Quantitative Foot Muscle Magnetic Resonance Imaging Reliably Measures Disease Progression in Children and Adolescents with Charcot-Marie-Tooth Disease Type 1A.

Quantitative muscle fat fraction (FF) responsiveness is lower in younger Charcot-Marie-Tooth disease type 1A (CMT1A) patients with lower baseline calf-level FF. We investigated the practicality, validity, and responsiveness of foot-level FF in this cohort involving 22 CMT1A patients and 14 controls. The mean baseline foot-level FF was 25.9 ± 20.3% in CMT1A patients, and the 365-day FF (n = 15) increased by 2.0 ± 2.4% (p < 0.001 vs controls). Intrinsic foot-level FF demonstrated large responsiveness (12-month standardized response mean (SRM) of 0.86) and correlated with the CMT examination score (ρ = 0.58, P = 0.01). Intrinsic foot-level FF has the potential to be used as a biomarker in future clinical trials involving younger CMT1A patients. ANN NEUROL 2024.

Lower limb muscle MRI fat fraction is a responsive outcome measure in CMT X1, 1B and 2A.

OBJECTIVE: With potential therapies for many forms of Charcot-Marie-Tooth disease (CMT), responsive outcome measures are urgently needed for clinical trials. Quantitative lower limb MRI demonstrated progressive calf intramuscular fat accumulation in the commonest form, CMT1A with large responsiveness. In this study, we evaluated the responsiveness and validity in the three other common forms, due to variants in GJB1 (CMTX1), MPZ (CMT1B) and MFN2 (CMT2A). METHODS: 22 CMTX1, 21 CMT1B and 21 CMT2A patients and matched controls were assessed at a 1-year interval. Intramuscular fat fraction (FF) was evaluated using three-point Dixon MRI at thigh and calf level along with clinical measures including CMT examination score, clinical strength assessment, CMT-HI and plasma neurofilament light chain. RESULTS: All patient groups had elevated muscle fat fraction at thigh and calf levels, with highest thigh FF and atrophy in CMT2A. There was moderate correlation between calf muscle FF and clinical measures (CMTESv2 rho = 0.405; p = 0.001, ankle MRC strength rho = -0.481; p < 0.001). Significant annualised progression in calf muscle FF was seen in all patient groups (CMTX1 2.0 ± 2.0%, p < 0.001, CMT1B 1.6 ± 2.1% p = 0.004 and CMT2A 1.6 ± 2.1% p = 0.002). Greatest increase was seen in patients with 10-70% FF at baseline (calf 2.7 ± 2.3%, p < 0.0001 and thigh 1.7 ± 2.1%, p = 0.01). INTERPRETATION: Our results confirm that calf muscle FF is highly responsive over 12 months in three additional common forms of CMT which together with CMT1A account for 90% of genetically confirmed cases. Calf muscle MRI FF should be a valuable outcome measure in upcoming CMT clinical trials.

Nerve biopsy in T-cell lymphoma with neurolymphomatosis: where and when.

Peripheral T-cell lymphomas are rare heterogeneous haematological malignancies that may also involve peripheral nerves in a very small subset of cases. We report a patient with a diagnostically challenging cutaneous T-cell lymphoma and multifocal mononeuropathies in whom a targeted nerve biopsy identified lymphomatous infiltration of nerves and expedited combination treatment with chemotherapy and an autologous stem cell transplant. She showed an excellent response with a complete metabolic response on positron emission tomography imaging and significant clinical improvement, maintained 5 years post-treatment.

Muscle MRI in periodic paralysis shows myopathy is common and correlates with intramuscular fat accumulation.

