Torben Fog - A Danish pioneer in a multi-faceted spectrum of multiple sclerosis research.

Torben Fog was committed to multiple sclerosis (MS) research for more than four decades, starting before the defence of his thesis in 1948 and lasting until his death in 1987. His research was multi-facetted, making him one of the great pioneers in the study of essential parts of the pathology, immunology and treatment of MS. He has contributed with meticulous studies of the MS plaques, documenting the perivenous distribution of plaques in the spinal cord. He constructed a scoring system for the disability in MS and used a computer programme to calculate a total neurological deficit. Together with his co-workers, Fog in 1972 was the first to report the association between MS and the human leukocyte antigen system. Fog can be considered as the father of immunomodulatory therapy in MS, treating MS patients with the first transfer factor, and as early as 1980, he was the first to treat MS with intramuscular natural interferon.

Free-living energy expenditure reduced after deep brain stimulation surgery for Parkinson's disease.

BACKGROUND: The clinical picture in Parkinson's disease (PD) is characterized by bradykinesia, rigidity, resting tremor and postural instability. In advanced stages of the disease, many patients will experience reduced efficacy of medication with fluctuations in symptoms and dyskinesias. Surgical treatment with deep brain stimulation in the subthalamic nucleus (STN-DBS) is now considered the gold standard in fluctuating PD. Many patients experience a gain of weight following the surgery. The aim of this study was to identify possible mechanisms, which may contribute to body weight gain in patients with PD following bilateral STN-DBS surgery. METHODS: Ten patients with PD were studied before bilateral STN-DBS surgery, and seven patients were studied again 3 and 12 months postoperatively. Clinical examination and resting metabolic rate with and without medical treatment was measured before and after STN-DBS. Furthermore, free-living energy expenditure, body composition, energy intake, peak oxygen consumption, maximal workload and leisure time physical activity were measured before and 3 and 12 months after surgery. RESULTS: The STN-DBS operated patients had a significant weight gain of 4·7 ± 1·6 kg (mean ± SE) 12 months postoperatively, and the weight gain was in the fat mass. The free-living energy expenditure decreased postoperatively 13 ± 4% even though the reported dietary intake was reduced. A decreased energy expenditure took place in the non-resting energy expenditure. The reported daily leisure time activity, peak oxygen consumption and maximal workload were unchanged. CONCLUSION: The STN-DBS operated patients have a significant postoperative weight gain, as a result of a decrease in free-living energy expenditure concomitant with an insufficient decrease in energy intake.

Proteomic investigations of the ventriculo-lumbar gradient in human CSF.

Cerebrospinal fluid (CSF) is an ideal biological material in which to search for new biomarkers for improved diagnosis of neurological diseases. During a lumbar puncture between 5 and 15 mL of CSF are obtained. Previous studies have assessed the ventriculo-lumbar concentration gradient of a number of specific proteins. In the present study we took a proteomics approach to investigate the possible concentration gradient of a panel of proteins and peptides in the CSF of 16 patients with neurodegenerative diseases. Using two different mass spectrometry techniques, matrix assisted laser desorption ionization time of flight (MALDI-TOF) and surface enhanced laser desorption ionization time of flight (SELDI-TOF), we found that only one of the investigated proteins, apolipoprotein CI, was significantly decreased between the 1st and the 10th mL of CSF. Furthermore, we confirmed previous results showing a significant decrease in albumin concentration from the first to the last CSF aliquots. In conclusion, we found a significant gradient effect for only two of the measured proteins. However, a standardized procedure for CSF collection for diagnostic and research purposes is crucial to allow comparisons of results between patient groups and between laboratories. This is especially important since CSF is usually collected at several centres and variation in sampled CSF due to pre-analytical factors could complicate the interpretation of the results.

Chewing in patients with severe neurological impairment.

OBJECTIVE AND DESIGN: As degenerative disease, infarction and hemorrhage in the CNS may compromise chewing, the aim was to classify and analyse such chewing disturbances. The case series included clinical and electromyographic recordings from 10 patients (ages 12-78 years) with neurological disorders. RESULTS: Classifications were involuntary munching (two women with dystonia which was abolished during mastication), ceased chewing function (three men with impaired volitional motor control and spasticity from locked-in syndrome, restricted chewing range (two men and one woman with reduced jaw opening due to paradoxical activity after brainstem lesions), and distorted chewing pattern (two men with dystonia resulting in blockings during chewing). CONCLUSION: The effect of the neurological impairment illustrated the complex control of mastication and the interaction between central and peripheral mechanisms, and the variation of the chewing disturbances was surprisingly great, even with similar diagnosis.

