Judit Mally

Improvement in Parkinsonian symptoms after repetitive transcranial magnetic stimulation

Transcranial magnetic stimulation has been used in the diagnosis of neurological lesions, but has also been shown to be useful in the treatment of depression. We have now examined the effect of applying transcranial magnetic stimulation daily for 10 days in a sample of 10 patients with Parkinsons disease in whom maximal benefit was being obtained from drug therapy. The subjects were followed for six months and showed significant improvements over this period when assessed using a range of measures. It is suggested that transcranial magnetic stimulation may be a valuable technique in the treatment or adjunct treatment of Parkinsonism, possibly by inducing changes in brain monoamine levels.

THERAPEUTIC AND DOSE-DEPENDENT EFFECT OF REPETITIVE MICROELECTROSHOCK INDUCED BY TRANSCRANIAL MAGNETIC STIMULATION IN PARKINSON'S DISEASE

Transcranial magnetic stimulation (TMS) has been used in the diagnosis of neurological lesions and has been introduced into the therapy of central nervous diseases. Lately it has been claimed that TMS would be useful not only in the treatment of depression, but also in relieving symptoms of Parkinsons disease. In this study, we sought evidence of the effect of repetitive TMS on the symptoms of Parkinsons disease, the dose dependency between the applied elecromagnetic field and the Parkinsonian symptoms, and the maintenance of the improvement. Forty‐nine patients with Parkinsons disease were divided into four groups, each given one stimulus, repeated 30 times, once or twice a day (∼0.34Tesla (T), ∼0.57T, ∼0.80T). Patients were followed for 3 months and assessed using two different parkinsonian scales: the graded clinical rating scale and Unified Parkinson Disability Rating Scale (UPDRS), and with a short‐term memory test (Ziehen‐Ranschburg word pair test). No effect was seen in the group treated with ∼0.34T\30 stimuli once a day. In all of the groups receiving TMS twice a day, the parkinsonian scores were significantly decreased compared with that of baselines after 1 month of treatment. The greatest improvement in the hypokinesia was detected in the group treated with ∼0.57T\30 stimuli twice a day (baseline total UPDRS: 30.62 ± 15.23; 1 month after treatment: 17.08 ± 7.04, P < 0.01; 3 months after treatment: 16.08 ± 7.06, P < 0.01). A dose‐dependent difference was observed between the two groups after 3 months. The total UPDRS in Group II (∼0.34T\30 stimuli twice a day) significantly differed from Group III (∼0.57T\30 stimuli twice a day; 22.43 ± 8.87, 16.08 ± 7.06, P < 0.05). The long‐lasting improvement effect with TMS would seem to suggest it as an appropriate tool in the therapy of Parkinsons disease. J. Neurosci. Res. 57:935–940, 1999.

The effect of theophylline on parkinsonian symptoms

Abstract— Adenosine is known to inhibit the release of dopamine from central synaptic terminals. The present open trial was therefore conducted to determine whether the adenosine receptor‐antagonist theophylline would be of value in Parkinsons disease. Fifteen parkinsonian patients were treated for up to 12 weeks with a slow release oral theophylline preparation (150 mg day−1), yielding serum theophylline levels of 4·44 mg L−1 after one week. The patients exhibited significant improvements in mean objective disability scores and 11 reported moderate or marked subjective improvement. It is suggested that theophylline might be a useful adjunct to the routine therapy of parkinsonian patients.

Efficacy of an adenosine antagonist, theophylline, in essential tremor: comparison with placebo and propranolol

Propranolol, which has long been used as the standard treatment for essential tremor, has been compared with placebo and theophylline in ten newly diagnosed patients without other, prior drug treatments. Patients were treated for four weeks with one drug, followed by placebo for four weeks, and then the second drug for the same period, in a blind cross-over trial. Tremor was quantified using the volumetric method, and was decreased significantly after one week on propranolol, 80 mg/day. Theophylline 150 mg/day reduced tremor to the same extent, although the improvement was not significant until the second week. Three patients reported side effects on propranolol. It is suggested that theophylline may be a useful alternative agent in the treatment of essential tremor, probably due to a chronic up-regulation of adenosine receptors.

POTENTIAL ROLE OF ADENOSINE ANTAGONIST THERAPY IN PATHOLOGICAL TREMOR DISORDERS

The continuing lack of effective long-term therapies for Parkinsons disease and other disorders in which a primary symptom is involuntary tremor is leading to a search for alternative pharmacological strategies. Adenosine is a major modulator of neuronal activity and neurotransmitter release in the central nervous system, with A1 receptors inhibiting transmitter release and A2 receptors generally enhancing release of several transmitter systems relevant to the control of movement. The A2a subtype of receptor is especially concentrated in the neostriatum and is co-localised with D2 receptors for dopamine, the affinity of which are reduced by activation of the A2a population. Antagonists of adenosine, such as theophylline, have been reported to improve the tremor in cases of Parkinsons disease and essential tremor, and the development of better and more selective A2a receptor antagonists may prove of value in these disabling disorders.

Changes in the concentration of amino acids in serum and cerebrospinal fluid of patients with Parkinson's disease

The concentrations of sixteen amino acids have been measured in the serum and cerebrospinal fluid (CSF) of patients with Parkinsons disease and compared with those of control subjects. The levels of most amino acids were not different between the two groups, but the level of glutamate in CSF was decreased significantly, while the level of glutamine was increased. The results may be consistent with an alteration of glutamate neurotransmission in Parkinsons disease.

