Study reference

Study characteristics

Patient characteristics

Index test

(test of interest)

Reference test

Follow-up

Outcome measures and effect size

Comments

Grimm (2014)

Type of study: case-control

Setting:

1 center

Country: Germany

Source of funding: Not reported

Inclusion criteria:

Diagnosis of - PNP according to clinical signs (such as sensory loss or reduction, weakness, atrophy, and/or gait difficulty)

Nerve conduction studies according to criteria of the EFNS

Exclusion criteria:

history of neuromuscular disorders (bijvoorbeeld myopathy, myasthenia gravis etc.)

.

N=

Demyelinating P (I): 25

15 CIDP, 7 GBS, 3 MMN

Axonal (C): 20

Important prognostic factors²:

‘Disease duration’; demyelinating mean 27.4, axonal 15.5 and mixed 48.4

Sex:

‘I: 24 males /1 females

C: 14 males / 6 females

Groups comparable at baseline?

Yes, although men predominated in all groups

Describe index test: Nerve ultrasound: bilateral measurement of median nerve in axilla, before pronator teres, at mid- forearm, ulnar nerve at mid-humerus, mid-forearm, tibial nerve in popliteal space and medial malleolus, fibular nerve 2 cm above fibular head.

Nerves were screened in axial and longitudinal planes and each cross sectional area (CSA) was measured, CSA was traced inside the hyperechoic rim. Ultrasound was real life performed by one examiner blinded to NCS result and off-line evaluated by a second examiner blinded to NCS results

Describe reference test[1]:

Classification of demyelinating, axonal or mixed based on nerve conduction studies according to EFNS/PNS in combination with other information (clinical course, etiology, nerve biopsy results)

Time between the index test and reference test:

-

For how many participants were no complete outcome data available?

0

Sensitivity

For the protocol of enlargement of ≥ 5 nerve points (median nerve; proximal, middle, distal, ulnar nerve; proximal, distal)to discriminate demyelinating PNP no sensitivity is described. Per nerve point sensitivity was reported:

1) Median nerve proximal 84.6%, 2) Median nerve middle 84.6% 3) Median nerve distal 61.5%, 4) Ulnar nerve proximal 85.7% 5) Ulnar nerve distal 60.9% 6) Fibular nerve 65.2%

7) Tibial nerve proximal 76.9% 8) Tibial nerve distal 92.3%

Specificity:

For the protocol of 5 nerve points to discriminate demyelinating neuropathy no specificity is described

Per nerve point the specificity was reported.

1) Median nerve proximal 71.4%

2) Median nerve middle 71.4%

3) Median nerve distal 85.4%

4) Ulnar nerve proximal 85.7%

5) Ulnar nerve distal 91.7%

6) Fibular nerve 79.2

7) Tibial nerve proximal 85.7%

8) Tibial nerve distal 71.4%

1) Heterogeneity of patient characteristics;

- acute and subacute/chronic PNP mixed in intervention group,

 - variation of disease duration - different therapies

2) Mixed PNP group not described in evidence table because of PICO

Study reference

Study characteristics

Patient characteristics

Index test

(test of interest)

Reference test

Follow-up

Outcome measures and effect size

Comments

Rajabally (2012)

Type of study: case-control study

Setting:

1 center in UK

Country: UK

Source of funding: None

Inclusion criteria:

CIDP or SAN diagnosis at clinical and electrophysiological grounds

Exclusion criteria:

-

N=

CIDP (I): 14

Axonal (C): 14

Important prognostic factors²:

 ‘ I: 56.9 years

C: 66.1 years’

Age not significantly different

Sex:

I: 10 males /4 females

C: 4 males /10 females

Groups comparable at baseline?

No as men predominated in CIDP and women in SAN; p=0,057

Describe index test: Nerve ultrasound:

Measurement of median nerve at wrist and 1/3 forearm. Nerve width (lateral to medial border) and thickness (anterior to posterior border) were measured at both levels on transverse images using the largest distance between the hyperechoic rims. CSA was evaluated by tracing the nerve just inside the hyperechoic rim. Patients were investigated by an experienced radiologist blinded for the subtype of neuropathy

Describe reference test[2]:

1) CIDP; electrophysiological demyelination with slowing of motor conduction in at least one median nerve

2) Chronic distal sensory large fibre axonal polyneuropathy (SAN); no demyelinating range abnormalities of any electrophysiological parameters for any studied nerve

Time between the index test en reference test:

-

For how many participants were no complete outcome data available?

0

Reasons for incomplete outcome data described?

