Michelle L. Mauermann

The utility of plasma vascular endothelial growth factor levels in the diagnosis and follow-up of patients with POEMS syndrome

The POEMS syndrome is associated with elevated vascular endothelial growth factor (VEGF) levels. Several studies have compared serum VEGF levels between POEMS patients and other disease entities showing higher serum VEGF in POEMS syndrome; however, it is unknown whether serum levels are reliable and reproducible given variable platelet release of VEGF. We therefore compared plasma levels of VEGF in 29 patients with POEMS syndrome with those of other disorders (n = 76). We demonstrated that plasma VEGF levels are useful in differentiating POEMS from other plasma cell dyscrasias, neuropathic processes, and multisystem illnesses. Plasma VEGF is also useful in monitoring disease activity after treatment and correlates with clinical improvements better than hematologic response.

Mass spectrometric-based proteomic analysis of amyloid neuropathy type in nerve tissue

OBJECTIVE To determine the specific type of amyloid from nerve biopsies using laser microdissection (LMD) and mass spectrometric (MS)-based proteomic analysis. DESIGN, SETTING, AND PATIENTS Twenty-one nerve biopsy specimens (17 sural, 3 sciatic, and 1 root amyloidoma) infiltrated by amyloid were studied. Immunohistochemical subtyping was unable to determine the specific amyloid type for these 21 cases, but the clinical diagnosis was made based on additional testing. Clinical diagnosis was made through evaluation of serum monoclonal proteins, biopsy of bone marrow for acquired monoclonal immunoglobulin light chain amyloidosis, and kindred evaluations with DNA sequencing of transthyretin (TTR) and gelsolin (GSN) genes. Our study included 8 cases of acquired monoclonal immunoglobulin light chain amyloidosis, 11 cases of transthyretin amyloidosis (3 with the Val30Met mutation, 2 with the Val32Ala mutation, 2 with the Thr60Ala mutation, 1 with the Ala109Ser mutation, 1 with the Phe64Leu mutation, 1 with the Ala97Ser mutation, and 1 not sequenced), and 2 cases of gelsolin amyloidosis (1 with the Asp187Asn mutation and 1 not sequenced). One patient with transthyretin amyloidosis and 1 patient with gelsolin amyloidosis with no specific mutation identified were diagnosed based on genetic confirmation in their first-degree relative. Congophilic proteins in the tissues of these 21 cases underwent LMD, were digested into tryptic peptides, and were analyzed using liquid chromatography electrospray tandem MS. Identified proteins were reviewed using bioinformatics tools with interpreters blinded to clinical information. MAIN OUTCOME MEASURE Specific amyloid type was ascertained by LMD tandem MS and compared with clinical diagnosis. RESULTS Specific types of amyloid were accurately detected by LMD/MS in all cases (8 cases of acquired monoclonal immunoglobulin light chain amyloidosis, 2 cases of gelsolin amyloidosis, and 11 cases of transthyretin amyloidosis). Incidental serum monoclonal proteins did not interfere with detection of transthyretin amyloidosis in 2 patients. Additionally, specific TTR mutations were identified in 10 cases by LMD/MS. Serum amyloid P-component and apolipoprotein E proteins were commonly found among all cases. CONCLUSIONS Proteomic analysis of nerve tissue using LMD/MS distinguishes specific types of amyloid independent of clinical information. This new proteomic approach will enhance both diagnostic and research efforts in amyloidosis and other neurologic diseases.

Uniform demyelination and more severe axonal loss distinguish POEMS syndrome from CIDP

Objective POEMS syndrome (the acronym reflects the common features: Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein and Skin changes) is a paraneoplastic disorder with a ‘demyelinating’ peripheral neuropathy that is often mistaken for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). The nerve conduction study (NCS) and electromyography (EMG) attributes that might differentiate POEMS from CIDP and lead to earlier therapeutic intervention were explored. Methods NCS/EMG of POEMS patients identified through retrospective review from 1960 to 2007 were compared with matched CIDP controls. Results 138 POEMS patients and 69 matched CIDP controls were compared. POEMS patients demonstrated length dependent reduction in compound muscle action potentials, low conduction velocities, prolonged distal latencies and prolonged F wave latencies. Compared with CIDP controls, POEMS patients demonstrated: (1) greater reduction of motor amplitudes, (2) greater slowing of motor and sensory conduction velocities, (3) less prolonged motor distal latencies, (4) less frequent temporal dispersion and conduction block, (5) no sural sparing, (6) greater number of fibrillation potentials in a length dependent pattern and (7) higher terminal latency indices (TLI). TLI ≥0.38 in the median nerve demonstrated a sensitivity of 70% and specificity of 77% in discriminating POEMS from CIDP. Conclusions NCS/EMG of POEMS syndrome suggests both axonal loss and demyelination. Compared with CIDP, there is greater axonal loss (reduction of motor amplitudes and increased fibrillation potentials), greater slowing of the intermediate nerve segments, less common temporal dispersion and conduction block, and absent sural sparing. These findings imply that the pathology of POEMS syndrome is diffusely distributed (uniform demyelination) along the nerve where the pathology of CIDP is probably predominantly proximal and distal. Median motor TLI may be useful in clinically distinguishing these disorders.

