Upper and extra-motoneuron involvement in early motoneuron disease: a diffusion tensor imaging study.

Motoneuron disease is a term encompassing three phenotypes defined largely by the balance of upper versus lower motoneuron involvement, namely amyotrophic lateral sclerosis, primary lateral sclerosis and progressive muscular atrophy. However, neuroradiological and pathological findings in these phenotypes suggest that degeneration may exceed the neuronal system upon which clinical diagnosis is based. To further delineate the phenotypes within the motoneuron disease spectrum, this controlled study assessed the upper- and extra-motoneuron white matter involvement in cohorts of patients with motoneuron disease phenotypes shortly after diagnosis by comparing diffusion tensor imaging data of the different cohorts to those of healthy controls and directly between the motoneuron disease phenotypes (n = 12 for each cohort). Furthermore, we acquired follow-up data 6 months later to evaluate fractional anisotropy changes over time. Combined use of diffusion tensor tractography of the corticospinal tract and whole-brain voxel-based analysis allowed for comparison of the sensitivity of these techniques to detect white matter involvement in motoneuron disease. The voxel-based analysis demonstrated varying extents of white matter involvement in different phenotypes of motoneuron disease, albeit in quite similar anatomical locations. In general, fractional anisotropy reductions were modest in progressive muscular atrophy and most extensive in primary lateral sclerosis. The most extensive patterns of fractional anisotropy reduction were observed over time in the voxel-based analysis, indicating progressive extra-motor white matter degeneration in limb- and bulbar onset amyotrophic lateral sclerosis and in progressive muscular atrophy. The observation of both upper motor and extra-motoneuron involvement in all phenotypes of motoneuron disease shortly after diagnosis suggests that these are all part of a single spectrum of multisystem neurodegenerative disease. Voxel-based analysis was more sensitive to detect longitudinal changes than diffusion tensor tractography of the corticospinal tract. Voxel-based analyses may be particularly valuable in the evaluation of motor and extra-motor white matter involvement in the early symptomatic stages of motoneuron disease, and for monitoring the spread of pathology over time.

Second intravenous immunoglobulin dose in patients with Guillain-Barré syndrome with poor prognosis (SID-GBS): a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Treatment with one standard dose (2 g/kg) of intravenous immunoglobulin is insufficient in a proportion of patients with severe Guillain-Barré syndrome. Worldwide, around 25% of patients severely affected with the syndrome are given a second intravenous immunoglobulin dose (SID), although it has not been proven effective. We aimed to investigate whether a SID is effective in patients with Guillain-Barré syndrome with a predicted poor outcome. METHODS: In this randomised, double-blind, placebo-controlled trial (SID-GBS), we included patients (≥12 years) with Guillain-Barré syndrome admitted to one of 59 participating hospitals in the Netherlands. Patients were included on the first day of standard intravenous immunoglobulin treatment (2 g/kg over 5 days). Only patients with a poor prognosis (score of ≥6) according to the modified Erasmus Guillain-Barré syndrome Outcome Score were randomly assigned, via block randomisation stratified by centre, to SID (2 g/kg over 5 days) or to placebo, 7-9 days after inclusion. Patients, outcome adjudicators, monitors, and the steering committee were masked to treatment allocation. The primary outcome measure was the Guillain-Barré syndrome disability score 4 weeks after inclusion. All patients in whom allocated trial medication was started were included in the modified intention-to-treat analysis. This study is registered with the Netherlands Trial Register, NTR 2224/NL2107. FINDINGS: Between Feb 16, 2010, and June 5, 2018, 327 of 339 patients assessed for eligibility were included. 112 had a poor prognosis. Of those, 93 patients with a poor prognosis were included in the modified intention-to-treat analysis: 49 (53%) received SID and 44 (47%) received placebo. The adjusted common odds ratio for improvement on the Guillain-Barré syndrome disability score at 4 weeks was 1·4 (95% CI 0·6-3·3; p=0·45). Patients given SID had more serious adverse events (35% vs 16% in the first 30 days), including thromboembolic events, than those in the placebo group. Four patients died in the intervention group (13-24 weeks after randomisation). INTERPRETATION: Our study does not provide evidence that patients with Guillain-Barré syndrome with a poor prognosis benefit from a second intravenous immunoglobulin course; moreover, it entails a risk of serious adverse events. Therefore, a second intravenous immunoglobulin course should not be considered for treatment of Guillain-Barre syndrome because of a poor prognosis. The results indicate the need for treatment trials with other immune modulators in patients severely affected by Guillain-Barré syndrome. FUNDING: Prinses Beatrix Spierfonds and Sanquin Plasma Products.

Prospective, blind study of the triple stimulation technique in the diagnosis of ALS.

OBJECTIVE: To evaluate the diagnostic yield of magnetic cortical stimulation with the triple stimulation technique (TST) to identify upper motor neuron (UMN) involvement in patients suspected of having ALS. METHODS: Fifty-nine patients were recruited to undergo TST in addition to the standard work-up for suspected motor neuron disease. TST combines transcranial magnetic stimulation of the motor cortex with collision studies, which results in a higher sensitivity in detecting UMN involvement. Primary outcome was the number of abnormal TST results in patients with possible ALS. The positivity rate was converted to the number needed to test with TST (NN-TST) for one extra diagnosis of ALS. RESULTS: Fifty patients underwent TST. In the total group (n=59), 18 patients had a motor neuron disorder but did not fulfil criteria for 'probable' or 'definite' ALS. In four of these patients TST was abnormal (NN-TST, 4.5). One TST was erroneously interpreted as abnormal. TST findings were normal in inclusion body myositis and peripheral nerve disorders. CONCLUSION: This prospective and blind study confirms open studies of TST in the evaluation of ALS. We suggest that TST can be used to arrive at a diagnosis of 'probable' or 'definite' ALS in patients lacking UMN signs in the upper extremities.

