Background
Methods
Clinical question
Registration and reporting
Information sources and search
# | Searches |
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1 | peripheral nervous system neoplasms/ OR nerve compression syndromes/ OR nerve sheath neoplasms/ OR neuralgia/ OR neuritis/ OR (neuralgia$1 OR neuritis OR entrapment$1 OR (nerve ADJ5 compression)).ti,ab. |
2 | neurilemmoma/ OR neuroma/ OR neurofibroma/ OR (neurilemmoma$1 OR neuroma$1 OR neurofibroma$1).ti,ab. |
3 | foot diseases/ OR foot/ OR forefoot/ OR (foot OR forefoot).ti,ab. |
4 | metatarsus/ OR metatarsal bones/ OR metatarsophalangeal joint/ OR toes/ OR (metatarsus OR metatarsal$1 OR intermetatarsal OR metatarsophalangeal OR toe$1 OR interdigital OR (plantar ADJ5 digital)).ti,ab. |
5 | (morton$1 ADJ5 (disease$1 OR neuroma$1 OR neuralgia$1)).ti,ab. OR metatarsalgia/ OR metatarsalgia$1.ti,ab. |
6 | 1 OR 2 |
7 | 3 OR 4 |
8 | 6 AND 7 |
9 | 5 OR 8 |
10 | exp animals/ NOT humans.sh. |
11 | 9 NOT 10 |
12 | (treat$5 OR intervention$2 OR therap$5 OR manag$5 OR procedur$2).ti,ab. |
13 | 11 AND 12 (apply English language filter) |
Study selection
Data collection process
Risk of bias in individual studies
Summary measures and synthesis of results
Results
Overview of studies
Outcome measures
Types of intervention
Study ID | Sample Size Female/Male | Age (years) Mean, Range | Inclusion Criteria | Intervention | Study Duration | Outcome Measure |
---|---|---|---|---|---|---|
Bennett 1995 [4] | 115, 99/16 | 48.0, 18–79 | Clinical | Wider, properly fitted footwear and a metatarsal pad proximal to the inflamed nerve | 3 months | Satisfaction |
Cashley 2015 [2] | 38, 23/15 | NR | Mulder’s sign, and positive digital nerve stretch test | Manipulation of the MTPJ (Distraction and plantarflexion of the MTPJ) 1/week × 4 weeks and 1 per 2 weeks × 2 (total = 6 treatments) | 8 weeks | VAS (0–100) Pain pressure threshold |
Cazzato 2016 [51] | 20, 15/5 | 50.3, 24–67 | Symptoms and US and MRI | 1 x MRI guided cryoablation (00 × 150 s) Some received additional cryoablation for 90 s but details NR | Mean 19.7 (1–50) months | VAS (0–10) Johnson scale |
Chuter 2013 [10] | 25, 21/4 | 55.0, 33–73 | US | Mean 1.6 (1–3) x US guided radiofrequency ablation (810, 5 × 2 min) 4 weeks apart | 6 months | VAS (0–10) |
Climent 2013 [6] | 17, 7/10 | 58.2, SD 2.6 | MRI or US | 1 x Botox injection (50 units of onabotulinumtoxinA dissolved in 0.5 ml of normal saline) | 3 months | VAS (0–10) FHSQ (foot pain, foot function, footwear, foot health) |
Deniz 2015 [9] | 20, 16/4 | 48.4, 21–67 | Clinical and US | 1 x US guided pulsed radiofrequency ablation (420 × 5 min) | Mean 9 (7–15) months | Satisfaction Comfort when walking VAS (0–10) |
Dockery 1999 [5] | 100, 73/27 | 51.0, 20–75 | Clinical but not specified | 3–7 x alcohol and anaesthetic injection (0.5 ml of 4% sclerosing solution consisting of 48 ml of 0.5% bupivacaine HCI with epinephrine (1:200,000) and 2 ml of ethyl alcohol 98%) repeated at 5–10 day intervals | Mean 13 (6–24) months | Improvement |
Fanucci 2003 [20] | 40, 33/7 | 48.0, 28–65 | Clinical and US | 4 x US guided alcohol and anaesthetic injections (0.35 ml carbocaine and 0.15 ml ethylic alcohol 95%) 15 days apart | 10 months | Johnson scale |
Friedman 2012 [49] | 5, 5/0 | 55.0, 47–60 | US | 1 x US guided cryoneurolysis (− 750, 1–3 freeze/thaw × 2–3 min cycles) | Mean 16 (4–56) months | Treatment response |
