Proteomic studies in VWA1-related neuromyopathy allowed new pathophysiological insights and the definition of blood biomarkers.

Bi-allelic variants in VWA1, encoding Von Willebrand Factor A domain containing 1 protein localized to the extracellular matrix (ECM), were linked to a neuromuscular disorder with manifestation in child- or adulthood. Clinical findings indicate a neuromyopathy presenting with muscle weakness. Given that pathophysiological processes are still incompletely understood, and biomarkers are still missing, we aimed to identify blood biomarkers of pathophysiological relevance: white blood cells (WBC) and plasma derived from six VWA1-patients were investigated by proteomics. Four proteins, BET1, HNRNPDL, NEFM and PHGDH, known to be involved in neurological diseases and dysregulated in WBC were further validated by muscle-immunostainings unravelling HNRNPDL as a protein showing differences between VWA1-patients, healthy controls and patients suffering from neurogenic muscular atrophy and BICD2-related neuromyopathy. Immunostaining studies of PHGDH indicate its involvement in apoptotic processes via co-localisation with caspase-3. NEFM showed an increase in cells within the ECM in biopsies of all patients studied. Plasma proteomics unravelled dysregulation of 15 proteins serving as biomarker candidates among which a profound proportion of increased ones (6/11) are mostly related to antioxidative processes and have even partially been described as blood biomarkers for other entities of neuromuscular disorders before. CRP elevated in plasma also showed an increase in the extracellular space of VWA1-mutant muscle. Results of our combined studies for the first time describe pathophysiologically relevant biomarkers for VWA1-related neuromyopathy and suggest that VWA1-patient derived blood might hold the potential to study disease processes of clinical relevance, an important aspect for further preclinical studies.

Amyloid myopathy: expanding the clinical spectrum of transthyretin amyloidosis-case report and literature review.

We identified two patients with transthyretin (ATTR) amyloid myopathy (one ATTR variant amyloidosis, ATTRv; one wild-type ATTR amyloidosis, ATTRwt). Myopathy was the initial manifestation in ATTRwt, whereas it followed neuropathy and cardiomyopathy in ATTRv. The ATTRwt patient showed muscular tracer uptake on 99mTc-DPD planar scintigraphy at the time of initial diagnosis, consistent with ATTR amyloid myopathy. The ATTRv patient underwent heart transplantation because of progressive heart failure. Within the next two years, progressive myopathic symptoms and extracardiac tracer uptake on 99mTc-DPD planar scintigraphy were documented, attributable to ATTR amyloid myopathy. Interstitial amyloid deposits were confirmed by muscle biopsy in both patients, with a particularly high amyloid burden in the adipose tissue. This case report highlights the frequent concomitant presence of cardiac ATTR amyloidosis and ATTR amyloid myopathy. ATTR amyloid myopathy may precede cardiac manifestation in ATTRwt or occur after heart transplantation in ATTRv. Due to the high diagnostic accuracy of 99mTc-DPD scintigraphy for detecting ATTR amyloid myopathy and the emergence of novel therapeutics, it is important to increase the awareness of its presence.

Ultrasound-guided dry needling of masticatory muscles in trigeminal neuralgia - A case series of 35 patients.

Background: Trigeminal neuralgia (TGN) is considered a sensory neuropathy. However, reports of pain on chewing/speaking suggest a masticatory myofascial involvement. Objective: To examine the effect of ultrasound-guided dry needling (USGDN), which deactivates myofascial trigger points in masticatory, neck, and facial muscles on TGN symptoms. Methods: Charts of 35 patients treated for TGN were retrospectively reviewed. Treatment was USGDN alone or combined with trigeminal ganglion/mandibular nerve pulsed radiofrequency (PRF), followed by yoga mudras to stretch masticatory and facial muscles. Patients were followed for 1-8 years. Outcome parameters were reduction of medications with reduction in neuralgic attack frequency and Numeric Rating Scale (NRS) score. Results: 23 patients (65.7%) received USGDN alone, 12 patients (34.3%) received PRF treatment before USGDN. A significant reduction in the mean (SD) NRS (5.7 [1.2] vs 8.8 [1.6]; P < .001) and neuralgic attack frequency (47 [27] vs 118 [70] attacks/day; P < .001) was seen after PRF compared with baseline, respectively. Following USGDN, the mean (SD) NRS further decreased significantly to 1.0 (0.9) (P < .001). USGDN alone produced a similar improvement in the NRS (8.9 [1.5] at baseline reduced to 0.6 [0.7] post-USGDN; P < .001). Patients in both groups reported a cessation in neuralgic attacks after USGDN. Post-USGDN, 18/27 patients completely discontinued medication, with the mean (SD) carbamazepine dose significantly reducing from 716.7 (260.9) mg/day at baseline to 113.0 (250.2) mg/day post-USGDN (P < .001). Conclusion: Decisive relief of TGN by USGDN suggests neuromyalgia involving masticatory muscles. Prospective, controlled studies could confirm these findings.