Potential of Adenosine A 2A Receptor Antagonists in the Treatment of Movement Disorders

The current pharmacological treatment of Parkinson’s disease, based largely on levodopa and directly acting dopamine receptor agonists, remains unsatisfactory for many patients if long term treatment is required. An alternative strategy may be to reduce the activity of endogenous pathways that antagonise dopaminergic systems. One such pathway is the adenosine pathway. Adenosine receptors are present throughout the CNS, but with the A2A receptor subtype being highly localised to the basal ganglia, especially intrinsic cholinergic neurons and the enkephalin-containing γ-aminobutyric acid (GABA) striopallidal projection neurons. A subtype of A2A receptors may exist in extrastriatal areas. Agonists at these receptors increase neuronal excitability and facilitate neurotransmitter release, but they also interact with dopamine receptors to suppress the effects of dopamine. Conversely, A2A receptor antagonists in general stimulate locomotor behaviour in a wide variety of experimental paradigms and show related behavioural properties consistent with their preventing the activation of adenosine receptors by the endogenous agonist purine, thereby facilitating the activation of dopamine receptors.Preliminary studies in humans with nonselective adenosine receptor antagonists have indicated that this motor stimulant activity may extend to a reduction of the hypokinesia and tremor associated with Parkinson’s disease. The development of selective antagonists of A2A receptors, recently reported by several pharmaceutical companies, may therefore herald the advent of a new pharmacological approach to the treatment of Parkinson’s disease.

The effect of theophylline on essential tremor: the possible role of GABA.

The chronic administration of theophylline was studied in twenty patients with essential tremor in a double-blind cross-over trial. The tremor was improved significantly after four weeks of treatment. In mice the chronic administration of theophylline was compared with propranolol on the modulation by adenosine, 5-HT, (-)isoprenaline or GABA of NMDA-induced depolarisation of neocortical slices. Adenosine depolarisation was abolished by two-weeks treatment with theophylline but not propranolol. Potentiation by (-)isoprenaline of NMDA responses was reduced by theophylline (100 mg/kg/day) and propranolol treatment (25 mg/kg/day), but a lower dose of propranolol further increased it. The enhancement by 5-HT of NMDA-induced depolarisation was unaffected by the pretreatment with theophylline, while the higher dose of propranolol blocked it. GABA caused no significant change of NMDA depolarisation in control slices, but after theophylline treatment (100 mg/kg/day) and propranolol administration at both doses it significantly potentiated NMDA depolarisation. The enhancement of GABA sensitivity might be an important common factor in decreasing the essential tremor after propranolol and theophylline treatment.

Long-term follow-up study with repetitive transcranial magnetic stimulation (rTMS) in Parkinson's disease

Several studies have claimed the effectiveness of repetitive transcranial magnetic stimulation (rTMS) in Parkinsons disease (PD). The rTMS therapy has to be repeated regularly to achieve a permanent effect but the side effects of long-term administration of low frequency rTMS are not known. Further, there is no information about its influence on the development of Parkinsons disease. Two different groups of patients with PD were compared in a retrospective study for 3 years. The first group (A) was treated with drugs, the second group (B) was treated with drugs + rTMS (1 Hz, 0.6 T, 100 stimuli per day for 7 days using a round coil). rTMS was repeated at least twice each year for 3 years. Symptoms of PD were assessed using the Graded Rating Scale. Although at the onset of the study group B patients had greater disease severity and were receiving higher doses of levodopa, this group (receiving rTMS) showed no deterioration in these parameters, whereas those in group A receiving drugs alone showed a marked deterioration. Hoehn-Yahr (H-Y) stages at the onset of the study and 3 years later were: group A: 1.93 +/- 0.75, 3.03 +/- 1.01; group B: 2.50 +/- 0.83, 2.45 +/- 0.62. The dose of levodopa (mg/day) was at the onset of trial and 3 years later was: group A: 124.4 +/- 144.0, 555.5 +/- 247.2; group B: 287.7 +/- 217.1, 333.4 +/- 181.0. The yearly increment in the scores was: group A: 1.308 +/- 0.307 (P < 0.001), group B: 0.642 +/- 0.389 (P < 0.1). Accordingly, this retrospective study using regularly repeated rTMS with 1 Hz for 7 days, at least twice yearly for 3 years, significantly slowed the development of Parkinsons disease. Unwanted side effects were not observed during the 3 years.

New advances in the rehabilitation of CNS diseases applying rTMS

Transcranial magnetic stimulation (TMS) can directly stimulate the CNS, modifying the brain’s plasticity to enhance the behavior of the paretic extremities. Studies with low-frequency repetitive TMS (rTMS) on the intact hemisphere and those with high frequencies on the affected hemisphere could increase the speed of movement in the hand affected by CNS injury. Stimulation of the motor pathway may contribute to faster improvement in patients with spinal cord injury. Symptoms of Parkinson’s disease (such as cognition and working memory, neglect syndrome and global aphasia) can be influenced by rTMS. However, the site of stimulation and the parameters of rTMS are different. Processes that contribute to the behavior of rTMS include the modification of brain plasticity, induction of neurogenesis, growth of new fibers in the spinal cord or all of these together. According to previous research, rTMS may be suitable as an add-on therapy to rehabilitation in CNS diseases.