Govender 2007 [48] | 20, NR, VS 20, NR Split for combined 10:3 | 50.0, NR, VS 53.0, NR Range for combined 23–79 | Symptoms or clinical findings | Manipulation and mobilisation of foot and ankle joints (6 different techniques which may include distraction and plantarflexion of the MTPJ) AND 5 min detuned US 2/week × 3 weeks (total = 6 treatments) VS 5 min detuned US | 3 weeks | VAS (0–100) Short-form McGill Pain Questionnaire Foot Function Index - Pain Foot Function Index - Disability Pain pressure threshold Pain pressure tolerance |
Hassouna 2007 [22] | 39, 32/7 | 55.8, 26–83 | Clinical and US | 1 x US guided steroid and anaesthetic injection (mixture of 2 ml 0.5% bupivacaine and 20 mg of triamcinolone acetonide) | Mean 11.4 (range NR) months | Activity restriction Footwear requirements Johnson scale |
Hughes 2007 [7] | 101, 84/17 | 53.8, 30–74 | Clinical and US | 4 x US guided alcohol and anaesthetic injections (0.1 ml ethyl alcohol 100% and 0.4 ml bupivacaine 0.25%) 14 days apart 4 additional injections provided to unknown number of subjects | Mean 10.5 (7–19) months | Johnson scale – modified VAS (0–10) |
Hyer 2005 [19] | 6, 4/2 | 61.7, 50–81 | Clinical | 3–9 x alcohol and anaesthetic injection (0.5 ml of 4% sclerosing solution consisting of 48 ml of 0.5% bupivacaine HCI with epinephrine (1:200,000) and 2 ml of ethyl alcohol 98%) weekly injections | Mean 346, SD 50.3 days | VAS (0–10) |
Kilmartin 1994 [50] | 10, NR, VS 11, NR Combined 19/2 | 40.0, SD 12.0 VS 46.0, SD 10.5 | Clinical | Varus foot wedge made of 7 mm hard compressed felt on the under surface of a fibreboard inner to supinate the rearfoot and fitted into the subject’s shoes (low heeled lace-up or loose fitting slip on shoes). Felt was replaced at 4, 8 and 12 weeks. VS Valgus wedge to pronate the rearfoot | 12 months | VAS (0–10) |
Lizano-Diez 2017 [41] | 16, 12/4 VS 19, 17/2 | 57.7, SD 9.8 VS 60.7, SD 11.6 | Clinical, Mulder’s sign and MRI | 1 x corticosteroid and anaesthetic injection (1 ml triamcinolone 40 mg and 1 ml mepivacaine 2%) 1/week for 3 weeks VS 1 x anaesthetic injection (2 ml mepivacaine 2%) 1/week for 3 weeks | 6 months | VAS (0–100) AOFAS Johnson scale - modified |
Magnan 2005 [23] | 65, 55/10 | 51.5, 19–80 | Clinical | 1 or 2 electrostimulation guided alcohol and anaesthetic injections (2.5 ml phenol 5% water solution followed by 3 ml carbocaine 2%) (19 ft received 2nd injection within 3 months) | Mean 36 (24–55) months | VAS (effective / ineffective) |
Mahadevan 2016 [40] | 23, NR VS 22, NR | 57.1, SD 11.7 VS 58.6 SD 14.3 | Clinical and positive web space squeeze test and US | 1 x US guided corticosteroid and anaesthetic injection (1 ml triamcinolone acetonide 40 mg and 2 ml lignocaine 1%) VS 1 x corticosteroid and anaesthetic injection (1 ml triamcinolone acetonide 40 mg and 2 ml lignocaine 1%) | 12 months | VAS (0–100) Manchester-Oxford Foot Questionnaire Index Johnson scale |
Markovic 2008 [1] | 35, 28/7 | 54.0, 29–77 | Symptoms and US | 1 x US guided corticosteroid and anaesthetic injection (1 ml celestone chronodose 5.7 mg and 0.5 ml lidocaine 1%) | 9 months | Johnson scale Lower extremity functional scale |
Masala 2018 [53] | 52, 46/6 | 53.0, 33–75 | Symptoms and US and MRI | 1 x US guided continuous radiofrequency ablation (850 × 90 s) | 12 months | VAS (0–10) FHSQ |
Park 2017 [54] | 201, 158/43 | 55.9, 23–80 | Symptoms and Mulder’s sign and US | 1 x US guided corticosteroid and anaesthetic (1 ml dexamethasone 5 mg and 1 ml lidocaine 1%) | 6 months | VAS (0–10) Johnson scale |