Bi-allelic truncating mutations in VWA1 cause neuromyopathy.

The von Willebrand Factor A domain containing 1 protein, encoded by VWA1, is an extracellular matrix protein expressed in muscle and peripheral nerve. It interacts with collagen VI and perlecan, two proteins that are affected in hereditary neuromuscular disorders. Lack of VWA1 is known to compromise peripheral nerves in a Vwa1 knock-out mouse model. Exome sequencing led us to identify bi-allelic loss of function variants in VWA1 as the molecular cause underlying a so far genetically undefined neuromuscular disorder. We detected six different truncating variants in 15 affected individuals from six families of German, Arabic, and Roma descent. Disease manifested in childhood or adulthood with proximal and distal muscle weakness predominantly of the lower limbs. Myopathological and neurophysiological findings were indicative of combined neurogenic and myopathic pathology. Early childhood foot deformity was frequent, but no sensory signs were observed. Our findings establish VWA1 as a new disease gene confidently implicated in this autosomal recessive neuromyopathic condition presenting with child-/adult-onset muscle weakness as a key clinical feature.

Critical illness neuro-myopathy (CINM) and focal amyotrophy in intensive care unit (ICU) patients with SARS-CoV-2: a case series.

We found four patients with some characteristic phenotype in our ICU, characterized by focal hypotrophies of the shoulder girdle and the bilateral peroneal district and underlying critical illness neuro-myopathy. In our opinion, these hypotrophies are secondary to the prone position. Is our intention to start early treatment protocol with electrostimulation to evaluate the effectiveness in the prevention of critical illness and focal hypotrophies in ICU SARS-CoV-2 patients, to increase chances of returning to a preinfection functional status.

[Chronic intestinal pseudoobstruction: difficulties in diagnosis and treatment. Case report].

The article presents a clinical case of a 23-year-old patient with an extremely severe congenital form of chronic intestinal pseudoobstruction coupled with a neuromyopathy,colon malrotation, malabsorption, bacterial overgrowth syndrome, cholelithiasis and gastrostasis, which excluded bowel transplantation. Long-term treatment in the intensive care unit with combined, mainly parenteral nutrition for 6 months, using antibiotics, prokinetics, intestinal decompression allowed to achieve partial stabilization of the patients condition and transfer to home treatment with the continuation of adequate complex therapy.

Transthyretin amyloidosis: Putting myopathy on the map.

INTRODUCTION: Although peripheral neuropathy and cardiomyopathy are well-recognized manifestations of transthyretin (ATTR) amyloidosis, myopathy has been rarely reported. METHODS: In this study we reviewed our muscle biopsy database (January 1998 to June 2018) to identify patients with ATTR amyloid myopathy confirmed by molecular or proteomic analysis. Clinical and laboratory findings were reviewed. RESULTS: We identified eight ATTR amyloid myopathy patients (5 hereditary ATTR [ATTRv] and 3 wild-type ATTR [ATTRwt]). Myopathy was the initial manifestation in all ATTRwt patients and followed peripheral neuropathy (4 patients) or cardiomyopathy (1 patient) in ATTRv patients. One ATTRv patient developed myopathy after liver transplant. Peripheral neuropathy and cardiac amyloidosis occurred in seven and six patients, respectively. Muscle biopsy showed interstitial amyloid deposition in all patients, rare necrotic/regenerating fibers in six, and vacuoles in four. DISCUSSION: Myopathy can be the initial manifestation of ATTRwt amyloidosis and can precede the peripheral neuropathy or occur after liver transplant in ATTRv amyloidosis.