Oromandibular dystonia involving the lateral pterygoid muscles: four cases with different complexity.

The report describes oromandibular dystonia (OMD) in four women with involuntary activity of the lateral pterygoid muscles (LP), causing incapacitating protrusive and lateral jaw movements and displacements, and treatment with botulinum toxin type A (BTX). For initial survey and treatment control, OMD was analyzed with several, independent, and standardized methods. OMD severity and functional difficulties were evaluated subjectively and scored from videotapes. Jaw movements were assessed graphically with a magnetic tracking system, and electromyographical activity (EMG) of LP was recorded with needle electrodes using an intraoral approach, whereas activity of masseter muscles was recorded with surface electrodes. EMG-guided BTX injections (25-40 units Botox per muscle) into the muscles were performed with cannula electrodes. Compared with reference values for LP, OMD was associated with a markedly increased level of spontaneous activity, but almost normal level of maximum voluntary activity. The central pattern generator for mastication seemed to override the dystonic activity, as all patients were able to chew despite some distortion. BTX reduced both the spontaneous and the maximum activity for 3-9 months. Concomitantly, a marked reduction of the OMD severity, mandibular movements and functional disturbances were also present with the best effect in localized OMD with late onset.

Lower urinary tract symptoms and bladder control in advanced Parkinson's disease: effects of deep brain stimulation in the subthalamic nucleus.

Deep brain stimulation in the subthalamic nucleus (STN) leads to significant improvement in motor function in patients with advanced Parkinson's disease (PD). In this prospective study including 16 patients with PD, we investigated (1) lower urinary tract symptoms (LUTS) by questionnaires International Prostate Symptom Score (IPSS, symptoms only) and Danish Prostate Symptom Score (DanPSS, symptoms and bother of symptoms) and (2) bladder control (assessed by urodynamics) before and after implantation of electrodes in the STN. PD symptoms (Unified Parkinson's Disease Rating Scale score) improved significantly (P < 0.0001), and symptoms of overactive bladder (IPSS) decreased along with the troublesome symptoms of overactive bladder (DanPSS; P < 0.01 for both). Urodynamic parameters before and after implantation of electrodes in the STN, evaluated with and without the stimulation on, did not change significantly.

Prevalence of bladder dysfunction in Parkinsons disease.

BACKGROUND AND AIMS: Prevalence of lower urinary tract symptoms (LUTS) in Parkinsons disease (PD) is reported as 27%-39% based on validated questionnaires which do not consider the degree of bother. To estimate the prevalence of LUTS in patients with PD, the severity of symptoms, the volume of postmicturitional urine, and to estimate differences compared to non-PD patients referred for urological evaluation. METHODS: One hundred seven patients with PD were evaluated using two sets of validated questionnaires (Dan-PSS and IPSS) about LUTS; postmicturitional residual urine was recorded, and compared to 61 patients without PD presenting at an urological clinic for examination. RESULTS: Bothersome LUTS measured using Dan-PSS scores correlated significantly with Hoehn and Yahr stage of disease (P = 0.02), but not with duration of disease or age. IPSS scores did not correlate to stage of disease, duration of disease or age. Two arbitrary cut-offs were applied, identifying patients with significant LUTS, Dan-PSS > 10 and IPSS > 10. There were no significant differences between the age or duration of disease of patients with and without significant LUTS. The most frequent symptom was nocturia (IPSS: 86%) followed by frequency (IPSS: 71%) and urgency (IPSS: 68%). The most frequently reported bothersome bladder symptom was urgency (Dan-PSS: 61%), followed by nocturia (Dan-PSS: 50%) and urge incontinence (Dan-PSS: 44%). The prevalence of bothersome frequency is low (Dan-PSS: 37%). The postmicturitional volumes (PMV) did not correlate to stage of disease, duration of disease or age, or to scores on questionnaires. Mean PMV was 34 ml. Seven patients (6%) with PD had a PMV larger then 100 ml. DISCUSSION: The prevalence of severe LUTS was similar with other studies, but the correlation between Dan-PSS and stage of disease, and not IPSS indicates that despite seeing no increase in frequency and severity of LUTS as PD progresses, patients find symptoms more bothersome. This may be due to progression in gait difficulties or a decreasing ability to separate and integrate sensory input, or both.

Treatment of severe temporomandibular joint clicking with botulinum toxin in the lateral pterygoid muscle in two cases of anterior disc displacement.