NA

Sensitivity

Optimal cut-of value of median nerve thickness at any site of 2.55 mm with sensitivity of 57.1%

Specificity

Optimal cut-of value of median nerve thickness at any site of 2.55 mm with specificity of

92.9%

 1) Possibility of sub-clinical CTS in both groups

2) 13/14 patient therapy at some time

3) Small sample size

4) Limited sonographic protocol

Study reference

Study characteristics

Patient characteristics

Index test

(test of interest)

Reference test

Follow-up

Outcome measures and effect size

Comments

Zaidman (2009)

Type of study: case-control

Setting:

1 center

Country: US

Source of funding: Not reported

Inclusion criteria:

Patients with Acquired axonal neuropathy, CIDP, GBS, demyelinating CMT-1a

With all complaints of sensory or sensory motor polyneuropathy documented by a neurologist

Exclusion criteria:

-

N=

CIDP (I): 36

Demyelinating CMT-1A (I): 11

Axonal (C): 36

Important prognostic factors²:

CIDP average NSI increased with longer time from disease onset (p=0.006) and slower average motor conduction velocity (median and ulnar nerves) (p=0.004)

Sex:

Not reported

Groups comparable at baseline?

Unclear

Describe index test:

Unilateral transverse images of median and ulnar nerve were obtained at three locations; level of mid-humerus, distal forearm, wrist (median nerve) and mid-humerus distal forearm and sulcus (ulnar nerve). The nerve cross sectional area was measured by tracing the nerve just inside the hyperechoic rim, three measurements were averaged at each nerve site. Nerve size index was calculated to correct for height. Enlargement: NSI > 2 SD above the mean NSI in controls. Ultrasound was performed by one investigator.

Describe reference test¹:

CIDP: Clinical and nerve conduction features that met diagnostic criteria described in van den Bergh et al 2014

Axonal: Clinical and electrodiagnostic features included small motor or sensory peak amplitudes with normal or moderately (within 80% of normal limits) prolonged onset latencies or slowed conduction velocities

CMT-1A; genetic confirmation or nerve conduction studies consistent with an inherited demyelinating polyneuropathy and a genetically confirmed first-degree relative

Time between the index test en reference test:

NA

For how many participants were no complete outcome data available?

7 axonal neuropathies without NCS of median and ulnar nerve

Reasons for incomplete outcome data described?

No

Sensitivity

Demyeliniserend vs axonaal

89%

CIDP vs axonaal:

86%

CMT1-A vs axonaal:100%

Specificity:

Demyeliniserend vs rest = 81%

CIDP vs axonaal:

81%

CMT1-A vs axonaal:

81%

1) Heterogeneity of patient characteristics; CIDP already treatment before start of the study

2) Healthy controls not described in evidence table because of PICO

3) CMT1-a patients no NCS in study performed

4) Limitied sonographic protocol; only unilateral measurements

Study reference

Study characteristics

Patient characteristics

Index test

(test of interest)

Reference test

Follow-up

Outcome measures and effect size

Comments

Goedee (2017)

Type of study:

Nested case-control study

Setting:

One center

Country: Netherlands

Source of funding:

Prinses Beatrix Spierfonds

Inclusion criteria:

Diagnosis of CIDP, LSS of MMN or acquired axonal neuropathy or amyotrophic lateral sclerosis after testing of the reference standard according to relevant diagnostic consensus criteria

Exclusion criteria:

Previous diagnosis of PNP, patients already on treatment

N=

(I): CIDP (n=44), MMN (n=22), LSS (n=9)

(C): axonal (n=50), ALS (n=20)

Important prognostic factors²:

‘Sex’

Sex:

I:56 males / 19 females

C: 48 males / 22 females

Groups comparable at baseline?

Yes except for disease duration ALS (p<0.05) and higher MRC sum score in axonal neuropathies (p<0.001)

Describe index test:

Bilaterally measurement of previously described protocol of nerve points (median, ulnar fibular tibial sural nerves, brachial plexus and brachial plexus. Cross sectional area was measured with the ellipse tool within the hyperechoic rim on transverse images.

Cut-off values 99% specific for chronic inflammatory neuropathy were defined as the maximal thickness that occurred in axonal neuropathy and ALS. Ultrasound was performed by an investigator blinded for the NCS results and final diagnosis and evaluated for a second time by a second examiner blinded for the NCS results and final diagnosis

Describe reference test:

Clinical presentation and NCS according to relevant diagnostic consensus criteria

Time between the index test en reference test:

Unclear

For how many participants were no complete outcome data available?

0

Reasons for incomplete outcome data described?

