Marit Otto

Algorithm for neuropathic pain treatment: an evidence based proposal.

&NA; New studies of the treatment of neuropathic pain have increased the need for an updated review of randomized, double‐blind, placebo‐controlled trials to support an evidence based algorithm to treat neuropathic pain conditions. Available studies were identified using a MEDLINE and EMBASE search. One hundred and five studies were included. Numbers needed to treat (NNT) and numbers needed to harm (NNH) were used to compare efficacy and safety of the treatments in different neuropathic pain syndromes. The quality of each trial was assessed. Tricyclic antidepressants and the anticonvulsants gabapentin and pregabalin were the most frequently studied drug classes. In peripheral neuropathic pain, the lowest NNT was for tricyclic antidepressants, followed by opioids and the anticonvulsants gabapentin and pregabalin. For central neuropathic pain there is limited data. NNT and NNH are currently the best way to assess relative efficacy and safety, but the need for dichotomous data, which may have to be estimated retrospectively for old trials, and the methodological complexity of pooling data from small cross‐over and large parallel group trials, remain as limitations.

Subcutaneous immunoglobulin in responders to intravenous therapy with chronic inflammatory demyelinating polyradiculoneuropathy

We hypothesized that subcutaneous administration of immunoglobulins (SCIG) in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is feasible, safe and superior to treatment with saline for the performance of muscle strength.

Valproic acid has no effect on pain in polyneuropathy A randomized, controlled trial

The aim of this randomized, double-blind, placebo-controlled cross-over study was to test whether valproic acid relieves painful polyneuropathy. Thirty-one patients completed two treatment phases of 4 weeks’ duration with valproic acid (1,500 mg daily) and placebo. There was no significant difference between valproic acid and placebo in the rating of total pain (median, 5 in the valproic acid period vs 6 in the placebo period; p = 0.24) or in individual pain ratings.

Motor Unit Number Index (MUNIX) : A novel neurophysiological marker for neuromuscular disorders; test-retest reliability in healthy volunteers

OBJECTIVE To investigate the intra-rater and inter-rater test-retest reliability of the Motor Unit Number Index (MUNIX) in healthy subjects in a multicentre setting. METHODS Six study centres applied the MUNIX technique in 66 healthy subjects. Five to six muscles (biceps brachii, BB; abductor digiti minimi, ADM; abductor pollicis brevis, APB; tibialis anterior, TA; extensor digitorum brevis, EDB and abductor hallucis, AH) were measured in each volunteer four times by two independent examiners. RESULTS The method was easy to perform and well tolerated. The intraclass correlation coefficient (ICC) varied between centres and muscles. Intra-rater reliability was greatest for the AH (ICC 0.83) and EDB (ICC 0.81). Inter-rater reliability was greatest for the AH (ICC 0.69) and ADM muscles (ICC 0.69). The most critical muscle was the APB muscle (ICC 0.52, total variability). This was mostly due to variability in the compound muscle action potential (CMAP) measurements. MUNIX values of the APB, ADM and TA fell into the same range as in other motor unit number estimation (MUNE) studies. CONCLUSION MUNIX measurements in multiple muscles show good inter- and intra-rater reliability in healthy subjects. CMAP amplitude must be controlled to optimize reliability. SIGNIFICANCE Results suggest that MUNIX could serve as a reliable marker for motor neuron loss in diseases like amyotrophic lateral sclerosis.

Motor Unit Number Index (MUNIX): reference values of five different muscles in healthy subjects from a multi-centre study.

Motor Unit Number Index (MUNIX) : Reference values of five different muscles in healthy subjects from a multi-centre study

Health-related quality of life and its predictive role for analgesic effect in patients with painful polyneuropathy.

Painful polyneuropathy is a common neuropathic pain condition. The present study describes health‐related quality of life (HRQL) in a sample of patients with painful polyneuropathy of different origin and the possible predictive role of HRQL for analgesic effect.

