Tag: neuroinflammatory theory

Charcot Osteoarthropathy

  • Charcot neuropathic osteoarthropathy (CNO) is a noninfective, inflammatory condition affecting periarticular soft tissue and bone in patients with peripheral neuropathy which if not properly treated may lead to progressive resorption of bone, disruption of soft tissues and disorganization of joints resulting in permanent deformity, altered biomechanics, predisposition to skin ulceration, infection and osteomyelitis.
  • It most commonly affects the foot and ankle region.
  • In the early stages there are local inflammatory changes followed by progressive bone loss, tissue disruption, joint dislocation and development of deformities.
  • The deformities lead to abnormal loading patterns, skin break down, infection and ultimately result in osteomyelitis.
  • Most common cause is diabetic peripheral neuropathy.
  • Lifetime prevalence of CNO in diabetic patients is 0.1-10% which increases to 29-35% if there is peripheral neuropathy.
  • The prevalence in diabetics, depend upon the diagnostic method, with MRI showing positive findings in up to 75% and x-ray findings in 30%. 
  • 28% mortality rate has been reported within 5 years of diagnosis (Sohn 2009).
  • In the early phase, differentiation from acute osteomyelitis is difficult.
  • Natural history (Saltzman 2005)
    • Risk of amputation increased 15-40 fold.
    • 2.7% annual amputation rate.
    • 40% chance of ulceration.
    • 28% mortality within 5 years of diagnosis (Sohn 2009).

History

1703 – Musgrave described CNO as an arthralgia caused by venereal disease.

1831 – JK Mitchell described the relationship with spinal lesion.

1868 – Jean Martin Charcot described the neuropathic aspect.

1881 – JM Charcot at the 7th International Medical Congress described the association with tabes dorsalis.

1936 – WR Jordan described CNO in association with diabetes mellitus.

Pathogenesis

  • Development of CNO is due to interplay between several pathways leading to dysregulation of  bone formation and resorption, persistent inflammatory response, increased glycation of collagen and accumulation of advanced glycation end products (AGLEPs) in the tissues. 
  • In genetically predisposed individuals with peripheral neuropathy, decreased neuropeptides such as nitrous oxide and calcitonin gene related peptide leads to increased levels of receptor activator nuclear factor kappa beta ligand (RANKL). Increased RANKL potentiates osteoclastogenesis resulting in uncoupling of bone formation and resorption. 
  • 3 theories – 
    • Neuro-traumatic theory – Damage to sensory feedback results in repeated trauma. Repeated trauma leads to increased proinflammatory cytokines such as interleukin-1β, interleukin-6, tumour necrosis factor α which causes bone resorption.
    • Neurovascular theory – Due to changes in vascularity caused by dysregulation of vasomotor and trophic nerve supply. 
    • Neuro-inflammatory theory – Abnormal persistence of inflammatory response and inability to terminate the inflammatory response are thought to be important in the pathogenesis. Unregulated inflammatory process triggers increased expression of receptor activator of nuclear kappa ligand (RANKL) in susceptible individuals. RANKL increases production of nuclear factor kappa beta (NF-κβ) which stimulates maturation of osteoclast precursor cells to osteoclasts. RANKL also stimulates synthesis of osteoprotogerin (OPG) by the osteoblasts. The decreased secretion of calcitonin gene related peptide (CGRP) which is an antagonist of RANKL by the damaged nerve endings is also theorized as a cause. Dysfunction of Wnt/βcatenin pathway  which regulate bone and vascular metabolism is also proposed as a cause. Increased RANKL expression is thought to be mediated by advanced glycation end products (AGEs), reactive oxygen species and oxidized lipids. Increased AGEs in diabetes is due to hyperglycemia as well as increased oxidative stress. Increased blood glucose and decreased circulating receptor for AGEs leads to nonenzymatic glycation of collagen and accumulation of AGEs in the tissues. AGEs induce apoptosis in the mesenchymal cells and hence may affect the mechanical parameters of type I collagen.
  • Causes of CNO
    • Diabetes mellitus
    • Leprosy
    • Peripheral neuropathy
    • Syringomyelia
    • Poliomyelitis
    • Multiple sclerosis
    • Tabes dorsalis
    • Toxins
    • Rheumatoid arthritis

