Botulinum toxin is used primarily for the treatment of focal and segmental dystonia. For successful therapy, the muscles involved in the dystonic movement pattern must be correctly identified. During intramuscular injection, a control technique (sonography and/or electromyography) is used to check whether the injection needle has actually been placed in the correct muscle. In spasticity, the use of botulinum toxin can relieve pain and restore physiological movement by reducing pathologically increased muscle activity. The use of botulinum toxin can prevent contractures, incorrect strain and joint damage.
Botulinum toxin is a bacterial toxin produced during growth and reproduction of Clostridium botulinum. This bacterium grows preferentially in poorly preserved canned sausages, hence the name (Latin: botulus, the sausage). J. Kerner first described the clinical picture of botulism in 1815, and in 1820 he associated the symptoms with the poison. As early as 1822, he proposed the use of the poison in small doses for therapeutic purposes [1]. However, it took until the 1940s before the substance could be produced in pure form, and it was not until the 1970s that it began to be used therapeutically, first for blepharospasm and later for cervical dystonia [2–4].
Dystone movement disorders
Dystonic movement disorders are classified according to clinical characteristics (age at symptom onset, body parts affected, temporal onset, coexistence of other movement disorders, occurrence in the setting of other neurological disorders) and etiology (inherited, acquired, idiopathic, familial).
The definition of dystonia was last defined in 2013: “Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions that result in abnormal, often repetitive movements and/or postures. Dystonic movements typically follow a pattern, are rotational, and may result in tremor-like movement. Dystonia is often triggered or exacerbated by voluntary movements, and dystonic movements are associated with disproportionate activation of the muscles necessary for the movements and their adjacent muscle groups” [5]. Botulinum toxin is used primarily for the treatment of focal and segmental dystonia.
Overview of pathophysiology
After dystonia was understood as a psychiatric disorder until the 1970s, Charles Marsden’s finding that structural changes in the basal ganglia can lead to dystonic movement patterns revolutionized the understanding of how dystonic movement patterns develop [6].
It is now known that reduced inhibition at cortical, striatal, and spinal levels both promote the development of dystonic movements, as do increased cortical plasticity and cortical hyperexcitability. Furthermore, reduced temporal and spatial discrimination of sensory stimuli and altered muscle spindle afferents have been described in patients with dystonia [7].
Effect of botulinum toxin
Botulinum toxin binds specifically and irreversibly to the cell membrane of the neuron. The toxin is taken up into the cell as a vesicle, the carrier protein is proteolytically cleaved, and the active toxin is released into the cytosol. The active toxin cleaves SNAP-25, a membrane protein necessary for the release of acetylcholine [8]. Decreased release of acetylcholine leads to chemodenervation with consecutive flaccid paresis of the muscle.
Injection of botulinum toxin reduces the muscle spindle afferents of the affected muscle, this results in cortical reorganization with normalization of cortical plasticity [9]. For successful therapy of dystonic disorders using botulinum toxin, the muscles involved in the dystonic movement pattern must be correctly identified.
Blepharospasm
Blepharospasm is the involuntary, repetitive closing of both eyes. Blepharospasm often occurs later in life, begins with isolated blinking or a foreign body sensation, and is often exacerbated by bright light. In blepharospasm, identification of the dystonic muscles is straightforward; it is a dystonic disorder of the orbicularis oculi muscle. With a small dose of botulinum toxin at the beginning, which is distributed over 4-6 periocular injection points depending on the regimen and gradually increased, a majority of blepharospamus patients can be helped.
Rarely, it is a variant of blepharospamus that does not respond or responds inadequately to the classic botulium toxin injection regimen: so-called pretarsal blepharospasm. The fibers of the orbicularis oculi muscle close to the lid margin are mainly involved in the spasm. By injecting very close to the lid margin, patients with this form of blepharospasm can also benefit well from botulinum toxin injections [10].
Clinically, classic blepharospasm can be distinguished from pretarsal blepharospasm by the patient’s voluntary closing and reopening of the eyes. The delay in voluntary eye opening or the need to open the closed eyes with the aid of the frontalis muscle or with the hand suggests a pretarsal component [11].
