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HYPERKINETIC SYNDROMES

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1 HYPERKINETIC SYNDROMES
SAMIH BADARNY Parkinson and other movement disorders clinic Neurology Department Carmel Medical Center- Haifa

2 TREMOR Definition: Oscillatory , usually rhythmical and regular movements affecting one or more body parts. Usually caused by alternating contraction of agonist and antagonist muscles

3 Classification by state of activity
Rest Tremor: is present when a limb is fully supported against gravity and the relevant muscles are not voluntarily activated. Action tremor: occurring during any voluntary muscle contraction which includes postural, kinetic, isometric and task specific tremors. Postural tremor: is apparent during the voluntary maintenance of a particular posture which is opposed by the force of gravity.

4 Kinetic tremor: is evident during any type of
movement. Intention or terminal tremor: is the pronounced exacerbation of kinetic tremor towards the end of a goal directed movement. Task specific tremor: only occurs during the performance of a highly skilled activity

5 Isometric tremor: Occurs when a voluntary muscle
contraction is opposed by a rigid stationary object. Orthostatic tremor: A 14-16Hz tremor that appears a few seconds after standing and subside on sitting or walking

6 Classification by etiology:
Physiological and enhanced physiological: Present at action. Is more pronounced during periods of fatigue fear or excitement. Results from numerous factors including the heart beat, low pass filtering properties of striated muscles, motor neurons firing and synchronization by spindle feed back.

7 Parkinsonian tremor: Slow 3-5 Hz rest tremor (pill rolling) involving the limbs and/or tongue chin and lips. May be asymmetrical. May be accompanied by postural (“re-mergent”) tremor.

8 Dystonic Tremor: A jerky irregular action tremor intermingled with sustained muscular spasms that can last several seconds. May involve the muscles of the neck (tremulous spasmodic torticollis), face (orofacial dyskinesia), trunk and limbs.

9 Midbrain (“rubral”, “Cerebellar outflow”) tremor:
A tremor which is present at rest, worse on posture and is further exacerbated by movement. This type of tremor is most commonly seen in MS and brainstem vascular lesions. Cerebellar Tremor: A kinetic tremor with marked intentional component. The tremor is usually accompanied by disorders of ocular motility ( dysmetria, nystagmus) incordination, DDK pendular reflexes and unsteady gait.

10 ESSENTIAL TREMOR Essential tremor (ET) is the most common movement disorder. It is a syndrome characterized by a slowly progressive, rapid (4-12Hz), postural and/or kinetic tremor, usually affecting both upper extremities.

11 Epidemiology The estimated prevalence of ET is 0.3- 5.6% of the
general population. Both sexes are affected equally although head tremor may be more frequent in women. The prevalence of ET increases with age. Age of onset has bimodal peaks - one in late adolescence to early adulthood and a second in older adulthood. The mean age at presentation is 35-45 years. No association has been found between age of onset and severity or disability.

12 ET- Disability 85% percent of individuals with ET report significant changes in their livelihood and socializing. 15% percent report being seriously disabled by ET.

13 Decreased quality of life results from both loss of
function and embarrassment. In a study of hereditary ET, 25% changed jobs or took early retirement; 65% did not dine out; 30% did not attend parties, shop alone, partake of a favorite hobby or sport, or use public transportation; and 20% stopped driving. An estimated % of affected individuals seek medical attention

14 ET- Genetics ET is familial in at least 50-70% of cases. Transmission is autosomal dominant, with incomplete penetrance. Some cases are sporadic with unknown etiology. Two susceptibility loci have been found; The FET1 gene is located at 3q13 and was identified in 75 members of 16 Icelandic families. ETM2 gene at 2p25-22, was identified in 15 members of 4 generations of Americans.

15 ET-pathophysiology Two neural circuits have been proposed to explain the pathophysiology of tremor. A basal ganglia-thalamocortical motor loop involving the globus pallidum, anterior VL thalamic nucleus, and supplementary motor area may be affected in extrapyramidal tremor diseases such as PD and ET. Another loop, involving the cerebellum, posterior VL thalamic nucleus, and motor cortex, may explain tremor of other etiologies (eg, cerebellar tremor).