-

Sensitivity

95%

If the following condition is fulfilled:

Enlargement of ≥1 nerve points (median nerve upper arm > 13 mm2, median nerve forearm >10 mm2, any trunk/root (C5-C6-C7) of brachial plexus >8mm2)

Specificity:

98% if the following condition is fulfilled:

Enlargement of ≥1 nerve points (median nerve upper arm > 13 mm2, median nerve forearm >10 mm2, any trunk/root (C5-C6-C7) of brachial plexus >8mm2)

98%

Study reference

Study characteristics

Patient characteristics

Index test

(test of interest)

Reference test

Follow-up

Outcome measures and effect size

Comments

Grimm (2015)

Type of study:

Case-control

Setting:

Two centers

Country: Germany

Source of funding: not reported

Inclusion criteria:

Acute or subacute onset polyneuropathies (no longer than 9 months symptoms) of axonal or demyelinating NCS results

Exclusion criteria:

Rare neuropathies such as MMN, anti-myelin-associated glycoprotein neuropathy or paraneoplastic neuropathies

N=

(I): 15 (CIDP n=12, LSS n=3)

(C): Axonal neuropathies n =20

Important prognostic factors²:

‘sex’

Sex:

I: 12 males / 3 females

C: 13 males / 7 females

Groups comparable at baseline?

Yes except for disease duration CIDP median 3 months, Axonal median 6 months

Describe index test:

Ultrasonography was performed bilaterally in different nerves; median nerve in axilla (proximal), before pronator teres muscle (middle), and at the mid-forearm (distal); ulnar nerve at mid-humerus (proximal) and at the mid-forearm (distal); tibial nerve in popliteal space (proximal) and at medial malleolus before the nerve division into plantar nerves (distal); fibular nerve 2 cm above fibular head; and sural nerve between lateral and medial gastrocnemic head. Nerves were scanned in axial planes, and the cross-sectional area (CSA) was traced inside the hyperechoic rim of the nerve. Ultrasound was real life performed by one examiner blinded to NCS result and off-line evaluated by a second examiner blinded to NCS results

4 subscores were created

UPSS; Overall sum score, UPS-A, UPS-B and UPS-C (Grimm et al 2014 muscle and nerve, J neurological sciences, J neurol Neurosurg)

Describe reference test:

Diagnosis of all patients was ascertained by the diagnostic standards (EFNS guidelines)

Time between the index test en reference test:

NA

For how many participants were no complete outcome data available?

Some sonographic score not calculated due to missing data;

CIDP (n=7) and axonal (n=5)

Reasons for incomplete outcome data described?

-

Sensitivity

UPS-A: 80%

UPSS:

78.5%

UPS-B à GBS

UPS-C no additional value

Specificity:

UPS-A: 95.9%

UPSS:

97.3%

Note:

1) In axonal group: vascultic neuropathy combined with 3 CIP, 2 alcohol, 2 diabetes, 2 vitamin 12 deficiency and 3 graft versus host disease, 2) Control group for CIDP mixed with GBS, axonal neuropathy and healthy controls?

3)

10 patients included for prospective validation of sumscores of which 2 CIDP patients that were diagnosed correctly.

4) 14 consecutive patient included for prospective validations; 2 CIDP patient with abnormal UPSS and UPSB, 1 MADSAM patients with abnormal UPA-A, UPS-B, UPS-C and UPSS

5) possible overlap study population with previous studies

Study reference

Study characteristics

Patient characteristics

Index test

(test of interest)

Reference test

Follow-up

Outcome measures and effect size

Comments

Loewenbrück (2016)

Type of study:

Case-control

Setting:

One center

Country: Germany

Source of funding: Bundesministerium für Bildung und Forschung and an unrestricted research grant from the Roland-Ernst Foundation

The financial sponsors of the study had no role in

the study design, data collection, data analysis, data interpretation, or

writing of the report.

Inclusion criteria:

Cohort I

Diagnosis of minimal possible ALS according to revised El-Escorial criteria

or predominant lower motor neuron involvement; presence of paresis without clinical or electrophysiological signs of upper motor neuron involvement or minimal possible MMN according to EFNS/PNS criteria

Cohort II

Suspected diagnosis of AlS/Lower motor neuron disease (LMND) or MMN and this differential diagnostic focus had to be confirmed by the attending senior physician during initial clinical ward rounds

Exclusion criteria:

Patients not able to follow the study protocol due to advanced impairment

N=

Cohort I

(I): 8 MMN

(C): 16 ALS

Cohort II

(I): 5 MMN

(C): 8 ALS, 17 other

Important prognostic factors²:

 ‘MRC sum score’

Sex:

Cohort I

I: 6 males / 2females

C: 12 males / 4 females

Cohort II

I: 3 males/ 2females

C: 2 males /6 females

Groups comparable at baseline?

