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Fisiopatologia Dei Tremori

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Fisiopatologia Dei Tremori FISIOPATOLOGIA DEI TREMORI Enrico Alfonsi Neurofisiopatologia IRCCS-Istituto Neurologico Nazionale «Casimiro Mondino» Pavia TREMOR A rhythmic involuntary movement of one or several regions of the body. It represents the most common neurological sign, as everyone has a ‘’physiological’’ tremor, which can only be measured with instrumental tools. 1 BACKGROUND Relation to Voluntary Movement Relation to Body Part Rest tremor Head tremor Parkinson’s disease Cerebellar disease Other parkinsonian syndromes Dystonia Tardive (drug-induced) parkinsonism Essential tremor (rarely when isolated) Vascular parkinsonism Chin tremor Hydrocephalus Parkinson’s disease Common Psychogenic (functional) tremor Hereditary geniospasm tremor Action tremor Jaw tremor disorders Postural tremor Parkinson’s disease classified Physiologic tremor and enhanced physiologic tremor Dystonia according Essential tremor Palatal tremor to two main Dystonic tremor Idiopathic (essential) criteria Parkinsonism Owing to brainstem lesions (secondary) Fragile X premutation (fragile X tremor–ataxia syndrome) Owing to degenerative disease (adult-onset Alexander’s disease) Neuropathies Arm tremor Tardive tremor Cerebellar disease Toxins (e.g., mercury) Dystonia Metabolic disorder (e.g., hyperthyroidism, hypoglycemia) Essential tremor Psychogenic (functional) tremor Parkinson’s disease Kinetic tremor Leg tremor Cerebellar disease Parkinson’s disease Holmes’ tremor Orthostatic tremor Wilson’s disease Psychogenic (functional) tremor 2 Essential tremor Features considered typical of the essential tremor syndrome Feature Description Tremor 4–12 Hz action tremor that occurs when patients voluntarily attempt • A resting tremor can appear only in advanced to maintain a steady posture stages. Other neurological signs (with the against gravity (postural tremor) or move (kinetic tremor) exception of cog-wheel phenomenon and Tremor may be suppressed by difficulties with tandem gait) are typically performing skilled manual tasks absent. Isolated head tremor without evidence Tremor resolves when the body of abnormal posture may occur. The aetiology part relaxes as well as during sleep and clinical definition of essential tremor is Tremor at rest is not uncommon and observed in approximately currently under debate. The potential 20% of patients distinction between late-onset essential tremor Age at onset Adolescence (15–20 years) or late (≥ 65 years old) and postural tremor of old age adulthood (50–70 years) (‘’senile tremor’’) remains unclear. Distribution Bilateral with minimal asymmetry • No causative gene has been identified to date. Affected body sites Upper limbs >> head >> voice >> face/jaw >> tongue >> trunk >> Recently, genetic variants in the gene for lower limbs LINGO1 have been identified as risk factors for Progression Tremor may initially be ET. intermittent, occurring during • Importance of cerebello-thalamo-cortical periods of emotional activation, and then becomes persistent over projections, with the primary role of the time cerebellum. Response to alcohol Beneficial alcohol response present in 50–75% of patients Family history Positive family history present in 30–60% of patients 3 Clinical heterogeneity of ET is reflected in heterogeneous pathophysiological findings Three mutually nonexclusive hypotheses: • The neurodegeneration hypothesis • The oscillating network hypothesis • The GABA hypothesis 4 NEURODEGENERATION HYPOTHESIS Argouments put forward: • ET begins insidiously, follows a progressive course, and is associated with age • In some studies ET is associated with increased risk of PD and Alzheimer disease Argouments against this hypothesis: • Many pathologial abnormalities fall in the normal range • These abnormalities do not correlate with the duration of ET There is evidence for neurodegeneration of the cerebellum in ET (Voxel- based mophometry studies), although more indipendent samples are necessary to confirm this. There is some evidence for neurodegeneration of the locus coeruleus and there is no evidence for inferior olive disease. The Oscillating Network Hypothesis for ET 5 The Oscillating Network Hypothesis for ET • In physiological tremor , during movement, inhibitory nucleo-olivary cells increase their activity, activating climbing fibers of the inhibitory Purkinje cells with a strong and synchronous inhibition onto the cerebellar nuclear neurons. This generates an oscillatory rebound potentials in these cells which are relayed to the motor cortex via the thalamus resulting in a physiological tremor of about 10 Hz • Recenltly, the idea that single oscillators can produce the tremor has been questioned: many group of neurons are only intermittently coherent with tremulous muscle activity: 1. cortico-muscular coherence in ET was lost intermittently without observable changes in peripheral tremor activity; similar findings for pallidomuscular coherence in PD tremors. 