The anticonvulsant levetiracetam for the treatment of pain in polyneuropathy: A randomized, placebo-controlled, cross-over trial

Levetiracetam is an anticonvulsant which is assumed to act by modulating neurotransmitter release via binding to the vesicle protein SV2A. This could have an impact on signaling in the nociceptive system, and a pilot study indicated relief of neuropathic pain with levetiracetam.UNLABELLED Levetiracetam is an anticonvulsant which is assumed to act by modulating neurotransmitter release via binding to the vesicle protein SV2A. This could have an impact on signaling in the nociceptive system, and a pilot study indicated relief of neuropathic pain with levetiracetam. OBJECTIVES The aim of this study was to test the analgesic effect of levetiracetam in painful polyneuropathy. METHODS This was a randomized, double-blind, placebo-controlled, cross-over trial with levetiracetam 3000 mg/day versus placebo (6-week treatment periods). Patients with diagnosed polyneuropathy and symptoms for more than 6 months, age between 20 and 80 years, pain intensity of more than 4 on a 0-10-point numeric rating scale, and pain at least 4 days a week were included in the study. The primary outcome measure was pain relief at the end of each treatment period as measured on a 6-point verbal scale. RESULTS Ninety-three patients were screened for participation and 39 patients entered the study. Thirty-five patients were included in the data analysis. There were no differences in the ratings of pain relief (levetiracetam 2.29 versus placebo 2.28, p=0.979), total pain intensity (levetiracetam 5.5 versus placebo 5.3, p=0.293) or any of the other outcome measures (p=0.147-1.00). CONCLUSION This study indicates that the anticonvulsant levetiracetam has no clinically relevant effect on painful polyneuropathy.

Assessment of neuroinflammation in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a case-control study

BACKGROUND Findings from longitudinal follow-up studies in patients with idiopathic rapid-eye-movement sleep behaviour disorder (IRBD) have shown that most patients will eventually develop the synucleinopathies Parkinsons disease, dementia with Lewy bodies, or multiple system atrophy. Neuroinflammation in the form of microglial activation is present in synucleinopathies and is a potential therapeutic target to halt or delay the neurodegenerative process. We aimed to investigate whether neuroinflammation is present in patients with IRBD and its possible relation to nigrostriatal dopamine function. METHODS In this prospective, case-control, PET study, patients with IRBD and no clinical evidence of parkinsonism and cognitive impairment were recruited from tertiary sleep centres in Spain (Barcelona) and Denmark (Aarhus). We included patients with polysomnography-confirmed IRBD according to established criteria. Healthy controls were recruited through newspaper advertisements. Controls had no motor or cognitive complaints, a normal neurological examination, and a mean group age similar to the IRBD group. In patients with IRBD, we assessed microglial activation in the substantia nigra, putamen, and caudate with 11C-PK11195 PET, and dopaminergic axon terminal function in the putamen and caudate with 18F-DOPA PET. Controls underwent either 11C-PK11195 PET or 18F-DOPA PET. We compared 18F-DOPA uptake and 11C-PK11195 binding potential between groups with an unpaired, two-tailed Students t test. FINDINGS Between March 23, 2015, and Oct 19, 2016, we recruited 20 consecutive patients with IRBD and 19 healthy controls. 11C-PK11195 binding was increased on the left side of the substantia nigra in patients with IRBD compared with controls (Students t test, mean difference 0·153 [95% CI 0·055 to 0·250], p=0·003), but not on the right side (0·121 [-0·007 to 0·250], p=0·064). 11C-PK11195 binding was not significantly increased in the putamen and caudate of patients with IRBD. 18F-DOPA uptake was reduced in IRBD in the left putamen (-0·0032 [-0·0044 to -0·0021], p<0·0001) and right putamen (-0·0032 [-0·0044 to -0·0020], p<0·0001), but not in the caudate. INTERPRETATION In patients with IRBD, increased microglial activation was detected by PET in the substantia nigra along with reduced dopaminergic function in the putamen. Further studies, including more participants than were in this study and longitudinal follow-up, are needed to support our findings and evaluate whether the presence of activated microglia in patients with IRBD represents a marker of short-term conversion to a clinically defined synucleinopathy in the near future. FUNDING Danish Council for Independent Research, Instituto de Salud Carlos III (Spain).