A novel treatment procedure is introduced for severe clicking of the temporomandibular joint (TMJ) associated with anterior disc displacement (ADD), using injections with botulinum toxin (BTX-A) in the lateral pterygoid muscle (LP). It has been suggested that ADD may be caused, precipitated, or maintained by LP activity, but the role of the LP in the dynamics of the TMJ clicking is uncertain. The case report includes 2 women, followed with clinical examinations, TMJ imaging, and electromyography (EMG), in whom local anesthetics in the LP could abolish the clicking for several days. BTX-A block of the LP (30 U Botox, given twice under EMG guidance with 6-month interval) temporarily reduced the action of the muscle, but the clicking was permanently eliminated and did not return during the observation period of 1 year, and a small but distinctive positional improvement in the disc-condyle relationship was obtained. However, the precise mechanisms behind the favourable treatment outcome are unclear.

Increased intracranial volume in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) and multiple system atrophy (MSA) are neurodegenerative diseases that can be difficult to diagnose and distinguish from each other. STUDY AIMS AND METHODS: Patients with PD and MSA and controls were studied with magnetic resonance imaging (MRI) using tissue segmentation and outlining of regions in order to identify regional volume changes that might be useful in the diagnosis of the two diseases. RESULTS: Patients with PD had significantly larger intracranial volumes (ICVs) and significantly smaller putaminal and sustantia nigra volumes than controls. MSA patients had significantly smaller substantia nigra and caudate volumes than controls but normal intracranial volume. In both patient groups there was a further trend towards smaller amygdala volumes. DISCUSSION: Increased ICV in PD patients is a new finding that may be explained by genetic factors or compensatory responses to early CNS damage. Atrophy of the amygdala in MSA patients has not been demonstrated with MR before. It might explain why these patients can have hyposmia. The putaminal atrophy found in the PD group may be a trait of the later stages of PD. Segmentation of the substantia nigra can be a useful aid in the diagnosis of PD and MSA.

Corticospinal tract degeneration and possible pathogenesis in ALS evaluated by MR diffusion tensor imaging.

BACKGROUND: MR diffusion tensor imaging (DTI) appears to be a powerful method to investigate the neuronal and axonal fibre distribution in the human brain. Changes in diffusion characteristics of water molecules in the white matter can be estimated as the apparent diffusion coefficient (ADC) and the fractional anisotropy index (FA). OBJECTIVES: To characterize DTI changes at three different levels in the corticospinal tract (CST) (corona radiata, internal capsule and pons) in order to elucidate if pathogenesis of ALS is due to an anterograde or retrograde axonal degeneration. METHODS: We studied eight ALS patients with clinical signs of upper motor neuron involvement. The patients were compared with 11 healthy age-matched controls. RESULTS: ADC was significantly increased in the CST in ALS patients at the level of the internal capsule and also increased in the pons, but without statistical significance. ADC was unchanged at the level of the corona radiata. FA was significantly reduced at the lowest level (pons), only tended to be reduced in the internal capsule, but was also unchanged in the corona radiata. CONCLUSIONS: Segmentation of the CST into three regions supports the hypothesis of a 'dying back' mechanism in ALS and suggests that ADC is a more sensitive measure than FA to detect pathological changes in ALS.

Effects of dopaminergic treatment on bladder function in Parkinson's disease.

AIMS: To evaluate the nature of voiding complaints, findings on urodynamics and the effects of medication on bladder control in a group of Parkinson's disease (PD) patients between the ages of 30-60 years. METHODS: Thirty-two patients with PD were evaluated by questionnaires, PD rating scales, and full urodynamics evaluation. To evaluate lower urinary tract symptoms (LUTS), we used the Danish Prostate Symptom Score (Dan-PSS). PD was evaluated using Unified Parkinson's Disease Rating Scale (UPDRS), and Hoehn and Yahr rating scale for PD. Urodynamics were performed while the patients were on dopaminergic therapy, and after stopping this for three half lives. RESULTS: There was a significant correlation between the Dan-PSS score and UPDRS, Spearman's rho = 0.50, (P = 0.004), and between the score of irritative symptoms in Dan-PSS and motor symptoms (UPDRS(III)) is seen (Spearman's rho = 0.50, P = 0.003). Patients with significant bladder symptoms (> or =10 points in Dan-PSS) had a significantly higher bladder capacity in the medicated state than after wash out (P = 0.04), while patients with out bladder symptoms had no difference. Patients with a significant increase in bladder capacity on medication had a significantly higher interval between the volume of first sensation of bladder filling and bladder capacity when medicated (P = 0.01) than after wash out. Patient who did not benefit from medication had a significant lower interval off medication (P = 0.008). CONCLUSIONS: The effects of dopaminergic treatment on bladder control and urodynamic parameters are unpredictable in the individual patient, though most patients experience significant changes. We have also demonstrated the complexity of bladder control, and that patients with PD may be particularly susceptible to develop complex micturitional dysfunction. Our data indicates that cortical dysfunction may play a significant role in bladder dysfunction in PD parallel to the pontine lesion.

