis.

On neurologic examination, abnormal findings were limited to minimal weakness of the right abductor pollicis brevis muscle and reduced pinprick perception in the right median nerve distribution, maximally on the thumb and the tip of the second and third finger, with sparing of the thenar eminence. Phalen's test was positive. There was no Tinel's sign.

Electrodiagnostic testing showed evidence of a mild median nerve entrapment at the wrist on the right. Treatment with a resting wrist splint failed to adequately relieve the symptoms. Surgical carpal tunnel release was followed by marked improvement.

Biological basis

Etiology and pathogenesis

The pathogenesis of carpal tunnel syndrome is attributed to nerve dysfunction secondary to chronic mechanical compression of the median nerve at the carpal tunnel. The floor and walls of the carpal tunnel are formed by the carpal bones. The roof is formed by the flexor retinaculum, a ligamentous structure that attaches the hamate and pisiform on the medial side and the scaphoid and trapezium on the lateral side. The carpal tunnel serves as a passageway for nine flexor tendons with their sheaths along with the median nerve. Just before entering the carpal tunnel, the median nerve gives off the palmar cutaneous branch that carries sensory fibers from the thenar eminence. After the median nerve exits from the carpal tunnel, it gives off the thenar motor branch innervating abductor pollicis brevis, opponens pollicis, and first and second lumbricals, and in most of the hands, flexor pollicis brevis (48). The other branches are sensory digital branches that supply the thumb, index, middle finger, and the lateral half of the ring finger.

An elegant previous study demonstrated that when a pneumatic cuff was applied to the upper arm, patients with carpal tunnel syndrome had a greater and quicker drop in the motor nerve action potential than the normal controls, suggestive of increased sensitivity of entrapped nerves to ischemia (22). Therefore, positional paresthesias are postulated to reflect spontaneous activity in the damaged nerve induced by ischemia. Muscle weakness and clinical sensory loss correlate with the severity of abnormalities in nerve conduction studies, whereas pain and paresthesias may not correlate with electrodiagnostic data.

Carpal tunnel syndrome is a compression neuropathy that can occur in conditions that increase compartmental pressure, resulting in microvascular changes and, consequently, intraneural ischemia and demyelination (42). With prolonged compression, the endoneural vessels can be compromised, disrupting the blood-nerve barrier and resulting in endoneural edema. The longer the duration of compression and nerve ischemia causes axonal degeneration and, therefore, less reversal of neuropathic changes and recovery (42). The most detailed histological data are from studies in guinea pigs who spontaneously develop entrapment neuropathy in the feet when housed in wire cages (49). Histological abnormalities of compressive neuropathies consist of paranodal myelin retraction with bulbous paranodal swellings, segmental demyelination, and variable degrees of axonal degeneration as well as remyelination and axonal regeneration. There is also a focal increase in endoneurial and perineurial connective tissue, thickening of the blood vessels, and a presence of enroneurial fusiform structures (Renaut bodies) (42; 74).

Pressure measurements in the carpal tunnel with a wick catheter support the concept of increased pressure as a cause of carpal tunnel syndrome (24). Increased pressures of 30 mm Hg, which is just below the threshold for sensory symptoms, have been demonstrated in patients with carpal tunnel syndrome at rest. Wrist flexion and extension produce further increases and eventual neurologic dysfunction as they increase synovial pressure by 3- to 10-fold (24; 50).

Reduced space in the carpal tunnel may result from synovial tissue hypertrophy, such as in tenosynovitis and rheumatoid arthritis, ganglion cysts, osteophytes, osteosis, anomalous muscles, or tumors. Fluid retention is implicated in pregnancy, during lactation, or with the use of estrogens. Other conditions with increased susceptibility to carpal tunnel syndrome are diabetes, hypothyroidism, hereditary neuropathy with pressure palsies, acromegaly, and focal amyloid deposition. The latter can be secondary to a familial or wild-type transthyretin amyloidosis, amyloid light chain deposits, or chronic dialysis.

Work-related carpal tunnel syndrome occurs with repetitive hand and wrist movement and is seen with various activities and occupations. Increased pressure within the carpal tunnel due to certain positions of the hand and wrist and edema of the flexor tendons are thought to contribute to occupational carpal tunnel syndrome. Excessive computer use, particularly mouse usage, might be a minor risk factor for carpal tunnel syndrome compared to other occupational groups (64). In fact, a retrospective study looking at 100 patients with carpal tunnel syndrome showed a predominance of elements unrelated to working at a computer. Carpal tunnel syndrome was also seen in people working physically and even among unemployed people (31).