Diabetic cervical radiculoplexus neuropathy: a distinct syndrome expanding the spectrum of diabetic radiculoplexus neuropathies

Diabetic lumbosacral radiculoplexus neuropathy is a subacute painful, asymmetrical lower limb neuropathy due to ischaemic injury and microvasculitis. The occurrence of a cervical diabetic radiculoplexus neuropathy has been postulated. Our objective was to characterize the clinical features and pathological alterations of diabetic cervical radiculoplexus neuropathy, to see if they are similar to diabetic lumbosacral radiculoplexus neuropathy and due to ischaemic injury and microvasculitis. We identified patients with diabetic cervical radiculoplexus neuropathy by review of the Mayo Clinic database from 1996 to 2008. We systematically reviewed the clinical features, laboratory studies, neurophysiological findings, neuroimaging and pathological features and compared the findings with a previously published diabetic lumbosacral radiculoplexus neuropathy cohort. Eighty-five patients (56 males, 67 with Type 2 diabetes mellitus) were identified. The median age was 62 years (range 32-83). The main presenting symptom was pain (53/85). At evaluation, weakness was the most common symptom (84/85), followed by pain (69/85) and numbness (56/85). Neuropathic deficits were moderate (median motor neuropathy impairment score 10.0 points) and improved at follow-up. Upper, middle and lower brachial plexus segments were involved equally and pan-plexopathy was not unusual (25/85). Over half of patients (44/85) had at least one additional body region affected (30 contralateral cervical, 20 lumbosacral and 16 thoracic) as is found in diabetic lumbosacral radiculoplexus neuropathy. Recurrent disease occurred in 18/85. Neurophysiology showed axonal neuropathy (80/80) with paraspinal denervation (21/65), and abnormal autonomic (23/24) and sensory testing (10/13). Cerebrospinal fluid protein was elevated (median 70 mg/dl). Magnetic resonance imaging showed brachial plexus abnormality in all (38/38). Nerve biopsies (11 upper and 11 lower limbs) showed ischaemic injury (axonal degeneration, multifocal fibre loss 15/22, focal perineurial thickening 16/22, injury neuroma 5/22) and increased inflammation (epineural perivascular inflammation 22/22, haemosiderin deposition 6/22, vessel wall inflammation 14/22 and microvasculitis 5/22). We therefore conclude that (i) diabetic cervical radiculoplexus neuropathy is a predominantly monophasic, upper limb diabetic neuropathy with pain followed by weakness and involves motor, sensory and autonomic fibres; (ii) the neuropathy begins focally and often evolves into a multifocal or bilateral condition; (iii) the pathology of diabetic cervical radiculoplexus neuropathy demonstrates ischaemic injury often from microvasculitis; and (iv) diabetic cervical radiculoplexus neuropathy shares many of the clinical and pathological features of diabetic lumbosacral radiculoplexus neuropathy, providing evidence that these conditions are best categorized together within the spectrum of diabetic radiculoplexus neuropathies.

The Neuropathies of Waldenström’s Macroglobulinemia (WM) and IgM-MGUS

BACKGROUND Neuropathy is common in Waldenströms macroglobulinemia (WM, an IgM-associated lymphoplasmacytic lymphoma) and in IgM-monoclonal gammopathy of undetermined significance (IgM-MGUS). Paraneoplastic or paraimmune mechanisms are thought to be involved in the pathogenesis of these neuropathies. Attempts at distinguishing WM and IgM-MGUS neuropathies are lacking especially among bone marrow (BM) confirmed patients. METHODS Retrospective analyses were performed on BM confirmed WM (N=30) and IgM-MGUS (N=73) neuropathy patients with neurologic assessments and hematologic features. RESULTS The presence of anemia and quantity of IgM monoclonal protein were significantly greater in WM. Based on multiple neurologic assessments differences were not found for: 1) length of time from neurologic symptom onset to evaluation; 2) chief complaint of painless loss of feeling in the feet, Rombergs sign and tremor; and 3) clinical motor, sensory and reflex abnormalities. Autonomic testing was normal in both diseases. Using nerve conduction (NCS) criteria for demyelination, 62% of IgM-MGUS and 27% of WM met this criteria (p=0.013). IgM MGUS patients had greater terminal conduction slowing by ulnar residual latency calculation (<0.01). The degree of axonal loss as measured by summated compound muscle action potentials and available nerve biopsy was not significantly different between diseases. CONCLUSION Although WM and IgM-MGUS must be distinguished for hematologic prognosis and treatment, clinical neuropathy presentations of WM and IgM-MGUS are similar and likely related to comparable axonal loss in both conditions. Despite these similarities, evidence of demyelination was found by electrophysiologic studies much more commonly in IgM-MGUS. This difference may reflect varied immune mechanism(s) in the two disorders.