Pasquali 2015 [8] | 508, 464/44 | 57.0, 29–81 | Symptoms, clinical and US | Mean 3 (1–4) x US guided alcohol injection (0.3 ml ethyl alcohol 95% and 0.3 ml of mepivacaine 2%) 2 weeks apart then 4 weeks apart for 3rd and 4th injections | 12 months | Satisfaction VAS (0–10) |
Perini 2016 [55] | 220, 187/33 | 55.8, 19–82 | Clinical and US | 1 x US guided alcohol and anaesthetic injection (0.6–1.0 ml of 50% absolute alcohol and 50% lidocaine 2%) every 2nd week for a median of 3 treatments (IQR 3–3) | Mean 19 (15–24) months | VAS (0–10) |
Saygi 2005 [3] | 35, 31/4 VS 34, 29/5 | 52.0, SD 11.8 VS 51.9, SD 11.0 | Clinical and US | Shoes with wide toe boxes and low heels and metatarsal pad (custom fitted inserts) VS 2 x corticosteroid and anaesthetic injection (1 ml methylprednisolone acetate 40 mg and 1 ml prilocaine 4%) 3 weeks apart | 6 months | Satisfaction |
Seok 2016 [52] | 14, 9/5 VS 12, 8/4 | 58.5, SD 13.4 VS 54.5, SD 14.3 | Symptoms, Mulder’s sign and US | 1 x ESWT (1000 shocks at 3 Hz) with energy level set to maximum patient tolerance (0.12–0.24 mJ/mm2) VS 1 x ESWT with probe perpendicular to energy delivery and energy level set to 0.03mJ/mm2 | 4 weeks | VAS (0–100) AOFAS Johnson scale |
Thomson 2013 [39] | 64, 54/10 VS 67, 57/10 | 54.7, SD 17.4 VS 51.6, SD 12.9 | Symptoms and US | 1 x US guided corticosteroid and anaesthetic injection (1 ml methylprednisolone 40 mg and 1 ml lignocaine 2%) VS 1 x US guided anaesthetic injection (1 ml lignocaine 2%) | 3 months | Foot health thermometer VAS (0–100) MFPDI – pain MFPDI – walking MFPDI – work |
Study ID | NHMRC | Quality Index | Adverse Events (participants, %) | VAS MD (95% CI) | SR (95% CI) |
---|---|---|---|---|---|
Corticosteroid injection | |||||
Thomson 2013 [39] | RCT | High | Corticosteroid group Several, (unknown %) increased foot pain 1–2 days post injection 3, (5.0%) dorsal skin hypopigmentation over injection site at 3 months 2, (3.0%) plantar fat pad atrophy at 3 months | − 23.9 (− 30.4 to − 17.4) | NR |
Lizano-Diez 2017 [41] | RCT | Moderate | 3, (18.7%) mild skin atrophy at the area of infiltration | −20.1 (− 21.8 to − 18.4) | 38% (15 to 65) |
Mahadevan 2016 [40] | RCT | Moderate | 1, (2.2%) localised depigmentation | Ultrasound −40.8 (− 55.4 to − 26.2) Non-Ultrasound − 34.1 (− 48.7 to − 19.5) | Ultrasound 30% (13 to 53) Non-Ultrasound 5% (0 to 23) |
Saygi 2005 [3] | RCT | Low | NR | NR | 50% (32 to 68) |
Park 2017 [54] | Case series | Moderate | NR | −57.0 (−59.4 to − 54.6) | 20% (15 to 27) |
Hassouna 2007 [22] | Case series | Low | NR | NR | 31% (17 to 48) |
Markovic 2008 [1] | Case series | Low | NR | NR | 63% (41 to 81) |
Sclerosing injection | |||||
Perini 2016 [55] | Case series | Moderate | Common, (unknown %) short term pain at injection site 178, (80.9%) hypo anaesthesia of the innervated area | −60.0 (− 65.7 to − 54.3) | NR |
Dockery 1999 [5] | Case series | Low | Common, (unknown %) post-injection neuritis for 48 h | NR | 82% (73 to 89) |
Fanucci 2003 [20] | Case series | Low | 6, (15.0%) transitory plantar pain | NR | 53% (36 to 68) |
Hughes 2007 [7] | Case series | Low | Common, (unknown %) 5–10 s of moderate transient discomfort during injection 17, (16.8%) increased plantar pain 2 to 21 days 1, (1.0%) complex regional pain syndrome which resolved | − 55.0 (− 56.7 to − 53.2) | 62% (52 to 72) |
Hyer 2005 [19] | Case series | Low | NR | −61.2 (− 80.2 to − 42.2) | NR |
Magnan 2005 [23] | Case series | Low | 1, (1.8%) developed 4th toe pain but unsure if related to intervention | NR | 80% (69 to 89) |
Pasquali 2015 [8] | Case series | Low | Mean local inflammatory reaction 1-week post procedure 0.7, (range, 0 to 2)** | −51.0 (−52.9 to − 49.1) | 74% (71 to 78) |
