Paraneoplastic movement disorders.

Paraneoplastic movement disorders are diverse autoimmune neurological illnesses occurring in the context of systemic cancer, either in isolation or as part of a multifocal neurological disease. Movement phenomena may be ataxic, hypokinetic (parkinsonian), or hyperkinetic (myoclonus, chorea, or other dyskinetic disorders). Some disorders mimic neurodegenerative or hereditary illnesses. The subacute onset and coexisting nonclassic features of paraneoplastic disorders aid distinction. Paraneoplastic autoantibodies provide further information regarding differentiating cancer association, disease course, and treatment responses. A woman with cerebellar ataxia could have metabotropic glutamate receptor 1 autoimmunity, in the setting of Hodgkin lymphoma, a mild neurological phenotype and response to immunotherapy. A different woman, also with cerebellar ataxia, could have Purkinje cytoplasmic antibody type 1 (anti-Yo), accompanying ovarian adenocarcinoma, a rapidly progressive phenotype and persistent disabling deficits despite immune therapy. The list of antibody biomarkers is growing year-on-year, each with its own ideal specimen type for detection (serum or CSF), accompanying neurological manifestations, cancer association, treatment response, and prognosis. Therefore, a profile-based approach to screening both serum and CSF is recommended. Immune therapy trials are generally undertaken, and include one or more of corticosteroids, IVIg, plasma exchange, rituximab, or cyclophosphamide. Symptomatic therapies can also be employed for hyperkinetic disorders.

Autoimmune Axonal Neuropathies.

OBJECTIVE: This article reviews autoimmune axonal neuropathies, their characteristic clinical features, disease and antibody associations, appropriate ancillary testing, treatment, and prognosis. LATEST DEVELOPMENTS: In 2021, the American College of Rheumatology and the Vasculitis Foundation released new summary guidelines for the treatment of antineutrophil cytoplasmic autoantibody-associated vasculitides. In addition, novel autoantibodies have been recently identified; they are often paraneoplastic and associated with axonal neuropathies. ESSENTIAL POINTS: Recognition of autoimmune axonal neuropathies is important because of the potential for effective treatment to either reverse deficits or slow the progression of disease. It is necessary to properly assess for associations with other systemic disorders (eg, systemic vasculitis, connective tissue disease, neoplasm) so that adequate treatment for both neurologic and non-neurologic aspects of the disease can be initiated.

Treatment-responsive glycogen storage myopathy in a patient with POEMS syndrome: A new monoclonal gammopathy-associated myopathy.

BACKGROUND: Myopathies associated with monoclonal gammopathy are relatively uncommon and underrecognized, treatable myopathies, and include sporadic late onset nemaline myopathy, light chain amyloid myopathy, and a recently described vacuolar myopathy with monoclonal gammopathy and stiffness (VAMGS). Herein, we report a new subtype of monoclonal gammopathy-associated myopathy (MGAM) in a polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) patient. METHOD: Case report. RESULTS: A 51-year-old woman presented with a 6-month history of progressive bilateral foot drop, lower limb edema, and a 15-lb weight loss. She denied muscle stiffness. Neurologic exam showed severe distal weakness, mild proximal weakness, and length-dependent sensory deficits. Laboratory studies revealed biclonal gammopathy (IgG kappa and IgA lambda), thrombocytosis, and elevated vascular endothelial growth factor. Creatine kinase was normal. Electrodiagnostic studies identified mixed demyelinating and axonal polyradiculoneuropathy and a superimposed proximal myopathy. Gluteus medius biopsy demonstrated scattered fibers with glycogen-filled vacuoles, similar to VAMGS, with additional rare myofibers containing polyglucosan bodies. She was diagnosed with POEMS syndrome and concomitant glycogen storage myopathy. Next-generation sequencing of glycogen storage and polyglucosan body myopathy-related genes was unrevealing. Proximal weakness resolved after autologous stem cell transplant. CONCLUSIONS: This patient expands a spectrum of MGAM. Recognition of this condition and other subtypes of MGAM is of utmost important because they are treatable.

Ureteral stent extraction strings in children: Stratifying the risk of post operative urinary tract infection.