INTRODUCTION/AIMS: The periodic paralyses are muscle channelopathies: hypokalemic periodic paralysis (CACNA1S and SCN4A variants), hyperkalemic periodic paralysis (SCN4A variants), and Andersen-Tawil syndrome (KCNJ2). Both episodic weakness and disabling fixed weakness can occur. Little literature exists on magnetic resonance imaging (MRI) in muscle channelopathies. We undertake muscle MRI across all subsets of periodic paralysis and correlate with clinical features. METHODS: A total of 45 participants and eight healthy controls were enrolled and underwent T1-weighted and short-tau-inversion-recovery (STIR) MRI imaging of leg muscles. Muscles were scored using the modified Mercuri Scale. RESULTS: A total of 17 patients had CACNA1S variants, 16 SCN4A, and 12 KCNJ2. Thirty-one (69%) had weakness, and 9 (20%) required a gait-aid/wheelchair. A total of 78% of patients had intramuscular fat accumulation on MRI. Patients with SCN4A variants were most severely affected. In SCN4A, the anterior thigh and posterior calf were more affected, in contrast to the posterior thigh and posterior calf in KCNJ2. We identified a pattern of peri-tendinous STIR hyperintensity in nine patients. There were moderate correlations between Mercuri, STIR scores, and age. Intramuscular fat accumulation was seen in seven patients with no fixed weakness. DISCUSSION: We demonstrate a significant burden of disease in patients with periodic paralyses. MRI intramuscular fat accumulation may be helpful in detecting early muscle involvement, particularly in those without fixed weakness. Longitudinal studies are needed to assess the role of muscle MRI in quantifying disease progression over time and as a potential biomarker in clinical trials.

Muscle magnetic resonance imaging involvement patterns in nemaline myopathies.

OBJECTIVE: Characterise the diagnostic and prognostic value of muscle MRI patterns as biomarkers in a genetically heterogeneous nemaline myopathy (NM) patient cohort. METHODS: Modified Mercuri scoring of lower limb MRI in genetically characterised NM patients referred to the highly specialised service for congenital myopathies at Great Ormond Street Hospital. Findings were compared to clinical data and MRI patterns derived from collated published data. RESULTS: Twenty-seven patients with MRI were identified (8 NEB-NM, 13 ACTA1-NM, 6 TPM3-NM). NEB-NM demonstrated sparing of the thigh. ACTA1-NM demonstrated diffuse thigh involvement, notable in the vasti, sartorius and biceps-femoris, with relative adductor and gracilis sparing. TPM3-NM demonstrated diffuse thigh involvement notable in biceps-femoris and adductor magnus with relative rectus femoris, adductor longus and gracilis sparing. In the lower leg, the soleus and tibialis anterior are notably involved in all three genotypes. NEB-NM and ACTA1-NM demonstrated relative gastrocnemii and tibialis posterior sparing, while TPM3-NM showed significantly more tibialis posterior involvement (P =< 0.05). Comparison of involvement patterns with literature datasets highlighted preferential adductor and gracilis sparing in our ACTA1-NM cohort, consistent tibialis posterior involvement in our TPM3-NM cohort and a distinct MRI pattern from those derived from other NM genotypes and congenital myopathies. Greater tibialis anterior involvement correlated with foot drop (P = 0.02). Greater tibialis anterior and extensor hallucis longus involvement correlated with worse mobility (P =< 0.04). INTERPRETATION: This is the widest NM MRI data set described to date; we describe distinct muscle involvement patterns for NEB-NM, ACTA1-NM and TPM3-NM which may have utility as diagnostic and prognostic biomarkers and aid in genetic variant interpretation.

Sacral Tarlov cysts: Neurophysiology abnormalities and correlation with pelvic sensory and visceral symptoms.