[Chronic intestinal pseudo-obstruction].

Chronic intestinal pseudo-obstruction a rare violation of the motor skills of the gastrointestinal complex, similar to mechanical obstruction, but without a mechanical obstacle. The development of chronic intestinal pseudo-obstruction is caused by a disturbance on the part of the smooth muscles and the nervous system of the gastrointestinal system. Common symptoms include constipation, abdominal pain, nausea, vomiting, bloating. Violation of peristalsis leads to food stagnation in the hinges of the small intestine, their dilation, the development of bacterial insemination syndrome. Eating disorders, bacterial contamination syndrome (CDDs) lead to impaired suction syndrome, cahexia. Treatment is aimed at providing adequate nutrition, the use of drugs that activate motor skills, suppress the growth of microbes in the small intestine, the implementation of intestinal decompression. Surgical treatment: resection of the affected segment of the gut. In the refractory course of the disease intestinal transplantation.

The unfolding spectrum of inherited distal myopathies.

Distal myopathies are a group of rare muscle diseases characterized by distal weakness at onset. Although acquired myopathies can occasionally present with distal weakness, the majority of distal myopathies have a genetic etiology. Their age of onset varies from early-childhood to late-adulthood while the predominant muscle weakness can affect calf, ankle dorsiflexor, or distal upper limb muscles. A spectrum of muscle pathological changes, varying from nonspecific myopathic changes to rimmed vacuoles to myofibrillar pathology to nuclei centralization, have been noted. Likewise, the underlying molecular defect is heterogeneous. In addition, there is emerging evidence that distal myopathies can result from defective proteins encoded by genes causative of neurogenic disorders, be manifestation of multisystem proteinopathies or the result of the altered interplay between different genes. In this review, we provide an overview on the clinical, electrophysiological, pathological, and molecular aspects of distal myopathies, focusing on the most recent developments in the field. Muscle Nerve 59:283-294, 2019.

Ultrasound-Guided Dry Needling As a Treatment For Postmastectomy Pain Syndrome - A Case Series of Twenty Patients.

CONTEXT: Existing interventions for postmastectomy pain syndrome (PMPS) address the neural component while overlooking a possible myofascial component. AIM: The aim of the study is to investigate the myofascial contribution to PMPS, by examining the effectiveness of myofascial trigger point release by ultrasound-guided dry needling (USGDN). PATIENTS AND METHODS: This retrospective review assessed the efficacy of USGDN in addressing myofascial pain in twenty consecutive patients with treatment-refractory PMPS. Patients in Group 1 (n = 16) received USGDN after neural interventions (NIs) such as neuraxial blocks, intrathecal pump implant, or pulsed radiofrequency, while those in Group 2 (n = 4) received USGDN alone. Outcome measures were changes in Numerical Rating Scale (NRS), PainDETECT (PD), Disabilities of Arm, Shoulder, and Hand (DASH), Patient Health Questionnaire-9 (PHQ-9) scores, and opioid use. RESULTS: In Group 1, the mean (standard deviation) NRS and PD scores (9.6 [0.9] and 28.3 [4.3], respectively, at baseline) reduced to 5.2 (1.1) and 16.1 (3.7) at 1-week post-NI. The post-NI DASH reduction was below the cutoff for clinical relevance (80.9 [10.5] at baseline vs. 71.1 [10.5] post-NI). The opioid dose remained unchanged. Following USGDN, NRS, PD, and DASH scores further reduced to 2.3 (0.8), 6.6 (1.2), and 34.6 (14.4), respectively. Patients receiving USGDN alone also showed reduction in NRS, PD, and DASH (7.8 [1.7], 20.0 [8.0], and 61.0 [14.4] at baseline vs. 1.3 [0.5], 6.0 [1.6], and 22.5 [10.4] post-USGDN, respectively). In all patients, opioid use and PHQ-9 scores reduced only post-USGDN. CONCLUSIONS: USGDN reduced pain, disability, and opioid use, whereas NI reduced only pain. This suggests a myofascial contribution to pain and disability in PMPS.

