OTHER HYPERKINETIC MOVEMENT DISORDERS PART II

II. ABSTRACT

Hyperkinetic movement disorders may arise as isolated phenomena or be manifestations of a systemic disorder. The disorders discussed in this section present with diverse clinical findings, and vary in incidence from relatively common to extremely rare. There is only limited information available regarding the specific mechanisms underlying their development. This section will briefly describe the pertinent features of essential tremor, palatal tremor, tics, stiff-person syndrome, myoclonus, and isolated muscle spasm. An organized, methodical search for characteristic features of these disorders will facilitate an accurate clinical diagnosis and support identification of an appropriate treatment option. For some of these conditions, injection of botulinum toxin into involved muscles may be considered as an effective adjunct to standard medical therapies.

III. ESSENTIAL TREMOR

a) Introduction

Tremor is an involuntary rhythmic, repetitive movement of a body part. It is usually described clinically by whether it occurs at rest or during action. Tremor may be further defined by other criteria relevant to research or epidemiological study, such as severity or periodicity.¹ The degree of disability associated with tremor depends upon the anatomical target (e.g., head, hands, lower extremities), the frequency of oscillation, and the distance traversed by the affected part during each cycle. Tremor may range from trivial motion unreported by an individual to coarse, rhythmic excursions causing profound social and functional impairment.

Essential tremor (ET) is the most common non–Parkinson’s disease tremor syndrome and one of the most common movement disorders encountered in clinical practice (Figure 1).^{1, 2}. Although once considered a “pure” (essential) tremor disorder, ET is in fact a progressive disorder that is often associated with functional disability and degraded quality of life, and it may confer an enhanced risk of cognitive deficits and personality change.^{3, 4}

Figure 1. Tremor syndrome classification, modified from Dueschl et al.¹ The three most common types of tremors are rest tremor, action-postural tremor, and action-kinetic tremor,⁵ with this last encompassing classical intention tremor. The hands are most frequently affected. Tremor elements are key components of several clinical syndromes, encompassing normal physiological states as well as severe, debilitating neurological disorders. Oscillation frequencies and provocative maneuvers of tremors in clinical tremor syndromes are depicted.¹

b) Epidemiology of ET

Crude estimates of the prevalence of ET have varied considerably across studies. Persons with the condition may not present for evaluation if the tremor is mild and functional disability is minimal. Clinical criteria for identifying ET have been inconsistent across studies, case definitions have not been uniform, reliance on questionnaires for subject selection is common, and differentiating mild forms of ET from exaggerated physiological tremor can be difficult. Importantly, the criteria for calling an apparent postural tremor either ET or exaggerated physiological tremor are not clinically established.⁶ Best current evidence from population-based studies that incorporate examination of all subjects by a neurologist indicate that the overall prevalence of ET is 4% to 5.6% among persons 40 years of age or older. The age of onset may range from early teenage years to late life. Prevalence rates increase with advancing age, and the disorder tends to be more common in the male population.^{5, 7, 8}

A family history of tremor is common in ET; reports in the literature range from 17% to 100% for cases of ET with a positive family history.⁶ Several chromosomal loci for susceptibility genes have been identified.⁹ The pattern of inheritance is thought to be autosomal dominant, and penetrance of the genetic tendency is believed to be high, with most cases phenotypically apparent by age 70. In cases where a genetic predisposition cannot be ascertained, it is likely that sporadic mutation or some other provocative factor is implicated.⁶

Environmental factors have long been suspect in the etiology of ET, although supporting literature is limited or preliminary. These factors include harmane (a β-carboline alkaloid found in high concentration in cooked meat), lead and pesticide exposure, possibly occupational exposure to manganese or organic solvents, and ethanol use.¹⁰ In classical ET presentations, alcohol use by patients temporarily lessens the amplitude of tremor. However, ethanol is a known cerebellar toxin, and it has been proposed that having ET might lead to increased ethanol consumption rather than the converse.¹⁰ Action-postural tremors may also be induced by drugs, such as valproic acid, lithium, and theophylline derivatives, or by metabolic disorders such as pulmonary or hepatic failure, although these are largely reversible and thought to be forms of exaggerated physiological tremor.⁵

c) Clinical Features of ET

The most common method for clinical classification of tremor assesses whether tremor is present at rest or with action.¹

• Rest tremor is defined as tremor that occurs in a body part that is not voluntarily activated and is supported against gravity (i.e., the body part is resting on a couch, bed, etc.).¹ An attribute of rest tremor is that its amplitude increases during mental stress (such as counting backwards) or when movements of other body parts are activated (such as walking). Rest tremor is the hallmark tremor of Parkinson’s disease and is mostly found in that condition, although it may be present in other extrapyramidal disorders
• Action tremor is any tremor produced by voluntary contraction of muscle. Action tremor encompasses three main subtypes: postural, isometric, and kinetic¹ 
  • Postural tremor is present when a body part is voluntarily maintained in a position against gravity
  • Isometric tremor is any tremor occurring with muscle contraction against a stationary object, such as while making a fist or squeezing an examiner’s finger
  • Kinetic tremor occurs during voluntary movements and includes two main subcategories:
    • Simple kinetic tremor occurs during movements that are not target directed, such as pronation/supination or flexion/extension of an extremity
    • Intention tremor is present when the amplitude of the tremor increases during visually guided movements toward a specific target. The tremor retains rhythmicity even as it increases during pursuit of the goal

ET most often presents as a visible action-postural tremor (range, 4-12 Hz), usually involving both forearms and hands during voluntary movements and provocative tests (Figure 2).³ The kinetic tremor of ET may have an intentional component.¹ Tremors of the head (“no-no”) and voice may be present. Patients with ET may also demonstrate abnormalities in tandem gait. The majority of those who present for medical attention will report some degree of disability with activities of daily living.³

Figure 2. Archimedean spirals drawn by individuals with (A) and without (B) essential tremor. Most ET patients presenting for medical attention report some degree of disability.³

d) Pathophysiology of ET

Muscle groups that exhibit tremor are believed to be responding to rhythmic motor commands generated from regions in the central nervous system undergoing spontaneous, sustained oscillation. Central oscillators may arise from individual neurons, from interactions of neuronal networks, or through some combination of both.¹¹ A key feature differentiating these autonomous central signal generators from reflex pathways is their relative isolation from sensory input.¹¹ The provocative agents or processes by which central oscillators in different central nervous system regions transform to pathological signal generation in human motor disease are not known.¹¹

e) Diagnosis of ET

Standardized diagnostic criteria for definite ET have been developed (Table 1).³  History and thorough physical exam will generally suffice for the diagnosis, so laboratory and advanced imaging or neurophysiological studies are not typically needed in most patients unless there is sufficient concern to exclude other conditions known to be associated with tremor (e.g., Wilson’s disease, thyroid conditions).³ Patients with tremor due to other disorders might display additional symptoms consistent with an alternative diagnosis. Specialist referral should be considered in all unclear or complicated cases.

Table 1. Clinical Diagnostic Criteria for Definite Essential Tremor3        

Care should be taken to prevent misdiagnosis of Parkinson’s disease in a patient with ET. Even though the differentiation of ET from Parkinson’s disease may initially appear straightforward, such as absence of bradykinesia and mask-like facies, the distinction can be challenging when a patient with classical postural-action tremor displays rest tremor, which is more likely to occur in patients who have had longstanding, severe disease.¹² Depending upon the clinical locale, an estimated 30% to 50% of patients with ET are initially misdiagnosed with Parkinson’s disease or other tremor disorder.^{13, 14} Dystonic tremor can also be difficult to distinguish from ET, particularly in regard to head tremor.

f) Treatment of ET

Pharmacological Treatment

Pharmacological treatment of ET should be initiated when tremor interferes with satisfactory performance of daily activities or becomes embarrassing to the patient. Pharmacological agents should be introduced in concert with a careful search for additional factors that may exacerbate tremor, such as concurrent medications (e.g., anticholinergics, antihistamines, bronchodilators),³ or potentially tremorigenic lifestyle behaviors (e.g., stress, excessive caffeine use).² Patients should be cautioned against recourse to regular alcohol use to mitigate the amplitude of their tremors.²