BACKGROUND AND PURPOSE: Recent studies suggest a possible association between Tarlov cysts (TCs), usually considered as incidental radiological findings, and neurological symptoms such as pain, numbness and urogenital complaints. The aim was to explore the relationship between TCs and sacral nerve root functions using pelvic neurophysiology tests, and to correlate changes with clinical symptoms and magnetic resonance imaging (MRI) findings. METHODS: Consecutive patients with sacral TCs, referred for pelvic neurophysiology testing and presenting with at least one symptom related to the pelvic area, participated in a cross-sectional review of symptoms using validated questionnaires. Findings of pelvic neurophysiology (pudendal sensory evoked potentials, sacral dermatomal sensory evoked potentials, external anal sphincter electromyography) and urodynamics testing were collected retrospectively. The relationship between neurophysiology, MRI findings and patients' symptoms was assessed using Fisher and ANOVA tests. RESULTS: Sixty-five females were included (mean age 51.2 ± 12.1 years). The commonest symptom was pain (92%). Urinary (91%), bowel (71%) and sexual (80%) symptoms were also frequently reported. Thirty-seven patients (57%) had abnormal neurophysiology findings reflecting sacral root dysfunction. No association was seen between MRI findings (size, location of the cysts, severity of compression) and neurophysiology. A negative association was observed between neurophysiology abnormalities and occurrence of urgency urinary incontinence (p = 0.03), detrusor overactivity (p < 0.01) and stress urinary incontinence (p = 0.04); however, there was no association with voiding difficulties. CONCLUSIONS: Contrary to current understanding, TCs are associated with injury to the sacral somatic innervation in the majority of patients with presumed symptomatic cysts. However, urinary incontinence is unlikely to be related to TC-induced nerve damage.

Anti-HMGCR myopathy: barriers to prompt recognition.

Anti-HMGCR (3-hydroxy-3-methylglutaryl coenzyme A reductase) myopathy is an immune-mediated necrotising myopathy. Atypical presentations hinder its recognition and its prompt treatment. We present two patients with atypical clinical or pathological features. A 45-year-old woman had an asymptomatic serum creatine kinase (CK) of ~10 000 IU/L and muscle biopsy showing minimal changes. She then developed slowly progressive proximal weakness, diagnosed as limb-girdle muscular dystrophy but with negative genetics. Twelve years later, now with severe proximal weakness, her MR scan of muscle showed diffuse asymmetrical fatty degeneration, with conspicuous hyperintense STIR signal abnormalities. HMGCR antibodies were positive and she partially improved with immunosuppression. The second patient developed slowly progressive proximal limb weakness with a high serum CK (~4000 IU/L); muscle biopsy showed a lymphocyte infiltrate with angiocentric distribution suggesting vasculitis. Serum HMGCR antibodies were positive. Anti-HMGCR myopathy can present as a slowly progressive myopathy with atypical pathology. HMGCR antibody screening is indicated for people with suspected limb-girdle muscular dystrophy or atypical inflammatory muscle conditions.

Evidence of nerve hypertrophy in patients with inclusion body myositis on lower limb MRI.

INTRODUCTION/AIMS: Inclusion body myositis (IBM) is a myopathic condition but in some patients has been associated with an axonal length-dependent polyneuropathy. In this study, we quantified the cross-sectional area of the sciatic and tibial nerves in patients with IBM comparing with Charcot-Marie-Tooth disease type 1A (CMT1A) and healthy controls using magnetic resonance neurography (MRN). METHODS: MRN of the sciatic and tibial nerves was performed at 3T using MPRAGE and Dixon acquisitions. Nerve cross-sectional area (CSA) was measured at the mid-thigh and upper third calf regions by an observer blinded to the diagnosis. Correlations were performed between these measurements and clinical data. RESULTS: A total of 20 patients with IBM, 20 CMT1A and 29 healthy controls (age- and sex-matched) were studied. Sciatic nerve CSA was significantly enlarged in patients with IBM and CMT1A compared to controls (sciatic nerve mean CSA 62.3 ± 22.9 mm2 (IBM) vs. 35.5 ± 9.9 mm2 (controls), p < 0.001; and 96.9 ± 35.5 mm2 (CMT1A) vs. 35.5 ± 9.9 mm2 (controls); p < 0.001). Tibial nerve CSA was also enlarged in IBM and CMT1 patients compared to controls. DISCUSSION: MRN reveals significant hypertrophy of the sciatic and tibial nerves in patients with IBM and CMT1A compared to controls. Further studies are needed to correlate with neurophysiological measures and assess whether this finding is useful diagnostically.

