Lumbar Prolapse Intervertebral Disc

                   Lumbar Prolapse Intervertebral Disc

                                                 Dr. KS Dhillon

Anatomy of the Disc

The human spinal column has 23 fibrocartilage intervertebral discs. There are 6 in the cervical column, 12 in the thoracic, and 5 in the lumbar column. Each disc is a few millimeters thick and it lies between adjacent surfaces of the vertebrae. The discs make up roughly a quarter [1] to a third [2] of the height of the column.

The disc is formed of peripheral fibrous cartilage called the annulus fibrosus which surrounds a centrally located gelatinous core known as the nucleus pulposus. In adults, there is no clear boundary between the nucleus and the annulus within the disc. Superiorly and inferiorly the nucleus pulposus is coated by cartilage endplates.

The endplate is usually less than 1 mm thick. It contains horizontal collagen fibers that run parallel to the vertebral bodies and eventually become continuous with the disc.

Annulus fibrosus

The annulus fibrosus is a strong radial tire-like structure that contains fibroblast that constantly synthesizes type I and II collagen into lamellar fibers, forming concentric rings, or lamellae [2]. The lamellae are interconnected by bundles of smaller fibers which consist of fibrillin, lubricin, elastin, aggrecan, and type VI collagen [3]. 

The lamellae of the annulus are thicker anteriorly and on the lateral sides. Posteriorly the lamellae are finer and more tightly packed [4]. This probably accounts for the fact that most often the nucleus pulposus protrudes posteriorly. 

Between the lamellae are elastin fibers that bind the lamella together. Most of these elastin fibers are concentrated near the attachment of the annulus fibrosus to the vertebral endplate. The elasticity provided by this elastin becomes reduced with aging. The stress and strain placed on the annulus results in small fissures with loss of interwoven collagen fibers. This results in the tearing and extrusion of parts of the nucleus.

The annulus has two distinct layers, the inner and outer annulus fibrosus. The inner layer contains an extracellular matrix composed of type II collagen, proteoglycans, and water. The cells of the inner annulus are oval-shaped. The outer layer is rich in type I collagen and has a higher resistance to tension.

Sixty to seventy of the annulus is water. The water content gradually decreases with age. 

Nucleus pulposus

The typical nucleus pulposus consists of a semi-fluid mass of mucoprotein ground substance and it occupies about 40% of the disc’s cross-sectional area. It contains a few chondrocyte-like cells, collagen fibers, elastin fibers, and aggrecan-containing gel [4]. The chondrocyte-like cells produce type II collagen and proteoglycans.

The nucleus is usually situated between the middle and posterior thirds of the disc. The nucleus pulposus has 70-90% water content which decreases with age. The proteoglycans interact with water and resist compression. The aggrecan is primarily responsible for maintaining the water content of the disc.

Vertebral Endplate

The vertebral endplates are situated at the cranial and caudal ends of the intervertebral disc. The endplates are usually less than 1 mm in thickness. The endplates are made up of both hyaline cartilage and fibrocartilage. The endplates prevent the nucleus pulposus from herniating into the adjacent vertebrae.

Vertebral endplates also contain high concentrations of proteoglycans, water (50-60%), and type II collagen fibers. Along the collagen fibers, there are cartilage cells.

The loss of proteoglycans with age from the endplate cartilage is associated with the loss of proteoglycans from the nucleus pulposus. The depletion of proteoglycans eventually leads to intervertebral disc degeneration.

Blood Supply

The adult nucleus pulposus and inner annulus fibrosus have no blood supply and are completely avascular. There are, however, a few blood vessels around the peripheral annulus. These peripheral annulus and endplate capillaries come from segmental arteries, which are branches of the aorta. These capillaries provide nutrients to the region of the outer annulus fibrosus. This blood then drains into the subchondral venous plexus and into the veins of the marrow of the adjacent vertebral body [3].

Nutrition to the nucleus pulposus reaches through diffusion through pores in the vertebral endplates.

Innervation

Only the outer annulus fibrosus is innervated by sensory and sympathetic perivascular nerve fibers, from the grey rami communicantes, branches from the sinuvertebral nerve, or from the ventral rami of spinal nerves. Beyond the superficial fibers, there is no innervation. Neuropeptides thought to participate in the sensory transmission include substance P, calcitonin, vasoactive intestinal polypeptide, neuropeptide Y, C-flanking peptide, and synaptophysin [3].

Lumbar Intervertebral Discs

There are five intervertebral discs in the lumbar region the lowest of which sits atop the sacrum. The lumbar discs are taller and wider than the cervical and thoracic disc. The lumbar disc measures about 7–10 mm in thickness and 4 cm in diameter (AP plane) [2]. The discs are cylindrical in shape. The anterior height of the lumbar discs is greater than the posterior height and this is especially noticeable in the fifth lumbar disc. This shape of the disc is responsible for the lordosis especially In the upper segment of the lumbar spine. In the lower lumbar regions, the shape of the vertebral body is a contributing factor [1].

Lumbar radiculopathy can result from chemical irritation from proteoglycan released from the disc due to degeneration and fissuring of the disc. This release creates an inflammatory reaction from the exposed disc tissue leading to radiculopathy.

The spinal nerve roots leave the dural sac just above the level of each intervertebral foramen. The lumbar nerves lie sufficiently high in the foramina and they are usually unaffected by a degenerated disc at the same level unless segments of the disc migrate cranially. Hence, the fifth lumbar nerve root is more likely to be compressed by an L4-L5 disc than by a L5-S1 disc [1]. About 40% of intervertebral disc abnormalities affect the fourth and fifth lumbar nerve roots [5].

Biomechanics of the intervertebral disc

The function of the disc is to maintain flexibility and motion. The facet joints and disc are responsible for carrying the compressive loads and stresses the spine is subjected to. Some of these loads and stresses include static loads, dynamic loads, tensile stresses, shear stresses, torsional loads, and a combination of tensile, compressive, and shear stresses.

The annulus carries the tensile stresses and the nucleus carries the compressive loads. This changes when disc degeneration occurs when the hydration of the disc is less, then the tensile stresses in the collagen fibers of the annulus become compressive stresses. The stress distributions inside the degenerated disc changes as compared to healthy disc. The intradiscal pressure is position-dependent. It is lowest when lying supine, intermediate when standing and the pressure is highest when sitting and flexed forward with weights in the hands.

Pathophysiology of intervertebral disc degeneration and prolapse

There are several factors that are believed to influence the etiology of disc degeneration. These include age, genes, mechanical factors, such as compressive loading, shear stress, and vibration as well as systemic and toxic factors. 

1.Ageing

As the disc ages changes occur in the disc. There is an impaired synthesis of the matrix and the cell concentration declines especially in the annulus.

The proteoglycans synthesis rate also declines with a decline in the concentration of proteoglycans in the nucleus. There is a decline in link proteins and type IX collagen which leads to the production of proteoglycans which are smaller and less aggregated. The concentration of chondroitin sulfate also falls. An increase in collagen and a change from type II to type I collagen makes the nucleus more fibrous. The nucleus and annulus merge. There is less binding of water and the nucleus becomes more solid, dry, and granular with cracks in the fibrous nucleus. The lamellae of the annulus increase in thickness and become more fibrillated. Cracks and cavities develop in the annulus. Declining nutrition, accumulation of degraded matrix products, cell senescence, and fatigue failure of the nucleus may be the cause of these changes.

Aging intervertebral discs lose their ability to proliferate. There is decreased anabolism or increased catabolism in the senescent cells. An increased degree of senescence leads to disc herniation [6].

2.Genetic factors

A genetic predisposition to disc degeneration has been shown by studies in twins.

A study by Videman et al [7] showed that specific vitamin D receptor alleles were associated with intervertebral disc degeneration. They showed for the first time the existence of genetic susceptibility to progressive, age-related degenerative disease of the spine.

Several studies have implicated, the Taq I and Fok I of the vitamin D receptor gene, in disc degeneration [7,8,9]. The prevalence of the t-allele of Taq I differs among races, and hence the risk for disc degeneration also differs. It is present in about 8% Asians, 31% of Africans, and 43% of Caucasians [10]. 

