Elena Gallardo

Ultrasound in the diagnosis of peripheral neuropathy: structure meets function in the neuromuscular clinic

Peripheral nerve ultrasound (US) has emerged as a promising technique for the diagnosis of peripheral nerve disorders. While most experience with US has been reported in the context of nerve entrapment syndromes, the role of US in the diagnosis of peripheral neuropathy (PN) has recently been explored. Distinctive US findings have been reported in patients with hereditary, immune-mediated, infectious and axonal PN; US may add complementary information to neurophysiological studies in the diagnostic work-up of PN. This review describes the characteristic US findings in PN reported to date and a classification of abnormal nerve US patterns in PN is proposed. Closer scrutiny of nerve abnormalities beyond assessment of nerve calibre may allow for more accurate diagnostic classification of PN, as well as contribute to the understanding of the intersection of structure and function in PN.

Charcot–Marie–Tooth disease type 1A duplication with severe paresis of the proximal lower limb muscles: a long-term follow-up study

Objective: To describe a large pedigree with Charcot–Marie–Tooth disease type 1A (CMT1A) duplication in which severe pelvic and thigh musculature weakness occurred in two patients, detected by analysing the leg muscle atrophy pattern on magnetic resonance imaging (MRI). Methods: The pedigree comprised 18 patients, aged between 15 and 85 (median 46) years, who were serially evaluated for up to three decades. All 18 patients and 13 non-affected at-risk people underwent electrophysiological examination. An MRI study of lower limb musculature was carried out in four patients. Three patients underwent sural-nerve biopsy. Genetic testing was carried out in 17 patients and in all 13 at-risk normal people. Results: Fourteen patients were asymptomatic or slightly disabled. The two oldest patients, aged 84 and 80, showed a moderate phenotype. Two other patients, aged 70 and 53, showed late-onset and gradually progressive peroneal paresis extending up to the thigh and pelvic musculature, resulting in waddling gait. MRI scans of all three patients with a mild phenotype showed subtle and subclinical fatty infiltration of calf anterolateral muscle compartments, with thigh muscle involvement in one patient, and extensive atrophy of intrinsic foot muscles. In the youngest patient with proximal leg weakness, the MRI scan showed massive fatty atrophy of all the calf muscles, posteromedial thigh muscle compartments, and internal and external hip rotator muscles. Sural-nerve biopsy specimens showed hypertrophic neuropathy with no superimposed inflammation. Good correlation was seen between electrophysiological and genetic testing. Conclusions: Late in the clinical course, a small proportion of patients with CMT1A develop severe proximal leg weakness, and long-term follow-up is essential for its detection. MRI scans may show subclinical involvement of the thigh musculature.

Magnetic resonance imaging findings of leg musculature in Charcot-Marie-Tooth disease type 2 due to dynamin 2 mutation

The purpose of the study was to prospectively assess magnetic resonance (MR) imaging findings of lower limb musculature in an axonal Charcot-Marie-Tooth disease (CMT2) pedigree due to mutation in the dynamin 2 gene (DNM2). The series comprises a proband patient aged 55 years and her two affected daughters aged 32 and 23. MR imaging study included T1- and fat suppressed T2-weighted spin-echo sequences. MR imaging study showed extensive fatty infiltration of all calf muscle compartments with relative preservation of the deep posterior one. Fatty muscle infiltration increased distally in 19 out of 66 (23 %) visualized calf muscles in the three patients, but this percentage increased to 64 % in the youngest and least severe patient. Muscle edema without contrast enhancement was present in 23 % of calf muscles. There was massive fatty atrophy of foot musculature. We conclude that MR imaging study accurately depicts lower limb muscle involvement in CMT2 caused by DNM2 mutation.