Pragmatic guide to peripheral nerve disease and the role of clinical biomarkers.

In clinical neurology practice, there are few sensitive, specific and responsive serological biomarkers reflecting pathological processes affecting the peripheral nervous system. Instead, we rely on surrogate multimodality biomarkers for diagnosis and management. Correct use and interpretation of the available tests is essential to ensure that appropriate treatments are used and adjusted in a timely fashion. The incorrect application or interpretation of biomarkers can result in misdiagnosis and delays in appropriate treatment. Here, we discuss the uses and limitations of such biomarkers and discuss possible future developments.

Clinical assessment of a circadian-based antioxidant system combined with a comprehensive brightening serum in diverse subjects with moderate-to-severe facial hyperpigmentation.

BACKGROUND: Hyperpigmentation conditions can affect all skin types but occur more frequently in darker skin. Because many factors have been implicated in the etiologies of these disorders, multi-targeted approaches may be required to achieve a better overall outcome in a diverse patient population. AIMS: The purpose of this study was to investigate the safety and efficacy of a combination regimen of a comprehensive cosmetic brightening agent (LYT2) with a broad blend of antioxidants (LVS) to reduce hyperpigmentation and improve overall skin appearance. METHODS: The combination of LYT2 and LVS, in addition to a basic skincare routine, was evaluated in subjects of either Caucasian or Asian (a majority of whom were Indian) descent, presenting with moderate-to-severe hyperpigmentation. Efficacy evaluations consisted of investigator clinical grading of overall hyperpigmentation, skin tone evenness, and radiance, as well as subject self-assessment questionnaires. RESULTS: Immediate and progressive improvement was noted by the investigators for all assessed parameters. At the end of the 12-week study, investigators observed a 45% mean decrease from baseline for overall hyperpigmentation. In addition, a 50% improvement in skin tone evenness and a 58% increase in radiance was observed. These investigator assessments were matched by good patient scores for self-perceived efficacy parameters and high overall satisfaction. One patient (7%) showed a treatment-related adverse event. CONCLUSION: A combination skincare regimen that combines the pigmentation control of LYT2 with the broad antioxidant defense of LVS is a well-tolerated and effective treatment option to improve the appearance of facial hyperpigmentation and make skin more radiant.

Charcot-Marie-Tooth disease type 2CC due to NEFH variants causes a progressive, non-length-dependent, motor-predominant phenotype.

OBJECTIVE: Neurofilaments are the major scaffolding proteins for the neuronal cytoskeleton, and variants in NEFH have recently been described to cause axonal Charcot-Marie-Tooth disease type 2CC (CMT2CC). METHODS: In this large observational study, we present phenotype-genotype correlations on 30 affected and 3 asymptomatic mutation carriers from eight families. RESULTS: The majority of patients presented in adulthood with motor-predominant and lower limb-predominant symptoms and the average age of onset was 31.0±15.1 years. A prominent feature was the development of proximal weakness early in the course of the disease. The disease progressed rapidly, unlike other Charcot-Marie-Tooth disease (CMT) subtypes, and half of the patients (53%) needed to use a wheelchair on average 24.1 years after symptom onset. Furthermore, 40% of patients had evidence of early ankle plantarflexion weakness, a feature which is observed in only a handful of CMT subtypes. Neurophysiological studies and MRI of the lower limbs confirmed the presence of a non-length-dependent neuropathy in the majority of patients.All families harboured heterozygous frameshift variants in the last exon of NEFH, resulting in a reading frameshift to an alternate open reading frame and the translation of approximately 42 additional amino acids from the 3' untranslated region (3'-UTR). CONCLUSIONS: This phenotype-genotype study highlights the unusual phenotype of CMT2CC, which is more akin to spinal muscular atrophy rather than classic CMT. Furthermore, the study will enable more informative discussions on the natural history of the disease and will aid in NEFH variant interpretation in the context of the disease's unique molecular genetics.