In the elderly but not in the young, the 5A allele is a probable risk factor for accelerated degenerative changes of lumbar discs [11]. Trp2 and Trp3 alleles can cause substitution of the amino acids in type IX collagen by tryptophan. Patients with such types of collagen are at a higher risk for lumbar disc degeneration and sciatica [12,13]. The tryptophan-containing type IX collagen gene is believed to produce an unstable triple helix which makes the disc more susceptible to mechanical stress [14]. Trp3 is present in 24% of Finnish patients with disc degeneration but is absent in southern Chinese. Trp2 occurs in 20% of southern Chinese patients with disc degeneration but in only 4% of Finnish patients who have sciatica [13]. 

3.Nutrition

The intervertebral disc is to a large extent avascular. It is the largest avascular tissue in the body. The adult nucleus pulposus and inner annulus fibrosus have no blood supply and are completely avascular. There are a few blood vessels around the peripheral annulus. The blood vessels come from segmental arteries, which are branches of the aorta.

The outer annulus obtains nutrition directly from the blood vessel and the inner annulus and nucleus pulposus obtain nutrition through diffusion from the blood vessels. Reduction in the diffusion of nutrients can lead to disc degeneration.

Atheromatous lesions in the abdominal aorta, as well as congenital hypoplasia of the lumbar arteries, can cause disc degeneration [15,16,17]. The capillary network at the periphery of the disc diminishes after the first 10 years of life and that's when the first signs of disc degeneration become obvious [18,19].

With age, calcification of the endplate occurs which occludes the vascular opening within it, thereby blocking the transport of nutrients to the disc. Smoking causes vasoconstriction which leads to anoxia of the cells in the disc and therefore smoking is associated with an increased incidence of disc herniation and disc degeneration [20,21].

4.Metabolic disorders

Metabolic disorders can cause disc degeneration. In patients with alkaptonuria, there is intradiscal deposition of black pigment which can induce disc degeneration.

In diabetic patients, there is an increase in hydroxyproline and inactivity of enzymes involved in the metabolism of carbohydrates with a decrease in hexosamine content [22]. There are deficiencies in the incorporation of 35S-sulphate during proteoglycan synthesis in the disc. This disturbs the normal biochemistry of matrix synthesis and that can lead to disc degeneration. 

5.Toxic factors

Animal studies show that nicotine directly inhibits the proliferation of disc cells as well as the synthesis of the extracellular matrix [23]. Passive smoking leads to the downregulation of collagen genes which leads to degenerative histologic changes in the disc [24].

6.Autoimmune theory

Antigenic components of the nucleus pulposus can enter the circulation if there is damage to the endplate after a spinal compression injury. This antigenic material can trigger an immune response that produces a chronic inflammatory reaction leading to disc resorption at the affected level or may sometimes involve discs at different vertebral levels, leading to multilevel degeneration [25].

Experiments in animals show that a break in the physiological barrier of the disc by injury can alter the role of  Fas ligand in the disc leading to apoptosis of the disc cells [26]. 

7.Low-grade infection

Stirling et al [27] developed a new serological test which they used to diagnose deep-seated infections that were caused by low virulent gram-positive microorganisms. Forty-three of their 140 patients (31%) with sciatica, tested positive. Intervertebral disc material from 36 patients with severe sciatica who had microdiscectomy was cultured. Fifty-three percent of these patients had positive cultures after long-term incubation. Propionibacterium acnes was grown from 16 of the 19 (84%) positive cultures. They believed that low virulent microorganisms, in particular P acnes, might be causing a low-grade infection in the intervertebral discs of patients with severe sciatica. They were of the opinion that the microorganisms could have gained access to the disc from previous trauma.

8.Mechanical factors

Aihara et al [28] carried out a study to determine the influence of the lumbosacral transitional vertebra on disc degeneration. By using MRI they found that the lumbar discs which were immediately above the transitional vertebra had significantly more degeneration as compared to those between the transitional vertebrae and the sacrum, which had far less degeneration.

They also performed an anatomical study in 70 cadavers and they found that the iliolumbar ligament at the level immediately proximal to the transitional vertebra was thinner and weaker than it was in cadavers without a lumbosacral transitional vertebra. They concluded that the morphology of the iliolumbar ligament was involved in degeneration associated with a lumbosacral transitional vertebra [28]. This evidence shows that mechanical factors are involved in the aetiology of disc degeneration. 

Animal [29] and human [30] studies show that mechanical factors do produce disc degeneration adjacent to a lumbar fusion.

9.Compression

Although the lumbar discs are designed to sustain compression loads which are beneficial to the disc, excessive loading can be harmful to the disc. Loading provides a stimulus for matrix turnover [31]. Excessive loading reduces gene expression of anabolic proteins which has significant effects on aggrecan formation [32].

Compression forces lead to endplate damage which leads to depressurization of the nucleus and it increases stress in the posterior annulus [33]. The inner lamellae of the annulus begin to buckle inward and the outer lamellae buckle outwards because the depressurized nucleus is no longer able to brace the annulus. The interlaminar shear stresses are highest in the posterolateral annulus. These stresses lead to concentric tears in the annulus fibrosus [34].

Compression and endplate injuries can lead to biochemical changes in the matrix of the disc. The biosynthetic activity of cells in the disc is affected and there is an inflammatory response leading to degradation of the disc. 

10.Torsion

Torsional movements of the spine can damage the collagen fibers in the annulus. When the spine is flexed the facet joints permit rotation which allows stretching of the fibers leading to annular tears [35]. 

11.Vibration

Vibrations that match the resonant frequency of the lumbar spine (4 Hz to 6 Hz) can affect the nutrition [36] and metabolism [37] of the disc leading to disc degeneration.

Drivers of tractors, buses, trucks [38,39,40,41], and helicopter pilots [42] are exposed to whole-body vibrations. These people have been found to have a high incidence of back pain. 

There is some evidence to show that there is a high incidence of disc herniation in occupational drivers [43,44,45].

Disc degeneration is not a clinical diagnosis. It is an expression of the condition of the disc. Degeneration of the disc is caused by several factors acting collectively or individually. 

Most people believe that disc degeneration is the result of age-related changes. This belief is based on circumstantial evidence only. 

There is increasing evidence that disc degeneration is caused by mechanical factors. Injury to the vertebral endplate is central to the degenerative process. Compressive loading or torsion can cause fractures of the endplate and tears of the annulus. 

Endplate fractures and disc degeneration do not occur due to a single traumatic event. Repeated subliminal insults to the disc cause these endplate fractures and disc degeneration.

The disc degeneration eventually leads to a decrease in height of the disc with collapse of intervertebral space and the formation of osteophytes.

Clinical Presentation

Symptoms 

Pain is usually the chief complaint in patients with prolapsed disc. The pain is radicular but may be axial. It is more typically, radicular. It is useful to obtain information regarding the character of the pain, whether it is sharp, burning, or prickling in nature because such pain is usually due to nerve root irritation. It is important to know about the onset of pain, is it acute, subacute, or chronic.

Besides the pain, it is pertinent to know whether there are symptoms of motor weakness, sensory disturbances, and bladder or bowel dysfunction.   A progressive neurologic deficit is seen in patients with cauda equina syndrome which is a surgical emergency. 

The pain, sensory disturbances, and weakness are in the distribution of one or more lumbosacral nerve roots. The leg pain increases with straining, coughing, and sneezing. The pain increases when sitting because when we are sitting the disc pressure increases by nearly 40% [46].

Signs

When doing physical examination, the first indication that a patient may have a lumbar disk prolapse comes from the patient's gait. Patients with a prolapsed disc have a sciatic list. A sciatic list is an attempt to relieve the neuromeningeal tension on the nerve root by drawing the nerve root away from the prolapsed disc. When the herniation is lateral to the nerve root  (called a shoulder disc) the patient leans away from the side of the herniation. When the herniation is medial to the nerve root (called an axillary disk) the patient leans towards the side of the herniation. The examination may also show paraspinal muscle spasm with obliteration of the central furrow.

