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- Heldestad, Victoria, 1970-
(author)
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Methodological aspects and usefulness of Quantitative Sensory Testing in early small fiber polyneuropathy : a clinical study in Swedish hereditary transthyretin amyloidosis patients
- 2011
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Doctoral thesis (other academic/artistic)abstract
- Generalised polyneuropathy (PNP) is a common cause to neurological impairment, and may be an early symptom of a severe systemic disease. One such illness is hereditary transthyretin (TTR) amyloidosis (ATTR), a progressive fatal disorder caused by a mutation on the TTR gene. More than 100 such mutations have been found worldwide, of which Val30Met is the most common neuropathic variant with initial clinical manifestations indicating small fiber impairment. Differences in onset age, penetrance and phenotypes are present between endemic areas. Liver transplantation generally slows the progress of the symptom development, especially in patients with short disease duration. Ongoing research has also shown promising results with drug interventions. In any event, early diagnosis of PNP onset in ATTR patients is crucial to ensure early therapeutic interventions. Nerve conduction studies (NCS) and electromyography (EMG) provide the basis for evaluation of the functional state of the thick myelinated nerve fibres in patients with symptoms of PNP, but no such quantitative methods are available for the thin myelinated or unmyelinated fibers. Instead, a psychophysical method with thermal quantitative sensory testing (QST) can provide indirect information about the overall function in the afferent small fiber systems. The purpose of thesis was to evaluate the applicability of QST by the Method-of-limits (MLI) for early detection of PNP in Swedish ATTR patients with the Val30Met mutation. In healthy subjects the repeatability of the MLI was assessed, and reference values for thermal perception thresholds (TPT) in several body regions were determined. No significant differences in TPT or pain thresholds were found at repeated testing with MLI, indicating that the MLI is a reliable method. However, the results show that the arrangement of the testing order is of importance, as cold (CT) and warm (WT) perception thresholds were significantly elevated when tested after thermal pain assessments, instead of before. I general, the TPT was more elevated at lower parts of the body compared to the upper part, and with higher WT than CT, fully in accordance with the underlying anatomical and physiological prerequisites for QST. In biopsy verified ATTR patients lacking EMG and NCS abnormalities, significantly elevated TPT were found compared to controls. Furthermore, significantly more increased TPT were observed in patients with an early onset of the disease, compared those with a late onset. Finally, a combined detailed evaluation of QST and heart rate variability (HRV) analyses demonstrated correlations between QST and HRV abnormalities in patients with late onset, but not in those with early onset. The present thesis emphasizes the importance of incorporating QST early in the clinical evaluation of ATTR patients with a Val30Met mutation and with symptoms of thin fiber PNP. This is particularly indicated when patients report symptoms, or show signs, of neuropathic small fiber affection, but simultaneously exhibit normal EMG and NCS findings. The results furthermore underline the importance of performing both QST and HRV for a complete evaluation of both the thin somatic and autonomic nerve fibers, as both types of nerves may be affected early in the ATTR disease.
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| 2. |
- Lindh, Jonas, 1967-
(author)
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Cryptogenic Polyneuropathy : Clinical, Environmental, And Genetic Studies
- 2011
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Doctoral thesis (other academic/artistic)abstract
- Objectives: The purpose of this medical thesis was to describe the clinical and neurophysiological features and to evaluate the health related quality of life (HR-QoL) in patients with cryptogenic polyneuropathy. We also wanted to investigate different occupational, and leisure time exposures as determinants for cryptogenic polyneuropathy, and to analyze whether polymorphisms for the null alleles of Glutathione S-Transferase Mu-1 (GSTM1), and Theta-1 (GSTT1), and a low activity genetic variation of epoxide hydrolase (EPHX) affect the risk of developing polyneuropathy. These genes were chosen because their enzymes are important in the metabolism of toxic compounds.Methods: The medical records of all patients aged 40–79 years with the diagnosis of cryptogenic polyneuropathy from 1993 to 2000 were analyzed, and data regarding clinical symptoms, laboratory findings, and neurophysiological findings at diagnosis were collected. 255 cases were found. When the medical records were reevaluated assessment to a protocol 168 patients remained as cryptogenic. Two validated instruments (SF-36 and EQ-5D) for measuring HR-QoL were sent to patients, and a reference group from the general population. Additional clinical information, and data on occupational, and leisure time exposure was obtained from postal questionnaires. Crude odds ratios (COR), and logistic regression odds ratios (LOR) were calculated for exposures with five or more exposed cases and referents taken together. We also tested for genetic polymorphisms of GSTM1 and GSTT1, and epoxide hydrolase exon three, EPHX*3.Results: 68% of the patients were men. The mean age at first symptom was 61 years and at diagnosis 64 years. Distal numbness was the most common symptom, but pain, pedal paresthesias, and impairment of balance were also common. The most common clinical findings were decreased or lost proprioception or sense of vibration (80%), and loss of ankle jerks (78%). Neurography showed mixed sensorimotor polyneuropathy of axonal or mixed axonal and demyelinating type. QOL was significantly affected concerning motor functions, with 42% of the patients reporting problems to walk, 3% having problems with daily activities, and 85% were suffering from pain. Mental health was preserved. Mobility was declining with increasing age, but was not affected by disease duration. Increased risks were found in men for occupational exposure to sulphur dioxide, xylene, methyl ethyl ketone, and herbicides and in women for occupational exposure to lead, nitrous oxide, and insecticides. Interaction between occupational and leisure time exposure were seen for several exposures. No significant correlation was found between GSTM1, GSTT1, and EPHX1 polymorphisms in patients with cryptogenic polyneuropathy compared with controls. A tendency, however, was seen for the GSTT1 null phenotype, which was enhanced among smokers compared to controls (OR 3.7).Conclusions: Cryptogenic polyneuropathy is a slowly progressive sensorimotor nerve lesion of mainly axonal type. Patients with cryptogenic polyneuropathy have a lower QOL compared to the general population, although mental health scores did not differ between the groups. Our results show that known determinants could be confirmed, but also some new appeared i.e. sulphur dioxide, hydrogen sulphide, fungicides, and vibrations in the feet. Moreover our results point to a synergistic effect of various exposures. Our hypothesis is that the GSTT1 null polymorphism may be related to an impaired metabolism of toxic substances and reactive oxygen that could lead to nerve damage in the peripheral nervous system. Our results are indicating that components in cigarette smoke might increase the risk of axonal neuropathy in genetically predisposed patients.
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