Rarely, blepharospamus also occurs unilaterally. Hemifacial spasm, also unilateral, can be distinguished from unilateral blepharospamus by the so-called Babinski II sign (involuntary closing of one eye with simultaneous raising of the ipsilateral eyebrow).
Cervical dystonia
Before starting therapy with botulinum toxin, the etiology of cervical dystonia should be clarified. A detailed questioning regarding family history, medication history (neuroleptics?), symptom onset and development, diurnal dependence, triggering activities etc. is carried out. To differentiate idiopathic dystonia from structurally caused dystonia or dystonic disorders in the context of other underlying diseases, a detailed clinical examination, laboratory diagnostics with questions about metabolic disorders (e.g. Wilson’s disease, ferritinopathies, disorders of amino acid and lipid metabolism) and a morphological image of the brain using MRI are recommended.
In cervical dystonia, the group of muscles involved varies variably and interindividually. It is therefore important to observe the dystonic movement patterns both at rest (relaxed sitting with eyes closed, possibly under distraction) and in motion (walking) and preferably also to document them with video. Attention should be paid to whether other body parts are involved in the dystonic movement pattern and how the pattern changes with movement. Walking often brings out portions of the dystonia that are suppressed at rest, and especially when leaning the head while sitting.
Selection of muscles to treat based on inspection and palpation alone may be misleading, as compensatory muscles may also be severely hypertrophied. Paralysis of compensatory muscles may worsen the dystonic movement pattern. To identify the muscles most involved in the pathologic movement pattern, inspection and palpation of the muscles, close observation of head and neck movements and positioning, and an accurate history regarding symptom onset are helpful.
Before starting a therapy with botulinum toxin it is favorable to make a goal agreement with the patient (what bothers most? What should be achieved with the injections?). Dealing openly with the patient’s wishes and the possibilities and limits of botulinum toxin therapy as well as directly addressing possible side effects in advance (muscle weakness, dysphagia, flu-like infections) are important for establishing and maintaining a relationship of trust with the patient. Achieving complete symptom freedom is usually not possible. The targeted physiotherapeutic support for relearning physiological movement patterns and the targeted strengthening of the holding and supporting muscles of the neck and trunk positively complement the effect of botulinum toxin therapy. Close cooperation with the physiotherapist can significantly improve the success of the therapy.
Injection technology
For periocular injection, an ordinary hypodermic needle can be used. The puncture through the skin should be done quickly, as it is painful for the patient; the injection of the toxin should be done slowly, as it may cause an uncomfortable feeling of pressure. In the case of periocular injections, the direction of the puncture should always be remote from the eye in order to minimize the risk of injury. Good lighting helps to avoid damaging the smallest vessels during injection and thus prevent monocular hematoma. Cooling the eye area before injection reduces the risk of hematoma due to cold-induced vasoconstriction and reduces post-injection burning in sensitive patients.
During intramuscular injection, a control technique (sonography and/or electromyography [EMG]) should be used to verify that the injection needle has actually been placed in the correct muscle [12]. To derive muscle activity using EMG, it is sufficient to attach an alligator clip connected to an EMG device to the injection needle. Each technique has its advantages and disadvantages; the key is that the operator is familiar with it and can quickly and safely identify the muscles to be injected.
Writing cramp and musician’s cramp
Probably the greatest challenge for botulinum toxin therapy is function-specific dystonia (writer’s cramp/musician’s cramp). Here, above all, the exact analysis of the involved muscles is necessary, therefore it is recommended to observe the patient closely during the corresponding activity and preferably to film it. Especially in writer’s cramp, writing with the nondominant hand can cause dystonic movements in the dominant hand, even if it is not actively moved (mirror movements) [13]. These mirror movements are often diagnostically helpful. The dosage for function-specific dystonia should be very small, as too high a dosage can lead to hand function limitation.
Extremity dystonia in other neurological diseases.
