Coexisting sporadic late onset nemaline myopathy and AL amyloid myopathy - incidental or related?

Sporadic late onset nemaline myopathy (SLONM) and amyloid myopathy are frequently unrecognized acquired and treatable myopathies, which classically present with rapidly progressive and severe proximal muscle weakness. We report a case of SLONM and amyloid myopathy associated with IgM lambda monoclonal gammopathy in a 77-year-old Caucasian man. Creatine kinase (CK) was mildly elevated. Myositis panel was negative. Electromyogram showed prominent fibrillation potentials and positive sharp waves with myopathic motor unit action potentials. Muscle biopsy revealed nemaline rods and amyloid deposits with characteristic apple-green birefringence under polarized light, and liquid chromatography tandem mass spectroscopy detected a peptide profile consistent with AL (lambda) type amyloid deposition. Genetic testing for congenital nemaline rod myopathy was negative. The patient was treated with dexamethasone and chemotherapy x3 cycles with very good partial remission. CK and lambda light chain normalized. Our case emphasizes the importance of completing a thorough histochemical and pathological evaluation by muscle biopsy analysis, to provide timely and optimal treatment of these conditions.

Unusual cases of Anti-SRP necrotizing myopathy with predominant distal leg weakness and atrophy.

Anti-SRP necrotizing myopathy is classically characterized by subacute or chronic, severe, progressive and symmetric myositis which predominantly affects proximal muscles. We report two unusual cases presenting with predominantly distal, asymmetric weakness, with selective involvement of the posterior compartment of the thighs, gastrocnemius, and soleus muscles, in addition to inflammation and edema on STIR or T2-weighted, fat-saturated MRI. In each case, creatine kinase (CK) levels were >10 times normal and myositis panels returned positive for anti-SRP. ANA, ENA, RF, and HMGCR antibody were all negative. Nerve conduction study (NCS) was normal. Electromyography (EMG) confirmed diffuse myopathy with fibrillation potentials and positive sharp waves. Additional work up, including whole exome sequencing (WES), immunohistochemical staining for different types of muscular dystrophy, and western blot for calpain 3 and dysferlin were negative. The strength and CK levels of both patients markedly improved following immunosuppression. Our cases emphasize the importance of considering anti-SRP necrotizing myopathy in patients presenting with recent onset predominant asymmetric distal leg weakness of unclear etiology, and support the usefulness of MRI of the distal legs for early recognition. Given the potential consequences of delays in treatment of this condition, the recognition of this clinical pattern is important and can allow for prompt initiation of aggressive immunotherapies.

CIDP mimics: a case series.

BACKGROUND: To report our experience with a group of patients referred for refractory CIDP who fulfilled "definite" electrodiagnostic EFNS criteria for CIDP but were found to have an alternate diagnosis. METHODS: Patients who were seen between 2017 and 2019 for refractory CIDP that fulfilled "definite" electrodiagnostic ENFS criteria for CIDP, but had an alternate diagnosis, were included. Patients who correctly had CIDP, anti MAG neuropathy, or MMN with conduction block, were excluded from the study. Demographics, clinical and electrophysiological characteristics, pertinent workup, final alternate diagnoses, and outcomes were collected. RESULTS: Seven patients were included: POEMS (n = 5), CANOMAD (n = 1), and neurolymphomatosis (n = 1). Most patients reported neuropathic pain and leg swelling (n = 6) or significant weight loss (n = 4). All patients had a monoclonal protein, and most patients who were tested had an elevated VEGF and CSF cyto-albuminologic dissociation. Electrophysiology showed pronounced intermediate more than distal demyelination, and axonal loss in the lower extremities. Response to steroids or IVIG varied, but some patients did respond to these treatments, especially early in the disease. CONCLUSION: Pain, systemic symptoms, suggestive electrophysiological findings, and/or a serum monoclonal protein should raise suspicion for CIDP mimics. Initial response to steroids or IVIG, over reliance on CSF, and electrophysiology findings can all be misleading.

Nusinersen in adult patients with spinal muscular atrophy: Observations from a single center.