Although carpal tunnel syndrome usually occurs sporadically, genetic factors may play a role. Population and family-based studies have shown 17% to 39% of familial incidence, especially with bilateral carpal tunnel syndrome, suggesting a moderate genetic susceptibility (57). Genes involving the synthesis and breakdown of collagen and proteins involved in the oxidative stress pathways have been associated with the development of carpal tunnel syndrome (81). There is reportedly an autosomal dominant form of carpal tunnel syndrome (45). Rare, inherited connective tissue diseases, such as mucopolysaccharidosis, can cause severe carpal tunnel syndrome, and an increasing amount of literature looks at carpal tunnel syndrome and hereditary cardiac amyloidosis due to recent treatment availability for hereditary transthyretin amyloidosis.

Acute carpal tunnel syndrome is mostly seen in the setting of traumatic injury to the hand or wrist and occasionally the forearm. It can be caused by the common Colles' fracture of the distal radius. Furthermore, bleeding into the carpal canal due to coagulation disorders seen with leukemia, hemophilia, or anticoagulant therapy can provoke acute carpal tunnel syndrome. Urgent surgical release is indicated for acute severe carpal tunnel syndrome.

Subacute carpal tunnel syndrome, with symptoms usually presenting within 1 week, may occur after rear- or front-end automobile collisions, presumably through hyperextension of the wrist against the steering wheel (16). Manifestations of carpal tunnel syndrome can also be seen in a much more delayed fashion after traumatic injury and have been described after various fractures, lacerations, and burns.

Epidemiology

In a population study in Rochester, Minnesota (1961 to 1980), the incidence was estimated at 99 per 100,000 person-years (66). The incidence of carpal tunnel syndrome was 0.12 per 1000 person-years with a peak at ages 55 to 64 and a female-to-male ratio of 2:8. In another study, in Sweden, 2.7% of a population of 170,000 had clinically and electrophysiologically confirmed carpal tunnel syndrome (01). In a Washington state workers study (1984-1988), the incidence was 1.7 per 1000 person-years with a peak at ages 25 to 34 and a female-to-male ratio of 1:2 (21). Although the methodology in these studies is not identical, the findings support a correlation between manual work and carpal tunnel syndrome.

Pourmemari and colleagues reported that the lifetime prevalence and incidence of carpal tunnel syndrome are higher in women (56). The prevalence range in women was 1.8% to 26% and 0.7% to 1.2% in men. The incidence in women was 0.5 to 4.8 per 1000 person-years and 0.1 to 1.9 in men. In the same study, the risk factors explaining the highest rates in women were not well understood, but obesity and osteoarthritis were found to significantly increase the risk of carpal tunnel syndrome in women.

A study looking at a job exposure matrix of 3452 active workers from a public data source of several industries showed that workers with high-force and high-repetition jobs had the highest prevalence of carpal tunnel syndrome (odds ratio=2.14-2.95) (15).

Prevention

Because of the lack of controlled studies, recommendations for preventing carpal tunnel syndrome in the working population should be considered with caution. Ergonomic intervention may help prevent carpal tunnel syndrome by focusing on tool design, improvement of workstations, the avoidance of repetitive pinching, wringing, and grasping motions, and other measures. A systematic review suggests better results when applying multiple prevention measurements together rather than using single-focus approaches (68). Diagnosis of carpal tunnel syndrome should be confirmed by an EMG and nerve conduction study, particulary in patients with atypical features, as carpal tunnel decompression has been done unsuccessfully in patients with radiculopathy, motor neuron disease, and central nervous system disease, such as multiple sclerosis (77).

Differential diagnosis

Carpal tunnel syndrome should be differentiated from other neurologic disorders that can cause pain, numbness, tingling, and weakness in the hand, such as cervical radiculopathy, polyneuropathy, other entrapments of the median nerve, ulnar neuropathy, and brachial plexopathy. Non-neurologic causes of wrist and hand pain include de Quervain tenosynovitis of the abductor pollicis longus and extensor pollicis brevis tendons, trigger finger, nonspecific tenosynovitis, osteoarthritis of the basal joints of the thumb, and Raynaud disease. A thorough clinical examination in combination with electrodiagnostic testing usually leads to the correct diagnosis. Occasionally, radiological investigation is necessary, especially when cervical radiculopathy is suspected.

Confusing conditions

The combination of carpal tunnel syndrome with a more proximal cervical nerve root compression has led to the concept of the "double crush syndrome" (69). However, there is no convincing scientific evidence for additional vulnerability to carpal tunnel syndrome based on proximal axon damage from a cervical radiculopathy (76).