Treatment of perioral dystonia with botulinum toxin in 4 cases of Meige's syndrome.

OBJECTIVE: We describe the treatment of 4 patients (median age, 53.5 years) with incapacitating perioral dystonia and insufficient response to peroral medication. Their general treatment with clonazepam and anticholinergics was supplemented by intramuscular injections with botulinum toxin A (20-40 U) in the orbicularis oris muscle, guided by electromyography (EMG). STUDY DESIGN: Perioral dystonia and treatment effect were assessed by using subjective global and visual analog scales, examiner-based video movement counts and rating scales, and quantitative EMG. t Tests were used for statistical analysis. RESULTS: The result of the intramuscular botulinum toxin A injections was characterized by the patients as "much improved"; correspondingly, dystonia was significantly reduced in visual analog scale scores, on examiner-based assessments, and in recordings of EMG. The side effects were few and short-lasting. CONCLUSION: Incapacitating perioral dystonia in Meige's syndrome may be safely controlled by recurrent EMG-guided botulinum toxin A injections in the orbicularis oris muscle, in combination with general medication.

Clinical impact of diagnostic SPET investigations with a dopamine re-uptake ligand.

The diagnosis of Parkinson's disease is based on clinical features with pathological verification. However, autopsy has been found to confirm a specialist diagnosis in only about 75% of cases. Especially early in the course of the disease, the clinical diagnosis can be difficult. Imaging of presynaptic dopamine transporters (DAT receptors) has provided a possible diagnostic probe in the evaluation of Parkinson's disease. The cocaine analogue [(123)I]-2-beta-carboxymethoxy-3-beta(4-iodophenyl)tropane ([(123)I]-beta-CIT) is one of several radioligands that have been developed for single-photon emission tomography (SPET). The purpose of this study was to evaluate the impact of [(123)I]-beta-CIT SPET on the diagnosis and clinical management of patients with a primary, tentative diagnosis of parkinsonism. We undertook a retrospective evaluation of the clinical records of 90 consecutive patients referred to [(123)I]-beta-CIT SPET from the neurological department, Bispebjerg Hospital. In 58 subjects the scans revealed altered tracer uptake consistent with Parkinson's disease, progressive supranuclear palsy and multiple system atrophy. A significant change in the management or treatment because of the scan was found in 25 patients (28%). The sensitivity of the examination was 97% and the specificity 83%. In conclusion, a significant clinical impact of DAT receptor SPET imaging was found. DAT receptor imaging is a useful diagnostic probe in patients with a possible diagnosis of parkinsonism.

Human CCS gene: genomic organization and exclusion as a candidate for amyotrophic lateral sclerosis (ALS).

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive lethal disorder of large motor neurons of the spinal cord and brain. In approximately 20% of the familial and 2% of sporadic cases the disease is due to a defect in the gene encoding the cytosolic antioxidant enzyme Cu, Zn-superoxide dismutase (SOD1). The underlying molecular defect is known only in a very small portion of the remaining cases and therefore involvement of other genes is likely. As SOD1 receives copper, essential for its normal function, by the copper chaperone, CCS (Copper Chaperone for SOD), we considered CCS as a potential candidate gene for ALS. RESULTS: We have characterized the genomic organization of CCS and determined exon-intron boundaries. The 823 bp coding region of the CCS is organized in 8 exons. We have evaluated involvement of the CCS in ALS by sequencing the entire coding region for mutations in 20 sporadic ALS patients. CONCLUSIONS: No causative mutations for the ALS have been detected in the CCS gene in 20 sporadic ALS patients analyzed, but an intragenic single nucleotide polymorphism has been identified.

Inherited and de novo mutations in sporadic cases of DYT1-dystonia.

A study of Danish probands with primary torsion dystonia is presented. The probands were examined clinically and biochemically to exclude secondary dystonia. Mutation analyses for the GAG-deletion in the DYT1 gene were performed on 107 probands; and the mutation was detected in three. All three probands had the classical phenotype of DYT1-dystonia, but only one had a family history of dystonia. The other two probands had, obviously, sporadic DYT1-dystonia, one of which was caused by a de novo mutation, while the other one had a parent being an asymptomatic carrier. De novo mutations in the DYT1 gene are seldom reported although independent founder mutations are known to have occurred. The frequency of DYT1-dystonia was low in our study even though several probands had early onset generalised dystonia. None of the probands in our study with other types of dystonia had the GAG-deletion as reported in other studies. The difficulties in genetic counselling concerning the heterogeneity of dystonia exemplified by DYT1-dystonia are outlined.