Lasegue sign or Straight Leg Raising Test (SLRT) is a neurodynamic examination which is commonly used to assess nerve root irritation in the lumbosacral area. The test is performed with the patient supine and the lower limb is slowly raised by holding the ankle with the knee fully extended. Once the pain is elicited further leg elevation is stopped. The criteria for a true positive SLRT [47,48] is that the pain should radiate below the knee and that the pain occurs between 30 and 60 or 70 degrees from the horizontal.

The accuracy of SLRT can be better if it is interpreted with other nerve root tests. These include:

• Cross SLRT[49]: This test is also known as a well-leg raising test or Fajersztajn sign. This test is performed by raising the contralateral lower limb and the pain is felt on the affected side. This test is much more specific than ipsilateral SLRT. It is usually positive in patients with severe compression from a centrally located disc prolapse.  
• Reverse SLRT[50]: Also known as femoral stretch or Ely test. It is performed with the patient in a prone position and the lower limb is lifted off the table with both the hip and knee joints extended. When the test is positive it produces pain in the distribution of the femoral nerve. It is positive in patients with upper lumbar radiculopathy, far lateral lumbar disc prolapse, or femoral neuropathy. 
• Braggard test [51]: It is also known as sciatic stretch test or flip test. This test is performed by dorsiflexion of the ankle while the SLRT is performed and is positive when the pain in the leg increases on doing the test. 
• Reverse flip test: While doing the SLRT, plantarflexion of the ankle, will lessen the pain. If, on the other hand, the patient complains of more pain, it is likely that the patient is malingering.
• Bowstring sign[52]: This test is also known as the popliteal compression test or posterior tibial nerve stretch sign. In performing this test the examiner flexes the knee and applies pressure on the posterior tibial nerve in the popliteal fossa, evoking sciatica. 

Following inspection, palpation, and examination maneuvers a meticulous neurologic examination is carried out which will confirm the nerve root that is involved. In paracentral disc herniations, the traversing nerve root is affected while in far lateral disc herniations, the exiting nerve root is affected. A paracentral herniation at L4-5 would cause L5 radiculopathy and a far lateral herniation at the same level would cause L4 radiculopathy.

Manual muscle testing, sensory testing, and supine SLR test with its crossed leg variant are the gold standard for clinical diagnosis of LDH according to the North American Spine Society’s (NASS) Evidence-Based Guideline Development Committee. Tests such as the cough impulse test, femoral nerve stress test, hyperextension test, range of lumbar motion, and absence of reflexes are not clinically helpful. 

A meta-analysis by Petersen et al [53] concluded that screening by SLR test with three of the following four symptoms in a nerve root distribution was sufficient for clinical diagnosis of lumbar disc herniation with radiculopathy: dermatomal pain, reflex deficit, sensory deficits, and/or motor weakness.

Imaging

1.Radiographs

The first line imaging modality used for patients with low back pain is plain radiographs.  In the absence of a neurological deficit, there is no need for radiographs in the first 6 to 12 weeks. When radiographs are taken, besides the AP and lateral views flexion and extension views should also be taken to assess spinal instability. Features suggestive of a herniated disc include compensatory scoliosis, narrowed disc space, and the presence of osteophytes [54].

2.Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) is the gold standard for imaging to confirm the presence of a herniated disc. It has a diagnostic accuracy of 97% and high inter-observer reliability [55]. The presence of an increased T2-weighted signal in the posterior 10% of the disc diameter is highly suggestive of disc herniation [56]. MRI is not indicated for all patients with disc herniation. Indications for an MRI in the early period of disc herniation (< 6 weeks) include the presence of neurologic deficits and cauda equina syndrome.

3.Computed Tomography

Computed tomography (CT) was in the past clinically inferior to MRI in the detection of a herniated disc. This, however, has now changed with the introduction of the multidetector CT (MDCT) [57,58]. Now the diagnostic accuracy of CT is nearly equal to that of MRI [57,58]. The use of CT myelography is recommended when MRI is unavailable or cannot be used because of pacemakers or cochlear implants, and in patients who are excessively uncomfortable due to claustrophobia or intractable pain.

Treatment

Disc prolapse is common and it can be seen in up to a quarter of MRI scans. Disc prolapse can also be seen in asymptomatic individuals [59]. 

When confronted with a symptomatic patient with a prolapsed disc the question that comes to the mind is, what is the best treatment for lumbar disc herniation?

Non-operative treatment

Symptomatic patients with disc herniation can be treated conservatively without surgery. Conservative non-operative treatment is the treatment of choice for the majority of the patients.

A multimodal approach consisting of anti-inflammatory medications, education, and physical therapy forms the basis of non-operative management [60]. The radicular pain due to lumbar disc herniation (LDH) should improve within six to eight weeks with conservative management [61].

Nonsteroidal anti-inflammatory drugs such as ibuprofen are commonly used to treat patients with disc prolapse. Tramadol can be added if there is insufficient pain relief. Patients with more substantial pain can be treated with mild narcotic pain medication, such as hydrocodone-acetaminophen. Physiotherapy can be started which would include exercises, core strengthening, and joint mobility. Pain relief modalities, such as ultrasound, ice and heat pack therapy, whirlpool, electrical stimulation, and massage can be added 

Epidural steroid spinal injections are widely used to treat back pain and radiculitis. According to Dr. Deyo, despite the increase in the use of steroid spinal injections for back pain more patients are reporting functional and work limitations, rather than less patients [62]. He also cited a University of Washington study which showed that seven clinical trials found injections to be useful, another seven trials found that injections were no better or even worse than a placebo, and in three trials the outcome was unclear [63]. 

Epidural/transforaminal injections are associated with a wide variety of complications which include: Infection (discitis, osteomyelitis, epidural abscess, meningitis), intravascular injections (7.9-11.6%), epidural hematoma (0-1.9%), nerve and neurological injury leading to paralysis/quadriplegia, adhesive arachnoiditis, blindness, intravascular injections (7.9-11.6%), air embolism, urinary retention, CSF fistulas (up to 6%), persistent headaches (28%), allergic reactions, seizures and even death [62].

In 2014 FDA warned that injections of corticosteroids into the epidural space of the spine can result in rare but serious adverse effects, including stroke, loss of vision, paralysis, and death [64].

Saal and Saal [65] in a retrospective study reported that 90% of their 64 patients had a good or excellent outcome with conservative treatment at an average follow-up of 31.1 months. 

Spontaneous regression of symptomatic lumbar disc herniation (SLDH) is known to occur. Wang et al [66] carried out a systematic review and meta-analysis to study the incidence of regression after the non-surgical treatment of symptomatic lumbar disc herniation. They found that the overall incidence of regression was 63% in non-surgically treated SLDH patients. Based on their review, they suggested a follow-up timeline with time points 4 months and 10.5 months after the onset of symptoms when deciding whether to perform surgery for SLDH. They concluded that surgery can be performed in patients with severe symptoms who do not experience regression after 4 months of onset. They strongly recommended surgery for patients who do not experience regression after 10.5 months of onset.

Gugliotta et al [67] carried out a study to compare the effectiveness of surgical and conservative treatment in patients with symptomatic lumbar disc herniation. They found that the medium and long-term ( at 12 weeks to 52 weeks) outcomes for conservative and surgical treatment of (LDH) were similar.

Operative treatment

Operative treatment is essential in patients with progressive neurologic deficits, saddle anesthesia, and in those with bowel or bladder involvement. Patients with paresthesias or motor weakness with radicular pain may be candidates for surgery if conservative treatment fails. Patients with symptoms present for greater than six months may be candidates for surgical treatment [68].

Surgical treatment of herniated disc, in several studies, have shown

improved short-term benefits. In the medium to long-term, the value of surgery is not so clear with conflicting reports in the literature [69,70,71]. 

Osterman et al [72] carried out a randomized study comparing non-operative treatment with microdiscectomy for LHD. They found no clinically significant differences between the groups as far as leg or back pain intensity, subjective disability, or health-related quality of life was concerned at a 2-year follow-up. There was a more rapid initial recovery with discectomy. 