Autosomal dominant distal myopathy with a myotilin S55F mutation: sorting out the phenotype

Objective: To describe the clinical phenotype of an autosomal-dominant pedigree with myotilinopathy. Methods: Two symptomatic patients and six asymptomatic gene mutation carriers were examined. We performed serum chemistry, electrophysiological assessments, magnetic resonance imaging (MRI) of lower limb musculature, histochemical and immunohistochemical studies of a muscle biopsy and mutation analysis of the myotilin gene. Results: Both symptomatic patients, aged 76 and 61 years, presented with late-onset, distal lower-limb weakness involving the ankle and toe flexo-extensor muscles extending up to the thigh muscles; there was mild weakness of the intrinsic hand musculature in the eldest patient. Electromyography revealed a myopathic pattern. Serum creatine kinase levels were slightly elevated. Muscle biopsy revealed myopathic changes with myotilin- and desmin-positive aggregates. Gene sequencing identified a myotilin S55F mutation. In both patients, MRI showed moderate to severe fatty atrophy of all four leg muscle compartments, extending up to the thigh musculature, mainly involving the biceps, femoris, semimembranosus, vasti and glutei muscles; intrinsic foot musculature was involved but to a lesser degree. In all six gene mutation carriers, aged from 21 to 63 years, clinical examinations showed no myopathic signs. MRI was normal in the youngest individual, whereas in the remaining five individuals the outstanding finding was fatty infiltration of the soleus muscles. Conclusions: Myotilin S55F mutations may cause a clinically distinct autosomal-dominant late-onset and lower-limb distal myopathic syndrome involving all four leg muscle compartments. MRI helps to reliably depict the topography of fatty muscle atrophy and to detect early leg muscle changes in asymptomatic gene mutation carriers.

CMT1A duplication: refining the minimal adult phenotype.

Dear Editor, Charcot-Marie-Tooth disease type 1A (CMT1A) is an autosomal dominant demyelinating polyneuropathy usually associated with a large DNA duplication on the short arm of chromosome 17 (Lupski et al., 1991; Raeymaekers et al., 1991). Symptoms are present during the first decade of life in over 60% of cases (Harding and Thomas, 1980; Garcı́a et al., 1998). Whereas absence of signs on physical examination may occur in 50% of presymptomatic CMT1A children under 5 years of age (Garcı́a et al., 1998; Berciano et al., 2003), this is an extremely rare situation in adult patients (Lupski et al., 1991; Kaku et al., 1993). We describe clinico-electrophysiological features and magnetic resonance imaging (MRI) patterns of lower limb amyotrophy in subclinically affected CMT1A adult patients. We reviewed the clinical records of our cohort of 126 CMT1A duplication cases, aged from 10 to 93 years coming from 25 unrelated pedigrees, and found two subclinical patients (patient 1 and patient 2), both studied originally as asymptomatic secondary cases. We administered the functional disability scale (FDS) (Birouk et al., 1997) and the Charcot-Marie-Tooth disease neuropathy score (CMTNS) (Shy et al., 2005). MRI study of lower limb musculature and electrophysiological studies were performed as reported elsewhere (Garcı́a et al., 1998; Gallardo et al., 2006). Patient 1 is aged 48 years and has been serially evaluated since age 17; her repeated physical examinations revealing mild pes cavus (Figs. 1A and 1B) with no other neuropathic signs. Patient 2 is aged 58 years and has been serially evaluated since age 48; her repeated physical examinations revealing mild pes cavus. Both patients showed normal FDS score and CMTNS of 3. MRI showed a pattern of intrinsic foot musculature involvement (Figs. 1C and 1D) with distal fatty atrophy of lower leg musculature, which was more apparent in patient 2. Motor conduction velocity was uniformly reduced (25–32 m/s in median and ulnar nerves and 25–29 m/s in peroneal and tibial nerves) with normal (Figs. 1E and 1F) or reduced foot compound muscle action potential (CMAP) amplitudes. Sensory conduction velocity was reduced in median and ulnar nerves (from 23 to 27 m/s) with reduced sensory nerve action potential amplitudes; sural nerve showed similar findings in patient 1 and was absent in patient 2. F-wave latencies were prolonged in median, ulnar, and tibial nerves and absent in peroneal nerve. Myoelectric deep tendon reflex (T-reflex) responses from biceps and gastrocnemius muscles were preserved though delayed. The single electromyographic abnormality in patient 1 was a moderate increase of polyphasic potentials in tibialis anterior muscle. Patient 2 showed a reduced recruitment pattern with long-duration and high-amplitude action potentials in extensor digitorum brevis muscle; the recording in tibialis anterior being normal. Fibrillation and positive waves were not present in either patient. While pes cavus is a cardinal manifestation of Charcot-Marie-Tooth disease (Harding and Thomas, 1980), it is also the hallmark of ‘idiopathic’ pes cavus that represents one third of cases attended in any pes cavus clinic (Brewerton et al., 1963). Electrophysiological study is essential to distinguish between both disorders, especially if, as reported here, there is evidence of positive family history with well-defined electrophysiological phenotype. Although adult patients with mild disease constitute a significant subset in any CMT1A series, the situation described here of repeated normal neurologic examination in adult patients is unusual. In a large French Acadian CMT1A pedigree (HOU1), there were three at-risk individuals, of ages 19, 26, and 27 years, who appeared clinically normal; each was found to have symmetrically reduced nerve conduction velocities and 17p duplication (Lupski et al., 1991; Kaku et al., 1993). In contrast with the cases in this pedigree, clinical data from eight large CMT1A cohorts, comprising 523 patients with at least 188 of them being secondary cases, have corroborated the Harding and Thomas paradigm of absence of affected individuals with completely normal clinical findings (Hoogendijk et al., 1994; Birouk et al., 1997; Thomas et al., 1997; Fabrizi Address correspondence to: Prof. José Berciano, MD, PhD, Service of Neurology, University Hospital ‘‘Marqués de Valdecilla’’, IFIMAV and CIBERNED, University of Cantabria, 39008 Santander, Spain. Tel: 34-942-202520; Fax: 34-942-202655; E-mail: jaberciano@humv.es Journal of the Peripheral Nervous System 13:310–312 (2008)