Hematoma risk after needle electromyography.

Introduction: Although needle electromyography (EMG) appears to be a relatively safe procedure based primarily on clinical experience, no evidence‐based guidelines exist for EMG procedures in patients taking anticoagulant or antiplatelet medications. We sought to determine whether there is an increased risk of hematoma formation after EMG of potentially high‐risk muscles in patients taking anticoagulant or antiplatelet agents. Methods: After undergoing routine EMG, if any of seven predetermined high‐risk muscles were tested, study subjects then underwent ultrasound to evaluate for hematoma formation. Results: Patients were divided into three groups based on medication (warfarin, aspirin/clopidogrel, no blood‐thinning medication), with at least 100 muscles examined per group. Two small, subclinical hematomas were seen on ultrasound; there was no difference in hematoma risk between groups (P = 0.43). Conclusions: Our findings suggest that hematoma formation from standard needle EMG is rare even in high‐risk muscles, which have been avoided historically in anticoagulated patients. Muscle Nerve 45: 9–12, 2012

Diagnosis and Management of Waldenström Macroglobulinemia: Mayo Stratification of Macroglobulinemia and Risk-Adapted Therapy (mSMART) Guidelines 2016.

Importance Waldenström macroglobulinemia (WM), an IgM-associated lymphoplasmacytic lymphoma, has witnessed several practice-altering advances in recent years. With availability of a wider array of therapies, the management strategies have become increasingly complex. Our multidisciplinary team appraised studies published or presented up to December 2015 to provide consensus recommendations for a risk-adapted approach to WM, using a grading system. Observations Waldenström macroglobulinemia remains a rare, incurable cancer, with a heterogeneous disease course. The major classes of effective agents in WM include monoclonal antibodies, alkylating agents, purine analogs, proteasome inhibitors, immunomodulatory drugs, and mammalian target of rapamycin inhibitors. However, the highest-quality evidence from rigorously conducted randomized clinical trials remains scant. Conclusions and Relevance Recognizing the paucity of data, we advocate participation in clinical trials, if available, at every stage of WM. Specific indications exist for initiation of therapy. Outside clinical trials, based on the synthesis of available evidence, we recommend bendamustine-rituximab as primary therapy for bulky disease, profound hematologic compromise, or constitutional symptoms attributable to WM. Dexamethasone-rituximab-cyclophosphamide is an alternative, particularly for nonbulky WM. Routine rituximab maintenance should be avoided. Plasma exchange should be promptly initiated before cytoreduction for hyperviscosity-related symptoms. Stem cell harvest for future use may be considered in first remission for patients 70 years or younger who are potential candidates for autologous stem cell transplantation. At relapse, retreatment with the original therapy is reasonable in patients with prior durable responses (time to next therapy ≥3 years) and good tolerability to previous regimen. Ibrutinib is efficacious in patients with relapsed or refractory disease harboring MYD88 L265P mutation. In the absence of neuropathy, a bortezomib-rituximab–based option is reasonable for relapsed or refractory disease. In select patients with chemosensitive disease, autologous stem cell transplantation should be considered at first or second relapse. Everolimus and purine analogs are suitable options for refractory or multiply relapsed WM. Our recommendations are periodically updated as new, clinically relevant information emerges.

Neurological Complications Associated With Anti–Programmed Death 1 (PD-1) Antibodies