Associated or underlying disorders

In addition to associated disorders discussed in previous sections, carpal tunnel syndrome has also been described in some rare disorders. It is common in patients with hereditary neuropathy with liability to pressure palsy, an autosomal dominant disease resulting from the deletion of the PMP22 gene in chromosome 17 (02). Mucopolysaccharidoses and other lysosomal storage disorders are the most common causes of carpal tunnel syndrome in children, which is unfortunately often underdiagnosed given the age or cognitive status of these patients. Acromegaly is an insidious condition characterized by somatic overgrowth caused by increased secretion of growth hormone and insulin-like factor 1. Carpal tunnel has a prevalence of 19% to 64% in acromegaly and often precedes the other manifestations (51).

Carpal tunnel syndrome is a common feature and probably a harbinger of other manifestations of systemic amyloidosis. In a prospective study of 233 patients who underwent carpal tunnel syndrome release, the prevalence of cardiac amyloidosis was 1.2% (two with wild-type transthyretin and one with amyloid light chain amyloidosis) (80). The prevalence raised to 5.5% among patients with bilateral carpal tunnel syndrome and left ventricular hypertrophy, and to 13.6% when patients with an occupational risk factor were excluded. Another study of 56,032 patients who underwent carpal tunnel release, using the Danish nationwide registry, showed a significant association between future diagnosis of amyloidosis (hazard ratio 12.12) and heart failure (hazard ratio 1.5) compared to matched controls from the general population (18). On the other hand, a nerve conduction study in a cohort of 79 patients with wild-type transthyretin-related amyloidosis showed electrodiagnostic evidence for carpal tunnel syndrome in 94% of the patients (62). Only 50% of the patients in that study had a preexisting diagnosis of carpal tunnel syndrome, in whom the condition was bilateral in 76%.

Accumulating data suggest that carpal tunnel syndrome might also be predictive for the future occurrence of other manifestations of transthyretin-related amyloidosis. For example, a retrospective study on a cohort of patients with wild-type and mutant transthyretin-related amyloidosis revealed a history of carpal tunnel syndrome in about 60% of the patients and 10% of asymptomatic gene carriers (03). The mean latencies between the occurrence of carpal tunnel syndrome and other manifestations of amyloidosis were 10 and 5 years in wild-type and mutant cases, respectively

Diagnostic workup

No single parameter can accurately diagnose carpal tunnel syndrome; therefore, clinicians are encouraged to use a multiple-approach strategy. History and physical examination remain crucial screening tools with the caveat of variable sensitivity and specificity of their different components. The Boston Carpal Tunnel Questionnaire is a multiple-step, patient-oriented tool with great reliability and validity for assessomg symptoms and functional status (09). Reproduction of symptoms after provocative tests (Phalen’s maneuver or Tinel’s signs) has shown 93% sensitivity and 89% specificity. The monofilament test on lateral digits has 98% sensitivity, whereas specificity was high in pinch strength (78% to 95%) and the presence of thenar atrophy (96% to 100%). The carpal tunnel syndrome 6 (CTS-6) diagnostic tool, which is calculated based on symptoms of numbness in the median distribution, nocturnal exacerbation, thenar weakness and atrophy, positive Phalen and Tinel signs, and presence of abnormal 2-point discrimination, is proposed to be a sensitive clinical measure to diagnose carpal tunnel syndrome with comparable sensitivity to electrodiagnostic and imaging testing (20; 19; 78).

Provider opinions vary about whether to use electrodiagnostic testing to diagnose carpal tunnel syndrome (07; 78). Nerve conduction study and needle electromyography are employed for the diagnosis of carpal tunnel syndrome because they provide objective data as well as an assessment for an alternative diagnosis (such as other concomitant neuropathies and alternative diagnosis), assessment of severity, prognostication for surgical outcome, and an objective baseline for later comparison. Measurement of conduction velocity and axonal integrity of the median nerve across the carpal tunnel complements the clinical evaluation and can provide a better level of certainty for management decisions (51).

Electrodiagnostic testing usually includes motor and sensory nerve conduction studies of both median nerves and at least one ulnar nerve. Needle examination of the abductor pollicis brevis muscles is routinely performed to look for denervation. Needle examination of several other upper extremity muscles and the cervical paraspinal muscles is often necessary to evaluate for other entrapment neuropathies, plexopathy, or radiculopathy.