Early axonal Guillain-Barré syndrome with normal peripheral conduction: imaging evidence for changes in proximal nerve segments

In early Guillain-Barre syndrome (GBS), including in its axonal forms, the most frequent electrophysiological findings are abnormalities of late responses (H reflex and F response) pointing to dysfunction in the proximal segments of the peripheral nerves.1 Ultrasonography and MRI are the imaging techniques of choice in any pathology of the peripheral nerve trunks.2 We report nerve imaging findings in a patient with early axonal GBS. An 18-year-old woman was admitted with a 1-day history of lower limb weakness and calf myalgias. Two weeks prior, she had an episode of profuse diarrhoea of 4-day duration attended at home by her family physician; stool culture was not carried out. Initial examination revealed a waddling gait, weakness of proximal lower limb muscles mainly involving ilio-psoas (Medical Research Council grade 4/5), lower limb areflexia and absence of sensory loss. Upper limb reflexes were brisk. In the next few days the patients lower limb weakness progressed, so that on day 6 after onset she was unable to walk, her muscle power being 2–3/5 proximally and 3–4/5 distally. Treatment with standard intravenous immunoglobulin (2 g/kg in 5 days) was administered. There has been progressive improvement; 3 months after onset, examination revealed mild waddling gait, paresis of hip abductors/flexors (3–4/5) and foot dorsiflexors (4/5), and lower limb areflexia. No serum IgG antiganglioside antibodies were detected. Campylobacter jejuni serology was not available. Cerebrospinal fluid showed a protein content of 70 mg/dL and no cells. Sequential nerve conduction …

New insights into the pathophysiology of pes cavus in Charcot–Marie–Tooth disease type 1A duplication