Clinical features

  • Physical findings may be neurological, musculoskeletal and vascular abnormalities.
  • The onset may be following a triggering event, which may be trauma, surgery or infection.
  • Clinical findings depend on the stage of disease.
  • There are 3 stages clinico-radiologically.
    • Dissolution stage
    • Coalescence stage
    • Resolution stage
  • Patients present with acute onset unilateral swelling of foot and ankle which may extend up to the knee.
  • Pain is absent in 50% of patients. (Brodsky 1993) 
  • Some patients may complain of mild pain or discomfort.
  • Initial stages show marked inflammation evidenced by erythema, edema, warmth and more than 20C temperature difference when compared to opposite side.
  • Skin temperature measurement using surface temperature sensing devices such as infrared thermometer is useful in assessing severity of inflammation due to neuropathy.
  • Erythema due to CNO will dissipate if the limb is elevated above the level of heart for 10-15 minutes, while erythema due to infection will not.
  • During the coalescence stage, swelling and inflammation begins to dissipate but deformities start developing.
  • During the resolution stage, the signs of inflammation resolves completely and deformities persist.
  • Deformities lead to marked alteration of load bearing pattern of the sole of foot predisposing the high pressure areas to ulceration. 
  • Ulceration lead to infection which may progress to deep infection and osteomyelitis.
  • Deformities affect the forefoot, midfoot, hindfoot or the ankle.
  • Forefoot deformity may involve the first metatarsophalangeal joint in the form of dorsal or plantar dislocation.
  • Mid foot is affected in more than 60% of patients. Patients may develop abduction or adduction deformity at the Lisfranc joint or plantar dislocation of the tarsometatarsal joint leading to classical rocker bottum foot.
  • In the ankle, equinus or calcaneus deformity may develop. 
  • Sagittal instability of foot assessed by Assal and Stern method. The ankle is locked by dorsiflexion, pressure on the forefoot demonstrates instability leading to collapse of longitudinal arch.
  • Contracture of the tendoachilles leads to plantar flexion of the calcaneus and midfoot collapse leads to rocker bottom foot with dorsiflexion of forefoot.  
  • In severe cases the joints may be dislocated and unstable.

Diagnosis

  • Diagnosis needs establishment of the presence of peripheral sensory neuropathy with reduced pain perception and establishment of arthropathy by clinical findings and imaging studies,
  • Peripheral neuropathy diagnosed by
    • Decreased reflexes, reduced vibration sense and weakness
    • Decreased sensation on Semmes-Weinstein monofilament examination of sensation.
    • Pinprick sensation
    • Neurometer test
    • Electrophysiological studies
  • Diagnosis of osteomyelitis done by
    • Presence of ulceration or history of ulceration or previous amputation.
    • Ulcerations bigger than 2cm2and deeper than 3mm.
    • Probe-to-bone test – Thin probe can be inserted to the level of bone.
    • Leukocytosis, raised ESR, CRP and procalcitonin
    • X-ray showing lytic lesions and periosteal elevation.
    • Scintigraphy
    • MRI
    • Bone biopsy
    • Culture of tissue specimens
  • Diagnosis of vascular occlusion
    • History of claudication
    • Absent or low volume pulse
    • Trophic changes
    • Doppler study
    • Transcutaneous oxygen tension assessment
    • Angiography
  • Diabetic neuropathy starts as small fiber predominant neuropathy which progresses to bilateral distal symmetrical polyneuropathy.
  • Bone biopsy shows increased Howship’s lacunae, increased woven bone and inflammatory infiltrate in the marrow spaces consisting of lymphocytes and eosinophils.
  • Later stages show development of deformities especially rigid flat foot, rocker bottom foot with skin changes and ulcerations.