The outcome after discectomy is good in patients with higher severity of leg pain, severe preoperative low back pain, good mental health status, younger age, shorter symptom duration, and increased preoperative physical activity [73,74,75].

Postoperative outcomes are not affected by the presence of motor deficit, gender of the patient, vertebral level, or side of herniation, and the presence of type I Modic changes [54].

There are several approaches used for the surgical treatment of LDH. These include:

Minimally Invasive Surgery.

Minimally invasive surgery of the spine was introduced to reduce soft tissue and bony trauma and decrease hospital stay. Minimally invasive surgery is performed by using percutaneous endoscopic approaches to LDH which include transforaminal, posterolateral, interlaminar, and transiliac approaches [76,77]. 

A systematic review and meta-analysis comparing minimally invasive surgery with open discectomy by Phan et al [78] showed that

endoscopic discectomy is associated with decreased operative time as well as less blood loss when compared to open discectomy. The complication rates, reoperation rates, or wound infection rates were similar in the two groups. The postoperative leg pain scores and the postoperative Oswestry disability index scores were the same in the two groups.

A double-blind randomized control trial by Overdevest et al [79] failed 

to detect a difference between minimal invasive discectomy with tubular retractors and open microdiscectomy when long-term patient-centered outcomes were measured.

Choi et al [80] carried out a retrospective review of 149 patients who underwent percutaneous endoscopic lumbar discectomy (PELD) for a migrated herniated disc. They found that the outcome was favorable in 90.6% of the cases. In patients with high-grade disc herniations with upward migration of the disc, they found a 13% rate of remnant disc fragment and a 3% rate of revision surgery.

Bai et a [81] carried out a study to compare the outcome of L5-S1 discectomy by a transiliac approach and conventional transforaminal approach. They found no significant differences in outcome between the two groups. 

Although the interlaminar approach has the advantage that endoscopic guidance can be directly inserted, the approach, however, has the disadvantage that the nerve root and thecal sac has to be retracted which can be a challenge in patients with a large disc herniation [77]. 

The available data, of long term outcome after minimally invasive surgery, is conflicting in nature and is limited. 

Li et al [82] showed a 93% 5-year patient satisfaction rate in 134 patients who underwent combined percutaneous endoscopic lumbar discectomy (PELD) and percutaneous lumbar foraminoplasty (PLF). Tu et al [83] showed a 90% 5 years satisfaction rate in patients who underwent full-endoscopic interlaminar discectomy (FEID) and in patients who underwent microendoscopic discectomy (MED). 

There were dural tears in 5.9% of the patients, 1.3% had reoperation for hematoma and infection, 8.55% had recurrence out of which 1.9% require spinal fusion.

Eun et al [84] reported a 9.6% revision rate at the same level in 62 patients who underwent percutaneous endoscopic lumbar discectomy (PELD). This study had 11 years of follow up.

The risk factors for failure after PELD include central disc herniation, obesity, age > 50 and surgeon inexperience [54].

Open Discectomy

There are large studies such as the SPORT [85] and Maine trials [86] that have demonstrated the efficacy of open discectomy in LDH. 

The paracentral disc herniation is usually approached via the paracentral approach and the far lateral herniations are approached via Wiltse’s approach between the multifidus and longissimus muscles.

The main concern with open discectomy have been the risk of infection affecting the clinical outcome. Prolonged duration (more than 68 mins) of operation and absence of prophylactic antibiotics are known risk factors for infection [87].

There have been suggestions in recent literature that the risk of postoperative infection is higher in patients who receive lumbar epidural injections. A study by Seavey et al [88] showed that there is no significant difference in infection rate in patients who had an epidural infection and those who did not have an epidural injection before the disc surgery.  

Kotil et al [89] carried out a study to evaluate the use of close suction drains in patients undergoing single-level lumbar discectomy. With MRI done postoperatively on days 1, 180, and 365, they found that there were significantly higher rates of epidural hematoma and epidural fibrosis in patients where no drains were used.

A study by Murphy et al [90] showed that the use of a microscope during open discectomy was associated with an increase in operating time. 

Complications of discectomy

There are several complications which are associated with lumbar discectomy including dural tears, nerve root injury, new or worsening neurological deficit, wound complications (infection, dehiscence, or seroma), hematoma, worsening of functional status, and recurrent disc herniation. 

The incidence of dural tears following LDH surgery ranges from 1 to 17%. The incidence is higher in patients with obesity, advanced age, and in those undergoing revision procedures [91]. Dural tears are associated with higher hospitalization costs and increased incidence of wound dehiscence (2.4 times higher) [91].

The incidence of post-operative infection ranges from 1–5% and worsening of functional status can be seen in about 4% of the patients [89,90].

New or worsening neurological deficit can be seen in about 1.3% to 3.0% of the patients and direct nerve root injury in about 0.9% to 2.6% of the patients [92]. Hematomas develop in 0.5% to 1.2% of the patients [92]. The incidence of recurrent disc complications is between 3.1% to 4.4% and the incidence of reoperation is between 3.7%, to 10.2% [92].

There are several risk factors for recurrent herniation and these include, trauma, older age, pre-operative disc height index, smoking, disc protrusion, disc sequestration, workers’ compensation, longer duration of sick leave, diabetes, and greater preoperative symptom severity [75, 93,94,95,96,97,98]. 

The complication rates following discectomy are no different in patients with and without restriction of activity following the surgery [99]. Therefore there is no reason to restrict activity after surgery which should allow patients to return to work earlier.

Failed back surgery syndrome (FBSS)

Failed back surgery syndrome (FBSS) refers to the failure of back surgery to satisfactorily improve the patient’s symptoms. It is usually characterized by intractable pain and varying degrees of functional disability following lumbar spine surgery.

It is estimated that 10% to 40% of patients who undergo back surgery develop FBSS after lumbar spine surgery [100]. 

In the USA statistics suggest that there are 25,000 to 50,000 cases of failed back syndrome per year [101]. It is a major public health problem and probably the greatest single waste of health care resources in the USA [101]. In the UK there are around 2000 cases of failed back surgery syndrome each year [102]. For microdiscectomy, the failure rates are between 19% to 25% [103].

FBSS following disc surgery is known as post-discectomy-syndrome (PDS). Some of the causes of poor results after lumbar disc surgery include postoperative instability of the spine, recurrent disc herniation,    entrapment of the spinal nerve roots by scar tissue, arachnoiditis, psychological syndromes, and insurance-related issues[104]. 

Surgery for PDS is only indicated in patients with recurrent disc herniation and spinal instability. In all other situations surgery is not indicated and if surgery is carried out the patient's symptoms may worsen [104].

There are several modalities of non-surgical treatment FBSS [105]. These include:

