S P A S T I C I T Y Motor disorder characterized by velocity dependent increase in tonic stretch reflexes and exaggerated tendon jerks D.S.N.V. - UniGE

UPPER MOTONEURONE SYNDROME Negative phenomena - Weakness - Fatigability - Reduced MUs recruitment - Reduced dexterity Positive phenomena - Tone increase - Stretch hyperreflexia - Clonus - Flexor-extensor spasms - Abnormal cutaneous r. - Babinski sign - Cocontraction/Dystonia D.S.N.V. - UniGE

Higher Centres - - Descending + Pathways + Spinal Cord Circuitry Skeletal Muscle Peripheral Afferents - D.S.N.V. - UniGE

SPASTICITY and UMN Syndrome Pathophysiological Mechanisms Defective Inhibition  MNs Postsynaptic  MNs inhibition Presynaptic Ia inhibition Excitatory group II INs Defective Excitation Inhibitory Ia-INs ‘ Reciprocal’ Inhibitory Ib- INs ‘Autogenetic’ Renshaw cells ‘Recurrent’ D.S.N.V. - UniGE

SPASTICITY Ia Pre-synaptic Inhibition D.S.N.V. - UniGE

SPASTICITY Ia Reciprocal Inhibition D.S.N.V. - UniGE

SPASTICITY Interneuronal Excitability D.S.N.V. - UniGE

SPASTICITY and UMN Syndrome Pathophysiological Mechanisms Motor Units changes collateral sprouting transynaptic degeneration dendrite shortening silent synapses activation denervation supersensitivity Changes of Stiffnes and muscle properties D.S.N.V. - UniGE

Muscle & Nerve suppl 6 - 1997 D.S.N.V. - UniGE

TREATMENT of SPASTICITY Therapeutic Objectives TECHNICAL: - Promote: TONE REDUCTION - Improve: RANGE of MOTION, JOINT POSITION - Facilitate: REHABILITATION FUNCTIONAL: - Improve: GAIT, HYGIENE, ADL, EASE of CARE - Reduce: SPASMS, PAIN D.S.N.V.- UniGE

PHARMACOLOGIC TREATMENT OF SPASTICITY Recommended when spasticity produces a clinical disability by interfering with posture, motor capacity, nursing, ADL Indicated when muscle overactivity is diffusely distributed (spinal > cerebral) Timed in the early stages to prevent permanent musculoskeletal deformities or contractures The goal is to decrease spinal reflex excitability by: - reducing the release of excitatory neurotransmitters - potentiating the activity of inhibitory circuits D.S.N.V.- UniGE

NEUROTRANSMITTERS AND PHYSIOLOGICAL MECHANISMS INVOLVED IN SPASTICITY GABA Glycine Glutamate EAAs Noradrenaline Serotonine D.S.N.V. - UniGE

DIAZEPAM Aumenta l’affinità del GABA per il suo recettore ionoforico (GABA a) Livello postsinaptico: aumento conduttanza Cl, iperpolarizzazione, inibizione postsinaptica Livello presinaptico: aumento conduttanza Cl, depolarizzazione, inibizione rilascio aminoacidi eccitatori D.S.N.V. - UniGE

BACLOFEN Stimolazione recettori GABA b (metabotropici) - Livello postsinaptico: aumento conduttanza K, iperpolarizzazione cellulare, inibizione - Livello presinaptico: blocco dei canali del Ca, alterazione liberazione aminoacidi eccitatori D.S.N.V. - UniGE

D.S.N.V. - UniGE

DIAZEPAM (2) CLINICAL EFFECTS: SIDE EFFECTS: - Reduction of resistance to stretch (increased range of motion) - Reduction of deep tendon reflexes and of painful spasms SIDE EFFECTS: - Sedation & drowsiness, Attention & memory impairment - Weakness amd motor incoordination - Tolerance, dependency (withdrawal phenoemena) INDICATIONS: SCI - MS (possible: TBI - CP - CVA) EFFICACY SHOWN BY DOUBLE-BLIND PROTOCOLS IN SC LESIONS (POSSIBLE STRENGTH-GAIT DETERIORATION) D.S.N.V. - UniGE