Table 2. Treatments of Essential Tremor¹⁵  

Drug	Grade	Studies	Subjects	Dosage	Adverse Events	Benefits
Primidone	A	12	218	250-750 mg/d	Mild-moderate (sedation, drowsiness, fatigue, nausea, giddiness, vomiting, ataxia, malaise, dizziness, unsteadiness, confusion, vertigo, acute toxic reaction). Lower doses are associated with fewer side effects, and may provide clinical benefits equal or superior to higher doses16	50% mean improvement by CRS and accelerometry
Propranolol	A	32	533	60-800 mg/d	Mild to moderate (reduced arterial pressure, reduced pulse rate, tachycardia, bradycardia, impotency, drowsiness, exertional dyspnea, confusion, headache, dizziness)	50% mean improvement by CRS and accelerometry
Propranolol LA (Inderal LA)	A	2	33	80-320 mg/d	Mild (skin eruption, transient dizziness)	30%-38% improvement by accelerometry
Alprazolam	B	2	46	0.125-3 mg/d	Mild (fatigue, sedation; potential for abuse)	25%-34% mean improvement in CRS compared with baseline
Atenolol	B	5	79	50-150 mg/d	Mild-moderate (lightheadedness, nausea, cough, dry mouth, sleepiness)	25% mean improvement by CRS and 37% mean improvement by accelerometry compared with baseline
Gabapentin	B	3	61	1200-1800 mg/d	Mild (lethargy, fatigue, decreased libido, dizziness, nervousness, shortness of breath)	77% improvement by accelerometry and 33% improvement by CRS compared with baseline
Sotalol	B	3	50	75-200 mg/d	Mild (decreased alertness)	28% mean improvement by CRS compared with baseline
Topiramate	B	5	335	Up to 400 mg/d	Mild (appetite suppression, weight loss, paresthesias, anorexia, concentration difficulties)	22%-37% mean improvement in CRS compared with baseline
Clonazepam	C	3	44	0.5-6 mg/d	Mild-moderate drowsiness	71% mean improvement by accelerometry and 26%-57% improvement in CRS compared with baseline
Clozapine	C	2	27	6-75 mg/d	Mild (sedation); severe (potential agranulocytosis)	45% mean improvement by accelerometry
Nadolol	C	1	10	120-240 mg/d	None	60 to 70% improvement by accelerometry in patients who had previously responded to propranolol
Nimodipine	C	1	16	120 mg/d	Mild (headache, heartburn)	53% improvement by accelerometry and 45% improvement in CRS compared with baseline
BoNT-A (hand tremor)	C	6	206	50-100 U/arm	Moderate (hand and finger weakness, reduced grip strength, pain at injection site, stiffness, cramping, hematoma, paresthesias)	20% Improvement in CRS for low- and high-dose BoNT-A for postural tremor at 6, 12, and 16 weeks, and 27% improvement in kinetic tremor at 6 weeks (only significant scores listed)
BoNT-A (head tremor)	C	3	53	40-400 U	Mild-moderate (neck weakness, post-injection pain)	67% improvement by accelerometry, moderate to marked improvement by CRS, but did not differ from placebo
BoNT-A (voice tremor)	C	3	25	0.6-15 U	Mild-moderate (breathiness, weak voice, swallowing difficulty)	22% improvement with unilateral injection, 30% with bilateral injection, 67% improvement in self-report

*CRS = Clinical Rating Scale, as follows: A: Established as effective, ineffective, or harmful for the given condition in the specified population. (Level A rating requires at least two consistent Class I studies.) B: Probably effective, ineffective, or harmful for the given condition in the specified population. (Level B rating requires at least one Class I study or at least two consistent Class II studies.) C: Possibly effective, ineffective, or harmful for the given condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class III studies.) U: Data inadequate or conflicting given current knowledge, treatment is unproven.
* *Adverse events severity: mild = somewhat bothersome, moderate = very bothersome, severe = potentially harmful to patients.

A large proportion of patients with ET will not demonstrate benefit from multiple oral drugs, and factors determining response have not been identified. Many patients who do respond to drugs benefit partly, and complete abatement of tremor is rarely achieved. Oral medications are generally less effective for treating tremor of the head and neck.¹² 

Therapies for ET have been recently reviewed by an expert subcommittee of the American Academy of Neurology (Table 2).¹⁵(LINK: Table_ETtxRegimens ) Although no optimal oral agent or combination of agents has been identified in prospective studies, the most effective oral drugs at present for the treatment of ET are propranolol, a β-adrenergic blocker, and primidone, an anticonvulsant. Both have similar efficacy when used as initial therapy to manage limb tremor,¹⁵ and both are mainstays of ET management. Other oral medications have been used with variable efficacy. Alprazolam, atenolol, gabapentin, sotalol, and topiramate are probably effective in reducing limb tremor, and clonazepam, clozapine, nadolol, and nimodipine are possibly effective. An important concern with benzodiazepines as a treatment for ET is that their antitremor effect may require a dose that is associated with sedation or cognitive slowing.¹²

Surgical Treatment

Surgery should be limited to patients with intractable, disabling ET that does not respond to accepted pharmacological regimens. Unilateral thalamotomy can effectively treat contralateral limb tremor and may be used for medically refractory cases. As many as 47% of patients treated with unilateral thalamotomy experience adverse events, such as hemiparesis, dysarthria, verbal or cognitive deficit, weakness, and facial paresis. Bilateral thalamotomy is no longer performed.¹⁵ Deep brain stimulation (either unilateral or bilateral) of the ventral intermediate nucleus of the thalamus is another surgical option that has been shown to be effective for reduction of limb tremor; data are insufficient to guide recommendations for head or voice tremor.¹⁵

Role of Botulinum Neurotoxin

Intramuscular injections of BoNT can reduce tremor. Studies have shown variable improvement in function, as moderate hand and finger weakness is a common side effect.

In a clinical study, injection of onabotulinumtoxinA into wrist and finger flexors provided a substantial decrease in the amplitude of hand tremor for as long as 16 weeks. In a placebo-controlled trial of 133 patients with hand tremor ranging from probably not disabling to disabling were randomized to chemodenervation with low-dose (50 U) or high-dose (100 U) onabotulinumtoxinA, both doses were associated with significant reductions in postural tremor at 6, 12, and 16 weeks, but with reductions in kinetic tremor only at week 6. Compared with placebo, high-dose treatment significantly improved feeding and hygiene at 6 weeks; drinking at 6, 12, and 16 weeks; pouring and writing at 16 weeks; and fine movements at 6, 12, and 16 weeks. Grip strength was reduced in both onabotulinumtoxinA-treated groups. Adverse reactions consisted mainly of dose-dependent hand weakness.¹⁷

Intramuscular injections of BoNT can be effective for management of head and neck tremor.¹² In an open-label study of 43 patients with head tremor syndromes (cervical dystonia [CD], n=29; other head tremor [HT], n=14) all HT patients and 26 of 29 CD patients responded subjectively and objectively (per accelerometry) to abobotulinumtoxinA injections (administered into 2-4 neck sites for CD patients and bilaterally for all others). Pain reduction following treatment was significant in both groups. Mean response latency was 7 days for HT individuals, and mean duration of improvement was 8.5 weeks. Comparable proportions of patients experienced mild and transient side effects (local pain at the injection site, neck weakness, and dysphagia).¹⁸

REFERENCES

1. 1. Deuschl G, Bain P, Brin M. Consensus statement of the Movement Disorder Society on Tremor. Ad Hoc Scientific Committee. Mov Disord 1998;13 Suppl 3: 2-23.
2. 2.Jankovic J. Treatment of hyperkinetic movement disorders. Lancet Neurol 2009;8(9): 844-56.
3. 3. Benito-Leon J, Louis ED. Essential tremor: emerging views of a common disorder. Nat Clin Pract Neurol 2006;2(12): 666-78; quiz 2p following 91.
4. 4. Lorenz D, Schwieger D, Moises H, Deuschl G. Quality of life and personality in essential tremor patients. Mov Disord 2006;21(8): 1114-8.
5. 5. Kumar N, Greenlund A. Tremor and other involuntary movements. Available from URL: http: //www.aan.com/go/education/curricula/internal/chapter9 [accessed August 29, 2010].
6. 6. Brin MF, Koller W. Epidemiology and genetics of essential tremor. Mov Disord 1998;13 Suppl 3: 55-63.
7. 7. Dogu O, Sevim S, Camdeviren H, et al. Prevalence of essential tremor: door-to-door neurologic exams in Mersin Province, Turkey. Neurology 2003;61(12): 1804-6.
8. 8. Rautakorpi I, Takala J, Marttila RJ, Sievers K, Rinne UK. Essential tremor in a Finnish population. Acta Neurol Scand 1982;66(1): 58-67.
9. 9. Deng H, Le W, Jankovic J. Genetics of essential tremor. Brain 2007;130(Pt 6): 1456-64.
10. 10. Louis ED. Environmental epidemiology of essential tremor. Neuroepidemiology 2008;31(3): 139-49.
11. 11. Hallett M. Overview of human tremor physiology. Mov Disord 1998;13 Suppl 3: 43-8.
12. 12. Louis ED. Essential tremor. Lancet Neurol 2005;4(2): 100-10.
13. 13. Benito-Leon J, Louis ED. Clinical update: diagnosis and treatment of essential tremor. Lancet 2007;369(9568): 1152-4.
14. 14. Meara J, Bhowmick BK, Hobson P. Accuracy of diagnosis in patients with presumed Parkinson's disease. Age Ageing 1999;28(2): 99-102.
15. 15. Zesiewicz TA, Elble R, Louis ED, et al. Practice parameter: therapies for essential tremor: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2005;64(12): 2008-20.
16. 16. Serrano-Duenas M. Use of primidone in low doses (250 mg/day) versus high doses (750 mg/day) in the management of essential tremor. Double-blind comparative study with one-year follow-up. Parkinsonism Relat Disord 2003;10(1): 29-33.
17. 17. Brin MF, Lyons KE, Doucette J, et al. A randomized, double masked, controlled trial of botulinum toxin type A in essential hand tremor. Neurology 2001;56(11): 1523-8.
18. 18. Wissel J, Masuhr F, Schelosky L, Ebersbach G, Poewe W. Quantitative assessment of botulinum toxin treatment in 43 patients with head tremor. Mov Disord 1997;12(5): 722-6.