16 Treatment: Propranolol Primidone Clozapine Gabapentin Benzodiazepines
Topamax BTX-A

17 Definition: Dystonia is a movement disorder characterized by sustained muscle contractions that frequently cause twisting or repetitive movements and abnormal, sometimes painful, postures or positions

18 Classification : Etiology Distribution of body regions affected
primary secondary Distribution of body regions affected Age of onset

19 Etiology: Primary Secondary Dystonia the single sign
History,clinical and laboratory findings are normal Usually action dystonia Secondary Associated with hereditary neurological diseases Environmental (birth trauma or drug use) Psychogenic dystonia

20 Distribution of body: Focal Blepharospasm, cervical, laryngeal, hand.
Segmental Meige, OMD Multifocal Different types Hemidystonia Vascular or CP Generalized Torsion dystonia Dopa responsive dystonia

21 Age of onset:

22 Pathophysiology: Is not known
Reduced inhibition at various levels of motor system Sensory motor disintegration of BG and motor cortex. Alteration of discharge rate in GPI

23 Treatment : Levodopa and dopamine agonists Anticholinergics Clonazepam
Baclofen Atypical neuroleptics Tetrabenazine Botulinum toxin type A ( Botox, Dysport)

24 BOTULINUM TOXIN TYPE A (BTX-A)
BTX-A acts as presynaptically at nerve terminals to prevent release of acetylcholine. CHEMICAL DENERVATION

25 Dimention coefficient 19s 16s 12s 7s
Molecular weight (kdaltons) haemagglutinin Non-toxic protein neurotoxin LL L M S Toxin type A B C D E F G Complexes LL,L,M,S L,M,s L,M,S L,M,S M,S M,s

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30 Sites of action of BTX-A
Alpha motor neuron (Neuro-muscular junction) Gamma motor neurons (Muscle spindles) Autonomic nervous system (Cholinergic nerve endings) C and A delta fibers Central nervous system?

31 Clinical Applications of BTX-A
Focal Dystonias Blepharospasm (lid “apraxia”) Oromandibular-facial-lingual dystonia Cervical dystonia (torticollis) Laryngeal dystonia (spasmodic dysphonia) Task-specific dystonia (occupational cramps) Other focal dystonias (Idiopathic, secondary) Other Involuntary Movements Voice,head and limb tremor Palatal myoclonus Hemifacial spasm Tics Other Applications Protective ptosis Essential hyperhidrosis Cosmetic (wrinkles, facial asymmetry) Other Inappropriate Contractions Strabismus Nystagmus Myokymia Bruxism (TMJ) Stuttering Painful rigidity Muscle contraction headaches Lumbosacral strain and back spasms Radiculopathy with secondary muscle spasms Spasticity (CP included) Spastic bladder Achalasia (esophageal) Pelvirectal spasms (anismus,vaginismus)

32 BTX-A Side Effects Over Weakness Local Pain Blue Spots
Distant Effects - Rare Lost of Efficacy

33 CHOREOATHETOSIS Chorea (dance) - irregular, rapid, uncontrolled, involuntary,excessive dyskinetic movements. Athetosis (not fixed) - slow,sinuous writhing movements especially in the hands. Ballismus- a form of chorea with large amplitude of the affected extremity.

34 Chreoathetosis seems to result from damage of indirect pathways of the BG.
These indirect pathways normally inhibit the unwanted movements.

35 Etiology Vascular Immune mediated CP Metabolic Hereditary
Sydenham’s chorea CP Metabolic Hereditary Huntington disease Wilson disease

36 HUNTINGTON DISEASE Age 35-50 years Rare (4-10/105)
Autosomal dominant- chromosome 4 , mutation of IT15 gene  repeats of amino acids (CAG)  abnormal huntingtin (genetic anticipation, paternal) Degenerative changes in caudate nucleus and putamen (spiny neurons and GABA) Mitochondrial dysfunction  excessive activation and exitotoxicity of glutamate  apoptosis .