• Nonsteroidal anti-inflammatory drugs--The first line of treatment includes the use of nonsteroidal anti-inflammatory drugs (NSAIDs). Oral NSAIDs have been shown to be effective for persistent low back pain [106]. A recent Cochrane review, however, highlighted the lack of NSAID efficacy in chronic radicular pain [107]. In recent years the use of Cox 2 inhibitors has gained ground. There are, however, no human studies that have shown the advantage of Cox 2 inhibitors over other NSAIDs [108].
• Paracetamol+tramadol---Paracetamol has been used in the treatment of spinal pain. A recent meta-analysis by Machado et al [109] has shown that paracetamol is not effective in reducing pain and disability in patients with chronic back pain. A combination of paracetamol with tramadol is considered an efficient approach to the management of patients with low back pain [110]. 
• Muscle relaxants ---Thiocolchicoside a semi-synthetic derivative of colchicines has an affinity for the inhibitory glycine and gamma-aminobutyric acid (GABA)-A receptors and have glycomimetic and Gaba mimetic activity which produces muscle relaxant action. Muscle relaxation reduces back pain caused by excessive muscle spasm. The clinical efficacy of thiocolchicoside has been demonstrated in many clinical trials [111].  Thiocolchicoside produces muscle relaxation without any objective or subjective sedative side-effects.[112]. There are, however, no randomized trials to show the efficacy of muscle relaxants in the treatment of chronic low back pain [105].
• Opioids and their derivatives ---Opioids and their derivatives are frequently used in the management of FBSS. Tramadol and codeine which are weak opioid agonists do help improve pain and disability, particularly in the elderly patients. They are not associated with gastrointestinal side effects of NSAIDs and renal toxicity [113]. Major oral opiates such as morphine, oxycodone, and methadone can be used in patients with refractory pain. A combination of oxycodone and naloxone has better analgesic efficacy than oxycodone alone or morphine. The risk of constipation is lower with oxycodone and naloxone combination [114]. The risk of dependence can be reduced with careful prescriptions. 
• Antidepressants and antiepileptics---Many patients with FBSS have some element of depression and hence antidepressants such as duloxetine, amitriptyline, and venlafaxine are often used. These drugs also have analgesic effects [115]. Antiepileptics drugs such as pregabalin and gabapentin are often used to treat the neuropathic component of pain [116]. These drugs must be gradually introduced to prevent somnolence and dizziness. There was a recent randomized controlled trial that showed the ineffectiveness of gabapentin for analgesia in chronic low back pain and radicular pain [118]. 
• Spinal infiltration---Epidural steroids have been in the past used to treat FBSS. Epidural steroids provide short-term pain relief and improvement in activity levels. There is always a risk of infection with epidural infection in fragile patients using corticosteroids. In several patients, serious neurological complications, including paraplegia has been reported following lumbar epidural injections. Rare but serious risks of neurological complications such as loss of vision, stroke, paralysis, and sometimes death have been reported following epidural injection and the USA FDA has declared an alert and label change for injectable long term corticosteroids [119].
• Spinal cord stimulation---Spinal cord stimulation (SCS) was initially used for the treatment of neuropathic and radicular pain in patients who had failed to improve with other therapies. Now it is increasingly being used to treat FBSS.  There is now strong evidence for the efficacy of SCS in properly selected patients with FBSS [120]. For spinal cord stimulation electrodes are implanted in the epidural space and electrical current is produced by a pulse generator placed under the skin [120]. The analgesia produced by SCS is believed to occur via a gate-control mechanism and modulation of excitatory and inhibitory neurotransmitter release which occurs in the dorsal horn [120].
• Exercise Therapy/Physiotherapy---Patients with FBSS have weakness of the abdominal and paraspinal muscles which stabilizes the spine. Hence exercises to strengthen these muscles are useful in the treatment of FBSS. These exercises help to reduce pain, improve posture and fitness, stabilize the hypermobile segments of the spine, and reduce mechanical stress on the spine [121]. Patients are also taught active coping mechanisms for the pain [120]. Literature review shows that there are several exercise programs described but unfortunately there is no evidence to show the superiority of one program over another in terms of outcome [122]. A systematic by Hayden et al [123] identified the important components of an exercise program. They found that an individualized exercise program composed of supervision, strengthening, and stretching was associated with superior outcomes. Core muscle strengthening exercises of the trunk muscles have been shown to improve spinal stability and reduce pain [124]. A Cochrane review by Hayden et al [125] showed that in adults with chronic low back pain, exercise therapy appears to be slightly effective in decreasing pain and improving function.  This finding has been supported by 2 other systematic reviews [126,127]. 
• Psychological Therapy----Psychological factors are involved in the pathogenesis of FBSS. Therefore psychological therapy constitutes one arm of treatment of FBSS. Broadly, psychological therapy consists of behavioral (BT) and cognitive-behavioral treatment (CBT). In BT-CBT psychological principles are applied to change the thoughts, overt behavior and feelings of patients with chronic pain. This helps them experience less distress and make their lives more satisfying and productive [128]. BT-CBT also reduces the patients' pain and improves their daily functioning. In CBT patients are taught relaxation skills; goal setting and pacing strategies; perception changing strategies such as visual imagery, desensitization, hypnosis and promotion of self-management perspective. Recent reviews support the effectiveness of CBT in patients with chronic pain [129-133].

Conclusion

Low back pain is very common and the most common source of this pain is intervertebral degeneration leading to degenerative disc disease and lumbar disc herniation (LDH). Over the years substantial advancements have been made in understanding the cause of LDH as well as in the diagnosis, imaging, and treatment options available for patients with lumbar disc herniation (LDH).

The treatment of choice in the majority of patients with symptomatic LDH is non-operative management. In the event of failure of conservative treatment, surgery is usually recommended. There are several studies that have shown improved short-term benefits of surgical treatment but in the medium, to long term, the value of surgery is not so clear.

The complications after surgery can be as high as 17% and between 10% to 40% of the patients can develop failed back syndrome which can be very difficult to treat.

   

 

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Complex Regional Pain Syndromes

               Complex Regional Pain Syndromes

                                      DR KS Dhillon

Introduction

There are two types of complex regional pain syndromes (CRPS). The type 1 CRPS was formerly known as reflex sympathetic dystrophy (RSD) and the type II CRPS was formerly known as causalgia. The International Association for the Study of Pain (IASP) has agreed on the diagnostic criteria for these two syndromes. 

The natural course and pathophysiology of these debilitating pain syndromes remain elusive and their treatment remains controversial [1].

Epidemiology

The incidence of CRPS in the US is 5.5 per 100,000 person-years. It affects females more often then males (4:1). The incidence increases with age up until 70 years old. Sixty percent occurs in the upper limbs and 40% occurs in the lower limbs. Risk factors include, trauma with an exaggerated response to injury, prolonged immobilization, surgery, depression or anxiety, ACE inhibitors use at the time of trauma, smoking, history of migraines or asthma and fibromyalgia.

Pathophysiology

Despite the fact that these syndromes have been around for a century and despite the existence of a wealth of literature and discussions, the pathophysiology of CRPS remains elusive.

There are multiple pathophysiologic mechanisms involved in the pathogenesis of CRPS. These include:

1. Altered intradermal innervation after injury

More experimental and clinical evidence is accumulating which supports the hypothesis that even in CRPS 1 there is some form of nerve trauma that triggers events that leads to CRPS even though there are no clinical signs of nerve injury. There is a small nerve fiber neuropathy [2,3,4,5].

There is C-fiber and A-delta fiber abnormal excitation and firing and this is associated with the co-release of peptidergic neuropeptides [6,7,8,9]. Skin biopsies show significantly lower densities of epidermal neurites (up to 29% lower) in CRPS-affected limbs as compared to contralateral unaffected limbs [4]. Primarily the nociceptive fibers are affected. 

Albrecht et al [10]  found several neuropathologic alterations in CRPS affected skin including:

Presence of numerous abnormal thin caliber axons innervating hair follicles.

Decrease in epidermal, sweat gland, and vascular innervation.

Loss of Calcitonin gene-related peptide (CGRP) expression on    remaining innervation to vasculature and sweat glands. 

Inappropriate expression of Neuropeptide Y (NPY) on innervation to superficial arterioles and sweat glands. 

Loss of vascular endothelial integrity and vascular hypertrophy. 

There is evidence of widespread cutaneous neuropathologic changes in the skin of individuals with CRPS.

2.Central Sensitization.

When tissue injury or nerve injury produces persistent or intense noxious input, increased excitability of nociceptive neurons in the spinal cord can occur leading to central sensitization. This enhancement in the function of neurons and circuits in nociceptive pathways is caused by increases in membrane excitability and synaptic efficacy along with a reduction of inhibition. This is a manifestation of the plasticity of the somatosensory nervous system in response to inflammation and neural injury [11]. 

With central sensitization previously subthreshold synaptic inputs to nociceptive neurons can get recruited. Normal inputs can elicit sensory responses which produce pain hypersensitivity. 

With central sensitization there is an exaggerated response to nociceptive stimuli (hyperalgesia) and normally non painful stimuli such as light touch or cold can activate nociceptive pathways (allodynia) [12].