IV.PALATAL TREMOR

a) Introduction

Palatal tremor (PT), often also referred to as palatal myoclonus, is an unusual tremor syndrome characterized by brief, rhythmic, involuntary movements of the soft palate. PT occurs in two forms—symptomatic and essential—that differ in terms of their associated findings and target palatal muscle.¹

Symptomatic Palatal Tremor (SPT)

SPT occurs almost exclusively in adults,² arising in association with a lesion of the brainstem or cerebellum and an essential finding of hypertrophic degeneration of the inferior olive. The observed tremor is due mainly to movements of one of the muscles of the soft palate, the levator palatini, which is innervated by cranial nerves VII and IX. Symptomatic PT is often associated with other deficits, such as diplopia, hemiplegia, and cerebellar signs, that are attributable to involvement of other muscles innervated by the brainstem, as well as extremity muscle involvement consistent with a cerebellar lesion.¹

Essential Palatal Tremor(EPT)

EPT arises in the absence of any central lesion or olivary hypertrophy. This form is reported in children as well as adults. The tremor is due mainly to involvement of the tensor veli palatini muscle (which is innervated by cranial nerve V), which, in addition to causing rhythmic movements of the soft palate, yields a distinctive ear click due to its attachment to the eustachian tube. There is no associated involvement of extremity or bulbar musculature.²

b) Epidemiology of Palatal Tremor

PT is a very rare movement disorder, and only limited information regarding its prevalence and demographics is known. In a recent small series of children with EPT, the age of onset was between 6 and 7 years (consistent with historical reports), and the majority of children were boys.² Another review of 103 cases, including pre-1900 reports, concluded that the male:female ratio for EPT is 1:1, with an age of onset ranging from 4 to 74 years. No specific concurrent features or predisposing elements were identified.³ The prevalence of SPT is unknown.

 c) Pathophysiology of Palatal Tremor

The etiology of EPT and SPT is a matter of debate. The site of the abnormality in EPT is unknown: patients have normal cerebellar function, and magnetic resonance imaging (MRI) shows no evidence of structural abnormalities.⁴ SPT is believed to arise from a lesion of the brainstem or cerebellum. Patients with SPT have clinical signs of cerebellar dysfunction and abnormalities of monosynaptic, oligosynaptic and polysynaptic brainstem reflexes. MRI in these cases reveals hyperdense signaling of the ventral upper medulla in the region of the inferior olive.⁴

Figure 3.Symptomatic palatal tremor (SPT) and hypertrophic degeneration of the inferior olive. Axial sections of the brainstem and cerebellum in a patient with palatal tremor and multiple neurological deficits (SPT). These sections demonstrate hypertrophic degeneration of the olive, seen as a hyperintense, oval structure on the right side of the medulla. The hypertrophied inferior olive is proposed to be the pacemaker of tremor in this form of the syndrome. No hypertrophic degeneration is demonstrated for EPT. Reprinted from Deuschl.¹ Permission pending.

The hypertrophied olive has been proposed to function as a central generator or pacemaker in SPT, with persistent neuronal oscillation linking to the palatal muscle following the destruction of inhibitory cerebello-olivary tracts (Figure 3).⁵ The question of whether a central generator is implicated in the pathogenesis of EPT—or whether a single generator is involved—remains to be answered, but the final pathway must differ between the two conditions because the muscles involved are innervated by different nerves.⁴

d) Diagnosis of Palatal Tremor

Palatal movements rarely bring a patient to medical attention. The rhythmic movements of the soft palate in SPT will be discovered during examination of neurologically impaired patients who present with a spectrum of associated clinical findings, including nystagmus or other sign of bulbar involvement, ataxia, and hemiparesis, which are consistent with a predisposing neurological lesion.

Figure 4. Ear EPT: Relationship of palatal muscles and eustachian tube. Coronal section of human fetal head taken through the velum at the plane of the eustachian tube opening into the pharynx (1). The eustachian tube (2) is one tether of the tensor veli palatini (3), which is the muscle involved in essential palatal tremor. A defining characteristic of EPT is an audible click in the ear, heard not only by the patient but by the examiner. The click is thought to arise through rapid changes in surface tension across the eustachian tube consequent to repetitive contraction of the muscle. Other features depicted here include (4) lumen of nasopharynx, (5) velum of the palate, (6) levator veli palatini, and (7) oral cavity. Reprinted from Dickson.⁶ Permission pending.

Ear clicks are found in patients with EPT but not SPT (Figure 4).^{6, 7} These may be the only complaint, may be profoundly disabling, and are frequently audible to others. At the least, the clicks may be described as ticking, banging, popping, or crunching and can be distressing enough to provoke suicide attempts.³

The observed tremor in EPT is typically bilateral because of the existence of a small aponeurosis connecting the tensor muscle to palatal hamuli on both sides. SPT in theory may manifest as unilateral tremor if the amplitude of ipsilateral muscle contraction is sufficiently high. In series, however, all patients have bilateral tremor regardless of the syndrome, as mechanical factors related to insertions and fibrous connections override neuroinnervation.⁷ As a practical matter, laterality of the tremor is not crucial to formulating a diagnosis given other differentiating features.

No specific diagnostic tests have been developed for palatal tremor. Advanced imaging for EPT is not necessary, whereas imaging for SPT should reveal stigmata of the lesion and hypertrophic degeneration of the olive.

e) Treatment of Palatal Tremor

Pharmacological Treatment

Treatment is usually based on anticonvulsants and sedatives. No medication has proven reliably effective.

Surgical Treatment

No reliable surgical intervention has been identified.⁸

Role of Botulinum Neurotoxin

BoNT serotypes A and B (BoNT-A and BoNT-B) have been used successfully in the treatment of EPT, with much of this success noted in case reports lacking long-term follow-up. However, notable studies enrolling series of patients have emerged that clearly demonstrate effective and safe treatment of both EPT and SPT with the BoNT-A formulations onabotulinumtoxinA and abobotulinumtoxinA and the BoNT-B formulation rimabotulinumtoxinB.

In one of the largest single EPT series reported in the literature, abobotulinumtoxinA treatment was offered to adult patients presenting with audible ear clicks and PT. No intrinsic neuropathology was discovered on examination or MRI. Of 10 patients offered abobotulinumtoxinA treatment, five accepted. The five patients who declined treatment remained available to follow-up. Treatment was initiated with 5 to15 units of abobotulinumtoxinA to the affected side, with the larger doses providing greater symptom control. One patient reported complete resolution after the first injection, and three others reported complete resolution after the second injection. One patient reported only moderate symptomatic improvement. The duration of resolution in patients with complete responses varied from 2 to 6 months. One patient reported transient side effects of difficulty swallowing, change in voice quality, and velopharyngeal insufficiency.⁸ No cases of spontaneous resolution were reported among patients who declined intervention.