OBJECTIVE: To report our experience with adult patients with spinal muscular atrophy (SMA), some of whom were treated with nusinersen. METHODS: We reviewed charts of adult patients with SMA seen in our neuromuscular clinic between 2017 and 2019 and noted their demographics, clinical characteristics, treatment, and side effects. RESULTS: Twenty-two patients were included. Nine had type 2 and 13 type 3 SMA. Median age was 36 years (range 20-71). Most could not walk unassisted. Ten patients had significant respiratory impairment necessitating ventilation and 2 had tracheostomy. Seventeen had severe scoliosis. Ten patients were treated with nusinersen for 6-24 months (median 12 months), 3 of whom required bone laminectomy for intrathecal access. One developed bowel and bladder incontinence following the procedure. In the treated group, on average, % Medical Research Council change was 2.5% at 12 months and 3.9% at 24 months. Most untreated patients remained stable; 3 had slightly declined. Five treated patients reported subjective improvement. Treatment side effects included post lumbar puncture headache in 5 patients, 2 of whom needed blood patch, and 1 bacterial meningitis requiring inpatient treatment. Three patients stopped treatment after 12-24 months due to lack of improvement, recurrent pneumonia, or proteinuria. CONCLUSION: Side effects of nusinersen can be serious. Whereas half of treated patients reported modest improvement in function, there were no significant objective changes, which may point largely to a placebo effect. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for some adult patients with SMA, nusinersen improves subjective function and causes serious adverse effects.

TTR gene silencing therapy in post liver transplant hereditary ATTR amyloidosis patients.

OBJECTIVE: Patients with hereditary transthyretin (TTR) amyloidosis (hATTR) often experience disease progression after orthotopic liver transplant (POLT) due in part to wild type ATTR amyloid deposition. The management strategy is not defined. We propose that TTR gene silencing with an antisense oligonucleotide or a small interfering ribonucleic acid may be a treatment for these patients. METHODS: We reviewed the charts of hATTR patients POLT treated with a TTR gene silencing agent at 7 different Amyloid Clinics between 2018-2020. RESULTS: Nine hATTR patients with POLT were treated with TTR gene silencing therapy (Inotersen). The median age was 61 years. The median time from OLT to initiation of TTR gene silencing therapy was 7.5 years. The median duration of therapy was 12 months. Neuropathy impairment score remained stable or improved in all patients. Five patients stopped treatment: 3 because of thrombocytopenia, 2 because of reversible liver rejection. Three patients who discontinued treatment subsequently experienced worsening of their neuropathy. CONCLUSION: TTR gene silencing therapy in hATTR patients with POLT could be a treatment option. Vigilant monitoring of renal, liver and bone marrow functions is necessary because of frequent complications. Further studies are needed to determine efficacy.

Diagnosis of paraproteinemic neuropathy: Room for improvement.

OBJECTIVE: To report our institutional experience with paraproteinemic neuropathy. METHODS: We reviewed the charts of patients evaluated at our tertiary, academic neuromuscular clinic for neuropathy between 2017 and 2019 and selected those with a serum monoclonal protein. We collected patients' characteristics and reviewed their initial diagnoses and eventual outcomes. RESULTS: Fifty-four of 410 patients with neuropathy (13%) had a monoclonal protein. Of these patients, 25% had not had SPEP or IFE checked prior to referral. FLC was not checked in any of the patients prior to referral. The neuropathy was felt to be related to the monoclonal protein in 24 patients (44%). Ten patients (19%), had been misdiagnosed either because they were not screened for monoclonal protein or the monoclonal protein was considered a MGUS. AL amyloid and POEMS syndrome were the most frequently missed diagnoses. CONCLUSION: The diagnosis of paraproteinemic neuropathy was missed in nearly one in five patients in our cohort. Failure to accurately characterize a paraproteinemic neuropathy can have devastating effect on patients as some have underlying malignancies. We propose that testing serum free light chains in patients with peripheral neuropathy of unknow etiology, when SPEP/IFE are normal, may reduce the rate of misdiagnosis. Furthermore, patients with refractory CIDP should be carefully screened for POEMS syndrome.