An integrated approach to the evaluation of patients with asymptomatic or minimally symptomatic hyperCKemia.

INTRODUCTION/AIMS: Currently, there are no straightforward guidelines for the clinical and diagnostic management of hyperCKemia, a frequent and nonspecific presentation in muscle diseases. Therefore, we aimed to describe our diagnostic workflow for evaluating patients with this condition. METHODS: We selected 83 asymptomatic or minimally symptomatic patients with persistent hyperCKemia for participation in this Italian multicenter study. Patients with facial involvement and distal or congenital myopathies were excluded, as were patients with suspected inflammatory myopathies or predominant respiratory or cardiac involvement. All patients underwent a neurological examination and nerve conduction and electromyography studies. The first step of the investigation included a screening for Pompe disease. We then evaluated the patients for myotonic dystrophy type II-related CCTG expansion and excluded patients with copy number variations in the DMD gene. Subsequently, the undiagnosed patients were investigated using a target gene panel that included 20 genes associated with isolated hyperCKemia. RESULTS: Using this approach, we established a definitive diagnosis in one third of the patients. The detection rate was higher in patients with severe hyperCKemia and abnormal electromyographic findings. DISCUSSION: We have described our diagnostic workflow for isolated hyperCKemia, which is based on electrodiagnostic data, biochemical screening, and first-line genetic investigations, followed by successive targeted sequencing panels. Both clinical signs and electromyographic abnormalities are associated with increased diagnostic yields.

A novel mutation of Twinkle in Perrault syndrome: A not rare diagnosis?

Perrault syndrome is a rare disorder characterized by ovarian dysgenesis, bilateral sensorineural hearing loss and associated with mutations in six mitochondrial proteins. Additional neurological features were also described. Herein, we report on a 27-year-old woman with Perrault syndrome (PS), moderate ataxia and axonal sensory-motor peripheral neuropathy in whom we identified compound heterozygous mutations in the TWNK gene (p.Val507Ile and the novel p.Phe248Ser variant). Fewer than 30 patients with PS have been reported worldwide. Neurological involvement is more frequently associated with mutations in TWNK and indicates possible genotype-phenotype correlations. TWNK mutations should be searched in patients with sensory ataxia, early onset bilateral sensorineural hearing loss, and ovarian dysfunction in women.

Correspondence between neurophysiological and clinical measurements of chemotherapy-induced peripheral neuropathy: secondary analysis of data from the CI-PeriNomS study.

Chemotherapy-induced peripheral neuropathy (CIPN) lacks standardized clinical measurement. The objective of the current secondary analysis was to examine data from the CIPN Outcomes Standardization (CI-PeriNomS) study for associations between clinical examinations and neurophysiological abnormalities. Logistic regression estimated the strength of associations of vibration, pin, and monofilament examinations with lower limb sensory and motor amplitudes. Examinations were classified as normal (0), moderately abnormal (1), or severely abnormal (2). Among 218 participants, those with class 1 upper extremity (UE) and classes 1 or 2 lower extremity (LE) monofilament abnormality were 2.79 (95% confidence interval [CI]: 1.28-6.07), 3.49 (95%CI: 1.61-7.55), and 4.42 (95%CI: 1.35-14.46) times more likely to have abnormal sural nerve amplitudes, respectively, compared to individuals with normal examinations. Likewise, those with class 2 UE and classes 1 or 2 LE vibration abnormality were 8.65 (95%CI: 1.81-41.42), 2.54 (95%CI: 1.19-5.41), and 7.47 (95%CI: 2.49-22.40) times more likely to have abnormal sural nerve amplitudes, respectively, compared to participants with normal examinations. Abnormalities in vibration and monofilament examinations are associated with abnormal sural nerve amplitudes and are useful in identifying CIPN.

Meralgia Paraesthetica after Prone Position Ventilation in a Patient with COVID-19.

BACKGROUND AND OBJECTIVES: One of the most feared complications of COVID-19 is respiratory failure caused by acute respiratory distress syndrome. In order to improve oxygenation and survival, patients admitted to intensive care units and intubated may undergo prone position mechanical ventilation. Prolonged prone positioning may cause meralgia paraesthetica due to lateral femoral cutaneous nerve entrapment between the inguinal ligament and the anterior superior iliac spine. Reports of the first two cases have been recently published. CASE PRESENTATION: We describe the case of a 52-year-old man with respiratory failure during COVID-19 infection, who underwent prone position ventilation for 16 hours a day over 19 days and developed persistent burning pain and dysaesthesia on the lateral surface of the thigh bilaterally, diagnosed as meralgia paraesthetica. CONCLUSION: This is the second report describing meralgia paraesthetica following prone position ventilation in COVID-19. Given the ongoing pandemic and the inevitability of more patients with severe respiratory distress requiring prone position ventilation, this disabling entrapment condition should be considered and possibly prevented. LEARNING POINTS: COVID-19 may require intubation and mechanical ventilation because of respiratory distress.Prone position ventilation improves oxygenation, but may cause lateral femoral cutaneous nerve entrapment and meralgia paraesthetica.Medical personnel should be aware of the risk of meralgia paraesthetica as a disabling condition potentially affecting more patients as the COVID-19 pandemic persists.