In another series evaluating differences in BoNT (mostly abobotulinumtoxinA, but one patient received an initial injection of onabotulinumtoxinA), treatment outcome in three adults and two children with EPT, four of five subjects (including both children) demonstrated full resolution of symptoms 2-5 days postinjection and one patient reported a partial response. A total of 11 injections were performed. The duration of response in adult patients was between 4 and 32 weeks (mean, 20 weeks). The response in children included that of a 10-year-old girl who demonstrated complete resolution within 3 days of the first injection with no recurrence through almost 4 years of follow-up. (This, of course, might indicate that the disorder was psychogenic.) The second child, age 6, was symptom free for 24 weeks following the first injection; after recurrence and a second injection, he had been symptom free for nearly 2 years at the time the report was published. Adverse events in the group were mild and transient.⁹ A notable aspect of this report is the inclusion of a 6-year-old child; as of 2008, the youngest child documented to receive BoNT had been 8 years old, and that child experienced severe, complete palatal palsy following a second injection with a possibly excessive dose. He required hospitalization and nasogastric feeding for 3 weeks before recovering completely.¹⁰ Dosages of BoNT may need to be reduced in repeat-dose scenarios; this issue requires further study.

REFERENCES

1. 1. Deuschl G, Bain P, Brin M. Consensus statement of the Movement Disorder Society on Tremor. Ad Hoc Scientific Committee. Mov Disord 1998;13 Suppl 3: 2-23.
2. 2. Campistol-Plana J, Majumdar A, Fernandez-Alvarez E. Palatal tremor in childhood: clinical and therapeutic considerations. Dev Med Child Neurol 2006;48(12): 982-4.
3. 3. Zadikoff C, Lang AE, Klein C. The 'essentials' of essential palatal tremor: a reappraisal of the nosology. Brain 2006;129(Pt 4): 832-40.
4. 4. Deuschl G, Toro C, Valls-Sole J, Zeffiro T, Zee DS, Hallett M. Symptomatic and essential palatal tremor. 1. Clinical, physiological and MRI analysis. Brain 1994;117 ( Pt 4): 775-88.
5. 5. Deuschl G, Jost S, Schumacher M. Symptomatic palatal tremor is associated with signs of cerebellar dysfunction. J Neurol 1996;243(7): 553-6.
6. 6. Dickson DR. Normal and cleft palate anatomy. Cleft Palate J 1972;9: 280-93.
7. 7. Deuschl G, Toro C, Hallett M. Symptomatic and essential palatal tremor. 2. Differences of palatal movements. Mov Disord 1994;9(6): 676-8.
8. 8. Penney SE, Bruce IA, Saeed SR. Botulinum toxin is effective and safe for palatal tremor: a report of five cases and a review of the literature. J Neurol 2006;253(7): 857-60.
9. 9. Krause E, Heinen F, Gurkov R. Difference in outcome of botulinum toxin treatment of essential palatal tremor in children and adults. Am J Otolaryngol 2010;31(2): 91-5.
10. 10. Pal PK, Lakshmi PS, Nirmala M. Efficacy and complication of botulinum toxin injection in palatal myoclonus: experience from a patient. Mov Disord 2007;22(10): 1484-6.

V. TICS

a) Introduction

Tics are a subset of hyperkinetic movements that manifest as rapid, nonrhythmic, stereotyped motor or vocal behaviors.¹ Tics may be simple or complex, are characteristically of short duration, and are variable in intensity. Whether simple or complex, tics are unpredictable and recurrent, emerging at irregular intervals. Characteristically, tics tend to appear in response to an irresistible, premonitory urge that is relieved by execution of the behavior.^{1, 2} Tics may be suppressed for a variable period of time; however, when tics are suppressed, inner distress mounts and is only alleviated by an increased burst of more tics.¹

Motor tics are spontaneous and purposeless movements.³ Simple motor tics usually present as modest, transient clonic phenomena, such as a shoulder shrug, head jerks, blinking, or other motion of an isolated body part; if infrequent, these displays may be misinterpreted as normal volitional behavior. Complex motor tics are well-coordinated, patterned movements that may be vigorous, violent, grotesque, or bizarre, such as twiddling of hair, face wiping, head shaking, jumping, kicking, hitting, squatting, inappropriate touching or kissing, and obscene gesturing.^{1, 3} Tics may occasionally be executed languidly, leading to brief, sustained alterations of body posture (dystonic tics) or prolonged isometric contraction of a muscle group, such as the musculature of the abdominal wall (tonic tics).^{2, 4}

Vocal tics range from simple throat clearing, sniffing, hissing, grunting, or coughing to uncontrollable shouting of words or phrases, including rude, obscene, or scatological words.¹ Some authorities prefer the term phonic tic, because not all audible tics are verbal. In addition, they stress that the division between motor and vocal tics is somewhat arbitrary because phonic tics arise from hyperkinetic behavior of the respiratory, laryngeal, oropharyngeal, and nasal musculature.⁴

b) Epidemiology of Tics

Table 3. Primary and Secondary Causes of Tic²

Primary Causes	Transient motor or phonic tics (for <1 year)
	Chronic motor or phonic tics (for >1 year)
	Adult-onset tics
	Tourette’s Syndrome
	Primary dystonia
	Inherited tic disorders Huntington’s disease Neuroacanthocytosis Hallervorden–Spatz disease or neurodegeneration with brain iron accumulation type 1 Tuberous sclerosis Wilson’s disease
Secondary Causes	Infections
	Encephalitis
	Creutzfeldt-Jakob disease
	Neurosyphilis
	Sydenham’s chorea
	Drugs Amphetamines Methylphenidate Pemoline Levodopa Cocaine Carbamazepine Phenytoin Phenobarbital Lamotrigine Antipsychotics Other dopamine-receptor–blocking drugs
	Toxins, eg, carbon monoxide
	Developmental problems Mental retardation Chromosomal abnormalities Autistic-spectrum disorders
	Chromosomal disorders
	Other Head trauma Stroke Neurocutaneous syndromes Schizophrenia Neurodegenerative diseases

Note: Manifestations of tic disorders may wax and wane over time; consequently, the diagnosis of a primary tic disorder may require prolonged surveillance period.

Tics are not rare. They are expressed across a wide range of primary and secondary conditions (Table 3).² Estimations of prevalence are difficult because tics vary in manifestations, wax and wane in intensity, and may remit with growth and development. Best available evidence suggests a prevalence of tic disorder (usually referring to motor tics) of 7% to 28%, with much of the variability attributed to such factors as methodology and patient age and sex.⁵ A study of young schoolchildren found that approximately 0.8 % of this population experience chronic motor tics, 0.5% demonstrate chronic vocal tics, and approximately 4.8% experience transient tics.^{6, 7} In contrast, the prevalence of tic was <1% in a population of community-dwelling adults aged 50 to 89 years, with approximately one fifth of all observed movement disorders attributed to concurrent medication use.⁸ In general, tics are more prevalent in certain populations: children requiring special education, children and adolescents with autistic spectrum disorders, and individuals with behavioral problems, and subjects with learning difficulties.^{5, 7, 9, 10} Adult-onset tic disorders are under-recognized,⁵ and tics arising de novo in adults are frequently secondary to acquired conditions such as trauma, drugs, and toxins.⁴ Adult-onset tic disorders are more often associated with severe symptoms, greater social morbidity, a potential trigger event, and a less satisfactory response to therapy.¹¹

Tourette syndrome (TS; also called Tourette disorder) is the most well-known and best described primary tic disorder. The disorder appears to be hereditary for most patients and manifests with a wide array of motor and phonic tics. TS is the most common cause of chronic tics, with an overall worldwide prevalence of 1%.^{3, 5} As with other tic disorders, the prevalence of TS rises markedly in special education populations, healthcare-facility and group-home residents, and specialty-referral practices. TS arises in childhood, affecting male subjects approximately three times as frequently as female subjects.² Tics usually present between 3 and 8 years of age, and more than 96% of patients with TS are identified by age 11 years.² TS is closely associated with a psychiatric comorbidity, such as attention-deficit and obsessive-compulsive disorders (OCDs).² Obsessive-compulsive behaviors occur in about 20% to 60% of patients with TS, with some studies reporting them in up to 89%.¹² Although TS appears to have a strong hereditary predisposition, the search for specific genes has been unrewarding.

c) Pathophysiology of Tics

Although there is consensus that tics have an organic rather than psychogenic basis, the precise pathophysiological locations involved in their generation remain speculative. It is currently theorized that cortico-striatal-thalamocortical pathways are involved in the expression of TS and its accompanying neuropsychiatric comorbidities.¹²  Potential abnormalities include imbalance of excitation and inhibition; anatomical or chemical disruptions impeding signaling in the frontal cortex and striatum; and abnormalities of various neurotransmitters, with studies mostly focused on dopaminergic changes in the striatum and prefrontal regions.^{2, 12} Tics may arise from an aberrant limbic influence on the motor system.¹³