2. DBS in ET and tremor-dominant PD have showed that multiple, spatially separated tremor clusters within the VLp are capable of driving the tremor • These findings have shifted the attention to network properties such as strength and directionality of interregional connettivity. This contrasts with the single oscillator hypotheses which take into account the neural network in which the oscillator is embedded but not the interaction between the elements of the network and its connettivity structure. This hypothesis may explain why ET disappears after cerebellar stroke in some patients, whereas other patients develop ET after ipsilateral cerebellectomy. This also fits with the fact that lesions at several different localization within the cerebello-thalamocortical circuits can remove ET, which argues against a single oscillator. THE GABA HYPOTHESIS Several lines of evidence support the idea that ET is associated with abnormal function of the inhibitory neurotrasmitter GABA • Drugs that increase GABAergic transmission like primidone , topiramate , gabapentin , and ethanol are effective in ET treatment • Reduced levels of GABA in the CSF of patients with ET are observed • Experimental interference with GABAergic transmission in animals can evoke an ET-like postural tremor (hamaline evokes postural tremor by ihnibiting GABA-A receptors: enhancement of electrical coupling of cerebellar afferents in the inferior olive) • GABA-A receptors α1for knockout mice exhibit postural and kinetic tremor resembling ET • Nuclear imaging studies found altered binding to GABA receptors in ET • Using PET in ET, 11C-Flumazenil binding to GABA-A receptors increased in the ventrolateral thalamus, the dentate nucleus of the cerebellum, and the premotor cortex • Using PET in ET, Flumazenil binding increases with tremor severity • In post-mortem biopies GABA-A and GABA-B receptors in the dentate nucleus of the cerebellum of ET patients are less than those of PD patients and normals : the reduction of the levels of dentate GABA receptors may be a primary deficit in ET, restricting the post- synaptic action of GABA released from Purkinje cell axons, and thereby disinhibiting deep cerebellar nuclei neurons which spead up their ensuing overactivity through the cerebellar- thalamo-cortical circuits possibly resulting in tremor 6 THE GABA HYPOTHESIS The GABAergic abnormalities in ET do not have a know genetic basis: several studies have failed to find a relationship between GABA receptor and transporter polymorphisms and ET There is firm evidence for a reduction of GABAergic tone in ET, which, interestingly, is located in the same areas ( cerebellum and Locus coeruleus) where neurodegenerative changes have been found 7 8 9 Essential tremor: pharmacotherapy CLASS NAME OF DRUG (BRAND NAME) INITIATING TREATMENT (DAILY DOSE) MAINTENANCE DAILY DOSAGE RANGE MOST COMMON ADVERSE EFFECTS (DOSING REGIMEN) I. Anticonvulsants Primidone (Mysoline) (most effective in this class) 25 to 31.5 mg at night for 1 week and then weekly 25 mg to 750 mg/day Once daily or up to 3 times Sedation, dizziness, fatigue drowsiness, ataxia, increase as necessary and tolerated daily. Available tablet size varies in different confusion, nausea, vomiting countries. Available in liquid suspension. Topiramate (Topamax) 50 mg (2 divided doses) 50 mg to 325 mg/day (2 divided doses) Anorexia, weight loss, memory decline, cognitive difficulty, paresthesias, kidney stone II. Beta adrenergic receptor antagonists Propranolol IR (Inderal) (most effective in this class) 10 mg 1 dose gradually increase to 2 or 3 doses 10 mg to 320 mg/day (1 to 3 divided doses) Bradycardia, bronchospasm, fatigue, depression, decline in sexual function, hypotension Propranolol LA (long acting) (Inderal LA) 60 or 80 mg (1 dose) 60 mg 320 mg/day (1 or 2 divided doses) Similar to Propranolol IR Atenolol (Tenormin) 12.5 mg (1 dose) 50 mg to 150 mg/day (1 or 2 divided doses) Bradycardia, dry mouth, sleepiness Nadolol (Corgard) 20 mg (1 dose) 120 mg to 240 mg/day (1 dose) Bradycardia, dizziness, lightheadedness, hypotension III. Benzodiazepines/GABAergic agents Clonazepam (Klonopin) 0.25 mg (1 dose) (preferred use is for occasional Usual 0.5 mg to 6 mg/day (1 to 3 divided doses) Sleepiness, confusion, risk of drug dependency control of tremor) therefore to use with caution Alprazolam (Xanax) 0.125 mg (1 dose) 0.125 mg to 3 mg/day (1 to 3 divided doses) Sedation, fatigue. Caution for risk of drug dependency. Best used for occasional control of tremor. Gabapentin (Neurontin) 50 mg (1 dose, increase as necessary and tolerated) 50 mg to 1800 mg/day (1 to 3 divided doses) Lethargy, decreased
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