Pallidonigral TDP-43 pathology in Perry syndrome.

OBJECTIVE: Autosomal dominant parkinsonism, hypoventilation, depression and severe weight loss (Perry syndrome) is an early-onset rapidly progressive disease. At autopsy, previous studies have found severe neuronal loss in the substantia nigra without Lewy bodies. Transactive response DNA-binding protein of 43 kDa (TDP-43) has recently been identified as a major ubiquitinated constituent of neuronal and glial inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions and in amyotrophic lateral sclerosis. This study reports clinical, genetic and neuropathologic investigations of Perry syndrome. METHODS: Clinical data and autopsy brain tissue samples were collected from eight patients from four genealogically unrelated kindreds with Perry syndrome. Brain tissue was studied with immunohistochemistry and biochemistry for TDP-43. Patients were screened for mutations in the progranulin (GRN) and TDP-43 (TARDBP) genes. RESULTS: The mean age at onset was 47 years (range 40-56), and the mean age at death was 52 years (range 44-64). In all patients, we identified TDP-43-positive neuronal inclusions, dystrophic neurites and axonal spheroids in a predominantly pallidonigral distribution, and we demonstrated changes in solubility and electrophoretic mobility of TDP-43 in brain tissue. The inclusions were highly pleomorphic and predominated in the extrapyramidal system, sparing the cortex, hippocampus and motor neurons. There were no mutations in GRN or TARDBP. INTERPRETATION: Perry syndrome displays unique TDP-43 pathology that is selective for the extrapyramidal system and spares the neocortex and motor neurons.

Therapeutic options for continuous dopaminergic stimulation in Parkinson's disease.

Treatment of Parkinson's disease aims to replace dopaminergic transmission at striatal synapses. In the normal state, nigral neurons fire continuously, exposing striatal dopamine receptors to relatively constant levels of dopamine. In the disease state, periodic dosing and the short half-life of antiparkinsonian drugs leads to more intermittent stimulation. Abnormal pulsatile stimulation of striatal dopamine receptors may lead to dysregulation of genes and proteins in downstream neurons and consequently, alterations in neuronal firing patterns. This may ultimately lead to motor complications. In order to prevent the development of motor complications a therapy that provides continuous dopaminergic stimulation as observed in the normal state would be ideal. Different routes of administration of levodopa and other dopaminergic drugs have been tried to achieve continuous dopaminergic stimulation (CDS). This review discusses the various methods available to achieve this goal with particular emphasis on duodenal dopa administration.

Functional electrical stimulation in neurological disorders.

Functional electrical stimulation (FES) refers to electrical stimulation of muscles in order to improve the impaired motor function. This is achieved by activating skeletal muscles with constant frequency trains of stimulations. This method has been found useful in various neurological disorders like hemiplegia, foot drop and paraplegia including spinal cord injuries. The first half of this review focuses on the broad clinical applications of functional electrical stimulation, its mechanism of action and the complications of this mode of therapy. Advanced Parkinson's disease (PD) is characterized by marked slowing of gait and frequent freezing episodes. Medical and surgical treatments are often ineffective in managing freezing episodes. The second half of this review discusses briefly the gait abnormalities in PD and the available treatment options. The possible role of FES in improving gait in parkinsonism and the importance of future research in this direction are highlighted.

Local thrombolysis in patients with dural venous thrombosis unresponsive to heparin.

OBJECTIVE: We sought to study the efficacy and complications of local thrombolysis using urokinase in cases of cortical vein thrombosis unresponsive to conventional heparin therapy. METHODS: Patients with clinical and radiologic diagnosis of cortical vein thrombosis were taken for local thrombolysis using femoral vein approach if they did not respond to heparin therapy after 5 days of administration of the drug. Urokinase was used as the thrombolytic agent and dose was decided depending on the recanalization obtained during the procedure. RESULTS: Of the 3 patients treated, two had complete recanalization and one had partial recanalization. Two had dramatic recovery of the clinical symptoms. One patient in whom thrombolysis was delayed had partial recovery. None had any complications related to the treatment. CONCLUSION: Local thrombolytic therapy is effective in recanalization of thrombosed sinus. It is worth considering in dire circumstances especially when a patient fails to respond to heparin. However, randomized controlled trials are necessary before any firm recommendations can be made as to whether it can be used as a primary modality of treatment in cases of cortical vein thrombosis.