Many children with TS exhibit executive dysfunction, supporting a role for impaired cortical regulatory input.¹² An impaired capacity for self-regulatory control that derives from anomalous frontostriatal circuits may provide linkage between tic disorders and their psychiatric accompaniments (Figure 5).¹⁴ (LINK: TS and psych association) The abnormal paths potentially interact with normally occurring somatic sensations and motor urges, intrusive thoughts, sensations of hunger, and preoccupation with body shape and weight to contribute to, respectively, the development of the tics of Tourette syndrome (TS), the obsessions of OCD, the binge eating of bulimia, and the self-starvation of anorexia.¹⁴

Figure 5. Theoretical scheme linking dysregulated frontostriatal systems in Tourette syndrome with selected psychiatric disorders. The top row represents urges, thoughts, and drives that are present in both healthy and patient populations. An impaired capacity for self-regulatory control interacts with these normal urges, thoughts, and drives to produce egodystonic symptoms or behaviors (middle row). Attempts to relieve the anxiety associated with these symptoms or to compensate for these behaviors produce further behavioral abnormalities (bottom row). TS is frequently associated with obsessive-compulsive disorder (OCD). A high prevalence of OCD or obsessive-compulsive personality traits is seen in anorexia and bulimia, suggesting a shared neural substrate.¹⁴ 

d) Diagnosis of Tics

Tics are distinguished by their stereotypic quality, suppressibility, and associated urge.¹ Most primary tics are mild, transient, and present for less than 12 months.¹² Those that do not meet those criteria are likely to be part of the spectrum of TS or some other disorder. Because tic manifestations may fluctuate widely over time or become quiescent with growth and maturity, determining which tics are harbingers of a chronic tic disorder and which will be shown with the passage of time to have been transient phenomena can be challenging for the physician and stressful for patients and families. For that reason most diagnoses of TS are retrospective: given the absence of definitive biomarkers, imaging, or other findings pathognomonic for TS, there is no way to predict whether tics will resolve within months, become multiple, or become chronic.¹² Familiarity with the range of conditions, pharmacological therapies, or syndromes of toxicity presented in Table 3 may suggest an etiology for tics or stimulate a careful assessment for motor and phonic tics executed as part of the secondary disease process.

The American Psychiatric Association has published diagnostic criteria for TS (Table 4) and other chronic or transient tic disorders (Table 5).¹⁵ The central characteristic of TS is the combination of simple and complex motor and vocal tics manifesting in childhood or adolescence. Typically, symptoms wax and wane, increase with stress, and rebound after suppression. It is important to note that hyperkinetic movements executed by patients with TS may be misdiagnosed as tics, when they are in fact movements related either to conditions commonly associated with TS (such as OCD or attention deficit hyperactivity disorder), or represent treatment-emergent movements, such as akathisia and tardive dystonia, related to medications administered for TS or a comorbid condition.¹⁶ 

Table 4. Diagnostic Criteria for Tourette Syndrome (307.23)¹⁵

A. Both multiple motor and one or more vocal tics have been present at some time during the illness, although not necessarily concurrently.

B. The tics occur many times a day (usually in bouts) nearly every day or intermittently throughout a period of more than 1 year, and during this time  there was never a tic-free period of more than 3 consecutive months

C. The onset is before age 18 years.

D. The disturbance is not due to the direct physiological effects of a substance (e.g., stimulants) or a general medical condition (e.g., Huntington’s disease or postviral encephalitis

Reprinted from the Diagnostic and Statistical Manual of Mental Disorders, 4th ed, Text Revision. American Psychiatric Association, 2000. Permission pending.

Table 5. Criteria for Chronic and Transient Tic Disorders¹⁵

Chronic Motor or Vocal Tic Disorder

A. Single or multiple motor or vocal tics, but not both, have been present at some time during the illness

B. The tics occur many times a day, nearly every day, or intermittently throughout a period of more than 1 year, and during this period there was never a tic-free period of more than 3 consecutive months.

C. The onset is before age 18 years

D. The disturbance is not due to the direct physiological effects of a substance (e.g., stimulants) or a general medical condition (e.g., Huntington’s disease or postviral; encephalitits).

E. Criteria have never been met for Tourette’s Disorder.

Transient Tic Disorder

A. Single or multiple motor and/or vocal tics

B. The tics occur many times a day, nearly every day for at least 4 weeks, but for no longer than 12 consecutive months

C. The onset is before age 18 years.

D. The disturbance is not due to the direct physiological effects of a substance (e.g., stimulants) or a general medical condition (e.g., Huntington’s disease or postviral encephalitis).

E. Criteria have never been met for Tourette’s Disorder or Chronic Motor or Vocal Tic Disorder.

Reprinted from the Diagnostic and Statistical Manual of Mental Disorders, 4th ed, Text Revision/ © 2000, American Psychiatric Association. Permission pending.

e) Treatment of Tics

Tic-suppressing therapy should be considered for those patients whose tics are causing clear psychosocial distress (peer problems, academic or work difficulties, or family and social disruption) or musculoskeletal problems (injury or chronic pain). The presence of one or more tics is not sufficient indication for tic-suppressive therapy in the absence of compelling evidence supporting social or functional disability.

There is no cure for tics, nor should medications be given with a goal of abating tic behavior completely; the objective is to reduce tic executions sufficiently to improve psychosocial function. Care should be taken to consider the waxing and waning temporal pattern of tics as it informs decisions about when to initiate or change medications and when to provide only close monitoring: beginning or changing a treatment regimen at the end of a waxing period yields only an illusion of improvement regardless of the inherent efficacy of the intervention.¹⁷ The most troublesome symptoms should be targeted initially, administering medications at low doses, titrating gradually, and giving each medication and dosage regimen an adequate trial.¹⁸ Behavioral therapy includes habit-reversal training, conditioning models, and massed practice. It may be beneficial as monotherapy for patients with mild symptoms, but lack of continued compliance is a significant limitation. Behavioral therapy may also be used ancillary to pharmacological treatment.^{18, 19}

Pharmacological Treatment

Neuroleptics appear to be the most effective agent for tic suppression, but because of their potential for serious adverse effects, they are often used after trials of alpha-2 agonists.²⁰ Neuroleptics include dopamine receptor-blocking drugs and monoamine-depleting drugs such as fluphenazine, risperidone, and tetrabenazine.  Atypical neuroleptics—such as aripiprazole, clozapine, olanzapine, quetiapine, and ziprasidone—are not established as effective and are associated with prolonged QT interval as well as side effects associated with some of the classic neuroleptics, such as tardive dyskinesia.¹⁸ There is a lack of rigorously designed trials of clonazepam, flutamide, ondansetron, baclofen, donepezil, nicotine, and cannabinoids.¹⁸

The alpha-2 agonists clonidine and guanfacine are useful agents for treatment of tics in patients with comorbid attention deficit hyperactivity disorder. Guanfacine may cause less sedation and rebound hypertension than clonidine. Both agents may cause hypotension, and syncope has been reported in children receiving guanfacine.²⁰

Surgical Treatment

Surgical treatment is an effective intervention in patients with severely disabling or frankly injurious TS, but should only be undertaken when all medical therapy fails. There is increasing evidence that deep brain stimulation that targets specific brain regions, including the thalamus and globus pallidus, effectively treats uncontrollable and life-threatening motor tics.¹⁸ Benefits have been sustained for more than 12 months, although most patients require ongoing tic-suppressive medication. Complications include intracranial bleeding, altered libido, fatigue, weight loss, and psychosis.¹⁹

Behavioral Treatment

Biofeedback, relaxation methods, and other behavioral techniques may be helpful in alleviating stress that potentially aggravates tics. Individualized academic, vocational, social, or other supportive services may also prove beneficial.

Role of Botulinum Neurotoxin

Local injection of BoNT may be considered when one or a few tics become a significant source of distress.¹⁹ In a randomized, double-blind, placebo-controlled clinical trial enrolling 20 patients, injections of onabotulinumtoxinA reduced abnormal tic executions by a median value of 39% from baseline versus a 5.8% increase with placebo. Observations were based on videotape review by a blinded observer. The predominant tic treated in this study was blink (8 of 21 tic instances; patients could have more than 1 tic treated). OnabotulinumtoxinA reduced tic frequency as well as the premonitory urge associated with execution. Weakness of the injected muscle was noted by 50% of subjects, but none of the patients found it to be functionally disabling.²¹

In a nonrandomized, open-label study, onabotulinumtoxinA injections administered to 10 male patients 13 to 53 years of age provided moderate to marked improvement of a range of tics, including frequent blinking, severe blepharospasm, and severe dystonic tics targeting the neck; premonitory urges were also abated. All patients obtained at least partial benefit, usually within 2 to 7 days of injection, and benefits were observed for a period of 2 to 20 weeks (reflecting a total of 29 treatment sessions) One patient experienced remission of all tic behavior for 18 months after the last study injection .²²

OnabotulinumtoxinA treatment was associated with a mean duration of benefit of 14.4 weeks (with a maximum instance of 45 weeks) in an open-label trial enrolling 35 patients. Tics in this study were mainly localized to the cervical area, upper thoracic area, and upper face. The mean latency to benefit was 3.8 days.²³

Finally, several authors have evaluated botulinum toxin for the treatment of refractory vocal tics. All were case reports that demonstrated prompt onset of benefit.^24-26

It is fair to say that the data for BoNT therapy about tic, overall, is rather limited, and that it is not widely used. 