37 Clinical manifestations:
Behavioral, emotional and psychiatric disturbances. Cognitive decline Motor disturbances Chorea postural instability difficulty swallowing dysarthria motor impersistance

38 Treatment: Neuroleptics BD TBZ Riluzole Coenzyme Q10

39 WILSON DISEASE Autosomal recessive Frequency 1/105 Age 10-20 years
ATP7B gene , chromosome 13 Defect in transport of copper(ceruloplasmin)

40 Clinical manifestations:
Non neurological Kayser-Fleischer ring Cirrhosis Neurological Tremor, chorea,dysphagia,dysarthria, parkinsonism, hyperreflexia. Psychiatric From agitation to schizophrenia

41 Laboratory investigation:
Low ceruloplasmin and copper in serum Urine copper is high Liver enzymes and liver biopsy Normal CT or MRI of brain

42 Treatment : D-penicillamine amine (care pyridoxine)
Trientine or tetrathiomolybdate Zinc Diet (cocoa, chocolate, liver, mushroom, nuts, shellfish)

43 TICS AND TOURETTE Tics are involuntary movements or sounds
Motor and vocal , simple or complex Non rhythmic and repetitious Sporadic and sudden Simple motor- fast , brief involve one or some muscles. Complex motor- sequent and simultaneous movements, produce as purposeful movements

44 Simple vocal-solitary meaningless sounds and noise, as sniffing, throat clearing, humming or coughing Complex vocal-meaningful utterances and and verbalizations as partial or complete words and repeated, coprolalia, echolalia and palilalia

45 Spectrum of tic disorders:
Transient tic disorder Childhood and adolescence Four times boys more than girls Motor and or vocal tics Maximum one year Chronic single or multiple tic disorder Motor or vocal not both More than one year

46 TOURETTE’S SYNDROME (TS)
Genetic, childhood onset ( 1-20 years) Motor and vocal tics Accompanied with ADHD (80%), OCD, poor impulse control, anxiety, mood disorders and behavior disturbances (20%) Males > female (4:1) Affect of general population No definitive diagnostic test

47 Etiology of TS Treatment Is not known, 80% is genetic
Synaptic neurotransmission? Disinhibition of striatal-thalamic-cortical circuitry Environmental factors PANDAS? Treatment Neuroleptic agents(antagonists and depletors) Antidepressants Antianxiety BTX

48 MYOCLONUS Definition: Anatomic :
Sudden, brief, shock-like movements which can be positive or negative (asterixis or flapping tremor). Anatomic : cortical subcortical spinal peripheral (HFS)

49 Etiologic: physiologic essential  progressive myoclonic epilepsy
secondary  drugs, nocturnal, psyhogenic, myoclonus dystonia, neurodegenerative, trauma, opsoclonus – myoclonus

50 Treatment : Antiepileptics Benzodiazepines BTX-A

51 TARDIVE DYSKINESIA (TD)
Sigwald (1959) first described TD Involuntary movements typicallly of oro-buco- lingual muscles ,but any muscle in the body can be involved related to antipsychotic drugs. Mean prevalence 25% Annual incidence rate-5%in young and 12% in elderly.

52 Mechanism: hypersensitivity and excessive function of dopaminergic neurotransmitters in BG. High risk- young, female, affective disorders, poor treatment response to neuroleptics, dose duration and type of drug holidays or interruption or increase dose (mask TD) , anticholinergics, lithium, parkinsonism.

53 Treatment of TD: Vit E Valproic acid Clonazepam Propranolol
Ca channel blockers Dopamine agonists Atypical neuroleptics Dopamine Depletor- Tetrabenazine

54 Tetrabenazine (Xenazine ,Nituman)
Has two modes of action: 1- blocking postsynaptic dopamine receptors 2- depleting dopamine stores in presynaptic vesicles  reduced transmission along dopamine pathways. Depleting stores of biogenic amines: e.g., serotonin, noradrenaline, as well as dopamine binds to vesicular monoamine transporter 2 (VMAT2) VMAT2 found primarily in the CNS.

55 Vesicular monoamine transporter 2 (VMAT2)
Presynaptic vesicle Dopamine 2H+ VMAT2

56 Most common side effects:
Drowsiness/fatigue Parkinsonism Depression Nervousness/anxiety Akathisia Nausea/vomiting

57 THANK YOU


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