Bernhard F. Décard

Ultrasound of the peripheral nerves in systemic vasculitic neuropathies

INTRODUCTION Ultrasound of the peripheral nerves (PNUS) can be used to visualize nerve pathologies in polyneuropathies (PNP). The aim of this study was to investigate, whether PNUS provides additional information in patients with proven systemic vasculitic neuropathies (VN). MATERIAL AND METHODS Systematic ultrasound measurements of several peripheral nerves, the vagal nerve and the 6th cervical nerve root were performed in 14 patients and 22 healthy controls. Nerve conduction studies of the corresponding nerves were undertaken. Finally, the measured results were compared to a study population of demyelinating immune-mediated and axonal neuropathies. RESULTS Patients with VN displayed significant smaller amplitudes of compound muscle action potentials (CMAP) (p<0.05) and sensory nerve action potentials (SNAP) compared to healthy controls, while conduction velocity did not differ between groups. The mean nerve cross-sectional areas (CSA) were increased in several peripheral nerves compared to the controls, most prominent in tibial and fibular nerve (p<0.01). PNUS revealed nerve enlargement in most of the clinically and electrophysiologically affected nerves (22 out of 31) in VN. Nerve enlargement was more often seen in vasculitic neuropathies than in other axonal neuropathies, but significantly rarer than in demyelinating neuropathies. CONCLUSION Focal CSA enlargement in one or more nerves in electrophysiologically axonal neuropathies can be a hint for VN and thus facilitate diagnostic and therapeutic procedures.

The Ultrasound pattern sum score – UPSS. A new method to differentiate acute and subacute neuropathies using ultrasound of the peripheral nerves

OBJECTIVE Ultrasound differentiation of neuropathies is a great challenge. We, therefore, suggest a standardized score to operationalize differentiation between several acute and subacute onset neuropathies. METHOD We retrospectively analyzed the ultrasound data of 61 patients with acute or subacute neuropathies, e.g. chronic immune-mediated neuropathies, Guillain-Barré syndrome (GBS), and axonal/vasculitic neuropathies. We compared these data to 28 healthy controls. Based on these results an ultrasound pattern sum score (UPSS) with three sub-scores (UPS-A for the sensorimotor nerves, UPS-B for the cervical roots and the vagal nerve and UPS-C for the sural nerve) was developed. Afterwards, the applicability of the score was prospectively validated in 10 patients with chronic neuropathies and in 14 patients with unknown acute and subacute PNP before performing additional tests. RESULTS UPS-A and UPSS were significantly higher in CIDP than in other neuropathies and controls (p<0.001). UPS-B was significantly more often pathologic in GBS than in CIDP and other neuropathies (p<0.001). Using receiver operation characteristics curve analysis boundary values for each score were defined. Positive predictive value (PPV) of these scores for CIDP and GBS was >85%. Vasculitic neuropathies showed an intermediate type of UPSS compared to other axonal neuropathies (p<0.001). In the prospective application the pattern score could be used with good accuracy in several types of neuropathy. CONCLUSION UPS-A and UPSS operationalize to diagnose acute and subacute-onset CIDP and its variants with high sensitivity, specificity, and PPV. An increased UPS-B with normal UPSS and other sub scores may point to the diagnosis of GBS with high PPV and enables the differentiation from CIDP. SIGNIFICANCE Using the UPSS and its sub-scores gives a new diagnostic power to the method of the peripheral nerve ultrasound.