Motor conduction studies of the median nerve, particularly distal latencies, have low sensitivity and high specificity (65% and 95%, respectively), whereas reduced conduction velocity of the sensory response is the most sensitive in confirming the diagnosis (17). The distal motor latency alone has a sensitivity of 75% and a specificity of 93% (17). Special adaptations may be necessary to demonstrate mild carpal tunnel syndrome (75; 28); these include:

The presence of conduction block at the level of the carpal tunnel must be suspected when the motor and sensory amplitudes are low for the degree of slowing of the conduction velocity (26; 63). The presence of conduction block predicts a favorable response to treatment, which is in contrast to decreased amplitude of the motor and sensory responses due to axonopathy (63). In more severe carpal tunnel syndrome, acute or chronic denervation on needle examination of the abductor pollicis brevis suggests axon loss of median motor nerve axons.

Comparison of the median-second lumbrical distal latency and ulnar interossei or third lumbrical distal latency shows high sensitivity and specificity for the diagnosis of carpal tunnel syndrome, even in the most severe patients whose distal motor response recorded on abductor pollicis brevis is absent (36; 37).

Imaging studies have gained more attention in the last decades, and increasing data demonstrate their importance in evaluating carpal tunnel syndrome. They can complement clinical and electrophysiological assessments with valuable anatomic and structural information about the median nerve and its surrounding structures in the carpal tunnel area. MRI of the wrist can document abnormalities in the median nerve that are compatible with carpal tunnel syndrome (10; 29). MRI may be helpful if tumors or other structural abnormalities are suspected or after surgery has failed. A routine wrist x-ray is not useful (05). MRI tractography evaluates for reduced fiber density, axonal diameter, and degree of myelination, but its use is limited outside the clinical setting (40).

Ultrasound is another useful tool for the assessment of carpal tunnel syndrome. One study suggested that ultrasound and clinical diagnostic tools, such as carpal tunnel syndrome 6 (CTS 6), are highly accurate in the diagnosis of carpal tunnel syndrome and that nerve conduction studies are not necessary in most cases (19). Various measurements, including the wrist-to-forearm median nerve area ratio (WFR) and the cross-sectional area of the median nerve at the wrist (CSA-W), have been shown to have a high correlation with the severity grade of carpal tunnel syndrome. WFR has been shown to be superior to CSA-W for diagnosis and grading of severity of carpal tunnel syndrome (30). The pisiform CSA measurements are more reliable for diagnosing early stages of carpal tunnel syndrome. CSA (pisiform)/CSA (ulnar) have lower diagnostic value for diagnosing carpal tunnel syndrome (79). An evidence-based guideline was also published for the use of ultrasound in the diagnosis of carpal tunnel syndrome. Ultrasound measurement of the median nerve cross-sectional area has been found to be accurate and may be offered as a diagnostic test for carpal tunnel syndrome. The guideline also showed that ultrasound probably adds value to electrodiagnostic studies when diagnosing carpal tunnel syndrome and should be considered in screening for structural abnormalities at the wrist in those with carpal tunnel syndrome (12). In addition to diagnosis, ultrasonography may be valuable in staging carpal tunnel syndrome, especially by combining multiple measures. In a study of 104 participants, an 8-point scoring scale, including patient-reported symptoms, functional deficits, provocative testing, nerve cross-sectional area, and nerve longitudinal appearance, classified severity accurately for 79.8% of participants (60). A meta-analysis evaluating the accuracy of ultrasound in diagnosing carpal tunnel syndrome showed increased OR with a cross-sectional area of 9 mm² to 12.6 mm² carpal tunnel inlet (70).

Novel Doppler ultrasound techniques, such as superb microvascular imaging, have shown superior power in assessing intraneural vascularity with improved correlation with electrophysiologic when compared to high-resolution ultrasound. Ultrasound elastography is another novel method that evaluates the stiffness of the median nerve as a biomarker of median nerve pathology, although studies demonstrated excessive variability (25).

Management

Carpal tunnel syndrome, especially in a mild stage, is usually first treated conservatively with the use of a resting wrist splint and advice to reduce provoking activities. Orthotic intervention is supported by many studies demonstrating clinical and electrophysiological effectiveness.

Steroid injections into the carpal tunnel reduce inflammation and swelling of the median nerve and surrounding tissues.

