Differential Diagnosis of Acquired and Hereditary Neuropathies in Children and Adolescents—Consensus-Based Practice Guidelines
Abstract
:1. Introduction
2. Materials and Methods
- Strong recommendation: we recommend doing/recommend not doing
- Moderate recommendation: we suggest doing/suggest not doing
- Recommendation is open: may/can be done
- Strong consensus: >95% agreement of voters
- Consensus: >75–95% of voters
- Consent of majority: >50–75% of voters
- No consent of majority: <50% of voters
3. Definition and Classification of Neuropathies in Children and Adolescents
4. The Diagnostic Methods
4.1. History and Clinical Evaluation
4.2. Electrophysiological Diagnostics
- Evidence or exclusion of peripheral nerve damage
- Identification of the affected structures (motor, sensory or sensorimotor neuropathy)
- Determination of the pathomechanism (axonal, demyelinating, or mixed damage)
- Any signs of florid denervation or re-innervation
- Signs of any additional involvement of CNS structures
4.3. Sensory and Vegetative Functional Diagnostics
4.4. Imaging Diagnostics
4.5. Laboratory and Other Paraclinical Diagnostics
4.6. Neuropathological Diagnostics
4.7. Genetic Diagnostics
5. Differential Diagnosis of Acquired and Hereditary Neuropathies in Children and Adolescents
5.1. Nerve Injuries
5.2. Mononeuritis, Mononeuritis Multiplex
5.3. Guillain–Barré Syndrome (GBS) and Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
5.4. Toxic Neuropathies
5.5. Hereditary Non-Syndromic Neuropathies in Children and Adolescents
5.5.1. Hereditary Motor-Sensory Neuropathies (HMSN), Charcot–Marie–Tooth (CMT)-Neuropathy
5.5.2. Distal Hereditary Motor Neuropathies (dHMN)
5.5.3. Hereditary Sensory and Autonomous Neuropathies (HSAN, HSN)
5.5.4. Genetic Diagnostic Algorithms
5.6. Peripheral Neuropathies Associated with Complex Genetic Diseases
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Hereditary Neuropathies | Acquired Neuropathies |
---|---|
CMT2 (axonal, AD or AR) Intermediate CMT (AD or AR) CMT4 (demyelinating, AR) CMTX (demyelinating, axonal, XD, XR)
HSAN2-8 (AR)
DSMA (AR) DSMAX (XD)
HNA (AD)
Neuropathies in the context of neurodegenerative diseases |
Toxic (drugs, heavy metals) Metabolic/malnutrition (uremia, diabetes, dysproteinemia, vitamin deficiency, hypervitaminoses) Paraneoplastic Critical-illness neuropathy Small-fibre neuropathy
Traumatic Nerve tumours Nerve compression syndromes
Inflammatory |
Motor Neurography | EMG | |
---|---|---|
Demyelination | Slowing of NCV, prolongation of distal-motor latency, prolongated or deficient F-waves (in proximal demyelination), abnormal dispersion of CMAP and partial conduction block (acquired multifocal demyelination, for example CIDP) | Normal findings when axonal anomalies are absent |
Axonal damage | Lowered CMAP amplitude (can also be due to muscular atrophy/myopathy) | Florid denervation: fibrillation potentials, positive sharp waves, reduced interference pattern Chronic denervation with re-innervation: abnormal high-amplitude and polyphasic potentials, reduced interference pattern |
Disorder | Lab Diagnostics |
---|---|
Infectious neuropathy | Serology and possible swabs, Borrelia burgdorferi, VZV, etc. |
Inflammatory systemic diseases | ESR, CRP, ANA, double-stranded DNS-ab, C3 complement, ACE, lysozymes, immunoelectrophoretis, cryoglobulin |
GBS, CIDP | CSF protein, CSF cell count, pathogen serology (CMV, Mycopl. pneumoniae, Campylobacter jejuni), anti-gangliosid antibodies (seldom positive), antibodies against paranodal proteins (neurofascin, etc.) |