Uniparental isodisomy of chromosome 2 causing MRPL44-related multisystem mitochondrial disease.

Mutations in nuclear-encoded protein subunits of the mitochondrial ribosome are an increasingly recognised cause of oxidative phosphorylation system (OXPHOS) disorders. Among them, mutations in the MRPL44 gene, encoding a structural protein of the large subunit of the mitochondrial ribosome, have been identified in four patients with OXPHOS defects and early-onset hypertrophic cardiomyopathy with or without additional clinical features. A 23-year-old individual with cardiac and skeletal myopathy, neurological involvement, and combined deficiency of OXPHOS complexes in skeletal muscle was clinically and genetically investigated. Analysis of whole-exome sequencing data revealed a homozygous mutation in MRPL44 (c.467 T > G), which was not present in the biological father, and a region of homozygosity involving most of chromosome 2, raising the possibility of uniparental disomy. Short-tandem repeat and genome-wide SNP microarray analyses of the family trio confirmed complete maternal uniparental isodisomy of chromosome 2. Mitochondrial ribosome assembly and mitochondrial translation were assessed in patient derived-fibroblasts. These studies confirmed that c.467 T > G affects the stability or assembly of the large subunit of the mitochondrial ribosome, leading to impaired mitochondrial protein synthesis and decreased levels of multiple OXPHOS components. This study provides evidence of complete maternal uniparental isodisomy of chromosome 2 in a patient with MRPL44-related disease, and confirms that MRLP44 mutations cause a mitochondrial translation defect that may present as a multisystem disorder with neurological involvement.

Late onset depression: dopaminergic deficit and clinical features of prodromal Parkinson's disease: a cross-sectional study.

BACKGROUND: Late onset depression (LOD) may precede the diagnosis of Parkinson's disease (PD) or dementia with Lewy bodies (DLB). We aimed to determine the rate of clinical and imaging features associated with prodromal PD/DLB in patients with LOD. METHODS: In a cross-sectional design, 36 patients with first onset of a depressive disorder (Diagnostic and Statistical Manual of Mental Disorders IV criteria) diagnosed after the age of 55 (LOD group) and 30 healthy controls (HC) underwent a detailed clinical assessment. In addition, 28/36 patients with LOD and 20/30 HC underwent a head MRI and 29/36 and 25/30, respectively, had dopamine transporter imaging by 123I-ioflupane single-photon emission computed tomography (SPECT) imaging. Image analysis of both scans was performed by a rater blind to the participant group. Results of clinical assessments and imaging results were compared between the two groups. RESULTS: Patients with LOD (n=36) had significantly worse scores than HC (n=30) on the PD screening questionnaire (mean (SD) 1.8 (1.9) vs 0.8 (1.2); p=0.01), Movement Disorder Society Unified Parkinson's Disease Rating Scale total (mean (SD) 19.2 (12.7) vs 6.1 (5.7); p<0.001), REM-sleep behaviour disorder screening questionnaire (mean (SD) 4.3 (3.2) vs 2.1 (2.1); p=0.001), Lille Apathy Rating Scale (mean (SD) -23.3 (9.6) vs -27.0 (4.7); p=0.04) and the Scales for Outcomes in PD-Autonomic (mean (SD) 14.9 (8.7) vs 7.7 (4.9); p<0.001). Twenty-four per cent of patients with LOD versus 4% HC had an abnormal 123I-ioflupane SPECT scan (p=0.04). CONCLUSIONS: LOD is associated with increased rates of motor and non-motor features of PD/DLB and of abnormal 123I-ioflupane SPECTs. These results suggest that patients with LOD should be considered at increased risk of PD/DLB.

MRI quantifies lumbosacral nerve root and sciatic nerve hypertrophy in chronic inflammatory demyelinating polyradiculoneuropathy.