Ultrasonography of the peripheral nervous system in the early stage of Guillain‐Barré syndrome

Ultrasonography can be used to visualize peripheral nerve abnormalities in immune‐mediated neuropathies. The objective of this study was to prove the role of ultrasonography (US) in acute phase of Guillain‐Barré syndrome (GBS). Systematic ultrasonic measurements of several peripheral nerves including the vagal nerve as well as the sixth cervical nerve root were performed in 18 patients with GBS at days 1–3 after symptom onset and compared to 21 healthy controls. Nerve conduction studies (NCS) of corresponding nerves were undertaken. Consequently, significant differences between the groups were found in compound muscle action potential amplitudes, F‐wave latency, and persistency. Ultrasonic cross‐sectional areas (CSAs) showed significant enlargement in all nerves except of the ulnar nerve (upper arm) and the sural nerve compared to healthy controls, most prominent in proximal and middle median nerve (p < 0.01). The vagal nerve also showed enlargement compared to controls (p < 0.05), which was most pronounced in patients with autonomic dysfunction compared to patients without (p < 0.05). C6 root diameter showed a significant correlation to the amount of cerebrospinal fluid (CSF)‐protein (Pearson correlation, p < 0.05). US shows nerve enlargement in several peripheral nerves including vagal nerve and C6 root in acute phase of GBS and could be an additional diagnostic tool for example, in GBS of atypical onset and autonomic dysfunction.

Ultrasound pattern sum score, homogeneity score and regional nerve enlargement index for differentiation of demyelinating inflammatory and hereditary neuropathies.

OBJECTIVE To investigate the use of nerve ultrasound in the differentiation between Charcot-Marie Tooth hereditary neuropathy (CMT1) and chronic inflammatory demyelinating polyradiculoneuropathies (CIDP), multifocal motor neuropathy (MMN) and multifocal acquired demyelinating sensory and motor neuropathies (MADSAM). METHODS Ultrasound/electrophysiology of predefined nerves was performed in CMT1a/b, immunoneuropathies, and healthy controls. Ultrasound pattern sum score (UPSS, sum of the amount of 12 predefined measurement points), homogeneity score (HS) and regional nerve enlargement index (RNEI) in ulnar, median, and tibial nerve were used for evaluation of morphology. RESULTS 13 CMT1, 27 CIDP, 10 MADSAM, 12 MMN, and 23 controls were included. Significant enlargement was shown in all neuropathies compared to the controls, (p<0.001), however the amount of enlargement as evaluated by the UPSS was most prominent in CMT compared to the others (median UPSS 18 vs. 11/8.5/5 in CIDP/MADSAM/MMN, p<0.001). Homogeneous enlargement was significantly more often seen in CMT (67%, HS 6 vs. 2-3 in immune-mediated PNP, p<0.001), while in CIDP the enlargement was regional, homogeneous or inhomogeneous with equal contribution. In MMN and MADSAM regional enlargement (48%/40%) next to normal segments (∼20%) predominated (RNEI in MMN=2, in MADSAM=1 vs. 0 in the others). CSAs were inversely correlated with motor conduction velocity. CONCLUSION Ultrasound, quantified by UPSS, HS, and RNEI facilitates a reliable and reproducible differentiation of immunoneuropathies and hereditary neuropathies by the use of boundary values. SIGNIFICANCE By the use of quantitative scores, ultrasound differentiation of demyelinating neuropathies is operationalized and ameliorated compared to CSA measurements only.

Ultrasound and electrophysiologic findings in patients with Guillain–Barré syndrome at disease onset and over a period of six months

OBJECTIVE To investigate cross-sectional areas (CSAs) of several peripheral nerves including the vagus nerve and the diameter of spinal nerves as measured by nerve ultrasound (NUS) and nerve conduction studies (NCS) in Guillain-Barré syndrome (GBS) patients over at least six months compared to healthy controls. METHODS NUS and/or NCS of several nerves, the vagus nerve, and the 5th/6th cervical spinal nerves were performed in patients with GBS at days 2-3 after symptom onset, at days 10-14 after immunoglobulin therapy and after six months compared to healthy controls. RESULTS 27 GBS-patients and 31 controls were included. Using NUS significant enlargement was found in all measured nerves (P<0.001), except the sural nerve (P=0.086) compared to the controls at onset. The vagus (median 3.0 mm(2) vs. 2.0 mm(2), P<0.0001) and the cervical spinal nerves were significantly enlarged (median 3.5/4.0 mm vs. 2.6/3.2 mm, p<0.0001), the vagus most obviously in patients with autonomic dysregulation (AD, 4.0 mm(2)). Six months later, NCS showed persisting pathology in CMAP-amplitudes with amelioration of F-wave pathology. NUS showed restitution in the spinal nerves (median 2.6/3.2 mm) and the vagus (median 2.0 mm(2)) in all patients excluding the vagus in those with persistent AD (median 4.0 mm(2)). The peripheral nerves did not change significantly (P>0.05). CONCLUSION Ultrasonographic detection of cervical spinal nerve enlargement supports the diagnosis of GBS in the early phase. Its regression may be a good parameter for the clinical restitution over time. Vagus enlargement may be a risk marker for development of AD. SIGNIFICANCE Ultrasound is a reliable diagnostic follow-up tool in early GBS.