Mediation in central sensitization is by the nociception-induced release of neuropeptides, such as bradykinin and substance P. Amino acid glutamate acts at spinal N-methyl-d-aspartic acid receptors to produce the excitatory stimulus [12,13].

 3.Local peripheral sensitization

Tissue trauma can elicit local peripheral sensitization. Following peripheral tissue trauma, the primary afferent fibers in the injured area release several pronociceptive neuropeptides such as substance P and bradykinins. These neuropeptides increase background firing of nociceptors in response to nociceptive stimuli. They also decrease the firing threshold for thermal and mechanical stimuli [14,15]. These two effects lead respectively, to the hyperalgesia and allodynia that is seen in CRPS [16].

Peripheral and central sensitization leads to significantly reduced acute pain thresholds in the affected extremity in patients with chronic CRPS. 

4.Circulating Catecholamines

There is a change in the signs and symptoms of CPRS as the condition moves from the acute to the chronic phase. This is partly due to alteration  in catecholaminergic mechanisms. 

In the acute phase there is unilateral inhibition of sympathetic vasoconstrictor neurons and this leads to a warmer affected limb in the acute stage.

In the chronic stage secondary changes in neurovascular transmission occur and this leads to vasoconstriction and cold skin. The levels of norepinephrine drop on the affected side. With these lower norepinephrine levels there is diminished local sympathetic nervous system (SNS) outflow. Despite this reduced SNS outflow there are exaggerated vasoconstrictive responses in chronic CRPS patients. This paradoxical pattern is believed to be a result of receptor up-regulation of peripheral adrenergic receptors [2].

Hypersensitivity to circulating catecholamines leads to exaggerated sweating and vasoconstriction. This leads to a cool, blue, sweaty extremity which typically is seen in patients with chronic CRPS. The vasoconstriction  leads to local tissue hypoxia which contributes to development of trophic changes seen in patients with CRPS via  local tissue hypoxia [17].

5.Altered Sympathetic Nervous System Function

Excessive sympathetic nervous system (SNS) outflow leading to vasoconstriction is responsible for the  autonomic features of CRPS, such as a cool and bluish limb. The pain in CRPS is also sympathetically maintained [18]. After trauma adrenergic receptors become expressed on nociceptive fibers. This expression of adrenergic receptors on nociceptive fibers leads to sympatho-afferent coupling. SNS outflow can trigger these receptors leading to pain in patients with CRPS [2].

High SNS activity increases pain in patients with sympathetically mediated CRPS pain. Excessive SNS outflow is, however, not the only cause of CRPS pain and other symptoms [2]. 

6.Inflammatory Factors

After tissue trauma immune cells such as lymphocytes and mast cells secrete proinflammatory cytokines such as interleukin-1β, -2, -6, and tumor necrosis factor (TNF)-α which induces inflammation in patients with CRPS [19]. These substances can also increase plasma extravasation in tissue, leading to localized edema which is seen in patients with CRPS.

Various triggers such as nerve injury lead to release of proinflammatory cytokines and neuropeptides from nociceptive fibers. These cytokines and neuropeptides produce neurogenic inflammation in patients with CRPS [20]. Some of the neuropeptides which produce neurogenic inflammation include substance P, calcitonin gene-related peptide (CGRP), and bradykinin. 

These neuropeptides can produce vasodilation which leads to redness and warmth of the extremity. The neuropeptides also increase plasma extravasation which can produce an edematous extremity seen in patients  acute CRPS [7]. 

Substance P and TNF-α can activate osteoclasts which produce osteoporosis which can frequently be seen in CRPS patients. CGRP can increase hair growth and increase sweating which is sometimes seen in patients with CRPS [7,21]. 

7.Brain Plasticity

In patients with CRPS there is a reorganization of somatotopic maps in the brain. Neuroimaging studies show that in patients with CRPS there is reduction in size of representation of the affected limb in the cerebral cortex as compared to the non-affected limb [22,23,24,25,26]. Studies show that these alterations return to normal after the CRPS has been successfully treated [24,25]. This evidence suggests that brain plasticity occurs in the development of CRPS.

A study by Maihöfner et al [23] showed that the degree of somatotopic reorganization significantly correlated with CRPS pain intensity and the degree of hyperalgesia. 

CRPS patients with cerebral reorganization also demostrate impaired two-point tactile discrimination [25] and an impaired ability to localize tactile stimuli as well as perceive sensations outside of the stimulated nerve distribution [27]. 

Somatotopic reorganization can account for the fact that sensory deficit to pinprick and touch in CRPS patients is present throughout the affected body quadrant or the whole on side of the body [28].

8.Psychologic Factors

In the past many assumed that CRPS is a psychogenic disorder because the pathophysiology of the syndrome was poorly understood. There is however no evidence to show that CRPS is a psychogenic disorder. 

Psychological factors such as anxiety, depression and anger can be associated with increased catecholamine release which can exacerbate the vasomotor signs of CRPS and also increase pain intensity [29,30,31].

9.Genetic Factors

Several studies have shown that genetic factors may be involved in CRPS [32]. Genetic factors play an important role in causing familial aggregation of diseases. Several studies have reported familial aggregation in CRPS [32]. 

Genetic associations have been reported between CRPS and polymorphisms in human leukocyte antigens [33] and tumor necrosis factor [34]. Kimura et al [35] found that there is an association between CRPS and polymorphism in the ACE gene, which is located on the long arm of the chromosome.

Another indicator of increased genetic susceptibility for CRPS is the fact that patients with a more severe phenotype are of a younger age at onset as compared to patients in whom the disease has remitted or stabilized [36,37].

Classification of CRPS

CRPS is classified according to a classification by Lankford and Evans. Stages of RSD include:

• Acute stage: Onset is 0-3 months. There is burning pain, warmth, redness, hyperhidrosis, swelling, hyperesthesia, cold intolerance, joint stiffness. The x-rays are normal but the three-phase bone scan is positive
• Subacute (dystrophic): The onset is 3-12 months. There is worsening pain, stiffness, dry skin, cyanosis and skin atrophy. X rays show subchondral osteopenia.
• Chronic (atrophic): The onset is more then 12 months. There is diminished pain, fibrosis, glossy skin, joint contractures with loss of hair and nails. The x rays show extreme osteopenia.

Diagnosis of CRPS

The diagnosis of CRPS is made by using certain clinical criteria.  The most commonly used diagnostic criteria is one endorsed by the International Association for the Study of Pain (IASP). 

The 1996 IASP criteria for CRPS include:

(1) CRPS is a syndrome which develops after an initiating noxious event

(2) Spontaneous pain, hyperalgesia or allodynia occurs which is not limited to the territory of a single peripheral nerve, and is out of proportion to the inciting event;

(3) Presence of edema, changes in color and temperature, or abnormal sweating in the region of the pain since the inciting event and

(4) The diagnosis of CRPS is excluded by the presence of conditions that would account for the degree of pain and dysfunction.

To make a diagnosis of CRPS, criteria 2,3 and 4 must be fulfilled [38].

The original 1996 IASP criteria was later revised by the Budapest consensus group (accepted and codified by the Committee for

Classification of Chronic Pain of the International Association for the Study of Pain)

The general features of the syndrome include:

CRPS is characterized by a continuing (spontaneous and/or evoked) regional pain that is disproportionate in time or degree to the usual course of any known trauma or other lesion. 

The pain is regional (not in a specific nerve territory or dermatome) and usually has a distal predominance of abnormal motor, sensory, vasomotor, sudomotor, and/or trophic findings. The syndrome exhibits variable progression over time.

There are now two versions of the proposed diagnostic criteria: a clinical version and a research version. The clinical version is meant to maximize diagnostic sensitivity with adequate specificity and the research version is meant to equally balance optimal sensitivity and specificity [39].