PURPOSE: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a treatable, immune-mediated condition characterised by progressive or relapsing motor and sensory neurological deficits. The diagnosis is based on a combination of clinical, neurophysiological and supportive criteria, but can be challenging. In this study, we quantified the diameter and cross-sectional area of the lumbosacral nerve roots, and explored the imaging characteristics of the sciatic nerves, in patients with CIDP versus healthy controls using MRI. METHODS: MRI of the lumbosacral plexus and both thighs was performed at 3 T. Orthogonal diameter and cross-sectional area of the lumbosacral nerve roots were measured, along with sciatic nerve cross-sectional area at the mid-thigh level. The MRI appearance of the sciatic nerves was also evaluated qualitatively. All measurements were performed by an observer blinded to the diagnosis. RESULTS: 10 patients with CIDP and 10 healthy controls (age and sex-matched) were studied. Lumbosacral nerve root diameter and cross-sectional area were significantly increased in patients with CIDP compared to controls (mean diameter 6.0 ±â€¯1.1 mm vs 4.8 ±â€¯0.3 mm; p = 0.006), with a high sensitivity (89 %) and specificity (90 %) on ROC analysis. Sciatic nerve cross sectional area was also significantly increased in the CIDP group, and was accompanied by qualitative MRI changes. CONCLUSIONS: Quantitative MRI reveals significant hypertrophy of the lumbosacral nerve roots and sciatic nerves in patients with CIDP compared to controls. This study provides further evidence for the inclusion of lumbosacral nerve root and sciatic nerve hypertrophy on MRI as a supportive feature in the diagnostic criteria for CIDP.

Structural transitions and encapsulation selectivity of thermoresponsive polyelectrolyte complex micelles.

Polyelectrolyte complex (PEC) micelles are formed by mixing a block copolymer composed of a neutral block and a charged block, with an oppositely charged polymer. The micelles formed have a PEC core, capable of encapsulating charged molecules like nucleic acids or proteins, while the neutral block(s) forms the corona that offers protection that can prevent cargo from being degraded under physiological conditions. This work explores using a thermosensitive polymer, poly(N-isopropyl acrylamide) (pNIPAM), as the primary corona-forming block and how that can be leveraged in the context of drug delivery. pNIPAM has a lower critical solubility temperature (LCST), above which a hydrophilic to hydrophobic transition occurs. We are characterizing micelles formed using a diblock copolymer of pNIPAM-b-poly(acrylic acid) with (1) poly(lysine) and (2) poly(ethylene glycol)-b-poly(lysine) using dynamic light scattering, small angle X-ray scattering, absorbance and fluorescence spectroscopy, and transmission electron microscopy. Our results indicate that mixing pNIPAM-b-poly(acrylic acid) and poly(lysine) creates worm-like micelles, while mixing the same diblock with poly(ethylene glycol)-b-poly(lysine) forms spherical micelles. At temperatures above 35 °C, the transition temperature of pNIPAM-b-poly(acrylic acid), the worm-like micelles lose their structure, while the spherical micelles retain their structure, but both aggregate into larger assemblies. Lastly, we evaluate the ability of these micelles to encapsulate and release model charged therapeutics, using a cationic monoion, methylene blue and a cationic polyion, polylysine conjugated rhodamine. We find that methylene blue is not encapsulated by the micelle, and instead exhibits counterion-like behaviour upon polyelectrolyte complex formation. Conversely, fluorescence measurements of rhodamine-labelled polylysine show fluorescence quenching indicating that the polyion is encapsulated. By mixing quenched and unlabelled micelles, we show that both systems are immune to molecular exchange with their environment and instead the cargo remains trapped in the quenched micellar cores. Measurement of the micelle fluorescence above the LCST, decreases indicating no substantial release for either system. However, the increase in micelle quenching above the LCST and its persistence after cooling may offer an additional protective environment for cargo that can be triggered by temperature.