Factsheet by Søren Hein Sindrup

Group name: Peripheral Neuropathy
Group leader: Søren Hein Sindrup
Number of group members:
Søren Sindrup, Dr Med Sci, Professor
Jakob Holbech, PhD, Ass. Professor
Thomas Krøigård, PhD student
Mimmi Forsberg-Gilving, PhD stud.
Mustapha Itani, PhD student
Thomas Gaist, medical student
Laura Brok-Lauridsen, medical stud.

Department & University/Hospital/Other:
Department of Neurology and Neurology Research Unit.
Odense University and University of Southern Denmark
Funding sources:
Hospital research funds, Danish Cancer Society (KB), EU Innovative Medicines Initiative (IMI), Novo Nordisk Challenge Fund, Regionernes Medicinpulje, Danish Movement Disorder Society (DANMODIS), Novo Nordisk Foundation scolarstipendium, Lundbeck Foundation scolarstipendium in neurology, Danish Immune Neuropathy Group, drug companies.


Description of research:
Peripheral neuropathy
The research focuses on diseases or lesions of the peripheral somatic and autonomic nervous system.

1. Diagnosis and etiology
A research database on patients evaluated for suspected polyneuropathy has been established and has included patients since january 2016. Data from this database will evaluate the role of different diagnostic procedures such as nerve conduction, and nerve fibre density in skin biopsies and on the cornea by in-vivo confocal microscopy. The pattern of peripheral nerve affection will be compared between different etiologies of polyneuropathy. The data from the database will also be used to develop procedures to reduce the number of patients in which the etiology of polyneuropathy cannot be determined. Further, the purpose of the database is also to establish a cohort of well characterised patients which can be re-evaluated later.
A large cross-sectotional study on polyneuropathy in patients with type 2 diabetes is being performed in order to determine pathophysiological mehanisms and risk factors. In collaboration with researchers at the Danish Pain Research Center in Aarhus we will examine in total 600 patients with type 2 diabetes and 100 healthy controls.
Other clinical studies focuses on development of peripheral neuropathy due to treatment with oxaliplatin (chemotherapy), statins (cholesterol lowering drugs), and other drugs. We are also studying patients with newly diagnosed Parkinson’s disease to test if there is peripheral nerve affection in relation to this neurodegenerative disease and if peripheral nerves may be involved in the patogenesis of the disease via α-synuclein de-posits in relation to peripheral nerve structures.

2. Pharmacological treatment of peripheral neuropathic pain
Pharmacological treatment of peripheral neuropathic pain has for many years been an important area for the research group and we have performed numerous controlled clinical trials to improve treatment outcome and to search for relations between drug actions and mechanisms of pain. In the EuroPain collaboration (EU Innovative Medicines Innitiative) we contributed a large study clinical trial using patient stratification by pain phenotype as determined by an extensive quantitative sensory testing protocol. We were able to demontrate that the effect of a sodium channel blocking drug depended on pain phenotype. This study is recoqnized as the first step towards mechanism-based treatment of peripheral neuropathic pain, which has for decades been a goal within this area.
Present clinical studies are looking further into the mechanism-based pain treatment and are testing drugs targeting other potential pain mechanisms than the currently used drugs.

3. Treatment of immune mediated peripheral neuropathies
The first choice treatment for immune mediated peripheral neuropathies is immunoglobulins given intravenously or subcutaneously. We have been engaged in a number of clinical trials headed by the Danish Immune Neuropathy Group on the initiative of group members from the Neurology Department at Aarhus University Hospital. Further studies have been planned by this research collaboration. Our group has developped a new method to test physical function in patients with immune neuropathies and we plan to perform a study with a drug with a mechanism of action completely different from the supposed mechanism of action of immunoglobulins.

4. Guillain Barré Syndrome
During the past 5 years we have participated in the International Guillain Barré syndrome outcome study (IGOS). We have at our research unit contributed more than 50 patients to the database and more than 100 Danish patients have been enrolled. Researchers from both Aarhus and our group plan to do studies based on data from the international database which currently comprise more than 1500 patients.


Key publications (last 10 years):
1. Finnerup NB, Sindrup SH, Jensen TS. The evidence for pharmacological treatment of neuropathic pain. Pain 2010;150:573-81.

2. Demant DT, Lund K, Vollert J, Maier C, Segerdahl M, Finnerup NB, Jensen TS, Sindrup SH. The effect of oxcarbazepine in peripheral neuropathic pain depends on pain pheno-type. A randomized, double-blind, placebo-controlled and phenotype-stratified study. Pain 2014; 155:2263-2273.

3. Krøigård T, Schrøder HD, Qvortrup C, Eckhoff L, Pfeiffer P, Gaist D, Sindrup SH. Char-acterization and diagnostic evaluation of chronic polyneuropathies induced by oxaliplatin and docetaxel comparing skin biopsy to quantitative sensory testing and nerve conduc-tion studies. Eur J Neurol. 2014;21:623-9

4. Holbech JV, Bach FW, Finnerup NB, Brøsen K, Jensen TS, Sindrup SH. Imipramine and Pregabalin Combination for Painful Polyneuropathy. A Randomized Controlled Trial. Pain. 2015;156:958-66

5. Holbech JV, Bach FW, Finnerup NB, Jensen TS, Sindrup SH. Pain phenotype as a predictor for drug response in painful polyneuropathy A retrospective analysis of data from controlled clinical trials. Pain 2016;157:1305-13

6. Markvardsen LH, Sindrup SH, Christiansen I, Olsen NK, Jakobsen J, Andersen H; Danish CIDP and MMN Study Group. Subcutaneous immunoglobulin as first-line therapy in treatment-naive patients with chronic inflammatory demyelinating polyneuropathy: ran-domized controlled trial study. Eur J Neurol. 2017;24:412-418

7. Sindrup SH, Holbech JV, Bach FW, Finnerup NB, Brøsen K, Jensen TS. The Impact of Serum Drug Concentration on the Efficacy of Imipramine, Pregabalin and their Combina-tion in Painful Polyneuropathy. Clin J Pain. 2017 Mar 7. doi: 10.1097/AJP.0000000000000497. [Epub ahead of print]


Key collaborations:
Danish:
Danish Pain Research Center, Aarhus University
Danish Immune Neuropathy Group (neurology departments at university hospitals in Denmark)
Neuroepidemiology Group at Neurology Research Unit at SDU (David Gaist’s group)
Neuropathology and Oncology Research Units at SDU.

International:
EuroPain Collaboration on Chronic Pain (researchers from UK, Germany, Spain and Denmark. Funded by EU Innovative Medicines Innitiative)
International Diabetic Neuropathy Consortium (researchers from UK, US, and Denmark. Funded by Novo Challenge Fund).
International Guillain Barré Study Group (world wide research collaboration).


Infrastructure:
Clinical research, controlled clinical drug trials, clinical evaluation of physical function in relation to peripheral nerve diseases, peripheral nerve conduction (NC), quantitative sensory testing (QST), confocal microscopy of cornea (CCM) for determination of nervefibre density and length, skin biopsy for determination of intra-epidermal nerve fibre density (IENFD), treshold tracking in peripheral nerves to evaluate ion channel function, testing of the autonomous nervous system (sweat secretion with QSweat, heart rate variablity on deep breathing, valsalva, and tilt table procedure with TestWorks).