Another field of application of botulinum toxin is extremity dystonia in the context of other neurological clinical pictures, e.g. big toe dystonia in Parkinson’s disease. This often has little response to dopaminergic medication, but can lead to pain and pressure sores from wearing tight shoes. Botulinum toxin injection into the extensor hallucis longus muscle often provides relief and allows patients to wear sturdy shoes again without pain. The stability of walking can also be favorably influenced by the treatment of big toe dystonia.
Use for spasticity
In spasticity, as occurs after damage to the pyramidal tract, for example after stroke, in the context of an inflammatory CNS disease such as multiple sclerosis or encephalitis, or after perinatal cerebral damage, there is pathological overactivation of the limb muscles. On the arms, the flexors are most commonly affected; on the lower extremities, extensor and supination spasticity is common, with overactivation of the posterior tibialis and gastrocnemius muscles. Here, the use of botulinum toxin can relieve pain and restore physiological movement by reducing pathologically increased muscle activity. The early use of botulinum toxin can prevent contractures, incorrect strain and joint damage.
In children with cerebral palsy, the early use of botulinum toxin facilitates the learning of physiological motor skills. In stroke and MS patients, early reduction (already immediately after onset) of spasticity by botulinum toxin supports rapid recovery of physiological movement function. The use of botulinum toxin for spasticity is limited in Switzerland to cerebral palsy and spasticity after stroke, so that for other causes a cost approval must be requested from the health insurance company.
Unfortunately, most patients are referred for botulinum toxin therapy years after the onset of spasticity. By then, patients have often already acquired non-physiological movement patterns, and in some cases contractures including consequential damage have already developed.
A patient agreement is also recommended for patients with spasticity. To do this, it is important to know what is currently possible with the spastic limb and what botulinum toxin therapy is intended to improve (relieve pain, facilitate care options, improve function). Close cooperation with physiotherapists and occupational therapists is also very helpful in spasticity and can favorably influence the success of therapy.
Literature:
- Erbguth FJ, et al: Historical aspects of botulinum toxin: Justinus Kerner (1786-1862) and the “sausage poison”. Neurology 1999; 53: 1850.
- Scott AB, et al: Pharmacologic weakening of extraocular muscles. Invest Ophthalmol 1973; 12(12): 924-927.
- Scott AB, et al: Botulinum A toxin injection as a treatment for blepharospasm. Arch Ophthalmol 1985; 103(3): 347-350.
- Tsui JK, et al: A pilot study on the use of botulinum toxin in spasmodic torticollis. Can J Neurol Sci 1985; 12(4): 314-316.
- Albanese A, et al: Phenomenology and Classification of Dystonia: A Consensus Update. Mov Disord 2013; 28(7): 863-873.
- Marsden CD: Dystonia: the spectrum of the disease. Res Publ Assoc Res Nerv Ment Dis 1976; 55: 351-367.
- Grünewald RA, et al: Idiopathic focal dystonia: a disorder of muscle spindle afferent processing? Brain 1997; 120: 2179-2185.
- Williamson LC, et al: Clostridial neurotoxins and substrate proteolysis in intact neurons: botulinum neurotoxin C acts on synaptosomal-associated protein of 25 kDa. Biol Chem 1996; 271(13): 7694-7699.
- Kojovic M, et al: Botulinum toxin injections reduce associative plasticity in patients with primary dystonia. Mov Disord 2011; 26(7): 1282-1289.
- Albanese A, et al: Pretarsal injections of botulinum toxin improve blepharospasm in previously unresponsive patients. J Neurol Neurosurg Psychiatry 1996; 60(6): 693-694.
- Oertel WH, et al: Parkinson syndromes and other movement disorders. Thieme-Verlag 2012, 241-242.
- Hong JS, et al: Elimination of dysphagia using ultrasound guidance for botulinum toxin injections in cervical dystonia. Muscle Nerve 2012; 46(4): 535-539.
- Rana AQ, et al: Focal dystonia of right hand with mirror movements upon use of left arm. J Coll Physicians Surg Pak 2013; 23(5): 362-363.
InFo NEUROLOGY & PSYCHIATRY 2016; 14(5): 29-32.