TDP-43 pathology in familial frontotemporal dementia and motor neuron disease without Progranulin mutations.

Frontotemporal dementia is accompanied by motor neuron disease (FTD + MND) in approximately 10% of cases. There is accumulating evidence for a clinicopathological overlap between FTD and MND based on observations of familial aggregation and neuropathological findings of ubiquitin-positive neuronal cytoplasmatic inclusions (NCI) in lower motor neurons, hippocampus and neocortex in both conditions. Several familial forms exist with different genetic loci and defects. We investigated the familial aggregation and clinical presentation of FTD + MND cases in a large cohort of 368 FTD patients in The Netherlands. Immunohistochemistry of available brain tissue of deceased patients was investigated using a panel of antibodies including ubiquitin, p62 and TAR DNA-binding protein of 43 kDa antibodies. A total of eight patients coming from six families had a family history positive for FTD + MND (mean age at onset 53.2 +/- 8.4 years). Five patients presented with behavioural changes and cognitive changes followed by motor neuron disease, whereas symptoms of motor neuron disease were the presenting features in the remaining three patients. Other affected relatives in these families showed dementia/FTD, MND or FTD + MND reflecting the clinical interfamilial variation. No mutations were identified in any of the candidate genes, including Superoxide Dismutase 1, dynactin, angiogenin, Microtubule-Associated Protein Tau, valosin-containing protein and progranulin. Available brain tissue of five patients with familial FTD + MND showed NCI in hippocampus, neocortex and spinal cord in all, and neuronal intranuclear inclusions (NII) in two brains. TDP-43 antibody showed robust staining of neuronal inclusions similar in distribution and morphology to NCI and NII. Additionally, TDP-43 antibody also stained ubiquitin-negative glial inclusions in the basal striatum of one case. In conclusion, there exists considerable clinical variation within families with FTD + MND, which may be determined by other genetic or environmental factors. NII are also found in some cases of familial FTD + MND without Progranulin mutations. The observation of glial TDP-43 positive inclusions in one brain is very interesting, although their pathophysiological significance is yet unknown.

Does a carpal tunnel syndrome predict an underlying disease?

Carpal tunnel syndrome (CTS) may be the presenting symptom of an underlying disease such as diabetes mellitus, hypothyroidism or connective tissue disease (CTD). It was investigated whether additional blood tests (glucose level, thyroid-stimulating hormone level and erythrocyte sedimentation rate) are useful to detect diabetes mellitus, hypothyroidism or CTD in patients with CTS who have not been diagnosed with these diseases before. A group of 516 consecutive patients electromyographically diagnosed with CTS without known diabetes mellitus, hypothyroidism or CTD underwent blood tests and were followed up for incident diabetes mellitus, hypothyroidism or CTD to investigate whether these additional blood tests are useful to detect these diseases in patients with CTS. In our CTS population, only two patients were newly diagnosed with diabetes mellitus, two with hypothyroidism and none with CTD. In general, systematic screening for incident diabetes mellitus, hypothyroidism and CTD through additional blood tests seems to be of little additional value in otherwise typical cases of CTS.

[Low back pain and MRI-abnormalities: atypical polymyalgia rheumatica]. / Lage rugpijn en MRI-afwijkingen: atypische polymyalgia rheumatica.

A 64-year-old man was admitted to hospital with increasing low back pain, radiating to his upper legs. MRI of the lumbar spine showed inflammatory lesions of vertebrae L3-L5, after which the patient was treated with flucloxacilline for 6 weeks. However, he did not improve and the pain became more extensive. Finally, PET-CT study showed abnormalities in shoulders, back and hips, indicating a probable diagnosis of polymyalgia rheumatica. Upon treatment with prednisone, the pain quickly decreased and 3 months later the inflammatory changes visible on MRI were clearly reduced. Polymyalgia rheumatica (PMR) is often recognized by its typical clinical presentation, but in atypical cases, investigation using imaging may be helpful. Abnormalities in shoulder and hip joints are most common, but signs of cervical and lumbar interspinous bursitis might also be found in patients with PMR.

[Meningoencephalitis caused by varicella zoster virus]. / Meningo-encefalitis door varicella-zostervirus.

Varicella zoster virus (VZV) belongs to the group of herpes viruses. It can cause a number of nervous system infections. We present 2 of 4 patients seen recently suffering from acute meningoencephalitis, in which VZV proved to be the infectious agent. The first patient was a 57-year-old woman with headache, vomiting, and sudden aggressiveness. The second patient was a 60-year-old man with headache, nausea, and vomiting. Neither patient had skin eruptions usually associated with VZV reactivation, nor had either recently suffered from herpes zoster. Both patients had in their cerebrospinal fluid a lymphocytic pleocytosis, a decreased glucose concentration and and an elevated protein concentration. The patients recovered within a few days of starting intravenous treatment with aciclovir 10 mg/kg 3 times daily for one week. Recent literature shows that VZV is a common pathogen in meningoencephalitis and is probably underestimated as a putative cause of this condition. VZV meningoencephalitis usually has a mild course, but serious complications have been reported. Patients present with headache and usually fever. Nuchal rigidity and meningeal irritation are not always present. Since the advent of the PCR technique, VZV has been readily demonstrable. Anti-viral treatment is advised despite the lack of placebo-controlled studies, and may be combined with prednisone.