BACLOFEN (2) CLINICAL EFFECTS: - Reduction of flexor-extensor spasms - Reduction of mono- polysynaptic reflexes - Reduction of sphincter hyperreflexia SIDE EFFECTS: - Sedation, Drowsiness, Fatigue, Confusion, Dizziness - Hypotonia, Ataxia INDICATIONS: Spinal spasticity EFFICACY SUFFICIENTLY DOCUMENTED IN PATIENTS WITH SC LESIONS (LESS IN CEREBRAL) D.S.N.V. - UniGE

INTRATHECAL BACLOFEN Consists of direct long-term delivery of baclofen to the intrathecal space via an implanted programmable pump Indicated in patients with severe spasticity, not managed by oral baclofen (inadequate BBB penetration, side effects) or other oral medications Same clinical effects at much lower doses (1 %) - Selection - Screening - Implantation - Dose adjustment & maintenance D.S.N.V. - UniGE

INTRATHECAL BACLOFEN (2) Benefits have been documented by placebo-controlled studies in severely disabled nonambulatory patients with overactivity mainly in ther lower limbs and with flexor spasms Reduction of spasticity, spasms and pain Sleep improvement and better bladder management IMPROVEMENT IN QUALITY OF LIFE COMPLICATIONS: infection, pump dysfunction, high cost and invasiveness D.S.N.V. - UniGE

TIZANIDINA Attività 2-agonista (spinale e sopra-spinale) - riduce la liberazione di aminoacidi eccitatori nel midollo spinale - inibisce la via coerulo-spinale (questa via normalmente facilita i circuiti spinali) D.S.N.V. - UniGE

TIZANIDINE (2) INDICATIONS: MS - SCI (possible: cerebral spasticity) CLINICAL EFFECTS: - reduction of tonic stretch polysynaptic reflexes - reduction of co- contraction SIDE EFFECTS: sedation, dizziness, dry mouth, but not weakness INDICATIONS: MS - SCI (possible: cerebral spasticity) EFFICACY PROVEN BY PLACEBO-CONTROLLED STUDIES (> DIAZEPAM IN CEREBRAL). NO DEFINITE FUNCTIONAL CHANGES D.S.N.V. - UniGE

DANTROLENE INDICATIONS: CVA - CP (possible: TBI - SCI -MS) Peripheral inhibition of calcium release from sarcoplasmic reticulum. Decreased excitation-coupling reaction. CLINICAL EFFECTS: Reduction of muscle tone, phasic reflexes and spasms Increased range of passive motion INDICATIONS: CVA - CP (possible: TBI - SCI -MS) SIDE EFFECTS: hepatotoxicity, GE symptoms, weakness, but less sedation D.S.N.V. - UniGE

ANTISPASTIC DRUGS Clonazepam, Ketazolam, Tetrazepam Progabide, Gabapentin Piracetam Clonidine L-threonine Thymoxamine Cyproheptadine, Orphenadrine ONLY FEW CONTROLLED STUDIES MOSTLY OPEN OR ANECDOTICAL OBSERVATIONS D.S.N.V. - UniGE

Cochrane Database Syst. Rev. (2000) - To assess the effectiveness and safety of antispastic drugs in patients with SCI - 9 out of 53 parallel and crossover studies (up to 1998) included 2 studies (placebo controlled) showed a significant effect of intrathecal baclofen in reducing spasticity (Ashworth - ADL) 1 study (placebo controlled) showed a significant effect of tizanidine in improving Ashworth scale but not ADL No significant evidence for the other drugs (Gabapentin, Clonidine, Diazepam, oral Baclofen) D.S.N.V. - UniGE

Neurolytic Agents Phenol and alcohol injections may be used to induce a focal chemodenervation by: - protein denaturation - non-selective tissue destruction (nerve coagulation - muscle necrosis) - Wallerian degeneration Motor nerve block Motor point block D.S.N.V. - UniGE

Phenol and Alcohol (1) INDICATIONS: focal spasticity - proximal muscles (lower limb) CLINICAL EFFECTS Reduction of muscle tone (and clonus) without impairment of strength and voluntary contraction. Long duration. SIDE EFFECTS sensory damage (dysesthesia, causalgia, neuralgic pain) tissue damage (edema, venous thrombosis) NO CONTROLLED FUNCTIONAL DATA D.S.N.V. - UniGE