Forefoot pes cavus is a cardinal sign of Charcot–Marie–Tooth disease (CMT). This review is focused on the pathophysiology of pes cavus in CMT1A duplication, which is the most common subtype of the disease. Assessment of foot deformities in CMT1A, their prevalence and proposed mechanisms, and recent contributions of magnetic resonance imaging studies of lower-leg and foot musculature are revised. Special attention is given to papers on foot deformities at initial stages of the disease. We conclude that pes cavus is an early and age-dependent manifestation of CMT1A duplication. Selective denervation of intrinsic foot musculature, particularly of the lumbricals, and not imbalance of lower-leg muscles, seems to be the initial mechanism causing reduced ankle flexibility and forefoot cavus deformity.

Charcot–Marie–Tooth disease type 2G redefined by a novel mutation in LRSAM1

To identify the unknown genetic cause in a large pedigree previously classified with a distinct form of axonal Charcot–Marie–Tooth disease type 2G (CMT2G) and to explore its transcriptional consequences.

Clinical indications for musculoskeletal ultrasound updated in 2017 by European Society of Musculoskeletal Radiology (ESSR) consensus

ObjectivesTo update the 2012 European Society of Musculoskeletal Radiology (ESSR) clinical consensus guidelines for musculoskeletal ultrasound referral in Europe.MethodsTwenty-one musculoskeletal imaging experts from the ESSR participated in a consensus study based on a Delphic process. Two independent (non-voting) authors facilitated the procedure and resolved doubtful issues. Updated musculoskeletal ultrasound literature up to July 2017 was scored for shoulder, elbow, wrist/hand, hip, knee, and ankle/foot. Scoring of ultrasound elastography was included. The strength of the recommendation and level of evidence was scored by consensus greater than 67% or considered uncertain when the consensus was consensus less than 67%.ResultsA total of 123 new papers were reviewed. No evidence change was found regarding the shoulder. There were no new relevant articles for the shoulder, 10 new articles for the elbow, 28 for the hand/wrist, 3 for the hip, 7 for the knee, and 4 for the ankle/foot. Four new evidence levels of A were determined, one for the hip (gluteal tendons tears), one for the knee (meniscal cysts), one for the ankle (ankle joint instability), and one for the foot (plantar plate tear). There was no level A evidence for elastography, although for Achilles tendinopathy and lateral epicondylitis evidence level was B with grade 3 indication.ConclusionsFour new areas of level A evidence were included in the guidelines. Elastography did not reach level A evidence. Whilst ultrasound is of increasing importance in musculoskeletal medical practice, the evidence for elastography remains moderate.Key Points• Evidence and expert consensus shows an increase of musculoskeletal ultrasound indications.• Four new A evidence levels were found for the hip, knee, ankle, and foot.• There was no level A evidence for elastography.

Charcot-Marie-Tooth disease: a review with emphasis on the pathophysiology of pes cavus☆

Abstract Charcot-Marie-Tooth disease is the most frequent inherited neuropathy with a prevalence ratio in Spain of 28.2 cases / 100,000 inhabitants. It is a sensory-motor polyneuropathic syndrome, either demyelinating or axonal, which might be transmitted with autosomal dominant, autosomal recessive or X-linked pattern. Despite presenting with a stereotyped semiology, this a genetically complex syndrome comprising 36 localized loci with 30 cloned mutated genes. Here we briefly review the pathogenic mechanisms of these gene mutations. We address the pathophysiology of pes cavus, which is a cardinal manifestation of the disease. In the early clinical stages, forefoot pes cavus is most probably due to selective denervation of foot musculature, and particularly of the lumbricals, which causes an imbalance between intrinsic and extrinsic foot muscles leading to toe clawing, retraction of plantar fascia, approximation of the pillars of the longitudinal arch, and shortening of the Achilles tendon. We review the disease diagnosis and treatment.