Compound muscle action potential duration in critical illness neuromyopathy.

INTRODUCTION: We sought to determine the specificity of compound muscle action potential (CMAP) durations and amplitudes in a large critical illness neuromyopathy (CINM) cohort relative to controls with other neuromuscular conditions. METHODS: Fifty-eight patients with CINM who had been seen over a 17-year period were retrospectively studied. Electrodiagnostic findings of the CINM cohort were compared with patients with axonal peripheral neuropathy and myopathy due to other causes. RESULTS: Mean CMAP durations were prolonged, and mean CMAP amplitudes were severely reduced both proximally and distally in all nerves studied in the CINM cohort relative to the control groups. The specificity of prolonged CMAP durations for CINM approached 100% if they were encountered in more than 1 nerve. DISCUSSION: Prolonged, low-amplitude CMAPs occur more frequently and with greater severity in CINM patients than in neuromuscular controls with myopathy and axonal neuropathy and are highly specific for the diagnosis of CINM. Muscle Nerve 57: 395-400, 2018.

A New Perspective of Neuromyopathy to Explain Intractable Pancreatic Cancer Pains; Dry Needling as an Effective Adjunct to Neurolytic Blocks.

UNLABELLED: We present a new perspective of neuromyopathy in pancreatic cancer pain (PCP) referral to bodywall; proposal of new rationale to include ultrasound guided dry needling (USGDN) of body wall muscles as an effective adjunct to neurolytic coeliac plexus block (NCPB) or splanchnic nerve radiofrequency ablation (SRF) for comprehensive interventional management. METHODS: PCP response to SRF in 2 patients and NCPB in 3 patients was documented on numerical rating scale (NRS) on post procedure days 3 and 15. If the residual pain was >5 NRS on day 15, USGDN of abdominal and back muscles was started on a thrice weekly basis. The response to USGDN documented on day 30 after approximately 6 sessions of DN, showed a significant pain reduction (0-2 NRS) with 50% reduction of pre-treatment opioid consumption. This was sustained at 6 months or till their demise. Convergence of visceral and somatic nerves at the dorsal horn (viscerosomatic neurons) causes referral of visceral pain to the back and abdominal muscles. This leads to formation of myofascial trigger points (MTrPs) in the muscles which sets up a parallel network of sensitized peripheral and central motor nociceptive processing (neuromyopathy). USGDN specifically addressed the MTrPs that develop as an epiphenomenon of self-perpetuating neuromyopathy while SRF/NCPB, analgesics and neuromodulators could address only visceral nociceptive afferents (pain mediated through celiac plexus) which forms a meagre 10% of the total spinal cord afferent input. Thus, we conclude that combination of neuromyopathy and viscerosomatic convergence in PCP indicate a specific role for DN as an adjunct to SRF/NCPB in our patients.

Successful management of chronic postsurgical pain following total knee replacement.

We report reversal of chronic postsurgical pain (CPSP) along with functional restoration after total knee replacement (TKR) in two patients, using a combination therapy that included ultrasonography-guided pulsed radiofrequency (PRF) of nerves supplying the knee to provide pain relief, along with dry needling (DN) to relax myofascial triggers/bands that caused painful stiffness and restricted movement of muscles acting across the knee. Both patients showed demonstrable pain relief, as evidenced by changes in pain as assessed on the Numeric Rating Scale (patient 1: 4-9/10 [pre-treatment] to 0-3/10 [6 months post-treatment]; patient 2: 5-9/10 to 0-4/10), Oxford Knee Score (patient 1: 17 to 40; patient 2: 12 to 39), Self-Administered Leeds Assessment of Neuropathic Symptoms and Signs score (patient 1: 16 to 0; patient 2: 18 to 0), and Patient Health Questionnaire-9 score (patient 1: 17 to 2; patient 2: 20 to 2). The selection of the PRF-and-DN combination for treating post-TKR CPSP was based on a new idea that CPSP is a neuromyopathic phenomenon involving both sensory and motor neuropathy. It has evolved from our experience of 8 years. Physiotherapy worked synergistically with DN, optimizing muscle performance and pain relief.