Clinical diagnostic criteria for CRPS include [39]:

1) Continuing pain, which is disproportionate to the inciting event

2) Must have at least one symptom in three of the four following categories

• Sensory: Presences of hyperalgesia and/or allodynia
• Vasomotor: Presences of temperature asymmetry and/or skin color changes and/or skin color asymmetry
• Sudomotor/Edema: Presences of edema and/or sweating changes and/or sweating asymmetry
• Motor/Trophic: presences of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin)

3) Must display at least one sign at time of evaluation in two or more of the following categories

• Sensory: Evidence of hyperalgesia (to pinprick) and/or allodynia (to light touch and/or deep somatic pressure and/or joint movement)
• Vasomotor: Evidence of temperature asymmetry and/or skin color changes and/or asymmetry Sudomotor/Edema: Evidence of edema and/or sweating changes and/or sweating asymmetry
• Motor/Trophic: Evidence of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin)

4) There is no other diagnosis which better explains the signs and symptoms

A sign is counted only if it is observed at time of diagnosis.

Research diagnostic criteria for CRPS include [39]:

1) Continuing pain, which is disproportionate to the inciting event

2) Must have at least one symptom in each of the four following categories

• Sensory: Presences of hyperalgesia and/or allodynia
• Vasomotor: Presences of temperature asymmetry and/or skin color changes and/or skin color asymmetry
• Sudomotor/Edema: Presences of edema and/or sweating changes and/or sweating asymmetry
• Motor/Trophic: presences of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin)

3) Must display at least one sign at time of evaluation in two or more of the following categories

• Sensory: Evidence of hyperalgesia (to pinprick) and/or allodynia (to light touch and/or deep somatic pressure and/or joint movement)
• Vasomotor: Evidence of temperature asymmetry and/or skin color changes and/or asymmetry Sudomotor/Edema: Evidence of edema and/or sweating changes and/or sweating asymmetry
• Motor/Trophic: Evidence of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin)

4) There is no other diagnosis which better explains the signs and symptoms

A sign is counted only if it is observed at time of diagnosis.

Vascular and neurologic examinations should be carried out to help detect the presence of conditions which may mimic CRPS. Diabetic neuropathy, small-fiber peripheral neuropathies, entrapment neuropathies, discogenic disease, and thoracic outlet syndrome, should be ruled out. Other differential diagnoses include cellulitis, deep vein thrombosis, lymphedema, vascular insufficiency, and erythromelalgia [1].

Laboratory tests are not very useful in the diagnosis of CRPS. Certain tests can help to confirm clinical impressions.

Quantitative sensory tests, electromyogram, nerve conduction studies, quantitative sudomotor axon-reflex test, sympathetic block, thermography,

Doppler flowmetry, radiography and bone scintigraphy has been used to reinforce the diagnosis. Sympathetic blocks have been used to determine the involvement of the sympathetic nervous system in patients with CRPS.

Differential diagnosis

The differential diagnosis of CRPS include the following:

• Psychiatric disease
• Neuropathic pain
• Soft tissue infection
• Malingering
• Raynaud disease
• Chronic pain
• Thoracic outlet syndrome
• Erythromelalgia
• Arterial insufficiency

Treatment approach

Pain is usually the leading symptom of CRPS. Besides the pain, limb dysfunction is often seen in CRPS patients. Elements of psychological distress are common in most patients. Insomnia, anxiety and depression often develops in patients when pain persists. Hence the need for an integrated interdisciplinary treatment approach tailored to the individual patient [40]. 

The United Kingdom guidelines on CRPS list four pillars of CRPS care: 

1. Education 

2. Pain relief with medications and procedures 

3. Physical rehabilitation

4. Psychological intervention. 

All the four pillars are equally important and a range of specialties such as rheumatology, physiotherapy, neurology, pain medicine and surgery are required to address these pillars of care [40]. The main aim here is to reduce pain, restore function and enable the patients to manage their condition so that their quality of life can be improved. Full recovery is difficult to achieve in some patients, even when appropriate treatment is started early.

Functional restoration

Functional restoration is carried out by gradual and steady progression from activation of pre sensorimotor cortices to very gentle active movements [39]. This is followed by putting partial weight on the lower limb and walking and for the upper limb, start carrying light bags and objects. 

Progressive desensitization carried out by stimulating the skin silk, towels and other textiles.

Aggressive passive range of movement exercises should be avoided. There should be a gentle gradual increase in range of movements. The main aim is to achieve postural normalization, stabilization and a balanced use of the limb [41]. 

Vocational rehabilitation should be started. Attempts are made to help the patient return to work, school or homemaking or to any other endeavor necessary. All attempts are made to overcome psychological difficulties. Anxiety, depression, anger and personality disorders should be appropriately dealt with [41]. 

Pharmacological Management

There is a lack of good treatment trials for CRPS. Current practice is a bit chaotic and continues to use trial and error methods [41]. Some of the drugs used for treatment of CRPS include: 

1. Non-steroidal anti-inflammatory drugs (NSAIDs)

In the initial stages NSAIDs can be used to treat the pain and inflammation associated with CRPS. Long term use of NSAIDs can be harmful because of potential for gastric ulceration and renal failure. Pain relief is usually not very satisfactory with the use of NSAIDs.

2.Opoids

The use of opioids remains controversial and their efficacy varies. No controlled studies of opioid use in CRPS exists [41]. When NSAIDs are not effective opioids can be used. Opioids can initially be tried intravenously as patient controlled analgesia. In patients with a history of chemical dependence the use of opioids requires extreme caution. Opioid cannot be abruptly stopped. 

3.Tricyclic and heterocyclic antidepressants

Serotonin/norepinephrine reuptake blockers such as amitriptyline, desipramine and maprotiline have been found to be useful in the treatment of neuropathic pain syndromes. Shooting pain, spontaneous pain and allodynia can be treated with these agents. The dose needed for pain relief is usually lower then that used for depression.  

These antidepressants can overcome anxiety and also improve mood and sleep [41].

4.Corticosteroids

 Steroids are often used in CRPS patients who have redness, warmth and oedema of the limb due to inflammation. Steroids are useful for pain associated with joint movements and that associated with trophic changes [41].

5.Calcitonin Biphosphonates

Subcutaneous injections of calcitonin have been found to have some effect on reducing spontaneous pain in patients with CRPS [41].

6.Adrenergic Drugs

Systemic α blockers (phenoxybenzamine, prazosin, doxazosin, and terazosin) have been found to improve peripheral blood flow and tissue perfusion as well as reducing pain in patients with CRPS. A recent meta-analysis of medical therapies aimed at inhibiting sympathetic function however failed to establish the utility of sympathetic blockade [42]. Topical alpha-2 agonists such as clonidine have been found to be useful in treating discrete areas of hyperalgesia [43]. Epidural injections of clonidine have also been found to be effective for pain relief in patients with CRPS [44].

7.Capsaicin

High dose topical capsaicin has been found to be useful in treating localized areas of hyperalgesia in patients with CRPS [45].

8.Antiepileptic Drugs

Gabapentin, an anticonvulsant, is commonly prescribed for neuropathic pain in patients with CRPS. Gabapentin works by inhibitions of the K(+)-induced [Ca(2+) (i) [46].

A randomized, blinded trial in 58 patients with CRPS by van de Vusse et al [47] showed that gabapentin had a mild effect on pain. Another large placebo-controlled trial of gabapentin by Serpell [48] showed significant reduction in pain as compared to placebo in patients with CRPS.

Carbamazepine as well as phenytoin are widely used for treatment of CRPS pain [49,50].

9.Sodium Channel Blockers

Intravenous lidocaine through its sodium channel–blocking properties has demonstrated efficacy in treatment of neuropathic pain [51] and CRPS.

A study by Wallace et al [52] found that intravenous lidocaine caused a significant elevation of the hot pain thresholds in the painful areas. It also caused a significantly decreased response to stroking and cool stimuli in the allodynic areas. A decrease in pain scores to cool stimuli at all plasma levels was seen and also a decrease in spontaneous pain at the highest plasma level.

10.N-methyl-D-aspartate Antagonists

An increased expression of N-methyl-D-aspartate (NMDA) receptors play a role in neuropathic pain in CRPS. Hence, NMDA receptor antagonists can be used for the treatment of pain in CRPS patients. Drugs with relevant NMDA-blocking properties include ketamine, amantadine, memantine, dextromethorphan, and methadone [53].