No for

Cohort I

1) Age (p =0.008)

2) Diagnosis time point (p=0.04)

3) MRC sum score p =0.001

Cohort II

1) Sex (p=0.032)

2) MRC sum score (p=0.009)

Describe index test:

Transverse and longitudinal images were obtained in 11 nerves at 13 different sites to record CSA and diameter (protocol Zaidman et al muscle and nerve 2009). Examinations performed by two investigators blinded to group assignment

Describe reference test:

Cohort I:

Minimal ALS according to El Escorial criteria or LMND with presence of paresis without clinical or electrophysiological signs of upper motor neuron involvement or minimal possible MMN according to EFNS/PNS criteria

Time between the index test en reference test:

Not reported

For how many participants were no complete outcome data available?

0

Reasons for incomplete outcome data described?

-

Sensitivity:

For ultrasound model 1

(ulnar nerve, medial nerve, superior trunk, C7, sciatic nerve and tibial nerve)

MMN vs ALS and other:

100%

Specificity:

For ultrasound model 1 (ulnar nerve, medial nerve, superior trunk, C7, sciatic nerve and tibial nerve)

MMN vs ALS and other:

92%

Note:.

1) Only 1 axonal neuropathy in control group

2) Cohort II only definite MMN

3) Control group of cohort II various diagnoses

3) No correction for multiple testing

Study reference

Study characteristics

Patient characteristics

Index test

(test of interest)

Reference test

Follow-up

Outcome measures and effect size

Comments

Grimm (2017)

Type of study:

Case-control

Setting:

3 centers

Country: Germany

Source of funding: not reported

Inclusion criteria:

Diagnosis of suspected or known polyneuropathy according to clinical presentation examination or electrophysiology

Exclusion criteria:

-

N=

UPSS

(I);: 77 CIDP (n=54), LSS (n=9), MMN (n=7)?

(C); unclear; presumably 216 patients of which 89 axonal neuropathies

HOM + UPSS

(I);: 77 CIDP (n=54), LSS (n=9), MMN (n=7), CMT 1 (n=7)

(C); unclear ; presumably 216 patients of which 89 axonal neuropathies

Important prognostic factors²:

‘age’

Sex:

Not reported

Groups comparable at baseline?

No, age (p=0.015)

Describe index test:

In short axis the CSA inside the hypoechoic rim of the nerve was measured at predefined landmarks (median nerve; axilla, before pronator teres, at mid- forearm, ulnar nerve; at mid-humerus, mid-forearm, tibial; nerve in popliteal space and medial malleolus, fibular nerve; 2 cm above fibular head.

Iin long axis the nerve root diameter was measured (median nerve; wrist, elbow, mid humerus, ulnar nerve; Guyon, sulcus, mid humerus, radial nerve; spiral groove and the Frohse arcade, peroneal nerve; popliteal fossa, sural nerve; mid calf, vagus nerve; carotid artery at bifurcation level, 5^th/6^th cervical root; directly after intervertebral foramen. In symmetric clinical manifestation measurement on right side, in asymmetric clinical manifestation measurement on both sides

Describe reference test:

Reference test for UPSS and homogeneity scores unclear

Time between the index test en reference test:

-

For how many participants were no complete outcome data available?

Unclear

Reasons for incomplete outcome data described?

-

Sensitivity

UPS-A,UPSS for CIDP

Analysis n=270

For new cut-off values:

UPS-A ≥6 = 83.3%

UPSS ≥ 9 =81.5%

Homogeneity score:

Analysis n =270

CMT-1: ≥5; 100%

CIDP : ≥2; 80.0%

Combined Homogeneity score and UPS-A and UPSS

CIDP;

87.1%

Specificity:

UPS-A,UPSS for CIDP

Analysis n = 270

For new cut-off values:

UPS-A ≥ 6 = 90.1%

UPSS ≥ 9 =91.3%

Homogeneity score:

Analysis n=270

CMT-1: ≥5; 99.5%

CIDP : ≥2; 87.2%

Combined Homgeneity score and

UPS-A and UPSS

Analysis n = 270

CIDP;

PPV 85.5%

Note:.

1) Padua classifaction, Zaidman classification and BUS/NUP not described in evidence table because of PICO

2) UPSS Disease controls mixed group of different polyneuropathies

3)

possible overlap study population with previous studies

4) heterogeneity of patient characteristics;

- mixed prevalent and incident patients