Differential diagnosis

  • Cellulitis
  • Abscess
  • Osteomyelitis
  • Acute gout
  • Fractures
  • Complex regional pain syndrome
  • Deep vein thrombosis

Imaging

  • Basic work up needs weight bearing dorsoplantar view of foot, weight bearing lateral view of foot and ankle and the AP view of ankle.
  • Early stages show soft tissue edema, patchy osteoporosis, small flecks of bone, minor joint incongruence and bone infractions.
  • Bone destruction takes 6-12 months to be visible on the x-rays.
  • Later stage x-rays show fractures, subluxations and dislocations. Typical findings include gross disorganization of joints with osseous debris.
  • More than 60% of patients have involvement of the midfoot.
  • In the rocker bottom foot, plantar flexion of calcaneus, midfoot collapse with plantar subluxation of cuboid and navicular is seen on the weight bearing lateral view.
  • Talo-first metatarsal angle shows negative angle due to dorsal collapse of the forefoot.
  • Dorsoplantar view shows abduction or adduction deformity due to midtarsal malalignment and deformed metatarsals.
  • MRI imaging is very valuable in the early stages when the x-rays are normal as the condition is reversible if treated at this stage.
  • In the early stages, MRI shows periarticular bone marrow edema in 2 or more bones, adjacent soft tissue edema, fluid in multiple tarsal joints and microtrabecular fractures or stress fractures. 
  • 99mTc-MDP three or four phase scintigraphy is highly sensitive but has low specificity.
  • Scintigraphy with 99mTc-WBC nebo 111In-WBC labelled leukocytes is highly sensitive and specific but cannot differentiate between cellulitis and osteomyelitis.
  • PET-CT with fluorine 18 fluorodeoxyglucose (18F-FDG) is 100% sensitive and 93.8% sensitive in differentiating CNO from osteomyelitis. 
  • Patients with CNO show low-intensity diffuse uptake.

Classifications

Eichenholz classification

Classifies the stage of disease depending on clinical features and radiological findings

Sanders and Frykberg Classification

Classifies according to area of involvement of foot and ankle region.

Brodsky and Rouse Classification

Schon classification 

Classifies the area of involvement in the midfoot into four types I to IV. Severity of involvement is classified into three types A to C.

Sella and Barrette 5 stage classification

Classifies the midfoot involvement.

Rogers and Bevilacqua 2 Axis Classification

X-axis marks anatomic location. Y-axis describes degree of complication.