If conservative treatment is not effective, surgical carpal tunnel release is performed to release the pressure on the median nerve by transecting the transverse carpal ligament. There are three approaches: the open approach, open limited incision, and the endoscopic technique. It is not clear which is the optimal surgical approach, but the guidelines of the American Academy of Orthopedic Surgeons consider the use of endoscopic carpal tunnel release based on faster motor function recovery and lower rates of wound complications (27). Other novel procedures have been described for treatment, including sonographically guided percutaneous needle release of the carpal tunnel (44) and ultra-minimally invasive ultrasound-guided carpal tunnel release (59). Collagen nerve wrapping has been shown to inhibit nerve tissue adhesions and diminish inflammatory and immunologic reactions in nerve surgery (33). Failure of carpal tunnel surgery is reported in about 5% to 10% of surgeries. Incomplete sectioning of the transverse carpal ligament, scar formation, and hand symptoms due to other causes are some of the reasons for failure. The complications include persistent weakness and sensory loss in the distal median nerve distribution.

Nonsteroidal anti-inflammatory drugs and diuretics are generally ineffective for carpal tunnel syndrome (08). Medications used for neuropathic pain may be effective in the symptomatic management of mild to moderate cases; for example, pregabalin was effective in decreasing symptoms and increasing functionality in one study (06).

Outcomes

Wrist splinting significantly improves symptoms of carpal tunnel syndrome in about 30% of the patients (08).

Methylprednisolone injection might provide immediate relief (70% significant or total improvement, 30% slight to no change in the symptoms), but this is often not sustained beyond 6 months (08). Possible side effects of carpal tunnel corticosteroid injections are overall rare (less than 0.01%) and include cutaneous atrophy, tendon rupture, and severe median neuropathy due to intraneural injection (08). Steroid injections are generally effective in severe pregnancy-related carpal tunnel syndrome (63). The effectiveness of ultrasound-guided carpal tunnel injection using an in-plane ulnar approach is proposed to be more effective in symptom severity reduction, improving functional status, and improving electrophysiologic parameters and has fewer adverse effects than out-plane or blind injection (04; 73).

Extracorporeal shock wave and ultrasound therapy is a noninvasive approach that has been associated with decreased pain and functionality as well neurophysiological parameters (53; 71). The complications are mild erythema and pain.

A meta-analysis of randomized trials on the effectiveness of low-level laser therapy on carpal tunnel syndrome revealed that low-level laser improved hand drop, visual analog scale, and sensory nerve action potential after 3 months of follow-up in mild to moderate carpal tunnel syndrome (39).

There is a significant improvement in clinical and subjective outcomes after carpal tunnel syndrome surgery, independent of sociodemographic and clinical characteristics (14); patients can usually return to work in 2 to 3 weeks. Surgical treatment relieves symptoms significantly better than splinting (08; 72). In a review of literature published before 2007, 75% of patients improved completely or dramatically, and 8% deteriorated postoperatively, but there was a wide variation in outcome success across the centers (08). The success rate is proposed to be lower in patients with no abnormality than in those with abnormal nerve conduction study (07). The success rate is slightly lower in workers' compensation patients who return to work after a longer period. Elderly (older than 70 years) patients have more severe clinical and electrophysiological findings preoperatively but do show high satisfaction scores after surgery (47; 67). Patients with severe carpal tunnel syndrome, for example, those with visible flattening of the thenar eminence or absent or markedly abnormal motor response recorded on abductor pollicis brevis, should be informed that recovery may be more prolonged after surgery, and numbness may continue (34). A meta-analysis comparing the ECTR (endoscopic carpal tunnel release) versus OCTR (open carpal tunnel release) determined that ECTR had better satisfaction rates, improved pinch strength, and 1-week earlier return-to-work rates (38).

Lack of improvement postoperatively is mainly attributed to failure to completely transect the transcarpal ligament due to inadequate exposure or other technical reasons (08). Postoperative complications include lacerations of median or ulnar nerves or their branches (especially palmar cutaneous and recurrent median motor branches), vascular injuries, and postoperative infections. The most dreadful complication is complex regional pain syndrome, a condition characterized by severe pain, hyperalgesia, dysesthesia, and trophic disturbances (08). The long-term disability from postoperative complications is around 1% to 2%.

Special considerations

Pregnancy

Pregnancy is associated with an increased incidence of carpal tunnel syndrome, presumably due to fluid retention. Treatment is usually with conservative measures because spontaneous recovery occurs after delivery in about 50% of patients (54). If symptoms persist, steroid injection or surgical carpal tunnel release should be considered. The onset of pregnancy-related carpal tunnel syndrome may be in the postpartum or lactation period; such cases accounted for 31% of patients who underwent electrodiagnostic testing in one study (63). In the later study, conduction blocks of the median and sensory nerve responses at the carpal tunnel were more common in the pregnancy-related cases compared to the control group (women with idiopathic carpal tunnel syndrome); corticosteroid injection at the carpal tunnel resulted in significant improvement in more than 90% of the cases.