[A case of myofibrillary myopathy due to Bcl2-Associated Athanogene 3 (BAG3) mutation complicated by peripheral neuropathy].

A 19-year-old female, normal at birth, grew up without neck movement when getting up. She needed a handrail to climb stairs since the age of 10 years old, and walked slowly since the age of 16 years old. Neurological examination revealed loss of deep tendon reflexes, decreased vibratory sensation, weakness of distal muscles of the lower extremities, and weakness of mainly cervical trunk muscles suspected to be due to myopathy. Nerve conduction studies suggested axonal polyneuropathy, and needle EMG showed short duration MUP, myotonic discharge, and rimmed vacuoles on muscle biopsy. Genetic analysis revealed a previously reported pathological mutation (p.P209L, heterozygous) in Bcl2-Associated Athanogene 3 (BAG3), and a diagnosis of MFM6 was made. P209L is a poor prognosis myopathy that develops in childhood and is associated with cardiomyopathy. P209L is a solitary myopathy associated with axonal neuropathy and characterized by apex foot contracture and weak neck to trunk flexion. This disease is suspected in young-onset neuromyopathy.

Temporary and highly variable recovery of neuromuscular dysfunction by electrical stimulation in the follow-up of acute critical illness neuromyopathy: a pilot study.

BACKGROUND: In sepsis-associated critical illness neuromyopathy (CIPNM) serial electrical stimulation of motor nerves induces a short-lived temporary recovery of compound muscle action potentials (CMAPs) termed facilitation phenomenon (FP). This technique is different from other stimulation techniques published. The identification of FP suggests a major functional component in acute CIPNM. METHODS: From our previous study cohort of 18 intensive care unit patients with sepsis associated CIPNM showing profound muscle weakness and low or missing CMAPs on nerve conduction studies, six patients with different severity could be followed. In a pilot sub-study we analyzed the variability of FP during follow up. Over up to 6 weeks we performed 2-6 nerve conduction studies with our novel stimulation paradigm. Motor nerves were stimulated at 0.2-0.5 Hz with 60-100 mA at 0.2-0.5 ms duration, and CMAP responses were recorded. Standard motor nerve conduction velocities (NCV) could be done when utilizing facilitated CMAPs. Needle electromyography was checked once for spontaneous activity to discover potential denervation and muscle fiber degeneration. Serum electrolytes were checked before any examination and corrected if abnormal. RESULTS: In all six patients a striking variability in the magnitude and pattern of FP could be observed at each examination in the same and in different motor nerves over time. With the first stimulus most CMAPs were below 0.1 mV or absent. With slow serial pulses CMAPs could gradually recover with normal shape and near normal amplitudes. With facilitated CMAPs NCV measurements revealed low normal values. With improvement of muscle weakness subsequent tests revealed larger first CMAP amplitudes and smaller magnitudes of FP. Needle EMG showed occasional spontaneous activity in the tibialis anterior muscle. CONCLUSION: In this pilot study striking variability and magnitude of FP during follow-up was a reproducible feature indicating major fluctuations of neuromuscular excitability that may improve during follow-up. FP can be assessed by generally available electrophysiological techniques, even before patients could be tested for muscle strength. Large scale prospective studies of the facilitation phenomenon in CIPNM with or without sepsis are needed to define diagnostic specificity and to better understand the still enigmatic pathophysiology. TRIAL REGISTRATION: This trial was registered at the Leipzig University Medical Center in 2021 after approval by the Ethics Committee.

Use of Colchicine for Pericardial Inflammation: Risks and Toxicities-A Cautionary Tale.

Colchicine is commonly used as part of the treatment of acute and recurrent pericarditis. Neuromyopathy is a well-known, but probably underreported, side effect of colchicine. Here we present a unique case of a 56-year-old woman with recurrent episodes of colchicine-induced neuromyopathy over many years. (Level of Difficulty: Beginner.).

Temporary reversal of nerve and muscle dysfunction by serial electrical stimulation in critical illness neuromyopathy.