M. Refsum and other peroxisomopathies | Phytanic acid, VLCFA in serum |
Bassen–Kornzweig syndrome (a-betalipoproteinemia) | Electrophoresis, lipid electrophoresis, vitamin E |
Primary vitamin E resorption disorder | Vitamin E |
Secondary vitamin resorption disorders | Vitamin D (Ca, P, AP, parathormone), vitamin E, vitamin K (INR, quick value), folic acid, vitamin B12 (with holotranscobalamin and methylmalonic acid), thiamin, riboflavin. Vitamin B6 (overdose?) |
CDG syndromes | Isoelectric transferrin focussing |
Metachromatic leukodystrophy and M. Krabbe | CSF protein, lysosomal enzymes |
Mitochondriopathies | Lactate in plasma and CSF, possible muscle biopsy for biochemical analyses |
Site of Lesion | Motor Defect | Sensory Defect | Aetiologies |
---|---|---|---|
Upper brachial plexus | Shoulder abduction and external rotation, elbow flexion, supination | Lateral/radial arm from shoulder to metacarpo-phalangeal joint of thumb | Strain/tearing of the shoulder, perinatal trauma, neuralgic amyotrophy, serogenetic neuritis, tumour infiltration |
Lower brachial plexus | Finger and wrist flexion, finger ab- and -adduction, possibly Horner syndrome | Axillary and ulnar side of the arm from elbow to hand and finger IV and V | Trauma as above, abnormal cervical rib, scalenus syndrome, tumour infiltration |
Long thoracic nerve | Elevation and rotation of scapula, winged scapula on shoulder flexion | - | »back packer palsy«, neuralgic amyotrophy |
Radial nerve | Extension of wrist and metacarpo-phalangeal joints, abduction of thumb, extension of thumb and finger II (»flaccid drop of the hand«) | Back of the hand overlying metarcapals I and II | Humerus shaft fracture, pressure palsy |
Median nerve | Flexion of wrist, flexion of finger I–III (»Schwurhand«) | Volar side of the hand and fingers I to the radial side of IV, dorsal side of same fingers | Supracondylar fracture of humerus, pressure palsy, carpal tunnel syndrome |
Ulnar nerve | Flexion of wrist and metacarpo-phalangeal joint IV–V, ab-/adduction III–V, thumb adduction (»Krallenhand«) | Volar and dorsal side of hand and fingers IV and V (not radial side finger IV) | Supracondylar fracture of humerus, elbow fracture, pressure palsy |
Ischiadic nerve | Combination of tibial- and peroneal lesion | Combination of tibial- and peroneal lesion | Ischiadic lesion at misplaced injection, pelvic fractures |
Tibial nerve | Foot- and toe flexors, loss of Achilles tendon reflex | Plantar side of the foot, lateral side of the foot | Fractures, injury to the hollow of the knee |
Peroneal nerve | Foot extension (»Steppage gait«) | Lateral lower leg, back of the foot | Fibular fracture, pressure palsy |
Drugs | Heavy Metals and Solvents |
---|---|
Vincristin, cis-platinum | Lead |
Taxane, epothilone | Gold |
Bortezomib | Thallium |
Thalidomide | Arsenic |
Nitrofurantoin, isoniazid (INH) | Mercury |
Hydantoine | n-Hexane |
Chloramphenicol, metronidazol | Methyl-n-butylketone |
Amphotericin | Triorthocresylphosphate |
Disease | Diagnostics | Treatment |
---|---|---|
Refsum syndrome | Axonal or demyelinated NP, phytanic acid, pristanic acid | Phytanic acid-restricted diet, plasmapheresis |
Adrenoleukodystrophy | VLCFA | Presymptomatic BMT |
Metachromatic leukodystrophy | Demyelinated NP, lysosomal enzymes | Presymptomatic BMT |
Vitamin E malabsorption | Vitamin E in serum | Vitamin E |
Bassen–Kornzweig syndrome | Abetalipoproteinemia | Vitamin E |
B12 deficiencies in resorption and utilisation | Vit B12 in serum, methylmalonic acis, homocystein in serum | Vitamin B12 |
