Håkan Askmark

Duodenal levodopa infusion monotherapy vs oral polypharmacy in advanced Parkinson disease

Objectives: To compare daytime intraduodenal levodopa/carbidopa infusion as monotherapy with individually optimized conventional combination therapies in patients with advanced Parkinson disease (PD) for motor fluctuations and quality of life (QoL). Methods: Twenty-four patients with motor fluctuations and dyskinesia were studied in a randomized crossover design to compare individualized conventional treatment and intraduodenal infusion of a levodopa/carbidopa gel for 3 + 3 weeks. Video scoring of motor function was assessed by blinded assessors on a global Treatment Response Scale from −3 to 0 to +3 (from severe “off” to “on” to “on” with severe dyskinesia). Patient self-assessment of motor performance and QoL was done using an electronic diary. Results: Median percentage of ratings in a functional “on” interval (−1 to +1) was increased from 81 to 100% by infusion therapy (p < 0.01). This improvement was accompanied by a decrease in “off” state (p < 0.01) and no increase in dyskinesia. Median Unified Parkinsons Disease Rating Scale score decreased from 53 to 35 in favor of infusion (p < 0.05). QoL was improved, using the two instruments: Parkinsons Disease Questionnaire-39 and 15D Quality of Life Instrument (p < 0.01). Adverse events were similar for both treatment strategies. Conclusions: Continuous intraduodenal infusion of the levodopa/carbidopa enteral gel as monotherapy is safe and clinically superior to a number of individually optimized combinations of conventional oral and subcutaneous medications in patients with motor fluctuations. Intraduodenal infusion of levodopa offers an important alternative in treating patients with advanced Parkinson disease.

Optimizing levodopa pharmacokinetics: intestinal infusion versus oral sustained-release tablets.

Continuous duodenal infusion of carbidopa/levodopa has been shown to control motor fluctuations in advanced Parkinsons disease (PD). The authors compared the pharmacokinetics of levodopa and 3-O-methyldopa in patients with advanced PD after administration of an oral sustained-release levodopa preparation and after continuous intestinal levodopa infusion with a new formulation as a gel suspension. A randomized crossover trial was carried out in 12 patients. Carbidopa/levodopa was administered as an oral sustained-release tablet and by nasoduodenal continuous infusion for 3-week periods for each treatment. Plasma levodopa concentrations and motor performance were evaluated every 30 minutes during 3 test days of each treatment period. The average intraindividual coefficient of variation for the plasma levodopa concentrations after oral therapy was 34% and was significantly lower (14%, p < 0.01) during continuous infusion. Hourly video evaluations showed a significant increase in ON time during infusion and a significant decrease in OFF time and dyskinesia. Continuous intraduodenal delivery of a new carbidopa/levodopa formulation offers a means for markedly improved control of motor fluctuations in late stages of PD.

Decreased CSF-β-Amyloid 42 in Alzheimer’s Disease and Amyotrophic Lateral Sclerosis May Reflect Mismetabolism of β-Amyloid Induced by Disparate Mechanisms

Both tau and β-amyloid 42 (Aβ42) have been implicated in Alzheimer’s disease (AD) and tau alone in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). These proteins can be measured in the cerebrospinal fluid (CSF); differences from normal CSF levels may reflect pathophysiological mechanisms. Using ELISAs, we investigated the levels of total CSF-tau (here referred to as tau), phosphorylated CSF-tau (phosphotau), and Aβ42 in patients with AD (n = 19), FTD (n = 14), ALS (n = 11) and Parkinson’s disease (PD; n = 15) and in age-matched controls (n = 17). Both CSF-tau and CSF-phosphotau were increased in AD compared with FTD (p < 0.001), ALS (p < 0.001), PD (p < 0.001) and controls (p < 0.001). CSF-Aβ42 was markedly decreased in AD and ALS (both p < 0.001) and slightly decreased in FTD (p < 0.01) and PD (p < 0.05) compared with controls. Using CSF-phosphotau may improve the differentiation of AD from FTD and ALS in clinical praxis. Furthermore, decreased CSF-Aβ42 levels may be common in neurodegenerative disorders possibly reflecting changes in the metabolism of β-amyloid or axonal degeneration.

Evidence for astrocytosis in ALS demonstrated by [11C](L)-deprenyl-D2 PET.

OBJECTIVE To use deuterium-substituted [11C](L)-deprenyl PET to depict astrocytosis in vivo in patients with amyotrophic lateral sclerosis (ALS). BACKGROUND In human brain, the enzyme MAO-B is primarily located in astrocytes. L-deprenyl binds to MAO-B and autoradiography with 3H-L-deprenyl has been used to map astrocytosis in vitro. Motor neuron loss in ALS is accompanied by astrocytosis and astrocytes may play an active role in the neurodegenerative process. Deuterium-substituted [11C](L)-deprenyl PET provides an opportunity to localize astrocytosis in vivo in the brain of patients with ALS. METHODS Deuterium-substituted [11C](L)-deprenyl PET was performed in seven patients with ALS and seven healthy control subjects. RESULTS Increased uptake rate of [11C](L)-deprenyl was demonstrated in ALS in pons and white matter. CONCLUSION This study provides evidence that astrocytosis may be detected in vivo in ALS by the use of deuterium-substituted [11C](L)-deprenyl PET though further studies are needed to determine whether deuterium-substituted [11C](L)-deprenyl binding tracks disease progression and reflects astrocytosis.