Dextromethorphan, amantadine, and memantine, are weaker NMDA receptor blockers, and are expected to have fewer central nervous system side effects. 

A study by Kleinböhl et al [54] showed that Amantadine was beneficial for chronic musculoskeletal pain with reductions in experimental sensitization.  Memantine has been anecdotally useful for neuropathic pain but there are no published studies on the use of these drugs in CRPS patients. 

11.Thalidomide

Tumor necrosis factor alpha (TNF-α) is believed to be the cause of inflammation and pain in CRPS. Thalidomide inhibits TNF-α and hence can  reduce inflammation and pain in CRPS patients. Recently, there has been significant interest in the use of thalidomide as a treatment for CRPS. Although there are no published clinical trials on thalidomide use in CRPS, there are case reports demonstrating their efficacy [55, 56]. 

Neuromodulation for treatment in CRPS

A. Spinal Cord Stimulation (SCS)

SCS is used for pain relief in patients with neuropathic pain. It is applied with sophisticated techniques which include multi-output implanted pulse generators and a choice of electrodes. The pulse generators can be placed percutaneously or placed directly by way of a laminotomy. In SCS, low voltage electrical stimulation is delivered to the spinal cord or intraspinal nerve roots to block or decrease the sensation of pain.

There are several theories of mechanisms for the pain-relief with SCS. One of them is the gate control theory of pain, which was developed by Melzack and Wall. It proposes that when large sensory nerve fibers are stimulated there is activation of inhibitory interneurons which competitively inhibits the transmission of impulses from small nociceptive nerve fibers [57].

Studies in rats with neuropathic pain have shown that stimulation of the dorsal columns of the spine causes an increase in the release of g-amino butyric acid and a decrease in the release of the excitatory amino acid glutamate at the dorsal horn [58,59]. 

SCS can produce direct current blockade in neural tissue [60], activate supraspinal antinociceptive nuclei in the brain [61], and inhibit supraspinal and segmental sympathetic outflow [62] to achieve its antinociceptive effects. The aim of SCS is to achieve stimulation-induced paresthesias which is comfortable and can completely overlap the patient’s pain topography [63].

B.Peripheral Nerve Stimulation (PNS)

PNS can be used in patients with CRPS whose symptoms are mainly or entirely in the distribution of one major peripheral nerve.

Plate-type electrodes are placed surgically on affected nerves and tested for a few days. If 50% or more pain reduction and objective improvement in physical changes are achieved, then programmable generators are implanted.  

Hassenbusch et al [64] reported good long‐term results of peripheral nerve stimulation for reflex sympathetic dystrophy. Thirty (94%) of their 32 patients underwent permanent PNS placement. Sixty three percent of their patients had good or fair long term pain relief. In those patients in whom the treatment was successful the allodynic and spontaneous pain was reduced on a scale of 10 from 8.3 preimplantation to 3.5 at 2 to 4 years follow up. 

Though changes in vasomotor tone and patient activity levels were markedly improved, the motor weakness and trophic changes showed less improvement [64].

Behavioral Modification and Psychiatric Consultation

In the first 2 months of the disease no psychological intervention is needed because physcological issues would not have appeared because the patients expect to get well. 

From 2 to 6 months after the onset of the disease anxiety sets in because patients start wondering why they are not getting better. The International Association for the Study of Pain recommends that CRPS patients with pain after 2 months should receive psychological evaluation which includes psychometric testing, to identify and treat anxiety, depression, and or personality disorder [41]. 

Treatment includes behavioral modification, counselling, biofeedback, self-hypnosis, relaxation therapy and group therapy. Patient motivation and coping skills have to be improved. Low dose antidepressants can be given to reduce anxiety and pain.

Patients with pain longer than 6 months in duration invariably have some depression, anxiety and insomnia because the pain is not improving. At this stage, antidepressants such as amitriptyline are necessary. Continued support and education is essential. Biofeedback is needed for relaxation, temperature control and reduction of muscle tension. Family counselling and group therapy  with other patients, with spouse and other family members is useful at this stage. Sometimes use of strong opioids such as slow release morphine may be indicated [41].

Surgical Therapy

Surgical/ablative therapies  for CRPS include chemical sympathectomy, surgical sympathectomy and bilateral anterior cingulotomy.

1.Sympathectomy

The pain in CRPS is believed to sympathetically mediated and hence  

 attempts to interrupt the sympathetic nervous system have been used in the treatment of CRPS. 

Temporary and non-destructive interruption of the sympathetic nervous system can be carried out through injections of local anaesthetics or botulinum toxin. Longer-lasting destructive interruption can be carried out chemically or surgically. While carrying out chemical sympathectomies,  alcohol or phenol injections are used to destroy ganglia of the sympathetic chain. With chemical sympathectomy the effect is temporary until regeneration of the sympathetic chain occurs after three to six months [ 65]  Surgical ablation is performed by open removal or electrocoagulation of the sympathetic chain. It can be carried out through a minimally invasive procedure using stereotactic thermal or laser ablation. The effects of radiofrequency ablation can last up to one year [65]. 

When minimally invasive ablation is not possible, open sympathectomy  can be carried out.

Sympathectomy should be reserved for patients with severe CRPS who are refractory to other modalities of treatment. 

A Cochrane Database Systematic  Review by Strabue et al [66] found that the practice of surgical and chemical sympathectomy for CRPS is based on very little high quality evidence. They recommended that sympathectomy should be cautiously used in clinical practice, in carefully selected patients in whom other treatment options have failed.

Complications after sympathectomy are not uncommon. Most patients complain of soreness at the site of injections lasting 5 to 7 days.  Post sympathectomy neuralgia has been reported in patients undergoing ablation with phenol [66]. 

Furlan et al [67] carried out a systematic review of the late complications of surgical sympathectomies. They found that neuropathic complications occurred in about 11.9% of the patients undergoing cervico-dorsal and lumbar surgical sympathectomy. The incidence of compensatory hyperhidrosis was 52.3%, gustatory sweating 32.3%, phantom sweating 38.6%, and Horner’s syndrome 2.4%, in patients undergoing surgical cervico-dorsal sympathectomy. 

The authors concluded by saying that surgical sympathectomy can be  accompanied with several potentially disabling complications and that detailed informed consent should be taken when surgical sympathectomy is contemplated.

2.Bilateral anterior cingulotomy

Bilateral anterior cingulotomy has been used for treatment of patients with refractory chronic pain. 

Wilkinson et al [68] carried out a study to assess the outcome of bilateral anterior cingulotomy in patients with refractory chronic pain. Their study included 23 patients who underwent 28 cingulotomies. Eighteen patients were available for follow up study. Seventy-two percent of the patients reported improvement in their pain, 55% no longer needed narcotics, 67% had improvement in their family life, and 72% had improvement in their social interactions. Fifty-six percent of patients said that the cingulotomy was beneficial, and 28% of the patients had returned to their usual activities/work [68].

Post operative seizures were reported in some of the patients but the seizures were well controlled with medication.

The authors concluded that bilateral anterior cingulotomy is safe for patients with refractory chronic pain.

Prognosis

Some of the patients with CRPS make good early recovery but there are  others who develop lasting pain and disability. Unfortunately, there is little that is known about the prognostic factors which may be able to help differentiate between these two groups.

A Systematic Review by Jean et al [69] found that many CRPS patients recover within 6 to 13 months. There are a significant number of patients who experience some lasting symptoms, and some of these patients  experience chronic pain and disability. 

A 5.5 years follow up study of patients with upper limb CRPS by Geertzen et al in the Netherlands found that nearly 30% of the patients had to stop work for more then 1 year and 26% of the patients had to change jobs.

Severe cases of CRPS can lead to marked limitation of function. Most experts agree that the prognosis is poor when symptoms become chronic. 

Treatment is most effective when it is started early in the course of the disease. Hence early diagnosis and treatment may improve the prognosis. The prognosis in vast majority of children with CRPS is generally good.

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