Importance Neurological complications are an increasingly recognized consequence of the use of anti–programmed death 1 (PD-1) antibodies in the treatment of solid-organ tumors, with an estimated frequency of 4.2%. To date, the clinical spectrum and optimum treatment approach are not established. Objective To investigate the frequency, clinical spectrum, and optimum treatment approach to neurological complications associated with anti–PD-1 therapy. Design, Setting, and Participants This single-center, retrospective cohort study was conducted from either September or December 2014 (the approval dates of the study drugs by the US Food and Drug Administration) to May 19, 2016. All patients receiving anti–PD-1 monoclonal antibodies were identified using the Mayo Cancer Pharmacy Database. Patients with development of neurological symptoms within 12 months of anti–PD-1 therapy were included. Patients with neurological complications directly attributable to metastatic disease or other concurrent cancer-related treatments were excluded. Main Outcomes and Measures Clinical and pathological characteristics, time to development of neurological symptoms, and modified Rankin Scale (mRS) score. Results Among 347 patients treated with anti–PD1 monoclonal antibodies (pembrolizumab or nivolumab), 10 (2.9%) developed subacute onset of neurological complications. Seven patients were receiving pembrolizumab, and 3 patients were receiving nivolumab. The patients included 8 men and 2 women. Their median age was 71 years (age range, 31-78 years). Neurological complications occurred after a median of 5.5 (range, 1-20) cycles of anti–PD-1 inhibitors. Complications included myopathy (n = 2), varied neuropathies (n = 4), cerebellar ataxia (n = 1), autoimmune retinopathy (n = 1), bilateral internuclear ophthalmoplegia (n = 1), and headache (n = 1). Peripheral neuropathies included axonal and demyelinating polyradiculoneuropathies (n = 2), length-dependent neuropathies (n = 1), and asymmetric vasculitic neuropathy (n = 1). The time to maximum symptom severity varied from 1 day to more than 3 months. The median mRS score was 2.5 (range, 1-5), indicating mild to moderate disability. Five patients experienced other systemic immune-mediated complications, including hypothyroidism (n = 3), colitis (n = 2), and hepatitis (n = 1). Treatment with anti–PD-1 antibodies was discontinued in 7 patients. Treatment included corticosteroids (n = 7), intravenous immunoglobulin (n = 3), and plasma exchange (n = 1). Nine patients improved, with a median mRS score of 2 (range, 0-6). One patient with severe necrotizing myopathy died. Conclusions and Relevance Neurological adverse events associated with anti–PD-1 therapy have a diverse phenotype, with more frequent neuromuscular complications. Although rare, they will likely be encountered with increasing frequency as anti–PD-1 therapy expands to other cancers. The time of onset is unpredictable, and evolution may be rapid and life-threatening. Prompt recognition and discontinuation of anti–PD-1 therapy is recommended. In some cases, immune rescue treatment may be required.

Polyneuropathy improvement following autologous stem cell transplantation for POEMS syndrome

Objective: To study the evolution of the neuropathy and long-term disability in a large cohort of patients with POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) syndrome following autologous stem cell transplantation (ASCT). Methods: Retrospective chart review documenting the clinical, electrophysiologic, and laboratory characteristics of patients with POEMS syndrome undergoing ASCT at Mayo Clinic, Rochester. Results: Sixty patients with a median follow-up time of 61 months were studied. All patients had peripheral polyneuropathy and demonstrated neurologic improvement after ASCT (apart from one patient who died early). Before ASCT, 27 patients (45%) required a wheelchair and 17 (29%) required a walker or foot brace. At the end of the follow-up period, no patient was using a wheelchair and 23 patients (38%) were using a foot brace. The median Neuropathy Impairment Score improved from 66 to 48 points at 12 months and to 30 points at most recent follow-up (p < 0.0001). Median Rankin Scale score improved from 3 to 1.5 (p < 0.0001). Vascular endothelial growth factor levels decreased from a median of 452 to 63.5 pg/mL (p < 0.0001). The ulnar compound motor action potential amplitude (median) improved from 4.3 to 7.6 mV (p < 0.0001) and ulnar compound motor action potential conduction velocity (median) improved from 34 to 51 m/s (p < 0.0001). Predicted forced vital capacity improved from 81% to 88% (p < 0.0001). Periengraftment syndrome occurred in 24 patients. Fourteen patients required additional chemotherapy and/or radiation following ASCT, but there was no clinical deterioration in the neuropathy in any of these patients. Six patients died: 1 due to POEMS, 1 due to failed engraftment, and 4 due to other malignancies (2 myelodysplastic syndrome, 1 lymphoma, 1 metastatic lung cancer). Conclusion: Patients with POEMS syndrome who undergo ASCT have a significant and meaningful improvement of their neuropathy by multiple measurements during both short and long-term follow-up, which corresponds to reduction in morbidity and disability (none are in wheelchair long-term). Periengraftment syndrome was common but manageable. Fatal complications, although rare, did occur, usually in association with other malignancies. Classification of evidence: This study provides Class IV evidence that for patients with POEMS syndrome, ASCT improves neuropathy-related function.

Lesional REM sleep behavior disorder localizes to the dorsomedial pons

REM sleep behavior disorder (RBD) is characterized by dream enactment behaviors (DEB) and REM sleep without atonia (RSWA). A key structure in REM sleep muscle tone regulation in the rodent model is the sublateral dorsal (SLD) tegmental nucleus in the dorsomedial pons.1 Lesions of an analogous structure, the subceruleus (SC) nucleus are thought to mediate RSWA in humans, enabling DEB.1,2 However, in vivo human studies of discrete dorsomedial pontine lesions causing RBD in isolation have been limited.2–4 We report such a case of lesional RBD due to vasculitis. The Mayo Clinic Institutional Review Board approved this study.