INTRODUCTION: Ureteral stents facilitate recovery and avoid external drains in pediatric ureteral reconstruction. Extraction strings avoid the need for a secondary cystoscopy and anesthetic. Due to concerns regarding febrile UTIs in children with extraction strings, we retrospectively assessed the relative risk of UTI in children with extraction strings. OBJECTIVE: Our hypothesis was that stents with extraction strings do not increase the risk of UTI after pediatric ureteral reconstruction. METHODS: Records of all children undergoing pyeloplasty and ureteroureterostomy (UU) from 2014 to 2021 were reviewed. The incidences of UTI, fever, and hospitalization were recorded. RESULTS: 245 patients mean age 6.4 years (163M:82F) underwent pyeloplasty (n = 221) or UU (n = 24). 42% (n = 103) received prophylaxis. Of these, 15% developed UTI versus 5% of those not receiving prophylaxis (p < 0.05). 42 females had prior history of UTI, compared to 20 males (p < 0.05). 49 patients had an extraction string. Stents with extraction strings were removed on average 0.6 months post-op while others underwent cystoscopic removal on average 1.26 months post-op (p < 0.05). 9 (18.4%) required hospitalization for febrile UTI while the stent with extraction string was in place, while only 13 (6.6%) of those without extraction string did (p < 0.02). Of the 9 children with a febrile UTI in the extraction string group, 6 had history of prior UTI (46.1%), compared to only 3 (8.3%) without a prior UTI (p < 0.05). With no prior UTI, there was no difference in UTI risk between those with (3, 8.3%) and without (8, 6.4%) extraction string (p = 0.71). Females with prior UTI and extraction string were more likely to develop UTI than those with prior UTI and no extraction string (p = 0.01). There were not enough males with history of UTI to analyze alone. There were 5 (10%) stent dislodgements in the extraction string group, 2 required further intervention with cystoscopy or percutaneous drainage. DISCUSSION: Extraction strings provide the assurance of drainage while avoiding the need for a second general anesthetic procedure. There is not an increased risk of UTI with extraction string in those without prior history of UTI, but we no longer routinely leave extraction strings if there is history of UTI. CONCLUSION: Children, particularly females, with prior history of UTI have a significantly increased risk of febrile UTIs associated with the use of extraction strings. Prophylaxis does not seem to reduce this risk. Patients with no prior UTI had no higher risk of UTI with extraction string use for pyeloplasty or UU.

Plexus MRI helps distinguish the immune-mediated neuropathies MADSAM and MMN.

BACKGROUND: Among immune-mediated neuropathies, clinical-electrophysiological overlap exists between multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) and multifocal motor neuropathy (MMN). Divergent immune pathogenesis, immunotherapy response, and prognosis exist between these two disorders. MRI reports have not shown distinction of these disorders, but biopsy confirmation is lacking in earlier reports. MADSAM nerves are hypertrophic with onion bulbs, inflammation, and edema, whereas MMN findings are limited to multifocal axonal atrophy. OBJECTIVES: To understand if plexus MRI can distinguish MADSAM from MMN among pathologically (nerve biopsy) confirmed cases. METHODS: Retrospective chart review and blinded plexus MRI review of biopsy-confirmed MADSAM and MMN cases at Mayo Clinic. RESULTS: Nine brachial plexuses (MADSAM-5, MMN-4) and 6 lumbosacral plexuses (MADSAM-4, MMN-2) had fascicular biopsies of varied nerves. Median follow-up in MADSAM was 93 months (range: 7-180) and 27 (range: 12-109) in MMN (p = 0.34). MRI hypertrophy occurred solely in MADSAM (89%, 8/9) with T2-hyperintensity in both. There was no correlation between time to imaging for hypertrophy, symptom onset age, or motor neuropathy impairments (mNIS). At last follow-up, on diverse immunotherapies mNIS improved in MADSAM (median - 4, range: -22 to 0), whereas MMN worsened (median 3, range: 0 to 6, p = 0.03) on largely IVIG. CONCLUSION: Nerve hypertrophy on plexus MRI helps distinguish MMN from MADSAM, where better immunotherapy treatment outcomes were observed. These findings are consistent with the immune pathogenesis seen on biopsies. Radiologic distinction is possible independent of time to imaging and extent of motor deficits, suggesting MRI is helpful in patients with uncertain clinical-electrophysiologic diagnosis, especially motor-onset MADSAM.

Immune-mediated necrotizing myopathy: Unusual presentations of a treatable disease.

