Painful tonic spasms in
multiple sclerosis
Domenico A. Restivo
U.O. di Neurologia, P.O. “Nuovo Garibaldi”
Catania
PTS: DEFINITIONS
PTS are unilatral or bilateral, sterotyped, involuntary muscular
Contractions lasting less than 2 min and that may manifest several
times/day.
PTS usually continues for weeks or months and then disappear. They can be
triggered by touch, hyperventilation, emotions, movement and are seldom
preceded by a somesthesic “aura”.
They may start from the face, arm, or leg, and spread to the adjacent part of
the body.
They are more common in primary and secondary progressive forms
Carenza di dati di prevalenza
• Verosimilmente
(Solaro et al., 2004)
6-11%
•Si correlazione EDSS
•Si correlazione durata malattia
•No correlazione età
Si correlazione EDSS,
durata malattia ed età
(Solaro et al.,2004)
(Nurmikko et al., 2010)
The spasms originate in the CNS from hyperactivity in
the central motor fibres, caused by lesion in the
internal capsule, cerebral peduncle, medulla, or spinal
cord
Maimone et al., Arch Neurol 1994; Restivo et al., 2003; Solaro et al., 2004
O’Connor et al., Pain 2008;
Ephaptic spreading of abnormal transient electric discharges
throughout demyelinated axons, in the spinal cord, brainstem, or
hemispheric white matter
(Maimone et al., 1991, Solaro et al., 2004; Restivo et al., 2003; 2011)
PATHOPHYSIOLOGY
Although no direct evidence exists, the typically spasmodic muscle contraction
suggests ectopically generated high frequency discharges, due to Na channel
activation.
In the demyelinated part of a nerve fiber in which the internodal membrane is
exposed, membrane impedance is diminished, and the action current generated
in the adjacent nodal membrane is shunted. This is considered to depolarize the
nodal membrane.
During functional recovery a relatively small number of Na+ channels may
appear in the demyelinated internodal membrane and restore conduction,
which also facilitates propagation
Weiner et al., Ann Neurol 1980
A conferma di ciò, un farmaco bloccante i canali al sodio come la lidocaina che
agisce legandosi alla parte all’interno della membrana del canale, con una
attivazione dipendente dallo stato del canale e con una maggiore affinità per
cellule in cui il potenziale di membrana è depolarizzato (blocco Voltaggio
-dipendente) e per cellule che scaricano ad alta frequenza (blocco frequenzadipendente), potrebbe inibire l’esordio ed il perpetrarsi di una scarica ectopica
Sakurai et al. 1998
•Nocicettivo (Sveden et al., 2004)
•Neuropatico
(Bonica JJ 1991)
•Misto
(Truini et al., 2012)
Truini et al., J Neurol 2012
Because e the simultaneous activation of adjacent motor units, as in muscle
cramps, the spasmodic muscle contraction induces extreme vasculature
compression., ischemia, eventually giving rise to nociceptive pain (ischemic muscle
pain). As soon as the spasm ends, the blood flow returns to normal and pain
quickly recedes.
However, although patients with MS-associated PTS have a CNS
lesion, the key question is whether the pain is generated primarily in
the spasmodic muscles or in the CNS
Rog et al. Neurology 2005
PTS: SEDI
I PTS DI SOLITO TENDONO A
DIFFONDERE A DISTRETTI VICINIORI
SONO LOCALIZZATI SOLO AI MUSCOLI DEGLI ARTI E DEL TRONCO ?
Pharyngeal painful tonic spasms: paroxysmal
painful swallowing
Restivo DA, Solaro C, Maimone D, Pavone A, Marchese-Ragona R.
Ann Int Med 2011
Treatment
• Carbamazepine (Shapiro et al., 1997)
• Gabapentin (Solaro et al., 1999)
• Lidocaine iv/mexiletine x os (Sakurai and Kanazawa,
1997)
•
•
•
•
Phenytoin (Solaro et al., 2004)
Acetazolamide ? (Sathi et al., 1992)
Tiagabine (Solaro et al., 1997)
Benzodiazepines (Shapiro et al., 1997)
NO RCT STUDIES !!!
Because Lidocaine blocks the voltage-gated Na+
channels In a voltage- and frequency-dependent
manner., fibers mediating positive symptoms are
preferentially blocked.
Lidocaine almost completely abolished PTS
Similar effects were obtained with oral
mexiletine (300-400 mg/day), a derived
of lidocaine, but a lesser extension
Sakurai et al. 1998
Cannabinoids, theoretically effective in both neuropathic and nociceptive pain
components are efficacious, and are more efficacious in PTS than the purely
neuropathic pains in MS patients
Treatment
Solo un RCT: THC/cannabidiol (CBD)
Livello A di evidenza
Evaluation
•Pain Intensity Score (4-point pain score: 0= no pain; 1= mild; 2= moderate;
3= severe)
•Number of occurrences (diary)
•Polymyographic recordings from painful muscles
Muscular
hyperactivity
Transcranial direct current stimulation (t-DCS)
VA S
10
8
real
6
s ham
4
2
0
T0
T1
T2
T3
Number of oc c urrenc e
18
16
14
12
10
8
6
4
2
0
real
s ham
T0
T1
T2
T3