Natalizumab-induced POU2AF1/Spi-B upregulation: A possible route for PML development

Objectives: To assess messenger RNA (mRNA) expression of POU2AF1 and Spi-B and their potential regulatory microRNAs (miRNAs) in natalizumab-treated patients with multiple sclerosis and in therapy-associated progressive multifocal leukoencephalopathy (PML). Methods: Expression of POU2AF1/Spi-B was analyzed by using real-time reverse transcription PCR assays on isolated B/CD8+ T lymphocytes and peripheral blood mononuclear cells (PBMCs) from cohorts of untreated and natalizumab-treated patients with and without PML. Longitudinal expression analysis was performed on CD4+, CD8+ T and B cells from 14 patients who interrupted natalizumab therapy for 8 weeks. The miRNA profiling was conducted in PBMCs from 5 untreated and 5 natalizumab-treated patients using low-density arrays followed by validation with single miRNAs assays in untreated and natalizumab-treated patients. Results: POU2AF1 and Spi-B mRNAs were upregulated in B and CD8+ T cells from natalizumab-treated patients, which was validated in PBMCs from different cohorts of natalizumab-treated patients with and without PML, with a noteworthy higher expression of Spi-B in patients with PML. In contrast, downregulation of POU2AF1/Spi-B expression was measured in B and CD8+ T cells after natalizumab discontinuation. Seventeen differentially expressed miRNAs including miR-10b, a regulator of POU2AF1 mRNA, were identified in long-term natalizumab-treated patients compared with untreated ones. Conclusions: Upregulation of POU2AF1 and Spi-B, known transactivators of the JC virus, the causative agent for PML, and its association with occurrence of PML in natalizumab-treated patients, corroborates POU2AF1/Spi-B as potential biomarkers for PML risk, which merits further evaluation.

NERVE ULTRASOUND IN MILLER FISHER VARIANT OF GUILLAIN-BARRE SYNDROME

Introduction: Focal enlargement of the peripheral and spinal nerves, visualized using high‐resolution ultrasound (HRUS), has been reported in early Guillain–Barré syndrome, but not in the Miller Fisher variant. We report the use of HRUS in 2 patients who presented with acute ataxic neuropathy, areflexia, and ophthalmoparesis. Methods: Ultrasound and/or nerve conduction studies (NCS) of peripheral nerves, the vagus, and spinal nerves C5/6 were performed at onset and 2 weeks after immunoglobulin therapy. Results: Both patients fulfilled criteria for diagnosis of Miller Fisher syndrome (MFS). Laboratory findings revealed elevated ganglioside Q1b antibodies in both and an albuminolocytologic dissociation in 1 patient. In addition, 1 patient had NCS evidence for demyelinating neuropathy. However, ultrasound showed focal enlargement in the vagus, the spinal nerves, and/or in the peripheral nerves in both patients. After therapy, nerve enlargement decreased in parallel with clinical improvement. Conclusion: Spinal and/or peripheral nerve enlargement supports the diagnosis of MFS in early phases of the disease. Muscle Nerve 52: 1106–1110, 2015

Hepatitis-E virus associated neuralgic amyotrophy with sustained plexus brachialis swelling visualized by high-resolution ultrasound