Radiofrequency ablation | |||||
Masala 2018 [53] | Case series | Moderate | NR | −73.0 (−74.7 to − 71.3) | NR |
Chuter 2013 [10] | Case series | Low | 8, (32.0%) described intervention as unpleasant 1, (4.0%) posterior tibial nerve irritation for 3 weeks | − 43.0 (− 50.8 to − 35.2) | NR |
Deniz 2015 [9] | Case series | Low | 2, (10.0%) superficial cellulitis and moderate haematoma | −38.0 (− 48.5 to − 27.5) | 60% (36 to 81) |
Manipulation/mobilisation | |||||
Govender 2007 [48] | RCT | Moderate | NR | −24.0 (−31.3 to − 16.7) | NR |
Cashley 2015 [2] | Case series | Low | NR | −65.3 (− 69.8 to − 60.8) | NR |
Wider footwear and metatarsal padding | |||||
Saygi 2005 [3] | RCT | Low | NR | NR | 14% (5 to 30) |
Bennett 1995 [4] | Case series | Low | NR | NR | 38% (29 to 48) |
Cryoneurolysis | |||||
Cazzato 2016 [51] | Case series | Low | 1, (4.2%) local cellulitis around cryo-probe entry point | NR | 78% (52 to 94) |
Friedman 2012 [49] | Case series | Low | NR | NR | 60% (15 to 95) |
Extracorporeal shockwave therapy | |||||
Seok 2016 [52] | RCT | Moderate | NR | −28.3 (−37.8 to − 18.8) | 0% (0 to 22) |
Orthoses | |||||
Kilmartin 1994 [50] | RCT | Moderate | 1, (10%) lower limb pain with supination orthoses 2, (18.2%) lower limb pain with pronation orthoses | Supination −10.0 (− 28.3 to 8.3) Pronation − 15.0 (− 30.6 to 0.6) | NR |
Botox injection | |||||
Climent 2013 [6] | Case series | Low | NR | −32.6 (− 49.0 to − 16.2) | NR |
Quality of included studies
Quality Index Items | Bennett 1995 | Cashley 2015 | Cazzato 2016 | Chuter 2013 | Climent 2013 | Deniz 2015 | Dockery 1999 | Fanucci 2003 | Friedman 2012 | Govender 2007 | Hassouna 2007 | Hughes 2007 | Hyer 2005 | Kilmartin 1994 | Lizano-Diez 2017 | Magnan 2005 | Mahadevan 2016 | Markovic 2008 | Masala 2018 | Park 2017 | Pasquali 2015 | Perini 2016 | Saygi 2005 | Seok 2016 | Thomson 2013 |
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Reporting | |||||||||||||||||||||||||
1. Study hypothesis/aim/objective | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 0 | 1 | 1 | 1 | 1 | 1 | 1 | 0 | 1 | 1 | 0 | 1 | 1 | 1 | 1 | 1 | 1 |
2. Main outcomes | 1 | 1 | 1 | 0 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 |
3. Participant characteristics | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 0 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 |
4. Interventions of interest | 0 | 1 | 1 | 1 | 0 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 0 | 1 | 1 |
5. Distributions of principal confounders in each group | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 2 | 0 | 1 | 0 | 2 | 2 | 0 | 2 | 1 | 2 | 2 |
6. Main findings | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 0 | 1 | 0 | 1 | 1 | 1 | 1 | 1 | 1 | 1 |
7. Estimates of random variability for main outcomes | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 1 | 1 | 0 | 1 | 0 | 1 | 0 | 0 | 1 | 0 | 1 | 1 |
8. All the important adverse events that may be a consequence of intervention | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 1 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
9. Characteristics of patients lost to follow-up | 0 | 1 | 0 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 1 | 1 | 1 | 0 | 0 | 0 |
10. Actual probability values for main outcomes | 0 | 1 | 0 | 1 | 1 | 1 | 0 | 0 | 0 | 1 | 1 | 1 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 1 | 1 | 1 | 0 | 0 | 1 |
External validity | |||||||||||||||||||||||||