A candidate gene study of serotonergic pathway genes and pain relief during treatment with escitalopram in patients with neuropathic pain shows significant association to serotonin receptor2C (HTR2C).

PurposePrevious studies have shown that a small fraction of patients with peripheral neuropathic pain experiences >50% pain relief during treatment with selective serotonin reuptake inhibitors (SSRIs), whereas most patients have no or only slight relief. The aim of this study was to investigate the association between polymorphisms in genes involved in the serotonergic pathway and the effect of escitalopram on peripheral neuropathic pain.MethodsWe genotyped 34 participants from a placebo-controlled trial of escitalopram in peripheral neuropathic pain for polymorphisms in five genes: the serotonin receptor 2A (HTR2A) gene, the serotonin receptor 2C (HTR2C) gene, the ABCB1 gene encoding for the P-glycoprotein, the CYP2C19 gene, and the serotonin transporter gene (SLC6A4).ResultsThe SNP rs6318 (Cys23Ser) in the HTR2C gene showed significant association with treatment response in men (p = 0.047), with 75% carrying the C allele being responders. The same tendency was seen in women. Similarly, carriership of the C allele at rs6318 was associated with better pain relief during treatment with escitalopram [odds ratio (OR) 15.5, p = 0.014)] Furthermore, there was a tendency of better relief with increasing number of short alleles for the 5-HTTLPR polymorphism of the serotonin transporter (OR 5.7, p = 0.057). None of the other polymorphisms showed a significant association with treatment response to escitalopram.ConclusionThis study indicates that variation in the HTR2C gene is associated to the pain-relieving effect of escitalopram in patients with painful polyneuropathy.

Evaluation of the noradrenergic system in Parkinson’s disease: an 11C-MeNER PET and neuromelanin MRI study

Pathological involvement of the noradrenergic locus coeruleus occurs early in Parkinsons disease, and widespread noradrenaline reductions are found at post-mortem. Rapid eye movement sleep behaviour disorder (RBD) accompanies Parkinsons disease and its presence predicts an unfavourable disease course with a higher propensity to cognitive impairment and orthostatic hypotension. MRI can detect neuromelanin in the locus coeruleus while 11C-MeNER PET is a marker of noradrenaline transporter availability. Here, we use both imaging modalities to study the association of RBD, cognition and autonomic dysfunction in Parkinsons disease with loss of noradrenergic function. Thirty non-demented Parkinsons disease patients [16 patients with RBD and 14 without RBD, comparable across age (66.6 ± 6.7 years), sex (22 males), and disease stage (Hoehn and Yahr, 2.3 ± 0.5)], had imaging of the locus coeruleus with neuromelanin sensitive MRI and brain noradrenaline transporter availability with 11C-MeNER PET. RBD was confirmed with polysomnography; cognitive function was assessed with a neuropsychological test battery, and blood pressure changes on tilting were documented; results were compared to 12 matched control subjects. We found that Parkinsons disease patients with RBD showed decreased locus coeruleus neuromelanin signal on MRI (P < 0.001) and widespread reduced binding of 11C-MeNER (P < 0.001), which correlated with amount of REM sleep without atonia. Parkinsons disease with RBD was also associated with a higher incidence of cognitive impairment, slowed EEG activity, and orthostatic hypotension. Reduced 11C-MeNER binding correlated with EEG slowing, cognitive performance, and orthostatic hypotension. In conclusion, reduced noradrenergic function in Parkinsons disease was linked to the presence of RBD and associated with cognitive deterioration and orthostatic hypotension. Noradrenergic impairment may contribute to the high prevalence of these non-motor symptoms in Parkinsons disease, and may be of relevance when treating these conditions in Parkinsons disease.