MRI Classification

Treatment

  • When a patient with diabetes presents with an acute fracture, the sensation should be carefully assessed using Semmes -Weinstein monofilaments to rule out neuropathy. If neuropathy is present, look for early signs of CNO. Rule out peripheral vascular disease. If signs of inflammation are present, rule out infection.
  • Goal of treatment are the following;
    • Structural stability of foot and ankle.
    • Prevention of skin ulceration.
    • Plantigrade foot that can be fitted into prescription foot wear.
  • Treatment is mostly conservative.
  • Mainstay of treatment is immobilization in a total contact cast and offloading of weight till edema and warmth subside and the x-ray shows consolidation of bone.
  • Offloading is the most important aspect of management during the acute active stage.
  • In the active phase, immobilize and advise complete cessation of weight bearing.
  • Immobilization is by total contact cast which is changed after 3 days after first application and then every week.
  • During the dissolution stage, the patient advised to use wheel chair than crutches to prevent overloading and injury to normal limb.
  • Immobilize till the edema subsides and the skin temperature comes to be below 20C of the normal limb.
  • May take 6-12 weeks of immobilization.
  • Then use removable brace or Charcot Restraint Orthotic Walker (CROW) for 4-6 months.
  • In the resolution stage, custom total contact inserts and braces are needed to prevent ulcerations.
  • Bisphosphonates and intranasal calcitonin may be useful in the active stage.
  • Bisphosphonates efficacy has been shown to be not significant.
  • One randomized study showed intranasal calcitonin to be useful.
  • Foot reconstruction indications
    • Stable but nonplantigrade foot
    • Unstable foot
    • Recurrent ulcerations
    • To avoid amputation
  • Contraindications for surgery
    • Infection of bone or soft tissue
    • Eichenholz stage I disease
    • Uncontrolled diabetes or malnutrition
    • Peripheral vascular disease
    • Insufficient bone stock
    • Noncompliant or unreliable patient
  • Goals of surgery
    • Alignment of foot on the leg to provide a plantigrade foot that is stable, braceable and walkable
    • Restoration of stability
    • Clearance of infection
    • Relief of pressure points
    • Contouring of foot to allow fitting of orthosis
  • Surgical options
    • Foot reconstruction
    • Excision of bony prominences
    • Major amputations
  • Resection of bony prominences indications
    • Stable foot with isolated bone prominences causing skin problems
    • Stable foot with inability to fit an orthosis due to bony prominences
    • Resection of infected bone in patients being planned for foot reconstruction.
  • Exostosectomy is useful only in the midfoot.
  • Prerequisites for successful arthrodesis
    • Careful removal of all cartilage and debris
    • Debridement to bleeding bone
    • Reshaping to ensure maximum contact
    • Complete removal of soft tissues
    • Stable fixation
    • Immobilization and bracing till consolidation
  • Major amputation indications
    • Severe peripheral vascular disease
    • Severe bone destruction including osteomyelitis
    • Failed previous surgery
  • Transcutaneous oxygen tension of more than 35mm is successful healing after below knee amputation.
  • If an ulcer is present, first step is to get the ulcer heal by debridement, antibiotics and total contact casting.
  • Super-construction principles for foot reconstruction (Sammarco 2009)
    • Arthrodesis should be extended beyond affected area into neighboring joints.
    • Resection of bone to produce mild shortening to enable foot repositioning without overstretching of soft tissues to avoid tissue hypoperfusion.
    • Use strongest possible implant.
    • Place the implant in a manner that provides maximum mechanical stability.
  • External fixation using circular fixators have the advantage of three dimensional stability, gradual correction of deformity and avoidance of internal fixation that may increase the chance of infection.
  • Indications for external fixation
    • Poor soft tissue envelope
    • Active infection
    • Severe deformity that preclude acute correction
    • Poor bone quality
  • For internal fixation, axial screws are preferable as they provide long working length, better stability and least amount of surgical exposure.
  • Surgery is preferably done in the resolution stage.
  • Indications for surgery in the inflammatory stage. 
    • Severe instability
    • Progression of deformity
    • Prevention of dislocation
    • Failure of conservative treatment
  • Surgery in the acute inflammatory phase may worsen the inflammation and may increase the chance of infection.
  • Foot reconstruction depends on the localization of deformities as per the Sanders and Frykberg classification.
  • Sanders I is usually treated conservatively. If there is first metatarsophalangeal dislocation, arthrodesis using 2 screws or a plantar plate is done.
  • Sanders II is often associated with Sanders III deformity. Sanders II is corrected by resection arthrodesis to correct the abduction or adduction deformity of the forefoot and the dorsal dislocation of the Lisfranc joint.
  • Correction of Sanders III deformity proceeds in a stepwise manner. 
    • First step is correction of hindfoot.
    • Second step is correction of Lisfranc joint.
    • Third phase is correction of Chopart’s joint
    • Last step is insertion of  medial and lateral midfoot bolts
      • Medial bolt inserted from the first metatarsal head into the talus.
      • Lateral bolt inserted through the cuboid in the region of fourth metatarsal into the calcaneum. 
  • Operative treatment by medial or lateral column arthrodesis using large intramedullary bolts is called beaming.
  • Correction of equinus is done by either tendoachilles lengthening or gastrocnemius recession.
  • Gastrocnemius recession – 5 options
    • Silfverskiold -Proximal gastrocnemius recession
    • Baumann- Deep gastrocnemius recession
    • Strayer – Distal gastrocnemius recession
    • Endoscopic gastrocnemius recession
    • Baker – Superficial gastrocnemius recession
  • Sanders IV is treated by ankle and subtalar arthrodesis using external fixator. Severe cases may need talectomy and tibiocalcaneal fusion. Some very severe cases with infection and skin ulceration may need below knee amputation.
  • Sanders V with involvement of calcaneum is the least common. Majority are treated conservatively and some may need subtalar fusion.

References

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