11. Were subjects who were asked to participate representative of the entire population from which they were recruited? | 1 | 1 | 1 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 1 | 1 | 1 | 1 | 1 | 1 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 1 |
12. Were those subjects who were prepared to participate representative of the entire population from which they were recruited? | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 1 | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
13. Were the staff, places, and facilities where the patients were treated, representative of the treatment the majority of subjects received? | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 |
Internal validity (bias) | |||||||||||||||||||||||||
14. Was an attempt made to blind study subjects to the intervention they have received? | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
15. Was an attempt made to blind those measuring the main outcomes of the intervention? | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
16. If any of the results of the study were based on “data dredging”, was this made clear? | 1 | 1 | 1 | 1 | 0 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 0 | 1 | 1 | 1 | 1 | 0 | 1 | 1 |
17. Do analyses adjust for different lengths of follow-up? | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 1 | 1 | 0 | 1 | 1 | 1 | 1 | 1 | 0 | 1 | 1 | 1 |
18. Were the statistical tests used to assess the main outcomes appropriate? | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 1 | 0 | 1 | 1 | 0 | 1 | 0 | 1 | 1 | 1 | 1 | 1 | 1 | 1 |
19. Was compliance with the intervention reliable? | 0 | 1 | 1 | 0 | 1 | 1 | 1 | 1 | 1 | 0 | 1 | 1 | 1 | 1 | 1 | 0 | 1 | 1 | 1 | 1 | 0 | 1 | 0 | 1 | 0 |
20. Were the main outcome measures valid and reliable? | 1 | 1 | 1 | 1 | 1 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 0 | 1 | 0 | 1 | 1 |
Internal validity (selection bias) | |||||||||||||||||||||||||
21. Were the patients in different intervention groups recruited from the same population? | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 0 | 1 | 1 |
22. Were study subjects in different intervention groups recruited over the same period of time? | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 0 | 0 | 1 |
23. Were study subjects randomised to intervention groups? | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 1 |
24. Was the randomised intervention assignment concealed from both patients and staff until recruitment was complete and irrevocable? | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
25. Was there adequate adjustment for confounding in the analyses from which the main findings were drawn? | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 |
26. Were losses of patients to follow-up taken into account? | 1 | 1 | 0 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 0 | 1 | 0 | 1 | 0 | 1 | 1 | 0 | 1 | 1 | 1 | 1 | 0 | 0 | 1 |
Power | |||||||||||||||||||||||||
27. Did the study have sufficient power to detect a clinically important effect where the probability for a difference being due to chance is less than 5%? | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
Total score (/32) | 11 | 17 | 17 | 12 | 14 | 14 | 14 | 15 | 13 | 19 | 13 | 16 | 12 | 20 | 21 | 12 | 22 | 11 | 19 | 19 | 14 | 20 | 10 | 18 | 23 |
Quality Index (low 0–17, moderate 18–22, high 23–32) | low | low | low | low | low | low | low | low | low | moderate | low | low | low | moderate | moderate | low | moderate | low | moderate | moderate | low | moderate | low | moderate | high |