REFERENCES

1. 1. Kumar N, Greenlund A. Tremor and other involuntary movements. Available from URL: http: //www.aan.com/go/education/curricula/internal/chapter9 [accessed August 29, 2010].
2. 2. Jankovic J. Tourette's syndrome. N Engl J Med 2001;345(16): 1184-92.
3. 3. Jankovic J, Fahn S. The phenomenology of tics. Mov Disord 1986;1(1): 17-26.
4. 4. Jankovic J. Tourette syndrome. Phenomenology and classification of tics. Neurol Clin 1997;15(2): 267-75.
5. 5. Robertson MM. The prevalence and epidemiology of Gilles de la Tourette syndrome. Part 1: the epidemiological and prevalence studies. J Psychosom Res 2008;65(5): 461-72.
6. 6. Khalifa N, von Knorring AL. Prevalence of tic disorders and Tourette syndrome in a Swedish school population. Dev Med Child Neurol 2003;45(5): 315-9.
7. 7. Khalifa N, von Knorring AL. Tourette syndrome and other tic disorders in a total population of children: clinical assessment and background. Acta Paediatr 2005;94(11): 1608-14.
8. 8. Wenning GK, Kiechl S, Seppi K, et al. Prevalence of movement disorders in men and women aged 50-89 years (Bruneck Study cohort): a population-based study. Lancet Neurol 2005;4(12): 815-20.
9. 9. Mason A, Banerjee S, Eapen V, Zeitlin H, Robertson MM. The prevalence of Tourette syndrome in a mainstream school population. Dev Med Child Neurol 1998;40(5): 292-6.
10. 10. Robertson MM, Eapen V, Cavanna AE. The international prevalence, epidemiology, and clinical phenomenology of Tourette syndrome: a cross-cultural perspective. J Psychosom Res 2009;67(6): 475-83.
11. 11. Eapen V, Lees AJ, Lakke JP, Trimble MR, Robertson MM. Adult-onset tic disorders. Mov Disord 2002;17(4): 735-40.
12. 12. Singer HS. Tourette's syndrome: from behaviour to biology. Lancet Neurol 2005;4(3): 149-59.
13. 13. Bohlhalter S, Goldfine A, Matteson S, et al. Neural correlates of tic generation in Tourette syndrome: an event-related functional MRI study. Brain 2006;129(Pt 8): 2029-37.
14. 14. Marsh R, Maia TV, Peterson BS. Functional disturbances within frontostriatal circuits across multiple childhood psychopathologies. Am J Psychiatry 2009;166(6): 664-74.
15. 15. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. American Psychiatric Association, 2000.
16. 16. Kompoliti K, Goetz CG. Hyperkinetic movement disorders misdiagnosed as tics in Gilles de la Tourette syndrome. Mov Disord 1998;13(3): 477-80.
17. 17. Leckman JF. Phenomenology of tics and natural history of tic disorders. Brain Dev 2003;25 Suppl 1: S24-8.
18. 18.Jankovic J. Treatment of hyperkinetic movement disorders. Lancet Neurol 2009;8(9): 844-56.
19. 19. Shprecher D, Kurlan R. The management of tics. Mov Disord 2009;24(1): 15-24.
20. 20. Bestha DP, Jeevarakshagan S, Madaan V. Management of tics and Tourette's disorder: an update. Expert Opin Pharmacother 2010;11(11): 1813-22.
21. 21. Marras C, Andrews D, Sime E, Lang AE. Botulinum toxin for simple motor tics: a randomized, double-blind, controlled clinical trial. Neurology 2001;56(5): 605-10.
22. 22. Jankovic J. Botulinum toxin in the treatment of dystonic tics. Mov Disord 1994;9(3): 347-9.
23. 23. Kwak CH, Hanna PA, Jankovic J. Botulinum toxin in the treatment of tics. Arch Neurol 2000;57(8): 1190-3.
24. 24. Salloway S, Stewart CF, Israeli L, et al. Botulinum toxin for refractory vocal tics. Mov Disord 1996;11(6): 746-8.
25. 25. Scott BL, Jankovic J, Donovan DT. Botulinum toxin injection into vocal cord in the treatment of malignant coprolalia associated with Tourette's syndrome. Mov Disord 1996;11(4): 431-3.
26. 26. Trimble MR, Whurr R, Brookes G, Robertson MM. Vocal tics in Gilles de la Tourette syndrome treated with botulinum toxin injections. Mov Disord 1998;13(3): 617-9.

VI. STIFF-PERSON SYNDROME (SPS)

a) Introduction

Stiff-person syndrome (SPS) is an uncommon, progressive motor disorder characterized by marked muscle stiffness in axial and appendicular muscles, lumbar hyperlordosis, and episodic, painful spasms. SPS may present as a primary disorder, or it may be secondary to other conditions, most notably neoplasia. The precise mechanism is unknown, but there is good evidence to support an autoimmune etiology.

b) Epidemiology of SPS

SPS is a rare disease with unknown prevalence. Although originally called stiff-man syndrome, the condition appears to affect women twice as often as men. SPS presents most often in the fourth to sixth decade of life. The onset is typically insidious, and the clinical course is usually progressive.¹

c) Pathogenesis of SPS

The pathogenesis of SPS is unknown. No structural changes in the brain have been identified, and an autoimmune origin is likely in virtually all cases.¹ Patients with SPS frequently have antibodies against various substances, including, most importantly, glutamic acid decarboxylase, an enzyme required for synthesis of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Patients have significantly reduced levels of GABA in the sensorimotor cortex and posterior occipital cortex, but not in the cingulate cortex or pons.² SPS appears to be associated with autoimmune diseases, including type 1 diabetes, thyroid disorders, and others. Paraneoplastic SPS accounts for approximately 5% of cases, arising in association with thymoma, tumors of the breast, and other malignancies, often in association with an autoantibody directed against amphiphysin.³

d) Clinical Features of SPS

The most prominent manifestations of SPS are stiffness of truncal and proximal muscles with superimposed episodic spasms. Stiffness is present in agonist and antagonist muscles at the affected target. Stiffness leads to a characteristic hyperlordosis (Figure 6), which in turn causes difficulty bending or turning. Spasms are precipitated by noise, tactile or visual stimulation, or emotional distress.^{3, 4}

 

Figure 6. Enhanced lumbar lordosis in stiff person syndrome (SPS). Patients with SPS have difficult bending and turning, and an increased fear of falling. Cast visible on left arm in panel B resulted from recent fall. Patients with SPS usually develop a characteristic wide, slow, and deliberate gait to reduce risk of falls. Reprinted from Espay.³

Patients with SPS develop a slow, wide-based gait in an effort to maintain balance. Fear of falling may be so anxiety provoking that patients resort to canes or wheelchairs, or manifest task-specific phobias that may be confused with a psychiatric disorder.^3-5

e) Diagnosis of SPS

The diagnosis of SPS is suspected based on clinical features, and supported by demonstration of autoantibodies on serological testing. Electrophysiological testing, which would show continuous muscle activity, is also recommended in current diagnostic algorithms (Figure 7).³

Figure 7. Algorithm for diagnosis and initial management of patients with presumed stiff-person syndrome (SPS). CT = computed tomography; CSF = cerebrospinal fluid; EEG = electroencephalogram (to screen for SPS comorbidities); EMG = electromyography; GAD = glutamic acid decarboxylase; HbA1C = hemoglobin A1C; PERM = progressive encephalomyelitis with rigidity and myoclonus; SLS = stiff-limb syndrome; TSH = thyroid-stimulating hormone. The PERM variant can arise in either axial or limb-predominant forms. Comorbid diabetes, thyroid disease, and epilepsy have not been reported in association with SLS. Reprinted from Espay.³ Permission pending.

f) Treatment of SPS

Treatment of SPS is directed to enhancing GABA transmission, removing pathogenic antibodies, and immunosuppression. Interventions that have been employed to manage SPS include benzodiazepines, clonidine, tizanidine, antiepileptic drugs, monoclonal antibodies, corticosteroids, and intravenous immunoglobin.³

Role of Botulinum Neurotoxin

In a case report by Davis and Jabbari, injections of onabotulinumtoxinA reduced the tone of paraspinal and thigh muscles, and resulted in marked improvement of ambulation and a cessation of pain. Injections were administered weekly for 3 weeks (160, 200, and 200 U) at different lumbar paraspinal sites. Within 7 days following the last injection, the patient reported near-total relief from exertional pain and complete cessation of spasms. There was clinical and radiological evidence of improved lordosis; electromyography showed decreased firing of all muscles. The improvement lasted for 4 months.⁶

Liguori et al reported on two bedridden SPS patients who demonstrated bilateral improvement of rigidity and spasm by the tenth day following unilateral injection of 700 to 1000 U of abobotulinumtoxinA. The mechanism for this is unclear but presumably could involve hematogenous spread. Improvement following a second unilateral injection administered to muscle targets on the side not previously injected resulted in complete cessation of painful spasms and markedly decreased tone.⁷ BoNT would not be considered first-line therapy in this condition.