OBJECTIVE: Critical Illness Neuromyopathy (CIPNM) is a complication in sepsis patients with still enigmatic disease mechanisms. We investigated a novel electrical stimulation method to better define neuromuscular dysfunction in patients with CIPNM. METHODS: We studied 18 sepsis CIPNM patients on intensive care units, 13 at an early and 5 at a later disease stage, 7 sepsis control, and 8 neuropathy control patients. We applied slow conditioning electrical pulses at motor nerves and directly at the muscle to investigate a facilitation phenomenon (FP) of small or absent compound motor action potentials (CMAPs). RESULTS: Serial pulses induced a 2 to 490-fold increase in CMAP amplitudes in 17/18 Intensive Care Unit (ICU)-CIPNM patients (p < 0.001). These effects were short lived and reproducible. Direct muscle stimulation in the tibialis anterior muscle resulted in up to 130-fold FP in 7/9 patients tested (p < 0.01). In 4/5 post-ICU CIPNM patients FP was up to 10-fold. None of the 7 ICU sepsis control patients without CIPNM with similar disease severity and none of 8 neuropathy patients showed FP (p < 0.001). On needle EMG only 5/16 ICU patients tested revealed spontaneous activity. CONCLUSIONS: Conditioning electrical stimulation detected a functional component of the disease process showing temporary improvement in sepsis-associated CIPNM. SIGNIFICANCE: New test differentiates functional from degenerative pathology.

Chronic colchicine poisoning with neuromyopathy, gastric ulcers and myelosuppression in a gout patient: A case report.

BACKGROUND: Colchicine has been widely used as an anti-gout medication over the past decades. However, it is less commonly used due to its narrow therapeutic range, meaning that its lethal dose is close to its therapeutic dose. The lethal dose of colchicine is considered to be 0.8 mg/kg. As chronic colchicine poisoning has multiple manifestations, it poses a challenge in the clinician's differential diagnosis. Historically, the drug was important in treating gout; however, clinical studies are currently underway regarding the use of colchicine in patients with coronavirus disease 2019 as well as its use in coronary artery disease, making this drug more important in clinical practice. CASE SUMMARY: A 61-year-old male with a history of gout and chronic colchicine intake was admitted to our Emergency Department due to numbness and weakness of the lower limbs. The patient reported a history of colchicine intake for 23 years. After thorough examination, he was diagnosed with colchicine poisoning, manifesting as neuromyopathy, multiple gastric ulcers and myelosuppression. We advised him to stop taking colchicine and drinking alcohol. We also provided a prescription of lansoprazole and mecobalamin, and then asked him to return to the clinic for re-examination. The patient was followed up for 3-mo during which time his gout symptoms were controlled to the point where he was asymptomatic. CONCLUSION: Colchicine overdose can mimic the clinical manifestations of several conditions. Physicians easily pay attention to the disease while ignoring the cause of the disease. Thus, the patient's medication history should never be ignored.

Neuromuscular involvement in COVID-19 critically ill patients.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) has a high incidence of intensive care admittance due to the severe acute respiratory syndrome (SARS). Intensive care unit (ICU)-acquired weakness (ICUAW) is a common complication of ICU patients consisting of symmetric and generalised weakness. The aim of this study was to determine the presence of myopathy, neuropathy or both in ICU patients affected by COVID-19 and whether ICUAW associated with COVID-19 differs from other aetiologies. METHODS: Twelve SARS CoV-2 positive patients referred with the suspicion of critical illness myopathy (CIM) or polyneuropathy (CIP) were included between March and May 2020. Nerve conduction and concentric needle electromyography were performed in all patients while admitted to the hospital. Muscle biopsies were obtained in three patients. RESULTS: Four patients presented signs of a sensory-motor axonal polyneuropathy and seven patients showed signs of myopathy. One muscle biopsy showed scattered necrotic and regenerative fibres without inflammatory signs. The other two biopsies showed non-specific myopathic findings. CONCLUSIONS: We have not found any distinctive features in the studies of the ICU patients affected by SARS-CoV-2 infection. SIGNIFICANCE: Further studies are needed to determine whether COVID-19-related CIM/CIP has different features from other aetiologies. Neurophysiological studies are essential in the diagnosis of these patients.