Neuralgic amyotrophy (NA) also known as Parsonage–Turner syndrome is an acute brachial plexus disorder characterized by acute onset of neuropathic pain followed by multifocal paresis in the affected limb. Although the exact pathophysiological mechanisms of NA remain unclear, autoimmunological processes triggered by preceding infections, trauma or operations seem to play an important role especially in genetically susceptible patients [1]. Recently two case series of hepatitis-E virus (HEV) associated neurological disorders with affection of the peripheral nervous system have been described [2,3]. HEV genotypes 1 and 2 are human viruses that have been identified as causing epidemic hepatitis and are associated with waterborne and fecal-oral transmission. In developed countries hepatitis E is mainly caused by HEV genotypes 3 and 4 and transmitted via contaminated raw or insufficiently heated meet (notably pork or boar) [4].

Ultrasound assessment of peripheral nerve pathology in neurofibromatosis type 1 and 2

OBJECTIVE The neurofibromatoses (NF) type 1 and 2 are hereditary tumor predisposition syndromes caused by germline mutations in the NF1 and NF2 tumor suppressor genes. In NF1 and 2, peripheral nerve tumors occur regularly. For further characterizing nerve ultrasound was performed in patients with NF1 and 2. METHODS Patients with established diagnosis of NF1 (n=27) and NF2 (n=10) were included. Ultrasound of peripheral nerves and cervical roots was performed during routine follow-up visits. Healthy volunteers were studied for comparison. RESULTS In patients with NF1, median cross-sectional area (CSA) of most nerves was significantly increased compared to controls and to NF2 due to generalized plexiform tumors, which arose out of multiple fascicles in 23 of 27 patients (85%). These were often accompanied by cutaneous or subcutaneous neurofibromas. In NF2, the overall aspect of peripheral nerves consisted of localized schwannomas (80%) and, apart from that, normal nerve segments. CONCLUSION Nerve ultrasound is able to visualize different nerve pathologies in NF1 and NF2. It is a precise and inexpensive screening method for peripheral nerve manifestation in neurofibromatosis and should be considered as the first choice screening imaging modality for all peripheral nerves within reach of non-invasive ultrasound techniques. SIGNIFICANCE Ultrasound patterns of peripheral nerve pathologies are described for the first time in a large cohort of patients with NF1 and NF2. It is a suitable screening tool and enables targeted MRI analysis.

Ultrasound of the nerves - An appropriate addition to nerve conduction studies to differentiate paraproteinemic neuropathies.

OBJECTIVE To investigate the use of peripheral nerve ultrasound (PNUS) in addition to nerve conduction studies (NCS) in the diagnosis of paraproteinemic neuropathies (PN). METHODS PNUS/NCS of predefined peripheral nerves and the 5th/6th cervical roots were performed in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) (+/-paraprotein), patients with anti-MAG neuropathy, and patients with neuropathy and multiple myeloma or monoclonal gammopathy of uncertain significance (MGUS) - summarized as M-protein associated neuropathies (MPAN) and compared to controls (+/-paraprotein). RESULTS 39 patients and 27 age-matched controls were included. Nerve enlargement was most marked in patients with CIDP, while in anti-MAG neuropathies enlargement was significant in the legs. In MPAN, no nerve enlargement is found regularly. However, in two cases, the diagnostic steps were influenced by the finding of multiple enlarged nerves and finally immunotherapy response was successfully initiated. By the use of the ultrasound pattern sum score (UPSS), differentiation of PN can be simplified. DISCUSSION Due to the heterogeneous findings in NCS, correct diagnosis of PN, and straightforward therapeutic decisions often may be controversial. Particularly in cases of M-protein related neuropathy, the finding of multiple nerve enlargements facilitates the decision for therapeutic approaches or nerve biopsy. The UPSS enables the distinction of different PN from each other. CONCLUSION The use of an ultrasound quantification tool in addition to NCS facilitates a differentiation of PN.