Ghost spasticity in multiple sclerosis.

Spasticity is the velocity-dependent hypertonia frequently encountered in patients affected by Upper Motor Neuron Syndrome. It is due to a tonic stretch reflex, which is evoked in patients at rest. The aim of this study, performed using surface electromyography (EMG), was to investigate stretch reflex excitability in the hamstrings muscles of patients affected by progressive Multiple Sclerosis (MS) and to correlate EMG results with clinical findings. Thirty patients and 20 age-matched healthy controls were investigated. EMG activity was recorded from biceps femoris muscle with the patient at rest. To stretch hamstrings muscles, the patient's leg was manually moved from maximal flexion to maximal extension at 3 different velocities to investigate both phasic and tonic stretch reflex. Only 7 patients were affected by hypertonia of the hamstrings; 4 of them showed muscle contracture. A tonic stretch reflex was present in the vast majority of the recruited patients, whether they presented hypertonia of the hamstrings or not. Tonic stretch reflex is often present in the hamstrings muscles of progressive MS patients without producing increased muscle tone. This "ghost spasticity" is likely to be, for its intrinsic features, an important risk factor for the development of contractures in the hamstrings muscles.

Tailoring B cell depletion therapy in MS according to memory B cell monitoring.

OBJECTIVE: We wanted to evaluate efficacy on inflammatory parameters of rituximab (RTX)-personalized reinfusion scheme using a memory B cell-based treatment regimen. METHODS: This is a prospective, uncontrolled, open-label study including patients with MS treated with RTX in 2 Italian MS units. All patients were treated with RTX induction, followed by maintenance infusion at the dosage of 375 mg/m2, according to memory B cell repopulation (0.05% of peripheral-blood mononuclear cells [PBMCs] for the first 2 years, 0.1% of PBMC for the third year). MS activity was assessed as clinical or MRI activity. RESULTS: One hundred two patients were included in the analysis. Mean follow-up was 2.40 years (range 0.57-7.15 years). The annualized relapse rate (ARR) was 0.67 in the year before RTX start and decreased to 0.01 in the 3 years after RTX initiation (global ARR). The proportion of patient with MS activity (i.e., relapse or MRI activity) was 63.16% in the year before RTX start and decreased to 8.7% (0-6 months), 1.3% (6-12 months), 0% (12-24 months), and 0% (24-36 months). Annualized RTX infusion rates were 1.67 (95% confidence interval [CI]: 1.43-1.94), 0.76 (95% CI: 0.58-0.98), and 0.78 (95% CI: 0.52-1.12) for the first 3 years after RTX initiation, respectively. Patients were reinfused with a mean infusion interval of 367 days (range 181-839 days). CONCLUSION: The results of this study show that the memory B cell-based RTX reinfusion protocol is able to reduce the mean number of RTX reinfusions with persistent reduction of disease activity. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with MS, a memory B cell-based RTX reinfusion protocol can reduce the mean number of RTX reinfusions with persistent reduction of disease activity.

A novel mutation in the N-terminal acting-binding domain of Filamin C protein causing a distal myofibrillar myopathy.

Variants in Filamin C (FLNC) gene may cause either cardiomyopathies or different myopathies. We describe a family affected by a distal myopathy with autosomal dominant inheritance. The onset of the disease was in the third decade with gait impairment due to distal leg weakness. Subsequently, the disease progressed with an involvement of proximal lower limbs and hand muscles. Muscle biopsy, performed in one subject,identified relevant myofibrillar abnormalities. We performed a target gene panel testing for myofibrillar myopathies by NGS approach which identified a novel mutation in exon 3 of FLNC gene (c.A664G:p.M222V), within the N-terminal actin-binding (ABD) domain. This variant has been identified in all affected members of the family, thus supporting its pathogenic role. Differently from previously identified variants, our family showed a predominant leg involvement and myofibrillar aggregates, thus further expanding the spectrum of Filamin C related myopathies.

Autosomal-dominant transthyretin (TTR)-related amyloidosis is not a frequent CMT2 neuropathy "in disguise".

Transthyretin (TTR)-related familial amyloid polyneuropathy (TTR-FAP) is a life-threatening autosomal dominant, systemic disease. First symptoms usually occur from the second to over sixth decade of life with a length-dependent axonal neuropathy with prominent involvement of the small fibers and multi-organ systemic failure.Early diagnosis is pivotal for effective therapeutic options, but it is hampered by the heterogeneity of the clinical spectrum which can lead to misdiagnosis with other neurological condition/disorder such as axonal sensory-motor neuropathy (CMT2) as described in literature.The aim of our study was to search for TTR mutations in a large cohort of selected undiagnosed axonal sensory-motor neuropathy patients to establish if misdiagnosis is frequent or rare in the Italian population.No TTR pathogenic variants were found in our cohort. In conclusion, our study shows that TTR testing not should be straightforward recommended in CMT2 patients but only when "red flags" TTR's features are present.