Gdnf but not Bdnf is increased in cerebrospinal fluid in amyotrophic lateral sclerosis

Cerebrospinal fluid from 15 patients with ALS and 11 controls without neurological disease were analysed for levels of the neurotrophic factors BDNF and GDNF. Analyses were performed using a sensitive sandwich immunoassay (ELISA). There was no significant difference in BDNF levels between the ALS patients and the control subjects studied. Measurable levels of GDNF were found in 12 out of 15 ALS samples. GDNF was not detected in CSF from any of the control subjects. The finding of increased CSF levels of GDNF in ALS compared to controls, together with earlier findings of increased expression of GDNF mRNA in muscle in ALS, indicates that the capacity to synthesize GDNF is enhanced in this disorder.

Epidemiology of adverse reactions to carbamazepine as seen in a spontaneous reporting system

A survey was made of 505 reports on 713 adverse reactions to carbamazepine submitted to the Swedish Adverse Drug Reactions Advisory Committee from 1965–1987. For the period after 1972, the relation between the reports and sales statistics could be investigated. The total incidence of reported adverse reactions to carbamazepine was 4.5 per million defined daily doses (DDD), corresponding to 2.7 per million prescribed daily doses (PDD). Most often reported were skin reactions (48%), but reports on haematological (12%) and hepatic disorders (10%) were also frequent. Virtually all hepatic disorders and severe skin reactions, as well as the majority (60%) of the haematological reactions, occurred within the first 2 months of treatment. In view of the very low incidence of reported serious blood dyscrasias, such as pancytopenia (0.04/million PDD) and agranulocytosis (0.06/million PDD), continuous haematological monitoring seems to be of little value. The elderly appear to be at increased risk of developing blood dyscrasias and liver reactions, and alcohol abusers seem to represent a high‐risk group for developing serious skin reactions.

A double-blind randomized clinical trial in amyotrophic lateral sclerosis using lamotrigine: effects on CSF glutamate, aspartate, branched-chain amino acid levels and clinical parameters

Objectives – A study was conducted to examine the effect of lamotrigine (LTG) in amyotrophic lateral sclerosis (ALS).

Cholinergic neuromuscular hyperactivity in patients with myasthenia gravis seropositive for MuSK antibody

A 75‐year‐old man with severe oculobulbar myasthenia gravis (MG) treated with acetylcholine esterase inhibitors (AChEIs) was found to have muscle‐specific tyrosine kinase (MuSK) antibodies. Neurophysiological examination displayed extra repetitive discharges after the compound motor action potential (CMAP) at low‐frequency stimulation, possibly triggered by AChEI. This indicates an abnormal sensitivity to acetylcholine in patients with MuSK antibodies and may be a useful indicator of the adverse effect of AChEI treatment in these patients. Muscle Nerve, 2006

A pilot trial of dextromethorphan in amyotrophic lateral sclerosis.

Assuming the presence of glutamate-induced neurotoxicity in amyotrophic lateral sclerosis 14 patients were treated with dextromethorphan, an N-methyl-D-aspartate receptor antagonist. The patients were treated with 150 mg dextromethorphan or placebo daily for 12 weeks in a double-blind crossover trial, with a wash out period of 4 weeks between the two treatment periods. Thereafter the surviving patients were treated with 300 mg dextromethorphan daily for up to 6 months in an open trial. No positive effects on clinical or neurophysiological parameters (relative number of axons, and compound muscle action potentials in the abductor digiti minimi muscle) were observed either in the double-blind trial or in the open trial.

Treatable dropped head syndrome in hypothyroidism

Neck extensor weakness resulting in dropped head is more often a part of a generalized neuromuscular disorder such as MG, ALS, or polymyositis. The term “dropped head syndrome” (isolated neck extension myopathy) usually refers to a condition characterized by severe weakness of the neck extensors in the absence of a generalized neuromuscular disorder and may be due to a restricted noninflammatory myopathy.1,2⇓ In such a case, there may, in fact, be additional weakness affecting periscapular, shoulder, and thoracic muscles or even more extensive distribution of weakness—“dropped head plus syndrome.”3 Hypothyroidism is often accompanied by a myopathy with proximal distribution.4 In 1880, William M. Ord described a woman with myxedema who had, among many other symptoms, head drop.5 There are, to our knowledge, no reports in the literature on isolated neck extensor weakness caused by hypothyroidism. We report a case of hypothyroidism presenting as an isolated dropped head syndrome, which subsided almost completely during treatment with levothyroxine. A 53-year-old man presented with a 4-year history of slowly progressive neck weakness and pain in the neck. He had “head drop” while sitting and standing and had noticed that his posterior neck muscles had increased in volume. For 6 months, he had also experienced a slight weakness in the arms and legs. His local neurologist had assessed the …