 

REFERENCES

1. 1. Lockman J, Burns TM. Stiff-person syndrome. Curr Treat Options Neurol 2007;9(3): 234-40.
2. 2. Levy LM, Levy-Reis I, Fujii M, Dalakas MC. Brain gamma-aminobutyric acid changes in stiff-person syndrome. Arch Neurol 2005;62(6): 970-4.
3. 3. Espay AJ, Chen R. Rigidity and spasms from autoimmune encephalomyelopathies: stiff-person syndrome. Muscle Nerve 2006;34(6): 677-90.
4. 4. Dalakas MC. Stiff person syndrome: advances in pathogenesis and therapeutic interventions. Curr Treat Options Neurol 2009;11(2): 102-10.
5. 5. Ameli R, Snow J, Rakocevic G, Dalakas MC. A neuropsychological assessment of phobias in patients with stiff person syndrome. Neurology 2005;64(11): 1961-3.
6. 6. Davis D, Jabbari B. Significant improvement of stiff-person syndrome after paraspinal injection of botulinum toxin A. Mov Disord 1993;8(3): 371-3.
7. 7. Liguori R, Cordivari C, Lugaresi E, Montagna P. Botulinum toxin A improves muscle spasms and rigidity in stiff-person syndrome. Mov Disord 1997;12(6): 1060-3.

VII. MYOCLONUS

a) Introduction

Myoclonus is a sudden, brief, shock-like involuntary jerking motion caused by muscle contraction (positive myoclonus) or, conversely, by the brief absence of muscle contraction (negative myoclonus). The myoclonic jerk is a hyperkinetic motor finding that appears across a broad range of conditions; it is a useful sign for clinicians who understand its implications for diagnosis, treatment, and prognosis of the underlying disorder.¹

Table 6. Causes of Myoclonus, by Classification Scheme²

By Etiology	By Phenomenology
Physiological Hypnic jerks Hiccups Anxiety induced Exercise induced	Distribution Focal Segmental Multifocal Generalized
Essential Sporadic Hereditary	Stimulus Spontaneous Action Reflex (stimulus induced)
Epileptic Childhood epilepsies Progressive myoclonic epilepsies
	Timing Rhythmic Irregular Periodic
Symptomatic (secondary) Metabolic (hepatic, renal, electrolyte disturbances) Toxicities (especially medications, alcohol) Storage diseases Trauma (post-hypoxic) Neoplastic/paraneoplastic (opsoclonus-myoclonus) Infections Dementia (Creutzfeldt-Jakob) Other neurodegenerative Atypical parkinsonism Other basal ganglia degeneration Spinocerebellar degeneration
	By Pathophysiology
	Cortical Focal Multifocal Generalized
	Subcortical Thalamic Brainstem Reticular Hyperexplexia (startle) Palatal
	Spinal Segmental Propriospinal
	Peripheral

Myoclonus is a nonspecific clinical sign that may be identified across a range of disorders and that may be classified in various ways. Myoclonus may be classified by etiology, phenomenology, pathophysiology, or other scheme (Table 7).² It may be a primary or secondary finding associated with a broad range of disorders ranging from the relatively common to the exceedingly rare. Four major clinical syndrome categories of myoclonus have been identified²:

• Physiological myoclonus is present in normal subjects
• Essential (or primary) myoclonus is a syndrome in which the jerks are the primary symptom that underlie the presentation for medical attention, and the clinical history is not progressive. Such disorders are now recognized as being likely genetic in etiology
• Epileptic myoclonus is a syndrome in which seizures are an established, predominant aspect of the clinical disorder
• Symptomatic myoclonus is characterized by the presence of involuntary jerking in the context of an associated nonepileptic central nervous system disorder. Symptoms are secondary to a provocative factor and may be progressive. Encephalopathy may be present, as with asterixis and hepatic disease.

Physiological myoclonus is a normal process and includes jerks experienced as one drifts off to sleep (hypnic jerks) and hiccups. Overall, nonphysiological myoclonus arises most commonly secondary to an underlying disorder, especially medications, alcohol, and metabolic derangements. Emphasis must be made that each category may contain forms of myoclonus with various physiological properties; the same causal factor may produce vastly different types of myoclonus; and more than one type of myoclonus may be present in the same patient.²

b) Epidemiology of Myoclonus

Myoclonus is an important cause of abnormal movement. Precise epidemiological data for nonphysiological myoclonus are limited. Because most toxic-metabolic and drug-induced cases are transient, they are often missed in epidemiological studies. The best available evidence found the average annual incidence of pathological and persistent myoclonus to be 1 to 3 cases per 100,000 person-years, and a lifetime prevalence of 8.6 cases per 100,000 population. Symptomatic (or secondary) causes of myoclonus are most common. Primary (essential) myoclonus constitutes only a small proportion of cases, and epileptic myoclonus is an intertwined component of chronic seizure disorders.^{3, 4}

c) Pathophysiology of Myoclonus

The main physiological classification categories of myoclonus (cortical, subcortical, spinal, and peripheral) have been derived from sophisticated neurophysiological testing and provide insight into the generation of the myoclonus. Myoclonus requires abnormal bidirectional paroxysmal connections, a spontaneous neural generator, or degeneration at the relevant site. Clinical features consequently reflect the affected motor systems. Cortical myoclonus predominantly affects body parts with the biggest cortical representations (such as the hands and face). Because motor areas of the cerebral cortex are responsible for voluntary action, jerks arising here tend to manifest on action. Myoclonus that arises from brainstem sites may be reflected in jerky axial and bilateral movements or exaggerated primitive reflex responses to stimuli, such as sound (e.g., excessive startle reflex). Spinal segmental systems that become hyperexcitable may produce myoclonus that is resistant to supraspinal influences and not overridden by voluntary movement or sleep. Myoclonus arising from the propriospinal system manifests as predominantly axial jerks that, unlike brainstem myoclonus, spare the face and are not provoked by sound. Myoclonus is a variable manifestation of spinocerebellar, basal ganglia, and cortical dementia disorders.⁴

d) Diagnosis of Myoclonus

Among subjects presenting for medical attention, myoclonus is a clinical sign that most often points to an underlying disorder. Nonphysiological myoclonus is usually secondary to another condition, and a careful history, physical examination, medication review, and basic ancillary testing should be focused on defining the comorbid issue (Table 7).⁴

Table 7. Assessment of Myoclonus: A Suggested Protocol⁴

Full history	Assess Mode of myoclonus onset Associated neurological problems History of seizures Current and past drug or toxin exposure Past or current medical problems Family history
Physical examination	Distribution Focal Segmental Multifocal Hemi Generalized Temporal profile Rhythmic or irregular Continuous Intermittent Activation profile Rest (spontaneous myoclonus) Voluntary movement (action myoclonus) Reflex stimuli (any combination of touch, light, sound, muscle stretch)
Basic ancillary testing	Electrolytes Glucose Renal function tests Hepatic function tests Paraneoplastic antibodies Drug and toxin screen Brain imaging Electroencephalography Spine imaging (if focal or segmental) Thyroid antibodies and function
Determine major clinical syndrome category	Physiological Essential Epileptic Symptomatic
Clinical neurophysiology testing	Obtain specialist consultations
Advanced testing	Body imaging for occult cancer Cerebrospinal fluid exam (for infectious and inflammatory disorders, Creutzfeldt-Jakob disease, etc) Tests for malabsorption disorders Enzyme assays for deficiency Tissue biopsy of skin or leukocytes Copper studies for Wilson’s disease α-Fetoprotein Genetic testing for inherited disorders Mitochondria function studies (lactate, muscle biopsy, etc) Other testing may be needed

e) Treatment of Myoclonus

Treatment of myoclonus should in most cases be focused on appropriate correction of the underlying disorder, such as an acquired metabolic abnormality or adverse effect resulting from a medication or toxin. When an underlying disorder is chronic or progressive, symptomatic treatment of myoclonus may be derived from consideration of its physiological classification and presumed site of the aberrant neural generator. Unfortunately, little controlled evidence has been found upon which to base treatment recommendations.⁴