BOTULINUM TOXIN Potent neurotoxin 7 serotypes (A-G) with different antigenic properties reversible block of Acetylcholine release D.S.N.V. - UniGE

BOTULINUM TOXIN Mechanism of action D.S.N.V. - UniGE

D.S.N.V. - UniGE

BTX e SPASTICITA’ Indicazioni Trattamento della spasticità focale, cioè di limitati gruppi muscolari la cui iperattività o ipertonia interferisce con lo svolgimento di specifiche attività ‘funzionali’ statiche o dinamiche Lo scopo è ottenere un effetto locale, in assenza di effetti sistemici Controindicazioni: - mancanza di un’adeguata attività dinamica - presenza di contratture fisse o deformità D.S.N.V. - UniGE

BTX e SPASTICITA’ Possibili obiettivi E’ fondamentale la selezione dei pazienti e dei muscoli bersaglio e l’identificazione degli obiettivi terapeutici Prevenzione complicazioni (evitare chirurgia) Controllo del dolore Facilitazione dell’igiene e/o assistenza Miglioramenti funzionali - adattabilità ortesi, ampliamento ROM - incremento autonomia (controllo motorio, appoggio, autonomia) D.S.N.V. - UniGE

BTX e SPASTICITA’ Effetti principali Riduzione dell’iperattività muscolare: - riflesso tonico da stiramento (Ashworth Scale) dolore - ‘range’ di movimento passivo Evidenze neurofisiologiche: - modificazioni attività riflesse spinali - effetti di tipo centrale ? D.S.N.V. - UniGE

BTX e SPASTICITA’ Effetti principali Modificazioni funzionali: - scale di autovalutazione (patient/caregiver) - scale di valutazione funzionale (ADL, FIM, Rivermead) - test motori (Frenchay Arm test, reaching, tapping) - analisi EMG/Video del cammino INCERTEZZA SULLE MISURE DI OUTCOME D.S.N.V. - UniGE

BTX e SPASTICITA’ Problemi metodologici Sede d’iniezione: Quali criteri ?? valutazione clinica e/o infiltrazione EMG-guidata - pattern MUPs - localizzazione punto motore - ‘turns amplitude analysis’ - stimolazione elettrica Childers et al., 1996 - Finsterer et al., 1997 Numero iniezioni e volume diluizione ?? D.S.N.V. - UniGE

BTX e SPASTICITA’ Problemi metodologici Dosaggio ?? - l’entità (ma non la durata) del miglioramento funzionale può essere dose-dipendente Wissel et al., 1999; Hyman et al., 2000; Smith et al., 2000; Bakheit et al., 2000 - problema della ‘immunoresistenza’ - ‘basse dosi’ in associazione a procedure riabilitative D.S.N.V. - UniGE

BTX e SPASTICITA’ Trattamenti concomitanti La stimolazione elettrica o l’attività muscolare potenzia l’attività della tossina Hesse et al., 1995 e 1998, Eleopra et al. 1997 D.S.N.V. - UniGE

BTX e SPASTICITA’ Follow-up Efficacia nel tempo del trattamento ?? - analogia con altre indicazioni Lagalla et al. 2000 - efficacia invariata a 3 anni in pz. con ‘stroke’ dose invariata, > intervallo D.S.N.V. - UniGE

SURGICAL TECHNIQUES in Spasticity Objective: to treat permanently static or dynamic consequernces opf UMN sundrome in stable patients Timing: early and before severe and fixed deformities Methods: specific interventions for individual muscle/joints - TENDON LENGTHENING - INTRAMUSCULAR LENGTHENING - TENDON TRANSFER - NEURECTOMY D.S.N.V. - UniGE

Management of Spasticity Prevent: - provocative factors or noxious stimuli (medication if necessary) - delayed consequences (surgery if necessary) Treat muscle overactivity with different strategies MEDICAL THERAPY PHYSICAL THERAPY GENERAL ORAL DRUGS REGIONAL IT/BACLOFEN NERVE BLOCKS FOCAL BTX INJECTIONS D.S.N.V. - UniGE