INTRODUCTION/AIMS: Immune-mediated necrotizing myopathy (IMNM) is an immune-mediated myopathy typically presenting with progressive subacute weakness and characteristic, but nonspecific, myopathological findings. Atypical cases however can mimic other inherited or acquired myopathies, depriving patients of treatment. We describe a cohort of such patients. METHODS: We retrospectively identified IMNM patients who either previously carried a diagnosis of an inherited myopathy established on clinicopathological grounds or whose muscle biopsies displayed atypical features suggestive of a different myopathy. RESULTS: Among 131 IMNM patients, seven previously unreported patients (5%) met one of the above criteria. Three patients were diagnosed with limb-girdle muscular dystrophy on the basis of a chronic progressive course of weakness and family history of myopathy or cardiomyopathy. The other four patients displayed atypical histological features (two prominent mitochondrial abnormalities, one myofibrillar pathology, and one granulomatous inflammation). Immunostaining of biopsies from 12 additional IMNM patients did not identify myofibrillar pathology. The patient with granulomatous inflammation was known to have pulmonary sarcoidosis. Genetic testing for inherited myopathies was unrevealing. Antibodies against 3-hydroxy-3-methylglutaryl-CoA reductase or signal recognition particle were identified in 5 and 1 patients, respectively. Four patients presented with slowly progressive weakness over 3-13 y, while weakness was subacute over ≤6 mo in three patients. All patients responded to immunomodulatory therapy. DISCUSSION: Atypical clinical and histological features can occur in IMNM patients, causing delays in diagnosis and treatment. Clinicians should, therefore, consider IMNM in the differential diagnosis of unexplained proximal myopathies in spite of atypical clinical and myopathological findings.

Neuronal intermediate filament IgGs in CSF: Autoimmune Axonopathy Biomarkers.

OBJECTIVES: To describe CSF-defined neuronal intermediate filament (NIF) autoimmunity. METHODS: NIF-IgG CSF-positive patients (41, 0.03% of 118599 tested, 1996-2019) were included (serum was neither sensitive nor specific). Criteria-based patient NIF-IgG staining of brain and myenteric NIFs was detected by indirect immunofluorescence assay (IFA); NIF-specificity was confirmed by cell-based assays (CBAs, alpha internexin, neurofilament light [NF-L]), heavy-[NF-H] chain). RESULTS: Sixty-one percent of 41 patients were men, median age, 61 years (range, 21-88). Syndromes were encephalopathy predominant (23), cerebellar ataxia predominant (11), or myeloradiculoneuropathies (7). MRI abnormalities (T2 hyperintensities of brain, spinal cord white matter tracts. and peripheral nerve axons) and neurophysiologic testing (EEG, EMG, evoked potentials) co-localized with clinical neurological phenotypes (multifocal in 29%). Thirty patients (73%) had ≥ 1 immunological perturbation: cancer (paraneoplastic), 22; systemic infection (parainfectious [including ehrlichosis, 3] or HIV), 7; checkpoint-inhibitor cancer immunotherapy, 4; other, 5. Cancers were as follows: neuroendocrine-lineage carcinomas, 12 (small cell, 6; Merkel cell, 5; pancreatic, 1 [11/12 had NF-L-IgG detected, versus 8/29 others, P = 0.0005]) and other, 11. Onset was predominantly subacute (92%) and accompanied by inflammatory CSF (75%), and immunotherapy response (77%). In contrast, CSF controls (15684 total) demonstrated NIF-IgG negativity (100% of test validation controls), and low frequencies of autoimmune diagnoses (20% of consecutively referred clinical specimens) and neuroendocrine-lineage carcinoma diagnosis (3.1% vs. 30% of NIF cases), P < 0.0001. Median NF-L protein concentration was higher in 8 NF-L-IgG-positive patients (median, 6718 ng/L) than 16 controls. INTERPRETATION: Neurological autoimmunity, defined by CSF-detected NIF-IgGs, represents a continuum of treatable axonopathies, sometimes paraneoplastic or parainfectious.

Development of a risk indicator score for the identification of interstitial lung disease in patients with rheumatoid arthritis.

BACKGROUND: Clinically evident interstitial lung disease (ILD) affects 10%-42% of RA patients with prognostic implications. The aim of this study was to discern which factors are associated with the presence of ILD in RA patients and to develop a score that could help to stratify the risk of having ILD in RA patients. METHODS: Case-control study. We included RA patients recruited from ILD and rheumatology clinics. We retrieved the following data: gender, age, presence of extra articular manifestations, disease activity scores, antibodies status, ESR, and medication use. Multivariate logistic regression was performed. A risk indicator score was developed. RESULTS: Of 118 patients included in this study, 52 (44%) had RA-ILD (cases) and 66 (56%) had RA without ILD (controls). Twenty-six patients were male (22%), the mean age was 56.6±15.6 years. Five variables were significantly associated with the presence of ILD: male gender, smoking, extraarticular manifestations, a CDAI score>28, and ESR>80mm/h. The AUC of the final model curve was 0.86 (95%CI 0.79-0.92). Two potential cut-off points of the risk indicator score were chosen: a value of 2 points showed a sensitivity of 90.38% and a specificity of 63.64%, while a value of 4 points showed a sensitivity of 51.9% and a specificity of 90.9%. CONCLUSION: This study identified risk factors that could help identify which RA patients are at risk of having ILD through the development of a risk indicator score. This score needs to be validated in an independent cohort.