Folate deficiencies in resorption and utilisation | Folate, 5-Methyltetrahydrofolate | Folate, folinic acid |
Cerebrotendinous xanthomatosis | Plasma cholestanol | Diet, chenodesoxycholic acid |
Brown–Vialetto–van Laere syndrome | Bulbar paralysis, deafness, riboflavin in serum | Riboflavin |
CD59 mutation | Anemia, paroxysmal nocturnal hematuria, relapsing NP | Eculizumab |
Acute intermittent porphyria | Porphobilinogen | Glucose, haematin |
Pyruvate dehydrogenase deficiency | Lactate, enzyme diagnostics, genetics | Ketogenic diet |
Morbus Fabry (alpha-galactosidase A deficiency) | Severe acroparesthesias, autonomous neuropathy, angiokeratoma, corneal dystrophy, cardiovascular disease, stroke, renal impairment | Enzyme replacement therapy with agalsidase alfa or agalsidase beta |
Familial amyloid polyneuropathy (onset from adolescence) | Symmetric sensory-motor and autonomic neuropathy, family history of neuropathy and/or cardiomyopathy, gi involvement, weight loss, carpal tunnel syndrome, TTR genetics | Liver transplantation, TTR stabilizers and gene modifying approaches in preparation [16] |
Initially Presenting with PNP | +Ataxia | +Spasticity | +Ataxia +Spasticity +EPMS | +Global Developmental Delay | Multisystem Involvement |
---|---|---|---|---|---|
Metachromatic Leukodystrophy (ARSA) | Vitamin E deficiency (TTPA, MTP, acquired) * Vitamin B12 deficiency * Refsum syndrome (PHYA) * Sensory PNP in Friedreich Ataxia (FXN) EAOH (APTX) SCAR1(SETX) SCA27 (FGF14) AT (ATM) NARP (MTATP6) SCAR23 (PDYN) Microcephaly, seizures, and developmental delay (MCSZ) ARSACS (SACS) SCAN1 (TDP1) | Adrenoleukodystrophy (ABCD1) * Methylmalonic aciduria Vit. B12 deficiency * SPG (4, 9a, 12, 17, 39 ...) | Spastic Aataxia 5 (AFG3L2) LBSL (DARS2) Hypomyelinating leukodystrophy (TUBB4A) Leigh (-like) (SURF1/MFF, SUCLA2) | PDHC (PDHAl) * Krabbe (GALC) * Metachrom. Leukodystrophy (ARSA) * Aicardi-Goutieres syndrome * Global insensitivity to pain (CTLC1) Giant axonal neuropathy (GAN) NBIA2a (PLA2G6) CDG (NGLYl) MCSZ (PNKP) CEDNIK (SNAP29) Ponto-cerebellar hypoplasia (EXOSC3/AMPD2) Infantile Refsum (PEX7) | Mitochondriopathy * multi. acyl CoADH deficiency * Hexosaminidase A/B deficiency (HEXA/HEXB) * Brown–Vialetto–Van Laere (SLC52A2/3) * Peroxisomal 6 (PEX10) ACPHD (ABHD12) PHARC SPOE NBIA (C1901f12) SCAR21 (SCYLl) Familial Dystautonomia (TECPR2) Triple A (AAAS) MEDNIK (AP151) PTRH2 Galaktosialidosis (CTSA) |
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Korinthenberg, R.; Trollmann, R.; Plecko, B.; Stettner, G.M.; Blankenburg, M.; Weis, J.; Schoser, B.; Müller-Felber, W.; Lochbuehler, N.; Hahn, G.; et al. Differential Diagnosis of Acquired and Hereditary Neuropathies in Children and Adolescents—Consensus-Based Practice Guidelines. Children 2021, 8, 687. https://doi.org/10.3390/children8080687
Korinthenberg R, Trollmann R, Plecko B, Stettner GM, Blankenburg M, Weis J, Schoser B, Müller-Felber W, Lochbuehler N, Hahn G, et al. Differential Diagnosis of Acquired and Hereditary Neuropathies in Children and Adolescents—Consensus-Based Practice Guidelines. Children. 2021; 8(8):687. https://doi.org/10.3390/children8080687
Chicago/Turabian StyleKorinthenberg, Rudolf, Regina Trollmann, Barbara Plecko, Georg M. Stettner, Markus Blankenburg, Joachim Weis, Benedikt Schoser, Wolfgang Müller-Felber, Nina Lochbuehler, Gabriele Hahn, and et al. 2021. "Differential Diagnosis of Acquired and Hereditary Neuropathies in Children and Adolescents—Consensus-Based Practice Guidelines" Children 8, no. 8: 687. https://doi.org/10.3390/children8080687