Pharmacological Treatment

Typical first-line medications include clonazepam, valproic acid, primidone, piracetam, and levetiracetam. Antimyoclonic agents are usually administered in combination; only rarely will one agent achieve control of myoclonus. Side effects are frequently dose limiting. In clinical practice, treatment of myoclonus is frequently unsuccessful from the patient viewpoint.^{4, 5}

Role of Botulinum Neurotoxin

BoNT can be effective in case reports of its use for myoclonus, but the literature is very sparse. Disabling, violent spinal segmental myoclonus of an upper extremity was suppressed by the 10th day following administration of 100 units of onabotulinumtoxinA, with complete absence for 4 months.⁶ Painful, segmental myoclonus of the thigh unresponsive to a wide variety of medications was substantially aborted by onabotulinumtoxinA (280 U) within 2 weeks; pain was suppressed completely, and the modest residual movements were well tolerated. Benefits in this case lasted for close to 5 months, and repeat injection of onabotulinumtoxinA was described as providing similar benefits. No side effects were reported.⁷
A very unusual manifestation of essential myoclonus resulting in frequent ear movements was significantly suppressed but not aborted entirely within 2 weeks of abobotulinumtoxinA (60 U) injection.⁸ In another case study, facial myoclonus associated with Rasmussen encephalitis with seizure subsided within 2 days following treatment, with improvements lasting more than 6 months.⁹

REFERENCES

1. 1. Caviness JN. Myoclonus. Mayo Clin Proc 1996;71(7): 679-88.
2. 2. Chang VC, Frucht SJ. Myoclonus. Curr Treat Options Neurol 2008;10(3): 222-9.
3. 3. Caviness JN, Alving LI, Maraganore DM, Black RA, McDonnell SK, Rocca WA. The incidence and prevalence of myoclonus in Olmsted County, Minnesota. Mayo Clin Proc 1999;74(6): 565-9.
4. 4. Caviness JN, Brown P. Myoclonus: current concepts and recent advances. Lancet Neurol 2004;3(10): 598-607.
5. 5. Agarwal P, Frucht SJ. Myoclonus. Curr Opin Neurol 2003;16(4): 515-21.
6. 6. Lagueny A, Tison F, Burbaud P, Le Masson G, Kien P. Stimulus-sensitive spinal segmental myoclonus improved with injections of botulinum toxin type A. Mov Disord 1999;14(1): 182-5.
7. 7. Polo KB, Jabbari B. Effectiveness of botulinum toxin type A against painful limb myoclonus of spinal cord origin. Mov Disord 1994;9(2): 233-5.
8. 8. Godeiro-Junior C, Felicio AC, Felix EP, et al. Moving ear syndrome: the role of botulinum toxin. Mov Disord 2008;23(1): 122-4.
9. 9. Browner N, Azher SN, Jankovic J. Botulinum toxin treatment of facial myoclonus in suspected Rasmussen encephalitis. Mov Disord 2006;21(9): 1500-2.

VIII. ISOLATED MUSCLE SPASM OR CRAMP

Note is made in this section of benefits reported for BoNT in the management of severe, isolated spasms or neuromyotonia affecting various body sites. These are idiosyncratic conditions, and no common mechanisms are proposed. All were chronic conditions intractable to medical management. It is important to recognize that the benefits associated with BoNT in some of these difficult cases endured for clinically meaningful periods, allowing the patients a period of improved function. Data are presented in Table 9.

a) Role of BoNT

Table 8. Benefits of Botulinum Neurotoxin (BoNT) in Management of Severe, Isolated Neurospasms or Neuromyotonia

Author (Year)	Affected Site	BoNT Dose or Dose Sequence	Duration of Benefit	Adverse Events	Comments
Hobson (2009)1	Masseter, unilateral	onabotulinumtoxinA 75 U initially, 175 U subsequently at 7 months	3 months	None reported	Spasms and jaw clamping suppressed. Pain markedly reduced
Lim (2009)2	Abdominal wall, presumed postsurgical	onabotulinumtoxinA 90 U initially, 240 U at 3 months	Not specified	None reported	Abdominal movements improved, not eliminated. Pain remained prominent.
Aburahma (2009)3	Schwartz-Jampel syndrome (congenital blepharospasm and generalized myopathy)	BoNT-A highly variable across 4 enrolled patients	Not specified	Transiently worsened cosmetic appearance	Benefits reported for 2 of 4 patients per parent impressions
Joyce (2005)4	Congenital torticollis	BoNT-A 25–50 IU into 3 or 4 sites in affected muscle	22 months	None reported	14 of 15 children responded sufficiently well to avoid surgical release >14 of 15 children responded sufficiently well to avoid surgical release
Kern (2004)5	Stump pain with palpable, hypertonic muscle trigger points	rimabotulinumtoxinB 2500–5000 U	Up to 3 months	None reported	Authors report having completed a prospective, randomized, controlled trial using BoNT-A to determine if there is a placebo effect of stump trigger point injection
Sedano (2000)6	Hemifacial myokymia (“bag of worms”)	onabotulinumtoxinA 2.5 U to multiple sites	11 and 19 months	None reported	Series of 2 patients with multiple sclerosis
Schwartz (1998)7	Mammoplasty flap (latissimus dorsi) resulting in visibly convulsing breast reconstruction	abobotulinumtoxinA 300 U every 3 months for 3 doses	3 months	None reported	Onset of benefit within 2 weeks; patient had discontinued carbamazepine and phenytoin due to drowsiness
Bertolasi (1997)8	Calf and small foot flexors in patients with inherited cramp-fasciculation syndrome	abobotulinumtoxinA 350 U or 400 U to gastrocnemius; 80 U or 100 U to small foot flexors	Onset within 4-6 days; peak effect attained at 10th day, lasting approximately 3 months	None reported	5 patients were enrolled; all demonstrated benefit
Lou (1995)9	Trismus	onabotulinumtoxinA 25 U injected into each affected muscle (masseter and mylohyoid)	Onset after 3 days; durable for 5 weeks	None reported	Interincisor opening distance more than doubled to 4 cm during period of benefit; no fasciculations noted at time of maximum benefit

REFERENCES

1. 1. Hobson DE, Kerr P, Hobson S. Successful use of botulinum toxin for post-irradiation unilateral jaw neuromyotonia. Parkinsonism Relat Disord 2009;15(8): 617-8.
2. 2. Lim EC, Seet RC. Botulinum toxin injections to treat belly dancer's dyskinesia. Mov Disord 2009;24(9): 1401.
3. 3. Aburahma SK, Al-Khateeb T, Alrefai A, Amarin Z. Botulinum toxin A injections for the treatment of Schwartz-Jampel syndrome: a case series. J Child Neurol 2009;24(1): 5-8.
4. 4. Joyce MB, de Chalain TM. Treatment of recalcitrant idiopathic muscular torticollis in infants with botulinum toxin type a. J Craniofac Surg 2005;16(2): 321-7.
5. 5. Kern U, Martin C, Scheicher S, Muller H. Effects of botulinum toxin type B on stump pain and involuntary movements of the stump. Am J Phys Med Rehabil 2004;83(5): 396-9.
6. 6. Sedano MJ, Trejo JM, Macarron JL, Polo JM, Berciano J, Calleja J. Continuous facial myokymia in multiple sclerosis: treatment with botulinum toxin. Eur Neurol 2000;43(3): 137-40.
7. 7. Schwartz MS, Wren DR, Filshie J. Neuromyotonia in a muscle flap producing a convulsing breast: successful treatment with botulinum toxin. Mov Disord 1998;13(1): 188-90.
8. 8. Bertolasi L, Priori A, Tomelleri G, et al. Botulinum toxin treatment of muscle cramps: a clinical and neurophysiological study. Ann Neurol 1997;41(2): 181-6.
9. 9. Lou JS, Pleninger P, Kurlan R. Botulinum toxin A is effective in treating trismus associated with postradiation myokymia and muscle spasm. Mov Disord 1995;10(5): 680-1.