Novel imaging techniques using 18 F-florbetapir PET/MRI can guide fascicular nerve biopsy in amyloid multiple mononeuropathy.

BACKGROUND: Multiple mononeuropathy is a rare presentation of primary (AL) amyloidosis and nerve biopsy is usually needed for diagnosis. Conventional imaging is useful to identify proximal nerve involvement but may be inadequate. We report a patient with multiple mononeuropathy whose presentation was suggestive of AL amyloid neuropathy and in whom repeated tissue biopsies were negative for amyloid (including two sensory nerves and one muscle). METHODS: The patient underwent magnetic resonance imaging (MRI) and whole body 18 F-florbetapir positron emission tomography (PET)/MRI. RESULTS: Whole body 18 F-florbetapir PET/MRI revealed abnormal low-level florbetapir uptake in the right proximal tibial and peroneal nerves, which provided a target for a sciatic bifurcation fascicular nerve biopsy that was diagnostic of AL amyloidosis. CONCLUSIONS: 18 F-florbetapir PET/MRI imaging is a promising diagnostic tool for patients with suspected peripheral nerve amyloidosis (including multiple mononeuropathy) in whom conventional imaging and nerve and muscle biopsies miss the pathology.

GYG1: A distal myopathy with polyglucosan bodies.

Mutations in glycogenin-1 (GYG1) cause an adult-onset polyglucosan body myopathy. We report here a patient presenting with late-onset distal myopathy. We wish to highlight this rare clinical phenotype of GYG1-related myopathy and the histological clues leading to its diagnosis.

Nerve Pathology Distinguishes Focal Motor Chronic Inflammatory Demyelinating Polyradiculoneuropathy From Multifocal Motor Neuropathy.

OBJECTIVES: The objective of the study is to distinguish the mechanisms of disease for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN), which we believe to be fundamentally different. However, distinguishing the mechanisms is more difficult when the presentation of CIDP is motor-predominant, focal, or asymmetric. METHODS: We describe 3 focal, motor-predominant, representative cases that could be interpreted on clinical and/or electrophysiological grounds as either MMN or focal CIDP, and present pathological findings. RESULTS: We highlight pathological differences in these cases, and provide an argument that CIDP and MMN are distinct entities with different pathophysiological mechanisms-chronic demyelination for CIDP, and an immune-mediated attack on paranodal motor axons for MMN. CONCLUSIONS: Based on clinical evaluation, electrophysiology, and nerve biopsy pathology, we can divide the conditions into inflammatory demyelinating neuropathy (focal CIDP) versus chronic axonal neuropathy (MMN). The divergent pathological findings provide further evidence that CIDP and MMN are fundamentally different disorders.

Congenital myopathies in the adult neuromuscular clinic: Diagnostic challenges and pitfalls.

OBJECTIVE: To investigate the spectrum of undiagnosed congenital myopathies (CMs) in adults presenting to our neuromuscular clinic and to identify the pitfalls responsible for diagnostic delays. METHODS: We conducted a retrospective review of patients diagnosed with CM in adulthood in our neuromuscular clinic between 2008 and 2018. Patients with an established diagnosis of CM before age 18 years were excluded. RESULTS: We identified 26 patients with adult-onset CM and 18 patients with pediatric-onset CM who were only diagnosed in adulthood. Among patients with adult onset, the median age at onset was 47 years, and the causative genes were RYR1 (11 families), MYH7 (3 families) and ACTA1 (2 families), and SELENON, MYH2, DNM2, and CACNA1S (1 family each). Of 33 patients who underwent muscle biopsy, only 18 demonstrated histologic abnormalities characteristic of CM. Before their diagnosis of CM, 23 patients had received other diagnoses, most commonly non-neurologic disorders. The main causes of diagnostic delays were mildness of the symptoms delaying neurologic evaluation and attribution of the symptoms to coexisting comorbidities, particularly among pediatric-onset patients. CONCLUSIONS: CMs in adulthood represent a diagnostic challenge, as they may lack the clinical and myopathologic features classically associated with CM. Our findings underscore the need for a revision of the terminology and current classification of these disorders.

Peripheral Nerve Vasculitis: Classification and Disease Associations.

"The vasculitic neuropathies encompass a wide range of disorders characterized by ischemic injury to the vasa nervorum. Patients with vasculitic neuropathies develop progressive, painful sensory or sensorimotor deficits that are typically multifocal or asymmetric. Depending on the underlying etiology, the vasculitis may be confined to the peripheral nervous system; may be one manifestation of a primary systemic vasculitis; or one manifestation of a systemic vasculitis that is secondary to underlying connective tissue disease, drug exposure, viral infection, or paraneoplastic syndrome. This article reviews the classification, clinical presentation, diagnostic approach, etiologies, and treatment of the vasculitic neuropathies."

Onion-bulb patterns predict acquired or inherited demyelinating polyneuropathy.

INTRODUCTION: Onion-bulbs (OB) are concentrically layered Schwann-cell processes, surrounding nerve fibers, occurring in both inherited and acquired demyelinating polyneuropathies. We investigated whether OB patterns (generalized, mixed, or focal) correlate with acquired or inherited neuropathies. METHODS: One hundred thirty-one OB-rich nerve biopsies were graded for OB pattern and inflammation without knowledge of clinical history. We classified inherited (n = 49) or acquired (n = 82) neuropathies based solely on clinical history. RESULTS: Fifty-one biopsies had generalized (34 inherited vs. 17 acquired, P < 0.001), 54 mixed (48 acquired vs. 6 inherited, P < 0.001), and 26 focal/multifocal (inherited [n = 9], acquired [n = 17]) OB. Inflammation occurred more frequently in acquired (n = 54) than inherited (n = 14) neuropathy (P = 0.004). DISCUSSION: Generalized OB correlates with inherited neuropathy; mixed OB with acquired. Inflammation occurs more in acquired neuropathy cases. OB patterns are best explained by ubiquitous Schwann-cell involvement in inherited and multifocal Schwann-cell involvement in acquired neuropathies and predict the electrophysiology of uniform demyelination in inherited and unequal demyelination in acquired neuropathies. Muscle Nerve 59:665-670, 2019.

Pompe Disease Could Mimic Exam Findings of Amyloidosis: Two Rare Diagnoses Bona Fide.

A 70-year-old female presented with a three-year history of evolving macroglossia causing dysphagia and dysarthria, with proximal muscle weakness. Given the classic physical finding of macroglossia, the patient underwent extensive evaluation for amyloidosis which proved to be negative apart from a bone marrow biopsy which stained positive for transthyretin without amino acid sequence abnormality, thus giving wild-type transthyretin amyloidosis. Since the wild-type transthyretin amyloidosis could not entirely explain her clinical presentation and evaluation, further studies were conducted in a sequential manner, thus leading to a diagnosis of Pompe disease explaining her presenting signs and symptoms including her macroglossia. Through this fascinating case, we attempt to highlight the approach for the diagnoses of two rare diseases in a patient by emphasizing the importance of having a broad differential diagnosis when presented with findings which may have been thought as pathognomonic for certain diseases.

History, Diagnosis, and Management of Chronic Inflammatory Demyelinating Polyradiculoneuropathy.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is probably the best recognized progressive immune-mediated peripheral neuropathy. It is characterized by a symmetrical, motor-predominant peripheral neuropathy that produces both distal and proximal weakness. Large-fiber abnormalities (weakness and ataxia) predominate, whereas small-fiber abnormalities (autonomic and pain) are less common. The pathophysiology of CIDP is inflammatory demyelination that manifests as slowed conduction velocities, temporal dispersion, and conduction block on nerve conduction studies and as segmental demyelination, onion-bulb formation, and endoneurial inflammatory infiltrates on nerve biopsies. Although spinal fluid protein levels are generally elevated, this finding is not specific for the diagnosis of ClDP. Other neuropathies can resemble CIDP, and it is important to identify these to ensure correct treatment of these various conditions. Consequently, metastatic bone surveys (for osteosclerotic myeloma), serum electrophoresis with immunofixation (for monoclonal gammopathies), and human immunodeficiency virus testing should be considered for testing in patients with suspected CIDP. Chronic inflammatory demyelinating polyradiculoneuropathy can present as various subtypes, the most common being the classical symmetrical polyradiculoneuropathy and the next most common being a localized asymmetrical form, multifocal CIDP. There are 3 well-established, first-line treatments of CIDP-corticosteroids, plasma exchange, and intravenous immunoglobulin-with most experts using intravenous immunoglobulin as first-line therapy. Newer immune-modulating drugs can be used in refractory cases. Treatment response in CIDP should be judged by objective measures (improvement in the neurological or electrophysiological examination), and treatment needs to be individualized to each patient.